Disclosure of Invention
The invention aims to provide biodegradable polymer particles, wherein the polymer particles are copolymers of lactic acid and/or glycolic acid repeating units, and the particle size of the polymer particles is 10-150 mu m.
In a preferred embodiment of the present invention, the polymer fine particles have a particle size of 20 to 120. mu.m, preferably 30 to 100. mu.m.
In a preferred embodiment of the present invention, the D (3,2) of the polymer fine particles is 10 μm to 50 μm, preferably 20 μm to 30 μm, and more preferably 20 μm to 25 μm.
In a preferred embodiment of the present invention, D (4,3) of the polymer fine particles is 10 μm to 50 μm, preferably 30 μm to 40 μm, and more preferably 30 μm to 35 μm.
In a preferred embodiment of the present invention, the weight average molecular weight of the polymer particles is 10,000-100,000, preferably 20,000-75,000, and more preferably 30,000-50,000.
In a preferred embodiment of the present invention, the repeating unit of the polymer microparticle is selected from any one of levolactic acid, dextrolactic acid, racemic lactic acid, and glycolic acid, or a combination thereof.
In a preferred embodiment of the present invention, the polymer particles are selected from the group consisting of poly (L-lactic acid) (PLLA), poly (D-lactic acid) (PDLA), poly (racemic lactic acid) (PDLLA), poly (lactic acid-co-glycolic acid) (PLGA), and poly (glycolic acid) (PGA), or a copolymer thereof.
In a preferred embodiment of the present invention, the polymer fine particles have an irregular shape.
In a preferred embodiment of the present invention, the irregular shape of the polymer microparticles is selected from any one of or a combination of approximately square, approximately spherical, approximately rectangular, approximately rhombic, approximately triangular, approximately circular, approximately elliptical, approximately trapezoidal, approximately conical, and approximately cylindrical shapes.
In a preferred embodiment of the present invention, the irregular shape of the polymer fine particles is selected from any one of a sheet shape, a block shape, a spherical shape, a strip shape, a filament shape, and a granular shape, or a combination thereof.
In a preferred embodiment of the present invention, the irregular outer shape is selected from any one of a laminated shape and a wound shape, or a combination thereof.
In a preferred embodiment of the present invention, the polymer fine particles have a rough surface or a matte surface.
In a preferred embodiment of the present invention, the rough surface or the matte surface of the polymer fine particles has irregular pore diameters.
In a preferred embodiment of the present invention, the total heat of fusion of the polymer particles heated from 40 ℃ to 230 ℃ at a heating rate of 10 ℃/min is 40J/g to 80J/g, preferably 45J/g to 70J/g, and more preferably 55J/g to 65J/g.
Another object of the present invention is to provide a method for preparing biodegradable polymer microparticles, comprising the steps of: (1) dissolving a biodegradable polymer in a benign solvent; (2) dripping a poor solvent, and crystallizing; (3) filtering and washing; (4) and (5) drying to obtain the product.
In a preferred embodiment of the present invention, the biodegradable polymer is a copolymer of lactic acid and/or glycolic acid repeating units.
In a preferred embodiment of the present invention, the benign solvent is selected from one or a combination of tetrahydrofuran, 1, 4-dioxane, dichloromethane, chloroform, N-dimethylformamide, dimethyl sulfoxide, ethylene glycol diethyl ether, ethylene glycol dimethyl ether, toluene and p-xylene.
In a preferred embodiment of the invention, the amount of the benign solvent is 5 to 50 times, preferably 10 to 40 times, and more preferably 12 to 20 times that of the biodegradable polymer.
In a preferred embodiment of the present invention, the poor solvent is selected from any one of methanol, ethanol, isopropanol, n-propanol, butanol, acetone, butanone, 4-methyl-2-pentanone, ethyl acetate, butyl acetate, isopropyl acetate, n-hexane, cyclohexane, n-heptane, and n-octane, or a combination thereof.
In a preferred embodiment of the present invention, the amount of the poor solvent is 30 to 90 times, preferably 40 to 80 times, and more preferably 50 to 70 times that of the biodegradable polymer.
In a preferred embodiment of the present invention, the preparation method of the biodegradable polymer comprises the following steps: (1a) adding L-lactide into a reaction vessel, heating and melting; (1b) adding an initiator and a catalyst into the L-lactide molten liquid, and keeping the temperature until the reaction is complete; (1c) cooling the reaction solution to room temperature, adding a benign solvent, stirring and dissolving; (1d) and (3) dripping a poor solvent into the filtrate, crystallizing, filtering and drying to obtain the compound.
