WO2021179495A1 - Amphiphilic block copolymer, absorbable bone wax and preparation method therefor - Google Patents

Amphiphilic block copolymer, absorbable bone wax and preparation method therefor Download PDF

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WO2021179495A1
WO2021179495A1 PCT/CN2020/099818 CN2020099818W WO2021179495A1 WO 2021179495 A1 WO2021179495 A1 WO 2021179495A1 CN 2020099818 W CN2020099818 W CN 2020099818W WO 2021179495 A1 WO2021179495 A1 WO 2021179495A1
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block copolymer
amphiphilic block
polyethylene glycol
polyoxyethylene
trimethylene carbonate
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PCT/CN2020/099818
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French (fr)
Chinese (zh)
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潘高峰
高建丰
曾静雯
郑少东
朱志远
Original Assignee
成都颐合恒瑞医疗科技有限公司
北京颐合恒瑞医疗科技有限公司
新乡颐合恒瑞医疗科技有限公司
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Publication of WO2021179495A1 publication Critical patent/WO2021179495A1/en

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    • 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
    • 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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • 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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A61L24/0042—Materials resorbable by the body
    • 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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/046—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • 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
    • C08G63/64—Polyesters containing both carboxylic ester groups and carbonate 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
    • C08G63/78—Preparation processes
    • 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
    • C08G63/78—Preparation processes
    • C08G63/82—Preparation processes characterised by the catalyst used
    • C08G63/85—Germanium, tin, lead, arsenic, antimony, bismuth, titanium, zirconium, hafnium, vanadium, niobium, tantalum, or compounds thereof
    • 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
    • A61L2400/04—Materials for stopping bleeding

Definitions

  • the invention belongs to the technical field of hemostatic materials, and specifically relates to an amphiphilic block copolymer, absorbable bone wax and a preparation method.
  • bone destruction is often involved in surgical procedures such as orthopedics, thoracic surgery, and neurosurgery, causing blood oozing on the cancellous bone wound.
  • Cancellous bone wounds have loose tissue structure, abundant blood supply, forming dense sinusoids, poor vasoconstriction in the tissues, platelet aggregation, blood clots difficult to adhere to bone wounds, etc. It is often difficult to stop bleeding by vasoconstriction during surgery. It is also difficult to effectively stop bleeding by conventional methods such as electrocoagulation, clamp, hemostatic gauze, and gelatin sponge packing.
  • bone wax is commonly used clinically to stop bleeding from cancellous bone wounds.
  • the mechanism of hemostasis of bone wax is physical packing, which mechanically seals the bleeding wound of cancellous bone to achieve hemostasis.
  • the main components of traditional bone wax are beeswax, petrolatum, etc., which can stop bleeding quickly, have excellent blocking performance, and have good softening properties. After being softened by hand rubbing, it can be well shaped and has a wide range of clinical applications.
  • traditional bone wax has poor biocompatibility and cannot be degraded and absorbed by the body. It will remain in the body as a foreign body for a long time, which not only hinders bone repair, but may also trigger foreign body reactions, causing local pain, wound infection and other complications.
  • US patents US6387391, US9433639 and domestic patent CN 108939138 A disclose the application of degradable polyester and copolyester in bone wax.
  • the product has excellent biological safety and operability, and has good sealing performance, and can be used to stop bleeding on the wound with a large amount of bleeding.
  • the material has high hydrophobicity, slow disintegration and degradation speed, which affects bone healing, and the foreign body reaction time is long.
  • the product degradation cycle disclosed in CN 108939138 A is 6 months.
  • CN 109675094 A, CN 109481726, CN109200332A, CN109432487A and other patents also disclose some absorbable bone waxes with natural materials as main components (such as hyaluronic acid, starch, keratin, gelatin, chitosan, etc.).
  • This type of material is often spongy or powdery, and has a significant hemostatic effect in routine soft tissue bleeding. However, it is often not ideal for bleeding from cancellous bone wounds.
  • natural material sources and process stability are poor, and there are various problems such as immunogenicity and allergies.
  • One of the objectives of the present invention is to provide an amphiphilic block copolymer which, when used as a bone wax, has good sealing performance, rapid disintegration without occupying space, without affecting bone healing, rapid degradation and no long-term foreign body reaction , Hand feel, good performance, good cell compatibility, low local acidity, easy to stabilize production.
  • the second objective of the present invention is to provide a method for preparing the amphiphilic block copolymer.
  • the third object of the present invention is to provide a bone wax containing the amphiphilic block copolymer.
  • the fourth object of the present invention is to provide a preparation method of the bone wax.
  • amphiphilic block copolymer of the present invention is characterized in that the hydrophilic segment is a water-soluble polyoxyethylene chain, and the hydrophobic segment is a semi-crystalline ester chain; the ester chain is trimethylene carbonate and ⁇ - A binary copolymer of caprolactone; the general structure of the amphiphilic block copolymer is as follows:
  • PEG polyethylene glycol or polyethylene glycol monomethyl ether
  • PTCL is a binary copolymer of trimethylene carbonate and ⁇ -caprolactone.
  • the amphiphilic block copolymer of the present invention has an amphiphilic structure of a hydrophilic ether chain and a hydrophobic ester chain, and is a highly hydrophilic but insoluble degradable polymer.
  • the ether chain can effectively improve the hydrophilicity of the ester chain, greatly shortening the disintegration and degradation time of the product; the ester chain can keep the material insoluble in water, and significantly improve the sealing effectiveness of the material.
  • the amphiphilic block copolymer is a multiaxial polymer or a uniaxial polymer;
  • amphiphilic block copolymer when the amphiphilic block copolymer is a multiaxial polymer, it is composed of a multi-arm polyoxyethylene tailed with a semi-crystalline ester chain; more preferably, the multi-arm polyoxyethylene has a molecular weight of 5000-20000 One or more of three-arm polyethylene glycol, four-arm polyethylene glycol or other multi-arm polyethylene glycols;
  • the amphiphilic block copolymer when it is a uniaxial polymer, it is composed of a uniaxial polyoxyethylene tailed with a semi-crystalline ester chain; more preferably, the uniaxial polyoxyethylene has a molecular weight of 600- One or two of 1500 polyethylene glycol or polyethylene glycol monomethyl ether.
  • n 3-8.
  • n 1 ⁇ 2.
  • the mass fraction of the polyoxyethylene chain is 15%-45%, and the rest is ester chain;
  • amphiphilic block copolymer is a uniaxial polymer
  • the mass fraction of the polyoxyethylene chain is 8%-13%, and the rest are ester chains.
  • the ester chain includes two parts: an amorphous section and a crystalline section;
  • the mole percentage of the crystalline section is 25%-65%, and the rest are non-crystalline sections; more preferably, the mole percentage of the crystalline section is 30%, 35%, 40%, 45%, 50%, 60% A sort of.
  • the molar ratio of trimethylene carbonate and ⁇ -caprolactone in the amorphous section is 40-80:20-60;
  • Or/and the molar ratio of trimethylene carbonate and ⁇ -caprolactone in the crystalline section is 0-30:70-100.
  • the amphiphilic block copolymer has good support strength and can play the role of blocking and hemostasis; by setting the non-crystalline section, the amphiphilic block copolymer has good rubbing performance, which is convenient operate.
  • the molar percentage of trimethylene carbonate is 20-50%, and the rest is ⁇ -caprolactone; preferably, the molar percentage of trimethylene carbonate is 25%, One of 30%, 35%, 40%, 45%.
  • the preparation method of the amphiphilic block copolymer of the present invention is made by a two-step method, using polyoxyethylene containing hydroxyl functional groups as the initiator, stannous octoate as the catalyst, and trimethylene carbonate, ⁇ -hexyl
  • the lactone monomer undergoes melting and ring-opening polymerization, and after a certain period of reaction, ⁇ -caprolactone monomer is added and the reaction is continued to obtain.
  • the ester chain is provided with a non-crystalline section through the first step of the melting ring-opening reaction; and then the second step of the reaction is continued by adding ⁇ -caprolactone monomer, so that the ester chain is provided with a crystalline section.
  • the initiator and catalyst undergo melt ring-opening polymerization with trimethylene carbonate and ⁇ -caprolactone monomer at 130-160°C under the protection of inert gas;
  • the reaction time of the melt ring-opening polymerization in the first step is 2-36 h;
  • the polyoxyethylene containing a hydroxyl functional group is selected from any one or more of polyethylene glycol, polyethylene glycol monomethyl ether, three-arm polyethylene glycol, and four-arm polyethylene glycol.
  • the inert gas is preferably nitrogen.
  • the absorbable bone wax according to the present invention comprises one or more of the above-mentioned amphiphilic block copolymers.
  • the absorbable bone wax further includes one or more other components; the other components are selected from compounds that can accelerate disintegration, compounds that promote bone repair, and adjust absorbable bone. Any one or more of the wax performance compounds;
  • the compound for accelerating disintegration is selected from one or a mixture of two of polyethylene glycol and polyoxyethylene-polyoxypropylene copolymer;
  • the compound for promoting bone repair is selected from one or a mixture of two of hydroxyapatite and ⁇ -tricalcium phosphate;
  • the compound for adjusting the performance of the absorbable bone wax is selected from one or a mixture of two of fatty acid esters and fatty acid salts;
  • the total mass fraction of the other components is less than or equal to 15%, and more preferably, it is one of 1%, 5%, and 10%.
  • the method for preparing absorbable bone wax according to the present invention is obtained by melting and blending the amphiphilic block copolymer with other components.
  • the preparation method of the absorbable bone wax of the present invention may also include processes such as purification, drying, and sterilization.
  • the resorbable bone wax is packaged and sterilized to obtain the finished medical absorbable bone wax.
