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Preparation method of paliperidone palmitate suspension

A technology of paliperidone and palmitic acid, which is applied in the field of preparation of paliperidone palmitate suspension, can solve the problems of high risk of organic solvent residue, long production time, medium residue, etc., and avoid the problem of solvent residue , Improve safety, mild condition effect

Active Publication Date: 2021-03-09
ZHEJIANG SUNDOC PHARMA SCI & TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The above products prepared by ball milling have achieved great success worldwide, but the "Top-down" method of preparing nanocrystals based on complex equipment such as homogenizers or ball mills also has certain limitations, such as production time Longer, before homogenization or ball milling, it may be necessary to preliminarily reduce the particle size through jet milling equipment, and when using media grinding, there may be problems such as media residues
[0011] In addition to the "Top-down" method mentioned above, there is another method commonly used in the preparation of nanocrystals, that is, the "Bottom-up" method, also known as the "nanoprecipitation" or "microprecipitation" method. This method mainly involves an anti-solvent precipitation technology. Compared with the "Top-down" method, it does not require complicated production equipment and longer production time, and there is no worry about residual media; but this method usually uses organic Solvents, therefore, solvent carryover is a common drawback of this type of method
[0012] Chinese patent CN109400602 discloses a method for preparing paliperidone palmitate nanocrystalline suspension, which utilizes the solubility difference of paliperidone palmitate in dichloromethane and n-heptane, and is prepared by means of microprecipitation A nanosuspension preparation with a smaller particle size has been obtained. Although this method is simple to prepare and does not require complicated and expensive production equipment, it cannot avoid the common defect of the microprecipitation method, that is, the residue of organic solvents, and the method used The good solvents and non-good solvents received are not aqueous solutions, and the risk of organic solvent residues is greater;
[0016] It can be seen from the above patents and literature technologies that the main means of preparing paliperidone palmitate nanocrystalline preparations are still high-energy media grinding, high-pressure homogenization or solvent precipitation methods, no matter from the production equipment, production process, or medium residues and solvents. In terms of residues, these preparation methods have certain limitations

Method used

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  • Preparation method of paliperidone palmitate suspension

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Experimental program
Comparison scheme
Effect test

Embodiment approach

[0045] A preparation method of paliperidone palmitate suspension, comprising the following steps:

[0046] (1) Dispersing and dissolving the paliperidone palmitate drug particles in a first water-soluble good solvent containing a surfactant to obtain a drug solution; the first water-soluble good solvent is an acid solution. The acid solution is an acetic acid solution, and the concentration of the acetic acid solution is 30-80%. The weight percent content of the surfactant in the first water-soluble good solvent containing the surfactant is 1.2-3.6%.

[0047] (2) the drug solution is slowly added to the second water-soluble solvent containing the stabilizer, the drug solution is added to the second water-soluble solvent containing the stabilizer while adding energy to make the drug particles precipitate rapidly, and the resuspended can be mixed Suspension; remove acetic acid from the suspension through one or more of heating evaporation, vacuum removal and rotary evaporation,...

Embodiment 1

[0049] Preparation of a suspension with a final concentration of the active substance (pharmaceutical ingredient) of approximately 1%:

[0050] 5g of glacial acetic acid and 0.6g of polysorbate 20 were stirred and dissolved in 6g of ultrapure water in turn. After the solution was clear, 5g of paliperidone palmitate particles (average particle size of about 5 μm) were dispersed and dissolved in the above solution at room temperature. In the aqueous solution, stir and mix well until the solution is clear;

[0051] The above dissolved clear solution was added dropwise through a peristaltic pump (Cole-Parmer, 07523-80) and an injection needle (the speed was controlled so that the solubility of the dissolved hydrophobic drug particles was rapidly reduced and precipitated) to 450 g containing 2% polysorbate. 20 °C in ice water (the water temperature is controlled at 0-3 °C), and at the same time, high shear (IKA, T25 shear head) is added to the ice water bath, and the rotation speed...

Embodiment 2

[0054] Preparation of a suspension with a final concentration of active substances of approximately 5%:

[0055] 5g of glacial acetic acid and 0.45g of polysorbate 20 were stirred and dissolved in 2g of ultrapure water in turn. After the solution was clear, 5g of paliperidone palmitate particles (average particle size of about 76 μm) were dispersed and dissolved in the above solution at room temperature. In the aqueous solution, stir and mix well until the solution is clear;

[0056] The above dissolved clear solution was added dropwise through a peristaltic pump (Cole-Parmer, 07523-80) and an injection needle (the speed was controlled so that the solubility of the dissolved hydrophobic drug particles was rapidly reduced and precipitated) to 85 g containing 3% polyethylene glycol. Alcohol 4000 in ice water (the water temperature is controlled at 0-3 ℃), and high shear (IKA, T25 shear head) is added to the ice water bath at a speed of 13000 rpm; during the dropping process, the...

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Abstract

The invention discloses a preparation method of a paliperidone palmitate suspension. The preparation method comprises the following steps of (1) dispersing and dissolving paliperidone palmitate drug particles in a first water-soluble good solvent containing a surfactant to obtain a drug solution; and (2) slowly adding the drug solution into a second water-soluble solvent, simultaneously adding energy to enable the drug particles to be rapidly precipitated, and performing resuspending to obtain the suspension. According to the invention, complex equipment is not needed, the preparation processis simple, and the problem of metal medium or organic solvent residues is avoided.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical production, in particular to a preparation method of a suspension of paliperidone palmitate. Background technique [0002] Since the 1990s, a large number of new candidate drug molecules have been discovered one after another, but one of the great challenges facing these new drug molecules in the market is the low bioavailability in vivo, mainly due to their extremely low water solubility, It is understood that 40% of new drug molecules belong to this class of poorly soluble drugs. To address this problem, formulation scientists have developed a variety of formulations to increase their solubility and thus bioavailability, including inclusion complexes with cyclodextrins, amphiphilic materials to form micelles or lipids Nanoparticles, solubilization with surfactants, particle size reduction, etc. Among them, by reducing the size of drug particles and increasing the specific surface area, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/10A61K31/519A61K47/54A61P25/18
CPCA61K9/10A61K31/519A61K47/542A61P25/18
Inventor 高梦华王新石朱思琪陈晓杰
Owner ZHEJIANG SUNDOC PHARMA SCI & TECH CO LTD
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