Hydrophilic and lipophilic balanced microemulsion formulations of free-form and/or conjugation-stabilized therapeutic agents such as insulin

• US 6,191,105 B1
• Filed: 10/27/1997
• Issued: 02/20/2001
• Est. Priority Date: 05/10/1993
• Status: Expired due to Fees

• Current Assignee: Biocon Limited (Biocon Incorporated)
• Original Assignee: Protein Delivery Inc.
• Inventors: Ramaswamy, Muthukumar, Allaudeen, HameedSulthan S., Radhakrishnan, Balasingam, Ekwuribe, Nnochiri Nkem
• Primary Examiner(s): CELSA, BENNETT M
• Application Number:
  US08/958,383
• Time in Patent Office: 1,212 Days
• Field of Search: 514/2-3, 424/400-455
• US Class Current: 514/6.5
• 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 47/56 the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
• 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 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: A61K 9/4858 Organic compounds
• CPC Class Codes: C07K 1/1077 by covalent attachment of residues other than amino acids or peptide residues, e.g. sugars, polyols, fatty acids
• CPC Class Codes: C07K 14/62 Insulins
• CPC Class Codes: C12N 9/96 Stabilising an enzyme by forming an adduct or a composition; Forming enzyme conjugates

Abstract

A therapeutic formulation comprising a microemulsion of a therapeutic agent in free and/or conjugatively coupled form, wherein the microemulsion comprises a water-in-oil (w/o) microemulsion including a lipophilic phase and a hydrophilic phase, and has a hydrophilic and lipophilic balance (HLB) value between 3 and 7, wherein the therapeutic agent may for example be selected from the group consisting of insulin, calcitonin, ACTH, glucagon, somatostatin, somatotropin, somatomedin, parathyroid hormone, erythropoietin, hypothalamic releasing factors, prolactin, thyroid stimulating hormones, endorphins, enkephalins, vasopressin, non-naturally occurring opioids, superoxide dismutase, interferon, asparaginase, arginase, arginine deaminease, adenosine deaminase, ribonuclease, trypsin, chymotrypsin, papain, Ara-A (Arabinofuranosyladenine), Acylguanosine, Nordeoxyguanosine, Azidothymidine, Dideoxyadenosine, Dideoxycytidine, Dideoxyinosine Floxuridine, 6-Mercaptopurine, Doxorubicin, Daunorubicin, or I-darubicin, Erythromycin, Vancomycin, oleandomycin, Ampicillin; Quinidine and Heparin. In a particular aspect, the invention comprises an insulin composition suitable for parenteral as well as non-parenteral administration, preferably oral or parenteral administration, comprising insulin covalently coupled with a polymer including (i) a linear polyalkylene glycol moiety and (ii) a lipophilic moiety, wherein the insulin, the linear polyalkylene glycol moiety and the lipophilic moiety are conformationally arranged in relation to one another such that the insulin in the composition has an enhanced in vivo resistance to enzymatic degradation, relative to insulin alone. The microemulsion compositions of the invention are usefully employed in therapeutic as well as non-therapeutic, e.g., diagnostic, applications.

Claims

1. A composition for presentation or delivery of an insulin-methyl(ethyleneglycol)₇-O-hexanoic acid conjugate, said composition:

(a) comprising a water-in-oil (w/o) microemulsion including;

(i) a lipophilic component; and

(ii) a hydrophilic component; and

(iii) a therapeutically effective amount of insulin conjugated to 1, 2, and/or 3 methyl(ethyleneglycol)₇-O-hexanoic acid conjugates; and

(b) having an HLB value between 3 and 7.

2. A composition according to claim 1, wherein the HLB value is from about 5 to about 6.5.

3. A composition according to claim 1, wherein the HLB value is from about 5 to about 6.

4. A composition according to claim 1, wherein the HLB value is between 5 and 6.

5. A composition according to claim 1, wherein the lipophilic phase constitutes from about 30 to about 90 percent by weight of the composition.

6. A composition according to claim 1, wherein the lipophilic phase comprises mono, di, and triglycerides of medium chain or long chain fatty acids.

7. A composition according to claim 1, wherein the hydrophilic phase comprises a surfactant with an HLB value greater than 8.

