Compositions and methods for improved delivery of hydrophobic agents

• US 6,451,339 B2
• Filed: 07/02/2001
• Issued: 09/17/2002
• Est. Priority Date: 02/26/1999
• Status: Expired due to Term

• Current Assignee: Lipocine Inc.
• Original Assignee: Lipocine Inc.
• Inventors: Chen, Feng-Jing, Patel, Mahesh V.
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): CHANNAVAJJALA, LAKSHMI SARADA
• Application Number:
  US09/898,553
• Publication Number:
  US 20020012680A1
• Time in Patent Office: 442 Days
• Field of Search: 424/450, 424/451, 424/455, 424/456, 424/463, 424/489, 424/499, 424/502, 424/435, 424/464, 514/937, 514/938, 514/939, 514/940, 514/941, 514/943, 514/975
• US Class Current: 424/451
• CPC Class Codes: A61K 31/57 substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• CPC Class Codes: A61K 38/13 Cyclosporins
• CPC Class Codes: A61K 9/4808 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 capsules filled with granules or microparticles A61K9/16; filled with microcapsules or coated microparticles A61K9/50; with mixture of different granules, microcapsules, (coated) microparticles A61K9/5084
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/06 Antiabortive agents; Labour repressants
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 5/24 of the sex hormones
• CPC Class Codes: A61P 5/26 Androgens
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

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.

Claims

1. A pharmaceutical formulation for administration of a hydrophobic lipid-regulating agent, comprising a therapeutically effective amount of the lipid-regulating agent and a carrier comprised of

(a) at least one hydrophilic surfactant selected from the group consisting of hydrophilic non-ionic surfactants, hydrophilic ionic surfactants, and combinations thereof, and

(b) at least one hydrophobic surfactant having an HLB value less than about 10 and selected from the group consisting of alcohols;

polyoxyethylene alkylethers;

fatty acids;

glycerol fatty acid monoesters;

glycerol fatty acid diesters;

acetylated glycerol fatty acid monoesters;

acetylated glycerol fatty acid diesters, lower alcohol fatty acid esters;

polyethylene glycol fatty acid esters;

polyethylene glycol glycerol fatty acid esters;

polypropylene glycol fatty acid esters;

polyoxyethylene glycerides;

lactic acid derivatives of monoglycerides;

lactic acid derivatives of 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 products 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,

said hydrophilic and hydrophobic surfactants being present in amounts such that upon dilution with an aqueous solution at an aqueous solution to carrier ratio of 100;

1 by weight, the carrier forms a clear aqueous dispersion having an absorbance of less than about 0.1 at a wavelength of about 400 nm, and wherein the composition is substantially free of glycerol triesters of C₆ to about C₂₅ fatty acids.

2. The formulation of claim 1, wherein the lipid regulating agent is selected from the group consisting of atorvastatin, bezafibrate, cerivastatin, ciprofibrate, clofibrate, fenofibrate, fluvastatin, gemfibrozil, pravastatin, probucol, simvastatin, and combinations thereof.

3. The formulation of claim 2, wherein the lipid regulating agent is fenofibrate.

4. The formulation of claim 2, wherein the lipid regulating agent is ciprofibrate.

5. The formulation of claim 1, wherein the lipid regulating agent is selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, pravastatin, simvastatin, and combinations thereof.

6. The formulation of claim 1, further including a therapeutically effective amount of an antiviral agent.

7. The formulation of claim 6, wherein the antiviral agent is selected from the group consisting of abacavir, amprenavir, delaviridine, efavirenz, indinavir, lamivudine, nelfinavir, nevirapine, ritonavir, saquinavir, stavudine, and combinations thereof.

8. The formulation of claim 7, wherein the antiviral agent is nelfinavir.

9. The formulation of claim 7, wherein the antiviral agent is ritonavir.

10. The formulation of claim 7, wherein the antiviral agent is saquinavir.

11. The formulation of claim 1, further including a therapeutically effective amount of an antidiabetic agent.

12. The formulation of claim 11, wherein the antidiabetic agent is selected from the group consisting of cetohexamide, chlorpropamide, glibenclamide, gliclazide, glipizide, glimepiride, miglitol, pioglitazone, repaglinide, rosiglitazone, tolazamide, tolbutamide, troglitazone, and combinations thereof.

