JP5375324B2 - Method for producing polymer fine particles - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing polymer fine particles from an O/W emulsion or an S/O/W emulsion. <P>SOLUTION: The method for producing polymer fine particles includes a process for removing an oil phase portion from an O/W emulsion or an S/O/W emulsion. In the method, the oil phase portion to be removed is a water-immiscible ester-based or carbonic acid-based organic solvent, and the O/W volume ratio is 0.25-3 when the O/W emulsion or the S/O/W emulsion is prepared. <P>COPYRIGHT: (C)2011,JPO&amp;INPIT

Description

  The present invention relates to a method for producing polymer fine particles from an O / W emulsion or an S / O / W emulsion.

  The use of a microparticle formulation in which a drug is encapsulated in polymer-based microparticles as a drug carrier has been studied, and a method for producing a polymer microparticle in which a drug is encapsulated includes a volatile organic solvent in which a polymer is dissolved. There is known a method of forming polymer fine particles by forming an O / W emulsion by emulsifying an oil phase in an aqueous phase and removing an organic solvent from the emulsion.

  Specifically, Patent Document 1 discloses the production of polymer fine particles encapsulating a polypeptide using a poly (lactic acid-glycolic acid) copolymer, which is a biodegradable polymer. Here, as an organic solvent for dissolving the polymer, dichloromethane is exemplified, and after forming an O / W emulsion using a turbine mixer, particles are produced by a submerged drying method. However, there is no specific description about the average particle size of the particles produced by this method.

  Non-Patent Document 1 discloses a method for producing particles encapsulating proteins using an amphiphilic block polymer composed of polylactic acid and polyethylene glycol by the same method as Patent Document 1. Further, Non-Patent Document 1 examines the relationship between the particle production conditions and the average particle size, and shows that the average particle size varies between 1 and 3 μm.

  Patent Document 2 discloses a method for producing polymer fine particles capable of efficiently encapsulating a protein using an amphiphilic polymer. In this document, a method for producing polymer fine particles from an S / O / W emulsion comprising fine particles obtained by freeze-drying a W / O emulsion using an amphiphilic polymer is disclosed. ing. However, no specific mention is made regarding the average particle size of the polymer fine particles produced by this method.

JP-A-8-3055 JP 2008-88158 A

International Journal of Pharmaceuticals 1999, Vol. 178, p. 245-255

  The average particle size required for the fine polymer particles encapsulating a drug varies greatly depending on the purpose, but for the purpose of infiltration into the skin and transport into tissue cells, the particle size of the polymer fine particles is less than 1 μm. It is required to be. However, it is difficult to produce polymer fine particles having an average particle diameter of less than 1 μm in the conventional method for producing polymer fine particles via emulsion. Accordingly, an object of the present invention is to provide a method for producing polymer fine particles having an average particle diameter of less than 1 μm.

  As a result of intensive studies to solve the above problems, the present inventors have completed the present invention comprising the following (1) to (6).

  (1) A method for producing polymer fine particles comprising a step of removing an oil phase component from an O / W emulsion or an S / O / W emulsion, wherein the oil phase component to be removed is a water-immiscible ester or carbonate organic A method for producing polymer fine particles, which is a solvent and has an O / W volume ratio of 0.25 to 3 at the time of preparing an O / W emulsion or an S / O / W emulsion.

  (2) The method for producing polymer fine particles according to (1), wherein the polymer is a biodegradable polymer or an amphiphilic polymer containing a biodegradable polymer as a constituent component.

  (3) The method for producing polymer fine particles according to (2), wherein the amphiphilic polymer includes a biodegradable hydrophobic portion.

  (4) The method for producing the S / O / W emulsion comprises a step of dehydrating a W / O emulsion containing a hydrophilic substance in an aqueous phase to obtain a solid content, and the solid content is converted into the water-immiscible ester. Production of polymer fine particles according to any one of (1) to (3), comprising a step of obtaining an S / O suspension by dispersing in an organic solvent or a carbonated organic solvent, and a step of emulsifying the S / O suspension in an aqueous solvent. Method.

