CN114668890A - Mixed gel containing calcium carbonate microspheres for injection and preparation method thereof - Google Patents
Mixed gel containing calcium carbonate microspheres for injection and preparation method thereof Download PDFInfo
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- CN114668890A CN114668890A CN202210313651.0A CN202210313651A CN114668890A CN 114668890 A CN114668890 A CN 114668890A CN 202210313651 A CN202210313651 A CN 202210313651A CN 114668890 A CN114668890 A CN 114668890A
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- gel
- calcium carbonate
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- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 title claims abstract description 232
- 229910000019 calcium carbonate Inorganic materials 0.000 title claims abstract description 116
- 239000004005 microsphere Substances 0.000 title claims abstract description 111
- 238000002347 injection Methods 0.000 title claims abstract description 35
- 239000007924 injection Substances 0.000 title claims abstract description 35
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims abstract description 70
- 229920002674 hyaluronan Polymers 0.000 claims abstract description 70
- 229960003160 hyaluronic acid Drugs 0.000 claims abstract description 70
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 28
- 239000012266 salt solution Substances 0.000 claims abstract description 6
- 239000002158 endotoxin Substances 0.000 claims abstract description 4
- 241000894006 Bacteria Species 0.000 claims abstract description 3
- 239000000499 gel Substances 0.000 claims description 125
- 238000003756 stirring Methods 0.000 claims description 52
- 238000006243 chemical reaction Methods 0.000 claims description 44
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 36
- 239000000243 solution Substances 0.000 claims description 25
- 238000005406 washing Methods 0.000 claims description 21
- 230000003204 osmotic effect Effects 0.000 claims description 15
- 239000008055 phosphate buffer solution Substances 0.000 claims description 15
- 230000001954 sterilising effect Effects 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 12
- 238000002156 mixing Methods 0.000 claims description 12
- 239000002245 particle Substances 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 11
- SHKUUQIDMUMQQK-UHFFFAOYSA-N 2-[4-(oxiran-2-ylmethoxy)butoxymethyl]oxirane Chemical compound C1OC1COCCCCOCC1CO1 SHKUUQIDMUMQQK-UHFFFAOYSA-N 0.000 claims description 10
- 239000007853 buffer solution Substances 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 9
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 8
- 150000001413 amino acids Chemical class 0.000 claims description 8
- 239000003431 cross linking reagent Substances 0.000 claims description 7
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 claims description 6
- 229910001424 calcium ion Inorganic materials 0.000 claims description 6
- 239000003589 local anesthetic agent Substances 0.000 claims description 6
- 150000004676 glycans Chemical class 0.000 claims description 5
- 150000002632 lipids Chemical class 0.000 claims description 5
- 229920001184 polypeptide Polymers 0.000 claims description 5
- 229920001282 polysaccharide Polymers 0.000 claims description 5
- 239000005017 polysaccharide Substances 0.000 claims description 5
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 5
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 5
- 239000002994 raw material Substances 0.000 claims description 5
- 239000011782 vitamin Substances 0.000 claims description 5
- 229940088594 vitamin Drugs 0.000 claims description 5
- 229930003231 vitamin Natural products 0.000 claims description 5
- 235000013343 vitamin Nutrition 0.000 claims description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- 239000008215 water for injection Substances 0.000 claims description 4
- AFOSIXZFDONLBT-UHFFFAOYSA-N divinyl sulfone Chemical compound C=CS(=O)(=O)C=C AFOSIXZFDONLBT-UHFFFAOYSA-N 0.000 claims description 3
- 229920005862 polyol Polymers 0.000 claims description 3
- 150000003077 polyols Chemical class 0.000 claims description 3
- 108090000623 proteins and genes Proteins 0.000 claims description 3
- 102000004169 proteins and genes Human genes 0.000 claims description 3
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 2
- PTHCMJGKKRQCBF-UHFFFAOYSA-N Cellulose, microcrystalline Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC)C(CO)O1 PTHCMJGKKRQCBF-UHFFFAOYSA-N 0.000 claims description 2
- 229920001661 Chitosan Polymers 0.000 claims description 2
- 108010010803 Gelatin Proteins 0.000 claims description 2
- 239000006173 Good's buffer Substances 0.000 claims description 2
- 229920005654 Sephadex Polymers 0.000 claims description 2
- 239000008351 acetate buffer Substances 0.000 claims description 2
- 239000007979 citrate buffer Substances 0.000 claims description 2
- 239000000512 collagen gel Substances 0.000 claims description 2
- 239000013078 crystal Substances 0.000 claims description 2
- 239000008273 gelatin Substances 0.000 claims description 2
- 229920000159 gelatin Polymers 0.000 claims description 2
- 235000019322 gelatine Nutrition 0.000 claims description 2
- 235000011852 gelatine desserts Nutrition 0.000 claims description 2
- 229960005015 local anesthetics Drugs 0.000 claims description 2
- 239000000661 sodium alginate Substances 0.000 claims description 2
- 235000010413 sodium alginate Nutrition 0.000 claims description 2
- 229940005550 sodium alginate Drugs 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- 150000005846 sugar alcohols Polymers 0.000 claims description 2
- 150000003722 vitamin derivatives Chemical class 0.000 claims description 2
- 230000007935 neutral effect Effects 0.000 abstract description 7
- 229920000642 polymer Polymers 0.000 description 15
- 238000011049 filling Methods 0.000 description 13
- 229940071643 prefilled syringe Drugs 0.000 description 9
