IN SITU-FORMING HYDROGEL FOR TISSUE ADHESIVES AND BIOMEDICAL USE THEREOF

• US 20120156164A1
• Filed: 09/02/2010
• Published: 06/21/2012
• Est. Priority Date: 09/04/2009
• Status: Active Grant

• Current Assignee: Ajou University Industry
• Original Assignee: Ajou University Industry
• Inventors: Park, Ki-Dong, Joung, Yoon-ki, Park, Kyung-Min, Lih, Eu-Gene
• Granted Patent: US 8,968,716 B2
• Time in Patent Office: Days
• US Class Current: 424/78.3
• 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 2300/426 Immunomodulating agents, i.e. cytokines, interleukins, interferons
• 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 24/0015 Medicaments; Biocides
• CPC Class Codes: A61L 24/0031 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 24/0042 Materials resorbable by the body
• CPC Class Codes: A61L 24/046 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds A61L24/043 takes precedence
• CPC Class Codes: A61L 27/18 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• 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 27/58 Materials at least partially resorbable by the body
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• 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 25/00 : Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/02 : Ophthalmic agents
• 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 37/04 : Immunostimulants
• CPC Class Codes: A61P 41/00 : Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/04 : Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: C08L 71/02 : Polyalkylene oxides

Abstract

Disclosed herein are an in situ-forming, bioadhesive hydrogel and the medical uses thereof. Being formed by in situ crosslinking through an enzymatic reaction, the hydrogel has an advantage over conventional bioadhesive hydrogels in terms of biocompatibility. In addition, the in situ-forming bioadhesive hydrogel has excellent biocompatibility and mechanical strength and has excellent tissue adhesiveness thanks to modification with/without dopa derivatives. The hydrogel finds a variety of applications in the biomedical field, including bioadhesives or hemostats, implant substances for tissue regeneration and augmentation, carriers for delivering biologically active materials or drugs, etc.

Claims

1. An in situ-forming, bioadhesive hydrogel, represented by one of the following Chemical Formulas 4 to 7, in which two or more homogeneous or heterogeneous polymers selected from a group consisting of:

i) a star-shaped polymer, represented by the following Chemical Formula 1, in which one or more compounds selected from among phenol, aniline and derivatives thereof are modified with one or more compounds selected from among dopa and derivatives thereof;

ii) a heterogeneous blend, comprising the star-shaped polymer of Chemical Formula 1 and a branched polymer, represented by the following Chemical Formula 2, in which a polymer backbone is grafted with one or more compounds selected from among phenol, aniline and, derivatives thereof, with or without a water-soluble polymer serving as a linker therebetween; and

iii) a branched polymer, represented by the following Chemical Formula 3, in which a polymer backbone is grafted with one or more compounds selected from among phenol, aniline and derivatives thereof, with or without a water-soluble polymer serving as a linker therebetween, are bonded to each other through dehydrogenation between the phenol, aniline, dopa and derivatives thereof on adjacent polymers.

2. The in situ-forming, bioadhesive hydrogel according to claim 1, wherein the polymers are in situ crosslinked in vivo or in vitro when horseradish peroxidase and hydrogen peroxide are added thereto.

3. The in situ-forming, bioadhesive hydrogel according to claim 1, wherein the polymers of Chemical Formulas 1 to 3 are prepared by grafting a compound selected from among phenol, aniline, dopa, dopaquinone and derivatives thereof to a polymer backbone having amino, hydroxyl or carboxyl groups through an amide, urethane, urea or ester bond, with or without a water-soluble polymer serving as a linker.

4. The in situ-forming, bioadhesive hydrogel according to claim 1, wherein the polymer 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, multi-armed polymers, and a combination thereof.

5. The in situ-forming, bioadhesive hydrogel according to claim 4, wherein the multi-armed polymer is selected from a group consisting of a multi-arm-polyethyleneglycol, a tetronic series (4-arm-PPO-PEO), and a combination thereof, said multi-arm-polyethyleneglycol being selected from among 3-arm-polyethyleneglycol (3armPEG), 4-arm-polyethyleneglycol (4armPEG), 6-arm-polyethyleneglycol (6armPEG), 8-arm-polyethyleneglycol (8armPEG) and a combination thereof.

6. The in situ-forming, bioadhesive hydrogel according to claim 1, wherein the phenol derivative is one or more compounds selected from a group consisting of tyramine, hydroxyphenylacetic acid, hydroxypropionic acid and derivatives thereof.

7. The in situ-forming, bioadhesive hydrogel according to claim 1, wherein the aniline derivative is one or more compounds selected from a group consisting of hydroxyethylaniline, aminoethylaniline, aminobenzylalcohol and derivatives thereof.