In a preferred embodiment of the present invention, the heating temperature in step (1a) or the reaction temperature in step (1b) is 50-200 ℃, preferably 100-160 ℃, and more preferably 120-140 ℃.
In a preferred embodiment of the present invention, the reaction time in step (1b) is 5 to 72 hours, preferably 12 to 60 hours, and more preferably 24 to 48 hours.
In the preferable technical scheme of the invention, the initiator is lauryl alcohol; the catalyst is selected from any one or combination of stannous isooctanoate, stannous chloride and zinc chloride, preferably selected from any one or combination of stannous isooctanoate and stannous chloride, and more preferably selected from stannous isooctanoate.
In a preferred embodiment of the present invention, the benign solvent is selected from one or a combination of tetrahydrofuran, 1, 4-dioxane, dichloromethane, chloroform, N-dimethylformamide, dimethyl sulfoxide, ethylene glycol diethyl ether, ethylene glycol dimethyl ether, toluene and p-xylene.
In a preferred embodiment of the present invention, the amount of the benign solvent is 3 to 25 times, preferably 5 to 20 times, and more preferably 10 to 15 times that of the L-lactide.
In a preferred embodiment of the present invention, the poor solvent is selected from any one of methanol, ethanol, isopropanol, n-propanol, butanol, acetone, butanone, 4-methyl-2-pentanone, ethyl acetate, butyl acetate, isopropyl acetate, n-hexane, cyclohexane, n-heptane, and n-octane, or a combination thereof.
In a preferred embodiment of the present invention, the amount of the poor solvent is 30 to 70 times, preferably 40 to 60 times, and more preferably 45 to 55 times that of the L-lactide.
In a preferred embodiment of the present invention, the method for preparing the polymer microparticles comprises the step (5): the resulting polymer particles were sieved through a 200 mesh sieve.
In a preferred embodiment of the present invention, the polymer fine particles have a particle size of 10 to 150. mu.m, preferably 20 to 120. mu.m, and more preferably 30 to 100. mu.m.
In a preferred embodiment of the present invention, the weight average molecular weight of the polymer particles is 10,000-100,000, preferably 20,000-75,000, and more preferably 30,000-50,000.
In a preferred embodiment of the present invention, the repeating unit of the polymer microparticle is selected from any one of levolactic acid, dextrolactic acid, racemic lactic acid, and glycolic acid, or a combination thereof.
In a preferred embodiment of the present invention, the polymer particles are selected from the group consisting of poly (L-lactic acid) (PLLA), poly (D-lactic acid) (PDLA), poly (racemic lactic acid) (PDLLA), poly (lactic-co-glycolic acid) (PLGA), and poly (glycolic acid) (PGA), or a copolymer thereof.
In a preferred embodiment of the present invention, the polymer fine particles have an irregular shape.
In a preferred embodiment of the present invention, the irregular shape of the polymer microparticles is selected from any one of or a combination of approximately square, approximately spherical, approximately rectangular, approximately rhombic, approximately triangular, approximately circular, approximately elliptical, approximately trapezoidal, approximately conical, and approximately cylindrical shapes.
In a preferred embodiment of the present invention, the irregular shape of the polymer fine particles is selected from any one of a sheet shape, a block shape, a spherical shape, a strip shape, a filament shape, and a granular shape, or a combination thereof.
In a preferred embodiment of the present invention, the irregular shape of the polymer microparticles is selected from any one of a laminated shape and a wound shape, or a combination thereof.
In a preferred embodiment of the present invention, the polymer fine particles have a rough surface or a matte surface.
In a preferred embodiment of the present invention, the rough surface or the matte surface of the polymer particles has irregular pore diameters.
In a preferred embodiment of the present invention, the total heat of fusion of the polymer particles heated from 40 ℃ to 230 ℃ at a heating rate of 10 ℃/min is 40J/g to 80J/g, preferably 45J/g to 70J/g, and more preferably 55J/g to 65J/g.
It is another object of the present invention to provide a use of biodegradable polymer microparticles for enhancing the filling effect of an injectable filling.
