CN104606143B - Drug sustained-release type polyester drug loaded nanoparticle and preparation method thereof - Google Patents

Abstract

The invention discloses a sustained and controlled release type polyester drug-loaded nanoparticle and a preparation method thereof, which belong to the technical field of biomedical polymer materials and medicaments, and are used to solve the problems of the existing drug-loaded microspheres with relatively large particle size and particle size Uneven distribution and drug release cannot be effectively controlled. The drug sustained and controlled release polyester drug-loaded nanoparticles described in the present invention are composed of a biodegradable polyester molecular network structure and drugs embedded in it, and the particle size is 50~ 1000nm, the drug load is 0.5-28% (wt%); it adopts aliphatic dihydric alcohol and aliphatic dibasic acid or acid anhydride to prepare unsaturated polyester, and achieves drug encapsulation through radiation crosslinking. The particle size of the drug-loaded nanoparticles of the present invention is small and uniform, and has good fluidity in blood vessels. The drug is embedded in the polyester nanoparticles, which can be better protected, with good slow-controlled release effect and stable drug stability. High, high utilization rate.

Description

A drug sustained and controlled release polyester drug-loaded nanoparticles and preparation method thereof

technical field

The invention relates to the technical field of biomedical polymer materials and medicaments, in particular to a sustained and controlled drug-loaded drug-loaded nanoparticle made of biodegradable polyester molecules through radiation crosslinking and a preparation method thereof.

Background technique

Drug carrier nanoparticles are an important high-end drug sustained and controlled release preparation. The high-end drug slow and controlled release preparation can maintain the regular and quantitative release of the drug, reduce the number of times of taking, reduce the toxicity and side effects, avoid the "peak and valley" fluctuation of the blood drug concentration caused by the frequent administration of common preparations, and improve the safety of the drug , efficacy, and patient compliance.

Usually, degradable natural polymers and synthetic polymers are the main raw materials for the preparation of drug sustained and controlled release drug carriers. Natural polymers mainly include polysaccharides (such as chitosan, cyclodextrin), proteins (such as collagen, albumin, etc.); synthetic polymers mainly include aliphatic polyesters, polyanhydrides, amino acid polymers, polyphosphoric acid ester, polyphosphazene, polycarbonate, etc. Due to the differences in sources and processing methods of natural polymer materials, it is easy to cause defects such as poor performance reproducibility, poor mechanical properties and processing properties, and it is difficult to meet the requirements of medical applications. In contrast, synthetic polymer materials can make up for the shortcomings of natural polymer materials, and have the following advantages, such as less dependence on drug properties, good biocompatibility, more stable drug release rate, and To maintain a constant drug release rate, etc., at present, degradable synthetic polymer materials have become the main drug carrier materials for drug controlled release systems.

Invention patent ZL200810051452.7 "Biodegradable polyester drug-loaded microspheres of peroxidase mimics and its preparation method", using polylactic acid (PLA) or polylactic acid-glycolic acid (PLGA) as the coating material, obtained The drug-loaded microsphere with a drug encapsulation rate exceeding 90% has a drug-loaded amount of 0.5%-13% (wt%). The particle size of the drug-loaded microspheres prepared in this patent is 10-35 μm. The microspheres are too large to flow easily in blood vessels, and the quantitative release of drugs is difficult to control, which limits its drug loading and application range.

Invention patent ZL200710055413.X "A biodegradable fluorouracil polyester drug-loaded nanosphere and its preparation method" introduces a biodegradable fluorouracil (FU) polyester drug-loaded nanosphere and its preparation method. The covering material is polylactic acid, polylactic acid-glycolic acid, polylactic acid-polyethylene glycol block copolymer or polylactic acid-glycolic acid-polyethylene glycol block copolymer. Invention patent ZL200410013340.4 "Injectable Drug Sustained Release Carrier and Its Preparation Method" adopts high vacuum melt polymerization method to synthesize dibasic fatty acid, unsaturated dibasic acid or dibasic acid anhydride and diol into liquid unsaturated poly Ester resin, the liquid unsaturated polyester is a carrier material with slow-release properties for hydrophilic drugs. A variety of curing agents, curing accelerators and cross-linking agents are added during the drug loading process to realize the drug polyester The rapid curing reaction after the carrier enters the human body, the preparation process is more complicated, and the biocompatibility between curing agents such as benzoyl peroxide and curing accelerators and the human body is poor.

