CN115154665B - Lubricating fluid containing recombinant III type humanized collagen, filling agent and application thereof - Google Patents
Lubricating fluid containing recombinant III type humanized collagen, filling agent and application thereof Download PDFInfo
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- CN115154665B CN115154665B CN202210640406.0A CN202210640406A CN115154665B CN 115154665 B CN115154665 B CN 115154665B CN 202210640406 A CN202210640406 A CN 202210640406A CN 115154665 B CN115154665 B CN 115154665B
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- sodium hyaluronate
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- hyaluronate gel
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- 102000008186 Collagen Human genes 0.000 title claims abstract description 62
- 108010035532 Collagen Proteins 0.000 title claims abstract description 62
- 229920001436 collagen Polymers 0.000 title claims abstract description 62
- 230000001050 lubricating effect Effects 0.000 title claims abstract description 24
- 239000012530 fluid Substances 0.000 title claims abstract description 13
- 239000000945 filler Substances 0.000 title claims abstract description 12
- 229920002385 Sodium hyaluronate Polymers 0.000 claims abstract description 102
- 229940010747 sodium hyaluronate Drugs 0.000 claims abstract description 102
- 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 102
- 239000000314 lubricant Substances 0.000 claims abstract description 41
- 238000011049 filling Methods 0.000 claims abstract description 26
- 238000002156 mixing Methods 0.000 claims abstract description 18
- 239000002537 cosmetic Substances 0.000 claims abstract description 3
- 239000000463 material Substances 0.000 claims abstract description 3
- 239000003480 eluent Substances 0.000 claims description 64
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 36
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 31
- 239000002994 raw material Substances 0.000 claims description 27
- 238000004132 cross linking Methods 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 23
- 239000002245 particle Substances 0.000 claims description 18
- 239000011780 sodium chloride Substances 0.000 claims description 16
- 230000001954 sterilising effect Effects 0.000 claims description 16
- 230000008569 process Effects 0.000 claims description 15
- 239000007863 gel particle Substances 0.000 claims description 13
- 239000000243 solution Substances 0.000 claims description 13
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 12
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 12
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 12
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 239000007788 liquid Substances 0.000 claims description 10
- 238000007789 sealing Methods 0.000 claims description 8
- 239000003431 cross linking reagent Substances 0.000 claims description 7
- 238000004659 sterilization and disinfection Methods 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 4
- 238000000502 dialysis Methods 0.000 claims description 3
- 239000008363 phosphate buffer Substances 0.000 claims description 3
- 238000004321 preservation Methods 0.000 claims description 2
- 238000002347 injection Methods 0.000 abstract description 17
- 239000007924 injection Substances 0.000 abstract description 17
- 239000000047 product Substances 0.000 abstract description 8
- 230000000694 effects Effects 0.000 abstract description 7
- 230000029663 wound healing Effects 0.000 abstract description 5
- 230000002500 effect on skin Effects 0.000 abstract description 4
- 239000012467 final product Substances 0.000 abstract description 4
- 230000036560 skin regeneration Effects 0.000 abstract description 4
- 230000008591 skin barrier function Effects 0.000 abstract description 3
- 238000000518 rheometry Methods 0.000 abstract description 2
- 238000010828 elution Methods 0.000 description 44
- 238000003756 stirring Methods 0.000 description 25
- 238000004090 dissolution Methods 0.000 description 18
- SHKUUQIDMUMQQK-UHFFFAOYSA-N 2-[4-(oxiran-2-ylmethoxy)butoxymethyl]oxirane Chemical compound C1OC1COCCCCOCC1CO1 SHKUUQIDMUMQQK-UHFFFAOYSA-N 0.000 description 11
- 239000008215 water for injection Substances 0.000 description 11
- 239000000203 mixture Substances 0.000 description 10
- 230000008961 swelling Effects 0.000 description 10
- 230000001105 regulatory effect Effects 0.000 description 9
- 238000005303 weighing Methods 0.000 description 9
- 210000001519 tissue Anatomy 0.000 description 7
- 238000000855 fermentation Methods 0.000 description 6
- 230000004151 fermentation Effects 0.000 description 6
- 230000008439 repair process Effects 0.000 description 6
- 102000001187 Collagen Type III Human genes 0.000 description 5
- 108010069502 Collagen Type III Proteins 0.000 description 5
- 239000007853 buffer solution Substances 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 230000006978 adaptation Effects 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- AFOSIXZFDONLBT-UHFFFAOYSA-N divinyl sulfone Chemical compound C=CS(=O)(=O)C=C AFOSIXZFDONLBT-UHFFFAOYSA-N 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 102000012422 Collagen Type I Human genes 0.000 description 1
- 108010022452 Collagen Type I Proteins 0.000 description 1
- 239000004971 Cross linker Substances 0.000 description 1
- AZKVWQKMDGGDSV-BCMRRPTOSA-N Genipin Chemical compound COC(=O)C1=CO[C@@H](O)[C@@H]2C(CO)=CC[C@H]12 AZKVWQKMDGGDSV-BCMRRPTOSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 208000028990 Skin injury Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- AZKVWQKMDGGDSV-UHFFFAOYSA-N genipin Natural products COC(=O)C1=COC(O)C2C(CO)=CCC12 AZKVWQKMDGGDSV-UHFFFAOYSA-N 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 230000037311 normal skin Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
Classifications
-
- 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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/20—Polysaccharides
-
- 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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
- A61L27/24—Collagen
-
- 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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
-
- 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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/52—Hydrogels or hydrocolloids
-
- 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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/58—Materials at least partially resorbable by the body
-
- 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
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/06—Flowable or injectable implant compositions
-
- 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
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/34—Materials or treatment for tissue regeneration for soft tissue reconstruction
Abstract
The invention relates to the field of cosmetic filling materials, in particular to a lubricating fluid containing recombinant type III human collagen, a filling agent and application thereof. The micro-crosslinked sodium hyaluronate gel containing the recombinant type III human collagen is obtained by mixing the micro-crosslinked sodium hyaluronate gel with a lubricant of the recombinant type III human collagen tissue. Because the final product has proper rheology and low viscoelastic performance, the micro-crosslinked sodium hyaluronate gel injection filling and dermal tissue are used for repairing the appearance and correcting the contour so as to achieve satisfactory effects, and meanwhile, the recombinant type III human collagen with high bioactivity can effectively improve the skin regeneration speed and shorten the wound healing time, thereby recovering the skin barrier function and improving the product quality.
