Method of preparing microsphere containing poorly soluble drug

Abstract

The present invention relates to a method for manufacturing microparticles containing poorly soluble drugs and microparticles manufactured by such method. The method for manufacturing microparticles uses two or more organic solvents to produce microparticles that have uniform and excellent quality, a high encapsulation rate of poorly soluble drugs, and a low amount of residual organic solvent.

Description

Technology Field

[0001] The present invention relates to a method for manufacturing microparticles containing a poorly soluble drug. Background Technology

[0002] To manufacture microparticles or sustained-release formulations containing poorly soluble drugs, it is common practice to dissolve the poorly soluble drug together with a biodegradable polymer in an organic solvent and disperse it in an aqueous phase to prepare an emulsion. For example, a sustained-release formulation containing a poorly soluble drug can be manufactured by preparing an oil-in-water (O / W) emulsion to form microspheres containing the poorly soluble drug, followed by a process of removing the organic solvent from the emulsion. However, during the process of preparing the emulsion to form microspheres, it is important to ensure that both the poorly soluble drug and the biodegradable polymer are well dissolved in the oil phase solution and to prevent the poorly soluble drug from escaping into the aqueous phase solution to increase the encapsulation rate of the poorly soluble drug within the biodegradable polymer. Furthermore, it is crucial to ensure that the poorly soluble drug does not transfer to the aqueous phase and be lost during the process of removing the organic solvent after microsphere formation. Since this can vary depending on the choice of organic solvent, the selection of the solvent is a critical issue in the method of manufacturing microparticles containing poorly soluble drugs.

[0003] In the process of preparing emulsions for the formation of microparticles or sustained-release formulations, dissolving the biodegradable polymer is as important as dissolving the drug component in the solvent, because the drug must be encapsulated within the biodegradable polymer to achieve sustained release. Generally, dichloromethane, for example, can be used as an organic solvent to dissolve biodegradable polymers. However, since some poorly soluble drugs exhibit relatively low solubility in dichloromethane, a large amount of solvent must be used to dissolve these poorly soluble drugs in the dichloromethane solvent. However, as the amount of solvent used increases, the likelihood of residual organic solvent remaining increases, and the possibility of the poorly soluble drug escaping from the oil phase to the aqueous phase during the microparticle manufacturing process also increases. Consequently, there are problems such as the loss of the drug component within the microparticles and a decrease in the drug encapsulation rate within the biodegradable polymer.

[0004] In addition, methods for manufacturing these microparticles include, for example, using a porous membrane, microfluidics using microchannels, emulsion methods, or spray drying methods.

[0005] In the method for manufacturing the aforementioned microparticles, the viscosity of the oil phase solution containing poorly soluble drugs and biodegradable polymers plays a crucial role in the manufacturing process, and selecting the type and content of the organic solvent to control the viscosity of the oil phase solution is an important issue. However, increasing the content of the organic solvent to control viscosity presents problems, such as the increased likelihood of poorly soluble drugs being lost and the increased possibility of residual organic solvent remaining, as mentioned above.

[0006] Furthermore, since the method of removing solvent from microparticles may vary depending on the properties of the solvent, the choice of solvent used to prepare the oil phase solution can affect the encapsulation rate of poorly soluble drugs within biodegradable polymers, the content of residual organic solvent, and the economic efficiency of the preparation method. Methods for removing solvent from microparticles include solvent evaporation and solvent extraction.

[0007] The above solvent evaporation method is a method of removing a solvent by raising the temperature to the boiling point of a volatile solvent with a relatively low boiling point to evaporate the solvent. While this method has the advantages of being easier and faster than the solvent extraction method, problems may arise depending on the characteristics of the drug corresponding to the active ingredient of the microparticles. These problems include the drug being lost along with the solvent due to the temperature increase, and a decrease in the encapsulation rate of the drug within the biodegradable polymer.

[0008] The above solvent extraction method is a method of removing a non-volatile solvent with a relatively high boiling point by diffusing it from microparticles into an external solvent due to a difference in concentration. To prevent the drug from being extracted along with the solvent, solvent extraction is carried out at a low temperature, and an auxiliary solvent such as ethyl acetate or ethanol is added to the external aqueous solution of the microparticles to efficiently carry out solvent extraction such as benzyl alcohol.

[0009] In an attempt to increase the solubility of poorly soluble drugs, methods to improve solubility using benzyl alcohol as a solubilization aid have been studied, and in this case, solvent extraction is used. That is, since benzyl alcohol has a high boiling point of 205.4 °C, to effectively remove it, benzyl alcohol must be removed using solvent extraction rather than solvent evaporation. For example, an oil phase solution is prepared by dissolving poorly soluble drugs and biodegradable polymers together with dichloromethane and benzyl alcohol, and after dispersing the oil phase solution in an aqueous phase to form microparticles, the benzyl alcohol is removed using ethyl acetate or ethanol as an extraction solvent.