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 229920000747 poly(lactic acid) Polymers 0.000 description 7
- 239000004626 polylactic acid Substances 0.000 description 7
- 206010040954 Skin wrinkling Diseases 0.000 description 6
- 230000015556 catabolic process Effects 0.000 description 6
- 238000006731 degradation reaction Methods 0.000 description 6
- 230000037303 wrinkles Effects 0.000 description 5
- 239000000945 filler Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 102000008186 Collagen Human genes 0.000 description 3
- 108010035532 Collagen Proteins 0.000 description 3
- 229920001436 collagen Polymers 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 238000005054 agglomeration Methods 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000003796 beauty Effects 0.000 description 2
- 230000037319 collagen production Effects 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 229910021532 Calcite Inorganic materials 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 235000019738 Limestone Nutrition 0.000 description 1
- 206010040925 Skin striae Diseases 0.000 description 1
- 229920002385 Sodium hyaluronate Polymers 0.000 description 1
- 208000031439 Striae Distensae Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000000476 body water Anatomy 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000005482 chemotactic factor Substances 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229920006237 degradable polymer Polymers 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 230000001815 facial effect Effects 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 210000001061 forehead Anatomy 0.000 description 1
- 230000009477 glass transition Effects 0.000 description 1
- 125000003827 glycol group Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000006028 limestone Substances 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 210000000651 myofibroblast Anatomy 0.000 description 1
- 206010033675 panniculitis Diseases 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229920001610 polycaprolactone Polymers 0.000 description 1
- 239000004632 polycaprolactone Substances 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000001172 regenerating effect Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 229940010747 sodium hyaluronate Drugs 0.000 description 1
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 210000004304 subcutaneous tissue Anatomy 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 238000009827 uniform distribution Methods 0.000 description 1
Images
Classifications
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- 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
- A61L27/02—Inorganic materials
- A61L27/025—Other specific inorganic materials not covered by A61L27/04 - A61L27/12
-
- 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
- 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 belongs to the technical field of medical and American products, and particularly relates to a mixed gel containing calcium carbonate microspheres for injection and a preparation method thereof, wherein the mixed gel comprises the following components: calcium carbonate microspheres and a salt solution containing a gel; wherein the calcium carbonate microspheres are uniformly distributed within the crosslinked gel; the invention creatively mixes the calcium carbonate microspheres with the gel to prepare the mixed gel containing the calcium carbonate microspheres for injection, firstly, the calcium carbonate microspheres can remove bacteria and endotoxin by adopting a high-temperature dry baking mode, and the calcium carbonate microspheres can not be decomposed after the dry baking; in addition, after the calcium carbonate microspheres and the hyaluronic acid gel are mixed, the pH is neutral or alkaline, the calcium carbonate microspheres can stably exist in a neutral water phase environment, are not decomposed, and can be stored for a long time.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a mixed gel containing calcium carbonate microspheres for injection and a preparation method thereof.
Background
In recent years, with the rise of the internet and the economic value of the face, the public acceptance of medical and beauty is gradually increased, and the demand group is expanded from middle-aged women to young beauty-seeking group, and the demand for beauty is also diversified. The injectable gel in the medical and aesthetic fields is developed rapidly, and the injectable gel can realize the cosmetic effect in a minimally invasive treatment mode, so that the injectable gel is widely concerned.
The hyaluronic acid gel filling injection products on the market at present can be divided into short-acting hyaluronic acid and long-acting hyaluronic acid, the short-acting hyaluronic acid injection products are generally metabolized and completed within 2 to 3 months, the injection frequency is high, the long-acting hyaluronic acid can be maintained for 6 months, and even so, the hyaluronic acid gel is difficult to realize the medium-and-long-term beautifying effect. With the development of regenerative medical and aesthetic injection products, fillers containing polymers are continuously marketed, after the polymers are injected into a body, the polymers can stimulate the immune response of a host, attract a large number of subcutaneous macrophages and other immune cells, so as to generate chemotactic factors and cytokines, cause the proliferation of fibroblasts and the differentiation of myofibroblasts thereof, gradually increase the content of synthesized collagen, and possibly achieve long-acting filling effects of different degrees according to different degradation rates of the polymers. However, the polymer filler is still mainly in the form of freeze-dried powder, and the poor hydrophilicity and the in-vivo and in-vitro agglomeration phenomenon of the polymer filler make the polymer unsuitable for being mixed with hyaluronic acid gel.
