NSAID formulations, based on highly adaptable aggregates, for improved transport through barriers and topical drug delivery

• US 7,473,432 B2
• Filed: 02/04/2003
• Issued: 01/06/2009
• Est. Priority Date: 10/11/2002
• Status: Expired due to Fees

• Current Assignee: IDEA AG
• Original Assignee: IDEA AG
• Inventors: Cevc, Gregor, Vierl, Ulrich
• Primary Examiner(s): Kishore; Gollamudi
• Application Number:
  US10/357,617
• Publication Number:
  US 20040071767A1
• Time in Patent Office: 2,163 Days
• Field of Search: 424/450
• US Class Current: 424/450
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 31/196 the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
• CPC Class Codes: A61K 31/405 Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
• CPC Class Codes: A61K 31/5415 ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
• 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 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/16 containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
• CPC Class Codes: A61K 47/20 containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
• 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 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• CPC Class Codes: A61K 9/127 Liposomes
• CPC Class Codes: A61K 9/1272 with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids with cholesterol as the only non-phosphatidyl surfactant A61K9/127; lipids as modifying agent A61K47/543
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Abstract

The invention describes novel formulations of nonsteroidal anti-inflammatory drugs (NSAIDs) based on complex aggregates with at least three amphipatic components suspended in a suitable, e.g. pharmaceutically acceptable, polar liquid medium. A suitably ionised NSAID is one of the two, amongst said three, components that tends to destabilise lipid membranes, the other system component with such activity being typically a surfactant. In contrast, the remaining amongst said at least three amphipatic components typically forms a stable lipid membrane on it'"'"'s own. An essential characteristics of the resulting, relatively large, aggregates is an improved ability to penetrate pores, in a semi-permeable barrier, at least 30%, and often much smaller than the average diameter of the complex aggregate. This enables said aggregates to mediate NSAID transport through semi-permeable barriers including mammalian skin. As a result of the skin penetration by NSAID loaded large aggregates, the drug delivered transcutaneously with such carriers gets deeper into the tissue than the corresponding NSAID from a solution on the skin surface. This is believed to be due to the special ability of suitable large carriers to bypass the local sink of blood capillaries at the epidermal-dermal junction in the skin. The carrier-mediated delivery of locally applied NSAIDs thus allows therapy of deep tissues under the drug administration site, which is medically highly desirable.

Claims

1. A vesicular composition comprising:

1) vesicles having a lipid bilayer and consisting essentially of;

i) a phosphatidylcholine;

ii) a polyethyleneglycol-sorbitan-monooleate, a polyoxyethylene-oleoyl ether, or a nonaethyleneglycoloctylphenyl ether surfactant; and

iii) a salt of an NSAID wherein said NSAID is diclofenac, ibuprofen or ketoprofen; and

2) a pharmaceutically acceptable, polar liquid medium, wherein

the phosphatidylcholine and the surfactant of the vesicles are present in a molar ratio of between about 20/1 and about 7.5/1,

the molar ratio of phosphatidylcholine to NSAID is between about 10/1 to about 1/1,

the lipid bilayer is in the fluid lamellar phase, and

the pH of the composition is above the pKa of the NSAID.

2. The composition of claim 1, wherein the phosphatidylcholine is from soy bean, coconut, olive, safflower, or sunflower, linseed, evening primrose, primrose, or castor oil.

3. The composition of claim 1, wherein the total dry mass of the phosphatidylcholine, the surfactant, and the NSAID is between 0.01 weight-% and 50 weight-% of the composition.

4. The composition of claim 1, further comprising a lower aliphatic alcohol.

5. The composition of claim 4, wherein the alcohol is n-propanol, isopropanol, 2-propanol, n-butanol, 2-butanol, 1,2-propanediol, 1,2-butanediol, or ethanol.

6. The composition of claim 1, wherein the pH of the composition is between 6.4 and 8.3.

7. The composition of claim 1, wherein the ionic strength of the composition is between 0.005 and 0.3.

8. The composition of claim 1, wherein the viscosity of the composition is between 50 mPas and 30,000 mPas.

9. A method for treating peripheral pain or inflammation comprising applying the composition of claim 1 to the skin of a warm blooded mammal.

10. A non-occlusive patch comprising the composition of claim 1.

11. The composition of claim 1, wherein the total dry mass of, the polyethyleneglycol-sorbitan-monooleate, polyoxyethylene-oleoyl ether, or nonaethyleneglycol octylphenyl ether surfactant;

and the NSAID is between 0.01 weight-% and 50 weight-%.

