Stabilizing alkylglycoside compositions and methods thereof

1. A pharmaceutical composition for increasing the stability, reducing aggregation or reducing immunogenicity of glucagon-like peptide-1 (GLP-1) or an analog thereof comprising:

glucagon-like peptide-1 (GLP-1) or the analog thereof; and

a stabilizing agent comprising at least one alkylglycoside,

wherein the alkylglycoside stabilizes the glucagon-like peptide-1 (GLP-1) or the analog thereof, and wherein the alkylglycoside is dodecyl-β-D-maltoside, with the proviso that the composition is insulin free.

2. The composition of claim 1 , further comprising a buffering agent.

3. The composition of claim 1 , further comprising a mucosal delivery-enhancing agent selected from the group consisting of an aggregation inhibitory agent, a charge-modifying agent, a pH control agent, a degradative enzyme inhibitory agent, a mucolytic or mucus clearing agent, a chitosan, and a ciliostatic agent.

4. The composition of claim 3 , wherein the mucosal delivery-enhancing agent is a chitosan.

5. The composition of claim 3 , wherein the mucosal delivery-enhancing agent is a ciliostatic agent.

6. The composition of claim 3 , further comprising benzalkonium chloride or chloroethanol.

7. The composition of claim 1 , further comprising a membrane penetration-enhancing agent selected from the group consisting of a surfactant, a bile salt, a phospholipid additive, a mixed micelle, a liposome, a carrier, an alcohol, an enamine, a nitric oxide donor compound, a long-chain amphipathic molecule, a small hydrophobic penetration enhancer, a sodium or a salicylic acid derivative, a glycerol ester of acetoacetic acid, a cyclodextrin or beta-cyclodextrin derivative, a medium-chain fatty acid, a chelating agent, an amino acid or salt thereof, an N-acetylamino acid or salt thereof, an enzyme degradative to a selected membrane component and any combination thereof.

8. The composition of claim 1 , further comprising a modulatory agent of epithelial junction physiology.

9. The composition of claim 1 , further comprising a vasodilator agent.

10. The composition of claim 1 , further comprising a selective transport-enhancing agent.

11. The composition of claim 1 , wherein the composition is in a lyophilized form.

12. The composition of claim 11 , wherein the lyophilized composition retains greater than 50% biological activity upon reconstitution.

13. The composition of claim 1 , wherein the composition is stable for at least one month when stored at temperatures from about 25 to 37 degrees Celsius.

14. The composition of claim 12 , wherein the composition is stable for at least two months.

15. The composition of claim 1 , wherein the composition is stable for at least one year when stored at about 4 degrees Celsius.

16. The composition of claim 1 , wherein the stability of the composition is determined by determining the bioactivity of the glucagon-like peptide-1 (GLP-1) or the analog thereof.

17. The composition of claim 11 , wherein the lyophilized composition further comprises a bulking agent selected from the group consisting of albumin, collagen, alginate, and mannitol.

18. The composition of claim 11 , wherein the lyophilized composition is reconstituted prior to administering to a mammalian subject.

19. The composition of claim 1 , wherein the composition is formulated for intransal, pulmonary, or buccal delivery.

20. A method for increasing the stability of a glucagon-like peptide-1 (GLP-1) or an analog thereof comprising:

admixing the glucagon-like peptide-1 (GLP-1) or the analog thereof and a stabilizing agent to form a composition, wherein the stabilizing agent is at least one alkylglycoside surfactant, thereby increasing the stability of the glucagon-like peptide-1 (GLP-1) or the analog thereof, and wherein the alkylglycoside is dodecyl-β-D-maltoside, with the proviso that the composition is insulin free.

21. The method of claim 20 , wherein the composition further comprises a mucosal delivery-enhancing agent selected from the group consisting of an aggregation inhibitory agent, a charge-modifying agent, a pH control agent, a degradative enzyme inhibitory agent, a mucolytic or mucus clearing agent, a chitosan, and a ciliostatic agent.

22. The method of claim 21 , wherein the mucosal delivery-enhancing agent is a chitosan.

23. The method of claim 21 , wherein the mucosal delivery-enhancing agent is a ciliostatic agent.

24. The method of claim 21 , wherein the composition further comprises benzalkonium chloride or chloroethanol.

25. The method of claim 20 , wherein the composition further comprises a membrane penetration-enhancing agent selected from the group consisting of a surfactant, a bile salt, a phospholipid additive, a mixed micelle, a liposome, a carrier, an alcohol, an enamine, a nitric oxide donor compound, a long-chain amphipathic molecule, a small hydrophobic penetration enhancer, a sodium or a salicylic acid derivative, a glycerol ester of acetoacetic acid, a cyclodextrin or beta-cyclodextrin derivative, a medium-chain fatty acid, a chelating agent, an amino acid or salt thereof, an N-acetylamino acid or salt thereof, an enzyme degradative to a selected membrane component and any combination thereof.