Description
Technical Field
The invention relates to the field of cosmetic filling materials, in particular to a lubricating fluid containing recombinant III type humanized collagen, a filling agent and application thereof.
Background
The prior conventional preparation method of the crosslinked sodium hyaluronate gel mainly comprises the following steps: weighing, dissolving, crosslinking, swelling (eluting), dialyzing, sieving (crushing), filling and sterilizing, wherein the rheological properties of the finally formed gel are greatly different due to the difference of the conditions of the crosslinking reaction and the types of the selected crosslinking agents, and the finally formed gel is generally in a hard particle state, so that the crosslinked sodium hyaluronate gel particles are generally used together with a lubricant for facilitating smooth injection in the clinical use process. And typically the major component of the lubricant during the selection process is uncrosslinked sodium hyaluronate.
However, during the injection filling of the crosslinked sodium hyaluronate gel, it is possible to trigger a protective response in the host, resulting in damage of connective tissue at the injection site. Therefore, when the micro-crosslinked sodium hyaluronate gel injection filling and dermal tissue are used for repairing the appearance and correcting the contour so as to achieve a satisfactory effect, how to repair the external injury generated in the injection process, effectively improve the skin regeneration speed and shorten the wound healing time is an urgent problem in the field.
Disclosure of Invention
The invention provides a lubricating liquid containing recombinant type III human collagen, a filling agent and application thereof for overcoming the defects, and aims to solve the problem that the prior art cannot quickly repair damage of human tissues caused by crosslinking sodium hyaluronate gel in the injection process.
In order to achieve the aim of the invention, the invention is realized by the following technical scheme:
a lubricating fluid containing recombinant III type human collagen,
the sodium hyaluronate gel lubricating liquid comprises recombinant type III human collagen.
Some existing studies indicate that in normal skin tissue, collagen exists mainly in the form of I, III type collagen fibers. Among them, type III collagen is closely related to the skin injury repair process and repair quality, and in general, the higher the content of type III collagen, the stronger the repair ability to skin tissues. Type III collagen accounts for 60% of normal infant skin, and as the infant grows, type III collagen is continuously reduced and type I collagen is continuously increased. Therefore, increasing the content of type III collagen at the sodium hyaluronate gel injection section is a great help to shorten the wound healing time.
The invention is different from the prior art in that the lubricating substance selected in the sodium hyaluronate gel lubricating liquid is not conventional non-crosslinked sodium hyaluronate, but recombinant type III human collagen. Compared with non-crosslinked sodium hyaluronate, the recombinant human Collagen (Reallagen) also called RHC (Recombinant Human-source Collagen) is a high-molecular biological protein produced by a microorganism (such as active yeast) high-density fermentation and green separation and purification process according to the structural characteristics of the human Collagen and by utilizing advanced biological science technology and international leading fermentation technology, and is highly similar to the human Collagen. Therefore, the invention can effectively supplement the III type collagen in the skin by adding the recombinant III type human collagen into the lubricating liquid.
Therefore, after the lubricating fluid containing the recombinant type III human collagen is compounded with the sodium hyaluronate gel particles, the effects of repairing the appearance and correcting the contour by injecting and filling the micro-crosslinked sodium hyaluronate gel and the dermal tissue can be achieved, the skin regeneration speed can be effectively improved, the wound healing time is shortened, the skin barrier function is recovered, and the product quality is improved
Preferably, it is obtained by dissolving recombinant type III human collagen in a buffer solution.
The preparation method of the lubricating fluid containing the recombinant type III human collagen is simple, and the lubricating fluid can be obtained by only dissolving the recombinant type III human collagen in a buffer solution according to the measured parts, so that the subsequent use and operation are simplified.
Preferably, the buffer solution contains sodium chloride, a phosphate buffer system and water for injection.
Preferably, the buffer solution contains 0.7% -1.0% sodium chloride, 0.56% disodium hydrogen phosphate, 0.04% sodium dihydrogen phosphate and water for injection.
Preferably, the concentration of the recombinant type III human collagen in the lubricating liquid is 15-24 mg/ml.
The concentration of the recombinant type III human collagen in the lubricating fluid has a great influence on the actual performance of the lubricating fluid.