12. The composition of claim 1, wherein the phosphatidylcholine is soy phosphatidylcholine or egg lecithin.

13. The composition of claim 1 wherein the salt of the NSAID is the sodium salt of ketoprofen.

14. The composition of claim 1, wherein the phosphatidylcholine is soy phosphatidylcholine, the surfactant is polyethyleneglycol-sorbitan-monooleate, and the salt of the NSAID is the sodium salt of ketoprofen.

15. The composition of claim 1, wherein the molar ratio of phosphatidylcholine to NSAID is between about 3/1 to about 1/1.

16. The composition of claim 15, wherein the molar ratio of phosphatidylcholine to NSAID is between about 2.5/1 to about 1/1.

17. The composition of claim 16, wherein the molar ratio of phosphatidylcholine to NSAID is between about 2/1 to about 1/1.

18. The composition of claim 17, wherein the molar ratio of phosphatidylcholine to NSAID is about 1/1.

19. The composition of claim 14, wherein the molar ratio of phosphatidylcholine to NSAID is between about 3/1 to about 1/1.

20. The composition of claim 19, wherein the molar ratio of phosphatidylcholine to NSAID is between about 2.5/1 to about 1/1.

21. The composition of claim 20, wherein the molar ratio of phosphatidylcholine to NSAID is between about 2/1 to about 1/1.

22. The composition of claim 21, wherein the molar ratio of phosphatidylcholine to NSAID is about 1/1.

23. The method of claim 9, wherein the molar ratio of phosphatidylcholine to NSAID is between about 3/1 to about 1/1.

24. The method of claim 23, wherein the molar ratio of phosphatidylcholine to NSAID is between about 2.5/1 to about 1/1.

25. The method of claim 24, wherein the molar ratio of phosphatidylcholine to NSAID is between about 2/1 to about 1/1.

26. The method of claim 25, wherein the molar ratio of phosphatidylcholine to NSAID is about 1/1.

27. A method for treating peripheral pain or inflammation comprising applying the patch of claim 1, to the skin of a warm blooded mammal.

28. The method of claim 27, wherein the molar ratio of phosphatidylcholine to NSAID is between about 3/1 to about 1/1.

29. The method of claim 28, wherein the molar ratio of phosphatidylcholine to NSAID is between about 2.5/1 to about 1/1.

30. The method of claim 29, wherein the molar ratio of phosphatidylcholine to NSAID is between about 2/1 to about 1/1.

31. The method of claim 30, wherein the molar ratio of phosphatidylcholine to NSAID is about 1/1.

32. The composition of claim 1, wherein the pH of the composition is between 0.2 and 2.2 pH units above the pKa of the NSAID.

33. The composition of claim 32, wherein the pH of the composition is between 0.5 and 1.9 pH units above the pKa of the NSAID.

34. The composition of claim 33, wherein the pH of the composition is between 0.8 and 1.6 pH units above the pKa of the NSAID.

35. The composition of claim 1, wherein the phosphatidylcholine is from egg or soya beans.

36. The composition of claim 1, further comprising a thickening agent;

an antioxidant, or a microbicide.

37. The composition of claim 1, wherein the phosphatidylcholine and the surfactant are present in a molar ratio of between about 14/1 and about 10/1.

38. The composition of claim 1, wherein the pH is between 0.2 and 2.2 pH units above the pKa of the NSAID.

39. A method for treating peripheral pain or inflammation comprising applying the composition of claim 38, to the skin of a warm blooded mammal.

40. The method of claim 39, wherein the pH is between 0.2 and 2.2 pH units above the pKa of the NSAID.

41. A vesicular composition comprising:

1) vesicles consisting essentially of;

i) a phosphatidylcholine;

ii) a polyethyleneglycol-sorbitan-monooleate, a polyoxyethylene-oleoyl ether, or a nonaethyleneglycoloctylphenyl ether surfactant; and

iii) a salt of an NSAID wherein said NSAID is diclofenac, ibuprofen or ketoprofen; and

2) a pharmaceutically acceptable, polar liquid medium, wherein

the phosphatidylcholine and the surfactant of the vesicles are present in a molar ratio of between about 20/1 and about 7.5/1,

the molar ratio of phosphatidylcholine to NSAID is between about 10/1 to about 1/1,

the vesicles are capable of penetrating a barrier with pores having an average pore diameter at least 50% smaller than the average vesicle diameter before the penetration, and

the pH of the composition is above the pKa of the NSAID.

42. The composition of claim 41, wherein the phosphatidylcholine is from soy bean, coconut, olive, safflower, or sunflower, linseed, evening primrose, primrose, or castor oil.

43. The composition of claim 41 wherein the total dry mass of the phosphatidylcholine, the surfactant, and the NSAID is between 0.01 weight-% and 50 weight-% of the composition.

