Method for producing fine particles of 9-hydroxy risperidone fatty acid ester

Abstract

To provide a method for effectively producing fine particles of 9-hydroxy risperidone fatty acid ester.SOLUTION: Provided is a method for producing fine particles of 9-hydroxy risperidone fatty acid ester. The production method includes: mixing a first solution which is created by dissolving 9-hydroxy risperidone fatty acid ester expressed by formula (1) into an organic solvent in the presence of surfactant, and water to obtain a suspension; precipitating fine particles of 9-hydroxy risperidone fatty acid ester expressed by the formula (1) in the suspension to obtain a first dispersion liquid; and demulsifying the first dispersion liquid.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a method for producing fine particles of 9-hydroxyrisperidone fatty acid esters. [Background technology]

[0002] A suspension of fine particles of paliperidone palmitate dispersed in water is used as a therapeutic agent for schizophrenia. Paliperidone palmitate is represented by the following formula:

[0003] [ka] [Prior art documents] [Patent documents]

[0004] [Patent Document 1] International Publication No. 1999 / 025354 [Patent Document 2] International Publication No. 2018 / 037431 Summary of the Invention [Problem to be solved by the invention]

[0005] An object of the present invention is to provide an efficient method for producing fine particles of 9-hydroxyrisperidone fatty acid esters. [Means for solving the problem]

[0006] According to one aspect, there is provided a method for producing microparticles of 9-hydroxyrisperidone fatty acid ester, which includes the steps of: mixing a first solution, in the presence of a surfactant, in an organic solvent to obtain a suspension, with water; precipitating microparticles of the 9-hydroxyrisperidone fatty acid ester of formula (1) in the suspension to obtain a first dispersion; and demulsifying the first dispersion.

[0007] [ka]

[0008] In formula (1), R 1 is a linear alkyl group having 9 to 19 carbon atoms. [Effects of the Invention]

[0009] According to the present invention, an efficient method for producing fine particles of 9-hydroxyrisperidone fatty acid esters is provided. DETAILED DESCRIPTION OF THE INVENTION

[0010] In a suspension in which fine particles of paliperidone palmitate are dispersed in water, the fine particles of paliperidone palmitate may be required to have a very small size, for example, a D90 of 2.0 μm or less. To obtain such fine particles, methods such as wet-milling paliperidone palmitate solids in a solvent or filtering the fine particle dispersion multiple times through a filter with a small pore size are conceivable. However, wet-milling requires multiple steps, such as slurrying and drying. This requires a large-scale wet-milling apparatus, which poses a problem of high equipment costs. Furthermore, multiple filtering processes result in the removal of large particles, resulting in a low yield.

[0011] The manufacturing method according to the embodiment includes the steps of: mixing a first solution in which the 9-hydroxyrisperidone fatty acid ester represented by the above formula (1) is dissolved in an organic solvent in the presence of a surfactant with water to obtain a suspension; precipitating fine particles of the 9-hydroxyrisperidone fatty acid ester represented by formula (1) in the suspension to obtain a first dispersion; and demulsifying the first dispersion.

[0012] That is, the method according to the embodiment produces microparticles of 9-hydroxyrisperidone fatty acid ester by emulsification using a surfactant, an organic solvent, and water. This method can produce microparticles with a D90 of 2.0 μm or less, for example, without using a large-scale apparatus such as a wet mill.

[0013] The method according to the embodiment will now be described in detail.

[0014] <Method of producing fine particles> (1. Preparation of First Solution) In this production method, first, a 9-hydroxyrisperidone fatty acid ester represented by the following formula (1) is dissolved in an organic solvent to prepare a first solution.

[0015] [ka]

[0016] In formula (1), R 1 is a linear alkyl group having 9 to 19 carbon atoms. 1 The number of carbon atoms is preferably 12 or more and 16 or less, and more preferably 15.

[0017] The organic solvent is a good solvent capable of dissolving the 9-hydroxyrisperidone fatty acid ester represented by formula (1). The organic solvent preferably contains an aromatic compound because of the high solubility of the 9-hydroxyrisperidone fatty acid ester represented by formula (1). The organic solvent more preferably contains a compound selected from the group consisting of toluene, xylene, cumene, and benzyl alcohol.

