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Details for Patent: 6,761,903

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Details for Patent: 6,761,903

Title: Clear oil-containing pharmaceutical compositions containing a therapeutic agent
Abstract:The present invention relates to pharmaceutical compositions and methods for improved solubilization of triglycerides and improved delivery of therapeutic agents. Compositions of the present invention include a carrier, where the carrier is formed from a combination of a triglyceride and at least two surfactants, at least one of which is hydrophilic. Upon dilution with an aqueous medium, the carrier forms a clear, aqueous dispersion of the triglyceride and surfactants.
Inventor(s): Chen; Feng-Jing (Salt Lake City, UT), Patel; Mahesh V. (Salt Lake City, UT), Fikstad; David T. (Salt Lake City, UT)
Assignee: Lipocine, Inc. (Salt Lake City, UT)
Filing Date:Jun 08, 2001
Application Number:09/877,541
Claims:1. A pharmaceutical composition comprising: (a) a carrier comprising a triglyceride and at least two surfactants, at least one of the surfactants being hydrophilic; and (b) a therapeutically effective amount of a polysaccharide drug, wherein the triglyceride and surfactants are present in amounts such that upon mixing with an aqueous medium in an aqueous medium to carrier ratio of about 100:1 by weight, the carrier forms a clear aqueous dispersion having an absorbance of less than about 0.3 at 400 nm.

2. The pharmaceutical composition of claim 1, wherein the triglyceride is selected from the group consisting of vegetable oils, fish oils, animal fats, hydrogenated vegetable oils, partially hydrogenated vegetable oils, synthetic triglycerides, modified triglycerides, fractionated triglycerides, and mixtures thereof.

3. The pharmaceutical composition of claim 1, wherein the triglyceride is selected from the group consisting of almond oil; babassu oil; borage oil; blackcurrant seed oil; canola oil; castor oil; coconut oil; corn oil; cottonseed oil; evening primrose oil; grapeseed oil; groundnut oil; mustard seed oil; olive oil; palm oil; palm kernel oil; peanut oil; rapeseed oil; safflower oil; sesame oil; shark liver oil; soybean oil; sunflower oil; hydrogenated castor oil; hydrogenated coconut oil; hydrogenated palm oil; hydrogenated soybean oil; hydrogenated vegetable oil; hydrogenated cottonseed and castor oil; partially hydrogenated soybean oil; soy oil; glyceryl tricaproate; glyceryl tricaprylate; glyceryl tricaprate; glyceryl triundecanoate; glyceryl trilaurate; glyceryl trioleate; glyceryl trilinoleate; glyceryl trilinolenate; glyceryl tricaprylate/caprate; glyceryl tricaprylate/caprate/laurate; glyceryl tricaprylate/caprate/linoleate; glyceryl tricaprylate/caprate/stearate; saturated polyglycolized glycerides; linoleic glycerides; caprylic/capric glycerides; modified triglycerides; fractionated triglycerides; and mixtures thereof.

4. The pharmaceutical composition of claim 1, wherein the triglyceride is selected from the group consisting of coconut oil; corn oil; olive oil; palm oil; peanut oil; safflower oil; sesame oil; soybean oil; hydrogenated castor oil; hydrogenated coconut oil; partially hydrogenated soybean oil; glyceryl tricaprate; glyceryl trilaurate; glyceryl trioleate; glyceryl trilinoleate; glyceryl tricaprylate/caprate; glyceryl tricaprylate/caprate/laurate; glyceryl tricaprylate/caprate/linoleate; glyceryl tricaprylate/caprate/stearate; saturated polyglycolized glycerides; linoleic glycerides; caprylic/capric glycerides; modified triglycerides; fractionated triglycerides; and mixtures thereof.

5. The pharmaceutical composition of claim 1, wherein the triglyceride is selected from the group consisting of a medium chain triglyceride, a long chain triglyceride, a modified triglyceride, a fractionated triglyceride, and mixtures thereof.

