CN117137828A - Physical cross-linked gel film and preparation method and application thereof - Google Patents
Physical cross-linked gel film and preparation method and application thereof Download PDFInfo
- Publication number
- CN117137828A CN117137828A CN202311112655.3A CN202311112655A CN117137828A CN 117137828 A CN117137828 A CN 117137828A CN 202311112655 A CN202311112655 A CN 202311112655A CN 117137828 A CN117137828 A CN 117137828A
- Authority
- CN
- China
- Prior art keywords
- sodium hyaluronate
- solution
- freezing
- film
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Links
- 108010025899 gelatin film Proteins 0.000 title claims abstract description 49
- 238000002360 preparation method Methods 0.000 title claims abstract description 47
- 239000000499 gel Substances 0.000 claims abstract description 71
- 229920002385 Sodium hyaluronate Polymers 0.000 claims abstract description 51
- 229940010747 sodium hyaluronate Drugs 0.000 claims abstract description 51
- 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 claims abstract description 51
- 230000008014 freezing Effects 0.000 claims abstract description 44
- 238000007710 freezing Methods 0.000 claims abstract description 44
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 42
- 238000010257 thawing Methods 0.000 claims abstract description 35
- 238000000034 method Methods 0.000 claims abstract description 29
- 230000003014 reinforcing effect Effects 0.000 claims abstract description 13
- 238000002791 soaking Methods 0.000 claims abstract description 3
- 239000000243 solution Substances 0.000 claims description 73
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 36
- 239000000463 material Substances 0.000 claims description 30
- 210000004379 membrane Anatomy 0.000 claims description 18
- 239000012528 membrane Substances 0.000 claims description 18
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 16
- 239000007864 aqueous solution Substances 0.000 claims description 16
- 230000008018 melting Effects 0.000 claims description 16
- 238000002844 melting Methods 0.000 claims description 16
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 16
- 229920000728 polyester Polymers 0.000 claims description 15
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 12
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 12
- 229940079593 drug Drugs 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 9
- POJWUDADGALRAB-UHFFFAOYSA-N allantoin Chemical compound NC(=O)NC1NC(=O)NC1=O POJWUDADGALRAB-UHFFFAOYSA-N 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N squalane Chemical compound CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 claims description 8
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 6
- 239000000385 dialysis solution Substances 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 239000000679 carrageenan Substances 0.000 claims description 5
- 229920001525 carrageenan Polymers 0.000 claims description 5
- 235000010418 carrageenan Nutrition 0.000 claims description 5
- 229940113118 carrageenan Drugs 0.000 claims description 5
- 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 description 5
- POJWUDADGALRAB-PVQJCKRUSA-N Allantoin Natural products NC(=O)N[C@@H]1NC(=O)NC1=O POJWUDADGALRAB-PVQJCKRUSA-N 0.000 claims description 4
- 229920001661 Chitosan Polymers 0.000 claims description 4
- 102000008186 Collagen Human genes 0.000 claims description 4
- 108010035532 Collagen Proteins 0.000 claims description 4
- 102000009024 Epidermal Growth Factor Human genes 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
- MVORZMQFXBLMHM-QWRGUYRKSA-N Gly-His-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CC1=CN=CN1 MVORZMQFXBLMHM-QWRGUYRKSA-N 0.000 claims description 4
- 241000530268 Lycaena heteronea Species 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- DFPAKSUCGFBDDF-ZQBYOMGUSA-N [14c]-nicotinamide Chemical compound N[14C](=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-ZQBYOMGUSA-N 0.000 claims description 4
- 229960000458 allantoin Drugs 0.000 claims description 4
- 229920001436 collagen Polymers 0.000 claims description 4
- 229960005188 collagen Drugs 0.000 claims description 4
- 239000000835 fiber Substances 0.000 claims description 4
- 229940126864 fibroblast growth factor Drugs 0.000 claims description 4
- 229960005150 glycerol Drugs 0.000 claims description 4
- 239000003102 growth factor Substances 0.000 claims description 4
- 229940119170 jojoba wax Drugs 0.000 claims description 4
- JXTPJDDICSTXJX-UHFFFAOYSA-N n-Triacontane Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCC JXTPJDDICSTXJX-UHFFFAOYSA-N 0.000 claims description 4
- UWJJYHHHVWZFEP-UHFFFAOYSA-N pentane-1,1-diol Chemical compound CCCCC(O)O UWJJYHHHVWZFEP-UHFFFAOYSA-N 0.000 claims description 4
- 229920002643 polyglutamic acid Polymers 0.000 claims description 4
- 210000000813 small intestine Anatomy 0.000 claims description 4
- 229940032094 squalane Drugs 0.000 claims description 4
- 210000004876 tela submucosa Anatomy 0.000 claims description 4
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 3
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 3
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 3
- 239000004744 fabric Substances 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 230000001105 regulatory effect Effects 0.000 claims description 3
- 229920001817 Agar Polymers 0.000 claims description 2
- 229920002749 Bacterial cellulose Polymers 0.000 claims description 2
- 229920000742 Cotton Polymers 0.000 claims description 2
- 108010010803 Gelatin Proteins 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- 229920002302 Nylon 6,6 Polymers 0.000 claims description 2
- 239000004952 Polyamide Substances 0.000 claims description 2
- 229920000297 Rayon Polymers 0.000 claims description 2
- 229920002125 Sokalan® Polymers 0.000 claims description 2
- 239000008272 agar Substances 0.000 claims description 2
- 229940023476 agar Drugs 0.000 claims description 2
- 235000010419 agar Nutrition 0.000 claims description 2
- 239000005016 bacterial cellulose Substances 0.000 claims description 2
- 210000002469 basement membrane Anatomy 0.000 claims description 2
- 229960001631 carbomer Drugs 0.000 claims description 2
- 229940105329 carboxymethylcellulose Drugs 0.000 claims description 2
- 235000013399 edible fruits Nutrition 0.000 claims description 2
- 239000008273 gelatin Substances 0.000 claims description 2
- 229920000159 gelatin Polymers 0.000 claims description 2
- 229940014259 gelatin Drugs 0.000 claims description 2
- 235000019322 gelatine Nutrition 0.000 claims description 2
- 235000011852 gelatine desserts Nutrition 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 239000008055 phosphate buffer solution Substances 0.000 claims description 2
- 229920002647 polyamide Polymers 0.000 claims description 2
- 229940068984 polyvinyl alcohol Drugs 0.000 claims description 2
- 235000019422 polyvinyl alcohol Nutrition 0.000 claims description 2
