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WO2023082634A1 - 一种可生物降解的共聚物及其制备方法和应用 - Google Patents

一种可生物降解的共聚物及其制备方法和应用 Download PDF

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Publication number
WO2023082634A1
WO2023082634A1 PCT/CN2022/099058 CN2022099058W WO2023082634A1 WO 2023082634 A1 WO2023082634 A1 WO 2023082634A1 CN 2022099058 W CN2022099058 W CN 2022099058W WO 2023082634 A1 WO2023082634 A1 WO 2023082634A1
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copolymer
present
preferred technical
polyethylene glycol
technical solution
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PCT/CN2022/099058
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English (en)
French (fr)
Inventor
闫瑞国
王爽
杨全飞
刘喆
武秋红
Original Assignee
渼颜空间(河北)生物科技有限公司
北京渼颜空间生物医药有限公司
渼颜空间生物科技(吉林)有限公司
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Publication of WO2023082634A1 publication Critical patent/WO2023082634A1/zh

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    • A—HUMAN NECESSITIES
    • A43—FOOTWEAR
    • A43B—CHARACTERISTIC FEATURES OF FOOTWEAR; PARTS OF FOOTWEAR
    • A43B13/00—Soles; Sole-and-heel integral units
    • A43B13/02—Soles; Sole-and-heel integral units characterised by the material
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • 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
    • A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • 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
    • A61L27/58—Materials at least partially resorbable by the body
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29B—PREPARATION OR PRETREATMENT OF THE MATERIAL TO BE SHAPED; MAKING GRANULES OR PREFORMS; RECOVERY OF PLASTICS OR OTHER CONSTITUENTS OF WASTE MATERIAL CONTAINING PLASTICS
    • B29B9/00—Making granules
    • B29B9/12—Making granules characterised by structure or composition
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/02—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds
    • C08G63/06—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds derived from hydroxycarboxylic acids
    • C08G63/08—Lactones or lactides
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/66—Polyesters containing oxygen in the form of ether groups
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/66—Polyesters containing oxygen in the form of ether groups
    • C08G63/664—Polyesters containing oxygen in the form of ether groups derived from hydroxy carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/88—Post-polymerisation treatment
    • C08G63/90—Purification; Drying
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L51/00—Compositions of graft polymers in which the grafted component is obtained by reactions only involving carbon-to-carbon unsaturated bonds; Compositions of derivatives of such polymers
    • C08L51/06—Compositions of graft polymers in which the grafted component is obtained by reactions only involving carbon-to-carbon unsaturated bonds; Compositions of derivatives of such polymers grafted on to homopolymers or copolymers of aliphatic hydrocarbons containing only one carbon-to-carbon double bond
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02W—CLIMATE CHANGE MITIGATION TECHNOLOGIES RELATED TO WASTEWATER TREATMENT OR WASTE MANAGEMENT
    • Y02W90/00—Enabling technologies or technologies with a potential or indirect contribution to greenhouse gas [GHG] emissions mitigation
    • Y02W90/10—Bio-packaging, e.g. packing containers made from renewable resources or bio-plastics

Definitions

  • the invention relates to the field of medical cosmetology, in particular but not limited to a biodegradable copolymer and its preparation method and application.
  • poly-L-lactic acid When poly-L-lactic acid is used as a medical cosmetic filling material, it usually needs to be prepared into micron-sized particles or microspheres, and then injected into the deep tissue of the skin through a syringe to achieve the effect of filling cosmetics.
  • FDA approved and The main active ingredients of the drug are poly-L-lactic acid, and sodium carboxymethylcellulose is used as a suspending agent, but it needs to be pre-infiltrated for more than 2 hours before it can be used for intradermal injection. If the suspension is not uniform, it is easy to cause the appearance of subcutaneous nodules, which brings inconvenience to the doctor and reduces the experience of the patient; the particle size of the product is different (10-150 ⁇ m), and it is very easy to cause needle blocking in clinical use. It increases the possibility of bacterial infection during clinical use; due to the size of the microsphere itself and the dispersion of the water phase, its stability and needle penetration are extremely poor, and it is also very easy to aggregate after being injected into the tissue. higher risk.
  • CN104592727B discloses a biodegradable physical hydrogel capable of rapid gelation in situ, consisting of an aqueous solution of component A and an aqueous solution of component B, wherein component A is a diblock copolymer of PEG-PDLA or PEG-PLLA ; Component B is a triblock copolymer of PLLA-PEG-PLLAPDLA-PEG-PDLA.
  • CN112354018A discloses a soft tissue filling hydrogel for medical cosmetology, including poly-L-lactic acid-polyethylene glycol-poly-L-lactic acid copolymer or poly-lactide-polyethylene glycol-poly-lactide copolymer.
  • the object of the present invention is to provide a biodegradable copolymer formed from polylactic acid and polyethylene glycol derivatives.
  • polylactic acid is selected from poly-L-lactic acid, poly-D-lactic acid (Poly-D-Lactic acid, PDLA) and polyracemic lactic acid (Poly(D, L-lactide), PDLLA), Preferred is PLLA.