Invention patent ZL200510101591.2 "Preparation method of fat-soluble drug nanoparticles", the fat-soluble drug is completely dissolved in an organic solvent, and then non-ionic surfactant is added to make the drug microemulsified, and the granules are obtained by freeze-drying or vacuum distillation. Drug particles with a diameter of 30-60 nanometers, but the drug particles are not added with carrier materials to control the quantitative release of drugs, so the release of drugs cannot be effectively controlled.

Contents of the invention

In order to solve the above problems, the present invention provides a sustained and controlled release polyester drug-loaded nanoparticle with uniform particle size, capable of timing and quantitative release of drugs and a preparation method thereof.

The drug sustained and controlled release polyester drug-loaded nanoparticle of the present invention is composed of a biodegradable polyester molecular network structure and a drug embedded therein, and the biodegradable polyester molecule is cross-linked by radiation to form a network The structure is used for encapsulating medicine, the particle size of the nanoparticle is 50-1000nm, the drug loading is 0.5-28% (wt%), and the particle size of the nanoparticle is preferably 100-800nm.

The preparation method of drug sustained and controlled release type polyester drug-loaded nanoparticles of the present invention comprises the following steps:

(1) Synthesis of aliphatic unsaturated polyester

Mix component a and component b at a molar ratio of 0.95-1.2:1.0, stir and heat up to 160-180°C, and perform esterification reaction under nitrogen protection for 1-3 hours to obtain a polyester prepolymer, and then add the above-mentioned components The total mass of component a and component b is 0.01-1% of catalyst and 0.02-0.4% of polymerization inhibitor, and the temperature is raised to 180-220°C in the pressure range of 1 atmosphere to 1000Pa, and the reaction is 2-4 hours to obtain fat aliphatic unsaturated polyester; add the radiation sensitizer of 0-8% of the total mass of the above components a and b to the aliphatic unsaturated polyester prepared above, and stir evenly to obtain a paste-like aliphatic unsaturated polyester Saturated polyester/radiation sensitizer mixture;

Component a used in the above polyester synthesis is aliphatic dihydric alcohol, and component b is aliphatic dibasic acid or acid anhydride.

(2) Preparation of drug-loaded unsaturated polyester emulsion

①According to the mass ratio of 1:0.05～1.2, weigh the unsaturated polyester/radiation sensitizer mixture and drug respectively, and dissolve them in dichloromethane until the oil phase system is completely dissolved;

② Prepare an aqueous solution of polyvinyl alcohol with a concentration of 0.01g/ml to 0.1g/ml. The specific operation is to stir at 30 to 95°C for 2 to 7 hours until it is completely dissolved in the water phase. The polyvinyl alcohol is preferably analytically pure. The number average molecular weight is 1750±50;

③Slowly add the oil phase system prepared by ① into the mixed water phase prepared by ②, and perform ultrasonic or homogenization treatment. The treatment time is 0-20 minutes to form an oil-in-water emulsion, which is heated in a water bath at 30-50°C until the dichloromethane is completely volatilized to form a drug-loaded unsaturated polyester emulsion; The volume ratio of the phase system is 1:5-50.

(3) Radiation crosslinking and drug re-encapsulation of drug-loaded polyester emulsion

The drug-loaded unsaturated polyester emulsion prepared in the above step (2) is irradiated and cross-linked by gamma rays or high-energy electron beams to realize the cross-linking between the drug-loaded polyester molecules and the re-encapsulation of the drug; the radiation dose range 5 to 300 kGy; preferably 20 to 200 kGy. Then spray-dry the drug-loaded polyester emulsion after radiation crosslinking to prepare drug-loaded polyester nanoparticles.

Preferably, the number-average molecular weight of the aliphatic unsaturated polyester synthesized in step (1) is 1,000-12,000, and the weight-average molecular weight is 3,000-50,000.

Preferably, in step (1), component a is selected from one or more of 1,2-propanediol, 1,4-butanediol, 2,3-butanediol or 1,10-decanediol Mixture, the mixture can be mixed in any proportion.

