Method for producing microparticles containing poorly soluble drugs

Abstract

The present invention relates to a method for producing microparticles containing a poorly soluble drug and microparticles produced by such a method, which uses two or more types of organic solvents to produce microparticles that are uniform and of excellent quality, have a high encapsulation rate of the poorly soluble drug, and have a low amount of residual organic solvent.

Description

[Technical Field]

[0001] The present invention relates to a method for producing microparticles containing poorly soluble drugs. [Background technology]

[0002] To prepare microparticles or sustained-release formulations containing poorly soluble drugs, the poorly soluble drug is typically dissolved in an organic solvent together with a biodegradable polymer and dispersed in an aqueous phase to form an emulsion. For example, sustained-release formulations containing poorly soluble drugs can be prepared by preparing an oil-in-water (O / W) emulsion, forming microspheres containing the poorly soluble drug, and then removing the organic solvent from the emulsion. However, during the emulsion preparation and microparticle formation process, it is important to thoroughly dissolve the poorly soluble drug and biodegradable polymer in the oil phase to prevent the poorly soluble drug from escaping into the aqueous phase and losing it, thereby increasing the encapsulation rate of the poorly soluble drug within the biodegradable polymer. Furthermore, after microparticle formation, it is important to prevent the poorly soluble drug from transferring to the aqueous phase and being lost during the organic solvent removal process. Because this depends on the organic solvent selected, the selection of the solvent is an important issue in the preparation of microparticles containing poorly soluble drugs.

[0003] During the preparation of emulsions for forming microparticles or preparing sustained-release formulations, dissolving the biodegradable polymer is as important as dissolving the drug component in the solvent, because the drug must be encapsulated in the biodegradable polymer to achieve sustained drug release. Typically, dichloromethane, for example, can be used as an organic solvent for dissolving the biodegradable polymer. However, some poorly soluble drugs have relatively low solubility in dichloromethane, so a large amount of solvent must be used to dissolve the poorly soluble drug in dichloromethane. However, increasing the amount of solvent used increases the likelihood of residual organic solvent remaining, which increases the likelihood of the poorly soluble drug escaping from the oil phase solution to the aqueous phase solution during the preparation of microparticles. This can result in loss of the drug component in the microparticles and a decrease in the encapsulation rate of the drug in the biodegradable polymer.

[0004] Methods for producing such microparticles include, for example, methods using porous membranes, microfluidics using microchannels, emulsion methods, or spray drying methods.

[0005] In the method for preparing the microparticles, the viscosity of the oil phase solution containing the poorly soluble drug and the biodegradable polymer plays an important role in the preparation process, and selecting the type and content of the organic solvent to adjust the viscosity of the oil phase solution is an important issue. However, when the content of the organic solvent is increased to adjust the viscosity, there is a problem that the poorly soluble drug is likely to be lost and the organic solvent is likely to remain, as described above.

[0006] In addition, since the method for removing the solvent from the microparticles differs depending on the properties of the solvent, the solvent used to prepare the oil phase solution can affect the encapsulation rate of the poorly soluble drug in the biodegradable polymer, the content of residual organic solvent, the economic efficiency of the manufacturing method, etc. Methods for removing the solvent from the microparticles include solvent evaporation and solvent extraction.

[0007] The solvent evaporation method is a method of removing a solvent by increasing the temperature to the boiling point of a volatile solvent with a relatively low boiling point, thereby evaporating the solvent. This method has the advantage of being easier and taking less time than the solvent extraction method, but due to the characteristics of the drug corresponding to the active ingredient of the microparticles, problems may occur, such as the drug disappearing together with the solvent as the temperature increases, resulting in a decrease in the encapsulation rate of the drug in the biodegradable polymer.

[0008] The solvent extraction method involves diffusing a non-volatile solvent with a relatively high boiling point from the microparticles into an external solvent due to the difference in concentration. To prevent the drug from being extracted with the solvent, the solvent extraction is performed at a low temperature. To efficiently extract the solvent, such as benzyl alcohol, a co-solvent, such as ethyl acetate or ethanol, is added to the external aqueous phase solution of the microparticles.

[0009] In an attempt to increase the solubility of poorly soluble drugs, methods using benzyl alcohol as a solubilizer have been studied, but these involve solvent extraction. Because benzyl alcohol has a high boiling point of 205.4°C, effective removal requires solvent extraction rather than solvent evaporation. For example, poorly soluble drugs and biodegradable polymers are dissolved in dichloromethane and benzyl alcohol to prepare an oil phase solution, which is then dispersed in an aqueous phase to form microparticles. The benzyl alcohol is then removed using ethyl acetate or ethanol as an extraction solvent.

[0010] However, in the above-mentioned solvent extraction method, the extraction occurs according to a concentration gradient, and therefore the solvent is removed in proportion to the extraction time.

[0011] Therefore, complete removal of residual organic solvents requires a significant amount of work. If solvents such as benzyl alcohol remain without being completely removed, they may act as a solubilizer for the drug component, which may deviate from the release mechanism of the biodegradable polymer, which should be a slow release, resulting in a burst effect, in which the drug is released all at once from the microparticles, making release control difficult.

[0012] As described above, the solvent extraction method has the disadvantages of being more complicated and taking longer to produce than the solvent evaporation method.

[0013] Therefore, in a method for producing microparticles containing a poorly soluble drug, there is a need to develop an economical and efficient production method that can dissolve the poorly soluble drug well, increase the encapsulation rate of the drug in the biodegradable polymer, increase the convenience of production through a simple production method, and produce uniform microparticles. [Prior art documents] [Patent documents]

[0014] [Patent Document 1] KR10-2005-0093236A1 Summary of the Invention [Problem to be solved by the invention]

[0015] An object of the present invention is to provide a method for producing microparticles containing poorly soluble drugs.

[0016] Another object of the present invention is to provide a manufacturing method that uses two or more organic solvents to dissolve a poorly soluble drug, and that can easily produce a drug with uniform and excellent quality, a high encapsulation rate of the poorly soluble drug, and a low amount of residual organic solvent.

