JP2016102093A - Production method of microcapsule containing basic nucleophilic compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for conveniently producing a stable microcapsule containing a basic nucleophilic compound, while retaining the molecular weight of biodegradable polymer.SOLUTION: The invention provides a production method of a microcapsule containing a basic nucleophilic compound comprising the steps of (A) preparing a first phase including biodegradable polymer, a basic nucleophilic compound, and halogenated hydrocarbon as a solvent; (B) mixing the first phase and a second phase which is an aqueous phase to prepare an emulsion; and (C) drying, in water, the obtained emulsion.SELECTED DRAWING: Figure 1

Description

  The present invention relates to a method for producing a microcapsule containing a basic nucleophilic compound, and more particularly to a production method characterized by using a halogenated hydrocarbon as a solvent.

  So far, various drug delivery systems have been developed in which drugs useful for treatment are encapsulated in microcapsules such as biodegradable polymers to form sustained-release or delayed-release preparations. For example, in a microcapsule using a biodegradable polymer such as a lactic acid-glycolic acid copolymer, a drug to be encapsulated is dissolved, dispersed or emulsified in a benzyl alcohol and ethyl acetate solution of the biodegradable polymer that becomes the capsule shell, A method of obtaining microcapsules by washing and drying a solvent with an aqueous ethyl acetate solution as a quenching solution is disclosed (Patent Document 1).

  On the other hand, risperidone, a basic nucleophilic compound, is an atypical antipsychotic drug called serotonin-dopamine antagonist (SDA), which is used for the treatment of schizophrenia, and is biodegradable. It has the effect | action which accelerates | stimulates hydrolysis of a conductive polymer. Therefore, for the purpose of controlling the molecular weight of the microcapsule shell-forming polymer, an organic phase prepared by mixing a biodegradable polymer solution dissolved in an ethyl acetate solution and a solution obtained by dissolving risperidone in benzyl alcohol is prepared. There is disclosed a method in which a molecular weight loss commensurate with the starting material is promoted by maintaining this at a temperature of 25 ± 5 ° C. for a sufficient duration, followed by an emulsification step (Patent Document 2).

JP 9-505308 A Special table 2003-534268 gazette

  Although the method of Patent Document 1 teaches that the polymer exposure time of risperidone is as short as possible, a biodegradable polymer such as a lactic acid-glycolic acid copolymer is still decomposed, and a stable molecular weight polymer. There was a problem that it was difficult to produce microcapsules having Since the molecular weight of the biodegradable polymer is one of the factors that determine the degradation rate, it is extremely important to maintain a stable molecular weight. Further, the method of Patent Document 2 is a complicated process in which a necessary holding time is calculated from the molecular weight of the biodegradable polymer as a starting material and must be set as appropriate in order to obtain a desired molecular weight. .

  Therefore, an object of the present invention is to provide a method for easily producing a stable microcapsule containing a basic nucleophilic compound while maintaining the molecular weight of a biodegradable polymer.

  The present inventors have found that the decomposition of a biodegradable polymer can be suppressed by using a halogenated hydrocarbon as a solvent in the production of a microcapsule of a basic nucleophilic compound, thereby completing the present invention.

That is, the present invention
[1] A method for producing a microcapsule containing a basic nucleophilic compound,
(A) preparing a first phase comprising a biodegradable polymer, a basic nucleophilic compound, and a halogenated hydrocarbon as a solvent;
(B) a production method comprising the steps of preparing an emulsion by mixing the first phase and the second phase, which is an aqueous phase, and (C) drying the obtained emulsion in water;
[2] The production method according to the above [1], wherein at least one of the first phase and the second phase is cooled,
[3] In step (A), a halogenated hydrocarbon solution of a biodegradable polymer and a halogenated hydrocarbon solution of a basic nucleophilic compound are separately prepared and mixed immediately before step (B). The production method according to the above [1] or [2], wherein the first phase is prepared by
[4] The production method according to the above [3], wherein the mixing in the step (A) is performed using a static mixer,
[5] The production method according to any one of [1] to [4], wherein the mixing in the step (B) is performed continuously with the step (A) by a static mixer, a homomixer, or a high-pressure homomixer,
[6] The production method according to any one of [1] to [5] above, wherein the halogenated hydrocarbon is dichloromethane or chloroform, and [7] the biodegradable polymer is a lactic acid-glycolic acid copolymer. The production method according to any one of the above [1] to [6], and [8] the basic nucleophilic compound according to any one of the above [1] to [7], wherein risperidone, oxybutynin or naltrexone is used. It relates to a manufacturing method.

