TW201247179A - Polyelectrolyte complex gels and soft tissue augmentation implants comprising the same - Google Patents
Polyelectrolyte complex gels and soft tissue augmentation implants comprising the same Download PDFInfo
- Publication number
- TW201247179A TW201247179A TW100118946A TW100118946A TW201247179A TW 201247179 A TW201247179 A TW 201247179A TW 100118946 A TW100118946 A TW 100118946A TW 100118946 A TW100118946 A TW 100118946A TW 201247179 A TW201247179 A TW 201247179A
- Authority
- TW
- Taiwan
- Prior art keywords
- kda
- weight
- particles
- polyelectrolyte complex
- acid
- Prior art date
Links
- 239000000499 gel Substances 0.000 title claims abstract description 97
- 229920000867 polyelectrolyte Polymers 0.000 title claims abstract description 89
- 239000007943 implant Substances 0.000 title claims abstract description 51
- 210000004872 soft tissue Anatomy 0.000 title claims abstract description 46
- 230000003416 augmentation Effects 0.000 title abstract 3
- 229920001661 Chitosan Polymers 0.000 claims abstract description 37
- 239000000945 filler Substances 0.000 claims abstract description 21
- 150000003839 salts Chemical class 0.000 claims abstract description 21
- 229920002643 polyglutamic acid Polymers 0.000 claims abstract description 16
- 239000007864 aqueous solution Substances 0.000 claims abstract description 14
- 239000000654 additive Substances 0.000 claims abstract description 10
- 230000000996 additive effect Effects 0.000 claims abstract description 7
- 239000000017 hydrogel Substances 0.000 claims abstract description 3
- 239000002245 particle Substances 0.000 claims description 72
- 238000011049 filling Methods 0.000 claims description 37
- -1 alginic acid Propylene glycol ester Chemical class 0.000 claims description 34
- 239000000203 mixture Substances 0.000 claims description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 claims description 20
- 229910052588 hydroxylapatite Inorganic materials 0.000 claims description 19
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 15
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 15
- 229920001577 copolymer Polymers 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 13
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 13
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 13
- 229920002678 cellulose Chemical class 0.000 claims description 13
- 239000001913 cellulose Chemical class 0.000 claims description 13
- 235000010980 cellulose Nutrition 0.000 claims description 13
- MCMNRKCIXSYSNV-UHFFFAOYSA-N Zirconium dioxide Chemical compound O=[Zr]=O MCMNRKCIXSYSNV-UHFFFAOYSA-N 0.000 claims description 12
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 11
- 210000004027 cell Anatomy 0.000 claims description 11
- 229920000642 polymer Polymers 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- 229910017053 inorganic salt Inorganic materials 0.000 claims description 10
- 229920002125 Sokalan® Polymers 0.000 claims description 9
- 108700022290 poly(gamma-glutamic acid) Proteins 0.000 claims description 9
- 102000008186 Collagen Human genes 0.000 claims description 8
- 108010035532 Collagen Proteins 0.000 claims description 8
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 8
- 229920001436 collagen Polymers 0.000 claims description 8
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 7
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 7
- 229910052791 calcium Inorganic materials 0.000 claims description 7
- 239000011575 calcium Substances 0.000 claims description 7
- 229920002674 hyaluronan Polymers 0.000 claims description 7
- 229960003160 hyaluronic acid Drugs 0.000 claims description 7
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 7
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 7
- 229920001432 poly(L-lactide) Polymers 0.000 claims description 7
- 229920001282 polysaccharide Polymers 0.000 claims description 7
- 239000005017 polysaccharide Substances 0.000 claims description 7
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- 229910052586 apatite Inorganic materials 0.000 claims description 6
- 239000001506 calcium phosphate Substances 0.000 claims description 6
- VSIIXMUUUJUKCM-UHFFFAOYSA-D pentacalcium;fluoride;triphosphate Chemical compound [F-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O VSIIXMUUUJUKCM-UHFFFAOYSA-D 0.000 claims description 6
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 6
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical group [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims description 6
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 5
- 229910000389 calcium phosphate Inorganic materials 0.000 claims description 5
- 235000011010 calcium phosphates Nutrition 0.000 claims description 5
- 210000005258 dental pulp stem cell Anatomy 0.000 claims description 5
- 229920001983 poloxamer Polymers 0.000 claims description 5
- 229920001223 polyethylene glycol Polymers 0.000 claims description 5
- 210000000130 stem cell Anatomy 0.000 claims description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- 229920000896 Ethulose Polymers 0.000 claims description 4
- 239000001856 Ethyl cellulose Substances 0.000 claims description 4
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 4
- 239000001859 Ethyl hydroxyethyl cellulose Substances 0.000 claims description 4
- 108050007372 Fibroblast Growth Factor Proteins 0.000 claims description 4
- 102000018233 Fibroblast Growth Factor Human genes 0.000 claims description 4
- 108010010803 Gelatin Proteins 0.000 claims description 4
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims description 4
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 claims description 4
- 229920002774 Maltodextrin Polymers 0.000 claims description 4
- 239000005913 Maltodextrin Substances 0.000 claims description 4
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 4
- 108010020346 Polyglutamic Acid Proteins 0.000 claims description 4
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 4
- 229940088623 biologically active substance Drugs 0.000 claims description 4
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 4
- 229920001249 ethyl cellulose Polymers 0.000 claims description 4
- 235000019326 ethyl hydroxyethyl cellulose Nutrition 0.000 claims description 4
- 229940126864 fibroblast growth factor Drugs 0.000 claims description 4
- 239000008273 gelatin Substances 0.000 claims description 4
- 229920000159 gelatin Polymers 0.000 claims description 4
- 235000019322 gelatine Nutrition 0.000 claims description 4
- 235000011852 gelatine desserts Nutrition 0.000 claims description 4
- 235000011187 glycerol Nutrition 0.000 claims description 4
- 239000008187 granular material Substances 0.000 claims description 4
- 239000003102 growth factor Substances 0.000 claims description 4
- 229940035034 maltodextrin Drugs 0.000 claims description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N monopropylene glycol Natural products CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 4
- 229960000502 poloxamer Drugs 0.000 claims description 4
- 229920001451 polypropylene glycol Polymers 0.000 claims description 4
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 4
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 4
- 235000018102 proteins Nutrition 0.000 claims description 4
- 102000004169 proteins and genes Human genes 0.000 claims description 4
- 108090000623 proteins and genes Proteins 0.000 claims description 4
- 239000004698 Polyethylene Substances 0.000 claims description 3
- 229920002472 Starch Chemical class 0.000 claims description 3
- 229960001631 carbomer Drugs 0.000 claims description 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 3
- 150000002632 lipids Chemical class 0.000 claims description 3
- 235000010987 pectin Nutrition 0.000 claims description 3
- 229920001277 pectin Polymers 0.000 claims description 3
- 239000001814 pectin Substances 0.000 claims description 3
- 229920000573 polyethylene Polymers 0.000 claims description 3
- 229920002338 polyhydroxyethylmethacrylate Polymers 0.000 claims description 3
- 229940051841 polyoxyethylene ether Drugs 0.000 claims description 3
- 229920000056 polyoxyethylene ether Polymers 0.000 claims description 3
- 239000008107 starch Chemical class 0.000 claims description 3
- 235000019698 starch Nutrition 0.000 claims description 3
- 239000004094 surface-active agent Substances 0.000 claims description 3
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 2
- 244000215068 Acacia senegal Species 0.000 claims description 2
- 229920001817 Agar Polymers 0.000 claims description 2
- 108010088751 Albumins Proteins 0.000 claims description 2
- 102000009027 Albumins Human genes 0.000 claims description 2
- 240000001592 Amaranthus caudatus Species 0.000 claims description 2
- 235000009328 Amaranthus caudatus Nutrition 0.000 claims description 2
- 108010027529 Bio-glue Proteins 0.000 claims description 2
- 229920000623 Cellulose acetate phthalate Polymers 0.000 claims description 2
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- 229920002307 Dextran Polymers 0.000 claims description 2
- 229920001353 Dextrin Polymers 0.000 claims description 2
- 239000004375 Dextrin Substances 0.000 claims description 2
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 2
- 108010073385 Fibrin Proteins 0.000 claims description 2
- 102000009123 Fibrin Human genes 0.000 claims description 2
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 claims description 2
- 229920001503 Glucan Polymers 0.000 claims description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 2
- 229920000084 Gum arabic Polymers 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 claims description 2
- 239000004166 Lanolin Substances 0.000 claims description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 2
- 239000004472 Lysine Substances 0.000 claims description 2
- 235000011430 Malus pumila Nutrition 0.000 claims description 2
- 235000015103 Malus silvestris Nutrition 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 2
- 229920001311 Poly(hydroxyethyl acrylate) Polymers 0.000 claims description 2
- 229920002845 Poly(methacrylic acid) Polymers 0.000 claims description 2
