Microarray for delivery of therapeutic agent and methods of use

• US 10,384,046 B2
• Filed: 03/13/2014
• Issued: 08/20/2019
• Est. Priority Date: 03/15/2013
• Status: Active Grant

• Current Assignee: Corium Pharma Solutions, Inc.
• Original Assignee: Corium, Inc.
• Inventors: Bayramov, Danir, Chen, Guohua, Ding, Zhongli, Ghartey-Tagoe, Esi, Singh, Parminder, Bourne, Doug
• Primary Examiner(s): Park, H. Sarah
• Application Number:
  US14/210,402
• Publication Number:
  US 20140276589A1
• Time in Patent Office: 1,986 Days
• 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 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 37/0015 by using microneedles
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 9/12 Antihypertensives

Abstract

Microstructure arrays and methods for using and manufacturing the arrays are described.

Claims

1. A microstructure apparatus, comprising:

an approximately planar substrate having a first surface and a second surface opposed thereto; and

a microstructure array comprising a plurality of microstructures contacting the first surface of the substrate and fixedly attached thereto, at least a distal end of the microstructures being formed of a polymer matrix comprising at least one of;

(a) a formulation comprising;

(i) at least one low molecular weight polymer having a molecular weight of between about 1-10K Da,

(ii) at least one high molecular weight polymer having a molecular weight of between about 50-300K Da, where the ratio of low molecular weight polymer to high molecular weight polymer is about 4;

1, and

(iii) at least one therapeutic agent;

or

(b) a formulation comprising;

(i′

) at least one water-insoluble biodegradable polymer,

(ii′

) a hydrophilic component at about 10-20% of the polymer matrix, and

(iii′

) at least one therapeutic agent; and

wherein the polymer matrix is prepared by a process comprising dissolving the at least one therapeutic agent in a polymer solution and dispensing the polymer solution on a mold having an array of microstructure cavities, whereby the therapeutic homogenously in the polymer matrix forming the at least distal end of the microstructures;

wherein the polymer matrix is composed to thereby release the therapeutic agent from the polymer matrix sustained for a period of time, the period of time having a minimum duration of about 1 hour; and

wherein the polymer matrix is composed to release the therapeutic agent from the polymer matrix at an initial release rate of about 0.05-10%/minute.

2. The microstructure apparatus of claim 1, wherein at least one of the low molecular weight polymer, the high molecular weight polymer, and the water-insoluble biodegradable polymer is selected from polylactide, polyglycolide, and co-polymers thereof.

3. The microstructure apparatus of claim 1, wherein the polymer matrix of (b) comprises at least one of:

i) about 1-50% therapeutic agent; and

ii) about 50-99% of the water-insoluble biodegradable polymer.

4. The microstructure apparatus of claim 1, wherein at least a portion of the microstructures are detachable from the substrate.

5. The microstructure apparatus of claim 1, wherein the therapeutic agent is selected from a drug, a small molecule, a peptide or protein, or a vaccine.

6. The microstructure apparatus of claim 1, wherein the polymer matrix comprises the formulation of part (a).

7. The microstructure apparatus of claim 1, wherein the polymer matrix of (b) comprises about 15-20% of the hydrophilic component.

8. The microstructure apparatus of claim 1, wherein the hydrophilic component of (b) is polyethylene glycol-polylactic-co-glycolic acid (PEG-PLGA).

9. The microstructure apparatus of claim 1, wherein the biodegradable polymer of (b) is a hydrophobic polymer selected from, α

-hydroxy acids, polycaprolactones, polyanhydrides, and co-polymers thereof.

10. The microstructure apparatus of claim 9, wherein the α

-hydroxy acid is polylactic-co-glycolic acid (PLGA).

11. The microstructure apparatus of claim 1, wherein the ratio of therapeutic agent to polymer in the polymer matrix is between about 1:

2 to 1;

25.

12. The microstructure apparatus of claim 1, further comprising:

a backing layer positioned between a proximal portion of the plurality of microstructures and the substrate, the backing layer being formed of a second polymer matrix comprising

(i) a biodegradable polymer, and

(ii) the at least one therapeutic agent.