26. The method of claim 20 , wherein the composition further comprises a modulatory agent of epithelial junction physiology.

27. The method of claim 20 , wherein the composition further comprises a vasodilator agent.

28. The method of claim 20 , wherein the composition further comprises a selective transport-enhancing agent.

29. The method of claim 20 , wherein the composition is in a lyophilized form.

30. The method of claim 29 , wherein the composition retains greater than 50% biological activity upon reconstitution.

31. The method of claim 20 , wherein the composition is stable for at least one month when stored at temperatures from about 25 to 37 degrees Celsius.

32. The method of claim 31 , wherein the composition is stable for at least two months when stored at temperatures from about 25 to 37 degrees Celsius.

33. The method of claim 20 , wherein the composition is stable for at least one year when stored at about 4 degrees Celsius.

34. The method of claim 20 , wherein the stability of the composition is determined by determining the bioactivity of the glucagon-like peptide-1 (GLP-1) or the analog thereof.

35. The method of claim 20 , wherein the composition further comprises a bulking agent selected from the group consisting of albumin, collagen, alginate, and mannitol.

36. The method of claim 29 , wherein the composition is reconstituted prior to administering to a mammalian subject.

37. A method for reducing aggregation of a glucagon-like peptide-1 (GLP-1) or analog thereof comprising:

admixing the glucagon-like peptide-1 (GLP-1) or analog thereof and an aggregation reducing agent to form a composition, wherein the aggregation reducing agent is at least one alkylglycoside surfactant, thereby reducing aggregation of the glucagon-like peptide-1 (GLP-1) or analog thereof, and wherein the alkylglycoside is dodecyl-β-D-maltoside, with the proviso that the composition is insulin free.

38. A method according to claim 37 , wherein the composition further comprises a buffering agent.

39. The method of claim 37 , wherein the composition further comprises a mucosal delivery-enhancing agent selected from the group consisting of an aggregation inhibitory agent, a charge-modifying agent, a pH control agent, a degradative enzyme inhibitory agent, a mucolytic or mucus clearing agent, a chitosan, and a ciliostatic agent.

40. The method of claim 39 , wherein the mucosal delivery-enhancing agent is a chitosan.

41. The method of claim 39 , wherein the mucosal delivery-enhancing agent is a ciliostatic agent.

42. The method of claim 39 , further comprising benzalkonium chloride or chloroethanol.

43. The method of claim 37 , wherein the composition further comprises a membrane penetration-enhancing agent selected from the group consisting of a surfactant, a bile salt, a phospholipid additive, a mixed micelle, a liposome, a carrier, an alcohol, an enamine, a nitric oxide donor compound, a long-chain amphipathic molecule, a small hydrophobic penetration enhancer, a sodium or a salicylic acid derivative, a glycerol ester of acetoacetic acid, a cyclodextrin or beta-cyclodextrin derivative, a medium-chain fatty acid, a chelating agent, an amino acid or salt thereof, an N-acetylamino acid or salt thereof, an enzyme degradative to a selected membrane component and any combination thereof.

44. The method of claim 37 , wherein the composition further comprises a modulatory agent of epithelial junction physiology.

45. The method of claim 37 , wherein the composition further comprises a vasodilator agent.

46. The method of claim 37 , wherein the composition further comprises a selective transport-enhancing agent.

47. The method of claim 37 , wherein the composition is in a lyophilized form.

48. The method of claim 47 , wherein the composition retains greater than 50% biological activity upon reconstitution.

49. The method of claim 37 , wherein the composition is stable for at least one month when stored at temperatures from about 25 to 37 degrees Celsius.

50. The method of claim 49 , wherein the composition is stable for at least two months when stored at temperatures from 25 to 37 degrees Celsius.

51. The method of claim 37 , wherein the composition is stable for at least one year when stored at about 4 degrees Celsius.

52. The method of claim 37 , wherein the stability of the composition is determined by a physical characterization method selected from the group consisting of light scattering, circular dichroism, ultracentrifugation and size exclusion chromatography.

53. The method of claim 37 , wherein the composition further comprises a bulking agent selected from the group consisting of albumin, collagen, alginate, and mannitol.

