CN101039683A - Compositions and methods using hyaluronic acid and hyaluronidase inhibitors - Google Patents

Compositions and methods using hyaluronic acid and hyaluronidase inhibitors Download PDF

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CN101039683A
CN101039683A CN 200580035142 CN200580035142A CN101039683A CN 101039683 A CN101039683 A CN 101039683A CN 200580035142 CN200580035142 CN 200580035142 CN 200580035142 A CN200580035142 A CN 200580035142A CN 101039683 A CN101039683 A CN 101039683A
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compositions
acid
hyaluronic
hyaluronic acid
polymer
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威廉·L·亨特
大卫·M·格雷维特
飞利浦·M·特雷科斯
约翰·K·杰克逊
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University of British Columbia
Angiotech International AG
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University of British Columbia
Angiotech International AG
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Abstract

Compositions and devices including hyaluronic acid and a compound that inhibits degradation of hyaluronic acid, and methods of making and using same.

Description

Use the compositions and the method for hyaluronic acid and Hyaluronidase inhibitor
The cross reference of related application
The application requires the rights and interests of No. the 60/601st, 214, the U.S. Provisional Patent Application submitted on August 13rd, 2004 and 60/601, No. 218, and the full content that this paper introduces this provisional application as a reference.
Background
Technical field
The present invention relates generally to pharmaceutical composition, apparatus and method, and relate more specifically to compositions, the apparatus and method relevant with activity with the persistent period of the hyaluronic acid material that strengthens implantation.
Description of related art
Hyaluronic acid (HA) is a naturally occurring general material in many bodily tissues of vitreous humor, cartilage, blood vessel, extracellular matrix, skin and umbilical cord in comprising synovial joint fluid, eye.Keeping moisture is one of hyaluronic most important biological function, and being only second to the cell that does not have direct blood supply provides nutrient and therefrom remove refuse, and this cell for example is a chondrocyte.The structure of the bonded ability formative tissue of HA and water, lubricated and buffering be such as health moveable portion such as joint (for example knee) and muscle, and the skin volume is had contribution.
Hyaluronic acid is as lubricant and provide the ability of structural support that it is widely used in the multiple medical applications, for example comprises that ophthalmology, soft tissue increase (for example the HA implant is used for shaping and reconstructive surgery), wound are looked after, joint viscosity is replenished (for example intra-articular injection), osteanagenesis, avoided adhesion, drug conveying, cell preservation, pan coating and humidizer.Compare with the biomaterial (for example collagen) of multiple other type, the special benefits of HA is, because HA is the part of natural extracellular matrix, do not reply so health does not produce immunity (allergic) to the implant based on HA.
Yet when hyaluronic acid was implanted, it had the relatively limited life-span.Multiple digestive enzyme can endanger the durability of implants in vivo, and described digestive enzyme for example is a hyaluronidase.Hyaluronidase be often referred to can catalysis animal connective tissue in the hydrolytic enzyme of internal sugar glycosidic bond fracture of some acid mucopolysaccharide (sodium salt of for example hyaluronic sodium salt and chondroitin sulfate A and C), this hydrolytic enzyme for example is hyaluronic acid lyase and hyaluronoglucuronidase.For example, the hydrolysis of N-acetyl-glucosamine in the Hyaluronoglucosaminidase catalysis hyaluronic acid and β at random-1,4 key between the D-glucuronic acid residue.It is hydrolysis chrondroitin, chondroitin-4-suleate and 6-chondroitin sulfate and chondroitin sulfate B also.The hydrolysis of glucuronic acid among the hyaluronoglucuronidase catalysis HA and β-1,3 key between the N-acetyl-glucosamine residue.Hyaluronic acid lyase is by the fracture of elimination reaction catalysis HA, and wherein two keys are also introduced in the bond fission between N-acetyl-glucosamine and the glucuronic acid.As the zymolytic result who implants HA in the body of back, the functional activation of the interior HA of body is limited after the administration.Because like this, use HA often to need repeat administration regularly as the medical care precess of implant (especially, for example improve looks reinforcing agent or tissue filling agent).For example, skin implant and the additional drug treatment of viscosity based on HA must repeat once in per 6 to 9 months.
Solution of the present invention is with hyaluronic acid and be used for the relevant shortcoming of medical applications, and other relevant advantage is provided.
General introduction
In brief, the invention provides active compositions, the apparatus and method of prolongation based on hyaluronic implant.Use based on hyaluronic implant so that structure, holder and lubrication to be provided in multiple medical care precess, described medical care precess for example comprises the corium injection (to reduce wrinkle, cicatrix, profile defective) of cosmetic purpose, intra-articular injection is to alleviate arthralgia, blood vessel " plug " is with generation anastalsis after the vascular puncture operation, and " filler " is with treatment urinary incontinence, fecal incontinence and gastroesophageal reflux.
On the one hand, the invention provides the compositions that combination has hyaluronic acid and suppresses chemical compound (being inhibitor), wherein said inhibition chemical compound can suppress the activity of hyaluronidase.The HA compositions that contains such chemical compound is not decomposed rapidly by body and can be used to provide generation based on hyaluronic implant, and this implant has persistency and the life-span that increases in the body.
Multiple inhibition chemical compound has been described in the present invention.In independent embodiment, each inhibition chemical compound described herein can suppress hyaluronic degraded.In certain embodiments, suppress the hyaluronic degraded that chemical compound suppresses the enzyme induction that caused by hyaluronidase.On the one hand, the invention provides the compositions that comprises hyaluronic acid and gold compound, wherein said gold compound (for example organic gold compound) suppresses hyaluronic degraded.Described compositions can also comprise polymer.On the one hand, described gold compound is Aurothiomalate or Kidon (Ono).On the other hand, described gold compound is an auranofin.On the other hand, described gold compound is a Sanocrysin.On the other hand, the invention provides the compositions that comprises hyaluronic acid and indomethacin or its analog or derivant, wherein said indomethacin suppresses hyaluronic degraded.On the other hand, the invention provides the compositions that comprises hyaluronic acid and contain the polysaccharide of sulfuric ester, the wherein said polysaccharide that contains sulfuric ester suppresses hyaluronic degraded.Described compositions can also comprise polymer.The described polysaccharide that contains sulfuric ester for example can be a fucosan, for example fucoidin or its analog or derivatives thereof; Dextran sulfate or its analog or derivatives thereof; Or heparin or its analog or derivatives thereof.On the other hand, the invention provides the compositions that comprises hyaluronic acid and polymer, wherein said polymer suppresses hyaluronic degraded.On the other hand, described polymer is a diblock copolymer.On the one hand, described polymer comprises and has (O-CH (CH 3The lactic acid residue of the structure of)-CO-).On the other hand, described polymer comprises and has (OCH 2CH 2-) ethylene oxide residue of structure.On the other hand, described polymer comprises polylactic acid-co-Polyethylene Glycol (PLA-PEG).On the other hand, described polymer comprises poly-(L-lactic acid)-co-methoxy poly (ethylene glycol) (MePEG-PLLA) (60: 40).On the other hand, described polymer comprises poly-(lactic acid-co-glycolic)-co-Polyethylene Glycol (PLGA-PEG).On the other hand, described polymer comprises polycaprolactone-co-Polyethylene Glycol (PCL-PEG).On the other hand, described polymer is the copolymer of sorbitan ester or oxirane and epoxypropane polymer.Described polymer can be a mixture of polymers.On the other hand, described polymer is the mixture of polylactic acid-co-Polyethylene Glycol (PLA-PEG) and poly-(L-lactic acid)-co-methoxy poly (ethylene glycol) (MePEG-PLLA).On the other hand, HI is an octylphenol ethoxylate.On the other hand, the invention provides the compositions that combination has hyaluronic acid and cosolvent type molecule, wherein these agent suppress the vivo degradation of the active of hyaluronidase and inhibition HA.On the other hand, the invention provides the compound compositions that contains hyaluronic acid and be selected from Polyethylene Glycol, propylene glycol or carboxymethyl cellulose (CMC), wherein said chemical compound suppresses hyaluronic degraded.On the other hand, the compositions that comprises hyaluronic acid and HI is provided, wherein said HI is a vitamin C, aescine, tranilast, traxanox, the Caulis Hederae Sinensis sapogenin, guanidine hydrochloride, the L-arginine, norlignane, urolithin B, glycyrrhizin, baicalin, isoliquiritigenin, disodium cromoglycate (DSCG), 7-sulphuric acid chrysin, flavanone-7-sodium sulfate, 5-flavonol-7-sodium sulfate, 1-(2-hydroxyl-4, the 6-Dimethoxyphenyl)-3-(4-methoxyphenyl) acetone, 1-(2-hydroxyl-4, the 6-Dimethoxyphenyl)-3-(4-chlorphenyl) acetone, 7-fluoro-4 '-flavonol-4 '-chloro-4,6-dimethoxy chalcone derivative, luteolin, morin, myricetin, Phenylbutazone, crovaril, fenoprofen, Kidon (Ono), the phosphorylation Hesperidin, Echinacea Species, rosmarinic acid, the acidifying β of sulfonic acid-(1,4)-breast-oligosaccharide (n=2-6) with sulfonation degree of 0.2 to 1; Flavonoid class, for example condensed tannin, tannin, kaempferol, Quercetin, apigenin; And Sulfonated chemical compound, for example single lactobiose glycosides of sulfonic acid neomycin, sulfonated planetose, sulphuric acid hydroquinone digalactosyl glycosides or sulphuric acid-2-hydroxyphenyl; And silymarin, phloretin, Taxifolin, daidzein (4 ', the 7-dihydroxy isoflavone), Rhizoma Iridis Tectori kind aglycon (4 ', 7-dihydroxy-6-methoxyl group isoflavone), 7-sulphuric acid chrysin, 4 '-chloro-4,6-dimethoxy chalcone derivative, diphenylacrylate, diphenyl-propionic acid, 3-(4-trifluoromethyl-phenyl)-3-phenylpropionic acid, 3-(4-trifluoromethyl-phenyl)-3-phenylpropionic acid or indole-2-carboxylic acid; And described compositions at random contains polymer.Arbitrary described compositions can also comprise gold compound, and wherein said gold compound (for example organic gold compound or Aurothiomalate or its analog or derivatives thereof) suppresses hyaluronic degraded.The GPC molecular weight analyse that can use hyaluronic acid viscosimetry that embodiment 1 provides or embodiment 22 to provide is differentiated the chemical compound of the hyaluronic acid degradation that inhibition is caused by hyaluronidase.On the one hand, compositions is provided, the chemical compound that it comprises hyaluronic acid and is selected from Aurothiomalate, indomethacin, fucoidin, dextran sulfate, heparin, ethylene glycol, propylene glycol, carboxymethyl cellulose (CMC) or their analog and derivant, the viscosity of wherein said compositions be hyaluronic acid contrast viscosity 50% or be higher than 50%, wherein use the hyaluronic acid viscosimetry to measure viscosity.On the other hand, compositions is provided, the chemical compound that it comprises hyaluronic acid and is selected from the copolymer of octylphenol ethoxylate, sorbitan ester or oxirane and epoxypropane polymer, the viscosity of wherein said compositions be hyaluronic acid contrast viscosity 50% or be higher than 50%, wherein use the hyaluronic acid viscosimetry to measure viscosity.On the other hand, provide compositions, it comprises hyaluronic acid and polymer, and this polymer is selected to comprise has (O-CH (CH 3The polymer of the lactic acid residue of the structure of)-CO-), comprise and have (OCH 2CH 2-) polymer of the polymer of the ethylene oxide residue of structure, polylactic acid-co-Polyethylene Glycol (PLA-PEG), poly-(L-lactic acid)-co-methoxy poly (ethylene glycol) (MePEG-PLLA) (60: 40), poly-(lactic acid-co-glycolic)-co-Polyethylene Glycol (PLGA-PEG), polycaprolactone-co-Polyethylene Glycol (PCL-PEG), or its mixture, the viscosity of wherein said compositions be hyaluronic acid contrast viscosity 50% or be higher than 50%, wherein use the hyaluronic acid viscosimetry to measure viscosity.On the other hand, compositions is provided, it comprises hyaluronic acid and HI, this HI is selected from vitamin C, aescine, tranilast, traxanox, the Caulis Hederae Sinensis sapogenin, guanidine hydrochloride, the L-arginine, norlignane, urolithin B, glycyrrhizin, baicalin, isoliquiritigenin, disodium cromoglycate (DSCG), 7-sulphuric acid chrysin, flavanone-7-sodium sulfate, 5-flavonol-7-sodium sulfate, 1-(2-hydroxyl-4, the 6-Dimethoxyphenyl)-3-(4-methoxyphenyl) acetone, 1-(2-hydroxyl-4, the 6-Dimethoxyphenyl)-3-(4-chlorphenyl) acetone, 7-fluoro-4 '-flavonol-4 '-chloro-4,6-dimethoxy chalcone derivative, luteolin, morin, myricetin, Phenylbutazone, crovaril, fenoprofen, Kidon (Ono), the phosphorylation Hesperidin, Echinacea Species, rosmarinic acid, the acidifying β of sulfonic acid-(1,4)-breast-oligosaccharide (n=2-6) with sulfonation degree of 0.2 to 1; Flavonoid class, for example condensed tannin, tannin, kaempferol, Quercetin, apigenin; And Sulfonated chemical compound, for example single lactobiose glycosides of sulfonic acid neomycin, sulfonated planetose, sulfonic acid hydroquinone digalactosyl glycosides or sulphuric acid-2-hydroxyphenyl; And silymarin, phloretin, Taxifolin, daidzein (4 ', the 7-dihydroxy isoflavone), Rhizoma Iridis Tectori kind aglycon (4 ', 7-dihydroxy-6-methoxyl group isoflavone), 7-sulphuric acid chrysin, 4 '-chloro-4,6-dimethoxy chalcone derivative, diphenylacrylate, diphenyl-propionic acid, 3-(4-trifluoromethyl-phenyl)-3-phenylpropionic acid, 3-(4-trifluoromethyl-phenyl)-3-phenylpropionic acid or indole-2-carboxylic acid, the viscosity of wherein said compositions be hyaluronic acid contrast viscosity 50% or be higher than 50%, wherein use the hyaluronic acid viscosimetry to measure viscosity.On the other hand, compositions is provided, the chemical compound that it comprises hyaluronic acid and is selected from heparin (sodium salt), Kidon (Ono), carboxymethyl cellulose, dextran sulfate, fucoidin and their analog and derivant, wherein said hyaluronic molecular weight be higher than hyaluronic acid contrast molecular weight about 10% or be higher than about 25% or be higher than about 50% or be higher than about 75% or be higher than approximately 90%, wherein use the GPC molecular weight analyse to measure molecular weight.
In some aspects, described compositions can comprise two or more HI.In others, described compositions comprises one or more HI, and wherein said one or more HI have extra therapeutic effect.For example, described HI can also reduce treatment site tissue inflammation (for example aurotherapy chemical compound), can have anticoagulant effect or can have anti-proliferative effect.
In others, the invention provides the compositions formed by Hyaluronidase inhibitor and drug conveying medium (carrier) so that the slow release of this agent to be provided at the HA implantation site.On the one hand, described carrier is a polymer.This polymer can be biodegradable or abiotic degradable.On the one hand, described polymer comprises carbohydrate, for example starch, cellulose and glucosan.On the other hand, described polymer comprises protein, for example collagen, gelatin, Fibrinogen and albumin.On the other hand, described polymer comprises polyester (for example poly-(D, L-lactide)), poly-(D, L-lactide-co-Acetic acid, hydroxy-, bimol. cyclic ester) or poly-Acetic acid, hydroxy-, bimol. cyclic ester.On the other hand, described polymer comprises poly-(6-caprolactone), poly butyric ester, poly-alkyl carbonate, polyanhydride or poe.On the other hand, described polymer comprises ethylene-vinyl acetate copolymer (EVA), silicone rubber, polyurethane or acrylate copolymer or copolymer.On the other hand, described polymeric carrier comprises Polyethylene Glycol.On the other hand, described polymeric carrier comprises 4-arm sulfydryl PEG and 4-arm NHS PEG and can at random comprise collagen or collagen derivant, for example methylated collagen.
On the other hand, compositions is provided, it comprises hyaluronic acid and HI (for example heparin (sodium salt), Kidon (Ono), carboxymethyl cellulose, dextran sulfate, fucoidin and their analog and derivant), and wherein said HI is comprised in the microgranule.Can with microparticulate in liquid, semisolid or solid HA graft, perhaps contain microgranule in liquid, semisolid or the solid HA graft, to impel HI slow release from described compositions.In certain embodiments, the microgranule that contains load HI in HA film or the net.In other embodiments, with the microparticulate of load HI in the HA of liquid or semi-solid form.In certain embodiments, the microgranule with load HI is evenly dispersed in or is included in the implant.
On the other hand, described compositions can also comprise pottery, for example bata-tricalcium phosphate, hydroxyapatite, calcium carbonate, calcium sulfate, calcium phosphate, bone and remove the mineral bone.On the one hand, described compositions can also comprise bone morphogenetic protein (for example BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 or BMP-7), somatomedin (for example fibroblast growth factor (FGF), transforming growth factor (TGF) or platelet derived growth factor (PDGF)).
Arbitrary compositions described herein can also comprise anesthetis (for example prilocaine, lignocaine or benzocaine) and/or the compositions of sterile form can be provided.
Others the invention provides method, wherein HA Hyaluronidase inhibitor compositions as herein described can also be used for the various clinical indication, for example comprise: as the skin implant in the orthopedic applications; The stickiness fill-in that is used for the joint; As the medical treatment device that increases osteogenesis; As the implant in the spinal fusion surgery; As surgery sling, net or paster; As the implant that is used for the treatment of periodontal disease (for example as dental implant); As skin graft (for example being used for the generation of artificial skin); As corneal optic; As the tissue filling agent that is used for the treatment of urinary incontinence, fecal incontinence or gastroesophageal reflux; Screen as surgical adhesions; Perhaps as the glaucoma drainage system.On the one hand, the invention provides the method that increases bone or displacement wearing and tearing bone, it is included in the position that needs and carries compositions as herein described to the patient of this method of needs.On the other hand, the invention provides the method that reduces the pain relevant with postoperative scarization, it uses compositions as herein described to infiltrate perineural zone during being included in operation technique.On the other hand, the invention provides the method that prevents surgical adhesions, it comprises to the patient's of this method of needs the position that needs carries compositions as herein described.On the other hand, the invention provides the method for repairing or increasing skin or tissue, it comprises injection chemical compound as herein described in the patient's of this method of needs skin or tissue.For example can in the skin of lip or face, inject.On the other hand, the invention provides the method for keeping eyes tear volume during operated eye, it carries compositions as herein described to ophthalmic during being included in operated eye.Described operated eye for example can be that pioneering operation, intraocular lens are implanted, retina is put again, phacoemulsification operation, corneal transplantation or glaucoma filtration surgery.On the other hand, the invention provides the method that reduces the pain relevant with osteoarthritis, it comprises injection compositions as herein described in the patient's of this method of needs joint.On the other hand, the invention provides the method for treatment gastroesophageal reflux disease, it comprises near the injection compositions as herein described sphincter of gullet of patient's lower end.On the other hand, the invention provides the method for treatment or prevention urinary incontinence, it comprises the patient administration of compositions as herein described to this method of needs, so that treatment or prevention urinary incontinence.For example can be with described compositions urethra week administration or per urethra administration.On the other hand, the invention provides the method for treatment or prevention fecal incontinence, it comprises near the compositions as herein described administration patient's anus sphincter, so that treatment or prevention fecal incontinence.
The invention provides the medical implant that contains filler.Described filler comprises hyaluronic acid and suppresses the chemical compound (for example Aurothiomalate, indomethacin, propylene glycol, heparin, dextran sulfate, fucoidin and carboxymethyl cellulose) of hyaluronic acid degradation.Can be used for for example disposal of GERD, fecal incontinence and urinary incontinence by these medical implants of prescription.
On the other hand, provide medical treatment device, the inhibition chemical compound that it comprises medical implant and suppresses hyaluronic acid degradation.In certain embodiments, provide medical treatment device, it comprises the implant that use comprises hyaluronic acid and suppresses compound compositions bag quilt.On the one hand, the invention provides medical treatment device, it comprises medical implant, the compositions bag quilt of involved hyaluronic acid of wherein said implant and gold compound, and wherein said gold compound suppresses hyaluronic degraded.On the other hand, the invention provides medical treatment device, it comprises medical implant, wherein uses the implanted thing of compositions bag that comprises hyaluronic acid and indomethacin or its analog or derivatives thereof, and wherein said indomethacin suppresses hyaluronic degraded.On the other hand, the invention provides medical treatment device, it comprises medical implant, wherein uses the implanted thing of compositions bag that comprises hyaluronic acid and contain the polysaccharide of sulfuric ester, and the wherein said polysaccharide that contains sulfuric ester suppresses hyaluronic degraded.The described polysaccharide that contains sulfuric ester for example can be a fucosan, and this fucosan for example is fucoidin or its analog or derivatives thereof; Or dextran sulfate or its analog or derivatives thereof; Or heparin or its analog or derivatives thereof.On the other hand, the invention provides medical treatment device, it comprises medical implant, wherein uses the implanted thing of compositions bag that comprises hyaluronic acid and polymer, and wherein said polymer suppresses hyaluronic degraded.On the one hand, described polymer comprises and has (O-CH (CH 3The lactic acid residue of the structure of)-CO-).On the other hand, described polymer comprises and has (OCH 2CH 2-) ethylene oxide residue of structure.On the other hand, described polymer comprises polylactic acid-co-Polyethylene Glycol (PLA-PEG).On the other hand, described polymer comprises poly-(L-lactic acid)-co-methoxy poly (ethylene glycol) (MePEG-PLLA) (60: 40).On the other hand, described polymer comprises poly-(lactic acid-co-glycolic)-co-Polyethylene Glycol (PLGA-PEG).On the other hand, described polymer comprises polycaprolactone-co-Polyethylene Glycol (PCL-PEG).On the other hand, described polymer is selected from the copolymer of sorbitan ester and oxirane and epoxypropane polymer.On the other hand, described polymer is a mixture of polymers, for example is the mixture of polylactic acid-co-Polyethylene Glycol (PLA-PEG) and poly-(L-lactic acid)-co-methoxy poly (ethylene glycol) (MePEG-PLLA).On the other hand, the invention provides medical treatment device, it comprises medical implant, wherein use and comprise hyaluronic acid and such as Polyethylene Glycol, propylene glycol, octylphenol ethoxylate or the carboxymethyl cellulose implanted things of compound compositions bag such as (CMC), wherein said chemical compound suppresses hyaluronic degraded.On the other hand, the compositions that comprises inhibition chemical compound as herein described (for example Hyaluronidase inhibitor) can also comprise gold compound (for example Aurothiomalate), and wherein said gold compound suppresses hyaluronic degraded.
To become more clear by reference following detailed description and accompanying drawing above-mentioned and others of the present invention.
Brief description of drawings
Fig. 1 is a block diagram, and it shows the influence (solution viscosity, the % of HA contrast relatively) to the hyaluronic degraded of enzyme induction of heparin, Aurothiomalate and indomethacin.
Fig. 2 is a block diagram, and it shows the influence (solution viscosity, the % of HA contrast relatively) to the hyaluronic degraded of enzyme induction of dextran sulfate, fucoidin, heparin, propylene glycol and indomethacin.
Fig. 3 is a block diagram, and it shows through after hatching a night, the influence of the degraded of the HA that TRITON X-100 causes hyaluronidase.
Fig. 4 is a block diagram, and it shows the influence of the degraded of the HA that multiple chemical compound causes hyaluronidase.
Fig. 5 is a block diagram, its demonstration exist Calciparine/sodium salt and hyaluronidase (after hatching 15 hours, during 100 units/ml), the degraded of HA.
Fig. 6 is a block diagram, its demonstration exist Aurothiomalate and hyaluronidase (after hatching 15 hours, during 100 units/ml), the degraded of HA.
Fig. 7 is a block diagram, its demonstration exist CMC and hyaluronidase (after hatching 15 hours, during 100 units/ml), the degraded of HA.
Fig. 8 is a block diagram, its demonstration exist dextran sulfate and hyaluronidase (after hatching 15 hours, during 100 units/ml), the degraded of HA.
Fig. 9 is a block diagram, its shown exist fucoidin and hyaluronidase (after hatching 15 hours, during 100 units/ml), the degraded of HA.
Describe in detail
Before the present invention will be described, the definition of illustrating some term that hereinafter uses helped In understanding the present invention.
" hyaluronic acid " used herein or " HA " refer to described in this paper or the list of references The hyaluronic acid of form of ownership comprises that those are processed, or chemistry or physics modification is transparent Matter acid, and crosslinked hyaluronic acid (for example covalent cross-linking, ionomer, heat cross-linking or physics Crosslinked). The glycosaminoglycan that HA is made up of the straight chain of the disaccharide unit of about 2500 repetitions. Whenever One disaccharide unit is made up of the N-acetyl-glucosamine residue that links to each other with glucuronic acid. Described molecule Can have different length (being the repetition disaccharide unit of different numbers and different chain branch patterns) And can be modified in some sites (by adding or the different functional group of cancellation) and do not departed from The scope of the present disclosure.
This paper employed " hyaluronic acid enzyme inhibitor " or " HI " refer to direct or indirect change Or suppress the compound that hyaluronidase or other hydrolase are hydrolyzed hyaluronic ability. " HI " Also refer to prevent the interior decomposition of body of HA, the interior decomposition of body of minimizing HA or the interior branch of body of prolongation HA Separate any molecule of required time, and the specific mechanism of action of this molecule no matter. The reality of HI Example comprises Kaempferol, sulfuric acid-β-(Isosorbide-5-Nitrae)-four galactoside, neomycinsulphate, cyanidenon, poplar Plum flavine, phloretin, Quercetin, silymarin, glycyrrhizin, tranilast, baicalein, Traxanox, isoliquiritigenin, disodium chromoglycate, flavanone-7-sodium sulphate and 5-flavonol-7-Sodium sulphate, contain gold compound, Indomethacin, sulfated polysaccharides, medicine cosolvent, non-from Sublist surface-active agent, diblock copolymer and carboxymethyl cellulose. This paper has described in detail suitable Multiple compounds and copolymer that cooperation is used for HI.
This paper employed " analog " refers to that structure and parent compound are similar, but on forming It is again slightly different that (for example atom or functional group's difference add or remove an atom or sense Group) compound. Compare with original chemical, analog can have also can not have difference Chemistry or physical property, and can have the biologically active that also can not have improvement and/ Or chemism. For example, compare with parent compound, analog can be more hydrophilic or It can have the reactivity of change the person. Analog can simulate parent compound chemistry and/ Or biologically active (namely can have similar or identical activity), perhaps, in some cases, Can have activity increase or that reduce. Analog can be naturally occurring or non-natural is deposited The variant of (for example restructuring) original chemical. The example of analog be mutein (namely At least one amino acid is wherein deleted, added to the analog of protein, perhaps uses another 49-Phe ,82-Ser,115-Arg,144-Met,145-Asn ,161-Arg,169-Met Human Connective tissue growth factor at least one amino acid). The analog of other type comprises isomers (mapping Isomers, diastereomer etc.) and the chirality variant of other type of compound, and structure with Divide isomers. Analog can be variant side chain or ring-type of straight chain compound. For example, Straight chain compound can have analog that side chain or alternate manner replace to give some expectation Character (for example improving hydrophily and bioavilability).
This paper employed " derivative " refers to chemistry or the biological form of modifying of compound, institute State compound and parent compound structure similar and (in fact and in theory) derived from this parent Compound. Usually, " derivative " is different from " analog ", because parent compound can be Produce the initial substance of " derivative ", and that this parent compound must be used as not necessarily is initial Material is to produce " analog ". Analog can have different from parent compound chemistry or Physical property. For example, compare with parent compound, derivative can be more hydrophilic or passable Reactivity with change.
Derive (namely modify) can relate to the replacement of intramolecular one or more parts (sense for example The variation of group). For example, can use such as halogens such as fluorine or chlorines to replace hydrogen, perhaps can use The carboxylic acid part (COOH) replaces oh group (OH).
Term " derivative " also refers to whole solvates, and for example hydrate or adduct are (for example Adduct with ethanol), the salt of active metabolite and parent compound. The salt that can prepare Type depend on the character of each several part in the compound. For example, such as acidic groups such as carboxylic acid groups Group can form alkali metal salt or alkali salt (for example sodium salt, sylvite, magnesium salts and calcium salt, with And the acid-adducting salt and the physiology that have the salt of the quaternary ammonium ion that physiology can tolerate and have ammonia can tolerate Organic amine, for example triethylamine, monoethanolamine or three (2-ethoxy) amine). Basic group can shape Become acid-adducting salt, for example form acid-adducting salt with inorganic acid, described inorganic acid for example be hydrochloric acid, Sulfuric acid or phosphoric acid perhaps form acid-adducting salt with organic carboxylic acid and sulfonic acid, described organic carboxylic acid and Sulfonic acid for example be acetic acid, citric acid, lactic acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, Methanesulfonic acid or p-methyl benzenesulfonic acid. Contain simultaneously basic group and acid group compound can with Amphion exists, and for example contains carboxyl and basic nitrogen atom. Can pass through the art technology people The known conventional method of member obtains salt, for example passes through in solvent or diluent compound and nothing Machine or organic acid or alkali mix, and perhaps get from other salt by cation exchange or anion exchange Salt to expectation.
The derivative of other type comprises that the bond of parent compound and prodrug are (namely at the physiology bar Can be converted into the derivative of the chemical modification of original chemical under the part). For example, described prodrug can To be the inactive form of activating agent. Under physiological condition, can be with described being converted into of prodrug The activity form of compound. For example can by use on the carboxyl groups substituted nitrogen atom one or Two hydrogen atoms form prodrug (acyl group prodrug), perhaps by using carbamate groups to get Form prodrug (carbamate prodrugs) for one or two hydrogen atom on the nitrogen-atoms. Can At Fleisher et al., Advanced Drug Delivery Reviews 19 (1996) 115; Design of Prodrugs, H.Bundgaard (ed.), Elsevier, 1985; Or H. Bundgaard, Drugs of the Future finds about prodrug more in 16 (1991) 443 Detailed information.
" inhibition " used herein refers to compared with the control, enzyme (for example hyaluronidase) lived The property statistics, biology or clinical significant direct or indirect change, reduction or elimination.
Except as otherwise noted, any concentration range as herein described should be interpreted as and be included in institute State any integer in the scope and the concentration of mark thereof, for example 1/10th of integer and percent One. In addition, except as otherwise noted, should relate to appointing of any physics feature with as herein described What digital scope is interpreted as any integer that comprises in the described scope, and described physics feature for example is The subunit of polymer, size and thickness. Should be appreciated that, above with other local use of this paper Term " a " and " an " refer to the component that " one or more " are cited. Make as this paper With like that, the meaning of term " pact " is particular value, scope or structure ± 15%. As this Literary composition is employed like that, term " comprise (include) " and " comprising (comprise) " as same The justice word uses. Just as used herein such, term " mean value (average) " or " flat Average (mean) " comprise arithmetic mean of instantaneous value and any suitable weighted average, for example at table State the mean value that uses when polymerizable molecular amount or particle diameter distribute.
This paper is with reference to multiple references, and described list of references has for example been described certain in further detail A little operations or composition (such as compound, protein etc.). Introducing comprises patent and publishes an article At the full content of these interior lists of references as a reference. Be to be further noted that and work as with reference to PCT During application, this paper also is introduced as the full content conduct of its basis or its U. S. application of quoting Reference.
I. hyaluronic acid
Hyaluronic acid is a kind of natural materials that can find in the extracellular matrix of many tissues, and described tissue comprises vitreous humor, cartilage, blood vessel, skin and the umbilical cord of synovial joint fluid, eye.Hyaluronic acid with commercial form of about 1,200,000 to 1,500,000 dalton (Da) extracts from crest and other animal origin.Other HA source comprises the HA that separates from cell culture/sweat.Can also obtain the HA preparation of lower molecular weight from multiple commercial source.
Usually, the HA product that is suitable for the present invention's use has many commercial source, promptly has many commercially available HA products, and can be to wherein adding HI of the present invention.Example comprise be used for the treatment of osteoarthritis, be used for that viscosity is replenished, as eye with the viscoelasticity product, that be used for beautifying face (corium) and as the commercial compositions of vesicoureteral reflux implant (filler).These and other product concrete details more hereinafter will be provided.
The material that contains HA of intraarticular treatment that is used for other symptom of pain and osteoarthritis comprises following material.From Genzyme Biosurgery (Ridgefield, SYNVISC NJ) are the derivants that contains hylan[hyaluronic acid (hyaluronate) (hyaluronic acid (hyaluronan)) sodium from crest] elastico-viscous fluid of polymer.(Woburn, ORTHOVISC MA) are intended to alleviating pain and improve the joint mobility suffer from knee osteoarthritis (OA) patient and the HA of highly purified, the high molecular of range of activity, full-bodied injectable forms from AnikaTherapeutics.ORTHOVISC is injected in the knee joint to recover the elasticity and the viscosity of synovial fluid.HYVISC is by the high-molecular weight injectable HA product of Anika Therapeutics exploitation, is used for the treatment of the osteoarthritis and the limping of horse racing at present.Other is used for the treatment of osteoarthritis and can comprises from Medexus with the viscosity supplementary based on HA of HI combination of the present invention, Inc. the HYALGAN of (Canada), from the SUPARTZ of Seikagaku Corp. (Japan), from Bioniche Life Sciences, Inc. the SUPLASYN of (Canada), from DePuy Orthopaedics, Inc. (Warsaw, ARTHREASE IN) and from the DUROLANE of Q-Med AB (Sweden).
The viscoelastic solution with HA is used for the treatment of the ocular disease state, for example transplant in pioneering operation, intra-ocular lens, retina is put again, during phacoemulsification operation, corneal transplantation and the operation for glaucoma as Vitrea substitute.AMVISC and AMVISCPLUS are (all from Anika Therapeutics, Inc.) and OCUCOAT (Bausch ﹠amp; Lomb) be high-molecular weight, the viscoelastic and injectable HA solution that is used for during cataract extraction, corneal transplantation and operation for glaucoma, keeping eye shape and the accurate tissue of protection.Eye based on HA comprises PROVIS, VISCOAT, DUOVISC and CELLUGEL from Alcon Laboratories with the viscoelasticity product; From Pharmacia ﹠amp; The HEALON of Upjohn, HEALON G and HEALON 5 are from the VITRAX of Allergan; BIOLON from Bio-Technology General; STAARVISC from Anika Therapeutics/StaarSurgical; From the SHELLGEL of Anika Therapeutics/Cytosol Opthalmics and from the UNIVISC of Novartis.
Product based on HA can also be used as filler.This moment with this material be injected in the tissue with recover volume, provide support and restore funcitons-normally " filling " around the sphincteral tissue of incontinence.To be used for the treatment of urinary incontinence, fecal incontinence and gastroesophageal reflux based on the filler of HA; Cause leaking all morbid states of generation by sphincter incapability or damage.The representational example of the vesicoureteral reflux based on HA (urinary incontinence) product that the present invention uses is the DEFLUX from Q-Med/Priority Healthcare.
Can also use the adhesion after hyaluronic acid product prevents multiple operation technique.Adhesion is to occur in the connection of the scar tissue between adjacent tissue or bridging, and described adjacent tissue is impaired at intra-operative.The adhesion scar tissue can damage normal anatomy function and can cause countless clinical problems, comprises pain, intestinal obstruction, sterile and nerve root compression infringement.Biological absorbable cross-linked-hyaluronic acid (HA) product of INCERT family is designed to be placed on the formation that suppresses scar tissue between adjacent tissue as barrier at intra-operative.Other the surgical adhesions product based on HA comprises the Biosurgery from Genzyme, Inc. (Cambridge, MA) GYNECARE INTERGEL (LifeCore) and SEPRAFILM adhesion barrier.