Preferably, component b in step (1) is an aliphatic unsaturated dibasic acid or anhydride; or a mixture of an aliphatic unsaturated dibasic acid or anhydride, and an aliphatic saturated dibasic acid or anhydride, wherein the aliphatic The group unsaturated dibasic acid or acid anhydride accounts for 10%-60% of the total molar weight of the mixture.

Preferably, the aliphatic unsaturated dibasic acid is one or both of itaconic acid and fumaric acid, and the aliphatic unsaturated dibasic acid anhydride is one or both of itaconic anhydride and fumaric anhydride. Two kinds; the aliphatic saturated dibasic acid is a mixture of one or more of succinic acid, sebacic acid and adipic acid; the aliphatic saturated dibasic anhydride is succinic anhydride, adipic anhydride one or both.

Preferably, the catalyst in step (1) is selected from one or both of tetrabutyl titanate and p-toluenesulfonic acid.

Preferably, in the step (1), the polymerization inhibitor is selected from one or both of p-hydroxyanisole, hydroquinone, and o-methylhydroquinone.

In step (1), the radiation sensitizer is selected from one or more combinations of trifunctional sensitizers or tetrafunctional sensitizers. The trifunctional group sensitizer is one or both of trihydroxymethylpropane tri(meth)acrylate or pentaerythritol tri(meth)acrylate, and the four functional group radiation sensitizer is pentaerythritol tetrakis(meth)acrylate One or both of ethoxylated pentaerythritol tetra(meth)acrylate or ethoxylated pentaerythritol tetra(meth)acrylate.

Preferably, the drug is a drug that does not change its molecular structure during the radiation process, such as nisoldipine, indapamide, phenylpropridine; sulfonylurea hypoglycemic drugs or antineoplastic drugs such as paclitaxel, Semustine, etc.

Compared with prior art, the beneficial effect of the present invention is:

(1) The particle size of the prepared drug-loaded nanoparticles is at the nanometer level, the particle size is small and uniform, and the fluidity in the blood vessel is good. The drug is embedded in the polyester nanoparticle, which can be better protected and the drug is stable. Good performance and high utilization rate;

(2) The drug carrier of the prepared drug sustained and controlled release polyester drug-loaded nanoparticles is a biodegradable polyester, which is a degradable material in the body, and its degradation products are either excreted from the body or participate in life. Body metabolism, low side effects on the human body;

(3) The drug coating process is clean, energy-saving, pollution-free, and safe for human organs;

(4) The formation of drug-loaded polyester macromolecular cross-linked network and the re-encapsulation of drugs can be realized through radiation cross-linking technology. By controlling the cross-linking density of drug-loaded polyester, the degradation performance of drug-loaded polyester can be controlled. Control the release rate of the drug and improve the stability of the drug release.

detailed description

Below in conjunction with embodiment the present invention is further explained.

Example 1

A preparation method of drug sustained and controlled release polyester drug-loaded nanoparticles, comprising the steps of:

(1) Synthesis of aliphatic unsaturated polyester

Mix component a (0.50 mol of 1,4-butanediol) and component b (0.35 mol of adipic acid and 0.15 mol of itaconic acid), stir and heat up to 180°C, and esterify under nitrogen protection React for 1.5 hours to obtain a polyester prepolymer, then add 0.8% (0.926g) of catalyst tetrabutyl titanate and 0.2% (0.231g) of the polymerization inhibitor o-methyl of the above-mentioned component a and component b Hydroquinone was heated up to 200° C. in the range of reduced pressure to 1500 Pa, and reacted for 2 hours to obtain an aliphatic unsaturated polyester with a number average molecular weight of 2900, a weight average molecular weight of 7800, and a polydispersity coefficient of 2.69; Add the radiation sensitizer pentaerythritol tetramethacrylate of 8% (9.26g) of the total mass of the above components a and b to the aliphatic unsaturated polyester prepared above, and stir evenly to obtain a creamy fat Polymer unsaturated polyester/radiation sensitizer blend.

(2) Preparation of drug-loaded unsaturated polyester emulsion

①Weigh 1g of the aliphatic unsaturated polyester/radiation sensitizer mixture prepared in step (1) and 0.2g of indapamide, place it in a water bath container at 25°C, then add 10ml of dichloromethane, stir magnetically for 1 Hour, treat it to dissolve completely, make oily phase;

② Weigh 5g of polyvinyl alcohol and dissolve it in 500ml of water, place it in a water bath container at 70°C, stir for 5 hours, and wait for it to completely dissolve to obtain the water phase;

③Slowly add the oil phase prepared in ① into the water phase prepared in ②, homogenize at 10000r/min for 10min, then heat and stir at 40°C for 4 hours until the dichloromethane is completely volatilized, and the drug-loaded unsaturated Polyester emulsion.

