CN1109748A - Rapamycin preparation used for intravenous injection - Google Patents
Rapamycin preparation used for intravenous injection Download PDFInfo
- Publication number
- CN1109748A CN1109748A CN 94116781 CN94116781A CN1109748A CN 1109748 A CN1109748 A CN 1109748A CN 94116781 CN94116781 CN 94116781 CN 94116781 A CN94116781 A CN 94116781A CN 1109748 A CN1109748 A CN 1109748A
- Authority
- CN
- China
- Prior art keywords
- rapamycin
- injection
- concentration
- diluent
- concentrated solution
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 title claims abstract description 137
- 229960002930 sirolimus Drugs 0.000 title claims abstract description 137
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 title claims abstract description 137
- 238000002360 preparation method Methods 0.000 title claims description 18
- 238000010253 intravenous injection Methods 0.000 title claims description 9
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims abstract description 144
- 239000003085 diluting agent Substances 0.000 claims abstract description 49
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 36
- 239000000243 solution Substances 0.000 claims description 75
- 238000002347 injection Methods 0.000 claims description 62
- 239000007924 injection Substances 0.000 claims description 62
- 238000000034 method Methods 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 11
- 239000007788 liquid Substances 0.000 claims description 8
- 239000012141 concentrate Substances 0.000 abstract 1
- 210000003462 vein Anatomy 0.000 description 26
- 238000011017 operating method Methods 0.000 description 14
- 238000001914 filtration Methods 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 8
- 239000012456 homogeneous solution Substances 0.000 description 7
- 239000008215 water for injection Substances 0.000 description 7
- 239000003708 ampul Substances 0.000 description 6
- 238000007789 sealing Methods 0.000 description 6
- 239000004094 surface-active agent Substances 0.000 description 6
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical group CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 5
- 108010036949 Cyclosporine Proteins 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- 239000008389 polyethoxylated castor oil Substances 0.000 description 5
- 229920002685 Polyoxyl 35CastorOil Polymers 0.000 description 4
- 239000003978 infusion fluid Substances 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- QUANRIQJNFHVEU-UHFFFAOYSA-N oxirane;propane-1,2,3-triol Chemical compound C1CO1.OCC(O)CO QUANRIQJNFHVEU-UHFFFAOYSA-N 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- 229930105110 Cyclosporin A Natural products 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229960001265 ciclosporin Drugs 0.000 description 3
- 229930182912 cyclosporin Natural products 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 229960003444 immunosuppressant agent Drugs 0.000 description 3
- 230000001861 immunosuppressant effect Effects 0.000 description 3
- 239000003018 immunosuppressive agent Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 206010052779 Transplant rejections Diseases 0.000 description 2
- 239000004359 castor oil Substances 0.000 description 2
- 235000019438 castor oil Nutrition 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 239000003120 macrolide antibiotic agent Substances 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 229940063122 sandimmune Drugs 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000002054 transplantation Methods 0.000 description 2
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- ZEMPKEQAKRGZGQ-AAKVHIHISA-N 2,3-bis[[(z)-12-hydroxyoctadec-9-enoyl]oxy]propyl (z)-12-hydroxyoctadec-9-enoate Chemical compound CCCCCCC(O)C\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CC(O)CCCCCC)COC(=O)CCCCCCC\C=C/CC(O)CCCCCC ZEMPKEQAKRGZGQ-AAKVHIHISA-N 0.000 description 1
- 241000222122 Candida albicans Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000009386 Experimental Arthritis Diseases 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 229920002556 Polyethylene Glycol 300 Polymers 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- 229920002700 Polyoxyl 60 hydrogenated castor oil Polymers 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 241000187747 Streptomyces Species 0.000 description 1
- 241000187391 Streptomyces hygroscopicus Species 0.000 description 1
- 241001424438 Surendra Species 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 1
- 229940095731 candida albicans Drugs 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 238000002788 crimping Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 239000008355 dextrose injection Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- -1 glycerol hydroxy fatty acid Chemical class 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
Disclosed herein is an aqueous, injectable rapamycin solution comprising 40 to 75 volume percent of a concentrate solution of rapamycin in propylene glycol, at concentrations of rapamycin ranging from 0.25 mg/ml to 8 mg/ml, in combination with a diluent solution comprising water, wherein the diluent comprises 60 to 25 volume percent of the combined solution and the concentration of rapamycin in the combined solution ranges from 0.1mg/ml to 4 mg/ml.
