CN111205445B

CN111205445B - Amphiphilic block copolymer, absorbable bone wax and preparation method thereof

Info

Publication number: CN111205445B
Application number: CN202010157711.5A
Authority: CN
Inventors: 潘高峰; 高建丰; 曾静雯; 郑少东; 朱志远
Original assignee: Beijing Yihe Hengrui Medical Technology Co ltd; Xinxiang Yihe Hengrui Medical Technology Co ltd; Chengdu Yihe Hengrui Medical Technology Co ltd
Current assignee: Beijing Yihe Hengrui Medical Technology Co ltd; Xinxiang Yihe Hengrui Medical Technology Co ltd; Chengdu Yihe Hengrui Medical Technology Co ltd
Priority date: 2020-03-09
Filing date: 2020-03-09
Publication date: 2021-07-16
Anticipated expiration: 2040-03-09
Also published as: WO2021179495A1; CN111205445A

Abstract

The invention discloses an amphiphilic block copolymer, absorbable bone wax and a preparation method thereof, belonging to the technical field of medicines. The hydrophilic section of the amphiphilic block copolymer is a water-soluble polyoxyethylene chain, and the hydrophobic section of the amphiphilic block copolymer is a semi-crystalline ester chain; the ester chain is a binary copolymer of trimethylene carbonate and epsilon-caprolactone; the structural general formula of the amphiphilic block copolymer is as follows: PEG (-PTCL)_nWherein n is 1-8; wherein, PEG is polyethylene glycol or polyethylene glycol monomethyl ether; PTCL is a binary copolymer of trimethylene carbonate and epsilon-caprolactone. When the amphiphilic block copolymer is used as bone wax, the amphiphilic block copolymer has good plugging performance, can be quickly disintegrated without occupying space, does not influence bone healing and has hand feeling operation performanceGood cell compatibility, small local acidity and easy stable production.

Description

Amphiphilic block copolymer, absorbable bone wax and preparation method thereof

Technical Field

The invention belongs to the technical field of hemostatic materials, and particularly relates to an amphiphilic block copolymer, absorbable bone wax and a preparation method thereof.

Background

Clinically, bone destruction is often involved in operative procedures such as orthopedics, thoracic surgery, neurosurgery and the like, and cancellous bone wound bleeding is caused. The cancellous bone wound is difficult to stop bleeding automatically by vasoconstriction in the operation bleeding process and also difficult to effectively stop bleeding by conventional methods such as electric coagulation, clamping, hemostatic gauze, gelatin sponge filling and the like because the cancellous bone wound has loose tissue structure, abundant blood circulation to form densely distributed blood sinuses, poor vasoconstriction in tissues, platelet aggregation, difficult adhesion of blood clots to the cancellous bone wound and the like. Currently, cancellous bone wound hemostasis is generally performed by bone wax clinically. The bone wax hemostasis mechanism is physical packing, and mechanical plugging is carried out on the bleeding wound surface of the cancellous bone, so that hemostasis is realized.

The main components of the traditional bone wax are beeswax, vaseline and the like, the bone wax has the advantages of rapid hemostasis, excellent plugging performance and good softening performance, can be well molded after being softened by rubbing with hands, and is widely applied clinically. However, the traditional bone wax has poor biocompatibility, cannot be degraded and absorbed by organisms, can be kept in the body as a foreign body for a long time, not only hinders bone repair, but also can cause foreign body reaction to cause complications such as local pain, wound infection and the like.

Produced by Baxter corporation

Bone Hemostasis Material product (patent No. CN 1780596B, CN 104010669A) and Hemaquell from WNDM^TMThe product comprises a mixture of water-soluble alkoxy copolymers.

Is the absorbable bone wax product which is the most widely used in clinical application at present, has good operation performance and biological safety, can be completely dissolved within 48 hours, and does not influence bone healing. However, the product is a completely water-soluble component, and the surface of the product is rapidly liquefied after meeting blood, so that the plugging strength is reduced, and the hemostatic effect is poor.

US6387391, US9433639, domestic CN 108939138A disclose the use of degradable polyesters and copolyesters in bone waxes. The product has excellent biological safety and operability, has good plugging performance, and can be used for wound hemostasis with large bleeding amount. But the material has high hydrophobicity, slow disintegration and degradation speed, influences bone healing and has long foreign body reaction time. The product degradation period as disclosed in CN 108939138A was 6 months.