Other HA product comprise the implant that is used for during operated eye, using with filling defect, prevent cicatrix, tissue support and healing acceleration be provided.For example OSSIGEL is the viscosity preparation of hyaluronic acid (HA) and basic fibroblast growth factor (bFGF), its be used to accelerating union of bone fracture (Orquest, Inc.).
To use fastest-rising field may be treatment and other beauty treatment and the aesthetic applications that health increases (for example facial), wrinkle to the HA product in the medical science.In the beauty treatment operation, usually HA is injected into subcutaneous tissue to fill skin depressions and defective, so that reduce the appearance of lines or other undesired vestige.The hyaluronic acid derivatives that is used for the commercially available synthetic of this purpose comprises the HYLAFORM (being also referred to as HYLAN B) from Genzyme Biosurgery; RESTYLANE and PERLANE are (from Q-Med AB, Sweden).MACROLANE (Q-Med) is the product that is used to enlarge the bosom just under development.
Other application that use contains the material of HA comprises the treatment of drug conveying, treatment of cancer and interstitial cystitis.Be used for drug conveying and can comprise Hyaluronic Induced Targeting (HIT) (SkyePharma (UK)) and NASHA gel (Q-Med) with the example of the material that contains HA of HI combination.Topical formulations for example from SOLARESE and the SOLARASE of Meditech (Australia), is the topical gel that is used for the treatment of skin carcinoma.The commercially available material based on HA that is used for the treatment of interstitial cystitis comprises that (Bioniche Life Sciences, Inc.), it is for be used for substituting the aseptic sodium hyaluronate solution of glycosaminoglycans (GAG) layer on the urothelium temporarily for CYSTISTAT.
Therefore, the compositions that on the commercial market, obtains being used for the pure HA of various clinical sign easily and contain HA.These materials that contain HA are the examples that can be used as the material that contains HA in HA source in the present invention.
II. Hyaluronidase inhibitor
Multiple chemical compound can be used to suppress or reduce the enzymatic degradation of HA in the body and be adapted at using in the practice of the present invention.For example, chemical compound and HA combination can be resisted degraded and had the active HA implant of prolongation to be created in the various clinical sign.
The micromole can be used to suppress hyaluronic degraded in the body to the Hyaluronidase inhibitor (HI) of millimolar concentration scope.These chemical compounds and hyaluronic acid can be carried simultaneously or successively.For example, can be by in the preparation that hyaluronic acid is included in administration and HI and hyaluronic acid are carried to the patient simultaneously.Perhaps, or in addition, can be with these HI compound administrations after with the hyaluronic acid administration.In some aspects, the preferred sustained release of the polymerization dosage form by these chemical compounds and target tissue is exposed in these chemical compounds continuously.This paper will describe these compositionss and other combination in detail.
1. gold compound
Many gold compounds can be used as the inhibitor that decomposes in the HA body and are suitable in the practice of the present invention.As used herein gold compound comprises coordination compound, and wherein gold is with one or more part chelatings or combine organic gold compound, inorganic gold compound and salt thereof, and element (for example metal) gold.Described chemical compound can be hydrophilic, hydrophobic, amphoteric, and can be dissolved in solution or can be the form (for example gold colloidal) of granule suspension.Sometimes, organo-metallic compound can be deleterious-those skilled in the art will know that it is nontoxic how determining to use great amount to make these chemical compounds dock subject individuality.Below described can with the example of HA combination with the gold compound that produces HA-gold implant, described implant opposing degraded and in the various clinical sign, have the biologic activity of prolongation.
A. golden (I) coordination compound
On the one hand, gold compound is gold (I) coordination compound.Gold complex comprises and one or more part chelatings, combination, complexation or the gold (I) (for example coordinate complex) that otherwise is connected.The representational example of such gold (I) coordination compound comprises gold (I) phosphine compound, gold (I) phosphine thing or gold (I) phosphate mercaptides, two coordinate gold (I) salt and gold (I) chelate (for example referring to United States Patent (USP) the 5th, 527, No. 779).
Gold (I) phosphine thing and relevant chemical compound have general formula: R 3PAuX, wherein R is alkyl (for example methyl, ethyl, isopropyl or normal-butyl), aryl or heterocyclic radical, or their substitutive derivative, and X is a halogen.The representative example of gold (I) phosphine compounds for example comprises triphenylphosphine complex (Ph 3PAuCl) and Et 3PAuCl.
Another example has general formula R 3PAuX, wherein X is that imidazoles or X are 2-thiazolinyl, sulfo--2-benzimidazolyl or 2-benzoxazolyl sulfo-part.
Other example of gold (I) phosphine compounds comprises NSC652537, NSC652539, have AuSP and AuNP nuclear the coordinate triphenylphosphine gold of 2-(I) coordination compound (for example referring to Nomiya, K., et al.J.Inorg.Biochem.2003; 95 (2-3): 208-20), contain the coordination compound of single phosphine and two phosphine-derivatives, chlorine triphenylphosphine-1 for example, two (diphenylphosphine) propane gold (I) of 3-(for example referring to Caruso, F.J.Med.Chem.2003; 46 (9): 1737-42), have nitrogenous heterocyclic triphenylphosphine complex, described nitrogen heterocyclic ring for example pyrazoles and imidazoles (for example referring to Nomiya, K., et al.; J.Inorg.Biochem.2000 Mar; 78 (4): 363-70), chlorine (triphenylphosphine) gold (I) is (Et (TEPAu) 3PAuCl) and phosphonate coordination compound (and phosphine reaction product), and four ((trihydroxy methyl) phosphines) gold (I) chloride (for example referring to Pillarsetty, N., et al.J.Med.Chem.2003; 46 (7): 1130-1132).
The example of related compound comprises having general formula (RO) 3The Hydrogen thiocyanate gold compound of PAuX and have general formula R 3PAuSCN and (RO) 3The rhodanate gold complex of PAuSCN, wherein R is alkyl (for example methyl, ethyl), aryl (for example phenyl) or heterocycle, and can be that replace or unsubstituted, and X is a halogen.Gold (I) phosphine (or phosphite) mercaptides comprises that those have general formula R 3The chemical compound of PAuSR ', wherein R is alkyl (for example ethyl), alkoxyl or phenyl, and R ' is H, alkyl, aryl or heterocycle, and can be that replace or unsubstituted.For example, R ' can be the carbohydrate part that replaces, and chemical compound has following formula like this:
Figure A20058003514200341
Wherein X is H, acetyl group or formoxyl; Y is O or S; And n is 1 to 12.
The example of gold phosphine compound is auranofin (1-sulfo--β-D-Glucopyranose .-2,3,4, (triethyl phosphine) gold of 6-tetrem acyl-S)), and known its has antiinflammatory and antiheumatic character.
Other example of phosphine or phosphite gold (I) mercaptides comprises:
Figure A20058003514200342
And phosphine or phosphate gold (I) coordination compound comprise the derivant of mercaptan, thio-acid and phenylmercaptan, and comprise that those have general formula R 3The chemical compound of PAuX, wherein X is 2-thiazolinyl, sulfo--2-benzimidazolyl, and 2-benzoxazolyl sulfo--, those have general formula (R 3PAu) 2The chemical compound of S, and can use macro ring chelate as follows:
Figure A20058003514200343
Wherein X is H, alkyl, aryl or heterocycle, and can be that replace or unsubstituted.
Other example of gold chelate comprises Weinstock et ah, J.Med.Chem.17 (1): 139-140, the 1974 macro ring gold chelates of describing.
The example of two coordination gold (I) salt comprises that those have general formula [R 3PAuPR 3] +X -[R 2SAuSR 2] +X -[RC 5H 4NAuNC 5H 4R] +X -[R 3PAuNC 5H 4R] +X -Chemical compound, wherein R is alkyl, aryl or heterocycle, and can be that replace or unsubstituted; And X is halogenide, ClO 4, BF 4Any monovalence perhaps known in the art or dianion.
The representational example of gold (I) chelate has following general formula:
Figure A20058003514200351
Wherein R be any suitable bridged portion and can be replace or unsubstituted alkyl, aryl or heterocycle; X is O, N or SO 2NR 2And R 1Be H, alkyl, aryl or heterocycle and can be that replace or unsubstituted.For example R can be C 6H 4, X is O and R 1Be C 2H 5
B. organic gold compound
On the other hand, gold compound is organic gold compound.Can use the multiple organic gold compound that comprises organic gold compound described herein in the compositions of the present invention.
On the one hand, organic gold compound can have antiinflammatory and antiheumatic character (for example also referring to the aurotherapy chemical compound).The representational example of aurotherapy gold compound comprises auranofin (mentioned above), golden sulfo-polypeptide and Aurothiomalate and Kidon (Ono) (MYOCRISIN; Succinic acid, sulfydryl-a gold medal (1+) sodium salt (9CI)) (referring to J.Reprod.Fertil.1980; 60 (2): 461-7), it has following formula:
Figure A20058003514200352
●Au(I)
●x?Na
Other example of organic gold compound comprises aurothioglucose (1-sulfo--D-Glucopyranose .-O2, S1) gold and derivant thereof, for example two (thioglucose) gold (I), two (Thiomalate) gold (I) and aurate (1-) [3-[[2-acrylic amino) sulfo-oxygen methyl] imido grpup] benzoate (2-)]-, sodium }] (NSC617746 sodium salt), and comprise pyridine derivate, imdazole derivatives is at interior gold (I) coordination compound, pyridine derivate is NSC689418 and NSC689419 for example, imdazole derivatives for example clotrimazole and ketoconazole (for example referring to Navarro, N., et al.Inorg.Chem.2001; 40 (27): 6879-84), NSC652538, and double-core gold (I) phosphonodithioic acid salt complex (for example referring to Maspero, A., et al.Inorg.Chem.2003; 42 (17): 5311-9).
C. golden (III) coordination compound
On the other hand, gold compound is gold (III) coordination compound.The representational example of gold (III) coordination compound comprises CG salt (cholylglycinato) coordination compound, for example the two CG gold (III) of chlorine are (for example referring to Carrasco et al, J.Inorg.Biochem.84 (3-4): 287-92,2001), three and tetradentate phosphino-mercaptides coordination compound (for example Ortner et al., Inorg.Chem.39 (13): 2801-6,2000), and contain ethylenediamine, diethylenetriamines, tetraazacyclododecane tetradecane, 2,2;-two pyridines, 6-(1, the 1-dimethyl benzyl)-2,2 '-two pyridines), 1,4,8, the coordination compound of 11-tetraazacyclododecane tetradecane, phenanthrolene, three pyridine ligands is (for example referring to Messori et al., J.Med.Chem.43 (19): 3541-8,2000 and Marcon et al., Eur.J.Biochem.270 (23): 4655-61,2003).
D. inorganic gold compound
On the other hand, gold compound is inorganic gold compound.The representational example of inorganic gold compound comprises that golden III and golden IV chloride (are respectively AuCl 3And AuCl 4) and golden salt, for example gold (II) chloride, hydrochloride, the muriatic sodium salt of gold (III) and Sanocrysin.
E. gold grain
On the other hand, gold is a particle form.Can be called " gold colloidal " with having the Aurum metallicum granule that mean size is lower than about 50nm.Normally the gold colloidal preparation of liquid suspension form comprises gold grain, and its scope is about 0.5nm to about 40nm or less than about 40nm, and perhaps about 1nm is about 3nm extremely.Can prepare colloid gold particle and be available commercially colloid gold particle by method known to those skilled in the art.
Gold grain can 3 being functionalized or non-functionalized.Functionalized gold grain can combine with chemical compound, and described chemical compound for example is that oligonucleotide, lipid, peptide, protein, enzyme inhibitor, antibody or other have the chemical compound of suitable reactivity part.
Can be from Nanoprobes, (Yaphank NY) obtains multiple functionalized or non-functionalized gold grain to Inc..In the present composition, can use positively charged and electronegative NANOGOLD granule (1.4nm).The NANOGOLD of positively charged has a plurality of amine on its surface, and electronegative NANOGOLD has a plurality of carboxylic groups.Functionalized NANOGOLD granule can combine with multiple biologic artifact.For example single maleimide NANOGOLD can be used for covalent labeling Fab ', IgG, contain the protein or the peptide of cysteine, and other has the molecule of sulfydryl.(also from Nanoprobes, Inc.) have the nuclear of 11 gold atoms, the diameter of this nuclear only has 0.8nm and has a maleimide base group single maleimide 11 gold medals of similar products like, and this product can be used for the selected marker sulfydryl (SH).Single sulfo--NHS-NANOGOLD comprises with primary amine reaction and comes the sulfo--N-hydroxy-succinamide ester covalently bound with the oligonucleotide of protein, lipid, peptide, modification or other molecule that contains amine (sulfo--NHS).Can also obtain similar products (single sulfo--NHS-11 gold medals) based on 11 gold compounds.The NANOGOLD granule that can also obtain being connected with primary amine for use in other cross-linking reaction (for example with glycoprotein in sugar moieties covalently bound).Can (Agawam MA) obtains the cation gold grain of commodity BIOSITE by name, and this gold grain is combined and obtains with poly-L-Lysine by colloid gold particle from EnergyBeam Services.
Can use and suppress hyaluronic degraded such as gold compounds such as Aurothiomalates.These chemical compounds and hyaluronic acid can be carried simultaneously or successively.For example, can be by in the preparation that gold compound is included in administration and gold compound and hyaluronic acid are carried to the patient simultaneously.Perhaps, or in addition, can be with these compound administrations after with the hyaluronic acid administration.In some aspects, can be preferably by these chemical compounds the polymerization dosage form sustained release and target tissue is exposed in these chemical compounds continuously.
2. polysaccharide
On the one hand, Hyaluronidase inhibitor can be the analog or the derivant of polysaccharide or Sulfated (promptly containing sulfuric ester) polysaccharide or Sulfated polysaccharide.The representational example of polysaccharide comprises that alginic acid, pectin and glycosaminoglycans are (for example referring to Biosci.Biotechnol.Biochem.1997; 61 (6): 1030-2, J.Enzyme Inhib.Med.Chem.2002; 17 (3): 183-6).The representative example of sulfonated chemical compound comprises that the acidifying β of sulfonic acid-(1,4)-breast-oligosaccharide (n=2-6) with sulfonation degree of 0.2 to 1, sulfonic acid neomycin, the Sulfonated HA of O-are (for example referring to Arch.Biochem.Biophys.1999; 370 (2): 176-82), the single lactobiose glycosides of sulfonated planetose, sulphuric acid hydroquinone digalactosyl glycosides, sulphuric acid-2-hydroxyphenyl.The representational example of Sulfated polysaccharide comprises that heparin sulfate/heparinoid is (for example referring to Arch.Biochem.Biophys.1999; 370 (2): 176-82; Matrix Biol.2002; 21 (1): 31-7), dextran sulfate and fucosan (for example fucoidin).
Dextran sulfate is a polyanion soluble in water, and it can interact with cation and polycation.Therefore, dextran sulfate can combine with multiple film, particularly combines with those films with positive charge.Reported that dextran sulfate has the various clinical purposes.Shown dextran sulfate and derivant thereof can anticancer growth (Bittoun P., Carbohydrate Research 1999 (3-4) p 247-255); Has anticoagulant effect (Mauray S., 1998 J Biomat.Sci.Poly ed.1998 94p 373-87); Prevent that the syncytium that takes place from forming or the leukocyte grumeleuse in AIDS patient; And the stabilizing agent (drug excipient) that can be used as responsive natural component.
Heparin is one group of allogenic straight chain anion mucopolysaccharide that is called as glycosaminoglycans with anticoagulant character.The glycosaminoglycans that its main active is made up of D-glucuronic acid and D-glycosamine (the two is all by sulphation) and with 1, that 4-α key connects, according to the method and the source of preparation, its molecular weight is about 6000-20, and 000.Different heparin samples can have the N-and the O-sulphation of varying level in hexosamine and anti-bad blood residue.May throwing into question in many blood coagulations, heparin (comprising its derivant) is widely used as anticoagulant in the vascular condition of (for example open heart surgery and dialysis).
Fucosan (for example fucoidin) is the high-molecular weight Sulfated polysaccharide that extracts from Brown algae.These chemical compounds have in the multiple body and the vitro inhibition effect, comprise antithrombase, antiproliferative, anticomplementary, anticancer and Antineutrophil migration effect (Riou D et al, Anticancer Research, 16 (3A): 1213-1218,1996; Itoh, AnticancerResearch 13 (6A): 2045-2052,1993; Nishiro et al, Thromb.Res.62:765-773,1991; Blondin et al, Mol.Immunol.31:247-253,1994; Patankaret al, J.Biol Chem.268:21770-21776,1993.).On the market fucoidin is sold as health food and be proposed as enamel or skin agent (for example referring to JP 01031707 and JP 01085905).
Can will be used to suppress hyaluronic degraded such as Sulfated polysaccharide such as heparin, heparitin sulfate, dextran sulfate and fucoidin.These chemical compounds and hyaluronic acid can be carried simultaneously or successively.For example, can be by in the preparation that Sulfated polysaccharide is included in administration and Sulfated polysaccharide and hyaluronic acid are carried to the patient simultaneously.Perhaps, or in addition, can be with these compound administrations after with the hyaluronic acid administration.In some aspects, can be preferably by these chemical compounds the polymerization dosage form sustained release and target tissue is exposed in the Sulfated polysaccharide continuously.
3.PLA, the copolymer of PLGA and other material
On the other hand, Hyaluronidase inhibitor (HI) can be a polymeric material.This polymer can be homopolymer or copolymer (for example diblock or triblock copolymer).On the one hand, described polymer can be a homopolymer, for example polylactic acid (PLA).On the other hand, described polymer is a diblock copolymer.Multiple diblock copolymer can be used as the interior HA decomposing inhibitor use of body and is suitable for using in practice of the present invention.
Can comprise the diblock copolymer of lactic acid and/or hydroxyacetic acid and Polyethylene Glycol with the example of the diblock copolymer that produces HA-diblock copolymer implant with HA combination, described implant opposing degraded and in the various clinical sign, have the biological activity of prolongation.On the one hand, described polymer can comprise having (O-CH (CH 3The lactic acid residue of the structure of)-CO-), has (OCH 2CH 2-) ethylene oxide residue, the hydroxyacetic acid (O-CH of structure 2-CO-) residue or caprolactone (O-(CH 2) 5-CO-) residue.For example, described diblock copolymer can be polylactic acid-co-Polyethylene Glycol (PLA-PEG); Poly-(lactic acid-co-glycolic)-co-Polyethylene Glycol (PLGA-PEG) and polycaprolactone-co-Polyethylene Glycol (PCL-PEG).On the one hand, described polymer is to have the methoxy poly (ethylene glycol) of 60: 40 ratios and the copolymer (MePEG-PLLA) of poly-(L-lactic acid).In all these chemical compounds, methoxy poly (ethylene glycol) (MePEG) can substitute PEG.On the one hand, described copolymer is poly-(L-lactic acid)-co-methoxy poly (ethylene glycol) (PLA-MePEG).
Monomer in the diblock copolymer can be in chain random alignment or can be that individual polymer is associated in chain together.Usually use the combination of hydrophobic polymer and hydrophilic polymer to make such copolymer that is connected.For example, hydrophobic PLA can be used for and hydrophilic Polyethylene Glycol combination.Gained amphipathic copolymer contain hydrophilic area and hydrophobic region.Such molecule is often used in pharmaceuticals industry, because it can link to each other to modify its character with drug molecule by any one district.Ampholyte copolymer can also be used as admixture with other polymer to modify the gross properties of main polymer.Such character can change the ability of diblock to form micelle and to stablize non-water-soluble medicine, perhaps make such as rigid polymer plasticising such as PLGA, therefore they more bio-compatible and can discharge more apace drug coated (for example referring to, Liggins, R.T., et al., Advanced Drug Delivery Reviews (2002) 54, p 191-202; Kwon G, et al. (1995) 16, p 295-309; And Jackson, J.K., et al. (2004), Int.Journal of Pharmaceutics (in press)).
On the one hand, described HI is the copolymer of poly(ethylene oxide) or Polyethylene Glycol.The structure of PEG and PEO is identical, and PEG is often referred to molecular weight and is lower than 20,000 polymer, and PEO refers to have more high molecular weight polymers.The chemical combination that a large amount of research makes great efforts to pay close attention to Polyethylene Glycol (PEG) or poly(ethylene oxide) (PEO) and PLA or PLGA comprises the copolymer of PEG hydrophilic and biocompatibility and PLGA degraded character with generation.According to the composition of copolymer, the character of the polymer of gained can be hydrophilic or hydrophobic and can be nondegradable or degradable.
At exploitation PLA 100Relate to PEO not commensurability in the copolymer with some early stage work of the block copolymer of poly(ethylene oxide), so that the equilibrium water content of polymeric matrix can reach and is higher than 60% (Cohn and Younes in 1988).For these special copolymers, the scope of lactic acid part be 20 to 84mol% and the MW of PEO chain be about 600 to 6000.Other research work of the block copolymer at random of PLA and PEG has been assessed the degradation behavior of these materials and as the effectiveness of drug conveying microgranule.As if degradation rate depend on the content of PEG more, and in the PLA fragment of part degraded before from bulk polymer, discharging, the PEG dissolving that they are attached sometimes.
On the one hand, the described copolymer PLA chain that comprises the central block of PEG or PEO and be positioned at any end.Can begin by the PEG fragment by given length, polymerization PLA meanwhile uses PEG to prepare these polymer as the inhibitor of polyreaction then.The length of PEG block and PLA 100Length can influence the water absorption and the degraded of these copolymers.A series of paper studies of Kissel the microenvironment of PLA-PEO-PLA microgranule between biocompatibility and degradative phase in synthetic, the external degradation of these three block species, drug conveying, the external biological compatibility, the body.Study on biocompatibility shows that the PLA-PEO-PLA polymer has shown closely similar and minimum harmful structure reaction.Contrast is by PLA100-PEO-PLA 100And PLA 50-GA 50-PEO-PLA 50-GA 50The microsome of polymer manufacture carries the drug conveying of BSA studies show that outward, the polymer that contains PLAGA has quite successive release, and the release that contains the polymer of PLA has two stages, and the release in these two stages is the typical more features of PLAGA microgranule.Cytochrome C and FITC-glucosan are from PLA 50-GA 50-PEO-PLA 50-GA 50Releasing research in the microgranule has also shown external continuous release.
On the other hand, described HI comprises the monomeric unit from 6-caprolactone.For example, described HI can be the copolymer of 6-caprolactone and PLA or PGA.A large amount of research groups after deliberation the copolymer of PLA or PGA and 6-caprolactone.In a research, the terpolymer of having studied a series of 66 kinds of different DL-lactide, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactones is to determine degradation rate and other character (Sawhney and Hubbell) of cast film.They find that the polymer of Acetic acid, hydroxy-, bimol. cyclic ester, lactide and the 6-caprolactone of 2: 1: 7 ratios has the longest degradation time, and ratio of polymer degraded in 6: 3: 1 is the fastest.Have been found that the physical property of the copolymer of lactide and 6-caprolactone is elastomeric from hard changing to when the content of 6-caprolactone increases to 20wt% by 5wt%.The porous copolymers that contains 50% 6-caprolactone is cited as the implant that is used for the meniscus of knee joint tissue regeneration.This polymer has shown the behavior of a large amount of degradeds, and has been divided into crystalline phase that mainly contains the L-lactide and the amorphous phase of mainly being made up of 6-caprolactone between degradative phase.
On the other hand, described copolymer comprises the monomeric unit from glycine, P-hydroxybenzoic acid and p-Coumaric Acid or aspartic acid.For example, described copolymer can be to comprise from the monomeric unit of glycine, P-hydroxybenzoic acid and p-Coumaric Acid or aspartic acid and the copolymer of PLA or PGA.These materials are to have the degraded that is different from independent PLA or PGA and the biodegradable material of releasing properties.
By simply with these reagent mix in or be dissolved in the hyaluronic acid preparation of administration, these diblock copolymers (for example polycaprolactone-co-PEG or PLA-PEG) can be used to suppress hyaluronic degraded.Perhaps, after with the hyaluronic acid administration with they administrations.
Above-mentioned polymer and copolymer (for example diblock copolymer) can be used to suppress hyaluronic degraded.These chemical compounds and hyaluronic acid can be carried simultaneously or successively.For example, can be by in the preparation that polymer is included in administration and polymer and hyaluronic acid are carried to the patient simultaneously.Perhaps, or in addition, can be with these compound administrations after with the hyaluronic acid administration.In some aspects, can be preferably by these chemical compounds the polymerization dosage form sustained release and target tissue is exposed in these chemical compounds continuously.
4. drug excipient
On the other hand, described HI can be a drug excipient.As used herein drug excipient refers to additive like that, and it is used for pharmaceutical active compounds is converted into the dosage form that is suitable for patient's administration.
Excipient can be used to improve the bioavailability and the bioequivalence of medicine agent.The excipient that uses in the prescription dosage form includes but not limited to filler, adhesive, disintegrating agent, lubricant, coating agent, solvent, suspending agent and dyestuff.Can use these excipient to be because they have high bioavailability, so they improve the preparation nature of medicine and don't can cause any undesired toxicity in the patients.
The example that is suitable for use as the excipient of HI comprises that carboxymethyl cellulose (CMC) sodium, expoxy propane and oxirane (can be from BASF Corporation, Mount Olive, NJ is purchased a series of these chemical compounds with trade name PLURONIC and PLURONIC R) and the triblock polymer of selecting of Polyethylene Glycol (PEG).
According to the transporting pattern of using and expecting, use the Polyethylene Glycol of multiple physical form.Solid PEG is used as water-soluble ointment base.In aqueous medium, can use PEG to regulate viscosity and denseness.When uniting use with other emulsifying agent, PEG can be used as emulsion stabilizer.Liquid PEG can be as the miscible medium of water of soft capsule content.Can improve the water solubility of insoluble compound or the character of decomposition by the solid dispersion that manufacturing contains suitable PEG.High-molecular weight PEG can improve the effectiveness of tablet binder and can make granule have plasticity.When being used for the thermoplastic granulating, will contain 10 to 15%PEG 6000 powdery components mixture heated to 70 to 75 ℃.This material becomes pasty state, and if in cooling stirring simultaneously, it forms granule.This technology is useful for the dosage form that prolongs disintegrate such as needs such as lozenge.PEG is used as plasticizer in film coating.For film coating tablet, can use solid grade and this solid grade can be used as hydrophilic polishing material separately.With the combination of film forming polymer in they are widely used as plasticizer.When in film, having PEG, when especially having the liquid grade, be tending towards increasing its water penetration, and can reduce the protection of anti-low PH in the enteric coating thin film.When microcapsule is pressed into tablet, little bag by product in PEG can be used as plasticizer to avoid breaking of coating membrane.PEG 6000 and above grade can be used as lubricant, particularly in soluble tablets.Its lubrication is not as magnesium stearate, and if in pressing process material become too hot, may adhere so.It also has anti-adhesion effect, need avoid overheated equally.
On the other hand, described drug excipient is sorbitan ester (SPAN), for example SPAN20, SPAN 40 and SPAN 85 (Adolor Corporation, Exton, PA).
On the other hand, described drug excipient is the polysorbate chemical compound, and for example (NJ), it is usually as oil-in-water emulsifiers and be used for the preparation of Emulsion, emulsifiable paste, ointment and suppository base for ICI Americas Inc., Bridgewater for TWEEN.TWEEN is the polyoxyethylene deriv of sorbitan ester.The existence of polyoxyethylene chain makes that these derivants are hydrophilic.When oral, polysorbate is well-tolerated and has very low toxic level, does not also cause partial stimulation in the practice.
On the other hand, described drug excipient is the propylene glycol that is widely used as solvent, extractant and antiseptic.
Can will be used to suppress hyaluronic degraded such as but not limited to drug excipients such as propylene glycol, carboxymethyl cellulose, PLURONIC and SPAN.These chemical compounds and hyaluronic acid can be carried simultaneously or successively.For example, can be by in the preparation that polymer is included in administration and polymer and hyaluronic acid are carried to the patient simultaneously.Perhaps, or in addition, can be with these compound administrations after with the hyaluronic acid administration.In some aspects, can be preferably by these chemical compounds the polymerization dosage form sustained release and target tissue is exposed in these chemical compounds continuously.
5. other Hyaluronidase inhibitor
Other can comprise flavonoid, antiinflammatory and surfactant with the exemplary compounds that produces the HA implant with HA combination, perhaps their combination in any, described HA implant opposing degraded and have the activity of prolongation in the various clinical sign.Listed compound classification be not mutually repel-as known in the art, chemical compound can belong to classification more than one (for example glycyrrhizin (glychyrrhizin) be flavonoid be again antiinflammatory).
On the one hand, described HI can be a flavonoid.Flavonoid is the ubiquitous polyphenolic substance of occurring in nature, and according to chemical constitution, polyphenolic substance can be divided into flavonol, flavone, flavanone, isoflavone, catechuic acid, anthocyanidin, chalcone derivative and neoflavonoid.Knownly in such as high plants such as fruits and vegetables and in beverage (for example tea, coffee, medicated beer, wine, fruit drink), found flavonoid.Exemplary flavonoid as HI as herein described comprises condensed tannin (tannin), tannin (tannic acid), kaempferol, Quercetin, apigenin, hydrangenol from hydrangea, curcumin from the flavoring agent Fructus Foeniculi, glycyrrhizin, isoliquiritin, glabridin, glycyrrhizin, Fructus rhamni (Rhamnus davurica Pall.) glycyrrhizin (rhamnoliquirtin), Neoliquiritin, Licoflavonol., licoisoflavone A and B, licoisoflavanone, the formononetin glabrol, glabrone (glabrone), glabrene., hispglabridin A, hispglabridin B, baicalin, tranilast, silymarin, phloretin, Taxifolin, daidzein (4 ', the 7-dihydroxy isoflavone), Rhizoma Iridis Tectori kind aglycon (4 ', 7-dihydroxy-6-methoxyl group isoflavone), luteolin, xanthohumol (xanthohumol), isoxanthohumol (isoxanthohumol), genistein, naringin is former, chalconaringenin, myricetin, the phosphorylation Hesperidin, biochanin A, morin, phloretin, silymarin, 4-phenyl-coumarin, 7-fluoro-4 '-flavonol-4 '-chloro-4,6-dimethoxy chalcone derivative, flavanone-7-sodium sulfate, 5-flavonol-7-sodium sulfate, 4 '-chloro-4,6-dimethoxy chalcone derivative or the like.For example referring to Matrix Biol.2002,21 (1): 31-7; BiolReprod.1997,56 (6): 1383-9; Experientia 1991,47 (11-12): 1196-200; Biochem Pharmacol.1990; 40 (2): 397-491.
On the other hand, described HI can be a phenolic compounds.Representational phenolic compound comprises diphenylacrylate, diphenyl-propionic acid, 3-(4-trifluoromethyl-phenyl)-3-phenylpropionic acid, 3-(4-trifluoromethyl-phenyl)-3-phenylpropionic acid, 1-(2-hydroxyl-4, the 6-Dimethoxyphenyl)-3-(4-methoxyphenyl) acetone, 1-(2-hydroxyl-4,6-Dimethoxyphenyl)-3-(4-chlorphenyl) acetone, indole-2-carboxylic acid, norlignane, elladitannin (ellagitannins) and urolithin B.
On the other hand, described HI can be an antiinflammatory, and it can be steroidal or on-steroidal.Representational antiinflammatory comprises that indomethacin is (for example referring to Matrix Biol.2002; 21 (1): 31-7), aescine, traxanox, Salicylate be (for example referring to Matrix Biol.2002; 21 (1): 31-7), eicosatrienoic acid is (for example referring to J.Enzyme Inhib.Med.Chem.2002; 17 (3): 183-6), glycyrrhizin is (for example referring to Biol.Pharm.Bull.1997; 20 (9): 973-7); Regulate allergic reagent, for example disodium cromoglycate (DSCG), tranilast, glycyrrhizin, isoliquiritigenin, baicalin are (for example referring to Chem.Pharm.Bull.1992; 40 (6): 1439-42; Toxicon.2003; 42:635-646); Kayexalate (N-PSS) is (for example referring to J.Androl.2000; 21 (6): 862-75); Saccharic acid is (for example referring to J.Enzyme Inhib.Med.Chem.2003; 18 (4): 377-382); The deutero-oligosaccharide of chondroitin sulfate A (ChSAO) is (for example referring to Biol.Reprod.2005; 1061), Phenylbutazone, crovaril, gamma-Linolenic acid, fenoprofen or the like 72 (4):.
On the other hand, described HI can be an indomethacin.Indomethacin be used to handle rheumatoid arthritis, osteoarthritis and gout on-steroidal, antiphlogistic, analgesic and antipyretic medicament.On the other hand, described HI can be a surfactant, and for example sodium tetradecyl sulfate is (referring to J.Reprod.Fertil.1983; 68 (2): 257-63), perhaps solid non-ionic surface active agent octylphenol ethoxylate, its trade name is TRITON X-100 (Dow Chemical Co., Midland MI).Indomethacin and TRITON X-100 can be used to suppress hyaluronic degraded in the body.These chemical compounds and hyaluronic acid can be carried simultaneously or successively.For example, can be by in the preparation that polymer is included in administration and polymer and hyaluronic acid are carried to the patient simultaneously.Perhaps, or in addition, can be with these compound administrations after with the hyaluronic acid administration.In some aspects, can be preferably by these chemical compounds the polymerization dosage form sustained release and target tissue is exposed in these chemical compounds continuously.
Can comprise ascorbic acid with other exemplary compounds that produces the HA implant with the HA combination, for example vitamin C or L-ascorbic acid-6-hexadecane ester (J.Biol.Chem.2004,279 (44): 45990-97); Saponin is (for example referring to J.Enzyme Inhib.Med.Chem.2002; 17 (3): 183-6), Caulis Hederae Sinensis sapogenin for example; Cysteamine; Echinacea Species; Rosmarinic acid; Guanidine hydrochloride; The L-arginine.
III. preparation
Can prepare compositions of the present invention by several different methods.For example, HI directly can be dissolved in or be suspended in the HA solution, described HI for example is Aurothiomalate or fucoidin.If chemical compound is stable in HA solution, can in the device of single application, prepares so and contain HA and this compound compositions.If chemical compound can not be stablized the time of remarkable length in HA solution, compositions can be made bicomponent system so, wherein blending ingredients immediately before use.
Sulfated polysaccharide (for example dextran sulfate, heparin and fucoidin and their analog or derivant) is normally water miscible and can be used as solution with the hyaluronic acid administration.In some cases, can be when using hyaluronic acid with these materials with the solid form administration.When conveying occurred in the surgical site that has exposure, it was actual carrying with solid form.Perhaps, can inject or use these chemical compounds by the suspension of non-water injection medium (carrier).Can be before the hyaluronic acid administration, simultaneously, inject afterwards.
Normally water miscible and can be used as solution such as drug excipients such as Polyethylene Glycol, propylene glycol, SPAN, PLURONIC and diblock copolymer and TRITON X-100 with the hyaluronic acid administration.In some cases, can be when using hyaluronic acid with these materials with the solid form administration, for example when the surgical site that exposes.Perhaps, can inject or use these chemical compounds by the suspension of non-water injection medium (carrier).Can be before the hyaluronic acid administration, simultaneously, inject afterwards.The special advantage of drug excipient, diblock copolymer and TRITON X-100 is that they self can become hyaluronic good injectable media, thereby hyaluronic acid can dissolve in these reagent or suspendible is used for using to the injection of appropriate site.For example the diblock copolymer based on PCL-PEG at room temperature is that waxy substance and slight fever can make it become the thick liquid that is easy to be injected into health.
