[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

WO2023083265A1 - 一种聚乙二醇单甲醚聚乳酸共聚物及其制备方法和其应用 - Google Patents

一种聚乙二醇单甲醚聚乳酸共聚物及其制备方法和其应用 Download PDF

Info

Publication number
WO2023083265A1
WO2023083265A1 PCT/CN2022/131171 CN2022131171W WO2023083265A1 WO 2023083265 A1 WO2023083265 A1 WO 2023083265A1 CN 2022131171 W CN2022131171 W CN 2022131171W WO 2023083265 A1 WO2023083265 A1 WO 2023083265A1
Authority
WO
WIPO (PCT)
Prior art keywords
polyethylene glycol
preparation
mpeg
copolymer
polylactic acid
Prior art date
Application number
PCT/CN2022/131171
Other languages
English (en)
French (fr)
Inventor
闫瑞国
王爽
杨全飞
刘喆
武秋红
Original Assignee
北京渼颜空间生物医药有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 北京渼颜空间生物医药有限公司 filed Critical 北京渼颜空间生物医药有限公司
Publication of WO2023083265A1 publication Critical patent/WO2023083265A1/zh

Links

Classifications

    • 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 technical field of medicine, in particular to a biodegradable polyethylene glycol monomethyl ether polylactic acid copolymer, a preparation method thereof and an application thereof.
  • Polymer medical carriers include natural macromolecules (such as polysaccharides and proteins) and synthetic macromolecules (such as homopolymers and copolymers). Due to the single structure and composition of the homopolymer, the performance is single, which limits its application in medical carriers. Copolymers prepared by copolymerization modification methods are widely used as medical carriers. Polyethylene glycol (PEG) has good hydrophilicity and biocompatibility and has become the most widely used hydrophilic block, and can avoid being damaged by the reticuloendothelial system (RES) and liver, spleen, kidney, etc. Organ recognition capture with longer blood circulation time.
  • RES reticuloendothelial system
  • the polyethylene glycol-polylactic acid polymer block copolymer prepared by polymerizing polylactic acid and PEG contains hydrophilic segments and hydrophobic segments, and there is no peptide chain on the molecule, no immunogenicity, biodegradable and degradable
  • the product is a metabolite in the body, which is easy to be excreted from the body without accumulation, and is developed as a carrier of hydrophobic drugs.
  • Genexol-PM developed and marketed by Samyang Company, which is polylactic acid polyethylene glycol micelles of paclitaxel, was approved for marketing in South Korea in 2007 for the treatment of breast cancer and non-small cell lung cancer.
  • polyethylene glycol-polylactic acid copolymer requires the use of polyethylene glycol or its derivatives as an initiator, and the ring-opening polymerization of lactide with a tin catalyst.
  • tin-based catalysts are toxic, and stannous ions are easily oxidized. For this reason, it is necessary to detect and monitor the tin content in the polyethylene glycol-polylactic acid copolymer within a safe range to ensure safe and effective use.
  • CN105315444A discloses a method for purifying poly(ethylene glycol monomethyl ether) polylactic acid using a strong acidic cation exchange resin chromatography column.
  • the method uses a 0.22 ⁇ m microporous membrane to filter, but the operation is extremely cumbersome and is not suitable for large-scale industrial production, and It is difficult to solve the problem of tin residue in the copolymer.
  • the organic solvent extraction method can remove the residual tin in the copolymer, it affects the production efficiency and yield.
  • the molecular weight distribution of polyethylene glycol-polylactic acid copolymer is directly related to its biodegradation period and filling effect, which affects the batch-to-batch difference and dispersion stability of the copolymer, and the hydrophilicity and biocompatibility of the copolymer need to be improved. fill effect. For this reason, it is necessary to develop a poly(ethylene glycol) derivative polylactic acid copolymer with better hydrophilicity and biocompatibility, a more uniform molecular weight distribution, a longer degradation cycle, and a safe and effective method for its preparation.
  • the present invention provides a preparation method of polyethylene glycol derivative polylactic acid copolymer on the one hand, and scientifically selects the feed ratio and purification method of polyethylene glycol derivatives and lactide to prepare medically acceptable polylactic acid copolymers. required copolymer.
  • the object of the present invention is to provide a kind of preparation method of polyethylene glycol derivative polylactic acid copolymer, comprises the following steps:
  • polyethylene glycol derivatives and lactide are heated at 80°C Melt at -150°C, then add 0.1%-1% tin catalyst, and complete the polymerization reaction at 80°C-150°C to obtain polyethylene glycol derivative polylactic acid copolymer, wherein the polyethylene glycol derivative It is the blocked polyethylene glycol that reacts with a terminal hydroxyl group, and the blocked polyethylene glycol is selected from polyethylene glycol monomethyl ether (mPEG), ethoxylated polyethylene glycol, propoxylated polyethylene glycol Any one or combination thereof, the lactide is selected from any one of L-lactide, D-lactide, DL-lactide or a combination thereof, and the inert gas is selected from nitrogen, argon Any one of gas, helium or its combination, the tin catalyst is selected from stannous octoate,
  • the molecular weight distribution of the obtained polyethylene glycol derivative polylactic acid copolymer is 1.01-1.5, and tin residue is less than 10ppm.
  • the polylactic acid is selected from any one of poly-L-lactic acid PLLA, poly-D-lactic acid PDLA, poly-racemic lactic acid PDLLA or a combination thereof.
  • the copolymer is composed of PLLA and mPEG
  • the mPEG is selected from mPEG-400, mPEG-1000, mPEG-2000, mPEG-4000, mPEG-5000, mPEG-8000, mPEG- Any one of 10000 or its combination.
  • the polyethylene glycol derivative and/or lactide are dehydrated.
  • the dewatering method is selected from any one or a combination of azeotropic solvent dewatering and vacuum dewatering, preferably the azeotropic solvent is selected from benzene, toluene, xylene, dioxane Either or a combination.
  • the weight ratio of polyethylene glycol derivatives to lactide in the reaction system is selected from 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1 , 4:1, 4.5:1, 5:1, 5.5:1, 6:1, 6.5:1, 7:1, 7.5:1, 8:1, 8.5:1, 9:1, 9.5:1, 10 : Either of 1.
  • the polymerization reaction is completed at 100°C-140°C, preferably at 110°C-135°C.
  • the time for completing the polymerization reaction is 5-15 hours, preferably 8-12 hours.
  • the modified silica gel in the modified silica gel column chromatography or modified silica gel adsorption method is mercapto-modified silica gel.
  • the modified silica gel in the modified silica gel column chromatography or the modified silica gel adsorption method is high-purity mercapto-modified silica gel.
  • the amount of silica gel used in the modified silica gel adsorption method accounts for 0.5%-2% by mass of the copolymer to be purified, preferably 1%-1.5%.
  • the weight average molecular weight of the prepared copolymer is 2000Da-25000Da, preferably 4000Da-22000Da, more preferably 10000Da-13000Da.
  • the molecular weight distribution of the prepared copolymer is 1.02-1.25.
  • the tin residue of the prepared copolymer is any of ⁇ 9ppm, ⁇ 8ppm, ⁇ 7ppm, ⁇ 6ppm, ⁇ 5ppm, ⁇ 4ppm, ⁇ 3ppm, ⁇ 2ppm, ⁇ 1ppm.
  • the tin residue of the copolymer is not detected.
  • the present invention also provides the preparation method of the aqueous solution of the polyethylene glycol derivative polylactic acid copolymer that above preparation method makes, and described preparation method comprises:
  • the pore size of the filter membrane is selected from 1 ⁇ m, 0.45 ⁇ m, Any one of 0.22 ⁇ m or its combination.
  • the water is selected from any one of ultrapure water, distilled water, and deionized water or a combination thereof.
  • the present invention also provides an application of the polyethylene glycol derivative polylactic acid copolymer obtained by the above preparation method in the preparation of a hydrophobic drug carrier.
  • the present invention also provides an application of the polyethylene glycol derivative polylactic acid copolymer obtained by the above preparation method in the preparation of medical cosmetic products.
  • the present invention also provides an application of the polyethylene glycol derivative polylactic acid copolymer obtained by the above preparation method in the preparation of a biodegradable injection filler.
  • the filling site of the filler is selected from any one of face, neck, abdomen, chest, buttocks, thigh, calf, upper arm, lower arm or a combination thereof.
  • the object of the present invention is also to provide a composition comprising the polyethylene glycol derivative polylactic acid copolymer obtained by the above preparation method.
  • the molecular weight of the copolymer in the composition is 7000Da-1,5000Da.
  • the molecular weight of the copolymer in the composition is 9000Da-1,4000Da.
  • the molecular weight of the copolymer in the composition is 1,2000Da-1,4000Da.
  • 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 Any one or a combination of protein, hydroxypropylmethylcellulose, starch, pectinic acid, heparin, glucose, ⁇ -cyclodextrin, chitosan, sodium alginate.
