Nitric oxide delivery system using thermosensitive synthetic polymers

• US 9,212,259 B2
• Filed: 10/04/2011
• Issued: 12/15/2015
• Est. Priority Date: 10/04/2010
• Status: Active Grant

• Current Assignee: Postech Academy-Industry Foundation
• Original Assignee: Postech Academy-Industry Foundation
• Inventors: Kim, Won Jong, Lee, Yanggy, Park, Kwideok, Kim, Jihoon, Han, Dong Keun
• Primary Examiner(s): Arnold, Ernst V
• Application Number:
  US13/877,384
• Publication Number:
  US 20130189340A1
• Time in Patent Office: 1,533 Days
• US Class Current: 1/1
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• CPC Class Codes: A61L 2300/114 Nitric oxide, i.e. NO
• CPC Class Codes: A61L 27/34 Macromolecular materials
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• CPC Class Codes: C08G 63/6852 derived from hydroxy carboxylic acids
• CPC Class Codes: C08G 73/0206 Polyalkylene(poly)amines
• CPC Class Codes: C08G 73/024 Polyamines containing oxygen in the form of ether bonds in the main chain
• CPC Class Codes: C08L 71/02 Polyalkylene oxides

Abstract

A donor capable of controlled release of nitric monoxide and a prosthetic implant whose surface is coated with this donor are disclosed. The donor comprises a main chain of an organic polymer and a side chain that is covalently linked to the main chain and has a diazeniumdiolate functional group. The donor for controlled release of nitric monoxide exists in a fluid state such as liquid at room temperature and undergoes a sol-to-gel phase transition at a physiological pH as the temperature increases above the critical temperature. The critical temperature of the phase transition is in the range of 25 to 35° C., and the gel is a hydrogel without chemical cross-links.

Claims

1. A donor for controlled release of nitric oxide, wherein the donor comprises a polymer comprising:

a main chain of organic polymer; and

a side chain directly covalently linked to the main chain and having an N-bound diazeniumdiolate functional group,

wherein the backbone of the main chain comprises a block copolymer selected from the group consisting of an ethylene glycol/propylene glycol copolymer, a lactate/glycolate copolymer, a lactate/ethylene glycol copolymer, a lactate-glycolate-ethylene glycol copolymer, a lactate-glycolate-propylene glycol-ethylene glycol copolymer, an ε

-caprolactone/ethylene glycol copolymer, a 3-hydroxybutyrate/propylene glycol copolymer, a propylene fumarate/ethylene glycol copolymer, an organophosphagen/ethylene glycol copolymer, and a polypeptide-based block copolymer,

wherein the backbone of the side chain comprises a polymer selected from the group consisting of polyethyleneimine, polypropyleneimine, polypeptide, and chitosan, and

wherein the polymer of the donor undergoes a sol-to-gel phase transition upon a temperature rise, wherein the critical temperature of the phase transition is in the range of 25 to 35°

C. and the polymer of the donor forms a hydrogel without chemical cross-links above the critical temperature and at an in vivo pH.

2. The donor of claim 1, wherein the backbone of the main chain comprises an ethylene glycol/propylene glycol copolymer.

3. The donor of claim 1, further comprising, in the hydrogel, at least one pharmaceutically active material selected from the group consisting of vascular endothelial growth factor (VEGF), anti-inflammatory agents, vitamin C, acetylsalicylate, cholesterol-lowering drugs, thrombolytic agents, antithrombotic agent, heparin, anticancer drugs and oligonucleotides with anti-proliferative activity.

4. The donor of claim 3, wherein the pharmaceutically active material is not covalently linked to the donor, but is dispersed in the hydrogel.

5. The donor of claim 3, wherein the pharmaceutically active material is a conjugate covalently linked to oxygen atoms of the diazeniumdiolate functional group.

6. A prosthetic implant coated with the donor for controlled release of nitric oxide of claim 1 on its surface.

7. The prosthetic implant of claim 6, wherein the prosthetic implant is selected from the group consisting of stents, catheters, leads, subcutaneous implants, chemical sensors, pacemakers, vascular grafts, dressing for wound, penile implants, implantable pulse generators (IPG), implantable cardiac defibrillators, and nerve stimulators.