CN1593660A - Injectable pharmaceutical slow-release carrier and preparation method thereof - Google Patents
Injectable pharmaceutical slow-release carrier and preparation method thereof Download PDFInfo
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Abstract
The invention provides a unsaturated polyester block polymer capable of direct injection and in vivo curing for medicinal slow release material, i.e. liquid polyanhydride. The invention employs the high vacuum melting polymerization method, and using dibasic alcohol, maleic anhydride or trans-butene diacid, C[10-16] diacid anhydride as raw material, the material can be injected directly without the need of performing an operation.
Description
Technical Field
The present invention relates to a method for preparing injectable and in-vivo solidified liquid polyanhydride-unsaturated polyester block polymer used as a medicine slow release material by adopting the copolymerization of dibasic fatty acid, unsaturated dibasic acid and dihydric alcohol, and a chemical synthesis method thereof.
Technical Field
The biodegradable matrices used as drug sustained-release materials are divided into two major classes, one class is natural high molecular materials such as albumin, gelatin, modified polysaccharides, and the like. Another class is chemically synthesized polymeric materials such as polyanhydrides, polyesters, and the like. The polyanhydride is Langer et al (Rosen HB) of the national institute of technology, Massachusetts, in the early eighties of the twentieth century, etc.: bioeriobleBiomaterials, 1983, 4: 131-133), and the novel synthetic biodegradable polymer material has excellent performances of good biocompatibility, unique surface erosion degradation, adjustable degradation speed, easy processability and the like, and can be quickly applied in the medical frontier fields of drug controlled release and the like. In particular to poly [1, 3-bis (p-carboxyphenoxy) propane-sebacic acid of one type of polyanhydride][P(CPP-SA)]The copolymer as a novel skeleton type drug controlled release material has systematic research of nearly twenty years, and the skeleton type controlled release tablet GliadelTMIn 1996, FDA approval was obtained for postoperative adjuvant chemotherapy for recurrent glioblastoma (Langer R: Biomaterials in drug delivery and tissue engineering: one laboratory's experiment. Acc Chem Res, 2000, 33 (2): 94-101). And the other polyanhydride poly (erucic acid dimer-sebacic acid) [ P (EAD-SA)]Cylindrical controlled-release drug stick Septacin composed of copolymer and gentamicinTMIt has been used in clinical trials for the treatment of osteomyelitis (Stephens D et al: Investigation of the in vitro Release of genetic from polypeptide matrix. J Control Release, 2000: 63 (3): 305-317). . The materials have good biocompatibility and can be degraded and absorbed in vivo. Biodegradable materials currently approved by the FDA for use in the biomedical field are also polyesters such as PLA (Coombers a.g.a.; Major d.; woodj.m.; Biom 1998, 19, 1073-. The present inventors have filed for: "polyanhydride for drug slow-release carrier and its synthesis method", patent application number is: 200310111439.3.the invention adopts a high vacuum melt polycondensation method to obtain important intermediates Dimer Acid (DA) and C by deep processing of vegetable oil11-16Fatty diacid is monomer, and a series of polyanhydride materials with different monomer ratios are synthesized by a high vacuum melt polycondensation method. However, the drug sustained-release material is a high molecular polymer with the weight-average molecular weight of 1-4 ten thousand, is solid at normal temperature, has the common defect that the solid sustained-release pill needs to be implanted into a focus part after operation, and has difficulty in secondary administration treatment of some diseases which are easy to relapse, such as glioma and osteomyelitisSo that its application is limited. Several classes of liquid injectable drug delivery materials have recently emerged, such as sustained release emulsions (a.t. florence, d.whitehill, int.j.pharm.11(1982) 277-.
The invention adopts a melt polycondensation method, and takes dihydric alcohol and maleic anhydride (or fumaric acid) as raw materials to synthesize a drug sustained-release material suitable for injection: the room temperature viscous liquid polyanhydride-unsaturated polyester block polymer has the molecular weight of 4000-10000.