[0010] However, since the solvent extraction method described above involves extraction occurring due to a concentration gradient, the solvent is removed in proportion to the extraction time.

[0011] Therefore, the complete removal of residual organic solvents requires a significant amount of processing time. If solvents such as benzyl alcohol are not completely removed and remain, they act as solubilizers for the drug components. This can bypass the release mechanism of biodegradable polymers, which require slow release, potentially leading to a burst effect where the drug is released all at once from the microparticles, making release control difficult.

[0012] As such, the solvent extraction method has the disadvantage that the process is more complex and the manufacturing time is longer compared to the solvent evaporation method.

[0013] Therefore, regarding the method for manufacturing microparticles containing poorly soluble drugs, there is a need to develop an economical and efficient manufacturing method that effectively dissolves the poorly soluble drug, increases the encapsulation rate of the drug within the biodegradable polymer, simplifies the manufacturing method to enhance ease of production, and yields uniform microparticles. Prior art literature

[0014] (Patent Document 0001) KR 10-2005-0093236 A1 The problem to be solved

[0015] The object of the present invention is to provide a method for manufacturing microparticles containing a poorly soluble drug.

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

[0017] Another objective of the present invention is to provide a method for producing microparticles that have a high encapsulation rate of insoluble drugs while having homogeneous and excellent quality, by using a small amount of organic solvent to dissolve insoluble drugs and biodegradable polymers in an organic solvent, thereby lowering the viscosity or density of the oil phase solution and maintaining laminar flow within microchannels when microparticles are produced by microfluidic methods. means of solving the problem

[0018] To achieve the above objective, the present invention relates to a method for manufacturing microparticles containing a poorly soluble drug, comprising: 1) a step of 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) a step of preparing an aqueous solution by dissolving a surfactant in water; and 3) a step of manufacturing microparticles using the oil phase solution and the aqueous solution.

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

[0020] The above co-solvent has a density of 1.3 g / cm³ 3 or less, or a polarity index of 3 or less, a boiling point of 50°C or less, or a water solubility of 2 20 to 820 It can be g / 100g water.

[0021] The first solvent and co-solvent may be included in a weight ratio of 1:0.5 to 1:10.

[0022] The above-mentioned poorly soluble drug is Naltrexone, Donepezil, Finasteride, Aripiprazole, Olanzapine, Palonosetron, Minocycline, Memantine, Alendronate, Deoxycholate, Risedronate, Ibandronate, Zoledronate, Liraglutide, Exenatide, Lanreotide, Octreotide, Deslorelin, Leuprorelin, Goserelin, Triptorelin, or Dutasteride. It is possible.

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

[0024] The poorly soluble drug and biodegradable polymer of step 1) above may be included in a weight ratio of 1:0.5 to 1:10.

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

[0026] The above 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 ester, polyoxyethylene castor oil derivative, sodium stearate, esteramine, linear diamine, patiamine, and combinations thereof.

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

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

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

[0030] The above stirring process may include a first stirring step at 10°C to 20°C at 200 to 400 rpm for 30 minutes to 2 hours; a second stirring step at 25°C to 35°C at 200 to 400 rpm for 30 minutes to 2 hours; and a third stirring step at 45°C to 55°C at 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 manufactured by the above manufacturing method.

[0032] The above microparticles have an encapsulation rate of 90% or more for poorly soluble drugs, and may have a smooth surface and a perfect spherical shape. Effects of the invention

[0033] The present invention allows for the easy production of a poorly soluble drug with uniform and excellent quality, a high encapsulation rate of the poorly soluble drug, and a low residual organic solvent amount by using two or more organic solvents when dissolving the poorly soluble drug.

[0034] In addition, by using a small amount of organic solvent, the viscosity or density of the oil phase solution can be lowered by dissolving poorly soluble drugs and biodegradable polymers in the organic solvent, and when microparticles are prepared using a microfluidic method, laminar flow can be maintained within the microchannels, thereby enabling the production of microparticles that are homogeneous and of excellent quality, while also producing microparticles with a high encapsulation rate of poorly soluble drugs. Specific details for implementing the invention

[0035] Hereinafter, embodiments of the present invention are described in detail so that those skilled in the art can easily implement the invention. However, the present invention may be embodied in various different forms and is not limited to the embodiments described herein.

[0036] For microparticles containing poorly soluble drugs to exhibit excellent therapeutic effects, the poorly soluble drugs must be well dissolved and contained within the microparticles in a high proportion, the residual amount of organic solvents irrelevant to drug efficacy must be low, and the size of the microparticles must be uniform.