  • trimethylene carbonate TMC
  • ⁇ -caprolactone CL
  • the present invention has the following beneficial effects:
  • the present invention creatively polymerizes water-soluble components directly onto the hydrophobic degradable polyester chain to form a material with good hydrophilicity but not water-soluble as a whole.
  • the amphiphilic block copolymer of the present invention is used as a bone wax, has good sealing performance, can meet the use requirements of various bone bleeding, not only can effectively seal the bone wound with less bleeding, but also can effectively seal the bleeding Bone holes and bone defects with large blood volume are suitable for various clinical bone hemostasis needs.
  • the amphiphilic block copolymer of the present invention has both an amorphous section and a crystalline section.
  • the composition of the crystalline section is also limited.
  • the safety and safety of the material are further improved. Operational performance.
  • the present invention uses caprolactone in various commonly used crystalline degradable materials.
  • the melting point of PCL is much lower than that of PLA and PGA. It is easier to obtain a melting point slightly higher than human body temperature when copolymerized with TMC. At the same time a polymer with certain operational properties.
  • the present invention limits the type and molecular weight of ether chains, which significantly reduces the cytotoxicity often exhibited by surfactant analogs such as amphiphilic molecules.
  • the polyester chain uses a copolymer of TMC and ⁇ -CL, the degradation product of TMC is neutral, and the degradation product of ⁇ -CL is weakly acidic, which is more acidic than the degradation product. Glycolide and lactide have a smaller effect on bone healing.
  • amphiphilic block copolymer of the present invention adopts ⁇ -CL and TMC copolymerization, it is easier to obtain a uniform polymer, and can significantly improve the product process stability and use performance.
  • the present invention provides a product with good sealing performance, rapid disintegration without occupying space, no influence on bone healing, good handling performance, good cytocompatibility, low local acidity, and easy to stabilize production.
  • New synthetic biodegradable aliphatic polyester bone wax
  • Figure 1 is a diagram of the bone wax product prepared in Example 1 of the present invention (before application).
  • FIG. 2 is a diagram of the bone wax product prepared in Example 1 of the present invention (after application).
  • Fig. 3 is a micro-CT image of the bone defect of the rabbit femurs of samples 1#, 3#, 6#, 10#, C1# and existing product 1 and existing product 2 8 weeks after drilling.
  • Figure 4 shows the cytotoxicity test results of samples No. 1#, 3#, 6#, C3#, C4# and similar products 2;
  • This embodiment discloses the preparation method of the amphiphilic block copolymer of the present invention, specifically:
  • This embodiment discloses the preparation method of the amphiphilic block copolymer of the present invention, specifically:
  • This embodiment discloses the preparation method of the bone wax of the present invention, specifically:
  • This embodiment discloses the preparation method of the bone wax of the present invention, specifically:
  • This embodiment discloses the preparation method of the amphiphilic block copolymer of the present invention, specifically:
  • This embodiment discloses the preparation method of the amphiphilic block copolymer of the present invention, specifically:
  • This embodiment discloses the preparation method of the amphiphilic block copolymer of the present invention, specifically:
  • This embodiment discloses the preparation method of the amphiphilic block copolymer of the present invention, specifically:
  • This embodiment discloses the preparation method of the amphiphilic block copolymer of the present invention, specifically:
  • In vitro sealing performance test method pressure test method is adopted, specifically, a self-made cylinder similar to cancellous bone structure inside, one end of the cylinder is connected with a hose, and the hose is filled with a human body simulation fluid at 37°C, and the application is controlled by the level of the liquid. Test the liquid pressure on the end of the cylinder. The surface of the gap at the other end of the cylinder is completely smeared with the absorbable bone wax sample or reference substance of the present invention according to the clinical use method to test the effective blocking time of the material. The test results are as follows:
  • the disintegration time is the time when the material cannot continue to maintain its complete form, that is, it does not continue to occupy a place.
  • the material should disintegrate within 2 weeks during the critical period of callus formation, so as not to affect the subsequent bone healing.
  • New bone is continuously generated with the gradual disintegration of the material at the defect and the space is released; the experimental animal using the C1# sample and the existing product 1 has almost no change in the size of the defect. There is no new bone formation, and it is still a large round defect, indicating that the non-degradable existing product 1 occupies a long-term position after hemostasis and affects bone healing.
  • the degradation product of C1# sample with greater acidity degrades rapidly, it is due to the critical period. The internal concentration releases a large amount of acid degradation products, which also has a greater impact on bone healing.
  • the cytotoxicity of No. 1#, 3#, 6#, C3#, C4# bone wax was evaluated, and the existing product 2 was used as a control group for evaluation.
  • Extraction solution preparation Add serum-containing medium at a ratio of 0.2g/mL, and place it on a constant temperature shaker at 37°C for 24 hours. After the extraction is completed, samples 1#, 3#, and 6# are clear and transparent, and the C4# sample extract is whitish and has high turbidity, indicating that the material has high hydrophilicity and is easy to be leached in the extract to form a gel bundle.
  • the C3# sample extract is slightly turbid, and a large number of fine material particles are deposited on the bottom of the tube.
  • the original sample leaching solution was in the 100% concentration group, which was diluted down to 50% and 25%, respectively, in three concentration groups.
  • the samples of each concentration group were added to a 96-well plate that had been inoculated with L929 cells, and then placed in an incubator for 24 hours. After 24h, observe and record the cell morphology and number under the microscope. Then add CCK-8, after incubating for 2h, take out the 96-well plate, put it into the microplate reader for detection, set the wavelength to 450nm, and analyze the detection results.
  • the cell survival rate of the 100% extract group of 1#, 3#, 6# and the existing product 2 is higher than 70%, has no cytotoxicity, and all meets the requirements of medical implant materials.
  • the cell survival rate of C3# and C4# sample 100% extract group is less than 70%, which does not meet the requirements of medical implant materials, indicating that micelles have a certain impact on cell growth.
  • the polymer is uniaxial, the polymer The length of the oxyethylene chain has a significant effect on the cytotoxicity of the copolymer.
  • the softening point is the initial endothermic temperature of the sample.
  • the DSC curves of some samples (1#, 2#, 5#, 7#, 9#, C1#, C2#, C3#) are shown in 5.
  • the melting point of each sample of the embodiment is above 37°C and below 50°C, and begins to endothermic softening at room temperature. It is proved that the material not only has good hardness at human body temperature, but also guarantees the effectiveness of the material, and the material has good operating performance at room temperature.
  • Comparative Example C1# has obvious crystals, and its melting point is as high as 184°C, the hardness is very high at room temperature, and it lacks operability.
  • Comparative Example C2# The melting point of Comparative Example C2# is lower than the temperature of the human body, and the effectiveness of the product cannot be effectively guaranteed. Comparative Example C3# has ideal melting point and initial softening point, but due to the high crystallization temperature, the hardness at room temperature is high, and the handling performance is poor.

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Abstract

The present invention relates to the technical field of medicines. Disclosed are an amphiphilic block copolymer, absorbable bone wax and a preparation method therefor. In the amphiphilic block copolymer of the present invention, a hydrophilic segment is a water-soluble polyoxyethylene chain, and a hydrophobic segment is a semi-crystalline ester chain; the ester chain is a bipolymer of trimethylene carbonate and ε-caprolactone; the structural general formula of the amphiphilic block copolymer is as follows: PEG(-PTCL)n, wherein n is 1-8, the PEG is polyethylene glycol or methoxypolyethylene glycol, and the PTCL is a bipolymer of trimethylene carbonate and ε-caprolactone. In the present invention, when the amphiphilic block copolymer is used as bone wax, the amphiphilic block copolymer has the advantages of good blocking performance, rapid disintegration without space occupation, no influence on bone healing, good hand feeling operation performance, good cell compatibility, small local acidity, and easiness in stable production.

Description

一种双亲性嵌段共聚物、可吸收骨蜡及制法Amphiphilic block copolymer, absorbable bone wax and preparation method 技术领域Technical field
本发明属于止血材料技术领域，具体涉及一种双亲性嵌段共聚物、可吸收骨蜡及制法。The invention belongs to the technical field of hemostatic materials, and specifically relates to an amphiphilic block copolymer, absorbable bone wax and a preparation method.
背景技术Background technique
临床上，骨科、胸外科、神经外科等手术过程中常会涉及到骨质破坏，造成松质骨创面渗血。骨松质创面因为组织结构松散、血运丰富形成密布的血窦、组织中血管收缩性差、血小板聚集、血凝块难以粘附于骨创面等原因，术中出血时往往难以靠血管收缩自行止血，亦难以靠电凝、钳夹、止血纱布、明胶海绵填塞等常规方法进行有效止血。目前，临床常用骨蜡进行松质骨创面止血。骨蜡止血的作用机理是物理填塞，对松质骨出血创面进行机械封堵，从而实现止血。Clinically, bone destruction is often involved in surgical procedures such as orthopedics, thoracic surgery, and neurosurgery, causing blood oozing on the cancellous bone wound. Cancellous bone wounds have loose tissue structure, abundant blood supply, forming dense sinusoids, poor vasoconstriction in the tissues, platelet aggregation, blood clots difficult to adhere to bone wounds, etc. It is often difficult to stop bleeding by vasoconstriction during surgery. It is also difficult to effectively stop bleeding by conventional methods such as electrocoagulation, clamp, hemostatic gauze, and gelatin sponge packing. At present, bone wax is commonly used clinically to stop bleeding from cancellous bone wounds. The mechanism of hemostasis of bone wax is physical packing, which mechanically seals the bleeding wound of cancellous bone to achieve hemostasis.