Compared with the general drug sustained-release material, the synthesis method firstly synthesizes oligomer with small molecular weight instead of high polymer with large molecular weight, and the oligomer is liquid with small viscosity after being added with diluent, so that the drug sustained-release material is suitable for injection. Compared with the polyanhydride material mentioned in the patent of the invention of the patent inventor, the polyanhydride-unsaturated polyester block polymer belongs to polyanhydride modified polyester, contains both acid anhydride groups and ester groups, has smaller molecular weight (the weight-average molecular weight is 4000-10000), is flowable liquid, contains double bonds in the main chain for crosslinking, and becomes solid after crosslinking; can be rapidly crosslinked and solidified into crosslinked high polymer solid within 5-30min at the body temperature. The polyanhydride material only contains anhydride groups, has larger molecular weight (weight-average molecular weight of 10000-. In terms of the synthesis method, although the high vacuum melt polycondensation method is used, the conditions are different: when the polyanhydride-unsaturated polyester block polymer is synthesized, unsaturated polyester and polyanhydride oligomer are synthesized, and then the mixture of the unsaturated polyester and the polyanhydride oligomer is heated to 170 ℃ for vacuum melt polymerization for 1.0 hour, wherein nitrogen is used for protection. After the polymerization is finished, cooling to 80 ℃, adding a crosslinking agent with the mass ratio of 30%, and cooling to obtain the polyanhydride-unsaturated polyester block polymer with certain viscosity. And the oligomer is not used in the polyanhydride synthesis, but the monomer mixture is subjected to vacuum decompression at 170-200 ℃ to 30-50Pa for 1.5 hours under the protection of nitrogen. And after the polymerization is finished, cooling to room temperature to obtain a high molecular product. The relevant content of the research is not reported at present, and the research has great practical value.
Disclosure of Invention
Aiming at the defects that the existing drug sustained-release material is solid at normal temperature and needs an operation to implant the solid sustained-release pill into a focus part.
The invention adopts a melt polycondensation method, takes dihydric alcohol and maleic anhydride (or fumaric acid) as raw materials to synthesize unsaturated polyester oligomer, and takes C10-16The polyanhydride oligomer is synthesized by taking dianhydride as a raw material, and then the unsaturated polyester oligomer and the polyanhydride oligomer are subjected to melt polycondensation to obtain the polyanhydride-unsaturated polyester block polymer oligomer. Dimer acid, oleic acid and N-vinyl pyrrolidone are used as a diluent and a cross-linking agent of the polyanhydride-unsaturated polyester block polymer oligomer, and the purpose is to prepare a polyanhydride-unsaturated polyester block polymer material for a drug sustained release carrier.
The invention synthesizes a drug sustained-release material suitable for injection: the room temperature viscous liquid polyanhydride-unsaturated polyester block polymer has the molecular weight of 4000-10000.
The structural formula of the polyanhydride-unsaturated polyester block polymer is as follows:
wherein x is 2-4, y is 8-14, m is the mole number of the chain link of the polymaleic acid-diol ester anhydride or the fumaric acid-diol ester, n is the mole number of the chain link of the saturated dicarboxylic acid-diol ester, and m/n is 1/5-5/1.
The specific preparation technology of the invention is as follows:
1. synthesis of dibasic acid anhydride
Acetic anhydride is respectively mixed with one of the following seven dibasic acids: sebacic Acid (SA), Undecanedioic Acid (UA), Dodecanedioic Acid (lauryl Acid, DDDA), tridecanedioic Acid (Brassylic Acid, BA), Tetradecanedioic Acid (TA), Pentadecanedioic Acid (PA), Hexadecanedioic Acid (HA) in a molar ratio of 1: 2-5, respectively, in a nitrogen-protected container; 140 ℃ and 200 ℃ reflux reaction for 15-100 minutes, cooling to 60-100 ℃, decompressing and steaming acetic acid and acetic anhydride which are not completely reacted, dissolving the product by using dichloromethane, precipitating by using petroleum ether or cyclohexane, filtering by using a sand core funnel, washing by using anhydrous ether or methyl ethyl ether or tetrahydrofuran, and drying in vacuum to obtain seven binary acid anhydrides.
2. Synthesis of unsaturated polyester oligomers
Mixing maleic anhydride or fumaric acid and dihydric alcohol according to a mol ratio of 1: 1.1, loading into a polymerization tube, placing into a silicon oil bath, and electromagnetically stirring; heating to 170-00 ℃ for reaction for 1.5 hours, cooling to 80 ℃, reducing the pressure to 30-50Pa in vacuum, pumping away water, heating to 170 ℃ after 0.5 hour, and carrying out melt polymerization for 1.0 hour; introducing nitrogen for 10-20 seconds every 5-20 minutes, and vacuumizing; after the polymerization is finished, the unsaturated polyester oligomer with certain viscosity is obtained after cooling.