(3) Radiation crosslinking and drug re-encapsulation of drug-loaded polyester emulsion

The drug-loaded unsaturated polyester emulsion prepared in step (2) is cross-linked by γ-ray irradiation, and the radiation dose is 25 kGy, so as to realize the network of polyester molecules and the re-encapsulation of the drug.

Then the irradiated drug-loaded polyester emulsion is spray-dried, and the process parameters are as follows: the inlet temperature of the spray dryer is 160° C., the outlet temperature is 55° C.; the spray pressure is 0.3 MPa. The drug-loaded polyester particles with a drug loading of 7.8% and an average particle size of 145nm were prepared, and the in vitro release test was carried out in a phosphate buffer solution with a pH of 7.4 at 37°C, and the release medium was detected by high performance liquid chromatography (HPLC). The sustained-release time was measured to be 9 days, wherein about 15% of the loaded drug amount was released on the first day, and then began to release at a uniform rate, and the final cumulative release amount was about 98%.

Example 2

A preparation method of drug sustained and controlled release polyester drug-loaded nanoparticles, comprising the steps of:

(1) Synthesis of aliphatic unsaturated polyester

Mix component a (0.55 mol of 2,3-butanediol) and component b (0.4 mol of 1,4-butanedioic acid, 0.1 mol of fumaric acid), stir and raise the temperature to 175°C, under nitrogen protection Esterification under state for 1.5 hours, obtain polyester prepolymer, then add the catalyst p-toluenesulfonic acid of above-mentioned component a and component b gross mass 0.5% (0.522g), the polymerization inhibitor of 0.1% (0.104g) O-methylhydroquinone, in the pressure range of decompression to 1000Pa, the temperature is raised to 200°C, and the reaction is carried out for 3 hours to obtain an aliphatic unsaturated polyphenol with a number average molecular weight of 7600, a weight average molecular weight of 26300, and a polydispersity coefficient of 3.46. Polyester; add the radiation sensitizer trimethylolpropane triacrylate of above-mentioned component a and component b gross mass 6% (6.26g) in the aliphatic unsaturated polyester that above-mentioned makes, stir evenly, prepare An aliphatic unsaturated polyester/radiation sensitizer mixture is obtained in the form of a paste.

(2) Preparation of drug-loaded unsaturated polyester emulsion

① Take 1g of the aliphatic unsaturated polyester/radiation sensitizer mixture prepared in step (1) and 0.5g of sulfonylurea hypoglycemic drug, put them in a water bath container at 30°C, then add 10ml of dichloromethane, magnetically Stir for 0.5 hours, until it is completely dissolved to obtain an oil phase;

② Weigh 5g of polyvinyl alcohol and dissolve it in 100ml of water, place it in a water bath container at 85°C, stir for 5 hours, and wait until it is completely dissolved to obtain the water phase;

③Slowly add the oil phase prepared in ① into the water phase prepared in ②, homogenize at a speed of 5000r/min for 10min, then heat and stir at 45°C for 4.5 hours until the dichloromethane is completely volatilized, and the drug-loaded unsaturated Polyester emulsion.

(3) Radiation crosslinking and drug re-encapsulation of drug-loaded polyester emulsion

The drug-loaded unsaturated polyester emulsion prepared in step (2) is cross-linked by γ-ray irradiation, and the radiation dose is 100 kGy, so as to realize the network of polyester molecules and the re-encapsulation of the drug.

Then the irradiated drug-loaded polyester emulsion is spray-dried, and the process parameters are as follows: the inlet temperature of the spray dryer is 160° C., the outlet temperature is 55° C.; the spray pressure is 0.3 MPa. The prepared drug-loaded polyester nanoparticles with a drug loading of 21.3% and an average particle size of 571nm were released in vitro in a phosphate buffer solution with a pH of 7.4 at 37°C. The drug content in the release medium was detected by HPLC. The sustained-release time is 28 days, in which about 5% of the loaded drug is released on the first day, and then begins to be released at a uniform speed, and the final cumulative release is about 94%.

