Fatty acid formulations for oral delivery of proteins and peptides, and uses thereof

• US 20060018874A1
• Filed: 07/19/2005
• Published: 01/26/2006
• Est. Priority Date: 07/19/2004
• Status: Active Grant

• Current Assignee: Biocon Limited (Biocon Incorporated)
• Original Assignee: Biocon Limited (Biocon Incorporated)
• Inventors: James, Kenneth D., Ferro, Michelle, Radhakrishnan, Balasingam, Ekwuribe, Nnochiri N., Aggarwal, Diti, Malkar, Navdeep B., Pavliv, Leo, Puskas, Monica, Miller, Mark A., Polowy, Karen
• Granted Patent: US 7,605,123 B2
• Time in Patent Office: Days
• US Class Current: 424/85.400
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 33/30 Zinc; Compounds thereof
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 47/69 the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
• CPC Class Codes: A61K 9/0095 Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches A61K9/0007 takes precedence; eatable gels or foams A61K9/0056; oral mucosa adhesive forms A61K9/006
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 5/48 of the pancreatic hormones
• CPC Class Codes: A61P 5/50 for increasing or potentiating the activity of insulin
• CPC Class Codes: C07K 14/62 Insulins

Abstract

Fatty acid compositions for administration of of pharmaceutical agents, such as proteins and peptides, protein and peptide conjugates, and/or cation-polypeptide conjugate complexes. In particular, the invention provides a solid pharmaceutical composition formulated for oral administration by ingestion, having from about 0.1 to about 75% w/w fatty acid component, where the fatty acid component comprises saturated or unsaturated C4, C5, C6, C7, C8, C9, C10, C11, or C12 fatty acids and/or salts of such fatty acids; and a therapeutic agent. Further, the invention provides a liquid pharmaceutical composition formulated for oral administration by ingestion, comprising: from about 0.1 to about 10% w/v fatty acid component, where the fatty acid component comprises saturated or unsaturated C4, C5, C6, C7, C8, C9, C10, C11, or C12 fatty acids and/or salts of such fatty acids; and a therapeutic agent.

Claims

1. A solid pharmaceutical composition formulated for oral administration by ingestion, comprising:

(a) from about 0.1 to about 75% w/w fatty acid component, where the fatty acid component comprises saturated or unsaturated C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, or C₁₂ fatty acids and/or salts of such fatty acids;

(b) a therapeutic agent.

2. The pharmaceutical composition of claim 1 comprising from about 5 to about 65% w/w fatty acid component.

3. The pharmaceutical composition of claim 1 comprising from about 40 to about 60% w/w fatty acid component.

4. The pharmaceutical composition of claim 1 where the therapeutic agent is a protein or peptide.

5. The pharmaceutical composition of claim 1 where the therapeutic agent is a protein or peptide having from 2 to 200 amino acids, from 10 to 65 amino acids, or from 25 to 55 amino acids.

6. The pharmaceutical composition of claim 1 where the therapeutic agent is a selected from the group consisting of insulin compounds, calcitonins, interferons, growth hormones, growth factors, GLP-1, PTH, somatostatins, LCRF, natriuretic peptides, BNP, ANP, exenatide, erythropoetins having less than 200 amino acids, antibody fragments, vaccines, and analogs of any of the foregoing.

7. The pharmaceutical composition of claim 1 where the therapeutic agent is a conjugated protein or peptide, an acylated protein or peptide, or a PEGylated protein or peptide.

8. The pharmaceutical composition of claim 1 where the therapeutic agent is a conjugated insulin compounds, calcitonins, interferons, growth hormones, growth factors, GLP-1, PTH, somatostatins, LCRF, natriuretic peptides, BNP, ANP, exenatide, erythropoetins having less than 200 amino acids, antibody fragments, vaccines, and analogs of any of the foregoing.

9. The pharmaceutical composition of claim 1 where the therapeutic agent is an insulin compound.

10. The pharmaceutical composition of claim 1 where the therapeutic agent is a complexed protein or peptide or a complexed conjugated protein or peptide.

11. The pharmaceutical composition of claim 1 where the therapeutic agent is a complexed insulin compound or a complexed conjugated insulin compound.

