US20020012680A1 - Compositions and methods for improved delivery of lipid regulating agents - Google Patents

Compositions and methods for improved delivery of lipid regulating agents Download PDF

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US20020012680A1
US20020012680A1 US09/898,553 US89855301A US2002012680A1 US 20020012680 A1 US20020012680 A1 US 20020012680A1 US 89855301 A US89855301 A US 89855301A US 2002012680 A1 US2002012680 A1 US 2002012680A1
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pharmaceutical composition
fatty acid
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Mahesh Patel
Feng-Jing Chen
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A61K38/13—Cyclosporins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/06—Antiabortive agents; Labour repressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/26—Androgens

Definitions

  • the present invention relates to drug delivery systems, and in particular to pharmaceutical compositions for the improved delivery of hydrophobic compounds.
  • Hydrophobic therapeutic agents i.e., therapeutic compounds having poor solubility in aqueous solution
  • a well-designed formulation must, at a minimum, be capable of presenting a therapeutically effective amount of the hydrophobic compound to the desired absorption site, in an absorbable form. Even this minimal functionality is difficult to achieve when delivery of the hydrophobic therapeutic agent requires interaction with aqueous physiological environments, such as gastric fluids and intestinal fluids.
  • Pharmaceutical compositions for delivery of such hydrophobic therapeutic agents must carry the hydrophobic compound through the aqueous environment, while maintaining the hydrophobic compound in an absorbable form, and avoiding the use of physiologically harmful solvents or excipients.
  • a number of approaches to formulating hydrophobic therapeutic agents for oral or parenteral delivery are known.
  • One well-known approach uses surfactant micelles to solubilize and transport the therapeutic agent.
  • Micelles are agglomerates of colloidal dimensions formed by amphiphilic compounds under certain conditions.
  • Micelles, and pharmaceutical compositions containing micelles have been extensively studied and are described in detail in the literature; see, e.g., Remington's Pharmaceutical Sciences, 17 th ed. (1985), the disclosure of which is incorporated herein in its entirety.
  • micelles can incorporate hydrophobic therapeutic agents in the hydrocarbon core of the micelle, or entangled at various positions within the micelle walls.
  • micellar formulations can solubilize a variety of hydrophobic therapeutic agents, the loading capacity of conventional micelle formulations is limited by the solubility of the therapeutic agent in the micelle surfactant. For many hydrophobic therapeutic agents, such solubility is too low to offer formulations that can deliver therapeutically effective doses.
  • Another conventional approach takes advantage of the increased solubility of hydrophobic therapeutic agents in oils (triglycerides). Hydrophobic therapeutic agents, while poorly soluble in aqueous solution, could be sufficiently lipophilic that therapeutically effective concentrations of the therapeutic agents can be prepared in triglyceride-based solvents.
  • one conventional approach is to solubilize a hydrophobic therapeutic agent in a bioacceptable triglyceride solvent, such as a digestible vegetable oil, and disperse this oil phase in an aqueous solution.
  • the dispersion may be stabilized by emulsifying agents and provided in emulsion form.
  • the therapeutic agent can be provided in a water-free formulation, with an aqueous dispersion being formed in the in vivo gastrointestinal environment.
  • the properties of these oil-based formulations are determined by such factors as the size of the triglyceride/therapeutic agent colloidal particles and the presence or absence of surfactant additives.
  • a triglyceride-containing formulation suitable for delivering hydrophobic therapeutic agents through an aqueous environment is an oil-in-water emulsion.
  • Such emulsions contain the hydrophobic therapeutic agent solubilized in an oil phase which is dispersed in an aqueous environment with the aid of a surfactant.
  • the surfactant may be present in the oil-based formulation itself, or may be a compound provided in the gastrointestinal system, such as bile salts, which are known to be in vivo emulsifying agents.
  • the colloidal oil particles sizes are relatively large, ranging from several hundred nanometers to several microns in diameter, in a broad particle size distribution. Since the particle sizes are on the order of or greater than the wavelength range of visible light, such emulsions, when prepared in an emulsion dosage form, are visibly “cloudy” or “milky” to the naked eye.
  • triglyceride-based pharmaceutical compositions are useful in solubilizing and delivering some hydrophobic therapeutic agents, such compositions are subject to a number of significant limitations and disadvantages.
  • Emulsions are thermodynamically unstable, and colloidal emulsion particles will spontaneously agglomerate, eventually leading to complete phase separation.
  • the tendency to agglomerate and phase separate presents problems of storage and handling, and increases the likelihood that pharmaceutical emulsions initially properly prepared will be in a less optimal, less effective, and poorly-characterized state upon ultimate administration to a patient.
  • Uncharacterized degradation is particularly disadvantageous, since increased particle size slows the rate of transport of the colloidal particle and digestion of the oil component, and hence the rate and extent of absorption of the therapeutic agent.
  • a further disadvantage of triglyceride-containing compositions is the dependence of therapeutic agent absorption on the rate and extent of lipolysis.
  • colloidal emulsion particles can transport hydrophobic therapeutic agents through the aqueous environment of the gastrointestinal tract, ultimately the triglyceride must be digested and the therapeutic agent must be released in order to be absorbed through the intestinal mucosa.
  • the triglyceride carrier is emulsified by bile salts and hydrolyzed, primarily by pancreatic lipase. The rate and extent of lipolysis, however, are dependent upon several factors that are difficult to adequately control.
  • the amount and rate of bile salt secretion affect the lipolysis of the triglycerides, and the bile salt secretion can vary with stomach contents, with metabolic abnormalities, and with functional changes of the liver, bile ducts, gall bladder and intestine.
  • Lipase availability in patients with decreased pancreatic secretory function, such as cystic fibrosis or chronic pancreatitis may be undesirably low, resulting in a slow and incomplete triglyceride lipolysis.
  • the activity of lipase is pH dependent, with deactivation occurring at about pH 3, so that the lipolysis rate will vary with stomach contents, and may be insufficient in patients with gastric acid hyper-secretion.
  • surfactants commonly used in the preparation of pharmaceutical emulsions such as polyethoxylated castor oils
  • certain surfactant combinations when used in combination with digestible oils in emulsion preparations, can substantially decrease the lipolysis-inhibiting effect of some common pharmaceutical surfactants (see, U.S. Pat. No. 5,645,856), such formulations are still subject to the other disadvantages of pharmaceutical emulsions and triglyceride-based formulations.
  • microemulsions Like an emulsion, a microemulsion is a liquid dispersion of oil in water, stabilized by surfactants. The microemulsion particles are smaller than those of an emulsion, rendering the microemulsion essentially optically clear. Microemulsions, however, are thermodynamically stable, and are not subject to the particle agglomeration problems of conventional emulsions. It is generally believed that microemulsions are micelle-like particles, having an essentially micellar structure but containing a distinct oil phase in the micelle “core”. These micelle-like particles are often referred to as “swollen micelles”, a term which emphasizes their close relationship to true micellar particles.
  • microemulsions function quite differently in drug delivery systems.
  • the majority of hydrophobic therapeutic agents are lipophilic, and have greater solubility in triglycerides than in surfactants.
  • the hydrophobic therapeutic agent in a microemulsion-based delivery system is preferentially solvated in the triglyceride phase, which is in turn encapsulated in the swollen micelle.
  • the preferential partitioning in the triglyceride phase results in higher loading capacities than in comparable micelle-based systems, but at the cost of introducing into the delivery system the lipolysis-dependence and other disadvantages associated with the presence of triglycerides.
  • the larger size of microemulsion particles, relative to true micelles results in a slower rate of particle diffusion, and thus a slower rate of therapeutic agent absorption.
  • the present invention provides pharmaceutical compositions for improved delivery of hydrophobic therapeutic agents.
  • the present invention provides a triglyceride-free pharmaceutical composition including a hydrophobic therapeutic agent and a carrier.
  • the carrier includes a hydrophilic surfactant and a hydrophobic surfactant in amounts such that upon dilution with an aqueous solution such as simulated gastrointestinal fluids the carrier forms a clear aqueous dispersion of the hydrophilic and hydrophobic surfactants containing the hydrophobic therapeutic agent.
  • the present invention provides a clear aqueous dispersion containing a hydrophilic surfactant, a hydrophobic surfactant and a hydrophobic therapeutic agent.
  • the dispersion is substantially free of triglycerides.
  • the present invention relates to a triglyceride-free pharmaceutical composition which includes a hydrophilic surfactant and a hydrophobic surfactant in amounts such that upon dilution with an aqueous solution a clear aqueous dispersion is formed, a first amount of a hydrophobic therapeutic agent solubilized in the clear aqueous dispersion, and a second amount of the hydrophobic therapeutic agent that remains non-solubilized but dispersed.
  • the present invention relates to methods of increasing the rate and/or extent of absorption of hydrophobic therapeutic agents by administering to a patient a pharmaceutical composition of the present invention.
  • FIG. 1 shows the enhanced bioabsorption of a hydrophobic therapeutic agent in the compositions of the present invention, relative to a commercial formulation.
  • the present invention overcomes the problems described above characteristic of conventional formulations such as micelle formulations, emulsions, and microemulsions, by providing unique triglyceride-free pharmaceutical compositions.
  • compositions including a combination of a hydrophilic surfactant and a hydrophobic surfactant can solubilize therapeutically effective amounts of hydrophobic therapeutic agents without recourse to the use of triglycerides, thereby avoiding the lipolysis dependence and other disadvantages of conventional formulations.
  • Use of these formulations results in an enhanced rate and/or extent of absorption of the hydrophobic therapeutic agent.
  • the present invention provides a pharmaceutical composition including a carrier and a hydrophobic therapeutic agent.
  • the carrier includes a hydrophilic surfactant and a hydrophobic surfactant in amounts such that upon dilution with an aqueous solution the carrier forms a clear aqueous dispersion of the hydrophilic and hydrophobic surfactants containing the hydrophobic therapeutic agent.
  • the carrier is substantially free of triglycerides, thereby providing surprising and important advantages over conventional, triglyceride-containing formulations.
  • the carrier includes at least one hydrophilic surfactant and at least one hydrophobic surfactant.
  • hydrophilic and “hydrophobic” are relative terms.
  • a compound must necessarily include polar or charged hydrophilic moieties as well as non-polar hydrophobic (lipophilic) moieties; i.e., a surfactant compound must be amphiphilic.
  • An empirical parameter commonly used to characterize the relative hydrophilicity and hydrophobicity of non-ionic amphiphilic compounds is the hydrophilic-lipophilic balance (“HLB” value).
  • HLB hydrophilic-lipophilic balance
  • hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable.
  • hydrophobic surfactants are compounds having an HLB value less than about 10.
  • HLB value of a surfactant is merely a rough guide generally used to enable formulation of industrial, pharmaceutical and cosmetic emulsions.
  • HLB values can differ by as much as about 8 HLB units, depending upon the empirical method chosen to determine the HLB value (Schott, J. Pharm. Sciences, 79(1), 87-88 (1990)).
  • PLURONIC® surfactants BASF Corp.
  • the HLB values may not accurately reflect the true physical chemical nature of the compounds.
  • the hydrophilic surfactant can be any hydrophilic surfactant suitable for use in pharmaceutical compositions.
  • Such surfactants can be anionic, cationic, zwitterionic or non-ionic, although non-ionic hydrophilic surfactants are presently preferred. As discussed above, these non-ionic hydrophilic surfactants will generally have HLB values greater than about 10. Mixtures of hydrophilic surfactants are also within the scope of the invention.
  • the hydrophobic surfactant can be any hydrophobic surfactant suitable for use in pharmaceutical compositions.
  • suitable hydrophobic surfactants will have an HLB value less than about 10. Mixtures of hydrophobic surfactants are also within the scope of the invention.
  • hydrophobic and hydrophilic surfactants should be made keeping in mind the particular hydrophobic therapeutic agent to be used in the composition, and the range of polarity appropriate for the chosen therapeutic agent, as discussed in more detail below. With these general principles in mind, a very broad range of surfactants is suitable for use in the present invention.
  • Such surfactants can be grouped into the following general chemical classes detailed in the Tables below.
  • the HLB values given in the Tables below generally represent the HLB value as reported by the manufacturer of the corresponding commercial product. In cases where more than one commercial product is listed, the HLB value in the Tables is the value as reported for one of the commercial products, a rough average of the reported values, or a value that, in the judgment of the present inventors, is more reliable. It should be emphasized that the invention is not limited to the surfactants in the following Tables, which show representative, but not exclusive, lists of available surfactants.
  • PEG polyethylene glycol
  • PEG-fatty acid esters have useful surfactant properties.
  • PEG-fatty acid monoesters esters of lauric acid, oleic acid, and stearic acid are most useful.
  • preferred hydrophilic surfactants include PEG-8 laurate, PEG-8 oleate, PEG-8 stearate, PEG-9 oleate, PEG-10 laurate, PEG-10 oleate, PEG-12 laurate, PEG-12 oleate, PEG-15 oleate, PEG-20 laurate and PEG-20 oleate.
  • Polyethylene glycol fatty acid diesters are also suitable for use as surfactants in the compositions of the present invention.
  • preferred hydrophilic surfactants include PEG-20 dilaurate, PEG-20 dioleate, PEG-20 distearate, PEG-32 dilaurate and PEG-32 dioleate.
  • Representative PEG-fatty acid diesters are shown in Table 2.
  • mixtures of surfactants are also useful in the present invention, including mixtures of two or more commercial surfactant products.
  • PEG-fatty acid esters are marketed commercially as mixtures or mono- and diesters.
  • Representative surfactant mixtures are shown in Table 3.
  • Suitable PEG glycerol fatty acid esters are shown in Table 4.
  • preferred hydrophilic surfactants are PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-20 glyceryl oleate, and PEG-30 glyceryl oleate.
  • a large number of surfactants of different degrees of hydrophobicity or hydrophilicity can be prepared by reaction of alcohols or polyalcohols with a variety of natural and/or hydrogenated oils.
  • the oils used are castor oil or hydrogenated castor oil, or an edible vegetable oil such as corn oil, olive oil, peanut oil, palm kernel oil, apricot kernel oil, or almond oil.
  • Preferred alcohols include glycerol, propylene glycol, ethylene glycol, polyethylene glycol, sorbitol, and pentaerythritol.
  • preferred hydrophilic surfactants are PEG-35 castor oil (Incrocas-35), PEG-40 hydrogenated castor oil (Cremophor RH 40), PEG-25 trioleate (TAGAT® TO), PEG-60 corn glycerides (Crovol M70), PEG-60 almond oil (Crovol A70), PEG-40 palm kernel oil (Crovol PK70), PEG-50 castor oil (Emalex C-50), PEG-50 hydrogenated castor oil (Emalex HC-50), PEG-8 caprylic/capric glycerides (Labrasol), and PEG-6 caprylic/capric glycerides (Softigen 767).
  • Preferred hydrophobic surfactants in this class include PEG-5 hydrogenated castor oil, PEG-7 hydrogenated castor oil, PEG-9 hydrogenated castor oil, PEG-6 corn oil (Labrafil® M 2125 CS), PEG-6 almond oil (Labrafil® M 1966 CS), PEG-6 apricot kernel oil (Labrafil® M 1944 CS), PEG-6 olive oil (Labrafil® M 1980 CS), PEG-6 peanut oil (Labrafil® M 1969 CS), PEG-6 hydrogenated palm kernel oil (Labrafil® M 2130 BS), PEG-6 palm kernel oil (Labrafil® M 2130 CS), PEG-6 triolein (Labrafil® M 2735 CS), PEG-8 corn oil (Labrafil® WL 2609 BS), PEG-20 corn glycerides (Crovol M40), and PEG-20 almond glycerides (Crovol A40).
  • Polyglycerol esters of fatty acids are also suitable surfactants for the present invention.
  • preferred hydrophobic surfactants include polyglyceryl oleate (Plurol Oleique), polyglyceryl-2 dioleate (Nikkol DGDO), and polyglyceryl-10 trioleate.
  • Preferred hydrophilic surfactants include polyglyceryl-10 laurate (Nikkol Decaglyn 1-L), polyglyceryl-10 oleate (Nikkol Decaglyn 1-O), and polyglyceryl-10 mono, dioleate (Caprol® PEG 860).
  • Polyglyceryl polyricinoleates are also preferred hydrophilic and hydrophobic surfactants. Examples of suitable polyglyceryl esters are shown in Table 6. TABLE 6 Polyglycerized Fatty Acids COMPOUND COMMERCIAL PRODUCT (Supplier) HLB Polyglyceryl-2 stearate Nikkol DGMS (Nikko) 5-7 Polyglyceryl-2 oleate Nikkol DGMO (Nikko) 5-7 Polyglyceryl-2 Nikkol DGMIS (Nikko) 5-7 isostearate Polyglyceryl-3 oleate Caprol ® 3GO (ABITEC), Drewpol 6.5 3-1-O (Stepan) Polyglyceryl-4 oleate Nikkol Tetraglyn 1-O (Nikko) 5-7 Polyglyceryl-4 stearate Nikkol Tetraglyn 1-S (Nikko) 5-6 Polyglyceryl-6 oleate Drewpol 6-1-O (Stepan)
  • esters of propylene glycol and fatty acids are suitable surfactants for use in the present invention.
  • preferred hydrophobic surfactants include propylene glycol monolaurate (Lauroglycol FCC), propylene glycol ricinoleate (Propymuls), propylene glycol monooleate (Myverol P-O6), propylene glycol dicaprylate/dicaprate (Captex® 200), and propylene glycol dioctanoate (Captex® 800). Examples of surfactants of this class are given in Table 7.
  • mixtures of surfactants are also suitable for use in the present invention.
  • mixtures of propylene glycol fatty acid esters and glycerol fatty acid esters are suitable and are commercially available.
  • One preferred mixture is composed of the oleic acid esters of propylene glycol and glycerol (Arlacel 186). Examples of these surfactants are shown in Table 8. TABLE 8 Glycerol/Propylene Glycol Fatty Acid Esters COMPOUND COMMERCIAL PRODUCT (Supplier) HLB Oleic ATMOS 300, ARLACEL 186 (ICI) 3-4 Stearic ATMOS 150 3-4
  • a particularly important class of surfactants is the class of mono- and diglycerides. These surfactants are generally hydrophobic. Preferred hydrophobic surfactants in this class of compounds include glyceryl monooleate (Peceol), glyceryl ricinoleate, glyceryl laurate, glyceryl dilaurate (Capmul® GDL), glyceryl dioleate (Capmul® GDO), glyceryl mono/dioleate (Capmul® GMO-K), glyceryl caprylate/caprate (Capmul® MCM), caprylic acid mono/diglycerides (Imwitor® 988), and mono- and diacetylated monoglycerides (Myvacet® 9-45).
  • Peceol glyceryl monooleate
  • glyceryl ricinoleate glyceryl laurate
  • Capmul® GDL glyceryl dilaurate
  • Sterols and derivatives of sterols are suitable surfactants for use in the present invention. These surfactants can be hydrophilic or hydrophobic. Preferred derivatives include the polyethylene glycol derivatives. A preferred hydrophobic surfactant in this class is cholesterol. A preferred hydrophilic surfactant in this class is PEG-24 cholesterol ether (Solulan C-24). Examples of surfactants of this class are shown in Table 10.
  • PEG-sorbitan fatty acid esters are available and are suitable for use as surfactants in the present invention.
  • these surfactants are hydrophilic, although several hydrophobic surfactants of this class can be used.
  • preferred hydrophilic surfactants include PEG-20 sorbitan monolaurate (Tween-20), PEG-20 sorbitan monopalmitate (Tween-40), PEG-20 sorbitan monostearate (Tween-60), and PEG-20 sorbitan monooleate (Tween-80). Examples of these surfactants are shown in Table 11.
  • Ethers of polyethylene glycol and alkyl alcohols are suitable surfactants for use in the present invention.
  • Preferred hydrophobic ethers include PEG-3 oleyl ether (Volpo 3) and PEG-4 lauryl ether (Brij 30). Examples of these surfactants are shown in Table 12.
  • esters of sugars are suitable surfactants for use in the present invention.
  • Preferred hydrophilic surfactants in this class include sucrose monopalmitate and sucrose monolaurate. Examples of such surfactants are shown in Table 13. TABLE 13 Sugar Ester Surfactants COMPOUND COMMERCIAL PRODUCT (Supplier) HLB Sucrose distearate SUCRO ESTER 7 (Gattefosse), 3 Crodesta F-10 (Croda) Sucrose distearate/ SUCRO ESTER 11 (Gattefosse), 12 monostearate Crodesta F-110 (Croda) Sucrose dipalmitate 7.4 Sucrose monostearate Crodesta F-160 (Croda) 15 Sucrose monopalmitate SUCRO ESTER 15 (Gattefosse) >10 Sucrose monolaurate Saccharose monolaurate 15 1695 (Mitsubishi-Kasei)
  • hydrophilic PEG-alkyl phenol surfactants are available, and are suitable for use in the present invention. Examples of these surfactants are shown in Table 14. TABLE 14 Polyethylene Glycol Alkyl Phenol Surfactants COMMERCIAL COMPOUND PRODUCT (Supplier) HLB PEG-10-100 nonyl phenol Triton X series (Rohm & Haas), >10 Igepal CA series (GAF, USA), Antarox CA series (GAF, UK) PEG-15-100 octyl phenol ether Triton N-series (Rohm & Haas), >10 Igepal CO series (GAF, USA), Antarox CO series (GAF, UK)
  • the POE-POP block copolymers are a unique class of polymeric surfactants.
  • the unique structure of the surfactants, with hydrophilic POE and hydrophobic POP moieties in well-defined ratios and positions, provides a wide variety of surfactants suitable for use in the present invention.
  • These surfactants are available under various trade names, including Synperonic PE series (ICI); Pluronic® series (BASF), Emkalyx, Lutrol (BASF), Supronic, Monolan, Pluracare, and Plurodac.
  • the generic term for these polymers is “poloxamer” (CAS 9003-11-6). These polymers have the formula:
  • Preferred hydrophilic surfactants of this class include Poloxamers 108, 188, 217, 238, 288, 338, and 407.
  • Preferred hydrophobic surfactants in this class include Poloxamers 124, 182, 183, 212, 331, and 335.
  • Sorbitan esters of fatty acids are suitable surfactants for use in the present invention.
  • preferred hydrophobic surfactants include sorbitan monolaurate (Arlacel 20), sorbitan monopalmitate (Span-40), sorbitan monooleate (Span-80), sorbitan monostearate, and sorbitan tristearate. Examples of these surfactants are shown in Table 16.
  • esters of lower alcohols (C 2 to C 4 ) and fatty acids (C 8 to C 18 ) are suitable surfactants for use in the present invention.
  • preferred hydrophobic surfactants include ethyl oleate (Crodamol EO), isopropyl myristate (Crodamol IPM), and isopropyl palmitate (Crodamol IPP). Examples of these surfactants are shown in Table 17.
  • Ionic surfactants including cationic, anionic and zwitterionic surfactants, are suitable hydrophilic surfactants for use in the present invention.
  • Preferred anionic surfactants include fatty acid salts and bile salts.
  • preferred ionic surfactants include sodium oleate, sodium lauryl sulfate, sodium lauryl sarcosinate, sodium dioctyl sulfosuccinate, sodium cholate, and sodium taurocholate. Examples of such surfactants are shown in Table 18 below. For simplicity, typical counterions are shown in the entries in the Table. It will be appreciated by one skilled in the art, however, that any bioacceptable counterion may be used.
  • fatty acids are shown as sodium salts, other cation counterions can also be used, such as alkali metal cations or ammonium.
  • these ionic surfactants are generally available as pure compounds, rather than commercial (proprietary) mixtures. Because these compounds are readily available from a variety of commercial suppliers, such as Aldrich, Sigma, and the like, commercial sources are not generally listed in the Table.
  • Acyl lactylates lactylic esters of fatty acids calcium/sodium stearoyl-2-lactylate calcium/sodium stearoyl lactylate Alginate salts Propylene glycol alginate SULFATES AND SULFONATES Ethoxylated alkyl sulfates Alkyl benzene sulfones ⁇ -olefin sulfonates Acyl isethionates Acyl taurates Alkyl glyceryl ether sulfonates Octyl sulfosuccinate disodium Disodium undecylenamideo-MEA-sulfosuccinate CATIONIC Surfactants >10 Hexadecyl triammonium bromide Decyl trimethyl ammonium bromide Cetyl trimethyl ammonium bromide Dodecyl ammonium chloride Alkyl benzyldimethylammonium salts Diisobuty
  • hydrophilic and hydrophobic surfactants are present in the pharmaceutical compositions of the present invention in amounts such that upon dilution with an aqueous solution, the carrier forms a clear, aqueous dispersion of the hydrophilic and hydrophobic surfactants, containing the hydrophobic therapeutic agent.
  • the relative amounts of hydrophilic and hydrophobic surfactants are readily determined by observing the properties of the resultant dispersion; i.e., when the relative amounts of the hydrophobic and hydrophilic surfactants are within a suitable range, the resultant aqueous dispersion is optically clear.
  • the resulting dispersion is visibly “cloudy”, resembling a conventional emulsion or multiple phase system.
  • a visibly cloudy solution may be potentially useful for some applications, such a system would suffer from many of the same disadvantages as conventional prior art formulations, as described above.
  • a convenient method of determining the appropriate relative concentrations for any hydrophilic surfactant-hydrophobic surfactant pair is as follows. A convenient working amount of a hydrophilic surfactant is provided, and a known amount of a hydrophobic surfactant is added. The surfactants are stirred to form a homogeneous mixture, with the aid of gentle heating if desired. The resulting mixture is diluted with purified water to prepare an aqueous dispersion. Any dilution amount can be chosen, but convenient dilutions are those within the range expected in vivo, about a 10 to 250-fold dilution. The aqueous dispersion is then assessed qualitatively for optical clarity. The procedure can be repeated with incremental variations in the relative amount of hydrophobic surfactant added, to determine the maximum relative amount of hydrophobic surfactant that can be present for a given surfactant pair.
  • the optical clarity of the aqueous dispersion can be measured using standard quantitative techniques for turbidity assessment.
  • One convenient procedure to measure turbidity is to measure the amount of light of a given wavelength transmitted by the solution, using, for example, a UV-visible spectrophotometer. Using this measure, optical clarity corresponds to high transmittance, since cloudier solutions will scatter more of the incident radiation, resulting in lower transmittance measurements. If this procedure is used, care should be taken to insure that the surfactant mixture does not itself absorb light of the chosen wavelength, as any true absorbance necessarily reduces the amount of transmitted light and falsely increases the quantitative turbidity value.
  • suitable dispersions at a dilution of 10 ⁇ should have an apparent absorbance of less than about 0.3, preferably less than about 0.2, and more preferably less than about 0.1.
  • suitable dispersions should have an apparent absorbance of less than about 0.1, preferably less than about 0.05, and more preferably less than about 0.01.
  • a third method of determining optical clarity and carrier diffusivity through the aqueous boundary layer is to quantitatively measure the size of the particles of which the dispersion is composed. These measurements can be performed on commercially available particle size analyzers, such as, for example, a Nicomp particle size analyzer available from Particle Size Systems, Inc., of Santa Barbara, Calif. Using this measure, clear aqueous dispersions according to the present invention have average particle sizes much smaller than the wavelength of visible light, whereas dispersions containing excessive relative amounts of the hydrophobic surfactant have more complex particle size distributions, with much greater average particle sizes.
  • the average particle size be less than about 100 nm, preferably less than about 50 nm, more preferably less than about 30 nm, and still more preferably less than about 20 nm. It is also preferred that the particle size distribution be mono-modal. As is shown in more detail in the Examples herein, dispersions having an undesirably large relative amount of hydrophobic surfactant typically display bimodal particle size distributions, such distributions having a small particle size component, typically less than about 30 nm, and a large particle size component, typically on the order of 100 nm or more. It should be emphasized that these particle sizes are appropriate for the carrier particles in aqueous solution, in the absence of a hydrophobic therapeutic agent. It is expected that the presence of the hydrophobic therapeutic agent may result in an increase in the average particle size.
  • any or all of the available methods may be used to ensure that the resulting aqueous dispersions possess the requisite optical clarity.
  • the present inventors prefer to use the simple qualitative procedure; i.e., simple visible observation.
  • all three of the above measures are used to assess the dispersion clarity in the Examples herein.
  • any aqueous dispersion having the properties described above is within the scope of the present invention regardless of the specific relative amounts of hydrophobic and hydrophilic surfactants, it is expected that the amount of hydrophobic surfactant will generally be less than about 200% by weight, based on the amount of hydrophilic surfactant, and more specifically, in the range of about 1% to 200%. Further, based on observations reported in the Examples herein, it is expected that the amount of hydrophobic surfactant will generally be less than about 100%, and more specifically in the range of about 5% to about 100% by weight, or about 10% to about 100% by weight, based on the amount of hydrophilic surfactant.
  • cloudy solutions result when the amount of hydrophobic surfactant is greater than about 60% by weight, based on the amount of hydrophilic surfactant.
  • a preferred range for these surfactants is about 1% to about 60%, preferably about 5% to about 60%, and more preferably about 10% to about 60%. Addition of optional excipients as described below can further increase the maximum relative amount of hydrophobic surfactant that can be used.
  • hydrophobic and hydrophilic surfactants are also within the scope of the present invention. These considerations include the degree of bioacceptability of the surfactants, and the desired dosage of hydrophobic therapeutic agent to be provided. In some cases, the amount of hydrophobic surfactant actually used in a pharmaceutical composition according to the present invention will be less than the maximum that can be used, and it should be apparent that such compositions are also within the scope of the present invention.
  • Hydrophobic therapeutic agents suitable for use in the pharmaceutical compositions of the present invention are not particularly limited, as the carrier is surprisingly capable of solubilizing and delivering a wide variety of hydrophobic therapeutic agents.
  • Hydrophobic therapeutic agents are compounds with little or no water solubility.
  • Intrinsic water solubilities (i.e., water solubility of the unionized form) for hydrophobic therapeutic agents usable in the present invention are less than about 1% by weight, and typically less than about 0.1% or 0.01% by weight.
  • Such therapeutic agents can be any agents having therapeutic or other value when administered to an animal, particularly to a mammal, such as drugs, nutrients, and cosmetics (cosmeceuticals).
