Tunable nitric oxide-releasing macromolecules having multiple nitric oxide donor structures

Patent metadata

Field	Value
Publication number	US-11124476-B2
Application number	US-201916555673-A
Country	US
Kind code	B2
Filing date	Aug 29, 2019
Priority date	Aug 24, 2011
Publication date	Sep 21, 2021
Grant date	Sep 21, 2021

Abstract

Provided here are nitric oxide-releasing compounds that include at least two different NO donor functional groups of the same class. In some embodiments, such nitric oxide-releasing compounds are macromolecules such as dendrimer and co-condensed silica. Pharmaceutical compositions, wound dressings, kits and methods of treatments are also provided herein.

First claim

That which is claimed:

1. A nitric oxide-releasing macromolecule comprising a dendrimer that comprises at least two different nitric oxide (NO) donor structures of the same class,
wherein the at least two different NO donor structures are different in chemical structure, and
wherein the at least two different NO donor structures are diazeniumdiolate donor structures and have different nitric oxide release kinetics.

2. The nitric oxide-releasing macromolecule of claim 1 , wherein at least one of the diazeniumdiolate donor structures has the formula—R—N(NONO − X + )—R′, wherein R is a divalent organic functional group, R′ is a monovalent organic functional group, and X + is a monovalent cation.

3. The nitric oxide-releasing macromolecule of claim 2 , wherein R is selected from alkylene or arylalkylene; R′ is selected from alkyl, substituted alkyl, alkylnitrile, aryl, substituted alkyl, alkylaryl, polyether and alkylamine; and X + is selected from Na + and K + .

4. The nitric oxide-releasing macromolecule of claim 1 , wherein at least one diazeniumdiolate donor structure comprises the structure:

wherein R is —CN, —COO(CH 2 CH 2 O) 6-12 H, —CH 3 , —CH 2 CH 3 , -Ph, —C 6 H 12 CH═CH 2 ; Z is —H or —OH; and X is Na + or K + .

5. The nitric oxide-releasing macromolecule of claim 1 , wherein the dendrimer comprises at least one of a polypropyleneimine dendrimer; a polyamidoamine (PAMAM) dendrimer; a polyarylether dendrimer; a polypeptide dendrimer; a polyamide dendrimer; a dendritic polyglycerol; and a triazine dendrimer.

6. The nitric oxide-releasing macromolecule of claim 1 , wherein at least one of the diazeniumdiolate donor structures has a NO release half life in a range from 30 seconds to 10 minutes and at least one diazeniumdiolate donor structure has a NO release half life of greater than 60 minutes, as determined in aqueous buffer at pH 7.4 and 37° C.

7. The nitric oxide-releasing macromolecule of claim 1 , wherein at least one of the diazeniumdiolate donor structures has a NO release half life in a range from 30 seconds to 10 minutes and at least one diazeniumdiolate donor structure has a NO release half life greater than 10 minutes but less or equal to 60 minutes, as determined in aqueous buffer at pH 7.4 and 37° C.

8. The nitric oxide-releasing macromolecule of claim 1 , wherein at least one of the diazeniumdiolate donor structures has a NO release half life of more than 10 minutes but less or equal to 60 minutes and at least one diazeniumdiolate donor structure has a NO release half life greater than 60 minutes, as determined in aqueous buffer at pH 7.4 and 37° C.

9. The nitric oxide-releasing macromolecule of claim 1 , wherein at least one of the diazeniumdiolate donor structures has a maximum flux of NO in a range from 2000 ppb NO/mg to 20,000 ppb NO/mg and a half life in a range from 0.1 to 1 hour, and at least one diazeniumdiolate donor structure has a maximum flux of NO in a range from 100 ppb NO/mg to 2000 pp NO/mg and a half life in a range from 1 hour to 5 hours, as determined in aqueous buffer at pH 7.4 and 37° C.

10. The nitric oxide-releasing macromolecule of claim 6 , wherein at least one of the diazeniumdiolate donor structures comprises the structure:

wherein R is —CN, —COO(CH 2 CH 2 O) 6-12 H, —CH 3 , —CH 2 CH 3 , -Ph, —C 6 H 12 CH═CH 2 ; Z is —H or —OH; and X is Na + or K + .

11. A pharmaceutical composition comprising the nitric oxide-releasing macromolecule of claim 1 , at least one excipient and, optionally, at least one additional therapeutic agent.

12. A kit comprising at least two pharmaceutical compositions of claim 11 .

13. A wound dressing comprising a polymer matrix and the NO releasing macromolecule of claim 1 .

14. A method of treating a dermatological condition, comprising topically administering the nitric oxide-releasing macromolecule of claim 1 in an amount effective to actively promote healing of a wound associated with the dermatological condition.

15. The method of claim 14 , wherein the dermatological condition comprises at least one of a wound, microbial infection and inflammation.

16. The method of claim 14 , wherein the dermatological condition comprises acne.

Assignees

• Univ North Carolina Chapel Hill
• Novan Inc

Inventors

• Schoenfisch Mark
• Lu Yuan
• Stasko Nathan
• Bao Jian

Classifications

• C07C291/02 Primary

  containing nitrogen-oxide bonds · CPC title

• A61K31/655

  Azo (—N=N—), diazo (=N2), azoxy (>N—O—N< or N(=O)—N<), azido (—N3) or diazoamino (—N=N—N<) compounds · CPC title

• C07C247/10

  and containing rings · CPC title

• C07C281/20 Primary

  the two nitrogen atoms of the functional groups being doubly-bound to each other, e.g. azoformamide · CPC title

• Y10T428/2982

  Particulate matter [e.g., sphere, flake, etc.] · CPC title