12. The pharmaceutical composition of claim 1 where the ionized or non-ionized fatty acid content of the composition is greater than about 90% w/w a single fatty acid, about 95% w/w a single fatty acid, or about 99% w/w a single fatty acid.

13. The pharmaceutical composition of claim 1 prepared to survive passage through the stomach without substantial loss of the therapeutic agent and to substantially completely dissolve in the intestine for delivery of the therapeutic agent.

14. The pharmaceutical composition of claim 1 prepared to survive passage through the stomach without substantial loss of the therapeutic agent and to substantially completely dissolve in the intestine for delivery of the active ingredient, where the composition is substantially devoid of enteric coating.

15. The pharmaceutical composition of claim 1 further comprising an enteric coating.

16. The pharmaceutical composition of claim 1 lacking or substantially lacking an enteric coating.

17. The pharmaceutical composition of claim 1 comprising a diluent selected from the group consisting of binders, disintegrants, fillers, diluents, lubricants, glidants, flow enhancers, compression aids, colors, sweeteners, preservatives, suspensing agents, dispersing agents, film formers, coatings, flavors, printing inks, celluloses, sugars, mannitols, lactoses, dissolution enhancers, and crosscarmaloses.

18. The pharmaceutical composition of claim 1 prepared in a form selected from the group consisting of tablets, minitabs, powders, hard gelatin capsules, or soft gelatin capsules.

19. The pharmaceutical composition of claim 1, wherein the fatty acid component is capric acid and/or lauric acid and/or salts of capric acid and/or lauric acid.

20. The pharmaceutical composition of claim 1 comprising a buffer salt selected from the group consisting of phosphate buffer, sudium phosphate, tris buffer, citric acid buffer, and ethanolamine buffer.

21. The pharmaceutical composition of claim 1 comprising a buffer salt selected to achieve a buffering capacity at the site of absorbtion to maintain a local pH of from about 4.8 to about 9.5, or from about 5 to about 8.

22. The pharmaceutical composition of claim 1 provided as a capsule comprising a semi-solid fill.

23. The pharmaceutical composition of claim 1 comprising an insulin compound conjugate comprising an insulin compound coupled to a modifying moiety.

24. The pharmaceutical composition of claim 1 comprising an insulin compound coupled to a modifying moiety having a formula:

—

X—

R¹—

Y-PAG-Z-R² 

 

(Formula VI)

where,

X, Y and Z are independently selected linking groups and each is optionally present, and X, when present, is coupled to the insulin compound by a covalent bond,

either R¹ or R² is is a lower alkyl, optionally including a carbonyl group, and when R¹ is a lower alkyl, R² is a capping group, and

PAG is a linear or branched carbon chain incorporating one or more alkalene glycol moieties, and optionally incorporating one or more additional moieties selected from the group consisting of —

S—

, —

O—

, —

N—

, and —

C(O)—

, and

where the modifying moiety has a maximum number of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 heavy atoms.

25. The pharmaceutical composition of claim 1 comprising a polypeptide conjugate comprising a polypeptide compound coupled to a linear or branched, substituted carbon chain moiety having a backbone of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 19, 19, 20, 21, 22, 23, 24 or 25 atoms selected from the group consisting of —

C, —

C—

, —

O—

, ═

O, —

S—

, —

N—

, —

Si—

.

26. The pharmaceutical composition of claim 1 comprising an insulin compound conjugate comprising an insulin compound coupled to a linear or branched, substituted carbon chain moiety having a backbone of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 19, 19, 20, 21, 22, 23, 24 or 25 atoms selected from the group consisting of —

C, —

C—

, —

O—

, ═

O, —

S—

, —

N—

, —

Si—

.

27. The pharmaceutical composition of claim 26 comprising where the backbone comprises one or more carbon atoms and one or more non-carbon heavy atoms selected from the group consisting of —

O—

, —

S—

, —

N—

, and ═

O.

28. The pharmaceutical composition of claim 26 where the carbon chain moiety does not include any ring structures.

29. The pharmaceutical composition of claim 26 where the carbon chain moiety is not branched.

30. The pharmaceutical composition of claim 26 where the carbon chain moiety is not an alkyl.

31. The pharmaceutical composition of claim 26 where the backbone includes one or more carbon atoms and one or more non-carbon heavy atoms selected from the group consisting of —

O—

, N—

, and ═

O.