8. A composition according to claim 7, wherein the surfactant comprises a non-ionic surfactant.

9. A composition according to claim 1, wherein the hydrophilic phase comprises a mixture of polyhydroxy alcohols selected from the group consisting of polyethylene glycol, propylene glycol and mannitol.

10. A composition according to claim 1, of a pharmaceutically acceptable character.

11. A composition for presentation or delivery of an insulin-methyl(ethyleneglycol)₇-O-hexanoic acid conjugate, said composition:

(a) comprising a water-in-oil (w/o) microemulsion comprising;

(i) a lipophilic component selected from the group consisting of monoglycerides and diglycerides of medium chain fatty acids;

(ii) a hydrophilic component comprising propylene glycol;

(iii) a surfactant component comprising lecithin and tween 80; and

(iv) a therapeutically effective amount of insulin conjugated to 1, 2, and/or 3 methyl(ethyleneglycol)₇-O-hexanoic acid conjugates in an aqueous solution; and

(b) having an HLB value between 3 and 7.

12. The microemulsion formulation of claim 11 wherein the HLB value is from 5 to 6.5.

13. The microemulsion formulation of claim 11 wherein the HLB value is from 5 to 6.

14. The microemulsion formulation of claim 11 wherein the HLB value is between 5 and 6.

15. The microemulsion formulation of claim 11 wherein the HLB value is 5.59.

16. The microemulsion formulation of claim 11 wherein the HLB value is 5.6.

17. The microemulsion formulation of claim 11 wherein the aqueous solution is an NaP buffer.

18. The microemulsion formulation of claim 11 with the proviso that the formulation does not comprise a protease inhibitor.

19. A composition for presentation or delivery of an insulin-methyl(ethyleneglycol)₇-O-hexanoic acid conjugate, said composition:

(a) comprising a water-in-oil (w/o) microemulsion including;

(i) one or more lipophilic components selected from the group consisting of monoglycerides and diglycerides of medium chain fatty acids, and trans-esterification products of natural vegetable oil triglycerides and polyalkylene polyols;

(ii) a hydrophilic component comprising propylene glycol;

(iii) a surfactant comprising lecithin in a vegetable oil and/or tween 80; and

(iv) a therapeutically effective amount of insulin conjugated to 1, 2, and/or 3 methyl(ethyleneglycol)₇-O-hexanoic acid conjugates in a buffer solution; and

(b) having an HLB value between 3 and 7.

20. The microemulsion formulation of claim 19 wherein the HLB value is from 5 to 6.5.

21. The microemulsion formulation of claim 19 wherein the HLB value is from 5 to 6.

22. The microemulsion formulation of claim 19 wherein the HLB value is between 5 and 6.

23. The microemulsion formulation of claim 19 wherein the HLB value is 5.0.

24. The microemulsion formulation of claim 19 wherein the HLB value is 5.

25. The microemulsion formulation of claim 19 wherein the aqueous solution is an NaP buffer.

26. The microemulsion formulation of claim 19 further comprising one or more polyhydroxylic alcohols.

27. The microemulsion formulation of claim 19 with the proviso that the formulation does not comprise a protease inhibitor.

36. The microemulsion formulation of claim 19 with the proviso that the formulation does not comprise a protease inhibitor.

28. A composition for presentation or delivery of an insulin-methyl(ethyleneglycol)₇-O-hexanoic acid conjugate, said composition:

(a) comprising a water-in-oil (w/o) microemulsion including;

(i) a lipophilic component selected from the group consisting of monoglycerides and diglycerides of medium chain fatty acids;

(ii) a hydrophilic component comprising propylene glycol;

(iii) a surfactant comprising lecithin and mannitol; and

(iv) a therapeutically effective amount of insulin conjugated to 1, 2, and/or 3 methyl(ethyleneglycol)₇-O-hexanoic acid conjugates in a buffer solution; and

(b) having an HLB value between 3 and 7.

