CN115154665A - Lubricating fluid containing recombinant type III human collagen, filler and application of lubricating fluid and filler - Google Patents
Lubricating fluid containing recombinant type III human collagen, filler and application of lubricating fluid and filler Download PDFInfo
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- CN115154665A CN115154665A CN202210640406.0A CN202210640406A CN115154665A CN 115154665 A CN115154665 A CN 115154665A CN 202210640406 A CN202210640406 A CN 202210640406A CN 115154665 A CN115154665 A CN 115154665A
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- sodium hyaluronate
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- 102000008186 Collagen Human genes 0.000 title claims abstract description 67
- 108010035532 Collagen Proteins 0.000 title claims abstract description 67
- 229920001436 collagen Polymers 0.000 title claims abstract description 67
- 230000001050 lubricating effect Effects 0.000 title claims abstract description 32
- 239000000945 filler Substances 0.000 title claims abstract description 12
- 239000012530 fluid Substances 0.000 title claims description 19
- 229920002385 Sodium hyaluronate Polymers 0.000 claims abstract description 101
- 229940010747 sodium hyaluronate Drugs 0.000 claims abstract description 101
- 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 101
- 238000011049 filling Methods 0.000 claims abstract description 19
- 239000007788 liquid Substances 0.000 claims abstract description 12
- 239000002537 cosmetic Substances 0.000 claims abstract description 3
- 239000000463 material Substances 0.000 claims abstract description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 31
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 30
- 238000004132 cross linking Methods 0.000 claims description 16
- 239000011780 sodium chloride Substances 0.000 claims description 14
- 239000008215 water for injection Substances 0.000 claims description 12
- 239000007863 gel particle Substances 0.000 claims description 9
- 239000007853 buffer solution Substances 0.000 claims description 6
- 239000008363 phosphate buffer Substances 0.000 claims description 2
- 239000000314 lubricant Substances 0.000 abstract description 35
- 238000002347 injection Methods 0.000 abstract description 15
- 239000007924 injection Substances 0.000 abstract description 15
- 238000002156 mixing Methods 0.000 abstract description 13
- 230000000694 effects Effects 0.000 abstract description 8
- 230000029663 wound healing Effects 0.000 abstract description 5
- 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 63
- 239000003480 eluent Substances 0.000 description 46
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
- 238000003756 stirring Methods 0.000 description 17
- 238000000034 method Methods 0.000 description 15
- 239000002245 particle Substances 0.000 description 14
- 230000001954 sterilising effect Effects 0.000 description 14
- 238000004090 dissolution Methods 0.000 description 13
- 239000002994 raw material Substances 0.000 description 13
- 238000004659 sterilization and disinfection Methods 0.000 description 13
- SHKUUQIDMUMQQK-UHFFFAOYSA-N 2-[4-(oxiran-2-ylmethoxy)butoxymethyl]oxirane Chemical compound C1OC1COCCCCOCC1CO1 SHKUUQIDMUMQQK-UHFFFAOYSA-N 0.000 description 11
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 11
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 11
- 235000019799 monosodium phosphate Nutrition 0.000 description 11
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 239000000203 mixture Substances 0.000 description 10
- 230000008569 process Effects 0.000 description 10
- 230000008961 swelling Effects 0.000 description 10
- 238000005303 weighing Methods 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 9
- 238000001125 extrusion Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 210000001519 tissue Anatomy 0.000 description 7
- 102000001187 Collagen Type III Human genes 0.000 description 6
- 108010069502 Collagen Type III Proteins 0.000 description 6
- 230000008439 repair process Effects 0.000 description 6
- 239000003431 cross linking reagent Substances 0.000 description 5
- 238000000855 fermentation Methods 0.000 description 5
- 230000004151 fermentation Effects 0.000 description 5
- 229940071643 prefilled syringe Drugs 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 230000002500 effect on skin Effects 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 238000000502 dialysis 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
- 239000012467 final product Substances 0.000 description 2
- 208000014674 injury Diseases 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
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 208000028990 Skin injury Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000000605 extraction 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
- 239000008187 granular material Substances 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 238000007689 inspection Methods 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
- 238000004321 preservation Methods 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
- 238000000926 separation method Methods 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 239000012475 sodium chloride buffer Substances 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- 238000012414 sterilization procedure Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 238000012360 testing method Methods 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 lubricating liquid containing recombinant III-type human collagen, a filling agent and application thereof, wherein the sodium hyaluronate gel lubricating liquid contains the recombinant III-type human collagen. The invention obtains the micro-crosslinked sodium hyaluronate gel containing the recombinant III-type human collagen by mixing the micro-crosslinked sodium hyaluronate gel with the lubricant of the recombinant III-type human collagen tissue. Because the final finished product has proper rheology and low viscoelasticity, the recombinant III type human collagen with high bioactivity can effectively improve the skin regeneration speed and shorten the wound healing time while playing the effects of micro-crosslinked sodium hyaluronate gel injection filling and repairing the appearance and correcting the contour to achieve the satisfactory effect, 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 lubricating fluid containing recombinant III type human collagen, a filling agent and application thereof.