32. The pharmaceutical composition of claim 26 where the backbone includes 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and 2, 3, 4 or 5 —

O—

moities coupled between carbon atoms.

33. The pharmaceutical composition of claim 26 where the backbone includes 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and one or more non-carbon heavy atoms selected from the group consisting of —

O— and

═

O.

34. The pharmaceutical composition of claim 26 where the carbon atoms and non-carbon heavy atoms are present in a ratio of at least 1, 2, 3 or 4 carbon atom for every non-carbon heavy atom.

35. The pharmaceutical composition of claim 26 comprising carbon atoms and oxygen atoms in a ratio of at least 1, 2, 3 or 4 carbon atom for every oxygen atom.

36. The pharmaceutical composition of claim 26 including an —

C(O)O—

group in which the O—

is coupled to the insulin compound and the —

C is coupled to a linear carbon chain having 3, 4, 5, 6, 7, 8, or 9 carbon atoms and 2, 3, or 4 oxygen atoms in the form of oxy groups.

37. The pharmaceutical composition of claim 23 where modifying moiety comprises one or more capping groups.

38. The pharmaceutical composition of claim 23 where modifying moiety comprises one or more capping groups selected from the group consisting of branched or linear C_1-6, and carbonyl.

39. The pharmaceutical composition of claim 26 wherein the modifying moiety comprises 1, 2 or 3 polyethylene glycol units and 1, 2 or 3 polypropylene glycol units.

40. The pharmaceutical composition of claim 26 modifying moiety is selected to render the insulin compound conjugate equally as soluble or more soluble than a corresponding unconjugated insulin compound.

41. The pharmaceutical composition of claim 26 wherein the water solubility of the insulin compound conjugate is decreased by addition of the zinc.

42. The pharmaceutical composition of claim 26 where the insulin compound conjugate consists of human insulin coupled at A1, B1 and/or B29 to a modifying moiety having a structure:

43. The pharmaceutical composition of claim 26 where the insulin compound conjugate consists of human insulin coupled at B29 to a modifying moiety having a structure:

44. The pharmaceutical composition of claim 26 where the insulin compound conjugate consists of human insulin coupled at A1, B1 and/or B29 to a modifying moiety having a structure:

45. The pharmaceutical composition of claim 26 where the modifying moiety has a formula:

46. The pharmaceutical composition of claim 26 where the modifying moiety has a structure:

47. The pharmaceutical composition of claim 26 where the modifying moiety has a structure:

48. The pharmaceutical composition of claim 26 where the modifying moiety has a structure:

49. The pharmaceutical composition of claim 26 where the modifying moiety has a structure:

50. The pharmaceutical composition of claim 26 where the modifying moiety has a structure:

51. The pharmaceutical composition of claim 26 where the modifying moiety has a structure:

52. The pharmaceutical composition of claim 1 where the insulin compound conjugate is coupled at A1, B1 and/or B29 to a linear or branched PEG moiety having from 2 to 15 PEG or from 2 to 10 PEG subunits.

53. The pharmaceutical composition of claim 1 having a pharmaceutically acceptable level of purity.

54. A liquid pharmaceutical composition formulated for oral administration by ingestion, comprising:

(a) from about 0.1 to about 10% w/v fatty acid component, where the fatty acid component comprises saturated or unsaturated C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, or C₁₂ fatty acids and/or salts of such fatty acids;

(b) a therapeutic agent.

55. The pharmaceutical composition of claim 54 comprising from about 0.25 to about 6% w/v fatty acid component or from about 1.5 to about 3.5% w/v fatty acid component.

56. The pharmaceutical composition of claim 54 where the therapeutic agent is a protein or peptide.

57. The pharmaceutical composition of claim 54 where the therapeutic agent is a protein or peptide having from 2 to 200 amino acids, from 10 to 65 amino acids, or 25 to 55 amino acids.

58. The pharmaceutical composition of claim 54 where the therapeutic agent is a selected from the group consisting of insulin compounds, calcitonins, interferons, growth hormones, growth factors, GLP-1, PTH, somatostatins, LCRF, natriuretic peptides, BNP, ANP, exenatide, erythropoetins having less than 200 amino acids, antibody fragments, vaccines, and analogs of any of the foregoing.

