Biodegradable hydrogel copolymer as drug delivery matrix

• US 5,514,380 A
• Filed: 06/30/1994
• Issued: 05/07/1996
• Est. Priority Date: 05/17/1994
• Status: Expired due to Term

• Current Assignee: Samyang Biopharmaceuticals Corporation (Samyang Holdings Corporation)
• Original Assignee: SAM Yang Company Limited
• Inventors: Kim, Ho H., Song, Soo S., Yi, Yil W.
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): Benston, Jr., William E.
• Application Number:
  US08/268,915
• Time in Patent Office: 677 Days
• Field of Search: 424/426, 424/428, 424/486
• US Class Current: 424/426
• CPC Class Codes: A61K 9/204 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: C08G 63/664 derived from hydroxy carboxylic acids

Abstract

This invention concerns the thermoplastic, biodegradable hydrogel copolymer which is easily degraded and excreted in human body by the hydrolysis of intramolecular ester and amide bond. The structure of present copolymer comprises i) hydrophilic and swellable soft domain consisting of polyethyleneoxide (PEO), and ii) hydrophobic, biodegradable, crystallizable and non-swellable hard domain consisting of polylactide (PLA), polyglycolide (PGA), polylactideglycolide (PLGA) and polycaprolactone (PCL).

Claims

1. A process for preparing a thermoplastic, biodegradable hydrogel multi-block copolymer for use as a drug delivery matrix comprising the steps of:

i) preparing a hydrophilic block having a biodegradable linkage using a hydrophilic polymer selected from the group consisting of polyethyleneoxide having a number average molecular weight from 2,000 to 10,000 and a copolymer of polyethyleneoxide and polypropyleneoxide;

ii) introducing hydroxyl groups to both ends of said hydrophilic block;

iii) adding and polymerizing one or more monomers to form a hydrophobic block, said one or more monomers selected from the group consisting lactide, glycolide and caprolactone; and

iv) adding and anion polymerizing monomers of ethyleneoxide.

2. A process for preparing a thermoplastic, biodegradable hydrogel multi-block copolymer for use as a drug delivery matrix according to claim 1, wherein the hydrophilic block having a biodegradable linkage is prepared by the steps

i) anionizing ends of said hydrophilic polymer using an initiator selected from the group consisting of potassium naphthalene, sodium naphthalene, lithium diisopropylate, potassium-t-butylate, sodium-t-butylate, sodium hydroxide and/or potassium hydroxide;

ii) adding and polymerizing one or more hydrophobic monomers selected from the group consisting of glycolide, lactide and caprolactone into the anionized ends of the hydrophilic polymer to form a copolymer having anion ends; and

iii) adding and polymerizing ethyleneoxide into the anion ends of said copolymer.

3. A process for preparing a thermoplastic, biodegradable hydrogel multi-block copolymer useful as a drug delivery matrix according to claim 1, wherein the hydrophilic block is reacted with a reagent selected from the group consisting of tris (hydroxyalkyl) aminomethane and dihydroxyalkyl aminomethane in order to link the hydrophobic block.

4. A process for preparing a thermoplastic, biodegradable hydrogel multi-block copolymer useful as a drug delivery matrix according to claim 3, wherein said alkyl portion of said tris (hydroxyalkyl) aminomethane and said dihydroxyalkyl aminomethane is a C₁ -C₅ aliphatic compound.

5. A process for preparing a thermoplastic, biodegradable multi-block copolymer useful as a drug delivery matrix according to claim 3, wherein both ends of said hydrophilic block are protected by p-nitrophenyl-chloroformate before the introduction of said hydroxyl groups.