Description
The present invention relates to be used for intravenous rapamycin formulation and preparation method thereof.Invention disclosed herein provides a kind of intravenous injection use rapamycin formulation that does not need surfactant.One aspect of the present invention comprises the mixed liquor of the concentrated solution of rapamycin in propylene glycol and the diluent of being made up of water, and its ratio is as described below.
Rapamycin is a kind of macrolide antibiotics that is produced by streptomyces hygroscopicus, and it is found owing to have antifungal character at first.It is to fungi growth has adverse effect such as candida albicans and the little spore of Gypsum Fibrosum shape be mould etc.The United States Patent (USP) 3,929,992 that December in 1975 was authorized people such as Surendra on the 30th has been described rapamycin, its preparation method and antibiosis activity thereof.1977, Martel, R.R. wait people (Canadian Journal of Physiological Pharmacology 55:48-51,1977) to report the immunosuppressant character of rapamycin to EAE and adjuvant arthritis.1989, Calne, people such as R.Y. (Lancet 2:227,1989) and Morris, R.E. and Meiser, B.M(Medicinal Science Research, 17:609-10,1989) reported rapamycin effectiveness in the transplant rejection in suppressing the heteroplastic transplantation object respectively.There are many articles to describe the immunosuppressant and the repulsion inhibition activity of rapamycin subsequently, and begun to use the clinical research that rapamycin suppresses transplant rejection in the human body.
Rapamycin is water insoluble, and the solubilizer of using always when only being slightly soluble in the preparation parenteral administration is as propylene glycol, glycerol and PEG400.It only is slightly soluble in PEG300, insoluble or atomicly is dissolved in injection aqueous cosolvent system commonly used, as 20% ethanol/water, 10%DMA/ water, 20%Cremophor EL R/ water and 20% Spheron MD 30/70/water.Owing to these reasons, but be difficult to prepare clinical practice and can business-like rapamycin injection.December in 1981 disclosed European patent on the 16th discloses 0041795 and has described a kind of injection rapamycin compositions.In this injection, earlier rapamycin being dissolved in low boiling point organic solvent is in acetone, methanol or the ethanol, then this solution is mixed with non-ionic surface active agent, and described non-ionic surface active agent is selected from the fatty acid of polyoxyethyleneization; The aliphatic alcohol of polyoxyethyleneization; The glycerol hydroxy fatty acid of polyoxyethyleneization, for example the Oleum Ricini of polyoxyethyleneization is (as Cremophor
EL) and the castor oil hydrogenated of polyoxyethyleneization (as Cremophor
RH and Cremophor
RH60).The non-ionic surface active agent that uses among the embodiment mainly is Cremophor
EL.
The main immunosuppressant that is used to suppress allosome organ-graft refection in the human body at present is cyclosporin (Sandimmune
).Cyclosporin is a kind of annular polypeptide of being made up of 11 aminoacid.Sandimmune
Intravenous injection (IV) be a kind of aseptic ampoule, every milliliter contains 50mg cyclosporin, 650mg Cremophor
EL and pure Ph Helv.(volume content are 32.9%) (in nitrogen).Face with before, this mixture to further dilute with 0.9% sodium chloride injection or 5% dextrose injection (Physicians ' Desk Reference, 45 th ed., 1991, pp1962-64, Medical Economics Company, Inc.).At present also in the clinical research that the macrolide molecule that is called FK506 is suppressed allosome organ-graft refection in the human body.FK506 and rapamycin have certain structural similarity, separate from Streptomyces tsuskubaensis, and are described in nineteen ninety and authorize in people's such as Okuhara the United States Patent (USP) 4,894,366.People such as R.Venkataramanan (Transplantation Proceedings, 22, No.1, Suppl., lpp52-56, February nineteen ninety) report, made the intravenous injection of FK506, be the 10mg/ml solution of FK506 in polyoxyethylenated castor oil (HCO-60, a kind of surfactant) and alcohol.This intravenous formulations must dilute with saline or dextrose, and infusion 1-2 hour.