On the one hand, Hyaluronidase inhibitor can be placed carrier.Carrier can be used as to the medium of desired site transport of H I compositions and can give said composition other desirable properties (for example hydrophilic, bioavailability, viscosity or the like).
The representational example of carrier comprises polymerization and non-polymeric carrier (for example liposome or based on the carrier of vitamin), and they can be biodegradable or abiotic degradable.The representational example of biodegradable polymer comprises albumin, gelatin, starch.Cellulose, glucosan, polysaccharide, Fibrinogen, polyester (for example poly-(D, the L-lactide), poly-(D, L-lactide-co-Acetic acid, hydroxy-, bimol. cyclic ester), poly-(Acetic acid, hydroxy-, bimol. cyclic ester), poly-(6-caprolactone), and copolymer and mixture), poly butyric ester, poly-alkyl carbonate, polyanhydride and poe be (totally referring to Illum, L., Davids, S.S. (eds.) " Polymers in controlled Drug Delivery " (polymer in the control drug conveying) Wright, Bristol, 1987; Arshady, J., Controlled Release17:1-22 (1991); Pitt, Int.J.Pharm 59:173-196 (1990); Holland et al., J.Controlled Release 4:155-0180 (1986)).The representational example of abiotic degradable polymer comprises the block copolymer (being the copolymer of oxirane and epoxypropane polymer) based on oxirane and expoxy propane, for example can from BASF Corporation (MountOlive, the PLURONIC polymeric families that NJ) obtains, EVA copolymer, silicone rubber, based on polymethacrylates and based on the polymer of polyacrylate.In certain embodiments, described polymer can be copolymer and/or the copolymer of lactic acid and Polyethylene Glycol or methoxy poly (ethylene glycol) and their mixture of copolymer, polycaprolactone, poly-valerolactone, polyanhydride, caprolactone and/or the lactic acid of poly-(D, L-lactic acid) oligomer and polymer, poly-(L-lactic acid) oligomer and polymer, polyglycolic acid, lactic acid and hydroxyacetic acid.
Polymeric carrier (polymer) can be a various ways, for example comprise bar-shaped design, ball shape, tabular or capsule shape (for example referring to Goodell et al., Am.J.Hosp.Pharm.43:1454-1461 (1986); Langer et al., " Controlled release ofmacromolecules from polymers " (macromolecular sustained release in the polymer); InBiomedical polymers, Polymeric materials and pharmaceuticals forbiomedical use (biomedical biomedical polymer, polymeric material and the medicine that uses), Goldberg, E.P., Nakagim, A. (eds.) Academic Press, pp.113-137,1980; Rhine et al., J.Pharm.Sci 69:265-270 (1980); Brown et al., J.Pharm.Sci.72:1181-1185 (1983); And Bawa et al, J.Controlled Release 1:259-267 (1985)).Can these Hyaluronidase inhibitors be connected in the polymeric matrix by containing, these Hyaluronidase inhibitors can connect by covalent bond, perhaps are coated in the microcapsule.In certain embodiments of the invention, the compositions that contains Hyaluronidase inhibitor is provided in non-capsule preparations, and described non-capsule preparations for example is filament, film, net and the spray of microsphere (size is from the nanometer to the micron), paste, gel, all size.In certain embodiments, described compositions is the form that is fit to patient's desired site injection.
In certain embodiments, the compositions (it contains one or more Hyaluronidase inhibitor chemical compound and polymeric carriers in certain embodiments) that contains Hyaluronidase inhibitor of the present invention is the form that is fit to desired use.Aspect some, described compositions should be biocompatible and discharge one or more Hyaluronidase inhibitor chemical compounds in a couple of days to several months of the present invention.For example, an aspect of of the present present invention provides " rapid release " or " outburst discharges " to contain the compositions of Hyaluronidase inhibitor, and release is higher than 10%, 20% or 25% Hyaluronidase inhibitor chemical compound in 7 to 10 days.In certain embodiments, such " rapid release " compositions should be able to discharge the hyaluronidase inhibition level of the Hyaluronidase inhibitor chemical compound of expectation.In other embodiments, the compositions that provides " slowly discharging " to contain Hyaluronidase inhibitor discharged the Hyaluronidase inhibitor chemical compound that is less than 5% (w/v) in 7 to 10 days.In addition, the compositions that contains Hyaluronidase inhibitor of the present invention preferably should be stable in the several months and can produce under aseptic condition and keep.
Aspect some, according to specific purposes, the size that contains the compositions of Hyaluronidase inhibitor can be to the virtually any size between about 500 μ m at about 0.050nm of the present disclosure.For example, when purpose that the tissue that is used to improve looks increases (as hereinafter discussing), the compositions that usually preferably will contain Hyaluronidase inhibitor is made the microsphere or the microgranule of average diameter about 0.1 to about 100 μ m, and diameter preferably about 0.5 is to about 50 μ m, and most preferably from about 1 to about 25 μ m.Perhaps, such compositions can be used with solution, wherein the Hyaluronidase inhibitor chemical compound is dissolved in the micelle.The composition of micelle can be an aggregation property.For example the polymerization micelle can comprise the copolymer of MePEG and poly-(D, L-lactide).Perhaps, such compositions can be used with solution, wherein HI is coated on (referring to above) in the liposome.In some others, described HI not coated (for example involved) is in liposome.Perhaps, such compositions can be used with solution, wherein Hyaluronidase inhibitor chemical compound coated (for example involved) is in the oil phase of Emulsion or microemulsion.
On the one hand, HA can with second carrier combinations, this second carrier can be polymer or non-polymer, it comprises one or more HI.Described second carrier can be various ways and HI is provided slow release or the sustained release from compositions.
On the one hand, described second carrier is a particulate form." microgranule " used herein refers to one or more have rule or erose discontinuous solid particles.Usually the diameter (promptly crossing over the distance in the solstics of microgranule) of microgranule is no more than 500 μ m.The diameter of nano-particle is usually less than about 500nm.
Can absorb or abiotic absorbable polymer manufacturing microgranule by multiple biology." biological absorbable " used herein refers to that compositions or material can remove from body after human or animal's administration.Can realize bio-absorbable by one or more methods, for example pass through dissolving, oxidative degradation, hydrolytic degradation, enzymatic degradation, metabolism, removing such as component, its catabolite or its metabolite of approach such as kidney, intestinal, lung or skin.The mechanism of degradation of bio-absorbable is collectively referred to as " biodegradation ".
On the other hand, described microgranule can be the form of microsphere." microsphere " used herein refers to it is spheric microgranule basically.Microgranule can be spheric, oval-shaped or have almost spherical or oval in shape, and can be level and smooth or have such as crack or hole etc. and break.Usually the average diameter of microsphere is that about 500nm is to about 500 μ m.In certain embodiments, the preferred average diameter of described microsphere is at least about 200nm or 500nm, 1 μ m, 5 μ m, 10 μ m, 20 μ m, 50 μ m or 100 μ m, 150 μ m, 250 μ m, 500 μ m, 1000 μ m, 2500 μ m or 5000 μ m, according to the releasing properties of expectation medicine with should be used for determining optimum size.In certain embodiments, the preferred average diameter of described microsphere is for being no more than about 200nm or 500nm, 1 μ m, 5 μ m, 10 μ m, 20 μ m, 50 μ m or 100 μ m, 150 μ m, 250 μ m, 500 μ m, 1000 μ m, 2500 μ m or 5000 μ m, according to the releasing properties of expectation medicine with should be used for determining optimum size.
In certain embodiments, the synthetic polymer by one or more types forms microgranule.This synthetic polymer can be a polyester, it comprises and is selected from one or more following residues of monomers: lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, hydroxyacetic acid, 6-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, propylene carbonate, 1,4-diox-2-ketone and 1,5-dioxepan-2-one.Polyester can also comprise having chemical formula [OC 6H 4COOH] residue.Polyester can comprise poly-(L-lactide) (PLLA) or poly-(DL-lactide) (PDLLA) or poly-(Acetic acid, hydroxy-, bimol. cyclic ester) or poly-(DL-lactide-co-Acetic acid, hydroxy-, bimol. cyclic ester) (PLGA), poly-(6-caprolactone), poly-(δ-Gui Neizhi), poly-(δ-Wu Neizhi) or poly-(lactic acid) (PLA).In others, described polymer can comprise polyethers, for example comprises Polyethylene Glycol (PEG) or its copolymer (polyethers of residue of PLA-block-PEG or PLGA-block-PEG or poly(propylene oxide)-block-PEG) for example.Others, described polymer can comprise biologically-derived polymer, for example polysaccharide (for example chitosan, cellulose, alginate or their derivant).
Can make microgranule by degradable synthetic polymer.Degradable polymer can comprise polyester, wherein this polyester can comprise and is selected from one or more following residues of monomers: lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, hydroxyacetic acid, 6-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, propylene carbonate, 1,4-diox-2-ketone or 1,5-dioxepan-2-one, and X-Y, Y-X-Y, R-(Y-X) n, (wherein X is a polyalkylene oxide (Polyethylene Glycol for example to the block copolymer of R-(X-Y) n and X-Y-X form, polypropylene glycol, and the block copolymer of poly(ethylene oxide) and poly(propylene oxide) (for example polymer of PLURONIC and PLURONIC R series), and Y is biodegradable polyester, wherein said polyester can comprise and is selected from one or more following residues of monomers: lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, hydroxyacetic acid, 6-caprolactone, γ-Ji Neizhi, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, propylene carbonate, 1,4-diox-2-ketone or 1,5-dioxepan-2-one (for example PLG-PEG-PLG) and R are multi-functional initiators).
In others, the polymer that is used to prepare microgranule is can right and wrong biodegradable, for example polymethyl methacrylate, polystyrene or polydivinylbenezene.
According to the type of the HI that is used to prepare microgranule and the type of polymer, the concentration range of HI can be from about 0.0001% to being higher than 90% (weight of the weight/microgranule of medicine) in the microgranule.On the other hand, the concentration of HI can be about 0.0001% to 0.00l%, 0.001% to 0.01% or 0.01% to 0.1% or 0.1% to 0.1% or 1% to 10% or 10% to 25% or 25% to 50% or 50% to 75% or 75% to 85% or be higher than 90% (weight of the weight/microgranule of medicine) in the microgranule.
According to compositions and specific purposes, the microgranule in the scope of the invention can have release characteristics widely.Can prepare microgranule continue a few hours (for example 1 hour, 2 hours, 4 hours, 8 hours, 12 hours or 24 hours) to a couple of days (for example 1 day, 2 days, 3 days, 7 days or 14 days) to several months (1 month, 2 months, 3 months, 6 months or 12 months) to the several years the to provide slow release of HI of (for example up to 1 year, 2 years, 3 years).
Can use the time of initial rate, 50%, 90% or 100% drug release or pass through suitable kinetic model, for example zero level, one-level, DIFFUSION CONTROLLED (for example square root of time, Higuchi model) kinetics, perhaps the number (for example single phase, two-stage, three stages) of the different phase by rate of release characterizes and discharges spectrum.Can use the degree in its outburst (initially) stage to characterize the release spectrum.This outburst stage may cause a small amount of or a large amount of drug releases, therefore microgranule can be defined as " low " or " height " outburst system.For example, low outburst system can discharge in the release starting stage and be low to moderate about 30,20,10 even 5 or 1% of load total amount.High outburst system the outburst stage can discharge the medicine total amount at least about 50,60,70 even 100%.The persistent period in outburst stage depends on the general plan persistent period that discharges spectrum.For the microgranule of planning to discharge whole carrying medicaments in a few hours, several minutes (for example 1 to 30 minute) may take place in the outburst stage.For the microgranule of planning to discharge in a couple of days, the outburst stage can be a few hours (for example 1 to 24 hours).For the microgranule of planning to discharge in several weeks, the outburst stage can be (for example 12 hours to 7 days) from a few hours to a couple of days.The exemplary release spectrum of describing the microgranule release characteristic can be low outburst microsphere, discharges to be less than 10% in first 24 hours, be subsequently proximate zero level discharge the stage and after 5 days speed reduce gradually, finish until whole drug releases.
The multiple method for preparing microgranule known in the art.Method normally used, that may be adjusted to be suitable for introducing HI in microgranule comprises: (a) be separated, evaporating solvent in dispersion subsequently, described dispersion for example is o/o, w/o, an o/w or w/o/w (o=oil, w=water), (b) use supercritical fluid, (c) cohesion, (d) melt dispersion, (e) spray drying, (f) sprinkling is congealed, or (g) suspendible coating.United States Patent (USP) the 4th, 652,441,5,100,669,4,438,253 and 5,665, the representational example of the method for preparing microgranule is disclosed in No. 428.
In certain embodiments, can use lyophilization to prepare described microgranule, it comprises and will contain the composition freeze-drying of liquid particle so that produce freeze dried powder.This powder can directly mix with hyaluronic acid.Perhaps, with can make water or other aqueous medium dissolve freeze dried powder again before hyaluronic acid mixes.
The form that can also be multiple " pasty state " or gel with the preparation of compositions that contains Hyaluronidase inhibitor of the present invention.For example, in an embodiment of the present invention, HI is provided compositions, (for example temperature is higher than 37 ℃ to said composition under a certain temperature, for example 40 ℃, 45 ℃, 50 ℃, 55 ℃ or 60 ℃) be liquid, and be solid or semisolid (for example periphery body temperature or any temperature that is lower than 37 ℃) under another temperature.
To describe the method for in polymeric carrier, introducing the Hyaluronidase inhibitor chemical compound among the embodiment hereinafter in detail.
Compositions of the present invention can also comprise bioactive hydrophobic compound except containing hyaluronic acid and Hyaluronidase inhibitor chemical compound.On the one hand, described compositions comprises hyaluronic acid, Hyaluronidase inhibitor chemical compound, carrier (polymer or non-polymer) and bioactive hydrophobic compound.In others of the present invention, provide the carrier that is fit to comprise and discharge hydrophobic compound.In certain embodiments, described carrier is a polymer.Can with the described carrier that contains hydrophobic compound at random with carbohydrate, protein or polypeptides in combination.In certain embodiments, described carrier contains or comprises zone, bag or the granule that contains one or more hydrophobic compounds.For example, in an embodiment of the present invention, hydrophobic compound can be introduced and contain in the substrate of hydrophobic compound, then this substrate be introduced in the polymeric carrier.About this point, can use multiple substrate, for example comprise carbohydrate and polysaccharide, for example starch, cellulose, glucosan, methylcellulose and hyaluronic acid also comprise protein or polypeptide, for example albumin, hyaluronic acid and gelatin.In other embodiments, can in hydrophobic core, comprise hydrophobic compound, and this hydrophobic core is arranged in hydrophilic shell.For example, as described in embodiment hereinafter, indomethacin can be introduced (for example poly-(D, L-lactic acid-PEG or MePEG aggregation) in the hydrophobic core with hydrophilic shell.
Aspect some, the compositions that contains Hyaluronidase inhibitor can be following form: employed hyaluronic acid is covalently bound in Hyaluronidase inhibitor chemical compound and the application-specific of the present invention.This Hyaluronidase inhibitor chemical compound can directly link to each other with hyaluronic acid or link to each other with hyaluronic acid by link molecule (for example Polyethylene Glycol).In case this conjugate is introduced into or is administered to the expectation site, so described Hyaluronidase inhibitor chemical compound can suppress hyaluronidase, meanwhile still links to each other with hyaluronic acid.
Hyaluronidase inhibitor can be present in the compositions with a certain amount of, and this amount can effectively suppress the hyaluronic degraded that caused by hyaluronidase.The amount of HI depends on the type of HI and the position of potential and HA implant, the dosage and the multiple other factors of expectation in the described compositions.For example, in other embodiments, the concentration that is present in the HI in the compositions (for example compositions of fluid or semi-solid form) can be about 0.1mg/ml or still less or about 0.1mg/ml to 0.25mg/ml or about 0.25mg/ml to 0.5mg/ml or about 0.5mg/ml to 1mg/ml or about 1mg/ml to 5mg/ml or about 5mg/ml to 10mg/ml or about 10mg/ml to 25mg/ml or about 25mg/ml to 100mg/ml or about 100mg/ml to 250mg/ml or about 250mg/ml to 350mg/ml or about 350mg/ml to 500mg/ml.
For some HI (chemical compound that for example has definite MW), the amount that is present in the HI in the compositions can be expressed with molar concentration.For example, in certain embodiments, the concentration that is present in the HI in the compositions can be about 1mM or still less (for example about 1 μ m to 10 μ m or about 10 μ m to 100 μ mm or about 100 μ m to 1mM) or about 1mM to 2.5mM or about 2.5mM to 5mM or about 5mM to 10mM or about 10mM to about 25mM or about 25mM to 50mM or about 50mM to 100mM or about 100mM to 250mM or about 250mM about 350mM extremely.In other embodiments, the concentration that is present in the HI in the compositions can be lower than about 50% (weight ratio) or be lower than about 25% or be lower than approximately 10%, or is lower than about 5% or be lower than about 2% or be lower than about 1% or be lower than about 0.5% or be lower than about 0.25% or be lower than about 0.1%. or be lower than about 0.01% or be lower than about 0.001% or be lower than about 0.0001%.
For the HA compositions (for example material of film or net form formula) of some type, the concentration of HI can be explained with area.For example, in certain embodiments, described compositions can comprise that about 0.0001mg is to about 0.001mg material per square inch, or 0.001mg is to about 0.01mg material per square inch, 0.01mg to about 0.1mg material per square inch, or about 0.1mg is to about 1mg material per square inch, or about 1mg is to about 5mg material per square inch, or about 5mg is to about 10mg material per square inch, or about 10mg is to about 20mg material per square inch, or about 20mg is to about 50mg material per square inch, or about 50mg is to about 100mg material per square inch, or about 100mg is to about 250mg material per square inch.
In certain embodiments, the accumulated dose of the HI that is carried by the HA implant can be lower than 0.1mg or about 0.1mg to 0.5mg or about 0.5mg to 1mg or about 1mg to 5mg or about 5mg to 10mg or about 10mg to 20mg or about 20mg to 100mg or about 100mg to 200mg or about 200mg to 350mg or about 350mg to 500mg.The amount of the HI that can carry with the per unit volume aqueous body fluid is expressed accumulated dose.For example, in certain embodiments, the accumulated dose of the HI that is carried by the HA implant can be that about 0.01mg/ml to 0.1mg/ml or about 0.1mg/ml to 1mg/ml or about 1mg/ml to 10mg/ml or about 10mg/ml to 25mg/ml or about 25mg/ml are extremely in about 100mg/ml aqueous body fluid.
In certain embodiments of the invention, can also further modify compositions provided herein so that strengthen its effectiveness.For example, in one embodiment, can in compositions as herein described, add the auxiliary chemical compound or the factor (for example thrombin) of solidifying.The HA-HI compositions can also comprise neurotoxin and/or anesthetis, described neurotoxin for example is can be from Allergan, Inc. (described anesthetis for example is lignocaine, benzocaine or prilocaine for Irvine, the Botulinum toxin of the commodity that CA) are purchased BOTOX by name.Described anesthetis can also comprise polymeric carrier, and is as indicated above, and it can be used for assisting goes into the anesthetis prescription HA-HI compositions and/or regulate the release of anesthetis from the HA-HI compositions.Can add therapeutic agent so that extra treatment benefit to be provided in compositions of the present invention, described therapeutic agent for example is antibiotic, anti-infective (for example 5-fluorouracil), antiinflammatory (for example steroidal or on-steroidal), analgesic, anti-cicatrization (fibrosis) agent, cicatrization (fibrosis) agent.
In addition, described compositions can also comprise additive.The representational example of additive comprises solvent, antioxidant (for example sulphite and ascorbic acid), adhesive, the hole forming agent, antiseptic (p-Hydroxybenzoate for example, chlorobutanol, benzyl alcohol, phenethanol, dehydroactic acid, sorbic acid etc.), bacteriostatic agent (bismuth tribromophenate for example, methyl hydroxybenzoate, bacitracin, nipagin A, nipasol, erythromycin, chlorocresol, benzalkonium chloride or the like) and antibacterial (bactericidal) (being also referred to as biocide (bacteriacidal)).Can add dyestuff or other coloring agent to strengthen the visuality of described compositions.Described dyestuff or coloring agent can be permanent or temporary transient (for example methylene blues).The representational example of dyestuff comprises that those are suitable for the dyestuff of food, those dyestuffs that for example are called as F.D. and C. dyestuff, and natural colorant, for example Pericarpium Vitis viniferae extract, beet red powder, beta-carotene, roucou, carminum, sallow, Fructus Capsici powder or the like.Other example of the reagent that improves present composition visuality of clinical use comprises the opaque or X ray opaque material of radio, for example tantalum, and MRI contrast medium.
Any compositions as herein described all can provide with sterile form.In this embodiment, can be by industry acceptable or list in USP XXII＜1211〉in the accomplished in many ways sterilization, described method includes but not limited to autoclaving, xeothermic, gaseous sterilization and filtration.Preferably finish sterilization by the method for not decomposing HA or HI.Usually, use radiationless method to realize sterilization, HA is easy to decompose in the gamma-radiation because be exposed to.Can also be by USP XXII＜1211〉sterile working of definition keeps aseptic.The acceptable gas that is used for gaseous sterilization comprises oxirane.Can use the filter with suitable aperture and suitable material to realize filtering, described aperture is 0.22 μ m for example, and described material for example is TEFLON.In addition, can also be by being used in combination these sterilizing methods and optional sterile working realizes aseptic composite.Comprising diameter of the present invention aspect some greater than the microgranule of 200nm, use non-filtering sterilizing methods, because described granule can not pass the filter of 0.22 μ m.Because use single method can not realize whole components of certain embodiments of the present invention are sterilized, realize sterilization so can component of the present invention be sterilized and the component of sterilizing is mixed into compositions by substep.
IV. clinical practice
1. the hyaluronic acid orthopaedic implants of load HI
Developed the multiple hyaluronic acid implant that is used for plastic operation, this implant is as tissue filling agent and as healing and repairing the support that uses.Hyaluronic acid is the important organic component of connective tissue and cartilage, and it can repair product as tissue substituent or bone with mineral preparation, autologous bone marrow, bone graft and/or somatomedin (for example fibroblast growth factor (FGF) or bone morphogenetic protein (BMPs)) combination.Representative applications includes but not limited to total joint replacement operation (for example artificial hip, knee joint etc.), spinal fusion surgery, long bone fracture, traumatic bone is damaged, the reparation of space or breach, increase autograft and obtain the position as bone filler bone graft.For example, OSSIGEL be the hyaluronic acid (HA) that is used for accelerating union of bone fracture and basic fibroblast growth factor (bFGF) the viscosity preparation (Orquest, Inc.).
United States Patent (USP) the 6th, 764,517,6,514,514,6,730,129 and 6,652, the representational example of the hyaluronic acid compositions that is used for plastic surgery's operation has been described for No. 887.
In the present invention, Hyaluronidase inhibitor added separately contains in hyaluronic implant or the compositions, perhaps the hyaluronidase of slow release form is suppressed to add contain in hyaluronic implant or the compositions with the speed that reduces the HA degraded and the activity in vivo that prolongs compositions/implant to surpass activity when using HA separately (for example in surpassing 75% patient consistent surpassing 2 all and above period of greater than two months among 25% the patient).On the one hand, can be at the position delivering composition of expectation, for example in the site of fracture or the gap of bone, so that increase bone or substitute the bone that lacks.Can make accumulated dose, dosage rate of release and the medicine of the HI of conveying activity as required from the suitable significant prolongation hyaluronic acid implant of release duration of HA.As mentioned above, in certain embodiments, the HI-HA compositions further can be repaired product with mineral preparation, autologous bone marrow, bone graft and/or somatomedin (for example fibroblast growth factor (FGF), transforming growth factor (TGF), platelet derived growth factor (PDGF) or bone morphogenetic protein (BMPs)) combination as tissue substituent or bone.Following compositions ideally is suitable for this sign.
HI can make up so that the slow release of reagent to be provided with polymeric system.Be suitable in the plastic surgery uses, carrying the material of the HI agent of making up to form by non-degradable or degradable material with HA.The Resorbable ceramic that suitable degradable material includes but not limited to be made up of bata-tricalcium phosphate (for example by Orthovita, the VITOSS that Inc. makes, the PROOSTEON 500R that makes by E-Interpore-Cross International), hydroxyapatite or Ca 10(PO 4) 6OH (for example BIOOSS that makes by Geistlich Biomaterials Inc., the OSTEOGRAF that makes by Ceremed Denta Inc.), calcium carbonate or CaCO 3Calcium sulfate (for example OSTEOSET and the ALLOMATRIX that makes by Wright Medical), calcium phosphate (for example by Merck, the CALCIBON that NORIAN SRS makes), the PEG cross-linked material, gelatin, collagen, GELFOAM, decalcified bone matrix, (the ALLOGRO for example of bone allograft, ORTHOBLAST, OPTEFORM, GRAFTON), polysaccharide, carbohydrate, protein (albumin for example, casein, lactalbumin, vegetable protein, fish protein etc.), from the body bone, decalcified bone matrix, alginate, starch, cellulose derivative (HPC etc.), cellulose, cellulose esters, the mixture of cellulose esters or copolymer, chitosan, chitosan derivatives, the block copolymer of polyester-polyalkenyl oxide (PLGA-PEG-PLGA for example, MePEG-PLGA etc.), degradable polyester, polyanhydride, polyorthoesters, poly phosphate, poly-phosphazine and cyanoacrylate polymer.Useful especially degradable polymer comprises the injectable preparation that contains PEG in practice of the present invention, COSEAL (AngiotechBiomaterials Corp. for example, Palo Alto, CA), FOCALSEAL, SPRAYGEL, DURASEAL, or United States Patent (USP) the 5th for example, 874,500,6,051,648,6,166,130 and 6, that describes in 312, No. 725 comprises 4-arm sulfydryl PEG (10K), the compositions of 4-arm NHS PEG (10K) and methylated collagen, contain fibrinogenic preparation, for example FLOSEAL or TISSEAL, REPEL or FLOWGEL, and other can excretory low-molecular weight polymer.
Conveying is used for plastic surgery's suitable degradable substance with the HI HA combination that use and comprises the PVA that comprises formation polymethyl methacrylate (PMMA) when mixing, PVP, polyacrylamide, the cross-linked composition of methyl methacrylate (MMA) and methyl methacrylate styrene (MMA-styrene), perhaps bone cement (the SIMPLEX P that makes by Stryker Howmedica for example, ZIMMER REGULAR and ZIMMER LOWVISCOSITY CEMENT by the Zimmer manufacturing, PALACOS by Smith and Nephew manufacturing, CMW-1 and CMW-2 by Wright Medical manufacturing, DEPUYENDURANCE by the DePuy manufacturing), synthetic cancellus void filler (CORTOSS for example, Orthovita), pHEMA, poly-(vinyl PEG), the polystyrolsulfon acid ester, polyacrylic acid, other polymer of known formation hydrogel in polymethylacrylic acid and the document.Other compositions comprises the mixture or the copolymer of mentioned reagent.Calcium phosphate, for example basic calcium phosphate and hydroxyapatite can be used in combination with Hyaluronidase inhibitor.
In the practice of above-mentioned embodiment, those skilled in the art are appreciated that obviously that potentially any Hyaluronidase inhibitor all can be used singly or in combination.In plastic surgery operation, be used for comprising Sulfated polysaccharide with the example of the HI agent of HA combination; Drug excipient; Diblock copolymer and indomethacin or gold compound; Flavonoid class, condensed tannin for example, tannin, kaempferol, Quercetin, apigenin, hydrangenol from hydrangea, curcumin from the flavoring agent Fructus Foeniculi, glycyrrhizin, isoliquiritin, glabridin, glycyrrhizin, the Fructus rhamni (Rhamnus davurica Pall.) liquirtin, Neoliquiritin, Licoflavonol., licoisoflavone A and B, licoisoflavanone, the formononetin glabrol, glabrone, glabrene., hispglabridin A, hispglabridin B, baicalin, tranilast, silymarin, phloretin, Taxifolin, daidzein (4 ', the 7-dihydroxy isoflavone), Rhizoma Iridis Tectori kind aglycon (4 ', 7-dihydroxy-6-methoxyl group isoflavone), luteolin, xanthohumol, isoxanthohumol, genistein, 4,5, the 7-tri hydroxy flavanone, chalconaringenin, myricetin, the phosphorylation Hesperidin, biochanin A, morin, phloretin, silymarin, 4-phenyl-coumarin, 7-fluoro-4 '-flavonol-4 '-chloro-4,6-dimethoxy chalcone derivative, flavanone-7-sodium sulfate, 5-flavonol-7-sodium sulfate, 4 '-chloro-4,6-dimethoxy chalcone derivative; Antiinflammatory, for example indomethacin, aescine, traxanox, Salicylate, eicosatrienoic acid, glycyrrhizin; Regulate allergy's reagent, for example disodium cromoglycate (DSCG), tranilast, glycyrrhizin, isoliquiritigenin, baicalin, kayexalate (N-PSS), glucosaccharic acid, the deutero-oligosaccharide of chondroitin sulfate A (ChSAO), Phenylbutazone, crovaril, gamma-Linolenic acid, fenoprofen; Phenolic compound, for example diphenylacrylate, diphenyl-propionic acid, 3-(4-trifluoromethyl-phenyl)-3-phenylpropionic acid, 3-(4-trifluoromethyl-phenyl)-3-phenylpropionic acid, 1-(2-hydroxyl-4, the 6-Dimethoxyphenyl)-3-(4-methoxyphenyl) acetone, 1-(2-hydroxyl-4,6-Dimethoxyphenyl)-3-(4-chlorphenyl) acetone, indole-2-carboxylic acid, norlignane, elladitannin and urolithin B; Vitamin C, L-ascorbic acid-6-hexadecane ester; Saponin, for example Caulis Hederae Sinensis sapogenin; Cysteamine; Echinacea Species; Rosmarinic acid; Guanidine hydrochloride; The L-arginine; Surfactant, for example sodium tetradecyl sulfate or octylphenol ethoxylate.For example, relevant with effective transplanting of orthopaedic implants many problems relate to undesirable inflammatory reaction.Therefore, because indomethacin and gold compound all have anti-inflammatory property, so these chemical compounds can be served two kinds of purposes in these are used.
All these chemical compounds all can use separately or be used in combination with bone morphogenetic protein and/or osteogenic growth factor (for example transforming growth factor, platelet derived growth factor, fibroblast growth factor) and the above-mentioned analog of mentioning and derivant.The example of bone morphogenetic protein for example comprises BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 (Vgr-1), BMP-7 (OP-1), BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, BMP-14, BMP-15 and BMP-16.Wherein, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 and BMP-7 are particularly useful.For example United States Patent (USP) the 4th, 877, and 864,5,013,649,5,661,007,5,688,678,6,177,406,6,432,919 and 6,534, in No. 268 and Wozney, J.M., etal. (1988) Science:242 (4885); Bone morphogenetic protein has been described among the 1528-1534.
The proper dosage of these chemical compounds can be for example to provide the steady concentration of each agent to obtain the inhibition effect to the prolongation of hyaluronidase.These concentration are to adjust the time proximate and that can continue according to the usefulness and the effect needs of chemical compound: Aurothiomalate 10mM and other gold compound, indomethacin 1mg/ml, heparin 1mg/ml, Sulfated polysaccharide 2mg/ml and propylene glycol, TRITON X-100, PEG SPAN, PLURONICL101 and carboxymethyl cellulose are 10mg/ml.In order to obtain this concentration, in the volume that may be exposed to some milliliters of aqueous body fluid, may need about 10 times dosage (for example 10mg indomethacin, the Sulfated polysaccharide of 20mg, 100mg propylene glycol, TRITON X-100, PEG SPAN, PLURONIC or carboxymethyl cellulose) of every milliliter of necessary dosage.Therefore, if injection 1ml HA solution for example, wherein this injecting fluid may be exposed to about 2ml through this regional interstitial fluid, recommend so to inject 100mg each inhibitor in case after a period of time in guarantee to reach the dosage of every milliliter of 10mg.Required dosage depends primarily on the site of volume injected and application and the time that effect need continue.Site in the high fluid turnover can give more Hyaluronidase inhibitor.In addition, if use control method, release inhibitor from the polymerization dosage form, according to the turnover of the release spectrum of inhibitor, the site of using, this zone body fluid and such as other parameters such as age and comprehensive healths, those skilled in the art can the computing application accumulated dose so.
2. the hyaluronic acid spinal surgery implant of load HI
Backache is the first reason and 50,000,000,000 dollars (1,000 hundred million dollars in the whole world) of annual cost that causes the health care expenditure in the U.S..Have in the U.S. and to surpass 1,200 ten thousand people and suffer from the intervertebral disc degeneration disease (DDD) of certain form and have 10% (1,200,000) to need operation among them to correct their problem.
In healthy individual, spinal column is by what formed by the spinal column hone lamella of disc separation, and intervertebral disc forms firm joint and during movement absorbs the spinal column compression.Intervertebral disc is made up of the inside colloid sample material that is called as vertebral pulp, and described vertebral pulp is surrounded by the hard fibrous cartilage that is called as annulus fibrosis.Vertebral pulp is made up of collagen fiber in the gelatinised matrix that is embedded in glucosaminoglycan and water and connective tissue cell (similar fibroblast and chondrocyte).Annulus fibrosis is made up of the fibrocartilaginous concentric ring that is anchored in a large number in the vertebral body.When tearing in the annulus fibrosis forms local weakly when regional, the inducement of the most common DDD can appear, and described local weakness zone goes out bulging, the hernia of vertebral pulp and annulus fibrosis or isolates and enters spinal canal and/or spinal column hole.Intervertebral disc bulging or that hernia goes out often pushes nervous tissue, for example spinal cord fiber or spinal cord and nerve roots fiber.The intervertebral disc of damage causes neuron dysfunction (numbness, reduction, tingling), lame pain, intestinal or bladder disorder and often can cause long term disability the pressure of spinal cord or nerve root.Though the inducement of many DDD can solve by nature, but still have a large amount of needs of patients surgeries to get involved, the form that this surgery is got involved is that major operation excision, spinal fusion (fusion of the adjacent ridge pyramidal plate that use multiple technologies and device carry out) and/or the artificial intervertebral disk that minimally is invaded operation, micro-discectomy, intervertebral disc implanted.
The open operation that discharges the spinal nerves upward pressure is usually directed to excise disruptive waist and pushes away intercalated disc (and part is around the bone of spinal nerve root-be also referred to as laminectomy).Under general anesthesia, the patient is placed the position of kneeling of change.Back midline otch and with tissue dissection so that expose suitable gap; Cut ligamenta flava and in some cases, remove part bone thin plate so that obtain enough visuals field.Pull out fragment that nerve root goes out with the hernia that exposes in the ring and damaged carefully.Usually, the tear place by ring enters disc cavity and uses pituitary forceps that the loose fragment of vertebral pulp is removed.Also remove carefully and be isolated in the intervertebral disc space or any other intervertebral disc fragment that intervertebral disc space is outer and thoroughly clean intervertebral disc space to remove any residual fragment.If tearing appears in pachymeninx, use suture to sew up pachymeninx so, often use Fibrin Glue to strengthen this suture.Use absorbable suture to come suture tissue then.