59. The pharmaceutical composition of claim 54 where the therapeutic agent is a conjugated protein or peptide, an acylated protein or peptide, or a PEGylated protein or peptide.

60. The pharmaceutical composition of claim 54 where the therapeutic agent is a conjugated insulin compounds, calcitonins, interferons, growth hormones, growth factors, GLP-1, PTH, somatostatins, LCRF, natriuretic peptides, BNP, ANP, exenatide, erythropoetins having less than 200 amino acids, antibody fragments, vaccines, and analogs of any of the foregoing.

61. The pharmaceutical composition of claim 54 where the therapeutic agent is an insulin compound.

62. The pharmaceutical composition of claim 54 where the therapeutic agent is a complexed protein or peptide or is a complexed conjugated protein or peptide.

63. The pharmaceutical composition of claim 54 where the therapeutic agent is a complexed insulin compound or a complexed conjugated insulin compound.

64. The pharmaceutical composition of claim 54 where the ionized or non-ionized fatty acid content of the composition is greater than about 90% w/w a single fatty acid, greater than about 95% w/w a single fatty acid, or greater than about 99% w/w a single fatty acid.

65. The pharmaceutical composition of claim 54 prepared in a form selected from the group consisting of semisolids, suspensions, microemulsions, and emulsions.

66. The pharmaceutical composition of claim 54, wherein the fatty acid component is capric acid and/or lauric acid and/or salts of capric acid and/or lauric acid.

67. The pharmaceutical composition of claim 54 comprising a buffer salt selected from the group consisting of phosphate buffer, sudium phosphate, tris buffer, citric acid buffer, ethanolamine buffer, and triethylamine buffer.

68. The pharmaceutical composition of claim 54 comprising a buffer salt in an amount calculated to achieve a buffering capacity at the site of absorbtion to maintain a local pH of from about 4.8 to about 9.5 or about 5 to about 8.

69. The pharmaceutical composition of claim 54 comprising an insulin compound coupled to a modifying moiety.

70. The pharmaceutical composition of claim 69 wherein the modifying moiety has a formula:

—

X—

R¹—

Y-PAG-Z-R² 

 

(Formula VI)

where,

X, Y and Z are independently selected linking groups and each is optionally present, and X, when present, is coupled to the insulin compound by a covalent bond,

either R¹ or R² is is a lower alkyl, optionally including a carbonyl group, and when R¹ is a lower alkyl, R² is a capping group, and

PAG is a linear or branched carbon chain incorporating one or more alkalene glycol moieties, and optionally incorporating one or more additional moieties selected from the group consisting of —

S—

, —

O—

, —

N—

, and —

C(O)—

, and

where the modifying moiety has a maximum number of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 heavy atoms.

71. The pharmaceutical composition of claim 54 wherein the therapeutic agent comprises a polypeptide conjugate comprising a polypeptide compound coupled to a linear or branched, substituted carbon chain moiety having a backbone of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 19, 19, 20, 21, 22, 23, 24 or 25 atoms selected from the group consisting of —

C, —

C—

, —

O—

, ═

O, —

S—

, —

N—

, —

Si—

.

72. The pharmaceutical composition of claim 54 wherein the therapeutic agent comprises an insulin compound conjugate comprising an insulin compound coupled to a linear or branched, substituted carbon chain moiety having a backbone of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 19, 19, 20, 21, 22, 23, 24 or 25 atoms selected from the group consisting of —

C, —

C—

, —

O—

, ═

O, —

S—

, —

N—

, —

Si—

.

73. The pharmaceutical composition of claim 72 where the backbone comprises one or more carbon atoms and one or more non-carbon heavy atoms selected from the group consisting of —

O—

, —

S—

, —

N—

, and ═

O.

74. The pharmaceutical composition of claim 54 where the carbon chain moiety does not include any ring structures.

75. The pharmaceutical composition of claim 54 where the carbon chain moiety is not branched.

76. The pharmaceutical composition of claim 54 where the carbon chain moiety is not an alkyl.

77. The pharmaceutical composition of claim 54 where the backbone includes one or more carbon atoms and one or more non-carbon heavy atoms selected from the group consisting of —

O—

, N—

, and ═

O.