  • the composition is made into liquid injection or powder injection.
  • the liquid injection is selected from any one of hydrogel, suspension and solution.
  • the powder injection is freeze-dried powder injection.
  • the freeze-dried powder injection contains 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 "particle size" of the polyethylene glycol monomethyl ether polylactic acid copolymer microparticles described in the present invention refers to the particle size (D90) corresponding to 90% of the particle size distribution.
  • the "particle size distribution" of the polyethylene glycol monomethyl ether polylactic acid copolymer particles of the present invention adopts an ultra-high-speed intelligent particle size analyzer, under the condition of 2.0barg air pressure, 35% of the sampling speed, and a hopper of 1.50mm Gaps are measured.
  • the "scanning electron micrograph" of the polyethylene glycol monomethyl ether polylactic acid copolymer particles of the present invention is obtained by magnifying 5000 times with a scanning electron microscope (model: Thermo-Prisma E).
  • the present invention adopts the following methods to detect the molecular weight of the copolymer, the tin content in the copolymer and the residual amount of L-lactide.
  • the present invention adopts Gel Permeation Chromatography (GPC) method (Chinese Pharmacopoeia 2020 Edition Four General Rules 0514) to detect the molecular weight of the copolymer.
  • GPC Gel Permeation Chromatography
  • Reference substance solution Take 5-6 polystyrene reference substances with different molecular weights in appropriate amounts, weigh them accurately, add chloroform to dissolve and dilute to make a solution containing about 2mg of the reference substance in each 1ml, dissolve, and mix well.
  • the chromatographic conditions are gel chromatographic column (Styragel HR 4E THF, 7.8 ⁇ 300mm or equivalent chromatographic column); the mobile phase is chloroform; the flow rate is 0.7ml per minute; the detector is a differential refraction detector; the column temperature is 35 °C; injection volume 10 ⁇ L.
  • Determination method Accurately take the test solution and the reference solution, inject them into the liquid chromatograph respectively, and record the chromatograms.
  • the regression equation of the reference solution and the weight-average molecular weight (Mw), number-average molecular weight (Mn) and molecular weight distribution (Mw/Mn) of the test product were calculated by the GPC software.
  • the present invention uses an inductively coupled plasma mass spectrometer (ICP-MS) method (Chinese Pharmacopoeia 2020 Edition Sibu General Rules 0412) to detect the tin content of the copolymer.
  • ICP-MS inductively coupled plasma mass spectrometer
  • Solvent 2% nitric acid solution The test solution takes about 250 mg of this product, accurately weighs it, puts it in a digestion tank (55-TMF), adds 8 ml of nitric acid, and digests it according to the prescribed conditions. After the digestion is completed, rinse the digestion tank several times with a small amount of solvent and transfer it to a 25ml volumetric flask, dilute to the mark with solvent, shake well, then accurately measure 1ml into a 10ml volumetric flask, add 0.1ml of internal standard solution, and dilute with solvent To the mark, shake well, as the test solution. For the blank solution, take 8ml of nitric acid and place it in a digestion tank (55-TMF) for digestion according to the proposed conditions.
  • a digestion tank 55-TMF
  • Standard curve solution Precisely measure an appropriate amount of tin single element standard solution, dilute with solvent to make a solution containing about 600ng of tin per 1ml, as a stock solution; precisely measure 0ml, 0.1ml, 0.5ml, 1.0ml, 1.5ml of this solution , 2.0ml, put them in 10ml measuring bottles respectively, add 0.1ml of internal standard solution precisely, dilute to the mark with 2% nitric acid solution, shake well, and you get it. Respectively as Linear1 ⁇ Linear6. Determination method The standard curve solution is injected into an inductively coupled plasma mass spectrometer, and the mass spectrum is recorded.
  • the present invention uses gas chromatography (Chinese Pharmacopoeia 2020 Edition Sibu General Rules 0521) to detect the residual amount of L-lactide in the copolymer.
  • test solution takes an appropriate amount of this product, weighs it accurately, adds dichloromethane to dissolve and quantitatively dilutes to make a solution containing about 10 mg per 1 ml.
  • Chromatographic conditions Chromatographic column (Agilent HP-5, 30m ⁇ 0.32mm, 0.25 ⁇ m or a column with equivalent performance); the initial temperature is 80°C, and the temperature is raised to 170°C at a rate of 10°C per minute, and maintained for 1 minute; sample injection The mouth temperature is 160°C; the detector is a hydrogen flame ionization detector (FID), and the temperature is 250°C; the carrier gas is nitrogen, the flow rate is 2.5ml per minute, and the split ratio is 10:1; the injection volume is 1 ⁇ l.
  • FID hydrogen flame ionization detector
  • Determination method Precisely take the test solution and the reference solution, inject them into the gas chromatograph respectively, and record the chromatograms.
  • said percentage is volume/volume percentage;
  • said percentage is volume/weight percentage;
  • said percentages are weight/volume percentages; the remainder are weight/weight percentages.
  • the present invention has the following beneficial effects:
  • the present invention first uses mercapto-modified silica gel to remove tin catalyst residues from intermediate reaction products, and removes tin residues to undetected levels to ensure safe use; the second is to use modified silica gel to directly adsorb and remove tin from the solution Compared with the purification method of column chromatography, it is easy to operate, reduces energy consumption and production cost, and is especially suitable for large-scale industrial scale-up production.
  • the moisture in the system improves the reaction efficiency and produces a copolymer with a more concentrated molecular weight distribution; the fourth is to scientifically screen the first solvent and the second solvent to improve the purity and quality of the copolymer, and avoid the use of low boiling point and highly toxic ether solvents Potential safety hazards, improve purification efficiency and yield.
  • the present invention studies the influence of different feed ratios of polyethylene glycol monomethyl ether and lactide in the raw materials for the preparation of copolymers on the molecular weight of the final product and the properties of the preparation after being prepared with a suitable solvent, and obtains drug carriers that meet different needs Or medical beauty products.
  • the polyethylene glycol monomethyl ether polylactic acid copolymer obtained by the preparation method of the present invention has significantly improved hydrophilicity and biocompatibility, significantly improved the cell adhesion ability of the copolymer, and significantly prolonged the degradation cycle of the copolymer , and has good stability, which is beneficial to stimulate and accelerate the growth of collagen at the injection site, and is safer and more effective.
  • the high-purity mercapto-modified silica gel used in the examples of the present invention was purchased from Wansonghong (Guangzhou) Trading Co., Ltd.
  • Embodiment 1 Preparation of mPEG-PLLA of the present invention
  • Embodiment 2 Preparation of mPEG-PLLA of the present invention
  • Embodiment 3 Preparation of mPEG-PLLA of the present invention
  • Embodiment 4 Preparation of mPEG-PLLA of the present invention
  • Embodiment 5 Preparation of mPEG-PLLA of the present invention
  • the residual tin was 80.5ppm.
  • the residual L-lactide content was 0.29%.
  • Embodiment 6 Preparation of mPEG-PLLA of the present invention
  • the residual tin was 74.40ppm.
  • the residual amount of L-lactide is 0.27%.
  • Embodiment 7 Preparation of mPEG-PLLA of the present invention
  • Embodiment 8 Preparation of mPEG-PLLA of the present invention
  • Embodiment 9 Preparation of mPEG-PLLA of the present invention
  • the residual amount of L-lactide is 0.26%.
  • Embodiment 10-13 Preparation of mPEG-PLLA preparation of the present invention
  • Embodiment 14-15 In vitro degradation experiment of mPEG-PLLA of the present invention
  • polyethylene glycol monomethyl ether polylactic acid copolymers prepared in Examples 9 and 14-15 were respectively prepared as micellar solutions by referring to the methods of Examples 10-13, sealed, and placed in a 37°C constant temperature drying oven. After the samples are regularly taken out and freeze-dried, the method of the present invention is used to detect the change of its molecular weight. A total of 12 weeks were detected. The results are shown in Table 2 below.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Dermatology (AREA)
  • Polymers & Plastics (AREA)
  • Organic Chemistry (AREA)
  • Transplantation (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Engineering & Computer Science (AREA)
  • Dispersion Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Inorganic Chemistry (AREA)
  • Materials Engineering (AREA)
  • Mechanical Engineering (AREA)
  • Polyesters Or Polycarbonates (AREA)
  • Polyethers (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicinal Preparation (AREA)