Micro-lumbar discectomy (micro-diskectomy) can be used as that out-patient operation is carried out and it goes out being chosen in that intervertebral disc gets involved as hernia and has replaced laminectomy to a great extent.The otch of 1 inch of incision between the spinous process of spinous process above affected intervertebral disc to this affected intervertebral disc.Use operating microscope, tissue dissection is removed to ligamenta flava and from thin plate boned until can clearly discerning nerve root.Retract nerve root carefully and make the crack in the ring visual under enlargement ratio.Use micro-intervertebral disc tweezers to remove the intervertebral disc fragment in the ring crack seam and remove any isolated intervertebral disc fragment.Laminectomy is the same with using, and cleans intervertebral disc space to remove any intervertebral disc fragment, repairs any pachymeninx crack and uses the absorbable suture suture tissue.Should be noted that, can also use (abdominal part) method of front side that open with lumbar discectomy endoscope.The class of operation of the excision of neck and thoracic disc and waist like and also can use the method (use laminectomy) of dorsal part or use and have the front side diskectomy that merges otch.
Unfortunately, in a large amount of patients, the postoperative scarization in the tissue of nerve root has applied pressure to nerve, causes stimulation, and causes pain recurrence and other neurological symptoms result.In order to reduce the incidence rate of this complication, many surgeon use the implant of being made up of hyaluronic acid to infiltrate perineural zone.Tissue around HA prevents contacts with nerve and prevents that scar tissue from forming and finally oppressing spinal nerves.Yet HA absorbs rapidly by body in the time of a couple of days-and often be before healing is finished and allow scar tissue around nerve, to form.
In the present invention, Hyaluronidase inhibitor added separately contains in hyaluronic implant or the compositions, perhaps the Hyaluronidase inhibitor of slow release form is added contain in hyaluronic implant or the compositions with the speed that reduces the HA degraded and the activity in vivo that prolongs compositions/implant to surpass when using HA separately (for example in surpassing 75% patient consistent surpassing 2 all and above period of greater than two months among 25% the patient).Can make accumulated dose, dosage rate of release and the medicine of the HI of conveying activity as required from the suitable significant prolongation hyaluronic acid implant of release duration of HA.This will make this barrier performance function for more time and be reduced near the probability that forms scar tissue the nerve root in vivo.The HI-HA implant can reduce the incidence rate of spinal operation failure, avoids pain recurrence and other neurological symptoms result, and reduces the repetition surgery and get involved to remove the needs of scar tissue.
The example that is suitable for being combined in HI the commercial HA product that uses in the spinal operation comprises RESTYLANE, HYLAFORM, PERLANE, SYNVISC, SEPRAFILM, SEPRACOAT, INTERGEL and LUBRICOAT.
United States Patent (USP) the 6th, 719,797,5,258,043 and 4,904, the representational example of the hyaluronic acid compositions that uses in the spinal operation operation has been described in No. 260.
HI can also make up so that the slow release of reagent to be provided with polymeric system.The material that is suitable for transport of H I agent that is used for the object of the invention can be made up of non-degradable or degradable material; Yet, preferred degradable material.Suitable degradable material includes but not limited to the PEG cross-linked material, gelatin, collagen, GELFOAM, (the ALLOGRO for example of bone allograft, ORTHOBLAST, OPTEFORM, GRAFTON), polysaccharide, carbohydrate, protein (albumin for example, casein, lactalbumin, vegetable protein, fish protein etc.), from the body bone, decalcified bone matrix, alginate, starch, cellulose derivative (HPC etc.), cellulose, cellulose esters, the mixture of cellulose esters or copolymer, chitosan, chitosan derivatives, the block copolymer of polyester-polyalkenyl oxide (PLGA-PEG-PLGA for example, MePEG-PLGA etc.), degradable polyester, polyanhydride, polyorthoesters, poly phosphate, poly-phosphazine, cyanoacrylate polymer, the injectable preparation that contains PEG, for example COSEAL, FOCALSEAL, SPRAYGEL, DURASEAL, or United States Patent (USP) the 5th, 874,500,6,051,648,6,166,130 and 6,312, that describes in No. 725 comprises 4-arm sulfydryl PEG (10K), the compositions of 4-arm NHS PEG (10K) and methylated collagen, contain fibrinogenic preparation, for example FLOSEAL or TISSEAL, REPEL or FLOWGEL, and other can excretory low-molecular weight polymer.
In the practice of above-mentioned embodiment, those skilled in the art are appreciated that obviously that potentially any Hyaluronidase inhibitor all can be used singly or in combination.In spinal operation operation, be used for comprising: heparin, Aurothiomalate, dextran sulfate, fucoidin, propylene glycol with the example of the HI agent of HA combination; Flavonoid class, condensed tannin for example, tannin, kaempferol, Quercetin, apigenin, hydrangenol from hydrangea, curcumin from the flavoring agent Fructus Foeniculi, glycyrrhizin, isoliquiritin, glabridin, glycyrrhizin, the Fructus rhamni (Rhamnus davurica Pall.) liquirtin, Neoliquiritin, Licoflavonol., licoisoflavone A and B, licoisoflavanone, the formononetin glabrol, glabrone, glabrene., hispglabridin A, hispglabridin B, baicalin, tranilast, silymarin, phloretin, Taxifolin, daidzein (4 ', the 7-dihydroxy isoflavone), Rhizoma Iridis Tectori kind aglycon (4 ', 7-dihydroxy-6-methoxyl group isoflavone, luteolin, xanthohumol, isoxanthohumol, genistein, 4,5, the 7-tri hydroxy flavanone, chalconaringenin, myricetin, the phosphorylation Hesperidin, biochanin A, morin, phloretin, silymarin, 4-phenyl-coumarin, 7-fluoro-4 '-flavonol-4 '-chloro-4,6-dimethoxy chalcone derivative, flavanone-7-sodium sulfate, 5-flavonol-7-sodium sulfate, 4 '-chloro-4,6-dimethoxy chalcone derivative; Antiinflammatory, for example indomethacin, aescine, traxanox, Salicylate, eicosatrienoic acid, glycyrrhizin; Regulate allergic reagent, for example disodium cromoglycate (DSCG), tranilast, glycyrrhizin, isoliquiritigenin, baicalin, kayexalate (N-PSS), saccharic acid, the deutero-oligosaccharide of chondroitin sulfate A (ChSAO), Phenylbutazone, crovaril, gamma-Linolenic acid, fenoprofen; Phenolic compound, for example diphenylacrylate, diphenyl-propionic acid, 3-(4-trifluoromethyl-phenyl)-3-phenylpropionic acid, 3-(4-trifluoromethyl-phenyl)-3-phenylpropionic acid, 1-(2-hydroxyl-4, the 6-Dimethoxyphenyl)-3-(4-methoxyphenyl) acetone, 1-(2-hydroxyl-4,6-Dimethoxyphenyl)-3-(4-chlorphenyl) acetone, indole-2-carboxylic acid, norlignane, elladitannin and urolithin B; Vitamin C, L-ascorbic acid-6-hexadecane ester; Saponin, for example Caulis Hederae Sinensis sapogenin; Cysteamine; Echinacea Species; Rosmarinic acid; Guanidine hydrochloride; The L-arginine; Surfactant, for example sodium tetradecyl sulfate or octylphenol ethoxylate; And the analog of above-mentioned substance and derivant.
The proper dosage of these chemical compounds can be for example to provide the steady concentration of each agent to obtain the inhibition effect to the prolongation of hyaluronidase.These concentration are proximate and can adjust according to the usefulness of chemical compound, the time that the effect needs continue and the expection speed that relies on the hyaluronic acid degradation of anatomical position: Aurothiomalate 10mM, indomethacin 1mg/ml, heparin 1mg/ml, Sulfated polysaccharide 2mg/ml, and propylene glycol, TRITON X-100, PEG, SPAN, PLURONIC L101 and carboxymethyl cellulose are 10mg/ml.In order to obtain this concentration, in the volume that may be exposed to some milliliters of aqueous body fluid, may need about 10 times dosage (for example gross weight 10mg indomethacin, the Sulfated polysaccharide of 20mg, 100mg propylene glycol, TRITON, PEG, SPAN, PLURONIC or carboxymethyl cellulose) of every milliliter of necessary dosage.Therefore, if for example inject 1ml HA solution, wherein this injecting fluid may be exposed to the interstitial fluid of diffusion through about 2ml in this zone, and each inhibitor of suggestion injection 100mg is so that guarantee to reach the dosage of every milliliter of 10mg over time so.The dosage demand depends primarily on the site of volume injected and application.Site in high fluid turnover can give more Hyaluronidase inhibitor.In addition, if use control method release inhibitor from the polymerization dosage form, according to the release of inhibitor spectrum, the site of using, this regional body fluid turnover and such as other parameters such as age and comprehensive healths, those skilled in the art can the computing application accumulated dose so.
3. the hyaluronic acid surgical adhesions barrier of load HI
The formation of surgical adhesions is the process of a complexity, and the bodily tissue that wherein normally separates is grown or scabbed together.Adhesion is to occur in the connection of the scar tissue between adjacent tissue or bridging, and described adjacent tissue is damaged at intra-operative.The operation wound that causes owing to the existence of organizing drying, ischemia, hot injury, infection or foreign body is considered to the stimulating factor that the tissue adhesion forms for a long time.Mechanical injuries comprise that intestinal weighs (Choate et al., Arch.Surg.88:249-254,1964) wounded and intestinal wall is outer field and peel off or wipe (Gustavsson et al., ActaChir.Scand.109:327-333,1955).The main blood vessel that isolation links to each other with the intestinal ring can be induced the ischemia (James et al., J.Path.Bact.90:279-287,1965) that can cause adhesion.The foreign body that can introduce and cause adhesion in the zone comprises Talcum (Green et al., Proc.Soc.Exp.Biol.Med.133:544-550,1970), gauze sponge (Lehman and Boys, Ann.Surg 111:427-435,1940), toxic chemicals (Chancy, Arch.Surg.250:1151-1153,1950), antibacterial (Moin et al., Am.J.Med.Sci.250:675-679,1965), feces (Jackson, Surgery 44:507-518,1958).The result is, surgical adhesions be failure operative treatment principal element and be intestinal obstruction and sterile principal element.The complication that other adhesion is relevant comprises chronic pelvic pain, urethral obstruction and excretory function obstacle.According to estimates, at 60% to 90% annual charge of accepting among the patient of big gynecological and abdominal operation tissue adhesion to take place and estimating the adhesion of treatment abdominal part above 2,000,000,000 dollars.
Usually, it is inflammatory reaction that adhesion forms, and wherein the factor is released, and has improved vascular permeability and has caused Fibrinogen to flow into and fibrin deposition.Fibrin deposition formation bridging is performed the operation or the adjacent tissue of disease (for example inflammatory bowel, Crohn disease) damage or the substrate of organ.Under normal circumstances, the most of fibrin matrix between organ are degraded in agglutination.Yet when fibrin matrix was not degraded, fibroblast gathered, links to each other, deposits with substrate collagen and induction of vascular and takes place.The result is the permanent band that has formed the fibrous scar tissue that will should isolating organ or tissue under the normal condition link together.If can avoid this a series of incident in 4 to 5 days after surgery, can reduce the formation of adhesion so.
Developed behind multiple operation technique, prevent or reduce adhesion based on hyaluronic product.Hyaluronic acid (normally hyaluronate sodium) film, gel or spray can form the absorbable barrier of provisional biology of isolating adjacent tissue (promptly physics exists barrier to prevent that they directly are in contact with one another and scab in agglutination between two tissues).Unfortunately, after laying about 24 to 48 hours, film is by aquation and begin to be absorbed.Though this is suitable for some operation technique, but other the operation in (perhaps in low resistance patient, healing diabetics more slowly for example), this active duration and inadequate and before healing is finished barrier be absorbed-patient placed the condition of easier formation adhesion.
In the present invention, Hyaluronidase inhibitor added separately contains in hyaluronic surgical adhesions film, gel or the spray, perhaps the hyaluronidase of slow release form is suppressed to add contain in hyaluronic surgical adhesions thin film, gel or the spray with the speed that reduces the HA degraded and the activity in vivo that prolongs compositions/implant to surpass when using HA separately (for example in surpassing 90% patient consistent surpass 2 days and above among 50% the patient above 7 days).On the one hand, the preparation that will contain HI during operation technique is delivered to the position of expectation, and the surface of target tissue or organ for example is so that prevent the formation of adhesion.On behalf of the example on the surface of desired locations, these include but not limited to comprise the inner surface of the reproductive tract in fallopian tube, ovary and uterus, surround in the finger (toe) of tendon, spinal column, the inside muscle surface in abdominal cavity and comprise for example gastral outer surface of small intestinal and large intestine, stomach, and such as accessory organs' such as kidney, spleen and liver surface.
Can make accumulated dose, dosage rate of release and the medicine of the HI of conveying activity as required from the suitable significant prolongation hyaluronic acid implant of release duration of HA.This will make barrier in vivo performance function for more time and be reduced in adjacent organs or tissue between form the probability of scar tissue.The HI-HA implant can reduce the incidence rate and/or the seriousness of the adhesion that may form at abdominal part and gynecologic surgery.The minimizing of adhesion can be avoided pain generation, intestinal obstruction and sterile, and minimizing repeats the surgery intervention to remove the needs of scar tissue.
Use reagent provided herein, compositions and method can treat or prevent multiple surgical adhesions and postoperative complication.Accumulating/wrapping up of the formation of adhesion or the scar tissue of not expecting makes that multiple operation is complicated.As mentioned above, surgical adhesions can make the opening of any abdominal cavity or pelvic cavity or endoscopic surgery operate in visually complicated potentially.The parcel of surgery implant makes that also breasst reconstruction operation, joint replacement surgery, hernia prosthesis, artificial blood vessel's transplant operation and neural operation are complicated.In each case, implant is wrapped up by the fibrous connective tissue tunicle, the function of this tunicle harm or infringement surgery implant (for example breast implant, artificial joint, operation net, blood vessel graft, pachymeninx sticking patch, pericardium).Chronic inflammatory disease also occurs in the operation in other zone (for example foreign body, infection (fungus, mycobacteria)) of correcting chronic sinusitis or eliminating chronic inflammatory disease with scabbing.Also can in the morbid state of handling these operations, use the HI-HA implant.
Can comprise with the example that HI combination is used for the suitable commercialization HA product of abdominal part, gastrointestinal, crown, peripheral nervous and tendon, plastic surgery, gynecological and other operation: from RESTYLANE, HYLAFORM, PERLANE, SYNVISC and the LUBRICOAT of LifecoreBiomedical, INTERGEL and from Genzyme Biosurgery, the SEPRAFILM of Inc, SEPRAGEL and SEPRACOAT adhesion barrier.Other HA product comprises implant, for example from the crosslinked HA product of the OSSIGEL of Anika Therapeutics, for example biological absorbable cross-linked-hyaluronic acid (HA) product and the HA derivant of ATRISOL, INCERT family are for example from the HYALGEL-R of Genzyme Biosurgery.
United States Patent (USP) the 6th, 723,709,6,531,147 and 6,464, the representational example of the hyaluronic acid compositions that is used to prevent surgical adhesions has been described in No. 970.
HI can make up so that the slow release of reagent to be provided with polymeric system.Be suitable for carrying the material of the HI agent that is used for the object of the invention to form by non-degradable or degradable material; Yet, preferred degradable material.Suitable degradable material includes but not limited to the PEG cross-linked material, gelatin, collagen, GELFOAM, (the ALLOGRO for example of bone allograft, ORTHOBLAST, OPTEFORM, GRAFTON), polysaccharide, carbohydrate, protein (albumin for example, casein, lactalbumin, vegetable protein, fish protein etc.), from the body bone, decalcified bone matrix, alginate, starch, cellulose derivative (for example HPC), cellulose, cellulose esters, the mixture of cellulose esters or copolymer, chitosan, chitosan derivatives, the block copolymer of polyester-polyalkenyl oxide (PLGA-PEG-PLGA for example, MePEG-PLGA etc.), degradable polyester, polyanhydride, polyorthoesters, poly phosphate, poly-phosphazine, cyanoacrylate polymer, the injectable preparation that contains PEG, for example COSEAL, FOCALSEAL, SPRAYGEL, DURASEAL, or United States Patent (USP) the 5th, 874,500,6,051,648,6,166,130 and 6,312, that describes in No. 725 comprises 4-arm sulfydryl PEG (10K), the compositions of 4-arm NHS PEG (10K) and methylated collagen, contain fibrinogenic preparation, for example FLOSEAL or TISSEAL, REPEL or FLOWGEL, and other can excretory low-molecular weight polymer.
The surgical adhesions barrier that contains HI-HA can be used for comprising the multiple operation technique of abdominal operation, gynecological and operation on pelvis, spinal operation, operation on heart, tendon and peripheral nervous operation and Dou Shoushu.When the method for optimizing of HI-HA compositions administration is included in operation with described compositions as " gel ", " suspension ", " solution ", " paste ", " thin film " or " wrappage " (for example can wrap up the whole of body passageway, organ or tissue surface or thin film, net or film that it is a part of) to the mesentery surface directly application or use endoscope, ultrasonic, CT, MRI or fluoroscopic guidance with described compositions administration; Use HI compositions " bag quilt " HA surgery implant; Place the polymeric implants of HI eluting at surgical site.During endoscopic procedure, can use the HI-HA preparation of " spray " form by endoscope's delivery port to the mesentery of the abdominal part of intra-operative operation and pelvic organ.
In the practice of above-mentioned embodiment, those skilled in the art are appreciated that obviously that potentially any Hyaluronidase inhibitor all can be used singly or in combination.In avoiding surgical adhesions, be used for comprising: Aurothiomalate, dextran sulfate, fucoidin, propylene glycol with the example of the HI agent of HA combination; Flavonoid class, condensed tannin for example, tannin, kaempferol, Quercetin, apigenin, hydrangenol from hydrangea, curcumin from the flavoring agent Fructus Foeniculi, glycyrrhizin, isoliquiritin, glabridin, glycyrrhizin, the Fructus rhamni (Rhamnus davurica Pall.) liquirtin, Neoliquiritin, Licoflavonol., licoisoflavone A and B, licoisoflavanone, the formononetin glabrol, glabrone, glabrene., hispglabridin A, hispglabridin B, baicalin, tranilast, silymarin, phloretin, Taxifolin, daidzein (4 ', the 7-dihydroxy isoflavone), Rhizoma Iridis Tectori kind aglycon (4 ', 7-dihydroxy-6-methoxyl group isoflavone, luteolin, xanthohumol, isoxanthohumol, genistein, 4,5, the 7-tri hydroxy flavanone, chalconaringenin, myricetin, the phosphorylation Hesperidin, biochanin A, morin, phloretin, silymarin, 4-phenyl-coumarin, 7-fluoro-4 '-flavonol-4 '-chloro-4,6-dimethoxy chalcone derivative, flavanone-7-sodium sulfate, 5-flavonol-7-sodium sulfate, 4 '-chloro-4,6-dimethoxy chalcone derivative; Antiinflammatory, for example indomethacin, aescine, traxanox, Salicylate, eicosatrienoic acid, glycyrrhizin; Regulate allergic reagent, for example disodium cromoglycate (DSCG), tranilast, glycyrrhizin, isoliquiritigenin, baicalin, kayexalate (N-PSS), saccharic acid, the deutero-oligosaccharide of chondroitin sulfate A (ChSAO), Phenylbutazone, crovaril, gamma-Linolenic acid, fenoprofen; Phenolic compound, for example diphenylacrylate, diphenyl-propionic acid, 3-(4-trifluoromethyl-phenyl)-3-phenylpropionic acid, 3-(4-trifluoromethyl-phenyl)-3-phenylpropionic acid, 1-(2-hydroxyl-4, the 6-Dimethoxyphenyl)-3-(4-methoxyphenyl) acetone, 1-(2-hydroxyl-4,6-Dimethoxyphenyl)-3-(4-chlorphenyl) acetone, indole-2-carboxylic acid, norlignane, elladitannin and urolithin B; Vitamin C, L-ascorbic acid-6-hexadecane ester; Saponin, for example Caulis Hederae Sinensis sapogenin; Cysteamine; Echinacea Species; Rosmarinic acid; Guanidine hydrochloride; The L-arginine; Surfactant, for example sodium tetradecyl sulfate or octylphenol ethoxylate; And the analog of above-mentioned substance and derivant.
The suitable dose of these chemical compounds can be for example to provide the steady concentration of each agent to obtain the inhibition effect to the prolongation of hyaluronidase.These concentration are to adjust the time proximate and that can continue according to the usefulness and the effect needs of chemical compound: Aurothiomalate 10mM, indomethacin 1mg/ml, heparin 1mg/ml, dextran sulfate 2mg/ml and propylene glycol, TRITON X-100, PEG, SPAN, PLURONIC L101 and carboxymethyl cellulose are 10mg/ml.In order to obtain this concentration, in the volume that may be exposed to some milliliters of aqueous body fluid, may need about 10 times dosage (for example indomethacin of gross weight 10mg, the Sulfated polysaccharide of 20mg, 100mg propylene glycol, TRITON, PEG, SPAN, PLURONIC or carboxymethyl cellulose) of every milliliter of necessary dosage.Therefore, if injection 1ml HA solution for example, wherein this injecting fluid may be exposed to the about 2ml interstitial fluid of diffusion through this zone, so suggestion inject 100mg each inhibitor in case after a period of time in guarantee to reach the dosage of every milliliter of 10mg.Required dosage depends primarily on the site of volume injected and application.Site in the high fluid turnover can give more Hyaluronidase inhibitor.In addition, if use control method release inhibitor from the polymerization dosage form, according to the release of inhibitor spectrum, the site of using, this regional body fluid turnover and such as other parameters such as age and comprehensive healths, those skilled in the art can the computing application accumulated dose so.
4. the hyaluronic acid of load HI beauty treatment implant
Developed and be used for the multiple injectable hyaluronic acid product of soft tissue increase to correct facial cicatrix, to reduce facial line and thicken lip.Especially, such implant is pointed out to be used for the treatment of multiple profile defective, include, but is not limited to correct the acne cicatrix, the atrophy that disease or wound cause, the glabella lines of frowning, the muffle pleat perhaps is secondary to defective and other soft tissue defective of rhinoplasty, skin graft or other operation.The commercially available synthetic hyaluronic acid derivatives that is used for the manufacturing of above-mentioned purpose comprises from RESTYLANE, the PERLANE of Genzyme Corporation and HYLAFORM (being also referred to as HYLAN B).Can comprise with HI combination be used to improve looks other example of commodity HA product of injection: from MeijiSeika Kaisha, the ACHYAL of Ltd. (Japan), from the JUVEDERM of L.E.A.Derm (France), from the MACDERMOL of Laboratoires O.R.GE V.MacDermol (France) and from the ROFILAN Hylan Gel of Rofil Medical International (Holland).
Unfortunately, often need repetition " modification " operation, because implant is occupied by host's connective tissue cell and inflammatory cell, described cell produces can be along with hyaluronidase and other enzyme of the HA implant of degrading time lapse.The injectable hyaluronic acid that contains Hyaluronidase inhibitor (HI) independent or the slow releasing preparation form can cause the implant durability to increase and reduce reinjected subsequently number of times.Though any above-mentioned Hyaluronidase inhibitor all may be fit to be included in the corium HA injection, preferred especially following Hyaluronidase inhibitor: Aurothiomalate, indomethacin, propylene glycol, dextran sulfate, fucoidin, Caulis Hederae Sinensis sapogenin, flavonoid class, the allergic reagent of adjusting, phenolic compound and carboxymethyl cellulose.
Regardless of employed preparation, can carry out the HA drug administration by injection of load HI according to following method.Use contains HI-HA implant material and prefilled syringe that have thin scale syringe needle (30 or 32 is graduated).The patient is placed the table back of the body seat of inclination a little.Use topical lidocaine and/or prilocaine to anaesthetize.Syringe needle is inserted skin at a certain angle and stretches into the superficial dermis tissue.The implant material of extruding q.s is to repair soft tissue profile defective.Under the situation of the RESTYLANE of load HI, need excessively to correct (injection is more than the material that finally needs), because some injection masses can dissipate in a few hours after injection.Usually the PERLANE of working load HI correct dark lines and with its be injected into corium than the depths.
United States Patent (USP) the 5th, 633,001,5,256,140 and 6,703, the representational example of the hyaluronic acid compositions of having described to be used for cosmetic surgery in No. 041.
HI can make up so that the slow release of reagent to be provided with polymeric system.Be suitable for carrying the material of the HI agent that is used for the object of the invention to form by non-degradable or degradable material; Yet, preferred degradable material.Suitable degradable material includes but not limited to the PEG cross-linked material, gelatin, collagen, GELFOAM, polysaccharide, carbohydrate, protein (albumin for example, casein, lactalbumin, vegetable protein, fish protein etc.), alginate, starch, cellulose derivative (HPC etc.), cellulose, cellulose esters, the mixture of cellulose esters or copolymer, chitosan, chitosan derivatives, the block copolymer of polyester-polyalkenyl oxide (PLGA-PEG-PLGA for example, MePEG-PLGA etc.), degradable polyester, polyanhydride, polyorthoesters, poly phosphate, poly-phosphazine, cyanoacrylate polymer contains the injectable preparation of PEG, COSEAL for example, FOCALSEAL, SPRAYGEL, DURASEAL, or United States Patent (USP) the 5th, 874,500,6,051,648,6,166,130 and 6,312, that describes in No. 725 comprises pentaerythritol polyethylene glycol ether four sulfydryls (4-arm sulfydryl PEG), the compositions of pentaerythritol polyethylene glycol ether four succinimide base glutarates (4-arm NHS PEG) and methylated collagen contains fibrinogenic preparation, for example FLOSEAL or TISSEAL, REPEL or FLOWGEL, and other can excretory low-molecular weight polymer.
The HA-HI compositions can also comprise anesthetis, for example lignocaine, benzocaine or prilocaine and/or neurotoxin, for example Botulinum toxin.
In the practice of above-mentioned embodiment, those skilled in the art are appreciated that obviously that potentially any Hyaluronidase inhibitor all can be used alone or be used in combination.Be used in the injection operation comprising in beauty treatment: Aurothiomalate, indomethacin, propylene glycol, carboxymethyl cellulose, dextran sulfate, fucoidin and heparin, and the analog of above-mentioned substance and derivant with the example of the HI agent of HA combination.
The suitable dose of these chemical compounds can be for example to provide the steady concentration of each agent to obtain the inhibition effect to the prolongation of hyaluronidase.These concentration are to adjust the time proximate and that can continue according to the usefulness and the effect needs of chemical compound: Aurothiomalate 10mM, indomethacin 1mg/ml, heparin 1mg/ml, Sulfated polysaccharide 2mg/ml, and propylene glycol, TRITON X-100, PEG, SPAN, PLURONIC L101 and carboxymethyl cellulose are 10mg/ml.In order to obtain this concentration, in the volume that may be exposed to some milliliters of aqueous body fluid, may need about 10 times dosage (for example indomethacin of gross weight 10mg, the Sulfated polysaccharide of 20mg, 100mg propylene glycol, TRITON, PEG, SPAN, PLURONIC or carboxymethyl cellulose) of every milliliter of necessary dosage.Therefore, if injection 1ml HA solution for example, wherein this injecting fluid may be exposed to the about 2ml interstitial fluid of diffusion through this zone, so suggestion inject 100mg each inhibitor in case after a period of time in guarantee to reach the dosage of every milliliter of 10mg.The dosage demand depends primarily on the site of volume injected and application.Site in the high fluid turnover can give more Hyaluronidase inhibitor.In addition, if use control method release inhibitor from the polymerization dosage form, according to the release of inhibitor spectrum, the site of using, this regional body fluid turnover and such as other parameters such as age and comprehensive healths, those skilled in the art can the computing application accumulated dose so.
5. the HA ophthalmic implant of load HI
The viscoelastic solution of HA be used as organize the volume that also is used to keep tear in lubricant and the operation within the eye (for example transplant pioneering operation, intraocular lens, retina is put again, in phacoemulsification operation, corneal transplantation and the glaucoma filtration surgery as Vitrea substitute).AMVISC, AMVISC PLUS and OCUCOAT (Bausch ﹠amp; Lomb) be high-molecular weight viscoelasticity injectable HA solution, be used for keeping eye shape and the accurate tissue of protection at cataract extraction, corneal transplantation and operation for glaucoma.Eye based on HA comprises PROVIS, VISCOAT, DUOVISC and CELLUGEL from Alcon Laboratories with the viscoelasticity product; From Pharmacia ﹠amp; The HEALON of Upjohn, HEALON G and HEALON 5; VITRAX from Allergan; BIOLON from Bio-Technology General; STAARVISC from Anika Therapeutics/StaarSurgical; From the SHELLGEL of Anika Therapeutics/Cytosol Opthalmics and from the UNIVISC of Novartis.
United States Patent (USP) the 5th, 728,405,6,635,267,6,465,588 and 6,242,480,6,620,927,5,728,405,6,635,267,6,465,588 and 6,242, the representational example of the hyaluronic acid compositions of having described to be used for operated eye in No. 480.
According to the present invention, the not commensurability HI of load can be used for accurately controlling the rate of dissolution of ocular implants in the HA ocular implants.In the present invention, HI is joined in the implant that contains HA, perhaps in the compositions of slow release form with the speed that reduces hyaluronic acid degradation and the activity in vivo that prolongs compositions/implant to surpassing when using HA separately (for example consistent in surpassing 75% patient surpassing 1 month).Can make accumulated dose, dosage rate of release and the medicine of conveying be suitable for the activity of significant prolongation collagen implant from the release duration of substrate as required.
HI can make up so that the slow release of reagent to be provided with polymeric system.Be suitable for carrying the material of the HI agent that is used for the object of the invention to form by non-degradable or degradable material; Yet, preferred degradable material.Suitable degradable material includes but not limited to the PEG cross-linked material, gelatin, collagen, GELFOAM, polysaccharide, carbohydrate, protein (albumin for example, casein, lactalbumin, vegetable protein, fish protein etc.), alginate, starch, cellulose derivative (HPC etc.), cellulose, cellulose esters, the mixture of cellulose esters or copolymer, chitosan, chitosan derivatives, the block copolymer of polyester-polyalkenyl oxide (PLGA-PEG-PLGA for example, MePEG-PLGA etc.), degradable polyester, polyanhydride, polyorthoesters, poly phosphate, poly-phosphazine, cyanoacrylate polymer contains the injectable preparation of PEG, COSEAL for example, FOCALSEAL, SPRAYGEL, DURASEAL, or United States Patent (USP) the 5th, 874,500,6,051,648,6,166,130 and 6,312, that describes in No. 725 comprises 4-arm sulfydryl PEG (10K), the compositions of 4-arm NHS PEG (10K) and methylated collagen contains fibrinogenic preparation, for example FLOSEAL or TISSEAL, REPEL or FLOWGEL, and other can excretory low-molecular weight polymer.
In the practice of above-mentioned embodiment, those skilled in the art are appreciated that obviously that potentially any Hyaluronidase inhibitor all can be used singly or in combination.In eye operation, be used for comprising: Aurothiomalate, propylene glycol, dextran sulfate, fucoidin, heparin with the example of the HI agent of HA combination; Flavonoid class, condensed tannin for example, tannin, kaempferol, Quercetin, apigenin, hydrangenol from hydrangea, curcumin from the flavoring agent Fructus Foeniculi, glycyrrhizin, isoliquiritin, glabridin, glycyrrhizin, the Fructus rhamni (Rhamnus davurica Pall.) liquirtin, Neoliquiritin, Licoflavonol., licoisoflavone A and B, licoisoflavanone, the formononetin glabrol, glabrone, glabrene., hispglabridin A, hispglabridin B, baicalin, tranilast, silymarin, phloretin, Taxifolin, daidzein (4 ', the 7-dihydroxy isoflavone), Rhizoma Iridis Tectori kind aglycon (4 ', 7-dihydroxy-6-methoxyl group isoflavone, luteolin, xanthohumol, isoxanthohumol, genistein, 4,5, the 7-tri hydroxy flavanone, chalconaringenin, myricetin, the phosphorylation Hesperidin, biochanin A, morin, phloretin, silymarin, 4-phenyl-coumarin, 7-fluoro-4 '-flavonol-4 '-chloro-4,6-dimethoxy chalcone derivative, flavanone-7-sodium sulfate, 5-flavonol-7-sodium sulfate, 4 '-chloro-4,6-dimethoxy chalcone derivative; Antiinflammatory, for example indomethacin, aescine, traxanox, Salicylate, eicosatrienoic acid, glycyrrhizin; Regulate allergic reagent, for example disodium cromoglycate (DSCG), tranilast, glycyrrhizin, isoliquiritigenin, baicalin, kayexalate (N-PSS), saccharic acid, the deutero-oligosaccharide of chondroitin sulfate A (ChSAO), Phenylbutazone, crovaril, gamma-Linolenic acid, fenoprofen; Phenolic compound, for example diphenylacrylate, diphenyl-propionic acid, 3-(4-trifluoromethyl-phenyl)-3-phenylpropionic acid, 3-(4-trifluoromethyl-phenyl)-3-phenylpropionic acid, 1-(2-hydroxyl-4, the 6-Dimethoxyphenyl)-3-(4-methoxyphenyl) acetone, 1-(2-hydroxyl-4,6-Dimethoxyphenyl)-3-(4-chlorphenyl) acetone, indole-2-carboxylic acid, norlignane, elladitannin and urolithin B; Vitamin C, L-ascorbic acid-6-hexadecane ester; Saponin, for example Caulis Hederae Sinensis sapogenin; Cysteamine; Echinacea Species; Rosmarinic acid; Guanidine hydrochloride; The L-arginine; Surfactant, for example sodium tetradecyl sulfate or octylphenol ethoxylate; And the analog of above-mentioned substance and derivant.
The suitable dose of these chemical compounds can be for example to provide the steady concentration of each agent to obtain the inhibition effect to the prolongation of hyaluronidase.These concentration are to adjust the time proximate and that can continue according to the usefulness and the effect needs of chemical compound: Aurothiomalate 10mM, indomethacin 1mg/ml, heparin 1mg/ml, Sulfated polysaccharide 2mg/ml and propylene glycol, TRITON X-100, PEG, SPAN, PLURONIC L101 and carboxymethyl cellulose are 10mg/ml.In order to obtain this concentration, in the volume that may be exposed to some milliliters of aqueous body fluid, may need about 10 times dosage (for example indomethacin of gross weight 10mg, the Sulfated polysaccharide of 20mg, 100mg propylene glycol, TRITON, PEG, SPAN, PLURONIC or carboxymethyl cellulose) of every milliliter of necessary dosage.Therefore, if injection 1ml HA solution for example, wherein this injecting fluid may be exposed to the about 2ml interstitial fluid of diffusion through this zone, so suggestion inject 100mg each inhibitor in case after a period of time in guarantee to reach the dosage of every milliliter of 10mg.The dosage demand depends primarily on the site of volume injected and application.Site in the high fluid turnover can give more Hyaluronidase inhibitor.In addition, if use control method release inhibitor from the polymerization dosage form, according to the release of inhibitor spectrum, the site of using, this regional body fluid turnover and such as other parameters such as age and comprehensive healths, those skilled in the art can the computing application accumulated dose so.