Chinese patent ZL201410438010.3 discloses a polylactic acid microsphere and cross-linked hyaluronic acid mixed gel for injection and a preparation method thereof, because the polylactic acid microsphere has strong hydrophobicity, it is not easy to disperse in the aqueous environment in human body, and easy to agglomerate, and it is difficult to realize uniform distribution of the microsphere when mixed with hyaluronic acid gel.
Chinese patent ZL201510593332.X discloses hyaluronic acid mixed gel containing amphiphilic microspheres for injection and a preparation method thereof, amphiphilic polyethylene glycol groups are introduced to polylactic acid molecules, the hydrophilicity of the polylactic acid microspheres is improved, a copolymer of polylactic acid and polyethylene glycol with amphipathy is prepared, and the copolymer is mixed with hyaluronic acid gel to form a pre-filled syringe type product, however, the potential degradation problem exists in the aqueous gel of the polymer, and in addition, the influence of the glass transition problem of the polylactic acid is considered, and the physical properties of the microspheres can be changed by high-temperature high-pressure sterilization.
Disclosure of Invention
The invention provides a mixed gel containing calcium carbonate microspheres for injection and a preparation method thereof.
In order to solve the above technical problems, the present invention provides a mixed gel for injection, comprising: calcium carbonate microspheres and a salt solution containing a gel; wherein the calcium carbonate microspheres are uniformly distributed in the gel through a cross-linking agent.
In a second aspect, the present invention also provides a method for preparing a mixed gel for injection, comprising the following steps: step S1, heating and stirring the solution containing free calcium ions, adding the solution containing free carbonate ions, continuously stirring for reaction, and washing and filtering to obtain calcium carbonate microspheres; step S2, dissolving the gel raw material in water for injection containing sodium hydroxide, adding a cross-linking agent, heating and stirring, adjusting the pH to 6.0-8.0, and adjusting the osmotic pressure to 200-400 mOsm/L to obtain gel; and step S3, mixing the calcium carbonate microspheres and the gel, uniformly stirring, sterilizing by adopting high-pressure steam, and centrifuging to remove bubbles to obtain the mixed gel for injection, wherein the pH is 6.0-8.0, and the osmotic pressure is 200-400 mOsm/L.
In a third aspect, the invention also provides an application of the calcium carbonate microspheres in mixed gel for injection.
The invention has the beneficial effects that the calcium carbonate microspheres are creatively mixed with the gel to prepare the mixed gel containing the calcium carbonate microspheres for injection, firstly, the calcium carbonate microspheres can remove bacteria and endotoxin by adopting a high-temperature dry baking mode, the calcium carbonate microspheres cannot be decomposed after the dry baking, and the existing polymer microspheres cannot bear the high temperature of 150-300 ℃; in addition, after the calcium carbonate microspheres and the hyaluronic acid gel are mixed, the pH is neutral, the calcium carbonate microspheres can stably exist in a neutral water phase environment, are not decomposed, and are uniformly distributed under the coordination of a cross-linking agent, most of the existing products are polymer microspheres which can be hydrolyzed in the presence of water and gradually degraded into oligomers or small molecules, so that the inside of a gel product containing the polymers can be degraded in the product storage process, and the mixed gel product containing the calcium carbonate microspheres can be stably stored for a long time.
Additional features and advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.
In order to make the aforementioned and other objects, features and advantages of the present invention comprehensible, preferred embodiments accompanied with figures are described in detail below.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without creative efforts.
Fig. 1 is a distribution diagram of calcium carbonate microspheres prepared in example 1 of the present invention in a hyaluronic acid gel;
FIG. 2 is a comparison of the morphology of calcium carbonate microspheres prepared in example 2 of the present invention before and after high temperature dry baking;
fig. 3 is a hyaluronic acid gel product containing calcium carbonate microspheres of example 3 of the present invention.
Fig. 4 shows that the hyaluronic acid gel product containing calcium carbonate microspheres of example 1 of the present invention is effective in stimulating collagen production after being injected subcutaneously into rats.
Detailed Description
To make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings, and it is apparent that the described embodiments are some, but not all embodiments of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
In order to prepare a skin wrinkle correction product which is stable in storage and can be filled for a long time, the invention mixes the calcium carbonate microspheres and the cross-linked hyaluronic acid gel to prepare an injectable gel product so as to solve the defects of the prior art.