- 108010039918 Polylysine Proteins 0.000 claims description 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 2
- 229920002359 Tetronic® Polymers 0.000 claims description 2
- 235000010489 acacia gum Nutrition 0.000 claims description 2
- 239000000205 acacia gum Substances 0.000 claims description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 2
- 239000008272 agar Substances 0.000 claims description 2
- 235000010419 agar Nutrition 0.000 claims description 2
- 235000010443 alginic acid Nutrition 0.000 claims description 2
- 229920000615 alginic acid Polymers 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 229920013820 alkyl cellulose Polymers 0.000 claims description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 2
- 239000004178 amaranth Substances 0.000 claims description 2
- 235000012735 amaranth Nutrition 0.000 claims description 2
- RJGDLRCDCYRQOQ-UHFFFAOYSA-N anthrone Chemical compound C1=CC=C2C(=O)C3=CC=CC=C3CC2=C1 RJGDLRCDCYRQOQ-UHFFFAOYSA-N 0.000 claims description 2
- 229960000892 attapulgite Drugs 0.000 claims description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 2
- FNAQSUUGMSOBHW-UHFFFAOYSA-H calcium citrate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O FNAQSUUGMSOBHW-UHFFFAOYSA-H 0.000 claims description 2
- 239000001354 calcium citrate Substances 0.000 claims description 2
- 159000000007 calcium salts Chemical class 0.000 claims description 2
- 229940081734 cellulose acetate phthalate Drugs 0.000 claims description 2
- 229920001531 copovidone Polymers 0.000 claims description 2
- 235000019425 dextrin Nutrition 0.000 claims description 2
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 2
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 claims description 2
- 210000001671 embryonic stem cell Anatomy 0.000 claims description 2
- 239000000194 fatty acid Substances 0.000 claims description 2
- 229930195729 fatty acid Natural products 0.000 claims description 2
- 150000004665 fatty acids Chemical class 0.000 claims description 2
- 229950003499 fibrin Drugs 0.000 claims description 2
- 229910052587 fluorapatite Inorganic materials 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 2
- 229940071676 hydroxypropylcellulose Drugs 0.000 claims description 2
- 235000019388 lanolin Nutrition 0.000 claims description 2
- 229940039717 lanolin Drugs 0.000 claims description 2
- 159000000003 magnesium salts Chemical class 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 210000002901 mesenchymal stem cell Anatomy 0.000 claims description 2
- 239000000178 monomer Substances 0.000 claims description 2
- 210000001178 neural stem cell Anatomy 0.000 claims description 2
- 229910000392 octacalcium phosphate Inorganic materials 0.000 claims description 2
- 229910052625 palygorskite Inorganic materials 0.000 claims description 2
- 229960000292 pectin Drugs 0.000 claims description 2
- 239000004584 polyacrylic acid Substances 0.000 claims description 2
- 229920001748 polybutylene Polymers 0.000 claims description 2
- 229920000656 polylysine Polymers 0.000 claims description 2
- 229920005862 polyol Polymers 0.000 claims description 2
- 150000003077 polyols Chemical class 0.000 claims description 2
- 229920000136 polysorbate Polymers 0.000 claims description 2
- 229950008882 polysorbate Drugs 0.000 claims description 2
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims description 2
- 239000002243 precursor Substances 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 235000010413 sodium alginate Nutrition 0.000 claims description 2
- 239000000661 sodium alginate Substances 0.000 claims description 2
- 229940005550 sodium alginate Drugs 0.000 claims description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 2
- 159000000000 sodium salts Chemical class 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- 229910021653 sulphate ion Inorganic materials 0.000 claims description 2
- 239000006188 syrup Substances 0.000 claims description 2
- 235000020357 syrup Nutrition 0.000 claims description 2
- YIGWVOWKHUSYER-UHFFFAOYSA-F tetracalcium;hydrogen phosphate;diphosphate Chemical compound [Ca+2].[Ca+2].[Ca+2].[Ca+2].OP([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O YIGWVOWKHUSYER-UHFFFAOYSA-F 0.000 claims description 2
- 229920000428 triblock copolymer Polymers 0.000 claims description 2
- 235000013337 tricalcium citrate Nutrition 0.000 claims description 2
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical group C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 claims description 2
- 239000000052 vinegar Substances 0.000 claims description 2
- 235000021419 vinegar Nutrition 0.000 claims description 2
- 229920001285 xanthan gum Polymers 0.000 claims description 2
- 235000010493 xanthan gum Nutrition 0.000 claims description 2
- 239000000230 xanthan gum Substances 0.000 claims description 2
- 229940082509 xanthan gum Drugs 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical group OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims 4
- 150000004804 polysaccharides Chemical class 0.000 claims 3
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical class CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 claims 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims 2
- 229910000420 cerium oxide Inorganic materials 0.000 claims 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims 2
- BMMGVYCKOGBVEV-UHFFFAOYSA-N oxo(oxoceriooxy)cerium Chemical compound [Ce]=O.O=[Ce]=O BMMGVYCKOGBVEV-UHFFFAOYSA-N 0.000 claims 2
- RIWAPWDHHMWTRA-UHFFFAOYSA-N 1,2,3-triiodobenzene Chemical class IC1=CC=CC(I)=C1I RIWAPWDHHMWTRA-UHFFFAOYSA-N 0.000 claims 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims 1
- PYMYPHUHKUWMLA-UHFFFAOYSA-N 2,3,4,5-tetrahydroxypentanal Chemical compound OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 claims 1
- 241000416162 Astragalus gummifer Species 0.000 claims 1
- 244000303965 Cyamopsis psoralioides Species 0.000 claims 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims 1
- 239000005977 Ethylene Substances 0.000 claims 1
- 229920001615 Tragacanth Polymers 0.000 claims 1
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 claims 1
- ZUAAPNNKRHMPKG-UHFFFAOYSA-N acetic acid;butanedioic acid;methanol;propane-1,2-diol Chemical compound OC.CC(O)=O.CC(O)CO.OC(=O)CCC(O)=O ZUAAPNNKRHMPKG-UHFFFAOYSA-N 0.000 claims 1
- 229940023476 agar Drugs 0.000 claims 1
- 239000000783 alginic acid Substances 0.000 claims 1
- 229960001126 alginic acid Drugs 0.000 claims 1
- 210000004556 brain Anatomy 0.000 claims 1
- 235000010410 calcium alginate Nutrition 0.000 claims 1
- 239000000648 calcium alginate Substances 0.000 claims 1
- 229960002681 calcium alginate Drugs 0.000 claims 1
- OKHHGHGGPDJQHR-YMOPUZKJSA-L calcium;(2s,3s,4s,5s,6r)-6-[(2r,3s,4r,5s,6r)-2-carboxy-6-[(2r,3s,4r,5s,6r)-2-carboxylato-4,5,6-trihydroxyoxan-3-yl]oxy-4,5-dihydroxyoxan-3-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylate Chemical compound [Ca+2].O[C@@H]1[C@H](O)[C@H](O)O[C@@H](C([O-])=O)[C@H]1O[C@H]1[C@@H](O)[C@@H](O)[C@H](O[C@H]2[C@H]([C@@H](O)[C@H](O)[C@H](O2)C([O-])=O)O)[C@H](C(O)=O)O1 OKHHGHGGPDJQHR-YMOPUZKJSA-L 0.000 claims 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims 1
- 235000010418 carrageenan Nutrition 0.000 claims 1
- 229920001525 carrageenan Polymers 0.000 claims 1
- 239000000679 carrageenan Substances 0.000 claims 1
- 229940113118 carrageenan Drugs 0.000 claims 1
- 239000000571 coke Substances 0.000 claims 1
- 229960005168 croscarmellose Drugs 0.000 claims 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 claims 1
- IUNJANQVIJDFTQ-UHFFFAOYSA-N iopentol Chemical compound COCC(O)CN(C(C)=O)C1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C1I IUNJANQVIJDFTQ-UHFFFAOYSA-N 0.000 claims 1
- 229960000824 iopentol Drugs 0.000 claims 1
- 235000010445 lecithin Nutrition 0.000 claims 1
- 239000000787 lecithin Substances 0.000 claims 1
- 229940067606 lecithin Drugs 0.000 claims 1
- 229960001855 mannitol Drugs 0.000 claims 1
- 230000001272 neurogenic effect Effects 0.000 claims 1
- 230000003647 oxidation Effects 0.000 claims 1
- 238000007254 oxidation reaction Methods 0.000 claims 1
- 229960005489 paracetamol Drugs 0.000 claims 1
- 229920002098 polyfluorene Polymers 0.000 claims 1
- 229920002717 polyvinylpyridine Polymers 0.000 claims 1
- 235000019204 saccharin Nutrition 0.000 claims 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 claims 1
- 229940081974 saccharin Drugs 0.000 claims 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 claims 1
- 229960004793 sucrose Drugs 0.000 claims 1
- 150000003573 thiols Chemical class 0.000 claims 1
- 235000010487 tragacanth Nutrition 0.000 claims 1
- 239000000196 tragacanth Substances 0.000 claims 1
- 229940116362 tragacanth Drugs 0.000 claims 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 claims 1
- 238000006731 degradation reaction Methods 0.000 abstract description 8
- 230000015556 catabolic process Effects 0.000 abstract description 7
- 238000012423 maintenance Methods 0.000 abstract description 6
- 238000002347 injection Methods 0.000 description 18
- 239000007924 injection Substances 0.000 description 18
- 230000000052 comparative effect Effects 0.000 description 17
- 238000000034 method Methods 0.000 description 14
- 239000000725 suspension Substances 0.000 description 11
- 210000001519 tissue Anatomy 0.000 description 11
- 238000002360 preparation method Methods 0.000 description 10
- 239000000463 material Substances 0.000 description 9
- 238000004132 cross linking Methods 0.000 description 7
- 230000007547 defect Effects 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 206010040954 Skin wrinkling Diseases 0.000 description 5
- 230000032683 aging Effects 0.000 description 5
- 239000000969 carrier Substances 0.000 description 5
- 210000003491 skin Anatomy 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 4
- 150000004676 glycans Chemical class 0.000 description 4
- 239000011859 microparticle Substances 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 229920003229 poly(methyl methacrylate) Polymers 0.000 description 4
- 239000004926 polymethyl methacrylate Substances 0.000 description 4
- 238000001356 surgical procedure Methods 0.000 description 4
- 238000012384 transportation and delivery Methods 0.000 description 4