  • analgesics and anti-inflammatory agents such as aloxiprin, auranofin, azapropazone, benorylate, capsaicin, celecoxib, diclofenac, diflunisal, etodolac, fenbufen, fenoprofen calcium, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, leflunomide, meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxaprozin, oxyphenbutazone, phenylbutazone, piroxicam, refocoxib, sulindac, tetrahydrocannabinol, tramadol and tromethamine;
  • anthelmintics such as albendazole, bephenium hydroxynaphthoate, cambendazole, dichlorophen, ivermectin, mebendazole, oxamniquine, oxfendazole, oxantel embonate, praziquantel, pyrantel embonate and thiabendazole;
  • anti-arrhythmic agents such as amiodarone HCl, disopyramide, flecainide acetate and quinidine sulfate;
  • anti-asthma agents such as zileuton, zafirlukast, terbutaline sulfate, montelukast, and albuterol;
  • anti-bacterial agents such as alatrofloxacin, azithromycin, baclofen, benethamine penicillin, cinoxacin, ciprofloxacin HCl, clarithromycin, clofazimine, cloxacillin, demeclocycline, dirithromycin, doxycycline, erythromycin, ethionamide, furazolidone, grepafloxacin, imipenem, levofloxacin, lorefloxacin, moxifloxacin HCl, nalidixic acid, nitrofurantoin, norfloxacin, ofloxacin, rifampicin, rifabutine, rifapentine, sparfloxacin, spiramycin, sulphabenzamide, sulphadoxine, sulphamerazine, sulphacetamide, sulphadiazine, sulphafurazole, sulphamethoxazole
  • anti-viral agents such as abacavir, amprenavir, delavirdine, efavirenz, indivir, lamivudine, nelfinavir, nevirapine, ritonavir, saquinavir, and stavueline;
  • anti-coagulants such as cilostazol, clopidrogel, dicoumarol, dipyridamole, nicoumalone, oprelvekin, phenindione, ticlidopine, and tirofibran;
  • anti-depressants such as amoxapine, bupropion, citalopram, clomipramine, fluexetine HCl, maprotiline HCl, mianserin HCl, nortriptyline HCl, paroxetine HCl, sertraline HCl, trazodone HCl, trimipramine maleate, and venlafaxine HCl;
  • anti-diabetics such as acetohexamide, chlorpropamide, glibenclamide, gliclazide, glipizide, glymepride, miglitol, pioglitazone, repaglinide, rosiglitazone, tolazamide, tolbutamide and troglitazone;
  • anti-epileptics such as beclamide, carbamazepine, clonazepam, ethotoin, felbamate, fosphenytoin sodium, lamotrigine, methoin, methsuximide, methylphenobarbitone, oxcarbazepine, paramethadione, phenacemide, phenobarbitone, phenytoin, phensuximide, primidone, sulthiame, tiagabine HCl, topiramate, valproic acid, and vigabatrin;
  • anti-fungal agents such as amphotericin, butenafine HCl, butoconazole nitrate, clotrimazole, econazole nitrate, fluconazole, flucytosine, griseofulvin, itraconazole, ketoconazole, miconazole, natamycin, nystatin, sulconazole nitrate, oxiconazole, terbinafine HCl, terconazole, tioconazole and undecenoic acid;
  • anti-gout agents such as allopurinol, probenecid and sulphin-pyrazone
  • anti-hypertensive agents such as amlodipine, benidipine, benezepril, candesartan, captopril, darodipine, dilitazem HCl, diazoxide, doxazosin HCl, elanapril, eposartan losartan, mesylate, felodipine, fenolclopam, fosinopril, guanabenz acetate, irbesartan, isradipine, lisinopril, minoxidil, nicardipine HCl, nifedipine, nimodipine, nisolidipine, phenoxybenzamine HCl, prazosin HCl, quinapril, reserpine, terazosin HCl, telmisartan, and valsartan;
  • anti-malarials such as amodiaquine, chloroquine, chlorproguanil HCl, halofantrine HCl, mefloquine HCl, proguanil HCl, pyrimethamine and quinine sulfate;
  • anti-migraine agents such as dihydroergotamine mesylate, ergotamine tartrate, frovatriptan, methysergide maleate, naratriptan HCl, pizotifen maleate, rizatriptan benzoate, sumatriptan succinate, and zolmitriptan;
  • anti-muscarinic agents such as atropine, benzhexol HCl, biperiden, ethopropazine HCl, hyoscyamine, mepenzolate bromide, oxyphencylcimine HCl and tropicamide;
  • anti-neoplastic agents and immunosuppressants such as aminoglutethimide, amsacrine, azathioprine, bicalutamide, bisanthrene, busulphan, camptothecan, capecitabine, chlorambucil, cyclosporin, dacarbazine, ellipticine, estramustine, etoposide, irinotecan, lomustine, melphalan, mercaptopurine, methotrexate, mitomycin, mitotane, mitoxantrone, mofetil, mycophenolate, nilutamide, paclitaxel, procarbazine HCl, sirolimus, tacrolimus, tamoxifen citrate, teniposide, testolactone, topotecan HCl, and toremifene citrate;
  • immunosuppressants such as aminoglutethimide, amsacrine, azathioprine, bical
  • anti-protozoal agents such as atovaquone, benznidazole, clioquinol, decoquinate, diiodohydroxyquinoline, diloxanide furoate, dinitolmide, furzolidone, metronidazole, nimorazole, nitrofurazone, omidazole and tinidazole;
  • anti-thyroid agents such as carbimazole, paricalcitol, and propylthiouracil
  • anti-tussives such as benzonatate
  • anxiolytic, sedatives, hypnotics and neuroleptics such as alprazolam, amylobarbitone, barbitone, bentazepam, bromazepam, bromperidol, brotizolam, butobarbitone, carbromal, chlordiazepoxide, chlormethiazole, chlorpromazine, chlorprothiocene, clonazepam, clobazam, clotiazepam, clozapine, diazepam, droperidol, ethinamate, flunanisone, flunitrazepam, fluopromazine, flupenthixol decanoate, fluphenazine decanoate, flurazepam, gabapentin, haloperidol, lorazepam, lormetazepam, medazepam, meprobamate, mesoridiazine, methaqualone,
  • ⁇ -Blockers such as acebutolol, alprenolol, atenolol, labetalol, metoprolol, nadolol, oxprenolol, pindolol and propranolol;
  • cardiac inotropic agents such as amrinone, digitoxin, digoxin, enoximone, lanatoside C and medigoxin;
  • corticosteroids such as beclomethasone, betamethasone, budesonide, cortisone acetate, desoxymethasone, dexamethasone, fludrocortisone acetate, flunisolide, flucortolone, fluticasone propionate, hydrocortisone, methylprednisolone, prednisolone, prednisone and triamcinolone;
  • diuretics such as acetazolamide, amiloride, bendrofluazide, bumetanide, chlorothiazide, chlorthalidone, ethacrynic acid, frusemide, metolazone, spironolactone and triamterene.
  • anti-parkinsonian agents such as bromocriptine mesylate, lysuride maleate, pramipexole, robinirole HCl, and tolcapone;
  • gastro-intestinal agents such as bisacodyl, cimetidine, cisapride, diphenoxylate HCl, domperidone, famotidine, lanosprazole, loperamide, mesalazine, nizatidine, omeprazole, ondansetron HCL, rabeprazole sodium, ranitidine HCl and sulphasalazine;
  • histamine H,-receptor antagonists such as acrivastine, astemizole, chlophenisamine, cinnarizine, citrizine, clemastine fumarate, cyclizine, cyproheptadine HCl, dexchlopheniramine, dimenhydrinate, fexofenadine, flunarizine HCl, loratadine, meclozine HCl, oxatomide, andnadine;
  • acrivastine astemizole
  • chlophenisamine such as acrivastine, astemizole, chlophenisamine, cinnarizine, citrizine, clemastine fumarate, cyclizine, cyproheptadine HCl, dexchlopheniramine, dimenhydrinate, fexofenadine, flunarizine HCl, loratadine, meclozine HCl,
  • keratolytics such as acutretin, calciprotiene, calcifediol, calcitriol, cholecalciferol, ergocalciferol, etretinate, retinoids, targretin, and tazarotene;
  • lipid regulating agents such as atorvastatin, bezafibrate, cerivistatin, clinofibrate, clofibrate, fenofibrate, fluvastatin, gemfibrozil, pravastatin, probucol, and simvastatin;
  • muscle relaxants such as dantrolene sodium and tizanidine HCl
  • nitrates and other anti-anginal agents such as amyl nitrate, glyceryl trinitrate, isosorbide dinitrate, isosorbide mononitrate and pentaerythritol tetranitrate;
  • nutritional agents such as calcitriol, carotenes, dihydrotachysterol, essential fatty acids, non-essential fatty acids, phytonodione, vitamin A, vitamin B 2 , vitamin D, vitamin E and vitamin K.
  • opioid analgesics such as codeine, dextropropyoxyphene, diamorphine, dihydrocodeine, fentanyl, meptazinol, methadone, morphine, nalbuphine and pentazocine;
  • sex hormones such as clomiphene citrate, cortisone acetate, danazol, dihydro epiandrosterone, ethinyloestradiol, finasteride, fludrocortisone, fluoxymisterone, medroxyprogesterone acetate, megesterol acetate, mestranol, methyltestosterone, norethisterone, norgestrel, oestradiol, conjugated estrogens, progesterone, rimexolone, stanozolol, stiboestrol, testosterone and tibolone;
  • sex hormones such as clomiphene citrate, cortisone acetate, danazol, dihydro epiandrosterone, ethinyloestradiol, finasteride, fludrocortisone, fluoxymisterone, medroxyprogesterone acetate, megesterol acetate, mestranol,
  • stimulants such as amphetamine, dexamphetamine, dexfenfluramine, fenfluramine and mazindol;
  • Preferred hydrophobic therapeutic agents include sildenafil citrate, amlodipine, tramadol, celecoxib, refocoxib, oxaprozin, nabumetone, ibuprofen, terbenafine, itraconazole, zileuton, zafirlukast, cisapride, fenofibrate, tizanidine, nizatidine, fexofenadine, loratadine, famotidine, paricalcitol, atovaquone, nabumetone, tetrahydrocannabinol, megesterol acetate, repaglinide, progesterone, rimexolone, cyclosporine, tacrolimus, sirolimus, teniposide, paclitaxel, pseudo-ephedrine, troglitazone, rosiglitazone, finasteride, vitamin A, vitamin
  • compositions of the present invention are merely illustrative. Indeed, a particular feature, and surprising advantage, of the compositions of the present invention is the ability of the present compositions to solubilize and deliver a broad range of hydrophobic therapeutic agents, regardless of functional class. Of course, mixtures of hydrophobic therapeutic agents may also be used where desired.
  • compositions of the present invention can optionally include additional compounds to enhance the solubility of the hydrophobic therapeutic agent in the carrier system.
  • additional compounds include:
  • alcohols and polyols such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives;
  • ethers of polyethylene glycols having an average molecular weight of about 200 to about 6000 such as tetrahydrofurfuryl alcohol PEG ether (glycofurol, available commercially from BASF under the trade name Tetraglycol) or methoxy PEG (Union Carbide);
  • amides such as 2-pyrrolidone, 2-piperidone, ⁇ -caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide, and polyvinylpyrrolidone;
  • esters such as ethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ⁇ -caprolactone and isomers thereof, ⁇ -valerolactone and isomers thereof, ⁇ -butyrolactone and isomers thereof;
  • solubilizers such as dimethyl acetamide, dimethyl isosorbide (Arlasolve DMI (ICI)), N-methyl pyrrolidones (Pharmasolve (ISP)), monooctanoin, diethylene glycol monoethyl ether (available from Gattefosse under the trade name Transcutol), and water.
  • Preferred solubilizers include triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene glycol 200-600, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide.
  • Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propylene glycol.
  • the amount of solubilizer that can be included in compositions of the present invention is not particularly limited.
  • the amount of a given solubilizer is limited to a bioacceptable amount, which is readily determined by one of skill in the art.
  • the solubilizer can be in a concentration of 50%, 100%, 200%, or up to about 400% by weight, based on the amount of surfactant.
  • solubilizers may also be used, such as 25%, 10%, 5%, 1% or even less.
  • the solubilizer will be present in an amount of about 1% to about 100%, more typically about 5% to about 25% by weight.
  • additives conventionally used in pharmaceutical compositions can be included, and these additives are well known in the art.
  • additives include antioxidants, preservatives, chelating agents, viscomodulators, tonicifiers, flavorants, colorants odorants, opacifiers, suspending agents, binders, and mixtures thereof.
  • the amounts of such additives can be readily determined by one skilled in the art, according to the particular properties desired.
  • compositions of the present invention can be provided in the form of a solution preconcentrate; i.e., a composition as described above, and intended to be dispersed with water, either prior to administration, in the form of a drink, or dispersed in vivo.
  • the compositions can be provided in the form of a diluted preconcentrate (i.e., an aqueous dispersion), a semi-solid dispersion or a solid dispersion.
  • the compositions may be encapsulated in a hard or soft gelatin capsule, a starch capsule or an enteric coated capsule.
  • enteric coated capsule means a capsule coated with a coating resistant to acid; i.e., an acid resistant enteric coating.
  • solubilizers are typically used to enhance the solubility of a hydrophobic therapeutic agent, they may also render the compositions more suitable for encapsulation in hard or soft gelatin capsules.
  • a solubilizer such as those described above is particularly preferred in capsule dosage forms of the pharmaceutical compositions. If present, these solubilizers should be added in amounts sufficient to impart to the compositions the desired solubility enhancement or encapsulation properties.
  • compositions of the present invention can also be formulated for topical, transdermal, ocular, pulmonary, vaginal, rectal, transmucosal or parenteral administration, in the form of a triglyceride-free cream, lotion, ointment, suppository, gel or the like. If such a formulation is desired, other additives may be included, such as are well-known in the art, to impart the desired consistency and other properties to the formulation.
  • the compositions of the present invention can also be formulated as a spray or an aerosol.
  • the compositions may be formulated as a sprayable solution, and such formulation is particularly useful for spraying to coat a multiparticulate carrier, such as a bead.
  • multiparticulate carriers are well known in the art.
  • compositions of the present invention can be prepared by conventional methods well known to those skilled in the art. Of course, the specific method of preparation will depend upon the ultimate dosage form.
  • dosage forms substantially free of water i.e., when the composition is provided in a pre-concentrated form for later dispersion in an aqueous system, the composition is prepared by simple mixing of the components to form a pre-concentrate. The mixing process can be aided by gentle heating, if desired.
  • the pre-concentrate form is prepared, then the appropriate amount of purified water is added. Upon gentle mixing, a clear aqueous dispersion is formed. If any water-soluble additives are included, these may be added first as part of the pre-concentrate, or added later to the clear aqueous dispersion, as desired.
  • the present invention includes a multi-phase dispersion.
  • a pharmaceutical composition includes a carrier which forms a clear aqueous dispersion upon mixing with an aqueous solution, and an additional amount of non-solubilized hydrophobic therapeutic agent.
  • multi-phase as used herein to describe these compositions of the present invention means a composition which when mixed with an aqueous solution forms a clear aqueous phase and a particulate dispersion phase.
  • the carrier is as described above, and can include any of the surfactants, hydrophobic therapeutic agents, solubilizers and additives previously described. An additional amount of hydrophobic therapeutic agent is included in the composition.
  • the composition contains two phases: a clear aqueous dispersion of the hydrophilic and hydrophobic surfactants containing a first, solubilized amount of the hydrophobic therapeutic agent, and a second, non-solubilized amount of the hydrophobic therapeutic agent dispersed therein.
  • the resultant multi-phase dispersion will not have the optical clarity of a dispersion in which the hydrophobic therapeutic agent is fully solubilized, but will appear to be cloudy, due to the presence of the non-solubilized phase.
  • a formulation may be useful, for example, when the desired dosage of a hydrophobic therapeutic agent exceeds that which can be solubilized in the carrier of the present invention.
  • the formulation may also contain additives, as described above.
  • a hydrophobic therapeutic agent may have a greater solubility in the pre-concentrate carrier than in the aqueous dispersion, so that meta-stable, supersaturated solutions having apparent optical clarity but containing a hydrophobic therapeutic agent in an amount in excess of its solubility in the aqueous dispersion can be formed.
  • Such super-saturated solutions whether characterized as clear aqueous dispersions (as initially formed) or as multi-phase solutions (as would be expected if the meta-stable state breaks down), are also within the scope of the present invention.
  • the multi-phase formulation can be prepared by the methods described above.
  • a pre-concentrate is prepared by simple mixing of the components, with the aid of gentle heating, if desired. It is convenient to consider the hydrophobic therapeutic agent as divided into two portions, a first solubilizable portion which will be solubilized by the carrier and contained within the clear aqueous dispersion upon dilution, and a second non-solubilizable portion which will remain non-solubilized. When the ultimate dosage form is non-aqueous, the first and second portions of the hydrophobic therapeutic agent are both included in the pre-concentrate mixture.
  • the composition can be prepared in the same manner, and upon dilution in an aqueous system, the composition will form the two phases as described above, with the second non-solubilizable portion of the hydrophobic therapeutic agent dispersed or suspended in the aqueous system, and the first solubilizable portion of the hydrophobic therapeutic agent solubilized in the mixed surfactant carrier.
  • the pre-concentrate can be prepared including only the first, solubilizable portion of the hydrophobic therapeutic agent.
  • This pre-concentrate can then be diluted in an aqueous system to form a clear aqueous dispersion, to which is then added the second, non-solubilizable portion of the hydrophobic therapeutic agent to form a multi-phase aqueous composition.
  • the amount of hydrophobic therapeutic agent included in the pharmaceutical compositions of the present invention can be any amount desired by the formulator, up to the maximum amount that can be solubilized or suspended in a given carrier system. In general, the amount of hydrophobic therapeutic agent will be about 0.1% to about 60% by weight, based on the total weight of the pharmaceutical composition. In another aspect of the invention, described below, excess hydrophobic therapeutic agent can also be added, in a multi-phase dispersion.
  • the present invention relates to methods of improving delivery of hydrophobic therapeutic agents in an animal by administering to the animal a dosage form of the pharmaceutical compositions described herein.
  • the animal is a mammal, and more preferably, a human.
  • the pharmaceutical compositions of the present invention when administered to an animal enable the hydrophobic therapeutic agent contained therein to be absorbed more rapidly than in conventional pharmaceutical compositions.
  • the invention relates to a method of increasing the rate of and/or extent of bioabsorption of a hydrophobic therapeutic agent by administering the hydrophobic therapeutic agent to an animal in the pharmaceutical compositions described herein.
  • compositions of the present invention have the following characteristics:
  • Rapid formation upon dilution with an aqueous solution, the carrier forms a clear dispersion very rapidly; i.e., the clear dispersion appears to form instantaneously.
  • Optical clarity the dispersions are essentially optically clear to the naked eye, and show no readily observable signs of heterogeneity, such as turbidity or cloudiness. More quantitatively, dispersions of the pharmaceutical compositions of the present invention show a mono-modal distribution of very small particles sizes, typically 20 nm or less in average diameter; absorbances of less than about 0.3, typically less than about 0.1, at 10 ⁇ dilution; and absorbances of less than about 0.1, typically less than about 0.01, at 100 ⁇ dilution, as described more fully in the Examples herein. In the multi-phase embodiment of the compositions described herein, it should be appreciated that the optical clarity of the aqueous carrier dispersion phase will be obscured by the dispersed particulate non-solubilized hydrophobic therapeutic agent.
  • the dispersions are surprisingly stable to dilution in aqueous solution, including aqueous solutions simulating physiological fluids such as enzyme-free simulated gastric fluid (SGF) and enzyme-free simulated intestinal fluid (SIF).
  • SGF enzyme-free simulated gastric fluid
  • SIF enzyme-free simulated intestinal fluid
  • the hydrophobic therapeutic agent remains solubilized for at least the period of time relevant for absorption.
  • Triglyceride-free It is a particular feature of the present invention that the pharmaceutical compositions are substantially triglyceride-free.
  • triglyceride as used herein means glycerol triesters of C 6 to about C 25 fatty acids.
  • the present compositions surprisingly solubilize hydrophobic therapeutic agents using combinations of substantially triglyceride-free surfactants.
  • substantially triglyceride-free means compositions which contain triglycerides, if at all, only as minor components or impurities in surfactant mixtures. It is well known in the art that commercially available surfactants often are complex mixtures of compounds. For example, one preferred surfactant is Capmul® GMO-K, a widely-used blend of glyceryl mono- and dioleates.
  • Capmul® GMO-K contains the following distribution of glyceryl esters, in percent by weight based on the total weight of glyceryl esters: Palmitic acid 3.3% Stearic acid 4.0% Oleic acid 81.0% Linoleic acid 9.7% Linolenic acid 0.3%
  • the surfactant mixture in the particular lot reported contains 0.10% water and 0.95% free, unesterified glycerol. These specific percentages are expected to vary, lot-by-lot, as well, and it is expected that commercial surfactant products will generally possess similar variability, regardless of the specific major component and the specific manufacturer.
  • the present invention does not include surfactants which contain triglycerides as an intended component. Indeed, such surfactants are not common, since triglycerides themselves have no surfactant properties. However, it should be appreciated that the present invention does not exclude the use of surfactant products which contain small amounts of triglycerides as impurities or as unreacted starting material.
  • substantially triglyceride-free should be understood as meaning free of added triglycerides, and containing less than 5%, preferably essentially 0%, triglyceride impurities.
  • each micelle is composed of molecules (or ions) of both the hydrophilic and hydrophobic surfactants.
  • the hydrophobic therapeutic agent may be distributed in any part of the micelle, such as near the outer, more hydrophilic region, near the inner, more hydrophobic region, or at various points in between.
  • micelles exist in dynamic equilibrium with their component molecules, and it is expected that this equilibrium will include dynamic redistribution of the hydrophobic therapeutic agent.
  • triglyceride-containing formulations suffer the disadvantage that bioabsorption of the hydrophobic therapeutic agents contained therein is dependent upon enzymatic degradation (lipolysis) of the triglyceride components.
  • the pharmaceutical compositions of the present invention are substantially free of triglycerides, and thus do not depend upon lipolysis to enable release of the hydrophobic therapeutic agent for bioabsorption.
  • the hydrophobic therapeutic agent is in a dynamic equilibrium between the free compound in solution and the solubilized compound, thus promoting rapid release.
  • compositions of the present invention present a number of significant and unexpected advantages, including:
  • Efficient transport The particle sizes in the aqueous dispersions of the present invention are much smaller, typically less than 20 nm, than the larger particles characteristic of vesicular, emulsion or microemulsion phases, and the particle size distribution is mono-modal and narrow. This reduced and more uniform size enables more efficient drug transport through the intestinal aqueous boundary layer, and through the absorptive brush border membrane. More efficient transport to absorptive sites leads to improved and more consistent absorption of hydrophobic therapeutic agents.
  • Non-dependence on lipolysis The lack of triglyceride components provides pharmaceutical compositions not dependent upon lipolysis, and upon the many poorly characterized factors which affect the rate and extent of lipolysis, for effective presentation of a hydrophobic therapeutic agent to an absorptive site. Such factors include the presence of composition components which may inhibit lipolysis; patient conditions which limit production of lipase, such as pancreatic lipase secretory diseases; and dependence of lipolysis on stomach pH, endogenous calcium concentration, and presence of co-lipase or other digestion enzymes.
  • compositions of the present invention can make use of hydrophilic surfactants which might otherwise be avoided or limited due to their potential lipolysis inhibiting effects.
  • Non-dependence on bile and meal fat contents Due to the higher solubilization potential over bile salt micelles, the present compositions are less dependent on endogenous bile and bile related patient disease states, and meal fat contents. These advantages overcome meal-dependent absorption problems caused by poor patient compliance with meal-dosage restrictions.
  • compositions of the present invention enable superior loading capacity over conventional micelle formulations.
  • particular combination of surfactants used can be optimized for a specific hydrophobic therapeutic agent to more closely match the polarity distribution of the therapeutic agent, resulting in still further enhanced solubilization.
  • Aqueous dispersions of the present invention are thermodynamically stable for the time period relevant for absorption, and can be more predictably reproduced, thereby limiting variability in bioavailability—a particularly important advantage for therapeutic agents with a narrow therapeutic index.
  • compositions of the present invention are designed with components that help to keep the hydrophobic therapeutic agent solubilized for transport to the absorption site, but readily available for absorption, thus providing a more efficient transport and release.
  • the present compositions are less prone to gastric emptying delays, resulting in faster absorption. Further, the particles in dispersions of the present invention are less prone to unwanted retention in the gastro-intestinal tract.
  • the pharmaceutical compositions of the present invention allow for faster transport of the hydrophobic therapeutic agent through the aqueous boundary layer.
  • a simple pre-concentrate of a hydrophobic surfactant and a hydrophilic surfactant is prepared as follows. Predetermined weighed amounts of hydrophilic and hydrophobic surfactants are stirred together to form a homogeneous mixture. For surfactant combinations that are poorly miscible, the mixture can be gently heated to aid in formation of the homogeneous mixture. A chosen hydrophobic therapeutic agent in a predetermined amount is added and stirred until solubilized. Optionally, solubilizers or additives are included by simple mixing.
  • a predetermined amount of purified water, buffer solution, or aqueous simulated physiological solution is added to the pre-concentrate, and the resultant mixture is stirred to form a clear, aqueous dispersion.
  • Surfactant mixtures giving clear, aqueous dispersions were prepared according to the method of Example 1. Seven hydrophilic surfactants and sixteen hydrophobic surfactants were used to produce approximately one hundred clear aqueous dispersions suitable for use in the present invention. For simplicity, no hydrophobic therapeutic agent was included in these compositions, since it is believed that the presence of the hydrophobic therapeutic agent does not substantially affect the clear, aqueous nature of composition. For the same reason, these compositions were free of additional solubilizers and other additives.
  • Each entry in the Table represents the approximate maximum number of grams of hydrophobic surfactant per 100 g of hydrophilic surfactant giving acceptable optical clarity.
  • the numbers in the Table are illustrative only, and it is expected that further optimization of the surfactant systems with solubilizers, co-surfactants, and other additives will give still higher numbers.
  • Example 2 The procedure of Example 2 was repeated for compositions containing PEG-40 hydrogenated castor oil (Cremophor RH 40) as the hydrophilic surfactant, with eight different hydrophobic surfactants, and four different solubilizers, to study the effect of solubilizer on the relative amounts of hydrophobic and hydrophilic surfactants giving clear aqueous dispersions.
  • the amount of solubilizer was held constant at 20% by weight, based on the total weight of the two surfactants.
  • Table 20 As in Example 2, the numbers in the Table represent the approximate maximum number of grams of hydrophobic surfactant per 100 g of hydrophilic surfactant giving a clear aqueous dispersion.
  • Example 3 was repeated, this time choosing a single hydrophobic surfactant (Arlacel 186) and three different hydrophilic surfactants, with addition of either ethanol or triacetin (20% by weight, based on the total weight of the two surfactants). The results are shown in Table 21. The corresponding entry from Table 19 (with no solubilizer present) is included in Table 21 for reference.
  • Example 3 The procedure of Example 3 was repeated, with the following differences.
  • a single hydrophilic surfactant (Cremophor RH-40) and hydrophobic surfactant (Arlacel 186) were chosen, to examine the effect of increased solubilizer concentration.
  • compositions were tested at a solubilizer concentration of 50% by weight, based on the total weight of the surfactant pair.
  • the numbers in Table 22 represent the maximum hydrophobic surfactant concentration giving a clear aqueous dispersion.
  • Example 5 was repeated, using the same surfactant pair, but with an 80% concentration of solubilizer, based on the total weight of the surfactants.
  • the 80% solubilizer was either PEG-400, or a mixture of PEG-400 and one of three alcohols or polyols.
  • the results are shown in Table 23, with the numbers in the Table having the same meaning as in the previous Examples. TABLE 23 Large Solubilizer Concentrations and Solubilizer Mixtures* 60% 60% 60% PEG-400 + PEG-400 + (no 80% PEG-400 + 20% Propylene 20% solubilizer) PEG-400 20% Glycerol Glycol Isopropanol 20 25 25 25 25 25 25
  • compositions of the present invention produce clear, aqueous dispersions, with no visible cloudiness.
  • the particle size distribution shows very small particles, with average diameters of from about 6 to about 15 nm.
  • the distribution is mono-modal, with a standard deviation of approximately 20%, indicating a highly uniform distribution of very small particles.
  • This particle size distribution is consistent with a solution of particles of micellar structure, although the invention is not limited by any particular theoretical framework.
  • compositions were prepared having hydrophobic surfactant concentrations higher than those suitable for forming clear aqueous dispersions. These compositions were prepared by weighing the components and mixing well, with gentle warming. The compositions were then diluted 10 ⁇ to form dispersions, and these dispersions were subjected to the particle size measurements as described in Example 7. The results are shown in Table 25. For direct comparison with the compositions of the present invention, Examples 7, 9, 10, 11 and 12 are shown next to the corresponding comparative compositions. TABLE 25 Optical Clarity and Particle Size Example Surfactant Particle Size (nm)** No.
  • compositions containing Tween 80 and Plurol Oleique CC497, Tween 80 and Peceol, and Tween 80 and Capmul MCM were prepared at a surfactant ratio of 67 g hydrophobic surfactant per 100 g hydrophilic surfactant. Particle sizes were not measured for these compositions, but each was observed to form a milky or hazy aqueous dispersion.
  • compositions having excessive amounts of hydrophobic surfactant form milky or hazy solutions, whereas those of the present invention form clear solutions.
  • the particle size distributions of the milky solutions are bimodal, in contrast to the mono-modal solutions of the corresponding clear solutions. These bimodal particle size distributions show a first mode having a small mean particle size of about 12 to about 27 nm, and a second mode having particle sizes of up to more than 200 nm.
  • compositions having excessive hydrophobic surfactant are heterogeneous (multi-phasic), non-clear dispersions, having a complex bimodal distribution of particles of two distinct size ranges.
  • compositions of the present invention are homogeneous (single phase), clear dispersion, having a mono-modal distribution of very small particle sizes.
  • compositions were prepared according to Example 1, and diluted to 10 ⁇ and 100 ⁇ solutions.
  • the specific compositions measured also include a solubilizer, to further illustrate preferred aspects of the invention.
  • compositions according to the present invention wherein either the hydrophilic surfactant (Examples 20 and 27) or the hydrophobic surfactant (Examples 41 and 42) itself is a mixture of surfactants.
  • a clear aqueous dispersion should have a very high transmittance, indicating little scattering of light by large particles. Absorbance and transmittance are related by the simple expression
  • suitable clear aqueous dispersions of the present invention should have an absorbance at 10 ⁇ dilution of less than about 0.3.
  • compositions observed to be milky or cloudy were characterized by absorption, as in Examples 13-42. Where available, results for comparable solutions from Examples 13-42 are reproduced for comparison. In such cases, where a given surfactant combination is presented in Examples 13-42 more than once (with different solubilizer concentrations), the composition having the lowest solubilizer concentration is chosen, to facilitate more direct comparison. The results are shown in Table 27. TABLE 27 Comparative Spectroscopic Characterization Example Absorbance (400.2 nm) No.
  • the solubility experiment of Examples 43-44 was performed on four standard aqueous solutions.
  • the first comparison solution was purified water with no additives.
  • a standard simulated intestinal fluid (SIF) was used, to simulate the in vivo conditions to be encountered by the hydrophobic therapeutic agent.
  • a third solution was prepared with simulated intestinal fluid, plus an additional aliquot of 20 mM sodium taurocholate (a bile salt); this solution is designated SIFB in Table 29.
  • a fourth solution was prepared with simulated intestinal fluid, 20 mM sodium taurocholate, and 5 mM lecithin; this solution is designated SIFBL.
  • the solubility of the polyfunctional hydrophobic therapeutic agent in the compositions of the present invention is far greater than its solubility in aqueous and gastrointestinal aqueous solutions.
  • the solubility of the lipophilic hydrophobic therapeutic agent in the compositions of the present invention is far greater than its solubility in aqueous and gastrointestinal aqueous solutions.
  • compositions according to the present invention were prepared, with a typical polyfunctional hydrophobic therapeutic agent, cyclosporin, as the therapeutic agent.
  • the compositions were prepared as described in Example 1, except that the ingredients were added in the order listed in Table 32.
  • the pre-concentrates were diluted 100 ⁇ with purified water, and a visual observation was made immediately after dilution. The solutions were then allowed to stand 6 hours to assess dilution stability, then the cyclosporin concentration in solution was measured, using a drug-specific HPLC assay. The results are shown in Table 32. TABLE 32 Dilution Stability of Polyfunctional Therapeutic Agents Cyclosporin Example Concen- No.
  • compositions according to the present invention were prepared, with a typical lipophilic hydrophobic therapeutic agent, progesterone, as the therapeutic agent.
  • the compositions were prepared and analyzed as in Examples 50-57, and the results are shown in Table 33. TABLE 33 Dilution Stability of Lipophilic Therapeutic Agents Proges- terone Example Concen- No.
  • a representative preconcentrate of the present invention containing a cyclosporin hydrophobic therapeutic agent was used.
  • the composition had the following formulation: Cyclosporine 0.140 g Cremophor RH-40 0.41 g Arlacel 186 0.29 g Sodium taurocholate 0.26 g Propylene glycol 0.46 g
  • the preconcentrate was diluted with an isotonic aqueous HEPES buffer rather than purified water.
  • the resultant solution was spiked with radioactive active and perfused through isolated ileal lumen segment of known length and diameter. Loss of radioactivity from the lumenal side and appearance of radioactivity in the mesenteric blood from the other side was monitored as an indicator of absorption.
  • Jugular vein cannulation the animal was anesthetized using 2% halothane in 98% oxygen via a halothane vaporizer (Vapomatic, A. M. Bickford, Inc., NY). An opening in the jugular vein was made with a 21 ga needle and a jugular cannula consisting of a 4 cm segment of silastic tubing connected to polyethylene tubing was inserted in the jugular vein and secured with cyanoacrylate glue.