6. 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.

7. The pharmaceutical composition of claim 1, wherein the hydrophilic surfactant comprises at least one ionic surfactant.

8. The pharmaceutical composition of claim 6, which further comprises at least one ionic surfactant.

9. The pharmaceutical composition of claim 6, 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; 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.

10. The pharmaceutical composition of claim 6, 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.

11. The pharmaceutical composition of claim 10, wherein the glyceride is selected from the group consisting of a monoglyceride, a diglyceride, a triglyceride, and mixtures thereof.

12. The pharmaceutical composition of claim 10, 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.

13. The pharmaceutical composition of claim 11, wherein the polyol is selected from the group consisting of glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, a saccharide, and mixtures thereof.

14. The pharmaceutical composition of claim 6, wherein the hydrophilic surfactant is selected from the group consisting of 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, and mixtures thereof.

15. The pharmaceutical composition of claim 6, wherein the hydrophilic surfactant is selected from the group consisting of 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, and mixtures thereof.

16. The pharmaceutical composition of claim 6, wherein the hydrophilic surfactant is selected from the group consisting of 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, and mixtures thereof.

17. The pharmaceutical composition of claim 7, wherein the ionic surfactant is selected from the group consisting of alkyl ammonium salts; bile salts; fusidic acid; fatty acid conjugates of amino acids, oligopeptides, and polypeptides; glyceride esters of amino acids, oligopeptides, and polypeptides; acyl lactylates; mono- and diacetylated tartaric acid esters of mono- and diglycerides; succinylated monoglycerides; citric acid esters of mono- and diglycerides; alginate salts; propylene glycol alginate; lecithins and hydrogenated lecithins; lysolecithin and hydrogenated lysolecithins; lysophospholipids; camitine fatty acid ester salts; phospholipids; salts of alkylsulfates; salts of fatty acids; sodium docusate; and mixtures thereof.

18. The pharmaceutical composition of claim 7, wherein the ionic surfactant is selected from the group consisting of bile acids and; lecithins, lysolecithin, phospholipids, and lysophospholipids; carnitine fatty acid ester salts; salts of alkylsulfates; salts of fatty acids; sodium docusate; acyl lactylates; mono- and diacetylated tartaric acid esters of mono- and diglycerides; succinylated monoglycerides; citric acid esters of mono-, diglycerides; and mixtures thereof.

19. The pharmaceutical composition of claim 7, 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, lithocholate, tauroursodeoxycholate, glycoursodeoxycholate, cholylsarcosine, N-methyl taurocholate, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, tetraacetyl sulfate, docusate, lauroyl carnitine, palmitoyl carnitine, myristoyl carnitine, and salts and mixtures thereof.

20. The pharmaceutical composition of claim 7, 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, chenodeoxycholate, lithocholate, ursodeoxycholate, taurodeoxycholate, glycodeoxycholate, cholylsarcosine, caproate, caprylate, caprate, laurate, oleate, lauryl sulfate, docusate, lauroyl carnitine, palmitoyl carnitine, myristoyl carnitine, and salts and mixtures thereof.

21. The pharmaceutical composition of claim 7, 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, chenodeoxycholate, lithocholate, ursodeoxycholate, taurocholate, caprylate, caprate, oleate, lauryl sulfate, docusate, lauroyl carnitine, palmitoyl carnitine, myristoyl carnitine, and salts and mixtures thereof.

22. The pharmaceutical composition of claim 1, wherein the carrier comprises at least two hydrophilic surfactants.

23. The pharmaceutical composition of claim 1, wherein the carrier comprises at least one hydrophilic surfactant and at least one hydrophobic surfactant.

24. The pharmaceutical composition of claim 23 wherein the hydrophobic surfactant is a compound or mixture of compounds having an HLB value less than about 10.

