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WO2022048126A1 - Matériau adhésif à haute viscosité pour implantation non invasive orthopédique, son procédé de préparation et application - Google Patents

Matériau adhésif à haute viscosité pour implantation non invasive orthopédique, son procédé de préparation et application Download PDF

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WO2022048126A1
WO2022048126A1 PCT/CN2021/079870 CN2021079870W WO2022048126A1 WO 2022048126 A1 WO2022048126 A1 WO 2022048126A1 CN 2021079870 W CN2021079870 W CN 2021079870W WO 2022048126 A1 WO2022048126 A1 WO 2022048126A1
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solution
viscosity
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plga
tcp
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曹建中
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    • 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
    • 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
    • A61L24/0036—Porous materials, e.g. foams or sponges
    • 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
    • A61L24/02—Surgical adhesives or cements; Adhesives for colostomy devices containing inorganic materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/02—Inorganic materials
    • A61L27/025—Other specific inorganic materials not covered by A61L27/04 - A61L27/12
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/02—Inorganic materials
    • A61L27/12—Phosphorus-containing materials, e.g. apatite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/56—Porous materials, e.g. foams or sponges
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/58—Materials at least partially resorbable by the body
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/412—Tissue-regenerating or healing or proliferative agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/06—Flowable or injectable implant compositions
    • 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
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants

Definitions

  • the invention relates to the technical field of biological preparations, in particular to a non-invasive implanted high-viscosity adhesive material for orthopedics and a preparation method and application thereof.
  • Adhesives for bone must have good biocompatibility, degradability, no organ toxicity and cytotoxicity, no carcinogenic and teratogenic effects, and can achieve rapid adhesion at room temperature without affecting callus growth. Internally degradable, with good adhesive strength and durability to ensure fracture healing.
  • various adhesives in orthopedics mainly include ⁇ -cyanoacrylates; bone cement adhesives (bone cement, calcium phosphate bone cement, magnesium phosphate bone cement); composite adhesives (composite coagulant, composite water (blood) solvent, composite enhancer, composite plasticizer, composite biological activity factor); fibrin; sodium alginate mixed glue.
  • Biomaterials are classified according to their application properties, including anticoagulant materials (cardiovascular materials), dental materials, orthopedic materials, ophthalmic materials, adsorption and detoxification materials (for blood perfusion), prosthesis materials, sustained-release materials, and bioadhesive materials. , dialysis and ultrafiltration membrane materials, disposable medical materials, etc. Classified according to the use requirements of medical materials: non-implantable materials, implantable materials, blood-contact materials, degradable and absorbent materials.
  • the newly developed materials are polyglycolic acid (Polyglycolide) and polylactic acid (Polylactide)-based polymers, which are made into screws and internal fixation rods for the internal fixation of clinical fractures. After the fracture is healed, it can be degraded and absorbed by itself in the body, and there is no need to remove it by surgery. 48 hours after the polymer material is implanted into the body, the screws and rods absorb water and swell, can strengthen themselves, and have good internal fixation characteristics. And it does not interfere with fracture healing, and there is no osteolysis phenomenon. At present, it has become a commercial market, and is used in many foreign countries for internal fixation of intra-articular and peri-articular fractures and hand fractures. Among them, Finland has accumulated more than 20,000 cases in 1990, and China has also begun to apply it since 1993.
  • biodegradable materials are eventually decomposed into H 2 O 2 and CO 2 in the human body, the toxicity is extremely low, but they are highly irritating to tissues, causing tissue effusion and swelling; the particles degraded by the materials will also be regarded as foreign bodies by the human body. Stimulates the body to induce rejection - the macrophage response. Therefore, its histocompatibility is still not as good as that of the currently used metal internal fixation.
  • Fractures and bone defects of various diseases such as trauma, infection, tumor, bone necrosis and congenital deformities are common clinically, which makes the minimally invasive injectable biomaterials used for fracture and bone defect repair more and more important.
  • Various injectable materials such as natural derivatives and synthetic polymers.