  • Intestine cannulation after the animal was anesthetized, its body temperature was maintained at 37° C. using a heating pad. A vertical midline incision of approximately 3 cm was made through the skin to expose the small intestine. Approximately 6-10 cm segment of ileum was located. Using electro-cautery, a small incision was made at the ends of the segment and the lumenal contents were flushed with saline maintained at 37° C. Two 1.5 cm notched pieces of Teflon tubing were inserted into the intestinal lumen at each incision and tightened using 4-0 silk. A warm isotonic buffer was passed through the intestine using a 50-mL syringe. These Teflon cannula were used to perfuse the drug solution through the isolated intestinal segment using a syringe pump.
  • mesenteric vein cannulation the mesenteric vein draining blood from the resulting isolated mesenteric cascade venules was then cannulated using a 24 ga IV catheter and secured in place using 4-0 silk sutures. The cannula was then connected to a polyethylene tubing 25 cm long where the blood was collected in a vial kept under the animal level. Blood samples were collected continuously over 60 min. The infusion of blood via the jugular vein was initiated to replenish blood loss. The animal was then killed by a lethal injection of Phenobarbital after completion of the experiment.
  • FIG. 1 shows the accumulated radioactivity ( ⁇ Ci/cm 2 ⁇ Ci) in mesenteric blood as a function of time, over the course of 60 minutes, for the pharmaceutical compositions of the present invention (filled squares) and a commercial cyclosporin formulation (filled circles).
  • the bioabsorption of the hydrophobic therapeutic agent exceeds that of the commercial formulation at the earliest measurement point, and continues to increase relative to the commercial formulation over the course of the measurement interval.
  • the bioabsorption of the hydrophobic therapeutic agent from the compositions of the present invention exceeds that of the commercial formulation by nearly 100%.

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Abstract

The present invention relates to triglyceride-free pharmaceutical compositions for delivery of hydrophobic therapeutic agents. Compositions of the present invention include a hydrophobic therapeutic agent and a carrier, where the carrier is formed from a combination of a hydrophilic surfactant and a hydrophobic surfactant. Upon dilution with an aqueous solvent, the composition forms a clear, aqueous dispersion of the surfactants containing the therapeutic agent. The invention also provides methods of treatment with hydrophobic therapeutic agents using these compositions.

Description

    FIELD OF THE INVENTION
  • The present invention relates to drug delivery systems, and in particular to pharmaceutical compositions for the improved delivery of hydrophobic compounds. [0001]
    • BACKGROUND
  • Hydrophobic therapeutic agents, i.e., therapeutic compounds having poor solubility in aqueous solution, present difficult problems in formulating such compounds for effective administration to patients. A well-designed formulation must, at a minimum, be capable of presenting a therapeutically effective amount of the hydrophobic compound to the desired absorption site, in an absorbable form. Even this minimal functionality is difficult to achieve when delivery of the hydrophobic therapeutic agent requires interaction with aqueous physiological environments, such as gastric fluids and intestinal fluids. Pharmaceutical compositions for delivery of such hydrophobic therapeutic agents must carry the hydrophobic compound through the aqueous environment, while maintaining the hydrophobic compound in an absorbable form, and avoiding the use of physiologically harmful solvents or excipients. [0002]
  • A number of approaches to formulating hydrophobic therapeutic agents for oral or parenteral delivery are known. One well-known approach uses surfactant micelles to solubilize and transport the therapeutic agent. Micelles are agglomerates of colloidal dimensions formed by amphiphilic compounds under certain conditions. Micelles, and pharmaceutical compositions containing micelles, have been extensively studied and are described in detail in the literature; see, e.g., Remington's Pharmaceutical Sciences, 17[0003] th ed. (1985), the disclosure of which is incorporated herein in its entirety. In aqueous solution, micelles can incorporate hydrophobic therapeutic agents in the hydrocarbon core of the micelle, or entangled at various positions within the micelle walls. Although micellar formulations can solubilize a variety of hydrophobic therapeutic agents, the loading capacity of conventional micelle formulations is limited by the solubility of the therapeutic agent in the micelle surfactant. For many hydrophobic therapeutic agents, such solubility is too low to offer formulations that can deliver therapeutically effective doses.
  • Another conventional approach takes advantage of the increased solubility of hydrophobic therapeutic agents in oils (triglycerides). Hydrophobic therapeutic agents, while poorly soluble in aqueous solution, could be sufficiently lipophilic that therapeutically effective concentrations of the therapeutic agents can be prepared in triglyceride-based solvents. Thus, one conventional approach is to solubilize a hydrophobic therapeutic agent in a bioacceptable triglyceride solvent, such as a digestible vegetable oil, and disperse this oil phase in an aqueous solution. The dispersion may be stabilized by emulsifying agents and provided in emulsion form. Alternatively, the therapeutic agent can be provided in a water-free formulation, with an aqueous dispersion being formed in the in vivo gastrointestinal environment. The properties of these oil-based formulations are determined by such factors as the size of the triglyceride/therapeutic agent colloidal particles and the presence or absence of surfactant additives. [0004]
  • In simplest form, a triglyceride-containing formulation suitable for delivering hydrophobic therapeutic agents through an aqueous environment is an oil-in-water emulsion. Such emulsions contain the hydrophobic therapeutic agent solubilized in an oil phase which is dispersed in an aqueous environment with the aid of a surfactant. The surfactant may be present in the oil-based formulation itself, or may be a compound provided in the gastrointestinal system, such as bile salts, which are known to be in vivo emulsifying agents. The colloidal oil particles sizes are relatively large, ranging from several hundred nanometers to several microns in diameter, in a broad particle size distribution. Since the particle sizes are on the order of or greater than the wavelength range of visible light, such emulsions, when prepared in an emulsion dosage form, are visibly “cloudy” or “milky” to the naked eye. [0005]
  • Although triglyceride-based pharmaceutical compositions are useful in solubilizing and delivering some hydrophobic therapeutic agents, such compositions are subject to a number of significant limitations and disadvantages. Emulsions are thermodynamically unstable, and colloidal emulsion particles will spontaneously agglomerate, eventually leading to complete phase separation. The tendency to agglomerate and phase separate presents problems of storage and handling, and increases the likelihood that pharmaceutical emulsions initially properly prepared will be in a less optimal, less effective, and poorly-characterized state upon ultimate administration to a patient. Uncharacterized degradation is particularly disadvantageous, since increased particle size slows the rate of transport of the colloidal particle and digestion of the oil component, and hence the rate and extent of absorption of the therapeutic agent. These problems lead to poorly-characterized and potentially harmful changes in the effective dosage received by the patient. Moreover, changes in colloidal emulsion particle size are also believed to render absorption more sensitive to and dependent upon conditions in the gastrointestinal tract, such as pH, enzyme activity, bile components, and stomach contents. Such uncertainty in the rate and extent of ultimate absorption of the therapeutic agent severely compromises the medical professional's ability to safely administer therapeutically effective dosages. [0006]
  • A further disadvantage of triglyceride-containing compositions is the dependence of therapeutic agent absorption on the rate and extent of lipolysis. Although colloidal emulsion particles can transport hydrophobic therapeutic agents through the aqueous environment of the gastrointestinal tract, ultimately the triglyceride must be digested and the therapeutic agent must be released in order to be absorbed through the intestinal mucosa. The triglyceride carrier is emulsified by bile salts and hydrolyzed, primarily by pancreatic lipase. The rate and extent of lipolysis, however, are dependent upon several factors that are difficult to adequately control. For example, the amount and rate of bile salt secretion affect the lipolysis of the triglycerides, and the bile salt secretion can vary with stomach contents, with metabolic abnormalities, and with functional changes of the liver, bile ducts, gall bladder and intestine. Lipase availability in patients with decreased pancreatic secretory function, such as cystic fibrosis or chronic pancreatitis, may be undesirably low, resulting in a slow and incomplete triglyceride lipolysis. The activity of lipase is pH dependent, with deactivation occurring at about pH 3, so that the lipolysis rate will vary with stomach contents, and may be insufficient in patients with gastric acid hyper-secretion. Moreover, certain surfactants commonly used in the preparation of pharmaceutical emulsions, such as polyethoxylated castor oils, may themselves act as inhibitors of lipolysis. Although recent work suggests that certain surfactant combinations, when used in combination with digestible oils in emulsion preparations, can substantially decrease the lipolysis-inhibiting effect of some common pharmaceutical surfactants (see, U.S. Pat. No. 5,645,856), such formulations are still subject to the other disadvantages of pharmaceutical emulsions and triglyceride-based formulations. [0007]
  • Yet another approach is based on formation of “microemulsions.” Like an emulsion, a microemulsion is a liquid dispersion of oil in water, stabilized by surfactants. The microemulsion particles are smaller than those of an emulsion, rendering the microemulsion essentially optically clear. Microemulsions, however, are thermodynamically stable, and are not subject to the particle agglomeration problems of conventional emulsions. It is generally believed that microemulsions are micelle-like particles, having an essentially micellar structure but containing a distinct oil phase in the micelle “core”. These micelle-like particles are often referred to as “swollen micelles”, a term which emphasizes their close relationship to true micellar particles. Despite their close relationship to micelles, microemulsions function quite differently in drug delivery systems. The majority of hydrophobic therapeutic agents are lipophilic, and have greater solubility in triglycerides than in surfactants. As a result, the hydrophobic therapeutic agent in a microemulsion-based delivery system is preferentially solvated in the triglyceride phase, which is in turn encapsulated in the swollen micelle. The preferential partitioning in the triglyceride phase results in higher loading capacities than in comparable micelle-based systems, but at the cost of introducing into the delivery system the lipolysis-dependence and other disadvantages associated with the presence of triglycerides. In addition, the larger size of microemulsion particles, relative to true micelles, results in a slower rate of particle diffusion, and thus a slower rate of therapeutic agent absorption. [0008]
  • Thus, there is a need for pharmaceutical compositions that overcome the limitations of conventional micelle formulations, but without suffering from the disadvantages of triglyceride-containing formulations. [0009]
    • SUMMARY OF THE INVENTION
  • It is therefore an object of the present invention to provide pharmaceutical compositions capable of solubilizing therapeutically effective amounts of hydrophobic therapeutic agents. [0010]
  • It is another object of the invention to provide pharmaceutical compositions that are homogeneous and thermodynamically stable. [0011]
  • It is yet another object of the invention to provide pharmaceutical compositions having a small and narrow particle size distribution. [0012]
  • It is still another object of the invention to provide pharmaceutical compositions of a hydrophobic therapeutic agent that are not dependent upon lipolysis for bioabsorption. [0013]
  • It is still another object of the invention to provide methods of treating a patient with a hydrophobic therapeutic agent. [0014]
  • It is still another object of the invention to provide less greasy pharmaceutical compositions for topical/transdermal delivery. [0015]
  • In accordance with these and other objects and features, the present invention provides pharmaceutical compositions for improved delivery of hydrophobic therapeutic agents. In one embodiment, the present invention provides a triglyceride-free pharmaceutical composition including a hydrophobic therapeutic agent and a carrier. The carrier includes a hydrophilic surfactant and a hydrophobic surfactant in amounts such that upon dilution with an aqueous solution such as simulated gastrointestinal fluids the carrier forms a clear aqueous dispersion of the hydrophilic and hydrophobic surfactants containing the hydrophobic therapeutic agent. [0016]
  • In another embodiment, the present invention provides a clear aqueous dispersion containing a hydrophilic surfactant, a hydrophobic surfactant and a hydrophobic therapeutic agent. The dispersion is substantially free of triglycerides. [0017]
  • In another embodiment, the present invention relates to a triglyceride-free pharmaceutical composition which includes a hydrophilic surfactant and a hydrophobic surfactant in amounts such that upon dilution with an aqueous solution a clear aqueous dispersion is formed, a first amount of a hydrophobic therapeutic agent solubilized in the clear aqueous dispersion, and a second amount of the hydrophobic therapeutic agent that remains non-solubilized but dispersed. [0018]
  • In another embodiment, the present invention relates to methods of increasing the rate and/or extent of absorption of hydrophobic therapeutic agents by administering to a patient a pharmaceutical composition of the present invention. [0019]
  • These and other objects and features of the present invention will become more fully apparent from the following description and appended claims, or may be learned by the practice of the invention as set forth hereinafter.[0020]
    • BRIEF DESCRIPTION OF THE DRAWINGS
  • In order to illustrate the manner in which the above-recited and other advantages and objects of the invention are obtained, a more particular description of the invention briefly described above will be rendered by reference to the specific embodiments shown in the appended drawings. Understanding that these drawings depict only typical embodiments of the invention and are not therefore limiting of its scope, the invention will be described and explained with additional specificity and detail through the use of the accompanying drawing, in which: [0021]
  • FIG. 1 shows the enhanced bioabsorption of a hydrophobic therapeutic agent in the compositions of the present invention, relative to a commercial formulation. [0022]
    • DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
  • The present invention overcomes the problems described above characteristic of conventional formulations such as micelle formulations, emulsions, and microemulsions, by providing unique triglyceride-free pharmaceutical compositions. Surprisingly, the present inventors have found that compositions including a combination of a hydrophilic surfactant and a hydrophobic surfactant can solubilize therapeutically effective amounts of hydrophobic therapeutic agents without recourse to the use of triglycerides, thereby avoiding the lipolysis dependence and other disadvantages of conventional formulations. Use of these formulations results in an enhanced rate and/or extent of absorption of the hydrophobic therapeutic agent. [0023]
  • A. Pharmaceutical Compositions [0024]
  • In one embodiment, the present invention provides a pharmaceutical composition including a carrier and a hydrophobic therapeutic agent. The carrier includes a hydrophilic surfactant and a hydrophobic surfactant in amounts such that upon dilution with an aqueous solution the carrier forms a clear aqueous dispersion of the hydrophilic and hydrophobic surfactants containing the hydrophobic therapeutic agent. It is a particular feature of the present invention that the carrier is substantially free of triglycerides, thereby providing surprising and important advantages over conventional, triglyceride-containing formulations. [0025]
  • 1. Surfactants [0026]
  • The carrier includes at least one hydrophilic surfactant and at least one hydrophobic surfactant. As is well known in the art, the terms “hydrophilic” and “hydrophobic” are relative terms. To function as a surfactant, a compound must necessarily include polar or charged hydrophilic moieties as well as non-polar hydrophobic (lipophilic) moieties; i.e., a surfactant compound must be amphiphilic. An empirical parameter commonly used to characterize the relative hydrophilicity and hydrophobicity of non-ionic amphiphilic compounds is the hydrophilic-lipophilic balance (“HLB” value). Surfactants with lower HLB values are more hydrophobic, and have greater solubility in oils, while surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions. [0027]
  • Using HLB values as a rough guide, hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable. Similarly, hydrophobic surfactants are compounds having an HLB value less than about 10. [0028]
  • It should be appreciated that the HLB value of a surfactant is merely a rough guide generally used to enable formulation of industrial, pharmaceutical and cosmetic emulsions. For many important surfactants, including several polyethoxylated surfactants, it has been reported that HLB values can differ by as much as about 8 HLB units, depending upon the empirical method chosen to determine the HLB value (Schott, [0029] J. Pharm. Sciences, 79(1), 87-88 (1990)). Likewise, for certain polypropylene oxide containing block copolymers (PLURONIC® surfactants, BASF Corp.), the HLB values may not accurately reflect the true physical chemical nature of the compounds. Finally, commercial surfactant products are generally not pure compounds, but are complex mixtures of compounds, and the HLB value reported for a particular compound may more accurately be characteristic of the commercial product of which the compound is a major component. Different commercial products having the same primary surfactant component can, and typically do, have different HLB values. In addition, a certain amount of lot-to-lot variability is expected even for a single commercial surfactant product. Keeping these inherent difficulties in mind, and using HLB values as a guide, one skilled in the art can readily identify surfactants having suitable hydrophilicity or hydrophobicity for use in the present invention, as described herein.
  • The hydrophilic surfactant can be any hydrophilic surfactant suitable for use in pharmaceutical compositions. Such surfactants can be anionic, cationic, zwitterionic or non-ionic, although non-ionic hydrophilic surfactants are presently preferred. As discussed above, these non-ionic hydrophilic surfactants will generally have HLB values greater than about 10. Mixtures of hydrophilic surfactants are also within the scope of the invention. [0030]
  • Similarly, the hydrophobic surfactant can be any hydrophobic surfactant suitable for use in pharmaceutical compositions. In general, suitable hydrophobic surfactants will have an HLB value less than about 10. Mixtures of hydrophobic surfactants are also within the scope of the invention. [0031]
  • The choice of specific hydrophobic and hydrophilic surfactants should be made keeping in mind the particular hydrophobic therapeutic agent to be used in the composition, and the range of polarity appropriate for the chosen therapeutic agent, as discussed in more detail below. With these general principles in mind, a very broad range of surfactants is suitable for use in the present invention. Such surfactants can be grouped into the following general chemical classes detailed in the Tables below. The HLB values given in the Tables below generally represent the HLB value as reported by the manufacturer of the corresponding commercial product. In cases where more than one commercial product is listed, the HLB value in the Tables is the value as reported for one of the commercial products, a rough average of the reported values, or a value that, in the judgment of the present inventors, is more reliable. It should be emphasized that the invention is not limited to the surfactants in the following Tables, which show representative, but not exclusive, lists of available surfactants. [0032]
  • 1.1. Polyethoxylated Fatty Acids [0033]
  • Although polyethylene glycol (PEG) itself does not function as a surfactant, a variety of PEG-fatty acid esters have useful surfactant properties. Among the PEG-fatty acid monoesters, esters of lauric acid, oleic acid, and stearic acid are most useful. Among the surfactants of Table 1, preferred hydrophilic surfactants include PEG-8 laurate, PEG-8 oleate, PEG-8 stearate, PEG-9 oleate, PEG-10 laurate, PEG-10 oleate, PEG-12 laurate, PEG-12 oleate, PEG-15 oleate, PEG-20 laurate and PEG-20 oleate. Examples of polyethoxylated fatty acid monoester surfactants commercially available are shown in Table 1. [0034]
    TABLE 1
    PEG-Fatty Acid Monoester Surfactants
    COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
    PEG 4-100 monolaurate Crodet L series (Croda) >9
    PEG 4-100 monooleate Crodet O series (Croda) >8
    PEG 4-100 monostearate Crodet S series (Croda), Myrj Series >6
    (Atlas/ICI)
    PEG 400 distearate Cithrol 4DS series (Croda) >10
    PEG 100,200,300 Cithrol ML series (Croda) >10
    monolaurate
    PEG 100,200,300 Cithrol MO series (Croda) >10
    monooleate
    PEG 400 dioleate Cithrol 4DO series (Croda) >10
    PEG 400-1000 Cithrol MS series (Croda) >10
    monostearate
    PEG-1 stearate Nikkol MYS-1EX (Nikko), Coster 2
    K1 (Condea)
    PEG-2 stearate Nikkol MYS-2 (Nikko) 4
    PEG-2 oleate Nikkol MYO-2 (Nikko) 4.5
    PEG-4 laurate Mapeg ® 200 ML (PPG), Kessco ® 9.3
    PEG 200ML (Stepan), LIPOPEG 2L
    (LIPO Chem.)
    PEG-4 oleate Mapeg ® 200 MO (PPG), Kessco ® 8.3
    PEG200 MO (Stepan),
    PEG-4 stearate Kessco ® PEG 200 MS (Stepan), 6.5
    Hodag 20 S (Calgene), Nikkol
    MYS-4 (Nikko)
    PEG-5 stearate Nikkol TMGS-5 (Nikko) 9.5
    PEG-5 oleate Nikkol TMGO-5 (Nikko) 9.5
    PEG-6 oleate Algon OL 60 (Auschem SpA),
    Kessco ® PEG 300 MO (Stepan), 8.5
    Nikkol MYO-6 (Nikko), Emulgante A6
    (Condea)
    PEG-7 oleate Algon OL 70 (Auschem SpA) 10.4
    PEG-6 laurate Kessco ® PEG300 ML (Stepan) 11.4
    PEG-7 laurate Lauridac 7 (Condea) 13
    PEG-6 stearate Kessco ® PEG300 MS (Stepan) 9.7
    PEG-8 laurate Mapeg ® 400 ML (PPG), LIPOPEG 13
    4DL(Lipo Chem.)
    PEG-8 oleate Mapeg ® 400 MO (PPG), Emulgante 12
    A8 (Condea)
    PEG-8 stearate Mapeg ® 400 MS (PPG), Myrj 45 12
    PEG-9 oleate Emulgante A9 (Condea) >10
    PEG-9 stearate Cremophor S9 (BASF) >10
    PEG-10 laurate Nikkol MYL-10 (Nikko), Lauridac 10 13
    (Croda)
    PEG-10 oleate Nikkol MYG-10 (Nikko) 11
    PEG-10 stearate Nikkol MYS-10 (Nikko), Coster K100 11
    (Condea)
    PEG-12 laurate Kessco ® PEG 600ML (Stepan) 15
    PEG-12 oleate Kessco ® PEG 600MO (Stepan) 14
    PEG-12 ricinoleate (CAS #9004-97-1) >10
    PEG-12 stearate Mapeg ® 600 MS (PPG), Kessco ® 14
    PEG 600MS (Stepan)
    PEG-15 stearate Nikkol TMGS-15 (Nikko), Koster K15 14
    (Condea)
    PEG-15 oleate Nikkol TMGO-15 (Nikko) 15
    PEG-20 laurate Kessco ® PEG 1000 ML (Stepan) 17
    PEG-20 oleate Kessco ® PEG 1000 MO (Stepan) 15
    PEG-20 stearate Mapeg ® 1000 MS (PPG), Kessco ® 16
    PEG 1000 MS (Stepan), Myrj 49
    PEG-25 stearate Nikkol MYS-25 (Nikko) 15
    PEG-32 laurate Kessco ® PEG 1540 ML (Stepan) 16
    PEG-32 oleate Kessco ® PEG 1540 MO (Stepan) 17
    PEG-32 stearate Kessco ® PEG 1540 MS (Stepan) 17
    PEG-30 stearate Myrj 51 >10
    PEG-40 laurate Crodet L40 (Croda) 17.9
    PEG-40 oleate Crodet O40 (Croda) 17.4
    PEG-40 stearate Myrj 52, Emerest ® 2715 (Henkel), >10
    Nikkol MYS-40 (Nikko)
    PEG-45 stearate Nikkol MYS-45 (Nikko) 18
    PEG-50 stearate Myrj 53 >10
    PEG-55 stearate Nikkol MYS-55 (Nikko) 18
    PEG-100 oleate Crodet O-100 (Croda) 18.8
    PEG-100 stearate Myrj 59, Arlacel 165 (ICI) 19
    PEG-200 oleate Albunol 200 MO (Taiwan Surf.) >10
    PEG-400 oleate LACTOMUL (Henkel), Albunol 400 >10
    MO (Taiwan Surf.)
    PEG-600 oleate Albunol 600 MO (Taiwan Surf.) >10
  • 1.2 PEG-Fatty Acid Diesters [0035]
  • Polyethylene glycol fatty acid diesters are also suitable for use as surfactants in the compositions of the present invention. Among the surfactants in Table 2, preferred hydrophilic surfactants include PEG-20 dilaurate, PEG-20 dioleate, PEG-20 distearate, PEG-32 dilaurate and PEG-32 dioleate. Representative PEG-fatty acid diesters are shown in Table 2. [0036]
    TABLE 2
    PEG-Fatty Acid Diester Surfactants
    COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
    PEG-4 dilaurate Mapeg ® 200 DL (PPG), Kessco ® PEG 7
    200 DL (Stepan), LIPOPEG 2-DL
    (Lipo Chem.)
    PEG-4 dioleate Mapeg ® 200 DO (PPG), 6
    PEG-4 distearate Kessco ® 200 DS (Stepan— 5
    PEG-6 dilaurate Kessco ® PEG 300 DL (Stepan) 9.8
    PEG-6 dioleate Kessco ® PEG 300 DO (Stepan) 7.2
    PEG-6 distearate Kessco ® PEG 300 DS (Stepan) 6.5
    PEG-8 dilaurate Mapeg ® 400 DL (PPG), Kessco ® PEG 11
    400 DL (Stepan), LIPOPEG 4 DL
    (Lipo Chem.)
    PEG-8 dioleate Mapeg ® 400 DO (PPG), Kessco ® PEG 8.8
    400 DO (Stepan), LIPOPEG 4 DO
    (Lipo Chem.)