[0017] Another object of the present invention is to provide a method for producing microparticles that can reduce the viscosity or density of an oil phase solution by dissolving a poorly soluble drug and a biodegradable polymer in an organic solvent using a small amount of organic solvent, can maintain a laminar flow in a microchannel when producing microparticles by a microfluidic method, and has a high encapsulation rate of a poorly soluble drug while producing uniform and excellent quality microparticles. [Means for solving the problem]

[0018] In order to achieve the above object, the present invention relates to a method for producing microparticles containing a poorly soluble drug, which includes the steps of: 1) dissolving a poorly soluble drug and a biodegradable polymer in a mixed solvent containing two or more organic solvents to produce an oil phase solution; 2) dissolving a surfactant in water to produce an aqueous phase solution; and 3) producing microparticles using the oil phase solution and the aqueous phase solution.

[0019] The mixed solvent may include a first solvent and a co-solvent, and the first solvent may be dichloromethane.

[0020] The cosolvent has a density of 1.3 g / cm 3 or less, polarity index is 3 or less, boiling point is 50°C or less, water solubility is 2 20 ~8 20 g / 100g water.

[0021] The first solvent and the co-solvent are contained in a weight ratio of 1:0.5 to 1:10.

[0022] The poorly soluble drugs include naltrexone, donepezil, finasteride, aripiprazole, olanzapine, palonosetron, minocycline, memantine, alendronate, deoxycholate, risedronate, and the like. e), Ibandronate, Zoledronate, Liraglutide, Exenetide, Lanreotide, Octreotide, Deslorelin, Leuprorelin, Goserelin, Triptorelin, or Dutasteride.

[0023] The poorly soluble drug and the mixed solvent in step 1) can be mixed in a weight ratio of 1:7 to 1:30.

[0024] The poorly soluble drug and the biodegradable polymer in step 1) are contained in a weight ratio of 1:0.5 to 1:10.

[0025] The biodegradable polymer can be selected from the group consisting of polylactide, polylactic acid, polylactide-co-glycolide, polylactic-co-glycolic acid, polyphosphazene, polyiminocarbonate, polyphosphoester, polyanhydride, polyorthoester, polycaprolactone, polyhydroxyvalerate, polyhydroxybutyrate, polyamino acid, and combinations thereof.

[0026] The surfactant may be selected from the group consisting of polyethylene glycol sorbitan monooleate, sorbitan oleate, sodium lauryl sulfate, polyvinyl alcohol (PVA), methylcellulose, polyvinylpyrrolidone, lecithin, gelatin, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oil derivatives, sodium stearate, esteramines, linear diamines, fatty amines, and combinations thereof.

[0027] In the step 3), microparticles can be produced using an oil phase solution and an aqueous phase solution by an emulsion method, a porous membrane method, a spray drying method, or a microfluidic method.

[0028] The method may further include a step of removing residual organic solvent from the microparticles prepared in step 3).

[0029] The step of removing the residual organic solvent may involve placing the microparticles containing the residual organic solvent in an aqueous phase solution and stirring to remove the residual organic solvent.

[0030] The stirring process can include a first stirring step at 10°C to 20°C and 200 to 400 rpm for 30 minutes to 2 hours, a second stirring step at 25°C to 35°C and 200 to 400 rpm for 30 minutes to 2 hours, and a third stirring step at 45°C to 55°C and 200 to 400 rpm for 30 minutes to 2 hours.

[0031] Microparticles containing a poorly soluble drug according to another embodiment of the present invention can be prepared by the above-described method.

[0032] The microparticles may have an encapsulation rate of 90% or more of the poorly soluble drug, and may have a smooth surface and a perfectly spherical shape. [Effects of the Invention]

[0033] The present invention uses two or more organic solvents when dissolving a poorly soluble drug, and can easily produce a tablet with uniform and excellent quality, a high encapsulation rate of the poorly soluble drug, and a low amount of residual organic solvent.

[0034] In addition, the viscosity or density of the oil phase solution can be reduced by dissolving the poorly soluble drug and biodegradable polymer in the organic solvent using a small amount of organic solvent. When microparticles are produced by a microfluidic method, a laminar flow can be maintained within the microchannel, and the produced microparticles have uniformity and excellent quality, while also having a high encapsulation rate of the poorly soluble drug. DETAILED DESCRIPTION OF THE INVENTION

[0035] The present invention relates to a method for producing microparticles containing a poorly soluble drug, comprising the steps of: 1) dissolving a poorly soluble drug and a biodegradable polymer in a mixed solvent containing two or more organic solvents to produce an oil phase solution; 2) dissolving a surfactant in water to produce an aqueous phase solution; and 3) producing microparticles using the oil phase solution and the aqueous phase solution. [Example]

[0036] Although the present invention may be embodied in various different forms, it is not intended to be limited to the embodiments set forth herein, and the present invention is not limited to the embodiments set forth herein.

[0037] In order for microparticles containing poorly soluble drugs to exhibit excellent therapeutic effects, the poorly soluble drug must be well dissolved and contained in the microparticles at a high ratio, the amount of residual organic solvent unrelated to the efficacy of the drug must be small, and the microparticles must be uniform in size.

[0038] Some poorly soluble drugs are soluble in water to some extent in their salt form at room temperature (e.g., the hydrochloride salt of the poorly soluble drug naltrexone has an aqueous solubility of 100 mg / mL at 25°C), but in their free base form they are practically insoluble in water and do not completely dissolve even in organic solutions. The organic solvent used to prepare microparticles containing such poorly soluble drugs in free base form and having excellent properties must be able to dissolve the poorly soluble drug together with the biodegradable polymer, prevent the poorly soluble drug from being lost in the aqueous solution, and be easily removable after the microparticles are prepared.

[0039] Therefore, it is important to select an organic solvent with suitable properties.

[0040] In addition, the selection of solvent is important for economical and efficient production of uniformly sized microparticles. For example, in the case of microfluidic methods, laminar flow of the aqueous and oil phases must be maintained within the microchannel to produce uniformly sized microparticles.

[0041] Even with the same fluid, the Reynolds number (Re) varies within a microchannel depending on the fluid's viscosity, density, flow velocity, and channel length. Laminar flow occurs when the Reynolds number is below 2300, while turbulent flow occurs when the Reynolds number is above 4000. Turbulent flow exerts uneven forces on the oil-phase solution particles (i.e., the dispersed phase) when an oil-phase solution is injected into a microchannel carrying an aqueous-phase solution. This can prevent the formation of oil-phase solution particles of a consistent size, thereby hindering the quality and production yield of microparticles. Therefore, to form laminar flow, the fluid velocity must be reduced or the viscosity and / or density of the oil-phase solution must be reduced.

[0042] The method of reducing the velocity of the fluid has the advantage that a laminar flow can be easily formed by changing the production conditions, but the reduced velocity may result in a decrease in productivity.