When the concentration of the recombinant III type humanized collagen is lower than 15mg/ml, the skin repairing effect is not obvious through practical tests, and meanwhile, the pushing force of the lubricating liquid is lower, so that the hand feeling of injection is avoided;
when the concentration of the recombinant III type humanized collagen is higher than 24mg/ml, the pushing force in the injection process is greatly improved, the injection is not facilitated, and meanwhile, the cost of the product is greatly improved.
When the concentration of the recombinant type III human collagen is 15-24 mg/ml, the skin repair effect and the injection pushing force can be considered, and the pushing force of the product can be at a proper level (10-20N), so that the hand feeling in the injection process is better.
A sodium hyaluronate gel filler,
comprises crosslinked sodium hyaluronate gel particles; the method comprises the steps of,
a lubricating fluid comprising recombinant type III human collagen as described above.
Preferably, the preparation method of the sodium hyaluronate gel filler comprises the following steps:
(1) Dissolving: completely dissolving sodium hyaluronate raw material with sodium hydroxide solution;
(2) Crosslinking reaction: adding a cross-linking agent into the sodium hyaluronate dissolved in the step (1), uniformly mixing, and carrying out heat preservation in a water bath for cross-linking reaction to obtain micro-crosslinked sodium hyaluronate gel;
(3) Preparing an eluent: preparing an eluent containing sodium chloride and a phosphate buffer system for later use;
(4) Preparing a lubricant: preparing a lubricating liquid containing recombinant type III human collagen, wherein other components of the lubricating agent comprise sodium chloride, disodium hydrogen phosphate and sodium dihydrogen phosphate;
(5) Eluting: eluting the micro-crosslinked gel prepared in the step (2) by using the eluent prepared in the step (3), dispersing the micro-crosslinked gel into particles with the size of 0.5-2 cm in the process, and simultaneously replacing the eluent until the micro-crosslinked sodium hyaluronate gel swells to the required weight;
(6) Homogenizing: homogenizing the micro-crosslinked sodium hyaluronate gel subjected to the dialysis in the step (5) to prepare particles with the particle diameter of 150-400 mu m;
(7) And (3) sterilization: carrying out wet heat sterilization on the micro-crosslinked sodium hyaluronate gel particles homogenized in the step (6) by pure steam to achieve a sterile state;
(8) Sterile mixing: mixing the homogenized micro-crosslinked sodium hyaluronate gel particles in the step (7) with the lubricant prepared in the step (4) according to a certain proportion;
(9) And (3) filling: uniformly mixing the micro-crosslinked sodium hyaluronate gel particles prepared in the step (8) with a lubricant containing recombinant type III human collagen to obtain the micro-crosslinked sodium hyaluronate gel containing recombinant type III human collagen, and filling the micro-crosslinked sodium hyaluronate gel into a pre-filling and sealing syringe.
Preferably, in the step (1), the sodium hyaluronate raw material is prepared by a fermentation method or an extraction method, and the molecular weight is 120-230 ten thousand.
Preferably, in the step (1), the concentration of the sodium hydroxide-containing solution is 0.85% to 1.25%.
Preferably, in the step (2), the crosslinking agent is one or a mixture of two or more of 1, 4-butanediol diglycidyl ether (BDDE), divinyl sulfone (DVS), polyethylene glycol, genipin, and carbodiimide.
Preferably, in the step (2), the crosslinking reaction temperature is 35 ℃ to 58 ℃.
Preferably, in the step (2), the crosslinking reaction is carried out for a period of time of 60 to 150 minutes.
Preferably, in the step (2), the mass ratio of the cross-linking agent to the sodium hyaluronate raw material is 0.05-0.12.
Preferably, in the step (3), the content of sodium chloride in the eluent is 0.7% -1.0%.
Preferably, in the step (4), the concentration of the recombinant type III human collagen in the lubricant is 15-24 mg/ml.
Preferably, the mass of the eluent is 50-80 times of the gel mass after the crosslinking is completed.
Preferably, the first elution time in the eluting step is 2-4 hours, and the total eluting times are 3-6 times.
Preferably, in the step (5), the concentration of the sodium hyaluronate at the elution end point is 5mg/ml to 8mg/ml.
Preferably, in the step (6), the particle diameter of the micro-crosslinked sodium hyaluronate gel after being homogenized is 150-400 μm.
Preferably, in the step (6), the homogenization frequency of the micro-crosslinked sodium hyaluronate gel is 2-4 times.
Preferably, in the step (7), the sterilization temperature of the micro-crosslinked sodium hyaluronate gel is 115 ℃ to 125 ℃.
Preferably, in the step (7), the sterilization F0 value of the micro-crosslinked sodium hyaluronate gel is 8 to 12.
Preferably, in the step (8), the mass ratio of the crosslinked sodium hyaluronate gel particles to the lubricating liquid is (1 to 10): 1.
therefore, the invention has the following beneficial effects:
according to the invention, through designing reaction conditions and controlling the degree of crosslinking reaction of HA and BDDE, a low-crosslinking-degree sodium hyaluronate gel is obtained, and then a homogenization-sterilization process is carried out to obtain a sterile micro-crosslinking sodium hyaluronate gel, which is mixed with a lubricant of recombinant type III human collagen tissue to obtain the micro-crosslinking sodium hyaluronate gel containing recombinant type III human collagen. Because the final product has proper rheology and low viscoelastic performance, the micro-crosslinked sodium hyaluronate gel injection filling and dermal tissue are used for repairing the appearance and correcting the contour so as to achieve satisfactory effects, and meanwhile, the recombinant type III human collagen with high bioactivity can effectively improve the skin regeneration speed and shorten the wound healing time, thereby recovering the skin barrier function and improving the product quality.