  (5) The method for producing polymer fine particles according to any one of (1) to (4), wherein the water-immiscible ester organic solvent is ethyl acetate.

(6) The method for producing polymer fine particles according to any one of (1) to (4), wherein the water-immiscible carbonated organic solvent is dimethyl carbonate.

  According to the present invention, polymer fine particles having an average particle diameter of less than 1 μm suitable for a drug carrier can be produced.

  The polymer constituting the polymer fine particle produced in the present invention is not particularly limited, but when the polymer fine particle is used as a drug carrier, it is preferably biodegradable. Further, when an amphiphilic polymer is used, an O / W emulsion or a W / O emulsion can be easily formed, which is preferable. Accordingly, the polymer used in the present invention is more preferably an amphiphilic polymer and a polymer containing a biodegradable polymer as a constituent component. Furthermore, when an amphiphilic polymer is used, an amphiphilic polymer containing a biodegradable hydrophobic portion is more preferably used.

  Examples of the biodegradable polymer constituting the fine polymer particles include polyglycolic acid, polylactic acid, poly (lactic acid-glycolic acid) copolymer, poly (2-hydroxybutyric acid), poly (2-hydroxyvaleric acid), poly Preferred examples include (2-hydroxycaproic acid), poly (2-hydroxycapric acid), poly (malic acid) or derivatives and copolymers of these polymer compounds, but poly (lactic acid-glycolic acid) A copolymer is preferred.

  Moreover, as an amphiphilic polymer which comprises the said polymer microparticles | fine-particles, what contains the said biodegradable polymer as a hydrophobic part and contains a biocompatible polymer as a hydrophilic part is mentioned as a preferable example. Examples of the biodegradable polymer constituting the hydrophobic portion include polyglycolic acid, polylactic acid, poly (lactic acid-glycolic acid) copolymer, poly (2-hydroxybutyric acid), poly (2-hydroxyvaleric acid), and poly (2 -Hydroxycaproic acid) or poly (2-hydroxycapric acid) may be mentioned, and a poly (lactic acid-glycolic acid) copolymer is preferable. Examples of the biocompatible polymer constituting the hydrophilic portion include polysaccharides (cellulose, chitin, chitosan, gellan gum, alginic acid, hyaluronic acid, pullulan or dextran), polypropylene glycol or polyethylene glycol, and dextran or polyethylene glycol. It is preferable.

  The present invention is characterized in that polymer fine particles containing the polymer as a constituent component are produced from an O / W emulsion or an S / O / W emulsion. The O / W emulsion is a state in which an oil phase in which the polymer is dissolved is emulsified in an aqueous phase. Similarly, the S / O / W emulsion is a state in which the polymer is dissolved and an oil phase containing a solid component is emulsified in an aqueous phase.

  First, a method for producing polymer fine particles from an O / W emulsion will be described.

  The solvent used as the oil phase of the O / W emulsion is a water-immiscible organic solvent, and an ester-based or carbonate-based organic solvent is used. The ester organic solvent is an organic solvent having an ester skeleton in the molecule, and examples thereof include methyl acetate, ethyl acetate, propyl acetate, and butyl acetate, and ethyl acetate is preferable. The carbonic organic solvent is an organic solvent having a carbonic acid skeleton in the molecule, and examples thereof include dimethyl carbonate, methyl ethyl carbonate, and diethyl carbonate, and dimethyl carbonate is preferred.

  The aqueous phase of the O / W emulsion preferably contains a dispersion stabilizer. The dispersion stabilizer is preferably one that stabilizes the water-oil interface of the emulsion, more preferably an amphiphilic compound or a hydrophilic polymer, and a polyethylene oxide-polypropylene oxide-polyethylene oxide block polymer (for example, Pluronic (registered trademark) commercially available from BASF is more preferably used.