  According to the present invention, the degradation of the biodegradable polymer during the production process of the microcapsule is suppressed, and a stable microcapsule containing a basic nucleophilic compound can be easily obtained while maintaining the molecular weight of the biodegradable polymer as much as possible. Can be manufactured.

It is a graph which shows the molecular weight change rate of a lactic acid-glycolic acid copolymer. It is a graph which shows the molecular weight change rate of a lactic acid-glycolic acid copolymer.

  According to the present invention, the manufacture of microcapsules containing a basic nucleophilic compound comprises (A) a first phase comprising a biodegradable polymer, a basic nucleophilic compound, and a halogenated hydrocarbon as a solvent. Manufactured by a method comprising: (B) preparing an emulsion by mixing the first phase and the second phase which is an aqueous phase; and (C) drying the obtained emulsion in water. can do.

  As used herein, “microcapsule” means a particle comprising a polymer that acts as a matrix or binder of particles. Active agents or other materials dispersed or dissolved within the microcapsule polymer matrix may be included. The polymer is preferably biodegradable and biocompatible. “Biodegradable” means a property that is easily degraded and metabolized in the body, and “biocompatible” means a pharmaceutically acceptable property that is not toxic to the body.

  Examples of the basic nucleophilic compound include risperidone, oxybutynin, naltrexone, and the like.

で表される化学名：３−｛２−［４−（６−フルオロ−１，２−ベンズイソキサゾール−３−イル）ピペリジノ］エチル｝−６，７，８，９−テトラヒドロ−２−メチル−４Ｈ−ピリド［１，２−ａ］ピリミジン−４−オンのベンズイソキサゾール誘導体である。リスペリドンは、セロトニン・ドパミン・アンタゴニスト（ＳＤＡ：serotonin-dopamine antagonist）と呼ばれる非定型抗精神病薬であり、ドパミンＤ２受容体およびセロトニン５−ＨＴ２Ａ受容体の両方に拮抗作用を示す。この両作用により統合失調症の陽性症状と陰性症状の両方に改善作用を示す。 Risperidone has the formula:

3- {2- [4- (6-Fluoro-1,2-benzisoxazol-3-yl) piperidino] ethyl} -6,7,8,9-tetrahydro-2- It is a benzisoxazole derivative of methyl-4H-pyrido [1,2-a] pyrimidin-4-one. Risperidone is an atypical antipsychotic drug called a serotonin-dopamine antagonist (SDA) and exhibits antagonism to both the dopamine D2 receptor and the serotonin 5-HT2A receptor. Both of these effects show improvement in both positive and negative symptoms of schizophrenia.

で表される化学名：α−フェニルシクロヘキサングリコール酸４−（ジエチルアミノ）−２−ブチニルの抗コリン作動薬である。 Oxybutynin has the formula:

Is an anticholinergic agent of 4- (diethylamino) -2-butynyl α-phenylcyclohexaneglycolate.

で表される化学名：４，５α−エポキシ−３，１４−ジヒドロキシ−１７−（シクロプロピルメチル）モルフィナン−６−オンの麻酔拮抗薬である。 Naltrexone has the formula:

Is an anesthetic antagonist of 4,5α-epoxy-3,14-dihydroxy-17- (cyclopropylmethyl) morphinan-6-one.

  Biodegradable polymers include poly (glycolic acid), poly-D, L-lactic acid, poly-L-lactic acid, copolymers thereof and salts thereof, and lactic acid-glycolic acid copolymer (Poly (DL -Lactic-co-glicolide)), which can be produced by known methods, and various commercially available products can also be used.

  Examples of the salt of lactic acid-glycolic acid copolymer include inorganic bases including alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, organic amines such as triethylamine, and basic amines such as arginine. And salts and complex salts with transition metals such as zinc, iron and copper.