Detailed Description
The invention is further described below in connection with specific embodiments. Those of ordinary skill in the art will be able to implement the invention based on these descriptions. In addition, the embodiments of the present invention referred to in the following description are typically only some, but not all, embodiments of the present invention. Therefore, all other embodiments, which can be made by one of ordinary skill in the art without undue burden, are intended to be within the scope of the present invention, based on the embodiments of the present invention.
Description of the invention
1: the sodium hyaluronate raw material selected in the following examples was produced by fermentation and was the same batch.
2: the crosslinker used in the following examples was 1, 4-butanediol diglycidyl ether (BDDE)
3: the examples are not limited to the raw materials prepared by the fermentation method, but the effectiveness and versatility of the present invention will also be illustrated by taking the raw materials prepared by the extraction method as an example.
3: the recombinant type III human collagen raw material selected in the following examples is a freeze-dried sponge produced by a fermentation method, and is the same batch.
Example 1
Preparing 20L of eluent (sodium chloride-containing, sodium dihydrogen phosphate, disodium hydrogen phosphate and water for injection) for later use.
Weighing 5g of recombinant type III human collagen raw material, adding 250ml of eluent for dissolution, and preparing a lubricant with the concentration of 20mg/ml for later use.
50ml of 1.2% sodium hydroxide solution was prepared, and 5g of sodium hyaluronate raw material having a molecular weight of 180 ten thousand was added thereto and stirred to dissolve until no white undissolved HA was visible to the naked eye. After dissolution, 0.35ml of 1, 4-butanediol diglycidyl ether (BDDE) was added, and the mixture was stirred again and mixed well. Regulating the temperature of the water bath to 48 ℃, placing the gel into the water bath, and preserving the heat for 90min. And taking out the gel after crosslinking, adding 3.5L of eluent, stirring at a low speed for swelling for 3 hours, removing the eluent, and scattering the swelled gel, wherein the size is about 0.5-2 cm. Continuing the second elution for 16h, adding 3.5L of eluent after the second elution is finished, and adding 3.5L of eluent again for the third elution until the final weight of the gel is 1kg, stopping the elution, wherein the final concentration of the micro-crosslinked sodium hyaluronate is 5mg/ml after the time of 6 h. And (3) taking the dialyzed gel, and continuously homogenizing for 2 times by using a screen to obtain the gel with the particle diameter of 150-400 mu m. Taking 90g of gel, sterilizing under the conditions of 121 ℃ and F0=12 by moist heat, adding 10g of lubricant, stirring and mixing uniformly, and M Micro-crosslinked sodium hyaluronate ：M Lubricant =9:1, and finally a micro-crosslinked sodium hyaluronate gel containing recombinant type III human collagen was obtained, and filled into 1.0ml pre-filled syringes, sample No. a.
Example 2
Preparing 20L of eluent (sodium chloride-containing, sodium dihydrogen phosphate, disodium hydrogen phosphate and water for injection) for later use.
Weighing 5g of recombinant type III human collagen raw material, adding 250ml of eluent for dissolution, and preparing a lubricant with the concentration of 20mg/ml for later use.
50ml of 1.2% sodium hydroxide solution was prepared, and 5g of sodium hyaluronate raw material having a molecular weight of 230 ten thousand was added thereto and stirred to dissolve until no white undissolved HA was visible to the naked eye. After dissolution, 0.60ml of 1, 4-butanediol diglycidyl ether (BDDE) was added, and the mixture was stirred again and mixed well. Regulating the temperature of the water bath to 55 ℃, placing the gel into the water bath, and preserving the heat for 60min. And taking out the gel after crosslinking, adding 5L of eluent, stirring at a low speed for swelling for 3 hours, removing the eluent, and scattering the swelled gel, wherein the size is about 0.5-2 cm. Continuing the second elution for 16h, adding 5L of eluent after the second elution is finished, and adding 5L of eluent again to perform the third elution until the final weight of the gel is 1kg, stopping the elution, wherein the final concentration of the micro-crosslinked sodium hyaluronate is 5mg/ml after 10 h. And (3) taking the dialyzed gel, and continuously homogenizing for 2 times by using a screen to obtain the gel with the particle diameter of 150-400 mu m. Taking 80g of gel, sterilizing under the conditions of 121 ℃ and F0=12 by moist heat, adding 20g of lubricant, stirring and mixing uniformly, and M Micro-crosslinked sodium hyaluronate ：M Lubricant And (2) obtaining the micro-crosslinked sodium hyaluronate gel containing the recombinant type III human collagen, filling the micro-crosslinked sodium hyaluronate gel into a 1.0ml pre-filling and sealing syringe, and obtaining a sample number B.
Example 3
Preparing 20L of eluent (sodium chloride-containing, sodium dihydrogen phosphate, disodium hydrogen phosphate and water for injection) for later use.
Weighing 5g of recombinant type III human collagen raw material, adding 250ml of eluent for dissolution, and preparing a lubricant with the concentration of 20mg/ml for later use.
