PHARMACEUTICAL COMPOSITIONS

• US 20070048384A1
• Filed: 06/07/2006
• Published: 03/01/2007
• Est. Priority Date: 08/26/2005
• Status: Abandoned Application

• Current Assignee: Abbott Laboratories
• Original Assignee: Abbott Laboratories
• Inventors: Breitenbach, Joerg, Rosenberg, Joerg, Degenhardt, Matthias, Marsh, Kennan, Garg, Rajeev, Fastnacht, Katja
• Application Number:
  US11/422,728
• Publication Number:
  US 20070048384A1
• Time in Patent Office: Days
• US Class Current: 424/489
• CPC Class Codes: A61K 31/235 having an aromatic ring attached to a carboxyl group
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 47/44 Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin synthetic glycerides, e.g. medium-chain triglycerides, A61K47/14
• CPC Class Codes: A61K 9/10 Dispersions; Emulsions A61K9/06 takes precedence; composition of dispersions, emulsions A61K47/00
• CPC Class Codes: A61K 9/2027 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Abstract

The present invention relates to a pharmaceutical composition comprising primarily amorphous 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester.

Claims

1. An oral pharmaceutical composition comprising at least one active agent and at least one pharmaceutically acceptable polymer, wherein the active agent is primarily amorphous 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid,1-methylethyl ester.

2. The composition of claim 1 wherein said composition lacks a significant food effect on oral administration.

3. The composition of claim 1 wherein said composition exhibits improved bioavailability when compared to a 200 mg oral pharmaceutical composition comprising crystalline 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid,1-methylethyl ester.

4. The composition of claim 1 wherein the 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid,1-methylethyl ester is present in the composition in an amount of from about 5 weight percent to about 65 weight percent of the total composition.

5. The composition of claim 4 wherein the 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid,1-methylethyl ester is present in the composition in the amount of from about 10 weight percent to about 50 weight percent of the total composition.

6. The composition of claim 1 wherein said composition further comprises at least one pharmaceutically acceptable surfactant.

7. The composition of claim 1 wherein said composition is in the form of a solid dispersion.

8. The composition of claim 7 wherein said solid dispersion, upon contact with an aqueous medium forms a suspension comprising particles having a size of from about 100 nm to about 10,000 nm.

9. The composition of claim 8 wherein the particles in the suspension comprise crystalline 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid,1-methylethyl ester.

10. The composition of claim 8 wherein the particles in the suspension comprise amorphous 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid,1-methylethyl ester.

11. The composition of claim 8 wherein the particles in the suspension comprise a mixture of crystalline and amorphous 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid,1-methylethyl ester.

12. The composition of claim 1 wherein the pharmaceutically acceptable polymer is an ionic cellulosic polymer.

13. The composition of claim 12 wherein the ionic cellulosic polymer is selected from the group consisting of:

carboxymethylcellulose (CMC), carboxymethylcellulose (CMC) salts, carboxyethylcellulose (CEC), hydroxyethylmethylcellulose acette phthalate, hydroxyethylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose succinate, hydroxypropylcellulose acetate phthalate (HPCAP), hydroxypropylcellulose acetate succinate (HPCAS), hydroxypropylmethylcellulose acetate phthalate (HPMCAP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), hydroxypropylmethylcellulose acetate trimellitate (HPMCAT), hydroxypropylmethylcellulose acetate phthalate (HPMCAP), hydroxypropylcellulose butyrate phthalate, carboxymethylethylcellulose and salts thereof, cellulose acetate phthalate (CAP), methylcellulose acetate phthalate, cellulose acetate trimellitate (CAT), cellulose acetate terephthalate, cellulose acetate isophthalate, cellulose propionate phthalate, cellulose propionate trimellitate, cellulose butyrate trimellitate and combinations thereof.

14. The composition of claim 1 wherein the pharmaceutically acceptable polymer is a nonionic cellulosic polymer.

15. The composition of claim 14 wherein the nonionic cellulosic polymer is selected from the group consisting of methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate, hydroxyethylmethylcellulose, hydroxyethylcellulose acetate, hydroxyethylethylcellulose and combinations thereof.

16. The composition of claim 1 wherein the pharmaceutically acceptable polymer is selected from the group consisting of:

methyacrylic acid copolymers, aminoalkyl methacrylate copolymers, carboxylic acid functionalized polymethacrylates, amine-functionalized polymethacrylates, poly(vinyl acetal) diethylaminoacetate, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl alcohol/polyvinyl acetate copolymers and combinations thereof.

17. The composition of claim 16 wherein the polymer is selected from the group consisting of polyvinyl pyrrolidone, polyvinyl alcohol/polyvinyl acetate copolymers and combinations thereof.

