CN114146221A - Injectable dextran hydrogel microsphere filling agent and preparation method thereof - Google Patents

Injectable dextran hydrogel microsphere filling agent and preparation method thereof Download PDF

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CN114146221A
CN114146221A CN202111503230.6A CN202111503230A CN114146221A CN 114146221 A CN114146221 A CN 114146221A CN 202111503230 A CN202111503230 A CN 202111503230A CN 114146221 A CN114146221 A CN 114146221A
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dextran
injectable
dextran hydrogel
hydrogel microsphere
solution
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傅荣强
杜滨阳
董顺妮
吴黎明
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Hangzhou Palera Medical Technology Co ltd
Zhejiang University ZJU
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Hangzhou Palera Medical Technology Co ltd
Zhejiang University ZJU
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    • 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
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    • 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
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    • A61L2430/34—Materials or treatment for tissue regeneration for soft tissue reconstruction

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Abstract

The application relates to an injectable dextran hydrogel microsphere filling agent and a preparation method thereof, wherein the preparation method of the injectable dextran hydrogel microsphere filling agent comprises the steps of carrying out chemical modification on dextran to obtain polymerizable dextran, further carrying out cross-linking through a polymerization reaction to prepare dextran hydrogel microspheres, and finally mixing the dextran hydrogel microspheres with an injection water solution uniformly and fully swelling to obtain the injectable dextran hydrogel microsphere filling agent. The application also comprises the injectable dextran hydrogel microsphere filling agent prepared by the preparation method of the injectable dextran hydrogel microsphere filling agent. The preparation method of the injectable dextran hydrogel microsphere disclosed by the application has the advantages of simple preparation method, mild conditions and less residual cross-linking agent, is suitable for large-scale production, and the obtained injectable dextran hydrogel microsphere filling agent can realize long-acting filling and is suitable for various human soft tissue filling occasions.

Description

Injectable dextran hydrogel microsphere filling agent and preparation method thereof
Technical Field
The application relates to an injectable dextran hydrogel microsphere filling agent and a preparation method thereof, which are mainly suitable for long-acting and safe filling and medical cosmetology of soft tissue parts such as face, nose, lips and the like.
Background
Injection cosmetics are a means of reducing skin laxity or shaping by injecting a filler into the dermis or beneath the skin. The cosmetic filler mainly includes a water filler represented by sodium hyaluronate, a high molecular polymer, and a non-water filler represented by a tissue material. Hyaluronic acid has high water content, is natural in implanted touch but cannot be fixed and is basically absorbed within 6 months, and needs to be injected repeatedly; on the contrary, non-moisture fillers such as polylactic acid can be fixed through tissue reaction, but biocompatibility is poor, and needs a large amount of carrier supports, and the filling effect is poor and difficult to get rid of, and later stage safety risk is high. At present, cross-linked hyaluronic acid gel is mainly used in the cosmetic filling market, the cross-linked hyaluronic acid gel generally reacts with a cross-linking agent under an alkaline condition to form gel, and then gel fillers with different specifications and sizes are prepared by mechanical crushing and sieving, so that the problems of non-uniform cross-linking degree, irregular particle shapes and the like exist, and the cross-linked hyaluronic acid gel is used for cosmetic filling and is easy to cause inflammatory reaction and thrombus.
Dextran, also known as dextran, is a bacterial polysaccharide containing a large number of free hydroxyl groups and has been used as a plasma substitute for a long time to date, and compared with hyaluronic acid products, dextran has better biological safety and stability, is an ideal tissue filling material, and does not cause a thrombus risk. The problem of irregular particle shapes can be effectively solved by preparing the dextran hydrogel microspheres, and the smooth hydrogel microspheres without edges and corners can avoid side reactions such as red swelling and the like; compared with the body gel filling, the hydrogel microspheres are wrapped by macrophages after entering subcutaneous tissues, and the fibroblasts are stimulated to generate collagen tissues, so that the long-acting filling of the depressed parts is realized.
CN105348548A discloses a preparation method of dextran hydrogel microspheres, which comprises the steps of carrying out reverse emulsion crosslinking on aldehyde-based dextran by adding an amine crosslinking agent to obtain dextran microspheres, but the problems of amine crosslinking agent residue, nonuniform crosslinking and the like exist; CN105153440A discloses a preparation method of dextran microsphere gel, which is characterized in that dextran is dissolved in water and added into continuous oil for homogeneous emulsification, hydroxyl in dextran reacts with side chains of amino in a cross-linking agent under alkaline conditions, and the dextran microsphere gel is solidified into hydrogel microspheres with certain strength.
Disclosure of Invention
The technical problem solved by the application is to overcome the defects in the prior art, and provide the injectable dextran hydrogel microsphere filling agent and the preparation method thereof.