In the preferable technical scheme of the invention, the filling effect of the injection filler is improved by any one or combination of three-dimensional full filling part, soft and natural filling part, shortened filling swelling time and prolonged filling maintaining time.
In a preferred embodiment of the present invention, the active ingredient of the injectable filling is selected from any one or a combination of biodegradable polymer particles and other types of injectable filling ingredients.
In a preferred embodiment of the present invention, the other type of injection filling component is selected from any one or a combination of collagen, hyaluronic acid, polymethyl methacrylate, polyacrylamide, silica gel, and autologous fat.
It is another object of the present invention to provide the use of biodegradable polymer microparticles for the preparation of resorbable bone engaging materials.
In a preferred embodiment of the present invention, the absorbable bone joining material is selected from any one or a combination of fracture fixation and repair materials, bone fragment fixation materials in bone connection, and bone block fixation materials in osteosynthesis.
In a preferred embodiment of the present invention, the absorbable bone joining material is selected from any one of an intervertebral fusion device, a bone plate, a bone nail, a bone screw, a bone pin, a rib nail, a bone rod, an internal spinal fixation device, a patella concentrator, bone wax, a sternum fixation nail, a medullary bone screw, a washer, a drill, and a vertebra or a combination thereof.
In a preferred embodiment of the present invention, the absorbable bone graft material is used for preventing and/or treating any one of cruciate ligament tear, knee joint injury, maxillofacial surgery, and knee joint laxity, or complications thereof.
The invention also aims to provide application of the biodegradable polymer particles in preparing surgical sutures, dental filling materials, ophthalmic implant materials, tissue engineering scaffold materials and drug controlled release materials.
It is another object of the present invention to provide an injectable implant composition comprising biodegradable polymer microparticles and hyaluronic acid in an amount of not more than 0.1%.
In a preferred embodiment of the present invention, the polymer microparticles in the composition are a copolymer of lactic acid and/or glycolic acid repeating units, and the particle size of the polymer microparticles is preferably 10 μm to 150 μm.
In a preferred embodiment of the present invention, the polymer fine particles have a particle size of 20 to 120. mu.m, preferably 30 to 100. mu.m.
In a preferred embodiment of the present invention, the D (3,2) of the polymer fine particles is 10 μm to 50 μm, preferably 20 μm to 30 μm, and more preferably 20 μm to 25 μm.
In a preferred embodiment of the present invention, D (4,3) of the polymer fine particles is 10 μm to 50 μm, preferably 30 μm to 40 μm, and more preferably 30 μm to 35 μm.
In a preferred embodiment of the present invention, the weight average molecular weight of the polymer particles is 10,000-100,000, preferably 20,000-75,000, and more preferably 30,000-50,000.
In a preferred embodiment of the present invention, the repeating unit is selected from any one of or a combination of levolactic acid, dextrolactic acid, racemic lactic acid and glycolic acid.
In a preferred embodiment of the present invention, the polymer particles are selected from the group consisting of poly (L-lactic acid) (PLLA), poly (D-lactic acid) (PDLA), poly (racemic lactic acid) (PDLLA), poly (lactic-co-glycolic acid) (PLGA), and poly (glycolic acid) (PGA), or a copolymer thereof.
In a preferred embodiment of the present invention, the polymer fine particles have an irregular shape.
In a preferred embodiment of the present invention, the irregular shape of the polymer microparticles is selected from any one of or a combination of approximately square, approximately rectangular, approximately rhombic, approximately triangular, approximately circular, approximately elliptical, approximately trapezoidal, approximately conical, and approximately cylindrical shapes.
In a preferred embodiment of the present invention, the irregular shape of the polymer fine particles is selected from any one of a sheet shape, a block shape, a spherical shape, a strip shape, a filament shape, and a granular shape, or a combination thereof.
In a preferred embodiment of the present invention, the irregular shape of the polymer particles is selected from any one of a stacked shape and a wound shape, or a combination thereof.
In a preferred embodiment of the present invention, the polymer fine particles have a rough surface or a matte surface.
In a preferred embodiment of the present invention, the rough surface or the matte surface of the polymer particles has irregular pore diameters.
In a preferred embodiment of the present invention, the total heat of fusion of the polymer particles heated from 40 ℃ to 230 ℃ at a heating rate of 10 ℃/min is 40J/g to 80J/g, preferably 45J/g to 70J/g, and more preferably 55J/g to 65J/g.