13. The formulation of claim 6, further including a therapeutically effective amount of an antidiabetic agent.

14. The formulation of claim 13, wherein the antidiabetic agent is selected from the group consisting of cetohexamide, chlorpropamide, glibenclamide, gliclazide, glipizide, glimepiride, miglitol, pioglitazone, repaglinide, rosiglitazone, tolazamide, tolbutamide, troglitazone, and combinations thereof.

15. The formulation 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.

16. The formulation of claim 15, wherein the hydrophobic surfactant is present in an amount of less than about 100% by weight, relative to the amount of the hydrophilic surfactant.

17. The formulation of claim 16, wherein the hydrophobic surfactant is present in an amount of less than about 60% by weight, relative to the amount of the hydrophilic surfactant.

18. The formulation 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.

19. The formulation of claim 1, wherein the hydrophilic surfactant comprises at least one ionic surfactant.

20. The formulation of claim 1, which further comprises at least one ionic surfactant.

21. The formulation of claim 18, wherein the non-ionic hydrophilic surfactant is selected from the group consisting of alkylglucosides;

alkylmaltosides;

alkylthioglucosides;

lauryl macrogolglycerides;

polyoxyethylene alkyl ethers;

polyoxyethylene alkylphenols;

polyethylene glycol fatty acid 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 products 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.

22. The formulation of claim 18, wherein the non-ionic hydrophilic surfactant is selected from the group consisting of polyoxyethylene alkylethers;

polyethylene glycol fatty acid 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 products 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 formulation of claim 21 or claim 22, wherein the non-ionic hydrophilic surfactant comprises a reaction product of a polyol and a monoglyceride, diglyceride, triglyceride, or a mixture thereof.

24. The formulation of claim 23, wherein the non-ionic hydrophilic surfactant comprises a transesterification product of a polyol and a monoglyceride, diglyceride, triglyceride, or a mixture thereof.

25. The formulation of claim 24, wherein the polyol is glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol or a mixture thereof.

26. The formulation of claim 18, wherein the non-ionic 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, 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.

27. The formulation of claim 18, wherein the non-ionic 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.

28. The formulation of claim 18, wherein the non-ionic 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.

29. The formulation of claim 28, wherein the non-ionic hydrophilic surfactant is tocopheryl PEG-1000 succinate.

30. The formulation of claim 18, wherein the non-ionic hydrophilic surfactant is lauroyl macrogol-32 glyceride.

31. The formulation of claim 18, wherein the non-ionic hydrophilic surfactant is stearoyl macrogol glyceride.

32. The formulation of claim 19, 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;

monoacetylated tartaric acid esters of monoglycerides, monoacetylated tartaric acid esters of diglycerides, diacetylated tartaric acid esters of monoglycerides, diacetylated tartaric acid esters of diglycerides;

succinylated monoglycerides;

citric acid esters of monoglycerides;

citric acid esters of 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.

33. The formulation of claim 19, 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;

monoacetylated tartaric acid esters of monoglycerides, monoacetylated tartaric acid esters of diglycerides, diacetylated tartaric acid esters of monoglycerides, diacetylated tartaric acid esters of diglycerides;

succinylated monoglycerides;

citric acid esters of monoglycerides, citric acid esters of diglycerides; and

mixtures thereof.

34. The formulation of claim 19, 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, monoacetylated tartaric acid esters of monoglycerides, monoacetylated tartaric acid esters of diglycerides, diacetylated tartaric acid esters of monoglycerides, diacetylated tartaric acid esters of diglycerides, citric acid esters of monoglycerides, citric acid esters of 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.

35. The formulation of claim 19, 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, monoacetylated tartaric acid esters of monoglycerides, monoacetylated tartaric acid esters of diglycerides, diacetylated tartaric acid esters of monoglycerides, diacetylated tartaric acid esters of diglycerides, citric acid esters of monoglycerides, citric acid esters of diglycerides, cholate, taurocholate, glycocholate, deoxycholate, taurodeoxycholate, glycodeoxycholate, cholylsarcosine, caproate, caprylate, caprate, laurate, oleate, lauryl sulfate, docusate, and salts and mixtures thereof.