Chinese patents CN109908397A, CN1727013A and CN109453419A, and U.S. patent US6420454B1 blend water-insoluble polyester and water-soluble polymer, so that the material has excellent blocking performance, can quickly relieve space occupation and does not influence bone healing. The physical blending solves the problem that the disintegration of the polyester material is slow to influence the bone healing. However, after the physically blended water-soluble components are implanted into a human body, the physically blended water-soluble components can be quickly dissociated from the wax block under the action of surrounding tissue fluid, the hemostatic effectiveness of the material is obviously reduced, and the degradation performance of the residual water-insoluble polyester material cannot be improved. US9433639 discloses a copolymer of PEG, PLA and PGA, but does not disclose any material details, and PLA and PGA have melting points of 173-178 ℃ and 225-230 ℃ respectively, and the copolymerization with PEG can hardly obtain bone wax material with good sealing property, hardness, viscosity and chirality.

CN 109675094A, CN 109481726, CN109200332A, CN109432487A and other patents also disclose absorbable bone waxes containing natural materials as main ingredients (such as hyaluronic acid, starch, keratin, gelatin, chitosan and the like). The material is usually spongy or powdery, has obvious blood stopping effect in conventional soft tissue bleeding, but has unsatisfactory blood stopping effect when applied to cancellous bone wound bleeding. In addition, natural materials are poor in source and process stability, and have various problems such as immunogenicity and allergy. There is currently no absorbable bone wax product of this type on the market.

Therefore, the degradable bone wax provided by the invention can be degraded and absorbed by the body while rapidly stopping bleeding, does not affect the later bone healing, and is a problem to be solved by the technical personnel in the field.

Disclosure of Invention

One of the purposes of the invention is to provide an amphiphilic block copolymer which has good blocking performance, quick disintegration without occupying space, no influence on bone healing, quick degradation without long-term foreign body reaction, good hand feeling operation performance, good cell compatibility, small local acidity and easy stable production when used as bone wax.

Another object of the present invention is to provide a process for producing the amphiphilic block copolymer.

It is a further object of the present invention to provide a bone wax comprising the amphiphilic block copolymer.

The fourth purpose of the invention is to provide a preparation method of the bone wax.

In order to achieve the purpose, the technical scheme adopted by the invention is as follows:

the invention relates to an amphiphilic block copolymer, which is characterized in that a hydrophilic section of the amphiphilic block copolymer is a water-soluble polyoxyethylene chain, and a hydrophobic section of the amphiphilic block copolymer is a semi-crystalline ester chain; the ester chain is a binary copolymer of trimethylene carbonate and epsilon-caprolactone; the structural general formula of the amphiphilic block copolymer is as follows:

PEG(—PTCL)_nwherein n is 1-8;

wherein, PEG is polyethylene glycol or polyethylene glycol monomethyl ether; PTCL is a binary copolymer of trimethylene carbonate and epsilon-caprolactone.

The amphiphilic block copolymer is an amphiphilic structure of a hydrophilic ether chain and a hydrophobic ester chain, and is a degradable polymer with high hydrophilicity but insolubility. The ether chain can effectively improve the hydrophilicity of the ester chain and greatly shorten the disintegration and degradation time of the product; the ester chain can keep the material not directly soluble in water, and the plugging effectiveness of the material is obviously improved. In the technical scheme of the invention, the amphiphilic block copolymer is a multiaxial polymer or a uniaxial polymer;

preferably, when the amphiphilic block copolymer is a multiaxial polymer, the amphiphilic block copolymer is composed of multi-arm polyoxyethylene tail-connected semi-crystalline ester chains; more preferably, the multi-arm polyoxyethylene is one or more of three-arm polyethylene glycol, four-arm polyethylene glycol or other multi-arm polyethylene glycol with molecular weight of 5000-;

preferably, when the amphiphilic block copolymer is a monoaxial polymer, it is composed of monoaxial linear polyoxyethylene-terminated semicrystalline ester chains; more preferably, the uniaxial linear polyoxyethylene is one or two of polyethylene glycol with molecular weight of 600-1500 and polyethylene glycol monomethyl ether. In the technical scheme of the invention, when the amphiphilic block copolymer is a multiaxial polymer, n is 3-8.