  • Bone cement is a kind of bone repair material that is easy to operate in clinical surgery and can be arbitrarily shaped and self-solidified like cement, and has a wide range of applications in bone repair and other fields.
  • One of the materials currently used as bone cement is polymethyl methacrylate (PMMA). Since its composition is completely different from that of natural bone tissue, there is a great problem in biocompatibility.
  • PMMA polymethyl methacrylate
  • the traditional inorganic calcium phosphate bone cement has good biocompatibility and high biological activity, its mechanical strength is too low, the compressive strength is low, the tensile strength is low, the brittleness is high, and the elastic modulus is greatly high. in natural bones.
  • its injectable performance is poor, and it cannot accurately fill and repair the place that needs to be treated according to the defect site, and there are also problems in that it is difficult to solidify when encountering body fluids and blood.
  • molecular design is an important topic for biopolymer scientists at present. Analyzing "molecular design", that is, inferring, predicting, constituent atoms, molecular species, binding and aggregation states of polymer biomaterials, and describing the problem. The specific conformation of the structure, organization, and morphology of a molecule. The molecular design of medical biopolymers is carried out, and the purpose is how to synthesize and manufacture polymer biomaterials with specified properties and structures. The further connection between molecular design and practice is "material design", which belongs to the category of teleology and is a subject in the field of engineering.
  • biodegradable polymers Due to their excellent mechanical properties and good biocompatibility, biodegradable polymers have more and more applications in biomedical fields such as bone transplantation, bone cement, drug controlled release, and tissue engineering scaffolds.
  • autologous transplantation and synthetic material implantation are mostly used for the treatment of bone defects.
  • the number of autologous grafts is limited by the source, which will cause the pain of secondary surgery, and it is difficult to accurately shape the defect according to the location. Allogeneic transplantation may become a source of infection.
  • Synthetic materials such as PMMA bone cement are permanently implanted, but may cause many side effects such as infection and bone corrosion.
  • For artificial bone materials implanted in the human body it is required that she can withstand the corrosion and dissolution of body fluids. It has good biocompatibility and biological activity, as well as good chemical stability and mechanical properties.
  • ⁇ -TCP ( ⁇ -tricalcium phosphate), namely ⁇ -tricalcium phosphate, powder, has been used clinically as an artificial bone substitute material since the 1970s.
  • the composition of ⁇ -TCP is similar to the bone mineral composition.
  • the ratio of Ca and P ions in ⁇ -TCP is 1.5:1, which is degraded into Ca and P ions in the body and provided to the new bone tissue, and is gradually replaced by the new bone tissue. , with good biocompatibility.
  • As an implant material ⁇ -TCP has good biodegradability.
  • there are two pathways for the biodegradation process namely, the humoral-mediated process and the cell-mediated process.
  • ⁇ -TCP has a macroporous structure that facilitates the infiltration of body fluids and a microporous structure that facilitates the ingrowth of tissue cells.
  • the ceramic biodegrades, and finally no foreign matter remains.
  • the shape of the new stock is no longer affected by the existence of the material, and the strength of the new bone is due to the combination of the new bone and the material.
  • Strength changing the pore structure and physical and chemical properties (bioabsorption rate, mechanical strength, pore structure, etc.) of the material through different preparation processes can meet different clinical application requirements.
  • ⁇ -TCP has low fatigue strength, high brittleness, and its fracture resistance and impact resistance cannot meet the requirements of high-load artificial bone.
  • the biodegradable biomaterials used in tube meals include polyglycolic acid (PGA) and polylactic acid (PLA).
  • PGA polyglycolic acid
  • PLA polylactic acid
  • this type of bone adhesive used is a one-component, commercial, solvent-free adhesive, which is rapidly cured at room temperature and cured within 10 to 30 seconds after being implanted in the body through the polymerization of tissue fluid and blood. .
  • the curing time is not easy to control.
  • the dosage of bone adhesive used during the operation is also different, and sometimes a small amount is used, which is easy to cause the remaining bone adhesive to be unfavorable for preservation, or even because it is not used in time or Preservation and rapid curing, resulting in waste. Therefore, there is a need for a bone adhesive that is stable in storage and easy to use when used.