Background
The preparation method of the conventional crosslinked sodium hyaluronate gel mainly comprises the following steps: weighing, dissolving, crosslinking, swelling (eluting), dialyzing, sieving (crushing), filling and sterilizing, wherein the rheological property of the finally formed gel has larger difference due to the difference of the sodium hyaluronate along with the crosslinking reaction conditions and the type of the selected crosslinking agent, the gel is generally in a hard granular state, and the crosslinked sodium hyaluronate gel granules and the lubricant are generally used together for facilitating smooth injection in the clinical use process. And typically the major component of the lubricant during selection is uncrosslinked sodium hyaluronate.
However, during the injection filling of the cross-linked sodium hyaluronate gel, it is possible to trigger a protective reaction of the host, thereby causing damage to the connective tissue at the injection site. Therefore, the problem that how to repair the external injury generated in the injection process, effectively improve the skin regeneration speed and shorten the wound healing time is needed to be solved in the field while the micro-crosslinked sodium hyaluronate gel injection filling and the dermal tissue are exerted to repair the appearance and correct the contour so as to achieve the satisfactory effect.
Disclosure of Invention
The invention provides a lubricating liquid containing recombinant III type human collagen, a filling agent and application thereof, aiming at overcoming the problem that the crosslinked sodium hyaluronate gel cannot be quickly repaired to cause the injury of human tissues in the injection process in the prior art.
In order to realize the purpose 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 fluid contains recombinant III-type human collagen.
Some studies have shown that in normal skin tissue, collagen exists mainly in the form of collagen fibers of types I and III. Among them, type iii collagen is closely related to the process of skin injury repair and the quality of repair, and generally, the higher the content of type iii collagen, the stronger the ability of repairing skin tissues. The skin of normal infants contains 60% of type III collagen, and the type III collagen decreases and the type I collagen increases along with the growth and development. Therefore, increasing the collagen type iii content in the sodium hyaluronate gel injection site is of great help to shorten the wound healing time.
The difference between the invention and the prior art is that the lubricating substance selected in the sodium hyaluronate gel lubricating fluid is not conventional non-crosslinked sodium hyaluronate but recombined III type human collagen. Compared with non-crosslinked sodium hyaluronate, the Recombinant Human Collagen (Reallagen), also known as RHC (Recombinant Human-source Collagen), is a high molecular biological protein produced by high-density fermentation of microorganisms (such as active yeast) and a green separation and purification process according to the structural characteristics of Human Collagen by using advanced bioscience technology and international advanced fermentation technology, and is highly similar to the Human Collagen. Therefore, the invention can effectively supplement type III collagen in skin by adding the recombinant type III human collagen into the lubricating fluid.
Therefore, after the lubricating fluid containing the recombinant III type human collagen is compounded with the sodium hyaluronate gel particles, the micro-crosslinked sodium hyaluronate gel can be injected and filled with dermal tissues to repair the appearance and correct the contour so as to achieve a satisfactory effect, the skin regeneration speed can be effectively increased, the wound healing time can be shortened, the skin barrier function can be recovered, and the product quality can be improved
Preferably, the recombinant type III human collagen is obtained by dissolving the recombinant type III human collagen in a buffer solution.