13. The microstructure apparatus of claim 1, further comprising:

an adhesive coating applied to at least one of

i) at least a portion of at least some of the plurality of microstructures,

ii) at least a portion of the substrate first surface between the microstructures, or

iii) the apparatus further including a plurality of openings extending through the substrate and positioned between at least some of the plurality of microstructures, the adhesive coating being applied to at least a portion of the substrate second surface such that the adhesive is capable of contacting a subject'"'"'s skin through the openings when placed on the skin.

14. The microstructure apparatus of claim 13, wherein the adhesive coating comprises an adhesive selected from a medical adhesive, a tissue adhesive, a surgical adhesive, a fibrin adhesive, a bioactive film, a pressure sensitive adhesive, or a rubber-based adhesive.

15. The microstructure apparatus of claim 14, wherein the medical adhesive is selected from acrylic adhesives, silicone based adhesives, hydrogel adhesives, and synthetic elastomer adhesives.

16. The microstructure apparatus of claim 14, wherein the tissue adhesive is a cyanoacrylate polymer.

17. The microstructure apparatus of claim 16, wherein the cyanoacrylate polymer is selected from n-butyl-2-cyanoacrylate, and isobutyl cyanoacrylate.

18. The microstructure apparatus of claim 13, wherein the adhesive coating is non-continuous.

19. A method of making the microstructure apparatus of claim 1, where the microstructure apparatus is a sustained release microstructure apparatus comprising a polymer matrix comprising the formulation of part (b), the method comprising:

(a) dissolving or suspending the therapeutic agent in a first solvent to form a therapeutic agent solution or suspension;

(b) dissolving the at least one water insoluble, biodegradable polymer in a second solvent to form a polymer solution, wherein the second solvent can be the same or different from the first solvent;

(c) mixing the therapeutic agent solution or suspension and the polymer solution to form a polymer matrix solution or suspension;

(d) dispensing the polymer matrix solution or suspension on a mold having an array of microstructure cavities;

(e) filling the microstructure cavities in the mold;

(f) removing excess solution or suspension polymer matrix on the mold surface;

and drying the matrix to form a plurality of microstructures;

(g) dispensing a basement or backing layer on the mold surface; and

(h) drying the basement or backing layer.

20. The method of claim 19, further comprising:

affixing the basement or backing layer to a substrate.

21. The method of claim 19, wherein at least one of the first solvent and the second solvent is selected from DMSO and acetonitrile.

22. The method of claim 19, wherein filling the microstructure cavities further comprises pressurizing the mold.

23. The method of claim 19, wherein the therapeutic agent is crystalline, further comprising:

heating the plurality of microstructures to about 110°

C. for about 1 hour; and

storing the microstructures in a dry cabinet for about 10 days.

24. The method of claim 19, further comprising selecting the first solvent and the second solvent for preparing the polymer matrix that provides the desired initial release rate.

25. The method of claim 24, wherein selecting the first solvent or the second solvent comprises:

i) selecting DMSO to lower the initial release rate;

or

ii) selecting acetonitrile to increase the initial release rate.

26. A method of delivering a therapeutic agent to a subject for an extended period of time, comprising:

applying the microstructure apparatus of claim 1 to a skin site of the subject;

adhering the microstructure apparatus to the skin;

delivering the therapeutic agent from the microstructure array to the subject; and

removing the microstructure apparatus after at least about 10 minutes.

27. The method of claim 26, wherein the microstructure apparatus is removed after at least about 15 minutes to 5 days.

28. The method of claim 26, comprising delivering at least about 10-100% of a total dose of the therapeutic agent to the subject.

29. The method of claim 26, further comprising:

wherein applying the microstructure apparatus comprises;

positioning the microstructure apparatus on a plunger of an applicator;

actuating the applicator to release the plunger;

impacting the skin with the microstructure apparatus;

removing the applicator with the microstructure apparatus remaining on the skin site for an extended period of time.

30. The microstructure apparatus of claim 9, wherein the α

-hydroxy acid is polylactide (PLA).

31. The microstructure apparatus of claim 1, wherein the polymer matrix is composed to thereby release the therapeutic agent from the polymer matrix sustained for a period of time, the period of time having a minimum duration of about 144 hours.