In a preferred embodiment of the present invention, the content of the polymer particles in the composition is 3% to 30%, preferably 5% to 25%, and more preferably 10% to 20%.
In a preferred embodiment of the present invention, the hyaluronic acid in the composition is selected from any one of cross-linked hyaluronic acid and non-cross-linked hyaluronic acid, or a combination thereof.
In a preferred embodiment of the present invention, the weight average molecular weight of the hyaluronic acid is 600,000-2,300,000, preferably 800,000-2,000,000, and more preferably 1,500,000.
In a preferred embodiment of the present invention, the content of hyaluronic acid in the composition is not higher than 0.05%, preferably not higher than 0.04%, more preferably 0.02-0.04%.
In a preferred embodiment of the present invention, the content of hyaluronic acid in the composition is not 0.
In a preferred embodiment of the present invention, the injectable implant composition is a lyophilized powder preparation.
In a preferred technical scheme of the invention, the freeze-dried powder preparation contains 50% -90% of suspension stabilizer, 0.01% -5% of surfactant and optional buffering agent.
In the preferred technical scheme of the invention, the dosage of the suspension stabilizer in the freeze-dried powder preparation is 55-90%, preferably 60-90%, and more preferably 70-88%.
In the preferable technical scheme of the invention, the dosage of the surfactant in the freeze-dried powder preparation is 0.05% -4%, preferably 0.08% -3%, and more preferably 0.1% -2.5%.
In a preferred technical scheme of the invention, the suspension stabilizer is selected from any one of sucrose, maltose, lactose, fructose, dextran, mannitol, trehalose, sorbitol, xylitol, maltitol, oligosaccharide alcohol and polyethylene glycol or a combination thereof.
In a preferred embodiment of the present invention, the surfactant is selected from any one of stearic acid, sodium dodecyl sulfate, lecithin, alkyl glucoside, polysorbate, sorbitan fatty acid ester, poloxamer, or a combination thereof.
In a preferred technical scheme of the invention, the buffering agent is selected from any one of phosphate-phosphate, citric acid-citrate, EDTA-EDTA salt and citric acid-citrate or the combination thereof.
In a preferred embodiment of the present invention, the pH of the injectable implant composition is 4.5 to 7.5, preferably 5 to 7, and more preferably 5.5 to 6.5.
In a preferred technical scheme of the invention, the injection implant composition contains 10-20% of PLLA microparticles, 75-88% of mannitol, 0.1-2.5% of poloxamer and 0.02-0.05% of hyaluronic acid.
Another object of the present invention is to provide a method for preparing a lyophilized powder preparation of an injectable implant, comprising the steps of: suspending the polymer particles in an aqueous solution of a suspension stabilizer, a surfactant and optionally a buffer, and freeze-drying to obtain the polymer particles.
In a preferred technical scheme of the invention, the preparation method of the freeze-dried powder preparation comprises the following steps: weighing the required amount of the materials, putting the other components except the polymer particles into a closed container, adding water, stirring until the components are completely dissolved, then adding the PLLA particles, vacuumizing under the stirring condition, and freeze-drying to obtain the polymer particles.
In a preferred technical scheme of the invention, the preparation method of the freeze-dried powder preparation comprises the following steps: weighing mannitol, poloxamer and hyaluronic acid with required amounts, placing in a closed container, adding water, stirring, adding PLLA microparticles after dissolving completely, vacuumizing under stirring, and freeze drying to obtain the final product.
In the preferred technical scheme of the invention, the vacuum degree is-0.08 MPa.
In the preferred technical scheme of the invention, the stirring speed is 1500-.
It is another object of the present invention to provide a method for increasing the cellular affinity of PLLA polymer, comprising the steps of: (1) dissolving a biodegradable polymer in a benign solvent; (2) dripping a poor solvent, and crystallizing; (3) filtering and washing; (4) and (5) drying to obtain the product.
In a preferred embodiment of the present invention, the benign solvent is selected from one or a combination of tetrahydrofuran, 1, 4-dioxane, dichloromethane, chloroform, N-dimethylformamide, dimethyl sulfoxide, ethylene glycol diethyl ether, ethylene glycol dimethyl ether, toluene and p-xylene.
In a preferred embodiment of the invention, the amount of the benign solvent is 5 to 50 times, preferably 10 to 40 times, and more preferably 12 to 20 times that of the biodegradable polymer.