The lubricating liquid containing the recombinant III-type human collagen is simple in preparation method, and can be obtained by dissolving the recombinant III-type human collagen in a buffer solution according to a certain amount, so that subsequent use and operation are simplified.
Preferably, the buffer solution comprises sodium chloride, a phosphate buffer system and water for injection.
Preferably, the buffer solution contains 0.7% -1.0% of sodium chloride, 0.56% of disodium hydrogen phosphate, 0.04% of sodium dihydrogen phosphate and water for injection.
Preferably, the concentration of the recombinant type III human collagen in the lubricating liquid is 15 to 24mg/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 human collagen is lower than 15mg/ml, the skin repairing effect is not obvious through actual tests, and meanwhile, the extrusion force of the lubricating liquid is at a lower value and no injection hand feeling is caused;
when the concentration of the recombinant type III human collagen is higher than 24mg/ml, the extrusion force in the injection process is greatly improved, the injection is not facilitated, and the product cost is greatly improved.
When the concentration of the recombinant type III human collagen is 15 to 24mg/ml, the repairing effect on the skin and the extrusion force during injection can be considered, and the extrusion force of the product can be kept at a proper level (10 to 20N), so that the hand feeling during injection is better.
A sodium hyaluronate gel filler is prepared from sodium hyaluronate,
comprises cross-linked sodium hyaluronate gel particles; and the number of the first and second groups,
the lubricating fluid containing the recombinant type III human collagen as described above.
Preferably, the preparation method of the sodium hyaluronate gel filler comprises the following steps:
(1) Dissolving: dissolving sodium hyaluronate in sodium hydroxide solution;
(2) And (3) 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 carrying out a cross-linking reaction to obtain micro-cross-linked sodium hyaluronate gel;
(3) Preparing an eluent: preparing an eluent containing a sodium chloride and phosphate buffer system for later use;
(4) Preparing a lubricant: preparing lubricating liquid containing recombinant III-type human collagen, wherein other components of the lubricating liquid comprise sodium chloride, disodium hydrogen phosphate and sodium dihydrogen phosphate;
(5) And (3) elution: eluting the micro-crosslinked gel obtained 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 to 2cm in the process, and simultaneously replacing the eluent until the micro-crosslinked sodium hyaluronate gel is swelled to the required weight;
(6) Homogenizing: homogenizing the micro-crosslinked sodium hyaluronate gel obtained by dialysis in the step (5) to prepare particles with the particle diameter of 150-400 microns;
(7) And (3) sterilization: carrying out moist-heat sterilization on the micro-crosslinked sodium hyaluronate gel particles homogenized in the step (6) by adopting pure steam to reach an aseptic state;
(8) Aseptic mixing: mixing the micro-crosslinked sodium hyaluronate gel particles homogenized in the step (7) with the lubricant prepared in the step (4) according to a certain proportion;
(9) Filling: and (3) uniformly mixing the micro-crosslinked sodium hyaluronate gel particles prepared in the step (8) with a lubricant containing the recombinant III type human collagen to obtain the micro-crosslinked sodium hyaluronate gel containing the recombinant III type human collagen, and filling the micro-crosslinked sodium hyaluronate gel into a pre-filled and sealed syringe.
Preferably, in the step (1), the sodium hyaluronate raw material is prepared by a fermentation method or an extraction method, and has a molecular weight of 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 holding time is 60-150min.
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 to 24mg/ml.
Preferably, the mass of the eluent is 50 to 80 times of the mass of the gel after crosslinking is finished.
Preferably, in the elution step, the first elution time is 2 to 4 hours, and the total elution times are 3 to 6.
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 homogenization is 150 to 400 μm.
Preferably, in the step (6), the micro-crosslinked sodium hyaluronate gel is homogenized for 2 to 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, reaction conditions are designed, the crosslinking reaction degree of HA and BDDE is controlled, sodium hyaluronate gel with low crosslinking degree is obtained, sterile micro-crosslinked sodium hyaluronate gel is obtained through a homogenization-sterilization procedure, and the sterile micro-crosslinked sodium hyaluronate gel is mixed with a lubricant of a recombinant III type human collagen tissue, so that micro-crosslinked sodium hyaluronate gel containing recombinant III type human collagen is obtained. Because the final finished product has proper rheology and low viscoelasticity, the recombinant III-type human collagen with high biological activity can effectively improve the skin regeneration speed and shorten the wound healing time while playing the roles of micro-crosslinked sodium hyaluronate gel injection filling and dermal tissue to repair the appearance and correct the contour so as to achieve the satisfactory effect, thereby recovering the skin barrier function and improving the product quality.