78. The pharmaceutical composition of claim 54 where the backbone includes 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and 2, 3, 4 or 5 —

O—

moities coupled between carbon atoms.

79. The pharmaceutical composition of claim 54 where the backbone includes 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and one or more non-carbon heavy atoms selected from the group consisting of —

O— and

═

O.

80. The pharmaceutical composition of claim 54 where the carbon atoms and non-carbon heavy atoms are present in a ratio of at least 1, 2, 3 or 4 carbon atom for every non-carbon heavy atom.

81. The pharmaceutical composition of claim 54 comprising carbon atoms and oxygen atoms in a ratio of at least 1, 2, 3 or 4 carbon atom for every oxygen atom.

82. The pharmaceutical composition of claim 54 including an —

C(O)O—

group in which the O—

is coupled to the insulin compound and the —

C is coupled to a linear carbon chain having 3, 4, 5, 6, 7, 8, or 9 carbon atoms and 2, 3, or 4 oxygen atoms in the form of oxy groups.

83. The pharmaceutical composition of claim 54 where modifying moiety comprises one or more capping groups.

84. The pharmaceutical composition of claim 54 where modifying moiety comprises one or more capping groups selected from the group consisting of branched or linear C_1-6, and a carbonyl.

85. The pharmaceutical composition of claim 54 wherein the modifying moiety comprises 1, 2 or 3 polyethylene glycol units and 1, 2 or 3 polypropylene glycol units.

86. The pharmaceutical composition of claim 54 modifying moiety is selected to render the insulin compound conjugate equally as soluble or more soluble than a corresponding unconjugated insulin compound.

87. The pharmaceutical composition of claim 54 wherein the water solubility of the insulin compound conjugate is decreased by addition of the zinc.

88. The pharmaceutical composition of claim 69 where the insulin compound conjugate consists of human insulin coupled at A1, B1 and/or B29 to a modifying moiety having a structure:

89. The pharmaceutical composition of claim 69 where the insulin compound conjugate consists of human insulin coupled at B29 to a modifying moiety having a structure:

90. The pharmaceutical composition of claim 69 where the insulin compound conjugate consists of human insulin coupled at A1, B1 and/or B29 to a modifying moiety having a structure:

91. The pharmaceutical composition of claim 69 where the modifying moiety has a formula:

92. The pharmaceutical composition of claim 69 where the modifying moiety has a formula:

93. The pharmaceutical composition of claim 69 where the modifying moiety has a structure:

94. The complex of claim 69 where the modifying moiety has a structure:

95. The pharmaceutical composition of claim 69 where the modifying moiety has a structure:

96. The pharmaceutical composition of claim 69 where the modifying moiety has a structure:

97. The pharmaceutical composition of claim 69 where the modifying moiety has a structure:

98. The pharmaceutical composition of claim 69 where the modifying moiety has a structure:

99. The pharmaceutical composition of claim 69 where the modifying moiety has a structure:

100. The pharmaceutical composition of claim 69 where the modifying moiety has a structure:

101. The pharmaceutical composition of claim 69 where the modifying moiety has a structure:

102. The pharmaceutical composition of claim 69 where the modifying moiety has a structure:

103. The pharmaceutical composition of claim 69 where the modifying moiety has a structure:

104. The pharmaceutical composition of claim 69 where the modifying moiety has a structure:

105. The pharmaceutical composition of claim 69 where the modifying moiety has a structure:

106. The pharmaceutical composition of claim 69 where the modifying moiety has a structure:

107. The pharmaceutical composition of claim 69 where the modifying moiety has a structure:

108. The pharmaceutical composition of claim 69 where the modifying moiety has a structure:

109. The pharmaceutical composition of claim 69 where the insulin compound conjugate is coupled at A1, B1 and/or B29 to a linear or branched PEG moiety having from 2 to 20 PEG subunits.

110. The pharmaceutical composition of claim 69 where the insulin compound conjugate is coupled at A1, B1 and/or B29 to a linear or branched PEG moiety having from 2 to 15 PEG subunits.

111. The pharmaceutical composition of claim 69 where the insulin compound conjugate is coupled at A1, B1 and/or B29 to a linear or branched PEG moiety having from 2 to 10 PEG subunits.