In a preferred embodiment of the present invention, the poor solvent is selected from any one of methanol, ethanol, isopropanol, n-propanol, butanol, acetone, butanone, 4-methyl-2-pentanone, ethyl acetate, butyl acetate, isopropyl acetate, n-hexane, cyclohexane, n-heptane, and n-octane, or a combination thereof.
In a preferred embodiment of the present invention, the amount of the poor solvent is 30 to 90 times, preferably 40 to 80 times, and more preferably 50 to 70 times that of the biodegradable polymer.
In a preferred technical scheme of the invention, the preparation method further comprises the following step (5): the resulting polymer particles were sieved through a 200 mesh sieve.
In a preferred embodiment of the present invention, the polymer fine particles have a particle size of 10 to 150. mu.m, preferably 20 to 120. mu.m, and more preferably 30 to 100. mu.m.
In a preferred embodiment of the present invention, the weight average molecular weight of the polymer particles is 10,000-100,000, preferably 20,000-75,000, and more preferably 30,000-50,000.
In a preferred embodiment of the present invention, the repeating unit of the polymer microparticle is selected from any one of levolactic acid, dextrolactic acid, racemic lactic acid, and glycolic acid, or a combination thereof.
In a preferred embodiment of the present invention, the polymer particles are selected from the group consisting of poly (L-lactic acid) (PLLA), poly (D-lactic acid) (PDLA), poly (racemic lactic acid) (PDLLA), poly (lactic-co-glycolic acid) (PLGA), and poly (glycolic acid) (PGA), or a copolymer thereof.
In a preferred embodiment of the present invention, the polymer fine particles have an irregular shape.
In a preferred embodiment of the present invention, the irregular shape of the polymer microparticles is selected from any one of or a combination of approximately square, approximately spherical, approximately rectangular, approximately rhombic, approximately triangular, approximately circular, approximately elliptical, approximately trapezoidal, approximately conical, and approximately cylindrical shapes.
In a preferred embodiment of the present invention, the irregular shape of the polymer particles is selected from any one of a sheet shape, a block shape, a spherical shape, a strip shape, a filament shape, and a granular shape, or a combination thereof.
In a preferred embodiment of the present invention, the irregular shape of the polymer particles is selected from any one of a stacked shape and a wound shape, or a combination thereof.
In a preferred embodiment of the present invention, the polymer fine particles have a rough surface or a matte surface.
In a preferred embodiment of the present invention, the rough surface or the matte surface of the polymer particles has irregular pore diameters.
In a preferred embodiment of the present invention, the total heat of fusion of the polymer particles heated from 40 ℃ to 230 ℃ at a heating rate of 10 ℃/min is 40J/g to 80J/g, preferably 45J/g to 70J/g, and more preferably 55J/g to 65J/g.
It is another object of the present invention to provide the use of hyaluronic acid for the preparation of a composition for reducing the irritation of PLLA injection.
In a preferred technical scheme of the invention, the reduction of the PLLA injection irritation is selected from any one or a combination of reduction of injection pain, reduction of adverse reaction incidence and reduction of adverse reaction degree.
In a preferred embodiment of the present invention, the adverse reaction is selected from any one of red swelling, ecchymosis, bruise, edema, pimple, nodule, hardening of injection region, abscess, anaphylaxis, urticaria, skin hypertrophy and atrophy, angioedema, vascular embolism, telangiectasia, skin sarcoidosis, scar, skin discoloration, and blood oozing at the needle insertion site, or a combination thereof.
In a preferred embodiment of the present invention, the hyaluronic acid is selected from any one of cross-linked hyaluronic acid and non-cross-linked hyaluronic acid, or a combination thereof.
In a preferred embodiment of the present invention, the weight average molecular weight of hyaluronic acid in the composition is 600,000-2,300,000, preferably 800,000-2,000,000, and more preferably 1,500,000.
In a preferred embodiment of the present invention, the hyaluronic acid content of the composition is not higher than 0.1%, preferably not higher than 0.05%, more preferably not higher than 0.04%, and most preferably 0.02-0.04%.
In a preferred embodiment of the present invention, the content of hyaluronic acid in the composition is not 0.
