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CN-121371195-B - Polylactic acid based drug-loaded preparation and preparation method thereof

CN121371195BCN 121371195 BCN121371195 BCN 121371195BCN-121371195-B

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to a polylactic acid-based drug-loaded preparation and a preparation method thereof. The preparation method of the polylactic acid-based drug-carrying preparation comprises the following steps of (1) adding a polylactic acid-based carrier and thalictrum henryi alkali into deionized water to obtain a water phase, adding a hydrophobic drug into an organic solvent to obtain an oil phase, and (2) uniformly mixing the water phase and the oil phase, and then sequentially carrying out dialysis, ultrasonic treatment, filtration and freeze drying to obtain the polylactic acid-based drug-carrying preparation. The polylactic acid-based drug-loaded preparation can intelligently respond to release effective load, and release a large amount of hydrophobic drugs in a short time after reaching tumor tissues, so that the therapeutic effect is exerted.

Inventors

  • WANG XIAOGUANG
  • JIN XIN
  • ZHANG XINYAN
  • JIANG HAITAO
  • PENG JIANHUA
  • ZHAO QIUSHENG
  • YIN XUELIANG
  • CHEN JINYUE
  • YANG MO
  • LI SHUANG
  • CHEN JIANYU

Assignees

  • 哈药集团技术中心
  • 哈药集团股份有限公司

Dates

Publication Date
20260512
Application Date
20251225

Claims (9)

  1. 1. The preparation method of the polylactic acid-based drug-loaded preparation is characterized by comprising the following steps: (1) Adding the polylactic acid-based carrier and the thalictrum henryi alkali into deionized water to obtain a water phase, and adding the hydrophobic drug into an organic solvent to obtain an oil phase; (2) Mixing the aqueous phase with the oil phase, uniformly stirring, and sequentially carrying out dialysis, ultrasonic treatment, filtration and freeze drying to obtain the polylactic acid based drug-carrying preparation; The polylactic acid-based carrier has the following structural formula: ; the preparation method of the polylactic acid-based carrier comprises the following steps: Adding modified polylactic acid into a dichloromethane/methanol solution, adding modified polyethylene glycol for 3-5 times, stirring for reaction in a dark place, adding an iodine methanol solution after the reaction is finished, and purifying to obtain the polylactic acid-based carrier; The structural formula of the modified polylactic acid is as follows: the structural formula of the modified polyethylene glycol is as follows: 。
  2. 2. The preparation method of the polylactic acid based drug-loaded preparation according to claim 1, wherein the mass ratio of the modified polylactic acid to the modified polyethylene glycol is 1 (0.8-1.5), the concentration of the iodine methanol solution is 0.03-0.05g/mL, the stirring reaction time is 10-12h, and the volume ratio of the dichloromethane to the methanol in the dichloromethane/methanol solution is 1:1.
  3. 3. The method for preparing the polylactic acid-based drug-loaded formulation according to claim 2, wherein the preparation process of the modified polylactic acid is as follows: adding polylactic acid, EDC hydrochloride, N-hydroxysuccinimide and triethylamine into dichloromethane, stirring for 3-5h at room temperature, then adding 3,3' -dithiobis (propionyl hydrazine), continuously stirring for reacting for 48-60h, and purifying after the reaction is finished to obtain the modified polylactic acid.
  4. 4. The method for preparing the polylactic acid-based drug-loaded preparation according to claim 3, wherein the mass ratio of polylactic acid, 3' -dithiobis (propionyl hydrazine), EDC hydrochloride, N-hydroxysuccinimide and triethylamine is 1 (0.036-0.072): (0.03-0.058): (0.018-0.035): (0.015-0.03), and the number average molecular weight of the polylactic acid is 10000.
  5. 5. The method for preparing the polylactic acid-based drug-carrying preparation according to claim 2, wherein the method for preparing the modified polyethylene glycol is as follows: s1, adding L-cysteine and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide into N, N-dimethylformamide, adding 4-dimethylaminopyridine, stirring for 0.5-1h, adding polyethylene glycol, reacting for 20-24h at 40-50 ℃, and purifying after the reaction is completed to obtain an intermediate 1; the structural formula of the intermediate 1 is as follows: ; S2, adding 5, 7-dodecane diacetic acid, EDC hydrochloride, N-hydroxysuccinimide and triethylamine into N, N-dimethylformamide, stirring for 0.5-1h at 45-50 ℃, then adding the intermediate 1, continuing stirring for reacting for 48-60h, and purifying after the reaction is finished to obtain the modified polyethylene glycol.
  6. 6. The preparation method of the polylactic acid based drug-loaded preparation according to claim 5, wherein the mass ratio of polyethylene glycol, L-cysteine, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide and 4-dimethylaminopyridine in the step S1 is 1 (0.02-0.03): 0.03-0.04): 0.02-0.03, and the dosage ratio of the intermediate 1, 5, 7-dodecanediynoic acid, EDC hydrochloride, N-hydroxysuccinimide and triethylamine in the step S2 is 1 (0.04-0.07): 0.03-0.06): 0.02-0.04): 0.02-0.03.
  7. 7. The preparation method of the polylactic acid-based drug-loaded preparation according to claim 1, wherein in the step (1), the mass ratio of polylactic acid-based carrier, thalictrum henryi alkali and hydrophobic drug is 100 (4-8): 12-15), the concentration of the polylactic acid-based carrier in a water phase is 5-10mg/mL, the concentration of the hydrophobic drug in an oil phase is 2-5mg/mL, the hydrophobic drug is selected from one of paclitaxel, docetaxel, anastrozole and letrozole, and the organic solvent is selected from one of methanol, ethanol, acetonitrile, acetone, dichloromethane and dimethyl sulfoxide.
  8. 8. The method for preparing a polylactic acid-based drug-loaded formulation according to claim 7, wherein the stirring time in the step (2) is 3-8 hours, the dialysis time is 24-48 hours, and the ultrasonic treatment time is 10-15 minutes.
  9. 9. A polylactic acid-based drug-carrying preparation, characterized by being prepared by the preparation method of any one of claims 1 to 8.