[0018] The amount of the organic solvent relative to 1 g of the 9-hydroxyrisperidone fatty acid ester represented by formula (1) is, for example, 1 mL or more and 20 mL or less, preferably 2 mL or more and 10 mL or less, and more preferably 3 mL or more and 5 mL or less.

[0019] In the first solution, the proportion of the 9-hydroxyrisperidone fatty acid ester represented by formula (1) is, for example, 5% by mass or more and 50% by mass or less, and preferably 10% by mass or more and 30% by mass or less.

[0020] When preparing the first solution, the 9-hydroxyrisperidone fatty acid ester represented by formula (1) may be dissolved in a solvent by heating. The heating temperature is, for example, 40°C or higher and 100°C or lower, preferably 60°C or higher and 80°C or lower.

[0021] The first solution may be subjected to filtration using a filter or the like to remove dust.

[0022] (2. Emulsification) Next, this first solution is mixed with a surfactant and water to obtain a suspension. The surfactant may be added to the first solution and then water may be added, or the surfactant may be added to the first solution and then water may be added, or water mixed with a surfactant may be added to the first solution. By mixing the first solution, surfactant, and water, an O / W emulsion is formed in which water is the dispersion medium and the first solution is the dispersoid. This produces minute droplets of the first solution. The surfactant is unevenly distributed around the outline of the droplets.

[0023] The mixing of the first solution with water in the presence of a surfactant may be carried out by adding water at room temperature to the heated first solution. The temperature of the first solution is, for example, 40°C or higher and 100°C or lower, preferably 60°C or higher and 80°C or lower. Alternatively, water within the above temperature range may be added to the first solution at room temperature. In emulsification, it is preferable to add the surfactant and water in this order to the first solution at a temperature of 60°C or higher and 80°C or lower while stirring, and then continue stirring.

[0024] Preferably, the surfactant comprises a non-ionic surfactant, and more preferably, the surfactant comprises polyoxyethylene sorbitan monolaurate (Tween 20).

[0025] The amount of the surfactant relative to 1 g of the 9-hydroxyrisperidone fatty acid ester represented by formula (1) is, for example, 1.0 mL or more and 10 mL or less, and preferably 1.5 mL or more and 5 mL or less.

[0026] The ratio V1 / V2 of the volume V1 of the organic solvent to the volume V2 of the surfactant is, for example, 1 or more and 10 or less, preferably 1.5 or more and 5 or less.

[0027] The water may be pure water, ion-exchanged water, purified water, tap water, or a mixture thereof.

[0028] The amount of water per 1 g of the 9-hydroxyrisperidone fatty acid ester represented by formula (1) is, for example, 3 mL to 40 mL, preferably 4 mL to 30 mL, and more preferably 6 mL to 10 mL.

[0029] The ratio V1 / V3 of the volume V1 of the organic solvent to the volume V3 of water is, for example, 0.1 or more and 5 or less, and preferably 0.3 or more and 1 or less.

[0030] The ratio V3 / V2 of the volume V3 of water to the volume V2 of the surfactant is, for example, 1 or more and 10 or less, and preferably 2 or more and 6 or less.

[0031] Most preferably, the volume ratio of organic solvent, surfactant, and water is 2:1:4.

[0032] In the suspension, the proportion of the 9-hydroxyrisperidone fatty acid ester represented by formula (1) is, for example, 1% by mass or more and 30% by mass or less, and preferably 5% by mass or more and 15% by mass or less.

[0033] (3. Crystallization) Next, fine particles of the 9-hydroxyrisperidone fatty acid ester represented by formula (1) are precipitated in the resulting suspension to obtain a first dispersion. The first dispersion may be a white colloid.