29. The microemulsion formulation of claim 28 wherein the HLB value is from 5 to 6.5.

30. The microemulsion formulation of claim 28 wherein the HLB value is from 5 to 6.

31. The microemulsion formulation of claim 28 wherein the HLB value is between 5 and 6.

32. The microemulsion formulation of claim 28 wherein the HLB value is 5.5.

33. The microemulsion formulation of claim 28 wherein the HLB value is 5.49.

34. The microemulsion formulation of claim 28 wherein the aqueous solution is an NaP buffer.

35. The microemulsion formulation of claim 28 further comprising polyethylene glycol 300 and/or polyethylene glycol 400.

37. A composition for presentation or delivery of an insulin-methyl(ethyleneglycol)₇-O-hexanoic acid conjugate, said composition:

(a) comprising a water-in-oil (w/o) microemulsion including;

(i) a lipophilic component selected from the group consisting of monoglycerides and diglycerides of medium chain fatty acids;

(ii) a hydrophilic component comprising propylene glycol;

(iii) two or more surfactants, including lecithin and polyoxyethylene sorbitan monooleate; and

(iv) a therapeutically effective amount of insulin conjugated to 1, 2, and/or 3 methyl(ethyleneglycol)₇-O-hexanoic acid conjugates in a buffer solution; and

(b) having an HLB value between 3 and 7.

38. The microemulsion formulation of claim 37 wherein the HLB value is from 5 to 6.5.

39. The microemulsion formulation of claim 37 wherein the HLB value is from 5 to 6.

40. The microemulsion formulation of claim 37 wherein the HLB value is between 5 and 6.

41. The microemulsion formulation of claim 37 wherein the HLB value is 5.6.

42. The microemulsion formulation of claim 37 wherein the HLB value is 5.58.

43. The microemulsion formulation of claim 37 wherein the aqueous solution is an NaP buffer.

44. The microemulsion formulation of claim 37 wherein the hydrophilic component comprises polyethylene glycol 300 and polyethylene glycol 400.

45. The microemulsion formulation of claim 37 with the proviso that the formulation does not comprise a protease inhibitor.

46. A composition for presentation or delivery of an insulin-methyl(ethyleneglycol)₇-O-hexanoic acid conjugate, said composition:

(a) comprising a water-in-oil (w/o) microemulsion including;

(i) a lipophilic component selected from the group consisting of monoglycerides and diglycerides of medium chain fatty acids;

(ii) a hydrophilic component comprising propylene glycol esters;

(iii) two or more surfactants, including lecithin and sodium octanoate; and

(iv) a therapeutically effective amount of insulin conjugated to 1, 2, and/or 3 methyl(ethyleneglycol)₇-O-hexanoic acid conjugates in a buffer solution; and

(b) having an HLB value between 3 and 7.

47. The microemulsion formulation of claim 46 wherein the HLB value is from 5 to 6.5.

48. The microemulsion formulation of claim 46 wherein the HLB value is from 5 to 6.

49. The microemulsion formulation of claim 46 wherein the HLB value is between 5 and 6.

50. The microemulsion formulation of claim 46 wherein the HLB value is 5.9.

51. The microemulsion formulation of claim 46 wherein the HLB value is 5.85.

52. The microemulsion formulation of claim 46 wherein the aqueous solution is an NaP buffer.

53. The microemulsion formulation of claim 46 with the proviso that the formulation does not comprise a protease inhibitor.

54. A composition for presentation or delivery of an insulin-methyl(ethyleneglycol)₇-O-hexanoic acid conjugate, said composition:

(a) comprising a water-in-oil (w/o) microemulsion including;

(i) a lipophilic component selected from the group consisting of monoglycerides and diglycerides of medium chain fatty acids;

(ii) a hydrophilic component comprising propylene glycol esters;

(iii) a surfactant comprising lecithin; and

(iv) a therapeutically effective amount o insulin conjugated to 1, 2, and/or 3 methyl(ethyleneglycol)₇-O-hexanoic acid coniugates in a buffer solution; and

(b) having an HLB value between 3 and 7.

55. The microemulsion formulation of claim 54 wherein the HLB value is from 5 to 6.5.

56. The microemulsion formulation of claim 54 wherein the HLB value is from 5 to 6.

57. The microemulsion formulation of claim 54 wherein the HLB value is between 5 and 6.

58. The microemulsion formulation of claim 54 wherein the HLB value is 5.6.

59. The microemulsion formulation of claim 54 wherein the HLB value is 5.58.

60. The microemulsion formulation of claim 54 wherein the aqueous solution is an NaP buffer.

61. The microemulsion formulation of claim 54 with the proviso that the formulation does not comprise a protease inhibitor.