18. The composition of claim 1 wherein the pharmaceutically acceptable polymer is copovidone.

19. The composition of claim 1 wherein the pharmaceutically acceptable polymer is selected from the group consisting of polyethyleneoxide polyethylene glycol/polypropylene glycol copolymers, polyethylene/polyvinyl alcohol copolymers, dextran, pullulan, acacia, tragacanth, sodium alginate, propylene glycol alginate, agar powder, gelatin, starch, processed starch, glucomman, chitosan and combinations thereof.

20. The composition of claim 1 wherein the pharmaceutically acceptable polymer is present in the composition in an amount of from about 20 weight percent to about 95 weight percent.

21. The composition of claim 20 wherein the pharmaceutically acceptable polymer is present in the composition in an amount of from about 30 weight percent to about 75 weight percent.

22. The composition of claim 6 wherein the pharmaceutically acceptable surfactant has a hydrophile-lipophile balance value from about 1 to about 20.

23. The composition of claim 6 wherein the pharmaceutically acceptable surfactant is present in the composition in an amount of from about 0.5 weight percent to about 20 weight percent.

24. The composition of claim 23 wherein the pharmaceutically acceptable surfactant is present in the composition in an amount of from about 1 weight percent to about 8 weight percent.

25. The composition of claim 6 wherein the pharmaceutically acceptable surfactant is selected from the group consisting of:

triglycerides of caprylic/capric acid, propylene glycol laurate, glyceryl and polyethylene glycol esters, sorbitan monooleate, sorbitan monolaurate, mono or diglycerides of caprylic/capric acid in glycerol, sorbitan sesquioleate, polyoxyethylene (2) oleyl ether, polyoxypropylene 15 stearyl ether, unsaturated polyglycolyzed glycerides, glyceryl monolinoleate, decaglyceryl decaoleate, triisostearin polyethylene glycol 6 esters, triglyceryl monoleate, glyceryl monooleate, sorbide dioleate, polyoxyethylene castor wax, polyglycolysed glycerides, polyglycolysed glycerides, saturated C₈-C₁₀ polyglycolysed glycerides, polyoxyethlene (20) sorbitan monooleate, polyoxyethylene (20) sorbitan trioleate, copolymers of propylene oxide and ethylene oxide, polyoxyl 35 castor oil, palm kemelamide, polyoxyethylene 4 lauryl ether, polyoxyethylene (20) isohexadecyl ether, sorbitan monolaurate, alcohol ethoxylate, polyoxyethylene 80 sorbitan monolaurate, hexaglyceryl dioleate, polysorbate 80, sucrose laurate, quaternary ammonium salt, polyoxyethylene sorbitol hexaoleate, caprylic/capric acid partial glyceride-6 EO, polyglyceryl 4 oleate, and combinations thereof.

26. The composition of claim 25 wherein the pharmaceutically acceptable surfactant is selected from the group consisting of:

triglycerides of caprylic/capric acid, glyceryl and polyethylene glycol esters, sorbitan monolaurate, polyoxyethylene (20) sorbitan trioleate, polyoxyl 35 hydrogenated castor oil and combinations thereof.

27. The composition of claims 26 wherein the pharmaceutically acceptable surfactant is triglycerides of caprylic/capric acid and polyoxyl 35 hydrogenated castor oil.

28. The composition of claim 6 wherein the pharmaceutically acceptable surfactant is distillated acetylated monoglycerides, distilled acetylated monoglycerides, propylene glycol and mono or dicaprylate, polyoxypropylene (15) stearyl alcohol, glyceryl tricaprylate/caprate, olive oil, caprylic/capric triglycerides, sesame oil, oleyl alcohol and combinations thereof.

29. The composition of claim 1 wherein the composition further comprises at least one solubility-enhancing agent.

30. The composition of claim 29 wherein the solubility-enhancing agent is present in the composition in the amount of from about 1 weight percent to about 40 weight percent.

31. The composition of claim 30 wherein the solubility-enhancing agent is present in the composition in the amount of from about 1 weight percent to about 10 weight percent.

32. The composition of claim 29 wherein the solubility-enhancing agent is at least one surfactant, at least one pH control agent, glycerides, partial glycerides, glyceride derivatives, polyoxyethylene and polypropylene esters and copolymers, sorbitan esters, polyoxyethylene sorbitan esters, carbonate salts, alkyl sulfonates, cyclodextrins and combinations thereof.

33. The composition of claim 32 wherein the pH control agent is a buffer, organic acid, organic acid salts, organic bases, inorganic bases and combinations thereof.

34. The composition of claim 1 wherein the composition further comprises a at least one coating, tableting aid, water-soluble polymer, filler, binder, pigment, distintegrant, antioxidant, lubricant, flow aid, flavorant.

35. A method of treating dyslipidemia in a subject in need of treatment thereof, the method comprising the step of:

administering to said subject a therapeutically effective amount of the pharmaceutically acceptable composition of claim 1.