Abstract

一种聚乙二醇单甲醚聚乳酸共聚物的制备方法，通过控制聚乙二醇衍生物与丙交酯的投料比来调节终产品的分子量及性状，通过控制起始物料含水量以获得分子量分布更加均一的共聚物，采用高纯度巯基改性硅胶吸附除锡，具有操作简便、成本低的特点，并且可以达到重金属残留未检出的水平，特别适合大规模工业化放大生产。由上述方法制备得到的聚乙二醇单甲醚聚乳酸共聚物可以作为疏水性药物的载体或用于制备医疗美容类产品。

Description

一种聚乙二醇单甲醚聚乳酸共聚物及其制备方法和其应用 技术领域
本发明涉及医药技术领域，具体涉及一种可生物降解的聚乙二醇单甲醚聚乳酸共聚物及其制备方法和其应用。
背景技术
高分子医用载体包括天然高分子(如多糖类和蛋白质类)和合成高分子(如均聚物和共聚物)。因均聚物的结构和组成单一而导致性能单一，进而限制其在医用载体方面的应用。采用共聚改性方法制得的共聚物被广泛用作医用载体。聚乙二醇(PEG)具有良好的亲水性和生物相容性而成为最广泛使用的亲水性嵌段，且在体内可避免被网状内皮系统(RES)及肝、脾、肾等器官识别捕获，具有较长的血液循环时间。将聚乳酸和PEG聚合制备的聚乙二醇-聚乳酸高分子嵌段共聚物含有亲水性链段和疏水性链段，且分子上无肽链，无免疫原性，可生物降解且降解产物为体内代谢产物，易于从体内排出而不积蓄，而被开发用作疏水性药物的载体。例如，Samyang公司开发并上市的Genexol-PM，即为紫杉醇的聚乳酸聚乙二醇胶束，2007年在韩国获批上市用于治疗乳腺癌和非小细胞肺癌。
聚乙二醇聚乳酸共聚物的制备需要采用聚乙二醇或其衍生物作为起始剂，并采用锡类催化剂开环聚合丙交酯。但锡类催化剂存在毒性，且亚锡离子易被氧化。为此，需要检测并监控聚乙二醇聚乳酸共聚物中的锡含量在安全范围内，保障使用安全有效。
CN105315444A公开了采用强酸性阳离子交换树脂层析柱纯化聚乙二醇单甲醚聚乳酸的方法，该方法采用0.22μm的微孔滤膜过滤，但操作极其繁琐，不适宜大规模工业化生产，且难以解决共聚物中的锡残留问题。有机溶剂萃取法虽能去除共聚物中的残留锡，但影响生产效率和收率。另外，聚乙二醇聚乳酸共聚物的分子量分布直接与其生物降解周期及填充效果相关，影响共聚物的批间差异和分散稳定性，且有待共聚物的亲水性和生物相容性改善其填充效果。为此，需要开发具有更好亲水性和生物相容性、分子量分布更均一、降解周期更长、安全有效的聚乙二醇衍生物聚乳酸共聚物及其制备方法。
发明内容
针对现有技术的不足，本发明一方面提供一种聚乙二醇衍生物聚乳酸共聚物的制备方法，科学选择聚乙二醇衍生物与丙交酯的投料比及纯化方法以制备符合医用需求的共聚物。
本发明的目的在于提供一种聚乙二醇衍生物聚乳酸共聚物的制备方法，包括下述步骤：
(1)将聚乙二醇衍生物与丙交酯按照重量比为1-10：1称量，在搅拌条件下，将其均匀混合，抽真空并在惰性气体保护下，反应物料在80℃-150℃熔融，再加入0.1％-1％锡催化剂，在80℃-150℃条件下完成聚合反应，制得聚乙二醇衍生物聚乳酸共聚物，其中，所述聚乙二醇衍生物为一个末端羟基发生反应的封端聚乙二醇，所述封端聚乙二醇选自聚乙二醇单甲醚(mPEG)、乙氧基聚乙二醇、丙氧基聚乙二醇中的任一种或其组合，所述丙交酯选自L-丙交酯、D-丙交酯、DL-丙交酯的任一种或其组合，所述惰性气体选自氮气、氩气、氦气的任一种或其组合，所述锡催化剂选自辛酸亚锡、氯化亚锡、硫酸亚锡、二乙酸二丁基锡、二丁基二苯甲酸锡，二丁基二异氰酸锡、三正丁基甲氧基锡、二月桂酸二丁基锡、二乙基锡中的任意一种或其组合；
(2)反应结束后，将反应体系降温至20-35℃，在制得的聚乙二醇衍生物聚乳酸共聚物中加入其良溶剂，搅拌至完全溶解，制得共聚物溶解液，再采用选自有机溶剂萃取法、柱层析法、活性炭吸附法、改性硅胶柱层析法、改性硅胶吸附法的任一种或其组合的方法除锡，制得除锡液，其中，所述良溶剂选自四氢呋喃、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；
(3)将除锡液过滤，减压浓缩至良性溶剂挥干，在浓缩物中加入聚乙二醇衍生物聚乳酸共聚物的不良溶剂，析出固体，过滤，淋洗滤饼，干燥，制得聚乙二醇衍生物聚乳酸共聚物，其中，所述不良溶剂选自甲醇、乙醇、异丙醇、正丙醇、丁醇、丙酮、丁酮、乙酸乙酯、乙醚、异丙醚的任一种或其组合，
所述制得的聚乙二醇衍生物聚乳酸共聚物分子量分布为1.01-1.5，锡残留＜10ppm。
在本发明的优选技术方案中，所述聚乳酸选自聚左旋乳酸PLLA、聚右旋乳酸PDLA、聚外消旋乳酸PDLLA的任一种或其组合。
在本发明的优选技术方案中，所述共聚物由PLLA和mPEG组成，所述mPEG选自mPEG-400、mPEG-1000、mPEG-2000、mPEG-4000、mPEG-5000、mPEG-8000、mPEG-10000的任一种或其组合。
在本发明的优选技术方案中，对聚乙二醇衍生物和/或丙交酯进行除水的操作。
本发明优选的技术方案中，所述除水方法选自共沸溶剂除水、真空除水的任一种或其组合，优选共沸溶剂选自苯、甲苯、二甲苯、二氧六环的任一种或组合。
本发明优选的技术方案中，反应体系中的聚乙二醇衍生物与丙交酯的重量比选自1：1、1.5：1、2：1、2.5：1、3：1、3.5：1、4：1、4.5：1、5：1、5.5：1、6：1、6.5：1、7：1、7.5：1、8：1、8.5：1、9：1、9.5：1、10：1的任一种。
本发明优选的技术方案中，在100℃-140℃条件下完成聚合反应，优选在110℃-135℃条件下完成聚合反应。
本发明优选的技术方案中，完成聚合反应的时间为5-15h，优选为8-12h。
本发明优选的技术方案中，加入0.2％-0.5％锡催化剂。
本发明优选的技术方案中，改性硅胶柱层析法或者改性硅胶吸附法中的改性硅胶为巯基改性硅胶。
本发明优选的技术方案中，改性硅胶柱层析法或者改性硅胶吸附法中的改性硅胶为高纯度巯基改性硅胶。
本发明优选的技术方案中，改性硅胶吸附法中所用硅胶量占待纯化共聚物的质量百分数为0.5％-2％，优选为1％-1.5％。