50ml of 1.0% strength sodium hydroxide solution was prepared, and 5g of a sodium hyaluronate raw material having a molecular weight of 150 ten thousand was added thereto and dissolved by stirring until no white undissolved HA was visible to the naked eye. After dissolution, 0.40ml of 1, 4-butanediol diglycidyl ether (BDDE) was added, and the mixture was stirred again and mixed well. Regulating the temperature of the water bath to 50 ℃, placing the gel into the water bath, and preserving the heat for 120min. Will be crosslinked completelyTaking out the gel, adding 5L of eluent, stirring at a low speed for swelling for 3 hours, removing the eluent, and scattering the swelled gel, wherein the size is about 0.5-2 cm. Continuing the second elution for 16h, adding 5L of eluent after the second elution is finished, and adding 5L of eluent again to perform the third elution until the final weight of the gel is 0.62kg, and stopping the elution until the final weight of the gel reaches the end point of the elution, wherein the final concentration of the micro-crosslinked sodium hyaluronate is 8mg/ml after 6 h. And (3) taking the dialyzed gel, and continuously homogenizing for 2 times by using a screen to obtain the gel with the particle diameter of 150-400 mu m. Taking 80g of gel, sterilizing under the conditions of 121 ℃ and F0=12 by moist heat, adding 20g of lubricant, stirring and mixing uniformly, and M Micro-crosslinked sodium hyaluronate ：M Lubricant And (2) obtaining the micro-crosslinked sodium hyaluronate gel containing the recombinant type III human collagen, filling the micro-crosslinked sodium hyaluronate gel into a 1.0ml pre-filling and sealing syringe, and obtaining a sample number C.
Example 4
Preparing 20L of eluent (sodium chloride-containing, sodium dihydrogen phosphate, disodium hydrogen phosphate and water for injection) for later use.
Weighing 5g of recombinant type III human collagen raw material, adding 250ml of eluent for dissolution, and preparing a lubricant with the concentration of 20mg/ml for later use.
50ml of 1.0% strength sodium hydroxide solution was prepared, and 5g of a sodium hyaluronate raw material having a molecular weight of 150 ten thousand was added thereto and dissolved by stirring until no white undissolved HA was visible to the naked eye. After dissolution, 0.40ml of 1, 4-butanediol diglycidyl ether (BDDE) was added, and the mixture was stirred again and mixed well. Regulating the temperature of the water bath to 50 ℃, placing the gel into the water bath, and preserving the heat for 120min. And taking out the gel after crosslinking, adding 5L of eluent, stirring at a low speed for swelling for 3 hours, removing the eluent, and scattering the swelled gel, wherein the size is about 0.5-2 cm. Continuing the second elution for 16h, adding 5L of eluent after the second elution is finished, and adding 5L of eluent again to perform the third elution until the final weight of the gel is 0.62kg, and stopping the elution until the final weight of the gel reaches the end point of the elution, wherein the final concentration of the micro-crosslinked sodium hyaluronate is 8mg/ml after 6 h. And (3) taking the dialyzed gel, and continuously homogenizing for 2 times by using a screen to obtain the gel with the particle diameter of 150-400 mu m. Taking 60g of gel, sterilizing under the conditions of 121deg.C and F0=12 by wet heat, addingAdding 40g of lubricant, stirring and mixing uniformly, M Micro-crosslinked sodium hyaluronate ：M Lubricant =6:4, and finally a micro-crosslinked sodium hyaluronate gel containing recombinant type III human collagen was obtained, and filled into 1.0ml pre-filled syringes, sample No. D.
Example 5
Preparing 20L of eluent (sodium chloride-containing, sodium dihydrogen phosphate, disodium hydrogen phosphate and water for injection) for later use.
Weighing 5g of recombinant type III human collagen raw material, adding 250ml of eluent for dissolution, and preparing a lubricant with the concentration of 20mg/ml for later use.
50ml of 1.2% sodium hydroxide solution was prepared, and 5g of a sodium hyaluronate raw material having a molecular weight of 200 ten thousand was added thereto and dissolved by stirring until no white undissolved HA was visible to the naked eye. After dissolution, 0.48ml of 1, 4-butanediol diglycidyl ether (BDDE) was added, and the mixture was stirred again and mixed well. Regulating the temperature of the water bath to 48 ℃, placing the gel into the water bath, and preserving the heat for 75 minutes. And taking out the gel after crosslinking, adding 3.5L of eluent, stirring at a low speed for swelling for 3 hours, removing the eluent, and scattering the swelled gel, wherein the size is about 0.5-2 cm. Continuing the second elution for 16h, adding 3.5L of eluent after the second elution is finished, adding 3.5L of eluent again for the third elution until the final weight of the gel is 0.62kg, stopping the elution, and taking 9h until the final concentration of the micro-crosslinked sodium hyaluronate is 8mg/ml. And (3) taking the dialyzed gel, and continuously homogenizing for 2 times by using a screen to obtain the gel with the particle diameter of 150-400 mu m. Taking 90g of gel, sterilizing under the conditions of 121 ℃ and F0=12 by moist heat, adding 10g of lubricant, stirring and mixing uniformly, and M Micro-crosslinked sodium hyaluronate ：M Lubricant =9:1, and finally a micro-crosslinked sodium hyaluronate gel containing recombinant type III human collagen was obtained, and filled into 1.0ml pre-filled syringes, sample No. E.