In the technical scheme of the invention, when the amphiphilic block copolymer is a uniaxial polymer, n is 1-2.

In some embodiments of the present invention, when the amphiphilic block copolymer is a multiaxial polymer, the mass fraction of polyoxyethylene chains is 15% to 45%, and the rest are ester chains;

when the amphiphilic block copolymer is a uniaxial polymer, the mass fraction of the polyoxyethylene chain is 8-13%, and the balance is an ester chain.

In the technical scheme of the invention, the ester chain comprises an amorphous section and a crystalline section;

preferably, the mole percentage of the crystalline section is 25% -65%, and the rest is the non-crystalline section; more preferably, the mole percent of crystalline segments is one of 30%, 35%, 40%, 45%, 50%, 60%.

In the technical scheme of the invention, the molar ratio of the trimethylene carbonate and the epsilon-caprolactone in the amorphous segment in the ester chain is 40-80: 20-60 parts of;

or/and the molar ratio of the trimethylene carbonate and the epsilon-caprolactone in the crystalline section is 0-30: 70-100.

According to the invention, the amphiphilic block copolymer has good supporting strength by arranging the crystallization section, and can play a role in plugging and stopping bleeding; by arranging the amorphous segment, the amphiphilic block copolymer has good kneading performance and is convenient to operate.

In the technical scheme of the invention, in the ester chain, the mole percentage of trimethylene carbonate is 20-50%, and the rest is epsilon-caprolactone; preferably, the mole percent of trimethylene carbonate is one of 25%, 30%, 35%, 40%, 45%.

The preparation method of the amphiphilic block copolymer is prepared by adopting a two-step method, wherein polyoxyethylene containing hydroxyl functional groups is used as an initiator, stannous octoate is used as a catalyst, the initiator, trimethylene carbonate and epsilon-caprolactone monomers are subjected to melt ring-opening polymerization, and after a certain time of reaction, the epsilon-caprolactone monomers are added and continuously reacted to obtain the amphiphilic block copolymer.

In the invention, an ester chain is provided with an amorphous segment through the melt ring-opening reaction of the first step; then adding epsilon-caprolactone monomer to continue the second step reaction, so that the ester chain has a crystallization section.

Preferably, the initiator and the catalyst are subjected to melt ring-opening polymerization with trimethylene carbonate and epsilon-caprolactone monomers at the temperature of 130-160 ℃ under the protection of inert gas;

preferably, the reaction time of the melt ring-opening polymerization of the first step is 2-36 h;

preferably, adding epsilon-caprolactone monomer to continue the second-step reaction for 24-48 h;

preferably, the polyoxyethylene containing hydroxyl functional groups is any one or more selected from polyethylene glycol, polyethylene glycol monomethyl ether, three-arm polyethylene glycol and four-arm polyethylene glycol.

In the present invention, the inert gas is preferably nitrogen.

The absorbable bone wax comprises one or more amphiphilic block copolymers.

In some embodiments of the invention, the resorbable bone wax further comprises one or more additional components; the other components are selected from any one or more of compounds capable of accelerating disintegration, compounds for promoting bone repair and compounds for regulating the use performance of absorbable bone wax;

preferably, the compound for accelerating disintegration is selected from one or a mixture of two of polyethylene glycol and polyoxyethylene-polyoxypropylene copolymer;

preferably, the compound for promoting bone repair is selected from one or a mixture of two of hydroxyapatite and beta-tricalcium phosphate;

preferably, the compound for adjusting the use performance of the absorbable bone wax is selected from one or a mixture of two of fatty acid ester and fatty acid salt;

preferably, the sum of the mass fractions of the other components is 15% or less, and more preferably, is one of 1%, 5%, and 10%.

The preparation method of the absorbable bone wax provided by the invention is characterized in that the amphiphilic block copolymer and other components are subjected to melt blending to obtain the absorbable bone wax.

The preparation method of the absorbable bone wax can also comprise the processes of purification, drying, sterilization and the like. Packaging the absorbable bone wax, and sterilizing to obtain the final product of the medical absorbable bone wax.

Trimethylene carbonate is abbreviated herein as TMC and epsilon-caprolactone is abbreviated as CL.