    PEG-8 distearate Mapeg ® 400 DS (PPG), CDS 400 (Nikkol) 11
    PEG-10 dipalmitate Polyaldo 2PKFG >10
    PEG-12 dilaurate Kessco ® PEG 600 DL (Stepan) 11.7
    PEG-12 distearate Kessco ® PEG 600 DS (Stepan) 10.7
    PEG-12 dioleate Mapeg ® 600 DO (PPG), Kessco ® 600 10
    DO(Stepan)
    PEG-20 dilaurate Kessco ® PEG 1000 DL (Stepan) 15
    PEG-20 dioleate Kessco ® PEG 1000 DO (Stepan) 13
    PEG-20 distearate Kessco ® PEG 1000 DS (Stepan) 12
    PEG-32 dilaurate Kessco ® PEG 1540 DL (Stepan) 16
    PEG-32 dioleate Kessco ® PEG 1540 DO (Stepan) 15
    PEG-32 distearate Kessco ® PEG 1540 DS (Stepan) 15
    PEG-400 dioleate Cithrol 4DO series (Croda) >10
    PEG-400 distearate Cithrol 4DS series (Croda) >10
  • 1.3 PEG-Fatty Acid Mono- and Di-ester Mixtures [0037]
  • In general, mixtures of surfactants are also useful in the present invention, including mixtures of two or more commercial surfactant products. Several PEG-fatty acid esters are marketed commercially as mixtures or mono- and diesters. Representative surfactant mixtures are shown in Table 3. [0038]
    TABLE 3
    PEG-Fatty Acid Mono- and Diester Mixtures
    COMMERCIAL
    COMPOUND PRODUCT (Supplier) HLB
    PEG 4-150 mono, dilaurate Kessco ® PEG 200-6000 mono,
    dilaurate (Stepan)
    PEG 4-150 mono, dioleate Kessco ® PEG 200-6000 mono,
    dioleate (Stepan)
    PEG 4-150 mono, distearate Kessco ® 200-6000 mono,
    distearate (Stepan)
  • 1.4 Polyethylene Glycol Glycerol Fatty Acid Esters [0039]
  • Suitable PEG glycerol fatty acid esters are shown in Table 4. Among the surfactants in the Table, preferred hydrophilic surfactants are PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-20 glyceryl oleate, and PEG-30 glyceryl oleate. [0040]
    TABLE 4
    PEG Glycerol Fatty Acid Esters
    COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
    PEG-20 glyceryl laurate Tagat ® L (Goldschmidt) 16
    PEG-30 glyceryl laurate Tagat ® L2 (Goldschmidt) 16
    PEG-15 glyceryl laurate Glycerox L series (Croda) 15
    PEG-40 glyceryl laurate Glycerox L series (Croda) 15
    PEG-20 glyceryl stearate Capmul ® EMG (ABITEC), 13
    Aldo ® MS-20 KFG (Lonza)
    PEG-20 glyceryl oleate Tagat ® O (Goldschmidt) >10  
    PEG-30 glyceryl oleate Tagat ® O2 (Goldschmidt) >10  
  • 1.5. Alcohol-Oil Transesterification Products [0041]
  • A large number of surfactants of different degrees of hydrophobicity or hydrophilicity can be prepared by reaction of alcohols or polyalcohols with a variety of natural and/or hydrogenated oils. Most commonly, the oils used are castor oil or hydrogenated castor oil, or an edible vegetable oil such as corn oil, olive oil, peanut oil, palm kernel oil, apricot kernel oil, or almond oil. Preferred alcohols include glycerol, propylene glycol, ethylene glycol, polyethylene glycol, sorbitol, and pentaerythritol. Among these alcohol-oil transesterified surfactants, preferred hydrophilic surfactants are PEG-35 castor oil (Incrocas-35), PEG-40 hydrogenated castor oil (Cremophor RH 40), PEG-25 trioleate (TAGAT® TO), PEG-60 corn glycerides (Crovol M70), PEG-60 almond oil (Crovol A70), PEG-40 palm kernel oil (Crovol PK70), PEG-50 castor oil (Emalex C-50), PEG-50 hydrogenated castor oil (Emalex HC-50), PEG-8 caprylic/capric glycerides (Labrasol), and PEG-6 caprylic/capric glycerides (Softigen 767). Preferred hydrophobic surfactants in this class include PEG-5 hydrogenated castor oil, PEG-7 hydrogenated castor oil, PEG-9 hydrogenated castor oil, PEG-6 corn oil (Labrafil® M 2125 CS), PEG-6 almond oil (Labrafil® M 1966 CS), PEG-6 apricot kernel oil (Labrafil® M 1944 CS), PEG-6 olive oil (Labrafil® M 1980 CS), PEG-6 peanut oil (Labrafil® M 1969 CS), PEG-6 hydrogenated palm kernel oil (Labrafil® M 2130 BS), PEG-6 palm kernel oil (Labrafil® M 2130 CS), PEG-6 triolein (Labrafil® M 2735 CS), PEG-8 corn oil (Labrafil® WL 2609 BS), PEG-20 corn glycerides (Crovol M40), and PEG-20 almond glycerides (Crovol A40). The latter two surfactants are reported to have HLB values of 10, which is generally considered to be the approximate border line between hydrophilic and hydrophobic surfactants. For purposes of the present invention, these two surfactants are considered to be hydrophobic. Representative surfactants of this class suitable for use in the present invention are shown in Table 5. [0042]
    TABLE 5
    Transesterification Products of Oils and Alcohols
    COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
    PEG-3 castor oil Nikkol CO-3 (Nikko) 3
    PEG-5, 9, and 16 ACCONON CA series (ABITEC) 6-7
    castor oil
    PEG-20 castor oil Emalex C-20 (Nihon Emulsion), Nikkol 11
    CO-20 TX (Nikko)
    PEG-23 castor oil Emulgante EL23 >10
    PEG-30 castor oil Emalex C-30 (Nihon Emulsion), 11
    Alkamuls ® EL 620 (Rhone-Poulenc),
    Incrocas 30 (Croda)
    PEG-35 castor oil Cremophor EL and EL-P (BASF),
    Emulphor EL, Incrocas-35 (Croda),
    Emulgin RO 35 (Henkel)
    PEG-38 castor oil Emulgante EL 65 (Condea)
    PEG-40 castor oil Emalex C-40 (Nihon Emulsion), 13
    Alkamuls ® EL 719 (Rhone-Poulenc)
    PEG-50 castor oil Emalex C-50 (Nihon Emulsion) 14
    PEG-56 castor oil Eumulgin ® PRT 56 (Pulcra SA) >10
    PEG-60 castor oil Nikkol CO-60TX (Nikko) 14
    PEG-100 castor oil Thomley >10
    PEG-200 castor oil Eumulgin ® PRT 200 (Pulcra SA) >10
    PEG-5 hydrogenated Nikkol HCO-5 (Nikko) 6
    castor oil
    PEG-7 hydrogenated Simusol ® 989 (Seppic), Cremophor 6
    castor oil WO7 (BASF)
    PEG-10 hydrogenated Nikkol HCO-10 (Nikko) 6.5
    castor oil
    PEG-20 hydrogenated Nikkol HCO-20 (Nikko) 11
    castor oil
    PEG-25 hydrogenated Simulsol ® 1292 (Seppic), Cerex ELS 11
    castor oil 250 (Auschem SpA)
    PEG-30 hydrogenated Nikkol HCO-30 (Nikko) 11
    castor oil
    PEG-40 hydrogenated Cremophor RH 40 (BASF), Croduret 13
    castor oil (Croda), Emulgin HRE 40 (Henkel)
    PEG-45 hydrogenated Cerex ELS 450 (Auschem Spa) 14
    castor oil
    PEG-50 hydrogenated Emalex HC-50 (Nihon Emulsion) 14
    castor oil
    PEG-60 hydrogenated Nikkol HCO-60 (Nikko); Cremophor 15
    castor oil RH 60 (BASF)
    PEG-80 hydrogenated Nikkol HCO-80 (Nikko) 15
    castor oil
    PEG-100 hydro- Nikkol HCO-100 (Nikko) 17
    genated castor oil
    PEG-6 corn oil Labrafil ® M 2125 CS (Gattefosse) 4
    PEG-6 almond oil Labrafil ® M 1966 CS (Gattefosse) 4
    PEG-6 apricot Labrafil ® M 1944 CS (Gattefosse) 4
    kernel oil
    PEG-6 olive oil Labrafil ® M 1980 CS (Gattefosse) 4
    PEG-6 peanut oil Labrafil ® M 1969 CS (Gattefosse) 4
    PEG-6 hydrogenated Labrafil ® M 2130 BS (Gattefosse) 4
    palm kernel oil
    PEG-6 palm kernel oil Labrafil ® M 2130 CS (Gattefosse) 4
    PEG-6 triolein Labrafil ® M 2735 CS (Gattefosse) 4
    PEG-8 corn oil Labrafil ® WL 2609 BS (Gattefosse) 6-7
    PEG-20 corn Crovol M40 (Croda) 10
    glycerides
    PEG-20 almond Crovol A40 (Croda) 10
    glycerides
    PEG-25 trioleate TAGAT ® TO (Goldschmidt) 11
    PEG-40 palm Crovol PK-70 >10
    kernel oil
    PEG-60 corn Crovol M70(Croda) 15
    glycerides
    PEG-60 almond Crovol A70 (Croda) 15
    glycerides
    PEG-4 caprylic/capric Labrafac ® Hydro (Gattefosse), 4-5
    triglyceride
    PEG-8 caprylic/capric Labrasol (Gattefosse),Labrafac CM 10 >10
    glycerides (Gattefosse)
    PEG-6 caprylic/capric SOFTIGEN ® 767 (Hüls), Glycerox 19
    glycerides 767 (Croda)
    Lauroyl macrogol-32 GELUCIRE 44/14 (Gattefosse) 14
    glyceride
    Stearoyl macrogol GELUCIRE 50/13 (Gattefosse) 13
    glyceride
    Mono, di, tri, tetra SorbitoGlyceride (Gattefosse) <10
    esters of vegetable
    oils and sorbitol
    Pentaerythrityl Crodamol PTIS (Croda) <10
    tetraisostearate
    Pentaerythrityl Albunol DS (Taiwan Surf.) <10
    distearate
    Pentaerythrityl Liponate PO-4 (Lipo Chem.) <10
    tetraoleate
    Pentaerythrityl Liponate PS-4 (Lipo Chem.) <10
    tetrastearate
    Pentaerythrityl Liponate PE-810 (Lipo Chem.), <10
    tetracaprylate/ Crodamol PTC (Croda)
    tetracaprate
    Pentaerythrityl Nikkol Pentarate 408 (Nikko)
    tetraoctanoate
  • 1.6. Polyglycerized Fatty Acids [0043]
  • Polyglycerol esters of fatty acids are also suitable surfactants for the present invention. Among the polyglyceryl fatty acid esters, preferred hydrophobic surfactants include polyglyceryl oleate (Plurol Oleique), polyglyceryl-2 dioleate (Nikkol DGDO), and polyglyceryl-10 trioleate. Preferred hydrophilic surfactants include polyglyceryl-10 laurate (Nikkol Decaglyn 1-L), polyglyceryl-10 oleate (Nikkol Decaglyn 1-O), and polyglyceryl-10 mono, dioleate (Caprol® PEG 860). Polyglyceryl polyricinoleates (Polymuls) are also preferred hydrophilic and hydrophobic surfactants. Examples of suitable polyglyceryl esters are shown in Table 6. [0044]
    TABLE 6
    Polyglycerized Fatty Acids
    COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
    Polyglyceryl-2 stearate Nikkol DGMS (Nikko) 5-7
    Polyglyceryl-2 oleate Nikkol DGMO (Nikko) 5-7
    Polyglyceryl-2 Nikkol DGMIS (Nikko) 5-7
    isostearate
    Polyglyceryl-3 oleate Caprol ® 3GO (ABITEC), Drewpol 6.5
    3-1-O (Stepan)
    Polyglyceryl-4 oleate Nikkol Tetraglyn 1-O (Nikko) 5-7
    Polyglyceryl-4 stearate Nikkol Tetraglyn 1-S (Nikko) 5-6
    Polyglyceryl-6 oleate Drewpol 6-1-O (Stepan), Nikkol 9
    Hexaglyn 1-O (Nikko)
    Polyglyceryl-10 Nikkol Decaglyn 1-L (Nikko) 15
    laurate
    Polyglyceryl-10 oleate Nikkol Decaglyn 1-O (Nikko) 14
    Polyglyceryl-10 Nikkol Decaglyn 1-S (Nikko) 12
    stearate
    Polyglyceryl-6 Nikkol Hexaglyn PR-15 (Nikko) >8
    ricinoleate
    Polyglyceryl-10 Nikkol Decaglyn 1-LN (Nikko) 12
    linoleate
    Polyglyceryl-6 Nikkol Hexaglyn 5-O (Nikko) <10
    pentaoleate
    Polyglyceryl-3 dioleate Cremophor GO32 (BASF) <10
    Polyglyceryl-3 Cremophor GS32 (BASF) <10
    distearate
    Polyglyceryl-4 Nikkol Tetraglyn 5-O (Nikko) <10
    pentaoleate
    Polyglyceryl-6 dioleate Caprol ® 6G20 (ABITEC); Hodag 8.5
    PGO-62 (Calgene), PLUROL
    OLEIQUE CC 497 (Gattefosse)
    Polyglyceryl-2 dioleate Nikkol DGDO (Nikko) 7
    Polyglyceryl-10 Nikkol Decaglyn 3-O (Nikko) 7
    trioleate
    Polyglyceryl-10 Nikkol Decaglyn 5-O (Nikko) 3.5
    pentaoleate
    Polyglyceryl-10 Nikkol Decaglyn 7-O (Nikko) 3
    septaoleate
    Polyglyceryl-10 Caprol ® 10G4O (ABITEC); 6.2
    tetraoleate Hodag PGO-62 (CALGENE), Drewpol
    10-4-O (Stepan)
    Polyglyceryl-10
    decaisostearate Nikkol Decaglyn 10-IS (Nikko) <10
    Polyglyceryl-101 Drewpol 10-10-O (Stepan), Caprol 3.5
    decaoleate 10G10O (ABITEC), Nikkol Decaglyn
    10-O
    Polyglyceryl-10 mono, Caprol ® PGE 860 (ABITEC) 11
    dioleate
    Polyglyceryl Polymuls (Henkel)  3-20
    polyricinoleate
  • 1.7. Propylene Glycol Fatty Acid Esters [0045]
  • Esters of propylene glycol and fatty acids are suitable surfactants for use in the present invention. In this surfactant class, preferred hydrophobic surfactants include propylene glycol monolaurate (Lauroglycol FCC), propylene glycol ricinoleate (Propymuls), propylene glycol monooleate (Myverol P-O6), propylene glycol dicaprylate/dicaprate (Captex® 200), and propylene glycol dioctanoate (Captex® 800). Examples of surfactants of this class are given in Table 7. [0046]
    TABLE 7
    Propylene Glycol Fatty Acid Esters
    COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
    Propylene glycol Capryol 90 (Gattefosse), Nikkol Sefsol 218 <10
    monocaprylate (Nikko)
    Propylene glycol Lauroglycol 90 (Gattefosse), Lauroglycol <10
    monolaurate FCC (Gattefosse)
    Propylene glycol Lutrol OP2000 (BASF) <10
    oleate
    Propylene glycol Mirpyl <10
    myristate
    Propylene glycol ADM PGME-03 (ADM), LIPO PGMS (Lipo 3-4
    monostearate Chem.), Aldo ® PGHMS (Lonza)
    Propylene glycol <10
    hydroxy stearate
    Propylene glycol PROPYMULS (Henkel) <10
    ricinoleate
    Propylene glycol <10
    isostearate
    Propylene glycol Myverol P-O6 (Eastman) <10
    monooleate
    Propylene glycol Captex ® 200 (ABITEC), Miglyol ® 840 >6 
    dicaprylate/dicaprate (Hüls), Neobee ® M-20 (Stepan)
    Propylene glycol Captex ® 800 (ABITEC) >6 
    dioctanoate
    Propylene glycol LABRAFAC PG (Gattefosse) >6 
    caprylate/caprate
    Propylene glycol >6 
    dilaurate
    Propylene glycol Kessco ® PGDS (Stepan) >6 
    distearate
    Propylene glycol Nikkol Sefsol 228 (Nikko) >6 
    dicaprylate
    Propylene glycol Nikkol PDD (Nikko) >6 
    dicaprate
  • 1.8. Mixtures of Propylene Glycol Esters-Glycerol Esters [0047]
  • In general, mixtures of surfactants are also suitable for use in the present invention. In particular, mixtures of propylene glycol fatty acid esters and glycerol fatty acid esters are suitable and are commercially available. One preferred mixture is composed of the oleic acid esters of propylene glycol and glycerol (Arlacel 186). Examples of these surfactants are shown in Table 8. [0048]
    TABLE 8
    Glycerol/Propylene Glycol Fatty Acid Esters
    COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
    Oleic ATMOS 300, ARLACEL 186 (ICI) 3-4
    Stearic ATMOS 150 3-4
  • 1.9. Mono- and Diglycerides [0049]
  • A particularly important class of surfactants is the class of mono- and diglycerides. These surfactants are generally hydrophobic. Preferred hydrophobic surfactants in this class of compounds include glyceryl monooleate (Peceol), glyceryl ricinoleate, glyceryl laurate, glyceryl dilaurate (Capmul® GDL), glyceryl dioleate (Capmul® GDO), glyceryl mono/dioleate (Capmul® GMO-K), glyceryl caprylate/caprate (Capmul® MCM), caprylic acid mono/diglycerides (Imwitor® 988), and mono- and diacetylated monoglycerides (Myvacet® 9-45). Examples of these surfactants are given in Table 9. [0050]
    TABLE 9
    Mono- and Diglyceride Surfactants
    COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
    Monopalmitolein (Larodan) <10
    (C16:1)
    Monoelaidin (Larodan) <10
    (C18:1)
    Monocaproin (C6) (Larodan) <10
    Monocaprylin (Larodan) <10
    Monocaprin (Larodan) <10
    Monolaurin (Larodan) <10
    Glyceryl Nikkol MGM (Nikko) 3-4
    monomyristate (C14)
    Glyceryl monooleate PECEOL (Gattefosse), Hodag GMO-D, 3-4
    (C18:1) Nikkol MGO (Nikko)
    Glyceryl monooleate RYLO series (Danisco), DIMODAN 3-4
    series (Danisco), EMULDAN
    (Danisco), ALDO ® MO FG (Lonza),
    Kessco GMO (Stepan),
    MONOMULS ® series (Henkel),
    TEGIN O, DREWMULSE GMO
    (Stepan), Atlas G-695 (ICI), GMOrphic
    80 (Eastman), ADM DMG-40, 70,
    and 100 (ADM), Myverol (Eastman)
    Glycerol monooleate/ OLICINE (Gattefosse) 3-4
    linoleate
    Glycerol Maisine (Gattefosse), MYVEROL 3-4
    monolinoleate 18-92, Myverol 18-06 (Eastman)
    Glyceryl ricinoleate Softigen ® 701 (Hüls), HODAG 6
    GMR-D (Calgene), ALDO ®
    MR (Lonza)
    Glyceryl monolaurate ALDO ® MLD (Lonza), Hodag GML 6.8
    (Calgene)
    Glycerol Emalex GMS-P (Nihon) 4
    monopalmitate
    Glycerol monostearate Capmul ® GMS (ABITEC), Myvaplex 5-9
    (Eastman), IMWITOR ® 191 (Hüls),
    CUTINA GMS, Aldo ® MS (Lonza),
    Nikkol MGS series (Nikko)
    Glyceryl mono-, Capmul ® GMO-K (ABITEC) <10
    dioleate
    Glyceiyl CUTINA MD-A, ESTAGEL-G18 <10
    palmitic/stearic
    Glyceryl acetate Lamegin ® EE (Grünau GmbH) <10
    Glyceryl laurate Imwitor ® 312 (Hüls), 4
    Monomuls ® 90-45 (Grünau GmbH),
    Aldo ® MLD (Lonza)
    Glyceryl citrate/ Imwitor ® 375 (Hüls) <10
    lactate/oleate/
    linoleate
    Glyceryl caprylate Imwitor ® 308 (Hüls), Capmul ® 5-6
    MCMC8 (ABITEC)
    Glyceryl caprylate/ Capmul ® MCM (ABITEC) 5-6
    caprate
    Caprylic acid mono, Imwitor ® 988 (Hüls) 5-6
    diglycerides
    Caprylic/capric Imwitor ® 742 (Hüls) <10
    glycerides
    Mono-and diacetylated Myvacet ® 9-45, Myvacet ® 9-40, 3.8-4  
    monoglycerides Myvacet ® 9-08 (Eastman),
    Lamegin ® (Grünau)
    Glyceryl monostearate Aldo ® MS, Arlacel 129 (ICI), LIPO 4.4
    GMS (Lipo Chem.), Imwitor ® 191
    (Hüls), Myvaplex (Eastman)
    Lactic acid esters of LAMEGIN GLP (Henkel) <10
    mono,diglycerides
    Dicaproin (C6) (Larodan) <10
    Dicaprin (C10) (Larodan) <10
    Dioctanoin (C8) (Larodan) <10
    Dimyristin (C14) (Larodan) <10
    Dipalmitin (C16) (Larodan) <10
    Distearin (Larodan) <10
    Glyceryl dilaurate Capmul ® GDL (ABITEC) 3-4
    (C12)
    Glyceryl dioleate Capmul ® GDO (ABITEC) 3-4
    Glycerol esters GELUCIRE 39/01 (Gattefosse), 1
    of fatty acids GELUCIRE 43/01 (Gattefosse)
    GELUCIRE 37/06 (Gattefosse) 6
    Dipalmitolein (C16:1) (Larodan) <10
    1,2 and 1,3-diolein (Larodan) <10
    (C18:1)
    Dielaidin (C18:1) (Larodan) <10
    Dilinolein (C18:2) (Larodan) <10
  • 1.10. Sterol and Sterol Derivatives [0051]
  • Sterols and derivatives of sterols are suitable surfactants for use in the present invention. These surfactants can be hydrophilic or hydrophobic. Preferred derivatives include the polyethylene glycol derivatives. A preferred hydrophobic surfactant in this class is cholesterol. A preferred hydrophilic surfactant in this class is PEG-24 cholesterol ether (Solulan C-24). Examples of surfactants of this class are shown in Table 10. [0052]
    TABLE 10
    Sterol and Sterol Derivative Surfactants
    COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
    Cholesterol, sitosterol, <10
    lanosterol
    PEG-24 cholesterol ether Solulan C-24 (Amerchol) >10
    PEG-30 cholesterol Nikkol DHC (Nikko) >10
    Phytosterol GENEROL series (Henkel) <10
    PEG-25 phyto sterol Nikkol BPSH-25 (Nikko) >10
    PEG-5 soya sterol Nikkol BPS-5 (Nikko) <10
    PEG-10 soya sterol Nikkol BPS-10 (Nikko) <10
    PEG-20 soya sterol Nikkol BPS-20 (Nikko) <10
    PEG-30 soya sterol Nikkol BPS-30 (Nikko) >10
  • 1.11. Polyethylene Glycol Sorbitan Fatty Acid Esters [0053]
  • A variety of PEG-sorbitan fatty acid esters are available and are suitable for use as surfactants in the present invention. In general, these surfactants are hydrophilic, although several hydrophobic surfactants of this class can be used. Among the PEG-sorbitan fatty acid esters, preferred hydrophilic surfactants include PEG-20 sorbitan monolaurate (Tween-20), PEG-20 sorbitan monopalmitate (Tween-40), PEG-20 sorbitan monostearate (Tween-60), and PEG-20 sorbitan monooleate (Tween-80). Examples of these surfactants are shown in Table 11. [0054]
    TABLE 11
    PEG-Sorbitan Fatty Acid Esters
    COMMERCIAL
    COMPOUND PRODUCT (Supplier) HLB
    PEG-10 sorbitan laurate Liposorb L-10 (Lipo Chem.) >10
    PEG-20 sorbitan monolaurate Tween-20 (Atlas/ICI), Crillet 1 17
    (Croda), DACOL MLS 20
    (Condea)
    PEG-4 sorbitan monolaurate Tween-21 (Atlas/ICI), Crillet 11 13
    (Croda)
    PEG-80 sorbitan monolaurate Hodag PSML-80 (Calgene); >10
    T-Maz 28
    PEG-6 sorbitan monolaurate Nikkol GL-1 (Nikko) 16
    PEG-20 sorbitan monopalmitate Tween-40 (Atlas/ICI), Crillet 2 16
    (Croda)
    PEG-20 sorbitan monostearate Tween-60 (Atlas/ICI), Crillet 3 15
    (Croda)
    PEG-4 sorbitan monostearate Tween-61 (Atlas/ICI), Crillet 31 9.6
    (Croda)
    PEG-8 sorbitan monostearate DACOL MSS (Condea) >10
    PEG-6 sorbitan monostearate Nikkol TS106 (Nikko) 11
    PEG-20 sorbitan tristearate Tween-65 (Atlas/ICI), Crillet 35 11
    (Croda)
    PEG-6 sorbitan tetrastearate Nikkol GS-6 (Nikko) 3
    PEG-60 sorbitan tetrastearate Nikkol GS-460 (Nikko) 13
    PEG-5 sorbitan monooleate Tween-81 (Atlas/ICI), Crillet 41 10
    (Croda)
    PEG-6 sorbitan monooleate Nikkol TO-106 (Nikko) 10
    PEG-20 sorbitan monooleate Tween-80 (Atlas/ICI), Crillet 4 15
    (Croda)
    PEG-40 sorbitan oleate Emalex ET 8040 18
    (Nihon Emulsion)
    PEG-20 sorbitan trioleate Tween-85 (Atlas/ICI), Crillet 45 11
    (Croda)
    PEG-6 sorbitan tetraoleate Nikkol GO-4 (Nikko) 8.5
    PEG-30 sorbitan tetraoleate Nikkol GO-430 (Nikko) 12
    PEG-40 sorbitan tetraoleate Nikkol GO-440 (Nikko) 13
    PEG-20 sorbitan Tween-120 (Atlas/ICI), Crillet 6 >10
    monoisostearate (Croda)
    PEG sorbitol hexaoleate Atlas G-1086 (ICI) 10
    PEG-6 sorbitol hexastearate Nikkol GS-6 (Nikko) 3
  • 1.12. Polyethylene Glycol Alkyl Ethers [0055]
  • Ethers of polyethylene glycol and alkyl alcohols are suitable surfactants for use in the present invention. Preferred hydrophobic ethers include PEG-3 oleyl ether (Volpo 3) and PEG-4 lauryl ether (Brij 30). Examples of these surfactants are shown in Table 12. [0056]
    TABLE 12
    Polyethylene Glycol Alkyl Ethers
    COMMERCIAL
    COMPOUND PRODUCT (Supplier) HLB
    PEG-2 oleyl ether,oleth-2 Brij 92/93 (Atlas/ICI) 4.9
    PEG-3 oleyl ether,oleth-3 Volpo 3 (Croda) <10
    PEG-5 oleyl ether,oleth-5 Volpo 5 (Croda) <10
    PEG-10 oleyl ether,oleth-10 Volpo 10 (Croda), Brij 96/97 12
    (Atlas/ICI)
    PEG-20 oleyl ether,oleth-20 Volpo 20 (Croda), Brij 98/99 15
    (Atlas/ICI)
    PEG-4 lauryl ether, laureth-4 Brij 30 (Atlas/ICI) 9.7
    PEG-9 lauryl ether >10
    PEG-23 lauryl ether, laureth-23 Brij 35 (Atlas/ICI) 17
    PEG-2 cetyl ether Brij 52 (ICI) 5.3
    PEG-10 cetyl ether Brij 56 (ICI) 13
    PEG-20 cetyl ether Brij 58 (ICI) 16
    PEG-2 stearyl ether Brij 72 (ICI) 4.9
    PEG-10 stearyl ether Brij 76 (ICI) 12
    PEG-20 stearyl ether Brij 78 (ICI) 15
    PEG-100 stearyl ether Brij 700 (ICI) >10
  • 1.13. Sugar Esters [0057]
  • Esters of sugars are suitable surfactants for use in the present invention. Preferred hydrophilic surfactants in this class include sucrose monopalmitate and sucrose monolaurate. Examples of such surfactants are shown in Table 13. [0058]
    TABLE 13
    Sugar Ester Surfactants
    COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
    Sucrose distearate SUCRO ESTER 7 (Gattefosse), 3
    Crodesta F-10 (Croda)
    Sucrose distearate/ SUCRO ESTER 11 (Gattefosse), 12
    monostearate Crodesta F-110 (Croda)
    Sucrose dipalmitate 7.4
    Sucrose monostearate Crodesta F-160 (Croda) 15
    Sucrose monopalmitate SUCRO ESTER 15 (Gattefosse) >10
    Sucrose monolaurate Saccharose monolaurate 15
    1695 (Mitsubishi-Kasei)
  • 1.14. Polyethylene Glycol Alkyl Phenols [0059]
  • Several hydrophilic PEG-alkyl phenol surfactants are available, and are suitable for use in the present invention. Examples of these surfactants are shown in Table 14. [0060]
    TABLE 14
    Polyethylene Glycol Alkyl Phenol Surfactants
    COMMERCIAL
    COMPOUND PRODUCT (Supplier) HLB
    PEG-10-100 nonyl phenol Triton X series (Rohm & Haas), >10
    Igepal CA series (GAF, USA),
    Antarox CA series (GAF, UK)
    PEG-15-100 octyl phenol ether Triton N-series (Rohm & Haas), >10
    Igepal CO series (GAF, USA),
    Antarox CO series (GAF, UK)
  • 1.15. Polyoxyethylene-Polyoxypropylene Block Copolymers [0061]
  • The POE-POP block copolymers are a unique class of polymeric surfactants. The unique structure of the surfactants, with hydrophilic POE and hydrophobic POP moieties in well-defined ratios and positions, provides a wide variety of surfactants suitable for use in the present invention. These surfactants are available under various trade names, including Synperonic PE series (ICI); Pluronic® series (BASF), Emkalyx, Lutrol (BASF), Supronic, Monolan, Pluracare, and Plurodac. The generic term for these polymers is “poloxamer” (CAS 9003-11-6). These polymers have the formula: [0062]
  • HO(C2H4O)a(C3H6O)b(C2H4O)nH
  • where “a” and “b” denote the number of polyoxyethylene and polyoxypropylene units, respectively. [0063]
  • Preferred hydrophilic surfactants of this class include Poloxamers 108, 188, 217, 238, 288, 338, and 407. Preferred hydrophobic surfactants in this class include Poloxamers 124, 182, 183, 212, 331, and 335. [0064]
  • Examples of suitable surfactants of this class are shown in Table 15. Since the compounds are widely available, commercial sources are not listed in the Table. The compounds are listed by generic name, with the corresponding “a” and “b” values. [0065]
    TABLE 15
    POE-POP Block Copolymers
    a, b values in
    COMPOUND HO(C2H4O)a(C3H6O)b(C2H4O)aH HLB
    Poloxamer 105 a = 11 b = 16 8
    Poloxamer 108 a = 46 b = 16 >10
    Poloxamer 122 a = 5 b = 21 3
    Poloxamer 123 a = 7 b = 21 7
    Poloxamer 124 a = 11 b = 21 >7
    Poloxamer 181 a = 3 b = 30
    Poloxamer 182 a = 8 b = 30 2
    Poloxamer 183 a = 10 b = 30
    Poloxamer 184 a = 13 b = 30
    Poloxamer 185 a = 19 b = 30
    Poloxamer 188 a = 75 b = 30 29
    Poloxamer 212 a = 8 b = 35
    Poloxamer 215 a = 24 b = 35
    Poloxamer 217 a = 52 b = 35
    Poloxamer 231 a = 16 b = 39
    Poloxamer 234 a = 22 b = 39
    Poloxamer 235 a = 27 b = 39
    Poloxamer 237 a = 62 b = 39 24
    Poloxamer 238 a = 97 b = 39
    Poloxamer 282 a = 10 b = 47
    Poloxamer 284 a = 21 b = 47
    Poloxamer 288 a = 122 b = 47 >10
    Poloxamer 331 a = 7 b = 54 0.5
    Poloxamer 333 a = 20 b = 54
    Poloxamer 334 a = 31 b = 54
    Poloxamer 335 a = 38 b = 54
    Poloxamer 338 a = 128 b = 54
    Poloxamer 401 a = 6 b = 67
    Poloxamer 402 a = 13 b = 67
    Poloxamer 403 a = 21 b = 67
    Poloxamer 407 a = 98 b = 67
  • 1.16. Sorbitan Fatty Acid Esters [0066]
  • Sorbitan esters of fatty acids are suitable surfactants for use in the present invention. Among these esters, preferred hydrophobic surfactants include sorbitan monolaurate (Arlacel 20), sorbitan monopalmitate (Span-40), sorbitan monooleate (Span-80), sorbitan monostearate, and sorbitan tristearate. Examples of these surfactants are shown in Table 16. [0067]
    TABLE 16
    Sorbitan Fatty Acid Ester Surfactants
    COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
    Sorbitan monolaurate Span-20 (Atlas/ICI), Crill 1 (Croda), 8.6
    Arlacel 20 (ICI)
    Sorbitan monopalmitate Span-40 (Atlas/ICI), Crill 2 (Croda), 6.7
    Nikkol SP-10 (Nikko)
    Sorbitan monooleate Span-80 (Atlas/ICI), Crill 4 (Croda), 4.3
    Crill 50 (Croda)
    Sorbitan monostearate Span-60 (Atlas/ICI), Crill 3 (Croda), 4.7
    Nikkol SS-10 (Nikko)
    Sorbitan trioleate Span-85 (Atlas/ICI), Crill 45 (Croda), 4.3
    Nikkol SO-30 (Nikko)
    Sorbitan sesquioleate Arlacel-C (ICI), Crill 43 (Croda), 3.7
    Nikkol SO-15 (Nikko)
    Sorbitan tristearate Span-65 (Atlas/ICI) Crill 35 (Croda), 2.1
    Nikkol SS-30 (Nikko)
    Sorbitan monoisostearate Crill 6 (Croda), Nikkol SI-10 (Nikko) 4.7
    Sorbitan sesquistearate Nikkol SS-15 (Nikko) 4.2
  • 1.17. Lower Alcohol Fatty Acid Esters [0068]
  • Esters of lower alcohols (C[0069] 2 to C4) and fatty acids (C8 to C18) are suitable surfactants for use in the present invention. Among these esters, preferred hydrophobic surfactants include ethyl oleate (Crodamol EO), isopropyl myristate (Crodamol IPM), and isopropyl palmitate (Crodamol IPP). Examples of these surfactants are shown in Table 17.