The applicant now unexpectedly finds, in two parts system of rapamycin concentrated solution and diluent water, utilizes propylene glycol to make the rapamycin solubilising, just can make pharmaceutically useful rapamycin water type injection under the situation of not using surfactant.Its special benefits is to use water as the one pack system diluent, and water because of its tissue tolerance good but preferred injection diluent.In addition, also avoided sneaking into of other diluent components.Rapamycin injection of the present invention both had been suitable for bolus injection very much, was very suitable for infusion again.
One aspect of the present invention is a kind of water base rapamycin injection, and this injection comprises the concentrated solution of rapamycin in propylene glycol and the mixed liquor that contains water diluent.Specifically, the present invention is a kind of aqueous rapamycin injection, this injection comprises the 40-75%(volume) concentration be 0.25-8mg/ml the concentrated solution of rapamycin in propylene glycol with contain the water diluent mixed liquor, wherein diluent accounts for the 60-25% of mixeding liquid volume, and the concentration of rapamycin is 0.1-4mg/ml in the mixed liquor.Preferred aqueous rapamycin injection is the injection that diluent accounts for mixeding liquid volume 40-60%.Diluent preferred water, but also can contain other solvents is as the propylene glycol of a small amount of (as 10% volume or still less).
This on the one hand preferred aqueous rapamycin injection of the present invention, the concentration that is rapamycin in the propylene glycol concentrated solution is the injection of 0.5-4mg/ml.More preferably the concentration of rapamycin is the injection of 0.6-3.3mg/ml in the propylene glycol concentrated solution.The preferred aqueous rapamycin of the present invention injection also has: rapamycin concentration is the injection of 0.25-2mg/ml in the mixed liquor; And propylene glycol accounts for the injection of mixeding liquid volume 60-40%.
The particularly preferred aqueous rapamycin injection of this one side of the present invention, comprise that 40-60% rapamycin concentration is concentrated solution and the 60-40%(volume of rapamycin in propylene glycol of 0.5-4mg/ml) mixed liquor of aqueous diluent, wherein the concentration of rapamycin is 0.25-2mg/ml in the mixed liquor.
The present invention also provides the aqueous rapamycin that supplies bolus injection as mentioned above injection, and wherein the concentration of rapamycin is preferably 0.25-2mg/ml in the injection.
A second aspect of the present invention is a kind of aqueous rapamycin injection, and described injection comprises the rapamycin in the solution that is dissolved in propylene glycol and water, and wherein water accounts for the 40-75% of liquor capacity, and the concentration of rapamycin is 0.1-4mg/ml in the solution.
This on the one hand preferred aqueous rapamycin injection of the present invention is that rapamycin concentration is the injection of 0.25-1mg/ml in the solution.Independent mutually with it and also account for the injection of liquor capacity 60-40% for water preferably.
The present invention also provides a kind of product that contains rapamycin concentrated solution and diluent, this product is a kind of combination preparation, be used for before intravenous injection, mixing and obtain the solution that rapamycin concentration is 0.1-4mg/ml, described concentrated solution comprises the solution of rapamycin in propylene glycol that concentration is 0.25-8mg/ml, described diluent comprises water, the ratio of concentrated solution and diluent be 40: 60 to 75: the 25(percent by volume).
The preparation method of rapamycin vein concentrated solution comprises: be added to rapamycin in the propylene glycol and be mixed to formation solution, this process can at room temperature be carried out.Then in a known way with the solution filtration sterilization.With the concentrated solution of the proper volume ampoule of packing into, sealing in a known way then.According to the standard fabrication operating procedure of injection, in the whole process of filtration, fill and seal operation, all keep aseptic condition.The best cold preservation of rapamycin concentrated solution product.
The preparation method of each rapamycin intravenous diluents system comprises: the sterilized water of dress proper volume in phial, and then phial built, sealed and autoclaving.The rapamycin diluent of making can at room temperature be preserved or cold preservation.
