Transdermal delivery of high viscosity bioactive agents

• US 10,213,588 B2
• Filed: 01/20/2017
• Issued: 02/26/2019
• Est. Priority Date: 10/27/2011
• Status: Active Grant

• Current Assignee: Sorrento Therapeutics Inc.
• Original Assignee: Sorrento Therapeutics Inc.
• Inventors: Ross, Russell F.
• Primary Examiner(s): Eisenberg, Rebecca E
• Application Number:
  US15/411,318
• Publication Number:
  US 20170128707A1
• Time in Patent Office: 767 Days
• CPC Class Codes: A61K 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 31/5575 having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
• CPC Class Codes: A61K 31/70 Carbohydrates; Sugars; Derivatives thereof sorbitol A61K31/047
• CPC Class Codes: A61K 38/1808 Epidermal growth factor [EGF] urogastrone
• CPC Class Codes: A61K 38/191 Tumor necrosis factors [TNF], e.g. lymphotoxin [LT], i.e. TNF-beta
• CPC Class Codes: A61K 38/20 Interleukins [IL]
• CPC Class Codes: A61K 38/21 Interferons [IFN]
• CPC Class Codes: A61K 38/26 Glucagons
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 9/0021 Intradermal administration, e.g. through microneedle arrays, needleless injectors mechanical aspects A61M
• CPC Class Codes: A61M 2037/0007 having means for enhancing the permeation of substances through the epidermis, e.g. using suction or depression, electric or magnetic fields, sound waves or chemical agents
• CPC Class Codes: A61M 2037/0023 Drug applicators using microneedles
• CPC Class Codes: A61M 2037/003 having a lumen
• CPC Class Codes: A61M 2037/0038 having a channel at the side surface
• 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 37/0015 by using microneedles

Abstract

A device and method for delivering a high viscosity composition is described. The composition includes a bioactive agent for delivery to a subject in need thereof. The method delivers the bioactive agent at a high bioavailability and with little loss of agent to the natural defense mechanisms of the body. The device includes one or more microneedles with structures fabricated on a surface of the microneedles to form a nanotopography. A random or non-random pattern of structures may be fabricated such as a complex pattern including structures of differing sizes and/or shapes.

Claims

1. A device for delivery of a bioactive agent across a dermal barrier, the device comprising:

a microneedle and a plurality of nanostructures and microstructures fabricated on a surface of the microneedle, the nanostructures and microstructures being arranged in a predetermined pattern, wherein at least a portion of the microstructures have a cross-sectional dimension of greater than about 500 nanometers and less than about 10 micrometers and a height of from about 20 nanometers to about 1 micrometer, and wherein at least a portion of the nanostructures have a cross-sectional dimension of less than about 500 nanometers and greater than about 5 nanometers and an aspect ratio of from about 0.2 to about 5, wherein the microneedle further contains a channel; and

a reservoir that is in fluid communication with the channel of the microneedle and that contains a composition having a viscosity of greater than about 5 centipoise and comprising a bioactive agent.

2. The device according to claim 1, wherein the composition includes the bioactive agent in a concentration of greater than about 5 mg/mL.

3. The device according to claim 1, wherein the bioactive agent has a molecular weight of greater than about 100 kDa.

4. The device according to claim 1, wherein the bioactive agent is a protein therapeutic.

5. The device according to claim 1, the composition further comprising one or more pharmaceutically acceptable excipients.

6. The device according to claim 5, wherein the pharmaceutically acceptably excipient comprises a solvent, a penetration enhancer, a thickening agent, a wetting agent, a lubricant, or an emollient.

7. The device according to claim 1, wherein the microstructures have a cross-sectional dimension of greater than about 500 nanometers and the nanostructures have a cross-sectional dimension of less than about 300 nanometers.

8. The device according to claim 1, further comprising second nanostructures having a cross-sectional dimension less than the cross-sectional dimension of the microstructures and greater than the cross-sectional dimension of the first nanostructures.

9. The device according to claim 1, wherein at least a portion of the nanostructures have:

center-to-center spacing of from about 50 nanometers to about 1 micrometer.