6. the hyaluronic acid that is used for the load HI of intra-articular injection
Osteoarthritis (OA) is the millions of American pain degenerated joint disease states of influence.Though and do not know the accurate inducement of OA, possible inducement comprises damage, age, congenital body constitution and obesity.Hyaluronic acid is the normal composition in the knuckle synovia, and mechanical injuries are avoided in lubricated articular surface and help during normal activity (rest, walking), reduce the bump to the joint in high collision activity (for example run, jump).In suffering from the patient of OA, the hyaluronic acid concentration of the elasticity of synovial fluid and viscosity and synovial fluid reduces.Believe the damage that this has promoted the intraarticular articular cartilage.Penetrate articular cartilage surface, synovial tissue and joint capsule in the HA of intra-articular administration (normally hyaluronate sodium) a period of time after injection.By in the joint, injecting hyaluronic acid (being called as viscosity replenishes), might partly recover home, minimizing pain and the further damage and the deformity of prevention potentially of synovial fluid.
The material that will contain HA is usually treated (as the single therapy or the course of treatment in repetitive therapy cycle) the pain osteoarthritis of patient's knee with the intra-articular injection administration, uses this patient of expectant treatment to can not get sufficient pain relief.Once in a while also to such as other joint injection HA such as hip (use fluoroscopy injection), ankle, shoulder and elbow joinies to alleviate the disease symptoms in these particular joint.According to specific commercial product, HA material of injection and continuous 5 to 6 weeks in the joint weekly.When effective, the patient report they 6 months or the longer time in remission-this moment can repeat this circulation with the extended treatment activity.Though have lasting effect in some patient, the HA of injection is removed (removing) rapidly by body from the joint in a couple of days.Can expect and prolong the time of staying of HA in the joint to improve its usefulness and to increase persistent period of remission by the decomposition that suppresses HA.
On the one hand, compositions of the present invention can be used for handling the osteoarthritis of animal (for example horse).
In the present invention, HI is joined intraarticular contain in the implant of HA or the compositions with the speed that reduces the HA degraded and the activity in vivo that prolongs compositions/implant to surpass when using HA separately (among for example many patients consistent surpass 6 months and in some patient above 1 year).Can make accumulated dose, dosage rate of release and the medicine of the HI of conveying be suitable for the activity of significant prolongation hyaluronic acid implant from the release duration of substrate as required.
The material of many commercially available HA of containing can make up with HI, comprises, for example SYNVISC is the viscoelastic fluid that contains hylan ((derivant of hyaluronate sodium) is from cockscomb); ORTHOVISC, the HA of highly purified, high molecular, full-bodied injectable forms, HYALGAN (from Fidia/Sanofi-Synthelabo) and HPS and SUPARTZ are (from Seikagaku/Smith ﹠amp; Nephew).Should be noted that some HA products (especially Boehringer Ingelheim Vetmedica, St.Joseph, the HYVISC of MO) are used for veterinary's application (normally treating osteoarthritis and the limping of horse).
United States Patent (USP) the 6th, 654,120,6,645,945 and 6,635, the representational example that is used for the hyaluronic acid compositions that viscosity replenishes has been described in No. 287.
HI can make up so that the slow release of reagent to be provided with polymeric system.Be suitable for carrying the material of the HI agent of in OA handles, making up to form by non-degradable or degradable material with HA; Yet, preferred degradable material.Suitable degradable material includes but not limited to PEG cross-linked material, gelatin, collagen, GELFOAM, polysaccharide, carbohydrate, protein (albumin for example, casein, lactalbumin, vegetable protein, fish protein etc.), alginate, starch, cellulose derivative (HPC or the like), cellulose, cellulose esters, the mixture of cellulose esters or copolymer, chitosan, chitosan derivatives, the block copolymer of polyester-polyalkenyl oxide (PLGA-PEG-PLGA for example, MePEG-PLGA or the like), degradable polyester, polyanhydride, polyorthoesters, poly phosphate, poly-phosphazine, cyanoacrylate polymer.The useful especially degradable polymer that is used for the present invention's practice comprises the injectable preparation that contains PEG, for example COSEAL, FOCALSEAL, SPRAYGEL, DURASEAL, or United States Patent (USP) the 5th, 874,500,6,051,648,6,166,130 and 6,312, the compositions of describing in No. 725 that comprises 4-arm sulfydryl PEG (10K), 4-arm NHS PEG (10K) and methylated collagen contains fibrinogenic preparation, for example FLOSEAL or TISSEAL, REPEL or FLOWGEL, and other can excretory low-molecular weight polymer.Other compositions comprises the mixture and the copolymer of mentioned reagent.
In the practice of above-mentioned embodiment, those skilled in the art are appreciated that obviously that potentially any Hyaluronidase inhibitor all can be used singly or in combination.In handling osteoarthritis, be used for comprising: Aurothiomalate, propylene glycol, dextran sulfate, fucoidin, heparin with the example of the HI agent of HA combination; Flavonoid class, condensed tannin for example, tannin, kaempferol, Quercetin, apigenin, hydrangenol from hydrangea, curcumin from the flavoring agent Fructus Foeniculi, glycyrrhizin, isoliquiritin, glabridin, glycyrrhizin, the Fructus rhamni (Rhamnus davurica Pall.) liquirtin, Neoliquiritin, Licoflavonol., licoisoflavone A and B, licoisoflavanone, the formononetin glabrol, glabrone, glabrene., hispglabridin A, hispglabridin B, baicalin, tranilast, silymarin, phloretin, Taxifolin, daidzein (4 ', the 7-dihydroxy isoflavone), Rhizoma Iridis Tectori kind aglycon (4 ', 7-dihydroxy-6-methoxyl group isoflavone, luteolin, xanthohumol, isoxanthohumol, genistein, 4,5, the 7-tri hydroxy flavanone, chalconaringenin, myricetin, the phosphorylated hesperidin glycosides, biochanin A, morin, phloretin, silymarin, 4-phenyl-coumarin, 7-fluoro-4 '-flavonol-4 '-chloro-4,6-dimethoxy chalcone derivative, flavanone-7-sodium sulfate, 5-flavonol-7-sodium sulfate, 4 '-chloro-4,6-dimethoxy chalcone derivative; Antiinflammatory, for example indomethacin, aescine, traxanox, Salicylate, eicosatrienoic acid, glycyrrhizin; Regulate allergic reagent, for example disodium cromoglycate (DSCG), tranilast, glycyrrhizin, isoliquiritigenin, baicalin, kayexalate (N-PSS), saccharic acid, the deutero-oligosaccharide of chondroitin sulfate A (ChSAO), Phenylbutazone, crovaril, gamma-Linolenic acid, fenoprofen; Phenolic compound, for example diphenylacrylate, diphenyl-propionic acid, 3-(4-trifluoromethyl-phenyl)-3-phenylpropionic acid, 3-(4-trifluoromethyl-phenyl)-3-phenylpropionic acid, 1-(2-hydroxyl-4, the 6-Dimethoxyphenyl)-3-(4-methoxyphenyl) acetone, 1-(2-hydroxyl-4,6-Dimethoxyphenyl)-3-(4-chlorphenyl) acetone, indole-2-carboxylic acid, norlignane, elladitannin and urolithin B; Vitamin C, L-ascorbic acid-6-hexadecane ester; Saponin, for example Caulis Hederae Sinensis sapogenin; Cysteamine; Echinacea Species; Rosmarinic acid; Guanidine hydrochloride; The L-arginine; Surfactant, for example sodium tetradecyl sulfate or octylphenol ethoxylate; And the analog of above-mentioned substance and derivant.
The proper dosage of these chemical compounds can be for example to provide the steady concentration of each agent to obtain the inhibition effect to the prolongation of hyaluronidase.These concentration are to adjust the time proximate and that can continue according to the usefulness and the effect needs of chemical compound: Aurothiomalate 10mM, indomethacin 1mg/ml, heparin 1mg/ml, Sulfated polysaccharide 2mg/ml and propylene glycol, TRITON X-100, PEG, SPAN, PLURONIC L101 and carboxymethyl cellulose are 10mg/ml.In order to obtain this concentration, in the volume that may be exposed to some milliliters of aqueous body fluid, may need about 10 times dosage (for example indomethacin of gross weight 10mg, the Sulfated polysaccharide of 20mg, 100mg propylene glycol, TRITON, PEG, SPAN, PLURONIC or carboxymethyl cellulose) of every milliliter of necessary dosage.Therefore, if injection 1ml HA solution for example, wherein this injecting fluid can be exposed to the about 2ml interstitial fluid of diffusion through this zone, so suggestion inject 100mg each inhibitor in case after a period of time in guarantee to reach the dosage of every milliliter of 10mg.The dosage demand depends primarily on the site of volume injected and application.Site in the high fluid turnover can give more Hyaluronidase inhibitor.In addition, if use control method release inhibitor from the polymerization dosage form, according to the release of inhibitor spectrum, the site of using, this regional body fluid turnover and such as other parameters such as age and comprehensive healths, those skilled in the art can the computing application accumulated dose so.
7. the hyaluronic acid filler that is used for the load HI of GERD
Injectable agent based on HA is used to handle gastroesophageal reflux disease (GERD).When LES (muscle between the harmonization of the stomach esophagus) in the time of can not preventing that gastric content is back to esophagus, GERD will take place.Gastric acid and enzyme have serious corrosivity and can cause burn into ulcer, cicatrix and esophagostenosis the epithelial layer of esophagus.Backflow can cause irreversible damage and make the patient be easy to suffer from the esophageal carcinoma of particular form in esophagus repeatedly.Near the structure that injection HA filler can recovery organization the LES (LES) also reduces backflow to esophagus.Usually by direct injection under endoscopic observation with the administration of HA filler.In fact occur in all operations based on HA, subject matter is the degraded of implant, and this has limited the life-span of treatment.When hyaluronic acid has been lost its structural intergrity and can not have been kept LES again, need to use repeating that the injection again (or injecting another biomaterial, for example collagen) of HA or sphincteral open surgery strengthen to get involved.The representational example based on the filler of HA that is used for the treatment of GERD is the DEFLUX from Q-Med/Priority Healthcare.United States Patent (USP) the 6th, 736,823,6,736,854,6,316, the representational example of the hyaluronic acid compositions that is used for the GERD operation has been described for No. 011.
In the present invention, HI added separately contains in the implant or compositions of HA, perhaps the HI of slow release form is added in the implant that contains HA or the compositions with the speed that reduces the HA degraded and the activity in vivo that prolongs compositions/implant to surpass when using HA separately (for example in surpassing 75% patient consistent surpassing 6 months and above among 35% the patient above 1 year).Can make accumulated dose, dosage rate of release and the medicine of the HI of conveying be suitable for the activity of significant prolongation hyaluronic acid implant from the release duration of substrate as required.
HI can make up so that the slow release of reagent to be provided with polymeric system.Be suitable in handling GERD, carrying the material of the HI agent of making up to form by non-degradable or degradable material with HA.Suitable degradable material includes but not limited to the PEG cross-linked material, gelatin, collagen, GELFOAM, polysaccharide, carbohydrate, protein (albumin for example, casein, lactalbumin, vegetable protein, fish protein etc.), alginate, starch, cellulose derivative (for example HPC), cellulose, cellulose esters, the mixture of cellulose esters or copolymer, chitosan, chitosan derivatives, the block copolymer of polyester-polyalkenyl oxide (PLGA-PEG-PLGA for example, MePEG-PLGA or the like), degradable polyester, polyanhydride, polyorthoesters, poly phosphate, poly-phosphazine and cyanoacrylate polymer.Useful especially degradable polymer comprises the injectable preparation that contains PEG in practice of the present invention, for example COSEAL, FOCALSEAL, SPRAYGEL, DURASEAL or United States Patent (USP) the 5th, 874,500,6,051,648,6,166,130 and 6, the compositions of describing in 312, No. 725 that comprises 4-arm sulfydryl PEG (10K), 4-arm NHSPEG (10K) and methylated collagen, contain fibrinogenic preparation, for example FLOSEAL or TISSEAL, REPEL or FLOWGEL, and other can excretory low-molecular weight polymer.
Be suitable for carrying and be used to handle the non-degradable substance with the HI HA combination GERD and comprise the PVA that comprises formation polymethyl methacrylate (PMMA) when mixing, PVP, polyacrylamide, the cross-linked composition of methyl methacrylate (MMA) and methyl methacrylate styrene (MMA-styrene), perhaps bone cement (the SIMPLEX P that makes by Stryker Howmedica for example, ZIMMER REGULAR and ZIMMER LOWVISCOSITY CEMENT by the Zimmer manufacturing, PALACOS by Smith and Nephew manufacturing, CMW-1 and CMW-2 by Wright Medical manufacturing, DEPUYENDURANCE by the DePuy manufacturing), synthetic reticulated bone void filler (CORTOSS for example, Orthovita, Inc.), pHEMA, poly-(vinyl PEG), the polystyrolsulfon acid ester, polyacrylic acid, other polymer of known formation hydrogel in polymethylacrylic acid and the document.Other compositions comprises the mixture or the copolymer of mentioned reagent.
In the practice of above-mentioned embodiment, those skilled in the art are appreciated that obviously that potentially any Hyaluronidase inhibitor all can be used singly or in combination.In handling GERD, be used for comprising: Aurothiomalate, propylene glycol, heparin, dextran sulfate, fucoidin, carboxymethyl cellulose with the example of the HI agent of HA combination; Flavonoid class, condensed tannin for example, tannin, kaempferol, Quercetin, apigenin, hydrangenol from hydrangea, curcumin from the flavoring agent Fructus Foeniculi, glycyrrhizin, isoliquiritin, glabridin, glycyrrhizin, the Fructus rhamni (Rhamnus davurica Pall.) liquirtin, Neoliquiritin, Licoflavonol., licoisoflavone A and B, licoisoflavanone, the formononetin glabrol, glabrone, glabrene., hispglabridin A, hispglabridin B, baicalin, tranilast, silymarin, phloretin, Taxifolin, daidzein (4 ', the 7-dihydroxy isoflavone), Rhizoma Iridis Tectori kind aglycon (4 ', 7-dihydroxy-6-methoxyl group isoflavone, luteolin, xanthohumol, isoxanthohumol, genistein, 4,5, the 7-tri hydroxy flavanone, chalconaringenin, myricetin, the phosphorylation Hesperidin, biochanin A, morin, phloretin, silymarin, 4-phenyl-coumarin, 7-fluoro-4 '-flavonol-4 '-chloro-4,6-dimethoxy chalcone derivative, flavanone-7-sodium sulfate, 5-flavonol-7-sodium sulfate, 4 '-chloro-4,6-dimethoxy chalcone derivative; Antiinflammatory, for example indomethacin, aescine, traxanox, Salicylate, eicosatrienoic acid, glycyrrhizin; Regulate allergic reagent, for example disodium cromoglycate (DSCG), tranilast, glycyrrhizin, isoliquiritigenin, baicalin, kayexalate (N-PSS), saccharic acid, the deutero-oligosaccharide of chondroitin sulfate A (ChSAO), Phenylbutazone, crovaril, gamma-Linolenic acid, fenoprofen; Phenolic compound, for example diphenylacrylate, diphenyl-propionic acid, 3-(4-trifluoromethyl-phenyl)-3-phenylpropionic acid, 3-(4-trifluoromethyl-phenyl)-3-phenylpropionic acid, 1-(2-hydroxyl-4, the 6-Dimethoxyphenyl)-3-(4-methoxyphenyl) acetone, 1-(2-hydroxyl-4,6-Dimethoxyphenyl)-3-(4-chlorphenyl) acetone, indole-2-carboxylic acid, norlignane, elladitannin and urolithin B; Vitamin C, L-ascorbic acid-6-hexadecane ester; Saponin, for example Caulis Hederae Sinensis sapogenin; Cysteamine; Echinacea Species; Rosmarinic acid; Guanidine hydrochloride; The L-arginine; Surfactant, for example sodium tetradecyl sulfate or octylphenol ethoxylate; And the analog of above-mentioned substance and derivant.Following compositions is particularly suitable for using in this sign.
The proper dosage of these chemical compounds can for example provide the steady concentration of each agent to obtain the inhibition effect to the prolongation of hyaluronidase.These concentration are to adjust the time proximate and that can continue according to the usefulness and the effect needs of chemical compound: Aurothiomalate 10mM, indomethacin 1mg/ml, heparin 1mg/ml, Sulfated polysaccharide 2mg/ml and propylene glycol, TRITON X-100, PEG, SPAN, PLURONIC L101 and carboxymethyl cellulose are 10mg/ml.In order to obtain this concentration, in the volume that may be exposed to some milliliters of aqueous body fluid, may need about 10 times dosage (for example indomethacin of gross weight 10mg, the Sulfated polysaccharide of 20mg, 100mg propylene glycol, TRITON, PEG, SPAN, PLURONIC or carboxymethyl cellulose) of every milliliter of necessary dosage.Therefore, if injection 1ml HA solution for example, wherein this injecting fluid may be exposed to the about 2ml interstitial fluid of diffusion through this zone, so suggestion inject 100mg each inhibitor in case after a period of time in guarantee to reach the dosage of every milliliter of 10mg.The dosage demand depends primarily on the site of volume injected and application.Site in the high fluid turnover can give more Hyaluronidase inhibitor.In addition, if use control method release inhibitor from the polymerization dosage form, according to the release of inhibitor spectrum, the site of using, this regional body fluid turnover and such as other parameters such as age and comprehensive healths, those skilled in the art can the computing application accumulated dose so.
8. the hyaluronic acid filler that is used for the load HI of urinary incontinence
In the treatment urinary incontinence, often use injectable hyaluronic acid.Following embodiment has described the HA product composition of load Hyaluronidase inhibitor in detail and used these method for compositions in this routine medical conditions state of treatment.
In brief, incontinence, promptly be not intended to running off of urine is common medical conditions state, at certain time point in all one's life, urinary incontinence influences 20% women and the male of 1-2%.Modal incontinence form is a stress incontinence, and that promptly causes causing the activity that intra-abdominal pressure increases (for example sneeze, cough or firmly) response is not intended to leakage of urine.When intravesical pressure (pressure in the bladder) surpasses pressure in the urethra, when not forcing flesh (bladder muscle) to shrink, force urine to enter urethra, thereby urinary incontinence takes place from bladder.Some morbid states are considered to cause stress incontinence, comprising:
(1) decline of neck of bladder and inner sphincter of urethra skid off abdominal part.
(2) because the inside sphincter of urethra depletion that wound, operation, childbirth or malignant tumor cause.
Corrective measure mainly aim at by operation or non-operative treatment support in the abdominal cavity near urethra and neck of bladder.Second method relates to the urethra filler (comprising HA) that is used to increase urethra pressure and alleviates stress incontinence.
Though successfully used periurethral and transurethral HA injection in handling stress incontinence, because the limited durability of HA implant, most applications need surpass treatment once.The HA injection of working load HI can be kept demand and the frequency of the active and reduction of implant to urethra week and transurethral injection subsequently.
Some commercially available products based on HA can be used to handle stress incontinence.Based on the representational example of the product of the vesicoureteral reflux (urinary incontinence) of HA is DEFLUX from Q-Med/Priority Healthcare.Unfortunately, HA begins degraded and degraded fully in the several months in several weeks.Though it is 58-100% when initial that the treatment back shows the percentage of patients of urinary incontinence improvement, yet the absorption of HA causes Most patients to need repetitive operation in above-mentioned interval.In the present invention, HI is added separately in the injectable agent based on HA, perhaps the HI of slow release form is added based in the injectable agent of HA with the speed that reduces the HA degraded and the activity in vivo that prolongs compositions/implant to surpassing when using HA separately (consistent in most of patients surpass 1 year).
United States Patent (USP) the 6th, 605,294,6,699,471 and 6,423, the representational example of the hyaluronic acid compositions of having described to be used for urinary incontinence for No. 332.
In the present invention, HI added separately contains in the implant or compositions of HA, perhaps the HI of slow release form is added in the implant that contains HA or the compositions with the speed that reduces the HA degraded and the activity in vivo that prolongs compositions/implant to surpass when using HA separately (for example in surpassing 75% patient consistent surpassing 6 months and above among 35% the patient above 1 year).Can make accumulated dose, dosage rate of release and the medicine of the HI of conveying be suitable for the activity of significant prolongation hyaluronic acid implant from the release duration of substrate as required.
HI can make up so that the slow release of reagent to be provided with polymeric system.Be suitable in handling urinary incontinence, carrying the material of the HI agent of making up to form by non-degradable or degradable material with HA.Suitable degradable material includes but not limited to the PEG cross-linked material, gelatin, collagen, GELFOAM, polysaccharide, carbohydrate, protein (albumin for example, casein, lactalbumin, vegetable protein, fish protein etc.), alginate, starch, cellulose derivative (HPC etc.), cellulose, cellulose esters, the mixture of cellulose esters or copolymer, chitosan, chitosan derivatives, the block copolymer of polyester-polyalkenyl oxide (PLGA-PEG-PLGA for example, MePEG-PLGA etc.), degradable polyester, polyanhydride, polyorthoesters, poly phosphate, poly-phosphazine and cyanoacrylate polymer.Useful especially degradable polymer comprises the injectable formulation that contains PEG in practice of the present invention, for example COSEAL, FOCALSEAL, SPRAYGEL, DURASEAL or United States Patent (USP) the 5th, 874,500,6,051,648,6,166,130 and 6, the compositions of describing in 312, No. 725 that comprises 4-arm sulfydryl PEG (10K), 4-arm NHSPEG (10K) and methylated collagen, contain fibrinogenic preparation, for example FLOSEAL or TISSEAL, REPEL or FLOWGEL, and other can excretory low-molecular weight polymer.
Be suitable for carrying and be used to handle the non-degradable substance with the HI HA combination urinary incontinence and comprise the PVA that comprises formation polymethyl methacrylate (PMMA) when mixing, PVP, polyacrylamide, the cross-linked composition of methyl methacrylate (MMA) and methyl methacrylate styrene (MMA-styrene), perhaps bone cement (the SIMPLEX P that makes by Stryker Howmedica for example, ZIMMER REGULAR and ZIMMER LOWVISCOSITY CEMENT by the Zimmer manufacturing, PALACOS  by Smith and Nephew manufacturing, CMW-1 and CMW-2 by Wright Medical manufacturing, DEPUYENDURANCE by the DePuy manufacturing), synthetic reticulated bone void filler (CORTOSS for example TM, Orthovita), other polymer of known formation hydrogel in pHEMA, poly-(vinyl PEG), polystyrolsulfon acid ester, polyacrylic acid, polymethylacrylic acid and the document.Other compositions comprises above-mentioned dose mixture or copolymer.
A. per urethra technology
Regardless of employed preparation, the per urethra drug administration by injection of the HA of load HI can carry out according to following method.That use contains some milliliters of implant materials and have a thin scale syringe needle disposable prefilled syringe of (having the 23 graduated per urethra syringe needles of stablizing intubate).The patient placed the lithotomy position and 2% lignocaine of 10ml is injected into urethra anaesthetize.For the women, use cystoscope to observe neck of bladder.By cystoscopic injection port, inserting pin with acute angle away from neck of bladder 1-1.5cm place in the position at 4 o'clock, until the plane below bladder mucosa just.Use cystoscope that pin is advanced along the urethra major axis then, below lucky arrival neck of bladder mucosa.Slow HA to this site injection load HI.Then in the repetitive operation of the position at 8 o'clock.Can add visual with auxiliary injection of methylene blue or other non-toxicity stain to implant.
B. urethra week injection
The urethra week injection of the HA injection of load HI also can be used to treat incontinence.Use contains some milliliters of implant materials and disposable prefilled syringe that have thin scale syringe needle (urethra week syringe needle).The patient placed the lithotomy position and 2% lignocaine of 10ml is injected into urethra anaesthetize, and use cystoscope to observe neck of bladder (, can observe urethra) by cystoscope method on the pubis for the male.Insert urethra and the zone parallel of next-door neighbour with urethra with the pin transvaginal or on pubis.When near the correct position the pin arrival neck of bladder (as mentioned above as seen) by cystoscope, slow HA to this site injection load HI.Can add visual with auxiliary injection of methylene blue or other non-toxicity stain to implant.
In the practice of above-mentioned embodiment, those skilled in the art are appreciated that obviously that potentially any Hyaluronidase inhibitor all can be used singly or in combination.In handling urinary incontinence, be used for comprising: Aurothiomalate, propylene glycol, dextran sulfate, fucoidin, carboxymethyl cellulose with the example of the HI agent of HA combination; Flavonoid class, condensed tannin for example, tannin, kaempferol, Quercetin, apigenin, hydrangenol from hydrangea, curcumin from the flavoring agent Fructus Foeniculi, glycyrrhizin, isoliquiritin, glabridin, glycyrrhizin, the Fructus rhamni (Rhamnus davurica Pall.) liquirtin, Neoliquiritin, Licoflavonol., licoisoflavone A and B, licoisoflavanone, the formononetin glabrol, glabrone, glabrene., hispglabridin A, hispglabridin B, baicalin, tranilast, silymarin, phloretin, Taxifolin, daidzein (4 ', the 7-dihydroxy isoflavone), Rhizoma Iridis Tectori kind aglycon (4 ', 7-dihydroxy-6-methoxyl group isoflavone, luteolin, xanthohumol, isoxanthohumol, genistein, 4,5, the 7-tri hydroxy flavanone, chalconaringenin, myricetin, the phosphorylation Hesperidin, biochanin A, morin, phloretin, silymarin, 4-phenyl-coumarin, 7-fluoro-4 '-flavonol-4 '-chloro-4,6-dimethoxy chalcone derivative, flavanone-7-sodium sulfate, 5-flavonol-7-sodium sulfate, 4 '-chloro-4,6-dimethoxy chalcone derivative; Antiinflammatory, for example indomethacin, aescine, traxanox, Salicylate, eicosatrienoic acid, glycyrrhizin; Regulate allergic reagent, for example disodium cromoglycate (DSCG), tranilast, glycyrrhizin, isoliquiritigenin, baicalin, kayexalate (N-PSS), saccharic acid, the deutero-oligosaccharide of chondroitin sulfate A (ChSAO), Phenylbutazone, crovaril, gamma-Linolenic acid, fenoprofen; Phenolic compound, for example diphenylacrylate, diphenyl-propionic acid, 3-(4-trifluoromethyl-phenyl)-3-phenylpropionic acid, 3-(4-trifluoromethyl-phenyl)-3-phenylpropionic acid, 1-(2-hydroxyl-4, the 6-Dimethoxyphenyl)-3-(4-methoxyphenyl) acetone, 1-(2-hydroxyl-4,6-Dimethoxyphenyl)-3-(4-chlorphenyl) acetone, indole-2-carboxylic acid, norlignane, elladitannin and urolithin B; Vitamin C, L-ascorbic acid-6-hexadecane ester; Saponin, for example Caulis Hederae Sinensis sapogenin; Cysteamine; Echinacea Species; Rosmarinic acid; Guanidine hydrochloride; The L-arginine; Surfactant, for example sodium tetradecyl sulfate or octylphenol ethoxylate; And the analog of above-mentioned substance and derivant.Following compositions is particularly suitable for using in this sign.
The suitable dose of these chemical compounds can be for example to provide the steady concentration of each agent to obtain the inhibition effect to the prolongation of hyaluronidase.These concentration are to adjust the time proximate and that can continue according to the usefulness and the effect needs of chemical compound: Aurothiomalate 10mM, indomethacin 1mg/ml, heparin 1mg/ml, Sulfated polysaccharide 2mg/ml and propylene glycol, TRITON X-100, PEG, SPAN, PLURONIC L101 and carboxymethyl cellulose are 10mg/ml.In order to obtain this concentration, in the volume that may be exposed to some milliliters of aqueous body fluid, may need about 10 times dosage (for example indomethacin of gross weight 10mg, the Sulfated polysaccharide of 20mg, 100mg propylene glycol, TRITON, PEG, SPAN, PLURONIC or carboxymethyl cellulose) of every milliliter of necessary dosage.Therefore, if injection 1ml HA solution for example, wherein this injecting fluid may be exposed to the about 2ml interstitial fluid of diffusion through this zone, so suggestion inject 100mg each inhibitor in case after a period of time in guarantee to reach the dosage of every milliliter of 10mg.The dosage demand depends primarily on the site of volume injected and application.Site in the high fluid turnover can give more Hyaluronidase inhibitor.In addition, if use control method release inhibitor from the polymerization dosage form, according to the release of inhibitor spectrum, the site of using, this regional body fluid turnover and such as other parameters such as age and comprehensive healths, those skilled in the art can the computing application accumulated dose so.
9. the HA filler that is used for the load HI of fecal incontinence
The Local treatment that can also be used for fecal incontinence based on the injectable agent of HA.Fecal incontinence be common and social activity can not morbid state, its influence is up to 11% North America adult.Multiple factor can cause wind or feces incontinence, but more common in the women, and anal sphincter can be impaired when childbirth for the women (those women of prolonged labor when especially suffering from three grades of vaginas and tearing, need tweezers, the big baby of childbirth and/or vaginal delivery).Though the etiology of fecal incontinence often is multifactorial, inducement comprises sphincter damage (obstetrics, surgery, accident), anorectal disease (hemorrhoid, proctoptosis, inflammatory bowel, fistula, tumor, colectomy, fecal impaction, diarrhoea), inborn (spina bifida, outstanding, the Hirshsprung disease of meninges), (defecation opposing, dull-witted, intellectual retardation) special or behavior.Passive fecal incontinence (being to take place under patient's situation about not discovering) mainly is because the dysfunction of sphincter ani internus, and fecal incontinence (can not independently forbid defecation) initiatively is normally because the dysfunction of external anal sphincter.
The rectification means are to carry out expectant treatment at first or directly eliminate potential inducement (if apparent in view).In Most patients, the surgical repair that can't identify definite factor and attempt sphincter ani internus or external anal sphincter usually.Unfortunately, surpassing 50% among these patients does not reach secular successful result and needs the treatment of another kind of form.Those patients of operative failure, do not wish the patient that undergos surgery and because the patient that medical reasons can not undergo surgery carries out the candidate that the injectable sphincter increases.In this operation, with filler, for example HA is injected into zone around internal sphincter or the external sphincter to increase sphincteral pressure and to reduce fecal incontinence.
Though sphincter HA injection successfully has been used to handle fecal incontinence around the anus, because the limited durability of HA implant, most applications need be more than treatment once.The HA injection of working load HI can be kept the active of implant and reduce needs and the frequency thereof that crissum is injected.Some commercially available products based on HA can be used to handle fecal incontinence.Multiple filler based on HA can be used for the treatment of fecal incontinence, comprises injectable filler.The representational example based on the vesicoureteral reflux product of HA that also can be used for fecal incontinence is the DEFLUX from Q-Med/Priority Healthcare, and it is by the cross-linking dextran granulometric composition in the hyaluronic acid solution.
United States Patent (USP) the 6th, 129,761 and 5,490, the representational example of the hyaluronic acid compositions of having described to be used for fecal incontinence for No. 984.
Unfortunately, HA begins degraded and degraded fully in the several months in several weeks.Though the treatment back shows that the percentage of patients of its incontinence improvement is very high, yet the absorption of HA causes Most patients need repeat described operation.In the present invention, HI is added separately in the injectable agent based on HA, perhaps the HI of slow release form is added based in the injectable agent of HA with the speed that reduces the implant degraded and the activity in vivo that prolongs implant to surpassing when using HA separately (for example consistent in most of patients surpass 1 year).Can make accumulated dose, dosage rate of release and the medicine of the HI of conveying be suitable for the activity of significant prolongation hyaluronic acid implant from the release duration of substrate as required.
HI can make up so that the slow release of reagent to be provided with polymeric system.Be suitable for carrying and be used to handle the material with the HI agent HA combination fecal incontinence and can form by non-degradable or degradable material.Suitable degradable material includes but not limited to the PEG cross-linked material, gelatin, collagen, GELFOAM, polysaccharide, carbohydrate, protein (albumin for example, casein, lactalbumin, vegetable protein, fish protein etc.), alginate, starch, cellulose derivative (HPC etc.), cellulose, cellulose esters, the mixture of cellulose esters or copolymer, chitosan, chitosan derivatives, the block copolymer of polyester-polyalkenyl oxide (PLGA-PEG-PLGA for example, MePEG-PLGA etc.), degradable polyester, polyanhydride, polyorthoesters, poly phosphate, poly-phosphazine and cyanoacrylate polymer.Useful especially degradable polymer comprises the injectable formulation that contains PEG in practice of the present invention, for example COSEAL, FOCALSEAL, SPRAYGEL, DURASEAL or United States Patent (USP) the 5th, 874,500,6,051,648,6,166,130 and 6, the compositions of describing in 312, No. 725 that comprises 4-arm sulfydryl PEG (10K), 4-arm NHSPEG (10K) and methylated collagen, contain fibrinogenic preparation, for example FLOSEAL or TISSEAL, REPEL or FLOWGEL, and other can excretory low-molecular weight polymer.
Be suitable for carrying and be used to handle the non-degradable substance with the HI HA combination fecal incontinence and comprise the PVA that comprises formation polymethyl methacrylate (PMMA) when mixing, PVP, polyacrylamide, the cross-linked composition of methyl methacrylate (MMA) and methyl methacrylate styrene (MMA-styrene), perhaps bone cement (the SIMPLEX P that makes by Stryker Howmedica for example, ZIMMER REGULAR and ZIMMER LOWVISCOSITY CEMENT by the Zimmer manufacturing, PALACOS by Smith and Nephew manufacturing, CMW-1 and CMW-2 by Wright Medical manufacturing, DEPUYENDURANCE by the DePuy manufacturing), synthetic reticulated bone void filler (CORTOSS for example, Orthovita), pHEMA, poly-(vinyl PEG), the polystyrolsulfon acid ester, polyacrylic acid, other polymer of known formation hydrogel in polymethylacrylic acid and the document.Other compositions comprises the mixture or the copolymer of mentioned reagent.
Use following method to carry out the crissum sphincter injection of the HA of load HI.Use contains some milliliters of implant materials and disposable prefilled syringe that have thin scale syringe needle.According to selected injection areas, 2% lignocaine of 10ml is injected into perineal skin or mucous membrane of rectum.Pin is passed skin or mucous membrane of rectum enter the tela submucosa plane that surrounds anal sphincter.When pin arrives suitable position, to the site slowly inject load HI HA (usually at the linea anocutanea place or just on linea anocutanea around, pass sphincter, enter but away from anus edge injection 3 times) until around anal canal, forming symmetry.Can add visual with auxiliary injection of methylene blue or other non-toxicity stain to implant.
In the practice of above-mentioned embodiment, those skilled in the art are appreciated that obviously that potentially any Hyaluronidase inhibitor all can be used singly or in combination.In handling fecal incontinence, be used for comprising: Aurothiomalate, carboxymethyl cellulose, dextran sulfate, fucoidin, propylene glycol with the example of the HI agent of HA combination; Flavonoid class, condensed tannin for example, tannin, kaempferol, Quercetin, apigenin, hydrangenol from hydrangea, curcumin from the flavoring agent Fructus Foeniculi, glycyrrhizin, isoliquiritin, glabridin, glycyrrhizin, the Fructus rhamni (Rhamnus davurica Pall.) liquirtin, Neoliquiritin, Licoflavonol., licoisoflavone A and B, licoisoflavanone, the formononetin glabrol, glabrone, glabrene., hispglabridin A, hispglabridin B, baicalin, tranilast, silymarin, phloretin, Taxifolin, daidzein (4 ', the 7-dihydroxy isoflavone), Rhizoma Iridis Tectori kind aglycon (4 ', 7-dihydroxy-6-methoxyl group isoflavone, luteolin, xanthohumol, isoxanthohumol, genistein, 4,5, the 7-tri hydroxy flavanone, chalconaringenin, myricetin, the phosphorylation Hesperidin, biochanin A, morin, phloretin, silymarin, 4-phenyl-coumarin, 7-fluoro-4 '-flavonol-4 '-chloro-4,6-dimethoxy chalcone derivative, flavanone-7-sodium sulfate, 5-flavonol-7-sodium sulfate, 4 '-chloro-4,6-dimethoxy chalcone derivative; Antiinflammatory, for example indomethacin, aescine, traxanox, Salicylate, eicosatrienoic acid, glycyrrhizin; Regulate allergic reagent, for example disodium cromoglycate (DSCG), tranilast, glycyrrhizin, isoliquiritigenin, baicalin, kayexalate (N-PSS), saccharic acid, the deutero-oligosaccharide of chondroitin sulfate A (ChSAO), Phenylbutazone, crovaril, gamma-Linolenic acid, fenoprofen; Phenolic compound, for example diphenylacrylate, diphenyl-propionic acid, 3-(4-trifluoromethyl-phenyl)-3-phenylpropionic acid, 3-(4-trifluoromethyl-phenyl)-3-phenylpropionic acid, 1-(2-hydroxyl-4, the 6-Dimethoxyphenyl)-3-(4-methoxyphenyl) acetone, 1-(2-hydroxyl-4,6-Dimethoxyphenyl)-3-(4-chlorphenyl) acetone, indole-2-carboxylic acid, norlignane, elladitannin and urolithin B; Vitamin C, L-ascorbic acid-6-hexadecane ester; Saponin, for example Caulis Hederae Sinensis sapogenin; Cysteamine; Echinacea Species; Rosmarinic acid; Guanidine hydrochloride; The L-arginine; Surfactant, for example sodium tetradecyl sulfate or octylphenol ethoxylate; And the analog of above-mentioned substance and derivant.Following compositions is particularly suitable for using in this sign.
