Pharmaceutical compositions and methods for insulin treatment
Compositions and methods for treating a patient with insulin that combines insulin, a permeation enhancer, and a carrier that maintains an acidic pH, are disclosed.
1. A pharmaceutical composition in a form suitable for nasal delivery to a patient comprising: a therapeutically effective amount of insulin, a permeation enhancer, and a liquid carrier; said composition being at an acidic pH, but no greater than a pH of 4.5, and said permeation enhancer being a Hsieh enhancer having the following structure:
wherein X and Y are oxygen, sulfur or an imino group of the structure
or ═N—R with the proviso that when Y is the imino group, X is an imimo group, and when Y is sulfur, X is sulfur or an imino group, A is a group having the structure
wherein X and Y are defined above, m and n are integers having a value from 1 to 20 and the sum of m+n is not greater than 25, p is an integer having a value of 0 or 1, q is an integer having a value of 0 or 1, r is an integer having a value of 0 or 1, and each of R, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 is independently hydrogen or an alkyl group having from 1 to 6 carbon atoms which may be straight chained or branched provided that only one of R 1 to R 6 can be an alkyl group, with the proviso that when p, q and r have a value of 0 and Y is oxygen, m+n is at least 11, and with the further proviso that when X is an imino group, q is equal to 1, Y is oxygen, and p and r are 0, then m+n is at least 11.
2. The pharmaceutical composition of claim 1 , wherein said acidic pH is from about 2 to about 4.
3. The pharmaceutical composition of claim 1 , wherein said acidic pH is about 3.
4. The pharmaceutical composition of claim 1 , wherein said acidic pH is about 3.5
5. The pharmaceutical composition of claim 1 , further comprising a crystallization inhibitor.
6. The pharmaceutical composition of claim 1 , wherein said composition is in the form of an emulsion.
7. The pharmaceutical composition of claim 1 , wherein said composition is in the form of a spray emulsion.
8. The pharmaceutical composition of claim 1 , wherein said Hsieh enhancer is cyclopentadecalactone or cyclohexadecanone.
9. A method for treating a patient in need of insulin comprising treating said patient by nasally administering to said patient a pharmaceutical composition in a form suitable for nasal delivery to a patient comprising: a therapeutically effective amount of insulin, a permeation enhancer, and a liquid carrier; said composition being at an acidic pH, but no greater than a pH of 4.5, and said permeation enhancer being a Hsieh enhancer having the following structure:
wherein X and Y are oxygen, sulfur or an imino group of the structure
or ═N—R with the proviso that when Y is the imino group, X is an imino group, and when Y is sulfur, X is sulfur or an imino group, A is a group having the structure
wherein X and Y are defined above, m and n are integers having a value from 1 to 20 and the sum of m+n is not greater than 25, p is an integer having a value of 0 or 1, q is an integer having a value of 0 or 1, r is an integer having a value of 0 or 1, and each of R, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 is independently hydrogen or an alkyl group having from 1 to 6 carbon atoms which may be straight chained or branched provided that only one of R 1 to R 6 can be an alkyl group, with the proviso that when p, q and r have a value of 0 and Y is oxygen, m+n is at least 11, and with the further proviso that when X is an imino group, q is equal to 1, Y is oxygen, and p and r are 0, then m+n is at least 11.
10. The method of claim 9 , wherein said acidic pH is from about 2 to about 4.
11. The method of claim 9 , wherein said acidic pH is about 3.
12. The method of claim 9 , wherein said acidic pH is about 3.5
13. The method of claim 9 , wherein said composition further comprises a crystallization inhibitor.
14. The method of claim 9 , wherein said composition is in the form of an emulsion.
15. The method of claim 9 , wherein said composition is in the form of a spray emulsion.
16. The method of claim 9 , wherein said Hsieh enhancer is cyolopentadecalactone or cyclohexadecanone.
17. A product including the pharmaceutical composition of claim 1 , wherein said pharmaceutical composition is contained in, and deliverable from, an applicator selected from the group consisting of: nasal spray applicators, intra-nasal spray-dosing devices, and atomizers.
18. A method of treating a patient in need of insulin treatment comprising: using the product of claim 17 to effect a delivery of said pharmaceutical composition to the nasal mucosa of said patient.