The technical scheme adopted by the application for solving the technical problems comprises the following steps: a preparation method of an injectable dextran hydrogel microsphere filling agent comprises the following steps:
(1) preparation of polymerizable dextran
Dextran is added according to the solid-to-liquid ratio of 10 g: dissolving 100mL of the obtained solution in dimethyl sulfoxide, fully dissolving the solution, introducing nitrogen for 30min, injecting a certain amount of a modifier and a reaction auxiliary agent into a reaction system, reacting the mixture at room temperature for 48h, then transferring the obtained solution into a dialysis bag of regenerated cellulose, dialyzing the solution with deionized water for 5 to 10 days, replacing the deionized water every 4 to 6h, and freeze-drying the dialyzed solution to obtain the polymerizable dextran.
(2) Preparation of dextran hydrogel microspheres
Fully dissolving the polymerizable dextran obtained in the step (1) in deionized water, adding ammonium persulfate, and fully stirring at room temperature to obtain a dispersed phase solution A; adding an emulsifier into the oil liquid, and uniformly mixing to obtain a continuous phase solution B; then, dropwise adding the dispersed phase solution A into the continuous phase solution B at 30 ℃, introducing nitrogen, and fully stirring and emulsifying for 1 h; injecting tetramethylethylenediamine after emulsification is stable; and (3) after the polymerization reaction is carried out for 3 hours, introducing air to stop the polymerization reaction, fully standing for layering, removing the upper layer solution, transferring the lower layer solution into a dialysis bag made of regenerated cellulose, dialyzing with deionized water for 5-10 days, and freeze-drying to obtain the dextran hydrogel microspheres. Wherein the dosage of the ammonium persulfate and the tetramethylethylenediamine are respectively 3 percent and 0.8 percent of the mass of the polymerizable dextran.
(3) Preparation of injectable dextran hydrogel microsphere filler
And (3) dispersing the dextran hydrogel microspheres obtained in the step (2) in an injection water solution, fully swelling for 48 hours and storing at low temperature to obtain the injectable dextran hydrogel microsphere filling agent.
The molecular weight of the dextran in the step (1) is 40000g/mol-100000 g/mol.
The modifier in the step (1) is any one or more of glycidyl methacrylate, hydroxyethyl methacrylate activated by N, N '-carbonyldiimidazole, polylactic acid grafted hydroxyethyl methacrylate activated by N, N' -carbonyldiimidazole, acrylic anhydride and methacrylic anhydride, and the mass ratio of the addition amount of the modifier to the dextran is 5-15%.
The reaction auxiliary agent in the step (1) is any one or more of dimethylamino pyridine, triethylamine, dicyclohexyl carbodiimide and N-hydroxysuccinimide.
The volume ratio of the dispersed phase solution to the continuous phase solution in the step (2) is 4: 6, the mass concentration of the polymerizable dextran in the dispersed phase solution is 10-30%.
The emulsifier in the step (2) is any one or more of span 80, lecithin, monoglyceride and hydroxylated lanolin; the dosage of the emulsifier is 0.5 to 3 percent of the sum of the mass of the dispersed phase solution A and the mass of the continuous phase solution B.
And (3) the emulsification mode in the step (2) is mechanical stirring emulsification, and the stirring speed is constant at 550 r/min.
The oil liquid in the step (2) is any one or more of cyclohexane, normal hexane, soybean oil and olive oil.
The mass concentration of the dextran hydrogel microspheres in the dextran hydrogel microsphere filling agent in the step (3) is 6-16%.
The aqueous solution for injection in the step (3) is composed of water for injection, 3.0mg/mL lidocaine hydrochloride, 9.00mg/mL sodium chloride (NaCl), and 0.05mg/mL sodium dihydrogen phosphate (NaH)2PO4·H2O) and 0.22mg/mL disodium hydrogen phosphate (Na)2HPO4) And (4) forming.
The technical scheme that this application solved above-mentioned technical problem and adopted still includes: the dextran hydrogel microsphere filling agent capable of being injected is characterized by being prepared by adopting the preparation method of the dextran hydrogel microsphere filling agent capable of being injected.
Compared with the prior art, the application has the following advantages and effects: 1. the polymerizable dextran is obtained by modifying the dextran at first, so that the problem of residue of a modifier and a small molecule cross-linking agent is solved, the difficulty of later purification is reduced, and the safety of a filling agent product is improved.
2. According to the method, a cross-linking agent is not required to be additionally added in the emulsification process, the emulsification stability is enhanced, and the uniformity and the high efficiency of the cross-linking of the dextran hydrogel microspheres are ensured.
3. The obtained dextran hydrogel microspheres have uniform and controllable particle size, and spherical filling can effectively reduce thrombus risk, is beneficial to the wrapping of the microspheres by stimulating tissue collagen, is not easy to move and dissociate, and realizes long-acting filling.
4. The dextran hydrogel microsphere filling agent obtained by the application is suitable for filling different tissue parts.
5. The preparation process of the injectable dextran hydrogel microsphere filling agent has mild conditions, and is suitable for large-scale production.
Drawings
Fig. 1 is a photomicrograph of an injectable dextran hydrogel microsphere filler of example 1 of the present application.
Fig. 2 is a photomicrograph of the injectable dextran hydrogel microsphere filler of example 2 of the present application.
Fig. 3 is a photomicrograph of an injectable dextran hydrogel microsphere filler of example 3 of the present application.
