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

Patent metadata

Field	Value
Publication number	US-10196349-B2
Application number	US-201514961133-A
Country	US
Kind code	B2
Filing date	Dec 7, 2015
Priority date	Aug 24, 2011
Publication date	Feb 5, 2019
Grant date	Feb 5, 2019

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 (NO)-releasing co-condensed silica macromolecule comprising:
a co-condensation of a first aminoalkoxysilane, a second aminoalkoxysilane, and an alkoxysilane, wherein the first aminoalkoxysilane and the second aminoalkoxysilane are different in chemical structure, and wherein the different first and second aminoalkoxysilanes are NO loaded prior to co-condensation.

2. The nitric oxide-releasing macromolecule of claim 1 , wherein the first aminoalkoxysilane is selected from N-(6-aminohexyl)aminopropyltrimethoxysilane (AHAP3); N-(2-aminoethyl)-3-aminopropyltrimethoxysilane (AEAP3); (3-trimethoxysilylpropyl)di-ethylenetriamine (DET3); (amino ethylaminomethyl)phenethyltrimethoxysilane (AEMP3); [3-(methylamino)propyl]trimethoxysilane (MAP3); N-butylamino-propyltrimethoxysilane(n-BAP3); t-butylamino-propyltrimethoxysilane(t-BAP3); N-ethylaminoisobutyltrimethoxysilane (EAiB3); N-phenylamino-propyltrimethoxysilane (PAP3); and N-cyclohexylaminopropyltrimethoxysilane (cHAP3), and
wherein the second aminoalkoxysilane is selected from N-(6-aminohexyl)aminopropyltrimethoxysilane (AHAP3); N-(2-aminoethyl)-3-aminopropyltrimethoxysilane (AEAP3); (aminoethylaminomethyl)phenethyltrimethoxysilane (AEMP3); [3-(methylamino)propyl]trimethoxysilane (MAP3); N-butylamino-propyltrimethoxysilane(n-BAP3); t-butylamino-propyltrimethoxysilane(t-BAP3); N-ethylaminoisobutyltrimethoxysilane (EAiB3); N-phenylamino-propyltrimethoxysilane (PAP3); and N-cyclohexylaminopropyltrimethoxysilane (cHAP3).

3. The nitric oxide-releasing macromolecule of claim 1 , wherein the first aminoalkoxysilane is [3-(methylamino)propyl]trimethoxysilane (MAP3), and the second aminoalkoxysilane is N-ethylaminoisobutyltrimethoxysilane (EAiB3).

4. The nitric oxide-releasing macromolecule of claim 1 , wherein the different first and second aminoalkoxysilanes provide different first and second diazeniumdiolate donor structures and at least one of the different first and second 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, optionally 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 + .

5. The nitric oxide-releasing macromolecule of claim 1 , wherein the different first and second aminoalkoxysilanes provide different first and second diazeniumdiolate donor structures and at least one of the 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 + .

6. The nitric oxide-releasing macromolecule of claim 1 , wherein the different first and second aminoalkoxysilanes provide different first and second diazeniumdiolate donor structures and at least one of the different first and second diazeniumdiolate donor structures has a NO release half life in a range from 30 seconds to 10 minutes and at least one of the different first and second diazeniumdiolate donor structures 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 the different first and second aminoalkoxysilanes provide different first and second diazeniumdiolate donor structures and at least one of the different first and second diazeniumdiolate donor structures has a NO release half life in a range from 30 seconds to 10 minutes and at least one of the different first and second diazeniumdiolate donor structures 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 the different first and second aminoalkoxysilanes provide different first and second diazeniumdiolate donor structures and at least one of the different first and second 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 of the different first and second diazeniumdiolate donor structures 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 the different first and second aminoalkoxysilanes provide different first and second diazeniumdiolate donor structures and at least one of the different first and second 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 of the different first and second diazeniumdiolate donor structures 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 1 , wherein the different first and second aminoalkoxysilanes provide different first and second diazeniumdiolate donor structures and at least one of the different first and second diazeniumdiolate donor structures comprises

wherein n is 1-5 and X + is Na + or K + .

11. The nitric oxide-releasing macromolecule of claim 1 , wherein the silica is present as particles having a mean particle size of less than 10 μm.

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

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

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

15. A kit comprising at least two wound dressings of claim 14 .

16. A method of treating a dermatological condition, comprising topically administering the NO releasing macromolecule of claim 1 in an amount effective to actively promote healing of a wound associated with the dermatological condition.

17. The method of claim 16 , wherein the dermatological condition comprises at least one of a wound, microbial infection and inflammation.

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

19. The nitric oxide-releasing macromolecule of claim 1 , wherein the NO-releasing macromolecule has a NO release profile that is different than a NO release of a physical mixture of the first aminoalkoxysilane and alkoxysilane co-condensed to provide a first single donor co-condensed silica macromolecule and the second aminoalkoxysilane and alkoxysilane co-condensed to provide a second single donor co-condensed silica macromolecule.

20. The nitric oxide-releasing macromolecule of claim 1 , wherein the NO-releasing macromolecule has increased stability compared to a single donor co-condensed silica macromolecule of the first aminoalkoxysilane and alkoxysilane and/or compared to a single donor co-condensed silica macromolecule of the second aminoalkoxysilane and alkoxysilane co-condensed.

Assignees

• Univ North Carolina Chapel Hill
• Novan Inc

Inventors

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

Classifications

• 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

• 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

• C07C247/10

  and containing rings · CPC title

• C07C291/02 Primary

  containing nitrogen-oxide bonds · CPC title