Solvent-cast microprotrusion arrays containing active ingredient

• US 10,238,848 B2
• Filed: 07/01/2015
• Issued: 03/26/2019
• 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., Bayamov, Danir, Bowers, Danny Lee, Klemm, Andrew Richard, Klemm, Steven Richard, Chen, Guohua
• Primary Examiner(s): Hayman, Imani
• Application Number:
  US14/789,919
• Publication Number:
  US 20150297878A1
• Time in Patent Office: 1,364 Days
• 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 planar 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) one or more components to facilitate biodegradation selected from sugars, sugar alcohols, cyclodextrins and water-swellable polymers, and (iii) an active ingredient, wherein a ratio of weight percent of the biodegradable polymer to weight percent of the one or more components to facilitate biodegradation is in the range of about 6.25;

1 to about 1;

3.75.

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 the first layer comprises at least one of polyvinyl alcohol, dextran, and hydroxyethyl starch.

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

5. The array of claim 1, wherein the sugar alcohol is selected from sorbitol, lactitol, malitol or mannitol.

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

7. The array of claim 6, wherein the antioxidant is selected from 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 or ethanolamine.

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

9. The array of claim 8, 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.

10. 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, a polymethacrylate, a poly(hydroxyl alkanoate), poly(lactic acid), poly(glycolic acid), poly(lactic acid-co-glycolic acid), a polycaprolactone, or copolymers thereof.

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

12. The array of claim 11, wherein the active ingredient is selected from a vaccine, a therapeutic antibody or parathyroid hormone.

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

14. 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.

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

16. 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.

17. 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.

18. 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.