[0043] Therefore, a suitable solvent must be used to reduce the viscosity and density of the oil phase solution so that laminar flow can be maintained while still ensuring productivity.

[0044] In addition, when microparticles are produced using a porous membrane, the viscosity of the oil phase solution is important because the oil phase solution must easily pass through the pores of the membrane.

[0045] In the emulsion method, which is another method, the viscosity of the oil phase solution is also important because if the viscosity is too high, it becomes difficult to disperse the oil phase solution using external energy.

[0046] In the case of the spray drying method, the droplets are dispersed and the solvent is evaporated by air to produce microparticles, so it is important to use a highly volatile solvent. When producing microparticles, the selection of the solvent is also important in order to reduce the solvent evaporation energy.

[0047] When producing microparticles, if an excess amount of solvent is used to achieve sufficient viscosity, the microfluidic method can maintain laminar flow and facilitate the production of microparticles. However, it takes a lot of energy and time to remove the excess solvent, and it is difficult to quickly remove the organic solvent from the oil phase solution particles (dispersed phase), which increases the possibility of the drug being transferred to the aqueous phase solution and being lost.

[0048] Therefore, the present invention relates to a method for producing microparticles that solves the above problems, increases the encapsulation rate of poorly soluble drugs, and enables efficient removal of residual organic solvents in the microparticles.

[0049] Specifically, the method for producing microparticles containing a poorly soluble drug of the present invention includes the steps of: 1) dissolving the poorly soluble drug and a biodegradable polymer in a mixed solvent containing two or more organic solvents to produce an oil phase solution; 2) dissolving a surfactant in water to produce an aqueous phase solution; and 3) producing microparticles using the oil phase solution and the aqueous phase solution.

[0050] The mixed solvent for dissolving the poorly soluble drug and the biodegradable polymer includes a first solvent and a co-solvent, and the first solvent may be dichloromethane.

[0051] Generally, to prepare microparticles using an organic solvent, a solvent in which the drug and biodegradable polymer are easily soluble is used, and the most commonly used solvent is dichloromethane.

[0052] However, even when an organic solvent such as dichloromethane is used, some poorly soluble drugs have low solubility. To solve this problem, the present invention is characterized by including an additional co-solvent in addition to the first solvent, thereby increasing the solubility of the poorly soluble drug and subsequently making it easier to remove when the organic solvent is removed.

[0053] The cosolvent has a density of 1.3 g / cm 3 or less, polarity index is 3 or less, boiling point is 50°C or less, water solubility is 2 20 ~8 20 g / 100g water. Specifically, the co-solvent may have a density of 1.3 g / cm 3 or less, 0.5 to 1.3 g / cm 3 and 0.5 to 1.0 g / cm 3 and 0.6 to 0.9 g / cm 3 may be.

[0054] The polarity is 3 or less, 1 to 3, or 2 to 3.

[0055] The boiling point is 50°C or less, may be 30°C to 50°C, or may be 30°C to 40°C.

[0056] In addition, the water solubility is 2 20 ~8 20 g / 100g water, 3 20 ~8 20 g / 100g water, 5 20 ~820 g / 100g water.

[0057] When a cosolvent that satisfies the above density, polarity, boiling point, or water solubility conditions is mixed with the first solvent, it acts to increase the solubility of the poorly soluble drug by assisting the primary solvent. When a cosolvent is used to remove residual organic solvent from the prepared microparticles, the cosolvent is removed before the first solvent, dichloromethane, preventing the drug from escaping into the aqueous phase solution. It also increases the concentration or viscosity of the biodegradable polymer in the oil phase solution, strengthening the bond between the poorly soluble drug and the biodegradable polymer, thereby increasing the encapsulation rate of the drug within the biodegradable polymer.

[0058] Furthermore, since the boiling point of the co-solvent is 50°C or less, the properties of the biodegradable polymer do not change even when heated during the solvent removal process, and the release pattern of the microparticles is not altered. In addition, since the co-solvent has a low density, even a small amount can reduce the viscosity or density of the oil phase solution, thereby enabling the production of uniform, high-quality microparticles.

[0059] Such a co-solvent may specifically be a volatile organic solvent or a volatile non-polar organic solvent.

[0060] The volatile organic solvent can be selected from the group consisting of acetone, acetonitrile, benzene, butyl alcohol carbon disulfide, carbon tetrachloride, chloroform, cyclohexane, 1,1-dichloroethane, dimethoxyethane, ethanol, diethyl ether, ethyl acetate, heptane, hexane, methanol, methyl acetate, methyl t-butyl ether, pentane, propyl alcohol, tetrahydrofuran, and combinations thereof.

[0061] Additionally, the volatile non-polar organic solvent can be selected from the group consisting of cyclohexane, pentane, hexane, heptane, carbon tetrachloride, carbon disulfide, benzene, diethyl ether, methyl t-butyl ether, tetrahydrofuran, ethyl acetate, methyl acetate, chloroform, and combinations thereof.

[0062] When the cosolvent is used as a mixed solvent with the first solvent, even if the cosolvent does not dissolve poorly soluble drugs or biodegradable polymers well by itself, when it acts together with the first solvent, dichloromethane, it can actually increase the solubility of the poorly soluble drugs or biodegradable polymers and reduce the viscosity of the oil phase solution.

[0063] As described above, the co-solvent may have the property of volatilizing or evaporating earlier than dichloromethane. Generally, the transfer of the drug to the aqueous solution occurs on the surface of the microparticles that are not completely dried. As the organic solvent remaining inside the microparticles is removed, the internal viscosity increases and hardening occurs, which reduces the reactivity with the aqueous solution and reduces the probability of the drug transferring to the aqueous solution.

[0064] Therefore, when a cosolvent with the above-mentioned properties is used, the cosolvent is removed before the primary solvent, dichloromethane, preventing the drug from escaping into the aqueous phase solution, and increasing the concentration or viscosity of the biodegradable polymer present in the oil phase solution, thereby strengthening the bond between the poorly soluble drug and the biodegradable polymer and increasing the encapsulation rate of the drug within the biodegradable polymer.

[0065] In order to produce uniform and high-quality microparticles, the viscosity or density of the oil phase solution containing microparticles, a biodegradable polymer, and an organic solvent is important. The co-solvent has a lower density than the primary solvent, so even a small amount can reduce the density of the oil phase solution. When producing microparticles using a microfluidic method, the co-solvent maintains laminar flow between the oil phase solution and the aqueous phase solution within the microchannel, enabling the production of uniform and high-quality microparticles and facilitating the removal of residual organic solvent.