  • PLGA polylactic acid-glycolic acid copolymer
  • It is a degradable functional polymer organic compound with good biocompatibility, non-toxicity, Good encapsulation and film-forming properties are widely used in pharmaceutical, medical engineering materials and modern industrial fields.
  • PLGA has passed the FDA certification and was officially included in the US Pharmacopoeia as a pharmaceutical excipient.
  • the degradation products of PLGA are lactic acid and glycolic acid, which are also by-products of human metabolic pathways, so it has no toxic side effects when used in pharmaceuticals and biological materials. Except, of course, lactose deficient.
  • this method has been widely used in biomedical fields, such as: skin transplantation, wound closure, in vivo implantation, micro-nanoparticles, etc.
  • Polyhydroxypropyl fumarate is an unsaturated linear polyester, which is a water-degradable substance and an ideal biodegradable material. It can be degraded in vivo to generate fumaric acid and propylene glycol (PG) degradation products can be Normal metabolism is excreted and has no effect on body systems such as pH. PPF with an appropriate degree of polymerization can be cured at body temperature, and by controlling its molecular weight, a material with good mechanical properties can be obtained. And the fumaric acid unsaturated double bond of PPF can react with other cross-linking agent molecules to form a cross-linked polymer material, which can be used as a scaffold material to induce bone regeneration. With degradable propylene glycol fumarate. Since PPG is biodegradable and can be arbitrarily shaped at body temperature, PPF has good fluidity before curing. As an injectable filling material, it can be well used for the repair and reconstruction of bone defects without kneeling.
  • N-vinylpyrrolidone ie N-vinylpyrrolidone.
  • Chinese synonyms n-ethyl-2-pyrrolidone; 1-vinyl-2-pyrrolidone; 1-vinyl-2-pyrrolidone; 1-vinyl-2-pyrrolidone; 99%STAB.WITH0.1%SODIUMHYDROXID;Chemicalbook1 -Vinyl-2-pyrrolidone (with stabilizer N,N'-di-sec-butyl-p-phenylenediamine); 1-vinyl-2-pyrrolidone, 99% STAB.WITH0.1% SODIUMHYDROXIDE; vinyl-2- Pyrrolidone.
  • Ultrafine particles refer to fine particle powder materials with a diameter of less than 1 micron. Generally, particles with a size of 0.5 nm to 100 nm and in the junction area of atomic clusters and macroscopic objects are called ultrafine particles. Due to their electrical, thermal and optical properties, ultrafine particle materials have good applications in the fields of electronics, chemical industry, and nuclear technology.
  • Phosphate Buffered Saline is one of the most widely used buffer solutions commonly used in biological research.
  • PBS can be the English abbreviation of three solutions, namely phosphate buffered solution, phosphate buffered saline and phosphate buffered sodium. Due to their secondary dissociation, the buffers have a wide pH range. Its various concentrations are easy to configure, the pH value is less affected by temperature, the buffer capacity is strong, and the pH value changes little after dilution. Phosphate buffers adjust the pH without affecting the chemical reaction so that the chemical reaction can take place under optimal conditions.
  • phosphate buffer is easy to associate with common calcium ions Ca 2+ , Mg 2+ and some heavy metal ions to form precipitates; it will inhibit some biochemical reaction processes, such as inhibiting the catalytic process of some enzymes.
  • Buffers help maintain a constant pH, and the osmotic pressure and ionic concentration of the solution are usually close to the pH of the human body (isotonic).
  • PBS is a phosphate buffer with pH 7.4.
  • the pH value is fixed and isotonic with human blood, so it is generally used for molecular cloning and cell culture experiments. The more pH values used for protein experiments are PH6.8 and PH8.8. Its preparation method is different, the pH value is different, and its biological effect is not exactly the same.
  • PBS commonly used in biology is neutral phosphate buffered solution. Buffers help maintain a constant pH.
  • the osmotic pressure and ionic concentration of the solution are usually close to the pH of the human body (isotonic).