- 230000037314 wound repair Effects 0.000 claims description 2
- 239000000230 xanthan gum Substances 0.000 claims description 2
- 229920001285 xanthan gum Polymers 0.000 claims description 2
- 235000010493 xanthan gum Nutrition 0.000 claims description 2
- 229940082509 xanthan gum Drugs 0.000 claims description 2
- 230000003796 beauty Effects 0.000 claims 1
- 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 abstract description 13
- 229920002674 hyaluronan Polymers 0.000 abstract description 13
- 229960003160 hyaluronic acid Drugs 0.000 abstract description 13
- 238000004132 cross linking Methods 0.000 abstract description 8
- 230000008569 process Effects 0.000 abstract description 8
- 230000009471 action Effects 0.000 abstract description 6
- 238000010382 chemical cross-linking Methods 0.000 abstract description 6
- 239000003431 cross linking reagent Substances 0.000 abstract description 6
- 230000006870 function Effects 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 4
- 239000001257 hydrogen Substances 0.000 abstract description 4
- 238000004804 winding Methods 0.000 abstract description 4
- 239000000017 hydrogel Substances 0.000 abstract description 3
- 230000008439 repair process Effects 0.000 abstract description 3
- 238000004090 dissolution Methods 0.000 abstract 1
- 239000000843 powder Substances 0.000 description 11
- 238000005303 weighing Methods 0.000 description 11
- 230000000694 effects Effects 0.000 description 10
- 230000007935 neutral effect Effects 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000008363 phosphate buffer Substances 0.000 description 6
- 208000027418 Wounds and injury Diseases 0.000 description 5
- 239000002131 composite material Substances 0.000 description 5
- RBTBFTRPCNLSDE-UHFFFAOYSA-N 3,7-bis(dimethylamino)phenothiazin-5-ium Chemical compound C1=CC(N(C)C)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 RBTBFTRPCNLSDE-UHFFFAOYSA-N 0.000 description 4
- 206010052428 Wound Diseases 0.000 description 4
- 239000011159 matrix material Substances 0.000 description 4
- 229960000907 methylthioninium chloride Drugs 0.000 description 4
- 230000003020 moisturizing effect Effects 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 230000007547 defect Effects 0.000 description 3
- 230000035876 healing Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 239000000416 hydrocolloid Substances 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 230000001502 supplementing effect Effects 0.000 description 2
- 206010063560 Excessive granulation tissue Diseases 0.000 description 1
- 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
- 238000002835 absorbance Methods 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- 230000003712 anti-aging effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000001815 facial effect Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 210000001126 granulation tissue Anatomy 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 239000008274 jelly Substances 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 229960003966 nicotinamide Drugs 0.000 description 1
- 235000005152 nicotinamide Nutrition 0.000 description 1
- 239000011570 nicotinamide Substances 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 238000011056 performance test Methods 0.000 description 1
- 210000004224 pleura Anatomy 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 239000004814 polyurethane Substances 0.000 description 1
- 229920002635 polyurethane Polymers 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000002787 reinforcement Effects 0.000 description 1
- 230000002000 scavenging effect Effects 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/73—Polysaccharides
- A61K8/735—Mucopolysaccharides, e.g. hyaluronic acid; Derivatives thereof
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
- A61K8/0208—Tissues; Wipes; Patches
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
- A61K8/0212—Face masks
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/81—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions involving only carbon-to-carbon unsaturated bonds
- A61K8/8129—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an alcohol, ether, aldehydo, ketonic, acetal or ketal radical; Compositions of hydrolysed polymers or esters of unsaturated alcohols with saturated carboxylic acids; Compositions of derivatives of such polymers, e.g. polyvinylmethylether
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7007—Drug-containing films, membranes or sheets
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
- A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
- A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
- A61L15/24—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
- A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
- A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
- A61L15/28—Polysaccharides or their derivatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
- A61K2800/84—Products or compounds obtained by lyophilisation, freeze-drying
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
- A61L2300/602—Type of release, e.g. controlled, sustained, slow
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Birds (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Materials Engineering (AREA)
- Hematology (AREA)
- Inorganic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Dermatology (AREA)
- Biomedical Technology (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides a physical cross-linked gel film, a preparation method and application thereof, wherein the preparation method comprises the following steps: and combining the sodium hyaluronate solution with the pH value less than or equal to 3 with a reinforcing phase, and freezing, thawing and dialyzing to obtain the physical cross-linked gel film, wherein the reinforcing phase comprises a support film and/or a gel layer. The physical crosslinking gel film does not use a chemical crosslinking agent, and the hydrogel is formed by winding between molecules through hydrogen bond action, so that the biological safety is high, and the characteristic of poor mechanical property of the original gel film is overcome; the physical cross-linked gel film can prevent the hyaluronic acid from directly contacting with air by using the reinforcing phase, plays a role in slowing down the volatilization of water and improving the water retention capacity, is convenient for realizing the functions of skin care, repair and the like, and the preparation method only relates to the processes of dissolution, freezing, thawing, soaking, has simple process and low cost, and is convenient for large-scale and industrialized production.
Description
Technical Field
The invention belongs to the technical field of biomedical materials, and particularly relates to a physical cross-linked gel film, and a preparation method and application thereof.