Detailed Description
The invention is further described with reference to specific examples. Those skilled in the art will be able to implement the invention based on these teachings. Furthermore, the embodiments of the present invention described in the following description are generally only a part of the embodiments of the present invention, and not all of the embodiments. Therefore, all other embodiments obtained by a person of ordinary skill in the art based on the embodiments of the present invention without any creative effort shall fall within the protection scope of the present invention.
Description of the preferred embodiment
1: the sodium hyaluronate raw material selected in the following examples is produced by a fermentation method and is the same batch.
2: the crosslinker used in the following examples is 1, 4-butanediol diglycidyl ether (BDDE)
3: examples are not limited to fermentation-prepared feedstocks, but are also illustrative of the effectiveness and versatility of the invention in extraction-prepared feedstocks.
3: the recombinant type III human collagen raw material selected in the following examples is freeze-dried sponge produced by fermentation method, and is the same batch.
Example 1
20L of eluent (containing sodium chloride, sodium dihydrogen phosphate, disodium hydrogen phosphate and water for injection) is prepared for standby.
Weighing 5g of recombinant III type human collagen raw material, adding 250ml of eluent for dissolution, and preparing the lubricant with the concentration of 20mg/ml for later use.
50ml of sodium hydroxide solution with the concentration of 1.2 percent is prepared, 5g of sodium hyaluronate with the molecular weight of 180 ten thousand is added, stirred and dissolved until no white undissolved HA can be seen by naked eyes. After dissolution, 0.35ml of 1, 4-butanediol diglycidyl ether (BDDE) was added, and the mixture was stirred and mixed again. Adjusting the temperature of the water bath to 48 ℃, placing the gel in the water bath, and keeping the temperature for 90min. And taking out the crosslinked gel, adding 3.5L of eluent, stirring at a low speed for swelling for 3h, removing the eluent, and scattering the swollen gel with the size of about 0.5-2cm. Continuing to perform second elution for 16h with 3.5L of eluent, adding 3.5L of eluent again after the second elution is completed, performing third elution until the final weight of gel is 1kg, stopping elution, and using the gelAnd 6h, the final concentration of the micro-crosslinked sodium hyaluronate is 5mg/ml. And (3) taking the dialyzed gel, and continuously homogenizing for 2 times by using a screen to prepare the gel with the particle diameter of 150 to 400 mu m. Taking 90g of gel, carrying out moist heat sterilization under the conditions of 121 ℃ and F0=12, adding 10g of lubricant, stirring and mixing uniformly, and M Micro-crosslinked sodium hyaluronate ：M Lubricant agent =9, finally obtaining micro-crosslinked sodium hyaluronate gel containing recombinant type III human collagen, and filling the micro-crosslinked sodium hyaluronate gel into a 1.0ml pre-filled and sealed syringe, wherein the sample is numbered A.
Example 2
20L of eluent (containing sodium chloride, sodium dihydrogen phosphate, disodium hydrogen phosphate and water for injection) is prepared for standby.
Weighing 5g of recombinant III type human collagen raw material, adding 250ml of eluent for dissolution, and preparing the lubricant with the concentration of 20mg/ml for later use.