Compared with the prior art, the invention has the following beneficial effects:

1. the invention creatively polymerizes water-soluble components directly onto hydrophobic degradable polyester chains to form a material which has better hydrophilicity but is not water-soluble on the whole. The amphiphilic block copolymer disclosed by the invention is used as bone wax, has good plugging performance, can meet the use requirements of various bone haemorrhages, can effectively plug a bone wound surface with low blood seepage amount, can also effectively plug a bone hole and bone defect with large blood seepage amount, and is suitable for various clinical bone hemostasis requirements.

2. The amphiphilic block copolymer provided by the invention has an amorphous segment and a crystalline segment, and the components of the crystalline segment are limited, so that the safety and the operating performance of the material are further improved on the basis of ensuring the hemostatic effectiveness of the material. On the basis, caprolactone is selected from various common crystalline degradable materials, the melting point of PCL is far lower than that of PLA and PGA, and the PCL is copolymerized with TMC to obtain a polymer which has a melting point slightly higher than the temperature of a human body and has certain operating performance at room temperature.

3. The amphiphilic block copolymer provided by the invention utilizes the hydrophilic ether chain to adjust the hydrophilic property of the hydrophobic ester chain, so that the polymer can be rapidly disintegrated and degraded after the hemostasis requirement is finished, the occupation of a hemostasis part is timely eliminated, and the healing of bone tissues is not hindered.

4. In order to guarantee the biological safety performance of the material, the invention limits the type and molecular weight of the ether chain, and obviously reduces the cytotoxicity usually shown by surfactant analogues such as amphiphilic molecules.

5. According to the amphiphilic block copolymer disclosed by the invention, the polyester chain uses the copolymer of TMC and epsilon-CL, TMC degradation products are neutral, epsilon-CL degradation products are weakly acidic, and the amphiphilic block copolymer has smaller influence on bone tissue healing compared with glycolide and lactide of which the degradation products are acidic.

6. The amphiphilic block copolymer disclosed by the invention is copolymerized by adopting epsilon-CL and TMC, so that a uniform polymer can be obtained more easily, and the process stability and the service performance of a product can be obviously improved.

In conclusion, the invention provides the novel synthetic biodegradable aliphatic polyester bone wax which has good plugging performance, rapid disintegration without occupying space, no influence on bone healing, good hand feeling and operation performance, good cell compatibility, small local acidity and easy stable production.

Drawings

FIG. 1 is a drawing of a bone wax product (before application) prepared in example 1 of the present invention.

FIG. 2 is a drawing of a bone wax product (after application) prepared in example 1 of the present invention.

Fig. 3 is a microscopic CT image of bone defects at 8 weeks after rabbit femoral drilling of sample nos. 1#, 3#, 6#, 10#, and C1# and existing product nos. 1 and 2.

FIG. 4 is a chart showing the results of cytotoxicity tests on samples No. 1#, No. 3#, No. 6#, No. C3#, No. C4# and similar products No. 2;

FIG. 5 is a DSC chart of sample, in which FIG. 5a is a DSC chart of sample # 1, FIG. 5b is a DSC chart of sample # 3, FIG. 5C is a DSC chart of sample # 5, FIG. 5d is a DSC chart of sample # 7, FIG. 5e is a DSC chart of sample # 9, FIG. 5f is a DSC chart of sample # C1, FIG. 5g is a DSC chart of sample # C2, and FIG. 5h is a DSC chart of sample # C3.

Detailed Description

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, several specific embodiments of the present invention will be listed below. It is obvious that the following embodiments are only examples of the present invention, and that other embodiments can be obtained by those skilled in the art without inventive step.

Example 1

The embodiment discloses a preparation method of an amphiphilic block copolymer, which specifically comprises the following steps:

100010.2 g of dried polyethylene glycol, 29.4g of trimethylene carbonate and 14.0g of epsilon-caprolactone are weighed into a 250mL three-necked flask, and then 3mg of stannous octoate is added as a catalyst. Heating to 150 ℃ under the protection of nitrogen, stirring for reaction for 12h, adding 46.5g of epsilon-caprolactone, continuing stirring for reaction for 36h, cooling to room temperature, purifying and drying to obtain the amphiphilic block copolymer serving as the No. 1 bone wax.

