Pharmaceutical compositions and methods for insulin treatment

• US 7,112,561 B2
• Filed: 12/02/2004
• Issued: 09/26/2006
• Est. Priority Date: 12/08/2003
• Status: Expired due to Fees

• Current Assignee: CPEX Pharmaceuticals Incorporated
• Original Assignee: Bentley Pharmaceuticals, Inc. (Teva Pharmaceutical Industries Limited)
• Inventors: Gyurik, Robert J., Reppucci, Carl
• Primary Examiner(s): Tsang, Cecilia J.
• Assistant Examiner(s): AUDET, MAURY A
• Application Number:
  US11/002,858
• Publication Number:
  US 20050123592A1
• Time in Patent Office: 663 Days
• Field of Search: 514/3
• US Class Current: 514/6.5
• CPC Class Codes: A61K 38/28 Insulins
• 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 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• 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 47/44 Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin synthetic glycerides, e.g. medium-chain triglycerides, A61K47/14
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0043 Nose
• CPC Class Codes: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics

Abstract

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.

Claims

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;

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.

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.

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;

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.

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.

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;

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.

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.

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;

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.

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.