  Moreover, as for the molecular weight of a lactic acid-glycolic acid copolymer, 30000-150,000 are normally preferable at a weight average molecular weight Mw, and 60000-100000 are more preferable.

  A halogenated hydrocarbon is used as a solvent for the biodegradable polymer. By using the halogenated hydrocarbon, it is possible to suppress the decomposition of the biodegradable polymer, particularly the lactic acid-glycolic acid copolymer. In the present specification, a halogenated hydrocarbon means an alkane or alkene having 1 to 4 carbon atoms substituted with at least one halogen atom, and an alkane having 1 to 2 carbon atoms substituted with at least one halogen atom. Is more preferable. Specific examples of the halogenated hydrocarbon include dichloromethane and chloroform, with dichloromethane being more preferred.

  According to one embodiment of the present invention, when risperidone is used as the basic nucleophilic compound, the content of risperidone in the microcapsule is preferably 1 to 60% by mass, and more preferably 35 to 45% by mass. When the content of risperidone is less than 1% by mass with respect to the weight of the microcapsules, it is necessary to administer a large amount of microcapsule preparation to satisfy the clinical amount. When the content of risperidone exceeds 60% by mass with respect to the weight of the microcapsule, it takes time to dissolve risperidone or it is necessary to increase the amount of solvent so as not to cause undissolved matter. Occurs. The content of other basic nucleophilic compounds in the microcapsules can be appropriately set by those skilled in the art in consideration of the effective amount.

  According to one embodiment of the present invention, step (A) is not particularly limited, but is a halogenated hydrocarbon solution of a biodegradable polymer and a halogenated hydrocarbon solution of a basic nucleophilic compound. Are preferably prepared separately and mixed immediately before step (B) to prepare the first phase. Thereby, interaction with a biodegradable polymer and a basic nucleophilic compound can be suppressed as much as possible.

  Both the halogenated hydrocarbon solution of the biodegradable polymer and the first phase containing the basic nucleophilic compound are preferably used immediately after preparation. The first phase containing the hydrogen halide solution of the biodegradable polymer and the basic nucleophilic compound may be at room temperature, but is preferably cooled. The cooling may be performed by cooling the components before preparing the final first phase, or by cooling the process of preparing the first phase.

  According to a further embodiment of the present invention, the mixing of the halogenated hydrocarbon solution of the biodegradable polymer and the halogenated hydrocarbon solution of the basic nucleophilic compound can use general mixing means, It is preferable to use a static mixer because the time until mixing after the mixing can be eliminated. In this case, the cooling of the first phase is performed by mixing the two liquids with the static mixer during mixing by providing a cooling means in the static mixer (for example, providing a trap for flowing cooling water outside the static mixer). May be.

  The second phase in step (B) is an aqueous phase, and it is preferred to add a hydrophilic colloid or surfactant to stabilize the emulsion and adjust the size of the microcapsules in the emulsion. Examples of such a compound that can be used as a hydrophilic colloid or a surfactant include, but are not limited to, polyvinyl alcohol, carboxymethyl cellulose, gelatin, polyvinyl pyrrolidone, Tween 80, Tween 20, and the like.

  The concentration of hydrophilic colloid or surfactant in the second phase should be sufficient to stabilize the emulsion and can affect the final size of the microcapsules. Usually, the concentration of the hydrophilic colloid or the surfactant in the second phase varies depending on the kind of the hydrophilic colloid or the surfactant, but 0.01% by mass or more is preferable for polyvinyl alcohol, and 0.1% by mass. % Or more is more preferable, 10 mass% or less is preferable, and 5 mass% or less is more preferable. When the concentration of polyvinyl alcohol is less than 0.01% by mass, the microcapsule particles tend to agglomerate with each other to form an agglomerate. When the concentration exceeds 10% by mass, the foam generated during emulsification has a liquid surface during drying in water. There is a concern that the residual solvent in the microcapsule increases due to covering and hindering evaporation of the organic solvent.