传统骨蜡的主要成分是蜂蜡、凡士林等，其止血快速，封堵性能优异，并具有良好的软化性能，用手搓揉***后能很好的塑型，在临床上应用广泛。但传统骨蜡生物相容性差，且不能够被机体降解吸收，会作为异物长期留存于体内，不仅阻碍骨修复，还可能引发异物反应，引起局部疼痛、伤口感染等并发症。The main components of traditional bone wax are beeswax, petrolatum, etc., which can stop bleeding quickly, have excellent blocking performance, and have good softening properties. After being softened by hand rubbing, it can be well shaped and has a wide range of clinical applications. However, traditional bone wax has poor biocompatibility and cannot be degraded and absorbed by the body. It will remain in the body as a foreign body for a long time, which not only hinders bone repair, but may also trigger foreign body reactions, causing local pain, wound infection and other complications.
Baxter公司生产的
Figure PCTCN2020099818-appb-000001
Hemostasis Material产品(专利号CN1780596 B、CN104010669 A)以及WNDM公司的Hemaquell TM产品，其成分为水溶性的烷氧基共聚物的混合物。
Figure PCTCN2020099818-appb-000002
是目前临床应用最为广泛的可吸收骨蜡产品，具有良好的操作性能和生物安全性，且48h内即可完全溶解，不影响骨愈合。但该产品为完全水溶性成分，遇血液后表面快速液化导致封堵强度降低，止血效果不佳。 Made by Baxter
Figure PCTCN2020099818-appb-000001
Hemostasis Material products (patent numbers CN1780596 B, CN104010669 A) and WNDM's Hemaquell TM products are composed of a mixture of water-soluble alkoxy copolymers.
Figure PCTCN2020099818-appb-000002
It is currently the most widely used absorbable bone wax product in clinical applications. It has good operability and biological safety, and can be completely dissolved within 48 hours without affecting bone healing. However, the product is a completely water-soluble component, and the surface quickly liquefies after encountering blood, resulting in a decrease in the sealing strength and poor hemostatic effect.
美国专利US6387391、US9433639，国内专利CN 108939138 A公开了可降解聚酯和共聚酯在骨蜡中的应用。产品具有优异的生物安全性和操作性，且封堵性能良好，能用于出血量较大的创面止血。但该材料疏水性高，崩解及降解速度缓慢，影响骨愈合，且异物反应时间长。如CN 108939138 A中公开的产品降解周期为6个月。US patents US6387391, US9433639 and domestic patent CN 108939138 A disclose the application of degradable polyester and copolyester in bone wax. The product has excellent biological safety and operability, and has good sealing performance, and can be used to stop bleeding on the wound with a large amount of bleeding. However, the material has high hydrophobicity, slow disintegration and degradation speed, which affects bone healing, and the foreign body reaction time is long. For example, the product degradation cycle disclosed in CN 108939138 A is 6 months.
中国专利CN109908397A、CN1727013A、CN109453419A，美国专利US6420454B1将非水溶性的聚酯与水溶性聚合物共混，使材料同时不仅具有优异的封堵性能，又能快速解除占位，不影响骨愈合。物理共混解决了聚酯类材料崩 解慢影响骨愈合的问题。但物理共混的水溶性成分植入人体后在周围组织液的作用下会快速从蜡块中游离出，显著降低材料的止血有效性，且不能改善剩余非水溶性聚酯材料的降解性能。US9433639中公开了一种PEG、PLA、PGA的共聚物，但并未公开任何材料细节，而PLA和PGA的熔点分别为173-178℃和225-230℃，与PEG共聚很难得到密封性、硬度、粘手性等各方面均表现良好的骨蜡材料。Chinese patents CN109908397A, CN1727013A, CN109453419A, and US patent US6420454B1 blend non-water-soluble polyester and water-soluble polymer, so that the material not only has excellent sealing performance, but also can quickly release the space without affecting bone healing. Physical blending solves the problem of slow disintegration of polyester materials that affects bone healing. However, the physically blended water-soluble components will be quickly released from the wax block under the action of the surrounding tissue fluid after being implanted in the human body, significantly reducing the hemostatic effectiveness of the material, and cannot improve the degradation performance of the remaining non-water-soluble polyester material. US9433639 discloses a copolymer of PEG, PLA, and PGA, but does not disclose any material details. The melting points of PLA and PGA are 173-178°C and 225-230°C, respectively. It is difficult to obtain sealability by copolymerization with PEG. Bone wax material that performs well in various aspects such as hardness and stickiness.
CN 109675094 A、CN 109481726、CN109200332A、CN109432487A等专利还公开了一些以天然材料为主要成分(如透明质酸、淀粉、角蛋白、明胶、壳聚糖等)的可吸收骨蜡。这一类材料往往是海绵状或粉状，在常规软组织出血中止血效果显著，但应用于骨松质创面渗血往往止血效果不理想。此外，天然材料来源及工艺稳定性差，且存在免疫原性、过敏等各种问题。目前尚无任何该类型的可吸收骨蜡产品上市。CN 109675094 A, CN 109481726, CN109200332A, CN109432487A and other patents also disclose some absorbable bone waxes with natural materials as main components (such as hyaluronic acid, starch, keratin, gelatin, chitosan, etc.). This type of material is often spongy or powdery, and has a significant hemostatic effect in routine soft tissue bleeding. However, it is often not ideal for bleeding from cancellous bone wounds. In addition, natural material sources and process stability are poor, and there are various problems such as immunogenicity and allergies. Currently, there is no such type of absorbable bone wax product on the market.
因此，提供一种可降解骨蜡，在快速止血的同时能够被机体降解吸收，不影响后期骨愈合，成为了本领域技术人员亟待解决的问题。Therefore, to provide a degradable bone wax that can be degraded and absorbed by the body while quickly stopping bleeding, without affecting the bone healing in the later stage, has become an urgent problem for those skilled in the art.
发明内容Summary of the invention
本发明的目的之一在于，提供一种双亲性嵌段共聚物，其用作骨蜡时，具有良好的封堵性能、快速崩解不占位、不影响骨愈合、快速降解无长期异物反应、手感操作性能好、良好的细胞相容性、局部酸性小、易于稳定化生产。One of the objectives of the present invention is to provide an amphiphilic block copolymer which, when used as a bone wax, has good sealing performance, rapid disintegration without occupying space, without affecting bone healing, rapid degradation and no long-term foreign body reaction , Hand feel, good performance, good cell compatibility, low local acidity, easy to stabilize production.
本发明的目的之二在于，提供该双亲性嵌段共聚物的制备方法。The second objective of the present invention is to provide a method for preparing the amphiphilic block copolymer.
本发明的目的之三在于，提供一种包含该双亲性嵌段共聚物的骨蜡。The third object of the present invention is to provide a bone wax containing the amphiphilic block copolymer.
本发明的目的之四在于，提供该骨蜡的制备方法。The fourth object of the present invention is to provide a preparation method of the bone wax.
为实现上述目的，本发明采用的技术方案如下：In order to achieve the above objectives, the technical solutions adopted by the present invention are as follows:
本发明一种双亲性嵌段共聚物，其特征在于，其亲水段为水溶性的聚氧乙烯链，疏水段为半结晶的酯链；所述酯链为三亚甲基碳酸酯与ε-己内酯的二元共聚物；所述双亲性嵌段共聚物结构通式如下：The amphiphilic block copolymer of the present invention is characterized in that the hydrophilic segment is a water-soluble polyoxyethylene chain, and the hydrophobic segment is a semi-crystalline ester chain; the ester chain is trimethylene carbonate and ε- A binary copolymer of caprolactone; the general structure of the amphiphilic block copolymer is as follows:
PEG(—PTCL) n，其中n为1～8； PEG(—PTCL) n , where n is 1～8;
其中，PEG为聚乙二醇或聚乙二醇单甲醚；PTCL为三亚甲基碳酸酯与ε-己内酯的二元共聚物。Among them, PEG is polyethylene glycol or polyethylene glycol monomethyl ether; PTCL is a binary copolymer of trimethylene carbonate and ε-caprolactone.
本发明所述双亲性嵌段共聚物为亲水醚链与疏水酯链的双亲结构，是一种高亲水性，但不溶解的可降解聚合物。醚链能够有效改善酯链的亲水性，大幅度缩 短产品的崩解和降解时间；酯链能够保持材料不直接水溶，显著改善材料的封堵有效性。本发明的技术方案中，所述双亲性嵌段共聚物为多轴聚合物或单轴聚合物；The amphiphilic block copolymer of the present invention has an amphiphilic structure of a hydrophilic ether chain and a hydrophobic ester chain, and is a highly hydrophilic but insoluble degradable polymer. The ether chain can effectively improve the hydrophilicity of the ester chain, greatly shortening the disintegration and degradation time of the product; the ester chain can keep the material insoluble in water, and significantly improve the sealing effectiveness of the material. In the technical scheme of the present invention, the amphiphilic block copolymer is a multiaxial polymer or a uniaxial polymer;
优选地，所述双亲性嵌段共聚物为多轴聚合物时，由多臂聚氧乙烯尾接半结晶的酯链构成；更优选地，所述多臂聚氧乙烯为分子量5000-20000的三臂聚乙二醇、四臂聚乙二醇或其他多臂聚乙二醇中的一种或几种；Preferably, when the amphiphilic block copolymer is a multiaxial polymer, it is composed of a multi-arm polyoxyethylene tailed with a semi-crystalline ester chain; more preferably, the multi-arm polyoxyethylene has a molecular weight of 5000-20000 One or more of three-arm polyethylene glycol, four-arm polyethylene glycol or other multi-arm polyethylene glycols;
优选地，所述双亲性嵌段共聚物为单轴聚合物时，由单轴线性聚氧乙烯尾接半结晶的酯链构成；更优选地，所述单轴线性聚氧乙烯为分子量600-1500的聚乙二醇、或聚乙二醇单甲醚中的一种或两种。本发明的技术方案中，所述双亲性嵌段共聚物为多轴聚合物时，其n＝3～8。Preferably, when the amphiphilic block copolymer is a uniaxial polymer, it is composed of a uniaxial polyoxyethylene tailed with a semi-crystalline ester chain; more preferably, the uniaxial polyoxyethylene has a molecular weight of 600- One or two of 1500 polyethylene glycol or polyethylene glycol monomethyl ether. In the technical scheme of the present invention, when the amphiphilic block copolymer is a multiaxial polymer, n=3-8.
