Medical devices for delivery of siRNA

• US 9,522,262 B2
• Filed: 04/27/2011
• Issued: 12/20/2016
• Est. Priority Date: 04/28/2010
• Status: Active Grant

• Current Assignee: Sorrento Therapeutics Inc.
• Original Assignee: Kimberly-Clark Worldwide Incorporated (Kimberly-Clark Corporation)
• Inventors: Ross, Russell Frederick
• Primary Examiner(s): Stigell, Theodore
• Assistant Examiner(s): Stiles, Amber
• Application Number:
  US13/641,502
• Publication Number:
  US 20130158505A1
• Time in Patent Office: 2,064 Days
• US Class Current: 1/1
• CPC Class Codes: A61M 2037/0023 Drug applicators using microneedles
• CPC Class Codes: A61M 2037/0038 having a channel at the side surface
• CPC Class Codes: A61M 2037/0053 Methods for producing microneedles
• CPC Class Codes: A61M 2037/0061 Methods for using microneedles
• CPC Class Codes: A61M 37/00 Other apparatus for introducing media into the body for reproduction or fertilisation A61B17/425; apparatus for iontophoresis or cataphoresis A61N1/30; Percutany, i.e. introducing medicines into the body by diffusion through the skin salt baths A61H33/04
• CPC Class Codes: A61M 37/0015 by using microneedles
• CPC Class Codes: A61M 5/158 Needles for infusions; Accessories therefor, e.g. for inserting infusion needles, or for holding them on the body
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12N 15/89 using microinjection
• CPC Class Codes: C12N 2310/14 interfering N.A.
• CPC Class Codes: Y10T 29/49826 Assembling or joining

Abstract

Disclosed are medical devices that incorporate siRNA. In addition to one or more siRNA constructs, devices include nanostructures 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 incorporated on devices. The pattern including nanostructures may be formed on the surface of the microneedles.

Claims

1. A device for delivery of an siRNA construct across a dermal barrier, the device comprising:

a microneedle and a plurality of nanostructures and microstructures projecting directly outward from a surface of the microneedle 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 an siRNA construct.

2. The device of 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.

3. The device of claim 1, wherein at least a portion of the nanostructures have a center-to-center spacing of from about 50 nanometers to about 1 micrometer.

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

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

6. The device of claim 1, wherein the siRNA agent includes a duplexed region of between about 20 and about 30 pairs.

7. The device of claim 1, at least one strand of the siRNA including a 3′

overhang of two or three nucleotides.

8. The device of claim 1, the siRNA agent comprising additional nucleotides or nucleotide analogue.

9. The device of claim 1, wherein the siRNA agent comprises a nucleotide sequence that is identical to a portion of a targeted gene.

10. The device of claim 1, wherein the siRNA agent includes insertions, deletions, or single point mutations compared to a portion of a targeted gene.

11. The device of claim 1, wherein the siRNA agent is a single strand siRNA.

12. The device of any of claim 1, wherein the siRNA comprises a ligand tethered to the siRNA.

13. The device of claim 1, wherein the siRNA agent is incorporated into a delivery vehicle.

14. The device of claim 1, wherein the siRNA construct comprises a vector.

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

16. 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.

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

18. 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.

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

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

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

22. The device according to claim 21, wherein the channel has a length of from about 10 to about 800 micrometers.

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

24. The device according to claim 23, wherein the array contains a base having an aperture, wherein the aperture is in at least partial alignment with the channel of the microneedle.

25. The device according to claim 24, wherein the reservoir is attached to a substrate upon which the array is located.

26. The device according to claim 24, wherein the reservoir is removably connected to the array.

27. 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.

28. 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.

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

30. The device according to claim 29, wherein at least a portion of the microstructures have an aspect ratio of from about 0.15 to 1.

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

32. A method for delivering an siRNA construct across a dermal barrier, the method comprising:

penetrating a stratum corneum with a microneedle having a surface on which a plurality of nanostructures and microstructures project directly outward therefrom in a predetermined pattern, wherein the microneedle further contains a channel, wherein at least a portion of the microstructures nave 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-section dimension of less than about 500nanometers and greater than about 5 nanometers and an aspect ratio of from about 0.2 to about 5,

transporting an siRNA construct from a reservoir through the channel of the microneedle and across the stratum corneum.