  In one embodiment of the present invention, it is preferable to cool at least one of the first phase and the second phase. The first phase may be cooled by cooling each component before preparation, or the second phase may be cooled after preparation. By cooling any of these phases, it is possible to prevent the molecular weight of the biodegradable polymer from being lowered after mixing in the step (B). “Cooling” in this specification means, for example, a temperature lower than 15 ° C., preferably 15 ° C. or less, and more preferably 5 ° C. or less.

  Moreover, in one embodiment of this invention, it is preferable that mixing in a process (B) is continuously performed by the above-mentioned process (A) with various emulsifiers, for example, a static mixer, a homomixer, or a high pressure homogenizer. By carrying out continuously, degradation of the biodegradable polymer can be suppressed.

  Examples of the drying step of the emulsion in the present invention include methods in which the organic solvent evaporates, such as drying in water, freeze drying, and drying under reduced pressure. More preferably, the step of drying the emulsion is drying in water.

  In one embodiment of the present invention, all steps, especially the first phase preparation step and the second phase mixing step with the first phase containing the basic nucleophilic compound, are carried out under cooling. It is preferable to carry out at 15 ° C. or less, more preferably 5 ° C. or less. When each process is performed at a temperature higher than 15 ° C., the molecular weight maintaining effect of the biodegradable polymer of the present invention may not be sufficiently exhibited. Also, the drying process of the emulsion is preferably carried out at 15 ° C. or lower when drying in water.

  The microcapsules obtained by the production method of the present invention can be made into a preparation that can be used for pharmaceutical use such as injections by sieving with a suitable sieve before and after drying, or at least after drying.

  EXAMPLES Hereinafter, although an Example and a comparative example demonstrate this invention in detail, this invention is not limited to these Examples.

Example 1
2 g of risperidone and 3 g of lactic acid-glycolic acid copolymer (lactic acid: glycolic acid = 3: 1, weight average molecular weight 97000 / PLGA) were dissolved in 20 mL of dichloromethane. Immediately after dissolution, this solution was fed at a rate of 10 mL / min and a 0.1% by weight polyvinyl alcohol (PVA) aqueous solution at a rate of 1000 mL / min, and a pipeline homomixer (Primix Co., Ltd.). To obtain an O / W emulsion (emulsification time: 2 minutes). All operations were performed at room temperature (20-28 ° C).

  Next, the obtained emulsion was stirred at room temperature (20 to 28 ° C.) for 3 hours with a propeller stirrer, and the solvent was evaporated by drying in water.

  After removing the solvent, it was sieved using a 150 μm sieve to collect the sieved liquid, and then sieved with a 25 μm sieve. The residue on the obtained sieve was slowly washed with 1 L of water, then lyophilized, and further sieved with a 425 μm sieve to obtain 2.1 g of microcapsules.

Comparative Example 1
A solution (a) obtained by dissolving 4 g of risperidone in 12.68 g of benzyl alcohol and 6 g of lactic acid-glycolic acid copolymer (lactic acid: glycolic acid = 3: 1, weight average molecular weight 97000 / PLGA) were dissolved in 30 g of ethyl acetate. Solution (b) was prepared. The solution (c) which added ethyl acetate so that it might become 6.5 mass% in advance to 1 mass% polyvinyl alcohol (PVA) was prepared. Immediately after mixing the solution (a) and the solution (b), the solution (c) is fed at a rate of 50 mL / min and a pipeline homomixer (manufactured by Primics Co., Ltd.) is used. To obtain an O / W emulsion (emulsification time: 4.5 minutes).

  Next, 2500 mL of 2.5% ethyl acetate aqueous solution was added to the obtained emulsion, and the mixture was stirred for 3 hours at room temperature with a propeller stirrer, and the solvent was evaporated by drying in water.

  After removing the solvent, it was sieved using a 25 μm sieve, and the residue was washed with 1 L of water. The obtained microcapsules were dispersed in 400 mL of 25% ethanol solution, and stirred and washed for 1 hour. This was sieved with a 150 μm sieve, the sieved liquid was collected, and then sieved with a 25 μm sieve. The residue on the obtained sieve was collected, then freeze-dried, and further sieved with a 425 μm sieve to obtain 0.4 g of microcapsules.