    TABLE 17
    Lower Alcohol Fatty Acid Ester Surfactants
    COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
    Ethyl oleate Crodamol EO (Croda), Nikkol EOO (Nikko) <10
    Isopropyl myristate Crodamol IPM (Croda) <10
    Isopropyl palmitate Crodamol IPP (Croda) <10
    Ethyl linoleate Nikkol VF-E (Nikko) <10
    Isopropyl linoleate Nikkol VF-IP (Nikko) <10
  • 1.18. Ionic Surfactants [0070]
  • Ionic surfactants, including cationic, anionic and zwitterionic surfactants, are suitable hydrophilic surfactants for use in the present invention. Preferred anionic surfactants include fatty acid salts and bile salts. Specifically, preferred ionic surfactants include sodium oleate, sodium lauryl sulfate, sodium lauryl sarcosinate, sodium dioctyl sulfosuccinate, sodium cholate, and sodium taurocholate. Examples of such surfactants are shown in Table 18 below. For simplicity, typical counterions are shown in the entries in the Table. It will be appreciated by one skilled in the art, however, that any bioacceptable counterion may be used. For example, although the fatty acids are shown as sodium salts, other cation counterions can also be used, such as alkali metal cations or ammonium. Unlike typical non-ionic surfactants, these ionic surfactants are generally available as pure compounds, rather than commercial (proprietary) mixtures. Because these compounds are readily available from a variety of commercial suppliers, such as Aldrich, Sigma, and the like, commercial sources are not generally listed in the Table. [0071]
    TABLE 18
    Ionic Surfactants
    COMPOUND HLB
    FATTY ACID SALTS >10
    Sodium caproate
    Sodium caprylate
    Sodium caprate
    Sodium laurate
    Sodium myristate
    Sodium myristolate
    Sodium palmitate
    Sodium palmitoleate
    Sodium oleate 18
    Sodium ricinoleate
    Sodium linoleate
    Sodium linolenate
    Sodium stearate
    Sodium lauryl sulfate (dodecyl) 40
    Sodium tetradecyl sulfate
    Sodium lauryl sarcosinate
    Sodium dioctyl sulfosuccinate [sodium docusate (Cytec)]
    BILE SALTS >10
    Sodium cholate
    Sodium taurocholate
    Sodium glycocholate
    Sodium deoxycholate
    Sodium taurodeoxycholate
    Sodium glycodeoxycholate
    Sodium ursodeoxycholate
    Sodium chenodeoxycholate
    Sodium taurochenodeoxycholate
    Sodium glyco cheno deoxycholate
    Sodium cholylsarcosinate
    Sodium N-methyl taurocholate
    PHOSPHOLIPIDS
    Egg/Soy lecithin [Epikuron ™ (Lucas Meyer), Ovothin ™
    (Lucas Meyer)]
    Lyso egg/soy lecithin
    Hydroxylated lecithin
    Lysophosphatidylcholine
    Cardiolipin
    Sphingomyelin
    Phosphatidylcholine
    Phosphatidyl ethanolamine
    Phosphatidic acid
    Phosphatidyl glycerol
    Phosphatidyl serine
    PHOSPHORIC ACID ESTERS
    Diethanolammonium polyoxyethylene-10 oleyl ether phosphate
    Esterification products of fatty alcohols or fatty alcohol
    ethoxylates with phosphoric acid or anhydride
    CARBOXYLATES
    Ether carboxylates (by oxidation of terminal OH group of
    fatty alcohol ethoxylates)
    Succinylated monoglycerides [LAMEGIN ZE (Henkel)]
    Sodium stearyl fumarate
    Stearoyl propylene glycol hydrogen succinate
    Mono/diacetylated tartaric acid esters of mono- and diglycerides
    Citric acid esters of mono-, diglycerides
    Glyceryl-lacto esters of fatty acids (CFR ref. 172.852)
    Acyl lactylates:
    lactylic esters of fatty acids
    calcium/sodium stearoyl-2-lactylate
    calcium/sodium stearoyl lactylate
    Alginate salts
    Propylene glycol alginate
    SULFATES AND SULFONATES
    Ethoxylated alkyl sulfates
    Alkyl benzene sulfones
    α-olefin sulfonates
    Acyl isethionates
    Acyl taurates
    Alkyl glyceryl ether sulfonates
    Octyl sulfosuccinate disodium
    Disodium undecylenamideo-MEA-sulfosuccinate
    CATIONIC Surfactants >10
    Hexadecyl triammonium bromide
    Decyl trimethyl ammonium bromide
    Cetyl trimethyl ammonium bromide
    Dodecyl ammonium chloride
    Alkyl benzyldimethylammonium salts
    Diisobutyl phenoxyethoxydimethyl benzylammonium salts
    Alkylpyridinium salts
    Betaines (trialkylglycine):
    Lauryl betaine (N-lauryl,N,N-dimethylglycine)
    Ethoxylated amines:
    Polyoxyethylene-15 coconut amine
  • 1.19 Surfactant Concentrations [0072]
  • The hydrophilic and hydrophobic surfactants are present in the pharmaceutical compositions of the present invention in amounts such that upon dilution with an aqueous solution, the carrier forms a clear, aqueous dispersion of the hydrophilic and hydrophobic surfactants, containing the hydrophobic therapeutic agent. The relative amounts of hydrophilic and hydrophobic surfactants are readily determined by observing the properties of the resultant dispersion; i.e., when the relative amounts of the hydrophobic and hydrophilic surfactants are within a suitable range, the resultant aqueous dispersion is optically clear. When the relative amount of hydrophobic surfactant is too great, the resulting dispersion is visibly “cloudy”, resembling a conventional emulsion or multiple phase system. Although a visibly cloudy solution may be potentially useful for some applications, such a system would suffer from many of the same disadvantages as conventional prior art formulations, as described above. [0073]
  • A convenient method of determining the appropriate relative concentrations for any hydrophilic surfactant-hydrophobic surfactant pair is as follows. A convenient working amount of a hydrophilic surfactant is provided, and a known amount of a hydrophobic surfactant is added. The surfactants are stirred to form a homogeneous mixture, with the aid of gentle heating if desired. The resulting mixture is diluted with purified water to prepare an aqueous dispersion. Any dilution amount can be chosen, but convenient dilutions are those within the range expected in vivo, about a 10 to 250-fold dilution. The aqueous dispersion is then assessed qualitatively for optical clarity. The procedure can be repeated with incremental variations in the relative amount of hydrophobic surfactant added, to determine the maximum relative amount of hydrophobic surfactant that can be present for a given surfactant pair. [0074]
  • Alternatively, the optical clarity of the aqueous dispersion can be measured using standard quantitative techniques for turbidity assessment. One convenient procedure to measure turbidity is to measure the amount of light of a given wavelength transmitted by the solution, using, for example, a UV-visible spectrophotometer. Using this measure, optical clarity corresponds to high transmittance, since cloudier solutions will scatter more of the incident radiation, resulting in lower transmittance measurements. If this procedure is used, care should be taken to insure that the surfactant mixture does not itself absorb light of the chosen wavelength, as any true absorbance necessarily reduces the amount of transmitted light and falsely increases the quantitative turbidity value. In the absence of chromophores at the chosen wavelength, suitable dispersions at a dilution of 10× should have an apparent absorbance of less than about 0.3, preferably less than about 0.2, and more preferably less than about 0.1. At a dilution of 100×, suitable dispersions should have an apparent absorbance of less than about 0.1, preferably less than about 0.05, and more preferably less than about 0.01. [0075]
  • A third method of determining optical clarity and carrier diffusivity through the aqueous boundary layer is to quantitatively measure the size of the particles of which the dispersion is composed. These measurements can be performed on commercially available particle size analyzers, such as, for example, a Nicomp particle size analyzer available from Particle Size Systems, Inc., of Santa Barbara, Calif. Using this measure, clear aqueous dispersions according to the present invention have average particle sizes much smaller than the wavelength of visible light, whereas dispersions containing excessive relative amounts of the hydrophobic surfactant have more complex particle size distributions, with much greater average particle sizes. It is desirable that the average particle size be less than about 100 nm, preferably less than about 50 nm, more preferably less than about 30 nm, and still more preferably less than about 20 nm. It is also preferred that the particle size distribution be mono-modal. As is shown in more detail in the Examples herein, dispersions having an undesirably large relative amount of hydrophobic surfactant typically display bimodal particle size distributions, such distributions having a small particle size component, typically less than about 30 nm, and a large particle size component, typically on the order of 100 nm or more. It should be emphasized that these particle sizes are appropriate for the carrier particles in aqueous solution, in the absence of a hydrophobic therapeutic agent. It is expected that the presence of the hydrophobic therapeutic agent may result in an increase in the average particle size. [0076]
  • Other methods of determining optical clarity or particle size can be used as desired. Such methods are well know to those skilled in the art. [0077]
  • It should be emphasized that any or all of the available methods may be used to ensure that the resulting aqueous dispersions possess the requisite optical clarity. For convenience, however, the present inventors prefer to use the simple qualitative procedure; i.e., simple visible observation. However, in order to more fully illustrate the practice of the present invention, all three of the above measures are used to assess the dispersion clarity in the Examples herein. [0078]
  • Although it should be understood that any aqueous dispersion having the properties described above is within the scope of the present invention regardless of the specific relative amounts of hydrophobic and hydrophilic surfactants, it is expected that the amount of hydrophobic surfactant will generally be less than about 200% by weight, based on the amount of hydrophilic surfactant, and more specifically, in the range of about 1% to 200%. Further, based on observations reported in the Examples herein, it is expected that the amount of hydrophobic surfactant will generally be less than about 100%, and more specifically in the range of about 5% to about 100% by weight, or about 10% to about 100% by weight, based on the amount of hydrophilic surfactant. For some particular surfactant combinations, cloudy solutions result when the amount of hydrophobic surfactant is greater than about 60% by weight, based on the amount of hydrophilic surfactant. A preferred range for these surfactants is about 1% to about 60%, preferably about 5% to about 60%, and more preferably about 10% to about 60%. Addition of optional excipients as described below can further increase the maximum relative amount of hydrophobic surfactant that can be used. [0079]
  • Other considerations well known to those skilled in the art will further inform the choice of specific proportions of hydrophobic and hydrophilic surfactants. These considerations include the degree of bioacceptability of the surfactants, and the desired dosage of hydrophobic therapeutic agent to be provided. In some cases, the amount of hydrophobic surfactant actually used in a pharmaceutical composition according to the present invention will be less than the maximum that can be used, and it should be apparent that such compositions are also within the scope of the present invention. [0080]
  • 2. Hydrophobic Therapeutic Agents [0081]
  • Hydrophobic therapeutic agents suitable for use in the pharmaceutical compositions of the present invention are not particularly limited, as the carrier is surprisingly capable of solubilizing and delivering a wide variety of hydrophobic therapeutic agents. Hydrophobic therapeutic agents are compounds with little or no water solubility. Intrinsic water solubilities (i.e., water solubility of the unionized form) for hydrophobic therapeutic agents usable in the present invention are less than about 1% by weight, and typically less than about 0.1% or 0.01% by weight. Such therapeutic agents can be any agents having therapeutic or other value when administered to an animal, particularly to a mammal, such as drugs, nutrients, and cosmetics (cosmeceuticals). It should be understood that while the invention is described with particular reference to its value in the form of aqueous dispersions, the invention is not so limited. Thus, hydrophobic drugs, nutrients or cosmetics which derive their therapeutic or other value from, for example, topical or transdermal administration, are still considered to be suitable for use in the present invention. [0082]
  • Specific non-limiting examples of hydrophobic therapeutic agents that can be used in the pharmaceutical compositions of the present invention include the following representative compounds, as well as their pharmaceutically acceptable salts, isomers, esters, ethers and other derivatives: [0083]
  • analgesics and anti-inflammatory agents, such as aloxiprin, auranofin, azapropazone, benorylate, capsaicin, celecoxib, diclofenac, diflunisal, etodolac, fenbufen, fenoprofen calcium, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, leflunomide, meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxaprozin, oxyphenbutazone, phenylbutazone, piroxicam, refocoxib, sulindac, tetrahydrocannabinol, tramadol and tromethamine; [0084]
  • anthelmintics, such as albendazole, bephenium hydroxynaphthoate, cambendazole, dichlorophen, ivermectin, mebendazole, oxamniquine, oxfendazole, oxantel embonate, praziquantel, pyrantel embonate and thiabendazole; [0085]
  • anti-arrhythmic agents, such as amiodarone HCl, disopyramide, flecainide acetate and quinidine sulfate; [0086]
  • anti-asthma agents, such as zileuton, zafirlukast, terbutaline sulfate, montelukast, and albuterol; [0087]
  • anti-bacterial agents, such as alatrofloxacin, azithromycin, baclofen, benethamine penicillin, cinoxacin, ciprofloxacin HCl, clarithromycin, clofazimine, cloxacillin, demeclocycline, dirithromycin, doxycycline, erythromycin, ethionamide, furazolidone, grepafloxacin, imipenem, levofloxacin, lorefloxacin, moxifloxacin HCl, nalidixic acid, nitrofurantoin, norfloxacin, ofloxacin, rifampicin, rifabutine, rifapentine, sparfloxacin, spiramycin, sulphabenzamide, sulphadoxine, sulphamerazine, sulphacetamide, sulphadiazine, sulphafurazole, sulphamethoxazole, sulphapyridine, tetracycline, trimethoprim, trovafloxacin, and vancomycin; [0088]
  • anti-viral agents, such as abacavir, amprenavir, delavirdine, efavirenz, indivir, lamivudine, nelfinavir, nevirapine, ritonavir, saquinavir, and stavueline; [0089]
  • anti-coagulants, such as cilostazol, clopidrogel, dicoumarol, dipyridamole, nicoumalone, oprelvekin, phenindione, ticlidopine, and tirofibran; [0090]
  • anti-depressants, such as amoxapine, bupropion, citalopram, clomipramine, fluexetine HCl, maprotiline HCl, mianserin HCl, nortriptyline HCl, paroxetine HCl, sertraline HCl, trazodone HCl, trimipramine maleate, and venlafaxine HCl; [0091]
  • anti-diabetics, such as acetohexamide, chlorpropamide, glibenclamide, gliclazide, glipizide, glymepride, miglitol, pioglitazone, repaglinide, rosiglitazone, tolazamide, tolbutamide and troglitazone; [0092]
  • anti-epileptics, such as beclamide, carbamazepine, clonazepam, ethotoin, felbamate, fosphenytoin sodium, lamotrigine, methoin, methsuximide, methylphenobarbitone, oxcarbazepine, paramethadione, phenacemide, phenobarbitone, phenytoin, phensuximide, primidone, sulthiame, tiagabine HCl, topiramate, valproic acid, and vigabatrin; [0093]
  • anti-fungal agents, such as amphotericin, butenafine HCl, butoconazole nitrate, clotrimazole, econazole nitrate, fluconazole, flucytosine, griseofulvin, itraconazole, ketoconazole, miconazole, natamycin, nystatin, sulconazole nitrate, oxiconazole, terbinafine HCl, terconazole, tioconazole and undecenoic acid; [0094]
  • anti-gout agents, such as allopurinol, probenecid and sulphin-pyrazone; [0095]
  • anti-hypertensive agents, such as amlodipine, benidipine, benezepril, candesartan, captopril, darodipine, dilitazem HCl, diazoxide, doxazosin HCl, elanapril, eposartan losartan, mesylate, felodipine, fenolclopam, fosinopril, guanabenz acetate, irbesartan, isradipine, lisinopril, minoxidil, nicardipine HCl, nifedipine, nimodipine, nisolidipine, phenoxybenzamine HCl, prazosin HCl, quinapril, reserpine, terazosin HCl, telmisartan, and valsartan; [0096]
  • anti-malarials, such as amodiaquine, chloroquine, chlorproguanil HCl, halofantrine HCl, mefloquine HCl, proguanil HCl, pyrimethamine and quinine sulfate; [0097]
  • anti-migraine agents, such as dihydroergotamine mesylate, ergotamine tartrate, frovatriptan, methysergide maleate, naratriptan HCl, pizotifen maleate, rizatriptan benzoate, sumatriptan succinate, and zolmitriptan; [0098]
  • anti-muscarinic agents, such as atropine, benzhexol HCl, biperiden, ethopropazine HCl, hyoscyamine, mepenzolate bromide, oxyphencylcimine HCl and tropicamide; [0099]
  • anti-neoplastic agents and immunosuppressants, such as aminoglutethimide, amsacrine, azathioprine, bicalutamide, bisanthrene, busulphan, camptothecan, capecitabine, chlorambucil, cyclosporin, dacarbazine, ellipticine, estramustine, etoposide, irinotecan, lomustine, melphalan, mercaptopurine, methotrexate, mitomycin, mitotane, mitoxantrone, mofetil, mycophenolate, nilutamide, paclitaxel, procarbazine HCl, sirolimus, tacrolimus, tamoxifen citrate, teniposide, testolactone, topotecan HCl, and toremifene citrate; [0100]
  • anti-protozoal agents, such as atovaquone, benznidazole, clioquinol, decoquinate, diiodohydroxyquinoline, diloxanide furoate, dinitolmide, furzolidone, metronidazole, nimorazole, nitrofurazone, omidazole and tinidazole; [0101]
  • anti-thyroid agents, such as carbimazole, paricalcitol, and propylthiouracil; [0102]
  • anti-tussives, such as benzonatate; [0103]
  • anxiolytic, sedatives, hypnotics and neuroleptics, such as alprazolam, amylobarbitone, barbitone, bentazepam, bromazepam, bromperidol, brotizolam, butobarbitone, carbromal, chlordiazepoxide, chlormethiazole, chlorpromazine, chlorprothiocene, clonazepam, clobazam, clotiazepam, clozapine, diazepam, droperidol, ethinamate, flunanisone, flunitrazepam, fluopromazine, flupenthixol decanoate, fluphenazine decanoate, flurazepam, gabapentin, haloperidol, lorazepam, lormetazepam, medazepam, meprobamate, mesoridiazine, methaqualone, methyl phenidate, midazolam, molindone, nitrazepam, olanzapine, oxazepam, pentobarbitone, perphenazine pimozide, prochlorperazine, pseudo-ephedrine, quetiapine, risperodone, sertindole, sulpiride, temazepam, thioridazine, triazolam, zolpidem, and zopiclone; [0104]
  • β-Blockers, such as acebutolol, alprenolol, atenolol, labetalol, metoprolol, nadolol, oxprenolol, pindolol and propranolol; [0105]
  • cardiac inotropic agents, such as amrinone, digitoxin, digoxin, enoximone, lanatoside C and medigoxin; [0106]
  • corticosteroids, such as beclomethasone, betamethasone, budesonide, cortisone acetate, desoxymethasone, dexamethasone, fludrocortisone acetate, flunisolide, flucortolone, fluticasone propionate, hydrocortisone, methylprednisolone, prednisolone, prednisone and triamcinolone; [0107]
  • diuretics, such as acetazolamide, amiloride, bendrofluazide, bumetanide, chlorothiazide, chlorthalidone, ethacrynic acid, frusemide, metolazone, spironolactone and triamterene. [0108]
  • anti-parkinsonian agents, such as bromocriptine mesylate, lysuride maleate, pramipexole, robinirole HCl, and tolcapone; [0109]
  • gastro-intestinal agents, such as bisacodyl, cimetidine, cisapride, diphenoxylate HCl, domperidone, famotidine, lanosprazole, loperamide, mesalazine, nizatidine, omeprazole, ondansetron HCL, rabeprazole sodium, ranitidine HCl and sulphasalazine; [0110]
  • histamine H,-receptor antagonists, such as acrivastine, astemizole, chlophenisamine, cinnarizine, citrizine, clemastine fumarate, cyclizine, cyproheptadine HCl, dexchlopheniramine, dimenhydrinate, fexofenadine, flunarizine HCl, loratadine, meclozine HCl, oxatomide, and terenadine; [0111]
  • keratolytics, such as acutretin, calciprotiene, calcifediol, calcitriol, cholecalciferol, ergocalciferol, etretinate, retinoids, targretin, and tazarotene; [0112]
  • lipid regulating agents, such as atorvastatin, bezafibrate, cerivistatin, clinofibrate, clofibrate, fenofibrate, fluvastatin, gemfibrozil, pravastatin, probucol, and simvastatin; [0113]
  • muscle relaxants, such as dantrolene sodium and tizanidine HCl; [0114]
  • nitrates and other anti-anginal agents, such as amyl nitrate, glyceryl trinitrate, isosorbide dinitrate, isosorbide mononitrate and pentaerythritol tetranitrate; [0115]
  • nutritional agents, such as calcitriol, carotenes, dihydrotachysterol, essential fatty acids, non-essential fatty acids, phytonodione, vitamin A, vitamin B[0116] 2, vitamin D, vitamin E and vitamin K.
  • opioid analgesics, such as codeine, dextropropyoxyphene, diamorphine, dihydrocodeine, fentanyl, meptazinol, methadone, morphine, nalbuphine and pentazocine; [0117]
  • sex hormones, such as clomiphene citrate, cortisone acetate, danazol, dihydro epiandrosterone, ethinyloestradiol, finasteride, fludrocortisone, fluoxymisterone, medroxyprogesterone acetate, megesterol acetate, mestranol, methyltestosterone, norethisterone, norgestrel, oestradiol, conjugated estrogens, progesterone, rimexolone, stanozolol, stiboestrol, testosterone and tibolone; [0118]
  • stimulants, such as amphetamine, dexamphetamine, dexfenfluramine, fenfluramine and mazindol; [0119]
  • and others, such as becaplermin, donepezil HCl, L-thryroxine, methoxsalen, nerteporfin, physostigmine, pyridostigmine, raloxifene HCl, sibutramine HCl, sildenafil citrate, tacrine, tamsulosin HCl, and tolterodine. [0120]
  • Preferred hydrophobic therapeutic agents include sildenafil citrate, amlodipine, tramadol, celecoxib, refocoxib, oxaprozin, nabumetone, ibuprofen, terbenafine, itraconazole, zileuton, zafirlukast, cisapride, fenofibrate, tizanidine, nizatidine, fexofenadine, loratadine, famotidine, paricalcitol, atovaquone, nabumetone, tetrahydrocannabinol, megesterol acetate, repaglinide, progesterone, rimexolone, cyclosporine, tacrolimus, sirolimus, teniposide, paclitaxel, pseudo-ephedrine, troglitazone, rosiglitazone, finasteride, vitamin A, vitamin D, vitamin E, and pharmaceutically acceptable salts, isomers and derivatives thereof. Particularly preferred hydrophobic therapeutic agents are progesterone and cyclosporin. [0121]
  • It should be appreciated that this listing of hydrophobic therapeutic agents and their therapeutic classes is merely illustrative. Indeed, a particular feature, and surprising advantage, of the compositions of the present invention is the ability of the present compositions to solubilize and deliver a broad range of hydrophobic therapeutic agents, regardless of functional class. Of course, mixtures of hydrophobic therapeutic agents may also be used where desired. [0122]
  • 3. Solubilizers [0123]
  • If desired, the pharmaceutical compositions of the present invention can optionally include additional compounds to enhance the solubility of the hydrophobic therapeutic agent in the carrier system. Examples of such compounds, referred to as “solubilizers”, include: [0124]
  • alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; [0125]
  • ethers of polyethylene glycols having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol, available commercially from BASF under the trade name Tetraglycol) or methoxy PEG (Union Carbide); [0126]
  • amides, such as 2-pyrrolidone, 2-piperidone, ε-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide, and polyvinylpyrrolidone; [0127]
  • esters, such as ethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and isomers thereof, δ-valerolactone and isomers thereof, β-butyrolactone and isomers thereof; [0128]
  • and other solubilizers known in the art, such as dimethyl acetamide, dimethyl isosorbide (Arlasolve DMI (ICI)), N-methyl pyrrolidones (Pharmasolve (ISP)), monooctanoin, diethylene glycol monoethyl ether (available from Gattefosse under the trade name Transcutol), and water. [0129]
  • Mixtures of solubilizers are also within the scope of the invention. Except as indicated, these compounds are readily available from standard commercial sources. [0130]
  • Preferred solubilizers include triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene glycol 200-600, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propylene glycol. [0131]
  • The amount of solubilizer that can be included in compositions of the present invention is not particularly limited. Of course, when such compositions are ultimately administered to a patient, the amount of a given solubilizer is limited to a bioacceptable amount, which is readily determined by one of skill in the art. In some circumstances, it may be advantageous to include amounts of solubilizers far in access of bioacceptable amounts in order to maximize the concentration of hydrophobic therapeutic agent, with excess solubilizer removed prior to providing the composition to a patient using conventional techniques, such as distillation or evaporation. Thus, if present, the solubilizer can be in a concentration of 50%, 100%, 200%, or up to about 400% by weight, based on the amount of surfactant. If desired, very small amounts of solubilizers may also be used, such as 25%, 10%, 5%, 1% or even less. Typically, the solubilizer will be present in an amount of about 1% to about 100%, more typically about 5% to about 25% by weight. [0132]
  • 4. Other Additives [0133]
  • Other additives conventionally used in pharmaceutical compositions can be included, and these additives are well known in the art. Such additives include antioxidants, preservatives, chelating agents, viscomodulators, tonicifiers, flavorants, colorants odorants, opacifiers, suspending agents, binders, and mixtures thereof. The amounts of such additives can be readily determined by one skilled in the art, according to the particular properties desired. [0134]
  • 5. Dosage Forms [0135]
  • The pharmaceutical compositions of the present invention can be provided in the form of a solution preconcentrate; i.e., a composition as described above, and intended to be dispersed with water, either prior to administration, in the form of a drink, or dispersed in vivo. Alternatively, the compositions can be provided in the form of a diluted preconcentrate (i.e., an aqueous dispersion), a semi-solid dispersion or a solid dispersion. If desired, the compositions may be encapsulated in a hard or soft gelatin capsule, a starch capsule or an enteric coated capsule. The term “enteric coated capsule” as used herein means a capsule coated with a coating resistant to acid; i.e., an acid resistant enteric coating. Although solubilizers are typically used to enhance the solubility of a hydrophobic therapeutic agent, they may also render the compositions more suitable for encapsulation in hard or soft gelatin capsules. Thus, the use of a solubilizer such as those described above is particularly preferred in capsule dosage forms of the pharmaceutical compositions. If present, these solubilizers should be added in amounts sufficient to impart to the compositions the desired solubility enhancement or encapsulation properties. [0136]
  • Although formulations specifically suited to oral administration are presently preferred, the compositions of the present invention can also be formulated for topical, transdermal, ocular, pulmonary, vaginal, rectal, transmucosal or parenteral administration, in the form of a triglyceride-free cream, lotion, ointment, suppository, gel or the like. If such a formulation is desired, other additives may be included, such as are well-known in the art, to impart the desired consistency and other properties to the formulation. The compositions of the present invention can also be formulated as a spray or an aerosol. In particular, the compositions may be formulated as a sprayable solution, and such formulation is particularly useful for spraying to coat a multiparticulate carrier, such as a bead. Such multiparticulate carriers are well known in the art. [0137]
  • 6. Preparation of Pharmaceutical Compositions [0138]
  • The pharmaceutical compositions of the present invention can be prepared by conventional methods well known to those skilled in the art. Of course, the specific method of preparation will depend upon the ultimate dosage form. For dosage forms substantially free of water, i.e., when the composition is provided in a pre-concentrated form for later dispersion in an aqueous system, the composition is prepared by simple mixing of the components to form a pre-concentrate. The mixing process can be aided by gentle heating, if desired. For compositions in the form of an aqueous dispersion, the pre-concentrate form is prepared, then the appropriate amount of purified water is added. Upon gentle mixing, a clear aqueous dispersion is formed. If any water-soluble additives are included, these may be added first as part of the pre-concentrate, or added later to the clear aqueous dispersion, as desired. [0139]
  • In another embodiment, the present invention includes a multi-phase dispersion. In this embodiment, a pharmaceutical composition includes a carrier which forms a clear aqueous dispersion upon mixing with an aqueous solution, and an additional amount of non-solubilized hydrophobic therapeutic agent. Thus, the term “multi-phase” as used herein to describe these compositions of the present invention means a composition which when mixed with an aqueous solution forms a clear aqueous phase and a particulate dispersion phase. The carrier is as described above, and can include any of the surfactants, hydrophobic therapeutic agents, solubilizers and additives previously described. An additional amount of hydrophobic therapeutic agent is included in the composition. This additional amount is not solubilized by the carrier, and upon mixing with an aqueous system is present as a separate dispersion phase. The additional amount is optionally a milled, micronized, or precipitated form. Thus, upon dilution, the composition contains two phases: a clear aqueous dispersion of the hydrophilic and hydrophobic surfactants containing a first, solubilized amount of the hydrophobic therapeutic agent, and a second, non-solubilized amount of the hydrophobic therapeutic agent dispersed therein. It should be emphasized that the resultant multi-phase dispersion will not have the optical clarity of a dispersion in which the hydrophobic therapeutic agent is fully solubilized, but will appear to be cloudy, due to the presence of the non-solubilized phase. Such a formulation may be useful, for example, when the desired dosage of a hydrophobic therapeutic agent exceeds that which can be solubilized in the carrier of the present invention. The formulation may also contain additives, as described above. [0140]
  • One skilled in the art will appreciate that a hydrophobic therapeutic agent may have a greater solubility in the pre-concentrate carrier than in the aqueous dispersion, so that meta-stable, supersaturated solutions having apparent optical clarity but containing a hydrophobic therapeutic agent in an amount in excess of its solubility in the aqueous dispersion can be formed. Such super-saturated solutions, whether characterized as clear aqueous dispersions (as initially formed) or as multi-phase solutions (as would be expected if the meta-stable state breaks down), are also within the scope of the present invention. [0141]
  • The multi-phase formulation can be prepared by the methods described above. A pre-concentrate is prepared by simple mixing of the components, with the aid of gentle heating, if desired. It is convenient to consider the hydrophobic therapeutic agent as divided into two portions, a first solubilizable portion which will be solubilized by the carrier and contained within the clear aqueous dispersion upon dilution, and a second non-solubilizable portion which will remain non-solubilized. When the ultimate dosage form is non-aqueous, the first and second portions of the hydrophobic therapeutic agent are both included in the pre-concentrate mixture. When the ultimate dosage form is aqueous, the composition can be prepared in the same manner, and upon dilution in an aqueous system, the composition will form the two phases as described above, with the second non-solubilizable portion of the hydrophobic therapeutic agent dispersed or suspended in the aqueous system, and the first solubilizable portion of the hydrophobic therapeutic agent solubilized in the mixed surfactant carrier. Alternatively, when the ultimate dosage form is aqueous, the pre-concentrate can be prepared including only the first, solubilizable portion of the hydrophobic therapeutic agent. This pre-concentrate can then be diluted in an aqueous system to form a clear aqueous dispersion, to which is then added the second, non-solubilizable portion of the hydrophobic therapeutic agent to form a multi-phase aqueous composition. [0142]
  • The amount of hydrophobic therapeutic agent included in the pharmaceutical compositions of the present invention can be any amount desired by the formulator, up to the maximum amount that can be solubilized or suspended in a given carrier system. In general, the amount of hydrophobic therapeutic agent will be about 0.1% to about 60% by weight, based on the total weight of the pharmaceutical composition. In another aspect of the invention, described below, excess hydrophobic therapeutic agent can also be added, in a multi-phase dispersion. [0143]
  • B. Methods of Improved Delivery [0144]
  • In another aspect, the present invention relates to methods of improving delivery of hydrophobic therapeutic agents in an animal by administering to the animal a dosage form of the pharmaceutical compositions described herein. Preferably the animal is a mammal, and more preferably, a human. It has been found that the pharmaceutical compositions of the present invention when administered to an animal enable the hydrophobic therapeutic agent contained therein to be absorbed more rapidly than in conventional pharmaceutical compositions. Thus, in this aspect the invention relates to a method of increasing the rate of and/or extent of bioabsorption of a hydrophobic therapeutic agent by administering the hydrophobic therapeutic agent to an animal in the pharmaceutical compositions described herein. [0145]
  • C. Characteristics of the Pharmaceutical Compositions [0146]
  • The dispersions formed upon dilution of the pharmaceutical compositions of the present invention have the following characteristics: [0147]
  • Rapid formation: upon dilution with an aqueous solution, the carrier forms a clear dispersion very rapidly; i.e., the clear dispersion appears to form instantaneously. [0148]
  • Optical clarity: the dispersions are essentially optically clear to the naked eye, and show no readily observable signs of heterogeneity, such as turbidity or cloudiness. More quantitatively, dispersions of the pharmaceutical compositions of the present invention show a mono-modal distribution of very small particles sizes, typically 20 nm or less in average diameter; absorbances of less than about 0.3, typically less than about 0.1, at 10× dilution; and absorbances of less than about 0.1, typically less than about 0.01, at 100× dilution, as described more fully in the Examples herein. In the multi-phase embodiment of the compositions described herein, it should be appreciated that the optical clarity of the aqueous carrier dispersion phase will be obscured by the dispersed particulate non-solubilized hydrophobic therapeutic agent. [0149]
  • Robustness to dilution: the dispersions are surprisingly stable to dilution in aqueous solution, including aqueous solutions simulating physiological fluids such as enzyme-free simulated gastric fluid (SGF) and enzyme-free simulated intestinal fluid (SIF). The hydrophobic therapeutic agent remains solubilized for at least the period of time relevant for absorption. [0150]
  • Triglyceride-free: It is a particular feature of the present invention that the pharmaceutical compositions are substantially triglyceride-free. The term “triglyceride” as used herein means glycerol triesters of C[0151] 6 to about C25 fatty acids. Unlike conventional compositions such as oil-based solutions, emulsions, and microemulsions, which rely on the solubilizing power of triglycerides, the present compositions surprisingly solubilize hydrophobic therapeutic agents using combinations of substantially triglyceride-free surfactants.
