CN102552994B - Medical slow release material and preparation method thereof - Google Patents

Abstract

The invention relates to an injectable medical slow-release material, which is mainly composed of drug-loaded pulse release microspheres mixed with a temperature-sensitive polymer solution. The preparation method mainly includes: preparing drug-loaded pulse release microspheres; preparing temperature-sensitive polymer solution; mixing drug-loaded sustained-release microspheres with temperature-sensitive polymer solution and stirring uniformly to form a mixed solution. In the present invention, the microspheres loaded with factors or drugs are evenly dispersed in the solution of temperature-sensitive injectable carrier, and after being injected into the treatment site, the material solidifies rapidly, and then slowly degrades and releases drugs or factors to prolong the active time of the factors in the body , improve the controllability of factor release speed and release cycle, and realize the combination of the same or different drugs at predetermined positions, alternate release in different time periods and minimally invasive treatment methods.

Description

A kind of medical sustained-release material and preparation method thereof

technical field

The invention belongs to the field of bioactive materials, in particular to a temperature-sensitive injectable slow-release material loaded with microspheres and a preparation and use method thereof.

Background technique

In my country, there are 3 to 4 million patients with bone injuries caused by traffic accidents and production safety accidents every year. Coupled with orthopedic diseases such as bone tumors, bone tuberculosis, and avascular necrosis of the femoral head, there are many patients with bone defects. Therefore, bone defect has become a serious disease and social problem affecting people's healthy life. With the aging of my country's population, the improvement of people's health awareness and consumption ability, and the improvement of the national medical security system, the market demand for bone repair materials in my country has increased sharply. Autologous bone is an ideal material for bone defect repair, but the process of taking bone increases the patient's new trauma and pain, and the source is limited, not easy to shape, and it is difficult to meet the requirements of large-segment bone transplantation, and it is not suitable for children; while allograft bone There are risks of immune rejection, disease transmission, and surgical sequelae in bone xenografts, coupled with the limitation of donor sources and obstacles in medical ethics, which limit its clinical application.

In order to meet the clinical needs, in recent years, a variety of synthetic bone repair biomaterials have been widely used clinically, and injectable bone repair materials are one of the most important types. First, the injectable bone repair material can be implanted in the body by injection with less trauma, eliminating many complications associated with traditional bone grafting surgery; second, this bone material has good plasticity, can be solidified in situ in the body, and A scaffold material that forms a porous microstructure and plays an osteoconductive role; finally, the material slowly degrades after implantation in the body, accompanied by the growth of new bone in the host. In recent years, with the development of minimally invasive technology, injectable hydrogel materials have gradually attracted people's attention, and their research and application have become increasingly widespread. Injectable hydrogel not only has the advantages of strong plasticity, can fill defects of various shapes and solidify in situ, causes less trauma, and can reduce the pain of patients, but also has the biomimetic characteristics of extracellular matrix, The highly three-dimensional hydration network structure is conducive to the migration and growth of cells in the process of tissue regeneration and wound healing. The curing and molding conditions are mild, and it is especially suitable as a carrier for proteins and cells. Among them, injectable gels formed by temperature-sensitive phase transitions have attracted more and more attention from researchers, especially hydrogels with a lower critical solution temperature (LCST) slightly lower than body temperature, mainly because This type of gel is liquid at room temperature and can be rapidly cured at body temperature. The curing conditions and operations are simple, and it is very suitable for loading cells or protein factors.

In the process of treating various orthopedic diseases, some drugs or factors need to be used in combination, but these drugs or factors have a short half-life and are quickly diluted and metabolized when applied locally, and their bioavailability is extremely low; especially some growth factors, hormones Protein-based drugs are expensive to produce, making it unbearable for patients, which restricts the market expansion and application of such products. However, the existing technology cannot provide an efficient, safe and minimally invasive sustained-release system at present.

Contents of the invention

The technical problem to be solved by the present invention is to provide a temperature-sensitive injectable sustained-release material loaded with microspheres suitable for minimally invasive surgery, so as to solve the technical problem of safe and effective release of a small amount of drug factors in the prior art.