The invention provides a mixed gel for injection, which comprises the following components: calcium carbonate microspheres and a salt solution containing a gel; wherein the calcium carbonate microspheres are uniformly distributed within the crosslinked gel.
Wherein, optionally, the calcium carbonate microspheres include: one or more of heavy calcium carbonate, light calcium carbonate, colloidal calcium carbonate and crystal calcium carbonate; the average particle size of the calcium carbonate microspheres is 1-200 mu m, and the mass ratio of the calcium carbonate microspheres in the mixed gel is 0.1-50%.
Optionally, the gel comprises: one or more of hyaluronic acid gel, collagen gel, cellulose gel, sodium alginate gel, dextran gel, chitosan gel, amino acid gel, and gelatin; the molecular weight of the gel is 20000-3000000, preferably 1500000-3000000, and the mass fraction of the gel is 0.1-50%.
Optionally, the salt solution comprises: one or more of sodium chloride solution, phosphate buffer solution, carbonate buffer solution, citrate buffer solution, acetate buffer solution, Good's buffer solution.
Optionally, the cross-linking agent comprises: 1, 4-butanediol diglycidyl ether and divinyl sulfone.
Optionally, the mixed gel further comprises one or more of amino acids, polypeptides, proteins, polysaccharides, polyols, vitamins, lipids, and local anesthetics; wherein the content of the amino acid is 0-15 mg/mL, preferably 0.1-2 mg/mL; the content of the polypeptide is 0-20 mg/mL, preferably 0.1-5 mg/mL; the protein content is 0-10 mg/mL, preferably 0.1-2 mg/mL; the polysaccharide content is 0-30 mg/mL, preferably 5-10 mg/mL; the content of the polyhydric alcohol is 0-40 mg/mL, preferably 0.1-10 mg/mL; the content of the vitamin is 0-60 mug/mL, preferably 0.1-10 mug/mL; the lipid content is 0-20 mg/mL, preferably 0.1-5 mg/mL; the content of the local anesthetic is 0 to 10mg/mL, preferably 0.1 to 5 mg/mL.
Further, the invention also provides a preparation method of the mixed gel for injection, which comprises the following steps: step S1, heating and stirring the solution containing free calcium ions, adding the solution containing free carbonate ions, continuously stirring for reaction, and washing and filtering to obtain calcium carbonate microspheres; step S2, dissolving the gel raw material in water for injection containing sodium hydroxide, adding a cross-linking agent, heating and stirring, adjusting the pH to 6.0-8.0, and adjusting the osmotic pressure to 200-400 mOsm/L to obtain gel; and step S3, mixing the calcium carbonate microspheres and the gel, uniformly stirring, sterilizing by adopting high-pressure steam, and centrifuging to remove bubbles to obtain the mixed gel for injection, wherein the pH is 6.0-8.0, and the osmotic pressure is 200-400 mOsm/L.
Specifically, in the step S1, adding the solution containing the free calcium ions into a container, heating and stirring at the temperature of 25-95 ℃ and the stirring speed of 100-1000 rpm; adding the solution containing free carbonate ions into a container, and stirring for reacting for 1-60 minutes; washing and filtering to obtain the calcium carbonate microspheres.
Optionally, the preparation method of the calcium carbonate microspheres can also be one of the following methods: (A) stirring the solution containing free calcium ions and the solution containing free carbonate ions for reaction; (B) stirring and reacting the carbonic acid solution and calcium hydroxide; (C) producing calcium carbonate microspheres by using limestone as a raw material; (D) the calcium carbonate microspheres are obtained by using natural Baishi ore or calcite containing more than 90% of calcium carbonate as a raw material and performing coarse crushing, fine crushing and sieving.
Specifically, a solution containing free calcium ions and a solution containing free carbonate ions are stirred for reaction, filtered and then subjected to high-temperature dry baking sterilization at the temperature of 200-300 ℃. The preparation method of the cross-linked sodium hyaluronate gel comprises the following steps: dissolving hyaluronic acid in water for injection containing sodium hydroxide, stirring for dissolving, adding 1, 4-butanediol diglycidyl ether, heating and stirring to obtain hyaluronic acid gel, adjusting the pH to 6.0-7.5, fully washing with PBS (phosphate buffer solution), and adjusting the osmotic pressure to 200-400 mOsm/L to obtain the final hyaluronic acid gel. Adding calcium carbonate microspheres into the crosslinked hyaluronic acid gel, stirring for 1-72 hours at 100-1000 rpm until the calcium carbonate microspheres are uniformly mixed, sterilizing for 10-35 minutes by high-pressure steam at 110-125 ℃, and filling into a pre-filled syringe to obtain the hyaluronic acid mixed gel containing the calcium carbonate microspheres.