[0034] The method for precipitating the microparticles is not particularly limited. The temperature of the suspension may be lowered, or a poor solvent may be added to the suspension. Microparticles can be precipitated by lowering the temperature of the suspension by, for example, 10°C or more. The temperature may be lowered to 20°C or higher, 30°C or higher, or 60°C or higher. The temperature of the suspension is preferably lowered at a rate of 10°C / hour or more and 30°C / hour. Lowering the temperature of the suspension at this rate tends to further reduce the particle size of the microparticles. When the temperature of the suspension is 60°C to 80°C, it is preferable to precipitate the microparticles by lowering the temperature to 20°C to 60°C over 20 hours or more. During crystallization, the suspension may be continuously stirred or stirring may be stopped.

[0035] The first dispersion may be treated with an ultrasonic homogenizer, which results in fine particles of the 9-hydroxyrisperidone fatty acid ester having a smaller particle size.

[0036] (4. Demulsification) Next, the first dispersion is demulsified. As a result, the first dispersion is separated into an organic layer in which fine particles of the 9-hydroxyrisperidone fatty acid ester represented by formula (1) are dispersed, and an aqueous layer containing a surfactant. The organic layer is filtered, for example, using a filter, and the filtered fine particles are dried to obtain a powder containing fine particles of the 9-hydroxyrisperidone fatty acid ester represented by formula (1).

[0037] The demulsification method is not particularly limited. For example, the first dispersion can be demulsified by adding a pH adjuster or by heating. As the pH adjuster, for example, a sodium carbonate aqueous solution is used. The amount of the 10% by mass sodium carbonate aqueous solution is, for example, 10 mL to 50 mL per 1 g of the 9-hydroxyrisperidone fatty acid ester represented by formula (1).

[0038] The demulsification is preferably carried out after the first dispersion is obtained, i.e., after the precipitation of fine particles is observed in the suspension, and after the suspension is allowed to stand for at least 0.5 hours, preferably at least 2 hours, and more preferably at least 12 hours.

[0039] After demulsification, the first dispersion is preferably left to stand for at least one hour to allow the first dispersion to separate sufficiently, preferably for at least 10 hours, and more preferably for at least 20 hours.

[0040] (5. Fine particles) The D90 of the fine particles of the 9-hydroxyrisperidone fatty acid ester represented by formula (1) obtained by the above method is, for example, 2.00 μm or less, preferably 1.60 μm or less, more preferably 1.20 μm or less, and even more preferably 1.00 μm or less.

[0041] The D50 of the fine particles of the 9-hydroxyrisperidone fatty acid ester represented by formula (1) is, for example, 1.50 μm or less, preferably 1.00 μm or less, more preferably 1.75 μm or less, and even more preferably 1.60 μm or less.

[0042] The D10 of the fine particles of the 9-hydroxyrisperidone fatty acid ester represented by formula (1) is, for example, 1.00 μm or less, preferably 0.75 μm or less, more preferably 0.60 μm or less, and even more preferably 0.50 μm or less.

[0043] The D90, D50, and D10 of the 9-hydroxyrisperidone fatty acid ester represented by formula (1) respectively represent the 90%, 50%, and 10% values ​​of the cumulative distribution function of the particle size distribution obtained by a laser diffraction / scattering method. The measurement sample is a solution in which the 9-hydroxyrisperidone fatty acid ester is dispersed in an aqueous Tween 20 solution. The measurement device used is, for example, a laser diffraction particle size distribution analyzer manufactured by Malvern Panalytical.

[0044] The microparticles of 9-hydroxyrisperidone fatty acid ester represented by formula (1) obtained by this method can be used as a suspension dispersed in water. The suspension may be sold, for example, filled in a syringe, or used as an oral medication. This suspension may contain additives such as a surfactant, a pH adjuster, and a preservative. The microparticles of 9-hydroxyrisperidone fatty acid ester represented by formula (1) may be used as tablets or granules. [Example]