  In the present invention, the O / W volume ratio of the O / W emulsion is adjusted to 0.25 to 3, preferably 0.25 to 0.5. The O / W volume ratio is a volume ratio before emulsification of an oil phase containing a polymer and an aqueous phase, and the O / W volume ratio in an O / W emulsion is a polymer in which a polymer is dissolved in a water-immiscible organic solvent. It is a volume ratio of a solution (oil phase) and an aqueous phase. When the O / W volume ratio is less than 0.25, the average particle diameter of the obtained polymer fine particles exceeds 1 μm, which is not preferable. Moreover, when O / W volume ratio exceeds 3, since a stable O / W emulsion cannot be obtained, it is not preferable.

  As a method for preparing the O / W emulsion, first, the polymer is dissolved in a water-immiscible organic solvent. Next, a stable O / W emulsion is prepared by blending the polymer solution (oil phase) and the aqueous phase so that the O / W volume ratio is 0.25 to 3, and stirring with a high-pressure homogenizer or a high-speed mixer. Is formed. The fine polymer particles obtained by the present invention can be used as a drug carrier. However, when producing fine polymer particles as a drug carrier from an O / W emulsion, a hydrophobic drug is dissolved in a polymer solution in advance. Just keep it.

  By removing the oil phase from the O / W emulsion, a polymer fine particle dispersion in which polymer fine particles are dispersed in the aqueous phase can be obtained. Examples of the method for obtaining polymer fine particles by removing the oil phase from the O / W emulsion include in-liquid drying, freeze drying, and spray drying. However, the performance as a drug carrier (for example, sustained release of the drug) is maintained. Therefore, in-liquid drying is preferably applied.

  Next, a method for producing polymer fine particles from the S / O / W emulsion will be described.

  The S / O / W emulsion is obtained by emulsifying the S / O dispersion (S / O suspension) in an aqueous solvent (aqueous phase). The present invention is characterized in that the water-immiscible organic solvent is an ester-based or carbonate-based organic solvent as a solvent for preparing the S / O suspension. When an ester-based or carbonate-based organic solvent is not used, the average particle size of the obtained polymer fine particles exceeds 1 μm, which is not preferable.

  As a method for preparing the S / O suspension, first, a polymer solution (oil phase) and a solution (aqueous phase) in which the constituent components of the solid component in the S / O / W emulsion are dissolved in an aqueous solvent are mixed. It is preferable to prepare a S / O dispersion by preparing a W / O emulsion and dehydrating the W / O emulsion. In this case, since the constituent component of the solid component of the S / O / W emulsion to be dissolved in the aqueous solvent needs to be dissolved in the aqueous phase of the W / O emulsion, it is preferably a hydrophilic substance.

  The solvent used as the oil phase in the step of preparing the W / O emulsion is not particularly limited as long as it is a water-immiscible organic solvent that can be volatilized and removed by lyophilization or the like. An organic solvent is preferred. Further, as the aqueous phase of the W / O emulsion, an aqueous solvent used in the aqueous phase of the O / W emulsion is preferably used. Although the polymer fine particles obtained by the present invention can be used as a drug carrier, in the case of producing polymer fine particles as a drug carrier from an S / O / W emulsion, the solid component of the S / O / W emulsion As a constituent component, a hydrophilic drug may be dissolved in advance in the aqueous phase of the W / O emulsion.

  The W / O emulsion is formed by adding the aqueous phase to the oil phase and stirring as in the preparation of the O / W emulsion. The volume ratio (W / O volume ratio) between the water phase and the oil phase is preferably 0.001 to 2, more preferably 0.01 to 1. By setting the W / O volume ratio within the range shown on the left, a stable W / O emulsion can be prepared.