  • polyethylene glycol derivatives are selected from polyethylene glycol monomethyl ether (also known as methoxypolyethylene glycol, Methoxypolyethylene glycols, MPEG), ethoxypolyethylene glycol, propane Any one or combination of oxypolyethylene glycols, preferably MPEG.
  • polyethylene glycol monomethyl ether also known as methoxypolyethylene glycol, Methoxypolyethylene glycols, MPEG
  • ethoxypolyethylene glycol propane Any one or combination of oxypolyethylene glycols, preferably MPEG.
  • the copolymer is formed of PLLA and MPEG.
  • MPEG is selected from MPEG-1000, MPEG-2000, MPEG-4000, MPEG-5000 and MPEG-10000.
  • MPEG is MPEG-5000.
  • the molar ratio of hydrophilic group/hydrophobic group in the copolymer is 20:1-1:1, preferably 10:1-2:1, more preferably 9:1- 7:3.
  • the intrinsic viscosity of the copolymer is 1ml/g-25ml/g at 20°C.
  • the intrinsic viscosity of the copolymer is 16ml/g-20ml/g at 20°C.
  • the intrinsic viscosity of the copolymer is 20.53ml/g at 20°C.
  • the intrinsic viscosity of the copolymer is 20.47ml/g at 20°C.
  • the number average molecular weight of the copolymer is 7000-1,5000.
  • the number average molecular weight of the copolymer is 9000-1,4000.
  • the number average molecular weight of the copolymer is 1,2000-1,4000.
  • the particle size of the copolymer is ⁇ 450nm.
  • the object of the present invention is also to provide the preparation method of described biodegradable copolymer, and described preparation method comprises:
  • the lactide is selected from L-lactide, D-lactide and D,L-lactide, preferably L-lactide.
  • the weight ratio of lactide to polyethylene glycol is 1:1-10.
  • the weight ratio of lactide to polyethylene glycol is 1:2-8.
  • the weight ratio of lactide to polyethylene glycol is 1:4.
  • the polyethylene glycol derivative is selected from methoxy polyethylene glycol, ethoxy polyethylene glycol, propoxy polyethylene glycol, preferably MPEG.
  • the weight ratio of lactide to polyethylene glycol derivatives is 1:1-10.
  • the weight ratio of lactide to polyethylene glycol derivatives is 1:2-8.
  • the weight ratio of lactide to polyethylene glycol derivatives is 1:4.
  • the protective gas is selected from any one or more of nitrogen and argon, preferably nitrogen.
  • reaction vessel is heated to 80-120°C.
  • reaction vessel is heated to 80-100°C.
  • reaction vessel is heated to 90°C.
  • the catalyst is selected from any one of stannous octoate, stannous chloride, zinc chloride or a combination thereof.
  • the catalyst is selected from any one of stannous octoate and stannous chloride or a combination thereof, preferably stannous octoate.
  • the heating reaction is carried out at a temperature of 100-140°C.
  • the heating reaction is carried out at a temperature of 110-130°C.
  • the heating reaction is carried out at a temperature of 120°C.
  • the heating reaction lasts for 6-30 hours.
  • the heating reaction lasts for 8-24 hours.
  • the heating reaction continued for 12 hours.
  • the vacuuming lasts for 10-30 minutes, preferably 30 minutes.
  • the present invention also provides a purification method for the biodegradable copolymer, the purification method comprising:
  • the amount of the good solvent used is 3-25 times that of lactide, preferably 5-20 times, more preferably 10-15 times.
  • the amount of the poor solvent used is 30-70 times that of lactide, preferably 40-60 times, more preferably 45-55 times.
  • the ratio of the good solvent to the poor solvent is 1:3-10, preferably 1:6.
  • the benign solvent is selected from tetrahydrofuran, 1,4-dioxane, dichloromethane, chloroform, N,N-dimethylformamide, dimethyl sulfoxide, Any one of ethylene glycol diethyl ether, ethylene glycol dimethyl ether, toluene, p-xylene or a combination thereof, preferably dichloromethane.
  • described poor solvent is selected from methanol, ethanol, isopropanol, n-propanol, butanol, acetone, butanone, 4-methyl 2-pentanone, ethyl acetate, acetic acid Any one of butyl ester, isopropyl acetate, n-hexane, cyclohexane, n-heptane, n-octane, isopropyl ether or a combination thereof, preferably isopropyl ether.
  • the object of the present invention is also to provide a composition comprising the biodegradable copolymer, wherein the composition is made into a liquid injection or a powder injection.
  • the copolymer is formed of polylactic acid and polyethylene glycol derivatives.
  • polylactic acid is selected from poly-L-lactic acid, poly-D-lactic acid (Poly-D-Lactic acid, PDLA) and polyracemic lactic acid (Poly(D, L-lactide), PDLLA), Preferred is PLLA.
  • polyethylene glycol derivatives are selected from polyethylene glycol, polyethylene glycol monomethyl ether (also known as methoxypolyethylene glycol, Methoxypolyethylene glycols, MPEG), ethoxypolyethylene glycol Any one or combination of ethylene glycol, propoxypolyethylene glycol, preferably MPEG.
  • the copolymer is formed of PLLA and MPEG.
  • MPEG is selected from MPEG-1000, MPEG-2000, MPEG-4000, MPEG-5000 and MPEG-10000.
  • MPEG is MPEG-5000.