In order to solve the above technical problems, the present invention adopts the following technical scheme: a medical slow-release material, which is mainly a mixture formed by mixing slow-release microspheres in a temperature-sensitive polymer solution; the slow-release microspheres are loaded with drugs, And the microspheres with different release periods are mixed together according to a certain ratio to form pulse-type sustained-release microspheres that alternately release the same or different drugs.

The mass concentration range of the temperature-sensitive polymer solution at room temperature is 1-20%, and the solution can solidify rapidly in the range of 31-36°C to form a solid gel; the mass of the slow-release microspheres in the mixture is The volume ratio concentration is 0.01~10%. Preferably, the temperature-sensitive polymer solution is formed by dissolving the temperature-sensitive polymer in physiological saline or phosphate buffer solution until completely dissolved. The temperature-sensitive polymer is preferably poly-N-isopropylacrylamide PNIPAAm, PNIPAAm-grafted polyethylene glycol (PNIPAAm-g-PEG), PNIPAAm-grafted chitosan (PNIPAAm-g-Ch), PNIPAAm-grafted collagen (PNIPAAm-g-Col), PNIPAAm-grafted hyaluronic acid (PNIPAAm-g-HA), PNIPAAm-grafted chondroitin sulfate (PNIPAAm-g-CS), PNIPAAm-grafted sodium alginate (PNIPAAm-g-Alg) one or several of isothermal-sensitive polymers, the molecular weight of these polymers ranges from 5 to 50KDa.

The medicines contained are antibacterial medicines and/or growth factors; the content of the medicines in the microspheres accounts for 0.001-5% of the total mass of the microspheres; the mass-volume concentration of the slow-release microspheres in the mixture is 0.01-10%. The antibacterial drug is selected from streptomycin, cephradine, gentamicin, acetylspiramycin, erythromycin, leucomycin, amoxicillin, oxytetracycline, kanamycin, penicillin, metronidazole, salvia miltiorrhiza One or more of neomycin, ribomycin, tetracycline, vancomycin, and azithromycin. The growth factor is selected from one of rhBMP-2, rhBMP-7, insulin-like growth factor-1, transforming growth factor-β, vascular endothelial growth factor, basic fibroblast growth factor, platelet-derived factor or active polypeptide, etc. or several.

The microsphere raw material is selected from one or more of polylactic acid, polyglycolic acid, or lactic acid-glycolic acid copolymer, and at least contains lactic acid-glycolic acid copolymer; the molecular weight of the microsphere raw material ranges from 1 to 200KDa. When the molecular weight of the lactic acid-glycolic acid copolymer in the microspheres is 1-3KDa and accounts for more than 30% of the total mass of the microspheres, the release period of the microspheres can be adjusted within 1-2 weeks. When the molecular weight of the lactic acid-glycolic acid copolymer is greater than 3 KDa and less than 10 KDa, and accounts for more than 50% of the total mass of the microspheres, the release cycle can be adjusted within 3 to 6 weeks. When the molecular weight of the lactic acid-glycolic acid copolymer is greater than 10 KDa and less than 200 KDa, and accounts for less than 50% of the total mass of the microspheres, the release period can be adjusted within 7 to 12 weeks.

The pulse release microspheres include 5 kinds of microspheres with a release period of 1 week, 2 weeks, 4 weeks, 8 weeks and 12 weeks, and the mass ratio is (1~10): (1~10): (1~10 ): (1~10): (1~10); The drug loaded on the microspheres with the release period of 1 week and 2 weeks is an antibacterial drug; the drug loaded on the microspheres with the release cycle of 4 weeks, 8 weeks and 12 weeks is growth factor.

The medical sustained-release material of the present invention is in the form of injection.

The preparation method of the medical slow-release material of the present invention comprises the following steps:

1) Preparation of drug-loaded pulse release microspheres;

2) Preparation of thermosensitive polymer solution;

3) Mixing: Mix the drug-loaded pulse release microspheres prepared in step 1) with the solution prepared in step 2), and stir evenly to prepare a mixed solution of microspheres and polymers.

It further includes step 4): curing, specifically filling the mixed solution prepared in step 3 into a syringe, injecting it into the treatment site, and rapidly curing it.