The suitable dose of these chemical compounds can be for example to provide the steady concentration of each agent to obtain the inhibition effect to the prolongation of hyaluronidase.These concentration are to adjust the time proximate and that can continue according to the usefulness and the effect needs of chemical compound: indomethacin 1mg/ml, heparin 1mg/ml, Sulfated polysaccharide 2mg/ml and propylene glycol, TRITON X-100, PEG, SPAN, PLURONIC L101 and carboxymethyl cellulose are 10mg/ml.In order to obtain this concentration, in the volume that may be exposed to some milliliters of aqueous body fluid, may need every milliliter must dosage about 10 times dosage (for example the indomethacin of gross weight 10mg, the Sulfated polysaccharide of 20mg, 100mg propylene glycol, TRITON, PEG, SPAN, PLURONIC or carboxymethyl cellulose).Therefore, if injection 1ml HA solution for example, wherein this injecting fluid may be exposed to the about 2ml interstitial fluid of diffusion through this zone, so suggestion inject 100mg each inhibitor in case after a period of time in guarantee to reach the dosage of every milliliter of 10mg.The dosage demand depends primarily on the site of volume injected and application.Site in the high fluid turnover can give more Hyaluronidase inhibitor.In addition, if use control method release inhibitor from the polymerization dosage form, according to the release of inhibitor spectrum, the site of using, this regional body fluid turnover and such as other parameters such as age and comprehensive healths, those skilled in the art can the computing application accumulated dose so.
On the one hand, described HI is a gold compound, for example auranofin, Aurothiomalate and Kidon (Ono) or Sanocrysin.The dosage of these chemical compounds can be for example to provide the steady concentration of each agent to obtain the inhibition effect to the prolongation of hyaluronidase.The concentration of these agent can be equal to or higher than the concentration of about 10mM among the embodiment.In order to obtain this concentration, in the zone that may be exposed to a small amount of milliliter of aqueous body fluid, may need every milliliter must dosage about 10 times dosage (for example total concentration is the Aurothiomalate of 10mM).Therefore, if injection 1ml HA solution for example, wherein this injecting fluid may be exposed to the about 2ml interstitial fluid of diffusion through this zone, so suggestion inject 100mg each inhibitor in case after a period of time in guarantee to reach the dosage of every milliliter of 10mg.The dosage demand depends primarily on the site of volume injected and application.Site in the high fluid turnover can give more Hyaluronidase inhibitor.In addition, if use control method release inhibitor from the polymerization dosage form, according to the release of inhibitor spectrum, the site of using, this regional body fluid turnover and such as other parameters such as age and comprehensive healths, those skilled in the art can the computing application accumulated dose so.
10. the HA coating that is used for the load HI of medical treatment device
HA can be used as the coating of medical treatment device to strengthen the slickness of biocompatibility and/or apparatus surface.HA directly can be coated in the surface applied of the surperficial or elder generation of medical treatment device, and then further modify to strengthen the adhesiveness and/or the maintenance of HA at apparatus surface at medical treatment device.Modification to HA can comprise crosslinked.Can by use chemical crosslinking, ionomer, physical crosslinking or radiation-induced crosslinked finish crosslinked.The HA coating can also comprise Hyaluronidase inhibitor, so that reduce the degraded of the inductive HA of hyaluronidase.These HA-HI compositionss can be used to apply the medical treatment device of any kind, include but not limited to support, conduit, such as electric conductance connection, ocular implant, intraocular lens, contact lens, diverter, bypass graft, stent graft, suture and bone anchoring devices such as pacemaker lead.
HI can make up so that the slow release of reagent to be provided with polymeric system.Be suitable for carrying the material of the HI agent of making up to form by non-degradable or degradable material with HA.Suitable degradable material includes but not limited to the PEG cross-linked material, gelatin, collagen, GELFOAM, polysaccharide, carbohydrate, protein (albumin for example, casein, lactalbumin, vegetable protein, fish protein etc.), alginate, starch, cellulose derivative (HPC etc.), cellulose, cellulose esters, the mixture of cellulose esters or copolymer, chitosan, chitosan derivatives, the block copolymer of polyester-polyalkenyl oxide (PLGA-PEG-PLGA for example, MePEG-PLGA or the like), degradable polyester, polyanhydride, polyorthoesters, poly phosphate, poly-phosphazine and cyanoacrylate polymer.Useful especially degradable polymer comprises the injectable preparation that contains PEG in practice of the present invention, for example COSEAL, FOCALSEAL, SPRAYGEL, DURASEAL or United States Patent (USP) the 5th, 874,500,6,051,648,6,166,130 and 6, the compositions of describing in 312, No. 725 that comprises 4-arm sulfydryl PEG (10K), 4-arm NHS PEG (10K) and methylated collagen, contain fibrinogenic preparation, for example FLOSEAL or TISSEAL, REPEL or FLOWGEL, and other can excretory low-molecular weight polymer.Be suitable for carrying the degradable substance of the HI that makes up with HA to comprise the PVA that comprises formation polymethyl methacrylate (PMMA) when mixing, PVP, polyacrylamide, the cross-linked composition of methyl methacrylate (MMA) and methyl methacrylate styrene (MMA-styrene), perhaps bone cement (the SIMPLEX P that makes by Stryker Howmedica for example, ZIMMER REGULAR and ZIMMER LOW VISCOSITY CEMENT by the Zimmer manufacturing, PALACOS by Smith and Nephew manufacturing, CMW-1 and CMW-2 by Wright Medical manufacturing, DEPUY ENDURANCE by the DePuy manufacturing), synthetic reticulated bone void filler (CORTOSS for example, Orthovita), pHEMA, poly-(vinyl PEG), the polystyrolsulfon acid ester, polyacrylic acid, other polymer of known formation hydrogel in polymethylacrylic acid and the document.Other compositions comprises the mixture or the copolymer of mentioned reagent.
In the practice of above-mentioned embodiment, those skilled in the art are appreciated that obviously that potentially any Hyaluronidase inhibitor all can be used singly or in combination.In the medical treatment device coating, be used for comprising: Aurothiomalate, heparin, fucoidin, dextran sulfate, propylene glycol, carboxymethyl cellulose with the example of the HI agent of HA combination; Flavonoid class, condensed tannin for example, tannin, kaempferol, Quercetin, apigenin, hydrangenol from hydrangea, curcumin from the flavoring agent Fructus Foeniculi, glycyrrhizin, isoliquiritin, glabridin, glycyrrhizin, the Fructus rhamni (Rhamnus davurica Pall.) liquirtin, Neoliquiritin, Licoflavonol., licoisoflavone A and B, licoisoflavanone, the formononetin glabrol, glabrone, glabrene., hispglabridin A, hispglabridin B, baicalin, tranilast, silymarin, phloretin, Taxifolin, daidzein (4 ', the 7-dihydroxy isoflavone), Rhizoma Iridis Tectori kind aglycon (4 ', 7-dihydroxy-6-methoxyl group isoflavone, luteolin, xanthohumol, isoxanthohumol, genistein, 4,5, the 7-tri hydroxy flavanone, chalconaringenin, myricetin, the phosphorylation Hesperidin, biochanin A, morin, phloretin, silymarin, 4-phenyl-coumarin, 7-fluoro-4 '-flavonol-4 '-chloro-4,6-dimethoxy chalcone derivative, flavanone-7-sodium sulfate, 5-flavonol-7-sodium sulfate, 4 '-chloro-4,6-dimethoxy chalcone derivative; Antiinflammatory, for example indomethacin, aescine, traxanox, Salicylate, eicosatrienoic acid, glycyrrhizin; Regulate allergic reagent, for example disodium cromoglycate (DSCG), tranilast, glycyrrhizin, isoliquiritigenin, baicalin, kayexalate (N-PSS), saccharic acid, the deutero-oligosaccharide of chondroitin sulfate A (ChSAO), Phenylbutazone, crovaril, gamma-Linolenic acid, fenoprofen; Phenolic compound, for example diphenylacrylate, diphenyl-propionic acid, 3-(4-trifluoromethyl-phenyl)-3-phenylpropionic acid, 3-(4-trifluoromethyl-phenyl)-3-phenylpropionic acid, 1-(2-hydroxyl-4, the 6-Dimethoxyphenyl)-3-(4-methoxyphenyl) acetone, 1-(2-hydroxyl-4,6-Dimethoxyphenyl)-3-(4-chlorphenyl) acetone, indole-2-carboxylic acid, norlignane, elladitannin and urolithin B; Vitamin C, L-ascorbic acid-6-hexadecane ester; Saponin, for example Caulis Hederae Sinensis sapogenin; Cysteamine; Echinacea Species; Rosmarinic acid; Guanidine hydrochloride; The L-arginine; Surfactant, for example sodium tetradecyl sulfate or octylphenol ethoxylate; And the analog of above-mentioned substance and derivant.
The suitable dose of these chemical compounds can be for example to provide the steady concentration of each reagent to obtain the inhibition effect to the prolongation of hyaluronidase.The concentration of these reagent can be the micromole to the mM scope and concentration that can adjust these reagent according to the persistent period of the usefulness of chemical compound and needed effect.
Those skilled in the art can understand fairly obviously, and any aforesaid HI agent, its derivant and analog all can be used to above compositions is changed and without departing from the spirit and scope of the present invention.Be also to be understood that when containing or do not contain polymer support, all can in the hyaluronic acid implant, use HI and change carrier and not depart from scope of the present invention.The combination of HI agent can be used to form persistent HA implant and also be tangible without departing from the spirit and scope of the present invention.
Embodiment
Embodiment 1
Use the hyaluronic acid viscometric analysis to estimate the inhibition of hyaluronic acid degradation
The influence that the hyaluronic acid (HA) that uses viscometric analysis (hyaluronic acid viscometric analysis) to determine that different chemical compounds cause hyaluronidase is degraded (for example referring to, " RheologicalStudy on Mixtures of Different Molecular Weight Hyaluronates; " (Research on The Rheology of the mixture of the hyaluronate of different molecular weight) Berriaud, N., et al., Int.J.Biol.Macromol. (1994); 16 (3): p.137-142 and " Determination ofExtracellular Matrix Degradation by Free Radicals using ViscosityMeasurement of Hyaluronan; " (using the viscosimetric analysis of hyaluronan to determine the degradation of extracellular matrix that causes by free radical) Deguine V., et al., Clinica Chimica Acta (1997); 262 (1-2): p.147-52).The viscosity of HA is proportional in the time of sample process viscometer and the sample, and wherein the molecular weight of the viscosity of HA and HA is proportional in the sample.Because enzyme (hyaluronidase) decomposing H A, the reduction of the molecular weight of polymer, the viscosity degradation of solution, thereby solution more promptly passes through viscometer.So the short time of passing through shows the HA (being that hyaluronidase causes that more HA decomposes) of lower molecular weight, and the long time of passing through shows the HA (being that hyaluronidase causes that less HA decomposes) of higher molecular weight.
Be prepared as follows 0.07%HA solution: the phosphate buffer (1M) that in scintillation vial, mixes 15ml HA and 20 μ l pH5.5.Enzyme inhibitor (MePEG2000-PLLA (60: 40) diblock copolymer, heparin, Aurothiomalate and indomethacin) is weighed and be added in each scintillation vial to obtain the ultimate density shown in the table 1.Under 37 ℃, make solution dissolve a night.Detect pH and it is adjusted to 6.0.By measuring viscosity by the time analytical solution of Ubbelohde PC1 viscometer.(ultimate density is about 6 units/ml) and vibration is hatched a night to add the hyaluronidase (containing 4.2mg in the 620 μ l water) of 50 μ l in each scintillation vial.Hatch the viscometer reading of each solution of record after a night.Table 1 and Fig. 1 have provided result's (noting: all added hyaluronidase in the whole samples except the HA contrast).Data show that heparin, Aurothiomalate, indomethacin and diblock copolymer suppress the activity of hyaluronidase, because the viscosity of hyaluronic acid solution is kept above the viscosity of enzyme contrast.
Table 1
The viscosity sample of sample HA solution passes through viscometer
The time of (% of HA contrast) (minute)
HA contrasts 100 2.6
HA/ enzyme 20 0.53
HA/ enzyme/heparin (1mg/ml) 95 2.46
HA/ enzyme/mercaptosuccinic acid. gold 65 1.68
Salt (10mM)
HA/ enzyme/indomethacin (10 91 2.36
mg/ml)
HA/ diblock polymer 100 1.93
(45mg/ml)
HA/ enzyme/diblock polymer 89.6 1.73
(45mg/ml)
Embodiment 2
The inhibition of hyaluronic acid degradation
Utilize embodiment 1 described operation, the influence that the HA that uses viscosimetry to determine that Sulfated polysaccharide (dextran sulfate, fucoidin and heparin), propylene glycol and indomethacin cause hyaluronidase degrades.Table 2 and Fig. 2 have provided the result.Data show that heparin, indomethacin, propylene glycol, dextran sulfate and fucoidin suppress the effect of hyaluronidase, because the viscosity of hyaluronic acid solution is kept above the viscosity of enzyme contrast.
Table 2
The degraded of sample HA
(with respect to the viscosity % of contrast t=0)
HA contrast 82
Enzyme contrast 2
Enzyme contrast 2
Dextran sulfate (2mg/ml) 87
Fucoidin (2mg/ml) 92
Heparin (2mg/ml) 86
Propylene glycol (10mg/ml) 65
Indomethacin (1mg/ml) 73
Embodiment 3
TRITON X-100 is to the inhibition of hyaluronic acid degradation
Use embodiment 1 described method to analyze the influence of TRITON X-100 to the HA degraded that suppresses hyaluronidase and cause.Table 3 and Fig. 3 have provided the result who represents by the time of viscometer with sample.Data show that TRITON X-100 suppresses the effect of hyaluronidase, because the viscosity of hyaluronic acid solution is kept above the viscosity of enzyme contrast.
Table 3
The sample sample is by the time of viscometer
(minute)
HA contrast 5.2
HA/ enzyme 0.46
TRITON?X-100(1mg/ml) 5.83
TRITON X-100 (1mg/ml)/enzyme 2.33
TRITON?X-100(3.3mg/ml) 5.6
TRITON X-100 (3.3mg/ml)/enzyme 3.33
TRITON?X-100(10mg/ml) 5.46
TRITON X-100 (10mg/ml)/enzyme 4.33
Embodiment 4
The influence that the HA that different chemical compounds cause hyaluronidase degrades
Use embodiment 1 described method to analyze the influence of the HA degraded that dextran sulfate, TWEEN 40, SPAN80, PEG 3350, propylene glycol, PLURONIC F127, PLURONIC L101 and carboxymethyl cellulose (CMC) cause enzyme.Table 4 and Fig. 4 have provided the result.Data show that reagent of sulfuric acid glucosan, SPAN 80, PEG, propylene glycol, PLURONIC L101 and carboxymethyl cellulose (CMC) suppress the effect of hyaluronidase, because the viscosity of hyaluronic acid solution is kept above the viscosity of enzyme contrast.It is shocking that in addition two kinds of surfactant TWEEN 40 and PLURONIC F127 have same degree ground to suppress described enzyme.
Table 4
The sample sample is by the time of viscometer
(minute)
HA contrast 5.2
HA/ enzyme 0.46
Dextran sulfate (10mg/ml) 8.5
Dextran sulfate (10mg/ml)/enzyme 8
TWEEN?40(10mg/ml) 3.88
TWEEN 40 (10mg/ml)/enzyme 0.33
SPAN?80(10mg/ml) 5.5
SPAN 80 (10mg/ml)/enzyme 4.36
PEG?3350(10mg/ml) 6
PEG 3350 (10mg/ml)/enzyme 2.16
Propylene glycol (10mg/ml) 5.85
Propylene glycol (10mg/ml)/enzyme 5
PLURONIC?L101(10mg/ml) 6.3
PLURONIC L101 (10mg/ml)/enzyme 1.93
PLURONIC?F127(10mg/ml) 5.5
PLURONIC F127 (10mg/ml)/enzyme 0.12
CMC(10mg/ml) 14.23
CMC (10mg/ml)/enzyme 12.33
Embodiment 5
The dose response effect of Hyaluronidase inhibitor
Prepared the hyaluronic acid preparation that contains or do not contain different hyaluronic acid inhibitor.In order to test the dose response effect of these inhibitor, preparation contains the hyaluronic acid preparation of variable concentrations inhibitor, and described concentration range for example is 0.1mg/mL to 20mg/mL.Can regulate the concentration of inhibitor according to the usefulness of inhibitor.The example of inhibitor that can be tested is dextran sulfate, PLURONIC F127, CMC, TWEEN 40, propylene glycol, fucoidin, indomethacin, heparin and Kidon (Ono).According to standard technique preparation is sterilized.Obtain athymic mouse and preparation and contrast the subcutaneous injection that hyaluronic acid preparation or load have the preparation of inhibitor.The amount of ejection preparation can be 0.1mL to 0.5mL.The weight and the subcutaneous specified amount of injecting of record preparation typically form gel capsules on any side of the spinal column on the back, animal rear portion.For the animal of each injection, the position of injection should be identical.In the different time of a thoughtful several months, put to death animal and open skin in injection site, remove remaining preparation and weigh.The weight of preparation is relevant with the dosage of inhibitor and the persistent period in animal, thereby determines the influence that inhibitor decomposes hyaluronic acid preparation.Inhibitor type and the dosage range that has prolonged the time of being kept perfectly with respect to the hyaluronic acid preparation that contrasts show to make moderate progress to reducing hyaluronic acid degradation.Can be by so that control hyaluronic decomposition rate better this experiment being changed at adding hyaluronidase in animal injection forward direction preparation.
Embodiment 6
The microsphere for preparing the load indomethacin by spray drying
3.6g poly-(D, L-lactide-co-Acetic acid, hydroxy-, bimol. cyclic ester) [PLGA] (85: 15, AbsorbablePolymers International) is dissolved in the 200ml dichloromethane.In polymer solution, add the 400mg indomethacin and use the desk-top spray dryer of Buchi that gained solution is carried out spray drying.The parameter of spray dryer is as follows: 50 ℃ of inlet temperatures, outlet temperature＜39 ℃, getter 100%, flow velocity 700l/hr.Under the room temperature in a vacuum with the microsphere collected dry night to obtain the uniform spherical particle of magnitude range less than about 10 microns (normally about 0.5 to 2 microns).
Embodiment 7
The microsphere (＜10 microns) for preparing the load indomethacin by oil-in-water method
800mg PLG (85: 15, Absorbable Polymers International) is dissolved in the 20ml dichloromethane.In dissolved polymers solution, add the 160mg indomethacin.10% polyvinyl alcohol (PVA) solution of 100ml prepared fresh is added in the beaker of 600ml.Speed with 2000rpm stirred PVA solution 30 minutes.Dripping polymer/dichloromethane solution in PVA solution uses Fisher DYNA-MIX agitator to stir with the speed of 2000rpm simultaneously.Restir solution was 3 hours after adding was finished.Be transferred to microspheres solution in having of some 50mL of the graduated disposable polypropylene conical centrifuge tube and centrifugalize 10 minutes under the speed of 2600rpm.Water-yielding stratum and use deionized water with microsphere suspendible once more comes down in torrents.Centrifugalize, come down in torrents and once more the step of suspendible repeat 3 times.The microsphere of blended washing is transferred in the centrifuge tube, freezing in acetone/the dry ice bath, lyophilizing then.After the step of freeze drying in a vacuum with microsphere further dry about 24 hours.
Embodiment 8
The microsphere (50-100 micron) that contains indomethacin by the method preparation of oil-in-water emulsion
By identical operations among the embodiment 7, use the stir speed (S.S.) of 1%PVA solution and 500rpm to prepare the microsphere that mean size is about the 50-100 micron.
Embodiment 9
The microsphere for preparing the load heparin by the method for W/O/W
Be added to heparin (20 to 40mg) in the 750 μ L deionized waters and vortex vibration 2 minutes.200mg PLGA (85: 15, Absorbable Polymers International) is dissolved in the 7ml dichloromethane.In dichloromethane solution, add this aqueous pharmaceutical solution and use POLYTRON homogenizer (4 grades of speed) emulsifying mixture 20 seconds.Add this solution in the 50ml5%PVA solution and use POLYTRON homogenizer (2 grades of speed) emulsifying 10 seconds.Dilute resulting double emulsion then in 100ml 1%PVA solution, this system of electromagnetic agitation 3 hours is so that make the dichloromethane evaporation.Be transferred to microspheres solution in having of some 50mL of the graduated disposable polypropylene conical centrifuge tube and centrifugalize 10 minutes under the speed of 2600rpm.Water-yielding stratum and use deionized water with microsphere suspendible once more comes down in torrents.Centrifugalize, come down in torrents and once more the step of suspendible repeat 3 times.The microsphere of blended washing is transferred in the centrifuge tube, freezing in acetone/the dry ice bath, lyophilizing then.After the step of freeze drying in a vacuum with microsphere further dry about 24 hours.
Embodiment 10
The microsphere for preparing the load dextran sulfate by the method for W/O/W
Dextran sulfate (20mg) is added in the 750 μ L deionized waters and vortex vibration 2 minutes.200mg PDLLA (Absorbable Polymers International) is dissolved in the 7ml dichloromethane.In dichloromethane solution, add this aqueous HI solution and use POLYTRON homogenizer (4 grades of speed) emulsifying mixture 20 seconds.In 50ml 5%PVA solution, add this solution and use Polytron homogenizer (2 grades of speed) emulsifying 10 seconds.Dilute resulting double emulsion then in 100ml 1%PVA solution, this system of electromagnetic agitation 3 hours is so that make the dichloromethane evaporation.Be transferred to microspheres solution in having of some 50mL of the graduated disposable polypropylene conical centrifuge tube and centrifugalize 10 minutes under the speed of 2600rpm.Water-yielding stratum and use deionized water with microsphere suspendible once more comes down in torrents.Centrifugalize, come down in torrents and once more the step of suspendible repeat 3 times.The microsphere of blended washing is transferred in the centrifuge tube, freezing in acetone/the dry ice bath, lyophilizing then.After the step of freeze drying in a vacuum with microsphere further dry about 24 hours.
Embodiment 11
The microsphere of load fucoidin
200mg PLGA (85: 15, Absorbable Polymers International) is dissolved in the 7ml dichloromethane.The 2g fucoidin is placed the cryogrinding pipe and use 6850Freezer/Mill (AST Scientific) to carry out cryogrinding.In polymer solution, add the fucoidin that 40mg grinds.Use POLYTRON homogenizer (model PT6100) with this solution homogenization.5% polyvinyl alcohol (PVA) solution of 100ml prepared fresh is added in the beaker of 600ml.Speed with 2000rpm stirred PVA solution 30 minutes.Dripping polymer/dichloromethane solution in PVA solution uses Fisher DYNA-MIX agitator to stir with the speed of 2000rpm simultaneously.Restir solution was 3 hours after adding was finished.Be transferred to microspheres solution in having of some 50mL of the graduated disposable polypropylene conical centrifuge tube and centrifugalize 10 minutes under the speed of 2600rpm.Water-yielding stratum and use deionized water with microsphere suspendible once more comes down in torrents.Centrifugalize, come down in torrents and once more the step of suspendible repeat 3 times.The microsphere of blended washing is transferred in the centrifuge tube, freezing in acetone/the dry ice bath, lyophilizing then.After the step of freeze drying in a vacuum with microsphere further dry about 24 hours.
Embodiment 12
The microsphere for preparing the load Aurothiomalate by the method for W/O/W
Hydration Kidon (Ono) [Aldrich, cat:157201] (20 to 40mg) is added in the 750 μ L deionized waters and vortex vibration 2 minutes.200mg PLGA (85: 15, Absorbable Polymers International) is dissolved in the 7ml dichloromethane.In dichloromethane solution, add this aqueous pharmaceutical solution and use POLYTRON homogenizer (4 grades of speed) emulsifying mixture 20 seconds.In 50ml 5%PVA solution, add this solution and use POLYTRON homogenizer (2 grades of speed) emulsifying 10 seconds.Dilute resulting double emulsion then in 100ml 1%PVA solution, this system of electromagnetic agitation 3 hours is so that make the dichloromethane evaporation.Be transferred to microspheres solution in having of some 50mL of the graduated disposable polypropylene conical centrifuge tube and centrifugalize 10 minutes under the speed of 2600rpm.Water-yielding stratum and use deionized water with microsphere suspendible once more comes down in torrents.Centrifugalize, come down in torrents and once more the step of suspendible repeat 3 times.The microsphere of blended washing is transferred in the centrifuge tube, freezing in acetone/the dry ice bath, lyophilizing then.After the step of freeze drying in a vacuum with microsphere further dry about 24 hours.
Embodiment 13
The microsphere for preparing the load fucoidin by spray drying
3.6g poly-(D, L-lactide-co-Acetic acid, hydroxy-, bimol. cyclic ester) [PLGA] (85: 15, AbsorbablePolymers International) is dissolved in the 200ml dichloromethane.The 2g fucoidin is placed the freeze grinding pipe and use 6850Freezer/Mill (AST Scientific) to carry out cryogrinding.In polymer solution, add the fucoidin that 400mg grinds.Use POLYTRON homogenizer (model PT6100) with the solution homogenization.Use the desk-top spray dryer of Buchi gained solution to be carried out spray drying and stir polymer solution not precipitating to guarantee fucoidin.The parameter of the spray dryer that uses is as follows: 50 ℃ of inlet temperatures, outlet temperature＜39 ℃, getter 100%, flow velocity 700l/hr.Under the room temperature in a vacuum with the microsphere collected dry night, to obtain the uniform spherical particle of magnitude range less than about 10 microns (normally about 0.5 to 2 microns).
Embodiment 14
The SYNVISC of load HI
The 3mL that packs into of respectively microsphere of the load HI of 20mg such as embodiment 6-13 preparation being weighed has in the 3mL syringe of end cap.Piston is put into syringe and syringe is inverted.Remove end cap and piston is pushed into 0.1ml scale place.Cover end cap.Use the 2mL syringe that the double syringe adapter will contain SYNVISC to be connected with the syringe that contains microsphere.Then SYNVISC is transferred to also to shift once more in another syringe from a syringe and gets back in the original syringe, repeat at least 20 times.In case the SYNVISC/ mixture of microspheres is arranged in initial syringe, syringe is pulled down from the double syringe adapter, and said preparation be ready to operable.
Embodiment 15
The hyaluronic acid orthopaedic implant of working load HI prevents intervertebral disc operation or laminectomy
After the method for scarring
The hyaluronic acid implant that comprises the hyaluronic acid inhibitor is used in intervertebral disc or the laminectomy operation to form cicatrix and to avoid oppressing spinal nerve root around spinal nerve root avoiding, thereby reduces postoperative pain and other neurological symptoms result.In this sign,, will contain containing of Hyaluronidase inhibitor hyaluronic compositions and be injected in the tissue around the spinal nerve root as the part of the operation technique that reduces besieged spinal nerves pressure.
Be prepared as follows hyaluronic acid-Hyaluronidase inhibitor material:
1. following preparation contains 2ml hyaluronic acid (SYNVISC for example; HYLAN G-F 20 (Genzyme Biosurgery, Ridgefield, NJ)-should be noted that, also can use the HA in other source, for example RESTYLANE, HYLAFORM, PERLANE, SEPRAFILM, SEPRACOAT, INTERGEL and LUBRICOAT) the 2.25ml glass syringe to contain Hyaluronidase inhibitor:
A. use Aurothiomalate as Hyaluronidase inhibitor, this reagent is introduced slow release induction system (for example in the polymer microballoon described in the embodiment 7) so that in hyaluronic acid, obtain the Aurothiomalate concentration (being about to the Aurothiomalate that 10mg altogether is included in the microsphere is introduced among the SYNVISC of 2ml) of 5mg/ml.Should be appreciated that the about 0.2mg extremely Aurothiomalate of about 100mg scope is clinical useful, but 10mg is a preferred dosage.
B. use indomethacin as Hyaluronidase inhibitor, this reagent is introduced slow release induction system (for example in the polymer microballoon described in the embodiment 5,6 and 7) so that in hyaluronic acid, obtain the indomethacin concentration (being about to the indomethacin that 2mg altogether is included in the microsphere is introduced among the SYNVISC of 2ml) of 1mg/ml.Should be appreciated that the about 0.2mg extremely indomethacin of about 20mg scope is clinical useful, but 2mg is a preferred dosage.
C. use propylene glycol as Hyaluronidase inhibitor, this reagent is introduced slow release induction system (for example in the polymer microballoon described in the embodiment 6 to 13) so that in hyaluronic acid, obtain the propylene glycol concentration (being about to the propylene glycol that 20mg altogether is included in the microsphere is introduced among the SYNVISC of 2ml) of 10mg/ml.Should be appreciated that the about 0.5mg extremely propylene glycol of about 200mg scope is clinical useful, but 20mg is a preferred dosage.
D. use dextran sulfate as Hyaluronidase inhibitor, this reagent is introduced slow release induction system (for example in the polymer microballoon described in the embodiment 10) so that in hyaluronic acid, obtain the dextran sulfate concentration (being about to the dextran sulfate that 20mg altogether is included in the microsphere is introduced among the SYNVISC of 2ml) of 10mg/ml.Should be appreciated that the about 0.5mg extremely dextran sulfate of about 200mg scope is clinical useful, but 20mg is a preferred dosage.
E. use fucoidin to be Hyaluronidase inhibitor, this reagent is introduced slow release induction system (for example in the polymer microballoon described in the embodiment 11 and 13) so that in hyaluronic acid, obtain the fucoidin concentration (being about to the fucoidin that 10mg altogether is included in the microsphere is introduced among the SYNVISC of 2ml) of 5mg/ml.Should be appreciated that the about 0.2mg extremely fucoidin of about 100mg scope is clinical useful, but 10mg is a preferred dosage.
F. use heparin as Hyaluronidase inhibitor, this reagent is introduced slow release induction system (for example in the polymer microballoon described in the embodiment 9) so that in hyaluronic acid, obtain the heparin concentration (being about to the heparin that 2mg altogether is included in the microsphere is introduced among the SYNVISC of 2ml) of 1mg/ml.Should be appreciated that the about 0.2mg extremely heparin of about 100mg scope is clinical useful, but 2mg is a preferred dosage.
2. with SYNVISC/ microsphere hyaluronic acid inhibitor material sterilization and use following method to patient's administration.In the whole surgery operation, must adopt strict aseptic medicine-feeding technology.
The open operation that alleviates the spinal nerves upward pressure is usually directed to excise disruptive waist and pushes away intercalated disc (and part is around the bone of spinal nerve root-be also referred to as laminectomy).Under general anesthesia, the patient is placed the position of kneeling of change.The back midline carry out otch and with tissue dissection so that expose suitable space; Cut ligamenta flava and in some cases, remove part bone thin plate so that obtain enough visuals field.Pull out fragment that nerve root goes out with the hernia that exposes in the ring and damaged carefully.Usually, enter disc cavity and use pituitary forceps that the fragment of vertebral pulp is removed by the tear place in the ring.Also remove carefully and be isolated in the intervertebral disc space or any other fragment that intervertebral disc space is outer and thoroughly clean intervertebral disc space to remove any residual fragment.If the crack in pachymeninx, occurs, use warp Fibrin Glue commonly used to carry out enhanced suture so and sew up pachymeninx.Use absorbable suture to come suture tissue then.
As another selection with respect to open operation, micro-discectomy (micro-diskectomy) can be used as that out-patient operation is carried out and is chosen in as the intervention that hernia goes out intervertebral disc and replaced laminectomy to a great extent.Cut 1 inch otch between the spinous process under from the spinous process on the affected intervertebral disc to this affected intervertebral disc.Use operating microscope, tissue dissection is removed to ligamenta flava and from thin plate boned until can clearly discerning nerve root.Retract nerve root carefully and make crack in the ring under amplifying as seen.Use little intervertebral disc tweezers to remove the intervertebral disc fragment and remove any isolated intervertebral disc fragment by the crack in the ring.Laminectomy is the same with using, and cleans intervertebral disc space to remove any intervertebral disc fragment, repairs any pachymeninx crack and uses the absorbable suture suture tissue.Should be noted that, can use (abdominal part) method of front side that open with lumbar discectomy endoscope.The class of operation of the excision of neck and thoracic disc and waist like and can use the method (use laminectomy) of dorsal part or use and have the front side diskectomy that merges otch.
Unfortunately, in any case the operation that undergos surgery, in a large amount of patients, the postoperative scarization in the tissue of nerve root has applied pressure to nerve, has caused stimulation, and causes pain recurrence and other neurological symptoms result.In order to reduce the incidence rate of this complication, in open operation or micro-diskectomy, use the perineural zone of HA/ microsphere Hyaluronidase inhibitor implant (above-mentioned) infiltration.HA-Hyaluronidase inhibitor (HI) implant prevents that adjacent tissue from contacting with nerve and prevents that scar tissue is around formation on the spinal nerves and final pressure ridge nerve.Described HA-HI implant can reduce the incidence rate of spinal operation failure, prevents pain recurrence and other neurological symptoms result, and reduces and carry out the intervention of repetition surgery to remove the needs of scar tissue.
Embodiment 16
The hyaluronic acid surgical adhesions barrier of working load HI suppresses the method for surgical adhesions
The hyaluronic acid preparation that will contain HI is delivered to the surface of target tissue or organ; Especially in abdominal part or gynecilogical operation operating process to prevent that adhesion from forming.The HI of slow release form is added to contains in the hyaluronic surgical adhesions barrier (for example thin film, gel or spray), with the degradation rate that reduces HA and the activity in vivo that prolongs compositions/implant to surpassing when using HA separately.
The part that adhesion can be used as any operation technique takes place, but is considered to the ileac main inducing of abdominal postoperative and is gynecologic surgery pain and sterile main inducing.Though in fact organ can be the site of adhesion, female genital tract (particularly fallopian tube) and intestinal (small intestinal and large intestine) especially are easy to form adhesion.