  • the purpose of the present invention is to provide a non-invasive implantable high-viscosity adhesive material for orthopaedics, which has high viscosity, good plasticity, stable storage properties, and is convenient for preparation and implantation at the operation site, and its preparation method and application.
  • the present invention adopts the following technical solutions to achieve its purpose, a non-invasive implant high-viscosity adhesive material for orthopaedics, characterized in that it is made of the following raw materials:
  • a preparation method of a non-invasive implanted high-viscosity adhesive material for orthopedics which comprises the following steps:
  • step (3) centrifuging the product obtained in step (3) at 1000 rpm, washing with water and drying, to obtain a high-viscosity glue ultrafine particle powder, then adding a required amount of distilled water, dispersing uniformly, and then sub-packing to obtain a high-viscosity glue Glue dispersible granules;
  • step (6) After the high-viscosity glue dispersible granules obtained in step (4) and the adhesive solution obtained in step (5) are sterilized by cobalt 60 irradiation for 6 to 7 days, they are combined and packaged according to the proportion to be stored in the required specifications, that is, they are ready for use. Combination of high-viscosity adhesive materials for non-invasive implantation in orthopaedics.
  • the diameter of the ultrafine particles is 0.1-0.2 microns
  • drying is drying at 60°C ⁇ 120°C for 2 hours ⁇ 1 hour or freeze-drying
  • PPF polyhydroxypropyl fumarate
  • a non-invasive implant high-viscosity adhesive material for orthopedics in the treatment of fractures, bone diseases, and bone tumors which is proportional to high-viscosity
  • organic acid solvent and adhesive solution with no toxic and side effects to human body are added in turn to dissolve, polyhydroxypropyl fumarate (PPF) and N-vinylpyrrolidone are biodegradable, and can be combined with medical adhesive.
  • PPF polyhydroxypropyl fumarate
  • N-vinylpyrrolidone are biodegradable, and can be combined with medical adhesive.
  • adding high-viscosity glue dispersible granules and acetic acid can be compounded into a viscous suspension-like solution, that is, a high-viscosity glue solution for orthopedic non-invasive implantation is obtained.
  • the organic acid solvent of the present invention is acetic acid.
  • the medical adhesive of the present invention is a commercially available adhesive, produced by Beijing Kangpaite Medical Equipment Co., Ltd.
  • This product is colorless and transparent liquid, the main ingredient is n-butyl ⁇ -cyanoacrylate, with trace additives; according to clinical needs, it is equipped with a straw, a glue spray bottle, and a rotary arm spray pump. It can be used for surgery-free suture glue, and can be used for human hemostasis, beauty glue and animal experiments. It is non-toxic and has no side effects.
  • the N-vinylpyrrolidone of the present invention is produced by Jiangsu Nantong Runfeng Petrochemical Co., Ltd.
  • the PLGA of the present invention is produced by Shenzhen Lubao Biotechnology Co., Ltd., and the ratio is DL-LA/GA: 75/25;
  • DL-LA racemic lactide wood DL-LA, namely racemic lactide (3,6-dimethyl-1,4-dioxane-2,5-dione) English Name DL-Lactide (3, 6-Dimethyl-1, 4-dioxane-2, 5-dione) CAS.R.NO: 95-96-5 Molecular formula C6H8O4 Molecular weight 144.13 Melting point 125-127 °C, water content ⁇ 0.4%, Heavy metal ⁇ 5ppm, free acid (CH30Nag/kg) ⁇ 1, ash content ⁇ 0.05%, purity ⁇ 99.5%;
  • formaldehyde will further form paraformaldehyde or formic acid, soluble in water, soluble in methanol, ethanol, ethyl acetate, slightly soluble in ether, insoluble in hydrocarbons.
  • the ethyl acetate described in the present invention is commercially available analytical grade purchased.
  • the phosphate buffer of the present invention is a commercially available 99.9% phosphate buffer with a pH value of 7.2. It is a water-based salt solution containing sodium chloride, phosphate, and (in some formulations) potassium chloride and potassium phosphate. Sodium chloride enters and dissolves gradually to form pores and promote fracture healing. Therefore, the present invention adopts a phosphate buffer with a specific pH value of 7.2, and dissolves PLGA and ⁇ -TCP in the phosphate buffer solution.