Further, the invention also provides application of the calcium carbonate microspheres in mixed gel for injection.
In particular, the application of removing wrinkles may include, but is not limited to: facial wrinkles, french lines, herringbone lines, crow's feet, periocular lines, perioral lines, neck lines, forehead lines, nose lines, hand wrinkles, and stretch marks.
Example 1
(1) Adding the calcium chloride solution into a beaker, stirring at the speed of 600rpm at 60 ℃, adding the potassium carbonate solution under the stirring state after the temperature of a reaction system reaches 60 ℃, reacting for 60 minutes, obtaining light calcium carbonate with a target particle size of 25-45 microns by adopting a filtering method after the reaction is finished, fully washing with water, fully removing the water by using absolute ethyl alcohol, placing into a dry oven, drying for 120 minutes at 250 ℃, and cooling to room temperature after the reaction is finished to obtain the calcium carbonate microspheres.
(2) Dissolving hyaluronic acid with the molecular weight of 20000 in an aqueous solution for sodium hydroxide injection, adding 1, 4-butanediol diglycidyl ether, stirring for reaction, washing with a PBS buffer solution after the reaction is finished, adjusting the pH to 6.5-7.5, and adjusting the osmotic pressure to 200-400 mOsm/L to obtain the hyaluronic acid gel.
(3) And adding the prepared calcium carbonate microspheres into hyaluronic acid gel, wherein the mass ratio of the calcium carbonate microspheres is 1%, the mass ratio of the hyaluronic acid gel is 50%, adding 15mg/mL of amino acid, stirring and mixing uniformly at 500rpm, filling into a pre-filled syringe in an aseptic manner, and sterilizing with high-pressure steam at 110 ℃ for 35min to obtain the hyaluronic acid mixed gel containing the calcium carbonate microspheres.
As shown in figure 1, calcium carbonate microspheres are uniformly distributed in hyaluronic acid without agglomeration, and uniformly dispersed mixed gel is obtained.
Example 2
(1) Adding the calcium chloride solution into a beaker, stirring at the speed of 1000rpm at 25 ℃, adding the potassium carbonate solution under a stirring state after the temperature of a reaction system reaches 25 ℃, reacting for 60 minutes, obtaining light calcium carbonate with a target particle size of 1-10 microns by adopting a filtering method after the reaction is finished, fully washing with water, fully removing the water by using absolute ethyl alcohol, placing into a dry oven, drying for 180 minutes at 150 ℃, and cooling to room temperature after the reaction is finished to obtain the calcium carbonate microspheres.
As shown in fig. 2, the appearance of the calcium carbonate microspheres after high-temperature dry baking has no significant change, i.e., no decomposition occurs, and the physical properties after high-temperature dry baking are not affected.
(2) Dissolving hyaluronic acid with the molecular weight of 1000000 in a sodium hydroxide water solution for injection, adding 1, 4-butanediol diglycidyl ether, stirring for reaction, washing with a PBS buffer solution after the reaction is finished, adjusting the pH to 6.5-7.5, and adjusting the osmotic pressure to 200-400 mOsm/L to obtain the hyaluronic acid gel.
(3) And adding the prepared calcium carbonate microspheres into hyaluronic acid gel, wherein the mass ratio of the calcium carbonate microspheres is 50%, the mass ratio of the hyaluronic acid gel is 10%, adding vitamins with the content of 60 mu g/mL, stirring and mixing uniformly at 600rpm, filling into a pre-filled syringe in an aseptic manner, and sterilizing with high-pressure steam at 130 ℃ for 10min to obtain the hyaluronic acid mixed gel containing the calcium carbonate microspheres.
Example 3
(1) Adding the calcium chloride solution into a beaker, stirring at the speed of 100rpm at 95 ℃, adding the potassium carbonate solution under the stirring state after the temperature of a reaction system reaches 95 ℃, reacting for 30 minutes, obtaining heavy calcium carbonate with a target particle size of 25-60 mu m by adopting a filtration method after the reaction is finished, fully washing with water, fully removing the water by using absolute ethyl alcohol, placing into a dry oven, drying for 1 minute at 300 ℃, and cooling to room temperature after the reaction is finished to obtain the calcium carbonate microspheres.
(2) Dissolving hyaluronic acid with the molecular weight of 3000000 in an aqueous solution for sodium hydroxide injection, adding divinyl sulfone, stirring for reaction, washing with a PBS (phosphate buffer solution) after the reaction is finished, adjusting the pH to 6.5-7.5, and adjusting the osmotic pressure to 200-400 mOsm/L to obtain the hyaluronic acid gel.