In order in endoscope and open operation operation, to prevent adhesion, prepare hyaluronic acid-Hyaluronidase inhibitor adhesion barrier material in accordance with the following methods:
1. for endoscopic procedure, be prepared as follows 2ml fluid hyaluronic acid (SEPRAGEL; Hyaluronate sodium/the carboxymethyl cellulose of chemical modification, from Genzyme Biosurgery (Ridgefield, NJ) absorbable adhesion barrier-should be noted that, also can use the HA in other source, for example RESTYLANE, HYLAFORM, PERLANE, SEPRACOAT, INTERGEL and LUBRICOA) to contain Hyaluronidase inhibitor:
A. use Aurothiomalate as Hyaluronidase inhibitor, this reagent is introduced slow release induction system (for example in the polymer microballoon described in the embodiment 12) so that in hyaluronic acid, obtain the Aurothiomalate concentration (being about to the Aurothiomalate that 10mg altogether is included in the microsphere is introduced among the SEPRAGEL of 2ml) of 5mg/ml.Should be appreciated that about 0.2mg is clinical useful to the Aurothiomalate of about 100mg scope, still about 10mg is a preferred dosage.
B. use indomethacin as Hyaluronidase inhibitor, this reagent is introduced slow release induction system (for example in the polymer microballoon described in the embodiment 6,7 and 8) so that in hyaluronic acid, obtain the indomethacin concentration (being about to the indomethacin that 2mg altogether is included in the microsphere is introduced among the SEPRAGEL of 2ml) of 1mg/ml.Should be appreciated that about 0.2mg is clinical useful to the indomethacin of about 20mg scope, still about 2mg is a preferred dosage.
C. use propylene glycol as Hyaluronidase inhibitor, this reagent is introduced slow release induction system (for example in the polymer microballoon described in the embodiment 6 to 13) so that in hyaluronic acid, obtain the propylene glycol concentration (being about to the propylene glycol that 20mg altogether is included in the microsphere is introduced among the SEPRAGEL of 2ml) of 10mg/ml.Should be appreciated that about 0.5mg is clinical useful to the propylene glycol of about 200mg scope, still about 20mg is a preferred dosage.
D. use dextran sulfate as Hyaluronidase inhibitor, this reagent is introduced slow release induction system (for example in the polymer microballoon described in the embodiment 5) so that in hyaluronic acid, obtain the dextran sulfate concentration (being about to the dextran sulfate that 20mg altogether is included in the microsphere is introduced among the SEPRAGEL of 2ml) of 10mg/ml.Should be appreciated that about 0.5mg is clinical useful to the dextran sulfate of about 200mg scope, still about 20mg is a preferred dosage.
E. use fucoidin to be Hyaluronidase inhibitor, this reagent is introduced slow release induction system (for example in the polymer microballoon described in the embodiment 6 and 8) so that in hyaluronic acid, obtain the fucoidin concentration (being about to the fucoidin that 10mg altogether is included in the microsphere is introduced among the SEPRAGEL of 2ml) of 5mg/ml.Should be appreciated that about 0.2mg is clinical useful to the fucoidin of about 100mg scope, still about 10mg is a preferred dosage.
F. use heparin as Hyaluronidase inhibitor, this reagent is introduced slow release induction system (for example in the polymer microballoon described in the embodiment 4) so that in hyaluronic acid, obtain the heparin concentration (being about to the heparin that 2mg altogether is included in the microsphere is introduced among the SEPRAGEL of 2ml) of 1mg/ml.Should be appreciated that about 0.2mg is clinical useful to the heparin of about 100mg scope, still about 2mg is a preferred dosage.
2. for open operation operation, can use the HA thin film that contains Hyaluronidase inhibitor and can be prepared as follows: the hyaluronic acid thin film (SEPRAFILM of preparation 3 " * 5 " or 5 " * 6 "; Hyaluronate sodium/the carboxymethyl cellulose of chemical modification, from Genzyme Biosurgery, Ridgefield, the absorbable adhesion barrier of NJ-should be noted that, also can use the HA thin film in other source, for example INTERCEED) to contain Hyaluronidase inhibitor:
A. use Aurothiomalate as Hyaluronidase inhibitor, this reagent is introduced slow release induction system (for example in the polymer microballoon described in the embodiment 12) in case obtain containing in the hyaluronic acid thin film per square inch the 0.5mg Aurothiomalate concentration (be about to 7.5mg altogether be included in the SEPRAFILM sheet that Aurothiomalate in the microsphere is introduced into 3 " * 5 " or altogether the Aurothiomalate that is included in the microsphere of 15mg be introduced in the SEPRAFILM sheet of 5 " * 6 ").Should be appreciated that containing the 0.01mg that has an appointment per square inch in the hyaluronic acid thin film is clinical useful to the Aurothiomalate of about 5mg, still about 0.5mg/sq.in is a preferred dosage.
B. use indomethacin as Hyaluronidase inhibitor, this reagent is introduced slow release induction system (for example in the polymer microballoon described in the embodiment 5,6 and 7) in case obtain containing in the hyaluronic acid thin film per square inch the 1mg indomethacin concentration (be about to 15mg altogether be included in the SEPRAFILM sheet that indomethacin in the microsphere is introduced into 3 " * 5 " or altogether the indomethacin that is included in the microsphere of 30mg be introduced in the SEPRAFILM sheet of 5 " * 6 ").Should be appreciated that containing the 0.01mg that has an appointment per square inch in the hyaluronic acid thin film is clinical useful to the indomethacin of about 5mg, still about 1mg/sq.in is a preferred dosage.
C. use propylene glycol as Hyaluronidase inhibitor, this reagent is introduced slow release induction system (for example in the polymer microballoon described in the embodiment 6 to 13) in case obtain containing in the hyaluronic acid thin film per square inch the 1mg propylene glycol concentration (be about to 15mg altogether be included in the SEPRAFILM sheet that propylene glycol in the microsphere is introduced into 3 " * 5 " or altogether the propylene glycol that is included in the microsphere of 30mg be introduced in the SEPRAFILM sheet of 5 " * 6 ").Should be appreciated that containing the 0.01mg that has an appointment per square inch in the hyaluronic acid thin film is clinical useful to the propylene glycol of about 20mg, still about 1mg/sq.in is a preferred dosage.
D. use dextran sulfate as Hyaluronidase inhibitor, this reagent is introduced slow release induction system (for example in the polymer microballoon described in the embodiment 10) in case obtain containing in the hyaluronic acid thin film per square inch the 1mg dextran sulfate concentration (be about to 15mg altogether be included in the SEPRAFILM sheet that dextran sulfate in the microsphere is introduced into 3 " * 5 " or altogether the dextran sulfate that is included in the microsphere of 30mg be introduced in the SEPRAFILM sheet of 5 " * 6 ").Should be appreciated that containing the 0.01mg that has an appointment per square inch in the hyaluronic acid thin film is clinical useful to the dextran sulfate of about 20mg, still about 1mg/sq.in is a preferred dosage.
E. use fucoidin as Hyaluronidase inhibitor, this reagent is introduced slow release induction system (for example in the polymer microballoon described in the embodiment 11 and 13) in case obtain containing in the hyaluronic acid thin film per square inch the 0.5mg fucoidin concentration (be about to 7.5mg altogether be included in the SEPRAFILM sheet that fucoidin in the microsphere is introduced into 3 " * 5 " or altogether the fucoidin that is included in the microsphere of 15mg be introduced in the SEPRAFILM sheet of 5 " * 6 ").Should be appreciated that containing the 0.005mg that has an appointment per square inch in the hyaluronic acid thin film is clinical useful to the fucoidin of about 10mg, still about 0.5mg/sq.in is a preferred dosage.
F. use heparin as Hyaluronidase inhibitor, this reagent is introduced slow release induction system (for example in the polymer microballoon described in the embodiment 9) in case obtain containing in the hyaluronic acid thin film per square inch the 0.1mg heparin concentration (be about to 1.5mg altogether be included in the SEPRAFILM sheet that heparin in the microsphere is introduced into 3 " * 5 " or altogether the heparin that is included in the microsphere of 3.0mg be introduced in the SEPRAFILM sheet of 5 " * 6 ").Should be appreciated that containing the 0.001mg that has an appointment per square inch in the hyaluronic acid thin film is clinical useful to the heparin of about 5mg, still about 0.1mg/sq.in is a preferred dosage.
3. with HA/ microsphere Hyaluronidase inhibitor material sterilization and use following method to patient's administration.In the whole surgery operation, must adopt strict aseptic medicine-feeding technology.
Because the quantity of potential applicable suitable operation technique is very big, so describe general therapeutic laparoscopy and laparotomy.Intra-operative is cut, cleans or the abdominal part mesentery of processing and the adhesion barrier (as above-mentioned gel or thin film) of pelvic organs application load HI.For endoscopic procedure, preferably carry sprayable type preparation (for example liquid or gel) by the side opening of endoscope.For the open operation operation, to the intraperitoneal organizations HI-HA sheet of damage.In any case, operative region should be as much as possible the dry and thorough excessive fluid of sucking-off.
For the HI-HA thin film, use dry instrument and/or glove lightly film to be cut into desired size and shape.Expose the film of 1-2cm by the open end of product medium-height trestle.If desired, by bending film/support lightly or film/support is curved arch assist it to enter abdominopelvic cavity.Avoid during use contacting, until being applied directly on the site with tissue surface.If come in contact, can lightly film be removed from unexpected tissue surface by appropriate use standard flush liquid so.By using exsiccant glove or device lightly film to be pushed downwards, thereby make the barrier of exposure at first stick to desired locations on tissue or the organ, remove support then.Fully enlarging barrier makes its edge that surpasses otch and associated operation wound so that realize enough coverings.If desired, use standard flush liquid lightly the moistening barrier cover around profile of tissue or organ with auxiliary its.Make have between the single barrier enough overlapping to guarantee complete, the successive covering on wound tissue surface.Should use surgical standard technique to close up abdominopelvic cavity.
In the hyaluronic acid adhesion barrier, add Hyaluronidase inhibitor make barrier work in vivo for more time and be reduced in adjacent organs or tissue between form the probability of scar tissue.The HI-HA implant can reduce the incidence rate and/or the seriousness of the adhesion that abdominal part and gynecologic surgery may form.The adhesion guard can be avoided pain, intestinal obstruction and sterile generation, and reduces and carry out the repeat surgery intervention to remove the needs of scar tissue.Should be noted that, the surgical adhesions barrier that contains HI-HA can be used for multiple operation technique, comprise abdominal operation, gynecological and operation on pelvis, spinal operation, operation on heart, tendon and peripheral nervous operation and Dou Shoushu.
Embodiment 17
The hyaluronic acid implant of working load HI is come the damaged method of augmenting soft tissue
The HA-HI implant be used to moderate to degree of depth dermal transplantation to correct moderate to severe facial wrinkles and pleat.The injectable hyaluronic acid compositions that contains Hyaluronidase inhibitor (HI) can cause the activity in vivo of durability of prolongation (promptly reducing the degradation rate of HA) and prolongation compositions extremely to surpass when using HA separately, reduces reinjected subsequently number of times.
Be prepared as follows the hyaluronic acid-Hyaluronidase inhibitor material that is used for the corium injection:
1. prepare to contain 0.5ml or the 1.0ml implant material (can be from Q-Med AB, Sweden obtains, and is stable and be suspended in the physiological buffer of pH=7 and concentration is the RESTYLANE hyaluronic acid derivatives material of 20mg/ml) the medicine-carried glass syringe to contain Hyaluronidase inhibitor and this medicine-carried glass syringe installed aseptic thin scale syringe needle (30G * 1/2 ").Should be noted that, also can use the HA in other source, for example HYLAFORM (Genzyme Corporation), PERLANE, SEPRAGEL and INTERGEL.Following hyaluronidase is introduced in this HA injectable agent:
A. use Aurothiomalate as Hyaluronidase inhibitor, this reagent is introduced slow release induction system (for example in the polymer microballoon described in the embodiment 12) so that in hyaluronic acid, obtain the Aurothiomalate concentration (being about to the Aurothiomalate that 5mg altogether is included in the microsphere is introduced among the RESTYLANE of 1ml) of 5mg/ml.Should be appreciated that about 0.2mg is clinical useful to the Aurothiomalate of about 100mg scope, still about 5mg is a preferred dosage.
B. use indomethacin as Hyaluronidase inhibitor, this reagent is introduced slow release induction system (for example in the polymer microballoon described in the embodiment 6,7 and 8) so that in hyaluronic acid, obtain the indomethacin concentration (being about to the indomethacin that 1mg altogether is included in the microsphere is introduced among the RESTYLANE of 1ml) of 1mg/ml.Should be appreciated that about 0.2mg is clinical useful to the indomethacin of about 20mg scope, still about 1mg is a preferred dosage.
C. use propylene glycol as Hyaluronidase inhibitor, this reagent is introduced slow release induction system (for example in the polymer microballoon described in the embodiment 6 to 13) so that in hyaluronic acid, obtain the propylene glycol concentration (being about to the propylene glycol that 10mg altogether is included in the microsphere is introduced among the RESTYLANE of 1ml) of 10mg/ml.Should be appreciated that about 0.5mg is clinical useful to the propylene glycol of about 200mg scope, still about 10mg is a preferred dosage.
D. use dextran sulfate as Hyaluronidase inhibitor, this reagent is introduced slow release induction system (for example in the polymer microballoon described in the embodiment 10) so that in hyaluronic acid, obtain the dextran sulfate concentration (being about to the dextran sulfate that 10mg altogether is included in the microsphere is introduced among the RESTYLANE of 1ml) of 10mg/ml.Should be appreciated that about 0.5mg is clinical useful to the dextran sulfate of about 200mg scope, still about 10mg is a preferred dosage.
E. use fucoidin to be Hyaluronidase inhibitor, this reagent is introduced slow release induction system (for example in the polymer microballoon described in the embodiment 11 and 13) so that in hyaluronic acid, obtain the fucoidin concentration (being about to the fucoidin that 5mg altogether is included in the microsphere is introduced among the RESTYLANE of 1ml) of 5mg/ml.Should be appreciated that about 0.2mg is clinical useful to the fucoidin of about 100mg scope, still about 5mg is a preferred dosage.
F. use heparin as Hyaluronidase inhibitor, this reagent is introduced slow release induction system (for example in the polymer microballoon described in the embodiment 9) so that in hyaluronic acid, obtain the heparin concentration (being about to the heparin that 1mg altogether is included in the microsphere is introduced among the RESTYLANE of 1ml) of 1mg/ml.Should be appreciated that about 0.2mg is clinical useful to the heparin of about 100mg scope, still about 1mg is a preferred dosage.
3. with RESTYLANE/ microsphere Hyaluronidase inhibitor material sterilization and use following method to patient's administration.In the whole surgery operation, must adopt strict aseptic medicine-feeding technology.
The patient is placed the table back of the body seat of inclination a little.The pain management that evaluate patient is required.If desired, use partial lignocaine and/or prilocaine to anaesthetize.Use the zone that ethanol or other suitable antiseptic solution are cleared up needs treatment.
By thin scale syringe needle (30g or 32g) with the administration of RESTYLANE-HI implant.For treatment each time, the common consumption in each treatment site is lower than 2mL.Before injection, the piston rod that pushes syringe carefully is until observing droplet in the tip of syringe needle.Insert syringe needle to parallel about 30 ° of angles with wrinkle or pleat.Should be up and described material should be injected into the middle part of corium in the inclined-plane of syringe needle.Mid-dermis is settled, and the syringe needle profile should be visible but should not see its color.If RESTYLANE-HI injection too dark or to intramuscular, Zuo Yong persistent period will shorten so.If the RESTYLANE-HI injection is too shallow, can cause visible fritter and/or ash gray fading so.
Evenly push piston rod and use the RESTYLANE-HI implant, slowly pull back syringe needle simultaneously.Wrinkle should be raised and eliminate injecting at the end.Importantly, should be shortly just syringe needle pull out and stop injection before the skin to avoid material and leak or to terminate in the skin shallow excessively.
Importantly, only correct the volumetric of 100% expectation and excessively do not correct.For the contoured skin defective, if the manual position that is stretched to its elimination of defective can be able to be obtained optimal results so.Corrigent degree and persistent period are depended on defects property, the structural stress in implant site, the degree of depth and the injection technique of implant in tissue of needs treatment.Tangible hardened defective be difficult to corrigent.
Injection technique and dosage about injection depth can change.Successful Application linear suturing skill, the continuously combination of puncture injection or said two devices.
After injection was finished, the massage treatment site made it conform to the profile of surrounding tissue lightly.If excessive rectification has taken place, so firmly massage the zone between the finger or head on following surperficial bone and exert oneself massage so that obtain optimal results.
If observed so-called " bleaching ", promptly surface skin turns white, and should stop injection so immediately and massage this zone becoming normal color again until it.
If wrinkle needs further treatment, repeat same operation at some skin site place so, until obtaining satisfied result.May need to use the RESTYLANE-HI implant to carry out extra treatment to realize the rectification of expectation.For the patient who suffers from local swelling, be difficult to when treatment, estimate the rectification degree sometimes.In these cases, after 1 to 2 week of treatment, preferably invite patient's further consultation.
If the swelling immediately of treatment back area for treatment so can this site of short time ice compress.The patient may have slight injection site reaction to moderate, can disappear in a couple of days usually.
Can comprise with the example that HI combination is used for other suitable commodity HA product of face-lifting injection: from Meiji Seika Kaisha, the ACHYAL of Ltd. (Japan), from the JUVEDERM of L.E.A.Derm (France), from the MACDERMOL of Laboratoires O.R.GE V.MacDermol (France) and from the ROFILAN Hylan Gel of Rofil Medical International (Holland).The HA-HI compositions can also comprise anesthetis, for example lignocaine, benzocaine or prilocaine and/or neurotoxin, and described neurotoxin for example is a Botulinum toxin.
Embodiment 18
The hyaluronic method of working load HI in operated eye
In operated eye, contain the hyaluronic acid solution of Hyaluronidase inhibitor and intraocular lens's collaborative use of insertion.
The visco-elastic material for preparing load HI by mixed transparent matter acid enzyme inhibitor and hyaluronic acid.Multiple HA eye product can make up with Hyaluronidase inhibitor.For example, AMVISC, AMVISC PLUS and OCUCOAT (Bausch ﹠amp; Lomb) be the high-molecular weight viscoelasticity injectable HA solution that in cataract extraction, corneal transplantation and operation for glaucoma, is used to keep eye shape and the accurate tissue of protection.Eye based on HA comprises PROVIS, VISCOAT, DUOVISC and CELLUGEL from Alcon Laboratories with the viscoelasticity product; From Pharmacia ﹠amp; The HEALON of Upjohn, HEALON G and HEALON 5; VITRAX from Allergan; BIOLON from Bio-Technology General; STAARVISC from Anika Therapeutics/Staar Surgical; From the SHELLGEL of Anika Therapeutics/Cytosol Opthalmics and from the UNIVISC of Novartis.
Though any above-mentioned HA product all is potential operable, in following examples, use following method that HEALON GV (from Advanced Medical Optics) is made up with Hyaluronidase inhibitor:
1. prepare to contain HEALON GV (Advanced Medical Optics; Every mlHEALON GV contains 14mg hyaluronate sodium 7000) disposable 0.85ml or the 0.55ml glass syringe to contain Hyaluronidase inhibitor:
A. use Aurothiomalate as Hyaluronidase inhibitor, this reagent is introduced slow release induction system (for example in the polymer microballoon described in the embodiment 12) so that in hyaluronic acid, obtain the Aurothiomalate concentration (being about to the Aurothiomalate that 4.25mg altogether is included in the microsphere is introduced among the HEALON GV of 0.85ml) of 5mg/ml.Should be appreciated that about 0.2mg is clinical useful to the Aurothiomalate of about 100mg scope, still about 4.25mg is a preferred dosage.
B. use indomethacin as Hyaluronidase inhibitor, this reagent is introduced slow release induction system (for example in the polymer microballoon described in the embodiment 6,7 and 8) so that in hyaluronic acid, obtain the indomethacin concentration (being about to the indomethacin that 0.85mg altogether is included in the microsphere is introduced among the HEALON GV of 0.85ml) of 1mg/ml.Should be appreciated that about 0.05mg is clinical useful to the indomethacin of about 20mg scope, still about 0.85mg is a preferred dosage.
C. use propylene glycol as Hyaluronidase inhibitor, this reagent is introduced slow release induction system (for example in the polymer microballoon described in the embodiment 6 to 13) so that in hyaluronic acid, obtain the propylene glycol concentration (being about to the propylene glycol that 8.5mg altogether is included in the microsphere is introduced among the HEALON GV of 0.85ml) of 10mg/ml.Should be appreciated that about 0.5mg is clinical useful to the propylene glycol of about 200mg scope, still about 8.5mg is a preferred dosage.
D. use dextran sulfate as Hyaluronidase inhibitor, this reagent is introduced slow release induction system (for example in the polymer microballoon described in the embodiment 10) so that in hyaluronic acid, obtain the dextran sulfate concentration (being about to the dextran sulfate that 8.5mg altogether is included in the microsphere is introduced among the HEALON GV of 0.85ml) of 10mg/ml.Should be appreciated that about 0.5mg is clinical useful to the dextran sulfate of about 200mg scope, still about 8.5mg is a preferred dosage.
E. use fucoidin as Hyaluronidase inhibitor, this reagent is introduced slow release induction system (for example in the polymer microballoon described in the embodiment 11 and 13) so that in hyaluronic acid, obtain the fucoidin concentration (being about to the fucoidin that 4.25mg altogether is included in the microsphere is introduced among the HEALON GV of 0.85ml) of 5mg/ml.Should be appreciated that about 0.2mg is clinical useful to the fucoidin of about 100mg scope, still about 4.25mg is a preferred dosage.
F. use heparin as Hyaluronidase inhibitor, this reagent is introduced slow release induction system (for example in the polymer microballoon described in the embodiment 9) so that in hyaluronic acid, obtain the heparin concentration (being about to the heparin that 0.85mg altogether is included in the microsphere is introduced among the HEALON GV of 0.85ml) of 1mg/ml.Should be appreciated that about 0.05mg is clinical useful to the heparin of about 100mg scope, still about 0.85mg is a preferred dosage.
2. with HEALON GV/ microsphere Hyaluronidase inhibitor material sterilization and use following method to patient's administration.In the whole surgery operation, must adopt strict aseptic medicine-feeding technology.
The viscoelastic solution of HA be used as organize the volume of keeping tear in lubricant and the operation within the eye (for example transplant pioneering operation, intraocular lens, retina is put again, in phacoemulsification operation, corneal transplantation and the glaucoma filtration surgery as Vitrea substitute).Usually, in vitreous chamber, slowly introduce the HI-HEALON of q.s by the syringe of being furnished with 27 scale casings.By guiding this injection, for the release of safety excision and traction, HI-HEALON can be used to film (for example preretinal membrane) is separated from retina.HEALON can also be used to transfer the position of tissue to expectation, for example pushes back the retina that comes off lightly or launches the retina lobe, and auxiliaryly keep retina and leave sclera so that put again.
Embodiment 19
The hyaluronic acid implant of working load HI is handled the method for osteoarthritis
Carry the hyaluronic acid compositions that contains Hyaluronidase inhibitor to handle (reducing pain, stiff, swelling) to intraarticular with the symptom of carrying out osteoarthritis.The activity in vivo that the existence of HI is controlled hyaluronic degradation rate and prolonged compositions to surpass when using HA separately (for example in many patients consistent surpass 6 months and in some patient above 1 year).
Can be by Hyaluronidase inhibitor and hyaluronic acid be made up the intraarticular hyaluronic acid for preparing load HI.Multiple HA intraarticular product can make up with Hyaluronidase inhibitor.The material of many commercially available HA of containing is suitable for the combination with HI, comprises SYNVISC, ORTHOVISC, HYALGAN (from Fidia/Sanofi-Synthelabo) and HPS and SUPARTZ.Should be noted that some HA product (especially Boehringer IngelheimVetmedica, St.Joseph, the HYVISC of MO) is used for veterinary's application (normally treating osteoarthritis and the limping of horse).
Though any above-mentioned HA product all is potential operable, in following examples, use following method that SYNVISC and Hyaluronidase inhibitor are made up:
1. prepare to contain 2ml hyaluronic acid (SYNVISC; From the Hylan G-F 20 of Genzyme Biosurgery, the perhaps HA in other source, for example DUROLANE) the 2.25ml glass syringe to comprise Hyaluronidase inhibitor:
A. use Aurothiomalate as Hyaluronidase inhibitor, this reagent is introduced slow release induction system (for example in the polymer microballoon described in the embodiment 12) so that in hyaluronic acid, obtain the Aurothiomalate concentration (being about to the Aurothiomalate that 10mg altogether is included in the microsphere is introduced among the SYNVISC of 2ml) of 5mg/ml.Should be appreciated that about 0.2mg is clinical useful to the Aurothiomalate of about 100mg scope, still about 10mg is a preferred dosage.
B. use indomethacin as Hyaluronidase inhibitor, this reagent is introduced slow release induction system (for example in the polymer microballoon described in the embodiment 6,7 and 8) so that in hyaluronic acid, obtain the indomethacin concentration (being about to the indomethacin that 2mg altogether is included in the microsphere is introduced among the SYNVISC of 2ml) of 1mg/ml.Should be appreciated that about 0.2mg is clinical useful to the indomethacin of about 20mg scope, still about 2mg is a preferred dosage.
C. use propylene glycol to do, this reagent is introduced slow release induction system (for example in the polymer microballoon described in the embodiment 6 to 13) so that in hyaluronic acid, obtain the propylene glycol concentration (being about to the propylene glycol that 20mg altogether is included in the microsphere is introduced among the SYNVISC of 2ml) of 10mg/ml as Hyaluronidase inhibitor.Should be appreciated that the about 0.5mg extremely propylene glycol of about 200mg scope is clinical useful, but about 20mg preferred dosage.
D. use dextran sulfate as Hyaluronidase inhibitor, this reagent is introduced slow release induction system (for example in the polymer microballoon described in the embodiment 10) so that in hyaluronic acid, obtain the dextran sulfate concentration (being about to the dextran sulfate that 20mg altogether is included in the microsphere is introduced among the SYNVISC of 2ml) of 10mg/ml.Should be appreciated that about 0.5mg is clinical useful to the dextran sulfate of about 200mg scope, still about 20mg is a preferred dosage.
E. use fucoidin as Hyaluronidase inhibitor, this reagent is introduced slow release induction system (for example in the polymer microballoon described in the embodiment 11 and 13) so that in hyaluronic acid, obtain the fucoidin concentration (being about to the fucoidin that 10mg altogether is included in the microsphere is introduced among the SYNVISC of 2ml) of 5mg/ml.Should be appreciated that about 0.2mg is clinical useful to the fucoidin of about 100mg scope, still about 10mg is a preferred dosage.
F. use heparin as Hyaluronidase inhibitor, this reagent is introduced slow release induction system (for example in the polymer microballoon described in the embodiment 9) so that in hyaluronic acid, obtain the heparin concentration (being about to the heparin that 2mg altogether is included in the microsphere is introduced among the SYNVISC of 2ml) of 1mg/ml.Should be appreciated that about 0.2mg is clinical useful to the heparin of about 100mg scope, still about 2mg is a preferred dosage.
2. with SYNVISC/ microsphere Hyaluronidase inhibitor material sterilization and use following method to patient's administration.In the whole surgery operation, must adopt strict aseptic medicine-feeding technology.
The hyaluronic acid compositions that will contain Hyaluronidase inhibitor is injected into articular cavity to handle kneed osteoarthritis.Use ethanol or other suitable antiseptic solution wiping injection site before the injection.Before injection HA-HI implant, remove synovial fluid or sepage.Must use different syringes to remove the SYNVISC of synovial fluid and injection load HI.Yet, should use identical syringe needle.Use strict aseptic manipulation, the HA-HI implant is injected into knee joint by 18 to 22 scale syringe needles.Leak in order to ensure tight sealing and when avoiding administration, firmly fix syringe needle, the luer hub syringe of holding steadily simultaneously.When syringe needle being installed and removing needle guard, do not answer tension or excessively reverse, because this may make the tip of syringe break.When using the SYNVISC-HI treatment, not injecting narcotic or any other medicines in the knee joint intrinsic articulation.This may dilute implant material and influence its safety and effectiveness.
The syringe that contains HI-SYNVISC is disposable.After syringe takes out, use the material in the syringe immediately from packing.Whole 2ml only are injected in the knee joint.If treatment is both sides, must use independent syringe for each knee so.Abandon any untapped material.(be separated by a week) once in a week by intra-articular injection the administration of HA-HI implant, carry out three injections altogether and treat the knee pain osteoarthritis.
Those skilled in the art are apparent, use similar method to give described material to other joint (for example shoulder, hip, ankle, wrist etc.) and other species (horse, Canis familiaris L., cat etc.).
Embodiment 20
The hyaluronic acid filler of working load HI is handled the method for urinary incontinence
The HA filler of working load HI carries out urethra week and transurethral injection can be used for the treatment of urinary incontinence.The HA of load HI injection can reduce the speed of implant degraded and prolong its activity in vivo to surpassing when using HA separately (consistent in most of patients surpass 1 year), so that keep the active of implant and reduce needs and frequency to urethra is all and per urethra is injected subsequently.
DEFLUX is being that (it constitutes biocompatible and biodegradable implant to the stable hyaluronic acid carrier gel of inanimacy for NASHA, 17mg/ml) the aseptic high-viscosity gel (50mg/ml) of the dextranomer microsphere in.The size of dextranomer microsphere is the 80-250 micron, and mean size is about 130 microns.NASHA mainly as carrier, makes the dextranomer microsphere be positioned at the implant site.DEFLUX (Q-Med/Priority Healthcare) provides with the asepsis injector that the disposable single that contains 1ml uses, and is suitable for following method and Hyaluronidase inhibitor combination:
1. following preparation contains the syringe of 1ml DEFLUX to comprise Hyaluronidase inhibitor:
A. use Aurothiomalate as Hyaluronidase inhibitor, this reagent is introduced slow release induction system (for example in the polymer microballoon described in the embodiment 12 or introduce in the dextranomer microsphere) so that in hyaluronic acid, obtain the Aurothiomalate concentration (being about to the Aurothiomalate that 5mg altogether is included in the microsphere is introduced among the DEFLUX of 1ml) of 5mg/ml.Should be appreciated that about 0.2mg is clinical useful to the Aurothiomalate of about 100mg scope, still about 5mg is a preferred dosage.
B. use indomethacin as Hyaluronidase inhibitor, this reagent is introduced slow release induction system (for example in the polymer microballoon described in the embodiment 6,7 and 8) so that in hyaluronic acid, obtain the indomethacin concentration (being about to the indomethacin that 1mg altogether is included in the microsphere is introduced among the DEFLUX of 1ml) of 1mg/ml.Should be appreciated that about 0.2mg is clinical useful to the indomethacin of about 20mg scope, still about 1mg is a preferred dosage.
C. use propylene glycol as Hyaluronidase inhibitor, this reagent is introduced slow release induction system (for example in the polymer microballoon described in the embodiment 6 to 13 or introduce in the dextranomer microsphere) so that in hyaluronic acid, obtain the propylene glycol concentration (being about to the propylene glycol that 10mg altogether is included in the microsphere is introduced among the DEFLUX of 1ml) of 10mg/ml.Should be appreciated that about 0.5mg is clinical useful to the propylene glycol of about 200mg scope, still about 10mg is a preferred dosage.
D. use dextran sulfate as Hyaluronidase inhibitor, this reagent is introduced slow release induction system (for example in the polymer microballoon described in the embodiment 10 or introduce in the dextranomer microsphere) so that in hyaluronic acid, obtain the dextran sulfate concentration (being about to the dextran sulfate that 10mg altogether is included in the microsphere is introduced among the DEFLUX of 1ml) of 10mg/ml.Should be appreciated that about 0.5mg is clinical useful to the dextran sulfate of about 200mg scope, still about 10mg is a preferred dosage.
E. use fucoidin to be Hyaluronidase inhibitor, this reagent is introduced slow release induction system (for example in the polymer microballoon described in the embodiment 11 and 13 or introduce in the dextranomer microsphere) so that in hyaluronic acid, obtain the fucoidin concentration (being about to the fucoidin that 5mg altogether is included in the microsphere is introduced among the DEFLUX of 1ml) of 5mg/ml.Should be appreciated that about 0.2mg is clinical useful to the fucoidin of about 100mg scope, still about 5mg is a preferred dosage.
F. use heparin as Hyaluronidase inhibitor, this reagent is introduced slow release induction system (for example in the polymer microballoon described in the embodiment 9 or introduce in the dextranomer microsphere) so that in hyaluronic acid, obtain the heparin concentration (being about to the heparin that 1mg altogether is included in the microsphere is introduced among the DEFLUX of 1ml) of 1mg/ml.Should be appreciated that about 0.2mg is clinical useful to the heparin of about 100mg scope, still about 1mg is a preferred dosage.
2. with DEFLUX/ microsphere Hyaluronidase inhibitor material sterilization and use following method to patient's administration.
The per urethra injection of the DEFLUX compositions of load HI can be carried out according to following method.That use contains 1 milliliter of implant material and have a thin scale syringe needle nonrecoverable prefilled syringe of (having the 23 graduated per urethra injection needles of stablizing intubate).The patient placed the lithotomy clinostatism to put and 2% lignocaine of 10ml is injected into urethra anaesthetize.For the women, use cystoscope to observe neck of bladder.By cystoscopic injection port, insert pin in the position at 4 o'clock at distance neck of bladder 1-1.5cm place with acute angle, until just arriving below the mucous membrane of urinary bladder plane.Use cystoscope that pin is advanced along the urethra major axis then, until arriving below the neck of bladder mucosa.Slow DEFLUX to this site injection load HI.Then in the repetitive operation of the position at 8 o'clock.Can add visual with auxiliary injection of methylene blue or other non-toxicity stain to implant.
The urethra week injection of the DEFLUX compositions of load HI can be carried out according to following method.Use contains 1 milliliter of implant material and nonrecoverable prefilled syringe that have thin scale syringe needle (urethra week injection needle).The patient placed the lithotomy position and 2% lignocaine of 10ml is injected into urethra anaesthetize, and use cystoscope to observe neck of bladder (, can observe urethra) by cystoscope method on the pubis for the male.Insert the next-door neighbour and the side regions of urethra with the pin transvaginal or on pubic arch.When near the correct position the pin arrival neck of bladder (cystoscope is as seen as mentioned above), slow HA to this site injection load HI.Can add visual with auxiliary injection of methylene blue or other non-toxicity stain to implant.
Embodiment 21
The hyaluronic acid filler of working load HI is handled the method for fecal incontinence
Fecal incontinence be common and social activity can not morbid state, its influence is up to 11% North America adult.Multiple factor can cause the incontinence of wind or feces, but more common among the women, and its anal sphincter can be impaired in childbirth (those women of prolonged labor when especially suffering from three grades of vaginas and tearing, need tweezers, the big baby of childbirth and/or vaginal delivery).Though the etiology of fecal incontinence often is multifactorial, inducement comprises (defecation opposing, dull-witted, the intellectual retardation) of sphincter damage (obstetrics, surgery, accident), anorectal disease (hemorrhoid, proctoptosis, inflammatory bowel, fistula, tumor, colectomy, fecal impaction, diarrhoea), inborn (spina bifida, outstanding, the Hirshsprung disease of meninges), idiopathic or behavior.Passive fecal incontinence (being to take place under patient's situation about not discovering) mainly is because the dysfunction of sphincter ani internus, and fecal incontinence (can not independently suppress defecation) initiatively is normally because the dysfunction of external anal sphincter.The HA compositions of load HI can be injected into internal sphincter or external sphincter zone on every side to increase sphincteral pressure and to reduce fecal incontinence.The HA injection of working load HI can be kept the active of implant and reduce needs and the frequency that crissum is injected.