Detailed Description
The present application will be described in further detail below with reference to the accompanying drawings by way of examples, which are illustrative of the present application and are not limited to the following examples.
Example 1
(1) At room temperature, 20g of dextran powder with the molecular weight of 40000g/mol is fully dissolved in 200mL of dimethyl sulfoxide solution, nitrogen is introduced for 30min, 0.4g of dimethylaminopyridine and 1g N, N' -carbonyldiimidazole activated hydroxyethyl methacrylate are added, the reaction is stopped after the reaction is continued for 48h in a closed system. And dialyzing the mixed solution by using a regenerated cellulose dialysis bag with the molecular weight cutoff of 3000kDa, replacing deionized water every 4-6h, dialyzing for 7 days, and freeze-drying to obtain the polymerizable dextran.
(2) Fully dissolving 2g of the polymerizable dextran obtained in the step (1) in 15mL of deionized water, and adding 45mg of ammonium persulfate to obtain a dispersed phase solution A; adding lecithin accounting for 0.5 percent of the mass of the (A + B) into 35mL of cyclohexane solution, mechanically stirring, and uniformly mixing to obtain a continuous phase solution B; setting the temperature to be 30 ℃, dropwise adding the dispersed phase solution A into the continuous phase solution B, introducing nitrogen, and simultaneously mechanically stirring at the rotation speed of 550r/min, and fully emulsifying for 1 h; adding 15 mu L of tetramethylethylenediamine, and carrying out polymerization reaction for 3 h; and then introducing air to stop the reaction, fully standing for layering, removing the upper layer solution, transferring the lower layer solution into a regenerated cellulose dialysis bag with the cut-off molecular weight of 8000-14000kDa for dialysis, replacing deionized water every 4-6h, dialyzing for 10 days, and then freeze-drying to obtain the dextran hydrogel microspheres.
(3) And (3) dispersing the 100mg dextran hydrogel microspheres obtained in the step (2) in 1mL of water solution for injection, fully swelling for 48h, and storing at low temperature to obtain the injectable dextran hydrogel microsphere filler with the concentration of 10%. The injection solution is prepared from injection water, lidocaine hydrochloride, and chlorineSodium chloride (NaCl), sodium dihydrogen phosphate (NaH)2PO4·H2O) and disodium hydrogen phosphate (Na)2HPO4) The preparation method is characterized in that the concentration of lidocaine hydrochloride is 3.0mg/mL, the concentration of sodium chloride is 9.00mg/mL, the concentration of sodium dihydrogen phosphate is 0.05mg/mL, and the concentration of disodium hydrogen phosphate is 0.22 mg/mL.
Example 2
(1) At room temperature, 20g of dextran powder with molecular weight of 70000g/mol is fully dissolved in 200mL of dimethyl sulfoxide solution, nitrogen is introduced for 30min, 0.4g of triethylamine and 1.5g of glycidyl methacrylate are added, and the reaction is stopped after the reaction is continued for 48h in a closed system. And dialyzing the mixed solution by using a regenerated cellulose dialysis bag with the molecular weight cutoff of 3000kDa, replacing deionized water every 4-6h, dialyzing for 7 days, and freeze-drying to obtain the polymerizable dextran.
(2) Fully dissolving 3g of the polymerizable dextran obtained in the step (1) in 15mL of deionized water, and adding 45mg of ammonium persulfate to obtain a dispersed phase solution A; adding span 80 accounting for 1.5 percent of the mass of the (A + B) into 35mL of n-hexane solution, mechanically stirring, and uniformly mixing to obtain a continuous phase solution B; setting the temperature to be 30 ℃, dropwise adding the dispersed phase solution A into the continuous phase solution B, introducing nitrogen, and simultaneously mechanically stirring at the rotation speed of 550r/min, and fully emulsifying for 1 h; adding 15 mu L of tetramethylethylenediamine, and carrying out polymerization reaction for 3 h; and then introducing air to stop the reaction, fully standing for layering, removing the upper layer solution, transferring the lower layer solution into a regenerated cellulose dialysis bag with the cut-off molecular weight of 8000-14000kDa for dialysis, replacing deionized water every 4-6h, dialyzing for 7 days, and freeze-drying to obtain the dextran hydrogel microspheres.
(3) And (3) dispersing 80mg of dextran hydrogel microspheres obtained in the step (2) in 1mL of aqueous solution for injection, fully swelling for 48h, and storing at low temperature to obtain the injectable dextran hydrogel microsphere filler with the concentration of 8%. The injectable aqueous solution is prepared from injectable water, lidocaine hydrochloride, sodium chloride (NaCl), and sodium dihydrogen phosphate (NaH)2PO4·H2O) and disodium hydrogen phosphate (Na)2HPO4) Is prepared, wherein the hydrochloric acid LiduokaThe concentration of sodium chloride was 9.00mg/mL, the concentration of sodium dihydrogen phosphate was 0.05mg/mL, and the concentration of disodium hydrogen phosphate was 0.22 mg/mL.