The process of step 1) further includes:

First, the microsphere raw materials with different release periods and the drug are prepared into solutions respectively, wherein the microsphere raw materials are selected from one or more of polylactic acid, polyglycolic acid, or lactic acid-glycolic acid copolymer, and contain at least lactic acid - Glycolic acid copolymer, the molecular weight of the microsphere raw material ranges from 1 to 200KDa;

Microsphere droplets are atomized by an atomizer, and after volatilization and drying, drug-loaded microspheres with different release cycles are obtained: among them, when the molecular weight of the lactic acid-glycolic acid copolymer is 1~3KDa, and the total mass of the microspheres reaches When the molecular weight of the lactic acid-glycolic acid copolymer is greater than 3 KDa and less than 10 KDa, and it accounts for more than 50% of the total mass of the microspheres, the release period can be adjusted within 1-2 weeks. Microspheres adjusted for 3 to 6 weeks; when the molecular weight of the lactic acid-glycolic acid copolymer is greater than 10KDa and less than 200KDa, and accounts for less than 50% of the total mass of the microspheres, microspheres whose release cycle can be adjusted within 7 to 12 weeks are obtained;

Then, the microspheres with different release periods are mixed together according to a certain ratio to form pulse-type sustained-release microspheres that alternately release the same or different drugs.

The beneficial effects of the present invention are as follows: the present invention is a temperature-sensitive microsphere-loaded injectable sustained-release material suitable for minimally invasive surgery prepared on the basis of sustained-release microspheres and temperature-sensitive injectable gel . It has the function of pulse sustained release, which can realize the controlled release of different drugs in different time periods; it has the characteristics of good plasticity, degradability, can promote the regeneration of bone defects, good stability, and high safety. It can be used to fill bone defects of various complex shapes and sizes. The curing temperature of the material is between 31 and 36°C. It is liquid at room temperature and can self-cure at body temperature. The curing time is 3 to 15 minutes; It can maintain the proper shape during the cycle, and has good biocompatibility, which can promote bone regeneration.

Furthermore, the present invention uniformly disperses the microspheres loaded with factors or drugs in the temperature-sensitive injectable carrier solution. After being injected into the treatment site, the material solidifies rapidly, and then slowly degrades to release the drugs or factors, so as to prolong the time of the factors in the body. The active time improves the controllability of factor release speed and release cycle, and realizes the combination of the same or different drugs at predetermined positions and alternate releases in different time periods and minimally invasive treatment methods.

Detailed ways

During the treatment of various orthopedic diseases, some drugs or factors (such as genetically recombinant human bone morphogenetic protein-2 or -7, namely rhBMP-2 or rhBMP-7) are very beneficial to bone repair regeneration and antibacterial treatment.

Microspheres are a good sustained-release carrier. If the drug or factor can be gradually released through the degradation of the microsphere, the safe and effective delivery of the drug or factor can be realized. However, microspheres are difficult to fix on the treatment site, and are easy to lose and move, so other materials are needed as carriers to fix them on the treatment site. In addition, once the microspheres are degraded and broken, the drug or factor will be released rapidly.

The invention provides a medical slow-release material, which is mainly a mixture formed by mixing slow-release microspheres in a temperature-sensitive polymer solution. The slow-release microspheres are loaded with drugs, and the microspheres with different release periods are mixed together in a certain ratio to form pulse-type sustained-release microspheres that alternately release the same or different drugs. The mixing ratio of microspheres with different release periods can be adjusted and selected according to specific needs. For example, the mass ratio between microspheres with different release periods is (1~10):(1~10).

The mass concentration range of the temperature-sensitive polymer solution at room temperature is 1-20%, and the solution can solidify rapidly in the range of 31-36°C to form a solid gel; the mass of the slow-release microspheres in the mixture is The volume ratio concentration is 0.01~10%. Preferably, the temperature-sensitive polymer solution is formed by dissolving the temperature-sensitive polymer in physiological saline or phosphate buffer solution until completely dissolved.

The medicines contained are antibacterial medicines and/or growth factors; the content of the medicines in the microspheres accounts for 0.001-5% of the total mass of the microspheres; the mass-volume concentration of the slow-release microspheres in the mixture is 0.01-10%. The antibacterial drug is selected from streptomycin, cephradine, gentamicin, acetylspiramycin, erythromycin, leucomycin, amoxicillin, oxytetracycline, kanamycin, penicillin, metronidazole, salvia miltiorrhiza One or more of neomycin, ribomycin, tetracycline, vancomycin, and azithromycin. The growth factor is selected from one of rhBMP-2, rhBMP-7, insulin-like growth factor-1, transforming growth factor-β, vascular endothelial growth factor, basic fibroblast growth factor, platelet-derived factor or active polypeptide, etc. or several.

