Solvent-cast microprotrusion arrays containing active ingredient

• US 9,114,238 B2
• Filed: 04/16/2008
• Issued: 08/25/2015
• Est. Priority Date: 04/16/2007
• Status: Active Grant

• Current Assignee: Corium Pharma Solutions, Inc.
• Original Assignee: Corium International, Inc.
• Inventors: Singh, Parminder, Worsham, Robert Wade, Trautman, Joseph C., Bayramov, Danir, Bowers, Danny Lee, Klemm, Andy, Klemm, Steven Richard, Chen, Guohua
• Primary Examiner(s): Bosworth, Kami A
• Assistant Examiner(s): HAYMAN, IMANI N
• Application Number:
  US12/148,180
• Publication Number:
  US 20080269685A1
• Time in Patent Office: 2,687 Days
• Field of Search: 604/173, 604/191, 604/272, 604/46, 604/73, 606/186
• US Class Current: 1/1
• CPC Class Codes: A61K 38/29 Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
• CPC Class Codes: A61K 38/385 Serum albumin
• CPC Class Codes: A61K 9/0021 Intradermal administration, e.g. through microneedle arrays, needleless injectors mechanical aspects A61M
• CPC Class Codes: A61M 2037/0046 Solid microneedles
• CPC Class Codes: A61M 2037/0053 Methods for producing microneedles
• CPC Class Codes: A61M 2037/0061 Methods for using microneedles
• CPC Class Codes: A61M 2202/0007 introduced into the body
• CPC Class Codes: A61M 2202/07 Proteins
• CPC Class Codes: A61M 2202/30 Vaccines
• CPC Class Codes: A61M 2207/00 Methods of manufacture, assembly or production
• CPC Class Codes: A61M 37/0015 by using microneedles
• CPC Class Codes: A61M 5/3298 Needles arranged in parallel

Abstract

In an aspect of the invention, an array of microprotrusions is formed by providing a mold with cavities corresponding to the negative of the microprotrusions, casting atop the mold a first solution comprising a biocompatible material and a solvent, removing the solvent, casting a second solution atop the first cast solution, removing the solvent from the second solution, and demolding the resulting array from the mold. The first solution preferably contains an active ingredient.

Claims

1. A microprotrusion array, comprising:

an approximately planar base and a plurality of microprotrusions, wherein the microprotrusions comprise at least a first and a second layer arranged roughly parallel to the plane of the base, the first and second layers formed of different polymers, the first layer is contained in a distal end of the microprotrusions and comprised of (i) a biodegradable polymer, (ii) a component to facilitate biodegradation selected from sugars, sugar alcohols, cyclodextrins and water-swellable polymers, and (iii) an active ingredient, wherein about 12-70 wt % of the first layer is comprised of the component to facilitate biodegradation.

2. The array of claim 1, wherein the second layer is comprised of a polymer that is biodegradable.

3. The array of claim 1, wherein at least one of the first and second layers adheres to human skin.

4. The array of claim 1, wherein at least some of the microprotrusions detach from the base following insertion into skin.

5. The array of claim 4, wherein the microprotrusions that detach after insertion provide diffusive channels for the active ingredient or a second active ingredient.

6. The array of claim 1, wherein the rate at which portions of the microprotrusions degrade is dependent on the pH of the environment in which the portions of the microprotrusions find themselves following insertion.

7. The array of claim 6, wherein the rate of degradation is greater at a pH of about 4 than at a pH of about 7.

8. The array of claim 6, wherein the rate of degradation is greater at a pH of about 7 than at a pH of about 4.

9. The array of claim 1, wherein the first layer comprises a composition which degrades at different rates at different temperatures in the range of about 25°

C. to about 40°

C.

10. The array of claim 9, wherein the rate of degradation is greater at a temperature of 25°

C. than at a temperature of 40°

C.

11. The array of claim 9, wherein the rate of degradation is greater at a temperature of 30°

C. than at a temperature of 37°

C.

12. The array of claim 1, wherein at least the first layer comprises polyvinyl alcohol.

13. The array of claim 12, wherein at least the first layer comprises polyvinyl alcohol which is 0-90% hydrolyzed.

14. The array of claim 1, wherein at least the first layer comprises dextran.

15. The array of claim 1, wherein at least the first layer comprises hydroxyethyl starch.

16. The array of claim 15, wherein at least the first layer comprises hydroxyethyl starch which has a degree of substitution of 0-0.9.

17. The array of claim 1, wherein the first layer comprises the sugar selected from dextrose, fructose, galactose, maltose, maltylose, iso-maltulose, mannose, lactose, lactulose, sucrose, and trehalose.

18. The array of claim 1, wherein the first layer comprises the sugar alcohol selected from sorbitol, lactitol, malitol and mannitol.

19. The array of claim 1, wherein at least the first layer comprises at least one antioxidant.

20. The array of claim 19, wherein the antioxidant is chosen from the group consisting of methionine, cysteine, D-alpha tocopherol acetate, DL-alpha tocopherol, ascorbyl palmitate, ascorbic acid, butylated hydroxyanisole, butylated hydroxyquinone, hydroxycomarin, butylated hydroxytoluene, cephalin, ethyl gallate, propyl gallate, octyl gallate, lauryl gallate, propylhydroxybenzoate, trihydroxybutyrophenone, dimethylphenol, ditertbutylphenol, vitamin E, lecithin, and ethanolamine.