The finished products obtained in the above examples are inspected, the inspection indexes are the pushing force (27G disposable sterile injection needle), BDDE residues, particle size distribution, degradation performance, viscoelasticity modulus and other indexes, and the specific results are shown in the attached table:
table 1
Table 2:
from the above table, it can be concluded that the proportion of the crosslinking agent in the crosslinking process of sodium hyaluronate, the crosslinking reaction temperature, the dialysis end point (final product concentration) all have a great influence on the indexes of the final product, and directly influence the clinical use effect, wherein the push force (N), the viscoelastic modulus and the degradation performance (%) are particularly important, and the sample C process in example 3 is the preferred option by integrating the evaluation of each index.
Thus, we continued to use the process of example 3 with a configuration of lubricating fluids of varying concentrations of recombinant type III human collagen. The method comprises the following steps:
example 6
Preparing 20L of eluent (sodium chloride-containing, sodium dihydrogen phosphate, disodium hydrogen phosphate and water for injection) for later use.
Weighing 3.75g of recombinant type III human collagen raw material, adding 250ml of eluent for dissolution, and preparing the lubricant with the concentration of 15mg/ml for later use.
50ml of 1.0% strength sodium hydroxide solution was prepared, and 5g of a sodium hyaluronate raw material having a molecular weight of 150 ten thousand was added thereto and dissolved by stirring until no white undissolved HA was visible to the naked eye. After dissolution, 0.40ml of 1, 4-butanediol diglycidyl ether (BDDE) was added, and the mixture was stirred again and mixed well. Regulating the temperature of the water bath to 50 ℃, placing the gel into the water bath, and preserving the heat for 120min. And taking out the gel after crosslinking, adding 5L of eluent, stirring at a low speed for swelling for 3 hours, removing the eluent, and scattering the swelled gel, wherein the size is about 0.5-2 cm. Continuing the second elution for 16h, adding 5L of eluent after the second elution is completed, adding 5L of eluent again for the third elution until the final weight of the gel is 0.62kg, stopping the elution until the final weight of the gel reaches the end point of the elution, and using the solution for 6h to achieve the final concentration of the micro-crosslinked sodium hyaluronate8mg/ml. And (3) taking the dialyzed gel, and continuously homogenizing for 2 times by using a screen to obtain the gel with the particle diameter of 150-400 mu m. Taking 80g of gel, sterilizing under the conditions of 121 ℃ and F0=12 by moist heat, adding 20g of lubricant, stirring and mixing uniformly, and M Micro-crosslinked sodium hyaluronate ：M Lubricant And (2) obtaining the micro-crosslinked sodium hyaluronate gel containing the recombinant type III human collagen, filling the micro-crosslinked sodium hyaluronate gel into a 1.0ml pre-filling and sealing syringe, and obtaining a sample number F.
Example 7
Preparing 20L of eluent (sodium chloride-containing, sodium dihydrogen phosphate, disodium hydrogen phosphate and water for injection) for later use.
Weighing 6g of recombinant III type human collagen raw material, adding 250ml of eluent for dissolution, and preparing a lubricant with the concentration of 24mg/ml for later use.
50ml of 1.0% strength sodium hydroxide solution was prepared, and 5g of a sodium hyaluronate raw material having a molecular weight of 150 ten thousand was added thereto and dissolved by stirring until no white undissolved HA was visible to the naked eye. After dissolution, 0.40ml of 1, 4-butanediol diglycidyl ether (BDDE) was added, and the mixture was stirred again and mixed well. Regulating the temperature of the water bath to 50 ℃, placing the gel into the water bath, and preserving the heat for 120min. And taking out the gel after crosslinking, adding 5L of eluent, stirring at a low speed for swelling for 3 hours, removing the eluent, and scattering the swelled gel, wherein the size is about 0.5-2 cm. Continuing the second elution for 16h, adding 5L of eluent after the second elution is finished, and adding 5L of eluent again to perform the third elution until the final weight of the gel is 0.62kg, and stopping the elution until the final weight of the gel reaches the end point of the elution, wherein the final concentration of the micro-crosslinked sodium hyaluronate is 8mg/ml after 6 h. And (3) taking the dialyzed gel, and continuously homogenizing for 2 times by using a screen to obtain the gel with the particle diameter of 150-400 mu m. Taking 80g of gel, sterilizing under the conditions of 121 ℃ and F0=12 by moist heat, adding 20g of lubricant, stirring and mixing uniformly, and M Micro-crosslinked sodium hyaluronate ：M Lubricant And (2) obtaining the micro-crosslinked sodium hyaluronate gel containing the recombinant type III human collagen, filling the micro-crosslinked sodium hyaluronate gel into a 1.0ml pre-filling and sealing syringe, and obtaining a sample number G.
Comparative example 1
Preparing 20L of eluent (sodium chloride-containing, sodium dihydrogen phosphate, disodium hydrogen phosphate and water for injection) for later use.
Weighing 2.5g of recombinant type III human collagen raw material, adding 250ml of eluent for dissolution, and preparing the lubricant with the concentration of 10mg/ml for later use.