25. The pharmaceutical composition of claim 24, wherein the hydrophobic surfactant is selected from the group consisting of alcohols; polyoxyethylene alkylethers; fatty acids; bile 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 esters of mono/diglycerides; propylene glycol diglycerides; sorbitan fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; transesterified vegetable oils; sterols; 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.

26. The pharmaceutical composition of claim 24, wherein the hydrophobic surfactant is selected from the group consisting of fatty acids; bile 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 esters 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.

27. The pharmaceutical composition of claim 24, wherein the hydrophobic surfactant is selected from the group consisting of bile acids; 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 esters of mono/diglycerides; sorbitan fatty acid esters; polyoxyethylene vegetable oils; and mixtures thereof.

28. The pharmaceutical composition of claim 24, wherein the hydrophobic surfactant is selected from the group consisting of a glycerol fatty acid ester, an acetylated glycerol fatty acid ester, and mixtures thereof.

29. The pharmaceutical composition of claim 28, wherein the glycerol fatty acid ester is selected from the group consisting of a monoglyceride, diglyceride, and mixtures thereof.

30. The pharmaceutical composition of claim 29, wherein the fatty acid of the glycerol fatty acid ester is a C.sub.6 to C.sub.22 fatty acid or a mixture thereof.

31. The pharmaceutical composition of claim 24, 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.

32. The pharmaceutical composition of claim 31, 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.

33. The pharmaceutical composition of claim 31, wherein the polyol is selected from the group consisting of polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, a saccharide, and mixtures thereof.

34. The pharmaceutical composition of claim 24, 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 C.sub.6 to C.sub.22 fatty acid; monoglycerides of a C.sub.6 to C.sub.22 fatty acid; acetylated monoglycerides of a C.sub.6 to C.sub.22 fatty acid; diglycerides of C.sub.6 to C.sub.22 fatty acids; lactic acid esters of monoglycerides; lactic acid esters 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; cholic acid; ursodeoxycholic acid; glycocholic acid; taurocholic acid; lithocholic acid; deoxycholic acid; chenodeoxycholic acid; and mixtures thereof.

35. The pharmaceutical composition of claim 24, 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; cholic acid; ursodeoxycholic acid; glycocholic acid; taurocholic acid; lithocholic acid; deoxycholic acid; chenodeoxycholic acid; and mixtures thereof.

36. The pharmaceutical composition of claim 1, wherein the polysaccharide drug is selected from glucosamine, glycosaminoglycans, dextran, xylan, pentasaccharide, polygalacturonic acid, polymannuronic acid, chitin, pharmaceutically acceptable salts, esters or other derivatives thereof, and combinations of any of the foregoing.

37. The pharmaceutical composition of claim 1, wherein the polysaccharide drug is a glycosaminoglycan.

38. The pharmaceutical composition of claim 37, wherein the glycosaminoglycan is selected from heparin, heparan, chondroitin, dermatan, hyaluronic acid and pharmaceutically acceptable salts thereof.

39. The pharmaceutical composition of claim 37, wherein the glycosaminoglycan is selected from heparin, low molecular weight heparin, heparin sodium, heparan, heparan sulfate, and pharmaceutically acceptable salts of any of the foregoing formed with metallic cations or organic bases.

40. The pharmaceutical composition of claim 39, wherein the polysaccharide drug is low molecular weight heparin.

41. The pharmaceutical composition of claim 40, wherein the low molecular weight heparin is selected from the group consisting of enoxaparin, dalteparin, gammaparin, nadroparin, tinzaparin, certoparin, reviparin, pamaparin, and mixtures thereof.

42. The pharmaceutical composition of claim 39, wherein the polysaccharide drug is heparin sodium.

43. The pharmaceutical composition of claim 39, wherein the polysaccharide drug is heparan.

44. The pharmaceutical composition of claim 39, wherein the polysaccharide drug is heparan sulfate.

45. The pharmaceutical composition of claim 1, wherein the surfactants are present in amounts such that the triglyceride can be present in an amount greater than the amount of the triglyceride that remains solubilized in an aqueous dispersion of the triglyceride and a carrier having only one surfactant, the surfactant being hydrophilic, and having the same total surfactant concentration.