[0066] The co-solvent may preferably be diethyl ether or pentane, but is not limited to these examples. Any co-solvent that meets the requirements of the co-solvent, increases the solubility of the poorly soluble drug together with the first solvent, and has the property of volatilizing or vaporizing before the first solvent can be used without limitation.

[0067] In step 1), the weight ratio of the poorly soluble drug to the mixed solvent may be, but is not limited to, about 1:7 to about 1:30, about 1:7 to about 1:29, about 1:7 to about 1:28, about 1:7 to about 1:27, about 1:7 to about 1:26, about 1:7 to about 1:25, about 1:7 to about 1:24, about 1:7 to about 1:23, about 1:7 to about 1:22, about 1:7 to about 1:21, about 1:7 to about 1:20, about 1:7 to about 1:19, about 1:7 to about 1:18, about 1:7 to about 1:17, about 1:7 to about 1:16, or about 1:7 to about 1:15.

[0068] In step 1), the weight ratio of the poorly soluble drug to the biodegradable polymer may be, but is not limited to, about 1:0.5 to about 1:10, about 1:0.5 to about 1:9, about 1:0.5 to about 1:8, about 1:0.5 to about 1:7, about 1:0.5 to about 1:6, or about 1:1 to about 1:5.

[0069] In step 1), the weight ratio of the co-solvent to the primary solvent may be, but is not limited to, about 1:0.5 to about 1:10, about 1:0.5 to about 1:9, about 1:0.5 to about 1:8, about 1:0.5 to about 1:7, or about 1:0.5 to about 1:6.

[0070] Preferably, the weight ratio of the poorly soluble drug to the mixed solvent is 1:15 to 1:20, and the weight ratio of the co-solvent to the first solvent may be 1:0.5 to 1:6, but is not limited to these examples. The poorly soluble drug can be well soluble within the above ranges. If the mixed solvent is used in an amount below this range, the poorly soluble drug may recrystallize and precipitate, and the viscosity may become excessively high, making filtration and manufacturing difficult. Using an excessively large amount of solvent does not pose a significant problem in manufacturing, but the absolute amount of organic solvent used may increase, resulting in the poorly soluble drug being lost in the aqueous phase solution, making it difficult to remove the residual organic solvent.

[0071] The content of the biodegradable polymer in the organic solvent may be, but is not limited to, about 5 to about 50 wt. %, about 5 to about 40 wt. %, about 5 to about 30 wt. %, about 5 to about 20 wt. %, or about 5 to about 10 wt. Based on the amount of the biodegradable polymer (e.g., polylactide-co-glycolide copolymer) used, the total amount of the organic solvent used can be varied depending on the viscosity of the biodegradable polymer and the amount of the poorly soluble drug used. If the amount of the poorly soluble drug is large or the viscosity of the biodegradable polymer is high, the amount of the organic solvent used can be increased to reduce the total concentration. However, dissolving the biodegradable polymer in the organic solvent within the above range facilitates the preparation of microparticles and the removal of residual organic solvent.

[0072] The poorly soluble drugs include naltrexone, donepezil, finasteride, aripiprazole, olanzapine, palonosetron, minocycline, memantine, alendronate, deoxycholate, risedronate, and the like. e), Ibandronate, Zoledronate, Liraglutide, Exenetide, Lanreotide, Octreotide, Deslorelin, Leuprorelin, Goserelin, Triptorelin, or Dutasteride.

[0073] Naltrexone is also known as N-cyclopropyl-methylnoroxymorphone, N-cyclopropylmethyl-14-hydroxydihydro-morphinone, 17-(cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one, EN-1639A, or UM-792.

[0074] The naltrexone may be a compound represented by the following formula:

[0075] [ka]

[0076] Donepezil is also known as 1-Benzyl-4-[(5,6-dimethoxy-1-indanon-2-YL)methyl]piperidine.

[0077] The donepezil may be a compound represented by the following chemical formula:

[0078] [ka]

[0079] Finasteride is also known as N-(1,1-dimethylethyl)-3-oxo-(5α,17β)-4-azaandrost-1-ene-17-carboxamide.

[0080] The finasteride may be a compound represented by the following chemical formula:

[0081] [ka]

[0082] The poorly soluble drug of the present invention may be a solvate, stereoisomer, prodrug, metabolite (e.g., 6β-naltrexol), derivative (e.g., naloxone), free base, or a combination thereof of the poorly soluble drug.

[0083] The stereoisomers refer to compounds that have the same molecular formula and the same atomic connection method, but differ in the spatial arrangement of the atoms. The solvates refer to compounds solvated in an organic or inorganic solvent. The solvates are, for example, hydrates. The stereoisomers may be partial diastereomers or enantiomers. The prodrugs may be compounds that are converted into target compounds in vivo after administration. The metabolites may be compounds produced by metabolic processes in vivo. The derivatives refer to compounds obtained by substituting part of the structure of a poorly soluble drug with another atom or atomic group.

[0084] The biodegradable polymer may be selected from the group consisting of polylactide, polylactic acid, polylactide-co-glycolide, polylactic-co-glycolic acid, polyphosphazene, polyiminocarbonate, polyphosphoester, polyanhydride, polyorthoester, polycaprolactone, polyhydroxyvalerate, polyhydroxybutyrate, polyamino acid, and combinations thereof, but is not limited to the above examples.

[0085] As an example, the molar ratio of glycolide to lactide in polylactide-co-glycolide may be about 60:40 to about 90:10, about 60:40 to about 85:15, about 60:40 to about 80:20, about 60:40 to about 75:25, about 65:35 to about 90:10, about 70:30 to about 90:10, about 75:25 to about 90:10, about 65:35 to about 85:15, or about 70:30 to about 80:20. The molar ratio is not limited to the above examples, but preferably, the molar ratio of glycolide to lactide in polylactide-co-glycolide may be about 75:25.

[0086] The biodegradable polymer may include one or more polylactides and one or more polylactide-co-glycolides. In the present invention, the biodegradable polymer may include, for example, a combination of two polylactides, one polylactide and one polylactide-co-glycolide, two polylactide-co-glycolides, three polylactides, two polylactides and one polylactide-co-glycolide, or one polylactide and two polylactide-co-glycolides, and particularly, but is not limited to, one polylactide and one polylactide-co-glycolide, or two polylactide-co-glycolides.