Example 2

6008.6 g of dried polyethylene glycol monomethyl ether, 16.8g of trimethylene carbonate and 46.6g of epsilon-caprolactone are weighed and added into a 250mL three-necked flask, and then 3mg of stannous octoate is added as a catalyst. Heating to 150 ℃ under the protection of nitrogen, stirring for reaction for 24h, adding 28.0g of epsilon-caprolactone, continuing stirring for reaction for 48h, cooling to room temperature, purifying and drying to obtain the amphiphilic block copolymer serving as the No. 2 bone wax.

Example 3

The embodiment discloses a preparation method of bone wax, which specifically comprises the following steps:

weighing 86g of No. 1 bone wax and 1000014 g of four-arm polyethylene glycol, adding into a 250mL three-necked bottle, heating to 80 ℃ until the materials are melted, stirring and blending for 2h, and cooling to room temperature to obtain No. 3 bone wax.

Example 4

weighing 93g of 2# bone wax and 20007 g of polyethylene glycol monomethyl ether, adding into a 250mL three-necked bottle, heating to 80 ℃ until the materials are melted, stirring and blending for 2h, and cooling to room temperature to obtain 4# bone wax.

Example 5

500016.4 g of dried three-arm polyethylene glycol, 27.3g of trimethylene carbonate and 13.0g of epsilon-caprolactone are weighed and added into a 250mL three-necked flask, and then 2mg of stannous octoate is added as a catalyst. Under the protection of nitrogen, heating to 140 ℃, stirring for reaction for 4h, then adding 43.3g of epsilon-caprolactone, continuing to stir for reaction for 36h, cooling to room temperature, purifying and drying to obtain the amphiphilic block copolymer serving as 5# bone wax.

Example 6

1000036.1 g of dried four-arm polyethylene glycol, 17.8g of trimethylene carbonate and 19.8 g of epsilon-caprolactone are weighed into a 250mL three-necked flask, and then 2mg of stannous octoate is added as a catalyst. Under the protection of nitrogen, heating to 140 ℃, stirring for reaction for 8h, then adding 26.3g of epsilon-caprolactone, continuing stirring for reaction for 48h, cooling to room temperature, purifying and drying to obtain the amphiphilic block copolymer serving as the 6# bone wax.

Example 7

1000020.1 g of dried four-arm polyethylene glycol, 33.9g of trimethylene carbonate and 20.9g of epsilon-caprolactone are weighed and added into a 250mL three-necked flask, and then 2mg of stannous octoate is added as a catalyst. Heating to 145 ℃ under the protection of nitrogen, stirring for reacting for 2h, then adding 25.1g of epsilon-caprolactone, continuing stirring for reacting for 48h, cooling to room temperature, purifying and drying to obtain the amphiphilic block copolymer serving as 7# bone wax.

Example 8

2000042.2 g of dried four-arm polyethylene glycol, 21.71g of trimethylene carbonate and 15.0g of epsilon-caprolactone are weighed and added into a 250mL three-necked flask, and then 2mg of stannous octoate is added as a catalyst. Heating to 145 ℃ under the protection of nitrogen, stirring for reaction for 24h, then adding 21.1g of epsilon-caprolactone, continuing stirring for reaction for 48h, cooling to room temperature, purifying and drying to obtain the amphiphilic block copolymer serving as the 8# bone wax.

Example 9

500023.0 g of dried three-arm polyethylene glycol, 17.8g of trimethylene carbonate and 23.7g of epsilon-caprolactone are weighed and added into a 250mL three-necked flask, and then 2mg of stannous octoate is added as a catalyst. Heating to 145 ℃ under the protection of nitrogen, stirring for reaction for 12h, adding 35.5g of epsilon-caprolactone, continuing stirring for reaction for 48h, cooling to room temperature, purifying and drying to obtain the amphiphilic block copolymer serving as the 9# bone wax.

Example 10

weighing 30g of 1# bone wax and 70g of 8# bone wax, adding into a 250mL three-necked bottle, heating to 80 ℃ until the materials are melted, stirring and blending for 2h, and cooling to room temperature to obtain 10# bone wax.

Comparative example 1

100010.0 g of dried polyethylene glycol, 23.1g of lactide and 66.9g of glycolide are weighed and added into a 250mL three-necked flask, and then 2mg of stannous octoate is added as a catalyst. And under the protection of nitrogen, heating to 150 ℃, stirring for reacting for 36 hours, cooling to room temperature, purifying and drying to obtain a C1# sample.