Test example 1
The weight average molecular weight of the lactic acid-glycolic acid copolymer in the microcapsules obtained in Example 1 and Comparative Example 1 was measured by the following method. About 40 mg of microcapsules were dissolved in 5 mL of tetrahydrofuran to obtain a sample solution. Next, 10 μL of the sample solution was subjected to chromatography equipped with a molecular sieve column (manufactured by Tosoh Corporation: TSK-GEL SUPER H4000 × 2, H2000 × 1, column temperature 40 ° C.), and in a tetrahydrofuran mobile phase. Development was carried out at a flow rate of 0.6 mL / min, and the weight average molecular weight was measured. The respective molecular weight change rates were 2.2% and 13.9%. The molecular weight change rate was calculated by the following formula.
Molecular weight change rate (%) = (weight average molecular weight of PLGA at each time point−weight average molecular weight of PLGA of raw material) / weight average molecular weight of PLGA of raw material × 100

Example 2
Risperidone 1.5 g and lactic acid-glycolic acid copolymer (lactic acid: glycolic acid = 3: 1, weight average molecular weight 97000 / PLGA) 2.44 g were dissolved in 12 mL of dichloromethane. Immediately after dissolution, this solution was fed at a rate of 10 mL / min and 0.1% by mass polyvinyl alcohol (PVA) aqueous solution cooled to 15 ° C. at a rate of 1000 mL / min. Emulsified O / W emulsion was obtained using (Primics Co., Ltd.) (emulsification time: 1.2 minutes).

  Next, the obtained emulsion was stirred with a propeller stirrer at 15 ° C. for 3 hours, and the solvent was evaporated by drying in water.

  After removing the solvent, it was sieved using a 150 μm sieve to collect the sieved liquid, and then sieved with a 25 μm sieve. The residue on the obtained sieve was slowly washed with 1 L of water, then lyophilized, and further sieved with a 425 μm sieve to obtain 1.2 g of microcapsules.

Example 3
2 g of risperidone and 3 g of lactic acid-glycolic acid copolymer (lactic acid: glycolic acid = 3: 1, weight average molecular weight 97000 / PLGA) were dissolved in 20 mL of dichloromethane. Immediately after dissolution, this solution was fed at a rate of 10 mL / min and a 0.1% by mass polyvinyl alcohol (PVA) aqueous solution cooled to 5 to 10 ° C. at a rate of 1000 mL / min. The mixture was emulsified using a mixer (manufactured by Primemics) to obtain an O / W emulsion (emulsification time: 2 minutes).

  Next, the obtained emulsion was stirred with a propeller stirrer at 5 to 10 ° C. for 3 hours, and the solvent was evaporated by drying in water.

  After removing the solvent, it was sieved using a 150 μm sieve to collect the sieved liquid, and then sieved with a 25 μm sieve. The residue on the obtained sieve was slowly washed with 1 L of water, then lyophilized, and further sieved with a 425 μm sieve to obtain 1.6 g of microcapsules.

Test example 2
In the same manner as in Test Example 1, the weight average molecular weight of the lactic acid-glycolic acid copolymer in the microcapsules obtained in Example 2 and Example 3 was measured. The respective molecular weight change rates were 2.5% and 0.0%.

Experimental Example 1: Change in molecular weight of lactic acid-glycolic acid copolymer (for risperidone)
According to the formulation of Table 1, a solution (a) comprising risperidone and a solvent and a solution (b) comprising a lactic acid-glycolic acid copolymer (lactic acid: glycolic acid = 3: 1, weight average molecular weight 97000 / PLGA) and a solvent. Prepared. In each formulation, solutions (a) and (b) are mixed and stored at 4 ° C., 25 ° C. and 37 ° C., and the weight average molecular weight of the lactic acid-glycolic acid copolymer in the sample is 0 after preparation (immediately after preparation). Measurements were made at 1, 3, 6, 21, 24 hours.

  The weight average molecular weight of the lactic acid-glycolic acid copolymer was measured according to Test Example 1 by dissolving about 100 mg of the solution in 5 mL of tetrahydrofuran to obtain a sample solution.

