Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications

• US 8,282,967 B2
• Filed: 06/24/2011
• Issued: 10/09/2012
• Est. Priority Date: 05/27/2005
• Status: Active Grant

• Current Assignee: LNHC Incorporated, University of North Carolina At Chapel Hill (University of North Carolina System)
• Original Assignee: University of North Carolina At Chapel Hill (University of North Carolina System)
• Inventors: Schoenfisch, Mark H., Shin, Jae Ho, Stasko, Nathan
• Primary Examiner(s): Wax, Robert A
• Assistant Examiner(s): Park, H. Sarah
• Application Number:
  US13/168,597
• Publication Number:
  US 20120021055A1
• Time in Patent Office: 473 Days
• Field of Search: None
• US Class Current: 424/718
• CPC Class Codes: A61K 31/695 Silicon compounds
• CPC Class Codes: A61K 41/0042 Photocleavage of drugs in vivo, e.g. cleavage of photolabile linkers in vivo by UV radiation for releasing the pharmacologically-active agent from the administered agent; photothrombosis or photoocclusion
• CPC Class Codes: A61K 47/59 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
• CPC Class Codes: A61K 47/6923 the form being an inorganic particle, e.g. ceramic particles, silica particles, ferrite or synsorb
• CPC Class Codes: A61K 47/6929 the form being a nanoparticle, e.g. an immuno-nanoparticle
• CPC Class Codes: A61K 9/14 Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51
• CPC Class Codes: A61K 9/167 with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface with further drug-free outer coating A61K9/5073
• CPC Class Codes: A61K 9/5115 Inorganic compounds
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 39/00 : General protective or antinoxious agents
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: B82Y 10/00 : Nanotechnology for information processing, storage or transmission, e.g. quantum computing or single electron logic
• CPC Class Codes: B82Y 30/00 : Nanotechnology for materials or surface science, e.g. nanocomposites
• CPC Class Codes: B82Y 5/00 : Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: C07F 7/10 : containing nitrogen having a Si-N linkage
• CPC Class Codes: C07F 7/18 : Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages

Abstract

The presently disclosed subject matter relates to nitric oxide-releasing particles for delivering nitric oxide, and their use in biomedical and pharmaceutical applications.

Claims

1. A nitric oxide-releasing particle, the nitric oxide-releasing particle comprising:

a co-condensed silica network comprising a nitric oxide donor, wherein the nitric oxide donor is formed prior to condensation of the co-condensed silica network, wherein the co-condensed silica network is synthesized from the condensation of a silane mixture comprising an alkoxysilane and at least one aminoalkoxysilane having an amine substituted by a diazeniumdiolate.

2. The nitric oxide-releasing particle of claim 1, wherein the alkoxysilane comprises a tetraalkoxysilane of the formula Si(OR)₄, wherein R is alkyl;

and the aminoalkoxysilane has the formula R″

—

N(NONO⁻

X⁺)—

R′

—

Si(OR)₃, wherein R is alkyl, R′

is alkylene or aralkylene, R″

is alkyl or alkylamine, and X⁺is a cation selected from the group consisting of Na⁺ and K⁺.

3. The nitric oxide-releasing particle of claim 2, wherein the silane mixture comprises between about 10 mol % to about 99 mol % of the tetraalkoxysilane and about 1 mol % to about 90 mol % of the aminoalkoxysilane having an amine substituted by a diazeniumdiolate.

4. The nitric oxide-releasing particle of claim 3, wherein the silane mixture further comprises about 0 mol % to about 20 mol % of a fluorinated silane;

about 0 mol % to about 20 mol % of a cationic or anionic silane; and

about 0 mol % to about 20 mol % of an alkylsilane.

5. The nitric oxide-releasing particle of claim 2, wherein the tetraalkoxysilane is selected from the group consisting of tetraniethyl orthosilicate and tetraethyl orthosilicate.

6. The nitric oxide-releasing particle of claim 4, wherein the fluorinated silane is selected from the group consisting of:

(heptadecafluoro-1,1,2,2-tetrahydrodecyl)triethoxysilane;

(3,3,3-trifluoropropyl)trimethoxysilane; and

(perfluoroalkyl)ethyltriethoxysilane.

7. The nitric oxide-releasing particle of claim 4, wherein the cationic or anionic silane is selected from the group consisting of:

N—

N-didecyl-N-methyl-N-(3-trimethoxysilylpropyparrimoniurn chloride;

octadecyldimethyl(3-trimethoxysilylpropyl)ammonium chloride;

3-trihydroxysilylpropylmethyl phosphonate, sodium salt; and

carboxylethylsilanetriol, sodium salt.

8. The nitric oxide-releasing particle of claim 4, wherein the alkylsilane is selected from the group consisting of methyltrimethoxysilane, butyltrimethoxysilarie, butyltriethoxysilane, propyltrimethoxysilane, and octadecyltrimethoxysilane.

9. The nitric oxide-releasing particle of claim 1, wherein the particle has a diameter of from about 1 nm to about 1000 nm.

10. The nitric oxide-releasing particle of claim 1, wherein the particle has a diameter of from about 1 nm to about 5 nm.

11. The nitric oxide-releasing particle of claim 1, wherein the particle has a diameter of from about 2 nm to about 10 μ

m.