Background
Wet healing theory indicates that maintaining proper humidity is beneficial to accelerating cell growth and migration speed and promoting healing. Therefore, traditional skin care and wound treatment often rely on various moisturizing products, mainly including facial masks and various oily/aqueous ointments, lotions and hydrocolloid applications. For common mask products, the main problems are that the moisture retention time is short, the skin is excessively hydrated in a short time due to excessive free water, the mask is not suitable for long-time use, the mask cloth is only used as a mask liquid carrier, and the skin is directly contacted with the mask after the mask liquid is insufficient, so that uncomfortable and non-fitting feeling is shown. When in use, the mask liquid is dripped to wet clothes, so that the use experience is poor. The oily/aqueous jelly and paste are directly smeared on the required parts when in use, play a role in preventing the volatilization of the water or supplementing external water, and are convenient and fast. However, when large-area coating is needed, the moisturizing effect is limited, pain is obvious in the use process, and the defect that secondary injury risks are caused is remarkable, and the main manifestation is that the wound surface is further enlarged in the coating process, the isolation effect is poor, and infection is caused.
The existing hydrocolloid application products are mainly high polymer products which are synthesized by manual work, such as polyacrylate, cellulose derivatives, polyurethane and the like, and have good mechanical properties and good water retention. However, monomer, catalyst or cross-linking agent residues may be present, irritation may be present, and the healing process is affected. And most of materials cannot be degraded, new granulation tissues of the wound surface are easy to grow into the dressing, mechanical damage is easy to cause in the replacement process, and pain feeling of patients is obvious. The existing non-chemically crosslinked hyaluronic acid gel mainly has the problem of low mechanical strength. And the mechanical strength is poor, so that the method is difficult to be practically applied.
Based on the above, a better solution is to prepare a gel film with good biocompatibility, good mechanical property and strong water-retaining capacity. Sodium hyaluronate is an inherent glucuronic acid component in the human body and is not species specific. Has anti-inflammatory and moisturizing effects, and can be used for scavenging free radicals and supplementing endogenous sodium hyaluronate as nutrient substance, thereby having anti-aging and skin caring effects. However, the free linear sodium hyaluronate molecules have the problems of poor mechanical properties, incapability of forming gel and the like. Chemical crosslinking can solve the problems, but causes more troublesome problems such as residual crosslinking agent, reduced biocompatibility and the like. The preparation method of hyaluronic acid gel through non-chemical crosslinking has been reported in a small quantity, such as CN1101405C, CN1433432A, CN1288197C and CN103254447A, and mainly has the problems of low mechanical strength of single hyaluronic acid gel, residual risk of small organic molecules and potential biosafety after blending with other materials.
Therefore, the invention provides a physical cross-linked gel film with good biocompatibility and good water retention capacity and mechanical strength aiming at skin repair, which is a problem to be solved by the technicians in the field.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a physical cross-linked gel film, a preparation method and application thereof, wherein the physical cross-linked gel film improves the mechanical strength of hyaluronic acid gel and also has the functions of slowing down the volatilization of water and prolonging the slow release of substances, and the preparation method comprises freeze thawing cycle, does not add any chemical cross-linking agent and has good biocompatibility.
In order to achieve the aim of the invention, the invention adopts the following technical scheme:
in a first aspect, the present invention provides a method of preparing a physically cross-linked gel film, the method comprising the steps of:
and combining the sodium hyaluronate solution with the pH less than or equal to 3 with a reinforcing phase, alternately freezing and thawing, and then dialyzing to obtain the physical cross-linked gel film, wherein the reinforcing phase comprises a support film and/or gel layer material.
The preparation method of the physical cross-linked gel film does not use a chemical cross-linking agent, and the hydrogel is formed by hydrogen bond action and intermolecular winding, so that the biological safety is high. The physical crosslinking gel film overcomes the defect of poor mechanical property of the original physical crosslinking gel, and the used gel layer reinforcing phase can prevent the hyaluronic acid from directly contacting with air, thereby playing the roles of slowing down the volatilization of water and improving the water retention capacity.
Preferably, the preparation method of the sodium hyaluronate solution with the pH value less than or equal to 3 comprises the following steps: sodium hyaluronate is dissolved in water, and the pH value is adjusted to be less than or equal to 3 by adopting hydrochloric acid, so that the sodium hyaluronate solution with the pH value less than or equal to 3 is obtained, wherein the pH value less than or equal to 3 can be, for example, 0.1, 0.2, 0.3, 0.5, 0.7, 0.9, 1, 1.1, 1.3, 1.5, 2, 2.2, 2.4, 2.6, 2.8 and 3, and specific point values among the point values are included in the range, and the invention is not limited to the description of specific point values included in the range, and more preferably the pH value less than or equal to 1.5 for the sake of simplicity.
Preferably, the molecular weight of the sodium hyaluronate is 6 ten thousand to 400 ten thousand daltons, for example, 6 ten thousand daltons, 10 ten thousand daltons, 50 ten thousand daltons, 100 ten thousand daltons, 140 ten thousand daltons, 150 ten thousand daltons, 160 ten thousand daltons, 200 ten thousand daltons, 216 ten thousand daltons, 250 ten thousand daltons, 280 ten thousand daltons, 300 ten thousand daltons, 320 ten thousand daltons, 350 ten thousand daltons, 380 ten thousand daltons, 400 ten thousand daltons, and specific point values between the above point values, are limited in space and for the sake of brevity, and the present invention does not exhaustively enumerate specific point values included in the range.
Preferably, the acid comprises any one or a combination of at least two of nitric acid, sulfuric acid or hydrochloric acid.
Hydrochloric acid is more preferable in view of the final residual amount.
Preferably, the concentration of the acid is 0.5 to 1.5mol/L, for example, 0.5mol/L, 0.8mol/L, 1mol/L, 1.2mol/L, 1.5mol/L, and specific point values between the above point values, are limited in length and for brevity, the present invention is not intended to be exhaustive of the specific point values included in the range.