  • the molar ratio of hydrophilic group/hydrophobic group in the copolymer is 20:1-1:1, preferably 10:1-2:1, more preferably 9:1- 7:3.
  • the intrinsic viscosity of the copolymer is 1ml/g-25ml/g at 20°C.
  • the intrinsic viscosity of the copolymer is 16ml/g-20ml/g at 20°C.
  • the intrinsic viscosity of the copolymer is 20.53ml/g at 20°C.
  • the intrinsic viscosity of the copolymer is 20.47ml/g at 20°C.
  • the number average molecular weight of the copolymer is 7000-1,5000.
  • the number average molecular weight of the copolymer is 9000-1,4000.
  • the number average molecular weight of the copolymer is 1,2000-1,4000.
  • the particle diameter of the copolymer is ⁇ 450nm.
  • the composition further includes any one or a combination of polyols, amino acids, polypeptides, proteins, nucleic acids, vitamins, polysaccharides and local anesthetics.
  • the composition also includes polyvinyl alcohol, gelatin, gum arabic, guar gum, chondroitin sulfate, hyaluronic acid, sodium carboxymethylcellulose, polyvinylpyrrolidone, methylcellulose
  • polyvinyl alcohol hydroxypropylmethylcellulose, starch, pectinic acid, heparin, glucose, ⁇ -cyclodextrin, chitosan, sodium alginate.
  • the liquid injection is selected from any one of hydrogel, suspension, solution or a combination thereof.
  • the solution is an aqueous solution, wherein the weight ratio of the biodegradable copolymer to ultrapure water is 10-20:100, preferably 15:100.
  • the present invention also provides a preparation method for an aqueous solution comprising the biodegradable copolymer, the preparation method comprising:
  • the weight ratio of the purified copolymer to the ultrapure water is 10-20:100, preferably 15:100.
  • the filter membrane is a 1 ⁇ m filter membrane, a 0.45 ⁇ m filter membrane or a 0.22 ⁇ m filter membrane, preferably a 0.22 ⁇ m filter membrane.
  • the powder injection is freeze-dried powder.
  • the lyophilized powder formulation comprises any one or a combination of suspension stabilizers, surfactants and buffers.
  • suspension stabilizer is selected from sucrose, maltose, lactose, fructose, dextran, mannitol, trehalose, sorbitol, xylitol, maltitol, oligosaccharide alcohol, Any one or combination of polyethylene glycols.
  • the surfactant is selected from the group consisting of stearic acid, sodium lauryl sulfonate, lecithin, alkyl glucoside, polysorbate, sorbitan fatty acid ester, polysorbate Any one or combination of loxamers.
  • the buffer is selected from any one of phosphoric acid-phosphate, citric acid-citrate, EDTA-EDTA salt, citric acid-citrate or a combination thereof.
  • compositions are used in combination with any one or a combination of other types of injection fillers, anesthetics, anti-inflammatory agents, and anti-allergic agents.
  • the other types of injection fillers are selected from collagen, hyaluronic acid, polymethyl methacrylate, polyacrylamide, silica gel, autologous fat or any combination thereof.
  • the anesthetic is selected from the group consisting of lidocaine, procaine, tetracaine, bupivacaine, ropivacaine, diclofenac, morphine, hydrocodone, oxycodone, Any one of codeine, fentanyl, pentobarbital sodium, phenobarbital sodium, thiopental sodium, chloralose, ethyl carbamate, chloral hydrate, or a combination thereof.
  • the anti-inflammatory agent is selected from any one of steroidal anti-inflammatory agents, non-steroidal anti-inflammatory agents or a combination thereof.
  • the steroid anti-inflammatory agent is selected from any one of fluocinolone, hydrocortisone, betamethasone or a combination thereof.
  • the non-steroidal anti-inflammatory agent is selected from aspirin, magnesium salicylate, sodium salicylate, choline magnesium salicylate, diflunisal, salicylate, and ibuprofen Fen, Indomethacin, Flurbiprofen, Phenoxyibuprofen, Naproxen, Nabumetone, Piroxicam, Butazone, Diclofenac, Fenprofen, Ketoprofen, Ketorolac , tetraclofenamic acid, sulindac, tolmetin any one or a combination thereof.
  • the antiallergic agent is selected from the group consisting of diphenhydramine, promethazine, chlorpheniramine, cromolyn sodium, ketotifen, betahistine, montelukast, zalu Any one or a combination of glucocorticoids, salbutamol, calcium gluconate, and adrenal glucocorticoids.
  • the biodegradable copolymer of the present invention is uniform and stable, has good dispersibility and uniformity, and is not easy to produce nodules and redness reactions after entering the skin, thereby ensuring the effect, safety and quality of the product to be controllable;
  • Embodiment 1 the preparation of MPEG-PLLA
  • MPEG-PLLA was prepared according to the preparation method of Example 1.1, except that the methoxypolyethylene glycol was MPEG2000.
  • MPEG-PLLA was prepared according to the preparation method of Example 1.1, except that the methoxypolyethylene glycol was MPEG4000.
  • MPEG-PLLA was prepared according to the preparation method of Example 1.1, except that the methoxypolyethylene glycol was MPEG5000.