The microsphere raw material is selected from one or more of polylactic acid, polyglycolic acid, or lactic acid-glycolic acid copolymer, and at least contains lactic acid-glycolic acid copolymer; the molecular weight of the microsphere raw material ranges from 1 to 200KDa. When the molecular weight of the lactic acid-glycolic acid copolymer in the microspheres was 1-3 KDa and accounted for more than 30% of the total mass of the microspheres, the release period of the microspheres could be adjusted within 1-2 weeks. When the molecular weight of the lactic acid-glycolic acid copolymer is greater than 3KDa and less than 10KDa, and accounts for more than 50% of the total mass of the microspheres, the release period can be adjusted within 3 to 6 weeks. When the molecular weight of the lactic acid-glycolic acid copolymer is greater than 10KDa and less than 200KDa, and accounts for less than 50% of the total mass of the microspheres, the release cycle can be adjusted within 7 to 12 weeks.

The present invention combines the temperature-sensitive injectable gel with the preparation technology of pulse-type sustained-release microspheres. Firstly, the pulse-type sustained-release microspheres are prepared, and the microspheres and the pulse-type microsphere solution are evenly mixed, that is, the loading factor or drug The microspheres are uniformly dispersed in the temperature-sensitive injectable carrier solution. After being injected into the treatment site, the material solidifies rapidly, and then slowly degrades to release the drug or factor, so as to prolong the action time of the factor in the body and increase the release rate and cycle of the factor. controllability.

The preparation method of the temperature-sensitive microsphere-loaded injectable medical slow-release material of the present invention mainly includes the following steps:

1) Preparation of pulsed sustained-release microspheres: first prepare microspheres loaded with drugs or factors with different release periods, and then mix microspheres with different release periods in a certain proportion to form the same or different "Pulse sustained-release microspheres" for alternate release of drugs;

2) Preparation of temperature-sensitive polymer solution: at room temperature, dissolve the temperature-sensitive polymer with physiological saline or phosphate buffer until completely dissolved;

3) Mixing: Mix the "pulse slow-release microspheres" prepared in step 1 with the solution prepared in step 2, stir evenly, and prepare a mixed solution of microspheres and polymers.

The preparation method may further include step 4: curing, specifically filling the mixed solution prepared in step 3 into a syringe (the syringe can be designed as different needles according to clinical needs); injecting into the treatment site, and rapidly curing.

In the first step, the technology for preparing bone-loaded growth factor microspheres disclosed in Chinese Patent Publication No. CN101816634A is used. The microsphere raw material is selected from: polylactic acid (PLA), polyglycolic acid (PGA) or lactic acid-glycolic acid copolymer (PLGA). The microsphere raw material and some antibacterial drugs or factors are formulated into a solution, which is atomized by an atomizer to produce microsphere droplets, and then evaporated and dried to obtain solid microspheres. The method of drug addition is the same as that of protein factors. However, in order to prepare microspheres with different release periods, the molecular weight of polylactic acid (PLA), polyglycolic acid (PGA), lactic acid-glycolic acid copolymer (PLGA) and the ratio of raw materials in the microsphere raw materials are adjusted and controlled. First, the range of molecular weight selection is 1-200KDa, and each microsphere contains at least one raw material of PLGA. When the molecular weight of PLGA is less than 3 KDa and accounts for more than 30% of the total mass of microspheres, the release cycle can be adjusted within 1 to 2 weeks; when the molecular weight of PLGA is greater than 3KDa and less than 10 KDa, and accounts for more than 50% of the total mass of microspheres , the release period can be adjusted within 3-6 weeks; when the molecular weight of PLGA is greater than 10KDa and less than 200KDa, and accounts for less than 50% of the total mass of the microspheres, the release period can be adjusted within 7-12 weeks. More specifically, for example, the raw material ratio of microspheres with a release period of 1 week is to use PLGA with a molecular weight of 2 KDa and PLA with a molecular weight of 10 KDa, and the mass fraction of PLGA accounts for 60% of the total mass of the microspheres. The release period of the microspheres is 1 week. Similarly, microspheres with different release periods can be prepared respectively according to this method.