Example 3
(1) At room temperature, 20g of dextran powder with the molecular weight of 100000g/mol is fully dissolved in 200mL of dimethyl sulfoxide solution, nitrogen is introduced for 30min, 0.4g of triethylamine, 0.4g of dimethylaminopyridine, 0.5g of N, N' -carbonyldiimidazole activated polylactic acid grafted hydroxyethyl methacrylate and 1.5g of glycidyl methacrylate are added, and the reaction is stopped after the reaction is continued for 48h in a closed system. And dialyzing the mixed solution by using a regenerated cellulose dialysis bag with the molecular weight cutoff of 3000kDa, replacing deionized water every 4-6h, dialyzing for 8 days, and freeze-drying to obtain the polymerizable dextran.
(2) Fully dissolving 1.5g of the polymerizable dextran obtained in the step (1) in 15mL of deionized water, and adding 45mg of ammonium persulfate to obtain a dispersed phase solution A; adding span 80 accounting for 1.5 percent of the mass of (A + B) and monoglyceride accounting for 1.5 percent into a mixed solution of 30mL of normal hexane and 5mL of cyclohexane, mechanically stirring, and uniformly mixing to obtain a continuous phase solution B; setting the temperature to be 30 ℃, dropwise adding the dispersed phase solution A into the continuous phase solution B, introducing nitrogen, and simultaneously mechanically stirring at the rotation speed of 550r/min, and fully emulsifying for 1 h; adding 15 mu L of tetramethylethylenediamine, and carrying out polymerization reaction for 3 h; and then introducing air to stop the reaction, fully standing for layering, removing the upper layer solution, transferring the lower layer solution into a regenerated cellulose dialysis bag with the cut-off molecular weight of 8000-14000kDa for dialysis, replacing deionized water every 4-6h, and performing freeze drying after 6 days of dialysis to obtain the dextran hydrogel microspheres.
(3) And (3) dispersing the 60mg dextran hydrogel microspheres obtained in the step (2) in 1mL of water solution for injection, fully swelling for 48h, and storing at low temperature to obtain the injectable dextran hydrogel microsphere filler with the concentration of 6%. The injectable aqueous solution is prepared from injectable water, lidocaine hydrochloride, sodium chloride (NaCl), and sodium dihydrogen phosphate (NaH)2PO4·H2O) and disodium hydrogen phosphate (Na)2HPO4) Is prepared, wherein the hydrochloric acid is hydrochloric acidThe concentration of the cocaine was 3.0mg/mL, the concentration of the sodium chloride was 9.00mg/mL, the concentration of the sodium dihydrogen phosphate was 0.05mg/mL, and the concentration of the disodium hydrogen phosphate was 0.22 mg/mL.
Example 4
(1) At room temperature, 20g of dextran powder with the molecular weight of 80000g/mol is fully dissolved in 200mL of dimethyl sulfoxide solution, nitrogen is introduced for 30min, 0.4g of dicyclohexylcarbodiimide, 0.4g of dimethylaminopyridine, 0.8g of methacrylic anhydride and 0.8g of acrylic anhydride are added, and the reaction is stopped after the reaction is continued for 48h in a closed system. And dialyzing the mixed solution by using a regenerated cellulose dialysis bag with the molecular weight cutoff of 3000kDa, replacing deionized water every 4-6h, dialyzing for 5 days, and freeze-drying to obtain the polymerizable dextran.
(2) Fully dissolving 2g of the polymerizable dextran obtained in the step (1) in 15mL of deionized water, and adding 45mg of ammonium persulfate to obtain a dispersed phase solution A; adding hydroxylated lanolin accounting for 0.5 percent of the mass of (A + B) and monoglyceride accounting for 1.5 percent into a mixed solution of 30mL of olive oil and 5mL of cyclohexane, mechanically stirring, and uniformly mixing to obtain a continuous phase solution B; setting the temperature to be 30 ℃, dropwise adding the dispersed phase solution A into the continuous phase solution B, introducing nitrogen, and simultaneously mechanically stirring at the rotation speed of 550r/min, and fully emulsifying for 1 h; adding 15 mu L of tetramethylethylenediamine, and carrying out polymerization reaction for 3 h; and then introducing air to stop the reaction, fully standing for layering, removing the upper layer solution, transferring the lower layer solution into a regenerated cellulose dialysis bag with the cut-off molecular weight of 8000-14000kDa for dialysis, replacing deionized water every 4-6h, and carrying out freeze drying after 5 days of dialysis to obtain the dextran hydrogel microspheres.
(3) And (3) dispersing 70mg of dextran hydrogel microspheres obtained in the step (2) in 1mL of water solution for injection, fully swelling for 48h, and storing at low temperature to obtain the injectable dextran hydrogel microsphere filler with the concentration of 7%. The injectable aqueous solution is prepared from injectable water, lidocaine hydrochloride, sodium chloride (NaCl), and sodium dihydrogen phosphate (NaH)2PO4·H2O) and disodium hydrogen phosphate (Na)2HPO4) The concentration of the lidocaine hydrochloride is 3.0mg/mL, and the concentration of the sodium chloride is obtainedThe concentration of sodium dihydrogen phosphate was 9.00mg/mL, the concentration of sodium dihydrogen phosphate was 0.05mg/mL, and the concentration of disodium hydrogen phosphate was 0.22 mg/mL.