  • the phosphate buffer solution with a pH value of 7.2 produces a good foaming agent in this material. It can make the implanted material have enough pores to allow the tissue to grow in, thereby promoting bone healing and effectively shortening the healing time.
  • Orthopaedic non-invasive implantation of high-viscosity glue dispersible granules in high-viscosity adhesive materials is followed by adding acetic acid and adhesive solution to dissolve, and then implanting fractures and bone disease sites by minimally invasive injection. It can effectively fix the fractures by adhesive fixation. It can fill various bone defects of different shapes and sizes during open operation, and has appropriate mechanical properties and physical properties to meet special applications.
  • a plastic membrane-type skeleton-type fixing material is formed to reconstruct bone tissue. The material can be gradually degraded in the body after a certain period of time, and finally metabolized into water and carbon dioxide, which are absorbed by the human body and excreted from the body.
  • the present invention better achieves the purpose of the invention. It uses prefabricated non-invasive implanted high-viscosity adhesive materials for orthopaedics, adopts on-site mixing and preparation, and adds high-viscosity glue dispersible granules into adhesive solution, acetic acid It is made into a sticky liquid polymer biomaterial, that is, a high-viscosity adhesive solution for non-invasive implantation in orthopaedics. It does not solidify inside, and then solidifies rapidly at body temperature;
  • PLGA and ⁇ -TCP bone meal
  • they have good biocompatibility, and they can be made into porous solidified materials, which are conducive to the ingrowth of bone tissue, promote bone healing, and better induce and promote the proliferation and proliferation of chondrocytes during adhesion.
  • PPF polyhydroxypropyl fumarate
  • PPF polyhydroxyl fumarate Propyl ester
  • N-vinylpyrrolidone are biodegradable.
  • high-viscosity glue dispersible granules are added to form a viscous adhesive solution, which dissolves after implantation with sodium chloride. Absorption of re-formed pores can allow tissue to grow in and accelerate bone healing;
  • the solution can be implanted by minimally invasive injection, and solidifies rapidly at body temperature to form a "plastic film-shaped" film block material.
  • a material with good mechanical properties can be obtained, which can be directly and firmly fixed at body temperature.
  • the cross-linked polymer material increases the adsorption force, so it has the characteristics of high viscosity, at the same time, it can improve the strength of reconstruction and repair, and form a porous mesh-like strong protective film on the surface of the damaged tissue to prevent hyperplasia; it has Certain elasticity, stiffness (hardness), appropriate mechanical and physical properties to meet special applications, and during the degradation process, maintaining such mechanical properties, the degradation products have good biocompatibility, and can be The shape degrades and maintains the shape of a plastic membrane stent for a long time, and it has controllable biodegradation and no toxic side effects; it can be implanted by minimally invasive injection, and the implantation method is precise and convenient; after implantation, it can promote It also regulates the growth and differentiation of surrounding cells under the periosteum, accelerates the formation and mineralization of bone matrix, and promotes the rapid healing of fractures; the material can be gradually degraded in the body after a certain period of time, and finally metabol
  • a non-invasive implant high-viscosity adhesive material for orthopedics which is made of the following raw materials:
  • the ⁇ -TCP is nano-scale powder; the pH value of the phosphate buffer is 7.2.
  • a preparation method of a non-invasive implanted high-viscosity adhesive material for orthopedics which comprises the following steps:
  • step (3) centrifuging the product obtained in step (3) at 1000 rpm, washing with water and drying, to obtain a high-viscosity glue ultrafine particle powder, then adding a required amount of distilled water, dispersing uniformly, and then sub-packing to obtain a high-viscosity glue Glue dispersible granules;
  • step (6) After the high-viscosity glue dispersible granules obtained in step (4) and the adhesive solution obtained in step (5) are sterilized by cobalt 60 irradiation, they are combined and packaged according to the proportion and stored in the required specifications, that is, the orthopaedic combination for standby is obtained.