Example 3

A preparation method of drug sustained and controlled release polyester drug-loaded nanoparticles, comprising the steps of:

(1) Synthesis of aliphatic unsaturated polyester

Mix component a (0.6 mol of 1,10-decanediol) and component b (0.3 mol of 1,4-succinic anhydride, 0.2 mol of fumaric anhydride), stir and raise the temperature to 170°C, under nitrogen protection Under the condition of esterification reaction for 2 hours, polyester prepolymer was obtained, and then the catalyst tetrabutyl titanate of 1% (1.602g) of the total mass of above-mentioned component a and component b, 0.4% (0.641g) of polymerization inhibitor Add hydroquinone, heat up to 220°C in the pressure range of decompression to 1000Pa, and react for 2.5 hours to obtain an aliphatic unsaturated polyester with a number average molecular weight of 12000, a weight average molecular weight of 48200 and a polydispersity coefficient of 4.02 be cooled to 150°C, add the radiation sensitizer trimethylolpropane triacrylate of the above-mentioned component a and component b gross mass 4% (5.13g) in the above-mentioned aliphatic unsaturated polyester obtained, stir Homogeneous, after cooling, a paste-like aliphatic unsaturated polyester/radiation sensitizer mixture is obtained.

(2) Preparation of drug-loaded unsaturated polyester emulsion

①Weigh 1g of the aliphatic unsaturated polyester/radiation sensitizer mixture and 1.2g of paclitaxel prepared in step (1), place them in a water bath container at 30°C, then add 20ml of dichloromethane, stir magnetically for 45min, and wait for Completely dissolved to obtain an oil phase;

② Weigh 2.5g of polyvinyl alcohol and dissolve it in 500ml of water, place it in a water bath container at 60°C, stir for 3 hours, and wait until it is completely dissolved to obtain the water phase;

③Slowly add the oil phase prepared in step ① into the water phase prepared in step ②, adjust the ultrasonic frequency to 28kHz, ultrasonic for 10min, then heat and stir at 45°C for 4.5 hours until the dichloromethane is completely volatilized, and the drug-loaded Do not mix with polyester emulsions.

(3) Radiation crosslinking and drug re-encapsulation of drug-loaded polyester emulsion

The drug-loaded unsaturated polyester emulsion prepared in step (2) is cross-linked by γ-ray irradiation, and the radiation dose is 50 kGy, so as to realize polyester molecular network and re-encapsulation of drugs.

Then the irradiated drug-loaded polyester emulsion is spray-dried, and the process parameters are as follows: the inlet temperature of the spray dryer is 180° C., the outlet temperature is 60° C.; the spray pressure is 0.2 MPa. The drug-loaded polyester particles with a drug loading of 26.8% and an average particle size of 784nm were prepared. The in vitro release test was carried out in a phosphate buffer solution with a pH of 7.4 at 37°C. The drug content in the release medium was detected by HPLC. Its sustained release time is 31 days, in which about 5% of the loaded drug is released on the first day, and then begins to release at a constant speed, and the final cumulative release is about 95%.

Example 4

A preparation method of drug sustained and controlled release polyester drug-loaded nanoparticles, comprising the steps of:

(1) Synthesis of aliphatic unsaturated polyester

Mix component a (0.475mol of 1,2-propanediol), component b (0.3mol of succinic acid and 0.2mol of itaconic acid) (a:b=0.95:1), stir and heat up to 160°C, The esterification reaction was carried out for 3 hours under the protection of nitrogen to obtain the polyester prepolymer, and then the catalyst p-toluenesulfonic acid of 0.3% (0.293g) of the total mass of component a and component b, 0.2% (0.195g) of hindered Polymerization agent hydroquinone, in the pressure range of decompression to 1000Pa, heat up to 200 ℃, react for 2 hours, and prepare aliphatic unsaturated polystyrene with number average molecular weight of 1800, weight average molecular weight of 3700 and polydispersity coefficient of 2.06. Esters; add the radiation sensitizer pentaerythritol tetramethacrylate of component a and component b total mass 2% (1.8g) to the above-mentioned aliphatic unsaturated polyester, stir evenly, obtain paste Aliphatic unsaturated polyester/radiation sensitizer blend.

