Biocompatible and bioabsorbable derivatized chitosan compositions

• US 9,547,011 B2
• Filed: 03/14/2014
• Issued: 01/17/2017
• Est. Priority Date: 03/14/2013
• Status: Active Grant

• Current Assignee: Tricol Biomedical, Inc. (Tricol International Group Ltd.)
• Original Assignee: Tricol Biomedical, Inc. (Tricol International Group Ltd.)
• Inventors: McGrath, Barbara, McCarthy, Simon, Kuhn, Sam, Wold, Alysha, Stolten, Michael, Bennett, Amanda
• Primary Examiner(s): Krishnan, Ganapathy
• Application Number:
  US14/211,632
• Publication Number:
  US 20140275291A1
• Time in Patent Office: 1,040 Days
• Field of Search: 514/23, 514/55, 514/777, 536/20, 536/55.3, 106/135.1
• US Class Current: 1/1
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: A61K 49/0008 Screening agents using (non-human) animal models or transgenic animal models or chimeric hosts, e.g. Alzheimer disease animal model, transgenic model for heart failure
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61L 2400/04 Materials for stopping bleeding
• CPC Class Codes: A61L 27/20 Polysaccharides
• CPC Class Codes: A61L 27/26 Mixtures of macromolecular compounds
• CPC Class Codes: A61L 27/58 Materials at least partially resorbable by the body
• CPC Class Codes: C08B 37/003 Chitin, i.e. 2-acetamido-2-deoxy-(beta-1,4)-D-glucan or N-acetyl-beta-1,4-D-glucosamine; Chitosan, i.e. deacetylated product of chitin or (beta-1,4)-D-glucosamine; Derivatives thereof
• CPC Class Codes: C08L 2201/06 Biodegradable
• CPC Class Codes: C08L 5/08 Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
• CPC Class Codes: C08L 89/06 derived from leather or skin , e.g. gelatin
• CPC Class Codes: G01N 2333/545 IL-1
• CPC Class Codes: G01N 2400/28 Chitin, chitosan
• CPC Class Codes: G01N 33/5014 for testing toxicity
• CPC Class Codes: G01N 33/6869 Interleukin

Abstract

The invention relates to biocompatible, bioabsorbable derivatized non-crosslinked chitosan compositions optionally crosslinked to gelatin/collagen by 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (EDC) for biomedical use and methods of making and testing such compositions, including a modified acute systemic toxicity test. The compositions comprise derivatized chitosan reacetylated to a degree of N-deacetylation (DDA) of between about 15% and 40%. The compositions are typically bioabsorbed in about 90 days or less and can be made to bioabsorb at differing rates of speed. The compositions are initially soluble in aqueous solution below pH 6.5. The compositions have an acid content that can be adjusted between about 0% (w/w) and about 8% (w/w) to customize the composition for uses that require and/or tolerate differing levels of cytotoxicity, adhesion, composition cohesion, and cell infiltration into the composition.

Claims

1. A biocompatible, bioabsorbable deacetylated and reacetylated chitosan composition comprising a reacetylated chitosan having a molecular weight of at least about 90 kDa to about 170 kDa and a degree of N-deacetylation of between about 15% and 40% cross-linked with at least one of gelatin and collagen.

2. The composition of claim 1, further comprising an acid content between about 0% (w/w) and 8% (w/w).

3. The composition of claim 1, wherein the ratio of chitosan to gelatin is selected from a group consisting of about 1:

1, about 2;

1, and about 3;

1.

4. The composition of claim 1, wherein the composition is capable of in vivo bioabsorption in less than about 90 days.

5. The composition of claim 4, wherein the composition is at least 85% absorbed.

6. The composition of claim 1, wherein the composition has a degree of N-deacetylation of between about 15% to 30%.

7. The composition of claim 1, wherein the composition comprises one of a freeze-dried sponge, a freeze-dried foam, a non-freeze-dried foam, an implant, a tissue scaffold, an implant device surface coating, a matrix, a fiber, a powder, a sheet, a film, a membrane, a nanofiber, a nanoparticle, and a hydrogel.