Preferably, the sodium hyaluronate solution having a pH of 3 or less has a sodium hyaluronate content of 0.5-5wt%, such as 0.8wt%, 1wt%, 1.2wt%, 1.3wt%, 1.5wt%, 2wt%, 2.5wt%, 3wt%, 3.5wt%, 4wt%, 4.5wt%, 5wt%, and specific point values between the above point values, and the present invention is not exhaustive to list the specific point values included in the range, more preferably 0.8-3% for the sake of brevity.
The mass ratio of the sodium hyaluronate solution to the gel layer material is (1-10): (10-1), for example, may be 1: 10. 2: 9. 3: 8. 4: 7. 5: 6. 6: 5. 7: 4. 8: 3. 9: 2. 10:1, and specific point values between the above point values, are limited in space and for the sake of brevity, the present invention is not intended to exhaustively list the specific point values encompassed by the described range.
Preferably, the mass ratio of the sodium hyaluronate solution to the support film material is (1-1000): 1, for example, may be 1: 1. 5: 1. 10: 1. 50: 1. 100: 1. 200: 1. 500: 1. 800: 1. 1000:1, and specific point values between the above point values, are limited in space and for the sake of brevity, the present invention is not intended to exhaustively list the specific point values encompassed by the described range.
Preferably, the gel layer material comprises any one or a combination of at least two of polyvinyl alcohol, carrageenan, agar, xanthan gum, gelatin, carboxymethyl cellulose or carbomer.
The PVA can be selected from high-viscosity type, medium-viscosity type and low-viscosity type. Specific brands may be 17-99, 24-99, 26-99, 17-88, 24-88.
Preferably, the gel layer material further comprises any one or a combination of at least two of sodium hyaluronate, chitosan, propylene glycol, pentanediol, blue copper peptide, nicotinamide, squalane, glycerol, allantoin, collagen, gamma-polyglutamic acid, jojoba oil, concentrated growth factor CGF, fibroblast growth factor FGF, or epidermal growth factor EGF.
Preferably, the support membrane comprises any one or a combination of at least two of porcine small intestine submucosa tissue, porcine bladder basement membrane, polyester fiber, viscose fiber, silk, polyester tape Kong Shawang, nylon 66 gauze, polyamide gauze, bacterial cellulose membrane, fruit film or cotton membrane cloth.
Preferably, the gram weight of the support film is 25g/m 2 。
Preferably, the preparation method specifically comprises the following steps:
(1) Pouring the sodium hyaluronate solution with the pH less than or equal to 3 into a mould, freezing and melting, alternately repeating, and adding the supporting film and/or gel layer material during the period to obtain a composition;
(2) And (3) soaking and dialyzing the mixture obtained in the step (1) to obtain the physical cross-linked gel membrane.
When the polymer solution is frozen, water molecules can form numerous tiny ice crystals, so that the content of free water in the solution is reduced, and the concentration of the polymer in the solution is locally increased, which is called a low-temperature concentration effect. Under the action of low-temperature concentration effect, molecules are mutually close to form a regular and ordered binding area, and gel is formed through interaction of electrostatic action, hydrogen bond, chain winding and the like at a network crosslinking site. Finally, when the polymer solution in a frozen state is thawed, the ice crystals are gradually melted and exist in a liquid water mode, but intermolecular crosslinking formed in the freezing process is not completely destroyed, and the acidified sodium hyaluronate solution can be prepared into gel through freeze thawing.
Preferably, the shape of the mold comprises any one or a combination of at least two of a mask, an eye mask, a hand mask, a leg mask, a pleura, a neck mask, a rectangle, a triangle, a trapezoid, a circle, or an ellipse.
Preferably, the temperature of the freezing in step (1) is between-200 and-2 ℃, for example, -200 ℃, -180 ℃, -150 ℃, -100 ℃, -80 ℃, -70 ℃, -60 ℃, -50 ℃, -40 ℃, -30 ℃, -20 ℃, -18 ℃, -15 ℃, -10 ℃, -5 ℃, -2 ℃, and specific point values between the above point values, the invention is not exhaustive of the specific point values comprised in the range, preferably-80 to-8 ℃, more preferably-40 to-10 ℃, for reasons of brevity and conciseness.
Preferably, the freezing time in step (1) is 1-168h, for example, 1h, 5h, 10h, 15h, 20h, 21h, 22h, 23h, 24h, 25h, 26h, 27h, 28h, 30h, 50h, 100h, 120h, 140h, 160h, 168h, and specific point values between the above point values, are limited in length and for brevity, the present invention is not exhaustive list of specific point values included in the range, preferably 4-72h, more preferably 12-24h.
Preferably, the melting temperature in step (1) is 0-60 ℃, and may be, for example, 0 ℃, 5 ℃, 10 ℃, 15 ℃, 20 ℃, 21 ℃,25 ℃, 28 ℃, 30 ℃, 35 ℃, 40 ℃, 45 ℃, 5 ℃, 55 ℃, 60 ℃, and specific values between the above, although the invention is not limited in space and for simplicity, exhaustive list of specific values of the points included in the range, preferably 20-30 ℃.
Preferably, the melting time in step (1) is 2-5h, for example, 2h, 2.5h, 3h, 3.5h, 4h, 4.5h, 5h, and the specific point values between the above point values, which are limited in space and for simplicity, the present invention is not exhaustive of the specific point values included in the range.
Preferably, the number of repetitions of freezing and thawing in step (1) is 1-9, for example 1, 2, 3, 4, 5, 6, 7, 8, 9, preferably 3-6.
Preferably, the dialysis solution of step (4) comprises water or phosphate buffer solution.
Preferably, the dialysis solution further comprises any one or a combination of at least two of sodium hyaluronate, chitosan, propylene glycol, pentanediol, blue copper peptide, nicotinamide, squalane, glycerol, allantoin, collagen, gamma-polyglutamic acid, jojoba oil, concentrated growth factor CGF, fibroblast growth factor FGF or epidermal growth factor EGF.