本发明优选的技术方案中，制备所得共聚物的重均分子量为2000Da-25000Da，优选为4000Da-22000Da，更优选为10000Da-13000Da。
本发明优选的技术方案中，制得共聚物的分子量分布为1.02-1.25。
本发明优选的技术方案中，制得共聚物的锡残留为＜9ppm、＜8ppm、＜7ppm、＜6ppm、＜5ppm、＜4ppm、＜3ppm、＜2ppm、＜1ppm的任一种。
本发明优选的技术方案中，制得共聚物的锡残留为未检出。
本发明还提供以上制备方法制得的聚乙二醇衍生物聚乳酸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，加入至水中搅拌至完全溶解，将溶液转移至容量瓶中用水定容，将定容后的溶液用滤膜过滤，所述滤膜的孔径选自1μm、0.45μm、0.22μm的任一种或其组合。
本发明优选的技术方案中，所述水选自超纯水、蒸馏水、去离子水的任一种或其组合。
本发明还提供一种上述制备方法得到的聚乙二醇衍生物聚乳酸共聚物在制备作为疏水性药物的载体中的应用。
本发明还提供一种上述制备方法得到的聚乙二醇衍生物聚乳酸共聚物在制备作为医疗美容类产品中的应用。
本发明还提供一种上述制备方法得到的聚乙二醇衍生物聚乳酸共聚物在制备作为可生物降解的注射填充剂中的应用。
本发明的优选技术方案中，所述填充剂的填充部位选自面部、颈部、腹部、胸部、臀部、大腿、小腿、上臂、下臂的任一种或其组合。
本发明的目的还在于提供一种组合物，所述组合物包含由以上制备方法得到的聚乙二醇衍生物聚乳酸共聚物。
在本发明的优选技术方案中，所述组合物中的共聚物的分子量为7000Da-1,5000Da。
在本发明的优选技术方案中，所述组合物中的共聚物的分子量为9000Da-1,4000Da。
在本发明的优选技术方案中，所述组合物中的共聚物的分子量为1,2000Da-1,4000Da。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、海藻酸钠中的任一种或其组合。
在本发明的优选技术方案中，所述组合物制成液体针剂或粉针剂。
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。
在本发明的优选技术方案中，所述粉针剂为冻干粉针剂。
在本发明的优选技术方案中，所述冻干粉针剂包含悬浮稳定剂、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。
为了清楚地表述本发明的保护范围，本发明对下述术语做如下界定：
1、本发明所述的聚乙二醇单甲醚聚乳酸共聚物微粒的“粒径”，指粒径分布中占90％所对应的粒径(D90)。
2、本发明所述聚乙二醇单甲醚聚乳酸共聚物微粒的“粒度分布”采用超高速智能粒度分析仪，在2.0barg空气压力条件下，35％的进样速度，1.50mm的料斗间隙测定得到。
3、本发明所述聚乙二醇单甲醚聚乳酸共聚物微粒的“扫描电镜图”采用扫描电子显微镜(型号：Thermo-Prisma E)放大5000倍检测得到。
除非另有说明，本发明采用下述方法检测共聚物分子量、共聚物中的锡含量和L-丙交酯残留量。
1、本发明采用凝胶渗透色谱(GPC)法(中国药典2020年版四部通则0514)检测共聚物分子量。
供试品溶液取本品适量，精密称定，加三氯甲烷溶解并稀释制成每1ml中约含10mg的溶液，用0.22μm的有机滤膜过滤，取续滤液。
对照品溶液分别取5-6个不同分子量的聚苯乙烯对照品适量，精密称定，加三氯甲烷溶解并稀释制成每1ml中各约含对照品2mg的溶液，溶解，混匀。
色谱条件采用凝胶色谱柱(Styragel HR 4E THF，7.8×300mm或效能相当的色谱柱)；流动相为三氯甲烷；流速为每分钟0.7ml；检测器为示差折光检测器；柱温为35℃；进样体积10μL。
测定法精密量取供试品溶液及对照品溶液，分别注入液相色谱仪，记录色谱图。由GPC软件分别计算出对照品溶液的回归方程与供试品的重均分子量(Mw)、数均分子量(Mn)及分子量分布(Mw/Mn)。
2、本发明采用电感耦合等离子体质谱仪(ICP-MS)法(中国药典2020年版四部通则0412)检测共聚物的锡含量。
溶剂2％硝酸溶液供试品溶液取本品约250mg，精密称定，置消解罐(55-TMF)中，加入硝酸8ml，照拟定条件消解。消解完成后用溶剂少量多次冲洗消解罐合并转移至25ml量瓶 中，用溶剂稀释至刻度，摇匀，再精密量取1ml至10ml量瓶中，并加入内标溶液0.1ml，用溶剂稀释至刻度，摇匀，作为供试品溶液。空白溶液取硝酸8ml置消解罐(55-TMF)中照拟定条件消解。消解完成后用溶剂少量多次冲洗消解罐合并转移至25ml量瓶中，用溶剂稀释至刻度，摇匀，再精密量取1ml至10ml量瓶中，并加入内标溶液0.1ml，用溶剂稀释至刻度，摇匀，作为空白溶液。内标溶液精密量取铟标准溶液0.050ml，置100ml量瓶中，用溶剂稀释至刻度，摇匀。标准曲线溶液精密量取锡单元素标准溶液适量，用溶剂稀释制成每1ml约含锡元素600ng的溶液，作为贮备液；精密量取该溶液0ml、0.1ml、0.5ml、1.0ml、1.5ml、2.0ml，分别置10ml量瓶中，精密加入内标溶液0.1ml，用2％硝酸溶液稀释至刻度，摇匀，即得。分别作为Linear1～Linear6。测定法取标准曲线溶液注入电感耦合等离子体质谱仪，记录质谱图。以待测元素分析峰响应值与内标元素参比峰响应值的比值为纵坐标，浓度为横坐标，绘制标准曲线，计算回归方程，相关系数(r)应不小于0.99。再取供试品溶液与空白溶液，分别注入电感耦合等离子体质谱仪，记录质谱图，按照标准曲线法以空白校正计算待测元素的含量。
3、本发明采用气相色谱法(中国药典2020年版四部通则0521)检测共聚物中的L-丙交酯残留量。
供试品溶液取本品适量，精密称定，加二氯甲烷溶解并定量稀释制成每1ml中约含10mg的溶液。
对照品溶液取L-丙交酯适量，精密称定，用二氯甲烷溶解并定量稀释制成每1ml中含0.2mg的溶液。