Example 5
(1) 20g of dextran powder with a molecular weight of 60000g/mol is fully dissolved in 200mL of dimethyl sulfoxide solution at room temperature, nitrogen is introduced for 30min, 0.2g of dicyclohexylcarbodiimide, 0.2g of dimethylaminopyridine, 0.2g of triethylamine, 0.2g N-hydroxysuccinimide, 0.4g of methacrylic anhydride, 0.4g of acrylic anhydride, 0.5g of N, N' -carbonyldiimidazole activated polylactic acid grafted hydroxyethyl methacrylate and 0.5g of glycidyl methacrylate are added, and the reaction is stopped after the reaction is continued for 48h in a closed system. And dialyzing the mixed solution by using a regenerated cellulose dialysis bag with the molecular weight cutoff of 3000kDa, replacing deionized water every 4-6h, dialyzing for 10 days, and freeze-drying to obtain the polymerizable dextran.
(2) 4.5g of the polymerizable dextran obtained in the step (1) is fully dissolved in 15mL of deionized water, and 45mg of ammonium persulfate is added to obtain a dispersed phase solution A; adding 0.5% of hydroxylated lanolin, 0.5% of monoglyceride, 0.5% of span 80 and 0.5% of lecithin (based on the mass of (A + B)) into a mixed solution of 30mL of soybean oil and 5mL of n-hexane, mechanically stirring, and uniformly mixing to obtain a continuous phase solution B; setting the temperature to be 30 ℃, dropwise adding the dispersed phase solution A into the continuous phase solution B, introducing nitrogen, and simultaneously mechanically stirring at the rotation speed of 550r/min, and fully emulsifying for 1 h; adding 15 mu L of tetramethylethylenediamine, and carrying out polymerization reaction for 3 h; and then introducing air to stop the reaction, fully standing for layering, removing the upper layer solution, transferring the lower layer solution into a regenerated cellulose dialysis bag with the cut-off molecular weight of 8000-14000kDa for dialysis, replacing deionized water every 4-6h, dialyzing for 10 days, and then freeze-drying to obtain the dextran hydrogel microspheres.
(3) And (3) dispersing 90mg of dextran hydrogel microspheres obtained in the step (2) in 1mL of aqueous solution for injection, fully swelling for 48h, and storing at low temperature to obtain the injectable dextran hydrogel microsphere filler with the concentration of 9%. The injectable aqueous solution is prepared from injectable water, lidocaine hydrochloride, sodium chloride (NaCl), and sodium dihydrogen phosphate (NaH)2PO4·H2O) and disodium hydrogen phosphate (Na)2HPO4) The preparation method is characterized in that the concentration of lidocaine hydrochloride is 3.0mg/mL, the concentration of sodium chloride is 9.00mg/mL, the concentration of sodium dihydrogen phosphate is 0.05mg/mL, and the concentration of disodium hydrogen phosphate is 0.22 mg/mL.
Example 6
(1) At room temperature, 20g of dextran powder with the molecular weight of 60000g/mol is fully dissolved in 200mL of dimethyl sulfoxide solution, nitrogen is introduced for 30min, 0.4g of dimethylaminopyridine and 2g of glycidyl methacrylate are added, and the reaction is stopped after the reaction is continued for 48h in a closed system. And dialyzing the mixed solution by using a regenerated cellulose dialysis bag with the molecular weight cutoff of 3000kDa, replacing deionized water every 4-6h, dialyzing for 7 days, and freeze-drying to obtain the polymerizable dextran.
(2) Fully dissolving 3g of the polymerizable dextran obtained in the step (1) in 15mL of deionized water, and adding 45mg of ammonium persulfate to obtain a dispersed phase solution A; adding hydroxylated lanolin accounting for 0.5 percent of the mass of the (A + B) into 35mL of cyclohexane solution, mechanically stirring, and uniformly mixing to obtain a continuous phase solution B; setting the temperature to be 30 ℃, dropwise adding the dispersed phase solution A into the continuous phase solution B, introducing nitrogen, and simultaneously mechanically stirring at the rotation speed of 550r/min, and fully emulsifying for 1 h; adding 15 mu L of tetramethylethylenediamine, and carrying out polymerization reaction for 3 h; and then introducing air to stop the reaction, fully standing for layering, removing the upper layer solution, transferring the lower layer solution into a regenerated cellulose dialysis bag with the cut-off molecular weight of 8000-14000kDa for dialysis, replacing deionized water every 4-6h, and performing freeze drying after 6 days of dialysis to obtain the dextran hydrogel microspheres.
(3) And (3) dispersing 120mg of dextran hydrogel microspheres obtained in the step (2) into 1mL of water solution for injection, fully swelling for 48h, and storing at low temperature to obtain the injectable dextran hydrogel microsphere filler with the concentration of 12%. The injectable aqueous solution is prepared from injectable water, lidocaine hydrochloride, sodium chloride (NaCl), and sodium dihydrogen phosphate (NaH)2PO4·H2O) and disodium hydrogen phosphate (Na)2HPO4) Prepared by the concentration of lidocaine hydrochloride3.0mg/mL, 9.00mg/mL sodium chloride, 0.05mg/mL sodium dihydrogen phosphate, and 0.22mg/mL disodium hydrogen phosphate.