Being made into the final operating procedure of medicine composition of giving comprises: a rapamycin vein concentrated solution is injected the phial that the rapamycin intravenous diluents is housed, vibrated about one minute or until forming clear solutions.The solution for preparing should administration in the specified operating period.The operating period of the rapamycin injection for preparing is that the solution for preparing keeps clarification and colourless that time.Operating period can reach 4 hours at most, but preferred 1 hour operating period at the most.
Medicinal propylene glycol obtains from various commercial undertakings easily.
Therefore, the present invention also provides a kind of method for preparing aqueous rapamycin injection, this method comprises: make the 40-75%(volume) concentration be 0.25-8mg/ml the concentrated solution of rapamycin in propylene glycol with contain water diluent and mix, wherein diluent accounts for the 60-25% of mixeding liquid volume, is 0.1-4mg/ml thereby make the concentration of rapamycin in the injection.
The following example further specifies enforcement of the present invention.
Embodiment 1
The preparation of rapamycin injection (1mg/ml)
A.2mg/ml the preparation of the vein concentrated solution of rapamycin in propylene glycol:
Prescription (density: 1.036g/ml):
Become component
Rapamycin 100% 0.2g
Propylene glycol (American Pharmacopeia level) adds to 100ml or 103.6g
Operating procedure:
1. in container, take by weighing rapamycin through suitably calibration.
2. with propylene glycol volume is transferred to 100ml.
3. be mixed to the formation homogeneous solution.
4. with solution aseptic filtration.
5. pack in ampoule or the phial and sealing.
B.1.0mg/ml rapamycin vein diluent
Prescription (density: 1.00g/ml):
Become component
Water for injection (American Pharmacopeia level) adds to 100ml or 100g
Operating procedure:
1. 1.0ml ± the 0.01ml that in the colourless phial of each 5ml, packs into, sealing and crimping.
2. autoclaving.
C.1mg/ml rapamycin intravenous fluid (preparing)
Prescription (density: 1.035g/ml)
Become component
Rapamycin vein concentrated solution 2mg/ml 1ml
Rapamycin vein diluent 1ml
Operating procedure:
1. utilize strict aseptic technique, in the phial that 1ml rapamycin vein diluent is housed, injecting 1ml concentration is 2mg/ml rapamycin vein concentrated solution.
2. vibration is to forming settled solution.
3. administration in the operating period.
Embodiment 2
The preparation of rapamycin injection (2mg/ml)
A.4mg/ml the preparation of the vein concentrated solution of rapamycin in propylene glycol:
Prescription (density: 1.036g/ml):
Become component
Rapamycin 100% 0.4g
Propylene glycol (American Pharmacopeia level) adds to 100ml or 103.6g
Operating procedure:
1. in container, take by weighing rapamycin through suitably calibration.
2. with propylene glycol volume is transferred to 100ml.
3. be mixed to the formation homogeneous solution.
4. with solution aseptic filtration.
5. pack in ampoule or the phial and sealing.
B.2mg/ml rapamycin vein diluent
Become component
Propylene glycol (American Pharmacopeia level) 10ml
Water for injection (American Pharmacopeia level) adds to 100ml or 100g
Operating procedure:
1. propylene glycol is placed suitable containers.
2. with water for injection volume is transferred to 100ml.
3. be mixed to the formation homogeneous solution.
4. with solution aseptic filtration.
5. pack.
6. autoclaving.
C.4mg/ml rapamycin intravenous fluid (preparing)
Prescription (density: 1.035g/ml)
Become component
Rapamycin vein concentrated solution 4mg/ml 1ml
Rapamycin vein diluent 1ml
Operating procedure:
1. utilize strict aseptic technique, in the phial that 1ml rapamycin vein diluent is housed, injecting 1ml concentration is 2mg/ml. rapamycin vein concentrated solution.
2. vibration is to forming settled solution.
3. administration in the operating period.