色谱条件色谱柱(Agilent HP-5，30m×0.32mm，0.25μm或效能相当的色谱柱)；起始温度为80℃，以每分钟10℃的速率升温至170℃，维持1分钟；进样口温度为160℃；检测器为氢火焰离子化检测器(FID)，温度为250℃；载气为氮气，流速为每分钟2.5ml，分流比10:1；进样体积1μl。
测定法精密量取供试品溶液与对照品溶液，分别注入气相色谱仪，记录色谱图。
除非另有说明，本发明涉及液体与液体之间的百分比时，所述的百分比为体积/体积百分比；本发明涉及液体与固体之间的百分比时，所述百分比为体积/重量百分比；本发明涉及固体与液体之间的百分比时，所述百分比为重量/体积百分比；其余为重量/重量百分比。
与现有技术相比，本发明具有下述有益效果：
1.本发明一是采用巯基改性硅胶对中间反应产物去除锡催化剂残留，将锡残留除至未检出的水平，保障使用安全；二是采用了改性硅胶直接对溶液吸附除锡的方法，其相对柱层析的纯化方法，操作简便，降低能耗和生产成本，尤其适合大规模工业化放大生产，具有重要 的产业价值；三是对共聚物制备原料进行了除水操作，通过减少反应体系中的水分，提高了反应效率，制得分子量分布更加集中的共聚物；四是科学筛选第一溶剂和第二溶剂，提高共聚物的纯度和质量，且避免了使用低沸点高毒性乙醚溶剂的安全隐患，提高纯化效率和收率。
2.本发明研究了共聚物制备原料中聚乙二醇单甲醚与丙交酯的不同投料比对终产品的分子量、经合适溶剂配制后制剂性状的影响，制得满足不同需求的药物载体或者医疗美容产品。
3.本发明的制备方法得到的聚乙二醇单甲醚聚乳酸共聚物具有显著改善的亲水性和生物相容性，显著提高了共聚物的细胞黏附能力，显著延长了共聚物降解周期，并具有稳定性好，利于刺激并加快注射部位的胶原蛋白生长，更加安全有效等优点。
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，下文中将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。
本发明实施例中所采用的高纯度巯基改性硅胶购自万松红(广州)贸易有限公司。
实施例1本发明mPEG-PLLA的制备
在三口瓶中加入40g L-丙交酯和160g分子量为5000的聚乙二醇单甲醚，200rpm搅拌条件下，向反应体系中通入氮气或氩气30min后，油浴升温至120℃熔融；加入0.6g辛酸亚锡，120℃恒温反应10h；至反应结束后，反应体系降至室温，加入200ml二氯甲烷，溶解反应产物；在反应产物溶解液中加入1g高纯度巯基改性硅胶，搅拌2h；0.45μm滤膜过滤，收集滤液，减压浓缩除去大部分溶剂后，再向浓缩物中缓慢加入异丙醚3000ml，滴加完成后，继续搅拌0.5h，析出固体，滤纸过滤，收集滤饼，用异丙醚淋洗后，将其置于40～60℃真空干燥，制得mPEG-PLLA共聚物168g。
采用本发明的方法检测，制得mPEG-PLLA共聚物的分子量为Mw15026Da，Mn10889Da，Mw/Mn＝1.38。锡残留8ppm。L-丙交酯残留量0.33％。
实施例2本发明mPEG-PLLA的制备
在三口瓶中加入40g L-丙交酯和160g分子量为5000的聚乙二醇单甲醚，200rpm搅拌条件下，向反应体系中通入氮气或氩气30min后，油浴升温至120℃熔融；加入0.6g辛酸亚锡，120℃恒温反应10h；至反应结束后，反应体系降至室温，加入200ml二氯甲烷，溶解反应产物；在反应产物溶解液中加入2g高纯度巯基改性硅胶，搅拌2h；0.45μm滤膜过滤，收集滤 液，减压浓缩除去大部分溶剂后，再向浓缩物中缓慢加入异丙醚3000ml，滴加完成后，继续搅拌0.5h，析出固体，滤纸过滤，收集滤饼，用异丙醚淋洗后，将其置于30～50℃真空干燥，制得mPEG-PLLA共聚物173g。
采用本发明的方法检测，制得mPEG-PLLA共聚物的分子量为Mw14241Da，Mn10395Da，Mw/Mn＝1.37。锡残留3ppm。L-丙交酯残留量0.28％。
实施例3本发明mPEG-PLLA的制备
在三口瓶中加入40g L-丙交酯和160g分子量为5000的聚乙二醇单甲醚，200rpm搅拌条件下，向反应体系中通入氮气或氩气30min后，油浴升温至120℃熔融；加入0.6g辛酸亚锡，120℃恒温反应10h；至反应结束后，反应体系降至室温，加入200ml二氯甲烷，溶解反应产物；在反应产物溶解液中加入3g高纯度巯基改性硅胶，搅拌2h；0.45μm滤膜过滤，收集滤液，减压浓缩除去大部分溶剂后，再向浓缩物中缓慢加入异丙醚3000ml，滴加完成后，继续搅拌0.5h，析出固体，滤纸过滤，收集滤饼，用异丙醚淋洗后，将其置于30～50℃真空干燥，制得mPEG-PLLA共聚物170g。
采用本发明的方法检测，制得mPEG-PLLA共聚物的分子量为Mw12638Da，Mn9503Da，Mw/Mn＝1.33。锡残留未检出。L-丙交酯残留量0.26％。
实施例4本发明mPEG-PLLA的制备
在三口瓶中加入40g L-丙交酯和160g分子量为5000的聚乙二醇单甲醚，200rpm搅拌条件下，向反应体系中通入氮气或氩气30min后，油浴升温至120℃熔融；加入0.6g辛酸亚锡，120℃恒温反应10h；至反应结束后，反应体系降至室温，加入200ml二氯甲烷，溶解反应产物；在反应产物溶解液中加入3g高纯度巯基改性硅胶，搅拌2h；0.45μm滤膜过滤，收集滤液，减压浓缩除去大部分溶剂后，再向浓缩物中缓慢加入异丙醚5000ml，滴加完成后，继续搅拌0.5h，析出固体，滤纸过滤，收集滤饼，用异丙醚淋洗后，将其置于30～50℃真空干燥，制得mPEG-PLLA共聚物182g。
采用本发明的方法检测，制得mPEG-PLLA共聚物的分子量为Mw12858Da，Mn9525Da，Mw/Mn＝1.35。锡残留未检出。L-丙交酯残留量0.31％。
实施例5本发明mPEG-PLLA的制备
在三口瓶中加入40g L-丙交酯和160g分子量为5000的聚乙二醇单甲醚，200rpm搅拌条件下，向反应体系中通入氮气或氩气30min后，油浴升温至120℃熔融；加入0.6g辛酸亚锡， 120℃恒温反应10h；至反应结束后，反应体系降至室温，加入200ml二氯甲烷，溶解反应产物；在反应产物溶解液中加入10g活性炭，搅拌10h；0.22μm滤膜过滤，收集滤液，减压浓缩除去大部分溶剂后，再向浓缩物中缓慢加入异丙醚5000ml，滴加完成后，继续搅拌0.5h，析出固体，滤纸过滤，收集滤饼，用异丙醚淋洗后，将其置于30～50℃真空干燥，制得mPEG-PLLA共聚物180g。