36. The formulation of claim 19, wherein the ionic surfactant is selected from the group consisting of lecithin, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, monoacetylated tartaric acid esters of monoglycerides, monoacetylated tartaric acid esters of diglycerides, diacetylated tartaric acid esters of monoglycerides, diacetylated tartaric acid esters of diglycerides, citric acid esters of monoglycerides, citric acid esters of diglycerides, taurocholate, caprylate, caprate, oleate, lauryl sulfate, docusate, and salts and mixtures thereof.

37. The formulation of claim 1, 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 monoesters;

glycerol fatty acid diesters;

acetylated glycerol fatty acid monoesters;

acetylated glycerol fatty acid diesters;

lactic acid derivatives of monoglycerides;

lactic acid derivatives of diglycerides;

sorbitan fatty acid esters;

polyoxyethylene sorbitan fatty acid esters;

polyoxyethylene-polyoxypropylene block copolymers;

polyoxyethylene vegetable oils;

polyoxyethylene hydrogenated vegetable oils;

reaction products 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.

38. The formulation of claim 1, wherein the hydrophobic surfactant is selected from the group consisting of lower alcohol fatty acid esters;

polypropylene glycol fatty acid esters;

propylene glycol fatty acid esters;

glycerol fatty acid monoesters;

glycerol fatty acid diesters;

acetylated glycerol fatty acid monoesters;

acetylated glycerol fatty acid diesters;

lactic acid derivatives of mono/diglycerides;

sorbitan fatty acid esters;

polyoxyethylene vegetable oils; and

mixtures thereof.

39. The formulation of claim 38, wherein the hydrophobic surfactant is a glycerol fatty acid monoester, a glycerol fatty acid diester, an acetylated glycerol fatty acid monoester, an acetylated glycerol fatty acid diester, or a mixture thereof.

40. The formulation of claim 39, wherein the hydrophobic surfactant is glycerol fatty acid monoester, a glycerol fatty acid diester, or a mixture thereof.

41. The formulation of claim 40, wherein the fatty acid of the glycerol fatty acid ester is a C₆ to C₂₀ fatty acid or a mixture thereof.

42. The formulation of claim 1, wherein the hydrophobic surfactant is a reaction product of a polyol and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols.

43. The formulation of claim 42, wherein the hydrophobic surfactant comprises 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.

44. The formulation of claim 43, wherein the polyol is polyethylene glycol, sorbitol, propylene glycol, pentaerythritol or a mixture thereof.

45. The formulation of claim 1, 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 monoesters of a C₆ to C₂₀ fatty acid, propylene glycol 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.

46. The formulation of claim 1, 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.

47. The formulation of claim 1, wherein the clear aqueous dispersion has a particle size distribution having an average particle size of less than about 50 nm.

48. The formulation of claim 43, wherein the clear aqueous dispersion has a particle size distribution having an average particle size of less than about 20 nm.

49. The formulation of claim 1, wherein the absorbance is less than about 0.01.

50. The formulation of claim 1, wherein the intrinsic water solubility is less than about 0.1% by weight at 25°

C.

51. The formulation of claim 47, wherein the intrinsic water solubility is less than about 0.01% by weight at 25°

C.

52. The formulation of claim 1, wherein the carrier further comprises a solubilizer.

53. The formulation of claim 52, wherein the solubilizer is selected from the group consisting of alcohols, polyols, amides, esters, propylene glycol ethers and mixtures thereof.

54. The formulation of claim 53, wherein the solubilizer is an alcohol or polyol 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.

55. The formulation of claim 54, wherein the solubilizer is hydroxypropyl methylcellulose.

56. The formulation of claim 53, wherein the solubilizer is an amide 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.

57. The formulation of claim 56, wherein the solubilizer is polyvinylpyrrolidone.

58. The formulation of claim 53, wherein the solubilizer is an ester 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, 62 -butyrolactone and isomers thereof, and mixtures thereof.

59. The formulation of claim 52, 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, cyclodextrins 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.