Embodiment 3
The preparation of rapamycin injection (3mg/ml)
A.6mg/ml the preparation of the vein concentrated solution of rapamycin in propylene glycol:
Prescription (density: 1.036g/ml):
Become component
Rapamycin 100% 0.6g
Propylene glycol (American Pharmacopeia level) adds to 100ml or 103.6g
Operating procedure:
1. in container, take by weighing rapamycin through suitably calibration.
2. with propylene glycol volume is transferred to 100ml.
3. be mixed to the formation homogeneous solution.
4. with solution aseptic filtration.
5. pack in ampoule or the phial and sealing.
B.3mg/ml rapamycin vein diluent.
Prescription (density: 1.00g/ml):
Become component
Propylene glycol (American Pharmacopeia level) 10ml
Water for injection (American Pharmacopeia level) adds to 100ml or 100g
Operating procedure:
1. propylene glycol is placed suitable containers.
2. with water for injection volume is transferred to 100ml.
3. be mixed to the formation homogeneous solution.
4. with solution aseptic filtration.
5. pack.
6. autoclaving.
C.3mg/ml rapamycin intravenous fluid (preparing).
Prescription (density: 1.035g/ml):
Become component
Rapamycin vein concentrated solution 6mg/ml 1ml
Rapamycin vein diluent 1ml
Operating procedure:
1. utilize strict aseptic technique, in the phial that 1ml rapamycin vein diluent is housed, injecting 1ml concentration is 6mg/ml rapamycin vein concentrated solution.
2. vibration is to forming settled solution.
3. administration in the operating period.
Embodiment 4
The preparation of rapamycin injection (4mg/ml)
A.8mg/ml the preparation of the vein concentrated solution of rapamycin in propylene glycol:
Prescription (density: 1.036g/ml):
Become component
Rapamycin 100% 0.8g
Propylene glycol (American Pharmacopeia level) adds to 100ml or 103.6g
Operating procedure:
1. in container, take by weighing rapamycin through suitably calibration.
2. with propylene glycol volume is transferred to 100ml.
3. be mixed to the formation homogeneous solution.
4. with solution aseptic filtration.
5. pack in ampoule or the phial and sealing.
B.4mg/ml rapamycin vein diluent
Become component
Propylene glycol (American Pharmacopeia level) 10ml
Water for injection (American Pharmacopeia level) adds to 100ml or 100g
Operating procedure:
1. propylene glycol is placed suitable containers.
2. with water for injection volume is transferred to 100ml.
3. be mixed to the formation homogeneous solution.
4. with solution aseptic filtration.
5. pack.
6. autoclaving.
C.4mg/ml rapamycin intravenous fluid (preparing)
Prescription (density: 1.035g/ml):
Become component
Rapamycin vein concentrated solution 8mg/ml 1ml
Rapamycin vein diluent 1ml
Operating procedure:
1. utilize strict aseptic technique, in the phial that 1ml rapamycin vein diluent is housed, injecting 1ml concentration is 8mg/ml rapamycin vein concentrated solution.
2. vibration is to forming settled solution.
3. administration in the operating period.
Claims (18)
1, a kind of aqueous rapamycin injection, this injection can make with the method that may further comprise the steps: make 40-75% (volume) concentration be 0.25-8mg/ml the concentrated solution of rapamycin in propylene glycol with contain water diluent and mix, wherein diluent accounts for the 60-25% of mixeding liquid volume, is 0.1-4mg/ml thereby make the concentration of rapamycin in the injection.
2, the aqueous rapamycin injection of claim 1, wherein the concentrated solution of rapamycin in propylene glycol accounts for the 40-60% of injection volume.
3, claim 1 or 2 aqueous rapamycin injection, wherein the concentration of rapamycin is 0.5-4mg/ml in the propylene glycol concentrated solution.
4, a kind of aqueous rapamycin injection, this injection can make with the method that may further comprise the steps: make the 40-60%(volume) concentration is the concentrated solution of 0.5-4mg/ml rapamycin in propylene glycol and contain water diluent and mix, wherein diluent accounts for the 60-40% of mixeding liquid volume, is 0.25-2mg/ml thereby make the concentration of rapamycin in the injection.