  The W / O emulsion prepared as described above is dehydrated to prepare an S / O dispersion (S / O suspension). As a method for preparing an S / O suspension by dehydrating a W / O emulsion, a solid content is prepared by removing an aqueous phase and an oil phase from the W / O emulsion, and the solid content is redispersed in an oil phase. Is preferred. Methods for removing the aqueous and oil phases from the W / O emulsion include heating, vacuum drying, dialysis, lyophilization, centrifugation, filtration, reprecipitation, and combinations thereof. This is preferable because there is little structural change due to coalescence of particles in the O emulsion and modification of the hydrophilic substance due to high temperature can be avoided.

  An S / O / W emulsion can be obtained by dispersing the S / O suspension prepared as described above in an aqueous solvent. As an aqueous solvent here, what is used with the aqueous phase of O / W emulsion is used preferably. In the present invention, the volume ratio (O / W volume ratio) between the S / O suspension (oil phase) and the aqueous solvent (aqueous phase) at the time of preparing the S / O / W emulsion is defined as O / W emulsion. Like the / W volume ratio, it is characterized by being adjusted to 0.25 to 3, preferably 0.25 to 0.5. When the O / W volume ratio is less than 0.25, the average particle diameter of the obtained polymer fine particles exceeds 1 μm, which is not preferable. Moreover, when O / W volume ratio exceeds 3, since stable S / O / W cannot be obtained, it is unpreferable.

  An oil phase component is removed from the S / O / W emulsion, and a polymer fine particle dispersion in which polymer fine particles are dispersed in an aqueous phase is obtained. Examples of the method for obtaining the polymer fine particles by removing the oil phase from the S / O / W emulsion include in-liquid drying, freeze drying, spray drying, etc., but performance as a drug carrier (for example, sustained release of the drug) In-liquid drying is preferably applied from the viewpoint of maintaining the viscosity.

Reference Example 1 Synthesis of block polymer of polyethylene glycol and poly (lactic acid-glycolic acid) copolymer Polyethylene glycol monomethyl ether (manufactured by NOF Corporation, SUNBRIGHT MEH-20H, number average molecular weight 5128, Mw / Mn = 1.02) (0 .3 g), (DL) -lactide (2.16 g) and glycolide (1.74 g) were mixed and heated to 140 ° C. After stirring for 20 minutes, tin octylate (II) (0.05% by weight based on polyethylene glycol monomethyl ether) was added, and the mixture was stirred at 180 ° C. for 3 hours. The reaction solution is returned to room temperature, dissolved in chloroform (concentration to about 100 mg / ml), purified by reprecipitation with diethyl ether cooled to 0 ° C., and the resulting solid is filtered and dried under reduced pressure. A block polymer of polyethylene glycol and poly (lactic acid-glycolic acid) copolymer was obtained as a white solid.

Reference Example 2 Synthesis of graft polymer of dextran and poly (lactic acid-glycolic acid) copolymer Dextran (Nacalai Tesque Co., Ltd., Nacalai standard special grade product, number average molecular weight 13000, 5.0 g) was added to formamide (100 ml), Heated to 80 ° C. To this solution, 1,1,1,3,3,3-hexamethyldisilazane (100 ml) was added dropwise over 20 minutes. After completion of dropping, the mixture was stirred at 80 ° C. for 2 hours. After completion of the reaction, the reaction solution was returned to room temperature, and the two layers were separated using a separatory funnel. The upper layer was concentrated under reduced pressure, methanol (300 ml) was added, and the resulting solid was filtered and dried to obtain TMS-dextran (11.4 g) as a white solid. TMS-dextran and tert-butoxy potassium (35 mg) were dried under reduced pressure for 1 hour, tetrahydrofuran (10 ml) was added, and the mixture was stirred for 1 hour at room temperature. To this solution, a solution of (DL) -lactide (1.12 g) and glycolide (0.9 g) in tetrahydrofuran (15 ml) was added dropwise and stirred for 5 minutes. After completion of the reaction, the solvent was concentrated under reduced pressure, and TMS-dextran and poly (lactic acid-glycolic acid) copolymer graft polymer (1.96 g) were obtained as a white solid by reprecipitation purification in a chloroform-methanol system. It was. Methanol (6.3 ml) and 12N hydrochloric acid (0.7 ml) were added to a solution of TMS-dextran-PLGA (1.96 g) in chloroform (14 ml), and the mixture was stirred at room temperature for 30 minutes. After evaporating the solvent under reduced pressure, the residue was dissolved in chloroform (10 ml) and added dropwise to diethyl ether cooled to 0 ° C. to precipitate the product. The precipitate was filtered off and concentrated under reduced pressure to obtain a graft polymer (1.25 g) of dextran and poly (lactic acid-glycolic acid) copolymer.

