Pharmaceutical compositions and methods for insulin treatment
View Patent ↗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 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 the 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.
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 a macrocyclic permeation enhancer.
9. The pharmaceutical composition of claim 1 , wherein said Hsieh enhancer is cyclopentadecanolide, cyclopentadecalactone or cylcohexadecanone.
10. A pharmaceutical composition 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 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.
11. The pharmaceutical composition of claim 10 , wherein said Hsieh enhancer is a macrocyclic permeation enhancer.
12. The pharmaceutical composition of claim 10 , wherein said Hsieh enhancer is selected from the group consisting of macrocyclic ketones and macrocyclic esters.
13. The pharmaceutical composition of claim 12 , wherein said macrocyclic ketone is selected from the group consisting of 3 -methylcyclopentadecanone (muscone), 9-cycloheptadecen-1-one (civetone),cyclohexadecanone, cyclopentadecalactone and cyclopentadecanone (normuscone).
14. The pharmaceutical composition of claim 12 , wherein said macrocyclic ester is a pentadecalactone.
15. The pharmaceutical composition of claim 14 , wherein said pentadecalactone is oxacyclohexadecan-2-one (cyclopentadecanolide, ω-pentadecalactone).
16. The pharmaceutical composition of claim 10 , wherein said permeation enhancer is emulsified within said aqueous phase by a surfactant.
17. The pharmaceutical composition of claim 16 , wherein said surfactant is selected from the group consisting of: anionic surfactants, cationic surfactants, non-ionic surfactants, and mixtures thereof.
18. The pharmaceutical composition of claim 17 , wherein said non-ionic surfactant has a hydrophulic-lipophilic balance (HLB) of from about 7 to about 14.
19. The pharmaceutical composition of claim 10 , further comprising a crystallization inhibitor.
20. The pharmaceutical composition of claim 19 , wherein said crystallization inhibitor is selected from the group consisting of a natural oil, an oily substance, a wax, an ester, and a hydrocarbon.
21. The pharmaceutical composition of claim 20 , wherein said natural oil is cottonseed oil.
22. The pharmaceutical composition of claim 10 , wherein said acidic pH is from about 2 to about 4.
23. The pharmaceutical composition of claim 10 , wherein said acidic pH is about 3.
24. A method for treating a patient in need of insulin comprising administering to the patient a pharmaceutical composition 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 the 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.
25. The method of claim 24 , wherein said acidic pH is from about 2 to about 4.
26. The method of claim 24 , wherein said acidic pH is about 3.
27. The method of claim 24 , wherein said acidic pH is about 3.5.
28. The method of claim 24 , wherein said combination further comprises a crystallization inhibitor.
29. The method of claim 24 , wherein said combination is in the form of an emulsion.
30. The method of claim 24 , wherein said combination is in the form of a spray emulsion.
31. The method of claim 24 , wherein said Hsieh enhancer is a macrocyclic permeation enhancer.
32. The method of claim 24 , wherein said Hsieh enhancer is cyclopentadecanolide, cyclopentadecalactone or cylcohexadecanone.