[0037] Depending on the poorly soluble drug, in the salt form it is somewhat soluble in water at room temperature (e.g., the hydrochloride salt of the poorly soluble drug naltrexone has a water solubility of 100 mg / mL at 25°C), but in the free base form it is almost insoluble in water and does not completely dissolve in organic solutions, exhibiting poor solubility. As an organic solvent for manufacturing microparticles with excellent properties containing such poorly soluble drugs in the free base form, it must be able to dissolve the poorly soluble drug together with the biodegradable polymer, prevent the poorly soluble drug from being lost to the aqueous solution, and be easily removable after the microparticles are manufactured.

[0038] Therefore, it is important to select an organic solvent with suitable characteristics.

[0039] Furthermore, the selection of the solvent is important for the economical and efficient production of microparticles of uniform size. For example, in the case of microfluidics, the aqueous and oil phases must maintain laminar flow within the microchannel to produce microparticles of uniform size.

[0040] Even with the same fluid, the Reynolds number (Re) varies depending on the fluid's viscosity, density, flow rate, and channel length within the microchannel; laminar flow is formed when the Reynolds number is 2300 or lower, and turbulent flow is formed when the Reynolds number is 4000 or higher. Turbulent flow exerts non-uniform forces on the oil phase particles (i.e., dispersed phase) when an oil phase solution is injected into a microchannel through which an aqueous solution flows. This hinders the formation of oil phase particles of a uniform size, which can impair the quality and production yield of microparticles. Therefore, to form laminar flow, the fluid velocity must be lowered or the viscosity and / or density of the oil phase solution must be reduced.

[0041] The method of lowering the fluid velocity mentioned above has the advantage of allowing laminar flow to be easily formed by changing production conditions, but the reduced velocity may lead to a decrease in productivity.

[0042] Therefore, in order to maintain laminar flow while ensuring productivity, it is necessary to use an appropriate solvent that can lower the viscosity or density of the oil phase solution.

[0043] In addition, as a method for manufacturing microparticles, when manufacturing microparticles using a porous membrane, the viscosity of the oil phase solution is important because the oil phase solution must pass through the pores of the membrane well.

[0044] In the emulsion method, another method, if the viscosity is too high, the dispersion of the oil phase solution by external energy becomes unfavorable, so the viscosity of the oil phase solution is important.

[0045] Furthermore, in the case of the spray drying method, since microparticles are produced by dispersing droplets and volatilizing the solvent with air, it is important to use a highly volatile solvent. In the production of microparticles, the selection of the solvent to lower the solvent volatilization energy is also important.

[0046] When manufacturing microparticles, if an excess amount of solvent is used to achieve sufficient viscosity, or if the microfluidic method is used, it may be easy to maintain laminar flow or manufacture microparticles, but a lot of energy and time are consumed to remove the excess solvent, and since it is difficult to rapidly remove the organic solvent from the oil phase solution particles (dispersed phase), there is a high possibility that the drug will be transferred to the aqueous solution and lost.

[0047] Accordingly, the present invention relates to a method for manufacturing microparticles that solves the above-mentioned problems, increases the encapsulation rate of poorly soluble drugs, and efficiently removes residual organic solvents within the microparticles.

[0048] Specifically, the method for manufacturing microparticles containing a poorly soluble drug according to the present invention may include: 1) a step of 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) a step of preparing an aqueous solution by dissolving a surfactant in water; and 3) a step of manufacturing microparticles using the oil phase solution and the aqueous solution.

[0049] A mixed solvent for dissolving the above-mentioned poorly soluble drug and biodegradable polymer comprises a first solvent and a co-solvent, wherein the first solvent may be dichloromethane.

[0050] Generally, to manufacture microparticles using organic solvents, a solvent in which drugs and biodegradable polymers are easily dissolved is used, and in this case, the solvent commonly used may be dichloromethane.

[0051] However, even when using an organic solvent such as the above-mentioned dichloromethane, some poorly soluble drugs have low solubility. To solve this problem, the present invention is characterized by additionally including a co-solvent in addition to the first solvent to increase the solubility of poorly soluble drugs and to enable easy removal even when the organic solvent is subsequently removed.

[0052] The above co-solvent has a density of 1.3 g / cm³ 3 or less, or a polarity index of 3 or less, a boiling point of 50°C or less, or a water solubility of 2 20 to 8 20 It may be g / 100g water. Specifically, the above co-solvent has a density of 1.3 g / cm³ 3 Less than or equal to 0.5 to 1.3 g / cm³ 3 and 0.5 to 1.0 g / cm³ 3 and 0.6 to 0.9 g / cm³ 3 It could be.

[0053] In addition, the polarity may be 3 or less, 1 to 3, or 2 to 3.