本发明的技术方案中，所述双亲性嵌段共聚物为单轴聚合物时，其n＝1～2。In the technical scheme of the present invention, when the amphiphilic block copolymer is a uniaxial polymer, n=1˜2.
本发明的一些实施例中，所述双亲性嵌段共聚物中，所述双亲性嵌段共聚物为多轴聚合物时，聚氧乙烯链的质量分数为15％-45％，其余为酯链；In some embodiments of the present invention, in the amphiphilic block copolymer, when the amphiphilic block copolymer is a multiaxial polymer, the mass fraction of the polyoxyethylene chain is 15%-45%, and the rest is ester chain;
所述双亲性嵌段共聚物为单轴聚合物时，所述聚氧乙烯链的质量分数为8％-13％，其余为酯链。When the amphiphilic block copolymer is a uniaxial polymer, the mass fraction of the polyoxyethylene chain is 8%-13%, and the rest are ester chains.
本发明的技术方案中，所述酯链包含非结晶段和结晶段两部分；In the technical scheme of the present invention, the ester chain includes two parts: an amorphous section and a crystalline section;
优选地，结晶段的摩尔百分数为25％-65％，其余为非结晶段；更优选地，结晶段的摩尔百分数为30％、35％、40％、45％、50％、60％中的一种。Preferably, the mole percentage of the crystalline section is 25%-65%, and the rest are non-crystalline sections; more preferably, the mole percentage of the crystalline section is 30%, 35%, 40%, 45%, 50%, 60% A sort of.
本发明的技术方案中，所述酯链中，非结晶段的三亚甲基碳酸酯和ε-己内酯的摩尔比为40-80：20-60；In the technical scheme of the present invention, in the ester chain, the molar ratio of trimethylene carbonate and ε-caprolactone in the amorphous section is 40-80:20-60;
或/和结晶段的三亚甲基碳酸酯和ε-己内酯的摩尔比为0-30：70-100。Or/and the molar ratio of trimethylene carbonate and ε-caprolactone in the crystalline section is 0-30:70-100.
本发明中通过设置结晶段，使双亲性嵌段共聚物具备良好的支撑强度，能起到封堵止血的作用；通过设置非结晶段，使双亲性嵌段共聚物具备良好的揉搓性能，便于操作。In the present invention, by setting the crystalline section, the amphiphilic block copolymer has good support strength and can play the role of blocking and hemostasis; by setting the non-crystalline section, the amphiphilic block copolymer has good rubbing performance, which is convenient operate.
本发明的技术方案中，所述酯链中，三亚甲基碳酸酯的摩尔百分数为20-50％，其余为ε-己内酯；优选地，三亚甲基碳酸酯的摩尔百分数为25％、30％、35％、40％、45％中一种。In the technical scheme of the present invention, in the ester chain, the molar percentage of trimethylene carbonate is 20-50%, and the rest is ε-caprolactone; preferably, the molar percentage of trimethylene carbonate is 25%, One of 30%, 35%, 40%, 45%.
本发明所述的双亲性嵌段共聚物的制备方法，采用两步法制成，以含有羟基官能团的聚氧乙烯作为引发剂，以辛酸亚锡作为催化剂，与三亚甲基碳酸酯、ε- 己内酯单体进行熔融开环聚合，反应一定时间后，再加入ε-己内酯单体，继续反应，即得。The preparation method of the amphiphilic block copolymer of the present invention is made by a two-step method, using polyoxyethylene containing hydroxyl functional groups as the initiator, stannous octoate as the catalyst, and trimethylene carbonate, ε-hexyl The lactone monomer undergoes melting and ring-opening polymerization, and after a certain period of reaction, ε-caprolactone monomer is added and the reaction is continued to obtain.
本发明中，通过第一步的熔融开环反应，使酯链具备非结晶段；而后加入ε-己内酯单体继续进行的第二步反应，使酯链具备结晶段。In the present invention, the ester chain is provided with a non-crystalline section through the first step of the melting ring-opening reaction; and then the second step of the reaction is continued by adding ε-caprolactone monomer, so that the ester chain is provided with a crystalline section.
优选地，所述引发剂、催化剂在130-160℃，惰性气体保护下与三亚甲基碳酸酯、ε-己内酯单体进行熔融开环聚合；Preferably, the initiator and catalyst undergo melt ring-opening polymerization with trimethylene carbonate and ε-caprolactone monomer at 130-160°C under the protection of inert gas;
优选地，所述第一步的熔融开环聚合的反应时间为2-36h；Preferably, the reaction time of the melt ring-opening polymerization in the first step is 2-36 h;
优选地，加入ε-己内酯单体继续进行的第二步反应，反应24-48h；Preferably, adding ε-caprolactone monomer to continue the second step of the reaction for 24-48h;
优选地，所述含有羟基官能团的聚氧乙烯选自是聚乙二醇、聚乙二醇单甲醚、三臂聚乙二醇、四臂聚乙二醇中的任意一种或几种。Preferably, the polyoxyethylene containing a hydroxyl functional group is selected from any one or more of polyethylene glycol, polyethylene glycol monomethyl ether, three-arm polyethylene glycol, and four-arm polyethylene glycol.
本发明中，所述惰性气体优选为氮气。In the present invention, the inert gas is preferably nitrogen.
本发明所述的一种可吸收骨蜡，包含上述的一种或多种双亲性嵌段共聚物。The absorbable bone wax according to the present invention comprises one or more of the above-mentioned amphiphilic block copolymers.
本发明的一些实施例中，所述可吸收骨蜡，还包含一种及以上的其它组分；所述其它组分选自能加速崩解的化合物、促进骨修复的化合物、调节可吸收骨蜡使用性能的化合物中任意一种或多种；In some embodiments of the present invention, the absorbable bone wax further includes one or more other components; the other components are selected from compounds that can accelerate disintegration, compounds that promote bone repair, and adjust absorbable bone. Any one or more of the wax performance compounds;
优选地，所述加速崩解的化合物选自聚乙二醇、聚氧乙烯-聚氧丙烯共聚物中的一种或两种的混合物；Preferably, the compound for accelerating disintegration is selected from one or a mixture of two of polyethylene glycol and polyoxyethylene-polyoxypropylene copolymer;
优选地，所述促进骨修复的化合物选自羟基磷灰石、β-磷酸三钙中的一种或两种的混合物；Preferably, the compound for promoting bone repair is selected from one or a mixture of two of hydroxyapatite and β-tricalcium phosphate;
优选地，所述调节可吸收骨蜡使用性能的化合物选自脂肪酸酯、脂肪酸盐中的一种或两种的混合物；Preferably, the compound for adjusting the performance of the absorbable bone wax is selected from one or a mixture of two of fatty acid esters and fatty acid salts;
优选地，所述其它组分的质量分数总和小于等于15％，进一步优选地，为1％、5％、10％中的一种。Preferably, the total mass fraction of the other components is less than or equal to 15%, and more preferably, it is one of 1%, 5%, and 10%.
本发明所述的一种可吸收骨蜡的制备方法，将双亲性嵌段共聚物与其他组分时熔融共混，即得。The method for preparing absorbable bone wax according to the present invention is obtained by melting and blending the amphiphilic block copolymer with other components.
本发明所述可吸收骨蜡的制备方法还可以包括纯化、干燥、灭菌等过程。可吸收骨蜡包装、灭菌后即得成品医用可吸收骨蜡。The preparation method of the absorbable bone wax of the present invention may also include processes such as purification, drying, and sterilization. The resorbable bone wax is packaged and sterilized to obtain the finished medical absorbable bone wax.
本发明中三亚甲基碳酸酯的缩写为TMC，ε-己内酯的缩写为CL。In the present invention, the abbreviation of trimethylene carbonate is TMC, and the abbreviation of ε-caprolactone is CL.
与现有技术相比，本发明具有以下有益效果：Compared with the prior art, the present invention has the following beneficial effects:
1、本发明创造性地将水溶性组分直接聚合到疏水的可降解聚酯链上，整体上形成一种具有较好的亲水性，但却不水溶的材料。本发明的双亲性嵌段共聚物作为骨蜡使用，具有良好的封堵性能，能满足各种骨出血的使用要求，不但能有效封堵渗血量少的骨创面，也能有效封堵渗血量较大的骨洞及骨缺损，适合各类临床骨止血需求。1. The present invention creatively polymerizes water-soluble components directly onto the hydrophobic degradable polyester chain to form a material with good hydrophilicity but not water-soluble as a whole. The amphiphilic block copolymer of the present invention is used as a bone wax, has good sealing performance, can meet the use requirements of various bone bleeding, not only can effectively seal the bone wound with less bleeding, but also can effectively seal the bleeding Bone holes and bone defects with large blood volume are suitable for various clinical bone hemostasis needs.
2、本发明的双亲性嵌段共聚物，同时具有非结晶段和结晶段，对结晶段的组分也进行了限定，在保障材料止血有效性的基础上，进一步改善了材料的安全性和操作性能。在此基础上，本发明在各种常用的结晶可降解材料中选用了己内酯，PCL的熔点远低于PLA和PGA，与TMC共聚更容易获得熔点略高于人体温度，但在室温下同时具有一定操作性能的聚合物。2. The amphiphilic block copolymer of the present invention has both an amorphous section and a crystalline section. The composition of the crystalline section is also limited. On the basis of ensuring the effectiveness of the material for hemostasis, the safety and safety of the material are further improved. Operational performance. On this basis, the present invention uses caprolactone in various commonly used crystalline degradable materials. The melting point of PCL is much lower than that of PLA and PGA. It is easier to obtain a melting point slightly higher than human body temperature when copolymerized with TMC. At the same time a polymer with certain operational properties.