50ml of 1.2 percent sodium hydroxide solution is prepared, 5g of sodium hyaluronate with the molecular weight of 230 ten thousand is added, stirred and dissolved until no white undissolved HA is visible to the naked eye. After dissolution, 0.60ml of 1, 4-butanediol diglycidyl ether (BDDE) was added, and the mixture was stirred and mixed again. Adjusting the temperature of the water bath to 55 ℃, placing the gel in the water bath, and keeping the temperature for 60min. And taking out the crosslinked gel, adding 5L of eluent, stirring at a low speed for swelling for 3h, removing the eluent, and scattering the swollen gel with the size of about 0.5 to 2cm. And continuing to perform secondary elution for 16 hours, wherein the elution amount is 5L, and after the secondary elution is completed, adding 5L of elution amount again to perform tertiary elution until the final weight of the gel is 1kg, and stopping elution when the final weight of the gel reaches the elution end point, wherein the time is 10 hours, and the final concentration of the micro-crosslinked sodium hyaluronate is 5mg/ml. And (3) taking the dialyzed gel, and continuously homogenizing for 2 times by using a screen to prepare the gel with the particle diameter of 150 to 400 mu m. Taking 80g of gel, performing moist heat sterilization at 121 ℃ under the condition of F0=12, adding 20g of lubricant, stirring and mixing uniformly, and M Micro-crosslinked sodium hyaluronate ：M Lubricant agent =8, finally obtaining the micro-crosslinked sodium hyaluronate gel containing the recombinant type III human collagen, and filling the micro-crosslinked sodium hyaluronate gel into a 1.0ml pre-filled and sealed syringe, wherein the sample is numbered B.
Example 3
20L of eluent (containing sodium chloride, sodium dihydrogen phosphate, disodium hydrogen phosphate and water for injection) is prepared for standby.
Weighing 5g of recombinant III type human collagen raw material, adding 250ml of eluent for dissolution, and preparing the lubricant with the concentration of 20mg/ml for later use.
50ml of 1.0% sodium hydroxide solution is prepared, 5g of sodium hyaluronate with the molecular weight of 150 ten thousand is added, stirred and dissolved until no white undissolved HA is 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. Adjusting the temperature of the water bath to 50 ℃, placing the gel in the water bath, and keeping the temperature 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 swollen gel with the size of about 0.5 to 2cm. And continuing to perform secondary elution for 16 hours, wherein the elution amount is 5L, and after the secondary elution is completed, adding 5L of elution amount again to perform tertiary elution until the final weight of the gel is 0.62kg, and stopping elution when the final weight of the gel reaches the elution end point, wherein the final concentration of the micro-crosslinked sodium hyaluronate is 8mg/ml after the gel is used for 6 hours. And (3) taking the dialyzed gel, and continuously homogenizing for 2 times by using a screen to prepare the gel with the particle diameter of 150 to 400 mu m. Taking 80g of gel, performing moist heat sterilization at 121 ℃ under the condition of F0=12, adding 20g of lubricant, stirring and mixing uniformly, and M Micro-crosslinked sodium hyaluronate ：M Lubricant agent And =8, finally obtaining micro-crosslinked sodium hyaluronate gel containing recombinant type III human collagen, and filling the micro-crosslinked sodium hyaluronate gel into a 1.0ml pre-filled syringe with the sample number C.
Example 4
20L of eluent (containing sodium chloride, sodium dihydrogen phosphate, disodium hydrogen phosphate and water for injection) is prepared for standby.
Weighing 5g of recombinant type III human collagen raw material, adding 250ml of eluent for dissolving, and preparing into 20mg/ml lubricant for later use.
50ml of 1.0% sodium hydroxide solution is prepared, 5g of sodium hyaluronate with the molecular weight of 150 ten thousand is added, stirred and dissolved until no white undissolved HA is 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. Adjusting the temperature of the water bath to 50 deg.C, and standing the gelPreserving the temperature for 120min in a water bath. 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 swollen gel with the size of about 0.5 to 2cm. And continuing to perform secondary elution for 16 hours, wherein the elution amount is 5L, and after the secondary elution is completed, adding 5L of elution amount again to perform tertiary elution until the final weight of the gel is 0.62kg, stopping elution when the final weight of the gel reaches the elution end point, and after the final weight of the gel is used for 6 hours, 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 prepare the gel with the particle diameter of 150 to 400 mu m. Taking 60g of gel, carrying out moist heat sterilization under the conditions of 121 ℃ and F0=12, adding 40g of lubricant, stirring and mixing uniformly, and M Micro-crosslinked sodium hyaluronate ：M Lubricant agent And (4), finally obtaining micro-crosslinked sodium hyaluronate gel containing the recombinant type III human collagen, and filling the micro-crosslinked sodium hyaluronate gel into a 1.0ml pre-filled and sealed syringe, wherein the sample number is D.