  • As used herein, the term “substantially triglyceride-free” means compositions which contain triglycerides, if at all, only as minor components or impurities in surfactant mixtures. It is well known in the art that commercially available surfactants often are complex mixtures of compounds. For example, one preferred surfactant is Capmul® GMO-K, a widely-used blend of glyceryl mono- and dioleates. Due to difficulties in separating complex product mixtures, however, a typical lot of Capmul® GMO-K, as reported by the manufacturer's certificate of analysis, contains the following distribution of glyceryl esters, in percent by weight based on the total weight of glyceryl esters: [0152]
    Palmitic acid 3.3%
    Stearic acid 4.0%
    Oleic acid 81.0% 
    Linoleic acid 9.7%
    Linolenic acid 0.3%
  • In addition, the surfactant mixture in the particular lot reported contains 0.10% water and 0.95% free, unesterified glycerol. These specific percentages are expected to vary, lot-by-lot, as well, and it is expected that commercial surfactant products will generally possess similar variability, regardless of the specific major component and the specific manufacturer. Thus, the present invention does not include surfactants which contain triglycerides as an intended component. Indeed, such surfactants are not common, since triglycerides themselves have no surfactant properties. However, it should be appreciated that the present invention does not exclude the use of surfactant products which contain small amounts of triglycerides as impurities or as unreacted starting material. It is expected that commercial mixtures suitable for use in the present invention may contain as much as 5% triglycerides by weight as unintended components. Thus, “substantially triglyceride-free” should be understood as meaning free of added triglycerides, and containing less than 5%, preferably essentially 0%, triglyceride impurities. [0153]
  • Without wishing to be bound by theory, it is believed that the observed properties of the clear, aqueous dispersions formed by the compositions of the present invention are consistent with, and best explained by, the formation of mixed micelles of the hydrophobic and hydrophilic surfactants, with the hydrophobic therapeutic agent solubilized by the micelles. It should be emphasized that these dispersions are characterized by the properties described herein, regardless of the precise microscopic physical form of the dispersed particles. Nevertheless, in order to more fully explain the invention, and to illustrate its unexpected and important advantages, the following discussion is offered in terms consistent with the theoretical principles believed to be correct. [0154]
  • It is believed that the hydrophobic and hydrophilic surfactants form mixed micelles in aqueous solution. In this model, each micelle is composed of molecules (or ions) of both the hydrophilic and hydrophobic surfactants. Depending upon the detailed three-dimensional structure of the hydrophobic therapeutic agent, its distribution of polar moieties, if any, its polarizability in local regions, and other molecule-specific and complex factors, the hydrophobic therapeutic agent may be distributed in any part of the micelle, such as near the outer, more hydrophilic region, near the inner, more hydrophobic region, or at various points in between. Further, it is known that micelles exist in dynamic equilibrium with their component molecules, and it is expected that this equilibrium will include dynamic redistribution of the hydrophobic therapeutic agent. [0155]
  • As discussed above, triglyceride-containing formulations suffer the disadvantage that bioabsorption of the hydrophobic therapeutic agents contained therein is dependent upon enzymatic degradation (lipolysis) of the triglyceride components. The pharmaceutical compositions of the present invention, however, are substantially free of triglycerides, and thus do not depend upon lipolysis to enable release of the hydrophobic therapeutic agent for bioabsorption. The hydrophobic therapeutic agent is in a dynamic equilibrium between the free compound in solution and the solubilized compound, thus promoting rapid release. [0156]
  • The unique pharmaceutical compositions of the present invention present a number of significant and unexpected advantages, including: [0157]
  • Efficient transport: The particle sizes in the aqueous dispersions of the present invention are much smaller, typically less than 20 nm, than the larger particles characteristic of vesicular, emulsion or microemulsion phases, and the particle size distribution is mono-modal and narrow. This reduced and more uniform size enables more efficient drug transport through the intestinal aqueous boundary layer, and through the absorptive brush border membrane. More efficient transport to absorptive sites leads to improved and more consistent absorption of hydrophobic therapeutic agents. [0158]
  • Non-dependence on lipolysis: The lack of triglyceride components provides pharmaceutical compositions not dependent upon lipolysis, and upon the many poorly characterized factors which affect the rate and extent of lipolysis, for effective presentation of a hydrophobic therapeutic agent to an absorptive site. Such factors include the presence of composition components which may inhibit lipolysis; patient conditions which limit production of lipase, such as pancreatic lipase secretory diseases; and dependence of lipolysis on stomach pH, endogenous calcium concentration, and presence of co-lipase or other digestion enzymes. The lack of lipolysis dependence further provides transport which does not suffer from any lag time between administration and absorption caused by the lipolysis process, enabling a more rapid onset of therapeutic action and better bioperformance characteristics. In addition, pharmaceutical compositions of the present invention can make use of hydrophilic surfactants which might otherwise be avoided or limited due to their potential lipolysis inhibiting effects. [0159]
  • Non-dependence on bile and meal fat contents: Due to the higher solubilization potential over bile salt micelles, the present compositions are less dependent on endogenous bile and bile related patient disease states, and meal fat contents. These advantages overcome meal-dependent absorption problems caused by poor patient compliance with meal-dosage restrictions. [0160]
  • Superior solubilization: The surfactant combinations used in compositions of the present invention enable superior loading capacity over conventional micelle formulations. In addition, the particular combination of surfactants used can be optimized for a specific hydrophobic therapeutic agent to more closely match the polarity distribution of the therapeutic agent, resulting in still further enhanced solubilization. [0161]
  • Faster dissolution and release: Due to the robustness of compositions of the present invention to dilution, the hydrophobic therapeutic agents remain solubilized and thus do not suffer problems of precipitation of the therapeutic agent in the time frame relevant for absorption. In addition, the therapeutic agent is presented in small particle carriers, and is not limited in dilution rate by entrapment in emulsion carriers. These factors avoid liabilities associated with the poor partitioning of lipid solubilized drug in to the aqueous phase, such as large emulsion droplet surface area, and high interfacial transfer resistance, and enable rapid completion of the critical partitioning step. [0162]
  • Consistent performance: Aqueous dispersions of the present invention are thermodynamically stable for the time period relevant for absorption, and can be more predictably reproduced, thereby limiting variability in bioavailability—a particularly important advantage for therapeutic agents with a narrow therapeutic index. [0163]
  • Efficient release: The compositions of the present invention are designed with components that help to keep the hydrophobic therapeutic agent solubilized for transport to the absorption site, but readily available for absorption, thus providing a more efficient transport and release. [0164]
  • Less prone to gastric emptying delays: Unlike triglyceride-containing formulations, the present compositions are less prone to gastric emptying delays, resulting in faster absorption. Further, the particles in dispersions of the present invention are less prone to unwanted retention in the gastro-intestinal tract. [0165]
  • Small size: Because of the small particle size in aqueous dispersion, the pharmaceutical compositions of the present invention allow for faster transport of the hydrophobic therapeutic agent through the aqueous boundary layer. [0166]
  • These and other advantages of the present invention, as well as aspects of preferred embodiments, are illustrated more fully in the Examples which follow. [0167]
    • EXAMPLES Example 1
  • Preparation of Compositions [0168]
  • A simple pre-concentrate of a hydrophobic surfactant and a hydrophilic surfactant is prepared as follows. Predetermined weighed amounts of hydrophilic and hydrophobic surfactants are stirred together to form a homogeneous mixture. For surfactant combinations that are poorly miscible, the mixture can be gently heated to aid in formation of the homogeneous mixture. A chosen hydrophobic therapeutic agent in a predetermined amount is added and stirred until solubilized. Optionally, solubilizers or additives are included by simple mixing. [0169]
  • To form an aqueous dispersion of the pre-concentrate, a predetermined amount of purified water, buffer solution, or aqueous simulated physiological solution, is added to the pre-concentrate, and the resultant mixture is stirred to form a clear, aqueous dispersion. [0170]
    • Example 2
  • Surfactant Combinations Giving Clear Aqueous Dispersions [0171]
  • Surfactant mixtures giving clear, aqueous dispersions were prepared according to the method of Example 1. Seven hydrophilic surfactants and sixteen hydrophobic surfactants were used to produce approximately one hundred clear aqueous dispersions suitable for use in the present invention. For simplicity, no hydrophobic therapeutic agent was included in these compositions, since it is believed that the presence of the hydrophobic therapeutic agent does not substantially affect the clear, aqueous nature of composition. For the same reason, these compositions were free of additional solubilizers and other additives. [0172]
  • Multiple solutions were prepared for each surfactant combination, to determine the approximate maximum amount of hydrophobic therapeutic agent giving a clear aqueous dispersion with a given amount of hydrophilic therapeutic agent. Thus, for each gram of the hydrophilic surfactant, a predetermined amount of hydrophobic agent was used to prepare a 10× aqueous dispersion. If the dispersion appeared to be optically clear, a new dispersion was prepared according to Example 1, using a larger amount of hydrophobic surfactant. Similarly, if the dispersion appeared to be cloudy, a new dispersion was prepared using a smaller amount of hydrophobic surfactant. The results are shown in Table 19. [0173]
    TABLE 19
    Surfactant Combinations Giving Clear Dispersions
    Hydrophilic Surfactant
    PEG-35 PEG-40H PEG-60 PEG-8 PEG-25
    Castor Oil Castor Oil Polysorbate Polysorbate Corn Oil Capric/ Glyceryl
    Hydrophobic (Incrocas (Cremophor -20 80 (Crovol M- Caprylic trioleate
    Surfactant 35) RH-40) (Tween 20) (Tween 80) 70) (Labrasol) (Tagat TO)
    Glyceryl/Propylene 20 20 20 8 15 25 10
    Glycol Oleate
    (Arlacel 186)
    Glyceryl Oleate 15 40 10 12 10 35 10
    (Peceol)
    Acetylated 80 80 20 15 10 10 10
    Monoglycerides
    (Myvacet 9-45)
    PEG-6 Corn Oil 50 95 10 10 20 10 10
    (Labrafil M2125CS)
    Sorbitan Monooleate 25 65 5 5 20 15 10
    (Span 80)
    Sorbitan Monolaurate 30 20 20 10 15 30 10
    (Arlacel 20)
    Polyglyceryl oleate 10 5 35 10 10 35 10
    (Plurol Oleique CC497)
    Propylene Glycol Laurate 10 55 35 20 15 35 10
    (Lauroglycol FCC)
    Glyceryl Caprylate/ 10 50 20 25 25 20 10
    Caprate (Capmul MCM)
    PEG-20 Corn Oil 35 40 40 25 30 90 10
    (Crovol M-40)
    PEG-20 Almond Oil 30 35 40 25 30 90 10
    (Crovol A-40)
    Mono/diglycerides of 50 50 60 25 25 30 10
    Caprylic Acid (Imwitor
    988)
    PEG-4-lauryl ether 40 45 95 70 * 90 10
    (Brij 30)
    PEG-3-oleyl ether 20 30 25 20 20 25 10
    (Volpo 3)
    Glyceryl mono/dioleate * 10 * * 10 25 10
    (Capmul GMO-K)
    Ethyl Oleate 40 60 10 10 60 10 10
    (Crodamol EO)
  • Each entry in the Table represents the approximate maximum number of grams of hydrophobic surfactant per 100 g of hydrophilic surfactant giving acceptable optical clarity. The numbers in the Table are illustrative only, and it is expected that further optimization of the surfactant systems with solubilizers, co-surfactants, and other additives will give still higher numbers. [0174]
    • Example 3
  • Compositions Containing Solubilizers [0175]
  • The procedure of Example 2 was repeated for compositions containing PEG-40 hydrogenated castor oil (Cremophor RH 40) as the hydrophilic surfactant, with eight different hydrophobic surfactants, and four different solubilizers, to study the effect of solubilizer on the relative amounts of hydrophobic and hydrophilic surfactants giving clear aqueous dispersions. In each case, the amount of solubilizer was held constant at 20% by weight, based on the total weight of the two surfactants. The results are shown in Table 20. As in Example 2, the numbers in the Table represent the approximate maximum number of grams of hydrophobic surfactant per 100 g of hydrophilic surfactant giving a clear aqueous dispersion. For convenience, the corresponding entries from Table 19 (with no solubilizer present) are reproduced in Table 20 in the column labeled “none.” [0176]
    TABLE 20
    Effect of Solubilizer on Hydrophobic Surfactant Amounts
    Hydrophilic Surfactant
    (Cremophor RH40) + 20% Solubilizer
    PEG- Glyco-
    Hydrophobic Surfactant (None) Triacetin Ethanol 400 furol
    Glyceryl/Propylene 20 28 25 25 25
    Glycol Oleate (Arlacel
    186)
    Glyceryl Oleate 40 40 42 40 44
    (Peceol)
    Sorbitan Monooleate 65 40 40 25 30
    (Span 80)
    Sorbitan Monolaurate 20 65 * * 65
    (Span 20)
    PEG-6 Corn Oil 95 95 * 95 *
    (Labrafil M2125CS)
    Acetylated 80 80 80 80 80
    Monoglyceride
    (Myvacet 9-45)
    Ethyl Oleate 60 60 60 * 60
    (Crodamol EO)
    Mono/diglycerides of 50 80 * * 75
    Caprylic Acid (Imwitor
    988)
  • As is clear from the data in the Table, the effect of added solubilizer on the relative amount of hydrophobic surfactant that can be used varies considerably. For some surfactant combinations, the added solubilizer has a dramatic effect on the amount of hydrophobic surfactant (e.g., [0177] Span 20, Imwitor 988). In other systems, the effect is moderate (Arlacel 186, Peceol) or negligible (Crodamol EO, Myvacet 9-45). In the one case of Span 80, the presence of the solubilizer actually decreases the amount of hydrophobic surfactant that can be used.
    • Example 4
  • Compositions Containing Solubilizers [0178]
  • Example 3 was repeated, this time choosing a single hydrophobic surfactant (Arlacel 186) and three different hydrophilic surfactants, with addition of either ethanol or triacetin (20% by weight, based on the total weight of the two surfactants). The results are shown in Table 21. The corresponding entry from Table 19 (with no solubilizer present) is included in Table 21 for reference. [0179]
    TABLE 21
    Effect of Solubilizer on Hydrophobic Surfactant Amounts
    Hydrophobic Surfactant (Arlacel 186) +
    Hydrophilic 20% Solubilizer
    Surfactant (None) Ethanol Triacetin
    PEG-60 Corn Oil 15 20 20
    (Crovol M-70)
    PEG-35 Castor Oil 20 25 25
    (Incrocas 35)
    Polysorbate 20 20 25 25
    (Tween 20)
  • In each case, a moderate increase (20%) in the relative amount of hydrophobic surfactant was observed. [0180]
    • Example 5
  • Effect of Solubilizer Concentration [0181]
  • The procedure of Example 3 was repeated, with the following differences. A single hydrophilic surfactant (Cremophor RH-40) and hydrophobic surfactant (Arlacel 186) were chosen, to examine the effect of increased solubilizer concentration. For each of the four solubilizers tested at 20% concentrations in Example 3 (Table 20) plus an additional solubilizer (propylene glycol), compositions were tested at a solubilizer concentration of 50% by weight, based on the total weight of the surfactant pair. As in each of the previous examples, the numbers in Table 22 represent the maximum hydrophobic surfactant concentration giving a clear aqueous dispersion. Note that the “0” column in Table 22 reproduces the numbers shown in Table 19 (no solubilizer), and the “20%” column reproduces the numbers in Table 20, with the value for propylene glycol also supplied. [0182]
    TABLE 22
    Effect of Solubilizer Concentration on Hydrophobic
    Surfactant Amounts*
    Weight Percent of Solubilizer
    Solubilizer
    0 20 50
    PEG-400 20 25 25
    Propylene Glycol 20 28 30
    Triacetin 20 28 25
    Ethanol 20 25 30
    Glycofurol 20 25 30
  • As the Table shows, increasing the amount of solubilizer has a small to moderate effect on the amount of hydrophobic surfactant that can be present in a clear aqueous dispersion. It should be appreciated that the data equivalently show that very large amounts of solubilizer can be used, without detrimental effect on the ability of the surfactant system to form a clear, aqueous dispersion. [0183]
    • Example 6
  • Effect of High Solubilizer Concentration and Solubilizer Mixtures [0184]
  • Example 5 was repeated, using the same surfactant pair, but with an 80% concentration of solubilizer, based on the total weight of the surfactants. The 80% solubilizer was either PEG-400, or a mixture of PEG-400 and one of three alcohols or polyols. The results are shown in Table 23, with the numbers in the Table having the same meaning as in the previous Examples. [0185]
    TABLE 23
    Large Solubilizer Concentrations and Solubilizer Mixtures*
    60% 60%
    60% PEG-400 + PEG-400 +
    (no 80% PEG-400 + 20% Propylene 20%
    solubilizer) PEG-400 20% Glycerol Glycol Isopropanol
    20 25 25 25 25
  • It is clear from the data in the Table that very high concentrations of solubilizers, as well as mixtures of solubilizers, can be used effectively in the clear aqueous dispersions of the present invention. [0186]
    • Examples 7-12
  • Average Particle Size [0187]
  • In order to more quantitatively characterize the clear aqueous dispersions of the present invention, particle sizes were measured for several compositions of the present invention. For simplicity, the measurement were made for the dispersed carrier, in the absence of a hydrophobic therapeutic agent. In this Example, formulations were prepared as in Example 1, and diluted to form 10× or 100× aqueous dispersions. Each of the resulting dispersions was observed to be optically clear to the naked eye. Average particle sizes were measured with a Nicomp Particle Size Analyzer (Particle Size Systems, Inc., Santa Barbara, Calif.). The results of these measurements are shown in Table 24. [0188]
    TABLE 24
    Average Particle Size
    Ex- Particle
    am- Sur- Size
    ple factant Dilu- Observa- (nm) ±
    No. Formula Ratio* tion tion S.D.**
    7 Tween 80 520 mg 9.6 100X very clear  6.5 ± 1.1
    Lauroglycol 50 mg solution
    FCC
    8 Tween 80 500 mg 15  10X very clear  8.1 ± 1.6
    Capmul 73 mg solution
    MCM
    9 Cremophor 530 mg 28 100X clear 12.4 ± 3.0
    RH-40 150 mg solution
    Peceol
    10 Cremophor 500 mg 2.0 100X clear 14.7 ± 3.0
    RH-40 10 mg solution
    Plurol
    Oleique
    CC497
    11 Cremophor 550 mg 36 100X clear 14.3 ± 2.5
    RH-40 200 mg solution
    Lauroglycol
    FCC
    12 Cremophor 500 mg 40 100X clear 12.6 ± 2.9
    RH-40 200 mg solution
    Capmul
    MCM
  • As the data show, the compositions of the present invention produce clear, aqueous dispersions, with no visible cloudiness. The particle size distribution shows very small particles, with average diameters of from about 6 to about 15 nm. The distribution is mono-modal, with a standard deviation of approximately 20%, indicating a highly uniform distribution of very small particles. This particle size distribution is consistent with a solution of particles of micellar structure, although the invention is not limited by any particular theoretical framework. [0189]
    • Comparative Examples C1-C5
  • Optical Clarity and Particle Sizes of Compositions Not Forming Clear Aqueous Dispersions [0190]
  • For comparison to the clear aqueous dispersions of the present invention, several compositions were prepared having hydrophobic surfactant concentrations higher than those suitable for forming clear aqueous dispersions. These compositions were prepared by weighing the components and mixing well, with gentle warming. The compositions were then diluted 10× to form dispersions, and these dispersions were subjected to the particle size measurements as described in Example 7. The results are shown in Table 25. For direct comparison with the compositions of the present invention, Examples 7, 9, 10, 11 and 12 are shown next to the corresponding comparative compositions. [0191]
    TABLE 25
    Optical Clarity and Particle Size
    Example Surfactant Particle Size (nm)**
    No. Surfactants Ratio* Observation Mean 1 Mean 2
    C1 Tween 80 67 milky 26.6 209
    Lauroglycol solution
    FCC
    7 Tween 80 9.6 very clear 6.5 —
    Lauroglycol solution
    FCC
    C2 Cremophor 67 milky 25 116
    RH-40 solution
    Peceol
    9 Cremophor 28 clear 8.1 —
    RH-40 solution
    Peceol
    C3 Cremophor 67 milky 16.5 102
    RH-40 solution
    Plurol
    Oleique
    CC497
    10 Cremophor 2.0 clear 12.4 —
    RH-40 solution
    Plurol
    Oleique
    CC497
    C4 Cremophor 69 hazy 17.1 45.3
    RH-40 solution
    Lauroglycol
    FCC
    11 Cremophor 36 clear 14.3
    RH-40 solution
    Lauroglycol
    FCC
    C5 Cremophor 67 milky 11.6 176
    RH-40 solution
    Capmul
    MCM
    12 Cremophor 40 clear 12.6 —
    RH-40 solution
    Capmul
    MCM
  • In addition to the compositions shown in the Table, compositions containing Tween 80 and Plurol Oleique CC497, Tween 80 and Peceol, and Tween 80 and Capmul MCM were prepared at a surfactant ratio of 67 g hydrophobic surfactant per 100 g hydrophilic surfactant. Particle sizes were not measured for these compositions, but each was observed to form a milky or hazy aqueous dispersion. [0192]
  • As the data show, compositions having excessive amounts of hydrophobic surfactant form milky or hazy solutions, whereas those of the present invention form clear solutions. In addition, the particle size distributions of the milky solutions are bimodal, in contrast to the mono-modal solutions of the corresponding clear solutions. These bimodal particle size distributions show a first mode having a small mean particle size of about 12 to about 27 nm, and a second mode having particle sizes of up to more than 200 nm. Thus, compositions having excessive hydrophobic surfactant are heterogeneous (multi-phasic), non-clear dispersions, having a complex bimodal distribution of particles of two distinct size ranges. In contrast, compositions of the present invention are homogeneous (single phase), clear dispersion, having a mono-modal distribution of very small particle sizes. [0193]
    • Examples 13-42
  • Spectroscopic Characterization of Optical Clarity [0194]
  • The optical clarity of aqueous dispersions of the present invention was measured spectroscopically. Compositions were prepared according to Example 1, and diluted to 10× and 100× solutions. The specific compositions measured also include a solubilizer, to further illustrate preferred aspects of the invention. In addition, several of the compositions illustrate compositions according to the present invention wherein either the hydrophilic surfactant (Examples 20 and 27) or the hydrophobic surfactant (Examples 41 and 42) itself is a mixture of surfactants. [0195]
  • The absorbance of each solution was measured at 400.2 nm, using a purified water standard, and the results are shown in Table 26. [0196]
    TABLE 26
    Spectroscopic Characterization of Optical Clarity
    Example Absorbance (400.2 nm)
    No. Formulation 10X 100X
    13 Cremophor RH-40 430 mg 0.407 0.099
    Myvacet 9-45 310 mg
    Ethyl Alcohol 210 mg
    14 Cremophor RH-40 610 mg 0.299 0.055
    Peceol 160 mg
    Ethyl Alcohol 200 mg
    15 Cremophor RH-40 540 mg 0.655 0.076
    Span 80 260 mg
    Triacetin 220 mg
    16 Incrocas 35 470 mg 0.158 0.038
    Myvacet 9-45 250 mg
    Ethyl Alcohol 220 mg
    17 Incrocas 35 510 mg 0.064 0.009
    Imwitor 988 220 mg
    Triacetin 200 mg
    18 Tween 20 570 mg 0.031 0.003
    Lauroglycol FCC 140 mg
    Glycofurol 220 mg
    19 Crovol M70 610 mg 0.049 0.006
    Crovol M40 120 mg
    Ethyl Alcohol 200 mg
    20 Cremophor RH-40 250 mg 0.028 0.008
    Labrasol 250 mg
    Capmul GMO-K 110 mg
    Triacetin 100 mg
    21 Cremophor RH-40 220 mg 0.114 0.018
    Lauroglycol FCC 200 mg
    Ethyl Alcohol 75 mg
    22 Tween 80 170 mg 0.050 0.008
    Capmul MCM 30 mg
    Ethyl Alcohol 38 mg
    23 Cremophor RH-40 550 mg 0.029 0.006
    Capmul MCM 80 mg
    Ethyl Alcohol 53 mg
    24 Cremophor RH-40 230 mg 0.187 0.020
    Peceol 70 mg
    Ethyl Alcohol 54 mg
    25 Cremophor RH-40 500 mg 0.028 0.005
    Plurol Oleique 10 mg
    CC497 11 mg
    Ethyl Alcohol
    26 Tween 80 180 mg 0.036 0.003
    Lauroglycol FCC 20 mg
    Ethyl Alcohol 37 mg
    27 Tween 80 420 mg 0.036 0.009
    Labrasol 330 mg
    Arlacel 186 54 mg
    Ethyl Alcohol 140 mg
    28 Tagat O2 500 mg 0.077 0.005
    PGMG-03 50 mg
    Ethyl Alcohol 100 mg
    29 Incrocas 35 250 mg 0.053 0.005
    Gelucire 44/14 150 mg
    Triacetin 94 mg
    30 Cremophor RH-40 270 mg 0.232 0.047
    Labrafil 170 mg
    Ethyl Alcohol 100 mg
    31 Crovol M-70 380 mg 0.064 0.011
    Labrafil 50 mg
    Triacetin 100 mg
    32 Cremophor RH-40 300 mg 0.163 0.034
    Peceol 110 mg
    Triacetin 110 mg
    33 Tween 20 340 mg 0.038 0.005
    Lauroglycol FCC 110 mg
    Glycofurol 100 mg
    34 Incrocas-35 310 mg 0.101 0.020
    Labrafil 110 mg
    Ethyl Alcohol 100 mg
    35 Cremophor RH-40 300 mg 0.908 0.114
    Span 80 130 mg
    Triacetin 100 mg
    36 Cremophor RH-40 510 mg 0.039 0.008
    Arlacel 186 58 mg
    Propylene Glycol 55 mg
    37 Cremophor RH-40 510 mg 0.440 0.100
    Peceol 140 mg
    Propylene Glycol 58 mg
    38 Cremophor RH-40 500 mg 0.411 0.107
    Labrafil M2125CS 400 mg
    Propylene Glycol 88 mg
    39 Cremophor RH-40 550 mg 0.715 0.106
    Span 80 220 mg
    Propylene Glycol 78 mg
    40 Cremophor RH-40 500 mg 0.547 0.147
    Crodamol 280 mg
    Propylene Glycol 100 mg
    41 Cremophor RH-40 550 mg 0.419 0.055
    Labrafil M2125CS 340 mg
    Span 80 200 mg
    Ethyl Alcohol 110 mg
    42 Cremophor RH-40 500 mg 0.293 0.260
    Labrafil M2125CS 270 mg
    Crovol M-40 280 mg
    Ethyl Alcohol 100 mg
  • Ideally, a clear aqueous dispersion should have a very high transmittance, indicating little scattering of light by large particles. Absorbance and transmittance are related by the simple expression [0197]
  • A=−log T
  • where A is absorbance, and T is the transmittance expressed as a decimal. Thus, preferred solutions of the present invention will have small absorbances. As noted above, in the absence of true absorption (due to chromophores in solution), suitable clear aqueous dispersions of the present invention should have an absorbance at 10× dilution of less than about 0.3. [0198]
  • The data in Table 26 show 30 solutions, 22 of which have absorbances less than about 0.3 at 10× dilution. Of these solutions, 3 have absorbances between 0.2 and 0.3, 5 have absorbances between 0.1 and 0.2, and 14 have absorbances less than 0.1. Thus, for the majority of the solutions, absorbance provides an adequate measure of optical clarity. [0199]
  • Solutions having absorbances greater than 0.3 may still be suitable for use in the present invention, as these are observed to have acceptable optical clarity by visual examination. For these relatively high absorbance solutions, this simple spectroscopic measure of optical clarity is inadequate, and other methods are more well-suited to assessing optical clarity, such as visual observation and particle size. As an example, Example 37, which shows an absorbance of 0.440, has a surfactant ratio of 27, well below the value of 40 shown in Table 19, and is observed to be a clear solution. This same composition, without the additional solubilizer, is shown in Example 9 at a surfactant ratio of 28 to have a mono-modal, narrow particle size distribution, at an average particle size of 12.4 nm. It should be appreciated that direct particle size measurement and absorbance measurement are different ways of assessing optical clarity, and provide alternative criteria for quantifying clarity. However, it is believed that the simple, qualitative visual observation of optical clarity is a sufficient measure of suitable clarity for use in the present invention, particularly so since compositions outside the scope of the invention show marked and unmistakable cloudiness without recourse to quantitative measurement (See, e.g., Comparative Example 1). [0200]
    • Comparative Examples C6-C12
  • Spectroscopic Characterization of Compositions Not Forming Clear Aqueous Dispersions [0201]
  • For comparison to the clear aqueous dispersions of the present invention, compositions observed to be milky or cloudy were characterized by absorption, as in Examples 13-42. Where available, results for comparable solutions from Examples 13-42 are reproduced for comparison. In such cases, where a given surfactant combination is presented in Examples 13-42 more than once (with different solubilizer concentrations), the composition having the lowest solubilizer concentration is chosen, to facilitate more direct comparison. The results are shown in Table 27. [0202]
    TABLE 27
    Comparative Spectroscopic Characterization
    Example Absorbance (400.2 nm)
    No. Formulation 10X 100X
    C6 Tween 80 100 mg 2.938 2.827
    Lauroglycol FCC 67 mg
    26 Tween 80 180 mg 0.036 0.003
    Lauroglycol FCC 20 mg
    Ethyl Alcohol 37 mg
    C7 Tween 80 100 mg 0.980 0.932
    Capmul MCM 67 mg
    22 Tween 80 170 mg 0.050 0.008
    Capmul MCM 30 mg
    Ethyl Alcohol 38 mg
    C8 Cremophor RH-40 100 mg 2.886 1.595
    Plurol Oleique CC497 67 mg
    25 Cremophor RH-40 500 mg 0.028 0.005
    Plurol Oleique CC497 10 mg
    Ethyl Alcohol 11 mg
    C9 Cremophor RH-40 100 mg 2.892 1.507
    Peceol 67 mg
    24 Cremophor RH-40 230 mg 0.187 0.020
    Peceol 70 mg
    Ethyl Alcohol 54 mg
    C10 Cremophor RH-40 100 mg 1.721 0.491
    Capmul MCM 67 mg
    23 Cremophor RH-40 550 mg 0.029 0.006
    Capmul MCM 80 mg
    Ethyl Alcohol 53 mg
    C11 Tween 80 100 mg 1.585 1.357
    Plurol Oleique CC497 67 mg
    C12 Tween 80 100 mg 2.849 2.721
    Peceol 67 mg
  • The data in the Table demonstrate that the clear aqueous dispersions of the present invention show very different absorptive behavior from compositions having excessive hydrophobic surfactant concentrations, having apparent absorbances (through scattering losses) lower by at least a factor of ten, and in some cases by a factor of more than one hundred. [0203]
    • Examples 43 and 44
  • Solubility of a Polyfunctional Hydrophobic Therapeutic Agent [0204]
  • The enhanced solubility of a typical polyfunctional hydrophobic therapeutic agent, cyclosporin, in the pharmaceutical compositions of the present invention was measured using a conventional “shake flask” method. Compositions were prepared and diluted to 10× and 100× as in Example 1, without including the therapeutic agent. The solutions were then provided with an excess of cyclosporin, and agitated to allow the cyclosporin to achieve an equilibrium partitioning between the solubilized phase and the non-solubilized dispersion phase. Concentration of the solubilized cyclosporin was then determined using standard HPLC techniques, optimized for the quantitative detection of cyclosporin. The results are shown in Table 28. [0205]
    TABLE 28
    Solubility of Cyclosporin in Clear Aqueous Dispersions
    Ex-
    ample Solubility (μg/mL)
    No. Carrier Composition 10X Dilution 100X Dilution
    43 Cremophor RH-40 430 mg 13,205 1,008
    Myvacet 9-45 321 mg
    Ethyl Alcohol 210 mg
    44 Cremophor RH-40 540 mg 11,945 1,127
    Span 80 260 mg
    Triacetin 220 mg
  • This Example demonstrates the dramatically enhanced solubility of a hydrophobic therapeutic agent in the pharmaceutical compositions of the present invention. [0206]
    • Comparative Examples C13-C16
  • Solubility of a Polyfunctional Hydrophobic Therapeutic Agent [0207]
  • For comparison, the solubility experiment of Examples 43-44 was performed on four standard aqueous solutions. The first comparison solution was purified water with no additives. Next, a standard simulated intestinal fluid (SIF) was used, to simulate the in vivo conditions to be encountered by the hydrophobic therapeutic agent. A third solution was prepared with simulated intestinal fluid, plus an additional aliquot of 20 mM sodium taurocholate (a bile salt); this solution is designated SIFB in Table 29. Finally, a fourth solution was prepared with simulated intestinal fluid, 20 mM sodium taurocholate, and 5 mM lecithin; this solution is designated SIFBL. The 20 mM bile salt and 5 mM lecithin concentrations are believed to be representative of the average concentration of these compounds encountered in the gastrointestinal tract. As in the previous Examples, these comparison solutions were equilibrated with cyclosporin using the shake flask method, and analyzed by HPLC. The results of these measurements are presented in Table 29. [0208]
    TABLE 29
    Solubility of Cyclosporin in Aqueous Solutions
    Example No. Solution Solubility (μg/mL)
    C13 Water 6
    C14 SIF 6
    C15 SIFB 49
    C16 SIFBL 414
    43-44 (average at 10X) present invention 12,575
  • As the Table indicates, the solubility of the polyfunctional hydrophobic therapeutic agent in the compositions of the present invention is far greater than its solubility in aqueous and gastrointestinal aqueous solutions. [0209]
    • Examples 45-49
  • Solubility of a Lipophilic Hydrophobic Therapeutic Agent [0210]
  • The enhanced solubility of a typical lipophilic hydrophobic therapeutic agent, progesterone, in the pharmaceutical compositions of the present invention was measured as described in Examples 43-44. The results are shown in Table 30. [0211]
    TABLE 30
    Solubility of Progesterone in Clear Aqueous Dispersions
    Ex-
    ample Solubility (μg/mL)
    No. Carrier Composition 10X Dilution 100X Dilution
    45 Cremophor RH-40 1000 mg 1100 200
    Arlacel 186 120 mg
    Propylene Glycol 110 mg
    46 Cremophor RH-40 1000 mg 1240 140
    Peceol 240 mg
    Propylene Glycol 120 mg
    47 Cremophor RH-40 1000 mg 1760 190
    Labrafil M2125CS 800 mg
    Propylene Glycol 180 mg
    48 Cremophor RH-40 1000 mg 1360 160
    Span 80 350 mg
    Propylene Glycol 140 mg
    49 Cremophor RH-40 1000 mg 1720 190
    Crodamol EO 600 mg
    Propylene Glycol 160 mg
  • This Example demonstrates the dramatically enhanced solubility of a hydrophobic therapeutic agent in the pharmaceutical compositions of the present invention. [0212]
    • Comparative Examples C17-C20
  • Solubility of a Lipophilic Hydrophobic Therapeutic Agent [0213]
  • For comparison, the solubility experiment of Comparative Examples C13-C16 was repeated, using progesterone instead of cyclosporin. The results of these measurements are presented in Table 31. [0214]
    TABLE 31
    Solubility of Progesterone in Aqueous Solutions
    Example No. Solution Solubility (μg/mL)
    C17 Water   6
    C18 SIF  7-10
    C19 SIFB 32-40
    C20 SIFBL  80
    45-49 (average at 10X) present invention 1436
  • As the Table indicates, the solubility of the lipophilic hydrophobic therapeutic agent in the compositions of the present invention is far greater than its solubility in aqueous and gastrointestinal aqueous solutions. [0215]
    • Examples 50-57
  • Aqueous Dilution Stability of Compositions Containing a Polyfunctional Hydrophobic Therapeutic Agent [0216]
  • Compositions according to the present invention were prepared, with a typical polyfunctional hydrophobic therapeutic agent, cyclosporin, as the therapeutic agent. The compositions were prepared as described in Example 1, except that the ingredients were added in the order listed in Table 32. The pre-concentrates were diluted 100× with purified water, and a visual observation was made immediately after dilution. The solutions were then allowed to stand 6 hours to assess dilution stability, then the cyclosporin concentration in solution was measured, using a drug-specific HPLC assay. The results are shown in Table 32. [0217]
    TABLE 32
    Dilution Stability of Polyfunctional Therapeutic Agents
    Cyclosporin
    Example Concen-
    No. Composition Observation tration*
    50 Cremophor RH-40 430 mg clear solution 121
    Myvacet 9-45 310 mg
    Ethyl Alcohol 210 mg
    Cyclosporin  99 mg
    51 Cremophor RH-40 610 mg clear solution 99 
    Peceol 160 mg
    Ethyl Alcohol 200 mg
    Cyclosporin 100 mg
    52 Cremophor RH-40 540 mg clear solution 114
    Span 80 260 mg
    Triacetin 220 mg
    Cyclosporin  97 mg
    53 Incrocas 35 470 mg clear solution 96 
    Myvacet 9-45 250 mg
    Ethyl Alcohol 220 mg
    Cyclosporin 100 mg
    54 Cremophor RH-40 660 mg clear solution 105
    Arlacel 186 120 mg
    Propylene Glycol 100 mg
    Ethanol 100 mg
    Cyclosporin 100 mg
    55 Cremophor RH-40 550 mg clear solution 102
    Arlacel 186 120 mg
    Propylene Glycol 450 mg
    Cyclosporin 100 mg
    56 Cremophor RH-40 580 mg clear solution 108
    Arlacel 186 120 mg
    Propylene Glycol 100 mg
    Ethanol 100 mg
    Cyclosporin 100 mg
    57 Gelucire 44/14 120 mg clear solution 108
    Incrocas 35 200 mg (at 37° C.)