Preferably, the preparation method comprises the following steps:
(1) Dissolving sodium hyaluronate in water to obtain an aqueous solution of sodium hyaluronate;
the concentration of the sodium hyaluronate in the aqueous solution of the sodium hyaluronate is 0.5-5wt%;
(2) Mixing the aqueous solution of sodium hyaluronate obtained in the step (1) with hydrochloric acid, and regulating the pH to be less than 3 to obtain a solution A;
the concentration of the hydrochloric acid is 0.5-1.5mol/L;
(3) Pouring the solution A obtained in the step (1) into a mold, freezing and melting, repeating alternately, and adding a support film material and a gel layer material during the period to obtain a mixture;
the temperature of the freezing is-200 to-2 ℃; the freezing time is 1-168 hours; the melting temperature is 0-60 ℃; the melting time is 2-5h; the repeated times of freezing and thawing are 1-9 times;
(4) Dialyzing the composition obtained in the step (3) in a dialysis solution to obtain the physical cross-linked gel membrane.
In a second aspect, the present invention provides a physically cross-linked gel film prepared by the method of preparation according to the first aspect.
The physical cross-linked gel film provided by the invention has obviously enhanced tensile property, and the tensile property is greatly improved because the original gel matrix is combined with the introduced gel layer or/and the interface of the support film, so that the enhanced phase (the support film or/and the gel layer) is responsible for bearing tensile load, and the original matrix (mainly hyaluronic acid gel) realizes load transmission among hard substances through shear deformation, and the enhanced and toughened effects are achieved through cooperation of the enhanced phase and the support film. Specifically: 1. at the contact interface between the original matrix and the gel layer, sodium hyaluronate molecules and polyvinyl alcohol molecules are diffused to form an interface layer containing two phases. The interface is transformed into a transition phase of two gel phases in the freeze thawing process, so that the load can be effectively transferred to the reinforcing phase, and the mechanical property of the polyvinyl alcohol gel serving as the reinforcing phase is better, so that the overall mechanical property of the material is greatly improved; 2. in the gel containing the support membrane, the support membrane has a porous and loose structure and good mechanical properties. Therefore, in the process of forming the gel by freeze thawing of the hyaluronic acid, the gel is filled into a porous and loose structure, the formed interface contact area is large, and the support film dissipates energy through the deformation of the holes of the support film when bearing tensile load, so that the original hyaluronic acid gel also has shear deformation, and the mechanical property is improved. When the two reinforcements are the same, the gel film has better mechanical property.
In a third aspect, the present invention provides the use of a physically cross-linked gel film according to the second aspect for the preparation of skin care cosmetic products, wound repair materials, drug delivery materials.
Compared with the prior art, the invention has the following beneficial effects:
the invention provides a physical crosslinking gel film and a preparation method and application thereof, wherein the physical crosslinking gel film does not use a chemical crosslinking agent, forms hydrogel through hydrogen bond action and molecular winding, has high biological safety, overcomes the characteristic of poor mechanical property, has tensile strength of 3.5-16.2MPa, can prevent hyaluronic acid from directly contacting with air by using a reinforcing phase, plays a role of slowing down moisture volatilization, improves water retention capacity, has the water retention rate of 39-81%, adds required components into the physical crosslinking gel film, realizes slow release function under the action of temperature and concentration, is convenient for realizing functions of skin care, repair and the like, and has simple process, low cost and convenient mass and industrialized production.
Drawings
FIG. 1 is a flow chart of a process for preparing a physically cross-linked gel film according to one embodiment of the present invention;
FIG. 2 is a schematic illustration of a process for preparing a physically cross-linked gel film according to one embodiment of the present invention;
fig. 3 is a graph showing the drug release effect of the physically cross-linked gel films provided in examples 6, 7, and 9.
Detailed Description
The technical scheme of the invention is further described by the following specific embodiments. It will be apparent to those skilled in the art that the examples are merely to aid in understanding the invention and are not to be construed as a specific limitation thereof.
The experimental materials used in the examples and comparative examples of the present invention are as follows:
(1) Polyvinyl alcohol, trade mark, 24-99;
(2) Sodium hyaluronate, brand, HA-THM;
example 1
The embodiment provides a physical cross-linked gel film and a preparation method thereof, wherein the preparation method comprises the following steps: (1) Accurately weighing 1.0 g of sodium hyaluronate with the molecular weight of 220 ten thousand daltons, dissolving in a certain amount of water, and preparing into 1wt% aqueous solution; (2) Adding 1mol/L hydrochloric acid into the solution, and adjusting the pH of the solution to 1.5; (3) Transferring the acidified 80 g solution into a mask tray, standing for 30 minutes to remove bubbles, putting into an environment of-18 ℃ for freezing for 24 hours, taking out, putting into an environment of 25 ℃ for thawing for 4 hours, and repeating freezing and thawing for three times. Wherein a layer of support film (polyester tape Kong Shawang, polyester, 25 g/m) is laid on the upper layer when the original solution is melted in the first freeze-thawing cycle 2 ) The method comprises the steps of carrying out a first treatment on the surface of the (4) The mold was removed and immersed in phosphate buffer for 24 hours, during which time water was changed several times. After the pH of the gel is neutral, the preparation of the physically cross-linked gel membrane is completed.
Example 2
The embodiment provides a physical cross-linked gel film and a preparation method thereof, wherein the preparation method comprises the following steps: (1) Accurately weighing 1.0 g of sodium hyaluronate powder with molecular weight of 220 ten thousand daltons, dissolving in a certain amount of water, and preparing into 1wt% aqueous solution; (2) Adding 1mol/L hydrochloric acid into the solution, and adjusting the pH of the solution to 1.5; (3) Transferring the acidified 80 g solution into a mask tray, standing for 30 min to remove bubbles, freezing at-18deg.C for 24 hr, taking out, and placing in 25deg.CThe thawing was repeated three times for 4 hours. Wherein a layer of support film (polyester tape Kong Shawang, polyester, 25 g/m) is laid on the upper layer when the original solution is melted in the first freeze-thawing cycle 2 ). Freezing at-18deg.C for 24 hr, taking out, and dripping 20 g 7% polyvinyl alcohol solution (PVA, 24-99) onto the frozen solution; (4) The mold was taken out, immersed in pure water for 24 hours, and changed with water several times during the period. After the pH of the gel is neutral, the preparation of the physically cross-linked gel membrane is completed.