In a specific embodiment, the "pulse release microspheres" are composed of 5 kinds of microspheres with a release period of 1 week, 2 weeks, 4 weeks, 8 weeks and 12 weeks, and the mass ratio is (1~10): (1~ 10): (1~10): (1~10): (1~10); and the drugs contained in the microspheres can be selected according to actual needs, and the drugs are mainly selected from antibacterial drugs and growth factors or both One, the content in the microsphere accounts for 0.001~5% of the total mass of the microsphere. Antibacterial drugs are mainly selected from streptomycin, cephradine, gentamicin, acetylspiramycin, erythromycin, leucomycin, amoxicillin, oxytetracycline, kanamycin, penicillin, metronidazole, danshensu , neomycin, ribomycin, tetracycline, vancomycin, azithromycin one or more. The growth factor is selected from rhBMP-2, rhBMP-7, insulin-like growth factor-1 (IGF-1), transforming growth factor-β (TGF-β), vascular endothelial growth factor (VEGF), basic fibroblast growth factor ( One or more of bFGF), platelet-derived factor (PDGF) or active polypeptide, etc. It can be understood that the drugs carried by the microspheres can also be selected from other applicable drugs or factors according to specific needs, and are not limited to carrying antibacterial drugs and growth factors.

In the second step, the thermosensitive polymer is selected from poly N-isopropylacrylamide (PNIPAAm), PNIPAAm grafted polyethylene glycol (PNIPAAm-g-PEG), PNIPAAm grafted chitosan (PNIPAAm-g-Ch), PNIPAAm-grafted collagen (PNIPAAm-g-Col), PNIPAAm-grafted hyaluronic acid (PNIPAAm-g-HA), PNIPAAm-grafted chondroitin sulfate (PNIPAAm-g-CS) , PNIPAAm-grafted sodium alginate (PNIPAAm-g-Alg) and other temperature-sensitive polymers. The molecular weight of these polymers ranges from 5 to 50KDa. The concentration range of mass volume ratio is 1~20% (W/V), and its aqueous solution solidifies rapidly in the range of 31~36°C to form a solid gel.

In the third step, the mass-volume concentration range of the "pulse release microspheres" in the solution is 0.01-10% (W/V).

In step 4, the material can be directly injected to fill the cavity formed by osteoporosis and fill various irregular bone defects; The periosteum and cortical bone are peeled off, and then the material is injected. When this method is used to increase the alveolar bone mass, compared with the traditional bone grafting operation, the trauma is small and the cost is low.

In the present invention, the microspheres loaded with factors or drugs are evenly dispersed in the solution of temperature-sensitive injectable carrier, and after being injected into the treatment site, the material solidifies rapidly, and then slowly degrades and releases drugs or factors to prolong the active time of the factors in the body , improve the controllability of factor release speed and release cycle, and realize the combination of the same or different drugs at predetermined positions, alternate release in different time periods and minimally invasive treatment methods.

The following examples will further illustrate the bone repair material of the present invention, but it is not intended as a limitation of the present invention.

Example 1

The method for preparing and using the injectable slow-release material loaded with thermosensitive microspheres specifically comprises the following steps:

1) Five types of microspheres with release periods of 1 week, 2 weeks, 4 weeks, 8 weeks and 12 weeks were prepared, and then mixed together in a ratio of 1:1:1:1:1 to form an alternate release " Pulse-type slow-release microspheres", the drug contained in the microspheres with a release period of 1 week and 2 weeks is gentamicin, accounting for 3% of the total mass of the microspheres, which can play an antibacterial and anti-inflammatory role at the wound site; release The drug factor rhBMP-2 contained in three kinds of microspheres with cycle of 4 weeks, 8 weeks and 12 weeks accounted for 0.005% of the total mass of microspheres.

2) Dissolve PNIPAAm-g-Ch in phosphate buffer at room temperature until it is completely dissolved to prepare a 5% PNIPAAm-g-Ch solution;

3) Mix the "pulse slow-release microspheres" prepared in step 1 with the solution prepared in step 2, stir evenly, and prepare a mixed solution of microspheres and polymers, wherein the content of microspheres is 1% (W/V );

4) Fill the mixed solution prepared in step 3 into a syringe (the syringe can be designed with a suitable needle according to clinical needs);

5) Inject into the intended treatment site and solidify quickly.