[0045] The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples. <Evaluation test> (Particle size distribution measurement) The particle size distribution of the 9-hydroxyrisperidone palmitate obtained in the example was measured under the following conditions. Equipment: Laser diffraction particle size distribution measuring device Model: Mastersizer 3000 (Malvern Panalytical) Dispersion method: wet Particle refractive index: 1.600 Particle absorption rate: 0.000 Measurement time: 12 seconds Light scattering model: Mie theory Sample solution: Tween 20 solution (1 g / L) was added to 50 mg of sample and dispersed by ultrasonic irradiation. Example 1 A mixture of 2 g of 9-hydroxyrisperidone palmitate and 12 mL of toluene was stirred at 70°C to dissolve the 9-hydroxyrisperidone palmitate. 6 mL of Tween 20 and 24 mL of water were added dropwise to the resulting solution. The resulting solution was stirred at 70°C to prepare an emulsion, which was then stirred overnight at 5°C to precipitate microparticles. 48 mL of 10% aqueous sodium carbonate solution was added dropwise to the resulting solution, which was then demulsified by stirring at 5°C for 1 hour. After allowing the solution to stand, the organic and aqueous layers were separated. The organic layer containing the 9-hydroxyrisperidone palmitate microparticles was filtered through a 0.05 μm membrane filter and dried to obtain 1.65 g of 9-hydroxyrisperidone palmitate microparticles (recovery rate: 82.5%). <Example 2> The same procedure as in Example 1 was carried out except that the prepared emulsion solution was pulverized using an ultrasonic homogenizer, to obtain 1.23 g of fine particles of 9-hydroxyrisperidone palmitate (recovery rate: 61.5%). Example 3 The same procedure as in Example 1 was carried out except that xylene was used instead of toluene, to obtain 1.78 g of fine particles of 9-hydroxyrisperidone palmitate (recovery rate: 89.0%). Example 4 The same procedure as in Example 1 was carried out except that cumene was used instead of toluene, to obtain 1.80 g of fine particles of 9-hydroxyrisperidone palmitate (recovery rate: 90.0%). <Example 5> The same procedure as in Example 1 was carried out except that benzyl alcohol was used instead of toluene, to obtain 1.49 g of fine particles of 9-hydroxyrisperidone palmitate (recovery rate: 74.5%). <Comparative Example 1> 0.70 g of 9-hydroxyrisperidone palmitate, 0.11 g of Tween 20, 0.10 g of carboxymethylcellulose sodium 30 mPa.s, 0.15 g of benzyl alcohol, 0.90 g of anhydrous disodium hydrogen phosphate, and 0.60 g of sodium dihydrogen phosphate monohydrate were diluted to 10 g with water. After stirring and dissolving, 3 g of milling media was added and the mixture was milled at 50 rpm for 7 hours. The milling media was then removed by filtration through a 3 μm filter. The particle size distribution of the resulting solution containing 9-hydroxyrisperidone palmitate microparticles was measured. <Comparative Example 2> The particle size distribution of this liquid containing 9-hydroxyrisperidone palmitate microparticles obtained in the same manner as in Comparative Example 1, except that the time spent on the roller was changed to 38 hours, was measured. <Comparative Example 3> A mixture of 2 g of 9-hydroxyrisperidone palmitate and 26 mL of toluene was stirred at 30°C to dissolve the 9-hydroxyrisperidone palmitate. 22 mL of heptane was added dropwise to the mixture at 25°C and stirred at 160 rpm to form an emulsion. The mixture was stirred at 5°C for 3 hours, filtered, and dried to obtain 1.68 g of 9-hydroxyrisperidone palmitate microparticles (recovery rate: 84.0%). <Comparative Example 4> The same procedure as in Comparative Example 3 was carried out except that the stirring speed during emulsion formation was set to 165 rpm, to obtain 1.69 g of fine particles of 9-hydroxyrisperidone palmitate (recovery rate: 84.5%). <Comparative Example 5> A mixture of 2 g of 9-hydroxyrisperidone palmitate and 12 mL of ethanol was stirred under reflux to dissolve the 9-hydroxyrisperidone palmitate. The solution was cooled to 5°C and stirred overnight. The solution was filtered and dried to obtain 1.70 g of 9-hydroxyrisperidone palmitate microparticles (recovery rate: 85.0%). <Comparative Example 6> The same procedure as in Example 1 was carried out except that 0.6 mL of Tween 20 was used, to obtain 1.72 g of fine particles of 9-hydroxyrisperidone palmitate (recovery rate: 86.0%).