Example 3
The embodiment provides a physical cross-linked gel film and a preparation method thereof, wherein the preparation method comprises the following steps: (1) Accurately weighing 1.0 g of sodium hyaluronate powder with molecular weight of 220 ten thousand daltons, dissolving in a certain amount of water, and preparing into 1wt% aqueous solution; (2) Adding 1mol/L hydrochloric acid into the solution, and adjusting the pH of the solution to 1.5; (3) Transferring the acidified 80 g solution into a cuboid mould (100 x 10mm long x 10mm wide x high, acrylic material), standing for 30 minutes to remove bubbles, freezing for 24 hours in a-80 ℃ environment, taking out, melting for 4 hours in a 25 ℃ environment, and repeating freezing and thawing six times. Wherein a layer of support film (polyester tape Kong Shawang, polyester, 25 g/m) is laid on the upper layer when the original solution is melted at the beginning of the first freeze thawing cycle 2 ). Freezing at-18deg.C for 24 hr, taking out, and dripping 20 g 7% polyvinyl alcohol solution (PVA, 24-99) onto the frozen solution; (4) The mold was removed and immersed in phosphate buffer for 24 hours, during which time water was changed several times. After the pH of the gel is neutral, the preparation of the physically cross-linked gel membrane is completed.
Example 4
The embodiment provides a physical cross-linked gel film and a preparation method thereof, wherein the preparation method comprises the following steps: (1) Accurately weighing 1.0 g of sodium hyaluronate powder with molecular weight of 220 ten thousand daltons, dissolving in a certain amount of water, and preparing into 1wt% aqueous solution; (2) Adding 1mol/L hydrochloric acid into the solution, and adjusting the pH of the solution to 1.5; (3) Transferring the acidified 80 g solution into a mask tray, standing for 30 minutes to remove bubbles, putting into an environment of-18 ℃ for freezing for 24 hours, taking out, putting into an environment of 25 ℃ for thawing for 4 hours, and repeating freezing and thawing for three times. When the first freeze-thawing cycle is started, pouring 20 g of compound powder gel layer under the original solution freezing state. The compound powder gel consists of 0.5 weight percent of carrageenan and 0.5 weight percent of carboxymethyl cellulose water solution; (4) The mold was removed and immersed in a phosphate buffer containing 2wt% nicotinamide for 24 hours, during which time water was changed several times. After the pH of the gel is neutral, the preparation of the physically cross-linked gel membrane is completed.
Example 5
This example provides a physically cross-linked gel film and a method for preparing the same, which differs from example 1 only in that the support film material is changed from a polyester perforated gauze to a porcine small intestine submucosa SIS, available from the Cook Group.
Example 6
The embodiment provides a physical cross-linked gel film and a preparation method thereof, wherein the preparation method comprises the following steps: (1) Accurately weighing 1.0 g of sodium hyaluronate powder with the molecular weight of 140 ten thousand daltons, dissolving in a certain amount of water, and preparing into 1wt% aqueous solution; (2) Adding 1mol/L hydrochloric acid into the solution, and adjusting the pH of the solution to 1.5; (3) Transferring the acidified 80 g solution into a cuboid mould (100 x 10mm long x 10mm wide x high, acrylic material), standing for 30 minutes to remove bubbles, freezing for 24 hours in an environment of-18 ℃, taking out, melting for 4 hours in an environment of 25 ℃, and repeating freezing and thawing for three times. Wherein, when the first freeze-thawing cycle is started, a layer of support film (SIS (porcine small intestine submucosa, purchased from Cook Group) is paved on the upper layer in the original solution thawing state, and 20 g of 1% carrageenan solution (0.1 g of methylene blue is dissolved) is poured on the upper layer in the solution freezing state; (4) The mold was taken out, immersed in pure water for 24 hours, and changed with water several times during the period. After the pH of the gel is neutral, the preparation of the physically cross-linked gel membrane is completed.
The physical crosslinked gel film containing the model drug is stuck in a glass culture dish filled with a small amount of physiological saline (the mass of the physiological saline is 20 g), and is placed in a shaking table at 37 ℃, and the cumulative release rate of the drug is calculated by measuring the absorbance change of the leaching liquid, and the drug slow release effect graph of the physical crosslinked gel film is shown as figure 3, and shows that the physical crosslinked gel film has good drug slow release effect.
Example 7
The embodiment provides a physical cross-linked gel film and a preparation method thereof, wherein the preparation method comprises the following steps: (1) Accurately weighing 1.0 g of sodium hyaluronate powder with the molecular weight of 140 ten thousand daltons, dissolving in a certain amount of water, and preparing into 1wt% aqueous solution; (2) Adding 1mol/L hydrochloric acid into the solution, and adjusting the pH of the solution to 1.5; (3) Transferring the acidified 80 g solution into a cuboid mould (100 x 10mm long x 10mm wide x high, acrylic material), standing for 30 minutes to remove bubbles, freezing for 24 hours in an environment of-18 ℃, taking out, melting for 4 hours in an environment of 25 ℃, and repeating freezing and thawing for three times. Wherein, at the beginning of the first freeze-thawing cycle, 20 g of 1% carrageenan solution (0.1 g dissolved with methylene blue) was poured into the upper layer in the frozen state of the solution; (4) The mold was taken out, immersed in pure water for 24 hours, and changed with water several times during the period. After the pH of the gel is neutral, the preparation of the physically cross-linked gel membrane is completed.