Comparative example 2

1000038.8 g of dried four-arm polyethylene glycol, 20.0g of trimethylene carbonate and 41.2g of epsilon-caprolactone are weighed and added into a 250mL three-necked flask, and then 2mg of stannous octoate is added as a catalyst. And under the protection of nitrogen, heating to 140 ℃, stirring for reaction for 48 hours, cooling to room temperature, purifying and drying to obtain a C2# sample.

Comparative example 3

1000038.8 g of dried four-arm polyethylene glycol and 20.0g of trimethylene carbonate are weighed into a 250mL three-necked flask, and then 2mg of stannous octoate is added as a catalyst. Under the protection of nitrogen, heating to 140 ℃, stirring and reacting for 24h, then adding 41.2g of epsilon-caprolactone, continuing to react for 48h, cooling to room temperature, purifying and drying to obtain a C3# sample. Comparative example 4

200021.3 g of dried polyethylene glycol monomethyl ether, 21.9g of trimethylene carbonate and 24.3g of epsilon-caprolactone are weighed and added into a 250mL three-necked flask, and then 2mg of stannous octoate is added as a catalyst. Under the protection of nitrogen, heating to 140 ℃, stirring and reacting for 12h, then adding 32.4g of epsilon-caprolactone, continuing to react for 48h, cooling to room temperature, purifying and drying to obtain a C4# sample.

Performance testing

(1) In vivo hemostasis test

Healthy adult New Zealand rabbits with the weight of 2.0-3.0kg are anesthetized by administering pentobarbital sodium solution via the ear edge vein according to the weight ratio of 40 mg/kg. 1 circular defect with the diameter of 5mm and the depth of 3mm is manufactured on the middle part of the femur on two sides. The bone wax sample # 1-10 #, the comparative sample # C1-C4 #, the prior product 1 (consisting of 75% beeswax, 15% paraffin wax and 10% isopropyl palmitate), and the prior product 2 (a mixture of water-soluble alkylene oxide copolymers) were used to randomly perform a hemostasis test on defects of both femurs. The hemostasis was recorded at 5 min and 10 min for each experimental group.

The test results are shown in the following table:

v: indicating successful hemostasis; x: indicating failure of hemostasis

(2) Plugging Performance test

The in vitro plugging performance test method comprises the following steps: a pressure test method is adopted, specifically, a cylinder with an inner part similar to a cancellous bone structure is manufactured, one end of the cylinder is connected with a hose, human body simulation liquid with the temperature of 37 ℃ is filled in the hose, and the liquid pressure applied to the test end face of the cylinder is controlled according to the liquid level. The surface of the gap at the other end of the column body is completely coated with the absorbable bone wax sample or the reference substance according to the clinical use method, and the effective plugging time of the material is tested. The test results were as follows:

(3) disintegration time of material

Absorbable bone wax was put into phosphate buffer at a ratio of 1:50(w/v), and the disintegration time of the material was observed. The disintegration time is the time during which the material cannot continue to maintain intact morphology, i.e. does not continue to occupy space. The material should disintegrate within 2 weeks of the critical period of callus formation so as not to affect subsequent bone healing. The test results were as follows:

(4) effects on bone healing

The test animals using the samples No. 1, No. 3, No. 6, No. 10 and No. C1 in the hemostasis test, and the existing products 1 and 2 were sequentially sutured with muscle layer and skin after hemostasis, and were continuously raised. After 8w, the experimental animals were sacrificed, and the defect was examined by micro-CT to analyze the bone healing as shown in fig. 3. The experimental animal bone defect parts using the 3#, 6#, 10# samples and the prior product 2 are basically and completely covered by new bones, and no obvious defect residues exist on the surface, which indicates that the samples do not influence bone healing; covering a new bone at the bone defect part of the No. 1 sample to show that the defect has a healing trend, and the new bone is continuously generated along with the gradual disintegration and the elimination of the occupation of the material at the defect part; the experimental animals using the C1# sample and the existing product 1 have almost no change in defect size, no new bone formation and still form a large circular defect, which indicates that the existing product 1 which is not degradable occupies space for a long time after hemostasis and affects bone healing, and the C1# sample with a large degradation product acidity has a large effect on bone healing due to the concentrated release of a large amount of acidic degradation products in a critical period although the degradation speed is high.