60. The formulation of claim 52, 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-hydroxyalkylpyrrolidone, N-octylpyrrolidone, N-laurylpyrrolidone, dimethylacetamide, polyvinylpyrrolidone, and mixtures thereof.

61. The formulation of claim 52, 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.

62. The formulation of claim 52, wherein the solubilizer is triacetin, ethanol, polyethylene glycol 400, glycofurol, propylene glycol or a mixture thereof.

63. The formulation of claim 52, 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.

64. The formulation of claim 63, 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.

65. The formulation of claim 64, 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.

66. The formulation of claim 65, 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.

67. The formulation of claim 66, 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.

68. The formulation of claim 1, 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.

69. The formulation of claim 1, wherein the carrier is suitable for oral drug administration, and the therapeutically effective amount of the lipid regulating agent is an amount that is therapeutically effective for oral drug administration.

70. The formulation of claim 6, wherein the carrier is suitable for oral drug administration, and the therapeutically effective amounts of the lipid regulating agent and the antiviral agent are amounts that are therapeutically effective for oral drug administration.

71. The formulation of claim 11, wherein the carrier is suitable for oral drug administration, and the therapeutically effective amounts of the lipid regulating agent and the antidiabetic agent are amounts that are therapeutically effective for oral drug administration.

72. The formulation of claim 13, wherein the carrier is suitable for oral drug administration, and the therapeutically effective amounts of the lipid regulating agent, the antiviral agent and the antidiabetic agent are amounts that are therapeutically effective for oral drug administration.

73. The formulation of claim 1, comprising a preconcentrate, a diluted preconcentrate, a dispersion, or a sprayable solution.

74. The formulation of claim 73, comprising a dispersion.

75. The formulation of claim 74, wherein the dispersion is a semi-solid dispersion.

76. The formulation of claim 75, wherein the dispersion is a solid dispersion.

77. A dosage form comprising a capsule filled with the pharmaceutical formulation of any one of claims 69, 70, 71 or 72.

78. The dosage form of claim 77, wherein the capsule is a hard gelatin capsule, a soft gelatin capsule, a starch capsule or an enteric coated capsule.

79. A dosage form comprising a multiparticulate carrier coated with the pharmaceutical formulation of any one of claims 69, 70, 71 or 72.

80. The formulation of claim 1, comprising a solution, a cream, a lotion, an ointment, a suppository, a spray, an aerosol, a paste or a gel.

81. The formulation of claim 1, which further comprises water or an aqueous buffer.

82. The formulation of claim 1, further comprising an additional amount of the lipid regulating agent, said additional amount not solubilized in the carrier.

83. A method of administering a lipid regulating agent to an individual in need of such treatment, the method comprising orally administering to the individual the pharmaceutical formulation of claim 69.

84. A method of administering a lipid-regulating agent and an antiviral agent to an individual in need of such treatment, the method comprising orally administering to the individual the pharmaceutical formulation of claim 70.

85. A method of administering a lipid-regulating agent and an antidiabetic agent to an individual in need of such treatment, the method comprising orally administering to the individual the pharmaceutical formulation of claim 71.

86. A method of administering a lipid-regulating agent, all antiviral agent, and an antidiabetic agent to an individual in need of such treatment, the method comprising orally administering to the individual the pharmaceutical formulation of claim 72.

87. The formulation of claim 1, comprising the lipid-regulating agent suspended in the carrier.

88. The formulation of claim 1, wherein the formulation is contained in a capsule.

111. The formulation of claim 87, wherein the suspended lipid-regulating agent is in milled, micronized or precipitated form.