Example 8
The embodiment provides a physical cross-linked gel film and a preparation method thereof, wherein the preparation method comprises the following steps: (1) Accurately weighing 1.0 g of sodium hyaluronate powder with the molecular weight of 160 ten thousand daltons, dissolving in a certain amount of water, and preparing into 1.5wt% aqueous solution; (2) Adding 1mol/L hydrochloric acid into the solution, and adjusting the pH value of the solution to 1.0; (3) Transferring the acidified 80 g solution into a mask tray, standing for 30 minutes to remove bubbles, putting into an environment of-80 ℃ for freezing for 24 hours, taking out, putting into an environment of 30 ℃ for thawing for 4 hours, and repeating freezing and thawing for three times. Wherein a layer of support film (polyester tape Kong Shawang, polyester, 25 g/m) is laid on the upper layer when the original solution is melted at the beginning of the first freeze thawing cycle 2 ) Freezing at-18deg.C for 24 hr, taking out, and dripping 20 g 7% polyvinyl alcohol solution (PVA, 24-99) onto the frozen solution; (4) The water was taken out and immersed in pure water for 24 hours, during which time water was changed several times. After the pH of the gel is neutral, the preparation of the physically cross-linked gel membrane is completed.
Example 9
The embodiment provides a physical cross-linked gel film and a preparation method thereof, and uses methylene blue as a model drug to test the slow release function of the drug in a gel matrix, wherein the preparation method comprises the following steps:
(1) Accurately weighing 1.0 g of sodium hyaluronate powder with the molecular weight of 140 ten thousand daltons, dissolving in a certain amount of water, and preparing into 1wt% aqueous solution; (2) Adding 1mol/L hydrochloric acid into the solution, and adjusting the pH of the solution to 1.5; (3) Transferring the acidified 80 g solution into a cuboid mould (100 x 10mm, length x width x height, acrylic material), standing for 30 minutes to remove bubbles, freezing for 24 hours in an environment of-18 ℃, taking out, melting for 4 hours in an environment of 25 ℃, and repeating freezing and thawing for three times. Wherein, at the beginning of the first freeze-thawing cycle, a layer of support film (SIS, purchased from Cook Group) (4) was laid on the upper layer in the melted state of the original solution, taken out from the mold, and immersed in a phosphate buffer containing 1%o methylene blue (the concentration of which is equal to that of example 7) for 24 hours, and changed water several times during the period. After the pH of the gel is neutral, the preparation of the physically cross-linked gel membrane is completed.
Comparative example 1
This comparative example provides a physically cross-linked gel film and a method of preparing the same, the method comprising:
(1) Accurately weighing 1.0 g of sodium hyaluronate powder with the molecular weight of 216 ten thousand daltons, dissolving in a certain amount of water, and preparing into 1wt% aqueous solution; (2) Adding 1mol/L hydrochloric acid into the solution, and adjusting the pH of the solution to 1.5; (3) Transferring the acidified 80 g solution into a mask tray, standing for 30 minutes to remove bubbles, putting into an environment of-18 ℃ for freezing for 24 hours, taking out, putting into an environment of 25 ℃ for thawing for 4 hours, and repeating freezing and thawing for three times. (4) The mold was removed and immersed in phosphate buffer for 24 hours, during which time water was changed several times. After the pH of the gel is neutral, the preparation of the physically cross-linked gel membrane is completed.
Comparative example 2
This comparative example provides a physically cross-linked gel film and a method of preparing the same, the method comprising: (1) Accurately weighing 1.0 g of sodium hyaluronate powder with the molecular weight of 216 ten thousand daltons, dissolving in a certain amount of water, and preparing into 1wt% aqueous solution; (2) Adding 1mol/L hydrochloric acid into the solution, and adjusting the pH of the solution to 5; (3) Transferring the acidified 80 g solution into a mask tray, standing for 30 min to remove bubbles, freezing at-18deg.C for 24 hr, taking out, and placingThawing was repeated three times in a 25℃environment for 4 hours. Wherein a layer of support film (polyester tape Kong Shawang, polyester, 25 g/m) is laid on the upper layer when the original solution is melted at the beginning of the first freeze thawing cycle 2 ) The method comprises the steps of carrying out a first treatment on the surface of the (4) The mold was removed and immersed in phosphate buffer for 24 hours, during which time water was changed several times. The sample was not formed and was in a flowing liquid volume.
The physically crosslinked gel films obtained in examples 1 to 9 and the gel films obtained in comparative examples 1 to 2 were subjected to performance test as follows:
(1) Tensile strength: the mechanical properties of each group of samples were evaluated by measuring the tensile stress-strain curve of each group of samples under axial tensile load. Since the sample does not have a yielding process, the maximum mechanical tensile stress that the sample can load is chosen as the maximum tensile strength. The gel shape is selected to be long in the experiment, the specific specification is (100 mm is 30mm is 5mm, length is wide is thick), the equipment is an Instron 3400 universal tester, and the equipment is fixed by using a self-made clamp;
(2) Water retention rate: each group was prepared by taking 100 x 5mm (length x width x thickness) samples, spreading them on a petri dish, placing them in air (if there is a PVA layer, placing the PVA layer on top, simulating normal use), and weighing the gel mass at regular intervals. At this time, the indoor temperature was 23±4 ℃, the humidity was 55±10%, and the gel water retention= (mass after 24 hours/mass before evaporation) ×100%;
TABLE 1
The invention discloses a physically cross-linked hyaluronic acid composite gel film and a preparation method thereof. Specifically, the composite gel film is composed of a hyaluronic acid gel and a reinforcing phase, and the reinforcing phase may be composed of a support film and a gel layer. The composite gel containing the support film has great improvement of mechanical properties and has potential application in the field of moisturizing films; the gel composite gel containing the gel layer has improved mechanical properties, but the water retention performance and the drug slow release effect are remarkably improved, and has better application potential in the field of wound auxiliary materials. Therefore, the structure of the composite gel can be customized in combination with the actual use scene so as to meet the performance requirement of the actual application, and the water retention effect of the physical cross-linked gel film is obviously improved compared with that of the prior gel film after the polyvinyl alcohol is added, so that the gel film can effectively prevent the water from volatilizing, because the water retention performance of the hyaluronic acid is better than that of the polyvinyl alcohol.
