IN SITU FORMING HYDROGEL AND BIOMEDICAL USE THEREOF

• US 20120100103A1
• Filed: 07/01/2010
• Published: 04/26/2012
• Est. Priority Date: 07/02/2009
• Status: Active Grant

• Current Assignee: Ajou University Industry
• Original Assignee: Ajou University Industry
• Inventors: Park, Ki-Dong, Park, Kyung-Min, Joung, Yoon-Ki
• Granted Patent: US 8,815,277 B2
• Time in Patent Office: Days
• US Class Current: 424/85.2
• 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. An in situ-forming injectable hydrogel, represented by the following Chemical Formula 2, in which two or more homogeneous or heterogeneous polymers, represented by the following Chemical Formula 1, 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.

2. The in situ-forming injectable hydrogel according to claim 1, wherein the polymers are in situ crosslinked in vivo in the presence of horseradish peroxidase and hydrogen peroxide.

3. The injectable hydrogel 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:

4. The in situ-forming injectable hydrogel according to claim 1, wherein the polymer backbone is selected from a 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.

5. The in situ-forming injectable hydrogel according to claim 1, wherein the phenol derivative is selected from the group consisting of tyramine, hydroxyphenylacetic acid, hydroxypropionic acid, derivatives thereof, and a combination thereof.

6. The in situ-forming injectable hydrogel according to claim 1, wherein the aniline derivative is selected from the group consisting of hydroxyethylaniline, aminoethylaniline, aminobenzylalcohol and derivatives thereof, and a combination thereof.

7. The in situ-forming injectable hydrogel according to claim 1, wherein the linker is selected from polycationic, polyanionic, polyamphoteric, polynonionic, and combinations thereof.

8. The in situ-forming injectable hydrogel according to claim 1, wherein the linker is selected from the group consisting of polyester, polyanhydride, polyorthoester, polyurethane, polyamide, polypeptide, polyaliphatic, polyaromatic, and combinations thereof.

9. The in situ-forming injectable hydrogel according to claim 1, wherein the linker is selected from the group consisting of polyethylene glycol(PEG)-polylactic acid (PLA), polyethylene glycol(PEG)-polycarpropactone (PCL), polyethylene glycol(PEG)-poly(DL-lactic-co-glycolic acid) (PLGA), poly((propylene)fumarate), poly((ethylene)fumarate) and combinations thereof.

10. The in situ-forming injectable hydrogel according to claim 1, wherein the linker is selected from the group consisting of polyethyleneglycol (PEG), polyethylene oxide (PEO), polyethylenimine (PEI), polypropylene oxide (PPO), polyvinyl alcohol (PVA), poly(N-isopropylacrylamide) (polyNIPAM), polyfumarate, polyorganophosphazene, polyacrylic acid (polyAAc), polyacrylsulfonate, polyhydroxyethylmethacrylate(PolyHEMA) and copolymers thereof.

11. The in situ-forming injectable hydrogel according to claim 10, wherein the copolymer is selected from the group consisting of PEO-PPO-PEO (Pluronic™

series), 4-arm PEO-PPO-PEO (Tetronic™

series), PEG-PEI, PEG-PVA, PEG-PEI-PVA, PEI-PVA, poly(NIPAAM-co-AAc), poly(NIPAAM-co-HEMA), and combinations thereof.

12. The in situ-forming injectable hydrogel according to claim 1, being customized in terms of a physiological property selected from the group consisting of gelation time, gel stability (time taken to degrade), mechanical strength, water content and a combination thereof by controlling a concentration of horseradish peroxidase and hydrogen peroxide.

13. The in situ-forming injectable hydrogel according to claim 1, being customized in terms of a physiological property selected from the group consisting of gelation time, gel stability, mechanical strength, water content and a combination thereof by controlling a molecular weight of the water-soluble polymer.

14. The in situ-forming injectable hydrogel according to claim 1, being in situ crosslinked using a dual syringe kit.

15. The in situ-forming injectable hydrogel according to claim 14, wherein the dual syringe kit is combined with a spraying nozzle and thus endowed with an ability to spray.

16. The in situ-forming injectable hydrogel according to claim 14, being formed into a hydrogel sheet or disc using the dual syringe kit and a Teflon mold.

17. The in situ-forming injectable hydrogel according to claim 1, containing therein a biologically active substance having a phenol or aniline group.

18. The in situ-forming injectable hydrogel according to claim 17, wherein the biologically active substance is a peptide comprising tyrosine.

19. An implant material for tissue regeneration and augmentation, comprising the in situ-forming injectable hydrogel of claim 1 as an active ingredient.

20. The implant material according to claim 19, applicable to one selected from the group consisting of cartilage regeneration, bone regeneration, periodontal regeneration, skin regeneration, cardiac tissue regeneration, artificial intraocular lens, spinal cord regeneration, cranial regeneration, vocal regeneration and augmentation, adhesion barrier, urinary incontinence treatment, wrinkle removal, wound dressing, tissue augmentation and intervertebral disc treatment.

21. A carrier for delivering a biologically active substance or a drug, comprising the in situ-forming injectable hydrogel of claim 1 as an active ingredient.

22. The carrier according to claim 21, wherein the biologically active substance or drug is selected from the group consisting of a peptide, a protein drug, an anti-bacterial agent, an anti-cancer agent, an anti-inflammatory agent and combinations thereof.

23. The carrier according to claim 22, wherein the peptide or protein drug is selected from the group consisting of fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), transforming growth factor (TGF), bone morphogenetic protein (BMP), human growth hormone (hGH), pig growth hormone (pGH), granulocyte colony-stimulating factor (G-CSF), erythropoietin (EPO), macrophage colony-stimulating factor (M-CSF), tumor necrosis factor (TNF), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), interferon-α

, β

, γ

, interleukin-2 (IL-2), calcitonin, nerve growth factor (NGF), growth hormone releasing hormone, angiotensin, luteinizing hormone releasing hormone (LHRH), luteinizing hormone releasing hormone agonist (LHRH agonist), insulin, thyrotropin-releasing hormone (TRH), angiostatin, endostatin, somatostatin, glucagon, endorphine, bacitracin, mergain, colistin, monoclonal antibodies, vaccines, and a combination thereof.

24. The carrier according to claim 22, wherein the minocycline, tetracycline, ofloxacin, fosfomycin, mergain, profloxacin, ampicillin, penicillin, doxycycline, thienamycin, cephalosporin, nocardicin, gentamicin, neomycin, kanamycin, paromomycin, micronomicin, amikacin, tobramycin, dibekacin, cefotaxime, cefaclor, erythromycine, ciprofloxacin, levofloxacin, enoxacin, vancomycin, imipenem, fusidic acid, and a combination thereof.

25. The carrier according to claim 22, wherein the anti-cancer agent is selected from the group consisting of paclitaxel, taxotere, adriamycin, endostatin, angiostatin, mitomycin, bleomycin, cisplatin, carboplatin, doxorubicin, daunorubicin, idarubicin, 5-fluorouracil, methotrexate, actinomycin-D, and a combination thereof.

26. The carrier according to claim 22, wherein the anti-inflammatory agent is selected from the group consisting of acetaminophen, aspirin, ibuprofen, diclofenac, indometacin, piroxicam, fenoprofen, flubiprofen, ketoprofen, naproxen, suprofen, loxoprofen, cinnoxicam, tenoxicam, and a combination thereof.