50ml of 1.0% strength sodium hydroxide solution was prepared, and 5g of a sodium hyaluronate raw material having a molecular weight of 150 ten thousand was added thereto and dissolved by stirring until no white undissolved HA was visible to the naked eye. After dissolution, 0.40ml of 1, 4-butanediol diglycidyl ether (BDDE) was added, and the mixture was stirred again and mixed well. Regulating the temperature of the water bath to 50 ℃, placing the gel into the water bath, and preserving the heat for 120min. And taking out the gel after crosslinking, adding 5L of eluent, stirring at a low speed for swelling for 3 hours, removing the eluent, and scattering the swelled gel, wherein the size is about 0.5-2 cm. Continuing the second elution for 16h, adding 5L of eluent after the second elution is finished, and adding 5L of eluent again to perform the third elution until the final weight of the gel is 0.62kg, and stopping the elution until the final weight of the gel reaches the end point of the elution, wherein the final concentration of the micro-crosslinked sodium hyaluronate is 8mg/ml after 6 h. And (3) taking the dialyzed gel, and continuously homogenizing for 2 times by using a screen to obtain the gel with the particle diameter of 150-400 mu m. Taking 80g of gel, sterilizing under the conditions of 121 ℃ and F0=12 by moist heat, adding 20g of lubricant, stirring and mixing uniformly, and M Micro-crosslinked sodium hyaluronate ：M Lubricant And (2) obtaining the micro-crosslinked sodium hyaluronate gel containing the recombinant type III human collagen, filling the micro-crosslinked sodium hyaluronate gel into a 1.0ml pre-filling and sealing syringe, and carrying out sample number H.
Comparative example 2
Preparing 20L of eluent (sodium chloride-containing, sodium dihydrogen phosphate, disodium hydrogen phosphate and water for injection) for later use.
7.5g of recombinant III-type humanized collagen raw material is weighed, 250ml of eluent is added for dissolution, and the lubricant with the concentration of 30mg/ml is prepared for standby.
50ml of 1.0% strength sodium hydroxide solution was prepared, and 5g of a sodium hyaluronate raw material having a molecular weight of 150 ten thousand was added thereto and dissolved by stirring until no white undissolved HA was visible to the naked eye. After dissolution, 0.40ml of 1, 4-butanediol diglycidyl ether (BDDE) was added, and the mixture was stirred again and mixed well. Regulating water bath temperature to 50deg.C, placing the above gel in water bathIn the process, the temperature is kept for 120min. And taking out the gel after crosslinking, adding 5L of eluent, stirring at a low speed for swelling for 3 hours, removing the eluent, and scattering the swelled gel, wherein the size is about 0.5-2 cm. Continuing the second elution for 16h, adding 5L of eluent after the second elution is finished, and adding 5L of eluent again to perform the third elution until the final weight of the gel is 0.62kg, and stopping the elution until the final weight of the gel reaches the end point of the elution, wherein the final concentration of the micro-crosslinked sodium hyaluronate is 8mg/ml after 6 h. And (3) taking the dialyzed gel, and continuously homogenizing for 2 times by using a screen to obtain the gel with the particle diameter of 150-400 mu m. Taking 80g of gel, sterilizing under the conditions of 121 ℃ and F0=12 by moist heat, adding 20g of lubricant, stirring and mixing uniformly, and M Micro-crosslinked sodium hyaluronate ：M Lubricant And (2) obtaining the micro-crosslinked sodium hyaluronate gel containing the recombinant type III human collagen, filling the micro-crosslinked sodium hyaluronate gel into a 1.0ml pre-filling and sealing syringe, and obtaining a sample number I.
The finished products obtained in the examples and the comparative examples are inspected, the inspection indexes are the indexes of pushing force (27G disposable sterile injection needle), viscoelasticity modulus and the like, and the specific results are shown in the attached table:
table 3
[ data analysis ]
From the data, when the concentration of the recombinant type III human collagen is 15-24 mg/ml, the pushing force of the product can be at a proper level (10-20N), so that the hand feeling in the injection process is better.
The above description of the embodiments is only intended to assist in understanding the method of the invention and its core ideas. It should be noted that it will be apparent to those skilled in the art that various modifications and adaptations of the invention can be made without departing from the principles of the invention and these modifications and adaptations are intended to be within the scope of the invention as defined in the following claims.
Claims (4)
1. A method for preparing a sodium hyaluronate gel filler, comprising the steps of:
(1) Dissolving: completely dissolving sodium hyaluronate raw material with sodium hydroxide solution;
(2) Crosslinking reaction: adding a cross-linking agent into the sodium hyaluronate dissolved in the step (1), uniformly mixing, and carrying out heat preservation in a water bath for cross-linking reaction to obtain micro-crosslinked sodium hyaluronate gel;
the mass ratio of the using amount of the cross-linking agent to the sodium hyaluronate raw material is 0.05-0.12;
(3) Preparing an eluent: preparing an eluent containing sodium chloride and a phosphate buffer system for later use;
(4) Preparing a lubricant: preparing a lubricating liquid containing recombinant type III human collagen, wherein other components of the lubricating agent comprise sodium chloride, disodium hydrogen phosphate and sodium dihydrogen phosphate; the concentration of the recombinant type III human collagen in the lubricant is 15-24 mg/ml;
(5) Eluting: eluting the micro-crosslinked gel prepared in the step (2) by using the eluent prepared in the step (3), dispersing the micro-crosslinked gel into particles with the size of 0.5-2 cm in the process, and simultaneously replacing the eluent until the micro-crosslinked sodium hyaluronate gel swells to the required weight;
(6) Homogenizing: homogenizing the micro-crosslinked sodium hyaluronate gel subjected to the dialysis in the step (5) to prepare particles with the particle diameter of 150-400 mu m;
(7) And (3) sterilization: carrying out wet heat sterilization on the micro-crosslinked sodium hyaluronate gel particles homogenized in the step (6) by pure steam to achieve a sterile state;
(8) Sterile mixing: mixing the homogenized micro-crosslinked sodium hyaluronate gel particles in the step (7) with the lubricant prepared in the step (4) according to a certain proportion; the mass ratio of the crosslinked sodium hyaluronate gel particles to the lubricating liquid is (1-10): 1, a step of;
(9) And (3) filling: uniformly mixing the micro-crosslinked sodium hyaluronate gel particles prepared in the step (8) with a lubricant containing recombinant type III human collagen to obtain the micro-crosslinked sodium hyaluronate gel containing recombinant type III human collagen, and filling the micro-crosslinked sodium hyaluronate gel into a pre-filling and sealing syringe.