15. The composition of claim 1, further comprising an acid content between about 2% (w/w) and 5% (w/w).

16. The composition of claim 1, wherein the composition is freeze-dried.

17. The composition of claim 1, wherein the composition is foamed.

18. The composition of claim 1, wherein the reacetylated chitosan has a molecular weight of about 170 kDa.

27. The composition of claim 1, further comprising an acid content between about 1% (w/w) and 5% (w/w).

28. The composition of claim 1, wherein the composition has a degree of N-deacetylation of between about 20% to 30%.

30. The composition of claim 1, wherein the composition comprises chitosan that is initially soluble in an aqueous solution below or at about pH 6.5.

8. A method of making a biocompatible, bioabsorbable chitosan composition comprising:

obtaining deacetylated chitosan;

producing reacetylated chitosan from the deacetylated chitosan having a degree of N-deacetylation of between about 15% and 40%;

resolubilizing the reacetylated chitosan having a degree of N-deacetylation of between about 15% and 40% into an acidified aqueous solution;

volatilizing residual acid bound to the reacetylated chitosan having a degree of N-deacetylation of between about 15% and 40%; and

allowing an acid content between about 2% (w/w) and 8% (w/w) to remain.

9. The method of claim 8, further comprising selecting a deacetylated chitosan starting material having a purity of at least 99%.

10. The method of claim 8, further comprising reducing chitosan free amine functionality of deacetylated chitosan by at least one of reacetylation and derivatization of the glucosamine C-2 nitrogen with an electrophile.

11. The method of claim 8, further comprising cross-linking the composition by combining the reacetylated chitosan acidified aqueous solution and a gelatin aqueous solution.

12. The method of claim 8, further comprising cross-linking the reacetylated chitosan having a degree of N-deacetylation of between about 15% and 40% with at least one of gelatin and collagen.

13. The method of claim 12, further comprising using 1-ethyl-3-[3-dimethylaminopropyl] carbodiimide hydrochloride to accomplish the cross-linking.

14. The method of claim 8, further comprising processing the composition into a form selected from a group consisting of a freeze-dried sponge, a freeze-dried foam, a non-freeze-dried foam, an implant, a tissue scaffold, an implant device surface coating, a matrix, a fiber, a powder, a sheet, a film, a membrane, a nanofiber, a nanoparticle, and a hydrogel.

19. The method of claim 8, further comprising allowing an acid content of between about 2% (w/w) and 5% (w/w) to remain.

20. The method of claim 8, wherein the deacetylated chitosan has a degree of N-deacetylation of between 90% and about 100%.

21. The method of claim 8, further comprising resolubilizing the reacetylated chitosan having a degree of N-deacetylation of between about 15% and 40% into aqueous solution using carbonic acid.

22. The method of claim 8, further comprising at least one of freeze-drying and foaming the reacetylated chitosan having a degree of N-deacetylation of between about 15% and 40%.

23. The method of claim 8, wherein reacetylated chitosan having a degree of N-deacetylation of between about 15% and 30% is produced and is either volatilized or washed with water.

26. The method of claim 8, wherein the deacetylated chitosan has a degree of N-deacetylation of between 95% and about 100%.

29. The method of claim 8, wherein reacetylated chitosan having a degree of N-deacetylation of between about 20% and 30% is produced and is either volatilized or washed with water.

24. A biocompatible, bioabsorbable deacetylated and reacetylated chitosan composition having a degree of N-deacetylation of between about 15% and 30%.

25. A biocompatible, bioabsorbable deacetylated and reacetylated chitosan composition having a degree of N-deacetylation of between about 15% and 40% comprising an acid content between about 2% (w/w) and 5% (w/w).