Example 7
(1) At room temperature, 20g of dextran powder with the molecular weight of 80000g/mol is fully dissolved in 200mL of dimethyl sulfoxide solution, nitrogen is introduced for 30min, 0.4g of dicyclohexylcarbodiimide and 1g of acrylic anhydride are added, and the reaction is stopped after the reaction is continued for 48h in a closed system. And dialyzing the mixed solution by using a regenerated cellulose dialysis bag with the molecular weight cutoff of 3000kDa, replacing deionized water every 4-6h, dialyzing for 9 days, and freeze-drying to obtain the polymerizable dextran.
(2) Fully dissolving 3g of the polymerizable dextran obtained in the step (1) in 15mL of deionized water, and adding 45mg of ammonium persulfate to obtain a dispersed phase solution A; adding 0.5% of hydroxylated lanolin and 0.5% of span 80 by mass relative to (A + B) into 35mL of olive oil solution, mechanically stirring, and uniformly mixing to obtain a continuous phase solution B; setting the temperature to be 30 ℃, dropwise adding the dispersed phase solution A into the continuous phase solution B, introducing nitrogen, and simultaneously mechanically stirring at the rotation speed of 550r/min, and fully emulsifying for 1 h; adding 15 mu L of tetramethylethylenediamine, and carrying out polymerization reaction for 3 h; and then introducing air to stop the reaction, fully standing for layering, removing the upper layer solution, transferring the lower layer solution into a regenerated cellulose dialysis bag with the cut-off molecular weight of 8000-14000kDa for dialysis, replacing deionized water every 4-6h, and performing freeze drying after 8 days of dialysis to obtain the dextran hydrogel microspheres.
(3) And (3) dispersing the 100mg dextran hydrogel microspheres obtained in the step (2) in 1mL of water solution for injection, fully swelling for 48h, and storing at low temperature to obtain the injectable dextran hydrogel microsphere filler with the concentration of 10%. The injectable aqueous solution is prepared from injectable water, lidocaine hydrochloride, sodium chloride (NaCl), and sodium dihydrogen phosphate (NaH)2PO4·H2O) and disodium hydrogen phosphate (Na)2HPO4) The preparation method is characterized in that the concentration of lidocaine hydrochloride is 3.0mg/mL, the concentration of sodium chloride is 9.00mg/mL, the concentration of sodium dihydrogen phosphate is 0.05mg/mL, and the concentration of disodium hydrogen phosphate is 0.22 mg/mL.
Example 8
(1) At room temperature, 20g of dextran powder with the molecular weight of 80000g/mol is fully dissolved in 200mL of dimethyl sulfoxide solution, nitrogen is introduced for 30min, 0.4g N-hydroxysuccinimide and 2g N, N' -carbonyldiimidazole activated polylactic acid grafted hydroxyethyl methacrylate are added, and the reaction is stopped after the reaction is continued for 48h in a closed system. And dialyzing the mixed solution by using a regenerated cellulose dialysis bag with the molecular weight cutoff of 3000kDa, replacing deionized water every 4-6h, dialyzing for 7 days, and freeze-drying to obtain the polymerizable dextran.
(2) Fully dissolving 2g of the polymerizable dextran obtained in the step (1) in 15mL of deionized water, and adding 45mg of ammonium persulfate to obtain a dispersed phase solution A; adding span 80 accounting for 1.5 percent of the mass of the (A + B) into 35mL of n-hexane oil solution, mechanically stirring, and uniformly mixing to obtain a continuous phase solution B; setting the temperature to be 30 ℃, dropwise adding the dispersed phase solution A into the continuous phase solution B, introducing nitrogen, and simultaneously mechanically stirring at the rotation speed of 550r/min, and fully emulsifying for 1 h; adding 15 mu L of tetramethylethylenediamine, and carrying out polymerization reaction for 3 h; and then introducing air to stop the reaction, fully standing for layering, removing the upper layer solution, transferring the lower layer solution into a regenerated cellulose dialysis bag with the cut-off molecular weight of 8000-14000kDa for dialysis, replacing deionized water every 4-6h, and performing freeze drying after 9 days of dialysis to obtain the dextran hydrogel microspheres.
(3) And (3) dispersing the 160mg dextran hydrogel microspheres obtained in the step (2) into 1mL of water solution for injection, fully swelling for 48h, and storing at low temperature to obtain the injectable dextran hydrogel microsphere filler with the concentration of 16%. The injectable aqueous solution is prepared from injectable water, lidocaine hydrochloride, sodium chloride (NaCl), and sodium dihydrogen phosphate (NaH)2PO4·H2O) and disodium hydrogen phosphate (Na)2HPO4) The preparation method is characterized in that the concentration of lidocaine hydrochloride is 3.0mg/mL, the concentration of sodium chloride is 9.00mg/mL, the concentration of sodium dihydrogen phosphate is 0.05mg/mL, and the concentration of disodium hydrogen phosphate is 0.22 mg/mL.