46. The pharmaceutical composition of claim 22, wherein the surfactants are present in amounts such that the triglyceride can be present in an amount greater than the amount of the triglyceride that remains solubilized in an aqueous dispersion of the triglyceride and a carrier having only one surfactant, the surfactant being hydrophilic, and having the same total surfactant concentration.

47. The pharmaceutical composition of claim 23, wherein the surfactants are present in amounts such that the triglyceride can be present in an amount greater than the amount of the triglyceride that remains solubilized in an aqueous dispersion of the triglyceride and a carrier having a hydrophilic surfactant but not having a hydrophobic surfactant, and having the same total surfactant concentration.

48. The pharmaceutical composition of claim 1, wherein the triglyceride and surfactants are present in amounts such that upon mixing with an aqueous medium in an aqueous medium to carrier ratio of about 10:1 by weight, the carrier forms a clear aqueous dispersion.

49. The pharmaceutical composition of claim 1, wherein the absorbance of the carrier is less than about 0.2.

50. The pharmaceutical composition of claim 1, wherein the absorbance of the carrier is less than about 0.1.

51. The pharmaceutical composition of claim 1, which fuirther comprises a solubilizer.

52. The pharmaceutical composition of claim 51, wherein the solubilizer is selected from the group consisting of alcohols, polyols, amides, esters, propylene glycol ethers and mixtures thereof.

53. The pharmaceutical composition of claim 52, 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, maltol, maltodextrins, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulosic polymers, cyclodextrins, and mixtures thereof.

54. The pharmaceutical composition of claim 52, wherein the amide is selected from the group consisting of 2-pyrrolidone, 2-piperidone, .epsilon.-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide, polyvinylpyrrolidone, and mixtures thereof.

55. The pharmaceutical composition of claim 52, 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, .epsilon.-caprolactone and isomers thereof, .delta.-valerolactone and isomers thereof, .beta.-butyrolactone and isomers thereof, and mixtures thereof.

56. The pharmaceutical composition of claim 51, 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 cellulosic polymers, cyclodextrins, ethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol diacetate, .epsilon.-caprolactone and isomers thereof, .delta.-valerolactone and isomers thereof, .beta.-butyrolactone and isomers thereof, 2-pyrrolidone, 2-piperidone, .epsilon.-caprolactam, N-methylpyrrolidone, N-ethylpyrrolidone, N-hydroxyethyl pyrrolidone, N-octylpyrrolidone, N-laurylpyrrolidone, dimethylacetamide, polyvinylpyrrolidone, glycofurol, methoxy PEG, and mixtures thereof.

57. The pharmaceutical composition of claim 51, 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, .beta.-butyrolactone and isomers thereof, 2-pyrrolidone, N-methylpyrrolidone, N-ethylpyrrolidone, N-hydroxyethylpyrrolidone, N-octylpyrrolidone, N-laurylpyrrolidone, dimethylacetamide, polyvinylpyrrolidone, and mixtures thereof.

58. The pharmaceutical composition of claim 51, wherein the solubilizer is selected from the group consisting of 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 and mixtures thereof.

59. The pharmaceutical composition of claim 51, wherein the solubilizer is selected from the group consisting of triacetin, ethanol, polyethylene glycol 400, glycofurol, propylene glycol and mixtures thereof.

60. The pharmaceutical composition of claim 1, which further comprises at least one additive selected from the group consisting of an antioxidant, a bufferant, an antifoaming agent, a detackifier, a preservative, a chelating agent, a viscomodulator, a tonicifier, a flavorant, a colorant, an odorant, an opacifier, a suspending agent, a binder, a filler, a plasticizer, and a lubricant.

61. The pharmaceutical composition of claim 1, which further comprises an amount of an enzyme inhibiting agent sufficient to at least partially inhibit enzymatic degradation of the polysaccharide drug.