[0054] In addition, the boiling point may be 50°C or lower, 30°C to 50°C, or 30°C to 40°C.

[0055] In addition, the acceptance rate is 2 20 to 8 20 It is g / 100g water, and 3 20 to 8 20 It is g / 100g water, and 5 20 to 8 20 It can be g / 100g water.

[0056] When a co-solvent satisfying the above density, polarity, boiling point, or water solubility conditions is mixed with a first solvent and used, it assists the first solvent in increasing the solubility of poorly soluble drugs. When the co-solvent is used to remove residual organic solvent within the manufactured microparticles, the co-solvent is removed before the first solvent, dichloromethane, thereby preventing the drug from escaping into the aqueous solution, increasing the concentration or viscosity of the biodegradable polymer present in the oil phase solution, and strengthening the bond between the poorly soluble drug and the biodegradable polymer, which can increase the encapsulation rate of the drug within the biodegradable polymer.

[0057] In addition, since the boiling point of the above co-solvent is 50°C or lower, the properties of the biodegradable polymer do not change even when heated during the solvent removal process, and the release pattern of the microparticles can not be changed. Furthermore, since the above co-solvent has a low density, the viscosity or density of the oil phase solution can be lowered even when used in a small amount, and accordingly, it is possible to manufacture microparticles of uniform and excellent quality.

[0058] The above-mentioned co-solvent may specifically be a volatile organic solvent or a volatile non-polar organic solvent.

[0059] The above volatile organic solvent may 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.

[0060] In addition, the volatile nonpolar organic solvent may 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.

[0061] When the above co-solvent is used as a mixed solvent with the first solvent, even if the co-solvent itself does not effectively dissolve poorly soluble drugs or biodegradable polymers, when it acts together with the first solvent, dichloromethane, it can actually increase the solubility of poorly soluble drugs or biodegradable polymers and lower the viscosity of the oil phase solution.

[0062] In addition, as previously explained, the aforementioned co-solvent may have the property of volatilizing or evaporating before dichloromethane. Generally, the transfer of a drug to an aqueous solution occurs on the surface of microparticles that are not completely dried; as the organic solvent remaining inside the microparticles is removed, the internal viscosity increases and hardening occurs, which lowers the reactivity with the aqueous solution and reduces the probability of the drug transferring to the aqueous solution.

[0063] Accordingly, when using a co-solvent having the above characteristics, the co-solvent is removed before the primary solvent, dichloromethane, thereby preventing the drug from escaping into the aqueous solution, increasing the concentration or viscosity of the biodegradable polymer present in the oil solution, and strengthening the bond between the poorly soluble drug and the biodegradable polymer, which can increase the encapsulation rate of the drug within the biodegradable polymer.

[0064] 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. Since the co-solvent has a lower density than the primary solvent, the density of the oil phase solution can be lowered even when used in a small amount. Therefore, when producing microparticles by microfluidic methods, the oil phase solution and the aqueous solution can maintain laminar flow within the microchannel, thereby enabling the production of uniform and high-quality microparticles and allowing residual organic solvent to be easily removed.

[0065] The above co-solvent may preferably be diethyl ether or pentane, but is not limited to the above examples; any co-solvent that satisfies the conditions of the aforementioned co-solvent, increases the solubility of a poorly soluble drug together with the first solvent, and has the property of volatilizing or evaporating before the first solvent may be used without limitation.

[0066] In step 1) above, the weight ratio of the poorly soluble drug and the mixed solvent may be 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, and about 1:7 to about 1:15, but is not limited thereto. no.

[0067] In step 1) above, the weight ratio of the poorly soluble drug and the biodegradable polymer may be 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, and about 1:1 to about 1:5, but is not limited thereto.

[0068] In step 1) above, the weight ratio of the co-solvent and the primary solvent may be 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, but is not limited thereto.

[0069] Preferably, the weight ratio of the poorly soluble drug and the mixed solvent may be 1:15 to 1:20, and the weight ratio of the co-solvent and the first solvent may be 1:0.5 to 1:6, but is not limited to the above examples. Within the above range, the poorly soluble drug can be well dissolved. If the mixed solvent is included in an amount less than the above range, problems may arise where the poorly soluble drug recrystallizes and precipitates, and the viscosity becomes too high, which may cause difficulties in filtration and manufacturing. If too much solvent is used, there are no major problems in manufacturing, but the absolute amount of organic solvent used increases, which may result in the poorly soluble drug being lost to the aqueous solution and making it difficult to remove residual organic solvent.