10. The device according to claim 1, wherein the pattern has a fractal dimension of greater than about 1.

11. The device according to claim 1, wherein the microneedle surface containing the plurality of nanostructures has an average surface roughness between about 10 nanometers and about 200 nanometers.

12. The device according to claim 1, wherein the composition has a viscosity of from about 10 centipoise to about 50 centipoise.

13. The device according to claim 1, wherein the composition includes the bioactive agent in a concentration of from about 35 mg/mL to about 500 mg/mL.

14. The device according to claim 1, wherein at least a portion of the nanostructures have a height of from about 10 nanometers to about 1 micrometer.

15. The device according to claim 1, wherein at least a portion of the nanostructures have an aspect ratio of from about 0.5 to about 3.5.

16. The device according to claim 1, wherein the microneedle surface containing the plurality of nanostructures has an effective shear modulus between about 4 MPa and about 320 MPa.

17. The device according to claim 1, wherein at least a portion of the nanostructures have a cross-sectional dimension of from about 100 to about 300 nanometers.

18. The device according to claim 1, wherein the nanostructures have approximately the same cross-sectional dimension.

19. The device according to claim 1, wherein the ratio of the cross sectional dimension of two adjacent nanostructures to the center-to-center spacing between those two structures is between about 1:

1 and about 1;

4.

20. The device according to claim 1, wherein at least a portion of the nanostructures have an equidistant spacing.

21. The device according to claim 1, wherein at least a portion of the nanostructures are in the form of pillars.

22. The device according to claim 1, wherein the channel has a cross-sectional dimension of from about 1 to about 100 micrometers.

23. The device according to claim 22, wherein the channel has a length of from about 10 to about 800 micrometers.

24. The device according to claim 1, wherein the device contains a microneedle array that contains the microneedle.

25. The device according to claim 24, wherein the array contains a base having an aperture, wherein the aperture is in at least partial alignment with the channel of the microneedle.

26. The device according to claim 25, wherein the reservoir is attached to a substrate upon which the array is located.

27. The device according to claim 25, wherein the reservoir is removably connected to the array.

28. The device according to claim 1, wherein at least a portion of the nanostructures have a cross-sectional dimension of from about 20 to about 400 nanometers and at least a portion of the microstructures have a cross-sectional dimension of from about 600 nanometers to about 1.5 micrometers.

29. The device according to claim 1, wherein at least a portion of the microstructures have an aspect ratio of from about 0.2 to about 5.

30. The device according to claim 1, wherein the cross-sectional dimension of the microstructures is greater than the height of the microstructures.

31. The device according to claim 30, wherein at least a portion of the microstructures have an aspect ratio of from about 0.15 to 1.

32. The device according to claim 1, wherein at least a portion of the nanostructures have a height greater than a cross-sectional dimension.

33. A method for delivering a bioactive agent to a subject comprising:

penetrating the stratum corneum of the subject with a microneedle, the microneedle comprising a plurality of nanostructures and microstructures fabricated on a surface of the microneedle, the nanostructures and microstructures being arranged in a predetermined pattern, wherein at least a portion of the microstructures have a cross-sectional dimension of greater than about 500 nanometers and less than about 10 micrometers and a height of from about 20 nanometers to about 1 micrometer, and wherein at least a portion of the nanostructures have a cross-sectional dimension of less than about 500 nanometers and greater than about 5 nanometers and an aspect ratio of from about 0.2 to about 5; and

transporting a composition through the microneedle at a rate of greater than about 0.4 mg/hr/cm² based upon the surface area of the microneedle.

34. The method according to claim 33, wherein the stratum corneum is a layer of the subject'"'"'s skin, the skin including tight junctions between cells of the skin, the nanostructures rearranging tight junctions between the cells, thereby increasing porosity of the skin.

35. The method according to claim 34, wherein the rearrangement of the tight junctions leads to an increase in the porosity of a second tissue type that is not in contact with the microneedle.

36. The method according to claim 35, wherein the second tissue type is vascular tissue.

37. The method according to claim 33, wherein the composition has a viscosity of greater than about 5 centipoise.