(3) And (2) adding the prepared calcium carbonate microspheres into hyaluronic acid gel, wherein the mass ratio of the calcium carbonate microspheres is 0.1%, the mass ratio of the hyaluronic acid gel is 40%, adding protein, the content of which is 10mg/mL, stirring and mixing uniformly under the condition of 800rpm, filling the mixture into a pre-filling and sealing injector in an aseptic manner, and sterilizing the mixture by using high-pressure steam at 120 ℃ for 15min to obtain the hyaluronic acid mixed gel containing the calcium carbonate microspheres shown in the figure 3.
Example 4
(1) Adding the calcium chloride solution into a beaker, stirring at the speed of 500rpm at 70 ℃, adding the potassium carbonate solution under the stirring state after the temperature of a reaction system reaches 70 ℃, reacting for 45 minutes, obtaining heavy calcium carbonate with a target particle size of 150-200 mu m by adopting a filtration method after the reaction is finished, fully washing with water, fully removing the water by using absolute ethyl alcohol, placing into a dry oven, drying for 40 minutes at 180 ℃, and cooling to room temperature after the reaction is finished to obtain the calcium carbonate microspheres.
(2) Dissolving hyaluronic acid with the molecular weight of 1500000 in an aqueous solution for sodium hydroxide injection, adding 1, 4-butanediol diglycidyl ether, stirring for reaction, washing with a PBS buffer solution after the reaction is finished, adjusting the pH to 6.5-8.0, and adjusting the osmotic pressure to 200-400 mOsm/L to obtain the hyaluronic acid gel.
(3) And (2) adding the prepared calcium carbonate microspheres into hyaluronic acid gel, wherein the mass ratio of the calcium carbonate microspheres is 5%, the mass ratio of the hyaluronic acid gel is 45%, adding a local anesthetic with the content of 10mg/mL, stirring and mixing uniformly at 700rpm, filling into a pre-filled syringe in an aseptic manner, and sterilizing for 20min by using high-pressure steam at 125 ℃ to obtain the hyaluronic acid mixed gel containing the calcium carbonate microspheres.
Example 5
(1) Adding the calcium chloride solution into a beaker, stirring at the speed of 600rpm at the temperature of 65 ℃, adding the potassium carbonate solution in a stirring state after the temperature of a reaction system reaches 65 ℃, reacting for 35 minutes, filtering after the reaction is finished to obtain colloidal calcium carbonate with a target particle size, wherein the average particle size is 30-55 mu m, fully washing with water, fully removing the water with absolute ethyl alcohol, placing into a dry oven, drying at 210 ℃ for 70 minutes, and cooling to room temperature after the reaction is finished to obtain the calcium carbonate microspheres.
(2) Dissolving hyaluronic acid with the molecular weight of 1800000 in an aqueous solution for sodium hydroxide injection, adding 1, 4-butanediol diglycidyl ether, stirring for reaction, washing with a PBS (phosphate buffer solution) buffer solution after the reaction is finished, adjusting the pH to 6.0-7.0, and adjusting the osmotic pressure to 200-400 mOsm/L to obtain the hyaluronic acid gel.
(3) And adding the prepared calcium carbonate microspheres into hyaluronic acid gel, wherein the mass ratio of the calcium carbonate microspheres is 10%, the mass ratio of the hyaluronic acid gel is 50%, adding lipid with the content of 20mg/mL, adding polyol with the content of 40mg/mL, stirring and mixing uniformly under the condition of 500rpm, filling into a pre-filled syringe in an aseptic manner, and sterilizing for 30min by using high-pressure steam at the temperature of 110 ℃ to obtain the hyaluronic acid mixed gel containing the calcium carbonate microspheres.
Example 6
(1) Adding the calcium chloride solution into a beaker, stirring at the speed of 600rpm at the temperature of 65 ℃, adding the potassium carbonate solution in a stirring state after the temperature of a reaction system reaches 65 ℃, reacting for 30 minutes, obtaining light calcium carbonate with a target particle size of 40-65 mu m by adopting a filtering method after the reaction is finished, fully washing with water, fully removing the water by using absolute ethyl alcohol, placing into a dry oven, drying for 60 minutes at the temperature of 250 ℃, and cooling to room temperature after the reaction is finished to obtain the calcium carbonate microspheres.
(2) Dissolving hyaluronic acid with the molecular weight of 2500000 in an aqueous solution for sodium hydroxide injection, adding 1, 4-butanediol diglycidyl ether, stirring for reaction, washing with a PBS (phosphate buffer solution) buffer solution after the reaction is finished, adjusting the pH to 6.5-7.5, and adjusting the osmotic pressure to 200-400 mOsm/L to obtain the hyaluronic acid gel.