21. The array of claim 1, wherein a layer of the first and second layers comprises cellulose acetate butyrate, cellulose acetate, cellulose acetate propionate, ethyl cellulose, nitrocellulose, hydroxypropyl methyl cellulose phthalate, a polyacrylate, or a polymethacrylate.

22. The array of claim 1, wherein a layer of the first and second layers comprises a poly(hydroxyl alkanoate), poly(lactic acid), poly(glycolic acid), poly(lactic acid-co-glycolic acid), a polycaprolactone, or copolymers thereof.

23. The array of claim 1, wherein the active ingredient comprises a polypeptide, a protein, or a nucleic acid.

24. The array of claim 1, wherein the active ingredient comprises a vaccine.

25. The array of claim 1, wherein the active ingredient comprises a therapeutic antibody.

26. The array of claim 1, wherein the array achieves a skin penetration efficiency of at least about 80%.

27. The array of claim 1, wherein the array achieves a skin penetration efficiency of at least about 90%.

28. The array of claim 27, wherein the array achieves a skin penetration efficiency of at least about 95%.

29. The array of claim 1, wherein an adhesiveness of at least one of the first and second layers increases with increasing moisture content over a range of moisture contents.

30. The array of claim 1, wherein at least one of the first and second layers was produced by a process comprising solvent casting.

31. The array of claim 30, wherein at least one of the first and second layers was produced by a process comprising solvent casting with a water based solvent with water content 50% or higher.

32. The array of claim 30, wherein the second layer is produced by a process comprising solvent casting, and the first layer comprises at least one polymer or sugar which is not readily soluble in the solvent used to cast the second layer.

33. The array of claim 30, wherein at least one of the first and second layers was produced by a process comprising solvent casting with a substantially non-aqueous solvent or an organic solvent or a mixture of solvents with non-aqueous content 50% or higher.

34. The array of claim 30, wherein at least one of the first and second layers was produced by a process comprising solvent casting with a C₃-C₈ alcohol as a solvent.

35. The array of claim 1, wherein at least one microprotrusion has a cross sectional diameter in a plane parallel to that of the base which decreases as a function of the distance of the plane parallel from the base in such a way that the cross sectional diameter decreases more rapidly near the base than further away from it.

36. The array of claim 35, wherein a portion of at least one microprotrusion does not penetrate the skin when the microprotrusion is in use.

37. The array of claim 1, wherein at least one of the first and second layers comprises starches, 2-hydroxyethylstarches, hetastarch, dextran, pH sensitive hydroxypropyl methylcellulose, collagen and its derivatives, hyaluronic acid and its derivatives or polyphosphazene.

38. The array of claim 1, wherein at least one of the first and second layers comprises polystyrene.

39. The array of claim 1, wherein at least one of the first and second layers comprises an antimicrobial.

40. The array of claim 39, wherein the antimicrobial is chosen from the group consisting of benzalkonium chloride, benzyl alcohol, chlorbutanol, meta cresol, esters of hydroxyl benzoic acid, phenol, and thimerosal.

41. The array of claim 1, wherein the first layer contains only a portion of the microprojections.

42. The array of claim 1, wherein the first layer is more readily degradable in the human body than the second layer.

43. The array of claim 1, wherein the second layer contains no active ingredient or a lower concentration of active ingredient than the first layer.

44. The array of claim 1, wherein the first layer controls the rate at which active ingredient is released from the microprojections.

45. The array of claim 1, wherein the first layer comprises a polymer selected from the group consisting of poly(lactic acid), poly(glycolic acid), poly(lactic acid-co-glycolic acid), poly(caprolactone), polyanhydrides, polyamines, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyphosphoesters, polyorthocarbonates, polyphosphazenes, poly(malic acid), poly(amino acids), hydroxycellulose, polyphosphoesters, poly(hydroxyl alkonates), polysaccharides, chitin, and copolymers, terpolymers and mixtures thereof.

46. The array of claim 1, wherein the array comprises at least one polymer with a molecular weight of at least about 10 kD.

47. The array of claim 1, wherein the array comprises at least one polymer with a molecular weight of at least about 22 kD.

48. The array of claim 1, wherein a boundary between two adjacent layers of the at least first and second layers exhibits a meniscus.

49. The array of claim 1, wherein the active ingredient comprises parathyroid hormone.

50. The array of claim 1, further comprising an antibacterial agent selected from the group consisting of benzalkonium chloride, benzyl alcohol, chlorbutanol, meta cresol, esters of hydroxyl benzoic acid, phenol, and thimerosal.

51. The array of claim 1, wherein the second layer contains the entire base and a portion of the microprotrusions.

52. The array of claim 51, wherein the second layer is comprised of a biodegradable polymer selected from poly(lactic acid) (PLA), poly(glycolic acid) (PGA) and poly(lactic acid-co-glycolic acid)s (PLGAs).

53. The array of claim 52, wherein the biodegradable polymer in the first layer is selected from dextran and tetrastarch.

54. The array of claim 1, wherein the number of microprotrusions in the array is at least about 100.

55. The array of claim 1, wherein the number of microprotrusions in the array is at least about 50 per cm² of base area.

56. The array of claim 1, wherein the biodegradable polymer in the first layer is selected from dextran and tetrastarch.

57. The array of claim 1, wherein the biodegradable polymer in the first layer is dextran, the component to facilitate biodegradation is sorbitol, and the active ingredient is parathyroid hormone.

58. The array of claim 1, wherein about 12-62.8 wt % of the first layer is comprised of the component to facilitate biodegradation.