54. The method of claim 47 , wherein the composition is reconstituted prior to administering to a mammalian subject.

55. A method for reducing immunogenicity of a glucagon-like peptide-1 (GLP-1) or an analog thereof upon administration to a vertebrate, comprising:

admixing the glucagon-like peptide-1 (GLP-1) or the analog thereof with an agent to form a composition,

wherein the agent is at least one alkylglycoside surfactant,

wherein the surfactant reduces immunogenicity upon administration of the glucagon-like peptide-1 (GLP-1) or the analog thereof,

wherein the alkylglycoside is a β-anomer of dodecyl maltoside, tridecyl maltoside, tetradecyl maltoside, sucrose mono-dodecanoate, sucrose mono-tridecanoate, or sucrose mono-tetradecanoate, and

wherein the reduced immunogenicity of the composition is determined by injecting the composition into a suitable vertebrate host, waiting a suitable time to allow an immune response to develop, and determining the presence or absence of antibody in the host blood or plasma.

56. The method of claim 55 , wherein the composition further comprises a buffering agent.

57. The method of claim 55 , wherein administration is by injection.

58. The method of claim 55 , wherein the glucagon-like peptide-1 (GLP-1) or the analog thereof is brought into contact with a mucosal membrane.

59. The method of claim 55 , wherein the composition further comprises a mucosal delivery-enhancing agent selected from the group consisting of an aggregation inhibitory agent, a charge-modifying agent, a pH control agent, a degradative enzyme inhibitory agent, a mucolytic or mucus clearing agent, a chitosan, and a ciliostatic agent.

60. The method of claim 59 , wherein the mucosal delivery-enhancing agent is a chitosan.

61. The method of claim 59 , wherein the mucosal delivery-enhancing agent is a ciliostatic agent.

62. The method of claim 59 , wherein the composition further comprises benzalkonium chloride or chloroethanol.

63. The method of claim 55 , wherein the composition further comprises a membrane penetration-enhancing agent selected from the group consisting of a surfactant, a bile salt, a phospholipid additive, a mixed micelle, a liposome, a carrier, an alcohol, an enamine, a nitric oxide donor compound, a long-chain amphipathic molecule, a small hydrophobic penetration enhancer, a sodium or a salicylic acid derivative, a glycerol ester of acetoacetic acid, a cyclodextrin or beta-cyclodextrin derivative, a medium-chain fatty acid, a chelating agent, an amino acid or salt thereof, an N-acetylamino acid or salt thereof, an enzyme degradative to a selected membrane component and any combination thereof.

64. The method of claim 55 , wherein the composition further comprises a modulatory agent of epithelial junction physiology.

65. The method of claim 55 , wherein the composition further comprises a vasodilator agent.

66. The method of claim 55 , wherein the composition further comprises a selective transport-enhancing agent.

67. The method of claim 55 , wherein the composition is in a lyophilized form.

68. The method of claim 67 , wherein the composition retains greater than 50% biological activity upon reconstitution.

69. The method of claim 55 , wherein the composition is stable for at least one month when stored at temperatures from about 25 to 37 degrees Celsius.

70. The method of claim 69 , wherein the composition is stable for at least two months when stored at temperatures from about 25 to 37 degrees Celsius.

71. The method of claim 55 , wherein the composition is stable for at least one year when stored at about 4 degrees Celsius.

72. The method of claim 55 , wherein the suitable vertebrate host is selected from among the group consisting of rabbit, rat, and mouse.

73. The method of claim 55 , wherein the presence of antibody in the host blood or plasma is determined by ELISA (Enzyme Linked ImmunoSorbent Assay).

74. The method of claim 55 , wherein the suitable waiting time to allow an immune response to develop is at least two weeks.

75. The method of claim 55 , wherein the injection of the composition is periodically repeated.

76. The method of claim 55 , wherein the composition further comprises a bulking agent selected from the group consisting of albumin, collagen, alginate, and mannitol.

77. The method of claim 67 , wherein the composition is reconstituted prior to administering to a mammalian subject.

78. A method of manufacturing non-aggregated aqueous solutions of a glucagon-like peptide-1 (GLP-1) or an analog thereof comprising admixing at least one alkylglycoside surfactant with an aqueous solution comprising the glucagon-like peptide-1 (GLP-1) or the analog thereof to form a composition and concentrating the composition, wherein the alkylglycoside is dodecyl-β-D-maltoside.

79. The method of claim 78 wherein the composition is concentrated by ultrafiltration, affinity chromatography, selective absorption chromatography, ion exchange chromatography, lyophilization, dialysis, precipitation or salting-out.