  • MPEG-PLLA was prepared according to the preparation method of Example 1.1, except that the methoxypolyethylene glycol was MPEG10000.
  • Embodiment 2 the preparation of MPEG-PLLA
  • MPEG-PLLA was prepared according to the preparation method of Example 1.4, except that: 30 g of L-lactide and 170 g of MPEG5000.
  • Embodiment 3 the preparation of MPEG-PLLA
  • MPEG-PLLA was prepared according to the preparation method of Example 1.4, the difference being: nitrogen replacement and heating up to 130°C.
  • Embodiment 4 the purification of MPEG-PLLA
  • Example 1.4 Take about 200g of the product prepared in Example 1.4, add 1000ml of dichloromethane and stir to dissolve the reactant. After the sample is dissolved, add 10g of activated carbon, stir at 200rpm for 10 minutes, filter through a 0.22 ⁇ m filter membrane, and slowly add 6000ml of absolute ethanol. Stir at 100 rpm for 30 minutes, the solution becomes turbid, filter, rinse the filter cake with isopropyl ether, and dry the filter cake at 30-40°C for 15-24 hours to obtain mPEG-PLA copolymer.
  • Example 1.4 Take about 200g of the product prepared in Example 1.4, add 1000ml of dichloromethane and stir to dissolve the reactant. After the sample is dissolved, add 10g of activated carbon, stir at 200rpm for 10 minutes, and filter through a 0.22 ⁇ m filter membrane. After the sample is dissolved, slowly add 6000ml of water and methanol, stirred at 100rpm for 30min, the solution became turbid, filtered, rinsed with isopropyl ether, and dried at 30-40°C for 15-24 hours to obtain mPEG-PLA copolymer.
  • Example 1.4 Take about 200 g of the product prepared in Example 1.4, add 1000 ml of dichloromethane and stir to dissolve the reactant. After the sample is dissolved, add 10 g of activated carbon, stir at 200 rpm for 10 minutes, filter through a 0.22 ⁇ m filter membrane, and slowly add 6000 ml of isopropyl ether. Stir at 100 rpm for 30 minutes, a white solid precipitates out, filter, rinse the filter cake with isopropyl ether, and dry the filter cake at 30-40°C for 15-24 hours to obtain mPEG-PLA copolymer.
  • Example 1.4 Take about 200 g of the product prepared in Example 1.4, add 1000 ml of dichloromethane and stir to dissolve the reactant, add 10 g of activated carbon after the sample is dissolved, stir at 200 rpm for 10 minutes, filter through a 0.22 ⁇ m filter membrane, and slowly add 3000 ml of isopropyl ether, Stir at 100 rpm for 30 minutes, the solution becomes turbid, filter, rinse the filter cake with isopropyl ether, and dry the filter cake at 30-40°C for 15-24 hours to obtain mPEG-PLA copolymer.
  • Embodiment 5 the preparation of MPEG-PLLA preparation
  • Example 4.3 Take 15g of the product prepared in Example 4.3, add it to ultrapure water and stir until it is completely solvent, transfer the solution to a 100ml volumetric flask, and dilute to the mark with ultrapure water. After taking constant volume, the solution was filtered with a 1 ⁇ m filter membrane, and the liquid had light blue opalescence.
  • Example 4.3 Take 15g of the product prepared in Example 4.3, add it to ultrapure water and stir until it is completely solvent, transfer the solution to a 100ml volumetric flask, and dilute to the mark with ultrapure water. The solution was taken to a constant volume and filtered with a 0.45 ⁇ m filter membrane to obtain a liquid with light blue opalescence.
  • Example 4.3 Take 15g of the product prepared in Example 4.3, add it to ultrapure water and stir until it is completely solvent, transfer the solution to a 100ml volumetric flask, and dilute to the mark with ultrapure water. The solution was taken to a constant volume and filtered with a 0.22 ⁇ m filter membrane to obtain a clear liquid.

