Aripiprazole sustained-release microsphere and preparation method thereof

Abstract

The invention provides an aripiprazole sustained-release microsphere and a preparation method thereof. The microsphere comprises aripiprazole and polylactide-glycolide, wherein the microsphere is in astructure of spherical reticular framework, reticular pores are distributed on the spherical surface, the pores are filled with the aripiprazole, the average grain size of the microsphere is less than 20 micrometers; the content of the aripiprazole accounts for 65%-80% of the total weight of the microsphere. The aripiprazole sustained-release microsphere and the preparation method thereof have the advantages that because the average grain size of the aripiprazole sustained-release microsphere is less than 20 micrometers, the microsphere can be suitable for 5-type needle, thereby reducing thepain of a patient; in addition, the concentration of the microsphere can quickly reach effective medicine concentration in the medicine administration earlier stage, oral administration is not neededto achieve the therapeutic effect, and the sudden-release effect does not occur.

Description

technical field [0001] The invention relates to the field of pharmaceutical preparations, in particular to an aripiprazole sustained-release microsphere and a preparation method thereof. Background technique [0002] Aripiprazole is a new type of atypical anti-schizophrenia drug, which has two-way regulation on the nervous system and is a transmitter stabilizer. Aripiprazole has high affinity to D2, D3, 5-HT1A and 5-HT2A receptors, which is produced by partial agonism on D2 and 5-HT1A receptors and antagonism on 5-HT2A receptors Anti-schizophrenia effect, thus for the treatment of various types of schizophrenia. Foreign clinical trials have shown that aripiprazole has a significant effect on both positive and negative symptoms of schizophrenia, can also improve accompanying emotional symptoms, and reduce the recurrence rate of schizophrenia. However, due to the particularity of psychiatric patients, the phenomenon of refusal to take medicine is very prominent, and long-ter...

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Problems solved by technology

At the same time, the average diameter of the aripiprazole crystallites involved in this patent application is between 30 microns and 80 microns. According to the syringe needles corresponding to the particle diameters of the microsphere products on the market, it is speculated that a No. 7 or No. 8 needle (18 -21G), the diameter of the needle is 0.5-0.8mm, and the patient feels obvious pain during injection; in addition, due to the large particle size of the drug, it is necessary to increase the viscosity to keep the drug particles in the suspension in a suspended state, resulting in suspension Difficulty injecting

In addition, the suspension is prone to precipitation before injection. When the suspension drug solution is sucked into the syringe, it needs to be slowly and continuously inhaled and kept in a suspended state. Improper use can easily cause needle blockage and injection failure

The entire drug administration process requires medical staff to undergo special training before it can be completed, resulting in it not being widely applicable in ordinary medical institutions and bringing inconvenience to the promotion of drug use

[0005] Otsuka's patent CN101742989B and Shogo Hiraoka etc. (Preparation and Characterization of High-Content Aripiprazole-Loaded Core-Shell Structure Microsphere for Long-Release Injectable Formulation) disclosed documents relate to a microsphere of core / shell structure, which also There are problems such as the particle size of the microspheres is too large, the No. 5 needle cannot be used, the injection operation requires high requirements, and the patient feels great pain.

At the same time, the microspheres prepared according to the method disclosed in the patent showed a concentrated release of 10% of the drug on the first day, which may increase the risk of side effects due to the phenomenon of excessive drug concentration; the patent mentioned that most of the samples were released for more than 2 months , when the side effects of schizophrenia drugs are large and serious, developing products for one month has more advantages in terms of safety and timeliness of risk control

The developed core / shell structure, the release mode is more dependent on the composition of the core components, and the control of the release of the drug is relatively simple, which may cause concentrated release due to the rapid degradation of the shell, or slow drug release due to the slow degradation of the shell , the discontinuous release phenomenon occurs

[0006] Patent CN1870980B discloses the preparation method of aripiprazole aseptic injection. The preparation process of aripiprazole aseptic injection involved in this patent requires grinding and other processes, and the preparation cycle is long. At the same time, the aseptic conditions required in the preparation process are easily destroyed. , not suitable for industrialized mass production

[0007] The drug loading of microspheres in patent applications CN105078898A and CN105310997A is too low, and the aripiprazole long-acting injections disclosed in patents or patent applications CN102525915B, CN103301461A, and CN105012236A contain injection oil, which will lead to increased pain in patients during injection, and the clinical use significance is relatively large. Small

[0008] The particle size of the microspheres in the patent application CN106727358A cannot be controlled within 20 microns, and the No. 5 needle cannot be used, and the release period of the microspheres is 2 months

[0009] The document "D-Optimal Designing and Optimization of Long Acting Microsphere-Based Injectable Formulation of Aripiprazole" published by Tushar Nahata and Tulsi Ram Saini, the drug loading of aripiprazole microspheres disclosed in this document is within 30%, which cannot meet the clinical long-acting sustained release need

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