44. The composition of claim 41, further comprising a tower aliphatic alcohol.

45. The composition of claim 44, wherein the alcohol is n-propanol, isopropanol, 2-propanol, n-butanol, 2-butanol, 1,2-propanediol, 1,2-butanediol, or ethanol.

46. The composition of claim 41, wherein the pH of the composition is between 6.4 and 8.3.

47. The composition of claim 41, wherein the ionic strength of the composition is between 0.005 and 0.3.

48. The composition of claim 41, wherein the viscosity of the composition is between 50 mPa s and 30,000 mPa s.

49. The composition of claim 41, wherein the total dry mass of, the phosphatidylcholine;

the polyethyleneglycol-sorbitan-monooleate, polyoxyethylene-oleoyl ether, or nonaethyleneglycol octylphenyl ether surfactant; and

the NSAID is between 0.01 weight-% and 50 weight-%.

50. The composition of claim 41, wherein the phosphatidylcholine is soy phosphatidylcholine or egg lecithin.

51. The composition of claim 41 wherein the salt of the NSAID is the sodium salt of ketoprofen.

52. The composition of claim 41, wherein the molar ratio of phosphatidylcholine to NSATD is between about 3/1 to about 1/1.

53. The composition of claim 52, wherein the molar ratio of phosphatidylcholine to NSAID is between about 2.5/1 to about 1/1.

54. The composition of claim 53, wherein the molar ratio of phosphatidylcholine to NSAID is between about 2/1 to about 1/1.

55. The composition of claim 54, wherein the molar ratio of phosphatidylcholine to NSAID is about 1/1.

56. The composition of claim 41, wherein the phosphatidylcholine is soy phosphatidylcholine, the surfactant is polyethyleneglycol-sorbitan-monooleate, and the salt of the NSAID is the sodium salt of ketoprofen.

57. The composition of claim 56, wherein the molar ratio of phosphatidylcholine to NSAID is between about 3/1 to about 1/1.

58. The composition of claim 57, wherein the molar ratio of phosphatidylcholine to NSAID is between about 2.5/1 to about 1/1.

59. The composition of claim 58, wherein the molar ratio of phosphatidylcholine to NSAID is between about 2/1 to about 1/1.

60. The composition of claim 59, wherein the molar ratio of phosphatidylcholine to NSAID is about 1/1.

61. The composition of claim 41, wherein the pH of the composition is between 0.2 and 2.2 pH units above the pKa of the NSAID.

62. The composition of claim 61, wherein the pH of the composition is between 0.5 and 1.9 pH units above the pKa of the NSAID.

63. The composition of claim 62, wherein the pH of the composition is between 0.8 and 1.6 pH units above the pKa of the NSAID.

64. The composition of claim 41, wherein the phosphatidylcholine is from egg or soya beans.

65. The composition of claim 41, further comprising a thickening agent, an antioxidant, or a microbicide.

66. The composition of claim 41, wherein the phosphatidylcholine and the surfactant are present in a molar ratio of between about 14/1 and about 10/1.

67. The composition of claim 66, wherein the pH is between 0.2 and 2.2 pH units above the pKa of the NSAID.

68. A method for treating peripheral pain or inflammation comprising applying the composition of claim 41 to the skin of a warm blooded mammal.

69. The method of claim 68, wherein the molar ratio of phosphatidylcholine to NSAID is between about 3/1 to about 1/1.

70. The method of claim 69, wherein the molar ratio of phosphatidylcholine to NSAID is between about 2.5/1 to about 1/1.

71. The method of claim 70, wherein the molar ratio of phosphatidylcholine to NSAID is between about 2/1 to about 1/1.

72. The method of claim 71, wherein the molar ratio of phosphatidylcholine to NSAID is about 1/1.

73. A method for treating peripheral pain or inflammation comprising applying the composition of claim 66 to the skin of a warm blooded mammal.

74. The method of claim 73, wherein the pH is between 0.2 and 2.2 pH units above the pKa of the NSAID.

75. A non-occlusive patch comprising the composition of claim 41.

76. A method for treating peripheral pain or inflammation comprising applying the patch of claim 75 to the skin of a warm blooded mammal.

77. The method of claim 76, wherein the molar ratio of phosphatidylcholine to NSAID is between about 3/1 to about 1/1.

78. The method of claim 77, wherein the molar ratio of phosphatidylcholine to NSAID is between about 2.5/1 to about 1/1.

79. The method of claim 78, wherein the molar ratio of phosphatidylcholine to NSAID is between about 2/1 to about 1/1.

80. The method of claim 79, wherein the molar ratio of phosphatidylcholine to NSAID is about 1/1.