  • drying is drying at 60°C to 120°C for 2 hours to 1 hour or freeze-drying (in this example, drying at 120°C for 2 hours);
  • PPF polyhydroxypropyl fumarate
  • An orthopedic non-invasive implanted high-viscosity glue material is used in the operation of treating fractures, bone diseases, bone tumors (or open bone filling in surgery), and it is sequentially added to high-viscosity glue dispersible granules in proportion to the human body.
  • Organic acid solvents and adhesive solutions with toxic and side effects are dissolved, polyhydroxypropyl fumarate (PPF) and N-vinylpyrrolidone are biodegradable, cross-linked with medical adhesives, and added with high-viscosity glue dispersible granules, Acetic acid can be compounded into a viscous suspension-like solution, that is, a high-viscosity glue solution for non-invasive implantation in orthopedics can be obtained.
  • the organic acid solvent described in the application of the present invention is acetic acid.
  • PPF Polyhydroxypropyl fumarate
  • N-Vinyl Propiopyrrolidone 760mg: 240mg: 20mg: 8mL: 100mL: 19mL: 3mL:3mL.
  • drying is drying at 120° C. for 1 hour;
  • PPF Polyhydroxypropyl fumarate
  • drying is drying at 120° C. for 2 hours;
  • step (1) PLGA and ⁇ -TCP are dissolved in a phosphate buffer to obtain solution B, which is for later use;
  • drying is freeze-drying
  • PPF Polyhydroxypropyl fumarate
  • drying is drying at 120° C. for 2 hours;
  • drying is freeze-drying
  • drying is freeze-drying
  • (A) is a blank control group: physiological saline 10 mL/kg
  • (B) to (E) are respectively Examples 1 to 4 of the present invention.
  • kg acetic acid 0.0417mL/kg dissolved non-invasive implanted high-viscosity adhesive material for orthopedics;
  • a hacksaw was used to interrupt the 3mm defect of the left radius, and normal saline or test drugs were injected into the fractured end according to the dose design. The wounds and the activities of the left forelimb of the rabbits were carefully observed for 3 consecutive weeks;
  • Table 1 shows, group of the present invention just has more than medium callus to appear in the second week, and most of the fracture edges disappear in the third week, and the ratio of being connected into normal bone is large, and most of the fracture lines disappear in the fourth week, Fracture healing is good, and it can be seen that the present invention has obvious effect of promoting fracture healing.
  • Table II shows that compared with the blank group, the inventive group can greatly increase the flexural strength, especially at the end of fracture healing, the strength is almost three times that of the latter, and the stiffness and hardness after fracture healing are high.
  • the bone trabeculae in groups B, C, D, and E were obviously thickened and enlarged.
  • the bone cells and cartilage in the blank group were less generated in the first two weeks, and the morphological changes at each stage were at least one week slower than the fracture healing process of the present invention.
  • the length is 23cm
  • the middle width is 2cm
  • the thickness is 1.3cm
  • the net weight is 26g.
  • the proximal fracture segment is 3 cm long, the middle bone segment is about 15 cm long, and the distal fracture segment is 5 cm long); the proximal fracture is 2.5 cm wide and 1.3 cm thick; the distal fracture is 2 cm wide and 1.2 cm thick;
  • pig rib transverse fracture numbered No. 2, spare;
  • the other pig rib was sawed into two sections at 12 cm proximal to the joint with a hacksaw to artificially cause a comminuted fracture of the pig rib, numbered No. 3, for use.
  • the proximal (proximal fracture) broken end of sample No. 1 was only fixed to the back, the implant dose was 1.3 g, and no material was implanted on the ventral side (the convex surface of the rib was the dorsal side, and the concave surface was the ventral side); The whole implanted material around the broken end at the fracture of the end), the implant dose is 2.7g, and the net weight of No. 1 sample after fixation (two fixations) is 31g.