[0070] The content of the biodegradable polymer in the organic solvent may be about 5 to about 50 weight%, about 5 to about 40 weight%, about 5 to about 30 weight%, about 5 to about 20 weight%, and about 5 to about 10 weight% based on the amount of the biodegradable polymer (e.g., polylactide-co-glycolide copolymer), but is not limited thereto. The total amount of the organic solvent may be changed depending on the viscosity of the biodegradable polymer and the amount of poorly soluble drug. If the amount of poorly soluble drug is large or the viscosity of the biodegradable polymer is high, the amount of organic solvent may be increased to lower the total concentration. However, if the biodegradable polymer is dissolved in the organic solvent within the above range, convenience in manufacturing microparticles is achieved, and the removal of residual organic solvent may also be within a range that is easy.

[0071] The above-mentioned poorly soluble drug is Naltrexone, Donepezil, Finasteride, Aripiprazole, Olanzapine, Palonosetron, Minocycline, Memantine, Alendronate, Deoxycholate, Risedronate, Ibandronate, Zoledronate, Liraglutide, Exenatide, Lanreotide, Octreotide, Deslorelin, Leuprorelin, Goserelin, Triptorelin, or Dutasteride. It is possible.

[0072] The above naltrexone may also be called N-Cyclopropyl-methylnoroxymorphone, N-Cyclopropylmethyl-14-hydroxydihydro-morphinone, 17-(Cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one, EN-1639A, or UM-792.

[0073] The above naltrexone may be a compound represented by the following chemical formula:

[0074] .

[0075] The above donepezil may also be called 1-benzyl-4-[5,6-dimethoxy-1-indanon)-2-ylmethyl]piperidine.

[0076] The above donepezil may be a compound represented by the following chemical formula:

[0077] .

[0078] The above finasteride may also be referred to as N-(1,1-dimethylethyl)-3-oxo-(5α,17β)-4-azaandrost-1-ene-17-carboxamide.

[0079] The above finasteride may be a compound represented by the following chemical formula:

[0080]

[0081] The poorly soluble drug of the present invention may be in the form of a solvate, stereoisomer, prodrug, metabolite (e.g., 6β-naltrexol), derivative (e.g., naloxone), free base, or a combination thereof.

[0082] The above stereoisomer refers to a compound that has the same molecular formula and the method of linking constituent atoms, but differs in the spatial arrangement between atoms. The above solvate refers to a compound solvated in an organic or inorganic solvent. For example, the above solvate is a hydrate. The above stereoisomer may be a diastereomer or an enantiomer. The above prodrug may be a compound that transforms into a target compound within the body after administration. The above metabolite may be a compound generated through the metabolic process of the compound within the body. The above derivative refers to a compound obtained by substituting a part of the structure of a poorly soluble drug with other atoms or atomic groups.

[0083] The above-mentioned biodegradable polymer may be selected from the group consisting of polylactide, polylactic acid, polylactide-co-glycolide, polylactic-co-glycolic acid, polyphosphazine, polyiminocarbonate, polyphosphoester, polyanhydride, polyorthoester, polycaprolactone, polyhydroxyvalrate, polyhydroxybutyrate, polyamino acid, and combinations thereof, but is not limited to the above examples.

[0084] In the above example, the molar ratio of glycolide to lactide in the 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, and about 70:30 to about 80:20, but is not limited to the above example, preferably the molar ratio of glycolide to lactide in the polylactide-co-glycolide may be about 75:25.

[0085] The above-mentioned biodegradable polymer may include one or more types of polylactide and one or more types of polylactide-co-glycolides. In the present invention, the biodegradable polymer may include, for example, combinations such as two types of polylactide, one type of polylactide and one type of polylactide-co-glycolide, two types of polylactide-co-glycolides, three types of polylactide, two types of polylactide and one type of polylactide-co-glycolide, one type of polylactide and two types of polylactide-co-glycolides, and in particular, may include one type of polylactide and one type of polylactide-co-glycolide, or two types of polylactide-co-glycolides, but is not limited thereto.

[0086] The above biodegradable polymer may include two or more types of polylactide-co-glycolides.

[0087] The above aqueous solution may include water and a surfactant. Here, the surfactant may be used without limitation as long as it helps the oil phase solution form stable microparticles.

[0088] 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 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 ester, polyoxyethylene castor oil derivative, sodium stearate, esteramine, linear diamine, patiamine, and combinations thereof, but is not limited thereto.

[0089] The content of the surfactant included in the above aqueous solution may be 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), and 0.25 to 0.3% (w / v), but is not limited thereto. For example, the aqueous solution containing the surfactant may be a 0.5% (w / v) PVA solution, but is not limited to the above examples.

[0090] The viscosity of the oil phase solution in step 1) above may be within a range where the fluid viscosity (unit: cP; centipoise) maintains a laminar flow state within the microchannel. The viscosity of the fluid may be measured using a Brookfield Model LVT viscometer and may be measured at 80 to 100 rpm using an LV 01 or LV 02 spindle. The viscosity of the oil phase solution is measured at 25°C, and once the measurement is started with the viscometer, a constant viscosity value is measured after the solution is stabilized; generally, the stabilization of the solution proceeds within approximately 1 minute.