- 210000001260 vocal cord Anatomy 0.000 description 4
- 230000037303 wrinkles Effects 0.000 description 4
- 241000282887 Suidae Species 0.000 description 3
- 230000000975 bioactive effect Effects 0.000 description 3
- 210000000988 bone and bone Anatomy 0.000 description 3
- 210000000845 cartilage Anatomy 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 210000004207 dermis Anatomy 0.000 description 3
- 230000002500 effect on skin Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000002513 implantation Methods 0.000 description 3
- 229920002521 macromolecule Polymers 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 210000005070 sphincter Anatomy 0.000 description 3
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- 229920002101 Chitin Polymers 0.000 description 2
- 206010021639 Incontinence Diseases 0.000 description 2
- 235000019738 Limestone Nutrition 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 206010066218 Stress Urinary Incontinence Diseases 0.000 description 2
- 239000000560 biocompatible material Substances 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000003792 electrolyte Substances 0.000 description 2
- 210000000744 eyelid Anatomy 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 239000006028 limestone Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 239000004005 microsphere Substances 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 239000004810 polytetrafluoroethylene Substances 0.000 description 2
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 231100000241 scar Toxicity 0.000 description 2
- 239000004575 stone Substances 0.000 description 2
- 210000003708 urethra Anatomy 0.000 description 2
- 230000002485 urinary effect Effects 0.000 description 2
- RTBFRGCFXZNCOE-UHFFFAOYSA-N 1-methylsulfonylpiperidin-4-one Chemical compound CS(=O)(=O)N1CCC(=O)CC1 RTBFRGCFXZNCOE-UHFFFAOYSA-N 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- CFWRDBDJAOHXSH-SECBINFHSA-N 2-azaniumylethyl [(2r)-2,3-diacetyloxypropyl] phosphate Chemical compound CC(=O)OC[C@@H](OC(C)=O)COP(O)(=O)OCCN CFWRDBDJAOHXSH-SECBINFHSA-N 0.000 description 1
- YSFURVCPHRYSTN-UHFFFAOYSA-N 2-hydroxy-1,3,2-dioxaphosphetane Chemical compound OP1OCO1 YSFURVCPHRYSTN-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- OQLZINXFSUDMHM-UHFFFAOYSA-N Acetamidine Chemical class CC(N)=N OQLZINXFSUDMHM-UHFFFAOYSA-N 0.000 description 1
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- RGCKGOZRHPZPFP-UHFFFAOYSA-N Alizarin Natural products C1=CC=C2C(=O)C3=C(O)C(O)=CC=C3C(=O)C2=C1 RGCKGOZRHPZPFP-UHFFFAOYSA-N 0.000 description 1
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical compound N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 description 1
- 239000004135 Bone phosphate Substances 0.000 description 1
- 241000206575 Chondrus crispus Species 0.000 description 1
- 208000032544 Cicatrix Diseases 0.000 description 1
- 102100026735 Coagulation factor VIII Human genes 0.000 description 1
- 239000004971 Cross linker Substances 0.000 description 1
- 241000195493 Cryptophyta Species 0.000 description 1
- 102000002322 Egg Proteins Human genes 0.000 description 1
- 108010000912 Egg Proteins Proteins 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 102000009024 Epidermal Growth Factor Human genes 0.000 description 1
- 108010022355 Fibroins Proteins 0.000 description 1
- 229920002907 Guar gum Polymers 0.000 description 1
- 101000911390 Homo sapiens Coagulation factor VIII Proteins 0.000 description 1
- WOBHKFSMXKNTIM-UHFFFAOYSA-N Hydroxyethyl methacrylate Chemical compound CC(=C)C(=O)OCCO WOBHKFSMXKNTIM-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- 208000029578 Muscle disease Diseases 0.000 description 1
- 108010025020 Nerve Growth Factor Proteins 0.000 description 1
- 102000015336 Nerve Growth Factor Human genes 0.000 description 1
- 208000028389 Nerve injury Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 208000006735 Periostitis Diseases 0.000 description 1
- 229920000463 Poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) Polymers 0.000 description 1
- 229920000805 Polyaspartic acid Polymers 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- WINXNKPZLFISPD-UHFFFAOYSA-M Saccharin sodium Chemical compound [Na+].C1=CC=C2C(=O)[N-]S(=O)(=O)C2=C1 WINXNKPZLFISPD-UHFFFAOYSA-M 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 206010046543 Urinary incontinence Diseases 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- IYKJEILNJZQJPU-UHFFFAOYSA-N acetic acid;butanedioic acid Chemical compound CC(O)=O.OC(=O)CCC(O)=O IYKJEILNJZQJPU-UHFFFAOYSA-N 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 210000001789 adipocyte Anatomy 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- HFVAFDPGUJEFBQ-UHFFFAOYSA-M alizarin red S Chemical compound [Na+].O=C1C2=CC=CC=C2C(=O)C2=C1C=C(S([O-])(=O)=O)C(O)=C2O HFVAFDPGUJEFBQ-UHFFFAOYSA-M 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 125000002344 aminooxy group Chemical group [H]N([H])O[*] 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-N anhydrous glutaric acid Natural products OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 229920006318 anionic polymer Polymers 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 230000003796 beauty Effects 0.000 description 1
- MSWZFWKMSRAUBD-QZABAPFNSA-N beta-D-glucosamine Chemical compound N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-QZABAPFNSA-N 0.000 description 1
- 239000012867 bioactive agent Substances 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 229910052792 caesium Inorganic materials 0.000 description 1
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical class [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 1
- JUNWLZAGQLJVLR-UHFFFAOYSA-J calcium diphosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])(=O)OP([O-])([O-])=O JUNWLZAGQLJVLR-UHFFFAOYSA-J 0.000 description 1
- 229940043256 calcium pyrophosphate Drugs 0.000 description 1
- 229920006317 cationic polymer Polymers 0.000 description 1
- 239000000919 ceramic Substances 0.000 description 1
- 229910010293 ceramic material Inorganic materials 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- 230000007012 clinical effect Effects 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 239000012050 conventional carrier Substances 0.000 description 1
- 238000012864 cross contamination Methods 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 238000003381 deacetylation reaction Methods 0.000 description 1
- 125000006612 decyloxy group Chemical group 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 235000019821 dicalcium diphosphate Nutrition 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- QGKBPWOLFJRLKE-UHFFFAOYSA-J distrontium;phosphonato phosphate Chemical compound [Sr+2].[Sr+2].[O-]P([O-])(=O)OP([O-])([O-])=O QGKBPWOLFJRLKE-UHFFFAOYSA-J 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 235000013345 egg yolk Nutrition 0.000 description 1
- 210000002969 egg yolk Anatomy 0.000 description 1
- 230000009881 electrostatic interaction Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229940044949 eucalyptus oil Drugs 0.000 description 1
- 239000010642 eucalyptus oil Substances 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 210000004709 eyebrow Anatomy 0.000 description 1
- 230000001815 facial effect Effects 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 230000003176 fibrotic effect Effects 0.000 description 1
- 210000002683 foot Anatomy 0.000 description 1
- 210000004704 glottis Anatomy 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 235000010417 guar gum Nutrition 0.000 description 1
- 239000000665 guar gum Substances 0.000 description 1
- 229960002154 guar gum Drugs 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine group Chemical group NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 1
- GPRLSGONYQIRFK-UHFFFAOYSA-N hydron Chemical compound [H+] GPRLSGONYQIRFK-UHFFFAOYSA-N 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000004816 latex Substances 0.000 description 1
- 229920000126 latex Polymers 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 238000007443 liposuction Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000008764 nerve damage Effects 0.000 description 1
- 229940053128 nerve growth factor Drugs 0.000 description 1
- 150000004689 octahydrates Chemical class 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 206010033675 panniculitis Diseases 0.000 description 1
- 210000003516 pericardium Anatomy 0.000 description 1
- 210000003460 periosteum Anatomy 0.000 description 1
- 229920000724 poly(L-arginine) polymer Polymers 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 108010011110 polyarginine Proteins 0.000 description 1
- 108010064470 polyaspartate Proteins 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 231100000683 possible toxicity Toxicity 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 230000037390 scarring Effects 0.000 description 1
- 230000037387 scars Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000012798 spherical particle Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 210000004304 subcutaneous tissue Anatomy 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- GBNXLQPMFAUCOI-UHFFFAOYSA-H tetracalcium;oxygen(2-);diphosphate Chemical compound [O-2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O GBNXLQPMFAUCOI-UHFFFAOYSA-H 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000008467 tissue growth Effects 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 210000003371 toe Anatomy 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 230000000472 traumatic effect Effects 0.000 description 1
- 229940078499 tricalcium phosphate Drugs 0.000 description 1
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- 238000009827 uniform distribution Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
- VWQVUPCCIRVNHF-UHFFFAOYSA-N yttrium atom Chemical compound [Y] VWQVUPCCIRVNHF-UHFFFAOYSA-N 0.000 description 1
Abstract
Description
201247179 六、發明說明： 【發明所屬之技術領域】 本杂明係關於一種適用於軟組織植入物之聚電解質錯合 物（polyelectrolyte complex，PEC)凝膠及包含該聚電解質錯 合物凝膠之軟組織填補植入物。更特定而言，該聚電解質 錯合物凝膠為包含幾丁聚醣及丫_聚麩胺酸h_pGA)之聚電 解質錯合物凝膠。 【先前技術】 皮膚的填補在從受傷中恢復或於美容或支撐等目的中， 可能成為填補的重要因素。例如皮膚在正常老化下可能會 變得鬆散或形成如鼻唇皺摺、皺紋、坑洞及缺陷等。在臉 上的皺摺或皺紋可能會影響一個人的自信心’甚至是職業 生涯，因此以軟組織填補術矯正缺陷及對抗衰老的影響也 變得日益重要。目前，軟組織填補術可藉由諸如蠟狀物 質、膠原蛋白、脂肪、矽酮、聚乳酸、聚乙烯、聚四氟乙 稀或水膠為主之聚合物組成物等材料加以填補，這些材料 可根據使用的情況而有不同形式，例如濃溶液、凝膠、珠 或懸浮物等，且可做為植入物或運送植入物之載體。理相 的軟組織填補材料應具有足夠<耐久性並可維持於指定2 置，不應從植入部位遷移。 美國第4,綱，075號專利揭露—種用於軟組織填補術的注 射植入物組合物，其包括—種生物相容微粒（如交聯_ 原蛋白或諸如肝酷或麥芽糖等生物相容之流體潤滑齊。的 水性懸料，以改善該生物材料料液的可注射性。然 150467.doc , 201247179 而，該專利之組合物不具有足夠之耐久性，所以它們無法 在體内停留足夠長的時間。 美國第6,537,574號專利涉及一種生物相容材料其包括 由-種生物可相容性陶究物質之平滑、圓形、細碎的實質 球體顆粒所組成之基質，其彼此鄰近或接觸，且提供一支 架或結構以供自體性、三維、無定向的非瘢痕性軟組織於 強化位置生長；在其中—個實施例中，在將懸浮於鼓甲基 ，’隹素鈉中之20至45 μηι或75至125 μηι的顆粒狀羥磷灰石鈣 的滅菌樣本注射至組織後，甲基纖維素於三個月内被吸 收’留下麵基磷灰石鈣於組織中。雖不難將樣本植入於軟 組織内，但維持效果不易，須於三個月内補行第二次注 射。 英國第2222176號專利提供了一個用於填補凹陷性疤 痕'不對稱眼眶底及表面骨缺陷等的改良微植入方法與設 備。該專利採用具有約2〇至3〇〇〇微米之經表面處理的微 粒丄其可經適當的生理載體和皮下注射針及注射器注射到 預疋之位置，諸如凹陷瘢痕的底#、凹陷的皮膚區域之下 以及在月與軟骨表面不規則處的軟骨膜與骨膜之下。在需 要使用硬物質之情況下，可利用某㈣鹽（包括經基磷灰 石或其他類似之晶體材料）、生物相容陶瓷、生物相容金 屬（例如特疋不銹鋼顆粒）或玻璃等生物相容材料；在某此 月兄下可此需要使用完全惰性的載體，如矽油、脂肪及 玻尿自文知（例如乙基玻尿酸酯和聚乙烯吡咯烷酮等）。然 而’廷些载體會快速降解’因此無法長期支撐目標物。 150467.doc 201247179 美國第5,344,452號專利涉及一個具組織相容性固體為主 的異質性植入物，其特別適用於將皮膚之不規則處平坦 化’但亦可用於其他目的的整形外科。該專利係使用被結 締組織包覆或嵌入至結締組織纖維之20-40微米之聚甲基 丙烯酸甲酯（PMMA)顆粒，其懸浮於人體内之膠原蛋白。 然而’由於膠原蛋白係源自牛等動物，此種植入物有導致 過敏之可能。 美國專利第2008/0025950 A1號公開案揭露一種化合物 及製造方法及使用該化合物於無瘢痕傷口治療、傳輸生物 活性劑或活細胞及預防手術後或骨骼和軟骨的修復後沾黏 之方法。該化合物可為經修飾之大分子化合物，其係藉由 引進至少一個肼反應性基團和/或胺基氧基反應性基團以 促進交聯。然而，形成經修飾之大分子化合物必須使用交 聯反應。 R.A. Appell的「人工尿道括約肌與尿道周圍之注射作用 (The Artificial Urinary Sphincter and Periurethral Injections, Obstetrics and Gynecolocy Report Vol. 2, No. 3, pp. 334- =2’（199()))」回顧評論中揭露各種用以治療尿道括約肌機 能不全之方式，包括使用可注射物諸如尺寸約4至100微米 之不規則开/狀的聚四氟乙烯微聚合物顆粒以及甘油與聚山 木酉欠=另種尿道周圍的可注射構件包括高度純化之牛 真皮膠原蛋白，其係與戊二酸交聯及分散於―酸鹽緩衝的 生里广现水申。Kresa等人揭露一種用以治療聲門閉合不 全之聲帶調整之方法’其中包括將先前經乾燥成玻璃狀、 150467.doc 201247179 堅硬狀態之一親水性凝膠的造型植入物導入聲帶中（Kresa et al，「Hydron Gel Implants in Vocal Cords」 Otolaryngolocy Head and Neck Surgery, Vol. 98. No. 3, pp. 242-245，（March 1988))。在前述兩篇文獻中，體内降解時 間為s平估軟組織植入物的一個重要因素。舉例來說，膠原 蛋白會迅速在體内發生水解及降解並導致相對短的臨床效 果，因此患者必須於通常每隔數月的時間再接受額外注 射，以維持組織之支撐性。然而不斷進行的注射過程不但 昂貴，亦會造成不便、不適或者疼痛及其他副作用。此 外，任何包含注射等侵入性的療程都有交叉污染和感染的 風險。因此，在此技術領域中對於可用於軟組織填補術且 更持久之注射材料仍有需求。 【發明内容】 本發明係關於一種聚電解質錯合物凝膠，其包含幾丁聚 膽及具有分子量自約1 kDa至約400kDa0mγ_ PGA)或其鹽及—種水性溶液，其中幾丁聚醣及卜聚麵胺酸 錯合物凝料於該水㈣液巾_。本發明亦提供-種軟 組，填補植人物’彡包含做為载體或填充材之本發明聚電 解質錯口物凝膠及選用之添加劑。本發明之聚電解質錯合 ^ >及匕3彼等之軟組織填補植入物具有長降解時間與 更佳的支#性’因此對軟組織可提供良好的維持性。 本發明亦提供—種軟組織填補植人物，其包括本發明之 聚電解質錯合物、辞_ ^ Λ ^ 物凝膠、载體或填充材及選用之添加劑。 本&明之敕組織填補物為利用電荷相反的聚電解質（如 150467.doc 201247179 f醣與多肽）交聯形成之聚電解質錯合物凝膠。本發明係 精由混合電荷相反的聚電解質以形成聚電解質錯合物凝 膠，因此無需使用化學交聯劑。在典型的真皮植入系統 中’應包含至少填充材、載體及選用之添加劑，而本發明 所開發的聚電解質錯合物凝膠，可依其交聯程度的不同， 做為用於軟組織填補之載體或填充材。換言之，聚電解質 錯合物凝膠可扮演載體或填充材之角色。本發明之電解質 錯合物凝膝具有可傳輸物質的能力且無細胞潛在毒性，由 於其良好之可注入性’尤其適合經由細針頭微創注射入軟 組織中，加以填補。此外’該聚電解質錯合物凝膠具有較 長的降解時間及更佳的支樓性，從而為軟組織提供良好的 維持特性。 t在用於本說明書及所附的請求射_，除非文中有明確 指出相反之情況，單數形式的「_ ^ (a)」、「一（an)」及「該 (the)」等用語亦包含複數之情形。 在本文中使用「軟組織」一詞時，係指非骨骼組織。換 …其排除骨胳、韋刀帶、軟骨、椎間盤和纖維組織。 在本文中使用「軟組織填補」—詞時，其包含但不限於 下列内容：真皮組織填補m皴紋、輕微面部凹 陷、兔唇及類似情形之填充，特別是在面部及頸部；因老 化或疾病導致之輕微畸形之橋正，包括手部及腳部、手指 =趾；為恢復聲音能力所做之聲帶或聲門擴張；睡眠紋 =情紋之真皮填充；因老化造成真皮及皮下組織流失之 、α σΜ真補’魚尾紋及眼周圍眼眶溝線之填充；隆 150467.doc 201247179 胸；口腔填補、下巴填補、頰部及/或鼻部填補；因例如 過份抽脂或其他外傷導致之軟組織、真皮或皮下凹陷之填 充、痤瘡或外傷性症痕及皺紋填充；鼻唇紋'鼻眉紋及法 •7、’文真充’以及因尿失禁（尤其是壓力性尿失禁）之尿道組 織注射使用之填充。 生物及收」闺係指能夠被吸收並自人體排除。 「生物相容」一詞係指生理上能被活組織及器官接受。 :聚電解質錯合物凝勝」—詞係指由帶相反符號電荷之 大刀子組成之中性聚合錯合物膠，該相反符號之電荷藉由 靜電相互作用造成大分子之結合。聚電解f錯合物凝膠可 藉由陽離子聚合物（具有正電荷之聚電解質）及陰離子聚合 物（具有負電荷之聚電解質）混合後立即形成。 父聯J 一詞係指藉由帶相反電荷之聚電解質，如多醣 及多肽，形成一聚電解質錯合物凝膠之過程。 本文使用之「經注入（注射）」、「注入（注射）」或「可注 入性」等用語包括任何聚合物組合物之投予，如注射、浸 入或或通過任何環形輸送裝置傳送至個體。注射包括通過 一管狀物輸送。 本發明之一目的係提供一種聚電解質錯合物凝膠，其包 含幾丁聚醣、具有分子量自約i kDa至約4〇〇 kDaiY聚麩 胺酸（γ-PGA)或其鹽及一種水性溶液，其中該幾丁聚醣及 該γ-PGA形成之水膠該水性溶液中膨潤。 在一個實施例中，γ-PGA分子量之範圍係自約i kDa至約 3 50 kDa、約 1 kDa至約 300 kDa、約 1 kDa至約 250 kDa、約 I50467.doc 201247179 1 kDa 至約 200 kDa、約1 kDa 至約150 kDa、約1 kDa 至約 100 kDa、約1 kDa 至約50 kDa、約5 kDa 至 350 kDa、約5 kDa至約 300 kDa、約 5 kDa至約 250 kDa、約 5 kDa至約 200 kDa、約 5 kDa至約 150 kDa、約 5 kDa至約 100 kDa、約 5 kDa至約 50 kDa、約 10 kDa至約 400 kDa、約 10 kDa至約 350 kDa、約 10 kDa至約 300 kDa、約 10 kDa至約 250 kDa、 約 10 kDa至約 200 kDa、約 10 kDa至約 150 kDa、約 10 kDa 至約 100 kDa、約 10 kDa至約 50 kDa、約 50 kDa至約 400 kDa、約 50 kDa 至約 350 kDa、約 50 kDa 至約 300 kDa、約 50 kDa 至約 250 kDa、約 50 kDa 至約 200 kDa、約 50 kDa 至 約 150 kDa、約 50 kDa至約 100 kDa、約 100 kDa至約 400 kDa、約 100 kDa至約 350 kDa、約 100 kDa至約 300 kDa、 約 100 kDa 至約 250 kDa、約 100 kDa 至約 200 kDa 或約 100 kDa至約150 kDa或其任何組合。 在另一個實施例中，γ-PGA之鹽為Η形式或鹽形式（例如 鈉鹽、鉀鹽、鈣鹽或鎂鹽等）。 在另一個實施例中，幾丁聚醣及或其鹽具有自約 〇. 1重量％至約10重量％及約〇·丨重量％至約2〇重量％之範圍 的含量。較佳地，幾丁聚醣的含量為約〇.5重量％至約1〇重 量％、約1重量％至約1〇重量％、約2重量％至約1〇%、約〇.5 重里❶/。至約5重量％、約1重量％至約5重量％或約2重量％至 約5重量％。更佳地，γ_ρ(3Α或其鹽之含量為約〇 5重量％至 約20重量❶、約1重量％至約20重量％、約1重量％至約15重 量％、約1重量％至約1〇重量％或約j重量％至約5重量 150467.doc 201247179 在另一個實施例中，幾丁聚醣可由幾丁質之N_去乙醯化 獲付。幾丁聚醣是一種由隨機分佈之β_(1 _4)_連結_d_葡萄 胺糖（去乙醯化單元）及义乙醯_D_葡萄胺糖（乙醯化單元）組 成之線性多糖。用於本發明之組合中之幾丁聚醣係指原態 幾丁聚膽或其衍生物，衍生物包括但不限於羧曱基幾丁聚 聽、羧曱基幾丁聚醣、N-亞甲基亞磷酸幾丁聚醣、磺酸化幾丁 聚醣、三甲基幾丁聚醣、三乙基幾丁聚醣、N—醯基幾丁聚醣、 幾丁聚聽曱基丙烯酸酯、氮_異丙基丙烯醯胺幾丁聚醣及琥珀酸 化幾丁聚醣。任何市售之幾丁聚醣及幾丁質（包含有去乙醯 化單元）均可用於本發明。較佳地’幾丁聚醣之分子數量 超過1 00 kDa。較佳地，幾丁聚醣的分子量範圍係自約1 〇〇 kDa至約 2000 kDa、約 1〇〇 kDa至約 1500 kDa、約 1〇〇 kDa 至約 1 000 kDa、約 200 kDa至約 2000 kDa、約 200 kDa至約 1500 kDa、約 200 kDa 至約 1500 kDa、約 1〇〇 kDa 至約 7〇〇 kDa、約 100 kDa 至約 400 kDa 或約 400 kDa 至約 700 kDa， 或其任何組合。 根據本發明，聚電解質錯合物凝膠可被使用做為用於軟 組織填補之載體所承載之填充材或容納填充材之載體。本 發明之聚電解質錯合物凝膠藉由幾丁聚醣及具有自約i kDa至約400 kDa分子量之γ-PGA或其鹽交聯而形成。本發 明之聚電解質錯合物凝膠之流動性隨著交聯程度有所不 同’當幾丁聚醣與高分子量之γ-PG A交聯時，所形成的聚 電解質錯合物凝膠具有較低的流動性，而於此情形時，該 聚電解質錯合物凝膠可做為用於軟組織填補之填充材；當 150467.doc 201247179 幾丁聚聽與低分子量之γ-PGA交妈技 錯合物凝膠具有較佳的流動性、’所形成的聚電解質 膠可做為用於軟組織填補之载體。_聚電解質錯合物凝 2用任何能使本發明之聚電解f錯合物凝膠膨潤的合 適水性溶液。例如，聚電解質供 w心 解質錯合物凝膠可利用具有弱酸 ^值之水性溶㈣I較佳地，㈣圍為3.()到6.8。較 性溶液是水或Ϊ水酒精1性溶液的實例包括但 甘/由#丙醇、乙醇、乙二醇或其混合物。用 Γ載體之其他合適的溶劑對於技藝人士來說是顯而易 見的。界面活性劑、穩定劑、ΡΗ緩衝液和其他添加劑等亦 可使用，且對技藝人士來說為顯而易見之事。 根據本發明，形成本發明之聚電解質錯合物凝膠不需使 ^聯劑。本發明之聚電解f錯合物凝膠之形絲基於多 電何機制。本發明之聚電解質錯合物凝膠有足夠之耐久 性，能存留在體内足夠長的時間而仍具有良好的支揮能 力。較佳地’本發明之聚電解質錯合物凝膠可存留於體内 至少2個月、3個月、4個月、5個月或6個月。更佳地，本 發明之聚電解質錯合物凝谬可存留於體内至少6個月。較 佳地，本發明之聚電解質錯合物凝膠可存留於體内2至12 個月、3至12個月、4至12個月、5至12個月、a。個月、 7至12個月、8至12個月、9至12個月、1〇至 個月或4至8個月。 2至6 另一方面，本發明提供一種軟組織填補植入物，其包含 本發明之聚電解質錯合物凝膠以做為載體或填充材，以及 150467.doc 201247179 一選用之添加劑。 如前所述，本發明之聚電解質錯合物凝膠可做為載體或 真充材0此，本發明之聚電解質錯合物凝膠可做為載體 以承載填充材及選用之沐Λ逾丨 +加Μ。或者’本發明之聚電解質 錯合物凝膠可做為承載於葡和φ夕+古+ u 戰•、戰體中之填充材。視本發明之聚 電解質錯合物之角辛；. 同’/、可與載體或填充材及選用之 添加劑相結合以構成軟組織填補植入物。 在一實施例中，可制各種生物相容載體以支撐本發明 之聚電解質錯合物凝膠。合適載體之選擇將取決於顆粒大 小、填充材量、注射針頭大小及填充材之性質。載體之實 例包括但不限於：阿拉伯膠 '卡波姆(carbomer)共聚物及 單聚物、卡波姆互聚物、水膠、多醣'巨環多酿、寡聚 醣、殿粉、乙醯澱粉、纖維素、纖維素衍生物、甲基纖維 素 '羧甲基纖維素鈉、羧曱基纖維素（CMC)、乙基羥乙基 纖維素（EHEC)、乙基纖維素、羥丙基纖維素、羥丙基曱基 纖維素（HPMC)、乙基纖維素、烷基纖維素、烷氧基纖維 素、經基乙基纖維素、乙烯基。比B各咬酮-乙酸乙稀酯共聚 物（copovidone)、聚乙烯基吡咯啶酮（p〇vid〇ne)、明膠、瓜 爾膠、羥丙曱纖維素、羥丙曱纖維素醋酸琥珀酸酯、麥芽 糊精、糖漿、洋菜、蘋果醯胺酸、單硬脂酸鋁、綠坡縷石 (attapulgite)、結蘭膠、羥丙曱纖維素、麥芽糊精、果膠、 藻酸丙二醇酯、藻酸納、藻酸弼、膠體二氧化石夕、黃蓍 膠、黃原膠’卵麟脂、三蛾苯衍生物、蛾海醇（iohexyl)、 碘帕醇（iopamidol)、’碘喷拖（i〇pent〇i)、蔗糖，鹿角菜 150467.doc 12 201247179 膠、瓊脂、甘露糖醇、糖精鈉、山梨糖醇、腦磷脂、炔二 醇、卡波堪（carbowax)、聚有機續酸、院氧基化表面活性 劑、烷基苯酚聚氧乙烯醚、乙氧基化脂肪酸、乙醇聚氧乙 烯醚、乙醇聚氧烯醚、聚乙烯氧化物、聚（環氧丙烷）、聚 乙二醇（PEG)、聚（丙二醇）、聚乙烯醇（PVA)聚合物或共聚 物、聚丙烯醯胺、聚（乙烯羧酸）、聚甲基丙烯酸、聚丙烯 酸聚合物或共聚物、聚氨基酸、白蛋白、膠原蛋白，纖維 蛋白、生物膠（bioglue)、纖維素、卡波普（Carbopol)、泊 洛沙姆（Poloxamer)、普朗尼克（Pluronic)、，鐵窗尼克 (Tetronics)、PEO-PPO-PEO三區塊共聚物、PEO-PPO與伸 乙基二胺之四官能區塊聚合物或共聚物、聚HEMA聚合物 或共聚物、Hyp an聚合物或共聚物、殿粉乙醇酸聚合物或 共聚物鹽、聚氧基伸烷基醚、聚乙烯。比啶、聚賴氨酸、聚 精氨酸、聚天門冬胺酸及聚麩氨酸、聚伸丁基氧化物、聚 (羥基乙基丙烯酸酯）、聚（羥基曱基丙烯酸乙酯）、曱氧基 果膠凝膠、鄰苯二曱酸醋酸纖維素、有機油、B -葡聚 醣、聚山梨酯、乳酸酯、己酸酯、玻尿酸、糊精、葡聚 醣、葡萄糖、及上述之混合物。 在一個實施例中，可將各種生物相容填充材承載於做為 載體之本發明聚電解質錯合物凝膠中。填充材之實例包括 但不限於：多醣（如玻尿酸（HA))、無機鹽、膠原蛋白、多 元醇、羥基磷灰石（如羥基磷灰石鈣）、矽酮及明膠、聚曱 基丙烯酸甲酯或聚左旋乳酸（PLLA)、羧甲基纖維素、交聯 CMC水凝膠、脂肪及蠶絲蛋白。 I50467.doc -13- 201247179 根據本發明，顆粒形式之無機鹽包括但不限於：磷酸鈣 顆粒、矽酸鈣顆粒、碳酸鈣顆粒、氧化鋁顆粒、氧化锆顆 粒、經基磷灰石顆粒、含羥基磷灰石顆粒之氧化锆、焦磷 酸弼顆粒、四鈣磷酸鹽顆粒、三鈣磷酸鹽顆粒、八鈣磷酸 鹽顆粒、氟構灰石（Ca1Q(P〇4)6F2)顆粒，鈣磷灰石顆粒或其 混合物。較佳地，該無機鹽為磷酸鈣顆粒、氧化锆顆粒、 羥基磷灰石顆粒、含羥基磷灰石顆粒之氧化锆，或其混合 物。較佳地’該無機鹽為羥基磷灰石顆粒、焦磷酸鈣顆 粒、四#5碟酸鹽顆粒、三的鱗酸鹽顆粒、八好填酸鹽顆 粒、氟磷灰石（Ca1Q(P〇4)6F2)顆粒、鈣磷灰石顆粒或其混合 物。更佳地，該無機鹽是含羥基磷灰石顆粒之氧化锆。更 佳地，該無機鹽係羥基磷灰石顆粒。最佳地，該無機鹽係 磷酸鈣顆粒。 在個貫施例中，可選用於本發明之軟組織填補植入物 中之添加劑可為多種材料，包括但不限於蛋白質及生物活 性物質。 根據本發明，生物活性物質可具有治療性質，並且可例 如促進組織生長（即生長因子）或做為抗微生物劑。較佳 地，該生物活性物質為表皮生長因子（egf)、成纖維細胞 生長因子（FGF)、神經生長因子⑽F)或其混合物。較佳 地’該生物活性物質為EGF。這些物質可能被嫁接到顆粒 或被顆粒吸收，並可能具有隨時間釋放至周圍組織之特 性。依據不同應用，技術領域中之技藝人士應可了解节等 生物活性物質可併入植入物材料，及了解該等生物活性物 150467.doc 14 201247179 質之醫療價值。 根據本發明，細胞可為脂（脂肪）細胞、胚胎幹細胞、間 葉幹細胞、神經幹細胞、脂肪前驅細胞、脂肪幹細胞或牙 髓幹細胞。 在本發明之特定實施例中，軟組織填補植入物係以例如 注射器或關節鏡手術（arthroscopic)之儀器注入。這些方法 因侵入性相較其他方法（例如外科手術）小，然而具有較小 之感染、不適及併發症風險，且其注入量及注入位置能被 輕易控制，因此為較佳之方法。一個熟悉此領域之技藝人 士可了解各種注射方法。例如，在本發明之實施例中，可 使用18G(gauge)之注射器將具有約5〇〇微米大小之顆粒注 入，而在那些具有較小顆粒大小之實施例中，可使用更大 gauge之針頭注射，例如關節注射。 在本發明之實施例中，軟組織填補植入物係經皮下注射 至軟組織輪廓缺陷之區域。植入劑量為足夠完全消除缺 陷。這種缺陷可能包括諸如口腔、乳房、下巴、臉頰和/ 或鼻子的敵紋及缺陷。 在本發明之另-個實施例中，軟組織填補植入物可用以 控制失禁’特別是壓力性尿失禁。失禁可為疾病、老化或 神左肌肉病變所造成，亦可為因前列腺手術導致控制尿道 周圍之括約肌的神經受損所造成。 當此軟組織填補物植人軟組織時，將在植人物結構中及 其周圍形成緻密、纖維化且具可撓性的組織。此將發生於 支數天之内。植入物於身體内依然為惰性，且與新形 150467.doc -15· 201247179 成之組織、填補或塑形所需要的軟組織。 本技術領域中之技藝人士應可瞭解本發明之聚電解質錯 合物凝膠、軟組織填補植入物及方法，除前述實施例外， 尚可用於其他之多種用途中。本技術領域中之技藝人士亦 可明瞭前述說明書之内容及所附圖式之目的為說明本發 明，並非限制本發明。因此吾人應瞭解，只要不偏離本發 明之精神及範圍，可對於上述内容做各種之修飾及改變。 而本發明之範圍應僅為所附之申請專利範圍所限制。 【實施方式】 實例1本發明聚電解質錯合物凝膠之製備 將含有30克幾丁聚醣（Mw=2〇〇 kDa)及4〇克聚麩胺酸 (Mw=l〇 kDa) ’加入1〇〇〇克之}重量％醋酸水溶液中，於一 容器中快速混合約30秒；以ion NaOH滴定至中性後，混 合30分鐘。將獲得之聚電解質錯合物凝膠靜置12小時以 上。 對照例為習知之凝膠。對照例1為缓曱基纖維素（CMC) 載體，其係以下述方式製備：將30克CMC與150克甘油添 加至裝有520毫升水性溶液之容器中並混合約30秒；慢速 混合攪拌12小時以上使其混合均勻以形成CMC載體。 實例2本發明聚電解質錯合物凝膠之製備 將20克幾丁聚酵（Mw=2000 kDa)加入具有1000克之〇.5重 量％醋酸水溶液中，再添加1〇克Y_PGA(Mw=300 kDa)，並 快速混合約30秒；以1 ON NaOH滴定至中性後再混合30分 鐘。將所獲得之聚電解質錯合物凝膠靜置12小時以上。 I50467.doc -16- 201247179 實例3含羥基磷灰石之聚電解質錯合物凝膠植入物之製備 將實例1所述之聚電解質錯合物凝膠及43〇克之經基碌灰 石顆粒（顆粒尺寸範圍為25至45微米）完全摻混，以低速混 合器混合至所有顆粒均勻分布於1〇〇〇毫升之凝膠懸浮液。 此外，將對照例1之CMC載體與430克之羥基磷灰石顆粒 (顆粒尺寸範圍為25至45微米）完全摻混，以低速混合器混 合，直至所有顆粒均質地分布於1〇〇〇毫升之載體懸浮液以 开>成含經基鱗灰石顆粒之CMC載體混合物（對照例2)。 對照例3為市售商品微晶兗（Ra(jiesse®)，其係懸浮於 CMC載體中之含羥基磷灰石顆粒之微球體，由Bi〇F〇rm& 司製造。 實例4含聚左旋乳膠（PLLA)之聚電解質錯合物凝膠植入 物之製備 將貫例1之聚電解質錯合物凝膠載體及2〇〇克聚左旋乳酸 (PLLA)顆粒（顆粒尺寸範圍為4〇至63微米）完全摻混，以低 速混合器混合直至顆粒均勻分布於1〇〇〇毫升之凝膠懸浮 液。 實例5含聚甲基丙烯酸甲酯顆粒之聚電解質錯合物凝膠植 入物之製備 將實例1之聚電解質錯合物凝膠與127 8克之聚甲基丙烯 酸甲酯顆粒（顆粒尺寸範圍為1〇〇至18〇微米）完全摻混，以 低速展合器混合直至所有顆粒均勻分布於1〇〇〇毫升之凝 膠懸浮液。 實例6含蠶絲微顆粒之聚電解質錯合物凝膠植入物之製備 150467.doc •17- 201247179 將實例1之聚電解質錯合物凝膠與250克蠶絲微球體（顆 粒尺寸範圍為2〇至45微米）完全換混，以低速混合器混 合’直至所有顆粒均勻分布於丨〇〇〇毫升之凝膠懸浮液。 實例7含聚電解質錯合物顆粒之聚電解質錯合物凝膠植入 物之製備 將1克幾丁聚酿（Mw=100 kDa)加入100毫升之1重量。/〇醋 酉夂水/合液中，將0.3克γ·ρ〇Α鈣（Mw=1000 kDa)及0.2克CMC 加入1 00毫升之去離子水。將兩溶液以均質機快速混合約 3 〇心後，即形成聚電解質錯合物之微顆粒。將實例^之聚 電解質錯合物凝膠與25〇克聚電解質錯合物之微顆粒（顆粒 尺寸範圍為100至12〇微米）完全摻混，以低速混合器混合 直至顆粒均質分布於1〇〇〇毫升之凝膠懸浮液。 實例8含牙趙幹細胞之聚電解質錯合物凝膠植入物之製備 將實施1之聚電解質錯合物凝膠與1毫升之ΐχΐ〇6個牙髓 幹細胞完全捧混’以低速混合器混合直至所有細胞均質分 布於9毫升之凝膠懸浮液。 實例9含牙趙幹細胞及經基填灰石之聚電解質錯合物凝膠 植入物之製備 將貫％ 3之忒電解質錯合物凝膠及羥基磷灰石顆粒混合 物’、1毫升之1 X 1 〇個牙趟幹細胞完全摻混，以低速混合器 混口直至所有細胞均勻分布於9毫升之凝膠懸浮液。 此外做為對照例之含牙髓幹細胞之羥基磷灰石/CMC 載體扣合物（對照例4)可由下述方式製備H照例2之經 基％灰石/CMC載體混合物與i毫升之卜ι〇6個牙髓幹細胞 I50467.doc •18· 201247179 完全摻混’以低速混合器混合直至所有細胞均質分布於9 毫升之凝膠懸浮液。 實例ίο本發明聚電解質錯合物凝膠之體外降解試驗 將實例1之聚電解質錯合物凝膠及對照例1以冷凍乾燥方 式處理以取得乾燥粉末；秤取〇_5克之樣品，放置於含有201247179 VI. Description of the Invention: [Technical Field of the Invention] The present invention relates to a polyelectrolyte complex (PEC) gel suitable for a soft tissue implant and a gel comprising the polyelectrolyte complex. Soft tissue fills the implant. More specifically, the polyelectrolyte complex gel is a polyelectrolyte complex gel comprising chitosan and 丫_polyglutamic acid h_pGA). [Prior Art] The filling of the skin may be an important factor in the recovery from the recovery or in the purpose of beauty or support. For example, under normal aging, the skin may become loose or form such as nasolabial folds, wrinkles, potholes, and defects. Wrinkles or wrinkles on the face may affect a person's self-confidence, or even a career, so it is increasingly important to use soft tissue filling to correct defects and fight aging. At present, soft tissue filling can be filled by materials such as waxy substances, collagen, fat, ketone, polylactic acid, polyethylene, polytetrafluoroethylene or water-based polymer. There may be different forms depending on the conditions of use, such as concentrated solutions, gels, beads or suspensions, and the like, and may serve as an implant or carrier for transporting the implant. The soft tissue filling material of the phase should have sufficient & Durability and can be maintained at the specified position and should not migrate from the implant site. US Patent No. 4, No. 075 discloses an injection implant composition for soft tissue filling, which includes a biocompatible particle (such as cross-linking protein or biocompatible such as liver or maltose). Fluid-lubricated aqueous suspension to improve the injectability of the biomaterial feed. However, the composition of the patent does not have sufficient durability, so they cannot stay in the body enough. US Patent No. 6,537,574 is directed to a biocompatible material comprising a matrix of smooth, round, finely divided substantial spherical particles of a biocompatible ceramic material that are adjacent or in contact with one another. And providing a scaffold or structure for autologous, three-dimensional, non-oriented non-scarring soft tissue to grow in a strengthened position; in one of the embodiments, in suspension of the methyl group in the drum, the sodium of the alizarin 20 After a sterile sample of 45 μηι or 75 to 125 μηι of granular hydroxyapatite calcium is injected into the tissue, methylcellulose is absorbed within three months to leave the underlying apatite calcium in the tissue. The sample is implanted in soft tissue, but the maintenance effect is not easy, and a second injection must be made within three months. British Patent No. 2222176 provides a method for filling concave scars, asymmetric eyelids and surface bone defects. Improved micro-implantation methods and apparatus. The patent employs surface-treated microparticles having a size of about 2 to 3 micrometers which can be injected into the pre-clamped position, such as a depression, via a suitable physiological carrier and a hypodermic needle and syringe. The bottom of the scar, under the skin area of the depression, and under the pericardium and periosteum of the irregularities of the moon and cartilage surface. In the case where a hard substance is required, a certain (four) salt (including warp-base apatite or Other similar crystalline materials), biocompatible ceramics, biocompatible metals (such as special stainless steel particles) or biocompatible materials such as glass; under this month, you need to use completely inert carriers such as eucalyptus oil and fat. And hyaluronics are known from the literature (such as ethyl hyaluronic acid and polyvinylpyrrolidone). However, some of the carriers will degrade rapidly, so they cannot support the target for a long time. 467.doc 201247179 US Patent No. 5,344,452 relates to a heterogeneous implant based on a histocompatibility solid which is particularly suitable for planarizing the irregularities of the skin 'but can also be used for other purposes. The patent uses 20-40 micron polymethyl methacrylate (PMMA) particles coated with or embedded in connective tissue fibers, which are suspended in the human body. However, 'as the collagen is derived from cattle, etc. Animals, such implants have the potential to cause allergies. US Patent Publication No. 2008/0025950 A1 discloses a compound and method of manufacture and the use of the compound in the treatment of scarless wounds, delivery of bioactive agents or living cells, and prevention of surgery Or the method of sticking the bones and cartilage after repair. The compound can be a modified macromolecular compound which promotes crosslinking by introducing at least one hydrazine reactive group and/or an aminooxy reactive group. However, a crosslinking reaction must be used to form a modified macromolecular compound. RA Appell's "The Artificial Urinary Sphincter and Periurethral Injections, Obstetrics and Gynecolocy Report Vol. 2, No. 3, pp. 334- = 2' (199()))" Various methods for treating urinary sphincter insufficiency are disclosed, including the use of injectables such as irregular open/shaped polytetrafluoroethylene micropolymer particles having a size of about 4 to 100 microns, and glycerol and poly-amk 酉 另 = alternative Injectable components around the urethra include highly purified bovine dermal collagen, which is cross-linked with glutaric acid and dispersed in the acid-storing buffer. Kresa et al. disclose a method of vocal cord adjustment for the treatment of glottic insufficiency, which involves introducing a styling implant of a hydrophilic gel that was previously dried into a glass, 150467.doc 201247179 hard state, into the vocal cords (Kresa et Al, "Hydron Gel Implants in Vocal Cords" Otolaryngolocy Head and Neck Surgery, Vol. 98. No. 3, pp. 242-245, (March 1988)). In both of the above documents, in vivo degradation time is an important factor in the evaluation of soft tissue implants. For example, collagen rapidly hydrolyzes and degrades in the body and results in relatively short clinical effects, so patients must receive additional injections every few months to maintain tissue support. However, the ongoing injection process is not only expensive, but also causes inconvenience, discomfort or pain and other side effects. In addition, any invasive procedure, including injections, carries the risk of cross-contamination and infection. Therefore, there is still a need in the art for injection materials that are more durable for soft tissue filling. SUMMARY OF THE INVENTION The present invention relates to a polyelectrolyte complex gel comprising chitosan and a molecular weight of from about 1 kDa to about 400 kDa0 γ _ PGA) or a salt thereof and an aqueous solution thereof, wherein chitosan and A polyhedral acid complex is condensed on the water (four) liquid towel _. The present invention also provides a soft group for filling a plant character comprising a polyelectrolyte malware gel of the present invention as a carrier or filler and an additive selected therefrom. The polyelectrolyte mismatches of the present invention > and 匕3 of these soft tissue-filled implants have long degradation times and better support, thus providing good maintenance to soft tissues. The present invention also provides a soft tissue filling implant comprising the polyelectrolyte complex of the present invention, a gel, a carrier or a filler, and an additive selected. This & Mingzhi tissue pad is a polyelectrolyte complex gel formed by cross-linking of a polyelectrolyte with opposite charge (eg, 150467.doc 201247179 f sugar and peptide). The present invention is based on the mixing of polyelectrolytes of opposite charge to form a polyelectrolyte complex gel, thus eliminating the need for a chemical crosslinker. In a typical dermal implant system, 'at least fillers, carriers and additives should be included, and the polyelectrolyte complex gel developed by the present invention can be used for soft tissue filling according to the degree of cross-linking. Carrier or filler. In other words, the polyelectrolyte complex gel can act as a carrier or filler. The electrolyte complex compound of the present invention has the ability to transport a substance and has no cell potential toxicity, and is particularly suitable for injection into a soft tissue through a fine needle by a small needle. In addition, the polyelectrolyte complex gel has a longer degradation time and better branching properties, thereby providing good maintenance characteristics for soft tissues. t used in this specification and the accompanying request _, unless the context clearly states otherwise, the singular forms of "_ ^ (a)", "an" and "the" are also used. Contains the plural case. When the term "soft tissue" is used in this context, it refers to non-skeletal tissue. Change ... to exclude bones, scalpels, cartilage, intervertebral discs and fibrous tissue. In this article, when using "soft tissue filling" - the words include, but are not limited to, the following: dermal tissue to fill m crepe, slight facial depression, lip filling of the rabbit's lips and the like, especially on the face and neck; due to aging or disease The bridge that causes the slight deformity, including the hands and feet, the fingers = toes; the vocal cord or glottis expansion for the ability to restore sound; the sleep pattern = the dermis filling of the erotic; the loss of the dermis and subcutaneous tissue due to aging, α σΜ真补's crow's feet and filling of the eyelid groove line around the eye; Long 150467.doc 201247179 chest; oral filling, chin filling, cheek and/or nasal filling; soft tissue due to, for example, excessive liposuction or other trauma, Filling of dermis or subcutaneous depression, acne or traumatic lesions and wrinkles filling; Nasal lip pattern 'nose eyebrow pattern and method · 7, 'Yen Zhen Chong' and urethral tissue injection due to urinary incontinence (especially stress urinary incontinence) Use the padding. Biology and harvesting means being able to be absorbed and excluded from the body. The term "biocompatible" means physiologically acceptable to living tissues and organs. The term "polyelectrolyte complex" means a neutral polymeric complex gel consisting of a large knife with opposite sign charges, the charge of the opposite sign causing the binding of macromolecules by electrostatic interaction. The polyelectrolytic f complex gel can be formed immediately after mixing by a cationic polymer (polyelectrolyte having a positive charge) and an anionic polymer (polyelectrolyte having a negative charge). The term father-linked J refers to the process of forming a polyelectrolyte complex gel by means of oppositely charged polyelectrolytes, such as polysaccharides and polypeptides. As used herein, the terms "injected (injected)", "injected (injected)" or "injectable" include the administration of any polymeric composition, such as injection, infusion, or delivery to an individual via any endless delivery device. Injection includes delivery through a tube. One object of the present invention is to provide a polyelectrolyte complex gel comprising chitosan having a molecular weight of from about i kDa to about 4 〇〇 kDaiY poly glutamic acid (γ-PGA) or a salt thereof and an aqueous solution a solution in which the chitosan and the water gel formed by the γ-PGA are swollen in the aqueous solution. In one embodiment, the gamma-PGA molecular weight ranges from about i kDa to about 3 50 kDa, from about 1 kDa to about 300 kDa, from about 1 kDa to about 250 kDa, from about I50467.doc 201247179 1 kDa to about 200 kDa. , from about 1 kDa to about 150 kDa, from about 1 kDa to about 100 kDa, from about 1 kDa to about 50 kDa, from about 5 kDa to 350 kDa, from about 5 kDa to about 300 kDa, from about 5 kDa to about 250 kDa, about 5 kDa to about 200 kDa, about 5 kDa to about 150 kDa, about 5 kDa to about 100 kDa, about 5 kDa to about 50 kDa, about 10 kDa to about 400 kDa, about 10 kDa to about 350 kDa, about 10 kDa to About 300 kDa, about 10 kDa to about 250 kDa, about 10 kDa to about 200 kDa, about 10 kDa to about 150 kDa, about 10 kDa to about 100 kDa, about 10 kDa to about 50 kDa, about 50 kDa to about 400 kDa, from about 50 kDa to about 350 kDa, from about 50 kDa to about 300 kDa, from about 50 kDa to about 250 kDa, from about 50 kDa to about 200 kDa, from about 50 kDa to about 150 kDa, from about 50 kDa to about 100 kDa, From about 100 kDa to about 400 kDa, from about 100 kDa to about 350 kDa, from about 100 kDa to about 300 kDa, from about 100 kDa to about 250 kDa, from about 100 kDa to about 200 kDa or about 100 kDa About 150 kDa, or any combination thereof. In another embodiment, the salt of γ-PGA is in the form of a cesium or a salt (e.g., a sodium salt, a potassium salt, a calcium salt or a magnesium salt, etc.). In another embodiment, the chitosan and its salt have a content ranging from about 0.1% by weight to about 10% by weight and from about 3% by weight to about 3% by weight. Preferably, the chitosan is present in an amount of from about 5% by weight to about 1% by weight, from about 1% by weight to about 1% by weight, from about 2% by weight to about 1% by weight, and about 5% by weight. ❶/. To about 5% by weight, from about 1% by weight to about 5% by weight or from about 2% by weight to about 5% by weight. More preferably, γ_ρ (3Α or a salt thereof is present in an amount of from about 5% by weight to about 20% by weight, from about 1% by weight to about 20% by weight, from about 1% by weight to about 15% by weight, from about 1% by weight to about 1% by weight or about j% by weight to about 5 by weight 150467.doc 201247179 In another embodiment, chitosan can be obtained by N-deacetylation of chitin. Chitosan is a random a linear polysaccharide composed of β_(1 _4)_linked_d_glucosamine (de-acetylated unit) and yttrium-D-glucosamine (acetylated unit). It is used in the combination of the present invention. Chitosan refers to the original chitosan or its derivatives, including but not limited to carboxymethyl chitosan, carboxymethyl chitosan, N-methylene phosphite chitosan Sugar, sulfonated chitosan, trimethyl chitosan, triethyl chitosan, N-mercapto chitosan, chitosan thiol acrylate, nitrogen isopropyl isopropyl hydrazine Amino chitosan and succinicated chitosan. Any commercially available chitosan and chitin (including deacetylated units) can be used in the present invention. Preferably, 'chitosan The number of subunits exceeds 100 kDa. Preferably, the molecular weight of chitosan ranges from about 1 〇〇kDa to about 2000 kDa, from about 1 〇〇 kDa to about 1500 kDa, from about 1 〇〇 kDa to about 1 000 kDa. From about 200 kDa to about 2000 kDa, from about 200 kDa to about 1500 kDa, from about 200 kDa to about 1500 kDa, from about 1 〇〇 kDa to about 7 〇〇 kDa, from about 100 kDa to about 400 kDa or from about 400 kDa to about 700 kDa, or any combination thereof. According to the present invention, a polyelectrolyte complex gel can be used as a filler carried by a carrier for soft tissue filling or a carrier for containing a filler. The polyelectrolyte complex of the present invention The gel is formed by crosslinking chitosan and γ-PGA having a molecular weight of from about i kDa to about 400 kDa or a salt thereof. The fluidity of the polyelectrolyte complex gel of the present invention varies with the degree of crosslinking. The difference is that when the chitosan is crosslinked with the high molecular weight γ-PG A, the formed polyelectrolyte complex gel has a lower fluidity, and in this case, the polyelectrolyte complex condenses Glue can be used as a filler for soft tissue filling; when 150467.doc 201247179 The γ-PGA conjugated gel with low molecular weight has better fluidity, and the formed polyelectrolyte gel can be used as a carrier for soft tissue filling. _ Polyelectrolyte complex condensate 2 Any suitable aqueous solution capable of swelling the polyelectrolytic f-formate gel of the present invention. For example, a polyelectrolyte for a w-heart dissolving complex gel may utilize an aqueous solution having a weak acid value, preferably (4) It is 3. () to 6.8. Examples of the comparative solution being water or hydrophobic alcohol-type solution include but not limited to #propanol, ethanol, ethylene glycol or a mixture thereof. Other suitable solvents for the carrier are readily apparent to those skilled in the art. Surfactants, stabilizers, buffers and other additives may also be used and will be apparent to those skilled in the art. According to the present invention, it is not necessary to form a polyelectrolyte complex gel of the present invention. The shape of the polyelectrolytic f-clipped gel of the present invention is based on a multi-electromechanical mechanism. The polyelectrolyte complex gel of the present invention is sufficiently durable to remain in the body for a sufficient period of time while still having good support. Preferably, the polyelectrolyte complex gel of the present invention may remain in the body for at least 2 months, 3 months, 4 months, 5 months or 6 months. More preferably, the polyelectrolyte complex of the present invention may remain in the body for at least 6 months. Preferably, the polyelectrolyte complex gel of the present invention may remain in the body for 2 to 12 months, 3 to 12 months, 4 to 12 months, 5 to 12 months, a. Months, 7 to 12 months, 8 to 12 months, 9 to 12 months, 1 to months, or 4 to 8 months. 2 to 6 In another aspect, the present invention provides a soft tissue filling implant comprising the polyelectrolyte complex gel of the present invention as a carrier or filler, and an additive selected in 150467.doc 201247179. As described above, the polyelectrolyte complex gel of the present invention can be used as a carrier or a true filler. Thus, the polyelectrolyte complex gel of the present invention can be used as a carrier to carry a filler and a selected one.丨+plus. Alternatively, the polyelectrolyte complex gel of the present invention can be used as a filler which is carried in the Portuguese and φ + + ancient + u wars and warfare. According to the polyelectrolyte complex of the present invention, it can be combined with a carrier or a filler and an additive to form a soft tissue filling implant. In one embodiment, various biocompatible carriers can be made to support the polyelectrolyte complex gels of the present invention. The choice of suitable carrier will depend on the size of the granules, the amount of filler material, the size of the injection needle and the nature of the filler material. Examples of carriers include, but are not limited to, gum arabic carbomer copolymers and monomers, carbomer interpolymers, water gels, polysaccharides, giant rings, oligosaccharides, temple powders, acetamidines. Starch, cellulose, cellulose derivatives, methyl cellulose 'sodium carboxymethyl cellulose, carboxymethyl cellulose (CMC), ethyl hydroxyethyl cellulose (EHEC), ethyl cellulose, hydroxypropyl Cellulose, hydroxypropyl decyl cellulose (HPMC), ethyl cellulose, alkyl cellulose, alkoxy cellulose, transethyl cellulose, vinyl. Compared with B, each of the ketone-vinyl acetate copolymer (copovidone), polyvinylpyrrolidone (p〇vid〇ne), gelatin, guar gum, hydroxypropyl cellulose, hydroxypropyl cellulose acetate succinic acid Ester, maltodextrin, syrup, amaranth, apple lysine, aluminum monostearate, attapulgite, lanolin, hydroxypropyl cellulose, maltodextrin, pectin, algae Acid propylene glycol ester, sodium alginate, barium alginate, colloidal silica, yttrium gum, xanthan gum, egg yolk, trigonyl benzene derivative, iohexyl, iupamidol, 'I〇pent〇i, sucrose, carrageen 150467.doc 12 201247179 Gum, agar, mannitol, sodium saccharin, sorbitol, cephalin, acetylene glycol, carbowax, Polyorganic acid, oxylated surfactant, alkylphenol ethoxylate, ethoxylated fatty acid, ethanol polyoxyethylene ether, ethanol polyoxyalkylene ether, polyethylene oxide, poly(propylene oxide) , polyethylene glycol (PEG), poly(propylene glycol), polyvinyl alcohol (PVA) polymer or copolymer, polypropylene decylamine, poly ( Vinyl carboxylic acid), polymethacrylic acid, polyacrylic acid polymer or copolymer, polyamino acid, albumin, collagen, fibrin, bioglue, cellulose, Carbopol, poloxamer (Poloxamer), Pluronic, Tetronics, PEO-PPO-PEO triblock copolymer, PEO-PPO and ethylene diamine tetrafunctional block polymer or copolymer, poly HEMA polymer or copolymer, Hyp an polymer or copolymer, palace powder glycolic acid polymer or copolymer salt, polyoxyalkylene ether, polyethylene. Bipyridine, polylysine, polyarginine, polyaspartic acid and polyglutamic acid, polybutylene oxide, poly(hydroxyethyl acrylate), poly(hydroxyethyl methacrylate), Decyloxy pectin gel, cellulose acetate phthalate, organic oil, B-glucan, polysorbate, lactate, hexanoate, hyaluronic acid, dextrin, dextran, glucose, and a mixture of the above. In one embodiment, various biocompatible filler materials can be carried into the polyelectrolyte complex gel of the present invention as a carrier. Examples of fillers include, but are not limited to, polysaccharides (such as hyaluronic acid (HA)), inorganic salts, collagen, polyols, hydroxyapatite (such as calcium hydroxyapatite), anthrone and gelatin, and polyacrylic acid. Ester or poly-L-lactic acid (PLLA), carboxymethyl cellulose, cross-linked CMC hydrogel, fat and silk fibroin. I50467.doc -13- 201247179 According to the present invention, inorganic salts in particulate form include, but are not limited to, calcium phosphate particles, calcium citrate particles, calcium carbonate particles, alumina particles, zirconia particles, warp-base apatite particles, Zirconia, strontium pyrophosphate particles, tetracalcium phosphate particles, tricalcium phosphate particles, octacalcium phosphate particles, fluorostructured stone (Ca1Q(P〇4)6F2) particles, calcium phosphate ash of hydroxyapatite particles Stone particles or mixtures thereof. Preferably, the inorganic salt is calcium phosphate particles, zirconia particles, hydroxyapatite particles, zirconia particles containing hydroxyapatite particles, or a mixture thereof. Preferably, the inorganic salt is hydroxyapatite particles, calcium pyrophosphate particles, tetra #5 disc acid salt particles, tribasic sulphate particles, octahydrate acid granules, fluoroapatite (Ca1Q (P〇 4) 6F2) granules, calcium apatite particles or mixtures thereof. More preferably, the inorganic salt is zirconia containing hydroxyapatite particles. More preferably, the inorganic salt is a hydroxyapatite particle. Most preferably, the inorganic salt is a calcium phosphate particle. In a single embodiment, the additives useful in the soft tissue-filling implants of the present invention can be a variety of materials including, but not limited to, proteins and biologically active substances. According to the present invention, the biologically active substance may have therapeutic properties and may, for example, promote tissue growth (i.e., growth factors) or act as an antimicrobial agent. Preferably, the bioactive substance is epidermal growth factor (egf), fibroblast growth factor (FGF), nerve growth factor (10) F) or a mixture thereof. Preferably, the biologically active substance is EGF. These materials may be grafted onto or absorbed by the particles and may have the property of releasing to surrounding tissue over time. Depending on the application, those skilled in the art should be able to understand that bioactive substances can be incorporated into implant materials and to understand the medical value of such bioactive substances. According to the present invention, the cells may be lipid (fat) cells, embryonic stem cells, mesenchymal stem cells, neural stem cells, fat precursor cells, adipose stem cells or dental pulp stem cells. In a particular embodiment of the invention, the soft tissue filling implant is infused with an instrument such as a syringe or arthroscopic. These methods are preferred because they are less invasive than other methods (e. g., surgery), but have a lower risk of infection, discomfort, and complications, and the amount of injection and the location of the injection can be easily controlled. A skilled person familiar with this field can learn about various injection methods. For example, in an embodiment of the invention, an 18G (gauge) syringe can be used to inject particles having a size of about 5 microns, while in those embodiments having a smaller particle size, a larger gauge needle can be used. Injection, such as joint injection. In an embodiment of the invention, the soft tissue-filled implant is injected subcutaneously into the area of the soft tissue contour defect. The implant dose is sufficient to completely eliminate the defect. Such defects may include enemies and defects such as the mouth, breasts, chin, cheeks and/or nose. In another embodiment of the invention, a soft tissue filling implant can be used to control incontinence, particularly stress urinary incontinence. Incontinence can be caused by disease, aging, or left muscle disease, or by nerve damage caused by prostate surgery that controls the sphincter around the urethra. When this soft tissue is filled with soft tissue, dense, fibrotic and flexible tissue will be formed in and around the implant structure. This will happen within a few days. The implant is still inert in the body and is associated with the soft tissue required to organize, fill or shape the new form 150467.doc -15· 201247179. Those skilled in the art will appreciate that the polyelectrolyte complex gels, soft tissue filling implants and methods of the present invention, in addition to the foregoing, can be used in a variety of other applications. The above description of the present invention and the accompanying drawings are intended to illustrate the invention and not to limit the invention. Therefore, it should be understood that various modifications and changes can be made to the above without departing from the spirit and scope of the invention. The scope of the invention should be limited only by the scope of the appended claims. [Examples] Example 1 Preparation of the polyelectrolyte complex gel of the present invention comprises 30 g of chitosan (Mw=2〇〇kDa) and 4 g of polyglutamic acid (Mw=l〇kDa) In a 1% by weight aqueous solution of acetic acid, it was quickly mixed in a container for about 30 seconds; after titration with ion NaOH to neutrality, it was mixed for 30 minutes. The obtained polyelectrolyte complex gel was allowed to stand for 12 hours or more. The comparative example is a conventional gel. Comparative Example 1 is a buffered cellulose (CMC) carrier prepared by adding 30 g of CMC and 150 g of glycerin to a vessel containing 520 ml of an aqueous solution and mixing for about 30 seconds; slow mixing and stirring. The mixture was uniformly mixed over 12 hours to form a CMC carrier. Example 2 Preparation of the polyelectrolyte complex gel of the present invention 20 g of chitosan (Mw=2000 kDa) was added to an aqueous solution of 1000 g of 5% by weight acetic acid, and 1 g of Y_PGA was added (Mw=300 kDa). ) and mix quickly for about 30 seconds; titrate to neutral with 1 ON NaOH and mix for another 30 minutes. The obtained polyelectrolyte complex gel was allowed to stand for 12 hours or more. I50467.doc -16- 201247179 Example 3 Preparation of polyelectrolyte complex gel-containing implants containing hydroxyapatite The polyelectrolyte complex gel of Example 1 and 43 gram of base ash particles (Particle size ranged from 25 to 45 microns) was thoroughly blended and mixed in a low speed mixer to a gel suspension in which all particles were evenly distributed in 1 mL. Further, the CMC carrier of Comparative Example 1 was thoroughly blended with 430 g of hydroxyapatite particles (particle size ranging from 25 to 45 μm), and mixed in a low speed mixer until all the particles were homogeneously distributed in 1 mL. The carrier suspension was opened to form a CMC carrier mixture containing basal limestone particles (Comparative Example 2). Comparative Example 3 is a commercially available microcrystalline ruthenium (Ra(jiesse®), which is a microsphere containing hydroxyapatite particles suspended in a CMC carrier, manufactured by Bi〇F〇rm & Division. Example 4 contains poly-left-handed Preparation of Latex (PLLA) Polyelectrolyte Complex Gel Implants The polyelectrolyte complex gel carrier of Example 1 and 2 g of poly-L-lactic acid (PLLA) particles (particle size range of 4 〇 to 63 micron) fully blended, mixed in a low speed mixer until the particles are evenly distributed in 1 ml of gel suspension. Example 5 Polyelectrolyte complex gel implant containing polymethyl methacrylate particles Preparation The polyelectrolyte complex gel of Example 1 was thoroughly blended with 127 8 grams of polymethyl methacrylate particles (particle size ranging from 1 〇〇 to 18 〇 microns), mixed at low speed spreaders until all particles were uniform Distribution in 1 ml of gel suspension. Example 6 Preparation of polyelectrolyte complex gel implant containing silk microparticles 150467.doc • 17- 201247179 The polyelectrolyte complex gel of Example 1 With 250 grams of silk microspheres (particle size range 2 〇 to 45 μm) Completely mixed and mixed in a low speed mixer until all particles are evenly distributed in the 凝胶ml gel suspension. Example 7 Polyelectrolyte complex gel containing polyelectrolyte complex particles Preparation of the product 1 g of chitosan (Mw = 100 kDa) was added to 100 ml of 1 weight. / 〇 vinegar 酉夂 water / mixture, 0.3 g γ·ρ 〇Α calcium (Mw = 1000 kDa) And 0.2 g of CMC was added with 100 ml of deionized water. After the two solutions were quickly mixed by a homogenizer for about 3 〇, the micro-particles of the polyelectrolyte complex were formed. The microparticles of 25 gram polyelectrolyte complex (particle size ranging from 100 to 12 Å) were thoroughly blended and mixed in a low speed mixer until the particles were homogeneously distributed in a 1 liter gel suspension. Preparation of Polyelectrolyte Complex Gel Implants of Dentate Stem Cells Mix the polyelectrolyte complex gel of Example 1 with 1 ml of 6 dental pulp stem cells. Mix with low speed mixer until all cells Homogeneously distributed in 9 ml of gel suspension. Example 9 contains The preparation of the Zhao stem cells and the base-filled limestone polyelectrolyte complex gel implant will be a mixture of % 忒 electrolyte complex gel and hydroxyapatite particles, 1 ml of 1 X 1 The gingival stem cells were completely blended and mixed in a low speed mixer until all cells were evenly distributed in 9 ml of the gel suspension. Also as a control hydroxyapatite/CMC carrier-knot containing dental pulp stem cells (control) Example 4) Preparation of H according to Example 2, the base-based % graystone/CMC carrier mixture and i ml of bum, 6 dental pulp stem cells I50467.doc • 18·201247179 Completely mixed 'mixed in a low-speed mixer until All cells were homogeneously distributed in a 9 ml gel suspension. EXAMPLES In vitro degradation test of the polyelectrolyte complex gel of the present invention The polyelectrolyte complex gel of Example 1 and Comparative Example 1 were treated in a freeze-dried manner to obtain a dry powder; a sample of 〇_5 g was weighed and placed in contain
40毫升之緩衝液體中（100 mM NaCl，45 mM NaHC03, 2 mM K2C03)，分別於3天、1週、2週、4週、8週及12週時取 出。以清水洗淨後，過遽，乾燥，科重，並計算其樣品殘 留率（（原始重量-降解後重量）/原始重量），結果如圖1所 示。結果顯示實例1相較對照例1具有較長之降解時間，而 對照例1於3天即降到2.5%以下，一週幾乎殆盡。 實例11注射力試驗 將實例1及實例3之聚電解質錯合物凝膠為主的植入物移 至3毫升之注射筒中，前方裝置27G之針頭，利用質地分析 儀（Texture Analyzer，ΤΑ.χτ P1US，Texture Techn〇1〇gies40 ml of buffered liquid (100 mM NaCl, 45 mM NaHC03, 2 mM K2C03) was taken at 3 days, 1 week, 2 weeks, 4 weeks, 8 weeks, and 12 weeks, respectively. After washing with water, the crucible, drying, and weight were calculated, and the sample residual ratio ((original weight - post-degradation weight) / original weight) was calculated, and the results are shown in Fig. 1. The results showed that Example 1 had a longer degradation time than Comparative Example 1, while Comparative Example 1 fell below 2.5% in 3 days, almost exhausted in one week. Example 11 Injection Force Test The polyelectrolyte complex gel-based implants of Examples 1 and 3 were transferred to a 3 ml syringe, and the front device 27G needle was used, using a texture analyzer (Texture Analyzer, ΤΑ.χτ P1US, Texture Techn〇1〇gies
Corp，UK)以15公釐/分鐘之速度持續9〇秒推進，得到推力 數據。結果如圖2所示，其顯示實例丨及實例3之聚電解質 錯合物凝膠為主的植入物，所需推力較低，具有良好的可 注射性。 實例12動物試驗 以體重在25-3〇公斤範圍内之蘭喚豬為實驗動物。其施 以麻醉後靜躺於手術台上。於其耳朵背部之皮下各注入 〇.2耄升之實例1、實例3、實例8、實例9、對照例1、對照 例2、對照例3及對照例4之樣本。術後餵以規則飲食，每 150467.doc 19 201247179 組六隻豬。術後8週及24週後豬隻犧牲，作組織學分析， 利用馬森三色染色法（MaSS〇n，s triehr〇me _η)染色。結果 如圖3、4及5所示，其組織學切片圖顯示於每個時間:， 利用本發明之聚電解質錯合物凝膠之實例3均較對昭例2及 對照例3之支樓效果好，於兩個月後實例3之體積比相較 CMC組（對照例2及對照例3)多超過2〇% :於六個月後實例3 之南度比相較對照例2多超過4〇〇/0。 【圖式簡單說明】 圖1顯示本發明之聚電解質錯合物凝膠的體外降解試 驗。 圖2顯示本發明之聚電解質錯合物凝膠的可注射性試 驗。 圖3顯示本發明之聚電解質錯合物凝膠與習知載體/植入 物的組織切片圖。 圖4顯示本發明之聚電解質錯合物為主之植入物及習知 之植入物在植入後1 80天内之期間’體積維持率之變化。 圖5顯示本發明之聚電解質錯合物為主之植入物及習知 之植入物在植入後180天内之期間，高度維持率之變化。 150467.doc 20·Corp, UK) propelled at a speed of 15 mm/min for 9 sec seconds to obtain thrust data. The results are shown in Fig. 2, which shows an example of the polyelectrolyte complex gel-based implant of Example 3, which requires less thrust and good injectability. Example 12 Animal Test Lanhua pigs weighing from 25 to 3 kilograms were used as experimental animals. After being anesthetized, he lies on the operating table. Samples of Example 1, Example 3, Example 8, Example 9, Comparative Example 1, Comparative Example 2, Comparative Example 3, and Comparative Example 4 were injected under the skin of the back of the ear. Postoperatively fed a regular diet, each of the 150467.doc 19 201247179 group of six pigs. Pigs were sacrificed at 8 and 24 weeks postoperatively for histological analysis and stained with Mason's trichrome staining (MaSS〇n, s triehr〇me _η). The results are shown in Figures 3, 4 and 5, and histological sections are shown at each time: Example 3 using the polyelectrolyte complex gel of the present invention is compared to the branches of Scenario 2 and Comparative Example 3 The effect was good. After two months, the volume ratio of Example 3 was more than 2%% compared with the CMC group (Comparative Example 2 and Comparative Example 3): after six months, the south ratio of Example 3 was more than that of Comparative Example 2 4〇〇/0. BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 shows an in vitro degradation test of the polyelectrolyte complex gel of the present invention. Fig. 2 shows an injectability test of the polyelectrolyte complex gel of the present invention. Figure 3 shows a histological section of a polyelectrolyte complex gel of the present invention and a conventional carrier/implant. Figure 4 shows the change in volume maintenance rate of the polyelectrolyte complex-based implant of the present invention and the conventional implant during the 180 days after implantation. Figure 5 shows the change in height maintenance rate of the polyelectrolyte complex-based implant of the present invention and the conventional implant during the 180 days after implantation. 150467.doc 20·
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TW100118946A TWI536975B (en) | 2011-05-30 | 2011-05-30 | Polyelectrolyte complex gels and soft tissue augmentation implants comprising the same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TW100118946A TWI536975B (en) | 2011-05-30 | 2011-05-30 | Polyelectrolyte complex gels and soft tissue augmentation implants comprising the same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| TW201247179A true TW201247179A (en) | 2012-12-01 |
| TWI536975B TWI536975B (en) | 2016-06-11 |
Family
ID=48138375
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW100118946A TWI536975B (en) | 2011-05-30 | 2011-05-30 | Polyelectrolyte complex gels and soft tissue augmentation implants comprising the same |
Country Status (1)
| Country | Link |
|---|---|
| TW (1) | TWI536975B (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108078868A (en) * | 2018-02-01 | 2018-05-29 | 四川艾医生医疗科技有限公司 | A kind of antiallergic composition for skin care item |
| CN108102150A (en) * | 2017-12-18 | 2018-06-01 | 北京理工大学 | A kind of method for building the polyelectrolyte composite material based on chitosan |
| CN112566617A (en) * | 2018-08-15 | 2021-03-26 | 博姿有限公司 | Cosmetic composition |
| CN114652895A (en) * | 2020-12-23 | 2022-06-24 | 上海其胜生物制剂有限公司 | Preparation method of injectable tissue regeneration type chitosan composite gel scaffold |
| CN117599247A (en) * | 2023-12-14 | 2024-02-27 | 浙江来益美生物医药有限公司 | Silk fibroin microcarrier skin filling preparation, and preparation method and application thereof |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109125290B (en) * | 2018-08-28 | 2020-10-09 | 江南大学 | PH and reduction dual-response drug-loaded nanoparticle |
| CN109077983A (en) * | 2018-11-05 | 2018-12-25 | 山东福瑞达生物科技有限公司 | A kind of anti-wrinkle cosmetic of the glutamic acid containing oligomerization and preparation method thereof |
-
2011
- 2011-05-30 TW TW100118946A patent/TWI536975B/en not_active IP Right Cessation
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108102150A (en) * | 2017-12-18 | 2018-06-01 | 北京理工大学 | A kind of method for building the polyelectrolyte composite material based on chitosan |
| CN108102150B (en) * | 2017-12-18 | 2020-04-14 | 北京理工大学 | Method for constructing polyelectrolyte composite material based on chitosan |
| CN108078868A (en) * | 2018-02-01 | 2018-05-29 | 四川艾医生医疗科技有限公司 | A kind of antiallergic composition for skin care item |
| CN108078868B (en) * | 2018-02-01 | 2020-12-25 | 四川艾医生医疗科技有限公司 | Antiallergic composition for skin care products |
| CN112566617A (en) * | 2018-08-15 | 2021-03-26 | 博姿有限公司 | Cosmetic composition |
| CN112566617B (en) * | 2018-08-15 | 2023-08-29 | 博姿有限公司 | cosmetic composition |
| CN114652895A (en) * | 2020-12-23 | 2022-06-24 | 上海其胜生物制剂有限公司 | Preparation method of injectable tissue regeneration type chitosan composite gel scaffold |
| CN117599247A (en) * | 2023-12-14 | 2024-02-27 | 浙江来益美生物医药有限公司 | Silk fibroin microcarrier skin filling preparation, and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| TWI536975B (en) | 2016-06-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Xue et al. | Recent advances in design of functional biocompatible hydrogels for bone tissue engineering | |
| US20120301436A1 (en) | Polyelectrolyte complex gels and soft tissue augmentation implants comprising the same | |
| US20230293776A1 (en) | Composite material for tissue restoration | |
| Xue et al. | Hydrogels as emerging materials for translational biomedicine | |
| Lee et al. | Alginate: properties and biomedical applications | |
| ES2895947T3 (en) | Composition and assemblies for pseudoplastic microgel matrices | |
| JP7445274B2 (en) | Mesenchymal cell-bound composites for tissue repair | |
| US9295691B2 (en) | Method for repairing or replacing damaged tissue | |
| JP5684154B2 (en) | Biomaterial for injection | |
| TWI536975B (en) | Polyelectrolyte complex gels and soft tissue augmentation implants comprising the same | |
| US20080138416A1 (en) | Method and systems for using biopolymer-based beads and hydrogels | |
| Kouhi et al. | Injectable gellan gum/lignocellulose nanofibrils hydrogels enriched with melatonin loaded forsterite nanoparticles for cartilage tissue engineering: Fabrication, characterization and cell culture studies | |
| US20110097367A1 (en) | Monolithic in-situ cross-linked alginate implants | |
| JP2020506273A (en) | Hydrogel based on hyaluronic acid derivative modified with galol group and use thereof | |
| KR20110039533A (en) | Silica sol material having at least one therapeutically active substance for producing biologically degradable and/or resorbable silica gel materials for human medicine and/or medical technology | |
| Mellati et al. | Injectable hydrogels: A review of injectability mechanisms and biomedical applications | |
| KR20210018828A (en) | Nanofiber-hydrogel composite material for cell and tissue migration | |
| KR101732609B1 (en) | Polymer formulation to control sequential release of bioactive agents | |
| Wang et al. | In vitro and in vivo studies of a collagen-based scaffold carrying PLGA microspheres for sustained release of epidermal growth factor in skin regeneration | |
| Florence et al. | 18 Biomedical Applications | |
| Florence et al. | Biomedical Applications of Alginate Biopolymer | |
| Singh¹ et al. | Injectable in situ Gelling Hydrogels as Biomaterials | |
| Hutmacher et al. | Polysaccharides in tissue engineering applications | |
| Dipen et al. | TREND OF INJECTABLE HYDROGEL IN FORMULATION AND RESERACH. |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | Annulment or lapse of patent due to non-payment of fees |