[0087] The biodegradable polymer can include two or more types of polylactide-co-glycolide.

[0088] The aqueous phase solution may contain water and a surfactant, and any surfactant may be used without limitation as long as it can help the oil phase solution form stable microparticles.

[0089] Specifically, the surfactant may be one or more selected from the group consisting of nonionic surfactants, anionic surfactants, cationic surfactants, and combinations thereof. For example, the surfactant may be any one or more selected from the group consisting of polyethylene glycol sorbitan monooleate, sorbitan oleate, sodium lauryl sulfate, polyvinyl alcohol (PVA), methylcellulose, polyvinylpyrrolidone, lecithin, gelatin, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oil derivatives, sodium stearate, esteramines, linear diamines, fatty amines, and combinations thereof, but is not limited thereto.

[0090] The content of the surfactant in the aqueous phase solution may be, but is not limited to, 0.1 to 1.0% (w / v), 0.2 to 0.8% (w / v), 0.25 to 0.7% (w / v), 0.4 to 0.6% (w / v), 0.4 to 0.5% (w / v), 0.5 to 0.6% (w / v), 0.1 to 0.3% (w / v), 0.2 to 0.3% (w / v), or 0.25 to 0.3% (w / v). For example, the aqueous phase solution containing the surfactant may be, but is not limited to, a 0.5% (w / v) PVA solution.

[0091] The viscosity of the oil phase solution in step 1 is in a range where the fluid viscosity (unit: cP; centipoise) maintains the fluid in a laminar flow state within the microchannel. The fluid viscosity can be measured using a Brookfield Model LVT viscometer, using an LVO1 or LVO2 spindle at 80-100 rpm. The viscosity of the oil phase solution is measured at 25°C. After starting the measurement with the viscometer, the viscosity of the measured solution is measured at a constant value after stabilization. Typically, the solution stabilization takes about 1 minute.

[0092] The oil phase solution in step 1) may have a viscosity or density that allows it to maintain a laminar flow state with the aqueous phase solution in step 2). Specifically, the oil phase solution may have a viscosity or density that allows the fluid in the microchannel to maintain a laminar flow state when the oil phase solution is injected into the aqueous phase solution flowing in the microchannel. For example, the oil phase solution may have a viscosity or density that allows the Reynolds number of the fluid flowing in the microchannel to satisfy 2,300 or less.

[0093] In the step 3), microparticles can be produced using an oil phase solution and an aqueous phase solution by an emulsion method, a porous membrane method, a spray drying method, or a microfluidic method.

[0094] Specifically, the process for producing microparticles by the microfluidic method can include the steps of: a) injecting an oil phase solution into a linear microchannel; b) injecting an aqueous phase solution into one or both side microchannels; and c) collecting the microparticles.

[0095] The step a) involves injecting an oil phase solution into a linear microchannel to allow it to flow, and the step b) involves injecting an aqueous phase solution into a microchannel on one or both sides of the linear microchannel to form an intersection with the linear microchannel to allow it to flow, i.e., the oil phase solution flows along the linear microchannel, and the aqueous phase solution flows along a microchannel on one or both sides of the linear microchannel to form an intersection with the linear microchannel, and can meet the flow of the oil phase solution.

[0096] Furthermore, in order to make the flow of the aqueous phase solution that forms an intersection with the flow of the oil phase solution flow at a faster flow rate than the flow of the oil phase solution injected into the linear microchannel, it is possible to make the aqueous phase solution flow under higher pressure conditions.

[0097] As described above, by making the flow rates of the oil phase solution and the aqueous phase solution different and making the flow rate of the aqueous phase solution faster than the oil phase solution, the aqueous phase solution, which has a relatively faster flow rate, compresses the oil phase solution at the point where the oil phase solution flows and the aqueous phase solution flows meet. At this time, the repulsive force between the oil phase solution and the aqueous phase solution causes the biodegradable polymer and the poorly soluble drug in the oil phase solution to form spherical microparticles, and the spherical microparticles can be formed in a form in which the drug is evenly distributed on the spherical biodegradable polymer.

[0098] The microfluidic method for producing microparticles involves introducing an oil phase solution containing a poorly soluble drug, an organic solvent, and a biodegradable polymer into a microchannel together with an aqueous phase solution to form microparticles of a certain size. The microparticles thus formed are stabilized by a surfactant in the aqueous phase solution, and the organic solvent inside the formed particles is evaporated or volatilized depending on the drying conditions, thereby removing the organic solvent from the particles to form microparticles.

[0099] The emulsion method involves mixing an oil phase solution containing a poorly soluble drug, an organic solvent, and a biodegradable polymer with an aqueous phase solution containing a surfactant, and then applying external energy (such as ultrasound or high-speed rotation) to the mixture to cause the oil phase solution to form microparticles within the aqueous phase solution. Microparticles formed by the emulsion method are formed by removing the organic solvent from within the particles as the organic solvent evaporates or volatilizes depending on the drying conditions.

[0100] The porous membrane method involves flowing an oily phase solution (dispersed phase) containing a poorly soluble drug, an organic solvent, and a biodegradable polymer onto one side of a porous membrane with micropores, and flowing an aqueous phase solution (continuous phase) containing a surfactant onto the other side of the porous membrane, thereby cutting the oily phase solution with the flow of the aqueous phase solution to produce microparticles.

[0101] The spray drying method is a method for producing microparticles without using an aqueous phase solution, in which an oil phase solution containing a poorly soluble drug, an organic solvent, and a biodegradable polymer is sprayed in a spray dryer while heated air is blown in. Microparticles are formed by finely spraying the oil phase solution, and the organic solvent inside the particles is evaporated or volatilized by the heated air, removing the solvent and forming microparticles.

[0102] Specific examples of the emulsion method and spray drying method are described in, for example, the literature [Koerner, J. (2019). Harnessing Dendritic Cells for Poly(D,L-lactide-co-glycolide) Microspheres (PLGA MS) - Mediated Anti-tumor Therapy. Frontiers] and the literature [Wang, Y (2016). Manufacturing Techniques and Surface Engineering of Polymer Based Nanoparticles for Targeted Drug Delivery to Cancer. Nanomaterials 6 (2), 26], but are not limited thereto.

[0103] Microparticles containing a poorly soluble drug according to another embodiment of the present invention are microparticles prepared by the above-described method.