5, each aqueous rapamycin injection among the claim 1-4, wherein the concentrated solution of rapamycin in propylene glycol accounts for the 40-50% of injection volume.
6, each aqueous rapamycin injection among the claim 1-5, wherein the concentration of rapamycin is 0.6-3.3mg/ml in the propylene glycol concentrated solution.
7, each aqueous rapamycin injection among the claim 1-6, wherein the concentration of rapamycin is 0.5-1.5mg/ml in the injection.
8, the aqueous rapamycin injection for bolus injection of claim 1, wherein the concentration of rapamycin is 0.25-2mg/ml in the injection.
9, a kind of aqueous rapamycin injection, described injection comprises the rapamycin in the solution that is dissolved in propylene glycol and water, and wherein water accounts for the 40-75% of liquor capacity, and the concentration of rapamycin is 0.1-4mg/ml in the solution.
10, a kind of product that contains rapamycin concentrated solution and diluent, this product is a kind of combination preparation, be used for before intravenous injection, mixing and obtain the solution that rapamycin concentration is 0.1-4mg/ml, described concentrated solution comprises the solution of rapamycin in propylene glycol that concentration is 0.25-8mg/ml, described diluent comprises water, the ratio of concentrated solution and diluent be 40: 60 to 75: the 25(percent by volume).
11, the product of claim 10, wherein the ratio of concentrated solution and diluent be 60: 40 to 40: the 60(percent by volume).
12, claim 10 or 11 product, wherein the concentration of rapamycin is 0.5-4mg/ml in the propylene glycol concentrated solution.
13, the product for bolus injection of claim 10, wherein the mixed concentration of rapamycin concentrated solution and diluent is 0.25-2mg/ml.
14, a kind of product that contains rapamycin concentrated solution and diluent, this product is a kind of combination preparation, be used for before intravenous injection, mixing and obtain the solution that rapamycin concentration is 0.1-4mg/ml, described concentrated solution comprises the solution of rapamycin in propylene glycol that concentration is 0.5-4mg/ml, described diluent comprises water, the ratio of concentrated solution and diluent be 40: 60 to 75: the 25(percent by volume).
15, a kind of method for preparing aqueous rapamycin injection, this method comprises: make the 40-75%(volume) concentration be 0.25-8mg/ml the concentrated solution of rapamycin in propylene glycol with contain water diluent and mix, wherein diluent accounts for the 60-25% of mixeding liquid volume, is 0.1-4mg/ml thereby make the concentration of rapamycin in the injection.
16, the method for claim 15, wherein the concentrated solution of rapamycin in propylene glycol accounts for the 40-60% of injection volume.
17, claim 15 or 16 method, wherein the concentration of rapamycin is 0.5-4mg/ml in the propylene glycol concentrated solution.
18, a kind of method for preparing aqueous rapamycin injection, this method comprises: make the 40-60%(volume) concentration be 0.5-4mg/ml the concentrated solution of rapamycin in propylene glycol with contain water diluent and mix, wherein diluent accounts for the 60-40% of mixeding liquid volume, is 0.25-2mg/ml thereby make the concentration of rapamycin in the injection.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US12952693A | 1993-09-30 | 1993-09-30 | |
| US129,526 | 1993-09-30 | ||
| US08/302,190 US5616588A (en) | 1993-09-30 | 1994-09-12 | Rapamycin formulation for IV injection |
| US302,190 | 1994-09-12 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1109748A true CN1109748A (en) | 1995-10-11 |
Family
ID=26827650
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 94116781 Pending CN1109748A (en) | 1993-09-30 | 1994-09-29 | Rapamycin preparation used for intravenous injection |
Country Status (6)
| Country | Link |
|---|---|
| JP (1) | JP3584064B2 (en) |
| CN (1) | CN1109748A (en) |
| BR (1) | BR9403945A (en) |
| CA (1) | CA2133180A1 (en) |