Description

Polylactic acid based drug-loaded preparation and preparation method thereof Technical Field The invention relates to the technical field of pharmaceutical preparations, in particular to a polylactic acid-based drug-loaded preparation and a preparation method thereof. Background Most anticancer/antitumor drugs (such as paclitaxel, camptothecine, etc.) have remarkable hydrophobicity, and poor water solubility severely limits clinical application. In recent years, a rapidly developed polymer micelle drug delivery system provides a new strategy for solving the solubility problem of hydrophobic drugs and realizing synergy and attenuation. The polymer micelle is formed by self-assembling an amphiphilic block copolymer or a graft copolymer under the action of non-covalent bonds, has a typical core-shell structure, and the hydrophobic inner core of the polymer micelle can be used as a reservoir of a hydrophobic drug, so that the drug solubility is effectively improved. Compared with the traditional preparation, the polymer micelle nano-drug has better pharmacokinetic property and good biocompatibility, and is easy to carry out multifunctional modification. Polylactic acid is a polyester polymer material polymerized by taking lactic acid as a raw material, has excellent biocompatibility, degradability and mechanical property, and is a common carrier material for constructing polymer micelle nano-preparations. However, since it is inherently hydrophobic, it is often necessary to introduce hydrophilic segments to improve the hydrophilicity of the material. Among them, polyethylene glycol monomethyl ether-polylactic acid (mPEG-PLA) block copolymers are most widely used. However, the polymer micelle based on mPEG-PLA still has some defects such as larger particle size, wider distribution, poor stability after redissolution, limited drug loading, lack of intelligent stimulus responsiveness and the like. Therefore, there is a great need for an improvement in polylactic acid-based carriers to solve the above-mentioned problems. Disclosure of Invention In order to overcome the defects of the prior art, one of the purposes of the invention is to provide a preparation method of a polylactic acid-based drug-carrying preparation, which is simple. The second object of the present invention is to provide a polylactic acid based drug-loaded formulation which can intelligently respond to release of a payload in a tumor-specific redox microenvironment and release of a large amount of hydrophobic drug in a short time after reaching tumor tissue, thereby exerting therapeutic effects. One of the purposes of the invention is realized by adopting the following technical scheme: A method for preparing a polylactic acid-based drug-carrying preparation, comprising the following steps: (1) Adding the polylactic acid-based carrier and the thalictrum henryi alkali into deionized water to obtain a water phase, and adding the hydrophobic drug into an organic solvent to obtain an oil phase; (2) Mixing the aqueous phase with the oil phase, uniformly stirring, and sequentially carrying out dialysis, ultrasonic treatment, filtration and freeze drying to obtain the polylactic acid based drug-carrying preparation; The polylactic acid-based carrier has the following structural formula: 。 Preferably, the preparation method of the polylactic acid-based carrier comprises the following steps: Adding modified polylactic acid into a dichloromethane/methanol solution, adding modified polyethylene glycol for 3-5 times to carry out light-shielding stirring reaction, adding an iodine methanol solution after the reaction is finished, and purifying to obtain the polylactic acid-based carrier; The structural formula of the modified polylactic acid is as follows: the structural formula of the modified polyethylene glycol is as follows: 。 Preferably, the mass ratio of the modified polylactic acid to the modified polyethylene glycol is 1 (0.8-1.5), the concentration of the methanol solution of iodine is 0.03-0.05g/mL, the stirring reaction time is 10-12h, and the volume ratio of the dichloromethane to the methanol in the dichloromethane/methanol solution is 1:1. Preferably, the preparation process of the modified polylactic acid is as follows: adding polylactic acid, EDC hydrochloride, N-hydroxysuccinimide and triethylamine into dichloromethane, stirring for 3-5h at room temperature, then adding 3,3' -dithiobis (propionyl hydrazine), continuously stirring for reacting for 48-60h, and purifying after the reaction is finished to obtain the modified polylactic acid. Preferably, the mass ratio of the polylactic acid to the 3,3' -dithiobis (propionyl hydrazine), EDC hydrochloride to the N-hydroxysuccinimide to the triethylamine is 1 (0.036-0.072): (0.03-0.058): (0.018-0.035): (0.015-0.03), and the number average molecular weight of the polylactic acid is 10000. Preferably, the preparation method of the modified polyethylene glycol comprises the following steps: s1, adding