Water soluble nitric oxide-releasing polyglucosamines and uses thereof

Patent metadata

Field	Value
Publication number	US-10759877-B2
Application number	US-201715836121-A
Country	US
Kind code	B2
Filing date	Dec 8, 2017
Priority date	Aug 17, 2012
Publication date	Sep 1, 2020
Grant date	Sep 1, 2020

Abstract

The presently disclosed subject matter provides nitric oxide-releasing polysaccharides and oligosaccharides, in particular, polyglucosamines, and their use in biomedical and pharmaceutical applications. More particularly, in some embodiments, the presently disclosed subject matter provides nitric oxide-releasing polysaccharides and oligosaccharides that release nitric oxide in a controlled and targeted manner, thereby prolonging the therapeutic effects of nitric oxide and improving the specificity of nitric oxide delivery to targeted cells and/or tissues.

First claim

That which is claimed is:

1. A polyglucosamine comprising,
at least one structural unit:

and optionally, at least one structural unit:

wherein,
i. R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 , are each hydrogen;
ii. is a single bond;
iii. Q is —(CR c R d ) v —; wherein R c and R d are hydrogen and v is 2;
iv. p is an integer from 1 to 10;
v. A is

wherein, L is N and G is hydrogen;
vi. X is taken together with N to form a nitric oxide donor;
vii. B is hydrogen; and
viii. D is —NR a R b , wherein R a and R b are hydrogen.

2. The polyglucosamine of claim 1 , wherein p is 1.

3. The polyglucosamine of claim 1 , wherein the nitric oxide donor taken together with the atom on the polyglucosamine to which it is bound is selected from the group consisting of a diazeniumdiolate, nitrosothiol, a nitrosamine, a hydroxyl nitrosamine, a hydroxyl amine, a hydroxyurea, and combination thereof.

4. The polyglucosamine of claim 1 , wherein the nitric oxide donor is diazeniumdiolate.

5. The polyglucosamine of claim 1 , wherein the polyglucosamine is water soluble.

6. The polyglucosamine of claim 1 , wherein the polyglucosamine is water soluble such that >50 mg of the polyglucosamine dissolves per mL of water.

7. The polyglucosamine of claim 1 , wherein the polyglucosamine is water soluble such that >75 mg of the polyglucosamine dissolves per mL of water.

8. The polyglucosamine of claim 1 , wherein the polyglucosamine is water soluble such that >100 mg of the polyglucosamine dissolves per mL of water.

9. The polyglucosamine of claim 1 , wherein the viscosity average molecular weight (M v ) as determined by the equation [η]=1.81×10 −3 M v 0.93 is between about 2000 and about 11000 g/mol.

10. The polyglucosamine of claim 1 , wherein the viscosity average molecular weight (My) as determined by the equation [η]=1.81×10 −3 M v 0.93 is between about 3000 and about 6000 g/mol.

11. The polyglucosamine of claim 1 , wherein the elemental composition is:
between about 40% and about 50% C;
between about 6% and about 9% H; and
between about 3% and about 11% N.

12. The polyglucosamine of claim 1 , wherein the elemental composition is:
between about 42% and about 51% C;
between about 6% and about 9% H; and
between about 3% and about 11% N.

13. The polyglucosamine of claim 1 , wherein the polyglucosamine includes greater than about 0.3 μmol/mg of releasable nitric oxide.

14. The polyglucosamine of claim 1 , wherein the polyglucosamine includes greater than about 0.8 μmol/mg of releasable nitric oxide.

15. A method of delivering nitric oxide to a subject, comprising:
administering an effective amount of the polyglucosamine of claim 1 to the subject.

16. A method of treating a disease state, comprising:
administering an effective amount of the polyglucosamine of claim 1 to a subject in need thereof, wherein the disease state is selected from the group consisting of a cancer, a cardiovascular disease, a microbial infection; platelet aggregation and platelet adhesion caused by the exposure of blood to a medical device; pathological conditions resulting from abnormal cell proliferation; transplantation rejections, autoimmune diseases, inflammation, vascular diseases; scar tissue; wound contraction, restenosis, pain, fever, gastrointestinal disorders, respiratory disorders, sexual dysfunctions, and sexually transmitted diseases.

17. The method of claim 16 , wherein said disease state is cystic fibrosis.

18. A pharmaceutical formulation comprising:
the polyglucosamine of claim 1 ; and
a pharmaceutically acceptable carrier.

Assignees

• Univ North Carolina Chapel Hill

Inventors

• Schoenfisch Mark H
• Lu Yuan

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P15/10

  for impotence · CPC title

• A61P17/02

  for treating wounds, ulcers, burns, scars, keloids, or the like · CPC title

• C08B37/003 Primary

  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 title

• C08L5/08

  Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof · CPC title