The applicant states that the present invention is illustrated by the above examples as a physically cross-linked gel film and a method of making and using the same, but the present invention is not limited to, i.e., does not mean that the present invention must be practiced in dependence upon, the above examples. It should be apparent to those skilled in the art that any modification of the present invention, equivalent substitution of raw materials for the product of the present invention, addition of auxiliary components, selection of specific modes, etc., falls within the scope of the present invention and the scope of disclosure.
Claims (10)
1. A method of preparing a physically cross-linked gel film, the method comprising the steps of:
and combining the sodium hyaluronate solution with the pH less than or equal to 3 with a reinforcing phase, alternately freezing and thawing, and then dialyzing to obtain the physical cross-linked gel film, wherein the reinforcing phase comprises a support film and/or gel layer material.
2. The method according to claim 1, wherein the method for preparing the sodium hyaluronate solution having a pH of 3 or less comprises: dissolving sodium hyaluronate in water, and regulating the pH value to be less than or equal to 3 by adopting acid to obtain sodium hyaluronate solution with the pH value less than or equal to 3;
preferably, the molecular weight of the sodium hyaluronate is 6 ten thousand to 400 ten thousand daltons;
preferably, the acid comprises any one or a combination of at least two of nitric acid, sulfuric acid or hydrochloric acid;
preferably, the concentration of the acid is 0.5-1.5mol/L;
preferably, the mass percentage of sodium hyaluronate in the sodium hyaluronate solution with the pH less than or equal to 3 is 0.5-5wt%;
preferably, the mass ratio of the sodium hyaluronate solution to the gel layer material is (1-10): (10-1);
preferably, the mass ratio of the sodium hyaluronate solution to the support film is (1-1000): 1.
3. the preparation method according to claim 1 or 2, wherein the gel layer material comprises any one or a combination of at least two of polyvinyl alcohol, carrageenan, agar, xanthan gum, gelatin, carboxymethyl cellulose or carbomer;
preferably, the gel layer material further comprises any one or a combination of at least two of sodium hyaluronate, chitosan, propylene glycol, pentanediol, blue copper peptide, nicotinamide, squalane, glycerol, allantoin, collagen, gamma-polyglutamic acid, jojoba oil, concentrated growth factor CGF, fibroblast growth factor FGF, or epidermal growth factor EGF.
4. A method of preparation according to any one of claims 1 to 3 wherein the support film comprises any one or a combination of at least two of porcine small intestine submucosa tissue, porcine bladder basement membrane, polyester fiber, viscose fiber, silk, polyester tape Kong Shawang, nylon 66 gauze, polyamide gauze, bacterial cellulose film, fruit film or cotton film cloth.
5. The preparation method according to any one of claims 1 to 4, characterized in that it comprises in particular:
(1) Pouring the sodium hyaluronate solution with the pH less than or equal to 3 into a mould, freezing and melting, alternately repeating, and adding the supporting film and/or gel layer material during the period to obtain a composition;
(2) And (3) soaking and dialyzing the mixture obtained in the step (1) to obtain the physical cross-linked gel membrane.
6. The method of claim 5, wherein the freezing temperature in step (1) is-200 to-2 ℃;
preferably, the freezing time of step (1) is 1h-168h;
preferably, the melting temperature in the step (1) is 0-60 ℃;
preferably, the melting time in the step (1) is 2-5h;
preferably, the number of repetitions of freezing and thawing in step (1) is 1-9.
7. The method of claim 5 or 6, wherein the dialyzed dialysis solution of step (2) comprises water or phosphate buffer solution;
preferably, the dialysis solution further comprises any one or a combination of at least two of sodium hyaluronate, chitosan, propylene glycol, pentanediol, blue copper peptide, nicotinamide, squalane, glycerol, allantoin, collagen, gamma-polyglutamic acid, jojoba oil, concentrated growth factor CGF, fibroblast growth factor FGF or epidermal growth factor EGF.
8. The method of any one of claims 1-7, wherein the method of preparation comprises:
(1) Dissolving sodium hyaluronate in water to obtain an aqueous solution of sodium hyaluronate;
the concentration of the sodium hyaluronate in the aqueous solution of the sodium hyaluronate is 0.5-5wt%;
(2) Mixing the aqueous solution of sodium hyaluronate obtained in the step (1) with hydrochloric acid, and regulating the pH to be less than 3 to obtain a solution A;
the concentration of the hydrochloric acid is 0.5-1.5mol/L;
(3) Pouring the solution A obtained in the step (1) into a mold, freezing and melting, repeating alternately, and adding a support film material and a gel layer material during the period to obtain a mixture;
the temperature of the freezing is-200 to-2 ℃; the freezing time is 1-168 hours; the melting temperature is 0-60 ℃; the melting time is 2-5h; the repeated times of freezing and thawing are 1-9 times;
(4) Dialyzing the composition obtained in the step (3) in a dialysis solution to obtain the physical cross-linked gel membrane.
9. A physically cross-linked gel film prepared by the method of any one of claims 1 to 8.
10. Use of the physically cross-linked gel film according to claim 9 for the preparation of skin care and beauty products, wound repair materials, drug release materials, freeze-dried sponges.
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| CN117357700A (en) * | 2023-12-06 | 2024-01-09 | 上海威高医疗技术发展有限公司 | Hyaluronic acid gel and preparation method and application thereof |
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| CN117357700A (en) * | 2023-12-06 | 2024-01-09 | 上海威高医疗技术发展有限公司 | Hyaluronic acid gel and preparation method and application thereof |
| CN117357700B (en) * | 2023-12-06 | 2024-03-22 | 上海威高医疗技术发展有限公司 | Hyaluronic acid gel and preparation method and application thereof |
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