Example 2

The method for preparing and using the injectable slow-release material loaded with thermosensitive microspheres specifically comprises the following steps:

1) Five types of microspheres with release periods of 1 week, 2 weeks, 4 weeks, 8 weeks and 12 weeks were prepared, and then mixed together in a ratio of 2:1:1:1:1 to form alternate release " Pulse-type slow-release microspheres”, the drugs contained in the microspheres with a release period of 1 week and 2 weeks are vancomycin and gentamicin, respectively accounting for 3% of the total mass of the microspheres, which can treat severe infection in bone defects The site plays the role of antibacterial and anti-inflammatory; the drug factor rhBMP-2 contained in three kinds of microspheres with the release period of 4 weeks, 8 weeks and 12 weeks accounts for 0.008% of the total mass of the microspheres.

2) Dissolve PNIPAAm-g-HA in phosphate buffer solution at room temperature until it is completely dissolved to prepare a 10% PNIPAAm-g-HA solution;

3) Mix the "pulse slow-release microspheres" prepared in step 1 with the solution prepared in step 2, stir evenly, and prepare a mixed solution of microspheres and polymers, wherein the content of microspheres is 0.8% (W/V );

4) Put the mixed solution prepared in step 3 into the syringe (the syringe can also be designed with a special needle according to clinical needs);

5) Inject into the intended treatment site and solidify quickly.

When the material prepared in the above implementation examples is used for alveolar bone elevation, it can be carefully injected under the periosteum with biological saline first, and the periosteum and cortical bone are peeled off to form a certain gap, and then the material is injected into the part. Under the action, it can be solidified rapidly. After 2 months, the bone of the alveolar bone increases, and the bone is raised by 2~3mm. When the material is used for filling irregular bone defects, it can be directly injected into the defect to fill the entire defect. The material can quickly solidify under the action of body temperature and promote the repair of bone defects.

In conclusion, the above examples utilize the technology of sustained-release microspheres and temperature-sensitive injectable gel to prepare a temperature-sensitive microsphere-loaded injectable sustained-release material suitable for minimally invasive surgery. It has the function of pulse sustained release, which can realize the controlled release of different drugs in different time periods; it has the characteristics of good plasticity, degradability, can promote the regeneration of bone defects, good stability, and high safety. It can be used to fill bone defects of various complex shapes and sizes. The curing temperature of the material is between 31 and 36°C. It is liquid at room temperature and can self-cure at body temperature. The curing time is 3 to 15 minutes; It can maintain the proper shape during the repair cycle, and has good biocompatibility, which can promote bone regeneration.

Claims (10)