62. The pharmaceutical composition of claim 61, wherein the enzyme inhibitor is solubilized or suspended in the carrier.

63. The pharmaceutical composition of claim 1, which further comprises an aqueous medium comprising water, an aqueous palatable diluent or an aqueous beverage.

64. The pharmaceutical composition of claim 63, wherein the polysaccharide drug is provided to the composition in the aqueous medium.

65. The pharmaceutical composition of claim 63, wherein the aqueous medium further comprises an amount of an enzyme inhibiting agent sufficient to at least partially inhibit enzymatic degradation of the polysaccharide drug.

66. The pharmaceutical composition of claim 1 in the form of a preconcentrate in a liquid, semi-solid, or solid form, or as an aqueous or organic diluted preconcentrate.

67. The pharmaceutical composition of claim 1, wherein the polysaccharide drug is solubilized in the carrier.

68. The pharmaceutical composition of claim 1, wherein the polysaccharide drug is suspended in the carrier.

69. The pharmaceutical composition of claim 1, wherein the polysaccharide drug is partially suspended and partially solubilized in the carrier.

70. The pharmaceutical composition of claim 1, wherein the composition is substantially free of water.

71. A dosage form comprising the pharmaceutical composition of claim 1 processed by a technique selected from the group consisting of lyophilization, encapsulation, extruding, compression, melting, molding, spraying, coating, comminution, mixing, homogenization, sonication, granulation, and combinations thereof.

72. A dosage form comprising the pharmaceutical composition of claim 1, wherein the dosage form is selected from the group consisting of a pill, capsule, caplet, tablet, granule, bead and powder.

73. The dosage form of claim 72, comprising a capsule.

74. The dosage form of claim 73, wherein the capsule is selected from the group consisting of a starch capsule, a cellulosic capsule, a hard gelatin capsule and a soft gelatin capsule.

75. The dosage form of claim 74, wherein the capsule is selected from the group consisting of a starch capsule, a cellulosic capsule, and a soft gelatin capsule.

76. The dosage form of claim 72, which further comprises an enteric coating, a seal coating, or both.

77. A dosage form comprising the pharmaceutical composition of claim 1, wherein the dosage form is selected from the group consisting of a solution, suspension, emulsion, cream, ointment, lotion, suppository, spray, aerosol, paste, gel, drops, douche, ovule, wafer, troche, cachet, syrup and elixir.

78. A dosage form comprising a multiparticulate carrier coated onto a substrate with the pharmaceutical composition of claim 1.

79. The dosage form of claim 78, wherein the substrate is selected from the group consisting of a particle, a granule and a bead, and is formed of a material selected from the group consisting of the polysaccharide drug, a pharmaceutically acceptable material, and a mixture thereof.

80. The dosage form of claim 78, wherein the multiparticulate carrier is coated with a coating selected from the group consisting of an enteric coating, a seal coating, and a mixture thereof.

81. The dosage form of claim 77, wherein the dosage form is further processed by a technique selected from the group consisting of encapsulation, compression, extrusion or molding.

82. The dosage form of claim 77, wherein the dosage form is encapsulated in a capsule selected from the group consisting of a starch capsule, a cellulosic capsule, a hard gelatin capsule, and a soft gelatin capsule.

83. The dosage form of claim 82, wherein the dosage form is encapsulated in a capsule selected from the group consisting of a starch capsule, a cellulosic capsule, and a soft gelatin capsule.

84. A pharmaceutical composition comprising: (a) a carrier comprising a triglyceride and at least two surfactants, at least one of the surfactants being hydrophilic; and (b) a therapeutically effective amount of a polysaccharide drug, wherein the triglyceride and the surfactants are present in amounts such that upon mixing with an aqueous medium in an aqueous medium to carrier ratio of about 100:1 by weight, the carrier forms an aqueous dispersion having an average particle size less than about 200 nm.