Example 1 Production of microparticles made of poly (lactic acid-glycolic acid) copolymer using dimethyl carbonate <Method>
Poly (lactic acid-glycolic acid) copolymer (manufactured by Sigma (P2191), average molecular weight 40,000-75,000, lactic acid / glycolic acid ratio = 1/1) 5 mg was dissolved in 50 μL, 200 μL or 500 μL of dimethyl carbonate. It was. The polymer solution was dropped into a test tube with a stopper containing 2 mL of a 10% Pluronic F68 (BASF) aqueous solution, and stirred with a vortex mixer for 30 seconds to obtain an O / W emulsion solution. The O / W emulsion solution was distilled off under reduced pressure at 37 ° C. to remove dimethyl carbonate to obtain a polymer fine particle dispersion. The polymer fine particle dispersion was pre-frozen with liquid nitrogen and then freeze-dried for 12 hours to obtain polymer fine particle powder.

<Result>

The average particle diameter of the polymer fine particles was calculated using a scanning electron microscope. As a result, when 50 μL of dimethyl carbonate was used, 18.0 μm was obtained, and when 200 μL of dimethyl carbonate was used, 3.53 μm particles were obtained. When dimethyl 500 μL was used, the wavelength was 433 nm. That is, the average particle diameter of the polymer fine particles was less than 1 μm when the O / W volume ratio was 0.25, but exceeded 1 μm when the O / W volume ratio was less than 0.25 (Table 1). 1).

Example 2 Production of Fine Particles Comprising Block Polymer of Polyethylene Glycol and Poly (Lactic Acid-Glycolic Acid) Copolymer Using Dimethyl Carbonate <Method>
5 mg of a block polymer of polyethylene glycol and poly (lactic acid-glycolic acid) copolymer of Reference Example 1 was dissolved in 100 μL of dimethyl carbonate to prepare a 50 mg / mL polymer solution. After adding 20 μL of tert-butanol to the polymer solution, 50 μL of a 1 mg / mL fluorescent-labeled dextran aqueous solution was added dropwise and stirred for 10 seconds with a vortex mixer to produce a W / O emulsion. The W / O emulsion was pre-frozen with liquid nitrogen, and then lyophilized with a freeze dryer for 12 hours. The obtained solid content was dispersed in 50 μL, 200 μL or 500 μL of dimethyl carbonate to prepare an S / O suspension. The S / O suspension was added dropwise to a test tube with a stopper containing 2 mL of a 10% Pluronic F68 (BASF) aqueous solution, and stirred with a vortex mixer for 30 seconds to prepare an S / O / W emulsion. Dimethyl carbonate was removed from the S / O / W emulsion by drying in liquid to obtain a polymer fine particle dispersion. The polymer fine particle dispersion was pre-frozen with liquid nitrogen and then freeze-dried for 12 hours to obtain polymer fine particle powder.