The unsaturated polyester oligomer is synthesized according to the following formula:
where x is 2-4 and n is the mole number of fumaric acid, maleic anhydride may be used instead of fumaric acid.
3. Synthesis of polyanhydride oligomer
Synthesis of polyanhydride oligomer: homopolymerizing any one of the seven binary anhydrides prepared in the step 1 according to the following method: a certain amount of binary anhydride is put into a polymerization tube and placed in a silicon oil bath for electromagnetic stirring; heating the reaction to 160-200 ℃, reducing the pressure to 30-70 Pa in vacuum, and carrying out melt polymerization for 20-50 minutes; introducing nitrogen for 10-20 seconds every 5-10 minutes, and vacuumizing; after 30 minutes, stopping polymerization, cooling to obtain a light yellow solid product, dissolving the light yellow solid product by using dichloromethane, filtering by using a G4 sand core funnel, precipitating by using petroleum ether or cyclohexane, precipitating and filtering, washing by using one of anhydrous ether, methyl ethyl ether and tetrahydrofuran, and then drying to obtain light yellow seven types of anhydride homopolymer oligomers, or filling two types of binary anhydride into a polymerization tube according to the molar ratio m/n of 1/5-5/1, and copolymerizing according to the same reaction condition of the homopolymer to obtain the corresponding polyanhydride copolymer oligomer. The molecular weight of the polyanhydride homopolymer or copolymer is 2000-.
4. Synthesis of polyanhydride-unsaturated polyester block polymer
Mixing the synthesized polyanhydride and unsaturated polyester oligomer in a mass ratio of 1/5-5/1, putting into a polymerization tube, putting into a silicon oil bath, and electromagnetically stirring; heating the reaction to 170-200 ℃ for 1.5 hours, introducing nitrogen for 10-20 seconds every 5 minutes, and vacuumizing; after 30 minutes, stopping polymerization, cooling to 80 ℃, and adding one of the following diluting crosslinking agents with the mass ratio of 5-30 percent: dimer acid, oleic acid, N-vinyl pyrrolidone, isodecyl acrylate and 2-ethylhexyl acrylate, and coolingto obtain corresponding viscous liquid polyanhydride-unsaturated polyester block polymer with molecular weight of 4000-10000. The structural formula is as follows:
5. use method of polyanhydride-unsaturated polyester block polymer
Mixing the liquid polyanhydride-unsaturated polyester block polymer with 0.3 to 1.0 mass percent of one of the following curing agents: methyl ethyl ketone peroxide, benzoyl peroxide; 0.1 to 0.4 percent of one of the following curing accelerators in percentage by mass: cobalt naphthenate or triethanolamine; 5-30% of one of the following crosslinking agents by mass percent: dimer acid, oleic acid, N-vinyl pyrrolidone, isodecyl acrylate, oleic acid, linoleic acid glyceride, and the medicine to be mixed are stirred and mixed uniformly in a container, and the container is filled into an injector, so that the focus can be injected.
Characterization of
All of the synthesized polyanhydride-unsaturated polyester resins were characterized by FT-IR, GPC, and measured for viscosity using an Ubbelohde viscometer (chloroform as a solvent, measurement temperature 23 ℃). The experimental results show that the structure of all synthetic polymers is consistent with that which is expected by theory. All synthetic polymers have certain viscosity and fluidity and are suitable for injection, and can be rapidly cured (10-20min) at normal temperature after a proper amount of crosslinking curing agent is added. FT-IR spectra of all synthesized polyanhydride-unsaturated polyester resins are shown in 1713-1735cm-1Has strong absorption peak of C ═ O stretching vibration characteristic of unsaturated polyester, 1802cm-1And 1720cm-1Has a C ═ O stretching vibration characteristic absorption double peak at 1643cm-1Has an absorption peak of the unsaturated polyester C ═ C stretching vibration characteristic at 2926cm-1And 2854cm-1Has C-H stretching vibration absorption peak at 1043cm-1There is a C-O stretching vibration absorption peak. At 3510cm-1The weak-COOH absorption peaks on the left and right indicate that little-COOH remained in the polymer. GPC measurement results showed that the weight average molecular weight of the synthesized unsaturated polyester resin was 4000-10000.