DEFLUX is that (it constitutes biocompatible and biodegradable implant for NASHA, 17mg/ml) the aseptic high-viscosity gel (50mg/ml) of the dextranomer microsphere in for stable transparent matter acid vectors gel at inanimacy.The size of dextranomer microsphere is the 80-250 micron, and mean size is about 130 microns.NASHA mainly as carrier, makes the dextranomer microsphere be positioned at the implant site.DEFLUX (Q-Med/Priority Healthcare) provides with the asepsis injector that the disposable single that contains 1ml uses, and is suitable for following method and Hyaluronidase inhibitor combination:
1. the 1ml syringe of following preparation DEFLUX is to comprise Hyaluronidase inhibitor:
A. use Aurothiomalate as Hyaluronidase inhibitor, this reagent is introduced slow release induction system (for example in the polymer microballoon described in the embodiment 12 or introduce in the dextranomer microsphere) so that in hyaluronic acid, obtain the Aurothiomalate concentration (being about to the Aurothiomalate that 5mg altogether is included in the microsphere is introduced among the DEFLUX of 1ml) of 5mg/ml.Should be appreciated that the about 0.2mg extremely Aurothiomalate of about 100mg scope is clinical useful, but 5mg is a preferred dosage.
B. use indomethacin as Hyaluronidase inhibitor, this reagent is introduced slow release induction system (for example in the polymer microballoon described in the embodiment 6,7 and 8) so that in hyaluronic acid, obtain the indomethacin concentration (being about to the indomethacin that 1mg altogether is included in the microsphere is introduced among the DEFLUX of 1ml) of 1mg/ml.Should be appreciated that the about 0.2mg extremely indomethacin of about 20mg scope is clinical useful, but 1mg is a preferred dosage.
C. use propylene glycol as Hyaluronidase inhibitor, this reagent is introduced slow release induction system (for example in the polymer microballoon described in the embodiment 6 to 13 or introduce in the dextranomer microsphere) so that in hyaluronic acid, obtain the propylene glycol concentration (being about to the propylene glycol that 10mg altogether is included in the microsphere is introduced among the DEFLUX of 1ml) of 10mg/ml.Should be appreciated that the about 0.5mg extremely propylene glycol of about 200mg scope is clinical useful, but 10mg is a preferred dosage.
D. use dextran sulfate as Hyaluronidase inhibitor, this reagent is introduced slow release induction system (for example in the polymer microballoon described in the embodiment 10 or introduce in the dextranomer microsphere) so that in hyaluronic acid, obtain the dextran sulfate concentration (being about to the dextran sulfate that 10mg altogether is included in the microsphere is introduced among the DEFLUX of 1ml) of 10mg/ml.Should be appreciated that the about 0.5mg extremely dextran sulfate of about 200mg scope is clinical useful, but 10mg is a preferred dosage.
E. use fucoidin as Hyaluronidase inhibitor, this reagent is introduced slow release induction system (for example in the polymer microballoon described in the embodiment 11 and 13 or introduce in the dextranomer microsphere) so that in hyaluronic acid, obtain the fucoidin concentration (being about to the fucoidin that 5mg altogether is included in the microsphere is introduced among the DEFLUX of 1ml) of 5mg/ml.Should be appreciated that the about 0.2mg extremely fucoidin of about 100mg scope is clinical useful, but 5mg is a preferred dosage.
F. use heparin as Hyaluronidase inhibitor, this reagent is introduced slow release induction system (for example in the polymer microballoon described in the embodiment 9 or introduce in the dextranomer microsphere) so that in hyaluronic acid, obtain the heparin concentration (being about to the heparin that 1mg altogether is included in the microsphere is introduced among the DEFLUX of 1ml) of 1mg/ml.Should be appreciated that the about 0.2mg extremely heparin of about 100mg scope is clinical useful, but 1mg is a preferred dosage.
2. with DEFLUX/ microsphere Hyaluronidase inhibitor material sterilization and use following method to patient's administration.
Use following method under endoscopic observation by direct injection with the administration of HI-DEFLUX implant.Use contains 1 milliliter of implant material and nonrecoverable prefilled syringe that have thin scale syringe needle.According to selected injection areas, 2% lignocaine of about 10ml is injected into perineal skin or mucous membrane of rectum.Pin is passed the mucosa lower plane of skin or mucous membrane of rectum insertion encirclement anal sphincter.When pin reaches suitable position, to the site slowly inject load HI HA (usually around, pass sphincter, enter but away from 3 injections of anus edge punishment and at the linea anocutanea place or above linea anocutanea, locate injection just) until around anal canal, forming symmetry.Can add visual with auxiliary injection of methylene blue or other non-toxicity stain to implant.
Embodiment 22
Hyaluronic degraded: GPC molecular weight analyse
The influence of using gel permeation chromatography (GPC) to analyze (GPC molecular weight analyse) to determine that different chemical compounds degrade in time to hyaluronic acid (reduction of the hyaluronan molecule amount that causes with hyaluronidase cutting is represented).
Method:
The GPC system that uses in the analysis is the computerized GPC device of BREEZE (WatersCorporation, Milford, MA), this device is furnished with ULTRAHYDROGEL 1000 and ULTRAHYDROGEL 2000 (WatersCorporation) post that refractive index detects and contacts.Make water as mobile phase, its speed is per minute 1ml.Volume injected is 50 μ l, and be 25 minutes running time.
The use molecular weight is 11,000 to 2 megadaltons polysaccharide standard (PolymerLaboratories; Church Stretton, UK) logarithm of preparing with molecular weight is the linear calibration curve of the residence time of function.
To have molecular weight and be 200 ten thousand to 300 50 ten thousand daltonian hyaluronic acids (hyaluronate sodium, Lifecore, Chaska MN), to be diluted to concentration in water be 0.5%w/v.(Sigma Chemical Co.St Louis MO) is diluted to every milliliter 1000 unit and add suitable volume to realize the ultimate density of expectation with hyaluronidase in water.In all experiments, between 15 hours incubation period, use the hyaluronidase of every milliliter 100 unit.Under concentration was every milliliter 100 unit, enzyme was reduced to 100,000 dalton with molecular weight by 200 50 ten thousand in 5 hours.In each experiment, be that the HA (contain and do not contain 100 units/ml enzyme) of 0.1%w/v is with comparing with the concentration in the water.
The result:
Tested following compounds to determine its effect: heparin (sodium salt), Aurothiomalate, carboxymethyl cellulose, dextran sulfate, fucoidin to the hyaluronic acid degradation that causes by hyaluronidase.Directly inhibitor is added in the sample solution, or the small size concentrated solution of inhibitor is added in the sample solution.Each hyaluronic degraded that all suppresses to cause in 5 test compounds by hyaluronidase.
Having tested concentration is the heparin (sodium salt, Sigma Chemical Co.) of 1mg/ml, 0.5mg/ml, 0.25mg/ml and 0.1mg/ml.In each test concentrations, heparin has all suppressed hyaluronic degraded.Even when being low to moderate the concentration of 0.1mg/ml, the molecular weight of HA is reduced to by about 300 40 ten thousand that about 200 40 ten thousand (table 5, Fig. 5), this shows and has suppressed about 70% degraded.
Table 5
Sample A MW (% of HA value)
HA contrast 100
HA/ enzyme contrast 2.5
Heparin 1mg/ml 87
Heparin 0.5mg/ml 96
Heparin 0.25mg/ml 96
Heparin 0.1mg/ml 71
Concentration be the degraded that suppressed to surpass 50% HA of the Aurothiomalate (sodium salt, Sigma Chemical Co.) of 10mM, 5mM, 2.5mM and 1mM (table 6, Fig. 6).
Table 6
Sample B MW (% of HA value)
HA contrast 100
HA/ enzyme contrast 5
Aurothiomalate 10mM 62
Aurothiomalate 5mM 51
Aurothiomalate 2.5mM 59
Aurothiomalate 1mM 51
Concentration is that 0.05 to 1mg/ml carboxymethyl cellulose (Fisher Scientific) has suppressed the degraded that caused by hyaluronidase.Hatch the hyaluronic molecular weight in back still near 200 25 ten thousand original value (table 7, Fig. 7).
Table 7
Sample C MW (% of HA value)
HA contrast 100
HA/ enzyme contrast 3
CMC?1mg/ml 71
CMC?0.5mg/ml 100
CMC?0.1mg/ml 92
CMC?0.05mg/ml 100
Concentration be 0.05 to 1mg/ml dextran sulfate (Sigma Chemical Co.) suppressed hyaluronic degraded (table 8, Fig. 8).
Table 8
Sample D MW (% of HA value)
HA contrast 25
HA/ enzyme contrast 4
Glucosan 1mg/ml 94
Glucosan 0.8mg/ml 93
Glucosan 0.1mg/ml 100
Glucosan 0.05mg/ml 86
Concentration be 0.5 to 5mg/ml fucoidin (Sigma Chemical Co.) suppressed hyaluronic degraded (table 9, Fig. 9).
Table 9
Sample E MW (% of HA value)
HA contrast 100
HA/ enzyme contrast 2
Fucoidin 4.98mg/ml 100
Fucoidin 2.65mg/ml 83
Fucoidin 1.16mg/ml 100
Fucoidin 0.05mg/ml 100
Therefore, should be appreciated that, though this paper has described particular of the present invention for illustrative purposes, can carry out various modifications and without departing from the spirit and scope of the present invention.Therefore, the present invention only is subjected to the restriction of claims.

Claims (129)

1. compositions, it comprises hyaluronic acid, gold compound and polymer, and wherein said gold compound suppresses hyaluronic degraded.
2. compositions as claimed in claim 1, the inductive hyaluronic degraded of wherein said chemical compound inhibitory enzyme.
3. compositions as claimed in claim 2, wherein said enzyme is a hyaluronidase.
4. compositions as claimed in claim 1, wherein said gold compound are organic gold compounds.
5. compositions as claimed in claim 1, wherein said gold compound are Aurothiomalate or its analog or derivant.
6. compositions, it comprises hyaluronic acid, contains the polysaccharide and the polymer of sulfuric ester, and the wherein said polysaccharide that contains sulfuric ester suppresses hyaluronic degraded.
7. compositions as claimed in claim 6, the wherein said inductive hyaluronic degraded of polysaccharide inhibitory enzyme that contains sulfuric ester.
8. compositions as claimed in claim 7, wherein said enzyme is a hyaluronidase.
9. compositions as claimed in claim 6, the wherein said polysaccharide that contains sulfuric ester is a fucosan.
10. compositions as claimed in claim 9, wherein said fucosan are fucoidin or its analog or derivant.
11. compositions as claimed in claim 6, the wherein said polysaccharide that contains sulfuric ester are dextran sulfate or its analog or derivant.
12. compositions as claimed in claim 6, the wherein said polysaccharide that contains sulfuric ester are heparin or its analog or derivant.
13. compositions, it comprises hyaluronic acid and indomethacin or its analog or derivant, and wherein said indomethacin suppresses hyaluronic degraded.
14. compositions as claimed in claim 13, the inductive hyaluronic degraded of wherein said indomethacin inhibitory enzyme.
15. compositions as claimed in claim 14, wherein said enzyme is a hyaluronidase.
16. compositions, it comprises hyaluronic acid and polymer, and wherein said polymer suppresses hyaluronic degraded.
17. compositions as claimed in claim 16, the inductive hyaluronic degraded of wherein said polymer inhibitory enzyme.
18. compositions as claimed in claim 17, wherein said enzyme is a hyaluronidase.
19. comprising, compositions as claimed in claim 16, wherein said polymer have (O-CH (CH 3The lactic acid residue of the structure of)-CO-).
20. comprising, compositions as claimed in claim 16, wherein said polymer have (OCH 2CH 2-) ethylene oxide residue of structure.
21. compositions as claimed in claim 16, wherein said polymer comprise polylactic acid-co-Polyethylene Glycol (PLA-PEG).
22. compositions as claimed in claim 16, wherein said polymer comprise poly-(L-lactic acid)-co-methoxy poly (ethylene glycol) (MePEG-PLLA) (60: 40).
23. compositions as claimed in claim 16, wherein said polymer comprise poly-(lactic acid-co-glycolic)-co-Polyethylene Glycol (PLGA-PEG).
24. compositions as claimed in claim 16, wherein said polymer comprise polycaprolactone-co-Polyethylene Glycol (PCL-PEG).
25. compositions as claimed in claim 16, wherein said polymer is a mixture of polymers.
26. compositions as claimed in claim 16, wherein said polymer are the mixture of polylactic acid-co-Polyethylene Glycol (PLA-PEG) and poly-(L-lactic acid)-co-methoxy poly (ethylene glycol) (MePEG-PLLA).
27. compositions as claimed in claim 16 wherein also comprises gold compound.
28. compositions, it comprises hyaluronic acid and chemical compound, and described chemical compound is selected from the copolymer of sorbitan ester and oxirane and epoxypropane polymer, and wherein said chemical compound suppresses hyaluronic degraded.
29. compositions as claimed in claim 28, the inductive hyaluronic degraded of wherein said chemical compound inhibitory enzyme.
30. compositions as claimed in claim 29, wherein said enzyme is a hyaluronidase.
31. compositions, it comprises hyaluronic acid and chemical compound, and described chemical compound is selected from Polyethylene Glycol, propylene glycol, octylphenol ethoxylate and carboxymethyl cellulose (CMC), and wherein said chemical compound suppresses hyaluronic degraded.
32. compositions as claimed in claim 31, the inductive hyaluronic degraded of wherein said chemical compound inhibitory enzyme.
33. compositions as claimed in claim 32, wherein said enzyme is a hyaluronidase.
34. compositions, it comprises hyaluronic acid and chemical compound, described chemical compound is selected from the β-(1 of kaempferol, sulfuric acid acidation, 4)-four galactoside, polygynax, myricetin, phloretin, Quercetin, silymarin, glycyrrhizin, tranilast, baicalin, traxanox, isoliquiritigenin, disodium cromoglycate, flavanone-7-sodium sulfate and 5-flavonol-7-sodium sulfate, wherein said chemical compound suppresses hyaluronic degraded.
35. compositions as claimed in claim 34, the inductive hyaluronic degraded of wherein said chemical compound inhibitory enzyme.
36. compositions as claimed in claim 35, wherein said enzyme is a hyaluronidase.
37. compositions, it comprises hyaluronic acid and chemical compound, described chemical compound is selected from vitamin C, aescine, tranilast, traxanox, the Caulis Hederae Sinensis sapogenin, guanidine hydrochloride, the L-arginine, norlignane, urolithin B, glycyrrhizin, baicalin, isoliquiritigenin, disodium cromoglycate (DSCG), 7-sulphuric acid chrysin, flavanone-7-sodium sulfate, 5-flavonol-7-sodium sulfate, 1-(2-hydroxyl-4, the 6-Dimethoxyphenyl)-3-(4-methoxyphenyl) acetone, 1-(2-hydroxyl-4, the 6-Dimethoxyphenyl)-3-(4-chlorphenyl) acetone, 7-fluoro-4 '-flavonol-4 '-chloro-4,6-dimethoxy chalcone derivative, luteolin, morin, myricetin, fenoprofen, Kidon (Ono), the phosphorylation Hesperidin, Echinacea Species, rosmarinic acid, sulfonic acid acidifying β-(1 with sulfonation degree of 0.2 to 1,4)-and breast-oligosaccharide (n=2-6), wherein said chemical compound suppresses hyaluronic degraded.
38. compositions as claimed in claim 37, the inductive hyaluronic degraded of wherein said chemical compound inhibitory enzyme.
39. compositions as claimed in claim 38, wherein said enzyme is a hyaluronidase.
40. compositions, it comprises hyaluronic acid and chemical compound, and described chemical compound is selected from condensed tannin, tannin, kaempferol and Quercetin, and wherein said chemical compound suppresses hyaluronic degraded.
41. compositions as claimed in claim 40, the inductive hyaluronic degraded of wherein said chemical compound inhibitory enzyme.
42. compositions as claimed in claim 41, wherein said enzyme is a hyaluronidase.
43. compositions, it comprises hyaluronic acid and chemical compound, described chemical compound is selected from the single lactobiose glycosides of sulfonic acid neomycin, sulfonated planetose, sulphuric acid hydroquinone digalactosyl glycosides and sulphuric acid-2-hydroxyphenyl, and wherein said chemical compound suppresses hyaluronic degraded.
44. compositions as claimed in claim 43, the inductive hyaluronic degraded of wherein said chemical compound inhibitory enzyme.
45. compositions as claimed in claim 44, wherein said enzyme is a hyaluronidase.
46. compositions, it comprises hyaluronic acid and chemical compound, described chemical compound is selected from silymarin, phloretin, Taxifolin, daidzein (4 ', the 7-dihydroxy isoflavone), Rhizoma Iridis Tectori kind aglycon (4 ', 7-dihydroxy-6-methoxyl group isoflavone), 7-sulphuric acid chrysin, 4 '-chloro-4,6-dimethoxy chalcone derivative, diphenylacrylate, diphenyl-propionic acid, 3-(4-trifluoromethyl-phenyl)-3-phenylpropionic acid, 3-(4-trifluoromethyl-phenyl)-3-phenylpropionic acid and indole-2-carboxylic acid, wherein said chemical compound suppresses hyaluronic degraded.
47. compositions as claimed in claim 46, the inductive hyaluronic degraded of wherein said chemical compound inhibitory enzyme.
48. compositions as claimed in claim 47, wherein said enzyme is a hyaluronidase.
49. as the described compositions of arbitrary claim in the claim 1 to 48, it also comprises carrier.
50. compositions as claimed in claim 49, wherein said carrier is a polymer.
51. compositions as claimed in claim 50, wherein said polymer is biodegradable.
52. compositions as claimed in claim 50, wherein said polymer right and wrong are biodegradable.
53. compositions as claimed in claim 50, wherein said polymer comprises carbohydrate, and described carbohydrate is selected from starch, cellulose and glucosan.
54. compositions as claimed in claim 50, wherein said polymer comprises protein, and described protein is selected from collagen, gelatin, Fibrinogen and albumin.
55. compositions as claimed in claim 50, wherein said polymer comprises polyester.
56. compositions as claimed in claim 55, wherein said polymer are poly-(D, L-lactide), poly-(D, L-lactide-co-Acetic acid, hydroxy-, bimol. cyclic ester) or poly-Acetic acid, hydroxy-, bimol. cyclic ester.
57. compositions as claimed in claim 50, wherein said polymer comprise the material that is selected from poly-(6-caprolactone), poly butyric ester, poly-alkyl carbonate, polyanhydride and poe.
58. compositions as claimed in claim 50, wherein said polymer comprise the material that is selected from ethylene-vinyl acetate copolymer (EVA), silicone rubber, polyurethane and acrylate copolymer or copolymer.
59. compositions as claimed in claim 50, wherein said polymer comprises Polyethylene Glycol.
60. compositions as claimed in claim 50, wherein said polymer comprise 4-arm sulfydryl PEG and 4-arm NHS PEG.
61. compositions as claimed in claim 60, wherein said polymer also comprise collagen or collagen derivant.
62. compositions as claimed in claim 61, wherein said collagen derivant is methylated collagen.
63. as the described compositions of arbitrary claim in the claim 1 to 48, it also comprises anesthetis.
64. as the described compositions of claim 63, wherein said anesthetis is prilocaine, lignocaine or benzocaine.
65. as the described compositions of arbitrary claim in the claim 1 to 48, wherein said compositions is aseptic.
66. as the described compositions of arbitrary claim in the claim 1 to 48, it also comprises ceramic material, wherein said ceramic material is selected from bata-tricalcium phosphate, hydroxyapatite, calcium carbonate, calcium sulfate, calcium phosphate, bone and removes the mineral bone.
67. as the described compositions of arbitrary claim in the claim 1 to 48, it also comprises bone morphogenetic protein or somatomedin.
68. as the described compositions of claim 67, wherein said bone morphogenetic protein is BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 or BMP-7.
69. as the described compositions of claim 67, wherein said somatomedin is fibroblast growth factor (FGF), transforming growth factor (TGF) or platelet derived growth factor (PDGF).
70. increase the method for bone or displacement wearing and tearing bone, the described compositions of claim 67 is carried in it target location that comprises the patient who handles to this class of needs.
71. reduce the method for the pain relevant with postoperative scarization, it is included in and makes during the operation technique in the claim 1 to 48 the described compositions of arbitrary claim infiltrate perineural zone.
72. prevent the method for surgical adhesions, the described compositions of arbitrary claim in the claim 1 to 48 is carried in it target location that comprises the patient who handles to this class of needs.
73. repair or increase the method for skin or tissue, it comprises in the patient's that this class of needs is handled skin or tissue injects the described chemical compound of arbitrary claim in the claim 1 to 48.
74. as the described method of claim 73, wherein said injection is injection in the labiad.
75. as the described method of claim 73, wherein said injection is to inject in the skin of face.
76. keep the method for tear volume during the operated eye, it carries the described compositions of arbitrary claim in the claim 1 to 48 to ophthalmic during being included in operated eye.
77. as the described method of claim 76, wherein said operated eye is that pioneering operation, intraocular lens are implanted, retina is put again, phacoemulsification operation, corneal transplantation or glaucoma filtration surgery.
78. reduce the method for the pain relevant with osteoarthritis, it comprises in the patient's that this class of needs is handled joint injects the described compositions of arbitrary claim in the claim 1 to 48.
79. the method for treatment gastroesophageal reflux disease, it comprises injects the described compositions of arbitrary claim in the claim 1 to 48 near patient's LES.
80. the method for treatment or prevention urinary incontinence, it comprises the described compositions of arbitrary claim in the claim 1 to 48 to patient's administration of described treatment of needs or prevention, so that treat or prevent described urinary incontinence.
81. as the described method of claim 80, wherein with described compositions urethra week administration.
82. as the described method of claim 80, wherein with the administration of described compositions per urethra.
83. the method for treatment or prevention fecal incontinence, it comprises near the described compositions of the arbitrary claim administration patient's anus sphincter in the claim 1 to 48, so that treat or prevent described fecal incontinence.
84. medical implant, it comprises filler, and wherein said filler comprises hyaluronic acid and suppresses the chemical compound of described hyaluronic acid degradation.
85. as the described medical implant of claim 84, prescription is for handling the form of GERD.
86. as the described medical implant of claim 84, prescription is for handling the form of fecal incontinence.
87. as the described medical implant of claim 84, prescription is for handling the form of urinary incontinence.
88. as the described implant of claim 84, wherein said chemical compound is selected from Aurothiomalate, indomethacin, propylene glycol, heparin, dextran sulfate, fucoidin and carboxymethyl cellulose.
89. as the described implant of claim 84, wherein said chemical compound is selected from β-(1,4)-four galactoside, polygynax, luteolin, myricetin, phloretin, Quercetin, silymarin, glycyrrhizin, tranilast, baicalin, traxanox, isoliquiritigenin, disodium cromoglycate, flavanone-7-sodium sulfate and the 5-flavonol-7-sodium sulfate of kaempferol, sulfuric acid acidation.
90. medical treatment device, it comprises its medical implant, the quilt that compositions is wrapped of involved hyaluronic acid of wherein said implant and gold compound, and wherein said gold compound suppresses hyaluronic degraded.
91. as the described medical treatment device of claim 90, wherein said gold compound is organic gold compound.
92. as the described medical treatment device of claim 90, wherein said gold compound is Aurothiomalate or its analog or derivant.
93. medical treatment device, it comprises its medical implant, the quilt that compositions is wrapped of involved hyaluronic acid of wherein said implant and indomethacin or its analog or derivant, and wherein said indomethacin suppresses hyaluronic degraded.
94. medical treatment device, it comprises its medical implant, involved hyaluronic acid of wherein said implant and the quilt that compositions is wrapped that contains the polysaccharide of sulfuric ester, and the wherein said polysaccharide that contains sulfuric ester suppresses hyaluronic degraded.
95. as the described medical treatment device of claim 94, the wherein said polysaccharide that contains sulfuric ester is a fucosan.
96. as the described medical treatment device of claim 94, wherein said fucosan is fucoidin or its analog or derivant.
97. as the described medical treatment device of claim 94, the wherein said polysaccharide that contains sulfuric ester is dextran sulfate or its analog or derivant.
98. as the described medical treatment device of claim 94, the wherein said polysaccharide that contains sulfuric ester is heparin or its analog or derivant.
99. medical treatment device, it comprises its medical implant, the quilt that compositions is wrapped of involved hyaluronic acid of wherein said implant and polymer, and wherein said polymer suppresses hyaluronic degraded.
100. as the described medical treatment device of claim 99, wherein said polymer comprises and has (O-CH (CH 3The lactic acid residue of the structure of)-CO-).
101. as the described medical treatment device of claim 99, wherein said polymer comprises and has (OCH 2CH 2-) ethylene oxide residue of structure.
102. as the described medical treatment device of claim 99, wherein said polymer comprises polylactic acid-co-Polyethylene Glycol (PLA-PEG).
103. as the described medical treatment device of claim 99, wherein said polymer comprises poly-(L-lactic acid)-co-methoxy poly (ethylene glycol) (MePEG-PLLA) (60: 40).
104. as the described medical treatment device of claim 99, wherein said polymer comprises poly-(lactic acid-co-glycolic)-co-Polyethylene Glycol (PLGA-PEG).
105. as the described medical treatment device of claim 99, wherein said polymer comprises polycaprolactone-co-Polyethylene Glycol (PCL-PEG).
106. as the described medical treatment device of claim 99, wherein said polymer is selected from the copolymer of sorbitan ester and oxirane and epoxypropane polymer.
107. as the described medical treatment device of claim 99, wherein said polymer is a mixture of polymers.
108. as the described medical treatment device of claim 99, wherein said polymer is the mixture of polylactic acid-co-Polyethylene Glycol (PLA-PEG) and poly-(L-lactic acid)-co-methoxy poly (ethylene glycol) (MePEG-PLLA).
109. medical treatment device, it comprises its medical implant, involved hyaluronic acid of wherein said implant and the quilt that compositions is wrapped that is selected from following material, described material is selected from Polyethylene Glycol, octylphenol ethoxylate, propylene glycol and carboxymethyl cellulose (CMC), and wherein said material suppresses hyaluronic degraded.
110. medical treatment device, it comprises medical implant, the involved hyaluronic acid of wherein said implant and be selected from following quilt that compound compositions is wrapped, described chemical compound is selected from the β-(1 of kaempferol, sulfuric acid acidation, 4)-four galactoside, polygynax, luteolin, myricetin, phloretin, Quercetin, silymarin, glycyrrhizin, tranilast, baicalin, traxanox, isoliquiritigenin, disodium cromoglycate, flavanone-7-sodium sulfate and 5-flavonol-7-sodium sulfate, wherein said chemical compound suppresses hyaluronic degraded.
111. medical treatment device, it comprises medical implant, the involved hyaluronic acid of wherein said implant and be selected from following quilt that compound compositions is wrapped, described chemical compound is selected from vitamin C, aescine, tranilast, traxanox, the Caulis Hederae Sinensis sapogenin, guanidine hydrochloride, the L-arginine, norlignane, urolithin B, glycyrrhizin, baicalin, isoliquiritigenin, disodium cromoglycate (DSCG), 7-sulphuric acid chrysin, flavanone-7-sodium sulfate, 5-flavonol-7-sodium sulfate, 1-(2-hydroxyl-4, the 6-Dimethoxyphenyl)-3-(4-methoxyphenyl) acetone, 1-(2-hydroxyl-4, the 6-Dimethoxyphenyl)-3-(4-chlorphenyl) acetone, 7-fluoro-4 '-flavonol-4 '-chloro-4,6-dimethoxy chalcone derivative, luteolin, morin, myricetin, Phenylbutazone, crovaril, fenoprofen, Kidon (Ono), the phosphorylation Hesperidin, Echinacea Species, rosmarinic acid, sulfonic acid acidifying β-(1 with sulfonation degree of 0.2 to 1,4)-and breast-oligosaccharide (n=2-6), wherein said chemical compound suppresses hyaluronic degraded.
112. medical treatment device, it comprises medical implant, the involved hyaluronic acid of wherein said implant and be selected from following quilt that compound compositions is wrapped, described chemical compound is selected from condensed tannin, tannin, kaempferol and Quercetin, and wherein said chemical compound suppresses hyaluronic degraded.
113. medical treatment device, it comprises medical implant, the involved hyaluronic acid of wherein said implant and be selected from following quilt that compound compositions is wrapped, described chemical compound is selected from the single lactobiose glycosides of sulfonic acid neomycin, sulfonated planetose, sulphuric acid hydroquinone digalactosyl glycosides and sulphuric acid-2-hydroxyphenyl, and wherein said chemical compound suppresses hyaluronic degraded.
114. medical treatment device, it comprises medical implant, the involved hyaluronic acid of wherein said implant and be selected from following quilt that compound compositions is wrapped, described chemical compound is selected from silymarin, phloretin, Taxifolin, daidzein (4 ', the 7-dihydroxy isoflavone), Rhizoma Iridis Tectori kind aglycon (4 ', 7-dihydroxy-6-methoxyl group isoflavone, 7-sulphuric acid chrysin, 4 '-chloro-4,6-dimethoxy chalcone derivative, diphenylacrylate, diphenyl-propionic acid, 3-(4-trifluoromethyl-phenyl)-3-phenylpropionic acid, 3-(4-trifluoromethyl-phenyl)-3-phenylpropionic acid and indole-2-carboxylic acid, wherein said chemical compound suppresses hyaluronic degraded.
115. as the described medical treatment device of arbitrary claim in the claim 93 to 114, wherein said compositions also comprises gold compound, wherein said gold compound suppresses hyaluronic degraded.
116. compositions, it comprises hyaluronic acid and is selected from following chemical compound: Aurothiomalate, indomethacin, fucoidin, dextran sulfate, heparin, Polyethylene Glycol, propylene glycol, carboxymethyl cellulose (CMC) and their analog and derivant, the viscosity of wherein said compositions be hyaluronic acid contrast viscosity 50% or higher, wherein use the hyaluronic acid viscosimetry to measure described viscosity.
117. compositions, it comprises hyaluronic acid and is selected from following chemical compound: the copolymer of octylphenol ethoxylate, sorbitan ester and oxirane and epoxypropane polymer, the viscosity of wherein said compositions be hyaluronic acid contrast viscosity 50% or higher, wherein use the hyaluronic acid viscosimetry to measure described viscosity.
118. compositions, it comprises hyaluronic acid and be selected from following polymer: comprise and have (O-CH (CH 3The polymer of the lactic acid residue of the structure of)-CO-), comprise and have (OCH 2CH 2-) polymer, polylactic acid-co-Polyethylene Glycol (PLA-PEG), poly-(L-lactic acid)-co-methoxy poly (ethylene glycol) (MePEG-PLLA) (60: 40), poly-(lactic acid-co-glycolic)-co-Polyethylene Glycol (PLGA-PEG), the polycaprolactone-co-Polyethylene Glycol (PCL-PEG) of the ethylene oxide residue of structure, or its mixture, the viscosity of wherein said compositions be hyaluronic acid contrast viscosity 50% or higher, wherein use the hyaluronic acid viscosimetry to measure described viscosity.
119. compositions, it comprises hyaluronic acid and is selected from following chemical compound: the β of kaempferol, sulfuric acid acidation-(1,4)-four galactoside, polygynax, luteolin, myricetin, phloretin, Quercetin, silymarin, glycyrrhizin, tranilast, baicalin, traxanox, isoliquiritigenin, disodium cromoglycate, flavanone-7-sodium sulfate and 5-flavonol-7-sodium sulfate, the viscosity of wherein said compositions be hyaluronic acid contrast viscosity 50% or higher, wherein use the hyaluronic acid viscosimetry to measure described viscosity.
120. compositions, it comprises hyaluronic acid and chemical compound, the viscosity of wherein said compositions be hyaluronic acid contrast viscosity 50% or higher, wherein use the hyaluronic acid viscosimetry to measure described viscosity, and wherein said chemical compound is selected from vitamin C, aescine, tranilast, traxanox, the Caulis Hederae Sinensis sapogenin, guanidine hydrochloride, the L-arginine, norlignane, urolithinB, glycyrrhizin, baicalin, isoliquiritigenin, disodium cromoglycate (DSCG), 7-sulphuric acid chrysin, flavanone-7-sodium sulfate, 5-flavonol-7-sodium sulfate, 1-(2-hydroxyl-4, the 6-Dimethoxyphenyl)-3-(4-methoxyphenyl) acetone, 1-(2-hydroxyl-4, the 6-Dimethoxyphenyl)-3-(4-chlorphenyl) acetone, 7-fluoro-4 '-flavonol-4 '-chloro-4,6-dimethoxy chalcone derivative, luteolin, morin, myricetin, Phenylbutazone, crovaril, fenoprofen, Kidon (Ono), the phosphorylation Hesperidin, Echinacea Species, rosmarinic acid, the acidifying β of sulfonic acid-(1,4)-breast-oligosaccharide (n=2-6) with sulfonation degree of 0.2 to 1.
121. compositions, it comprises hyaluronic acid and is selected from following chemical compound: condensed tannin, tannin, kaempferol, Quercetin and apigenin, the viscosity of wherein said compositions be hyaluronic acid contrast viscosity 50% or higher, wherein use the hyaluronic acid viscosimetry to measure described viscosity.
122. compositions, it comprises hyaluronic acid and is selected from following chemical compound: the single lactobiose glycosides of sulfonic acid neomycin, sulfonated planetose, sulphuric acid hydroquinone digalactosyl glycosides and sulphuric acid-2-hydroxyphenyl, the viscosity of wherein said compositions be hyaluronic acid contrast viscosity 50% or higher, wherein use the hyaluronic acid viscosimetry to measure described viscosity.
123. compositions, it comprises hyaluronic acid and is selected from following chemical compound: silymarin, phloretin, Taxifolin, daidzein (4 ', the 7-dihydroxy isoflavone), Rhizoma Iridis Tectori kind aglycon (4 ', 7-dihydroxy-6-methoxyl group isoflavone, 7-sulphuric acid chrysin, 4 '-chloro-4,6-dimethoxy chalcone derivative, diphenylacrylate, diphenyl-propionic acid, 3-(4-trifluoromethyl-phenyl)-3-phenylpropionic acid, 3-(4-trifluoromethyl-phenyl)-3-phenylpropionic acid and indole-2-carboxylic acid, the viscosity of wherein said compositions be hyaluronic acid contrast viscosity 50% or higher, wherein use the hyaluronic acid viscosimetry to measure described viscosity.
124. compositions, it comprises hyaluronic acid and is selected from following chemical compound: heparin (sodium salt), Kidon (Ono), carboxymethyl cellulose, dextran sulfate, fucoidin, and their analog and derivant, wherein said hyaluronic molecular weight is higher than molecular weight about 10% of hyaluronic acid contrast, wherein uses the GPC molecular weight analyse to measure described molecular weight.
125. as the described compositions of claim 125, wherein said hyaluronic molecular weight be higher than the contrast of described hyaluronic acid molecular weight about 25%.
126. as the described compositions of claim 125, wherein said hyaluronic molecular weight be higher than the contrast of described hyaluronic acid molecular weight about 50%.
127. as the described compositions of claim 125, wherein said hyaluronic molecular weight be higher than the contrast of described hyaluronic acid molecular weight about 75%.
128. as the described compositions of claim 125, wherein said hyaluronic molecular weight be higher than the contrast of described hyaluronic acid molecular weight about 90%.
129. compositions, it comprises hyaluronic acid and is selected from following chemical compound: heparin (sodium salt), Kidon (Ono), carboxymethyl cellulose, dextran sulfate, fucoidin, and their analog and derivant, wherein said chemical compound is included in the microgranule.
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