89. A pharmaceutical formulation for administration of a hydrophobic therapeutic agent, comprising a therapeutically effective amount of the therapeutic agent and a carrier comprised of

(a) at least one hydrophilic surfactant selected from the group consisting of hydrophilic non-ionic surfactants, hydrophilic ionic surfactants, and combinations thereof, and

(b) at least one hydrophobic surfactant having HLB value less than about 10 and selected from the group consisting of alcohols;

polyoxyethylene alkylethers;

fatty acids;

glycerol fatty acid monoesters;

glycerol fatty acid diesters;

acetylated glycerol fatty acid monoesters;

acetylated glycerol fatty acid diesters, lower alcohol fatty acid esters;

polyethylene glycol fatty acid esters;

polyethylene glycol glycerol fatty acid esters;

polypropylene glycol fatty acid esters, polyoxyethylene glycerides;

lactic acid derivatives of monoglycerides;

lactic acid derivatives of 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 products 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,

said hydrophilic and hydrophobic surfactants being present in amounts such from upon dilution with an aqueous solution at an aqueous solution to carrier ratio of 10;

1 by weight, the carrier forms a clear aqueous dispersion having an absorbance of less than about 0.3 at a wavelength of about 400 nm, and wherein the composition is substantially free of glycerol triesters of C₆ to about C₂₅ fatty acids.

90. The formulation of claim 89, wherein the hydrophobic agent is selected from the group consisting of analgesics, anti-inflammatory agents, antihelminihics, anti-arrhythmic agents, anti-asthma agents, antibacterial agents, antiviral agents, anti-coagulants, antidepressants, anti-diabetic agents, anti-epileptic agents, anti-fungal agents, anti-gout agents, anti-hypertensive agents, anti-malarial agents, anti-migraine agents, anti-muscarinic agents, anti-neoplastic agents, immunosuppressants, anti-protozoal agents, anti-thyroid agents, anti-tussives, anxiolytic agents, hypnotic agents, sedatives, neuroleptic agents, β

-blockers, cardiac inotropic agents, corticosteroids, diuretics, anti-parkinsonian agents, gastro-intestinal agents, histamine H₁ and H₂-receptor antagonists, keratolytics, lipid regulating agents, muscle relaxants, anti-anginal agents, nutritional agents, sex hormones, stimulants, and combinations thereof.

91. The formulation of claim 90, wherein the hydrophobic agent is a sex hormone.

92. The formulation of claim 91, wherein the sex hormone is selected from the group consisting of clomiphene citrate, cortisone acetate, danazol, dehydroepiandrosterone, ethynyl estradiol, finasteride, fludrocortisone, fluoxymesterone, medroxyprogesterone acetate, megestrol acetate, mestranol, methyltestosterone, norethisterone, norgestrel, oestradiol, conjugated estrogens, progesterone, rimexolone, stanozolol, stilbestrol, testosterone, tibolone, and combinations thereof.

93. The formulation of claim 92, wherein the sex hormone is selected from the group consisting of oestradiol, progesterone and combinations thereof.

94. The formulation of claim 89, comprising the hydrophobic therapeutic agent suspended in the carrier.

95. The formulation of claim 89, wherein the formulation is contained in a capsule.

108. The formulation of claim 94, wherein the suspended hydrophobic therapeutic agent is in milled, micronized or precipitated form.

109. The formulation of either claim 89 or claim 96, wherein the formulation is a semi-solid dispersion.

110. The formulation of either claim 89 or claim 96, wherein the formulation is a solid dispersion.

96. A pharmaceutical formulation for administration of a hydrophobic lipid-regulating agent, comprising a therapeutically effective amount of the lipid-regulating agent and a carrier comprised of

(a) at least one hydrophilic surfactant selected from the group consisting of hydrophilic non-ionic surfactants, hydrophilic ionic surfactants, and combinations thereof, and

(b) at least one hydrophobic surfactant having an HLB value less than about 10 and selected from the group consisting of alcohols;

polyoxyethylene alkylethers;

fatty acids;

glycerol fatty acid monoesters;

glycerol fatty acid diesters;

acetylated glycerol fatty acid monoesters;

acetylated glycerol fatty acid diesters, lower alcohol fatty acid esters;

polyethylene glycol fatty acid esters;

polyethylene glycol glycerol fatty acid esters;

polypropylene glycol fatty acid esters;

polyoxyethylene glycerides;

lactic acid derivatives of monoglycerides;

lactic acid derivatives of digylcerides;

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 products 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,

said hydrophilic and hydrophobic surfactants being present in amounts such that upon dilution with an aqueous solution at an aqueous solution to carrier ratio of 10;

1 by weight, the carrier forms a clear aqueous dispersion having an absorbance of less than about 0.3 at a wavelength of about 400 nm, and wherein the composition is substantially free of glycerol triesters of C₆ to about C₂₅ fatty acids.