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  • Bioinformatics & Cheminformatics (AREA)
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  • Inorganic Chemistry (AREA)
  • Materials Engineering (AREA)
  • Mechanical Engineering (AREA)
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  • Polyethers (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract

一种可生物降解的共聚物，所述共聚物由聚乳酸和聚乙二醇衍生物形成。所述可生物降解的共聚物均匀稳定，分散性和均匀度好，进入皮肤后不易产生结节和红肿反应，保证了产品的效果、安全性和质量可控。

Description

一种可生物降解的共聚物及其制备方法和应用 技术领域
本发明涉及医疗美容领域，具体地涉及但不限于一种可生物降解的共聚物及其制备方法和应用。
背景技术
聚左旋乳酸在作为医疗美容填充材料使用时，通常需要将其制备成尺寸在微米级的微粒或微球，进而通过注射器将其注入到皮肤的深层组织，实现填充美容的功效。FDA批准的
Figure PCTCN2022099058-appb-000001
和
Figure PCTCN2022099058-appb-000002
的主要有效成分均为聚左旋乳酸，采用羧甲基纤维素钠作为助悬剂，但是需预先浸润2小时以上，才能用于皮内注射。如果混悬不均匀，容易造成皮下结节的出现，给医生的使用带来了不便，也降低了患者的体验；产品颗粒大小不一(10-150μm)，临床使用极易出现堵针情况，增加了临床使用过程中染菌的可能性；由于微球自身的尺寸和水相分散性问题，其稳定性和通针性极差，注射到组织内部后也极易聚集，在临床使用中具有较高的风险。
CN104592727B公开了可原位快速凝胶化的生物可降解物理水凝胶，由组分A水溶液和组分B水溶液构成，其中，组分A为PEG-PDLA或PEG-PLLA的二嵌段共聚物；组分B为PLLA-PEG-PLLAPDLA-PEG-PDLA的三嵌段共聚物。
CN112354018A公开了一种用于医疗美容的软组织填充水凝胶，包括聚左旋乳酸-聚乙二醇-聚左旋乳酸共聚物或聚消旋乳酸-聚乙二醇-聚消旋乳酸共聚物。
郝红等人(可注射PLLA-mPEG水凝胶的制备及性能研究，高校化学工程学报，第28卷第5期，2014.10,1126-1131)公开了一系列分子量在 7000以下的PLLA-MPEG共聚物作为盐酸乌拉地尔的控释载体。
鉴于现有技术，需要一种具有合适的黏度和分子量、分散性和均匀度良好，且进入皮肤后不易产生结节和红肿的不良反应的可生物降解的共聚物。
发明内容
本发明的目的在于提供一种可生物降解的共聚物，所述共聚物由聚乳酸和聚乙二醇衍生物形成。
在本发明的优选技术方案中，聚乳酸选自聚左旋乳酸、聚右旋乳酸(Poly-D-Lactic acid，PDLA)和聚外消旋乳酸(Poly(D,L-lactide)，PDLLA)，优选地为PLLA。
在本发明的优选技术方案中，聚乙二醇衍生物选自聚乙二醇单甲醚(也称甲氧基聚乙二醇，Methoxypolyethylene glycols，MPEG)、乙氧基聚乙二醇、丙氧基聚乙二醇中的任一种或其组合，优选地为MPEG。
在本发明的优选技术方案中，所述共聚物由PLLA和MPEG形成。
在本发明的优选技术方案中，MPEG选自MPEG-1000、MPEG-2000、MPEG-4000、MPEG-5000和MPEG-10000。优选地，MPEG为MPEG-5000。
在本发明的优选技术方案中，所述共聚物中亲水基团/疏水集团的摩尔比为20:1-1:1，优选地10:1-2:1，更优选地9:1-7:3。
在本发明的优选技术方案中，所述共聚物的特性粘数在20℃下为1ml/g-25ml/g。
在本发明的优选技术方案中，所述共聚物的特性粘数在20℃下为16ml/g-20ml/g。
在本发明的优选技术方案中，所述共聚物的特性粘数在20℃下为20.53ml/g。
在本发明的优选技术方案中，所述共聚物的特性粘数在20℃下为20.47ml/g。
在本发明的优选技术方案中，所述共聚物的数均分子量为7000-1,5000。
在本发明的优选技术方案中，所述共聚物的数均分子量为9000-1,4000。
在本发明的优选技术方案中，所述共聚物的数均分子量为1,2000-1,4000。
在本发明的优选技术方案中，所述共聚物的的粒径≤450nm。
本发明的目的还在于提供所述可生物降解的共聚物的制备方法，所述制备方法包括：
将丙交酯和聚乙二醇加入反应容器中，反应容器内部用保护气置换并通保护气，加热；
