Aripiprazole sustained-release microsphere composition

A technology of aripiprazole and sustained-release microspheres, which is applied in drug combinations, nervous system diseases, organic active ingredients, etc., can solve the problems of poor storage stability, unsuitable for industrialization, and low proportion, and achieve stable release behavior , reduce pain, improve success rate

Pending Publication Date: 2022-06-28
ZHEJIANG SUNDOC PHARMA SCI & TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In addition, its API also contains one or more excipients (antioxidants, buffers), so it can be said that its auxiliary materials are numerous, the process is complicated, and it is not suitable for industrialization.
[0008] Chinese patent CN105078898B discloses aripiprazole long-acting sustained-release microparticle injection and its preparation method. The aripiprazole long-acting preparation contains aripiprazole, a polymer, and a drug release characteristic regulator. The regulator is specifically benzene A mixed solvent of methanol and dimethyl sulfoxide, accounting for 2 to 4% (Original text: the proportion of regulators is low, and the improvement of drug release behavior is not obvious; exceeding a certain proportion will cause adhesion of particles), benzyl alcohol and dimethyl sulfoxide The boiling points of sulfoxide groups are all very high (>180°C), which means that the regulator has not been removed during the preparation process, and the residual solvents of the microspheres are abnormally high. It is predictable that these solvents will cause the glass transition temperature (Tg ) low, increased drug release rate, poor storage stability
Due to the low solubility of aripiprazole in dichloromethane (<60mg / mL), it dissolves when heated to 40-65°C, which is much higher than the boiling point of dichloromethane at 39°C, which adds great difficulty to the control of the experimental process. It is operated in a pressure tank, so the temperature in the process will have a great impact on the crystallization of the preparation, and it will also easily cause safety hazards

Method used

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Embodiment approach

[0050] An aripiprazole sustained-release microsphere composition, the starting materials for the preparation of the aripiprazole sustained-release microsphere composition include aripiprazole, acetic acid and a polymer, and the aripiprazole sustained-release microsphere composition is prepared. The final components of the ball composition are aripiprazole and polymer; wherein the molar ratio of acetic acid to aripiprazole is 2-5:1. The acetic acid is glacial acetic acid.

[0051] In the aripiprazole sustained-release microsphere composition, the weight content of aripiprazole is 30-45%, and the weight content of polymer is 55-70%. The polymer is selected from one or more of glycolide-lactide copolymer, polylactic-glycolic acid copolymer, polylactic acid, and polylactide.

[0052] The polymer is preferably a glycolide-lactide copolymer, and the molecular weight distribution of the glycolide-lactide copolymer is: 5-8% with a molecular weight ≥ 40000 Da, 15-17% with a molecular ...

Embodiment 1

[0058] 20.0g aripiprazole, 30.0g glycolide-lactide copolymer 7525 (Mw18000; molecular weight above 40000Da accounted for 6.73%, 25000 ~ 40000Da (excluding 40000, the same below) accounted for 15.77%, 17000 ~ 25000Da (no Including 25000, the same below) accounted for 39.82%, 10000 ~ 17000Da (excluding 17000, the same below) accounted for 22.01%, 5000 ~ 10000Da (excluding two endpoints, the same below) accounted for 10.11%, 5000Da or less accounted for 1.42 %) into 200.0 g of dichloromethane, stirred and dissolved at 32 °C for 1.5 h; then added 5.36 g of glacial acetic acid (2 times the molar ratio of aripiprazole), continued to stir and dissolve for 20 min to obtain an organic phase, and cooled to 25 °C for later use;

[0059] Add polyvinyl alcohol to 15L of water to a final concentration of 5g / L, stir and dissolve at 32°C to obtain an outer water phase, cool down to 25°C for later use;

[0060] The above-mentioned organic phase and external water phase were emulsified by an on...

Embodiment 2

[0063] 20.0g aripiprazole, 30.0g glycolide-lactide copolymer 7525 (Mw18000; molecular weight above 40000Da accounted for 5.42%, 25000~40000Da accounted for 15.01%, 17000~25000Da accounted for 38.54%, 10000~17000Da accounted for 22.92%, 5000-10000Da accounted for 11.301%, and below 5000Da accounted for 1.75%) into 200.0g of dichloromethane, stirred and dissolved at 32°C for 1.5h; then added 10.71g of glacial acetic acid (4 times the molar ratio of aripiprazole), Continue stirring and dissolving for 20min to obtain an organic phase, which is cooled to 25°C for later use;

[0064] Add polyvinyl alcohol to 15L of water to a final concentration of 5g / L, stir and dissolve at 32°C to obtain an outer water phase, cool down to 25°C for later use;

[0065] The above-mentioned organic phase and external water phase were emulsified by an online shearing machine at a ratio of 1:100 (v / v), and after emulsification, 25° C., 150 rpm was dried in liquid for 3 hours, and the solidified microsph...

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Abstract

The invention discloses an aripiprazole sustained-release microsphere composition, which is prepared from the following initial raw materials: aripiprazole, acetic acid and a polymer, and the final components of the aripiprazole sustained-release microsphere composition are aripiprazole and the polymer. Wherein the molar ratio of the acetic acid to the aripiprazole is (2-5): 1. After administration, the lagging period or burst release phenomenon is avoided, the average particle size of the microspheres is 15-25 microns, the stable blood concentration can be maintained within four weeks, and good storage stability and needle passing performance are achieved.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical injection production, in particular to an aripiprazole sustained-release microsphere composition. Background technique [0002] Aripiprazole is a second-generation atypical anti-schizophrenic drug that has a bidirectional regulatory effect on the nervous system and is a stabilizer of the dopamine (DA) neurotransmitter. Aripiprazole has high affinity for dopamine D2, D3, 5-HT1A and 5-HT2A receptors, and has a high affinity for D4, 5-HT2c, 5-HT7, a1, H1 receptors and 5-HT reabsorption sites Moderate affinity. It produces anti-schizophrenia effects through partial agonism at D2 and 5-HT1A receptors and antagonism at 5-HT2A receptors. Foreign clinical trials have shown that aripiprazole has obvious curative effect on both positive and negative symptoms of schizophrenia, and can also improve the accompanying emotional symptoms and reduce the recurrence rate of schizophrenia. Due to the partic...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/16A61K31/496A61K47/34A61K47/12A61P25/18
CPCA61K9/1647A61K9/1617A61K31/496A61P25/18
Inventor 于崆峒蒋朝军荆志宇
Owner ZHEJIANG SUNDOC PHARMA SCI & TECH CO LTD
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