    Glycofurol 100 mg
    Cyclosporin 100 mg
  • [0218]
  • The data in the Table indicate that large amounts of a polyfunctional hydrophobic therapeutic agent can be solubilized in the compositions of the present invention to produce clear, aqueous dispersions. These dispersions show no instability effects, such as hydrophobic therapeutic agent precipitation or particle agglomeration, upon standing. [0219]
    • Examples 58-74
  • Aqueous Dilution Stability of Compositions Containing a Lipophilic Hydrophobic Therapeutic Agent [0220]
  • Compositions according to the present invention were prepared, with a typical lipophilic hydrophobic therapeutic agent, progesterone, as the therapeutic agent. The compositions were prepared and analyzed as in Examples 50-57, and the results are shown in Table 33. [0221]
    TABLE 33
    Dilution Stability of Lipophilic Therapeutic Agents
    Proges-
    terone
    Example Concen-
    No. Composition Observation tration*
    58 Cremophor RH-40 1000 mg very clear 99.1
    Arlacel 186 120 mg solution
    Propylene Glycol 110 mg
    Progesterone 48 mg
    59 Cremophor RH-40 1000 mg very clear 99.3
    Peceol 240 mg solution
    Propylene Glycol 120 mg
    Progesterone 48 mg
    60 Cremophor RH-40 1000 mg very clear 100.2
    Labrafil 800 mg solution
    Propylene Glycol 180 mg
    Progesterone 45 mg
    61 Cremophor RH-40 1000 mg very clear 97.2
    Span 80 350 mg solution
    Propylene Glycol 140 mg
    Progesterone 50 mg
    62 Cremophor RH-40 1000 mg very clear 98.4
    Crodamol EO 600 mg solution
    Propylene Glycol 160 mg
    Progesterone 48 mg
    63 Cremophor RH-40 540 mg clear solution 104.4
    Labrafil M2125CS 350 mg
    Ethyl Alcohol 200 mg
    Progesterone 42 mg
    64 Cremophor RH-40 570 mg very slight tang 106.1
    Ethyl Oleate 260 mg blue color
    Ethyl Alcohol 200 mg solution
    Progesterone 42 mg
    65 Cremophor RH-40 600 mg very slight tang 104.6
    Peceol 210 mg blue color
    Triacetin 210 mg solution
    Progesterone 42 mg
    66 Cremophor RH-40 600 mg very clear 97.7
    Capmul MCM 200 mg solution
    Triacetin 200 mg
    Progesterone 44 mg
    67 Cremophor RH-40 590 mg clear solution 102.3
    Span 80 270 mg
    Triacetin 210 mg
    Progesterone 41 mg
    68 Crovol M-70 760 mg very clear 104.6
    Labrafil M2125CS 100 mg solution
    Triacetin 200 mg
    Progesterone 43 mg
    69 Tween 20 610 mg very slight tang 98.0
    Imwitor 988 300 mg blue color
    Triacetin 200 mg solution
    Progesterone 45 mg
    70 Tween 20 670 mg very clear 96.3
    Lauroglycol FCC 170 mg solution
    Glycofurol 200 mg
    Progesterone 43 mg
    71 Incrocas 35 620 mg very clear 99.5
    Labrafil M2125CS 220 mg solution
    Ethyl Alcohol 200 mg
    Progesterone 43 mg
    72 Incrocas 35 660 mg very clear 105.9
    Span 20 160 mg solution
    Ethyl Alcohol 210 mg
    Progesterone 41 mg
    73 Cremophor RH-40 980 mg very clear 103.7
    Arlacel 186 130 mg supernatant
    Propylene Glycol 110 mg
    Progesterone 110 mg
    74 Cremophor RH-40 520 mg very clear 103.1
    Labrafil 400 mg supernatant
    Propylene Glycol 110 mg
    Progesterone 100 mg
  • The data in the Table indicate that a lipophilic hydrophobic therapeutic agent can be solubilized in the compositions of the present invention to produce clear, aqueous dispersions. These dispersions show no instability effects, such as hydrophobic therapeutic agent precipitation or particle agglomeration, upon standing. [0222]
    • Example 75
  • Enhancement of Bioabsorption [0223]
  • Studies were performed to establish that the clear aqueous dispersions of the present invention facilitate an increased rate of bioabsorption of the hydrophobic therapeutic agent contained therein. The studies used a rat model with perfused intestinal loop along with cannulation of the mesenteric vein. This unique methodology enabled assessment of the “true” absorption potential free of any systemic metabolic interference. [0224]
  • A representative preconcentrate of the present invention containing a cyclosporin hydrophobic therapeutic agent was used. The composition had the following formulation: [0225]
    Cyclosporine 0.140 g
    Cremophor RH-40 0.41 g
    Arlacel 186 0.29 g
    Sodium taurocholate 0.26 g
    Propylene glycol 0.46 g
  • For this experiment, the preconcentrate was diluted with an isotonic aqueous HEPES buffer rather than purified water. The resultant solution was spiked with radioactive active and perfused through isolated ileal lumen segment of known length and diameter. Loss of radioactivity from the lumenal side and appearance of radioactivity in the mesenteric blood from the other side was monitored as an indicator of absorption. [0226]
    • Experimental Details
  • Young adult (275-300 g) male Sprague Dawley rats were used. The procedures were consistent with those reported by Winne et al., “In vivo studies of mucosal-serosal transfer in rat jejunum”, Naunyn-Schmeideberg's Arch. Pharmacol., 329, 70 (1985). [0227]
  • Jugular vein cannulation: the animal was anesthetized using 2% halothane in 98% oxygen via a halothane vaporizer (Vapomatic, A. M. Bickford, Inc., NY). An opening in the jugular vein was made with a 21 ga needle and a jugular cannula consisting of a 4 cm segment of silastic tubing connected to polyethylene tubing was inserted in the jugular vein and secured with cyanoacrylate glue. For the donor rat, approximately 20 mL of blood was freshly collected in the presence of heparin (1,000 units) and the collected blood was infused at a rate of 0.2 mL/min through the jugular vein in the experimental rat to replenish blood sampling. [0228]
  • Intestine cannulation: after the animal was anesthetized, its body temperature was maintained at 37° C. using a heating pad. A vertical midline incision of approximately 3 cm was made through the skin to expose the small intestine. Approximately 6-10 cm segment of ileum was located. Using electro-cautery, a small incision was made at the ends of the segment and the lumenal contents were flushed with saline maintained at 37° C. Two 1.5 cm notched pieces of Teflon tubing were inserted into the intestinal lumen at each incision and tightened using 4-0 silk. A warm isotonic buffer was passed through the intestine using a 50-mL syringe. These Teflon cannula were used to perfuse the drug solution through the isolated intestinal segment using a syringe pump. [0229]
  • Mesenteric vein cannulation: the mesenteric vein draining blood from the resulting isolated mesenteric cascade venules was then cannulated using a 24 ga IV catheter and secured in place using 4-0 silk sutures. The cannula was then connected to a polyethylene tubing 25 cm long where the blood was collected in a vial kept under the animal level. Blood samples were collected continuously over 60 min. The infusion of blood via the jugular vein was initiated to replenish blood loss. The animal was then killed by a lethal injection of Phenobarbital after completion of the experiment. [0230]
  • The experiment was performed twice using the compositions of the present invention as the drug carrier, and twice using a commercial cyclosporin microemulsion formulation for comparison (NeOral®). For each formulation, the results of the two trials were averaged. The results are presented graphically in FIG. 1. [0231]
  • FIG. 1 shows the accumulated radioactivity (μCi/cm[0232] 2μCi) in mesenteric blood as a function of time, over the course of 60 minutes, for the pharmaceutical compositions of the present invention (filled squares) and a commercial cyclosporin formulation (filled circles). As the Figure shows, the bioabsorption of the hydrophobic therapeutic agent exceeds that of the commercial formulation at the earliest measurement point, and continues to increase relative to the commercial formulation over the course of the measurement interval. At the final measurement point (60 min), the bioabsorption of the hydrophobic therapeutic agent from the compositions of the present invention exceeds that of the commercial formulation by nearly 100%.
  • The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The described embodiments are to be considered in all respects only as illustrative and not restrictive. The scope of the invention is, therefore, indicated by the appended claims rather than by the foregoing description. All changes which come within the meaning and range of equivalency of the claims are to be embraced within their scope.[0233]

Claims (140)

What is claimed and desired to be secured by United States Letters Patent is:
1. A pharmaceutical composition comprising:
(a) a hydrophobic therapeutic agent; and
(b) a carrier,
 said carrier comprising:
(i) at least one hydrophilic surfactant; and
(ii) at least one hydrophobic surfactant,
 said hydrophilic and hydrophobic surfactants being present in amounts such that upon mixing with an aqueous solution the carrier forms a clear aqueous dispersion of the hydrophilic and hydrophobic surfactants containing the hydrophobic therapeutic agent,
said composition being substantially free of triglycerides.
2. The pharmaceutical composition of claim 1, wherein the hydrophobic surfactant is present in an amount of less than about 200% by weight, relative to the amount of the hydrophilic surfactant.
3. The pharmaceutical composition of claim 2, wherein the hydrophobic surfactant is present in an amount of less than about 100% by weight, relative to the amount of the hydrophilic surfactant.
4. The pharmaceutical composition of claim 3, wherein the hydrophobic surfactant is present in an amount of less than about 60% by weight, relative to the amount of the hydrophilic surfactant.
5. The pharmaceutical composition of claim 1, wherein the hydrophilic surfactant comprises at least one non-ionic hydrophilic surfactant having an HLB value greater than or equal to about 10.
6. The pharmaceutical composition of claim 1, wherein the hydrophilic surfactant comprises at least one ionic surfactant.
7. The pharmaceutical composition of claim 5, which further comprises at least one ionic surfactant.
8. The pharmaceutical composition of claim 5, wherein the non-ionic surfactant is selected from the group consisting of alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyethylene alkyl ethers; polyoxyethylene alkylphenols; polyethylene glycol fatty acids esters; polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; polyglycerol fatty acid esters; polyoxyethylene glycerides; polyoxyethylene sterols, derivatives, and analogues thereof; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils; reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sugar esters, sugar ethers; sucroglycerides; and mixtures thereof.
9. The pharmaceutical composition of claim 5, wherein the non-ionic hydrophilic surfactant is selected from the group consisting of polyoxyethylene alkylethers; polyethylene glycol fatty acids esters; polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; polyglycerol fatty acid esters; polyoxyethylene glycerides; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils; reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; and mixtures thereof.
10. The pharmaceutical composition of claim 9, wherein the glyceride is a monoglyceride, diglyceride, triglyceride, or a mixture thereof.
11. The pharmaceutical composition of claim 9, wherein the reaction mixture comprises the transesterification products of a polyol and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols.
12. The pharmaceutical composition of claim 9, wherein the polyol is glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol or a mixture thereof.
13. The pharmaceutical composition of claim 5, wherein the hydrophilic surfactant is PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6 caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides, polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30 soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglyceryl-10 oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG 15-100 octyl phenol series, a poloxamer, or a mixture thereof.
14. The pharmaceutical composition of claim 5, wherein the hydrophilic surfactant is PEG-20 laurate, PEG-20 oleate, PEG-35 castor oil, PEG-40 palm kernel oil, PEG-40 hydrogenated castor oil, PEG-60 corn oil, PEG-25 glyceryl trioleate, polyglyceryl-10 laurate, PEG-6 caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides, PEG-30 cholesterol, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, PEG-24 cholesterol, sucrose monostearate, sucrose monolaurate, a poloxamer, or a mixture thereof.
15. The pharmaceutical composition of claim 5, wherein the hydrophilic surfactant is PEG-35 castor oil, PEG-40 hydrogenated castor oil, PEG-60 corn oil, PEG-25 glyceryl trioleate, PEG-6 caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides, polysorbate 20, polysorbate 80, tocopheryl PEG-1000 succinate, PEG-24 cholesterol, a poloxamer, or a mixture thereof.
16. The pharmaceutical composition of claim 6, wherein the ionic surfactant is selected from the group consisting of alkyl ammonium salts; bile acids and salts, analogues, and derivatives thereof; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; acyl lactylates; mono-,diacetylated tartaric acid esters of mono-,diglycerides; succinylated monoglycerides; citric acid esters of mono-,diglycerides; alginate salts; propylene glycol alginate; lecithins and hydrogenated lecithins; lysolecithin and hydrogenated lysolecithins; lysophospholipids and derivatives thereof; phospholipids and derivatives thereof; salts of alkylsulfates; salts of fatty acids; sodium docusate; and mixtures thereof.
17. The pharmaceutical composition of claim 6, wherein the ionic surfactant is selected from the group consisting of bile acids and salts, analogues, and derivatives thereof; lecithins, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; salts of alkylsulfates; salts of fatty acids; sodium docusate; acyl lactylates; mono-,diacetylated tartaric acid esters of mono-,diglycerides; succinylated monoglycerides; citric acid esters of mono-,diglycerides; and mixtures thereof.
18. The pharmaceutical composition of claim 6, wherein the ionic surfactant is selected from the group consisting of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, cholate, taurocholate, glycocholate, deoxycholate, taurodeoxycholate, chenodeoxycholate, glycodeoxycholate, glycochenodeoxycholate, taurochenodeoxycholate, ursodeoxycholate, tauroursodeoxycholate, glycoursodeoxycholate, cholylsarcosine, N-methyl taurocholate, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate, and salts and mixtures thereof.
19. The pharmaceutical composition of claim 6, wherein the ionic surfactant is selected from the group consisting of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, lysophosphatidylcholine, PEG-phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, cholate, taurocholate, glycocholate, deoxycholate, taurodeoxycholate, glycodeoxycholate, cholylsarcosine, caproate, caprylate, caprate, laurate, oleate, lauryl sulfate, docusate, and salts and mixtures thereof.
20. The pharmaceutical composition of claim 6, wherein the ionic surfactant is selected from the group consisting of lecithin, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, taurocholate, caprylate, caprate, oleate, lauryl sulfate, docusate, and salts and mixtures thereof.
21. The pharmaceutical composition of claim 1 wherein the hydrophobic surfactant is a compound or mixture of compounds having an HLB value less than about 10.
22. The pharmaceutical composition of claim 21, wherein the hydrophobic surfactant is selected from the group consisting of alcohols; polyoxyethylene alkylethers; fatty acids; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acids esters; polyethylene glycol fatty acids esters; polyethylene glycol glycerol fatty acid esters; polypropylene glycol fatty acid esters; polyoxyethylene glycerides; lactic acid derivatives of mono/diglycerides; propylene glycol diglycerides; sorbitan fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; transesterified vegetable oils; sterols; sterol derivatives; sugar esters; sugar ethers; sucroglycerides; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils; reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; and mixtures thereof.
23. The pharmaceutical composition of claim 21, wherein the hydrophobic surfactant is selected from the group consisting of fatty acids; lower alcohol fatty acid esters; polyethylene glycol glycerol fatty acid esters; polypropylene glycol fatty acid esters; polyoxyethylene glycerides; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lactic acid derivatives of mono/diglycerides; sorbitan fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils; reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; and mixtures thereof.
24. The pharmaceutical composition of claim 21, wherein the hydrophobic surfactant is selected from the group consisting of lower alcohol fatty acids esters; polypropylene glycol fatty acid esters; propylene glycol fatty acid esters; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lactic acid derivatives of mono/diglycerides; sorbitan fatty acid esters; polyoxyethylene vegetable oils; and mixtures thereof.
25. The pharmaceutical composition of claim 21, wherein the hydrophobic surfactant is a glycerol fatty acid ester, an acetylated glycerol fatty acid ester, or a mixture thereof.
26. The pharmaceutical composition of claim 25, wherein the glycerol fatty acid ester is a monoglyceride, diglyceride, or a mixture thereof.
27. The pharmaceutical composition of claim 26, wherein the fatty acid of the glycerol fatty acid ester is a C6 to C20 fatty acid or a mixture thereof.
28. The pharmaceutical composition of claim 21, wherein the hydrophobic surfactant is a reaction mixture of a polyol and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols.
29. The pharmaceutical composition of claim 28, wherein the reaction mixture is a transesterification product of a polyol and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols.
30. The pharmaceutical composition of claim 28, wherein the polyol is polyethylene glycol, sorbitol, propylene glycol, pentaerythritol or a mixture thereof.
31. The pharmaceutical composition of claim 21, wherein the hydrophobic surfactant is selected from the group consisting of myristic acid; oleic acid; lauric acid; stearic acid; palmitic acid; PEG 1-4 stearate; PEG 2-4 oleate; PEG-4 dilaurate; PEG-4 dioleate; PEG-4 distearate; PEG-6 dioleate; PEG-6 distearate; PEG-8 dioleate; PEG 3-16 castor oil; PEG 5-10 hydrogenated castor oil; PEG 6-20 corn oil; PEG 6-20 almond oil; PEG-6 olive oil; PEG-6 peanut oil; PEG-6 palm kernel oil; PEG-6 hydrogenated palm kernel oil; PEG-4 capric/caprylic triglyceride, mono, di, tri, tetra esters of vegetable oil and sorbitol; pentaerythrityl di, tetra stearate, isostearate, oleate, caprylate, or caprate; polyglyceryl 2-4 oleate, stearate, or isostearate; polyglyceryl 4-10 pentaoleate; polyglyceryl-3 dioleate; polyglyceryl-6 dioleate; polyglyceryl-10 trioleate; polyglyceryl-3 distearate; propylene glycol mono- or diesters of a C6 to C20 fatty acid; monoglycerides of a C6 to C20 fatty acid; acetylated monoglycerides of C6 to C20 fatty acid; diglycerides of C6 to C20 fatty acids; lactic acid derivatives of monoglycerides; lactic acid derivatives of diglycerides; cholesterol; phytosterol; PEG 5-20 soya sterol; PEG-6 sorbitan tetra, hexastearate; PEG-6 sorbitan tetraoleate; sorbitan monolaurate; sorbitan monopalmitate; sorbitan mono, trioleate; sorbitan mono, tristearate; sorbitan monoisostearate; sorbitan sesquioleate; sorbitan sesquistearate; PEG 2-5 oleyl ether; POE 2-4 lauryl ether; PEG-2 cetyl ether; PEG-2 stearyl ether; sucrose distearate; sucrose dipalmitate; ethyl oleate; isopropyl myristate; isopropyl palmitate; ethyl linoleate; isopropyl linoleate; poloxamers; and mixtures thereof.
32. The pharmaceutical composition of claim 21, wherein the hydrophobic surfactant is selected from the group consisting of oleic acid; lauric acid; glyceryl monocaprate; glyceryl monocaprylate; glyceryl monolaurate; glyceryl monooleate; glyceryl dicaprate; glyceryl dicaprylate; glyceryl dilaurate; glyceryl dioleate; acetylated monoglycerides; propylene glycol oleate; propylene glycol laurate; polyglyceryl-3 oleate; polyglyceryl-6 dioleate; PEG-6 corn oil; PEG-20 corn oil; PEG-20 almond oil; sorbitan monooleate; sorbitan monolaurate; POE-4 lauryl ether; POE-3 oleyl ether; ethyl oleate; poloxamers; and mixtures thereof.
33. The pharmaceutical composition of claim 1, wherein the clear aqueous dispersion has a particle size distribution having an average particle size of less than about 100 nm.
34. The pharmaceutical composition of claim 33, wherein the clear aqueous dispersion has a particle size distribution having an average particle size of less than about 50 nm.
35. The pharmaceutical composition of claim 33, wherein the clear aqueous dispersion has a particle size distribution having an average particle size of less than about 20 nm.
36. The pharmaceutical composition of claim 1, wherein the clear aqueous dispersion has an absorbance of less than about 0.1 at about 400 nm when the carrier is diluted with an aqueous solution in an aqueous solution to carrier ratio of 100:1 by weight.
37. The pharmaceutical composition of claim 36, wherein the absorbance is less than about 0.01.
38. The pharmaceutical composition of claim 1, wherein the hydrophobic therapeutic agent has an intrinsic water solubility of less than about 1% by weight at 25° C.
39. The pharmaceutical composition of claim 38, wherein the intrinsic water solubility is less than about 0.1% by weight at 25° C.
40. The pharmaceutical composition of claim 39, wherein the intrinsic water solubility is less than about 0.01% by weight at 25° C.
41. The pharmaceutical composition of claim 1, wherein the therapeutic agent is a drug, a vitamin, a nutritional supplement, a cosmeceutical, or a mixture thereof.
42. The pharmaceutical composition of claim 43, wherein the therapeutic agent is a polyfunctional hydrophobic drug, a lipophilic drug, a pharmaceutically acceptable salt, isomer or derivative thereof, or a mixture thereof.
43. The pharmaceutical composition of claim 41, wherein the therapeutic agent is selected from the group consisting of analgesics, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, anti-bacterial agents, anti-viral agents, anti-coagulants, anti-depressants, anti-diabetics, anti-epileptics, anti-fungal agents, anti-gout agents, anti-hypertensive agents, anti-malarials, anti-migraine agents, anti-muscarinic agents, anti-neoplastic agents, erectile dysfunction improvement agents, immunosuppressants, anti-protozoal agents, anti-thyroid agents, anxiolytic agents, sedatives, hypnotics, neuroleptics, β-Blockers, cardiac inotropic agents, corticosteroids, diuretics, anti-parkinsonian agents, gastro-intestinal agents, histamine H,-receptor antagonists, keratolytics, lipid regulating agents, anti-anginal agents, nutritional agents, opioid analgesics, sex hormones, stimulants, muscle relaxants, anti-osteoporosis agents, anti-obesity agents, cognition enhancers, anti-urinary incontinence agents, nutritional oils, anti-benign prostate hypertrophy agents, essential fatty acids, non-essential fatty acids, and mixtures thereof.
44. The pharmaceutical composition of claim 41, wherein the therapeutic agent is tramadol, celecoxib, etodolac, refocoxib, oxaprozin, leflunomide, diclofenac, nabumetone, ibuprofen, flurbiprofen, tetrahydrocannabinol, capsaicin, ketorolac, albendazole, ivermectin, amiodarone, zileuton, zafirlukast, albuterol, montelukast, azithromycin, ciprofloxacin, clarithromycin, dirithromycin, rifabutine, rifapentine, trovafloxacin, baclofen, ritanovir, saquinavir, nelfinavir, efavirenz, dicoumarol, tirofibran, cilostazol, ticlidopine, clopidrogel, oprevelkin, paroxetine, sertraline, venlafaxine, bupropion, clomipramine, miglitol, repaglinide, glymepride, pioglitazone, rosigiltazone, troglitazone, glyburide, glipizide, glibenclamide, carbamezepine, fosphenytion, tiagabine, topiramate, lamotrigine, vigabatrin, amphotericin B, butenafine, terbinafine, itraconazole, flucanazole, miconazole, ketoconazole, metronidazole, griseofulvin, nitrofurantoin, spironolactone, lisinopril, benezepril, nifedipine, nilsolidipine, telmisartan, irbesartan, eposartan, valsartan, candesartan, minoxidil, terzosin, halofantrine, mefloquine, dihydroergotamine, ergotamine, frovatriptan, pizofetin, sumatriptan, zolmitriptan, naratiptan, rizatriptan, aminogluthemide, busulphan, cyclosporine, mitoxantrone, irinotecan, etoposide, teniposide, paclitaxel, tacrolimus, sirolimus, tamoxifen, camptothecan, topotecan, nilutanide, bicalutanide, pseudo-ephedrine, toremifene, atovaquone, metronidazole, furazolidone, paricalcitol, benzonatate, midazolam, zolpidem, gabapentin, zopiclone, digoxin, beclomethsone, budesonide, betamethasone, prednisolone, cisapride, cimetidine, loperamide, famotidine, lanosprazole, rabeprazole, nizatidine, omeprazole, citrizine, cinnarizine, dexchlopheniramine, loratadine, clemastine, fexofenadine, chlorpheniramine, acutretin, tazarotene, calciprotiene, calcitriol, targretin, ergocalciferol, cholecalciferol, isotreinoin, tretinoin, calcifediol, fenofibrate, probucol, gemfibrozil, cerivistatin, pravastatin, simvastatin, fluvastatin, atorvastatin, tizanidine, dantrolene, isosorbide dinatrate, a carotene, dihydrotachysterol, vitamin A, vitamin D, vitamin E, vitamin K, an essential fatty acid source, codeine, fentanyl, methadone, nalbuphine, pentazocine, clomiphene, danazol, dihydro epiandrosterone, medroxyprogesterone, progesterone, rimexolone, megesterol acetate, osteradiol, finasteride, mefepristone, amphetamine, L-thryroxine, tamsulosin, methoxsalen, tacrine, donepezil, raloxifene, vertoporfin, sibutramine, pyridostigmine, a pharmaceutically acceptable salt, isomer, or derivative thereof, or a mixture thereof.
45. The pharmaceutical composition of claim 1, wherein the hydrophobic therapeutic agent is selected from the group consisting of tramadol, celecoxib, etodolac, refocoxib, oxaprozin, leflunomide, diclofenac, nabumetone, ibuprofen, flurbiprofen, tetrahydrocannabinol, capsaicin, ketorolac, albendazole, ivermectin, amiodarone, zileuton, zafirlukast, albuterol, montelukast, azithromycin, ciprofloxacin, clarithromycin, dirithromycin, rifabutine, rifapentine, trovafloxacin, baclofen, ritanovir, saquinavir, nelfinavir, efavirenz, miglitol, repaglinide, glymepride, pioglitazone, rosigiltazone, troglitazone, glyburide, glipizide, glibenclamide, carbamezepine, fosphenytion, tiagabine, topiramate, lamotrigine, vigabatrin, amphotericin B, butenafine, terbinafine, itraconazole, flucanazole, miconazole, ketoconazole, metronidazole, griseofulvin, nitrofurantoin, spironolactone, halofantrine, mefloquine, dihydroergotamine, ergotamine, frovatriptan, pizofetin, sumatriptan, zolmitriptan, naratiptan, rizatriptan, aminogluthemide, busulphan, cyclosporine, mitoxantrone, irinotecan, etoposide, teniposide, paclitaxel, tacrolimus, sirolimus, tamoxifen, camptothecan, topotecan, nilutanide, bicalutanide, pseudo-ephedrine, toremifene, atovaquone, metronidazole, furzolidone, paricalcitol, benzonatate, midazolam, zolpidem, gabapentin, zopiclone, digoxin, cisapride, cimetidine, loperamide, famotidine, lanosprazole, rabeprazole, nizatidine, omeprazole, citrizine, cinnarizine, dexchlopheniramine, loratadine, clemastine, fexofenadine, chlorpheniramine, acutretin, tazarotene, calciprotiene, calcitriol, targretin, ergocalciferol, cholecaliferol, isotreinoin, tretinoin, calcifediol, fenofibrate, probucol, gemfibrozil, cerivistatin, pravastatin, simvastatin, fluvastatin, atorvastatin, tizanidine, dantrolene, carotenes, dihyrotachysterol, vitamin A, vitamin D, vitamin E, vitamin K, essential fatty acid sources, codeine, fentanyl, methdone, nalbuphine, pentazocine, clomiphene, danazol, dihydro epiandrosterone, mmedroxyprogesterone, progesterone, rimexolone, megesterol acetate, osteradiol, finasteride, mefepristone, amphetamine, L-thryroxine, tamsulosin, methoxsalen, tacrine, donepezil, raloxifene, vertoporfin, sibutramine, pyridostigmine, pharmaceutically acceptable salts, isomers and derivatives thereof, and mixtures thereof.
46. The pharmaceutical composition of claim 1, wherein the therapeutic agent is selected from the group consisting of tramadol, celecoxib, etodolac, refocoxib, oxaprozin, leflunomide, diclofenac, nabumetone, ibuprofen, flurbiprofen, tetrahydrocannabinol, capsaicin, ketorolac, ivermectin, amiodarone, zileuton, zafirlukast, albuterol, montelukast, rifabutine, rifapentine, trovafloxacin, baclofen, ritanovir, saquinavir, nelfinavir, efavirenz, miglitol, repaglinide, glymepride, pioglitazone, rosigiltazone, troglitazone, glyburide, glipizide, glibenclamide, carbamezepine, fosphenytion, tiagabine, topiramate, lamotrigine, vigabatrin, terbenafine, itraconazole, flucanazole, miconazole, ketoconazole, metronidazole, nitrofurantoin, dihydroergotamine, ergotamine, frovatriptan, pizofetin, zolmitriptan, pseudo-ephedrine, naratiptan, rizatriptan, aminogluthemide, busulphan, cyclosporine, mitoxantrone, irinotecan, etoposide, teniposide, paclitaxel, tacrolimus, sirolimus, tamoxifen, camptothecan, topotecan, nilutanide, bicalutanide, toremifene, atovaquone, metronidazole, furzolidone, paricalcitol, benzonatate, cisapride, cimetidine, loperamide, famotidine, lanosprazole, rabeprazole, nizatidine, omeprazole, citrizine, cinnarizine, dexchlopheniramine, loratadine, clemastine, fexofenadine, chlorpheniramine, acutretin, tazarotene, calciprotiene, calcitriol, targretin, ergocalciferol, cholecaliferol, isotreinoin, tretinoin, calcifediol, fenofibrate, probucol, simvastatin, atorvastatin, tizanidine, dantrolene, carotenes, dihyrotachysterol, vitamin A, vitamin D, vitamin E, vitamin K, essential fatty acid sources, danazol, dihydro epiandrosterone, medroxyprogesterone, progesterone, rimexolone, megesterol acetate, osteradiol, finasteride, mefepristone, raloxifene, L-thryroxine, tamsulosin, methoxsalen, pharmaceutically acceptable salts, isomers and derivative thereof, and mixtures thereof.
47. The pharmaceutical composition of claim 1, wherein the hydrophobic therapeutic agent is selected from the group consisting of sildenafil citrate, amlodipine, tramadol, celecoxib, refocoxib, oxaprozin, nabumetone, ibuprofen, terbenafine, itraconazole, zileuton, zafirlukast, cisapride, fenofibrate, tizanidine, nizatidine, fexofenadine, loratadine, famotidine, paricalcitol, atovaquone, nabumetone, tetrahydrocannabinol, megesterol acetate, repaglinide, progesterone, rimexolone, cyclosporine, tacrolimus, sirolimus, teniposide, paclitaxel, pseudo-ephedrine, troglitazone, rosiglitazone, finasteride, vitamin A, vitamin D, vitamin E, pharmaceutically acceptable salts, isomers and derivatives thereof, and mixtures thereof.