<Result>
The average particle diameter of the polymer fine particles was calculated using a scanning electron microscope. As a result, when 50 μL of dimethyl carbonate was used, it was 12.1 μm, when 200 μL of dimethyl carbonate was used, 2.76 μm, and 500 μL of dimethyl carbonate. In the case of using, the thickness was 554 nm. That is, the average particle diameter of the polymer fine particles was less than 1 μm when the O / W volume ratio was 0.25, but exceeded 1 μm when the O / W volume ratio was less than 0.25 (Table 1). 1).

Example 3 Production of Fine Particles Consisting of Graft Polymer of Dextran and Poly (lactic acid-glycolic acid) Copolymer Using Dimethyl Carbonate <Method>
5 mg of the dextran and poly (lactic acid-glycolic acid) copolymer graft polymer of Reference Example 2 was dissolved in 100 μL of dimethyl carbonate to prepare a 50 mg / mL polymer solution. After adding 20 μL of tert-butanol to the polymer solution, 50 μL of a 1 mg / mL fluorescent-labeled dextran aqueous solution was added dropwise and stirred for 10 seconds with a vortex mixer to produce a W / O emulsion. The W / O emulsion was pre-frozen with liquid nitrogen and then lyophilized for 12 hours in a freeze dryer. The obtained solid content was dispersed in 50 μL, 100 μL, 200 μL, 350 μL, 500 μL, 1 mL, 2 mL, or 6 mL of dimethyl carbonate to prepare an S / O suspension. The S / O suspension was added dropwise to a test tube with a stopper containing 2 mL of a 10% Pluronic F68 (BASF) aqueous solution, and stirred with a vortex mixer for 30 seconds to prepare an S / O / W emulsion. Dimethyl carbonate was removed from the S / O / W emulsion by drying in liquid to obtain a polymer fine particle dispersion. The polymer fine particle dispersion was pre-frozen with liquid nitrogen and then freeze-dried for 12 hours to obtain polymer fine particle powder.

<Result>
As a result of calculating the average particle diameter of the fine polymer particles using a scanning electron microscope, 11.6 μm when dimethyl carbonate 50 μL is used, 8.45 μm when dimethyl carbonate 100 μL is used, and 200 μL dimethyl carbonate. Is used to be 4.94 μm, dimethyl carbonate 350 μL is used 1.56 μm, dimethyl carbonate 500 μL is used 410 nm, dimethyl carbonate 1 mL is used 290 nm, It was calculated as 440 nm when 2 mL of dimethyl was used, and 290 nm when 6 mL of dimethyl carbonate was used. That is, the average particle diameter of the polymer fine particles was less than 1 μm when the O / W volume ratio was 0.25 or more, but exceeded 1 μm when the O / W volume ratio was less than 0.25. (Table 1).

Example 4 Production of Fine Particles Consisting of Graft Polymer of Dextran and Poly (lactic acid-glycolic acid) Copolymer Using Ethyl Acetate <Method>
5 mg of the dextran and poly (lactic acid-glycolic acid) copolymer graft polymer of Reference Example 2 was dissolved in 100 μL of dimethyl carbonate to prepare a 50 mg / mL polymer solution. After adding 20 μL of tert-butanol to the polymer solution, 50 μL of a 1 mg / mL fluorescently labeled dextran aqueous solution was added dropwise and stirred for 10 seconds with a vortex mixer to prepare a W / O emulsion. The W / O emulsion was pre-frozen with liquid nitrogen, and then lyophilized with a freeze dryer for 12 hours. The obtained solid content was dispersed in 50 μL, 200 μL or 500 μL of ethyl acetate to prepare an S / O suspension. The S / O suspension was added dropwise to a test tube with a stopper containing 2 mL of a 10% Pluronic F68 (BASF) aqueous solution, and stirred with a vortex mixer for 30 seconds to prepare an S / O / W emulsion. Ethyl acetate was removed from the S / O / W emulsion by drying in liquid to obtain a polymer fine particle dispersion. The polymer fine particle dispersion was pre-frozen with liquid nitrogen and then freeze-dried for 12 hours to obtain polymer fine particle powder. The polymer fine particle dispersion was pre-frozen with liquid nitrogen and then freeze-dried to obtain polymer fine particle powder.