  From this result, the decrease in the molecular weight of the lactic acid-glycolic acid copolymer of Formula 1 was moderate compared to Formula 2, and in Formula 1 at 4 ° C., it hardly decreased until 3 hours after preparation ( FIG. 1). From this, it can be seen that the use of dichloromethane as a solvent can significantly suppress the change in molecular weight of a biodegradable polymer such as a lactic acid-glycolic acid copolymer.

Experimental Example 2: Change in molecular weight of lactic acid-glycolic acid copolymer (in the case of oxybutynin)
According to the formulation of Table 2, a solution (a) composed of oxybutynin and a solvent and a solution (b) composed of a lactic acid-glycolic acid copolymer (lactic acid: glycolic acid = 3: 1, weight average molecular weight 78000 / PLGA) and a solvent. Prepared. In each formulation, solutions (a) and (b) are mixed and stored at 4 ° C., 25 ° C. and 37 ° C., and the weight average molecular weight of the lactic acid-glycolic acid copolymer in the sample is 0 after preparation (immediately after preparation). Measurements were made at 1, 3, 6, 21, 24 hours.

  The weight average molecular weight of the lactic acid-glycolic acid copolymer was measured according to Test Example 1 by dissolving about 100 mg of the solution in 5 mL of tetrahydrofuran to obtain a sample solution.

  From this result, the molecular weight of the lactic acid-glycolic acid copolymer of the prescription 3 hardly decreased even after 24 hours, while the prescription 4 gradually decreased over time (FIG. 2). For this reason, it turns out that the change of the molecular weight of biodegradable polymers like a lactic acid-glycolic acid copolymer can be suppressed significantly by using a dichloromethane as a solvent.

As used herein, “microcapsule” means a particle comprising a polymer that acts as a matrix or binder of particles. The active agent or other substance dispersed or dissolved in a microcapsule polymer Mato Riku the scan may contain. The polymer is preferably biodegradable and biocompatible. “Biodegradable” means a property that is easily degraded and metabolized in the body, and “biocompatible” means a pharmaceutically acceptable property that is not toxic to the body.

Comparative Example 1
And Risuperido down 4 g was dissolved in benzyl alcohol 12.68g solution (a), lactic acid - glycolic acid copolymer (lactic acid: glycolic acid = 3: 1, weight average molecular weight 97000 / PLGA) dissolved in 30g of ethyl acetate to 6g Solution (b) was prepared. The solution (c) which added ethyl acetate so that it might become 6.5 mass% in advance to 1 mass% polyvinyl alcohol (PVA) was prepared. Immediately after mixing the solution (a) and the solution (b), the solution (c) is fed at a rate of 50 mL / min and a pipeline homomixer (manufactured by Primics Co., Ltd.) is used. To obtain an O / W emulsion (emulsification time: 4.5 minutes).

Claims (8)

A method for producing a microcapsule containing a basic nucleophilic compound,
(A) preparing a first phase comprising a biodegradable polymer, a basic nucleophilic compound, and a halogenated hydrocarbon as a solvent;
(B) A production method comprising a step of preparing an emulsion by mixing the first phase and a second phase which is an aqueous phase, and (C) a step of drying the obtained emulsion in water. The manufacturing method according to claim 1, wherein at least one of the first phase and the second phase is cooled. In the step (A), a halogenated hydrocarbon solution of a biodegradable polymer and a halogenated hydrocarbon solution of a basic nucleophilic compound are separately prepared and mixed immediately before the step (B). The production method according to claim 1 or 2, wherein the phase is prepared. The method according to claim 3, wherein the mixing in the step (A) is performed using a static mixer. The manufacturing method of any one of Claims 1-4 with which mixing in a process (B) is performed continuously with a process (A) by a static mixer, a homomixer, or a high-pressure homogenizer. The production method according to any one of claims 1 to 5, wherein the halogenated hydrocarbon is dichloromethane or chloroform. The production method according to claim 1, wherein the biodegradable polymer is a lactic acid-glycolic acid copolymer. The production method according to claim 1, wherein the basic nucleophilic compound is risperidone, oxybutynin, or naltrexone.

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