(3) And adding the prepared calcium carbonate microspheres into hyaluronic acid gel, wherein the mass ratio of the calcium carbonate microspheres is 50%, the mass ratio of the hyaluronic acid gel is 0.1%, adding polypeptide with the content of 20mg/mL, adding polysaccharide with the content of 30mg/mL, stirring and mixing uniformly under the condition of 500rpm, filling into a pre-filled syringe in an aseptic manner, and sterilizing for 30min by using high-pressure steam at the temperature of 110 ℃ to obtain the hyaluronic acid mixed gel containing the calcium carbonate microspheres.
Example 7
(1) Adding the calcium chloride solution into a beaker, stirring at the speed of 750rpm at 40 ℃, adding the potassium carbonate solution under a stirring state after the temperature of a reaction system reaches 40 ℃, reacting for 25 minutes, obtaining light calcium carbonate with a target particle size of 35-60 microns by adopting a filtering method after the reaction is finished, fully washing with water, fully removing the water by using absolute ethyl alcohol, placing into a dry oven, baking at 230 ℃ for 48 minutes, and cooling to room temperature after the reaction is finished to obtain the calcium carbonate microspheres.
(2) Dissolving hyaluronic acid with molecular weight of 2800000 in an aqueous solution for sodium hydroxide injection, adding 1, 4-butanediol diglycidyl ether, stirring for reaction, washing with a PBS buffer solution after the reaction is finished, adjusting the pH to 6.5-7.5, and adjusting the osmotic pressure to 200-400 mOsm/L to obtain the hyaluronic acid gel.
(3) And adding the prepared calcium carbonate microspheres into hyaluronic acid gel, wherein the mass ratio of the calcium carbonate microspheres is 2.5%, and the mass ratio of the hyaluronic acid gel is 15%, stirring and mixing uniformly under the condition of 500rpm, filling the mixture into a pre-filled syringe in an aseptic manner, and sterilizing the mixture for 30min by using high-pressure steam at the temperature of 115 ℃ to obtain the hyaluronic acid mixed gel containing the calcium carbonate microspheres.
Example 8
(1) Adding the calcium chloride solution into a beaker, stirring at the speed of 350rpm at 80 ℃, adding the potassium carbonate solution under a stirring state after the temperature of a reaction system reaches 80 ℃, reacting for 1 minute, obtaining crystalline calcium carbonate with a target particle size, wherein the average particle size is 2-10 mu m, fully washing with water, fully removing the water with absolute ethyl alcohol, placing into a dry oven, drying at 250 ℃ for 70 minutes, and cooling to room temperature after the reaction is finished to obtain the calcium carbonate microspheres.
(2) Dissolving hyaluronic acid with molecular weight of 1400000 in an aqueous solution for sodium hydroxide injection, adding 1, 4-butanediol diglycidyl ether, stirring for reaction, washing with a PBS buffer solution after the reaction is finished, adjusting the pH to 6.5-7.5, and adjusting the osmotic pressure to 200-400 mOsm/L to obtain the hyaluronic acid gel.
(3) And adding the prepared calcium carbonate microspheres into hyaluronic acid gel, wherein the mass ratio of the calcium carbonate microspheres is 3%, the mass ratio of the hyaluronic acid gel is 25%, adding 10mg/mL of amino acid, adding a local anesthetic with the content of 5mg/mL, stirring and mixing uniformly at 600rpm, filling into a pre-filled syringe in an aseptic manner, and sterilizing for 25min by using high-pressure steam at 120 ℃ to obtain the hyaluronic acid mixed gel containing the calcium carbonate microspheres.
As shown in fig. 4, after the hyaluronic acid gel product containing calcium carbonate microspheres of example 1 was injected into the subcutaneous tissues of rats, a large number of swirl-like collagen structures appeared, and it was found that the stimulation of collagen production was achieved after the injection of the product of the present invention.
In summary, the calcium carbonate microspheres are mixed with the hyaluronic acid gel, the calcium carbonate microspheres can stably exist under neutral or alkaline conditions, and can not be decomposed, so that the potential degradation problem of the existing degradable polymer microspheres in the aqueous phase gel is avoided, and theoretically, the degradation of the polymer microspheres in the aqueous phase environment is hydrolysis, such as the breakdown of ester groups of polymer materials such as polylactic acid, polycaprolactone and the like in water, the polymers are gradually degraded into oligomers and finally become small molecules, so that the degradation process can be triggered as long as the polymer microspheres contact with water, the existing polymer microsphere products can not be avoided in the storage process, however, the calcium carbonate microsphere mixed gel in the invention can fundamentally solve the problem, the calcium carbonate can stably exist under neutral and alkaline water environments, and can be decomposed only under acidic water environments, the pH of the mixed gel product containing the calcium carbonate microspheres is neutral or slightly alkaline, so that the decomposition of the microspheres cannot happen when the mixed gel product is stored under a sealed condition, and the calcium carbonate microspheres can be gradually decomposed by a local acidic environment generated by an organism only after the mixed gel product is injected into a human body.