1. A medical slow-release material, mainly a mixture formed by mixing slow-release microspheres in a temperature-sensitive polymer solution; Ratio mixed together to form pulse-type slow-release microspheres for the alternate release of the same or different drugs; the microsphere raw materials are selected from one or more of polylactic acid, polyglycolic acid, or lactic acid-glycolic acid copolymer, and at least Contains lactic acid-glycolic acid copolymer; in order to prepare microspheres with different release periods, the molecular weight of the microsphere raw materials and the ratio of raw materials are adjusted and controlled. The content accounts for 0.001%~5% of the total mass of microspheres. 2. The medical sustained-release material as claimed in claim 1, characterized in that: the temperature-sensitive polymer solution is a kind of injectable carrier solution, the mass concentration range at room temperature is 1 ~ 20%, and the solution is It can solidify rapidly within the range of 31-36°C to form a solid gel; the temperature-sensitive polymer solution is formed by dissolving the temperature-sensitive polymer in physiological saline or phosphate buffer until it is completely dissolved; the temperature-sensitive polymer The material is selected from polyN-isopropylacrylamide, polyethylene glycol grafted with polyN-isopropylacrylamide, chitosan grafted with polyN-isopropylacrylamide, polyN-isopropyl Collagen grafted with acrylamide, hyaluronic acid grafted with poly-N-isopropylacrylamide, chondroitin sulfate grafted with poly-N-isopropylacrylamide, alginic acid grafted with poly-N-isopropylacrylamide One and several kinds of sodium, the molecular weight of these polymers ranges from 0.5 to 5KDa. 3. The medical slow-release material according to claim 1, characterized in that: the drug contained therein is an antibacterial drug and/or a growth factor; the mass-volume concentration of the slow-release microspheres in the mixture is 0.01-10%. 4. The medical sustained-release material as claimed in claim 3, characterized in that: said antibacterial drug is selected from streptomycin, cephradine, gentamycin, acetylspiramycin, erythromycin, leucomycin, amoxicillin One or more of cillin, oxytetracycline, kanamycin, penicillin, metronidazole, danshensu, neomycin, ribomycin, tetracycline, vancomycin, azithromycin; the growth factor is selected from One or more of rhBMP-2, rhBMP-7, insulin-like growth factor-1, transforming growth factor-β, vascular endothelial growth factor, basic fibroblast growth factor, platelet-derived factor or active polypeptide. 5. The medical sustained-release material as claimed in claim 1, characterized in that: when the molecular weight of the lactic acid-glycolic acid copolymer in the microspheres is 1-3KDa, and accounts for more than 30% of the total mass of the microspheres, the release period of the microspheres It can be adjusted within 1 to 2 weeks; when the molecular weight of the lactic acid-glycolic acid copolymer is greater than 3 KDa and less than 10 KDa, and accounts for more than 50% of the total mass of the microspheres, the release period can be adjusted within 3 to 6 weeks; The molecular weight of the lactic acid-glycolic acid copolymer is greater than 10KDa and less than 200 KDa, and accounts for less than 50% of the total mass of the microspheres. The release period can be adjusted within 7 to 12 weeks. 6. The medical sustained-release material according to claim 1, characterized in that: the pulse-release microspheres include 5 kinds of microspheres whose release period is 1 week, 2 weeks, 4 weeks, 8 weeks and 12 weeks, and the mass The ratio is (1~10): (1~10): (1~10): (1~10): (1~10); the drug contained in the microspheres with a release period of 1 week and 2 weeks is an antibacterial drug; The drug contained in the microspheres with the release period of 4 weeks, 8 weeks and 12 weeks was a growth factor. 7. The medical sustained-release material according to any one of claims 1-6, which is an injectable dosage form. 8. The preparation method of the medical slow-release material according to any one of claims 1-7, comprising the following steps: 1) Preparation of drug-loaded pulse release microspheres; 2) Preparation of thermosensitive polymer solution; 3) Mixing: Mix the drug-loaded pulse release microspheres prepared in step 1) with the solution prepared in step 2), and stir evenly to prepare a mixed solution of microspheres and polymers. 9. The preparation method of medical slow-release material as claimed in claim 8, characterized in that: further comprising step 4): curing, specifically filling the mixed solution prepared in step 3 into a syringe, injecting it into the treatment site, and rapidly solidified. 10. The preparation method of medical sustained-release material according to claim 8, characterized in that: the process of step 1) further comprises: First prepare microsphere raw materials with different release periods and formulate solutions with the drug respectively, wherein the microsphere raw materials are selected from one or more of polylactic acid, polyglycolic acid, or lactic acid-glycolic acid copolymer, and contain at least Lactic acid-glycolic acid copolymer, the molecular weight of the microsphere raw material ranges from 1 to 200KDa; Microsphere droplets are atomized by an atomizer, and after volatilization and drying, drug-loaded microspheres with different release cycles are obtained: among them, when the molecular weight of the lactic acid-glycolic acid copolymer is 1~3KDa, and the total mass of the microspheres reaches When the molecular weight of the lactic acid-glycolic acid copolymer is greater than 3 KDa and less than 10 KDa, and it accounts for more than 50% of the total mass of the microspheres, the release period can be adjusted within 1-2 weeks. Microspheres adjusted for 3 to 6 weeks; when the molecular weight of the lactic acid-glycolic acid copolymer is greater than 10KDa and less than 200KDa, and accounts for less than 50% of the total mass of the microspheres, microspheres whose release cycle can be adjusted within 7 to 12 weeks are obtained; Then, the microspheres with different release periods are mixed together according to a certain ratio to form pulse-type sustained-release microspheres that alternately release the same or different drugs.