Performance of
1. Normal temperature curing property
A methyl ethyl ketone peroxide (or cyclohexanone peroxide) -cobalt naphthenate system or benzoyl peroxide-triethanolamine system is selected as a curing system, one of dimer acid and oleic acid is selected as a diluent and a cross-linking agent, and a curing experiment of the polyanhydride-unsaturated polyester resin is carried out at normal temperature. A certain amount of curing agent, diluent (0.3-1.0 percent) and crosslinking agent (5-30 percent) are evenly stirred and mixed with polyanhydride-unsaturated polyester resin (70-95 percent) on a watch glass, and the mixture is stood. After a period of time (5-30min), the resin is crosslinked and gelled, and gradually becomes hard, so that the resin becomes a strong and tough material.
2. In vitro degradation Properties
Mixing liquid resin with a certain amount of curing agent (0.3% -1.0%), diluent and cross-linking agent (5% -30%) on a watch glass, stirring, filling into 1ml disposable syringe, injecting 150mg resin into glass catheter with diameter of 4mm, curingThen the glass guide tube is smashed, and the cross-linked resin bar is taken out. The resin rods were placed in 20mL of 0.1mol/LpH7.4 phosphate buffer and subjected to degradation experiments (rotation speed 60rad/min) on a constant temperature shaker at 37 ℃. Taking out samples at regular intervals, washing the surfaces of the samples with distilled water, and adding P2O5And drying in a vacuum drier for 24h and weighing, and calculating the degradation rate according to the mass difference of the sample before and after degradation. The experimental results show that the time for degrading the obtained resin bar by 80 percent varies from 20 days to 6 months according to different compositions.
3. Drug Release Properties
The method comprises the steps of taking ciprofloxacin hydrochloride as a model drug, blending liquid resin with the ciprofloxacin hydrochloride, adding a certain amount of curing agent (0.3% -1.0%) and diluent and cross-linking agent (5% -30%) on a watch glass, stirring and mixing uniformly, filling into a 1ml one-time syringe, injecting 150mg of drug-loaded resin into a glass catheter with the diameter of 4mm, breaking the glass catheter after curing, and taking out a slow-release drug rod. The rods were placed in 20mL of 0.1mol/L phosphate buffer solution at pH7.4 and subjected to degradation experiments (rotation speed 60rad/min) on a constant temperature shaker at 37 ℃. Changing the buffer solution at regular intervals, measuring the absorbance of the release medium at the wavelength of 271nm by adopting UV spectrum, and determining the regression equation A (0.27465 rho-5.133X 10) of the UV absorption at the wavelength of 271nm in a phosphate buffer solution of 0.1mol/L and pH (7.4) of ciprofloxacin hydrochloride-4In the formula: a is absorbance; rho is the mass concentration of ciprofloxacin hydrochloride; the regression coefficient R is 0.99995; the concentration of drug released into the buffer solution can be calculated by measuring the linear range of 2.0-30.0. mu.g.
The experimental result shows that the medicine has no burst release effect in the release process. The drug release experiment result shows thatthe sustained-release drug rod has good controlled release performance on ciprofloxacin hydrochloride and has first-order release kinetic characteristics on the release of drugs. The slow release drug stick has the release period of the 80% ciprofloxacin hydrochloride from 20 days to 6 months, and is expected to be used as a long-acting local implantation preparation for the fixed-point long-acting administration treatment of osteomyelitis and the local chemotherapy of solid tumors. 4. Biocompatibility experiment
The histocompatibility and the degradation and absorption of the synthesized drug sustained-release material under the skin of a mouse are preliminarily studied. The result shows that the synthesized drug sustained-release material has good histocompatibility and biodegradable and absorbable characteristics in vivo as a novel subcutaneous implant material. Figure 2 reflects that the synthetic material has good histocompatibility in vivo.