[0104] The encapsulation rate of the poorly soluble drug in the microparticles may be about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%.

[0105] The microparticles are also called microspheres, and may refer to particles that can contain a poorly soluble drug as an active ingredient.

[0106] The median particle size (D50) of the microparticles may be about 30 μm to about 65 μm, about 30 μm to about 60 μm, about 30 μm to about 55 μm, about 30 μm to about 50 μm, about 35 μm to about 65 μm, about 40 μm to about 65 μm, about 45 μm to about 65 μm, about 35 μm to about 60 μm, about 40 μm to about 55 μm, or about 45 μm to about 50 μm.

[0107] In one embodiment, the microparticles may have a particle size distribution within the range of ±5 μm, ±7 μm, ±10 μm, ±12 μm, or ±15 μm based on the median particle size.

[0108] Furthermore, the microparticles may be present in such a particle size distribution range such that 60% by weight or more, 65% by weight or more, 70% by weight or more, 75% by weight or more, 80% by weight or more, 85% by weight or more, 90% by weight or more, 95% by weight or more, or 99% by weight or more of the total microparticles.

[0109] [Experimental Example 1] Comparison of solubility in combinations of dichloromethane and diethyl ether To compare the solubility of poorly soluble drugs depending on the type and combination of solvents, 0.5 g of the poorly soluble drug, free base naltrexone (Mallinckrodt; hereafter the same) and 1.0 g of a biodegradable polymer (Corbion; PDLG7504 (ester type); hereafter the same) were dissolved in the same total amount of organic solvent (7.0 g), and mixed as shown in Table 1 below. The dissolution of naltrexone and the biodegradable polymer was observed with the naked eye at room temperature. Complete dissolution was determined when the mixture was transparent, with no crystals or particles visible to the naked eye.

[0110] [Table 1]

[0111] Although excessive dichloromethane can dissolve naltrexone, it increases the total amount of solvent used, which can lead to problems such as residual organic solvents. To avoid these problems, dichloromethane can be used alone and in the smallest possible amount to dissolve naltrexone, as in Comparative Example 1. However, recrystallization, or precipitation of naltrexone, occurs. This is presumably due to changes in pressure caused by compressed air and solvent evaporation when the oil phase solution is sprayed through the module with the aqueous phase solution, causing naltrexone to crystallize in the saturated solution. Furthermore, in Comparative Example 2, in which diethyl ether was used alone as the organic solvent, neither naltrexone nor the biodegradable polymer dissolved at all. In contrast, in Examples 1 and 2, in which diethyl ether was mixed as a co-solvent with dichloromethane as the first solvent, naltrexone and the biodegradable polymer were completely dissolved, with much higher solubility than when each solvent was used alone, and no recrystallization occurred.

[0112] This is because the use of diethyl ether as a co-solvent, which has poor solubility for naltrexone and biodegradable polymers, affects the arrangement of the naltrexone molecules in the first solvent, dichloromethane, and increases the solubility of naltrexone and biodegradable polymers.

[0113] According to the experimental results, when dichloromethane or diethyl ether is used alone, neither naltrexone nor the biodegradable polymer dissolves. However, when diethyl ether is used as a co-solvent in combination with dichloromethane, the solubility of naltrexone and the biodegradable polymer increases.

[0114] As described above, it was confirmed that when dichloromethane and diethyl ether were used together, naltrexone and the biodegradable polymer could be completely dissolved even with a small amount of solvent.

[0115] Therefore, when microparticles are prepared using the mixed solvents as in Examples 1 and 2, the loss of naltrexone can be reduced, the encapsulation rate can be increased, the amount of organic solvent used can be reduced, and residual organic solvent can be effectively removed.

[0116] Further experiments were then carried out to confirm this effect.

[0117] [Experimental Example 2] Comparative experiment of encapsulation rate, residual organic solvent, and dissolution rate of naltrexone microparticles depending on the solvent (1) Preparation of naltrexone-containing microparticles Microparticles for use in the experiments were produced as follows, and the contents of the components used in producing the microparticles are summarized in Table 2.

[0118] [Example 3] 0.5 g of free base naltrexone and 1.0 g of DL-lactide / glycolide copolymer were mixed and dissolved in 10.0 g of dichloromethane and 2.3 g of diethyl ether. The mixed oil phase solution was applied to a microchannel, where microparticles were formed at the intersection of the oil phase solution and the aqueous phase solution. These microparticles were collected above the aqueous phase solution (10 °C). The aqueous phase solution was a 0.5% (w / v) PVA solution (0.5% (v / v) PVA mixed in water).

[0119] The prepared microparticles were stirred at 10°C for 1 hour, 30°C for 1 hour, and 50°C for 1 hour to remove the organic solvent. The prepared microparticles were separated by sieving and then freeze-dried to complete the preparation of dried microparticles.

[0120] [Example 4] The same preparation as in Example 3 was carried out, except that 8.0 g of dichloromethane and 2.0 g of diethyl ether were mixed.

[0121] Comparative Example 3 The same preparation as in Example 3 was carried out, except that 8.0 g of dichloromethane was mixed without diethyl ether.

[0122] Comparative Example 4 The same preparation as in Example 3 was carried out, except that 12.3 g of dichloromethane was mixed without diethyl ether.

[0123] [Table 2]

[0124] (2) Comparison of encapsulation rate, residual organic solvent, and precipitation depending on the use of co-solvent and the amount of organic solvent The solubility, encapsulation rate, and residual organic solvent of the microparticles prepared in Experimental Example 2.(1) were evaluated. The presence or absence of dissolution was confirmed by visual inspection to determine whether precipitation occurred, and the encapsulation rate was measured using high-performance liquid chromatography (HPLC). The residual organic solvent was analyzed by gas chromatography (GC). The results are shown in Table 3.

[0125] [Table 3]

[0126] When comparing Comparative Examples 3 and 4, because naltrexone is poorly soluble in dichloromethane, if the amount of dichloromethane is insufficient, naltrexone dissolved in the organic solvent during the preparation of the oil phase solution recrystallizes and precipitates, making it impossible to prepare microparticles. When comparing Comparative Example 4 with Examples 3 and 4, it was confirmed that using diethyl ether as a co-solvent increased the encapsulation rate by about 6% compared to using dichloromethane alone, and also reduced the amount of residual organic solvent in dichloromethane, thereby reducing the overall amount of residual organic solvent.

