Granted Patent B2

US 10,384,046 · App. 14/210,402 · Granted Aug 20, 2019

Abstract

Claims (76)

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.

Assignments (13)