2. Sodium hyaluronate gel filler, characterized in that it is prepared by the process according to claim 1,
comprises micro-crosslinked sodium hyaluronate gel particles; the method comprises the steps of,
the lubricating fluid containing the recombinant III type humanized collagen.
3. A sodium hyaluronate gel filler as set forth in claim 2, wherein,
the diameter of the micro-crosslinked sodium hyaluronate gel particles is 150-400 mu m.
4. Use of a sodium hyaluronate gel filler according to claim 2 or 3 for the preparation of a cosmetic filler material.
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Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4803075A (en) * | 1986-06-25 | 1989-02-07 | Collagen Corporation | Injectable implant composition having improved intrudability |
| CN103357066A (en) * | 2013-06-28 | 2013-10-23 | 陕西巨子生物技术有限公司 | Hydrogel with bioremediation activity and outstanding degradation performance and preparation method |
| WO2014039607A1 (en) * | 2012-09-06 | 2014-03-13 | Allergan, Inc. | Hyaluronic acid/collagen- based dermal filler compositions and methods for making same |
| CN103834053A (en) * | 2014-02-28 | 2014-06-04 | 陕西佰傲再生医学有限公司 | Injectable crosslinked hyaluronic acid gel and preparation method thereof |
| CN108395552A (en) * | 2017-12-15 | 2018-08-14 | 浙江景嘉医疗科技有限公司 | A kind of preparation method of single-phase cross-linking sodium hyaluronate gel |
| CN108774329A (en) * | 2018-06-13 | 2018-11-09 | 浙江景嘉医疗科技有限公司 | A kind of preparation method of medical cross-linking sodium hyaluronate gel |
| WO2021134084A1 (en) * | 2019-12-26 | 2021-07-01 | Allergan, Inc. | Physical mix ha-collagen dermal fillers |
| US11058640B1 (en) * | 2020-04-07 | 2021-07-13 | Amc Group, Llc | Hyaluronate compositions and soft tissue fillers |
| CN113549227A (en) * | 2021-06-15 | 2021-10-26 | 中芯生物科技(浙江)有限公司 | Chemical crosslinking hydrogel and microsphere thereof, preparation method and application |
| CN113842502A (en) * | 2021-09-29 | 2021-12-28 | 西安德诺海思医疗科技有限公司 | Injection filler containing deproteinized bone and preparation method thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20130116411A1 (en) * | 2011-09-06 | 2013-05-09 | Allergan, Inc. | Methods of making hyaluronic acid/collagen compositions |
| CN102863631B (en) * | 2012-09-29 | 2013-11-13 | 杭州嘉伟生物制品有限公司 | Cross-linked sodium hyaluronate gel for tissue filler for plastic surgery and method for preparing cross-linked sodium hyaluronate gel |
| US11801329B2 (en) * | 2018-05-03 | 2023-10-31 | Collplant Ltd. | Dermal fillers and applications thereof |
-
2022
- 2022-06-08 CN CN202210640406.0A patent/CN115154665B/en active Active
Patent Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4803075A (en) * | 1986-06-25 | 1989-02-07 | Collagen Corporation | Injectable implant composition having improved intrudability |
| WO2014039607A1 (en) * | 2012-09-06 | 2014-03-13 | Allergan, Inc. | Hyaluronic acid/collagen- based dermal filler compositions and methods for making same |
| CN103357066A (en) * | 2013-06-28 | 2013-10-23 | 陕西巨子生物技术有限公司 | Hydrogel with bioremediation activity and outstanding degradation performance and preparation method |
| CN103834053A (en) * | 2014-02-28 | 2014-06-04 | 陕西佰傲再生医学有限公司 | Injectable crosslinked hyaluronic acid gel and preparation method thereof |
| CN108395552A (en) * | 2017-12-15 | 2018-08-14 | 浙江景嘉医疗科技有限公司 | A kind of preparation method of single-phase cross-linking sodium hyaluronate gel |
| CN108774329A (en) * | 2018-06-13 | 2018-11-09 | 浙江景嘉医疗科技有限公司 | A kind of preparation method of medical cross-linking sodium hyaluronate gel |
| WO2021134084A1 (en) * | 2019-12-26 | 2021-07-01 | Allergan, Inc. | Physical mix ha-collagen dermal fillers |
| US11058640B1 (en) * | 2020-04-07 | 2021-07-13 | Amc Group, Llc | Hyaluronate compositions and soft tissue fillers |
| CN113549227A (en) * | 2021-06-15 | 2021-10-26 | 中芯生物科技(浙江)有限公司 | Chemical crosslinking hydrogel and microsphere thereof, preparation method and application |
| CN113842502A (en) * | 2021-09-29 | 2021-12-28 | 西安德诺海思医疗科技有限公司 | Injection filler containing deproteinized bone and preparation method thereof |
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