85. A pharmaceutical composition comprising: (a) a carrier comprising a triglyceride, at least one hydrophilic surfactant, and at least one hydrophobic surfactant; and (b) a therapeutically effective amount of a polysaccharide drug, wherein the triglyceride and surfactants are present in amounts such that upon mixing with an aqueous medium in an aqueous medium to carrier ratio of about 100:1 by weight, the carrier forms a clear aqueous dispersion having an absorbance of less than about 0.3 at 400 nm.

86. A pharmaceutical composition comprising: (a) a therapeutically effective amount of a polysaccharide drug; and (b) a carrier comprising a triglyceride and at least two surfactants, at least one of the surfactants being hydrophilic, wherein the triglyceride and surfactants are present in amounts such that upon mixing with an aqueous medium in an aqueous medium to carrier ratio of about 100:1 by weight, the carrier forms a clear aqueous dispersion having an absorbance of less than about 0.3 at 400 nm, and wherein the triglyceride is present in an amount greater than the amount of the triglyceride that remains solubilized in an aqueous dispersion of the triglyceride and a carrier having only one surfactant, the surfactant being hydrophilic, and having the same total surfactant concentration.

87. A pharmaceutical composition comprising: (a) a therapeutically effective amount of a polysaccharide drug; and (b) a carrier comprising a triglyceride, at least one hydrophilic surfactant, and at least one hydrophobic surfactant, wherein the triglyceride and surfactants are present in amounts such that upon mixing with an aqueous medium in an aqueous medium to carrier ratio of about 100:1 by weight, the carrier forms a clear aqueous dispersion having an absorbance of less than about 0.3 at 400 nm, and wherein the triglyceride is present in an amount greater than the amount of the triglyceride that remains solubilized in an aqueous dispersion of the triglyceride and one surfactant, the surfactant being hydrophilic, and having the same total surfactant concentration.

88. A method of treating a mammalian patient with a polysaccharide drug, the method comprising: (a) providing an initial dosage form of a pharmaceutical composition having a carrier comprising a triglyceride and at least two surfactants, at least one of the surfactants being hydrophilic wherein the triglyceride and surfactants are present in amounts such that upon mixing with an aqueous medium in an aqueous medium to carrier ratio of about 100:1 by weight, the carrier forms a clear aqueous dispersion having an absorbance of less than about 0.3 at 400 nm. (b) providing a polysaccharide drug; and (c) administering said dosage form to said animal.

89. The method of claim 88, further comprising providing at least one additional therapeutic agent selected from the group consisting of platelet aggregation inhibitors, platelet antagonists, anticoagulants, fibrinolytic agents and combinations thereof.

90. The method of claim 88, further comprising providing at least one additional therapeutic agent selected from the group consisting of aspirin, clopidrogel, ticlidopine, dipyridamole, coumarins, COX inhibitors and combinations thereof.

91. The method of claim 88, wherein the polysaccharide drug is in the initial dosage form.

92. The method of claim 88, wherein the polysaccharide drug is in a second dosage form.

93. The method of claim 91, wherein the at least one additional therapeutic agent is in the initial dosage form.

94. The method of claim 92, wherein the at least one additional therapeutic agent is in the second dosage form.

95. The method of claim 91, wherein the at least one additional therapeutic agent is in a second dosage form.

96. The method of claim 92, wherein the at least one additional therapeutic agent is in the initial dosage form.

97. The method of claim 88, wherein the dosage form is processed by a technique selected from the group consisting of lyophilization, encapsulation, extruding, compression, melting, molding, spraying, coating, comminution, mixing, homogenization, sonication, granulation, and combinations thereof.

98. The method of claim 88, wherein the dosage form is selected from the group consisting of a pill, capsule, caplet, tablet, granule, bead and powder.

99. The method of claim 98, wherein the dosage from is a capsule.

100. The method of claim 99, wherein the capsule is selected from the group consisting of a starch capsule, a cellulosic capsule, a hard gelatin capsule and a soft gelatin capsule.