待熔融完全后，将反应容器内部抽真空直至无爆沸现象，并通保护气；
向反应容器中加入催化剂，抽真空至无爆沸现象，并通保护气，升温反应，反应完毕即得。
在本发明的优选技术方案中，所述丙交酯选自L-丙交酯、D-丙交酯和D,L-丙交酯，优选地为L-丙交酯。
在本发明的优选技术方案中，丙交酯与聚乙二醇的重量比为1:1-10。
在本发明的优选技术方案中，丙交酯与聚乙二醇的重量比为1:2-8。
在本发明的优选技术方案中，丙交酯与聚乙二醇的重量比为1:4。
在本发明的优选技术方案中，所述聚乙二醇衍生物选自甲氧基聚乙二醇、乙氧基聚乙二醇、丙氧基聚乙二醇，优选地为MPEG。
在本发明的优选技术方案中，丙交酯与聚乙二醇衍生物的重量比为1:1-10。
在本发明的优选技术方案中，丙交酯与聚乙二醇衍生物的重量比为1:2-8。
在本发明的优选技术方案中，丙交酯与聚乙二醇衍生物的重量比为 1:4。
在本发明的优选技术方案中，所述保护气选自氮气、氩气中的任一种或更多种，优选地为氮气。
在本发明的优选技术方案中，将反应容器加热至80-120℃。
在本发明的优选技术方案中，将反应容器加热至80-100℃。
在本发明的优选技术方案中，将反应容器加热至90℃。
在本发明的优选技术方案中，所述催化剂选自辛酸亚锡、氯化亚锡、氯化锌中的任一种或其组合。
在本发明的优选技术方案中，所述催化剂选自辛酸亚锡、氯化亚锡中的任一种或其组合，优选为辛酸亚锡。
在本发明的优选技术方案中，升温反应在100-140℃温度下进行。
在本发明的优选技术方案中，升温反应在110-130℃温度下进行。
在本发明的优选技术方案中，升温反应在120℃温度下进行。
在本发明的优选技术方案中，升温反应持续6-30小时。
在本发明的优选技术方案中，升温反应持续8-24小时。
在本发明的优选技术方案中，升温反应持续12小时。
在本发明的优选技术方案中，抽真空持续10-30min，优选地30min。
本发明还提供所述可生物降解的共聚物的纯化方法，所述纯化方法包括：
将所述制备方法制得的产品加入良性溶剂，搅拌，溶解，加入活性炭，过滤；
滤液中缓慢加入不良溶剂，搅拌，过滤；
使用不良溶剂淋洗，在30℃-40℃干燥15-24小时，即得精制的产品。
在本发明的优选技术方案中，所述良性溶剂的用量为丙交酯的3-25倍，优选为5-20倍，更优选为10-15倍。
在本发明的优选技术方案中，所述不良性溶剂的用量为丙交酯的30-70倍，优选为40-60倍，更优选为45-55倍。
在本发明的优选技术方案中，所述良性溶剂与所述不良溶剂的用量比为1:3-10，优选地1:6。
在本发明的优选技术方案中，所述的良性溶剂选自四氢呋喃、1,4-二氧六环、二氯甲烷、三氯甲烷、N,N-二甲基甲酰胺、二甲亚砜、乙二醇二乙醚、乙二醇二甲醚、甲苯、对二甲苯中的任一种或其组合，优选地为二氯甲烷。
本发明的优选技术方案中，所述的不良性溶剂选自甲醇、乙醇、异丙醇、正丙醇、丁醇、丙酮、丁酮、4-甲基2-戊酮、乙酸乙酯、乙酸丁酯、乙酸异丙酯、正己烷、环己烷、正庚烷、正辛烷、异丙醚中的任一种或其组合，优选地为异丙醚。
本发明的目的还在于提供一种组合物，包含所述可生物降解的共聚物，其中所述组合物制成液体针剂或粉针剂。
本发明的优选技术方案中，所述共聚物由聚乳酸和聚乙二醇衍生物形成。
在本发明的优选技术方案中，聚乳酸选自聚左旋乳酸、聚右旋乳酸(Poly-D-Lactic acid，PDLA)和聚外消旋乳酸(Poly(D,L-lactide)，PDLLA)，优选地为PLLA。
在本发明的优选技术方案中，聚乙二醇衍生物选自聚乙二醇、聚乙二醇单甲醚(也称甲氧基聚乙二醇，Methoxypolyethylene glycols，MPEG)、乙氧基聚乙二醇、丙氧基聚乙二醇中的任一种或其组合，优选地为MPEG。
在本发明的优选技术方案中，所述共聚物由PLLA和MPEG形成。
在本发明的优选技术方案中，MPEG选自MPEG-1000、MPEG-2000、MPEG-4000、MPEG-5000和MPEG-10000。优选地，MPEG为MPEG-5000。
在本发明的优选技术方案中，所述共聚物中亲水基团/疏水集团的摩尔比为20:1-1:1，优选地10:1-2:1，更优选地9:1-7:3。
在本发明的优选技术方案中，所述共聚物的特性粘数在20℃下为1ml/g-25ml/g。
在本发明的优选技术方案中，所述共聚物的特性粘数在20℃下为16ml/g-20ml/g。
在本发明的优选技术方案中，所述共聚物的特性粘数在20℃下为20.53ml/g。
在本发明的优选技术方案中，所述共聚物的特性粘数在20℃下为20.47ml/g。
在本发明的优选技术方案中，所述共聚物的数均分子量为7000-1,5000。
在本发明的优选技术方案中，所述共聚物的数均分子量为9000-1,4000。
在本发明的优选技术方案中，所述共聚物的数均分子量为1,2000-1,4000。
在本发明的优选技术方案中，所述共聚物的粒径≤450nm。