Compared with the common drug sustained-release material, the material of the invention is an oligomer (with the weight-average molecular weight of 2000-8000) when not crosslinked, has certain fluidity after being added with a crosslinking agent, and has the properties of unsaturated polyester: can be rapidly crosslinked and solidified into crosslinked high polymer (5-30min) at body temperature (37 ℃), is biodegradable, and has the property of polyanhydride: better drug slow release performance, biocompatibility and degradation performance.
The liquid unsaturated polyester-polyanhydride oligomer is injected into animal bodies and crosslinked into solid-state structure macromolecules under the action of a crosslinking curing agent. Compared with solid drug sustained-release materials, the material has the common characteristics of proper drug release rate, degradability, metabolism and good biocompatibility, and also has the characteristics of injectability, rapid solidification at body temperature and high mechanical strength, and can solve the problems that the solid drug sustained-release materials need to be implanted by an operation and are difficult to treat by secondary administration. The slow release medicine prepared by the material and the medicine can be implanted into a focus part by an injection method, is quickly cross-linked and solidified (5-30min) at the body temperature, then slowly releases the medicine and finally degrades, and is expected to realize the non-operation or small-operation local slow release administration chemotherapy of solid tumor and osteomyelitis. For the brain glioma deeply hidden in the cranial cavity, the injection method is adopted to implant the sustained-release preparation containing the chemotherapeutic drug for local administration chemotherapy, and the method has the characteristics of no need of tumor excision by major operation, low risk, low treatment cost and repeated administration. For the advanced cancer which is difficult to be excised by operation and cured by the conventional treatment method, the local administration chemotherapy by implanting the sustained-release medicament at the focus part by injection method becomes an important treatment means. Injectable, rapidly setting at body temperature, mechanically strong degradable materials are also expected to be temporary substitutes for bone tissue and other tissue supporting materials. The preparation of injectable sustained-release medicaments is carried out at normal temperature and is vital to maintaining the efficacy of thermolabile medicaments such as doxorubicin hydrochloride.
Drawings
FIG. 1 shows the release pattern of ciprofloxacin hydrochloride-containing sustained release drug stick in 0.1M PBS buffer solution with pH7.4
The abscissa is thedrug release time (days) and the ordinate is the composition of the cumulative drug release percentage of polylauryl-poly (maleic anhydride-ethylene glycol) (PDDDA-P (MA-GLY) resin by mass:
(a) the mass ratio PDDDA/P (MA-GLY) is 5: 5;
(b) the mass ratio PDDDA/P (MA-GLY) is 4: 6;
(c) the mass ratio PDDDA/P (MA-GLY) is 3: 7.
FIG. 2A synthetic polylauryl-poly (maleic anhydride-ethylene glycol) (PDDDA-P (MA-GLY)) resin material (mass ratio PDDDA/P (MA-GLY) ═ 5: 5) was implanted subcutaneously in mice for 10 days (10 ×)
Detailed Description
Example 1: synthesis of Polylauranedioic acid-poly (maleic anhydride-ethylene glycol) (PDDDA-P (MA-GLY)) resin
3.92 g (0.040mol) of maleic anhydride and 2.73 g (0.044mol) of ethylene glycol were put into a polymerization tube having a diameter of 2cm and a length of 20cm, and the polymerization tube was placed in a silicone oil bath and stirred electromagnetically. The temperature was raised to 170 ℃ and melt-polymerized for 90 minutes, and nitrogen gas was introduced every 15 minutes for 15 seconds. Cooling to 80 ℃, vacuum-reducing to 30-50Pa, pumping away water, heating to 170 ℃ after 0.5 hour, carrying out melt polymerization for 1.0 hour, adding polylauryl acid with a certain mass percentage, carrying out melt polymerization for 1.0 hour, introducing nitrogen for 15 seconds every 15 minutes, and then vacuumizing; after the polymerization is finished, the temperature is reduced to 80 ℃, a diluent and a crosslinking agent N-vinyl pyrrolidone with the mass ratio of 30 percent are added, and the polyanhydride-unsaturated polyester resin (PDDDA-P (MA-GLY)) with certain viscosity is obtained after cooling. The FT-IR andthe physical and chemical properties of the polyanhydride-unsaturated polyester (PDDDA-P (MA-GLY)) are characterized in the following table:
FI-IR and physico-chemical Properties of Epimeric anhydride-unsaturated polyester (PDDDA-P (MA-GLY))
WPDDDA/ [η]vIR/cm-1
Mw/103Mn/103
WP(MA-Ecd)/dL.g-1Anhydride C ═ O ester C ═ O C-O
1802.49，
3∶7 6.938 5.578 0.37 1718.85 1043.19
1718.85
1801.70，
4∶6 7.672 6.866 0.41 1720.73 1046.81
1720.73
1801.51，
5∶5 8.048 6.974 0.42 1719.89 1046.37
1719.89
Example 2: medicine release characteristics of poly (lauryl acid-poly (maleic anhydride-ethylene glycol) (PDDDA-P (MA-GLY)) resin medicine bar containing ciprofloxacin hydrochloride
The ciprofloxacin hydrochloride is used as a model medicine, liquid resin is mixed with the ciprofloxacin hydrochloride, and a certain amount of curing agent (0.3-1.0 percent) and diluent and cross-linking agent (20-30 percent) are addedStirring and mixing on watch glassMixing, filling into 1ml disposable syringe, injecting 150mg drug-loaded resin into glass catheter with diameter of 4mm, breaking the glass catheter after curing, and taking out the sustained-release drug rod. The rods were placed in 20mL of 0.1mol/L phosphate buffer solution at pH7.4 and subjected to degradation experiments (rotation speed 60rad/min) on a constant temperature shaker at 37 ℃. Changing the buffer solution at regular intervals, measuring the absorbance of the release medium at the wavelength of 271nm by adopting UV spectrum, and determining the regression equation A (0.27465 rho-5.133X 10) of the UV absorption at the wavelength of 271nm in a phosphate buffer solution of 0.1mol/L and pH (7.4) of ciprofloxacin hydrochloride-4In the formula: a is absorbance; rho is the mass concentration of ciprofloxacin hydrochloride; the regression coefficient R is 0.99995; the concentration of drug released into the buffer solution can be calculated by measuring the linear range of 2.0-30.0. mu.g. The drug release rate of 3 polylauryl-poly (maleic anhydride-ethylene glycol) (PDDDA-P (MA-GLY)) resin drug sticks with different mixture ratios is shown in the figure I.
Example 3: biocompatibility experiment of polylauryl-poly (maleic anhydride-ethylene glycol) (PDDDA-P (MA-GLY)) resin in subcutaneous mouse
The biocompatibility of the polylauryl-poly (maleic anhydride-ethylene glycol) (PDDDA-P (MA-GLY)) resin under the skin of mice was evaluated according to the method of the post-implantation local reaction test, section 6 of the national Standard of the people's republic of China, biological evaluation of medical instruments (GB/T16886.1-1997).
By injection, 150mg of polylauryl-poly (maleic anhydride-ethylene glycol) (PDDDA-P (MA-GLY)) resin plus curing agent was injected aseptically into the axilla of the right forelimb of the mouse, and the resin quickly solidified into a hard mass (5-20 minutes). After a certain period of time, the mice were sacrificed by pulling their necks, the tissue of the implantation site was rapidly removed and fixed with 10% formalin. The sample is taken as a coronal section, the resin and the surrounding tissues are cut off together, the resin and the surrounding tissues are embedded by paraffin, the resin and the surrounding tissues are cut into slices by a microtome, hematoxylin-eosin (HE) staining is carried out, the inflammatory reaction of the tissues in the implantation area is observed under a microscope, and the reaction characteristics of the acute and chronic stages are described. Histology photographs, Kodak2000 color film, were taken using an OlympusBH2 camera. On day 10 of the subacute phase, the resin induced inflammatory response was observed to be less under a microscope (fig. 3). A small amount of neutrophil infiltration occurs around the resin, accompanied by necrotic features such as shrinkage and fragmentation of the core, and bleeding and edema have gradually subsided and are only seen in a few areas. The above reaction is caused by the polyatomic acid-poly (maleic anhydride-ethylene glycol) (PDDDA-P (MA-GLY)) resin material, which is lighter than gelatin sponge.
