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WO2021179495A1 - Copolymère séquencé amphiphile, cire à os absorbable et procédé de préparation associé - Google Patents

Copolymère séquencé amphiphile, cire à os absorbable et procédé de préparation associé Download PDF

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Publication number
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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WIPO (PCT)
Prior art keywords
block copolymer
amphiphilic block
polyethylene glycol
polyoxyethylene
trimethylene carbonate
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PCT/CN2020/099818
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English (en)
Chinese (zh)
Inventor
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/fr

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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

La présente invention se rapporte au domaine technique des médicaments. Un copolymère séquencé amphiphile, une cire à os absorbable et un procédé de préparation associé sont divulgués. Dans le copolymère séquencé amphiphile de la présente invention, un segment hydrophile est une chaîne de polyoxyéthylène soluble dans l'eau, et un segment hydrophobe est une chaîne d'ester semi-cristalline ; la chaîne d'ester est un bipolymère de carbonate de triméthylène et de ε-caprolactone ; la formule générale structurale du copolymère séquencé amphiphile est la suivante : PEG(-PTCL)n, dans laquelle n est compris entre 1 et 8, PEG est le polyéthylène glycol ou le méthoxypolyéthylène glycol, et PTCL est un bipolymère de carbonate de triméthylène et de ε-caprolactone. Dans la présente invention, lorsque le copolymère séquencé amphiphile est utilisé comme cire à os, le copolymère séquencé amphiphile présente les avantages suivants : une bonne efficacité de blocage, une désintégration rapide sans occupation d'espace, aucune influence sur la cicatrisation osseuse, une bonne efficacité de gestion de la sensation tactile, une bonne compatibilité cellulaire, une faible acidité locale et une facilité de production stable.
PCT/CN2020/099818 2020-03-09 2020-07-02 Copolymère séquencé amphiphile, cire à os absorbable et procédé de préparation associé WO2021179495A1 (fr)

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CN202010157711.5A CN111205445B (zh) 2020-03-09 2020-03-09 一种双亲性嵌段共聚物、可吸收骨蜡及制法

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CN111205445B (zh) * 2020-03-09 2021-07-16 成都颐合恒瑞医疗科技有限公司 一种双亲性嵌段共聚物、可吸收骨蜡及制法
CN113061255B (zh) * 2021-03-24 2022-04-01 北京市创伤骨科研究所 聚氧乙烯聚氧丙烯-壳聚糖嵌段共聚物、骨止血材料及其制备方法

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