Example 9
(1) 20g of dextran powder with a molecular weight of 70000g/mol is fully dissolved in 200mL of dimethyl sulfoxide solution at room temperature, nitrogen is introduced for 30min, 0.4g of dimethylaminopyridine, 0.4g of 0.4g N-hydroxysuccinimide, 1.0g of N, N' -carbonyldiimidazole activated hydroxyethyl methacrylate, 1.0g of methacrylic anhydride and 0.5g of glycidyl methacrylate are added, and the reaction is stopped after the reaction is continued for 48h in a closed system. And dialyzing the mixed solution by using a regenerated cellulose dialysis bag with the molecular weight cutoff of 3000kDa, replacing deionized water every 4-6h, dialyzing for 7 days, and freeze-drying to obtain the polymerizable dextran.
(2) Fully dissolving 3.5g of the polymerizable dextran obtained in the step (1) in 15mL of deionized water, and adding 45mg of ammonium persulfate to obtain a dispersed phase solution A; adding lecithin accounting for 0.5 percent of the mass of the (A + B) into 35mL of cyclohexane solution, mechanically stirring, and uniformly mixing to obtain a continuous phase solution B; setting the temperature to be 30 ℃, dropwise adding the dispersed phase solution A into the continuous phase solution B, introducing nitrogen, and simultaneously mechanically stirring at the rotation speed of 550r/min, and fully emulsifying for 1 h; adding 15 mu L of tetramethylethylenediamine, and carrying out polymerization reaction for 3 h; and then introducing air to stop the reaction, fully standing for layering, removing the upper layer solution, transferring the lower layer solution into a regenerated cellulose dialysis bag with the cut-off molecular weight of 8000-14000kDa for dialysis, replacing deionized water every 4-6h, dialyzing for 10 days, and then freeze-drying to obtain the dextran hydrogel microspheres.
(3) And (3) dispersing 150mg of dextran hydrogel microspheres obtained in the step (2) in 1mL of aqueous solution for injection, fully swelling for 48h, and storing at low temperature to obtain the injectable dextran hydrogel microsphere filler with the concentration of 15%. The injectable aqueous solution is prepared from injectable water, lidocaine hydrochloride, sodium chloride (NaCl), and sodium dihydrogen phosphate (NaH)2PO4·H2O) and disodium hydrogen phosphate (Na)2HPO4) The preparation method is characterized in that the concentration of lidocaine hydrochloride is 3.0mg/mL, the concentration of sodium chloride is 9.00mg/mL, the concentration of sodium dihydrogen phosphate is 0.05mg/mL, and the concentration of disodium hydrogen phosphate is 0.22 mg/mL.
Example 10
(1) At room temperature, 20g of dextran powder with the molecular weight of 100000g/mol is fully dissolved in 200mL of dimethyl sulfoxide solution, nitrogen is introduced for 30min, 0.4g of dimethylaminopyridine, 1.0g of glycidyl methacrylate, 0.5g of methacrylic anhydride and 1.5g of polylactic acid grafted hydroxyethyl methacrylate activated by N, N' -carbonyldiimidazole are added, and the reaction is stopped after the reaction is continued for 48h in a closed system. And dialyzing the mixed solution by using a regenerated cellulose dialysis bag with the molecular weight cutoff of 3000kDa, replacing deionized water every 4-6h, dialyzing for 7 days, and freeze-drying to obtain the polymerizable dextran.
(2) Fully dissolving 3.0g of the polymerizable dextran obtained in the step (1) in 15mL of deionized water, and adding 45mg of ammonium persulfate to obtain a dispersed phase solution A; adding lecithin accounting for 0.5 percent of the mass of the (A + B) into 35mL of cyclohexane solution, mechanically stirring, and uniformly mixing to obtain a continuous phase solution B; setting the temperature to be 30 ℃, dropwise adding the dispersed phase solution A into the continuous phase solution B, introducing nitrogen, and simultaneously mechanically stirring at the rotation speed of 550r/min, and fully emulsifying for 1 h; adding 15 mu L of tetramethylethylenediamine, and carrying out polymerization reaction for 3 h; and then introducing air to stop the reaction, fully standing for layering, removing the upper layer solution, transferring the lower layer solution into a regenerated cellulose dialysis bag with the cut-off molecular weight of 8000-14000kDa for dialysis, replacing deionized water every 4-6h, dialyzing for 10 days, and then freeze-drying to obtain the dextran hydrogel microspheres.
(3) And (3) dispersing the 100mg dextran hydrogel microspheres obtained in the step (2) in 1mL of water solution for injection, fully swelling for 48h, and storing at low temperature to obtain the injectable dextran hydrogel microsphere filler with the concentration of 10%. The injectable aqueous solution is prepared from injectable water, lidocaine hydrochloride, sodium chloride (NaCl), and sodium dihydrogen phosphate (NaH)2PO4·H2O) and disodium hydrogen phosphate (Na)2HPO4) The preparation method is characterized in that the concentration of lidocaine hydrochloride is 3.0mg/mL, the concentration of sodium chloride is 9.00mg/mL, the concentration of sodium dihydrogen phosphate is 0.05mg/mL, and the concentration of disodium hydrogen phosphate is 0.22 mg/mL.