97. The formulation of claim 96, wherein the lipid regulating agent is selected from the group consisting of atorvastatin, bezafibrate, cerivastatin, ciprofibrate, clofibrate, fenofibrate, fluvastatin, gemfibrozil, pravastatin, probucol, and simvastatin.

98. The formulation of claim 96, further including a therapeutically effective amount or an anticoagulant.

99. The formulation of claim 97 further including a therapeutically effective amount of an anticoagulant.

100. The formulation of claim 98, wherein the anticoagulant is selected from the group consisting of cilostazol, clopidogrel, dicumarol, dipyridamole, nicoumalone, oprelvekin, phenindione, ticlopidine, aid tirofiban.

101. The formulation of claim 99, wherein the anticoagulant is selected from the group consisting of cilostazol, clopidogrel, dicumarol, dipyridamole, nicoumalone, oprelvekin, phenindione, ticlopidine, and tirofiban.

102. The formulation of claim 100, wherein the anticoagulant is clopidogrel.

103. The formulation of claim 101, wherein the anticoagulant is clopidogrel.

104. The formulation of claim 96, comprising the lipid-regulating agent suspended in the carrier.

105. The formulation of claim 104, wherein the formulation is contained in a capsule.

106. The formulation of claim 98, comprising the lipid-regulating agent and the anti-coagulant suspended in the carrier.

107. The formulation of claim 106, wherein the formulation is contained in a capsule.

112. The formulation of claim 104, wherein the suspended lipid-regulating agent is in milled, micronized or precipitated form.

113. A pharmaceutical formulation for administration of a hydrophobic sex hormone, comprising a therapeutically effective amount of the sex hormone and a carrier comprised of

(a) at least one hydrophilic surfactant selected from the group consisting of hydrophilic non-ionic surfactants, hydrophilic ionic surfactants, and combinations thereof, and

(b) at least one hydrophobic surfactant having an HLB value less than about 10 and selected from the group consisting of alcohols;

polyoxyethylene alkylethers;

fatty acids;

glycerol fatty acid monoesters;

glycerol fatty acid diesters;

acetylated glycerol fatty acid monoesters;

acetylated glycerol fatty acid diesters, lower alcohol fatty acid esters;

polyethylene glycol fatty acid esters;

polyethylene glycol glycerol fatty acid esters;

polypropylene glycol fatty acid esters;

polyoxyethylene glycerides;

lactic acid derivatives of monoglycerides;

lactic acid derivatives of 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 products 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,

said hydrophilic and hydrophobic surfactants being present in amounts such that upon dilution with an aqueous solution at an aqueous solution to carrier ratio of 100;

1 by weight, the carrier forms a clear aqueous dispersion having an absorbance of less than about 0.1 at a wavelength of about 400 mn, and wherein the composition is substantially free of glycerol triesters of C₆ to about C₂₅ fatty acids.

114. The formulation of claim 113, wherein the sex hormone is selected from the group consisting of clomiphene citrate, cortisone acetate, danazol, dehydroepiandrosterone, ethynyl estradiol, finasteride, fludrocortisone, fluoxymesterone, medroxyprogesterone acetate, megestrol acetate, mestranol, methyltestosterone, norethisterone, norgestrel, oestradiol, conjugated estrogens, progesterone, rimexolone, stanozolol, stilbestrol, testosterone, tibolone, and combinations thereof.

115. The formulation of claim 114, wherein the sex hormone is selected from the group consisting of oestradiol, progesterone and combinations thereof.

116. The formulation of claim 113, comprised of the sex hormone is suspended in the carrier.

117. The formulation of claim 116, wherein the formulation is contained in a capsule.

118. The formulation of claim 116, wherein the suspended hydrophobic therapeutic agent is in milled, micronized or precipitated form.

119. The formulation of claim 113, wherein the formulation is a semi-solid dispersion.

120. The formulation of claim 113, wherein the formulation is a solid dispersion.