  • Sample No. 2 was implanted on the back and both sides of the fractured end (both sides in the thickness direction of pig rib), and the implant dose was 2g; Sample No. 3 was implanted on the back and both sides of the fracture end, and the implant dose was 3g. .
  • the lateral side of the fracture cementation tubercle was removed from the proximal end of the proximal fracture site (at 2cm) and the dorsal side (convex surface) of the bone skin graft was still held horizontally upward, and it was observed that: There is no loosening of the fractured end, and the distal end (3cm) from the distal fracture is not loosened, and it has been firmly fixed;
  • the cumulative implantation time was 24 hours, and it was observed that there was no abnormal loosening of the fracture end, the fracture was fixed firmly, and the proximal end was only fixed at the dorsal side without loosening;
  • the present invention is suitable for minimally invasive implantation treatment of traumatic fractures and other (pathological fractures, osteoporotic fractures) bone tumors (benign bone tumors).
  • the fracture adhesion site can be implanted with materials on the back and both sides of the fracture at the same time, and the effect of material fixation is satisfactory, which is equal to the firm fixation of the material implanted around the distal end of the sheep rib fracture, porcine rib transverse fracture and comminuted fracture. of. It is proved that 1.2g of material is implanted at the proximal fracture end of the sheep rib, the fixation site is the dorsal side of the bone, no material is implanted in the ventral side, and 2.7g of material is implanted at the distal end, and the strength (hardness) of the cementation is both in the test. quite. In 24 hours, two different parts were implanted with different materials.
  • the material used for the third sample of pig rib is 3g, which proves that the material used for comminuted fractures should be increased by 33% compared with the materials used for transverse fractures.
  • the strength (hardness) of the fracture fixation cement measured within 24 hours was comparable. It can also be considered that in order to protect the ventral side of the bone from damage to the larger blood vessels and nerves due to implantation, the dorsal side of the fracture can be implanted for fixation. Thus, the high viscosity, good plastic film properties of the present invention are demonstrated.
  • the present invention is suitable for minimally invasive implantation to treat various fractures, osteoporotic fractures of the elderly, and creative fractures (distal bone fractures, ankle fractures, finger fractures, toe fractures, etc.).
  • the storage properties of the present invention are stable, and in the in vitro adhesion and fixation test of the sheep rib, the fracture is firmly fixed after ten minutes at room temperature of 15°C.
  • the pig rib in vitro adhesion and fixation test was performed at room temperature below 20 °C, and there was an 8-minute time interval from the configuration of the non-invasive implant high-viscosity adhesive solution for orthopaedics to the implantation in the operating space. Facilitates preparation and implantation at the surgical site.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Dermatology (AREA)
  • Medicinal Chemistry (AREA)
  • Transplantation (AREA)
  • Surgery (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Dispersion Chemistry (AREA)
  • Materials For Medical Uses (AREA)

Abstract

Matériau adhésif à haute viscosité pour implantation non invasive orthopédique, son procédé de préparation et application. Le matériau adhésif à haute viscosité est constitué de PLGA, de β-TCP, de chlorure de sodium, d'acétate d'éthyle ou d'un tampon phosphate, d'eau distillée, d'un adhésif médical, de poly(fumarate de propylène) et de N-vinylpyrrolidone. Le procédé de préparation consiste : à préparer respectivement des granules de dispersion de colle à viscosité élevée et une solution adhésive, puis à mélanger. Le matériau adhésif à viscosité élevée peut être implanté dans le corps au moyen d'une injection mini-invasive, durcit rapidement à température corporelle, présente des effets tels qu'une viscosité élevée, une dégradabilité élevée et une accélération de la cicatrisation osseuse, et peut être appliqué en chirurgie pour traiter des fractures osseuses, des maladies osseuses et des tumeurs osseuses.
PCT/CN2021/079870 2020-09-04 2021-03-10 Matériau adhésif à haute viscosité pour implantation non invasive orthopédique, son procédé de préparation et application Ceased WO2022048126A1 (fr)

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CN115006609A (zh) * 2022-05-24 2022-09-06 曹建中 一种适用于骨折内固定术前制作的可降解材料及其制备方法及应用

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