[0127] According to the results, the use of diethyl ether, which has a boiling point lower than that of dichloromethane, resulted in an increase in the encapsulation rate. This is because as diethyl ether evaporates at a lower temperature than dichloromethane, the concentration of naltrexone and biodegradable polymer in the microparticles increases, increasing the viscosity of the oil phase solution present in the microparticles, thereby maintaining a stronger bond between naltrexone and the biodegradable polymer.

[0128] [Experimental Example 3] Comparative experiment on encapsulation rate, residual organic solvent, and dissolution of naltrexone microparticles depending on the solvent mixing ratio (1) Preparation of naltrexone-containing microparticles Microparticles for use in the experiments were produced as follows, and the contents of the components used in producing the microparticles are summarized in Table 4.

[0129] [Example 5] 0.5 g of naltrexone and 1.0 g of DL-lactide / glycolide copolymer were mixed and dissolved in 6.0 g of dichloromethane and 2.0 g of diethyl ether. The mixed oil phase solution was applied to a microchannel, and microparticles were formed at the intersection of the oil phase solution and the aqueous phase solution. These microparticles were collected above the aqueous phase solution (10°C). The aqueous phase solution was a 0.5% (w / v) PVA solution. The organic solvent was removed by stirring at 10°C for 1 hour, 30°C for 1 hour, and 50°C for 1 hour. The microparticles were filtered and then freeze-dried to complete the dry microparticle production.

[0130] [Example 6] The microparticles were prepared as in Example 5, except that the organic solvent was removed by stirring at 10° C. for 1.5 hours, 30° C. for 1.5 hours, and 50° C. for 1.5 hours.

[0131] [Example 7] The preparation was carried out in the same manner as in Example 5, except that 3.0 g of diethyl ether was added.

[0132] [Table 4]

[0133] (2) Comparison of naltrexone microparticle encapsulation rate, residual organic solvent, and dissolution rate depending on the solvent mixing ratio

[0134] [Table 5]

[0135] When comparing Example 5 and Example 6, it was confirmed that the encapsulation rate actually decreased as the organic solvent removal time increased, and this result confirmed that there was no significant difference in the amount of residual organic solvent as the organic solvent removal time increased.

[0136] Comparing Example 5 and Example 7, it was confirmed that the ratio of dichloromethane to diethyl ether used as the organic solvent affects the encapsulation rate. It was confirmed that the naltrexone encapsulation rate of the microparticles increased as the ratio of diethyl ether to dichloromethane increased.

[0137] [Experimental Example 4] Experiments using different organic solvents as co-solvents The encapsulation rate and residual organic solvent content of microparticles were evaluated when other cosolvents were used in addition to diethyl ether. Microparticles were produced using the same method as in Example 3 of Experimental Example 2. Table 6 summarizes the properties of usable cosolvents, including diethyl ether, and Table 7 summarizes examples using various cosolvents.

[0138] [Table 6]

[0139] (1) Preparation of donepezil-containing microparticles [Example 8] 0.98264 g of donepezil, 1.0 g of DL-lactide / glycolide copolymer, and 3.0 g of lactide copolymer were dissolved in 22.667 g of dichloromethane. The mixed oil phase solution was applied to a microchannel, and microparticles were formed at the intersection of the oil phase solution and the aqueous phase solution. These microparticles were collected above the aqueous phase solution (10°C). The aqueous phase solution was a 0.25% (w / v) PVA solution. The resulting microparticles were stirred at 10°C for 1 hour, 30°C for 1 hour, and 40°C for 3 hours to remove the organic solvent. The resulting microparticles were sieved and then freeze-dried to complete the preparation of dried microparticles.

[0140] [Example 9] 0.98264 g of donepezil, 1.0 g of DL-lactide / glycolide copolymer, and 3.0 g of lactide copolymer were dissolved in 6.0 g of dichloromethane and 4.5 g of diethyl ether, and the preparation method was the same as in Example 8.

[0141] [Example 10] 0.98264 g of donepezil, 1.0 g of DL-lactide / glycolide copolymer, and 3.0 g of lactide copolymer were mixed and dissolved in 8.0 g of dichloromethane and 3.0 g of pentane, and the manufacturing method was the same as in Example 8.

[0142] [Example 11] 0.98264 g of donepezil, 1.0 g of DL-lactide / glycolide copolymer, and 3.0 g of lactide copolymer were dissolved in a mixture of 6.0 g of dichloromethane and 4.5 g of methyl t-butyl ether, and the preparation method was the same as in Example 8.

[0143] [Table 7]

[0144] (2) Comparison of the encapsulation rate and residual organic solvent of donepezil microparticles depending on the type of cosolvent

[0145] [Table 8]

[0146] When comparing Example 8 and Example 9, the amount of dichloromethane used was reduced by using the co-solvent diethyl ether, and the residual dichloromethane solvent was lower in Example 9, which used diethyl ether under the same drying conditions.

[0147] In addition, in Example 10, the residual solvent content of pentane used as a co-solvent was measured to be very high. This is because although the boiling point of pentane is lower than that of diethyl ether, its solubility in water is poor and pentane could not be removed to the outside through water.

[0148] In Example 11, the boiling point of methyl t-butyl ether is higher than that of pentane, and its solubility in water is higher than that of pentane, so it is believed that the residual solvent was removed. However, since the boiling point was higher than the final drying temperature, the solvent was not sufficiently removed, and it was confirmed that the surface of the microparticles was not smooth and holes were formed.

[0149] [Experimental Example 5] Evaluation of increasing the polymer ratio in the oil phase solution by using a cosolvent When preparing the oil phase solution, the use of a co-solvent reduces the viscosity, making it possible to dissolve a higher concentration of polymer than when using dichloromethane as a sole solvent.

[0150] (1) Preparation of donepezil-containing microparticles

[0151] [Table 9]

[0152] [Example 12] The production method was the same as in Example 8, and 1.0 g of DL-lactide / glycolide copolymer and 3.0 g of lactide copolymer were mixed and dissolved in 22.667 g of dichloromethane.

[0153] [Example 13] 0.98264 g of donepezil, 1.0 g of DL-lactide / glycolide copolymer, and 3.0 g of lactide copolymer were mixed and dissolved in 6.0 g of dichloromethane, and the preparation method was the same as in Example 8.

[0154] [Example 14] 0.98264 g of donepezil, 1.0 g of DL-lactide / glycolide copolymer, and 3.0 g of lactide copolymer were mixed and dissolved in 10.5 g of dichloromethane, and the preparation method was the same as in Example 8.