采用本发明的方法检测，制得mPEG-PLLA共聚物的分子量为Mw14571Da，Mn10874Da，Mw/Mn＝1.34。锡残留为80.5ppm。L-丙交酯残留量0.29％。
实施例6本发明mPEG-PLLA的制备
在三口瓶中加入40g L-丙交酯和160g分子量为5000的聚乙二醇单甲醚，200rpm搅拌条件下，向反应体系中通入氮气或氩气30min后，油浴升温至120℃熔融；加入0.6g辛酸亚锡，120℃恒温反应10h；至反应结束后，反应体系降至室温，加入200ml二氯甲烷，溶解反应产物；在反应产物溶解液中加入10g活性炭，搅拌10h；0.22μm滤膜过滤，收集滤液，减压浓缩除去大部分溶剂后，再向浓缩物中缓慢加入异丙醚5000ml，滴加完成后，继续搅拌0.5h，析出固体，滤纸过滤，收集滤饼，用异丙醚淋洗后，将其置于30～50℃真空干燥，制得mPEG-PLLA共聚物184g。
采用本发明的方法检测，制得mPEG-PLLA共聚物的分子量为Mw15577Da，Mn11048Da，Mw/Mn＝1.41。锡残留为74.40ppm。L-丙交酯残留量0.27％。
实施例7本发明mPEG-PLLA的制备
在三口瓶中加入40g L-丙交酯和160g分子量为5000的聚乙二醇单甲醚，200rpm搅拌条件下，向反应体系中通入氮气或氩气30min后，油浴升温至120℃熔融；加入0.6g辛酸亚锡，120℃恒温反应10h；至反应结束后，反应体系降至室温，加入200ml二氯甲烷，溶解反应产物；采用高纯度巯基改性硅胶进行柱层析纯化，采用二氯甲烷和乙酸乙酯混合溶剂为洗脱剂；层析液蒸馏，除去大部分溶剂，缓慢滴入异丙醚5000ml，滴加完成后继续搅拌0.5h，析出固体，过滤，使用异丙醚淋洗滤饼，滤饼30～50℃真空干燥，得mPEG-PLLA共聚物171g。
采用本发明的方法检测，制得mPEG-PLLA共聚物的分子量为Mw12551Da，Mn9030Da，Mw/Mn＝1.39。锡残留未检出。L-丙交酯残留量0.10％。
实施例8本发明mPEG-PLLA的制备
取分子量为5000的聚乙二醇单甲醚样品400g，加入至圆底烧杯中，加入甲苯800ml，将 烧瓶连接油水分离器，放入至120℃油浴中共沸除水5小时；共沸后对样品进行旋蒸，除去残留的甲苯，并密封保存；样品除水前含水量1.13％，除水后含水量0.0103％；在三口瓶中加入40g L-丙交酯和160g聚乙二醇单甲醚，200rpm搅拌条件下，向反应体系中通入氮气或氩气30min后，油浴升温至120℃熔融；加入0.6g辛酸亚锡，120℃恒温反应10h；至反应结束后，反应体系降至室温，加入200ml二氯甲烷，溶解反应产物；在反应产物溶解液中加入3g高纯度巯基改性硅胶，搅拌2h；0.45μm滤膜过滤，收集滤液，减压浓缩除去大部分溶剂后，再向浓缩物中缓慢加入异丙醚5000ml，滴加完成后，继续搅拌0.5h，析出固体，滤纸过滤，收集滤饼，用异丙醚淋洗后，将其置于30～50℃真空干燥，制得mPEG-PLLA共聚物185g。
采用本发明的方法检测，制得mPEG-PLLA共聚物的分子量为Mw14425Da，Mn12766Da，Mw/Mn＝1.13。锡残留未检出。L-丙交酯残留量0.28％。
实施例9本发明mPEG-PLLA的制备
取丙交酯样品400g，加入至圆底烧杯中，加入甲苯800ml，将烧瓶连接油水分离器，放入至120℃油浴中共沸除水5小时；共沸后对样品进行旋蒸，除去残留的甲苯，并密封保存；样品除水前含水量0.685％，除水后含水量0.05％；在三口瓶中加入40g除水L-丙交酯和160g除水聚乙二醇单甲醚(样品同实施例8)，200rpm搅拌条件下，向反应体系中通入氮气或氩气30min后，油浴升温至120℃熔融；加入0.6g辛酸亚锡，120℃恒温反应10h；至反应结束后，反应体系降至室温，加入200ml二氯甲烷，溶解反应产物；在反应产物溶解液中加入3g高纯度巯基改性硅胶，搅拌2h；0.45μm滤膜过滤，收集滤液，减压浓缩除去大部分溶剂后，再向浓缩物中缓慢加入异丙醚5000ml，滴加完成后，继续搅拌0.5h，析出固体，滤纸过滤，收集滤饼，用异丙醚淋洗后，将其置于30～50℃真空干燥，制得mPEG-PLLA共聚物187g。
采用本发明的方法检测，制得mPEG-PLLA共聚物的分子量为Mw13990Da，Mn12835Da，Mw/Mn＝1.09。锡残留未检出。L-丙交酯残留量0.26％。
实施例10-13本发明mPEG-PLLA制剂的制备
实施例10-13的mPEG-PLLA制备方法中除所用聚乙二醇单甲醚与丙交酯的投料量不同外，其余条件同实施例9。
分别称取实施例9-13的mPEG-PLLA各15g，将其加入至超纯水中搅拌，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滤膜过滤，观察各制剂的外观。结果见表1。具体见表1。
表1
Figure PCTCN2022131171-appb-000001
实施例14-15本发明mPEG-PLLA的体外降解实验
实施例14-15的mPEG-PLLA制备方法中除所用聚乙二醇单甲醚的分子量不同外，其余实验条件同实施例9。
将实施例9、14-15制得的聚乙二醇单甲醚聚乳酸共聚物参照实施例10-13的方法分别制备为胶束溶液，密封后，放入37℃恒温干燥箱中。定期取出样品进行冷冻干燥后，采用本发明的方法检测其分子量的变化。共检测12周。结果见下表2。
表2
Figure PCTCN2022131171-appb-000002
虽然本发明所揭露的实施例如上，但所述的内容仅为便于理解本发明而采用的实施方式，并非用以限定本发明。任何本发明所属领域内的技术人员，在不脱离本发明所揭露的精神和范围的前提下，可以在实施的形式及细节上进行任何的修改与变化，但本发明的专利保护范围，仍须以所附的权利要求书所界定的范围为准。