| IL (1) | IL111008A (en) |
| TW (1) | TW438586B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008022557A1 (en) * | 2006-08-17 | 2008-02-28 | Jianmin Zhang | Liquid composition of sirolimus |
| CN100402031C (en) * | 2002-07-30 | 2008-07-16 | 惠氏公司 | Parenteral formulations containing rapamycin hydroxyester |
| CN109431997A (en) * | 2018-12-20 | 2019-03-08 | 武汉科福新药有限责任公司 | A kind of rapamycin locally injecting preparation and preparation method thereof |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001253824A (en) * | 2000-03-14 | 2001-09-18 | Mitsukazu Matsumoto | Formulated agent for local injection |
| US20080096972A1 (en) * | 2004-07-30 | 2008-04-24 | Thitiwan Buranachokpaisan | Compound formulations of 2-amino-1, 3-propanediol compounds |
-
1994
- 1994-09-19 IL IL11100894A patent/IL111008A/en active IP Right Grant
- 1994-09-26 TW TW83108922A patent/TW438586B/en not_active IP Right Cessation
- 1994-09-28 CA CA 2133180 patent/CA2133180A1/en not_active Abandoned
- 1994-09-29 CN CN 94116781 patent/CN1109748A/en active Pending
- 1994-09-29 JP JP23487494A patent/JP3584064B2/en not_active Expired - Fee Related
- 1994-09-29 BR BR9403945A patent/BR9403945A/en not_active Application Discontinuation
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100402031C (en) * | 2002-07-30 | 2008-07-16 | 惠氏公司 | Parenteral formulations containing rapamycin hydroxyester |
| WO2008022557A1 (en) * | 2006-08-17 | 2008-02-28 | Jianmin Zhang | Liquid composition of sirolimus |
| CN109431997A (en) * | 2018-12-20 | 2019-03-08 | 武汉科福新药有限责任公司 | A kind of rapamycin locally injecting preparation and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| IL111008A (en) | 1999-10-28 |
| JP3584064B2 (en) | 2004-11-04 |
| JPH07196507A (en) | 1995-08-01 |
| BR9403945A (en) | 1995-06-13 |
| CA2133180A1 (en) | 1995-03-31 |
| IL111008A0 (en) | 1994-11-28 |
| TW438586B (en) | 2001-06-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1108152C (en) | Rapamycin formulations for oral administration | |
| CN1246035C (en) | Medicine composition of macrolides or cyclosporin and polyoxide saturated hydoxy fatty acid | |
| CN1112924C (en) | Rapamycin formulation for IV injection | |
| CN1313154C (en) | Medicine composition of adding active component which undissolved in water in carrier composition and its preparing method | |
| JP4073503B2 (en) | Liquid formulation containing cyclosporine and method for its preparation | |
| CN1107500C (en) | Rapamycin formulations for oral administration | |
| CN1232244C (en) | Stable non-aqueous single-phase viscous carrier and preparation using the carrier | |
| CN1090509A (en) | Pharmaceutical composition | |
| CN1469735A (en) | Liposomal formulation of mitoxantrone | |
| CN1161652A (en) | pharmaceutical composition | |
| CN1291886A (en) | Formulations | |
| CN1248680C (en) | Injectable composition of paclitaxel | |
| CN1140268C (en) | Rapamycin formulations for oral administration | |
| CN1127350C (en) | Soft capsule preparation containing cyclosporine | |
| CN1283235C (en) | Clear and stable propofol composition | |
| CN1479610A (en) | Drondearone pharmaceutical composition for external gastrointestinal-tract administration | |
| EP0650730A1 (en) | Rapamycin formulations for oral administration | |
| CN1109748A (en) | Rapamycin preparation used for intravenous injection | |
| CN1183721A (en) | Pharmaceutical composition contg. tiagabine hydrochloride and process for its preparation | |
| US20110105387A1 (en) | Method of treatment with rapamycin | |
| CN1642576A (en) | Absorption enhancing agent | |
| CN115666579A (en) | Stable, ready-to-dilute formulations of carfilzomib | |
| CN1136841C (en) | Group gel type liposome and its composition and application | |
| CN1784237A (en) | Freeze-dried preparation containing methylcobalamin and process for producing the same | |
| CN1554340A (en) | Nimodipine novel nano liposome, its precursor freeze-dried product and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |