CN112569345A - Dispersion containing growth factor and preparation method and application thereof - Google Patents
Dispersion containing growth factor and preparation method and application thereof Download PDFInfo
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- CN112569345A CN112569345A CN202011433381.4A CN202011433381A CN112569345A CN 112569345 A CN112569345 A CN 112569345A CN 202011433381 A CN202011433381 A CN 202011433381A CN 112569345 A CN112569345 A CN 112569345A
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- growth factor
- dispersion
- hyaluronic acid
- dispersed phase
- dispersion containing
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- 239000003102 growth factor Substances 0.000 title claims abstract description 80
- 239000006185 dispersion Substances 0.000 title claims abstract description 54
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 229920002674 hyaluronan Polymers 0.000 claims abstract description 46
- 229960003160 hyaluronic acid Drugs 0.000 claims abstract description 46
- 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 abstract description 30
- 239000002612 dispersion medium Substances 0.000 claims abstract description 16
- 239000007787 solid Substances 0.000 claims abstract description 16
- 239000003814 drug Substances 0.000 claims abstract description 10
- WCDDVEOXEIYWFB-VXORFPGASA-N (2s,3s,4r,5r,6r)-3-[(2s,3r,5s,6r)-3-acetamido-5-hydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-4,5,6-trihydroxyoxane-2-carboxylic acid Chemical class CC(=O)N[C@@H]1C[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O)[C@H](O)[C@H]1O WCDDVEOXEIYWFB-VXORFPGASA-N 0.000 claims abstract description 5
- 101800003838 Epidermal growth factor Proteins 0.000 claims description 39
- 229940116977 epidermal growth factor Drugs 0.000 claims description 39
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound 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 39
- 230000012010 growth Effects 0.000 claims description 19
- 239000000203 mixture Substances 0.000 claims description 13
- 125000003172 aldehyde group Chemical group 0.000 claims description 10
- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical group [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 claims description 10
- 102000009024 Epidermal Growth Factor Human genes 0.000 claims description 9
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 claims description 7
- 239000003638 chemical reducing agent Substances 0.000 claims description 6
- 230000002209 hydrophobic effect Effects 0.000 claims description 5
- 238000011068 loading method Methods 0.000 claims description 5
- 239000007800 oxidant agent Substances 0.000 claims description 5
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical group [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims description 5
- 239000007962 solid dispersion Substances 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 3
- 239000002245 particle Substances 0.000 claims description 3
- 102000018233 Fibroblast Growth Factor Human genes 0.000 claims description 2
- 108050007372 Fibroblast Growth Factor Proteins 0.000 claims description 2
- 102000003972 Fibroblast growth factor 7 Human genes 0.000 claims description 2
- 108090000385 Fibroblast growth factor 7 Proteins 0.000 claims description 2
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 claims description 2
- 102000014429 Insulin-like growth factor Human genes 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 229940126864 fibroblast growth factor Drugs 0.000 claims description 2
- 229940014041 hyaluronate Drugs 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 230000001590 oxidative effect Effects 0.000 claims description 2
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical group OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 claims description 2
- 230000009467 reduction Effects 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 230000004071 biological effect Effects 0.000 abstract description 7
- 239000000126 substance Substances 0.000 abstract description 5
- 239000012876 carrier material Substances 0.000 abstract description 4
- 230000009286 beneficial effect Effects 0.000 abstract description 3
- 239000002861 polymer material Substances 0.000 abstract description 2
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- 102400001368 Epidermal growth factor Human genes 0.000 description 38
- 206010052428 Wound Diseases 0.000 description 19
- 208000027418 Wounds and injury Diseases 0.000 description 19
- 239000000243 solution Substances 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- 239000007864 aqueous solution Substances 0.000 description 18
- 210000004027 cell Anatomy 0.000 description 13
- 150000001299 aldehydes Chemical class 0.000 description 11
- -1 sucrose ester Chemical class 0.000 description 10
- 239000004533 oil dispersion Substances 0.000 description 9
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 8
- 229920002385 Sodium hyaluronate Polymers 0.000 description 8
- 230000008859 change Effects 0.000 description 8
- 229940010747 sodium hyaluronate Drugs 0.000 description 8
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 8
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(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- Chemical compound [Na+].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 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 description 8
- 239000012071 phase Substances 0.000 description 7
- 229920001184 polypeptide Polymers 0.000 description 7
- 102000004196 processed proteins & peptides Human genes 0.000 description 7
- 108090000765 processed proteins & peptides Proteins 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 230000000694 effects Effects 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 5
- 230000001737 promoting effect Effects 0.000 description 5
- 229930006000 Sucrose Natural products 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000004108 freeze drying Methods 0.000 description 4
- 239000005720 sucrose Substances 0.000 description 4
- 230000029663 wound healing Effects 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 230000004663 cell proliferation Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 239000002504 physiological saline solution Substances 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 238000000108 ultra-filtration Methods 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 239000002262 Schiff base Substances 0.000 description 2
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- 239000007788 liquid Substances 0.000 description 2
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- 238000012986 modification Methods 0.000 description 2
- IOQPZZOEVPZRBK-UHFFFAOYSA-N octan-1-amine Chemical compound CCCCCCCCN IOQPZZOEVPZRBK-UHFFFAOYSA-N 0.000 description 2
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- 239000002244 precipitate Substances 0.000 description 2
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- 241000894006 Bacteria Species 0.000 description 1
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- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- 229920002683 Glycosaminoglycan Polymers 0.000 description 1
- 108010003272 Hyaluronate lyase Proteins 0.000 description 1
- 102000001974 Hyaluronidases Human genes 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 108010087230 Sincalide Proteins 0.000 description 1
- 208000028990 Skin injury Diseases 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 206010048629 Wound secretion Diseases 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- AEMOLEFTQBMNLQ-WAXACMCWSA-N alpha-D-glucuronic acid Chemical compound O[C@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-WAXACMCWSA-N 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000010609 cell counting kit-8 assay Methods 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
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- 239000008367 deionised water Substances 0.000 description 1
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- 238000010586 diagram Methods 0.000 description 1
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- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
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- 238000009472 formulation Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229960002773 hyaluronidase Drugs 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 230000008105 immune reaction Effects 0.000 description 1
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- 102000006240 membrane receptors Human genes 0.000 description 1
- 108020004084 membrane receptors Proteins 0.000 description 1
- MBLBDJOUHNCFQT-UHFFFAOYSA-N n-(3,4,5,6-tetrahydroxy-1-oxohexan-2-yl)acetamide Chemical compound CC(=O)NC(C=O)C(O)C(O)C(O)CO MBLBDJOUHNCFQT-UHFFFAOYSA-N 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 239000003961 penetration enhancing agent Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 231100000241 scar Toxicity 0.000 description 1
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- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 230000009759 skin aging Effects 0.000 description 1
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- 239000007858 starting material Substances 0.000 description 1
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- 231100000419 toxicity Toxicity 0.000 description 1
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- 231100000397 ulcer Toxicity 0.000 description 1
- 238000001132 ultrasonic dispersion Methods 0.000 description 1
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Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
- A61K38/1808—Epidermal growth factor [EGF] urogastrone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
- A61K38/1825—Fibroblast growth factor [FGF]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Zoology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Dermatology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention belongs to the technical field of medical high polymer materials, and discloses a dispersion containing growth factors. The dispersion comprises a solid dispersed phase and a dispersion medium; the solid dispersed phase comprises a growth factor and hyaluronic acid or a hyaluronate salt loaded with the growth factor. Hyaluronic acid is used as a carrier material of the growth factor, the growth factor is loaded by utilizing a chemical bond, and the dispersion containing the growth factor is prepared in a dispersion medium, so that the biological activity of the growth factor is not influenced, the half-life period of the growth factor can be prolonged, and the protection of the growth factor is realized. The dispersion has good stability, and can be conveniently stored and used. The preparation method is simple and is beneficial to realizing industrialization. The dispersion containing the growth factor can be used for preparing medicaments.
Description
Technical Field
The invention belongs to the technical field of medical high polymer materials, and particularly relates to a dispersion containing a growth factor, and a preparation method and application thereof.
Background
The growth factor is a polypeptide substance which can regulate cell growth and other cell functions and other multiple effects by combining with a specific and high-affinity cell membrane receptor. Because of its function of promoting the growth, proliferation and differentiation of skin cells, it is widely used in clinical treatment of skin injuries such as wounds, burns, ulcers and the like, and as a cosmetic for removing scars, wrinkles and other skin aging problems.
In the prior art, the administration means of the growth factors are mostly aqueous agents and spraying agents, wherein most of the aqueous agents with larger use amount adopt the existing preparation of the freeze-dried powder of the growth factors, which leads to high cost of the growth factor preparation, and the existing preparation of the freeze-dried powder brings inconvenience for use and is not easy to store. More importantly, the administration mode of the aqueous solution has the problems that the medicine stays in the wound for a short time, needs to be administered for multiple times, is easily affected by bacteria and wound secretions, and the like, and limits the clinical use of the preparation.
Therefore, there is a need to provide a formulation or dispersion containing growth factors, which has good stability and does not affect the biological activity of the growth factors.
Disclosure of Invention
The present invention is directed to solving at least one of the problems of the prior art described above. To this end, the invention proposes a dispersion containing a growth factor, which has good stability and does not affect the biological activity of the growth factor.
The invention conception of the invention is as follows: the invention adopts hyaluronic acid to react with growth factors, then obtains a growth factor-hyaluronic acid compound through hydrophobic modification, and disperses the compound in a dispersion medium to prepare the dispersion containing the growth factors. The dispersion is a solid oil dispersion, can effectively maintain the biological activity of the growth factor, prolongs the half life period of the growth factor, and can be conveniently stored and used.
The invention provides a dispersion containing a growth factor, which comprises a solid dispersion phase and a dispersion medium; the solid dispersed phase comprises a growth factor and hyaluronic acid or a hyaluronate salt loaded with the growth factor.
Preferably, in the dispersion containing the growth factors, the content of the solid disperse phase is 0.1-3 mg/mL; the particle size of the solid dispersion phase is 0.1-20 μm.
Further preferably, in the dispersion containing the growth factors, the content of the solid disperse phase is 0.5-2 mg/mL; the particle size of the solid dispersion phase is 0.2-10 μm.
Preferably, in the solid dispersion phase, the loading rate (mass fraction) of the growth factor is 0.2% -2%.
Preferably, the growth factor is at least one of epidermal growth factor, fibroblast growth factor, keratinocyte growth factor or insulin-like growth factor.
Preferably, the dispersion medium comprises isopropyl myristate. Isopropyl myristate not only has good dispersing effect, but also can well disperse the growth factor-hyaluronic acid compound; and isopropyl myristate is a safe and harmless penetration enhancer, can help growth factors to penetrate through a phospholipid double-layer membrane, and increases the solubility of the growth factors in skin tissues, so that the effect of promoting the penetration of medicaments such as the growth factors and the like to the skin is achieved.
Further preferably, the dispersion medium further comprises a sucrose ester.
The invention also provides a method for preparing the dispersion containing the growth factor.
The preparation method of the dispersion containing the growth factors comprises the following steps:
(1) preparing an amphiphilic growth factor-hyaluronic acid complex;
(2) adding the amphiphilic growth factor-hyaluronic acid compound prepared in the step (1) into a dispersion medium, and dispersing to obtain the dispersion containing the growth factor.
Preferably, the preparation method of the dispersion containing the growth factor comprises the following steps:
(1) adding an oxidant into the hyaluronate or hyaluronic acid, and reacting to obtain aldehyde group hyaluronic acid; reacting the aldehyde group hyaluronic acid with organic base to generate aldehyde group hyaluronic acid-organic salt, then adding a growth factor, reacting, adding a reducing agent for reduction, and finally performing hydrophobic treatment and drying to prepare the growth factor-hyaluronic acid compound.
(2) Mixing the growth factor-hyaluronic acid complex in the step (1) with a solvent to obtain a mixture, then adding the mixture into a dispersion medium, removing the solvent, and dispersing to obtain the dispersion containing the growth factor.
Further preferably, in step (1), the molar amount of the oxidizing agent is 1 to 1.5 times the molar amount of the repeating unit of the sodium hyaluronate.
Further preferably, in the step (1), the molar amount of the reducing agent is 1 to 2 times that of the repeating unit of the sodium hyaluronate; more preferably, the molar amount of the reducing agent is 1 to 1.5 times the molar amount of the repeating unit of the sodium hyaluronate.
Further preferably, in the step (1), the hydrophobic treatment is performed with an organic amine compound; more preferably, the organic amine compound is a linear aliphatic amine; further preferably, the number of carbon atoms in the linear aliphatic amine is 8 to 14.
Preferably, the molar amount of the organic amine compound is 1.5 to 3 times the molar amount of the repeating unit of the sodium hyaluronate; more preferably, the molar amount of the organic amine compound is 1.8 to 2.5 times the molar amount of the repeating unit of the sodium hyaluronate.
Preferably, in step (1), the oxidizing agent is periodate.
Preferably, in step (1), the organic base is tetrabutylammonium hydroxide.
Preferably, in step (1), the reducing agent is sodium cyanoborohydride.
Preferably, in the step (2), the volume ratio of the mixture to the dispersion medium is (5-20): 1; further preferably, the volume ratio of the mixture to the dispersion medium is (8-15): 1.
specifically, the preparation method of the dispersion containing the growth factors comprises the following steps:
(1) dissolving sodium hyaluronate in distilled water to obtain 1-5 wt% sodium hyaluronate water solution, adding sodium periodate to react for 2-6 hr, adding excessive glycol to the system to react for 1-4 hr, removing unreacted sodium periodate, and dialyzing the solution in deionized water to obtain aldehyde hyaluronic acid. And then adding tetrabutylammonium hydroxide into the aldehyde hyaluronic acid, stirring for 2 hours, and freeze-drying to obtain aldehyde hyaluronic acid-tetrabutylammonium salt. Aldehyde group hyaluronic acid-tetrabutylammonium salt and a growth factor are dissolved in N-methyl pyrrolidone, and stirred for 1-4 hours at room temperature, so that aldehyde groups in the aldehyde group hyaluronic acid and amino terminal groups of the growth factor form Schiff bases. Adding sodium cyanoborohydride into the system, and reacting for 2-6 hours to reduce the Schiff base. Then, linear aliphatic amine (n ═ 8-14) is added to the system, and hydrophobic modification is achieved by binding with unreacted aldehyde groups. Finally, removing unreacted growth factors and other impurities by ultrafiltration and centrifugation. And freeze-drying the obtained solution to obtain the growth factor-hyaluronic acid compound.
(2) Sucrose ester (HLB ═ 2-4) was dissolved in isopropyl myristate under heating, and after cooling and filtration, a sucrose ester saturated isopropyl myristate solution was obtained. Adding the growth factor-hyaluronic acid compound into absolute ethyl alcohol to obtain an ethanol solution (mixture) of the growth factor-hyaluronic acid compound of 5-20 mg/mL. Under the condition of room temperature, mixing a sucrose ester saturated isopropyl myristate solution and a growth factor-hyaluronic acid complex ethanol solution according to a volume ratio (5-20): 1, removing ethanol by using a rotary evaporator, and performing ultrasonic dispersion on the mixture to obtain a dispersion containing the growth factors.
The invention also provides the application of the dispersion containing the growth factor in preparing medicines. Such as application in preparing oil for treating wound and burn.
A medicament comprising said growth factor-containing dispersion. The medicine comprises polypeptide medicine or protein medicine.
Hyaluronic acid is a natural high molecular weight linear mucopolysaccharide consisting of repeating disaccharide units consisting of D-glucuronic acid and D-N-acetylglucosamine. The hyaluronic acid has no antigenicity, no allergy, no inflammation, no immune reaction and capacity of being degraded by hyaluronidase in organism. As a carrier of the growth factor, the carrier has no side effect and good loading performance.
The protein/polypeptide solid-oil dispersion system can effectively isolate the contact of protein/polypeptide components in the protein/polypeptide solid-oil dispersion system with water, improve the stability of easily degradable protein/polypeptide in an aqueous solution and reduce the influence of other substances in the aqueous phase on the protein/polypeptide. The dispersion containing the growth factor is a solid oil dispersion system of the hyaluronic acid loaded with the growth factor, the hyaluronic acid is used as a carrier material of the growth factor, the growth factor is loaded by utilizing a chemical bond and is dispersed in a dispersion medium to form the solid oil dispersion system, the stability of the growth factor can be improved, the half-life period of the growth factor is effectively prolonged, and the chemical modification does not influence the biological activity of the growth factor.
Compared with the prior art, the invention has the following beneficial effects:
(1) the invention adopts hyaluronic acid as a carrier material of the growth factor, utilizes chemical bonds to load the growth factor, and prepares the dispersion containing the growth factor in a dispersion medium, thereby not only not influencing the biological activity of the growth factor, but also prolonging the half-life period of the growth factor and realizing the protection of the growth factor.
(2) The dispersion containing the growth factor has good stability, and can be conveniently stored and used.
(3) The dispersion containing the growth factors provided by the invention has the advantages of easily obtained carrier materials, lower cost and simple preparation method, and is beneficial to realizing industrialization.
Drawings
FIG. 1 is a graph of epidermal growth factor concentration as a function of time;
FIG. 2 is a diagram showing different systems of epidermal growth factor-promoted cell proliferation;
FIG. 3 is a graph of relative wound area of mice.
Detailed Description
In order to make the technical solutions of the present invention more apparent to those skilled in the art, the following examples are given for illustration. It should be noted that the following examples are not intended to limit the scope of the claimed invention.
Sodium hyaluronate (MW 100kDa) used in the following examples was purchased from tianjin schinseng biochemical technologies ltd; surface growth factor (EGF) provided by biomedical base of river-south university; other reagents were purchased from Shanghai Aladdin. Magnetic stirrers, purchased from Zhaohua instruments, Inc., of Ongsey; a freeze dryer, purchased from Ningbo Xinzhi Biotech GmbH; an ultrasonic cell disruptor was purchased from Shanghai Qiao electronics Co., Ltd. Other starting materials, reagents or equipment may be obtained from conventional commercial sources or may be obtained by known methods in the art, unless otherwise specified.
Example 1
530mg of sodium periodate was added to 100mL of a 1 wt% aqueous solution of hyaluronic acid, and the mixture was reacted at room temperature for 4 hours, then 1mL of ethylene glycol was added to the solution and reacted for 2 hours, and the resulting solution was dialyzed for 3 days to obtain an aldehyde-based aqueous solution of hyaluronic acid. To the obtained aldehyde hyaluronic acid aqueous solution was added 1.6mL of a 40% tetrabutylammonium hydroxide aqueous solution, stirred at room temperature for 2 hours, and then lyophilized to obtain aldehyde hyaluronic acid-tetrabutylammonium salt.
100mg of aldehyde hyaluronic acid-tetrabutylammonium salt and 1mg of epidermal growth factor were added to 10ml of N-methylpyrrolidone, and stirred at room temperature for 2 hours. To the solution was added 20mg of sodium cyanoborohydride, and the mixture was stirred at room temperature for 4 hours. Subsequently, 50. mu.L of n-octylamine was added to the reaction system, and the reaction was carried out for 12 hours. Dripping the obtained solution into anhydrous ether for precipitation, re-dissolving the precipitate with distilled water, purifying with ultrafiltration centrifuge tube with cut-off molecular weight of 10000Da, and freeze drying to obtain epidermal growth factor-hyaluronic acid compound.
10mg of the epidermal growth factor-hyaluronic acid complex was uniformly dispersed in 2mL of anhydrous ethanol using ultrasound, and then slowly dropped into a saturated sucrose ester (HLB ═ 3) solution of isopropyl myristate. The ethanol in the system was removed using a rotary evaporator at 40 ℃. Finally, dispersing the system by using an ultrasonic cell pulverizer to obtain a dispersion containing epidermal growth, wherein the solubility of the epidermal growth factor is 0.8 mu g/mL, and the loading capacity is 0.8%.
Example 2
Adding 530mg of sodium periodate into 100mL of hyaluronic acid aqueous solution containing 3 wt% of hyaluronic acid, reacting at room temperature for 4 hours, then adding 1mL of ethylene glycol into the solution, reacting for 2 hours, dialyzing the obtained solution for 3 days to obtain aldehyde-based hyaluronic acid aqueous solution. To the obtained aldehyde hyaluronic acid aqueous solution was added 2mL of a 40% tetrabutylammonium hydroxide aqueous solution, stirred at room temperature for 2 hours, and then lyophilized to obtain aldehyde hyaluronic acid-tetrabutylammonium salt.
100mg of aldehyde hyaluronic acid-tetrabutylammonium salt and 18mg of epidermal growth factor were added to 15ml of N-methylpyrrolidone, and stirred at room temperature for 2 hours. To the solution was added 20mg of sodium cyanoborohydride, and the mixture was stirred at room temperature for 4 hours. Subsequently, 50. mu.L of n-octylamine was added to the reaction system, and the reaction was carried out for 12 hours. Dripping the obtained solution into anhydrous ether for precipitation, re-dissolving the precipitate with distilled water, purifying with ultrafiltration centrifuge tube with cut-off molecular weight of 10000Da, and freeze drying to obtain epidermal growth factor-hyaluronic acid compound.
18mg of the epidermal growth factor-hyaluronic acid complex was uniformly dispersed in 2mL of anhydrous ethanol using ultrasound, and then slowly dropped into a saturated sucrose ester (HLB ═ 3) solution of isopropyl myristate. The ethanol in the system was removed using a rotary evaporator at 40 ℃. Finally, dispersing the system by using an ultrasonic cell pulverizer to obtain a dispersion containing the epidermal growth factor, wherein the concentration of the epidermal growth factor is 1.5 mu g/mL, and the loading capacity is 1.5%.
Product effectiveness testing
(1) The epidermal growth factor-containing dispersion obtained in example (1) was tested for its concentration as a function of time
The epidermal growth factor-containing dispersion prepared in example (1) and a physiological saline solution containing the same epidermal growth factor concentration as in example (1) were placed in the same room temperature environment to examine the concentration change of the epidermal growth factor in different systems. Respectively taking 10 mu L of liquid at preset time, measuring and calculating the concentration of the epidermal growth factor by using an epidermal growth factor ELISA kit, and drawing an epidermal growth factor concentration curve. FIG. 1 is a graph showing the change of the concentration of the EGF in an aqueous solution over time, wherein I represents the change of the concentration percentage of the EGF in the aqueous solution, and II represents the change of the concentration percentage of the EGF in the dispersion obtained in example (1). As can be seen from FIG. 1, the decrease rate of the epidermal growth factor concentration in the epidermal growth factor-containing dispersion was significantly smaller than that in the aqueous epidermal growth factor solution. The epidermal growth factor in the dispersion containing the epidermal growth factor has stronger stability, and the dispersion can effectively prolong the half-life period of the epidermal growth factor.
(2) The epidermal growth factor-containing dispersion obtained in example (1) was subjected to a cell proliferation promotion experiment
After 3T3 cells were co-cultured with an epidermal growth factor aqueous solution (epidermal growth factor concentration: 5ng/mL, 10ng/mL, 50ng/mL) and the epidermal growth factor-containing dispersion prepared in example (1) (epidermal growth factor concentration: 5ng/mL, 10ng/mL, 50ng/mL) for 24 hours, the Cell count Kit-8(CCK-8) was used to determine the Cell count of each group of 3T3 cells. Finally, the percentage survival rate of 3T3 cells in each group was calculated by comparing with a blank control group (physiological saline with epidermal growth factor concentration of 5ng/mL, 10ng/mL, 50 ng/mL).
Percent cell viability ═ 100% (number of cells in the administered group/number of cells in the blank control group)%
FIG. 2 is a graph showing the cell proliferation promoting effect of the epidermal growth factor in different systems, wherein I is the survival rate of 3T3 cells co-cultured with the epidermal growth factor aqueous solution, and II is the survival rate of 3T3 cells co-cultured with the epidermal growth factor-containing dispersion. As can be seen from FIG. 2, at the same EGF concentration, the EGF aqueous solution and the EGF-containing dispersion have the same ability to promote the proliferation of 3T3 cells, and it can be seen that the chemical modification has no effect on the biological activity of the EGF.
(3) Wound healing tests were carried out using the epidermal growth factor-containing dispersions prepared in example 2
Establishing a back wound rat model, carrying out unhairing treatment and disinfection on the back of an anesthetized rat, manufacturing 4 wound surfaces with similar sizes, cleaning and sucking residual liquid on the wound surfaces. The 4 wounds of the rat model with back trauma were treated with physiological saline (blank control group), hyaluronic acid solid oil dispersion, epidermal growth factor aqueous solution (epidermal growth factor content of 1.5 μ g) and epidermal growth factor-containing dispersion (epidermal growth factor content of 1.5 μ g), respectively. And binding after the wound surface is basically dry. The experimental rats are raised in the same environment, are allowed to freely enter water and feed, the wound healing conditions on the backs of the rats are observed, the observation is carried out on 3 days, 7 days, 10 days and 14 days respectively, and the wound areas are counted.
Wherein, the relative wound area% (t time wound area/initial wound area) × 100%.
Fig. 3 is a graph of relative wound area of mice, wherein I is the relative wound area change of the blank control group, II is the relative wound area change of the hyaluronic acid solid oil dispersion group, III is the relative wound area change of the epidermal growth factor aqueous solution group, and IV is the relative wound area change of the epidermal growth factor-containing dispersion group. As can be seen from fig. 3, the relative wound area changes of the hyaluronic acid solid oil dispersion group and the blank control group are substantially consistent, which indicates that the hyaluronic acid solid oil dispersion does not generate toxicity and has no wound healing promoting effect, while the dispersion group containing the epidermal growth factor and the epidermal growth factor aqueous solution group have similar effect on promoting wound healing, and the effect is obvious.
Claims (10)
1. A dispersion containing a growth factor, comprising a solid dispersed phase and a dispersion medium; the solid dispersed phase comprises a growth factor and hyaluronic acid or a hyaluronate salt loaded with the growth factor.
2. The growth factor-containing dispersion according to claim 1, wherein the content of the solid dispersed phase in the growth factor-containing dispersion is 0.1 to 3 mg/mL; the particle size of the solid dispersion phase is 0.1-20 μm.
3. The growth factor-containing dispersion of claim 1, wherein the loading rate of the growth factor in the solid dispersed phase is 0.2% to 2%.
4. A growth factor-containing dispersion according to any one of claims 1 to 3, wherein the growth factor is at least one of an epidermal growth factor, a fibroblast growth factor, a keratinocyte growth factor or an insulin-like growth factor.
5. The growth factor-containing dispersion of claim 1, wherein the dispersion medium comprises isopropyl myristate.
6. The method of preparing a growth factor-containing dispersion according to any one of claims 1 to 5, comprising the steps of:
(1) adding an oxidant into the hyaluronate or hyaluronic acid, and reacting to obtain aldehyde group hyaluronic acid; reacting the aldehyde group hyaluronic acid with organic base to generate aldehyde group hyaluronic acid-organic salt, then adding a growth factor, reacting, adding a reducing agent for reduction, and finally performing hydrophobic treatment and drying to prepare a growth factor-hyaluronic acid compound;
(2) mixing the growth factor-hyaluronic acid complex in the step (1) with a solvent to obtain a mixture, then adding the mixture into a dispersion medium, removing the solvent, and dispersing to obtain the dispersion containing the growth factor.
7. The method according to claim 6, wherein in the step (1), the oxidizing agent is periodate; the organic base is tetrabutylammonium hydroxide; the reducing agent is sodium cyanoborohydride.
8. The production method according to claim 6, wherein in the step (2), the volume ratio of the mixture to the dispersion medium is (5-20): 1.
9. use of a growth factor-containing dispersion according to any one of claims 1 to 5 for the preparation of a medicament.
10. A medicament comprising a growth factor-containing dispersion according to any one of claims 1 to 5.
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