Biodegradable triblock copolymers, synthesis methods therefore, and hydrogels and biomaterials made there from

• US 7,297,348 B2
• Filed: 07/18/2003
• Issued: 11/20/2007
• Est. Priority Date: 07/19/2002
• Status: Active Grant

• Current Assignee: Institute of Materials Research and Engineering, Omeros Corporation
• Original Assignee: Institute of Materials Research and Engineering, Omeros Corporation
• Inventors: Li, Xu, Li, Jun, Leong, Kam W., Ni, Xiping
• Primary Examiner(s): Hartley; Michael G.
• Assistant Examiner(s): ROGERS, JAMES WILLIAM
• Application Number:
  US10/624,136
• Publication Number:
  US 20040072799A1
• Time in Patent Office: 1,586 Days
• Field of Search: 424/485, 424/425, 424/426, 424/424, 424/486, 424/501, 424/497, 424/493, 424/489, 424/491
• US Class Current: 424/485
• CPC Class Codes: A61K 47/32 Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers , poly(meth)acrylates, or polyvinyl pyrrolidone
• 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: A61K 47/6903 the form being semi-solid, e.g. an ointment, a gel, a hydrogel or a solidifying gel
• CPC Class Codes: A61K 47/6951 using cyclodextrin cyclodextrins used as simple excipients A61K47/40
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence
• CPC Class Codes: A61K 9/5153 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61L 2300/602 Type of release, e.g. controlled, sustained, slow
• CPC Class Codes: A61L 2300/802 Additives, excipients, e.g. cyclodextrins, fatty acids, surfactants
• CPC Class Codes: A61L 27/34 Macromolecular materials
• CPC Class Codes: A61L 27/52 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61L 31/10 Macromolecular materials
• CPC Class Codes: A61L 31/145 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Abstract

A drug delivery system that includes a hydrogel formed from cyclodextrin and an amphiphilic copolymer that includes an A polymer block comprising a poly(alkylene oxide) and a B polymer block comprising a poly(hydroxyalkanoate), and a therapeutically effective amount of at least one therapeutic agent intimately contained within the hydrogel. In one preferred embodiment of the invention, the A polymer block is poly(ethylene oxide) (PEO) and the B polymer block is poly[(R)-3-hydroxybutyrate] (PHB), and the copolymer is the triblock ABA copolymer PEO-PHB-PEO. A method of synthesizing the amphiphilic triblock copolymer is also provided.

Claims

1. A drug delivery system, comprising:

a hydrogel formed from an inclusion complex comprising cyclodextrin and an amphiphilic copolymer, wherein the copolymer includes an A polymer block comprising a poly(alkylene oxide) and a B polymer block comprising a poly(hydroxyalkanoate), wherein the poly(alkylene oxide) A block polymer is selected from the group consisting of poly(ethylene oxide), poly(tetramethylene oxide) and poly(tetrahydrofuran) and the poly(hydroxyalkanoate) B block polymer is selected from the group consisting of poly[(R)-3-hydroxybutyrate], poly[(R)-4-hydroxybutyrate], poly[(R)-3-hydroxyvalerate], poly[(R)-3-hydroxybutyrate]-co-Poly[(R)-3-hydroxyvalerate], poly[(R)-3-hydroxyhexanoate], Poly[(R)-3-hydroxyheptanoate], (S) enantiomers of each of such (R) enantiomers, racemic mixtures of such (S) and (R) enantiomers, and mixtures thereof; and

a therapeutically effective amount of at least one therapeutic agent intimately contained within the hydrogel, wherein the copolymer is an amphiphilic triblock copolymer including a B polymer block mid-segment and two A polymer block end segments.

2. The system of claim 1, wherein the poly(alkylene oxide) A block polymer is poly(ethylene oxide).

4. The drug delivery system of claim 1, wherein the copolymer has a molecular weight of between 1,000 and 50,000.

5. The drug delivery system of claim 1, wherein the copolymer has a molecular weight of between 5,000 and 35,000.

6. The drug delivery system of claim 1, wherein the at least one therapeutic agent is selected from the group consisting of peptides, proteins, small molecules, genes, antigens, antibodies and fragments thereof and human recombinant proteins, DNA, RNA and DNA nanoparticles.

7. The drug delivery system of claim 1, wherein the at least one therapeutic agent is in a macromolecular form.

8. The drug delivery system of claim 1, wherein the at least one therapeutic agent is selected from the group consisting of analgesics, anesthetics, anti-arthritic drugs, disease modifying anti-rheumatic drugs, anti-asthma drugs, anticoagulants, anticonvulsants, antidepressants, antidiabetics, antineoplastics, antipsychotics, antihypertensives, antibiotics, antihistamines, decongestants, anti-inflammatories, muscle relaxants, anti-parasitic drugs, antiviral drugs, anti-restenotic agents, anti-spasm agents, chondroprotective agents, anti-adhesion agents, anti-tumor cell invasion agents, vasorelaxants, vasoconstrictors and immunosupressants.

9. The drug delivery system of claim 1, wherein the at least one therapeutic agent is selected from the group consisting of peptides, proteins including cytokines, growth factors, angiogenesis factors, soluble receptors, antibodies and fragments thereof and human recombinant proteins, small molecules, genes, antigens including vaccines, DNA, RNA and DNA nanoparticles.

3. A hydrogel comprising cyclodextrin and an amphiphilic copolymer in the form of an inclusion complex, wherein the copolymer includes an A polymer block comprising a poly(alkylene oxide) and a B polymer block comprising a poly(hydroxyalkanoate), wherein the copolymer is an amphiphilic triblock copolymer including a B polymer block mid-segment and two A polymer block end segments, wherein the poly(alkylene oxide) A block polymer is selected from the group consisting of poly(ethylene oxide), poly(tetramethylene oxide) and poly(tetrahydrofuran) and the poly(hydroxyalkanoate) B block polymer is selected from the group consisting of poly[(R)-3-hydroxybutyrate], poly[(R)-4-hydroxybutyrate], poly[(R)-3-hydroxyvalerate], poly[(R)-3-hydroxybutyrate]-co-Poly[(R)-3-hydroxyvalerate], poly[(R)-3-hydroxyhexanoate], Poly[(R)-3-hydroxyheptanoate], (S) enantiomers of each of such (R) enantiomers, racemic mixtures of such (S) and (R) enantiomers, and mixtures thereof.