<Result>
The average particle diameter of the polymer fine particles was calculated using a scanning electron microscope. As a result, when 50 μL of ethyl acetate was used, it was 9.8 μm, when 200 μL of ethyl acetate was used, 5.9 μm, and 500 μL of ethyl acetate. In the case of using, the thickness was 436 nm. That is, the average particle diameter of the polymer fine particles was less than 1 μm when 500 μL of ethyl acetate with an O / W volume ratio of 0.25 was used, but when the O / W volume ratio was less than 0.25. It exceeded 1 μm (Table 1).

Comparative Example 1 Production of Fine Particles Consisting of Graft Polymer of Dextran and Poly (lactic acid-glycolic acid) Copolymer Using Chloroform <Method>
A graft polymer of dextran and poly (lactic acid-glycolic acid) copolymer (5 mg) was dissolved in dimethyl carbonate (100 μL) to prepare a 50 mg / mL polymer solution. After adding 20 μL of tert-butanol to the polymer solution, 50 μL of a 1 mg / mL fluorescent-labeled dextran aqueous solution was added dropwise and stirred for 10 seconds with a vortex mixer to produce a W / O emulsion. The W / O emulsion was pre-frozen with liquid nitrogen and then lyophilized for 12 hours in a freeze dryer. The obtained solid content was dispersed in 50 μL, 200 μL or 500 μL of chloroform to prepare an S / O suspension. The S / O suspension was added dropwise to a test tube with a stopper containing 2 mL of a 10% Pluronic F68 (BASF) aqueous solution, and stirred with a vortex mixer for 30 seconds to prepare an S / O / W emulsion. Chloroform was removed from the S / O / W emulsion by in-liquid drying to obtain a polymer fine particle dispersion. The polymer fine particle dispersion was pre-frozen with liquid nitrogen and then freeze-dried for 12 hours to obtain polymer fine particle powder.

<Result>
The average particle diameter of the polymer fine particles was calculated using a scanning electron microscope. As a result, when 50 μL of chloroform was used, 1.2 μm was used. When 200 μL of chloroform was used, 500 μL of chloroform was used. In this case, it was 1.1 μm. The average particle diameter of the polymer fine particles exceeded 1 μm regardless of the O / W volume ratio.

  The application field of the polymer fine particles obtained by the present invention is wide and can be used in various ways. However, by encapsulating a drug in the polymer fine particles, it can be used as a pharmaceutical composition.

Claims (5)

A method for producing polymer fine particles comprising a step of removing an oil phase from an O / W emulsion or S / O / W emulsion, wherein the polymer comprises a hydrophobic biodegradable polymer or a hydrophobic part of a biodegradable polymer It is a water- soluble polymer, the oil phase to be removed is a water-immiscible ester-based or carbonate-based organic solvent, and the O / W volume ratio at the time of preparing the O / W emulsion or S / O / W emulsion is 0.25. A method for producing polymer fine particles, which is ~ 3. The method for producing polymer fine particles according to claim 1, wherein the polymer is an amphiphilic polymer including a hydrophobic portion of a biodegradable polymer . The method for producing the S / O / W emulsion includes a step of dehydrating a W / O emulsion containing a hydrophilic substance in an aqueous phase to obtain a solid content, and the solid content is converted into the water-immiscible ester system or carbonic acid. The method for producing polymer fine particles according to claim 1 or 2 , comprising a step of obtaining an S / O suspension by dispersing in an organic solvent, and a step of emulsifying the S / O suspension in an aqueous solvent. The method for producing polymer fine particles according to any one of claims 1 to 3 , wherein the water-immiscible ester organic solvent is ethyl acetate. The method for producing polymer fine particles according to any one of claims 1 to 3 , wherein the water-immiscible carbonate-based organic solvent is dimethyl carbonate.