(2) Preparation of drug-loaded unsaturated polyester emulsion

①Weigh 1g of the aliphatic unsaturated polyester/radiation sensitizer mixture prepared in step (1) and 0.05g of nisoldipine, place it in a water bath container at 25°C, then add 10ml of dichloromethane, and stir magnetically for 1 hour , and wait until it is completely dissolved to obtain an oil phase.

② Weigh 5g of polyvinyl alcohol and dissolve it in 500ml of water, place it in a water bath container at 80°C, stir for 4 hours, and wait for it to completely dissolve to obtain the water phase.

③Slowly add the oil phase prepared in ① into the water phase prepared in ②, wherein the volume ratio of the oil phase and the water phase satisfies the oil phase:water phase=1:50, homogenize at 18000r/min for 10min, and then Heating and stirring at 35° C. for 5 hours until the dichloromethane is completely volatilized to prepare a drug-loaded unsaturated polyester emulsion.

(3) Radiation crosslinking and drug re-encapsulation of drug-loaded polyester emulsion

The drug-loaded unsaturated polyester emulsion prepared in step (2) is cross-linked by gamma-ray irradiation, and the radiation dose is 25 kGy, so as to realize the network of polyester molecules and the re-encapsulation of drugs.

Then the irradiated drug-loaded polyester emulsion is spray-dried, and the process parameters are as follows: the inlet temperature of the spray dryer is 150° C. and the outlet temperature is 50° C.; the spray pressure is 0.4 MPa. The prepared drug-loaded polyester particles with a drug loading of 1.6% and an average particle size of 126nm were subjected to in vitro release experiments in a phosphate buffer solution with a pH of 7.4 at 37°C, and the drug content in the release medium was detected by HPLC. Its sustained-release time is 5 days, in which about 25% of the loaded drug is released on the first day, and then it begins to release at a constant speed, and the final cumulative release is about 98%.

Example 5

A preparation method of drug sustained and controlled release polyester drug-loaded nanoparticles, comprising the steps of:

(1) Synthesis of aliphatic unsaturated polyester

Mix component a (0.25mol of 1,2-propanediol, 0.25mol of 1,4-butanediol) and component b (0.35mol of adipic anhydride, and 0.15mol of fumaric acid), stir and heat up to 160 DEG C, under nitrogen protection state, esterification reaction is carried out for 3 hours, obtains polyester prepolymer, then adds above-mentioned component a and component b gross mass 0.4% (0.816g) catalyst tetrabutyl titanate, 0.2% ( 0.408g) inhibitor: hydroquinone (0.204g) and o-methylhydroquinone (0.204g), in the pressure range of decompression to 1000Pa, the temperature is raised to 200 ℃, reacted for 3 hours, and obtained several The average molecular weight is 5700, the weight average molecular weight is 13000, the polydispersity coefficient is the aliphatic unsaturated polyester of 2.28; Add above-mentioned component a and component b total mass 8% ( 16.3 g) of radiation sensitizer: 8.15 g of pentaerythritol tetramethacrylate and 8.15 g of trimethylolpropane triacrylate, stirred evenly to obtain a paste-like aliphatic unsaturated polyester/radiation sensitizer mixture.

(2) Preparation of drug-loaded unsaturated polyester emulsion

①Weigh 2g of the aliphatic unsaturated polyester/radiation sensitizer mixture prepared in step (1) and 0.35g of semustine, place it in a water bath container at 30°C, then add 20ml of dichloromethane, and stir magnetically for 45min , when it is completely dissolved, the oil phase is obtained;

② Weigh 5g of polyvinyl alcohol and dissolve it in 100ml of water, place it in a water bath container at 85°C, stir for 5 hours, and wait until it is completely dissolved to obtain the water phase;

③Slowly add the oil phase prepared in step ① into the water phase prepared in step ②, adjust the ultrasonic frequency to 40kHz, ultrasonic for 10min, then heat and stir at 45°C for 4.5 hours until the dichloromethane is completely volatilized, and the drug-loaded Unsaturated polyester emulsion.

(3) Radiation crosslinking and drug re-encapsulation of drug-loaded polyester emulsion

The drug-loaded unsaturated polyester emulsion prepared in step (2) is cross-linked by γ-ray irradiation, and the radiation dose is 50 kGy, so as to realize polyester molecular network and re-encapsulation of drugs.