36. A method of treating dyslipoproteinemia in a subject in need of treatment thereof, the method comprising the step of:

administering to said subject a therapeutically effective amount of the pharmaceutically acceptable composition of claim 1.

74. The composition of claim 8, wherein the particles remain stable for a period of from about five (5) minutes to about two (2) hours.

37. An oral pharmaceutical composition comprising at least one active agent and at least one pharmaceutically acceptable polymer, wherein the active agent is primarily amorphous 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid,1-methylethyl ester that upon contact with aqueous media forms a suspension.

38. An oral pharmaceutical composition comprising at least one active agent, at least one pharmaceutically acceptable surfactant and at least one pharmaceutically acceptable polymer, wherein the active agent is primarily amorphous 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid,1-methylethyl ester.

39. The composition of claim 38 wherein said composition lacks a significant food effect on oral administration.

40. The composition of claim 38 wherein said composition exhibits improved bioavailability when compared to a 200 mg oral pharmaceutical composition comprising crystalline 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid,1-methylethyl ester.

41. The composition of claim 38 wherein the 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid,1-methylethyl ester is present in the composition in an amount of from about 5 weight percent to about 65 weight percent of the total composition.

42. The composition of claim 41 wherein the 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid,1-methylethyl ester is present in the composition in the amount of from about 10 weight percent to about 50 weight percent of the total composition.

43. The composition of claim 38 wherein said composition is in the form of a solid dispersion.

44. The composition of claim 43 wherein said solid dispersion, upon contact with an aqueous medium forms a suspension comprising particles having a size of from about 100 nm to about 10,000 nm.

45. The composition of claim 44 wherein the particles in the suspension comprise crystalline 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid,1-methylethyl ester.

46. The composition of claim 44 wherein the particles in the suspension comprise amorphous 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid,1-methylethyl ester.

47. The composition of claim 44 wherein the particles in the suspension comprise a mixture of crystalline and amorphous 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid,1-methylethyl ester.

48. The composition of claim 38 wherein the pharmaceutically acceptable polymer is an ionic cellulosic polymer.

49. The composition of claim 48 wherein the ionic cellulosic polymer is selected from the group consisting of:

carboxymethylcellulose (CMC), carboxymethylcellulose (CMC) salts, carboxyethylcellulose (CEC), hydroxyethylmethylcellulose acette phthalate, hydroxyethylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose succinate, hydroxypropylcellulose acetate phthalate (HPCAP), hydroxypropylcellulose acetate succinate (HPCAS), hydroxypropylmethylcellulose acetate phthalate (HPMCAP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), hydroxypropylmethylcellulose acetate trimellitate (HPMCAT), hydroxypropylmethylcellulose acetate phthalate (HPMCAP), hydroxypropylcellulose butyrate phthalate, carboxymethylethylcellulose and salts thereof, cellulose acetate phthalate (CAP), methylcellulose acetate phthalate, cellulose acetate trimellitate (CAT), cellulose acetate terephthalate, cellulose acetate isophthalate, cellulose propionate phthalate, cellulose propionate trimellitate, cellulose butyrate trimellitate and combinations thereof.

50. The composition of claim 38 wherein the pharmaceutically acceptable polymer is a nonionic cellulosic polymer.

51. The composition of claim 50 wherein the nonionic cellulosic polymer is selected from the group consisting of methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate, hydroxyethylmethylcellulose, hydroxyethylcellulose acetate, hydroxyethylethylcellulose and combinations thereof.

52. The composition of claim 38 wherein the pharmaceutically acceptable polymer is selected from the group consisting of:

methyacrylic acid copolymers, aminoalkyl methacrylate copolymers, carboxylic acid functionalized polymethacrylates, amine-functionalized polymethacrylates, poly(vinyl acetal) diethylaminoacetate, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl alcohol/polyvinyl acetate copolymers and combinations thereof.

53. The composition of claim 52 wherein the polymer is selected from the group consisting of polyvinyl pyrrolidone, polyvinyl alcohol/polyvinyl acetate copolymers and combinations thereof.

54. The composition of claim 38 wherein the pharmaceutically acceptable polymer is copovidone.

55. The composition of claim 38 wherein the pharmaceutically acceptable polymer is selected from the group consisting of polyethyleneoxide polyethylene glycol/polypropylene glycol copolymers, polyethylene/polyvinyl alcohol copolymers, dextran, pullulan, acacia, tragacanth, sodium alginate, propylene glycol alginate, agar powder, gelatin, starch, processed starch, glucomman, chitosan and combinations thereof.

56. The composition of claim 38 wherein the pharmaceutically acceptable polymer is present in the composition in an amount of from about 20 weight percent to about 95 weight percent.