Claims (10)

  1. 一种聚乙二醇衍生物聚乳酸共聚物的制备方法，包括下述步骤：
    (1)将聚乙二醇衍生物与丙交酯按照重量比为1-10：1称量，在搅拌条件下，将其均匀混合，抽真空并在惰性气体保护下，反应物料在80℃-150℃熔融，再加入0.1％-1％锡催化剂，在80℃-150℃条件下完成聚合反应，制得聚乙二醇衍生物聚乳酸共聚物，其中，所述聚乙二醇衍生物为一个末端羟基发生反应的封端聚乙二醇，所述封端聚乙二醇选自聚乙二醇单甲醚(mPEG)、乙氧基聚乙二醇、丙氧基聚乙二醇中的任一种或其组合，所述丙交酯选自L-丙交酯、D-丙交酯、DL-丙交酯的任一种或其组合，所述惰性气体选自氮气、氩气、氦气的任一种或其组合，所述锡催化剂选自辛酸亚锡、氯化亚锡、硫酸亚锡、二乙酸二丁基锡、二丁基二苯甲酸锡，二丁基二异氰酸锡、三正丁基甲氧基锡、二月桂酸二丁基锡、二乙基锡中的任意一种或其组合；
    (2)反应结束后，将反应体系降温至20-35℃，在制得的聚乙二醇衍生物聚乳酸共聚物中加入其良溶剂，搅拌至完全溶解，制得共聚物溶解液，再采用选自有机溶剂萃取法、柱层析法、活性炭吸附法、改性硅胶柱层析法、改性硅胶吸附法的任一种或其组合的方法除锡，制得除锡液，其中，所述良溶剂选自四氢呋喃、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；
    (3)将除锡液过滤，减压浓缩至良性溶剂挥干，在浓缩物中加入聚乙二醇衍生物聚乳酸共聚物的不良溶剂，析出固体，过滤，淋洗滤饼，干燥，制得聚乙二醇衍生物聚乳酸共聚物，其中，所述不良溶剂选自甲醇、乙醇、异丙醇、正丙醇、丁醇、丙酮、丁酮、乙酸乙酯、乙醚、异丙醚的任一种或其组合，
    所述制得的聚乙二醇衍生物聚乳酸共聚物分子量分布为1.01-1.5，锡残留＜10ppm。
  2. 根据权利要求1所述的制备方法，其特征在于：所述聚乳酸选自聚左旋乳酸PLLA、聚右旋乳酸PDLA和聚外消旋乳酸PDLLA的任一种或其组合。
  3. 根据权利要求1-2任一项所述的制备方法，其特征在于：所述共聚物由PLLA和mPEG组成，所述mPEG选自mPEG-400、mPEG-1000、mPEG-2000、mPEG-4000、mPEG-5000、mPEG-8000和mPEG-10000的任一种或其组合。
  4. 根据权利要求1-3任一项所述的制备方法，其特征在于：对聚乙二醇衍生物和/或丙交酯进行除水的操作。
  5. 根据权利要求1-4任一项所述的制备方法，其特征在于：在100℃-140℃条件下完成聚合反应，优选在110℃-135℃条件下完成聚合反应。
  6. 根据权利要求1-5任一项所述的制备方法，其特征在于：完成聚合反应的时间为5-15h， 优选为8-12h。
  7. 根据权利要求1-6任一项所述的制备方法，其特征在于：加入0.2％-0.5％锡催化剂。
  8. 根据权利要求1-7任一项所述的制备方法，其特征在于：改性硅胶柱层析法或者改性硅胶吸附法中的改性硅胶为巯基改性硅胶。
  9. 权利要求1-8任一项所述的制备方法制备得到的共聚物在制备作为疏水性药物的载体中的应用。
  10. 权利要求1-8任一项所述的制备方法制备得到的共聚物在制备作为医疗美容类产品中的应用。
PCT/CN2022/131171 2021-11-10 2022-11-10 一种聚乙二醇单甲醚聚乳酸共聚物及其制备方法和其应用 WO2023083265A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202111330111.5 2021-11-10
CN202111330111 2021-11-10

Publications (1)

Publication Number Publication Date
WO2023083265A1 true WO2023083265A1 (zh) 2023-05-19

Family

ID=86255046

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/CN2022/099058 WO2023082634A1 (zh) 2021-11-10 2022-06-16 一种可生物降解的共聚物及其制备方法和应用
PCT/CN2022/131171 WO2023083265A1 (zh) 2021-11-10 2022-11-10 一种聚乙二醇单甲醚聚乳酸共聚物及其制备方法和其应用

Family Applications Before (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/099058 WO2023082634A1 (zh) 2021-11-10 2022-06-16 一种可生物降解的共聚物及其制备方法和应用

Country Status (2)

Country Link
CN (1) CN116102721A (zh)
WO (2) WO2023082634A1 (zh)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116617457A (zh) * 2023-07-21 2023-08-22 华清智美(深圳)生物科技有限公司 胶原蛋白复合物及其制备方法和应用