[0155] [Example 15] 0.98264 g of donepezil, 1.0 g of DL-lactide / glycolide copolymer, and 3.0 g of lactide copolymer were mixed and dissolved in 6.0 g of dichloromethane and 4.5 g of diethyl ether, and the preparation method was the same as in Example 8.

[0156] [Example 16] 0.98264 g of donepezil, 1.0 g of DL-lactide / glycolide copolymer, and 3.0 g of lactide copolymer were dissolved in 4.0 g of dichloromethane and 3.0 g of diethyl ether, and the preparation method was the same as in Example 8.

[0157] (2) Comparing the viscosity of the oil phase solution depending on the ratio of co-solvents and confirming whether it can be manufactured

[0158] [Table 10]

[0159] Compared with Example 8, the viscosity of Example 12, which is a placebo solution without dissolving the main ingredient, is similar, which means that the main ingredient does not have a significant effect on the viscosity.

[0160] In addition, it was confirmed from Examples 13 and 14 that it is impossible to prepare a high-concentration oil phase solution with a solid content exceeding 30% using a single solvent of dichloromethane.

[0161] However, in the case of Examples 15 and 16, in which diethyl ether was used as a co-solvent, the solid content exceeded 30%, but the viscosity was lower than that of the single solvent group of dichloromethane with the same solid content, confirming that microparticles could be produced without any problems.

[0162] Depending on the viscosity or density of the organic solution used for producing the microparticles, we evaluated how uniform the microparticles could be produced, how much the production time of the microparticles could be shortened, and how efficiently the residual organic solvent could be removed, thereby evaluating how easily the microparticles could be produced.

[0163] From the above description, those skilled in the art to which the present invention pertains will understand that the present invention can be embodied in other specific forms without changing the technical spirit or essential characteristics thereof. In this regard, it should be understood that the above-described embodiments are illustrative in all respects and are not limiting. The scope of the present invention should be interpreted as including all modifications and variations derived from the meaning and scope of the claims below, rather than the above detailed description, and equivalent concepts thereof. [Industrial Applicability]

[0164] The present invention relates to a method for producing microparticles containing poorly soluble drugs.

[0165] This invention was supported by the following national research and development programs:

[0166] [Project unique number]1465031634 [Assignment number] HI20C0936 [Department name] Ministry of Health and Welfare [Name of issue management (specialized) organization] Korea Health Industry Development Agency [Research Project Name] Biohealth Investment Infrastructure Collaborative R&D [Research title] Development of long-acting injectable drugs for the treatment of opioid and alcohol dependence using controlled and optimized manufacturing technology [Contribution rate] 1 / 1 [Project Execution Organization Name] Inventage Lab [Research Period] 2022.01.01~2022.12.31

Claims

1. 1) preparing an oil phase solution by dissolving a poorly soluble drug and a biodegradable polymer in a mixed solvent containing two or more organic solvents; 2) dissolving a surfactant in water to produce an aqueous phase solution; 3) producing microparticles using the oil phase solution and the aqueous phase solution; the mixed solvent comprises a first solvent and a co-solvent; the first solvent is dichloromethane; the poorly soluble drug is naltrexone or donepezil; When the poorly soluble drug is naltrexone, the co-solvent is diethyl ether; When the poorly soluble drug is donepezil, the co-solvent is selected from the group consisting of diethyl ether, pentane, and combinations thereof. A method for producing microparticles containing poorly soluble drugs.

2. The cosolvent has a density of 1.3 g / cm ３ Below is the A method for producing microparticles containing the poorly soluble drug according to claim 1.

3. The co-solvent has a polarity index of 3 or less. A method for producing microparticles containing the poorly soluble drug according to claim 1.

4. The co-solvent has a boiling point of 50°C or less. A method for producing microparticles containing the poorly soluble drug according to claim 1.

5. The co-solvent has a water solubility of 2 ２０ ~8 ２０ g / 100g water, A method for producing microparticles containing the poorly soluble drug according to claim 1.

6. The first solvent and the co-solvent are contained in a weight ratio of 1:0.5 to 1:

10. A method for producing microparticles containing the poorly soluble drug according to claim 1.

7. The poorly soluble drug and the mixed solvent in step 1) are mixed in a weight ratio of 1:7 to 1:30; A method for producing microparticles containing the poorly soluble drug according to claim 1.

8. The poorly soluble drug and the biodegradable polymer in step 1) are contained in a weight ratio of 1:0.5 to 1:

10. A method for producing microparticles containing the poorly soluble drug according to claim 1.

9. The biodegradable polymer is selected from the group consisting of polylactide, polylactic acid, polylactide-co-glycolide, polylactic-co-glycolic acid, polyphosphazene, polyiminocarbonate, polyphosphoester, polyanhydride, polyorthoester, polycaprolactone, polyhydroxyvalerate, polyhydroxybutyrate, polyamino acid, and combinations thereof. A method for producing microparticles containing the poorly soluble drug according to claim 1.

10. The surfactant is selected from the group consisting of polyethylene glycol sorbitan monooleate, sorbitan oleate, sodium lauryl sulfate, polyvinyl alcohol (PVA), methylcellulose, polyvinylpyrrolidone, lecithin, gelatin, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oil derivatives, sodium stearate, esteramines, linear diamines, fatty amines, and combinations thereof. A method for producing microparticles containing the poorly soluble drug according to claim 1.

11. The step 3) comprises preparing microparticles using the oil phase solution and the aqueous phase solution by an emulsion method, a porous membrane method, a spray drying method, or a microfluidic method. A method for producing microparticles containing the poorly soluble drug according to claim 1.

12. The method further comprises the step of removing residual organic solvent from the microparticles prepared in the step 3). A method for producing microparticles containing the poorly soluble drug according to claim 1.

13. The step of removing the residual organic solvent comprises: The microparticles containing the residual organic solvent are placed in an aqueous phase solution and stirred to remove the residual organic solvent; A method for producing microparticles containing the poorly soluble drug according to claim 12.

14. The stirring step includes a first stirring step at 10°C to 20°C and 200 to 400 rpm for 30 minutes to 2 hours; a second stirring step at 25°C to 35°C and 200 to 400 rpm for 30 minutes to 2 hours; and third stirring at 45°C to 55°C and 200 to 400 rpm for 30 minutes to 2 hours. A method for producing microparticles containing the poorly soluble drug according to claim 13.

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