48. The pharmaceutical composition of claim 1, wherein the hydrophobic therapeutic agent is progesterone or cyclosporin.
49. The pharmaceutical composition of claim 1, which further comprises a solubilizer.
50. The pharmaceutical composition of claim 49, wherein the solubilizer is selected from the group consisting of alcohols, polyols, amides, esters, propylene glycol ethers and mixtures thereof.
51. The pharmaceutical composition of claim 50, wherein the alcohol or polyol is selected from the group consisting of ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives, and mixtures thereof.
52. The pharmaceutical composition of claim 50, wherein the amide is selected from the group consisting of 2-pyrrolidone, 2-piperidone, ε-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide, polyvinylpyrrolidone, and mixtures thereof.
53. The pharmaceutical composition of claim 50, wherein the ester is selected from the group consisting of ethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and isomers thereof, δ-valerolactone and isomers thereof, β-butyrolactone and isomers thereof, and mixtures thereof.
54. The pharmaceutical composition of claim 49, wherein the solubilizer is selected from the group consisting of ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediol and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins, clodextrins and derivatives thereof, ethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol diacetate, ε-caprolactone and isomers thereof, δ-valerolactone and isomers thereof, β-butyrolactone and isomers thereof, 2-pyrrolidone, 2-2 piperidone, ε-caprolactam, N-methylpyrrolidone, N-ethylpyrrolidone, N-hydroxyethyl pyrrolidone, N-octylpyrrolidone, N-laurylpyrrolidone, dimethylacetamide, polyvinylpyrrolidone, glycofurol, methoxy PEG, and mixtures thereof.
55. The pharmaceutical composition of claim 49, wherein the solubilizer is selected from the group consisting of ethanol, isopropanol, benzyl alcohol, ethylene glycol, propylene glycol, 1,3-butanediol, glycerol, pentaerythritol, sorbitol, glycofurol, transcutol, dimethyl isosorbide, polyethylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, hydroxypropylcyclodextrins, sulfobutyl ether derivatives of cyclodextrins, ethyl propionate, tributylcitrate, triethylcitrate, ethyl oleate, ethyl caprylate, triacetin, β-butyrolactone and isomers thereof, 2-pyrrolidone, N-methylpyrrolidone, N-ethylpyrrolidone, N-hydroxyethylpyrrolidone, N-octylpyrrolidone, N-laurylpyrrolidone, dimethylacetamide, polyvinylpyrrolidone, and mixtures thereof.
56. The pharmaceutical composition of claim 49, wherein the solubilizer is triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene glycol 200-600, glycofurol, transcutol, propylene glycol, dimethyl isosorbide, or a mixture thereof.
57. The pharmaceutical composition of claim 49, wherein the solubilizer is triacetin, ethanol, polyethylene glycol 400, glycofurol, propylene glycol or a mixture thereof.
58. The pharmaceutical composition of claim 49, wherein the solubilizer is present in the composition in an amount of about 400% or less by weight, based on the total weight of the surfactants.
59. The pharmaceutical composition of claim 58, wherein the solubilizer is present in the composition in an amount of about 200% or less by weight, based on the total weight of the surfactants.
60. The pharmaceutical composition of claim 59, wherein the solubilizer is present in the composition in an amount of about 100% or less by weight, based on the total weight of the surfactants.
62. The pharmaceutical composition of claim 60, wherein the solubilizer is present in the composition in an amount of about 50% or less by weight, based on the total weight of the surfactants.
62. The pharmaceutical composition of claim 61, wherein the solubilizer is present in the composition in an amount about 25% or less by weight, based on the total weight of the surfactants.
63. The pharmaceutical composition of claim 1, which further comprises an antioxidant, a preservative, a chelating agent, a viscomodulator, a tonicifier, a flavorant, a colorant, an odorant, an opacifier, a suspending agent, a binder, or a mixture thereof.
64. The pharmaceutical composition of claim 1 in the form of a preconcentrate, a diluted preconcentrate, a semi-solid dispersion, a solid dispersion, or a sprayable solution.
65. A dosage form comprising a capsule filled with the pharmaceutical composition of claim 1.
66. A dosage form comprising a multiparticulate carrier coated with the pharmaceutical composition of claim 1.
67. A dosage form comprising the pharmaceutical composition of claim 1 formulated as a solution, a cream, a lotion, an ointment, a suppository, a spray, an aerosol, a paste or a gel.
68. The dosage form of claim 65, wherein the capsule is a hard gelatin capsule, a soft gelatin capsule, a starch capsule or an enteric coated capsule.
69. The pharmaceutical composition of claim 1, which further comprises water or an aqueous buffer.
70. The pharmaceutical composition of claim 1, which further comprises an additional amount of a hydrophobic therapeutic agent, said additional amount not solubilized in the carrier.
71. A pharmaceutical composition comprising:
(a) at least one hydrophilic surfactant;
(b) at least one hydrophobic surfactant; and
(c) a hydrophobic therapeutic agent,
said pharmaceutical composition being in the form of a clear, aqueous dispersion which is substantially free of triglycerides.
72. The pharmaceutical composition of claim 71, wherein the hydrophobic surfactant is present in an amount of less than about 200% by weight, relative to the amount of the hydrophilic surfactant.
73. The pharmaceutical composition of claim 72, wherein the hydrophobic surfactant is present in an amount of less than about 100% by weight, relative to the amount of the hydrophilic surfactant.
74. The pharmaceutical composition of claim 73, wherein the hydrophobic surfactant is present in an amount of less than about 60% by weight, relative to the amount of the hydrophilic surfactant.
75. The pharmaceutical composition of claim 71, wherein the hydrophilic surfactant comprises at least one non-ionic hydrophilic surfactant having an HLB value greater than or equal to about 10.
76. The pharmaceutical composition of claim 71, wherein the hydrophilic surfactant comprises at least one ionic surfactant.
77. The pharmaceutical composition of claim 75, which further comprises at least one ionic surfactant.
78. The pharmaceutical composition of claim 75, wherein the non-ionic surfactant is selected from the group consisting of alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyethylene alkylethers; polyoxyethylene alkylphenols; polyethylene glycol fatty acids esters; polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; polyglycerol fatty acid esters; polyoxyethylene glycerides; polyoxyethylene sterols, derivatives, and analogues thereof; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils; reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sugar esters, sugar ethers; sucroglycerides; and mixtures thereof.
79. The pharmaceutical composition of claim 75, wherein the non-ionic hydrophilic surfactant is selected from the group consisting of polyoxyethylene alkylethers; polyethylene glycol fatty acids esters; polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; polyglycerol fatty acid esters; polyoxyethylene glycerides; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils; reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; and mixtures thereof.
80. The pharmaceutical composition of claim 79, wherein the glyceride is a monoglyceride, diglyceride, triglyceride, or a mixture thereof.
81. The pharmaceutical composition of claim 79, wherein the reaction mixture comprises the transesterification products of a polyol and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols.
82. The pharmaceutical composition of claim 79, wherein the polyol is glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol or a mixture thereof.
83. The pharmaceutical composition of claim 75, wherein the hydrophilic surfactant is PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6 caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides, polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30 soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglyceryl-10 oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG 15-100 octyl phenol series, a poloxamer, or a mixture thereof.
84. The pharmaceutical composition of claim 75, wherein the hydrophilic surfactant is PEG-20 laurate, PEG-20 oleate, PEG-35 castor oil, PEG-40 palm kernel oil, PEG-40 hydrogenated castor oil, PEG-60 corn oil, PEG-25 glyceryl trioleate, polyglyceryl-10 laurate, PEG-6 caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides, PEG-30 cholesterol, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, PEG-24 cholesterol, sucrose monostearate, sucrose monolaurate, a poloxamer, or a mixture thereof.
85. The pharmaceutical composition of claim 75, wherein the hydrophilic surfactant is PEG-35 castor oil, PEG40 hydrogenated castor oil, PEG-60 corn oil, PEG-25 glyceryl trioleate, PEG-6 caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides, polysorbate 20, polysorbate 80, tocopheryl PEG-1000 succinate, PEG-24 cholesterol, a poloxamer, or a mixture thereof.
86. The pharmaceutical composition of claim 76, wherein the ionic surfactant is selected from the group consisting of alkyl ammonium salts; bile acids and salts, analogues, and derivatives thereof; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; acyl lactylates; mono-,diacetylated tartaric acid esters of mono-,diglycerides; succinylated monoglycerides; citric acid esters of mono-,diglycerides; alginate salts; propylene glycol alginate; lecithins and hydrogenated lecithins; lysolecithin and hydrogenated lysolecithins; lysophospholipids and derivatives thereof; phospholipids and derivatives thereof; salts of alkylsulfates; salts of fatty acids; sodium docusate; and mixtures thereof.
87. The pharmaceutical composition of claim 76, wherein the ionic surfactant is selected from the group consisting of bile acids and salts, analogues, and derivatives thereof; lecithins, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; salts of alkylsulfates; salts of fatty acids; sodium docusate; acyl lactylates; mono-,diacetylated tartaric acid esters of mono-,diglycerides; succinylated monoglycerides; citric acid esters of mono-,diglycerides; and mixtures thereof.
88. The pharmaceutical composition of claim 76, wherein the ionic surfactant is selected from the group consisting of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, cholate, taurocholate, glycocholate, deoxycholate, taurodeoxycholate, chenodeoxycholate, glycodeoxycholate, glycochenodeoxycholate, taurochenodeoxycholate, ursodeoxycholate, tauroursodeoxycholate, glycoursodeoxycholate, cholylsarcosine, N-methyl taurocholate, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate, and salts and mixtures thereof.
89. The pharmaceutical composition of claim 76, wherein the ionic surfactant is selected from the group consisting of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, lysophosphatidylcholine, PEG-phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, cholate, taurocholate, glycocholate, deoxycholate, taurodeoxycholate, glycodeoxycholate, cholylsarcosine, caproate, caprylate, caprate, laurate, oleate, lauryl sulfate, docusate, and salts and mixtures thereof.
90. The pharmaceutical composition of claim 76, wherein the ionic surfactant is selected from the group consisting of lecithin, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, taurocholate, caprylate, caprate, oleate, lauryl sulfate, docusate, and salts and mixtures thereof.
91. The pharmaceutical composition of claim 71 wherein the hydrophobic surfactant is a compound or mixture of compounds having an HLB value less than about 10.
92. The pharmaceutical composition of claim 91, wherein the hydrophobic surfactant is selected from the group consisting of alcohols; polyoxyethylene alkylethers; fatty acids; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acids esters; polyethylene glycol fatty acids esters; polyethylene glycol glycerol fatty acid esters; polypropylene glycol fatty acid esters; polyoxyethylene glycerides; lactic acid derivatives of mono/diglycerides; propylene glycol diglycerides; sorbitan fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; transesterified vegetable oils; sterols; sterol derivatives; sugar esters; sugar ethers; sucroglycerides; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils; reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; and mixtures thereof.
93. The pharmaceutical composition of claim 91, wherein the hydrophobic surfactant is selected from the group consisting of fatty acids; lower alcohol fatty acid esters; polyethylene glycol glycerol fatty acid esters; polypropylene glycol fatty acid esters; polyoxyethylene glycerides; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lactic acid derivatives of mono/diglycerides; sorbitan fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils; reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; and mixtures thereof.
94. The pharmaceutical composition of claim 91, wherein the hydrophobic surfactant is selected from the group consisting of lower alcohol fatty acids esters; polypropylene glycol fatty acid esters; propylene glycol fatty acid esters; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lactic acid derivatives of mono/diglycerides; sorbitan fatty acid esters; polyoxyethylene vegetable oils; and mixtures thereof.
95. The pharmaceutical composition of claim 91, wherein the hydrophobic surfactant is a glycerol fatty acid ester, an acetylated glycerol fatty acid ester, or a mixture thereof.
96. The pharmaceutical composition of claim 95, wherein the glycerol fatty acid ester is a monoglyceride, diglyceride, or a mixture thereof.
97. The pharmaceutical composition of claim 96, wherein the fatty acid of the glycerol fatty acid ester is a C6 to C20 fatty acid or a mixture thereof.
98. The pharmaceutical composition of claim 91, wherein the hydrophobic surfactant is a reaction mixture of a polyol and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols.
99. The pharmaceutical composition of claim 98, wherein the reaction mixture is a transesterification product of a polyol and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols.
100. The pharmaceutical composition of claim 98, wherein the polyol is polyethylene glycol, sorbitol, propylene glycol, pentaerythritol or a mixture thereof.
101. The pharmaceutical composition of claim 91, wherein the hydrophobic surfactant is selected from the group consisting of myristic acid; oleic acid; lauric acid; stearic acid; palmitic acid; PEG 1-4 stearate; PEG 2-4 oleate; PEG-4 dilaurate; PEG-4 dioleate; PEG-4 distearate; PEG-6 dioleate; PEG-6 distearate; PEG-8 dioleate; PEG 3-16 castor oil; PEG 5-10 hydrogenated castor oil; PEG 6-20 corn oil; PEG 6-20 almond oil; PEG-6 olive oil; PEG-6 peanut oil; PEG-6 palm kernel oil; PEG-6 hydrogenated palm kernel oil; PEG-4 capric/caprylic triglyceride, mono, di, tri, tetra esters of vegetable oil and sorbitol; pentaerythrityl di, tetra stearate, isostearate, oleate, caprylate, or caprate; polyglyceryl 2-4 oleate, stearate, or isostearate; polyglyceryl 4-10 pentaoleate; polyglyceryl-3 dioleate; polyglyceryl-6 dioleate; polyglyceryl-10 trioleate; polyglyceryl-3 distearate; propylene glycol mono- or diesters of a C6 to C20 fatty acid; monoglycerides of a C6 to C20 fatty acid; acetylated monoglycerides of C6 to C20 fatty acid; diglycerides of C6 to C20 fatty acids; lactic acid derivatives of monoglycerides; lactic acid derivatives of diglycerides; cholesterol; phytosterol; PEG 5-20 soya sterol; PEG-6 sorbitan tetra, hexastearate; PEG-6 sorbitan tetraoleate; sorbitan monolaurate; sorbitan monopalmitate; sorbitan mono, trioleate; sorbitan mono, tristearate; sorbitan monoisostearate; sorbitan sesquioleate; sorbitan sesquistearate; PEG 2-5 oleyl ether; POE 2-4 lauryl ether; PEG-2 cetyl ether; PEG-2 stearyl ether; sucrose distearate; sucrose dipalmitate; ethyl oleate; isopropyl myristate; isopropyl palmitate; ethyl linoleate; isopropyl linoleate; poloxamers; and mixtures thereof.
102. The pharmaceutical composition of claim 91, wherein the hydrophobic surfactant is selected from the group consisting of oleic acid; lauric acid; glyceryl monocaprate; glyceryl monocaprylate; glyceryl monolaurate; glyceryl monooleate; glyceryl dicaprate; glyceryl dicaprylate; glyceryl dilaurate; glyceryl dioleate; acetylated monoglycerides; propylene glycol oleate; propylene glycol laurate; polyglyceryl-3 oleate; polyglyceryl-6 dioleate; PEG-6 corn oil; PEG-20 corn oil; PEG-20 almond oil; sorbitan monooleate; sorbitan monolaurate; POE-4 lauryl ether; POE-3 oleyl ether; ethyl oleate; poloxamers; and mixtures thereof.
103. The pharmaceutical composition of claim 71, wherein the clear aqueous dispersion has a particle size distribution having an average particle size of less than about 100 nm.
104. The pharmaceutical composition of claim 103, wherein the clear aqueous dispersion has a particle size distribution having an average particle size of less than about 50 nm.
105. The pharmaceutical composition of claim 103, wherein the clear aqueous dispersion has a particle size distribution having an average particle size of less than about 20 nm.
106. The pharmaceutical composition of claim 71, wherein the clear aqueous dispersion has an absorbance of less than about 0.1 at 400 nm when the ratio of the weight of water to the total weight of the hydrophilic surfactant, the hydrophobic surfactant and the therapeutic agent is 100:1.
107. The pharmaceutical composition of claim 106, wherein the absorbance is less than about 0.01.
108. The pharmaceutical composition of claim 71, wherein the hydrophobic therapeutic agent has an intrinsic water solubility of less than about 1% by weight at 25° C.
109. The pharmaceutical composition of claim 108, wherein the intrinsic water solubility is less than about 0.1% by weight at 25° C.
110. The pharmaceutical composition of claim 109, wherein the intrinsic water solubility is less than about 0.01% by weight at 25° C.
111. The pharmaceutical composition of claim 71, wherein the therapeutic agent is a drug, a vitamin, a nutritional supplement, a cosmeceutical, or a mixture thereof.
112. The pharmaceutical composition of claim 111, wherein the therapeutic agent is a polyfunctional hydrophobic drug, a lipophilic drug, a pharmaceutically acceptable salt, isomer or derivative thereof, or a mixture thereof.
113. The pharmaceutical composition of claim 111, wherein the therapeutic agent is selected from the group consisting of analgesics, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, anti-bacterial agents, anti-viral agents, anti-coagulants, anti-depressants, anti-diabetics, anti-epileptics, anti-fungal agents, anti-gout agents, anti-hypertensive agents, anti-malarials, anti-migraine agents, anti-muscarinic agents, anti-neoplastic agents, erectile dysfunction improvement agents, immunosuppressants, anti-protozoal agents, anti-thyroid agents, anxiolytic agents, sedatives, hypnotics, neuroleptics, β-Blockers, cardiac inotropic agents, corticosteroids, diuretics, anti-parkinsonian agents, gastro-intestinal agents, histamine H,-receptor antagonists, keratolytics, lipid regulating agents, anti-anginal agents, nutritional agents, opioid analgesics, sex hormones, stimulants, muscle relaxants, anti-osteoporosis agents, anti-obesity agents, cognition enhancers, anti-urinary incontinence agents, nutritional oils, anti-benign prostate hypertrophy agents, essential fatty acids, non-essential fatty acids, and mixtures thereof.
114. The pharmaceutical composition of claim 111, wherein the therapeutic agent is tramadol, celecoxib, etodolac, refocoxib, oxaprozin, leflunomide, diclofenac, nabumetone, ibuprofen, flurbiprofen, tetrahydrocannabinol, capsaicin, ketorolac, albendazole, ivermectin, amiodarone, zileuton, zafirlukast, albuterol, montelukast, azithromycin, ciprofloxacin, clarithromycin, dirithromycin, rifabutine, rifapentine, trovafloxacin, baclofen, ritanovir, saquinavir, nelfinavir, efavirenz, dicoumarol, tirofibran, cilostazol, ticlidopine, clopidrogel, oprevelkin, paroxetine, sertraline, venlafaxine, bupropion, clomipramine, miglitol, repaglinide, glymepride, pioglitazone, rosigiltazone, troglitazone, glyburide, glipizide, glibenclamide, carbamezepine, fosphenytion, tiagabine, topiramate, lamotrigine, vigabatrin, amphotericin B, butenafine, terbinafine, itraconazole, flucanazole, miconazole, ketoconazole, metronidazole, griseofulvin, nitrofurantoin, spironolactone, lisinopril, benezepril, nifedipine, nilsolidipine, telmisartan, irbesartan, eposartan, valsartan, candesartan, minoxidil, terzosin, halofantrine, mefloquine, dihydroergotamine, ergotamine, frovatriptan, pizofetin, sumatriptan, zolmitriptan, naratiptan, rizatriptan, aminogluthemide, busulphan, cyclosporine, mitoxantrone, irinotecan, etoposide, teniposide, paclitaxel, tacrolimus, sirolimus, tamoxifen, camptothecan, topotecan, nilutanide, bicalutanide, ephedrine, toremifene, atovaquone, metronidazole, furazolidone, paricalcitol, benzonatate, midazolam, zolpidem, gabapentin, zopiclone, digoxin, beclomethsone, budesonide, betamethasone, prednisolone, cisapride, cimetidine, loperamide, famotidine, lanosprazole, rabeprazole, nizatidine, omeprazole, citrizine, cinnarizine, dexchlopheniramine, loratadine, clemastine, fexofenadine, chlorpheniramine, acutretin, tazarotene, calciprotiene, calcitriol, targretin, ergocalciferol, cholecalciferol, isotreinoin, tretinoin, calcifediol, fenofibrate, probucol, gemfibrozil, cerivistatin, pravastatin, simvastatin, fluvastatin, atorvastatin, tizanidine, dantrolene, isosorbide dinatrate, a carotene, dihydrotachysterol, vitamin A, vitamin D, vitamin E, vitamin K, an essential fatty acid source, codeine, fentanyl, methadone, nalbuphine, pentazocine, clomiphene, danazol, dihydro epiandrosterone, medroxyprogesterone, progesterone, rimexolone, megesterol acetate, osteradiol, finasteride, mefepristone, amphetamine, L-thryroxine, tamsulosin, methoxsalen, tacrine, donepezil, raloxifene, vertoporfin, sibutramine, pyridostigmine, a pharmaceutically acceptable salt, isomer, or derivative thereof, or a mixture thereof.
115. The pharmaceutical composition of claim 71, wherein the hydrophobic therapeutic agent is selected from the group consisting of tramadol, celecoxib, etodolac, refocoxib, oxaprozin, leflunomide, diclofenac, nabumetone, ibuprofen, flurbiprofen, tetrahydrocannabinol, capsaicin, ketorolac, albendazole, ivermectin, amiodarone, zileuton, zafirlukast, albuterol, montelukast, azithromycin, ciprofloxacin, clarithromycin, dirithromycin, rifabutine, rifapentine, trovafloxacin, baclofen, ritanovir, saquinavir, nelfinavir, efavirenz, miglitol, repaglinide, glymepride, pioglitazone, rosigiltazone, troglitazone, glyburide, glipizide, glibenclamide, carbamezepine, fosphenytion, tiagabine, topiramate, lamotrigine, vigabatrin, amphotericin B, butenafine, terbinafine, itraconazole, flucanazole, miconazole, ketoconazole, metronidazole, griseofulvin, nitrofurantoin, spironolactone, halofantrine, mefloquine, dihydroergotamine, ergotamine, frovatriptan, pizofetin, sumatriptan, zolmitriptan, naratiptan, rizatriptan, aminogluthemide, busulphan, cyclosporine, mitoxantrone, irinotecan, etoposide, teniposide, paclitaxel, tacrolimus, sirolimus, tamoxifen, camptothecan, topotecan, nilutanide, bicalutanide, pseudo-ephedrine, toremifene, atovaquone, metronidazole, furzolidone, paricalcitol, benzonatate, midazolam, zolpidem, gabapentin, zopiclone, digoxin, cisapride, cimetidine, loperamide, famotidine, lanosprazole, rabeprazole, nizatidine, omeprazole, citrizine, cinnarizine, dexchlopheniramine, loratadine, clemastine, fexofenadine, chlorpheniramine, acutretin, tazarotene, calciprotiene, calcitriol, targretin, ergocalciferol, cholecaliferol, isotreinoin, tretinoin, calcifediol, fenofibrate, probucol, gemfibrozil, cerivistatin, pravastatin, simvastatin, fluvastatin, atorvastatin, tizanidine, dantrolene, carotenes, dihyrotachysterol, vitamin A, vitamin D, vitamin E, vitamin K, essential fatty acid sources, codeine, fentanyl, methdone, nalbuphine, pentazocine, clomiphene, danazol, dihydro epiandrosterone, mmedroxyprogesterone, progesterone, rimexolone, megesterol acetate, osteradiol, finasteride, mefepristone, amphetamine, L-thryroxine, tamsulosin, methoxsalen, tacrine, donepezil, raloxifene, vertoporfin, sibutramine, pyridostigmine, pharmaceutically acceptable salts, isomers and derivatives thereof, and mixtures thereof.
116. The pharmaceutical composition of claim 71, wherein the therapeutic agent is selected from the group consisting of tramadol, celecoxib, etodolac, refocoxib, oxaprozin, leflunomide, diclofenac, nabumetone, ibuprofen, flurbiprofen, tetrahydrocannabinol, capsaicin, ketorolac, ivermectin, amiodarone, zileuton, zafirlukast, albuterol, montelukast, rifabutine, rifapentine, trovafloxacin, baclofen, ritanovir, saquinavir, nelfinavir, efavirenz, miglitol, repaglinide, glymepride, pioglitazone, rosigiltazone, troglitazone, glyburide, glipizide, glibenclamide, carbamezepine, fosphenytion, tiagabine, topiramate, lamotrigine, vigabatrin, terbenafine, itraconazole, flucanazole, miconazole, ketoconazole, metronidazole, nitrofurantoin, dihydroergotamine, ergotamine, frovatriptan, pizofetin, zolmitriptan, pseudo-ephedrine, naratiptan, rizatriptan, aminogluthemide, busulphan, cyclosporine, mitoxantrone, irinotecan, etoposide, teniposide, paclitaxel, tacrolimus, sirolimus, tamoxifen, camptothecan, topotecan, nilutanide, bicalutanide, toremifene, atovaquone, metronidazole, furzolidone, paricalcitol, benzonatate, cisapride, cimetidine, loperamide, famotidine, lanosprazole, rabeprazole, nizatidine, omeprazole, citrizine, cinnarizine, dexchlopheniramine, loratadine, clemastine, fexofenadine, chlorpheniramine, acutretin, tazarotene, calciprotiene, calcitriol, targretin, ergocalciferol, cholecaliferol, isotreinoin, tretinoin, calcifediol, fenofibrate, probucol, simvastatin, atorvastatin, tizanidine, dantrolene, carotenes, dihyrotachysterol, vitamin A, vitamin D, vitamin E, vitamin K, essential fatty acid sources, danazol, dihydro epiandrosterone, medroxyprogesterone, progesterone, rimexolone, megesterol acetate, osteradiol, finasteride, mefepristone, raloxifene, L-thryroxine, tamsulosin, methoxsalen, pharmaceutically acceptable salts, isomers and derivative thereof, and mixtures thereof.
117. The pharmaceutical composition of claim 71, wherein the hydrophobic therapeutic agent is selected from the group consisting of sildenafil citrate, amlodipine, tramadol, celecoxib, refocoxib, oxaprozin, nabumetone, ibuprofen, terbenafine, itraconazole, zileuton, zafirlukast, cisapride, fenofibrate, tizanidine, nizatidine, fexofenadine, loratadine, famotidine, paricalcitol, atovaquone, nabumetone, tetrahydrocannabinol, megesterol acetate, repaglinide, progesterone, rimexolone, cyclosporine, tacrolimus, sirolimus, teniposide, paclitaxel, pseudo-ephedrine, troglitazone, rosiglitazone, finasteride, vitamin A, vitamin D, vitamin E, pharmaceutically acceptable salts, isomers and derivatives thereof, and mixtures thereof.
118. The pharmaceutical composition of claim 71, wherein the hydrophobic therapeutic agent is progesterone or cyclosporin.
119. The pharmaceutical composition of claim 71, which further comprises a solubilizer.
120. The pharmaceutical composition of claim 119, wherein the solubilizer is selected from the group consisting of alcohols, polyols, amides, esters, polyethylene glycol ethers and mixtures thereof.
121. The pharmaceutical composition of claim 120, wherein the alcohol or polyol is selected from the group consisting of ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives, and mixtures thereof.
122. The pharmaceutical composition of claim 120, wherein the amide is selected from the group consisting of 2-pyrrolidone, 2-piperidone, ε-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide, polyvinylpyrrolidone, and mixtures thereof.
123. The pharmaceutical composition of claim 120, wherein the ester is selected from the group consisting of ethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and isomers thereof, δ-valerolactone and isomers thereof, β-butyrolactone and isomers thereof, and mixtures thereof.
124. The pharmaceutical composition of claim 119, wherein the solubilizer is selected from the group consisting of ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediol and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins, clodextrins and derivatives thereof, ethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol diacetate, ε-caprolactone and isomers thereof, δ-valerolactone and isomers thereof, β-butyrolactone and isomers thereof, 2-pyrrolidone, 2-piperidone, ε-caprolactam, N-methylpyrrolidone, N-ethylpyrrolidone, N-hydroxyethyl pyrrolidone, N-octylpyrrolidone, N-laurylpyrrolidone, dimethylacetamide, polyvinylpyrrolidone, glycofurol, methoxy PEG, and mixtures thereof.
125. The pharmaceutical composition of claim 119, wherein the solubilizer is selected from the group consisting of ethanol, isopropanol, benzyl alcohol, ethylene glycol, propylene glycol, 1,3-butanediol, glycerol, pentaerythritol, sorbitol, glycofurol, transcutol, dimethyl isosorbide, polyethylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, hydroxypropylcyclodextrins, sulfobutyl ether derivatives of cyclodextrins, ethyl propionate, tributylcitrate, triethylcitrate, ethyl oleate, ethyl caprylate, triacetin, β-butyrolactone and isomers thereof, 2-pyrrolidone, N-methylpyrrolidone, N-ethylpyrrolidone, N-hydroxyethylpyrrolidone, N-octylpyrrolidone, N-laurylpyrrolidone, dimethylacetamide, polyvinylpyrrolidone, and mixtures thereof.
126. The pharmaceutical composition of claim 119, wherein the solubilizer is triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene glycol 200-600, glycofurol, transcutol, propylene glycol, dimethyl isosorbide, or a mixture thereof.
127. The pharmaceutical composition of claim 119, wherein the solubilizer is triacetin, ethanol, polyethylene glycol 400, glycofurol, propylene glycol or a mixture thereof.
128. The pharmaceutical composition of claim 119, wherein the solubilizer is present in the composition in an amount of about 400% or less by weight, based on the total weight of the surfactants.
129. The pharmaceutical composition of claim 128, wherein the solubilizer is present in the composition in an amount of about 200% or less by weight, based on the total weight of the surfactants.
130. The pharmaceutical composition of claim 129, wherein the solubilizer is present in the composition in an amount of about 100% or less by weight, based on the total weight of the surfactants.
131. The pharmaceutical composition of claim 130, wherein the solubilizer is present in the composition in an amount of about 50% or less by weight, based on the total weight of the surfactants.
132. The pharmaceutical composition of claim 131, wherein the solubilizer is present in the composition in an amount about 25% or less by weight, based on the total weight of the surfactants.
133. The pharmaceutical composition of claim 71, which further comprises an antioxidant, a preservative, a chelating agent, a viscomodulator, a tonicifier, a flavorant, a colorant, an odorant, an opacifier or a mixture thereof.
134. The pharmaceutical composition of claim 71, which further comprises an additional amount of a hydrophobic therapeutic agent, said additional amount not solubilized in the carrier.
135. A pharmaceutical composition comprising:
(a) a carrier,
 said carrier comprising:
(i) at least one hydrophilic surfactant; and
(ii) at least one hydrophobic surfactant,
 said hydrophilic and hydrophobic surfactants being present in amounts such that upon mixing with an aqueous solution the carrier forms a clear aqueous dispersion of the hydrophilic and hydrophobic surfactants;
(b) a first amount of a hydrophobic therapeutic agent, said first amount being solubilized in the carrier; and
(c) a second amount of a hydrophobic therapeutic agent, said second amount not solubilized in the clear aqueous dispersion,
said composition being substantially free of triglycerides.
136. A method of treating an animal with a hydrophobic therapeutic agent, the method comprising:
providing a dosage form of a pharmaceutical composition comprising:
a hydrophobic therapeutic agent; and
a carrier,
 said carrier comprising:
at least one hydrophilic surfactant; and
at least one hydrophobic surfactant,
 said hydrophilic and hydrophobic surfactants being present in amounts such that upon mixing with an aqueous solution the carrier forms a clear aqueous dispersion of the hydrophilic and hydrophobic surfactants containing the hydrophobic therapeutic agent,
said composition being substantially free of triglycerides; and
administering said dosage form to said animal.
137. The method of claim 136, wherein the dosage form is a capsule, a cream, a lotion, an ointment, a suppository, a paste or a gel.
138. The method of claim 136, wherein the dosage form is administered by an oral, parenteral, topical, transdermal, ocular, pulmonary, vaginal, rectal or transmucosal route.
139. The method of claim 136, wherein the animal is a mammal.
140. The method of claim 139, wherein the mammal is a human.
US09/898,553 1999-02-26 2001-07-02 Compositions and methods for improved delivery of hydrophobic agents Expired - Lifetime US6451339B2 (en)

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