Then the irradiated drug-loaded polyester emulsion is spray-dried, and the process parameters are as follows: the inlet temperature of the spray dryer is 150° C., the outlet temperature is 50° C.; the spray pressure is 0.4 MPa. The drug-loaded polyester particles with a drug loading of 10.5% and a particle size of 363nm were prepared. The in vitro release test was carried out in a phosphate buffer solution with a pH of 7.4 at 37°C. The drug content in the release medium was detected by HPLC, and its The sustained release time is 23 days, in which about 7% of the loaded drug is released on the first day, and then begins to release at a constant speed, and the final cumulative release is about 96%.

Example 6

A preparation method of drug sustained and controlled release polyester drug-loaded nanoparticles, comprising the steps of:

(1) Synthesis of aliphatic unsaturated polyester

Mix component a (0.5 mol of 1,2-propanediol) and component b (0.2 mol of sebacic acid, 0.3 mol of itaconic acid), stir and heat up to 160°C, and perform esterification reaction under nitrogen protection for 2.5 Hour, obtain polyester prepolymer, then add the catalyzer p-toluenesulfonic acid of above-mentioned component a and component b gross mass 0.3% (0.353g), the polymerization inhibitor p-hydroxyanisole of 0.2% (0.235g), The temperature was raised to 180° C. under the pressure range of decompression to 1000 Pa, and reacted for 3 hours to obtain an aliphatic unsaturated polyester with a number average molecular weight of 3200, a weight average molecular weight of 6800 and a polydispersity coefficient of 2.13.

(2) Preparation of drug-loaded unsaturated polyester emulsion

① Weigh 1g of unsaturated polyester and 0.1g of paclitaxel prepared in step (1), put them in a water bath container at 30°C, then add 10ml of dichloromethane, stir for 1 hour, and wait until they are completely dissolved to obtain the oil phase ;

② Weigh 5g of polyvinyl alcohol and dissolve it in 200ml of water, place it in a water bath container at 80°C, stir for 5 hours, and wait until it is completely dissolved to obtain the water phase;

③Slowly add the oil phase prepared in step ① into the water phase prepared in step ②, homogenize at 15000r/min for 10min, then heat and stir at 40°C for 4 hours until the dichloromethane is completely volatilized to obtain the drug-loaded Unsaturated polyester emulsion.

(3) Radiation crosslinking and drug re-encapsulation of drug-loaded polyester emulsion

The drug-loaded polyester emulsion prepared in step (2) is cross-linked by γ-ray irradiation, and the radiation dose is 50 kGy, so as to realize the network of polyester molecules and the re-encapsulation of drugs.

Then the irradiated drug-loaded polyester emulsion is spray-dried, and the process parameters are as follows: the inlet temperature of the spray dryer is 165° C., the outlet temperature is 55° C.; the spray pressure is 0.3 MPa. The prepared drug-loaded polyester particles with a drug loading of 4.8% and an average particle size of 215nm were released in vitro in a phosphate buffer solution with a pH of 7.4 at 37°C, and were detected by high performance liquid chromatography (HPLC). The sustained-release time was measured to be 20 days, wherein about 8% of the loaded drug amount was released on the first day, and then began to release at a uniform rate, and the final cumulative release amount was about 96%.

Claims (10)