Example 5
20L of eluent (containing sodium chloride, sodium dihydrogen phosphate, disodium hydrogen phosphate and water for injection) is prepared for standby.
Weighing 5g of recombinant type III human collagen raw material, adding 250ml of eluent for dissolving, and preparing into 20mg/ml lubricant for later use.
50ml of sodium hydroxide solution with the concentration of 1.2 percent is prepared, 5g of sodium hyaluronate with the molecular weight of 200 ten thousand is added, stirred and dissolved until no white undissolved HA can be seen by naked eyes. After dissolution, 0.48ml of 1, 4-butanediol diglycidyl ether (BDDE) was added, and the mixture was stirred again and mixed. Adjusting the temperature of the water bath to 48 ℃, putting the gel in the water bath, and keeping the temperature for 75min. 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 swollen gel with the size of about 0.5 to 2cm. And continuing to perform secondary elution for 16 hours, wherein the elution amount is 3.5L, adding 3.5L of elution amount again after the secondary elution is completed, performing tertiary elution until the final weight of the gel is 0.62kg, stopping elution when the final weight of the gel reaches the elution end point, and performing elution for 9 hours 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 prepare the gel with the particle diameter of 150 to 400 mu m. Collecting 90g of gel, and adopting 1After moist heat sterilization at 21 ℃ and F0=12, 10g of lubricant is added, stirred and mixed uniformly, M Micro-crosslinked sodium hyaluronate ：M Lubricant agent =9, finally obtaining micro-crosslinked sodium hyaluronate gel containing the recombinant type III human collagen, and filling the micro-crosslinked sodium hyaluronate gel into a 1.0ml pre-filled and sealed syringe, wherein the sample is numbered E.
The finished products obtained in the above examples are inspected, the indexes are extrusion force (27G disposable sterile syringe needle), BDDE residue, particle size distribution, degradation performance, viscoelasticity modulus and the like, and the specific results are shown in the attached table:
attached table 1
Attached table 2:
from the above table, it can be concluded that the ratio of the cross-linking agent, the cross-linking reaction temperature, and the dialysis endpoint (final product concentration) during the cross-linking process of the sodium hyaluronate all have great influence on the indexes of the final product, and directly influence the clinical use effect, wherein the extrusion force (N), the viscoelastic modulus, and the degradation performance (%) are particularly important, and the process of sample C in example 3 is an optimal choice by integrating the evaluation of each index.
Therefore, we continued to use the process of example 3, with lubricating fluids of different concentrations of recombinant type III human collagen. The method comprises the following specific steps:
example 6
20L of eluent (containing sodium chloride, sodium dihydrogen phosphate, disodium hydrogen phosphate and water for injection) was prepared and used.
Weighing 3.75g of recombinant III type human collagen raw material, adding 250ml of eluent for dissolution, and preparing into a lubricant with the concentration of 15mg/ml for later use.
50ml of 1.0% sodium hydroxide solution is prepared, 5g of sodium hyaluronate with the molecular weight of 150 ten thousand is added, stirred and dissolved until no white undissolved HA is visible to the naked eye. SolutionAfter decomposition, 0.40ml of 1, 4-butanediol diglycidyl ether (BDDE) was added, and the mixture was stirred and mixed again. Adjusting the temperature of the water bath to 50 ℃, placing the gel in the water bath, and keeping the temperature for 120min. And taking out the crosslinked gel, adding 5L of eluent, stirring at a low speed for swelling for 3h, removing the eluent, and scattering the swollen gel with the size of about 0.5 to 2cm. And continuing to perform secondary elution for 16 hours, wherein the elution amount is 5L, and after the secondary elution is completed, adding 5L of elution amount again to perform tertiary elution until the final weight of the gel is 0.62kg, and stopping elution when the final weight of the gel reaches the elution end point, wherein the final concentration of the micro-crosslinked sodium hyaluronate is 8mg/ml after the gel is used for 6 hours. And (3) taking the dialyzed gel, and continuously homogenizing for 2 times by using a screen to prepare the gel with the particle diameter of 150 to 400 mu m. Taking 80g of gel, carrying out moist heat sterilization under the conditions of 121 ℃ and F0=12, adding 20g of lubricant, stirring and mixing uniformly, and M Micro-crosslinked sodium hyaluronate ：M Lubricant agent =8, finally obtaining micro-crosslinked sodium hyaluronate gel containing recombinant type III human collagen, and filling the micro-crosslinked sodium hyaluronate gel into a 1.0ml pre-filled syringe, wherein the sample is numbered F.
