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Preparation method of paliperidone sustained release microsphere injection

A technology of paliperidone and sustained-release microspheres, which is applied in the directions of non-active ingredient medical preparations, medical preparations containing active ingredients, and pharmaceutical formulas to achieve high drug loading, good sustained-release effect, and reduced dosage. The effect of the number of doses

Inactive Publication Date: 2015-09-30
HEILONGJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there is no structure modification and optimization of paliperidone in the prior art, and the PLA-acylated paliperidone biodegradable polymer has been synthesized to further prepare the technology of paliperidone sustained-release microspheres. It can be seen that, The method of the present invention is novel, and the method also has a very wide application prospect

Method used

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  • Preparation method of paliperidone sustained release microsphere injection
  • Preparation method of paliperidone sustained release microsphere injection

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Experimental program
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Effect test

Embodiment 1

[0038] The preparation of the first step reaction intermediate: add 42g paliperidone (0.1mol) and 84mL acetone and 336mL chloroform in the three-neck round bottom flask, add 30g succinic anhydride (0.3mol) therein under the condition of sufficient stirring ), 20mL (0.15mol) of triethylamine, the temperature is controlled at 65°C during the feeding process, after the feeding is completed, continue to stir and reflux at this temperature for 24h, after the reaction is completed, add 200mL of water to the reaction, fully stir, separate layers, and the organic layer anhydrous NaSO 4 After drying, the solvent was removed by rotary evaporation to obtain 45.4 g of a light orange solid. The purity of the product analyzed by high performance liquid chromatography (HPLC) was 95.3%, and the yield was 86.2%.

[0039]Preparation of the second-step reaction intermediate: dissolve 26g (95.3%, 0.05mol) of the first-step reaction intermediate in 200mL of anhydrous dichloromethane, add 1-2 drops...

Embodiment 2

[0043] The preparation of the first step reaction intermediate: add 42g paliperidone (0.1mol) and 84mL acetone and 336mL chloroform in the three-neck round bottom flask, add 30g succinic anhydride (0.3mol) therein under the condition of sufficient stirring ), 20mL (0.15mol) of triethylamine, the temperature is controlled at 70°C during the feeding process, after the feeding is completed, continue to stir and reflux at this temperature for 24h, after the reaction is completed, add 200mL of water to the reaction, fully stir, separate layers, and the organic layer anhydrous NaSO 4 After drying, the solvent was removed by rotary evaporation to obtain 46.6 g of a light orange solid. The purity of the product analyzed by high performance liquid chromatography (HPLC) was 96.1%, and the yield was 88.6%.

[0044] Preparation of the second-step reaction intermediate: Dissolve 25g (96.1%, 0.05mol) of the first-step reaction intermediate in 200mL of anhydrous dichloromethane, add 1-2 drop...

Embodiment 3

[0048] The preparation of the first step reaction intermediate: add 42g paliperidone (0.1mol) and 84mL acetone and 336mL chloroform in the three-neck round bottom flask, add 30g succinic anhydride (0.3mol) therein under the condition of sufficient stirring ), 20mL (0.15mol) of triethylamine, the temperature was controlled at 75°C during the feeding process, and continued to stir and reflux at this temperature for 24h after the feeding was completed. anhydrous NaSO 4 After drying, the solvent was removed by rotary evaporation to obtain 44.7 g of a light orange solid. The purity of the product analyzed by high performance liquid chromatography (HPLC) was 95.8%, and the yield was 84.9%.

[0049] Preparation of the second-step reaction intermediate: dissolve 26g (95.8%, 0.05mol) of the first-step reaction intermediate in 200mL of anhydrous dichloromethane, add 1-2 drops of DMF dropwise, and add thionyl chloride dropwise at 55°C 7mL (0.1mol), reflux for 2h after the dropwise addit...

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Abstract

The invention discloses a preparation method of a paliperidone sustained release microsphere injection. The preparation technology comprises the following steps: (1) paliperidone and an acid anhydrides reagent are respectively dissolved in a solvent to be subjected to esterification reaction under the effect of an alkaline catalyst; (2) the esterification product obtained in the step (1) is dissolved in anhydrous dichloromethane to be subjected to acylation reaction with the added acylation reagent with DMF (N, N- dimethylformamide) being the catalyst; (3) the acylated paliperidone is subjected to esterification reaction with polylactic acid (PLA) through chemical bond bonding; (4) paliperidone sustained release microspheres are prepared by adopting solvent evaporation method, and the paliperidone sustained release microspheres are prepared into the microsphere injection after being cooled and dried. The preparation method is safe to operate, mild in reaction condition and simple and clear in steps; the total yield reaches 50% or above; the particle sizes of the obtained paliperidone microspheres are 30-50 micron; the paliperidone sustained release microsphere injection provided by the invention is high in drug loading capacity, stable in drug release, long in drug release time and good in sustained release effect.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical preparations, in particular to a preparation method of paliperidone sustained-release microsphere injection. Background technique [0002] Paliperidone, English name is Paliperidone, chemical name: (±)-3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl )ethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido(1,2-a)pyrimidin-4-one, molecular formula: C 23 h 27 FN 4 o 3 , Molecular weight: 426.49, Paliperidone is almost insoluble in water, soluble in methanol and 0.1N hydrochloric acid, easily soluble in chloroform. [0003] Paliperidone is an atypical antipsychotic, the main plasma active metabolite of risperidone, and a derivative of benzisoxazole. The effect of paliperidone on receptors is basically similar to that of risperidone. Mainly by antagonizing 5-hydroxytryptamine 2A (5-HT 2A ) and dopamine D 2 (DA 2 ) receptors exert antipsychotic effects on other 5-HT receptor subtype...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/19A61K31/519A61K47/48A61P25/18
Inventor 李强张伟赵学玲
Owner HEILONGJIANG UNIV
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