The freeze-dried powder preparation of the invention is injected into rats subcutaneously, the application part of the freeze-dried powder preparation without hyaluronic acid slightly bleeds, and small erythema occurs, while the freeze-dried powder preparation added with hyaluronic acid does not have skin irritation reactions such as bleeding, erythema, edema and the like. The result shows that the hyaluronic acid added into the freeze-dried powder preparation can obviously reduce the injection irritation and improve the medication safety and the compliance.
The invention also aims to provide application of hyaluronic acid in improving the physical stability of reconstitution of a freeze-dried powder preparation.
In the preferable technical scheme of the invention, the improvement of the physical stability of the redissolution of the freeze-dried powder preparation is selected from any one or combination of reduction of the floating object on the liquid surface of the redissolution and prolongation of the sedimentation time of insoluble substances.
In a preferred embodiment of the invention, the extended insoluble settling time is selected from the group consisting of no visible settling in at least 3 minutes, preferably no visible settling in at least 5 minutes, more preferably no visible settling in at least 20 minutes, and most preferably no visible settling in at least 30 minutes.
In a preferred embodiment of the present invention, the hyaluronic acid is selected from any one of cross-linked hyaluronic acid and non-cross-linked hyaluronic acid, or a combination thereof.
In a preferred embodiment of the present invention, the weight average molecular weight of the hyaluronic acid is 600,000-2,300,000, preferably 800,000-2,000,000, and more preferably 1,500,000.
In a preferred embodiment of the present invention, the content of hyaluronic acid in the lyophilized powder preparation is not higher than 0.1%, preferably not higher than 0.05%, more preferably not higher than 0.04%, and most preferably 0.02-0.04%.
In a preferred embodiment of the present invention, the content of hyaluronic acid in the lyophilized powder preparation is not 0.
In a preferred embodiment of the present invention, the dosage of the injection implant composition or the lyophilized powder preparation is related to the age, sex, filling site and other factors of the patient, and the using method comprises: adding appropriate amount of water for injection into lyophilized powder preparation, and shaking and mixing well before use.
In a preferred embodiment of the present invention, the injection site of the composition is selected from any one of the superficial dermis, the deep dermis, the subcutaneous layer, and the intradermal layer, or a combination thereof.
The invention also aims to provide application of the injection implant freeze-dried powder preparation in preparing subcutaneous injection fillers for patients.
In a preferred embodiment of the present invention, the injection filling site is selected from any one or a combination of the face, neck, abdomen, chest, buttocks, thigh, calf, upper arm and lower arm, and preferably the injection filling site is the face.
In a preferred embodiment of the present invention, the patient's symptoms are selected from any one of facial wasting, lipoatrophy, cheek sinking, eye socket sinking, skin wrinkles or a combination thereof.
In the preferable technical scheme of the invention, the injection implant freeze-dried powder preparation is applied to the preparation of the composition for treating the facial lipoatrophy of HIV-infected patients.
In the preferable technical scheme of the invention, the injection implant freeze-dried powder preparation is applied to the preparation of the composition for treating acne scars on hills and valleys.
In a preferred technical scheme of the invention, the injection implant freeze-dried powder preparation is used for preparing a composition for filling facial wrinkles by injection.
In a preferred embodiment of the present invention, the facial wrinkles are selected from any one of or a combination of the superficial to deep nasolabial folds, glabellar folds, forehead, outer canthus, and canthus.
Another object of the present invention is to provide a combination of the lyophilized powder preparation for injection implant, which is used in combination with any one or a combination of other types of injection fillers, anesthetics, anti-inflammatory agents, and anti-allergic agents.
In a preferred embodiment of the present invention, the other type of injection filler is selected from any one of collagen, hyaluronic acid, polymethyl methacrylate, polyacrylamide, silica gel, autologous fat, or a combination thereof.
In a preferred embodiment of the present invention, the anesthetic is selected from any one of lidocaine, procaine, tetracaine, bupivacaine, ropivacaine, diclofenac, morphine, hydrocodone, oxycodone, codeine, fentanyl, sodium pentobarbital, sodium phenobarbital, thiopental, aldochloroketone, ethyl carbamate, and chloral hydrate, or a combination thereof.
In a preferred embodiment of the present invention, the anti-inflammatory agent is selected from any one of a steroidal anti-inflammatory agent and a non-steroidal anti-inflammatory agent, or a combination thereof.
In a preferred embodiment of the present invention, the steroidal anti-inflammatory agent is selected from one of fluocinolone, hydrocortisone and betamethasone, or a combination thereof.