Example 7
20L of eluent (containing sodium chloride, sodium dihydrogen phosphate, disodium hydrogen phosphate and water for injection) is prepared for standby.
Weighing 6g of recombinant III type human collagen raw material, adding 250ml of eluent for dissolution, and preparing into 24mg/ml lubricant for later use.
50ml of 1.0% sodium hydroxide solution is prepared, 5g of sodium hyaluronate with the molecular weight of 150 ten thousand is added, stirred and dissolved until no white undissolved HA is visible to the naked eye. After dissolution, 0.40ml of 1, 4-butanediol diglycidyl ether (BDDE) was added, and the mixture was stirred and mixed again. Adjusting the temperature of the water bath to 50 ℃, putting the gel in the water bath, and keeping the temperature for 120min. And taking out the crosslinked gel, adding 5L of eluent, stirring at a low speed for swelling for 3h, removing the eluent, and scattering the swollen gel with the size of about 0.5 to 2cm. Continuing to perform second elution for 16h with 5L of eluent, adding 5L of eluent again after the second elution is completed to perform third elution until the final weight of the gel is 0.62kg, stopping elution when the final weight of the gel reaches the end point, and performing micro-crosslinking on the sodium hyaluronate for 6hIt was 8mg/ml. And (3) taking the dialyzed gel, and continuously homogenizing for 2 times by using a screen to prepare the gel with the particle diameter of 150 to 400 mu m. Taking 80g of gel, carrying out moist heat sterilization under the conditions of 121 ℃ and F0=12, adding 20g of lubricant, stirring and mixing uniformly, and M Micro-crosslinked sodium hyaluronate ：M Lubricant agent And =8, finally obtaining micro-crosslinked sodium hyaluronate gel containing recombinant type III human collagen, and filling the micro-crosslinked sodium hyaluronate gel into a 1.0ml pre-filled syringe with the sample number G.
Comparative example 1
20L of eluent (containing sodium chloride, sodium dihydrogen phosphate, disodium hydrogen phosphate and water for injection) is prepared for standby.
Weighing 2.5g of recombinant type III human collagen raw material, adding 250ml of eluent for dissolving, and preparing into a lubricant with the concentration of 10mg/ml for later use.
50ml of 1.0% sodium hydroxide solution is prepared, 5g of sodium hyaluronate with the molecular weight of 150 ten thousand is added, stirred and dissolved until no white undissolved HA is visible to the naked eye. After dissolution, 0.40ml of 1, 4-butanediol diglycidyl ether (BDDE) was added, and the mixture was stirred and mixed again. Adjusting the temperature of the water bath to 50 ℃, placing the gel in the water bath, and keeping the temperature for 120min. And taking out the crosslinked gel, adding 5L of eluent, stirring at a low speed for swelling for 3h, removing the eluent, and scattering the swollen gel with the size of about 0.5 to 2cm. And continuing to perform secondary elution for 16 hours, wherein the elution amount is 5L, and after the secondary elution is completed, adding 5L of elution amount again to perform tertiary elution until the final weight of the gel is 0.62kg, and stopping elution when the final weight of the gel reaches the elution end point, wherein the final concentration of the micro-crosslinked sodium hyaluronate is 8mg/ml after the gel is used for 6 hours. And (3) taking the dialyzed gel, and continuously homogenizing for 2 times by using a screen to prepare the gel with the particle diameter of 150 to 400 mu m. Taking 80g of gel, carrying out moist heat sterilization under the conditions of 121 ℃ and F0=12, adding 20g of lubricant, stirring and mixing uniformly, and M Micro-crosslinked sodium hyaluronate ：M Lubricant agent And =8, finally obtaining micro-crosslinked sodium hyaluronate gel containing recombinant type III human collagen, and filling the micro-crosslinked sodium hyaluronate gel into a 1.0ml pre-filled syringe with the sample number H.