19. The method claim 18 , wherein said delivery is up to about 200 microliters.
20. The method claim 18 , wherein said delivery is between about 50 to about 150 microliters.
21. The pharmaceutical composition of claim 1 , wherein said permeation Hsieh enhancer is a macrocyclic permeation enhancer.
22. The pharmaceutical composition of claim 21 , wherein said macrocyclic permeation enhancer is cyclopentadecanolide.
23. A pharmaceutical composition in a form suitable for nasal delivery to a patient comprising: an aqueous phase containing a therapeutically effective amount of insulin and a permeation enhancer emulsified in said aqueous phase, said composition being at an acidic pH, but no greater than a pH of 4.5, and said permeation enhancer being a Hsieh enhancer having the following structure:
wherein X and Y are oxygen, sulfur or an imino group of the structure
or ═N—R with the proviso that when Y is the imimo group, X is an imino group, and when Y is sulfur, X is sulfur or an imino group, A is a group having the structure
wherein X and Y are defined above, m and n are integers having a value from 1 to 20 and the sum of m+n is not greater than 25, p is an integer having a value of 0 or 1, q is an integer having a value of 0 or 1, r is an integer having a value of 0 or 1, and each of R, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 is independently hydrogen or an alkyl group having from 1 to 6 carbon atoms which may be straight chained or branched provided that only one of R 1 to R 6 can be an alkyl group, with the proviso that when p, q and r have a value of 0 and Y is oxygen, m+n is at least 11, and with the further proviso that when X is an imino group, q is equal to 1, Y is oxygen, and p and r are 0, then m+n is at least 11.
24. The pharmaceutical composition of claim 23 , wherein said Hsieh enhancer is a macrocyclic permeation enhancer.
25. The pharmaceutical composition of claim 24 , wherein said macrocyclic permeation enhancer is selected from the group consisting of macrocyclic ketones and macrocyclic esters.
26. The pharmaceutical composition of claim 25 , wherein said macrocyclic ketone is selected from the group consisting of 3 methylcyclopentadecanone (muscone), 9-cycloheptadecen-1-one (civetone), cyclohexadecanone, and cyclopentadecanone (normuscone).
27. The pharmaceutical composition of claim 25 , wherein said macrocyclic ester is a pentadecalactone.
28. The pharmaceutical composition of claim 27 , wherein said pentadecalactone is oxacyclohexadecan-2-one (cyclopentadecanolide, ω-pentadecalactone).
29. The pharmaceutical composition of claim 23 , wherein said permeation enhancer is emulsified within said aqueous phase by a surfactant.
30. The pharmaceutical composition of claim 29 , wherein said surfactant is selected from the group consisting of: anionic surfactants, cationic surfactants, non-ionic surfactants, and mixtures of the foregoing.
31. The pharmaceutical composition of claim 30 , wherein said surfactant is a non-ionic surfactant.
32. The pharmaceutical composition of claim 31 , wherein said non-ionic surfactant has a hydrophulic-lipophilic balance (HLB) of from about 7 to about 14.
33. The pharmaceutical composition of claim 23 , further comprising a crystallization inhibitor capable of lowering the temperature of crystallization of said permeation enhancer to below about 25° C.
34. The pharmaceutical composition of claim 33 , wherein said crystallization inhibitor is capable of lowering the temperature of crystallization of said permeation enhancer to below about 50° C.
35. The pharmaceutical composition of claim 33 , wherein said crystallization inhibitor is selected from the group consisting of natural oils, oily substances, waxes, esters, and hydrocarbons.