(5) Cytotoxicity

Cytotoxicity of bone wax nos. 1#, 3#, 6#, C3# and C4# was evaluated according to MTT method in GB/T16886.5, and conventional product 2 was evaluated as a control group.

Preparing a leaching solution: the serum-containing culture medium is added according to the proportion of 0.2g/mL respectively, and the mixture is placed in a constant temperature shaking table at 37 ℃ for leaching for 24 hours. After leaching is completed, samples No. 1, No. 3 and No. 6 are clear and transparent, and the leaching liquor of the sample C4 is whitened and has high turbidity, which indicates that the material has high hydrophilicity and is easy to leach in the leaching liquor to form micelles. The C3# sample leach liquor was slightly cloudy and a large number of fine material particles were deposited on the bottom of the tube.

After dynamic leaching for 24h, the stock solution of the sample leaching liquor is a 100% concentration group and is respectively diluted downwards to three concentration groups of 50% and 25%. Samples of each concentration group were added to a 96-well plate that had been seeded with L929 cells, and then placed in an incubator for 24 hours. After 24h, the cell morphology, number, etc. were observed under a microscope and recorded. And then adding CCK-8, incubating for 2h, taking out the 96-well plate, putting the 96-well plate into an enzyme-labeling instrument for detection, setting the wavelength to be 450nm, and analyzing the data of the detection result. As shown in fig. 4, the cell survival rates of 100% leaching liquor groups of # 1, # 3, # 6 and the existing product 2 are all higher than 70%, and the leaching liquor groups have no cytotoxicity and all meet the requirements of medical implant materials. The cell survival rate of 100% leaching solution group of samples C3# and C4# is lower than 70%, which does not meet the requirement of medical implant materials, and shows that micelle has certain influence on cell growth, and when the polymer is uniaxial, the length of polyoxyethylene chain has a significant influence on the cytotoxicity of the copolymer.

(6) DSC detection

The samples were thermally analyzed using differential scanning calorimetry and the results are shown in the table below. The softening point is the initial endothermic temperature of the sample. The DSC chart of some samples (1#, 2#, 5#, 7#, 9#, C1#, C2#, C3#) is shown in fig. 5. In the examples, the melting point of each sample was 37 ℃ or higher and 50 ℃ or lower, and endothermic softening started at room temperature. The material is proved to have good hardness at human body temperature, the effectiveness of the material is guaranteed, and the material has good operation performance at room temperature. Comparative example No. C1 crystallized significantly and had a melting point as high as 184 deg.C, was very hard at room temperature and lacked operability. The melting point of the comparative example C2# is lower than the human body temperature, and the effectiveness of the product cannot be effectively ensured. Comparative example No. C3 has desirable melting point and initial softening point, but has poor handling properties due to high crystallization temperature and high hardness at room temperature.

Sample(s)	1#	2#	3#	4#	5#	6#	7#
								Melting Point/. degree.C	42	46	37/48	39/50	43	42	44
Softening point/. degree.C	2	18	3	7	4	14	31
								Sample(s)	8#	9#	10#	C1#	C2#	C3#	C4#
Melting Point/. degree.C	43	44	32/49	194	32	43	48
								Softening point/. degree.C	31	25	11	165	9	10	20

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, but not to limit the technical solutions, and certainly not to limit the patent scope of the present invention; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention; that is, the technical problems to be solved by the present invention, which are not substantially changed or supplemented by the spirit and the concept of the main body of the present invention, are still consistent with the present invention and shall be included in the scope of the present invention; in addition, the technical scheme of the invention is directly or indirectly applied to other related technical fields, and the technical scheme is included in the patent protection scope of the invention.

Claims

1. An absorbable bone wax, comprising an amphiphilic block copolymer having a hydrophilic segment of a water-soluble polyoxyethylene chain and a hydrophobic segment of a semi-crystalline ester chain; the ester chain is a binary copolymer of trimethylene carbonate and epsilon-caprolactone; the structural general formula of the amphiphilic block copolymer is as follows:

PEG(—PTCL)_n；

wherein n is 1-8, and PEG is polyethylene glycol or polyethylene glycol monomethyl ether; PTCL is a binary copolymer of trimethylene carbonate and epsilon-caprolactone;

the amphiphilic block copolymer is a multiaxial polymer or a uniaxial polymer;

when the amphiphilic block copolymer is a multiaxial polymer, the amphiphilic block copolymer is formed by a multi-arm polyoxyethylene tail-connected semi-crystalline ester chain; the multi-arm polyoxyethylene is one or more of three-arm polyethylene glycol, four-arm polyethylene glycol or other multi-arm polyethylene glycol with the molecular weight of 5000-;

when the amphiphilic block copolymer is a uniaxial polymer, the amphiphilic block copolymer is formed by tailing a semi-crystalline ester chain by uniaxial linear polyoxyethylene; the uniaxial linear polyoxyethylene is one or two of polyethylene glycol with the molecular weight of 600-1500 and polyethylene glycol monomethyl ether;

the amphiphilic block copolymer is prepared by adopting a two-step method, polyoxyethylene containing hydroxyl functional groups is used as an initiator, stannous octoate is used as a catalyst, the amphiphilic block copolymer and trimethylene carbonate and epsilon-caprolactone monomers are subjected to melt ring-opening polymerization, and after the reaction is carried out for a certain time, the epsilon-caprolactone monomers are added and continue to react, so that the amphiphilic block copolymer is obtained.

2. The absorbable bone wax of claim 1, wherein the amphiphilic block copolymer comprises 15-45% polyoxyethylene chains and the balance ester chains, when the amphiphilic block copolymer is a multiaxial polymer;

when the amphiphilic block copolymer is a uniaxial polymer, the mass fraction of polyoxyethylene chains is 8-13%, and the balance is ester chains.

3. The resorbable bone wax of claim 1, wherein the ester chains comprise two parts, an amorphous segment and a crystalline segment.

4. Absorbable bone wax of claim 3, characterized in that the molar percentage of crystalline segments is 25% -65% and the rest are non-crystalline segments.

5. The resorbable bone wax of claim 4, wherein the mole percentage of crystalline segments is one of 30%, 35%, 40%, 45%, 50%, 60%.

6. Absorbable bone wax according to any of claims 3 to 5, characterized in that the molar ratio of trimethylene carbonate and epsilon-caprolactone in the non-crystalline segment in the ester chain is 40-80: 20-60 parts of;

7. The absorbable bone wax of claim 1, wherein the ester chains comprise 20-50 mole percent trimethylene carbonate and the balance epsilon-caprolactone.

8. The resorbable bone wax of claim 7, wherein the trimethylene carbonate is present in a mole percentage of one of 25%, 30%, 35%, 40%, 45%.

9. The absorbable bone wax as claimed in claim 1, wherein the initiator and the catalyst are subjected to melt ring-opening polymerization with trimethylene carbonate and epsilon-caprolactone monomers at a temperature of 130-160 ℃ under the protection of inert gas.

10. The absorbable bone wax of claim 1, wherein the melt ring-opening polymerization has a reaction time of 2-36 hours.

11. The absorbable bone wax of claim 1, wherein the reaction is continued for 24-48h by adding epsilon caprolactone monomer.

12. The absorbable bone wax of claim 1, wherein the polyoxyethylene having hydroxyl functional groups is selected from one or more of polyethylene glycol, polyethylene glycol monomethyl ether, three-arm polyethylene glycol, and four-arm polyethylene glycol.

13. The resorbable bone wax of claim 1, further comprising one or more additional components; the other components are selected from any one or more of compounds capable of accelerating disintegration, compounds capable of promoting bone repair and compounds capable of regulating the use performance of absorbable bone wax.

14. Absorbable bone wax according to claim 13, characterized in that the disintegration-accelerating compound is selected from one or a mixture of two of polyethylene glycol, polyoxyethylene-polyoxypropylene copolymer.

15. The absorbable bone wax of claim 13, wherein the bone repair promoting compound is selected from one or a mixture of two of hydroxyapatite and β -tricalcium phosphate.

16. Absorbable bone wax as claimed in claim 13, wherein the compound for adjusting the use properties of absorbable bone wax is selected from one or a mixture of two of fatty acid ester and fatty acid salt.

17. Absorbable bone wax according to claim 13, characterized in that the sum of the mass fractions of the other components is less than or equal to 15%.

18. The absorbable bone wax of claim 17, wherein the sum of the mass fractions of the other components is one of 1%, 5%, and 10%.

19. The absorbable bone wax of claim 1, wherein the amphiphilic block copolymer is melt blended with the other components.