Comparative example 2
20L of eluent (containing sodium chloride, sodium dihydrogen phosphate, disodium hydrogen phosphate and water for injection) is prepared for standby.
Weighing 7.5g of recombinant type III human collagen raw material, adding 250ml of eluent for dissolving, and preparing the lubricant with the concentration of 30mg/ml for later use.
50ml of 1.0% sodium hydroxide solution is prepared, 5g of sodium hyaluronate with the molecular weight of 150 ten thousand is added, stirred and dissolved until no white undissolved HA is 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. Adjusting the temperature of the water bath to 50 ℃, placing the gel in the water bath, and keeping the temperature for 120min. And taking out the crosslinked gel, adding 5L of eluent, stirring at a low speed for swelling for 3h, removing the eluent, and scattering the swollen gel with the size of about 0.5 to 2cm. And continuing to perform secondary elution for 16 hours, wherein the elution amount is 5L, and after the secondary elution is completed, adding 5L of elution amount again to perform tertiary elution until the final weight of the gel is 0.62kg, and stopping elution when the final weight of the gel reaches the elution end point, wherein the final concentration of the micro-crosslinked sodium hyaluronate is 8mg/ml after the gel is used for 6 hours. And (3) taking the dialyzed gel, and continuously homogenizing for 2 times by using a screen to prepare the gel with the particle diameter of 150 to 400 mu m. Taking 80g of gel, performing moist heat sterilization at 121 ℃ under the condition of F0=12, adding 20g of lubricant, stirring and mixing uniformly, and M Micro-crosslinked sodium hyaluronate ：M Lubricant agent And =8, finally obtaining micro-crosslinked sodium hyaluronate gel containing recombinant type III human collagen, and filling the micro-crosslinked sodium hyaluronate gel into a 1.0ml pre-filled syringe, wherein the sample is numbered I.
The finished products obtained in the above examples and comparative examples are inspected, and the inspection indexes are extrusion force (27G disposable sterile syringe needle), viscoelasticity modulus and the like, and the specific results are shown in the attached table:
attached table 3
[ data analysis ]
From the data, when the concentration of the recombinant type III human collagen is 15 to 24mg/ml, the extrusion force of the product can be in a proper level (10 to 20N), so that the hand feeling in the injection process is better.
The above description of the embodiments is only intended to facilitate the understanding of the method of the invention and its core ideas. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention.
Claims (8)
1. A lubricating fluid containing recombinant type III human collagen is characterized in that,
the sodium hyaluronate gel lubricating fluid contains recombinant III-type human collagen.
2. The lubricating fluid containing recombinant type III human collagen according to claim 1,
the recombinant III-type human collagen is obtained by dissolving recombinant III-type human collagen in a buffer solution.
3. The lubricating fluid containing recombinant type III human collagen according to claim 2,
the buffer solution contains sodium chloride, a phosphate buffer system and water for injection.
4. The lubricating fluid containing recombinant type III human collagen according to claim 1, 2 or 3,
the concentration of the recombinant type III human collagen in the lubricating liquid is 15 to 24mg/ml.
5. A sodium hyaluronate gel filler is characterized in that,
comprises crosslinked sodium hyaluronate gel particles; and the number of the first and second groups,
the lubricating fluid containing recombinant type III human-derived collagen according to any one of claims 1 to 4.
6. The sodium hyaluronate gel filler of claim 5, wherein,
the mass ratio of the crosslinked sodium hyaluronate gel particles to the lubricating liquid is (1 to 10): 1.
7. the sodium hyaluronate gel filler according to claim 5 or 6,
the diameter of the crosslinked sodium hyaluronate gel particles is 150 to 400 mu m.
8. The use of the lubricating fluid for crosslinking sodium hyaluronate gel according to any one of claims 1 to 4 or the sodium hyaluronate gel filler according to any one of claims 5 to 7 in cosmetic filling materials.
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