在本发明的优选技术方案中，所述组合物还包含多元醇、氨基酸、多肽、蛋白质、核酸、维生素、多糖及局部类麻醉剂中的任一种或其组合。
在本发明的优选技术方案中，所述组合物还包含聚乙烯醇、明胶、阿拉伯胶、瓜尔胶、硫酸软骨素、透明质酸、羧甲基纤维素钠、聚乙烯吡咯烷酮、甲基纤维素、羟丙基甲基纤维素、淀粉、果胶酸、肝素、葡萄糖、β-环糊精、壳聚糖、海藻酸钠中的一种或多种。
在本发明的优选技术方案中，所述液体针剂选自水凝胶、混悬液、溶液中的任一种或其组合。
在本发明的优选技术方案中，所述溶液为水溶液，其中所述可生物降解的共聚物与超纯水的重量比为10-20:100，优选地为15:100。
本发明还提供包含所述可生物降解的共聚物的水溶液的制备方法，所 述制备方法包括：
将纯化后的共聚物，加入至超纯水中搅拌至完全溶解，将溶液用超纯水定容，将定容后的溶液用滤膜过滤。
在本发明的优选技术方案中，纯化的共聚物与超纯水的重量比为10-20:100，优选地为15:100。
在本发明的优选技术方案中，滤膜为1μm滤膜、0.45μm滤膜或0.22μm滤膜，优选地为0.22μm滤膜。
在本发明的优选技术方案中，所述粉针剂为冻干粉。
在本发明的优选技术方案中，所述冻干粉制剂包含悬浮稳定剂、表面活性剂和缓冲剂中的任一种或其组合。
在本发明的优选技术方案中，所述的悬浮稳定剂选自蔗糖、麦芽糖、乳糖、果糖、葡聚糖、甘露醇、海藻糖、山梨醇、木糖醇、麦芽糖醇、低聚糖醇、聚乙二醇的任一种或其组合。
在本发明的优选技术方案中，所述的表面活性剂选自硬脂酸、十二烷基磺酸钠、卵磷脂、烷基葡糖苷、聚山梨酸酯、脱水山梨醇脂肪酸酯、泊洛沙姆的任一种或其组合。
在本发明的优选技术方案中，所述的缓冲剂选自磷酸-磷酸盐、柠檬酸-柠檬酸盐、EDTA-EDTA盐、枸橼酸-枸橼酸盐的任一种或其组合。
本发明的还在于提供所述组合物的联用方式，将所述组合物与其他类型注射填充物、麻醉剂、消炎剂、抗过敏剂的任一种或其组合联合使用。
本发明的优选技术方案中，所述的其他类型注射填充物选自胶原蛋白、透明质酸、聚甲基丙烯酸甲酯、聚丙烯酰胺、硅胶、自体脂肪的任一种或其组合。
本发明的优选技术方案中，所述的麻醉剂选自利多卡因、普鲁卡因、丁卡因、布比卡因、罗哌卡因、双氯芬酸、吗啡、氢可酮、氧可酮、可待因、芬太尼、戊巴比妥钠、苯巴比妥钠、硫喷妥钠、氯醛糖、氨基甲酸乙酯、水合氯醛的任一种或其组合。
本发明的优选技术方案中，所述的消炎剂选自类固醇类消炎剂、非类固醇类消炎剂的任一种或其组合。
本发明的优选技术方案中，所述的类固醇类消炎剂选自氟轻松、氢化可的松、倍他米松的任一种或其组合。
本发明的优选技术方案中，所述的非类固醇类消炎剂选自阿司匹林、水杨酸镁、水杨酸钠、水杨酸胆碱镁、二氟尼柳、双水杨酸酯、布洛芬、吲哚美辛、氟比洛芬、苯氧基布洛芬、萘普生、萘丁美酮、吡罗昔康、保泰松、双氯灭痛、芬洛芬、酮基布洛芬、酮咯酸、四氯芬那酸、舒林酸、托美丁的任一种或其组合。
本发明的优选技术方案中，所述的抗过敏剂选自苯海拉明、异丙嗪、氯苯那敏、色甘酸钠、酮替芬、倍他司汀、孟鲁斯特、扎鲁斯特、沙丁胺醇、葡萄糖酸钙、肾上腺糖皮质激素的任一种或其组合。
本发明的可生物降解的共聚物具有以下有益效果：
本发明的可生物降解的共聚物均匀稳定，分散性和均匀度好，进入皮肤后不易产生结节和红肿反应，保证了产品的效果、安全性和质量可控；
改善通针性，促进成纤维细胞和胶原蛋白再生，达到改善皱纹、提亮肤色、收细毛孔、修复疤痕的功效；
通过与辅料复配，增强美白、保湿、抗皱等功效
适用范围广，可用于不同老化部位，实现面部整体年轻化。
具体实施方式
为使本发明的目的、技术方案和优点更加清楚明白，下文中对本发明的实施例进行详细说明。需要说明的是，在不冲突的情况下，本发明的实施例及实施例中的特征可以相互任意组合。
实施例
实施例1:MPEG-PLLA的制备
实施例1.1
取500ml的单口瓶中加入L-丙交酯40g、MPEG1000 160g，氮气置换3次，加入90℃的油浴锅中，熔融完全后用真空油泵抽至体系无爆沸现象(约30min)，氮气置换，通过微量注射针头向反应瓶中注入26mg辛酸亚锡，开启真空油泵，抽真空至体系无爆沸现象(约30min)，氮气置换，升温至120℃，保温反应12小时，停止加热并降至室温，获得MPEG-PLLA，特性黏数为16，Mn＝8581，Mw＝9379。
实施例1.2
按照实施例1.1的制备方法制备MPEG-PLLA，不同之处在于甲氧基聚乙二醇为MPEG2000。
实施例1.3
按照实施例1.1的制备方法制备MPEG-PLLA，不同之处在于甲氧基聚乙二醇为MPEG4000。
实施例1.4
按照实施例1.1的制备方法制备MPEG-PLLA，不同之处在于甲氧基聚乙二醇为MPEG5000。
实施例1.5
按照实施例1.1的制备方法制备MPEG-PLLA，不同之处在于甲氧基聚乙二醇为MPEG10000。
实施例2:MPEG-PLLA的制备
实施例2.1
按照实施例1.4的制备方法制备MPEG-PLLA，不同之处在于：L-丙交酯30g，MPEG5000170g。