3、本发明的双亲性嵌段共聚物，利用亲水的醚链调节疏水的酯链的亲水性能，使得聚合物在完成止血要求后，能快速崩解和降解，及时解除止血部位的占位，不妨碍骨组织自身愈合。3. The amphiphilic block copolymer of the present invention uses the hydrophilic ether chain to adjust the hydrophilic properties of the hydrophobic ester chain, so that the polymer can quickly disintegrate and degrade after completing the requirements of hemostasis, and remove the occupation of hemostasis in time. It does not prevent the bone tissue from healing itself.
4、本发明为了保障材料的生物安全性能，对醚链的种类和分子量进行了限定，显著降低了双亲性分子这类表面活性剂类似物常常表现出的细胞毒性。4. In order to ensure the biological safety performance of the material, the present invention limits the type and molecular weight of ether chains, which significantly reduces the cytotoxicity often exhibited by surfactant analogs such as amphiphilic molecules.
5、本发明的双亲性嵌段共聚物，聚酯链使用了TMC和ε-CL的共聚物，TMC降解产物为中性，ε-CL降解产物为弱酸性，相较于降解产物为酸性的乙交酯和丙交酯，对骨组织愈合的影响更小。5. In the amphiphilic block copolymer of the present invention, the polyester chain uses a copolymer of TMC and ε-CL, the degradation product of TMC is neutral, and the degradation product of ε-CL is weakly acidic, which is more acidic than the degradation product. Glycolide and lactide have a smaller effect on bone healing.
6、本发明的双亲性嵌段共聚物采用ε-CL和TMC共聚，更容易获得均一的聚合物，能显著提升产品工艺稳定性及使用性能。6. The amphiphilic block copolymer of the present invention adopts ε-CL and TMC copolymerization, it is easier to obtain a uniform polymer, and can significantly improve the product process stability and use performance.
综上所述，本发明提供了一种具有良好封堵性能、快速崩解不占位、不影响骨愈合、手感操作性能好、良好的细胞相容性、局部酸性小、易于稳定化生产的新型合成可生物降解脂肪族聚酯型骨蜡。In summary, the present invention provides a product with good sealing performance, rapid disintegration without occupying space, no influence on bone healing, good handling performance, good cytocompatibility, low local acidity, and easy to stabilize production. New synthetic biodegradable aliphatic polyester bone wax.
附图说明Description of the drawings
附图1为本发明实施例1制得的骨蜡产品图(涂抹前)。Figure 1 is a diagram of the bone wax product prepared in Example 1 of the present invention (before application).
附图2为本发明实施例1制得的骨蜡产品图(涂抹后)。Figure 2 is a diagram of the bone wax product prepared in Example 1 of the present invention (after application).
附图3为1#、3#、6#、10#、C1#号样品与现有产品1、现有产品2的兔股骨钻孔术后8周骨缺损处显微CT图。Fig. 3 is a micro-CT image of the bone defect of the rabbit femurs of samples 1#, 3#, 6#, 10#, C1# and existing product 1 and existing product 2 8 weeks after drilling.
附图4为1#、3#、6#、C3#、C4#号样品和同类产品2的细胞毒性试验结果图；Figure 4 shows the cytotoxicity test results of samples No. 1#, 3#, 6#, C3#, C4# and similar products 2;
附图5为样品的DSC曲线图，其中图5a为1#样品的DSC曲线图，图5b为3#样品的DSC曲线图，图5c为5#样品的DSC曲线图，图5d为7#样品的DSC曲线图，图5e为9#样品的DSC曲线图，图5f为C1#样品的DSC曲线图，图5g为C2#样品的DSC曲线图，图5h为C3#样品的DSC曲线图。Fig. 5 is the DSC curve of the sample, in which Fig. 5a is the DSC curve of the 1# sample, Fig. 5b is the DSC curve of the 3# sample, Fig. 5c is the DSC curve of the 5# sample, and Fig. 5d is the 7# sample Fig. 5e is the DSC curve of sample 9#, Fig. 5f is the DSC curve of sample C1#, Fig. 5g is the DSC curve of sample C2#, and Fig. 5h is the DSC curve of sample C3#.
具体实施方式Detailed ways
为了更清楚的说明本发明实施例或现有技术中的技术方案，下面将列举若干本发明的具体实施方式。显而易见地，下面的几种具体实施例仅仅是本发明的一些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些具体实施例，获得其他的实施方式。In order to explain the embodiments of the present invention or the technical solutions in the prior art more clearly, several specific implementation manners of the present invention will be listed below. Obviously, the following specific embodiments are only some embodiments of the present invention. For those of ordinary skill in the art, without creative work, other implementations can be obtained based on these specific embodiments. .
实施例1Example 1
本实施例公开了本发明的双亲性嵌段共聚物的制备方法，具体为：This embodiment discloses the preparation method of the amphiphilic block copolymer of the present invention, specifically:
称取干燥完成的聚乙二醇1000 10.2g，三亚甲基碳酸酯29.4g，ε-己内酯14.0g，加入250mL的三颈瓶中，再加入3mg辛酸亚锡作为催化剂。在氮气保护下，升温至150℃，搅拌反应12h后，再加入ε-己内酯46.5g，继续搅拌反应36h，冷却至室温，纯化、干燥后得双亲性嵌段共聚物，作为1#骨蜡。Weigh 10.2g of the dried polyethylene glycol 1000, 29.4g trimethylene carbonate, and 14.0g ε-caprolactone, add them to a 250mL three-necked flask, and then add 3mg of stannous octoate as a catalyst. Under the protection of nitrogen, the temperature was raised to 150°C, stirred for 12 hours, and then added 46.5 g of ε-caprolactone, continued to stir and react for 36 hours, cooled to room temperature, purified and dried to obtain the amphiphilic block copolymer as 1# bone wax.
实施例2Example 2
本实施例公开了本发明的双亲性嵌段共聚物的制备方法，具体为：This embodiment discloses the preparation method of the amphiphilic block copolymer of the present invention, specifically:
称取干燥完成的聚乙二醇单甲醚600 8.6g，三亚甲基碳酸酯16.8g，ε-己内酯46.6g，加入250mL的三颈瓶中，再加入3mg辛酸亚锡作为催化剂。在氮气保护下，升温至150℃，搅拌反应24h后，再加入ε-己内酯28.0g，继续搅拌反应48h，冷却至室温，纯化、干燥后得双亲性嵌段共聚物，作为2#骨蜡。Weigh 600 8.6 g of dried polyethylene glycol monomethyl ether, 16.8 g trimethylene carbonate, and 46.6 g ε-caprolactone, add them to a 250 mL three-necked flask, and add 3 mg of stannous octoate as a catalyst. Under the protection of nitrogen, the temperature was raised to 150°C, stirred for 24 hours, and then added 28.0 g of ε-caprolactone, continued to stir and react for 48 hours, cooled to room temperature, purified and dried to obtain the amphiphilic block copolymer as 2# bone wax.
实施例3Example 3
本实施例公开了本发明的骨蜡的制备方法，具体为：This embodiment discloses the preparation method of the bone wax of the present invention, specifically:
称取1#骨蜡86g，四臂聚乙二醇10000 14g，加入250mL的三颈瓶中，升温至80℃直至材料完成熔融，搅拌共混2h后，冷却至室温得3#骨蜡。Weigh 86g of 1# bone wax and 10000 14g of four-arm polyethylene glycol, add them to a 250mL three-necked flask, heat up to 80°C until the material is melted, stir and blend for 2h, cool to room temperature to obtain 3# bone wax.
实施例4Example 4
本实施例公开了本发明的骨蜡的制备方法，具体为：This embodiment discloses the preparation method of the bone wax of the present invention, specifically:
称取2#骨蜡93g，聚乙二醇单甲醚2000 7g，加入250mL的三颈瓶中，升温至80℃直至材料完成熔融，搅拌共混2h后，冷却至室温得4#骨蜡。Weigh 93g of 2# bone wax and 20007g of polyethylene glycol monomethyl ether, add it to a 250mL three-necked flask, heat up to 80°C until the material is melted, stir and blend for 2h, cool to room temperature to obtain 4# bone wax.
实施例5Example 5
本实施例公开了本发明的双亲性嵌段共聚物的制备方法，具体为：This embodiment discloses the preparation method of the amphiphilic block copolymer of the present invention, specifically:
称取干燥完成的三臂聚乙二醇5000 16.4g，三亚甲基碳酸酯27.3g，ε-己内酯13.0g，加入250mL的三颈瓶中，再加入2mg辛酸亚锡作为催化剂。在氮气保护下，升温至140℃，搅拌反应4h后，再加入ε-己内酯43.3g，继续搅拌反应36h，冷却至室温，纯化、干燥后得双亲性嵌段共聚物，作为5#骨蜡。Weigh 5000 16.4 g of the dried three-arm polyethylene glycol, 27.3 g of trimethylene carbonate, and 13.0 g of ε-caprolactone, add them to a 250 mL three-necked flask, and then add 2 mg of stannous octoate as a catalyst. Under the protection of nitrogen, the temperature was raised to 140°C, stirred for 4 hours, and then 43.3g of ε-caprolactone was added. The reaction was continued for 36 hours, cooled to room temperature, purified and dried to obtain the amphiphilic block copolymer, which was used as 5# bone. wax.