[0091] The oil phase solution of step 1) above may have a viscosity or density that maintains a laminar flow state with the aqueous solution of step 2) above. Specifically, when the oil phase solution is injected into the aqueous solution flowing in the microchannel, the oil phase solution may have a viscosity or density such that the fluid in the microchannel maintains a laminar flow state. For example, the oil phase solution may have a viscosity or density such that the Reynolds number of the fluid flowing in the microchannel satisfies 2,300 or less.

[0092] In step 3) above, microparticles can be prepared by the emulsion method, porous membrane method, spray drying method, or microfluidic method using an oil phase solution and an aqueous solution.

[0093] Specifically, the process of manufacturing microparticles by the microfluidic method described above may include a) a step of injecting an oil phase solution into a linear microchannel, b) a step of injecting an aqueous solution into a microchannel on both sides or on one side, and c) a step of collecting microparticles.

[0094] Step a) above involves injecting an oil phase solution into a linear microchannel to allow it to flow, and Step b) above involves injecting an aqueous solution into a microchannel on both sides or one side formed to form an intersection with the linear microchannel to allow it to flow. That is, the oil phase solution flows along the linear microchannel, and the aqueous solution flows along a microchannel on both sides or one side formed to form an intersection with the linear microchannel relative to the linear microchannel, and may meet with the flow of the oil phase solution.

[0095] In addition, the aqueous solution can be flowed at a faster flow rate than the oil phase solution injected into a straight microchannel to form an intersection with the oil phase solution. The aqueous solution can be flowed under higher pressure conditions.

[0096] As described above, by making the flow rates of the oil phase solution and the aqueous solution different and making the flow rate of the aqueous solution faster than the flow rate of the oil phase solution, the aqueous solution having a relatively faster flow rate at the point where the flow of the oil phase solution and the flow of the aqueous solution meet compresses the oil phase solution. At this time, due to the repulsive force between the oil phase solution and the aqueous solution, the biodegradable polymer and poorly soluble drug within the oil phase solution 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.

[0097] The preparation of microparticles by the above-described microfluidic method may be a method of preparing microparticles within an aqueous solution by introducing an oil phase solution, in which a sparingly soluble drug, an organic solvent, and a biodegradable polymer are dissolved, into a microchannel together with an aqueous solution to form microparticles of a certain size. The micro-sized particles thus formed are stabilized by a surfactant in the aqueous solution, and the formed particles can be formed by removing the organic solvent inside the particles as it evaporates or volatilizes according to drying conditions.

[0098] The above emulsion method may be a method in which an oil phase solution containing a poorly soluble drug, an organic solvent, and a biodegradable polymer is mixed with an aqueous solution containing a surfactant, and then external energy (such as ultrasound or high-speed rotational force) is applied to the mixture to cause the oil phase solution to form micro-sized particles within the aqueous solution. Microparticles formed by the above emulsion method may be formed by removing the organic solvent inside the particles as it evaporates or volatilizes under drying conditions.

[0099] The above porous membrane method is a method for producing microparticles by flowing an oil phase solution (dispersed phase) in which a sparingly soluble drug, an organic solvent, and a biodegradable polymer are dissolved, onto one side of a porous membrane having micropores, and flowing an aqueous solution (continuous phase) containing a surfactant onto the opposite side of the porous membrane, thereby interrupting the oil phase solution with the flow of the aqueous solution.

[0100] The above spray drying method is a method for producing microparticles without using an aqueous solution by spraying an oil-phase solution, in which a sparingly soluble drug, an organic solvent, and a biodegradable polymer are dissolved, in a spray dryer while blowing heated air. Micro-sized particles are formed as the oil-phase solution is finely sprayed, and the solvent is removed and microparticles can be formed as the organic solvent inside the particles evaporates or volatilizes due to the heated air.

[0101] Specific examples of the emulsion method and spray drying method described above are, for instance, described in 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.

[0102] A microparticle containing a poorly soluble drug according to another embodiment of the present invention is a microparticle produced by the above-described manufacturing method.

[0103] The encapsulation rate of the above microparticles for poorly soluble drugs may be about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, and about 100%.

[0104] The above microparticles may also be referred to as microspheres or microspheres, and may mean that they may contain a poorly soluble drug as an active ingredient within the particles.

[0105] The intermediate particle size (D50) of the above 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, and about 45 μm to about 50 μm.

[0106] In one aspect, the microparticles may have a particle size distribution in the range of ±5μm, ±7μm, ±10μm, ±12μm, or ±15μm based on the intermediate particle size.