36. The pharmaceutical composition of claim 35 , wherein said crystallization inhibitor is a natural oil.
37. The pharmaceutical composition of claim 36 , wherein said natural oil is cottonseed oil.
38. A method for treating a patient in need of insulin comprising treating said patient by nasally administering to said patient a pharmaceutical composition, in a form suitable for nasal delivery to a patient, comprising: an aqueous phase containing a therapeutically effective amount of insulin and a permeation enhancer emulsified in said aqueous phase, said composition being at an acidic pH, but no greater than a pH of 45 and said permeation enhancer being a Haich enhancer having the following structure;
wherein X and Y are oxygen, sulfur or an imino group of the structure
or ═N—R with the proviso that when Y is the imino group, X is an imino group, and when Y is sulfur, X is sulfur or an imino group, A is a group having the structure
wherein X and Y are defined above, m and n are integers having a value from 1 to 20 and the sum of m+n is not greater than 25, p is an Integer having a value of 0 or 1, q is an integer having a value of 0 or 1, r is an integer having a value of 0 or 1, and each of R, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 is independently hydrogen or an alkyl group having from 1 to 6 carbon atoms which may be straight chained or branched provided that only one of R 1 to R 6 can be an alkyl group, with the proviso that when p, q and r have a value of 0 and Y is oxygen, m+n is at least 11, and with the further proviso that when X is an imino group, q is equal to 1, Y is oxygen, and p and r are 0, then m+n is at least 11.
39. The method of claim 38 , wherein said permeation enhancer is a macrocyclic Hsieh enhancer.
40. The method of claim 39 , wherein said macrocyclic permeation enhancer is selected from the group consisting of macrocyclic ketones and macrocyclic esters.
41. The method of claim 40 , wherein said macrocyclic ketone is selected from the group consisting of 3 methylcyclopentadecanone (muscone), 9-cycloheptadecen-1 -one (civetone), cyclohexadecanone, and cyclopentadecanone (normuscone).
42. The method of claim 40 , wherein said macrocyclic ester is a pentadecalactone.
43. The method of claim 42 , wherein said pentadecalactone is oxacyclohexadecan-2-one (cyclopentadecanolide, ω-pentadecalactone).
44. The method of claim 38 , wherein said permeation enhancer is emulsified within said aqueous phase by a surfactant.
45. The method of claim 44 , wherein said surfactant is selected from the group consisting of: anionic surfactants, cationic surfactants, non-ionic surfactants, and mixtures of the foregoing.
46. The method of claim 45 , wherein said surfactant is a non-ionic surfactant.
47. The method of claim 46 , wherein said non-ionic surfactant has a hydrophilic-lipophilic balance (HLB) of from about 7 to about 14.
48. The method of claim 38 , wherein said pharmaceutical composition further comprises a crystallization inhibitor capable of lowering the temperature of crystallization of said permeation enhancer to below about 25° C.
49. The method of claim 48 , wherein said crystallization inhibitor is capable of lowering the temperature of crystallization of said permeation enhancer to below about 5° C.
50. The method of claim 48 , wherein said crystallization inhibitor is selected from the group consisting of natural oils, oily substances, waxes, esters, and hydrocarbons.
51. The method of claim 50 , wherein said crystallization inhibitor is a natural oil.
52. The method of claim 51 , wherein said natural oil is cottonseed oil.
53. A product including the pharmaceutical composition of claim 23 , wherein said pharmaceutical composition is contained in, and deliverable from, an applicator selected from the group consisting of: nasal spray applicators, intra-nasal spray-dosing devices, and atomizers.
54. A method of treating a patient in need of insulin treatment comprising: using the product of claim 53 to effect a delivery of said pharmaceutical composition to the nasal mucosa of said patient.
55. The method claim 54 , wherein said delivery is up to about 200 microliters.
56. The method claim 54 , wherein said delivery is between about 50 to about 150 microliters.
57. The pharmaceutical composition of claim 23 , wherein said acidic pH is from about 2 to about 4.
58. The pharmaceutical composition of claim 23 , wherein said acidic pH is about 3.
59. The pharmaceutical composition of claim 23 , wherein said acidic pH is about 3.5.
60. The pharmaceutical composition of claim 23 , wherein said Hsieh enhancer is cyclopentadecalactone or cyclohexadecanone.
61. The method of claim 38 , wherein said acidic pH is from about 2 to about 4.
62. The method of claim 38 , wherein said acidic pH is about 3.
63. The method of claim 38 , wherein said acidic pH is about 3.5.
64. The method of claim 38 , wherein said Hsieh enhancer is cyclopentadecalactone or cyclohexadecanone.
65. The method of claim 9 , wherein said Hsieh enhancer is a macrocyclic permeation enhancer.
66. The method of claim 65 , wherein said macrocyclic permeation enhancer is cyclopentadecanolide.