实施例6Example 6
本实施例公开了本发明的双亲性嵌段共聚物的制备方法，具体为：This embodiment discloses the preparation method of the amphiphilic block copolymer of the present invention, specifically:
称取干燥完成的四臂聚乙二醇10000 36.1g，三亚甲基碳酸酯17.8g，ε-己内酯19.8，加入250mL的三颈瓶中，再加入2mg辛酸亚锡作为催化剂。在氮气保护下，升温至140℃，搅拌反应8h后，再加入ε-己内酯26.3g，继续搅拌反应48h，冷却至室温，纯化、干燥后得双亲性嵌段共聚物，作为6#骨蜡。Weigh 10000 36.1 g of the dried four-arm polyethylene glycol, 17.8 g trimethylene carbonate, and 19.8 ε-caprolactone, add them to a 250 mL three-necked flask, and add 2 mg of stannous octoate as a catalyst. Under the protection of nitrogen, the temperature was raised to 140°C, stirred for 8 hours, and then added 26.3g of ε-caprolactone, continued to stir and react for 48 hours, cooled to room temperature, purified and dried to obtain the amphiphilic block copolymer as 6# bone wax.
实施例7Example 7
本实施例公开了本发明的双亲性嵌段共聚物的制备方法，具体为：This embodiment discloses the preparation method of the amphiphilic block copolymer of the present invention, specifically:
称取干燥完成的四臂聚乙二醇10000 20.1g，三亚甲基碳酸酯33.9g，ε-己内酯20.9g，加入250mL的三颈瓶中，再加入2mg辛酸亚锡作为催化剂。在氮气保护下，升温至145℃，搅拌反应2h后，再加入ε-己内酯25.1g，继续搅拌反应48h，冷却至室温，纯化、干燥后得双亲性嵌段共聚物，作为7#骨蜡。Weigh 10000 20.1 g of the dried four-arm polyethylene glycol, 33.9 g of trimethylene carbonate, and 20.9 g of ε-caprolactone, add them to a 250 mL three-necked flask, and add 2 mg of stannous octoate as a catalyst. Under the protection of nitrogen, the temperature was raised to 145℃, after stirring for 2h, 25.1g of ε-caprolactone was added, and the stirring was continued for 48h, cooled to room temperature, purified and dried to obtain the amphiphilic block copolymer as 7# bone wax.
实施例8Example 8
本实施例公开了本发明的双亲性嵌段共聚物的制备方法，具体为：This embodiment discloses the preparation method of the amphiphilic block copolymer of the present invention, specifically:
称取干燥完成的四臂聚乙二醇20000 42.2g，三亚甲基碳酸酯21.71g，ε-己内酯15.0g，加入250mL的三颈瓶中，再加入2mg辛酸亚锡作为催化剂。在氮气保护下，升温至145℃，搅拌反应24h后，再加入ε-己内酯21.1g，继续搅拌反应48h，冷却至室温，纯化、干燥后得双亲性嵌段共聚物，作为8#骨蜡。Weigh 20,000 42.2 g of the dried four-arm polyethylene glycol, 21.71 g of trimethylene carbonate, and 15.0 g of ε-caprolactone, add them to a 250 mL three-necked flask, and then add 2 mg of stannous octoate as a catalyst. Under the protection of nitrogen, the temperature was raised to 145°C, after stirring for 24 hours, 21.1g of ε-caprolactone was added, and the stirring was continued for 48 hours, cooled to room temperature, purified and dried to obtain the amphiphilic block copolymer as 8# bone wax.
实施例9Example 9
本实施例公开了本发明的双亲性嵌段共聚物的制备方法，具体为：This embodiment discloses the preparation method of the amphiphilic block copolymer of the present invention, specifically:
称取干燥完成的三臂聚乙二醇5000 23.0g，三亚甲基碳酸酯17.8g，ε-己内酯23.7g，加入250mL的三颈瓶中，再加入2mg辛酸亚锡作为催化剂。在氮气保护下，升温至145℃，搅拌反应12h后，再加入ε-己内酯35.5g，继续搅拌反应48h，冷却至室温，纯化、干燥后得双亲性嵌段共聚物，作为9#骨蜡。Weigh 5000 23.0 g of the dried three-arm polyethylene glycol, 17.8 g trimethylene carbonate, and 23.7 g ε-caprolactone, add them to a 250 mL three-necked flask, and add 2 mg of stannous octoate as a catalyst. Under the protection of nitrogen, the temperature was raised to 145°C, stirred for 12h, then 35.5g of ε-caprolactone was added, and the stirring was continued for 48h, cooled to room temperature, purified and dried to obtain the amphiphilic block copolymer as 9#bone wax.
实施例10Example 10
本实施例公开了本发明的双亲性嵌段共聚物的制备方法，具体为：This embodiment discloses the preparation method of the amphiphilic block copolymer of the present invention, specifically:
称取1#骨蜡30g，8#骨蜡70g，加入250mL的三颈瓶中，升温至80℃直至材料完成熔融，搅拌共混2h后，冷却至室温得10#骨蜡。Weigh 30g of 1# bone wax and 70g of 8# bone wax, add them to a 250mL three-necked flask, heat up to 80°C until the material is melted, stir and blend for 2h, cool to room temperature to obtain 10# bone wax.
对比例1Comparative example 1
称取干燥完成的聚乙二醇1000 10.0g，丙交酯23.1g，乙交酯66.9g，加入250mL的三颈瓶中，再加入2mg辛酸亚锡作为催化剂。在氮气保护下，升温至150℃，搅拌反应36h，冷却至室温，纯化、干燥后得C1#样品。Weigh 1000 10.0 g of dried polyethylene glycol, 23.1 g of lactide, and 66.9 g of glycolide into a 250 mL three-necked flask, and then add 2 mg of stannous octoate as a catalyst. Under the protection of nitrogen, the temperature was raised to 150°C, the reaction was stirred for 36h, cooled to room temperature, purified and dried to obtain the C1# sample.
对比例2Comparative example 2
称取干燥完成的四臂聚乙二醇10000 38.8g，三亚甲基碳酸酯20.0g，ε-己内酯41.2g，加入250mL的三颈瓶中，再加入2mg辛酸亚锡作为催化剂。在氮气保护下，升温至140℃，搅拌反应48h，冷却至室温，纯化、干燥后得C2#样品。Weigh 10000 38.8 g of the dried four-arm polyethylene glycol, 20.0 g trimethylene carbonate, and 41.2 g ε-caprolactone, add them to a 250 mL three-necked flask, and then add 2 mg of stannous octoate as a catalyst. Under the protection of nitrogen, the temperature was raised to 140°C, the reaction was stirred for 48h, cooled to room temperature, purified and dried to obtain the C2# sample.
对比例3Comparative example 3
称取干燥完成的四臂聚乙二醇10000 38.8g，三亚甲基碳酸酯20.0g，加入250mL的三颈瓶中，再加入2mg辛酸亚锡作为催化剂。在氮气保护下，升温至140℃，搅拌反应24h后，再加入ε-己内酯41.2g，继续反应48h，冷却至室温，纯化、干燥后得C3#样品。对比例4Weigh 10000 38.8 g of the dried four-arm polyethylene glycol and 20.0 g trimethylene carbonate into a 250 mL three-necked flask, and then add 2 mg of stannous octoate as a catalyst. Under the protection of nitrogen, the temperature was raised to 140°C, stirred for 24 hours, and 41.2 g of ε-caprolactone was added. The reaction was continued for 48 hours, cooled to room temperature, purified and dried to obtain a C3# sample. Comparative example 4
称取干燥完成的聚乙二醇单甲醚2000 21.3g，三亚甲基碳酸酯21.9g，ε-己内酯24.3g，加入250mL的三颈瓶中，再加入2mg辛酸亚锡作为催化剂。在氮气保护下，升温至140℃，搅拌反应12h后，再加入ε-己内酯32.4g，继续反应48h，冷却至室温，纯化、干燥后得C4#样品。Weigh 2000 21.3g of dried polyethylene glycol monomethyl ether, 21.9g trimethylene carbonate, and 24.3g ε-caprolactone, add them to a 250mL three-necked flask, and then add 2mg of stannous octoate as a catalyst. Under the protection of nitrogen, the temperature was raised to 140°C, after stirring for 12 hours, 32.4 g of ε-caprolactone was added, and the reaction was continued for 48 hours, cooled to room temperature, purified and dried to obtain a C4# sample.
