Method for increasing the permeability of an epithelial barrier

• US 10,342,965 B2
• Filed: 01/24/2017
• Issued: 07/09/2019
• Est. Priority Date: 04/28/2010
• Status: Active Grant

• Current Assignee: Sorrento Therapeutics Inc.
• Original Assignee: Sorrento Therapeutics Inc.
• Inventors: Ross, Russell Frederick
• Primary Examiner(s): Wax, Robert A
• Assistant Examiner(s): Al-Awadi, Danah
• Application Number:
  US15/413,475
• Publication Number:
  US 20170151424A1
• Time in Patent Office: 896 Days
• Field of Search: None
• CPC Class Codes: A61K 38/1793 for cytokines; for lymphokines; for interferons
• 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 2037/0053 Methods for producing microneedles
• CPC Class Codes: A61M 2037/0061 Methods for using microneedles
• CPC Class Codes: A61M 2205/0244 Micromachined materials, e.g. made from silicon wafers, microelectromechanical systems [MEMS] or comprising nanotechnology
• CPC Class Codes: A61M 37/0015 by using microneedles
• CPC Class Codes: A61N 1/306 Arrangements where at least part of the apparatus is introduced into the body

Abstract

Disclosed are nanotopography-based methods and devices for interacting with a component of epithelial tissue and increasing the permeability of the tissue. Devices include structures fabricated on a surface 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. Microneedles may be beneficially utilized for delivery of an agent to a cell or tissue. Devices may be utilized to directly or indirectly alter cell behavior through the interaction of a fabricated nanotopography with the components of epithelial tissue.

Claims

1. A method for increasing permeability of a cellular layer that comprises epithelial cells, the method comprising:

placing, in direct contact with the cellular layer, a microneedle device configured to deliver a drug compound thereto, the microneedle device comprising;

a support;

a plurality of microneedles extending from the support, each of the microneedles of the plurality of microneedles comprising a shaft extending from the support, the shaft including a tip and defining a channel extending from the support to the tip, the channel being sized and shaped for allowing the drug compound to pass therethrough; and

a plurality of nanostructures associated with each of the microneedles of the plurality of microneedles, at least some of the nanostructures of the plurality of nanostructures having a cross-sectional dimension from about 5 nanometers to about 500 nanometers, a height from about 10 nanometers to about 1 micrometer, and an aspect ratio from about 0.2 to about 5;

penetrating the cellular layer with at least some of the microneedles of the plurality of microneedles, the nanostructures associated with the at least some of the microneedles acting on the epithelial cells of the cellular layer to increase permeability of the cellular layer; and

delivering the drug compound through the channels in the shafts of the plurality of microneedles past the cellular layer while the cellular layer has increased permeability.

2. The method according to claim 1, wherein subsequent to delivering the drug compound, a transepithelial electrical resistance of the cellular layer is less than about 95% of the transepithelial electrical resistance of the cellular layer prior to contact with the microneedle.

3. The method according to claim 1, wherein subsequent to delivering the drug compound, a transepithelial electrical resistance of the cellular layer is less than about 85% of the transepithelial electrical resistance of the cellular layer prior to contact with the microneedle.

4. The method according to claim 1, wherein subsequent to delivering the drug compound, a transepithelial electrical resistance of the cellular layer is less than about 70% of the transepithelial electrical resistance of the cellular layer prior to contact with the microneedle.

5. The method according to claim 1, wherein the microneedle device further comprises a plurality of microstructures, and wherein each of the plurality of nanostructures has a cross-sectional dimension smaller than a cross-sectional dimension of each of the plurality of microstructures.

6. The method of claim 5, wherein the plurality of nanostructures includes a plurality of first nanostructures and a plurality of second nanostructures, wherein each second nanostructure of the plurality of second nanostructures has a cross-sectional dimension less than the cross-sectional dimension of each microstructure of the plurality of microstructures and greater than a cross-sectional dimension of each first nanostructure of the first plurality of nanostructures.

7. The method according to claim 1, wherein the cellular layer is skin.

8. The method according to claim 1, wherein penetrating the cellular layer with the at least some of the microneedles changes a structure of an intercellular junction.

9. The method according to claim 8, wherein the intercellular junction is a tight junction.

10. The method according to claim 1, wherein the drug compound is a protein therapeutic.

11. The method according to claim 10, wherein the drug compound has a molecular weight greater than about 100 kDa.

12. The method according to claim 1, wherein delivering the drug compound causes the drug compound to permeate across the cellular layer via paracellular transport.

13. The method according to claim 1, wherein delivering the drug compound causes the drug compound to permeate across the cellular layer via transcellular transport.

14. The method according to claim 1, wherein the plurality of nanostructures are arranged in a pattern having a fractal dimension greater than about 1.

15. The method according to claim 1, wherein the at least some of the nanostructures of the plurality of nanostructures have a cross-sectional dimension from about 100 to about 300 nanometers.

16. The method according to claim 1, wherein each nanostructure of the plurality of nanostructures has approximately the same cross-sectional dimension as one another.

17. The method according to claim 1, wherein the at least some of the nanostructures of the plurality of nanostructures have a center-to-center spacing from about 50 nanometers to about 1 micrometer.

18. The method according to claim 1, wherein a ratio of an average of a cross sectional dimension of two adjacent nanostructures to a center-to-center spacing between the two adjacent nanostructures is between about 1:

1 and about 1;

4.

19. The method according to claim 1, wherein the at least some of the nanostructures of the plurality of nanostructures have an equidistant spacing.

20. The method according to claim 1, wherein the at least some of the nanostructures of the plurality of nanostructures have a height from about 100 nanometers to about 700 nanometers.

21. The method according to claim 1, wherein each of the plurality of nanostructures is in a form of pillars.

22. The method according to claim 1, wherein the drug compound is a TNF-α

blocker.

23. The method according to claim 1, wherein the microneedle device includes a nanopatterned film disposed on each of the microneedles of the plurality of microneedles, the nanopatterned film including the plurality of nanostructures.

24. The method according to claim 23, the nanopatterned film further includes a microstructure, wherein the plurality of nanostructures includes a first nanostructure and a second nanostructure, and wherein each of the first nanostructure, the second nanostructure, and the microstructure has a cross-sectional dimension that is different from one another.