实施例2.2
按照实施例1.1的制备方法制备MPEG-PLLA，不同之处在于：L-丙交酯20g，MPEG5000 180g。
实施例3:MPEG-PLLA的制备
按照实施例1.4的制备方法制备MPEG-PLLA，不同之处在于：氮气置换，升温至130℃。
实施例4:MPEG-PLLA的纯化
实施例4.1
取实施例1.4制备的产品约200g，加入1000ml二氯甲烷并搅拌，使反应物溶解，待样品溶解后加入活性炭10g，200rpm搅拌10分钟，0.22μm滤膜过滤，并缓慢加入无水乙醇6000ml，100rpm搅拌30min，溶液变浑浊，过滤，使用异丙醚淋洗滤饼，滤饼30～40℃鼓风干燥15～24小时，得mPEG-PLA共聚物。
实施例4.2
取实施例1.4制备的产品约200g，加入1000ml二氯甲烷并搅拌，使反应物溶解，待样品溶解后加入活性炭10g，200rpm搅拌10分钟，0.22μm滤膜过滤，待样品溶解后并缓慢加入无水甲醇6000ml，100rpm搅拌30min，溶液变浑浊，过滤，使用异丙醚淋洗滤饼，滤饼30～40℃鼓风干燥15～24小时，得mPEG-PLA共聚物。
实施例4.3
取实施例1.4制备的产品约200g，加入1000ml二氯甲烷并搅拌，使反应物溶解，待样品溶解后加入活性炭10g，200rpm搅拌10分钟，0.22μm滤膜过滤，并缓慢加入异丙醚6000ml，100rpm搅拌30min，有白色固体析出，过滤，使用异丙醚淋洗滤饼，滤饼30～40℃鼓风干燥15～24小时，得mPEG-PLA共聚物。
实施例4.4
取实施例1.4制备的产品约200g，加入1000ml二氯甲烷并搅拌，使反应物溶解，待样品溶解后加入活性炭10g，200rpm搅拌10分钟，0.22μm滤膜过滤，并缓慢加入异丙醚3000ml，100rpm搅拌30min，溶液变浑浊，过滤，使用异丙醚淋洗滤饼，滤饼30～40℃鼓风干燥15～24小时，得mPEG-PLA共聚物。
实施例5:MPEG-PLLA制剂的制备
实施例5.1
取实施例4.3制备的产品15g，加入至超纯水中搅拌至完全溶剂，将溶液转移至100ml容量瓶中，用超纯水定容至刻度。取定容后溶液用1μm滤膜进行过滤，液体有淡蓝色乳光。
实施例5.2
取实施例4.3制备的产品15g，加入至超纯水中搅拌至完全溶剂，将溶液转移至100ml容量瓶中，用超纯水定容至刻度。取定容后溶液用0.45μm滤膜进行过滤，得到液体有淡蓝色乳光。
实施例5.3
取实施例4.3制备的产品15g，加入至超纯水中搅拌至完全溶剂，将溶液转移至100ml容量瓶中，用超纯水定容至刻度。取定容后溶液用0.22μm滤膜进行过滤，得到液体澄清。
以上所述仅是本发明的实施方式的举例，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明技术原理的前提下，还可以做出若干改进和变型，这些改进和变型也应视为本发明的保护范围。

Claims (10)

  1. 一种可生物降解的共聚物，所述共聚物由聚乳酸和聚乙二醇衍生物形成。
  2. 根据权利要求1所述的共聚物，其中所述聚乙二醇衍生物选自聚乙二醇单甲醚、乙氧基聚乙二醇、丙氧基聚乙二醇中的任一种或其组合，优选地为MPEG。
  3. 根据权利要求1所述的共聚物，其中所述共聚物中亲水基团/疏水集团的摩尔比为20:1-1:1，优选地10:1-2:1，更优选地9:1-7:3。
  4. 根据权利要求1所述的共聚物，其中所述共聚物的特性粘数在20℃下为1ml/g-25ml/g。
  5. 根据权利要求1所述的共聚物，其中所述共聚物的数均分子量为7000-1,5000。
  6. 根据权利要求1所述的共聚物，其中所述共聚物的的粒径≤450nm。
  7. 权利要求1-6中任一项所述的可生物降解的共聚物的制备方法，所述制备方法包括：
    将丙交酯和聚乙二醇加入反应容器中，反应容器内部用保护气置换并通保护气，加热；
    待熔融完全后，将反应容器内部抽真空直至无爆沸现象，并通保护气；
    向反应容器中加入催化剂，抽真空至无爆沸现象，并通保护气，升温反应，反应完毕即得。
  8. 权利要求1-6中任一项所述的可生物降解的共聚物的纯化方法，所述纯化方法包括：
    将所述制备方法制得的产品加入良性溶剂，搅拌，溶解，加入活性炭，过滤；
    滤液中缓慢加入不良溶剂，搅拌，过滤；
    使用不良溶剂淋洗，在30℃-40℃干燥15-24小时，即得精制的 产品。
  9. 一种组合物，包含权利要求1-6中任一项所述的可生物降解的共聚物，其中所述组合物制成液体针剂或粉针剂。
  10. 权利要求1-6中任一项所述的共聚物或权利要求9所述的组合物的联用方式，将所述共聚物或所述组合物与其他类型注射填充物、麻醉剂、消炎剂、抗过敏剂的任一种或其组合联合使用。
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