All simple variations and combinations of the technical features and technical solutions of the present application are considered to fall within the scope of the present application.

Claims (9)

1. A preparation method of an injectable dextran hydrogel microsphere filling agent is characterized by comprising the following steps:
s1: preparation of polymerizable dextran
Dextran is added according to the solid-to-liquid ratio of 10 g: dissolving 100mL of the mixture in dimethyl sulfoxide, fully dissolving the mixture, introducing nitrogen for 30min, then injecting modifier and reaction auxiliary agent, reacting for 48h at room temperature, transferring the obtained solution into a dialysis bag, dialyzing with deionized water for 5-10 days, replacing the deionized water every 4-6h, freeze-drying after dialysis to obtain polymerizable dextran, the modifier is one or more of glycidyl methacrylate, hydroxyethyl methacrylate activated by N, N '-carbonyldiimidazole, polylactic acid grafted hydroxyethyl methacrylate activated by N, N' -carbonyldiimidazole, acrylic anhydride and methacrylic anhydride, the reaction auxiliary is one or more of dimethylaminopyridine, triethylamine, dicyclohexylcarbodiimide and N-hydroxysuccinimide, and the molecular weight of dextran is 40000g/mol-100000 g/mol;
s2: preparation of dextran hydrogel microspheres
Fully dissolving the polymerizable dextran obtained in the step S1 in deionized water, adding ammonium persulfate, and fully stirring at room temperature to obtain a dispersed phase solution A; adding an emulsifier into the oil liquid, and uniformly mixing to obtain a continuous phase solution B; then at 30oC, dropwise adding the dispersed phase solution A into the continuous phase solution B, introducing nitrogen, and fully stirring and emulsifying for 1 h; injecting tetramethylethylenediamine after emulsification is stable; after the polymerization reaction is carried out for 3 hours, introducing air to stop the polymerization reaction, fully standing for layering, removing the upper layer solution, transferring the lower layer solution into a dialysis bag made of regenerated cellulose, dialyzing with deionized water for 5-10 days, and freeze-drying to obtain the dextran hydrogel microspheres; wherein the dosage of ammonium persulfate and tetramethylethylenediamine is 3% and 0.8% of the mass of the polymerizable dextran, the oil is one or more of cyclohexane, n-hexane, soybean oil and olive oil, and the emulsifier is span 80, lecithin, monoglyceride, hydroxylDissolving one or more of lanolin;
s3: preparation of injectable dextran hydrogel microsphere filler
And (5) dispersing the dextran hydrogel microspheres obtained in the step (S2) in an aqueous solution for injection, fully swelling for 48 hours, and storing at low temperature to obtain the injectable dextran hydrogel microsphere filling agent.
2. The method for preparing the injectable dextran hydrogel microsphere filling agent according to claim 1, which is characterized in that: the mass ratio of the addition amount of the modifier to the dextran is 5-15%.
3. The method for preparing the injectable dextran hydrogel microsphere filling agent according to claim 1, which is characterized in that: the volume ratio of the dispersed phase solution A to the continuous phase solution B is 4: 6, the mass concentration of the polymerizable dextran in the dispersed phase solution is 10-30%.
4. The method for preparing the injectable dextran hydrogel microsphere filling agent according to claim 1, which is characterized in that: the dosage of the emulsifier is 0.5-3% of the mass sum of the dispersed phase solution A and the continuous phase solution B.
5. The method for preparing the injectable dextran hydrogel microsphere filler, which is characterized in that: and the emulsification mode in the step S2 is mechanical stirring emulsification, and the stirring speed is 550 r/min.
6. The method for preparing the injectable dextran hydrogel microsphere filling agent according to claim 1, which is characterized in that: the mass concentration of the dextran hydrogel microspheres in the dextran hydrogel microsphere injectable filling agent is 6-16%.
7. The method for preparing the injectable dextran hydrogel microsphere filling agent according to claim 1, which is characterized in that: the water solution for injection consists of water for injection, 3.0mg/mL lidocaine hydrochloride, 9.00mg/mL sodium chloride, 0.05mg/mL sodium dihydrogen phosphate and 0.22mg/mL disodium hydrogen phosphate.
8. The method for preparing the injectable dextran hydrogel microsphere filling agent according to claim 1, which is characterized in that: the dialysis bag is made of regenerated cellulose.
9. An injectable dextran hydrogel microsphere filling agent is characterized in that: the injectable dextran hydrogel microsphere filler is prepared by adopting the preparation method of the injectable dextran hydrogel microsphere filler disclosed by any one of claims 1 to 8.
CN202111503230.6A 2021-12-09 2021-12-09 Injectable dextran hydrogel microsphere filling agent and preparation method thereof Pending CN114146221A (en)

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