The calcium carbonate microspheres can bear high-temperature dry baking, the appearance is not obviously changed before and after heating, and endotoxin can be more conveniently removed; the calcium carbonate microspheres can be uniformly distributed in the gel, and are not easy to agglomerate and agglomerate in human body water environment after being injected into a human body. After the hyaluronic acid gel containing the calcium carbonate microspheres provided by the invention is injected into skin as a filler, the production of collagen of a human body can be stimulated, the depressed and aged skin becomes more elastic, and the hyaluronic acid gel has a natural effect, an obvious curative effect and a lasting effect in a treatment process and can realize a high-quality filling effect. The hyaluronic acid mixed gel containing the calcium carbonate microspheres is uniform, fine, sterile, pyrogen-free, high in viscoelasticity and easy to inject, contains no irritation to skin, has biological safety, and has an obvious wrinkle eliminating effect; the preparation method provided by the invention has the advantages of few process conditions and operation steps, controllable influence factors and stable product quality, can be stored for a long time, and does not have potential degradation or decomposition risks.
In light of the foregoing description of the preferred embodiment of the present invention, many modifications and variations will be apparent to those skilled in the art without departing from the spirit and scope of the invention. The technical scope of the present invention is not limited to the content of the specification, and must be determined according to the scope of the claims.
Claims (9)
1. A hybrid gel for injection, comprising:
calcium carbonate microspheres and a salt solution containing a gel; wherein
The calcium carbonate microspheres are uniformly distributed in the crosslinked gel.
2. The hybrid gel of claim 1,
the calcium carbonate microspheres comprise: one or more of heavy calcium carbonate, light calcium carbonate, colloidal calcium carbonate and crystal calcium carbonate;
the average particle size of the calcium carbonate microspheres is 1-200 mu m, and the mass ratio of the calcium carbonate microspheres in the mixed gel is 0.1-50%.
3. The hybrid gel of claim 1,
the gel comprises: one or more of hyaluronic acid gel, collagen gel, cellulose gel, sodium alginate gel, dextran gel, chitosan gel, amino acid gel, and gelatin;
the molecular weight of the gel is 20000-3000000, and the mass fraction of the gel is 0.1-50%.
4. The hybrid gel of claim 1,
the salt solution comprises: one or more of sodium chloride solution, phosphate buffer solution, carbonate buffer solution, citrate buffer solution, acetate buffer solution, Good's buffer solution.
5. The hybrid gel of claim 1,
the crosslinking agent comprises: 1, 4-butanediol diglycidyl ether and divinyl sulfone.
6. The hybrid gel of claim 1,
the mixed gel further comprises one or more of amino acids, polypeptides, proteins, polysaccharides, polyols, vitamins, lipids, local anesthetics; wherein
The content of amino acid is 0-15 mg/mL;
the content of the polypeptide is 0-20 mg/mL;
the protein content is 0-10 mg/mL;
the content of polysaccharide is 0-30 mg/mL;
the content of the polyhydric alcohol is 0-40 mg/mL;
the content of the vitamin is 0-60 mug/mL;
the lipid content is 0-20 mg/mL;
the content of the local anesthetic is 0-10 mg/mL.
7. The preparation method of the mixed gel for injection is characterized by comprising the following steps:
step S1, heating and stirring the solution containing free calcium ions, adding the solution containing free carbonate ions, continuously stirring for reaction, and washing and filtering to obtain calcium carbonate microspheres;
step S2, dissolving the gel raw material in water for injection containing sodium hydroxide, adding a cross-linking agent, heating and stirring, adjusting the pH to 6.0-8.0, and adjusting the osmotic pressure to 200-400 mOsm/L to obtain gel;
and step S3, mixing the calcium carbonate microspheres and the gel, uniformly stirring, sterilizing by adopting high-pressure steam, and centrifuging to remove bubbles to obtain the mixed gel for injection, wherein the pH is 6.0-8.0, and the osmotic pressure is 200-400 mOsm/L.
8. The method for preparing a mixed gel for injection according to claim 7,
before mixing the calcium carbonate microspheres and the gel in the step S3, bacteria and endotoxin can be removed by adopting a high-temperature dry baking method, wherein the temperature is 150-300 ℃, and the dry baking time is 1-180 minutes.
9. An application of calcium carbonate microspheres in mixed gel for injection.
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