In situ forming hydrogel and biomedical use thereof

• US 8,815,277 B2
• Filed: 07/01/2010
• Issued: 08/26/2014
• Est. Priority Date: 07/02/2009
• Status: Active Grant

• Current Assignee: Ajou University Industry
• Original Assignee: Ajou University Industry
• Inventors: Park, Ki-Dong, Joung, Yoon-Ki, Park, Kyung-Min
• Primary Examiner(s): Fubara, Blessing M
• Application Number:
  US13/381,843
• Publication Number:
  US 20120100103A1
• Time in Patent Office: 1,517 Days
• Field of Search: 424/85.2, 424/141.1, 424/184.1, 424/649, 424/85.5, 424/85.6, 424/85.7, 514/11.3, 514/11.4, 514/11.9, 514/17.2, 514/6.5, 514/7.7, 514/8.1, 514/8.2, 514/8.4, 514/8.8, 514/8.9, 514/9.1, 514/9.6
• US Class Current: 424/423
• CPC Class Codes: A61K 47/42 Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein oligopeptides having up to five amino acids A61K47/183; polyamino acids A61K47/34
• 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: A61L 2300/252 Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
• CPC Class Codes: A61L 2300/256 Antibodies, e.g. immunoglobulins, vaccines
• CPC Class Codes: A61L 2300/406 Antibiotics
• CPC Class Codes: A61L 2300/41 Anti-inflammatory agents, e.g. NSAIDs
• CPC Class Codes: A61L 2300/414 Growth factors
• CPC Class Codes: A61L 2300/416 Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
• CPC Class Codes: A61L 2300/43 Hormones, e.g. dexamethasone
• CPC Class Codes: A61L 2300/602 Type of release, e.g. controlled, sustained, slow
• CPC Class Codes: A61L 2400/06 Flowable or injectable implant compositions
• 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: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 19/04 for non-specific disorders of the connective tissue
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• 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 31/04 Antibacterial agents
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system

Abstract

Disclosed are in situ-forming injectable hydrogel and medical uses thereof. In the in situ-forming injectable hydrogel two or more homogeneous or heterogeneous polymers are bonded to each other by a dehydrogenation reaction between phenol or aniline moieties on adjacent polymers, wherein a polymer backbone is grafted with a phenol or aniline moiety using a linker. In contrast to conventional hydrogel, the in situ-forming injectable hydrogel is superior in terms of in vivo stability and mechanical strength thanks to the introduction of a water-soluble polymer as a linker which leads to an improvement in the reactivity of phenol or aniline moieties. Having the advantage of superior bio stability and mechanical strength, the hydrogel finds a variety of applications in the biomedical field.

Claims

1. A composition of enzyme-triggered in situ-forming injectable hydrogel, represented by the following Chemical Formula 2, comprising:

two or more homogeneous or heterogeneous polymers, represented by the following Chemical Formula 1, bonding to each other by a dehydrogenation reaction between phenol or aniline moieties on adjacent polymers,

wherein a polymer backbone is grafted with one of the phenol or aniline moieties by a linker,

wherein the polymers are in situ crosslinked in vivo in the presence of horseradish peroxidase and hydrogen peroxide to form the hydrogel,

2. The composition according to claim 1, wherein the polymer of Chemical Formula 1 is prepared by grafting a phenol or aniline derivative represented by the following Chemical Formula 3 to a polymer backbone having amino, hydroxyl or carboxyl groups by an amide, urethane, urea or ester bond, with a water-soluble polymer serving as a linker:

3. The composition according to claim 1, wherein the polymer backbone is selected from the group consisting of gelatin, chitosan, heparin, cellulose, dextran, dextran sulfate, chondroitin sulfate, keratan sulfate, dermatan sulfate, alginate, collagen, albumin, fibronectin, laminin, elastin, vitronectin, hyaluronic acid, fibrinogen, a multi-arm polymer and a combination thereof.

4. The in situ forming injectable hydrogel composition according to claim 1, wherein the phenol is selected from the group consisting of tyramine, hydroxyphenylacetic acid, hydroxyphenylpropionic acid, and a combination thereof.