1. A preparation method of drug sustained and controlled release polyester drug-loaded nanoparticles, characterized in that, comprising the following steps: (1) Synthesis of aliphatic unsaturated polyester Mix component a and component b at a molar ratio of 0.95-1.2:1.0, stir and heat up to 160-180°C, and perform esterification reaction under nitrogen protection for 1-3 hours to obtain a polyester prepolymer, and then add the above-mentioned components The total mass of component a and component b is 0.01-1% of catalyst and 0.02-0.4% of polymerization inhibitor, and the temperature is raised to 180-220°C in the pressure range of 1 atmosphere to 1000Pa, and the reaction is 2-4 hours to obtain fat aliphatic unsaturated polyester; add a radiation sensitizer of 0-8% of the total mass of component a and component b to the aliphatic unsaturated polyester prepared above, and stir evenly to obtain a paste-like aliphatic unsaturated polyester Polyester/radiation sensitizer blends; Component a used in the above-mentioned polyester synthesis is an aliphatic dibasic alcohol, and component b is an aliphatic dibasic acid or an anhydride; (2) Preparation of drug-loaded unsaturated polyester emulsion ①According to the mass ratio of 1:0.05～1.2, weigh the aliphatic unsaturated polyester/radiation sensitizer mixture and the drug respectively, and dissolve them in dichloromethane to a completely dissolved oil phase system; ② Prepare a polyvinyl alcohol aqueous solution with a concentration of 0.01g/ml~0.1g/ml; ③Slowly add the oil phase system prepared by ① into the polyvinyl alcohol aqueous solution prepared by ②, ultrasonically or homogenize to form an oil-in-water emulsion; heat in a water bath at 30-50°C to completely volatilize the dichloromethane to form a The emulsion of drug-loaded unsaturated polyester micelles at the nanometer scale realizes the first encapsulation of drugs by polyester micelles. The volume ratio of the prepared oil phase system to the prepared polyvinyl alcohol aqueous phase system is 1:5 ~50; (3) Radiation crosslinking and drug re-encapsulation of drug-loaded polyester emulsion The drug-loaded unsaturated polyester emulsion prepared in the above step (2) is irradiated and cross-linked by gamma rays or high-energy electron beams, and the radiation dose is 5 to 300 kGy, and then spray-dried to obtain polyester drug-loaded nanoparticles. The drug loading amount of the nanoparticles is 0.5-28%, and the diameter of the nanoparticles is 50-1000nm. 2. The preparation method of drug sustained and controlled release polyester drug-loaded nanoparticles according to claim 1, characterized in that the number average molecular weight of the aliphatic unsaturated polyester prepared in step (1) is 1000～12000 , The weight average molecular weight is 3000～50000. 3. the preparation method of drug sustained and controlled release type polyester drug-loaded nanoparticles according to claim 1, is characterized in that, in step (1), component a is selected from 1,2-propanediol, 1,4-butanediol Alcohol, 2,3-butanediol or 1,10-decanediol or a mixture of one or more. 4. the preparation method of drug sustained and controlled release type polyester drug-loaded nanoparticles according to claim 1, is characterized in that, in step (1), component b is aliphatic unsaturated dibasic acid or acid anhydride; or aliphatic Mixture of unsaturated dibasic acid or anhydride, and aliphatic saturated dibasic acid or anhydride. 5. the preparation method of drug sustained and controlled release type polyester drug-loaded nanoparticles according to claim 4, is characterized in that, in described aliphatic unsaturated dibasic acid or acid anhydride, and aliphatic saturated dibasic acid or acid anhydride In the mixture, the aliphatic unsaturated dibasic acid or acid anhydride accounts for 10-60% of the total molar weight of the mixture. 6. The preparation method of the drug-slow and controlled-release polyester drug-loaded nanoparticles according to any one of claims 2 to 5, characterized in that: The aliphatic unsaturated dibasic acid is one or both of itaconic acid and fumaric acid; The aliphatic unsaturated dibasic acid anhydride is one or both of itaconic anhydride and fumaric anhydride; The aliphatic saturated dibasic acid is a mixture of one or more of succinic acid, sebacic acid and adipic acid; The aliphatic saturated dibasic acid anhydride is one or both of succinic anhydride and adipic anhydride. 7. The preparation method of drug sustained and controlled release polyester drug-loaded nanoparticles according to claim 6, characterized in that, the radiation sensitizer in step (1) is selected from three functional group sensitizers or four functional group sensitizers One or more compositions in the agent. 8. the preparation method of drug sustained and controlled release type polyester drug-loaded nanoparticles according to claim 7, is characterized in that, described trifunctional radiation sensitizer is trihydroxymethylpropane tri(meth)acrylate or One or both of pentaerythritol tri(meth)acrylates, and the four-functional radiation sensitizer is one or both of pentaerythritol tetra(meth)acrylates or ethoxylated pentaerythritol tetra(meth)acrylates kind. 9 . The method for preparing drug sustained and controlled release polyester drug-loaded nanoparticles according to claim 6 , wherein the drug is a drug whose molecular structure does not change during the radiation process. 10. A drug-sustained and controlled-release polyester drug-loaded nanoparticle prepared by the method according to any one of claims 1-9.