性能测试Performance Testing
(1)体内止血试验(1) In vivo hemostatic test
选取健康成年新西兰兔，体重2.0-3.0kg，按体重比40mg/kg经耳缘静脉给予戊巴比妥钠溶液进行麻醉。于两侧股骨中段制造1个直径5mm，深度3mm的圆形缺损。使用上述骨蜡样本1#-10#、对比样本C1#-C4#、现有产品1(成分为75％蜂蜡、15％石蜡和10％棕榈异丙酯)、现有产品2(水溶性环氧烷共聚物的混合物)随机对两侧股骨的缺损进行止血试验。记录各实验组5分钟、10分钟时止血情况。试验结果如下表所示，：Select healthy adult New Zealand rabbits, weighing 2.0-3.0 kg, and giving pentobarbital sodium solution via ear vein at a weight ratio of 40 mg/kg for anesthesia. A circular defect with a diameter of 5 mm and a depth of 3 mm was made in the mid-sections of the femurs on both sides. Use the above bone wax samples 1#-10#, comparative samples C1#-C4#, existing product 1 (composition of 75% beeswax, 15% paraffin wax and 10% isopropyl palmitate), existing product 2 (water-soluble ring A mixture of oxane copolymers) randomly conduct hemostasis tests on the defects of the femurs on both sides. Record the hemostasis of each experimental group at 5 minutes and 10 minutes. The test results are shown in the following table:
Figure PCTCN2020099818-appb-000003
Figure PCTCN2020099818-appb-000003
√：表示止血成功；×：表示止血失败√: indicates success of hemostasis; ×: indicates failure of hemostasis
(2)封堵性能测试(2) Plugging performance test
体外封堵性能试验方法：采用压力测试法，具体是自制内部类似松质骨结构的柱体，柱体一头接软管，软管内灌注37℃的人体模拟液，由液位高低来控制施加于圆柱测试端面的液体压力。将柱体另一端空隙表面按临床使用方法完全涂抹本发明的可吸收骨蜡样品或对照品，测试材料的有效封堵时间。测试结果如下：In vitro sealing performance test method: pressure test method is adopted, specifically, a self-made cylinder similar to cancellous bone structure inside, one end of the cylinder is connected with a hose, and the hose is filled with a human body simulation fluid at 37℃, and the application is controlled by the level of the liquid. Test the liquid pressure on the end of the cylinder. The surface of the gap at the other end of the cylinder is completely smeared with the absorbable bone wax sample or reference substance of the present invention according to the clinical use method to test the effective blocking time of the material. The test results are as follows:
Figure PCTCN2020099818-appb-000004
Figure PCTCN2020099818-appb-000004
(3)材料崩解时间(3) Material disintegration time
按照1:50(w/v)的比例将可吸收骨蜡投入磷酸盐缓冲液中，观察材料的崩解时间。崩解时间为材料不能继续保持完整形态的时间，即不继续占位。材料应在骨痂形成的关键期2周内崩解，从而不影响后续骨愈合。测试结果如下：Put the absorbable bone wax into the phosphate buffer at a ratio of 1:50 (w/v), and observe the disintegration time of the material. The disintegration time is the time when the material cannot continue to maintain its complete form, that is, it does not continue to occupy a place. The material should disintegrate within 2 weeks during the critical period of callus formation, so as not to affect the subsequent bone healing. The test results are as follows:
Figure PCTCN2020099818-appb-000005
Figure PCTCN2020099818-appb-000005
Figure PCTCN2020099818-appb-000006
Figure PCTCN2020099818-appb-000006
(4)对骨愈合的影响(4) Impact on bone healing
将上述止血试验中使用1#、3#、6#、10#、C1#号样本，以及现有产品1、现有产品2的试验动物在止血后依次缝合肌肉层和皮肤，继续饲养。8w后处死实验动物，取缺损处进行显微CT测试，分析骨愈合情况，愈合情况如附图3所示。使用3#、6#、10#样本以及现有品2的实验动物骨缺损处基本完全被新骨覆盖，表面无明显的缺损残留，说明样本不影响骨愈合；使用1#样本的骨缺损处部分覆盖新骨，说明该处缺损有愈合的趋势，新骨随缺损处材料的逐渐崩解解除占位而不断生成；使用C1#样本、现有产品1的实验动物，缺损大小几乎没有变化，无新骨生成，仍然为一个大的圆形缺损，说明不可降解的现有产品1止血后长期占位，影响骨愈合，降解产物酸性较大的C1#样本尽管降解速度快，但由于关键期内集中大量释放酸性降解产物，也对骨愈合有较大的影响。In the above-mentioned hemostasis test, the 1#, 3#, 6#, 10#, C1# samples, as well as the existing product 1 and the existing product 2 were used to suture the muscle layer and skin in sequence after hemostasis, and continue to raise them. After 8 weeks, the experimental animals were sacrificed, and the defect was taken for micro-CT test to analyze the bone healing. The healing situation is shown in Figure 3. The bone defect of the experimental animals using the 3#, 6#, 10# samples and the existing product 2 is almost completely covered with new bone, and there is no obvious defect residue on the surface, indicating that the sample does not affect the bone healing; the bone defect of the 1# sample is used Partial coverage of new bone indicates that the defect has a tendency to heal. New bone is continuously generated with the gradual disintegration of the material at the defect and the space is released; the experimental animal using the C1# sample and the existing product 1 has almost no change in the size of the defect. There is no new bone formation, and it is still a large round defect, indicating that the non-degradable existing product 1 occupies a long-term position after hemostasis and affects bone healing. Although the degradation product of C1# sample with greater acidity degrades rapidly, it is due to the critical period. The internal concentration releases a large amount of acid degradation products, which also has a greater impact on bone healing.
(5)细胞毒性(5) Cytotoxicity
按照GB/T 16886.5中的MTT法，评价1#、3#、6#、C3#、C4#号骨蜡的细胞毒性，现有产品2作为对照组一起进行评价。According to the MTT method in GB/T 16886.5, the cytotoxicity of No. 1#, 3#, 6#, C3#, C4# bone wax was evaluated, and the existing product 2 was used as a control group for evaluation.
浸提液制备：按0.2g/mL的比例分别加入含血清培养基，置于37度恒温摇床浸提24小时。浸提完成后，样本1#、3#、6#浸提澄清透明，C4#样本浸提液泛白，浑浊度高，说明材料亲水性高，在浸提液中容易被浸出，形成胶束。C3#样本浸提液轻微浑浊，大量细小材料颗粒沉积在管底。Extraction solution preparation: Add serum-containing medium at a ratio of 0.2g/mL, and place it on a constant temperature shaker at 37°C for 24 hours. After the extraction is completed, samples 1#, 3#, and 6# are clear and transparent, and the C4# sample extract is whitish and has high turbidity, indicating that the material has high hydrophilicity and is easy to be leached in the extract to form a gel bundle. The C3# sample extract is slightly turbid, and a large number of fine material particles are deposited on the bottom of the tube.
动态浸提24h后，样品浸提液原液为100％浓度组，分别向下稀释到50％、25％共三个浓度组。各浓度组样品加入到已接种L929细胞的96孔板中，然后置于培养箱中培养24h。24h后显微镜下观察细胞形态、数量等并记录。之后加入CCK-8，孵育2h后，将96孔板取出，放入酶标仪检测，波长设为450nm，检测结果进行数据分析。如附图4所示，1#、3#、6#、现有产品2的100％浸提液组的细胞存活率均高于70％，无细胞毒性，均符合医用植入材料要求。C3#、C4#样品100％浸提液组的细胞存活率低于70％，不符合医用植入材料的要求，说明胶束对细胞生长有一定的影响，当聚合物为单轴时，聚氧乙烯链的长度对共聚物的细胞毒性有显著影响。After 24 hours of dynamic leaching, the original sample leaching solution was in the 100% concentration group, which was diluted down to 50% and 25%, respectively, in three concentration groups. The samples of each concentration group were added to a 96-well plate that had been inoculated with L929 cells, and then placed in an incubator for 24 hours. After 24h, observe and record the cell morphology and number under the microscope. Then add CCK-8, after incubating for 2h, take out the 96-well plate, put it into the microplate reader for detection, set the wavelength to 450nm, and analyze the detection results. As shown in Figure 4, the cell survival rate of the 100% extract group of 1#, 3#, 6# and the existing product 2 is higher than 70%, has no cytotoxicity, and all meets the requirements of medical implant materials. The cell survival rate of C3# and C4# sample 100% extract group is less than 70%, which does not meet the requirements of medical implant materials, indicating that micelles have a certain impact on cell growth. When the polymer is uniaxial, the polymer The length of the oxyethylene chain has a significant effect on the cytotoxicity of the copolymer.
(6)DSC检测(6) DSC detection
采用差示扫描量热法对各样本进行热分析，测试结果如下表。软化点为样本的初始吸热温度。部分样本(1#、2#、5#、7#、9#、C1#、C2#、C3#)的DSC曲线图如5所示。实施例各样本的熔点均在37℃以上，50℃以下，且在室温下即开始吸热软化。证明材料不仅在人体温度下有良好的硬度，保障了材料的有效性，且材料在室温下有良好的操作性能。对比例C1#结晶明显，且熔点高达184℃，在室温下硬度很大，缺乏可操作性。对比例C2#熔点低于人体温度，无法有效保证产品的有效性。对比例C3#熔点和初始软化点均较为理想，但由于结晶温度高，室温下硬度高，操作性能差。Differential scanning calorimetry was used to conduct thermal analysis on each sample. The test results are as follows. The softening point is the initial endothermic temperature of the sample. The DSC curves of some samples (1#, 2#, 5#, 7#, 9#, C1#, C2#, C3#) are shown in 5. The melting point of each sample of the embodiment is above 37°C and below 50°C, and begins to endothermic softening at room temperature. It is proved that the material not only has good hardness at human body temperature, but also guarantees the effectiveness of the material, and the material has good operating performance at room temperature. Comparative Example C1# has obvious crystals, and its melting point is as high as 184°C, the hardness is very high at room temperature, and it lacks operability. The melting point of Comparative Example C2# is lower than the temperature of the human body, and the effectiveness of the product cannot be effectively guaranteed. Comparative Example C3# has ideal melting point and initial softening point, but due to the high crystallization temperature, the hardness at room temperature is high, and the handling performance is poor.
样本 sample 1#1# 2#2# 3#3# 4#4# 5#5# 6#6# 7#7#
熔点/℃Melting point/℃ 4242 4646 37/4837/48 39/5039/50 4343 4242 4444
软化点/℃Softening point/℃ 22 1818 33 77 44 1414 3131
样本 sample 8#8# 9#9# 10#10# C1#C1# C2#C2# C3#C3# C4#C4#
熔点/℃Melting point/℃ 4343 4444 32/4932/49 194194 3232 4343 4848
软化点/℃Softening point/℃ 3131 2525 1111 165165 99 1010 2020
最后应说明的是：以上各实施例仅仅为本发明的较优实施例用以说明本发明的技术方案，而非对其限制，当然更不是限制本发明的专利范围；尽管参照前述各实施例对本发明进行了详细的说明，本领域的普通技术人员应当理解：其依然可以对前述各实施例所记载的技术方案进行修改，或者对其中部分或者全部技术特征进行等同替换；而这些修改或者替换，并不使相应技术方案的本质脱离本发明各实施例技术方案的范围；也就是说，但凡在本发明的主体设计思想和精神上作出的毫无实质意义的改动或润色，其所解决的技术问题仍然与本发明一致的，均应当包含在本发明的保护范围之内；另外，将本发明的技术方案直接或间接的运用在其他相关的技术领域，均同理包括在本发明的专利保护范围内。Finally, it should be noted that the above embodiments are only preferred embodiments of the present invention to illustrate the technical solutions of the present invention, not to limit them, and certainly not to limit the patent scope of the present invention; although referring to the foregoing embodiments Having described the present invention in detail, those of ordinary skill in the art should understand that: they can still modify the technical solutions described in the foregoing embodiments, or equivalently replace some or all of the technical features; and these modifications or replacements , Does not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention; that is to say, any insubstantial changes or polishes made in the main design idea and spirit of the present invention will solve the problem Technical problems that are still consistent with the present invention should be included in the scope of protection of the present invention; in addition, direct or indirect application of the technical solution of the present invention to other related technical fields is included in the patent of the present invention for the same reason. Within the scope of protection.