In a preferred embodiment of the present invention, the non-steroidal anti-inflammatory agent is selected from any one of aspirin, magnesium salicylate, sodium salicylate, choline magnesium salicylate, diflunisal, salsalate, ibuprofen, indomethacin, flurbiprofen, phenoxyibuprofen, naproxen, nabumetone, piroxicam, phenylbutazone, diclofenac, fenprofen, ketoprofen, ketorolac, tetrachlorofenamic acid, sulindac, and tolmetin, or a combination thereof.
In a preferred technical scheme of the invention, the antiallergic agent is any one or a combination of diphenhydramine, promethazine, chlorpheniramine, cromolyn sodium, ketotifen, betahistine, montelukast, zafirlust, salbutamol, calcium gluconate and glucocorticoid.
Unless otherwise indicated, when the present invention relates to percentages between liquids, said percentages are volume/volume percentages; the invention relates to the percentage between liquid and solid, said percentage being volume/weight percentage; the invention relates to the percentages between solid and liquid, said percentages being weight/volume percentages; the balance being weight/weight percent.
In order to clearly convey the scope of the invention, the invention is defined by the following terms:
1. the "weight average molecular weight" of the PLLA fine particles of the present invention is obtained by gel permeation chromatography using hexafluoroisopropanol as a solvent, and the value is calculated as polymethyl methacrylate.
2. The "heat of fusion" of the PLLA fine particles of the present invention was measured by DSC from 40 ℃ at a rate of 20 ℃/min to 230 ℃ in a nitrogen atmosphere.
3. The "particle diameter" of the PLLA fine particles of the present invention means a particle diameter corresponding to 90% of the particle diameter distribution (D90).
4. The PLLA particles of the invention have a particle size distribution determined by an ultra-high speed intelligent particle size analyzer under the air pressure of 2.0barg and at a sample injection speed of 35% and a hopper gap of 1.50 mm.
5. The scanning electron microscope image of the PLLA particles is obtained by adopting a scanning electron microscope (model: Thermo-prism E) to amplify 1000 times and 5000 times for detection.
6. The "D (4, 3)" and "D (3, 2)" of the PLLA fine particles of the present invention were measured by using an average particle size meter HMK-22. D (4,3) refers to the volume average diameter of the microparticles, and D (3,2) refers to the surface area average diameter of the microparticles. The larger the values of D (4,3) and D (3,2), the broader the particle size distribution of the microparticles.
Compared with the prior art, the invention has the following beneficial technical effects:
1. the PLLA particles of the present invention have an irregular, unsmooth or rough microscopic appearance. The irregular shape contains a porous structure or forms a support structure, so that the contact area of the PLLA particles and cells is increased, the adhesion capacity and the residence time of the cells on the porous structure or the support structure are improved, the cell affinity of the PLLA particles is obviously improved, collagen cells are stimulated to feel physical and mechanical microenvironment stimulation and respond to the physical and mechanical microenvironment stimulation, and the collagen growth of an organism is stimulated and accelerated.
2. The PLLA particles have uniform particle size distribution, the maximum particle size is about 76 mu m, and the possibility of needle blockage in the injection process can be reduced to the maximum extent.
3. The hyaluronic acid is added into the biodegradable injection filling composition, so that the filling effect or filling effect of the composition is obviously improved, wrinkles are removed, the beauty of facial skin is enhanced, and the suspension stability of PLLA particles after freeze-drying and redissolving is favorably improved. The hydrophilicity of the hyaluronic acid obviously improves the hydrophobic property of the surface of the PLLA polymer scaffold, and promotes the adhesion growth of collagen cells on the surface of the PLLA polymer scaffold. The water-absorbing property of the hyaluronic acid is beneficial to reducing the hydrolysis and degradation of ester bonds of the PLLA and reducing the stimulation of acidic degradation products to surrounding tissues.
4. The hyaluronic acid dosage in the biodegradable injection filling composition scientifically screened by the invention can obviously improve the effects of smoothing wrinkles, reshaping skin contours, delaying aging and the like of the composition. Hyaluronic acid takes effect rapidly in vivo, and makes skin water full, fine and smooth; PLLA stimulates progressive collagen proliferation and the cosmetic effect is natural and lasting.
5. The biodegradable injection filler or the composition thereof is safe and effective, is simple and convenient to prepare, and is suitable for industrial mass production.