Claims (4)
1. An injectable drug sustained release carrier is characterized in that the carrier is prepared by polyanhydride-unsaturated polyester block polymer, curing agent and curing accelerator;
the structural formula of the polyanhydride-unsaturated polyester block polymer is as follows:
wherein x is 2-4, y is 8-14, m is the mole number of the chain link of the butenedioic acid-diol ester anhydride or the mole number of the chain link of the fumaric acid-diol ester, n is the mole number of the chain link of the saturated dicarboxylic acid-diol ester, and m/n is 1/5-5/1.
2. The process for preparing an injectable sustained-release carrier of a drug according to claim 1, which comprises the following steps:
① respectively mixing acetic anhydride with one of the following seven dibasic acids, sebacic acid, undecanedioic acid, dodecanedioic acid, tridecanedioic acid, tetradecanedioic acid, pentadecanedioic acid, and hexadecanedioic acid at a molar ratio of 1: 2-5, respectively placing in a container protected by nitrogen, refluxing at 140-;
② mixing maleic anhydride or fumaric acid with dihydric alcohol according to the mol ratio of 1: 1.1, loading into a polymerization tube, placing into a silicon oil bath, electromagnetically stirring, heating to 170-200 ℃ for reaction for 1.5 hours, cooling to 80 ℃, vacuum-reducing to 30-50Pa, pumping away water, heating to 170 ℃ after 0.5 hour, melting and polymerizing for 1.0 hour, introducing nitrogen for 10-20 seconds every 5-20 minutes, vacuumizing, after polymerization, cooling to obtain unsaturated polyester oligomer with certain viscosity, wherein the synthetic route is shown as the following formula:
wherein x is 2-4, and n is the mole number of fumaric acid;
③ homopolymerizing any one of the seven kinds of dibasic acid anhydrides prepared in step ① by putting a certain amount of dibasic acid anhydride into a polymerization tube, putting the polymerization tube into a silicon oil bath, electromagnetically stirring, reacting, heating to 160-200 ℃, vacuum-reducing to 30-70 Pa, performing melt polymerization for 20-50 minutes, introducing nitrogen for 10-20 seconds every 5-10 minutes, vacuumizing, stopping polymerization after 30 minutes, cooling to obtain a light yellow solid product, dissolving the light yellow solid product with dichloromethane, filtering, precipitating with petroleum ether or cyclohexane, precipitating, filtering, washing with one of anhydrous ether, methyl ethyl ether and tetrahydrofuran, and drying to obtain light yellow seven kinds of homopolymer oligomers of the dibasic acid anhydride, or putting the two kinds of dibasic acid anhydrides into the polymerization tube according to the molar ratio of m/n being 1/5-5/1, and copolymerizing under the same reaction conditions as the homopolymer to obtain the corresponding oligomer copolymer oligomers of the polybasic acid anhydride;
④ mixing synthesized polyanhydride and unsaturated polyester oligomer in the mass ratio of 1/5-5/1, placing the mixture into a polymerization tube, placing the mixture into a silicon oil bath, electromagnetically stirring, reacting, heating to 170-200 ℃ for 1.5 hours, introducing nitrogen every 5 minutes for 10-20 seconds, vacuumizing, stopping polymerization after 30 minutes, cooling to 80 ℃, adding 5-30% by mass of one of the following diluting crosslinking agents, namely dimer acid, oleic acid, N-vinyl pyrrolidone, isodecyl acrylate and 2-ethylhexyl acrylate, cooling to obtain the corresponding viscous liquid anhydride-unsaturated polyester block polymer, wherein the structural formula is as follows:
⑤ the liquid resin is mixed with 0.3-1.0 wt% of one of the following curing agents, methyl ethyl ketone peroxide and benzoyl peroxide, 0.1-0.4 wt% of one of the following curing accelerators, cobalt naphthenate or triethanolamine, and 5-30 wt% of one of the following crosslinking agents, dimer acid, oleic acid, N-vinyl pyrrolidone, isodecyl acrylate and 2-ethylhexyl acrylate, and the mixture is stirred and mixed uniformly in a container and filled into an injector, and the injection can be carried out on the focus.
3. The method for preparing an injectable sustained release carrier of claim 2, wherein the fumaric acid in the reacting step ② is replaced by maleic anhydride.
4. The injectable drug delivery vehicle of claim 1 wherein the polyanhydride-unsaturated polyester block polymer is used to prepare a directly injectable, in vivo setting drug delivery material.
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