Claims (10)

  1. 一种双亲性嵌段共聚物，其特征在于，其亲水段为水溶性的聚氧乙烯链，疏水段为半结晶的酯链；所述酯链为三亚甲基碳酸酯与ε-己内酯的二元共聚物；所述双亲性嵌段共聚物结构通式如下：An amphiphilic block copolymer, characterized in that the hydrophilic segment is a water-soluble polyoxyethylene chain, and the hydrophobic segment is a semi-crystalline ester chain; the ester chain is trimethylene carbonate and ε-caprolone The binary copolymer of ester; the general formula of the amphiphilic block copolymer is as follows:
    PEG(—PTCL) n； PEG(—PTCL) n ;
    其中n为1～8，PEG为聚乙二醇或聚乙二醇单甲醚；PTCL为三亚甲基碳酸酯与ε-己内酯的二元共聚物。Wherein n is 1-8, PEG is polyethylene glycol or polyethylene glycol monomethyl ether; PTCL is a binary copolymer of trimethylene carbonate and ε-caprolactone.
  2. 根据权利要求1所述的一种双亲性嵌段共聚物，其特征在于，所述双亲性嵌段共聚物为多轴聚合物或单轴聚合物；The amphiphilic block copolymer of claim 1, wherein the amphiphilic block copolymer is a multiaxial polymer or a uniaxial polymer;
    优选地，所述双亲性嵌段共聚物为多轴聚合物时，由多臂聚氧乙烯尾接半结晶的酯链构成；更优选地，所述多臂聚氧乙烯为分子量5000-20000的三臂聚乙二醇、四臂聚乙二醇或其他多臂聚乙二醇中的一种或几种；Preferably, when the amphiphilic block copolymer is a multiaxial polymer, it is composed of a multi-arm polyoxyethylene tailed with a semi-crystalline ester chain; more preferably, the multi-arm polyoxyethylene has a molecular weight of 5000-20000 One or more of three-arm polyethylene glycol, four-arm polyethylene glycol or other multi-arm polyethylene glycols;
    优选地，所述双亲性嵌段共聚物为单轴聚合物时，由单轴线性聚氧乙烯尾接半结晶的酯链构成；更优选地，所述单轴线性聚氧乙烯为分子量600-1500的聚乙二醇、或聚乙二醇单甲醚中的一种或两种。Preferably, when the amphiphilic block copolymer is a uniaxial polymer, it is composed of a uniaxial polyoxyethylene tailed with a semi-crystalline ester chain; more preferably, the uniaxial polyoxyethylene has a molecular weight of 600- One or two of 1500 polyethylene glycol or polyethylene glycol monomethyl ether.
  3. 根据权利要求1或2所述的一种双亲性嵌段共聚物，其特征在于，所述双亲性嵌段共聚物中，所述双亲性嵌段共聚物为多轴聚合物时，聚氧乙烯链的质量分数为15％-45％，其余为酯链；The amphiphilic block copolymer according to claim 1 or 2, wherein in the amphiphilic block copolymer, when the amphiphilic block copolymer is a multiaxial polymer, polyoxyethylene The mass fraction of the chain is 15%-45%, and the rest are ester chains;
    所述双亲性嵌段共聚物为单轴聚合物时，聚氧乙烯链的质量分数为8％-13％，其余为酯链。When the amphiphilic block copolymer is a uniaxial polymer, the mass fraction of the polyoxyethylene chain is 8%-13%, and the rest are ester chains.
  4. 根据权利要求1所述的一种双亲性嵌段共聚物，其特征在于，所述酯链包含非结晶段和结晶段两部分；The amphiphilic block copolymer of claim 1, wherein the ester chain comprises two parts: an amorphous segment and a crystalline segment;
    优选地，结晶段的摩尔百分数为25％-65％，其余为非结晶段；更优选地，结晶段的摩尔百分数为30％、35％、40％、45％、50％、60％中的一种。Preferably, the mole percentage of the crystalline section is 25%-65%, and the rest are non-crystalline sections; more preferably, the mole percentage of the crystalline section is 30%, 35%, 40%, 45%, 50%, 60% A sort of.
  5. 根据权利要求4所述的一种双亲性嵌段共聚物，其特征在于，所述酯链中，非结晶段的三亚甲基碳酸酯和ε-己内酯的摩尔比为40-80：20-60；The amphiphilic block copolymer according to claim 4, characterized in that, in the ester chain, the molar ratio of trimethylene carbonate and ε-caprolactone in the amorphous segment is 40-80:20 -60;
    或/和结晶段的三亚甲基碳酸酯和ε-己内酯的摩尔比为0-30：70-100。Or/and the molar ratio of trimethylene carbonate and ε-caprolactone in the crystalline section is 0-30:70-100.
  6. 根据权利要求1或2所述的所述的一种双亲性嵌段共聚物，其特征在于，所述酯链中，三亚甲基碳酸酯的摩尔百分数为20-50％，其余为ε-己内酯；优选地，三亚甲基碳酸酯的摩尔百分数为25％、30％、35％、40％、45％中的一种。The amphiphilic block copolymer according to claim 1 or 2, wherein in the ester chain, the mole percentage of trimethylene carbonate is 20-50%, and the rest is ε-hexyl Lactone; Preferably, the mole percentage of trimethylene carbonate is one of 25%, 30%, 35%, 40%, 45%.
  7. 权利要求1-6任意一项所述的双亲性嵌段共聚物的制备方法，其特征在于，采用两步法制成，以含有羟基官能团的聚氧乙烯作为引发剂，以辛酸亚锡作为催化剂，与三亚甲基碳酸酯、ε-己内酯单体进行熔融开环聚合，反应一定时间后，再加入ε-己内酯单体，继续反应，即得；The preparation method of the amphiphilic block copolymer according to any one of claims 1 to 6, characterized in that it is made by a two-step method, using polyoxyethylene containing hydroxyl functional groups as the initiator and stannous octoate as the catalyst. Melt ring-opening polymerization with trimethylene carbonate and ε-caprolactone monomer, after reacting for a certain period of time, add ε-caprolactone monomer and continue the reaction to obtain;
    优选地，所述引发剂、催化剂在130-160℃，惰性气体保护下与三亚甲基碳酸酯、ε-己内酯单体进行熔融开环聚合；Preferably, the initiator and catalyst undergo melt ring-opening polymerization with trimethylene carbonate and ε-caprolactone monomer at 130-160°C under the protection of inert gas;
    优选地，所述熔融开环聚合的反应时间为2-36h；Preferably, the reaction time of the melt ring-opening polymerization is 2-36h;
    优选地，加入ε-己内酯单体，继续反应24-48h；Preferably, ε-caprolactone monomer is added, and the reaction is continued for 24-48h;
    优选地，所述含有羟基官能团的聚氧乙烯选自是聚乙二醇、聚乙二醇单甲醚、三臂聚乙二醇、四臂聚乙二醇中的任意一种或几种。Preferably, the polyoxyethylene containing a hydroxyl functional group is selected from any one or more of polyethylene glycol, polyethylene glycol monomethyl ether, three-arm polyethylene glycol, and four-arm polyethylene glycol.
  8. 一种可吸收骨蜡，其特征在于，包含权利要求1-7任意一项所述的一种或多种双亲性嵌段共聚物。A resorbable bone wax, characterized by comprising one or more amphiphilic block copolymers according to any one of claims 1-7.
  9. 根据权利要求8所述的一种可吸收骨蜡，其特征在于，还包含一种及以上的其它组分；所述其它组分选自能加速崩解的化合物、促进骨修复的化合物、调节可吸收骨蜡使用性能的化合物中任意一种或多种；The absorbable bone wax according to claim 8, characterized in that it further comprises one or more other components; the other components are selected from compounds that can accelerate disintegration, compounds that promote bone repair, and adjust Any one or more of the compounds that can absorb the performance of bone wax;
    优选地，所述加速崩解的化合物选自聚乙二醇、聚氧乙烯-聚氧丙烯共聚物中的一种或两种的混合物；Preferably, the compound for accelerating disintegration is selected from one or a mixture of two of polyethylene glycol and polyoxyethylene-polyoxypropylene copolymer;
    优选地，所述促进骨修复的化合物选自羟基磷灰石、β-磷酸三钙中的一种或两种的混合物；Preferably, the compound for promoting bone repair is selected from one or a mixture of two of hydroxyapatite and β-tricalcium phosphate;
    优选地，所述调节可吸收骨蜡使用性能的化合物选自脂肪酸酯、脂肪酸盐中的一种或两种的混合物；Preferably, the compound for adjusting the performance of the absorbable bone wax is selected from one or a mixture of two of fatty acid esters and fatty acid salts;
    优选地，所述其它组分的质量分数总和小于等于15％，进一步优选地，为1％、5％、10％中的一种。Preferably, the total mass fraction of the other components is less than or equal to 15%, and more preferably, it is one of 1%, 5%, and 10%.
  10. 一种可吸收骨蜡的制备方法，其特征在于，将双亲性嵌段共聚物与其他组分熔融共混，即得。A preparation method of absorbable bone wax is characterized in that the amphiphilic block copolymer is melt-blended with other components to obtain it.
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