101. The method of claim 100, wherein the capsule is selected from the group consisting of a starch capsule, a cellulosic capsule, and a soft gelatin capsule.

102. The method of claim 99, wherein the capsule further comprises a coating selected from the group consisting of an enteric coating, a seal coating, and a combination thereof.

103. The method of claim 88, wherein the dosage form is selected from the group consisting of a solution, suspension, emulsion, cream, ointment, lotion, suppository, spray, aerosol, paste, gel, drops, douche, ovule, wafer, troche, cachet, syrup and elixir.

104. The method of claim 88, wherein the dosage form comprises a multiparticulate carrier coated onto a substrate with the pharmaceutical composition.

105. The method of claim 104, wherein the substrate is selected from the group consisting of a particle, a granule and a bead, and is formed of a material selected from the group consisting of the polysaccharide drug, a pharmaceutically acceptable material and a mixture thereof.

106. The method of claim 104, wherein the multiparticulate carrier is coated with a coating selected from the group consisting of an enteric coating, a seal coating, and a combination thereof.

107. The method of claim 104, wherein the dosage form is further processed by encapsulation, compression, extrusion or molding.

108. The method of claim 104, wherein the dosage form is a starch capsule, a cellulosic capsule, a hard gelatin capsule, or a soft gelatin capsule.

109. The method of claim 104, wherein the dosage form is a starch capsule, a cellulosic capsule, or a soft gelatin capsule.

110. The method of claim 88, wherein the polysaccharide drug is provided by solubilizing the therapeutic agent in the triglyceride, in the carrier, or in both the triglyceride and the carrier.

111. The method of claim 88, wherein the polysaccharide drug is provided separately from the dosage form of the pharmaceutical composition.

112. The method of claim 88, wherein the dosage form is administered by a route selected from the group consisting of oral, parenteral, buccal, topical, transdermal, ocular, pulmonary, vaginal, rectal and transmucosal.

113. The method of claim 88, wherein the mammalian patient is a human.

114. The method of claim 88, wherein the polysaccharide drug is solubilized in the carrier.

115. The method of claim 88, wherein the polysaccharide drug is suspended in the carrier.

116. The method of claim 88, wherein the composition is substantially free of water.

117. The method of claim 88, wherein the mammalian patient is in need of the prevention of blood coagulation or the treatment of thrombosis.

118. A method of treating a mammalian patient with a polysaccharide drug, the method comprising: (a) providing a dosage form of a pharmaceutical composition having a carrier comprising a triglyceride and at least two surfactants, at least one of the surfactants being hydrophilic, wherein the triglyceride and surfactants are present in amounts such that upon mixing with an aqueous medium in an aqueous medium to carrier ratio of about 100:1 by weight, the carrier forms a clear aqueous dispersion having an absorbance of less than about 0.3 at 400 nm; and (b) administering the dosage form to the mammalian patient.

119. The method of claim 118, wherein the mammalian patient is in need of prevention of blood coagulation or treatment of thrombosis.

120. A method for increasing the loading capacity of a pharmaceutical composition comprising the steps of: providing a pharmaceutical composition comprised of (a) a carrier comprising a triglyceride and a first surfactant, and (b) a therapeutically effective amount of a polysaccharide drug; and adding an absorption-enhancing amount of a second surfactant to the pharmaceutical composition, the second surfactant comprising a hydrophobic surfactant, wherein said aborption-enhancing amount is effective to increase the loading capacity of the pharmaceutical composition, wherein the triglyceride and the combined surfactants are present in amounts such that upon mixing with an aqueous medium in an aqueous medium to triglyceride and surfactants ratio of about 100:1 by weight, the triglyceride and surfactants form a clear aqueous dispersion.

121. The method of claim 120, wherein the clear aqueous dispersion formed has an average particle size of less than about 200 nm.

122. The method of claim 120, wherein the clear aqueous dispersion formed has an absorbance of less than about 0.3 at 400 nm.
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