8. The in situ-forming, bioadhesive hydrogel according to claim 1, wherein the dopa derivative is one or more compounds selected from a group consisting of L-dihydroxyphenylalanine (L-dopa), dopamine, norepinephrine, epinephrine, and derivatives thereof.

9. The in situ-forming, bioadhesive hydrogel according to claim 1, wherein the linker is one or more water-soluble polymers selected from polycationic, polyanionic, polyamphoteric, polynonionic, and combinations thereof.

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

11. The in situ-forming, bioadhesive 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.

12. The in situ-forming, bioadhesive 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, poly hydroxyethylmethacrylate (PolyHEMA) and copolymers thereof.

13. The in situ-forming, bioadhesive hydrogel according to claim 12, 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.

14. The in situ-forming, bioadhesive hydrogel according to claim 1, wherein a physicochemical property of the hydrogel is adjusted with concentrations of horseradish peroxidase and hydrogen peroxide, said physicochemical property being selected from among gelation time, gel stability, mechanical strength and water content.

15. The in situ-forming, bioadhesive hydrogel according to claim 1, wherein a physicochemical property of the hydrogel is adjusted by changing a molecular weight of the water-soluble polymer, said physicochemical property being selected from among gelation time, gel stability, mechanical strength and water content.

16. The in situ-forming, bioadhesive hydrogel according to claim 1, wherein an adhesive strength of the hydrogel is adjusted by changing a content of dopa or a derivative thereof, or a mixture ratio between the polymer having dopa or a derivative thereof and the polymer having phenol, aniline or a derivative thereof in the heterogeneous mixture.

17. The in situ-forming, bioadhesive hydrogel according to claim 1, wherein a dual syringe kit is used to help formation of in situ crosslinks.

18. The in situ-forming, bioadhesive hydrogel according to claim 17, wherein the dual syringe kit is mounted with a spraying nozzle through which the polymers can be sprayed.

19. The in situ-forming, bioadhesive hydrogel according to claim 17, being formed into a sheet or a disc using the dual syringe kit in combination with a Teflon mold.

20. The in situ-forming, bioadhesive hydrogel according to claim 1, further comprising a biologically active material having a functional group selected from among phenol, aniline, amine, thiol and a combination thereof.

21. The in situ-forming, bioadhesive hydrogel according to claim 20, wherein the biologically active material is a peptide containing tyrosine.

22. A substance for bioadhesives and hemostats, comprising the in situ-forming, bioadhesive hydrogel of claim 1.

24. An implant substance for tissue regeneration and augmentation, comprising the in situ-forming, bioadhesive hydrogel of claim 1.

25. The implant substance according to claim 24, applicable to one selected from among cartilage regeneration, bone regeneration, periodontal regeneration, skin regeneration, cardiac tissue regeneration, artificial intraocular lens care, spinal cord regeneration, cranial regeneration, vocal regeneration and augmentation, adhesion barrier care, urinary incontinence treatment, wrinkle removal, wound dressing, tissue augmentation and intervertebral disc treatment.

26. A carrier for delivering a biologically active substance or drug, comprising the in situ-forming, bioadhesive hydrogel of claim 1.

27. The carrier according to claim 26, wherein the biologically active substance or drug is selected from a group consisting of a peptide or protein drug, an antibacterial agent, an anti-cancer agent, an anti-inflammatory agent, and a combination thereof.

28. The carrier according to claim 27, wherein the peptide or protein drug is selected from a 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.

29. The carrier according to claim 27, wherein the antibacterial agent is selected from a group consisting of 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.

30. The carrier according to claim 27, wherein the anti-cancer agent is selected from a group consisting of paclitaxel, taxotere, adriamycin, endostatin, angiostatin, mitomycin, bleomycin, cisplatin, carboplatin, doxorubicin, daunorubicin, idarubicin, 5-fluorouracil, methotrexate, actinomycin-D and a combination thereof.

31. The carrier according to claim 27, wherein the anti-inflammatory agent is selected from a group consisting of acetaminophen, aspirin, ibuprofen, diclofenac, indometacin, piroxicam, fenoprofen, flubiprofen, ketoprofen, naproxen, suprofen, loxoprofen, cinnoxicam, tenoxicam, and a combination thereof.

23. The substance, applicable to a medical case selected from a group consisting of Cerebral nervous system surgery including vascular surgery, orthopedic surgery including bone bonding, hemostasis in patients with a laceration, closure of the femoral artery, closure after incision of an eye affected with a cataract, healing of cartilage and articular cartilage, dermal adhesion, hemostasis at incised portions in organs/secretory glands, anastomosis of gastrointestinal organs, and healing of ligaments and tendons.