[0107] In addition, the microparticles may comprise 60% or more by weight, 65% or more by weight, 70% or more by weight, 75% or more by weight, 80% or more by weight, 85% or more by weight, 90% or more by weight, 95% or more by weight, or 99% or more by weight, based on the total microparticles within this particle size distribution range.

[0108] [Experimental Example 1] Comparison of Solubility According to Combination of Dichloromethane and Diethyl Ether

[0109] To compare the solubility of poorly soluble drugs according to the type and combination of solvents, 0.5 g of naltrexone in the form of a free base (manufactured by Mallinckrodt; hereinafter the same), a poorly soluble drug, and 1.0 g of a biodegradable polymer (manufactured by Corbion; PDLG7504 (ester type) used; hereinafter the same) were dissolved in the same total amount of organic solvent (7.0 g), mixed as shown in Table 1 below, and the dissolution of naltrexone and the biodegradable polymer was observed visually at room temperature. At this time, a transparent state in which no crystals or particles were visible to the naked eye was judged to be complete dissolution.

[0110] Comparative Example 1 Comparative Example 2 Example 1 Example 2 Naltrekson 0.5 g 0.5 g 0.5 g 0.5 g 75 / 25 DL-lactide / glycolide copolymer 1.0 g 1.0 g 1.0 g 1.0 g dichloromethane 7.0 g - 5.0 g 4.0 g diethyl ether - 7.0 g 2.0 g 3.0 g Whether it dissolves Re-determination Neither naltrexone nor biodegradable polymers dissolve Complete dissolution Complete dissolution

[0111] While using an excess amount of dichloromethane can dissolve naltrexone, it increases the total amount of solvent used, which may lead to problems such as the aforementioned residual organic solvent. To avoid these issues, as in Comparative Example 1, dichloromethane was used alone in the smallest possible amount to dissolve naltrexone; however, a recrystallization phenomenon in which naltrexone precipitated occurred. This is presumed to be due to the precipitation of naltrexone as crystals in the saturated solution caused by pressure changes from compressed air and solvent volatilization when the oil phase solution is sprayed together with the aqueous solution through a module. Furthermore, in Comparative Example 2, where 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, where diethyl ether was mixed as a co-solvent with dichloromethane as the first solvent, both naltrexone and the biodegradable polymer were completely dissolved. Moreover, the solubility was much higher than when each solvent was used alone, and no recrystallization phenomenon occurred.

[0112] This may be because using diethyl ether, which has poor solubility for naltrexone and biodegradable polymers, as a co-solvent affects the arrangement between the first solvent, dichloromethane, and naltrexone molecules, thereby increasing the solubility for naltrexone and biodegradable polymers.

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

[0114] As described above, it was confirmed that using dichloromethane and diethyl ether together allows for the complete dissolution of naltrexone and biodegradable polymers even with a small amount of solvent.

[0115] Accordingly, when microparticles are prepared using a mixed solvent such as in Examples 1 and 2 above, the loss of naltrexone can be reduced to increase the encapsulation rate, and the amount of organic solvent used can be reduced, thereby effectively removing residual organic solvent.

[0116] Subsequently, additional experiments were conducted to verify these effects.

[0118] [Experimental Example 2] Comparative Experiment on Encapsulation Rate, Residual Organic Solvent, and Solubility of Naltrexone Microparticles According to Solvent

[0119] (1) Preparation of microparticles containing naltrexone

[0120] Microparticles for use in the experiment were prepared as follows, and the content of the components used in the preparation of the microparticles is summarized in Table 2.

[0121] [Example 3]

[0122] 0.5 g of naltrexone in the form of a free base 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 each microchannel to form microparticles at the intersection of the oil phase and the aqueous phase solution, and these were collected in the aqueous phase (10°C). The aqueous phase solution was a 0.5% (w / v) PVA solution (0.5% (v / v) PVA mixed with water).

[0123] The above-described 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 sieved and then freeze-dried to complete the preparation of dried microparticles.

[0124] [Example 4]

[0125] It was prepared in the same manner as Example 3, except that 8.0g of dichloromethane and 2.0g of diethyl ether were mixed.

[0126] [Comparative Example 3]

[0127] It was prepared in the same manner as Example 3, except that 8.0 g of dichloromethane was mixed without diethyl ether.

[0128] [Comparative Example 4]

[0129] It was prepared in the same manner as Example 3, except that 12.3g of dichloromethane was mixed without diethyl ether.