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20030059607A (ko) * 2002-01-03 2003-07-10 한국과학기술원 카프로락톤과 락티드의 랜덤공중합체와 폴리에테르를이용한 생분해성 블록공중합체의 제조방법 및 이의 응용
CN102219892A (zh) * 2010-06-30 2011-10-19 上海谊众生物技术有限公司 聚乙二醇单甲醚-dl-聚乳酸嵌段共聚物的制备方法
CN103601878A (zh) * 2013-11-25 2014-02-26 沈阳药科大学 高稳定性聚乙二醇-聚酯聚合物及其应用
CN104761710A (zh) * 2014-02-14 2015-07-08 苏州海特比奥生物技术有限公司 一种聚乙二醇单甲醚-聚乳酸嵌段共聚物及其制备方法
CN104892909A (zh) * 2015-06-03 2015-09-09 深圳万乐药业有限公司 一种聚乙二醇单甲醚-聚乳酸嵌段共聚物的制备方法
CN104961886A (zh) * 2015-04-30 2015-10-07 山西康宝生物制品股份有限公司 一种新型纳米胶束药用材料的制备方法
CN105315444A (zh) * 2014-07-16 2016-02-10 西南药业股份有限公司 注射用聚乙二醇单甲醚-聚乳酸两亲性嵌段共聚物的纯化方法
CN106995528A (zh) * 2016-01-26 2017-08-01 浙江大学 一种聚乙二醇单甲醚-聚乳酸嵌段共聚物的精制方法
WO2017190115A1 (en) * 2016-04-29 2017-11-02 i-novion, Inc. Sustained release formulation and use thereof
CN111978520A (zh) * 2020-02-25 2020-11-24 丽珠医药集团股份有限公司 聚乙二醇单甲醚-聚乳酸嵌段共聚物、聚合物胶束药物以及制备方法

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20050077916A (ko) * 2004-01-29 2005-08-04 학교법인 성균관대학 ｐＨ 및 온도 민감성 하이드로겔
CN106349466B (zh) * 2016-09-02 2019-09-20 广东众生药业股份有限公司 一种新的生物医用聚醚/聚酯嵌段共聚物的制备方法
CN111150883A (zh) * 2020-01-14 2020-05-15 北京四环制药有限公司 可生物降解的注射填充物及其制备方法和其应用
CN111617315B (zh) * 2020-01-14 2021-07-06 北京四环制药有限公司 可生物降解的注射填充物及其制备方法和其应用

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20030059607A (ko) * 2002-01-03 2003-07-10 한국과학기술원 카프로락톤과 락티드의 랜덤공중합체와 폴리에테르를이용한 생분해성 블록공중합체의 제조방법 및 이의 응용
CN102219892A (zh) * 2010-06-30 2011-10-19 上海谊众生物技术有限公司 聚乙二醇单甲醚-dl-聚乳酸嵌段共聚物的制备方法
CN103601878A (zh) * 2013-11-25 2014-02-26 沈阳药科大学 高稳定性聚乙二醇-聚酯聚合物及其应用
CN104761710A (zh) * 2014-02-14 2015-07-08 苏州海特比奥生物技术有限公司 一种聚乙二醇单甲醚-聚乳酸嵌段共聚物及其制备方法
CN105315444A (zh) * 2014-07-16 2016-02-10 西南药业股份有限公司 注射用聚乙二醇单甲醚-聚乳酸两亲性嵌段共聚物的纯化方法
CN104961886A (zh) * 2015-04-30 2015-10-07 山西康宝生物制品股份有限公司 一种新型纳米胶束药用材料的制备方法
CN104892909A (zh) * 2015-06-03 2015-09-09 深圳万乐药业有限公司 一种聚乙二醇单甲醚-聚乳酸嵌段共聚物的制备方法
CN106995528A (zh) * 2016-01-26 2017-08-01 浙江大学 一种聚乙二醇单甲醚-聚乳酸嵌段共聚物的精制方法
WO2017190115A1 (en) * 2016-04-29 2017-11-02 i-novion, Inc. Sustained release formulation and use thereof
CN111978520A (zh) * 2020-02-25 2020-11-24 丽珠医药集团股份有限公司 聚乙二醇单甲醚-聚乳酸嵌段共聚物、聚合物胶束药物以及制备方法

Also Published As

Publication number Publication date
WO2023082634A1 (zh) 2023-05-19
CN116102721A (zh) 2023-05-12

Similar Documents

Publication Publication Date Title
Liu et al. A rapid temperature-responsive sol–gel reversible poly (N-isopropylacrylamide)-g-methylcellulose copolymer hydrogel
Deng et al. In vitro degradation and release profiles for poly-dl-lactide-poly (ethylene glycol) microspheres containing human serum albumin
Ganji et al. Synthesis and characterization of a new thermosensitive chitosan–PEG diblock copolymer
Constantin et al. Poly (NIPAAm-co-β-cyclodextrin) microgels with drug hosting and temperature-dependent delivery properties
CN103450361A (zh) 羧甲基纤维素接枝聚乳酸两亲性聚合物及其制备方法与应用
Moogooee et al. Synthesis and in vitro studies of cross-linked hydrogel nanoparticles containing amoxicillin
Park et al. Nanoaggregate of thermosensitive chitosan-Pluronic for sustained release of hydrophobic drug
Karami et al. Naproxen conjugated mPEG–PCL micelles for dual triggered drug delivery
Zhang et al. Phenylboronic acid-functionalized polymeric micelles with a HepG2 cell targetability
US11179466B2 (en) Amphiphilic block copolymer composition having enhanced micelle stability, and pharmaceutical composition comprising same
Liu et al. Preparation and characterization of glutaraldehyde cross-linked O-carboxymethylchitosan microspheres for controlled delivery of pazufloxacin mesilate
CN103768013A (zh) 以精制两亲性嵌段共聚物为载体的紫杉醇聚合物胶束
Ding et al. Preparation and properties of modified chitosan as potential matrix materials for drug sustained-release beads
CN104262638A (zh) 透明质酸-胱胺-聚乳酸-羟基乙酸接枝聚合物及其制备方法
Omtvedt et al. Alginate hydrogels functionalized with β‐cyclodextrin as a local paclitaxel delivery system
Wang et al. Micelles of methoxy poly (ethylene glycol)–poly (ε-caprolactone) as a novel drug delivery vehicle for tacrolimus
WO2023083265A1 (zh) 一种聚乙二醇单甲醚聚乳酸共聚物及其制备方法和其应用
Sui et al. Self-assembly of an amphiphilic derivative of chitosan and micellar solubilization of puerarin
Shi et al. In vitro and in vivo study of pH-sensitive and colon-targeting P (LE-IA-MEG) hydrogel microspheres used for ulcerative colitis therapy
Wang et al. Synthesis and characterization of biodegradable pH-sensitive hydrogel based on poly (ε-caprolactone), methacrylic acid, and Pluronic (L35)
CN105820299B (zh) 一种亲疏水端同时具有pH响应的聚合物胶束及其制备和应用
CN105315444B (zh) 注射用聚乙二醇单甲醚‑聚乳酸两亲性嵌段共聚物的纯化方法
Dong et al. Assessment of the safety, targeting, and distribution characteristics of a novel pH-sensitive hydrogel
Song et al. Preparation and evaluation of insulin-loaded nanoparticles based on hydroxypropyl-β-cyclodextrin modified carboxymethyl chitosan for oral delivery
Zhang et al. Chitosan and chitosan/β‐cyclodextrin microspheres as sustained‐release drug carriers

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22892058

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 22892058

Country of ref document: EP

Kind code of ref document: A1