[0046] [Table 1]

[0047] Preferred aspects of the invention are listed below. [1] a first solution obtained by dissolving a 9-hydroxyrisperidone fatty acid ester represented by the following formula (1) in an organic solvent in the presence of a surfactant, and mixing the first solution with water to obtain a suspension; Precipitating fine particles of the 9-hydroxyrisperidone fatty acid ester represented by formula (1) in the suspension to obtain a first dispersion; and demulsifying the first dispersion:

[0048] [ka]

[0049] In formula (1), R 1 is a linear alkyl group having 9 to 19 carbon atoms. [2] The manufacturing method according to [1], wherein the 90% value of the cumulative distribution function of the particle size distribution of the fine particles by laser diffraction / scattering method is 2.0 μm or less. [3] The method according to [1] or [2], wherein the organic solvent contains an aromatic compound. [4] The method according to any one of [1] to [3], wherein the organic solvent comprises a compound selected from the group consisting of toluene, xylene, cumene, and benzyl alcohol. [5] The manufacturing method according to any one of [1] to [4], wherein the surfactant includes a nonionic surfactant. [6] The method according to any one of [1] to [5], wherein the surfactant includes polyoxyethylene sorbitan monolaurate. [7] The method according to any one of [1] to [6], wherein the amount of the organic solvent per 1 g of the 9-hydroxyrisperidone fatty acid ester represented by the formula (1) is 3 mL or more and 20 mL or less. [8] [7] The method according to any one of [1] to [7], wherein the amount of water per 1 g of the 9-hydroxyrisperidone fatty acid ester represented by the formula (1) is 6 mL or more and 40 mL or less. [9] The method according to any one of [1] to [8], wherein the amount of the surfactant per 1 g of the 9-hydroxyrisperidone fatty acid ester represented by the formula (1) is 1.5 mL or more and 10 mL or less.

[10] The manufacturing method according to any one of [1] to [9], wherein the first dispersion is allowed to stand for 0.5 hours or more, and then the demulsification is carried out.

[11] The manufacturing method according to any one of [1] to

[10] , wherein the first dispersion is treated with an ultrasonic homogenizer and then demulsified.

Claims

1. a first solution obtained by dissolving a 9-hydroxyrisperidone fatty acid ester represented by the following formula (1) in an organic solvent in the presence of a surfactant, and mixing the first solution with water to obtain a suspension; Precipitating fine particles of the 9-hydroxyrisperidone fatty acid ester represented by formula (1) in the suspension to obtain a first dispersion; and demulsifying the first dispersion. 【Chemistry 1】 In formula (1), R １ is a linear alkyl group having 9 to 19 carbon atoms.

2. 2. The method according to claim 1, wherein the 90% value of the cumulative distribution function of the particle size distribution of the fine particles as determined by a laser diffraction / scattering method is 2.0 μm or less.

3. The method of claim 1 , wherein the organic solvent comprises an aromatic compound.

4. The method of claim 1 , wherein the organic solvent comprises a compound selected from the group consisting of toluene, xylene, cumene, and benzyl alcohol.

5. The method of claim 1 , wherein the surfactant comprises a nonionic surfactant.

6. The method of claim 1 , wherein the surfactant comprises polyoxyethylene sorbitan monolaurate.

7. 2. The method according to claim 1, wherein the amount of the organic solvent per 1 g of the 9-hydroxyrisperidone fatty acid ester represented by formula (1) is 3 mL or more and 20 mL or less.

8. 2. The method according to claim 1, wherein the amount of water per 1 g of the 9-hydroxyrisperidone fatty acid ester represented by formula (1) is 6 mL or more and 40 mL or less.

9. 2. The method according to claim 1, wherein the amount of the surfactant per 1 g of the 9-hydroxyrisperidone fatty acid ester represented by formula (1) is 1.5 mL or more and 10 mL or less.

10. The method according to claim 1 , wherein the first dispersion is allowed to stand for 0.5 hours or more before the demulsification is carried out.

11. The method according to claim 1 , wherein the first dispersion is treated with an ultrasonic homogenizer and then demulsified.

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