57. The composition of claim 56 wherein the pharmaceutically acceptable polymer is present in the composition in an amount of from about 30 weight percent to about 75 weight percent.

58. The composition of claim 38 wherein the pharmaceutically acceptable surfactant has a hydrophile-lipophile balance value from about 1 to about 20.

59. The composition of claim 38 wherein the pharmaceutically acceptable surfactant is present in the composition in an amount of from about 0.5 weight percent to about 20 weight percent.

60. The composition of claim 59 wherein the pharmaceutically acceptable surfactant is present in the composition in an amount of from about 1 weight percent to about 8 weight percent.

61. The composition of claim 38 wherein the pharmaceutically acceptable surfactant is selected from the group consisting of:

triglycerides of caprylic/capric acid, propylene glycol laurate, glyceryl and polyethylene glycol esters, sorbitan monooleate, sorbitan monolaurate, mono or diglycerides of caprylic/capric acid in glycerol, sorbitan sesquioleate, polyoxyethylene (2) oleyl ether, polyoxypropylene 15 stearyl ether, unsaturated polyglycolyzed glycerides, glyceryl monolinoleate, decaglyceryl decaoleate, triisostearin polyethylene glycol 6 esters, triglyceryl monoleate, glyceryl monooleate, sorbide dioleate, polyoxyethylene castor wax, polyglycolysed glycerides, polyglycolysed glycerides, saturated C₈-C₁₀ polyglycolysed glycerides, polyoxyethlene (20) sorbitan monooleate, polyoxyethylene (20) sorbitan trioleate, copolymers of propylene oxide and ethylene oxide, polyoxyl 35 castor oil, palm kemelamide, polyoxyethylene 4 lauryl ether, polyoxyethylene (20) isohexadecyl ether, sorbitan monolaurate, alcohol ethoxylate, polyoxyethylene 80 sorbitan monolaurate, hexaglyceryl dioleate, polysorbate 80, sucrose laurate, quaternary ammonium salt, polyoxyethylene sorbitol hexaoleate, caprylic/capric acid partial glyceride-6 EO, polyglyceryl 4 oleate, and combinations thereof.

62. The composition of claim 61 wherein the pharmaceutically acceptable surfactant is selected from the group consisting of:

triglycerides of caprylic/capric acid, glyceryl and polyethylene glycol esters, sorbitan monolaurate, polyoxyethylene (20) sorbitan trioleate, polyoxyl 35 hydrogenated castor oil and combinations thereof.

63. The composition of claims 61 wherein the pharmaceutically acceptable surfactant is triglycerides of caprylic/capric acid and polyoxyl 35 hydrogenated castor oil.

64. The composition of claim 38 wherein the pharmaceutically acceptable surfactant is distillated acetylated monoglycerides, distilled acetylated monoglycerides, propylene glycol and mono or dicaprylate, polyoxypropylene (15) stearyl alcohol, glyceryl tricaprylate/caprate, olive oil, caprylic/capric triglycerides, sesame oil, oleyl alcohol and combinations thereof.

65. The composition of claim 38 wherein the composition further comprises at least one solubility-enhancing agent.

66. The composition of claim 65 wherein the solubility-enhancing agent is present in the composition in the amount of from about 1 weight percent to about 40 weight percent.

67. The composition of claim 66 wherein the solubility-enhancing agent is present in the composition in the amount of from about 1 weight percent to about 10 weight percent.

68. The composition of claim 65 wherein the solubility-enhancing agent is at least one pH control agent, glycerides, partial glycerides, glyceride derivatives, polyoxyethylene and polypropylene esters and copolymers, sorbitan esters, polyoxyethylene sorbitan esters, carbonate salts, alkyl sulfonates, cyclodextrins and combinations thereof.

69. The composition of claim 68 wherein the pH control agent is a buffer, organic acid, organic acid salts, organic bases, inorganic bases and combinations thereof.

70. The composition of claim 38 wherein the composition further comprises a at least one coating, tableting aid, water-soluble polymer, filler, binder, pigment, distintegrant, antioxidant, lubricant, flow aid, flavorant.

71. A method of treating dyslipidemia in a subject in need of treatment thereof, the method comprising the step of:

administering to said subject a therapeutically effective amount of the pharmaceutically acceptable composition of claim 38.

72. A method of treating dyslipoproteinemia in a subject in need of treatment thereof, the method comprising the step of:

administering to said subject a therapeutically effective amount of the pharmaceutically acceptable composition of claim 38.

75. The composition of claim 44, wherein the particles remain stable for a period of from about five (5) minutes to about two (2) hours.

73. An oral pharmaceutical composition comprising at least one active agent and at least one pharmaceutically acceptable polymer, wherein the active agent is primarily amorphous 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid,1-methylethyl ester that upon contact with aqueous media forms a suspension.