[0130] Comparative Example 3 Comparative Example 4 Example 3 Example 4 Naltrekson 0.5 g 0.5 g 0.5 g 0.5 g 75 / 25 DL-lactide / glycolide copolymer 1.0 g 1.0 g 1.0 g 1.0 g dichloromethane 8.0 g 12.3 g 10.0 g 8.0 g diethyl ether - - 2.3 g 2.0 g

[0131] (2) Comparison of encapsulation rate, residual organic solvent, and precipitation status according to the use of co-solvent and amount of organic solvent

[0132] The solubility, encapsulation rate, and residual organic solvent of the microparticles prepared from Experimental Example 2.(1) above were evaluated. Solubility was confirmed visually to see if precipitation had occurred, and the encapsulation rate was measured using high-performance liquid chromatography (HPLC). The residual organic solvent was analyzed using a gas chromatogram (GC). The results are listed in Table 3.

[0133] Encapsulation rate (%) Residual organic solvent (ppm) note Comparative Example 3 - - precipitation Comparative Example 4 84.67 Dichloromethane: 1,764.2 - Example 3 90.97 Dichloromethane: 806.9 Diethyl ether: 322.9 - Example 4 93.08 Dichloromethane: 1,000.5% Diethyl ether: 289.8% -

[0134] When comparing Comparative Example 3 and Comparative Example 4, since naltrexone is sparingly soluble in dichloromethane, if the amount of dichloromethane is insufficient, naltrexone dissolved in the organic solvent precipitates due to recrystallization during the process of preparing the oil phase solution, and consequently, microparticles could not be produced. When comparing Comparative Example 4 with Example 3 and Example 4, it was confirmed that when diethyl ether is used as a co-solvent, the encapsulation rate increases by about 6% compared to when dichloromethane is used alone, the amount of residual organic solvent in dichloromethane is reduced, and the amount of residual organic solvent in total is also reduced.

[0135] According to the above results, using diethyl ether, which has a lower boiling point than dichloromethane, together can be seen to increase the encapsulation rate. This may be because the solvent volatilization of diethyl ether occurs at a lower temperature than that of dichloromethane, which increases the concentration of naltrexone and biodegradable polymers within the microparticles, thereby increasing the viscosity of the oil phase solution present within the microparticles and consequently maintaining a stronger bond between naltrexone and the biodegradable polymers.

[0136] [Experimental Example 3] Comparative experiment on encapsulation rate, residual organic solvent, and solubility of naltrexone microparticles according to solvent mixing ratio

[0137] (1) Preparation of microparticles containing naltrexone

[0138] Microparticles for use in the experiment were prepared as follows, and the content of the components used in the preparation of the microparticles is summarized in Table 4.

[0139] [Example 5]

[0140] 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 each microchannel to form microparticles at the intersection of the oil phase and the aqueous phase, which were then collected from the aqueous phase (10°C). The aqueous phase was a 0.5% (w / v) PVA solution. 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 sieved and freeze-dried to complete the preparation of dried microparticles.

[0141] [Example 6]

[0142] Microparticles were prepared in the same manner as in Example 5, except that the organic solvent was removed by stirring at 10°C for 1.5 hours, at 30°C for 1.5 hours, and at 50°C for 1.5 hours.

[0143] [Example 7]

[0144] It was prepared in the same manner as Example 5, except that 3.0g of diethyl ether was mixed.

[0145] Example 5 Example 6 Example 7 Naltrekson 0.5 g 0.5 g 0.5 g 75 / 25 DL-lactide / glycolide copolymer 1.0 g 1.0 g 1.0 g dichloromethane 6.0 g 6.0 g 6.0 g diethyl ether 2.0 g 2.0 g 3.0 g

[0146] (2) Comparison of encapsulation rate, residual organic solvent, and solubility of naltrexone microparticles according to solvent mixing ratio

[0147] Encapsulation rate (%) Residual organic solvent (ppm) note Example 5 98.97 Dichloromethane: 1,360.0 Diethyl ether: 264.2 - Example 6 90.70 Dichloromethane: 1,827.7% Diethyl ether: 427.3% - Example 7 101.19 Dichloromethane: 1,207.2 Diethyl ether: 344.9 -

[0148] When comparing Example 5 and Example 6, it was confirmed that the longer the organic solvent removal time, the lower the encapsulation rate actually became. These results confirmed that there was no significant difference in the amount of organic solvent residue as the organic solvent removal time increased.

[0149] When comparing Example 5 and Example 7, it was confirmed that the ratio of dichloromethane and diethyl ether used as organic solvents affects the encapsulation rate. It was confirmed that as the ratio of diethyl ether to dichloromethane increases, the naltrexone encapsulation rate of microparticles increases.

[0150] [Experimental Example 4] Experiment according to the type of organic solvent as a co-solvent

[0151] When co-solvents other than diethyl ether were used, the encapsulation rate and residual organic solvent content of the microparticles were evaluated. Microparticles were prepared using the same method as in Example 3 of Experimental Example 2. The characteristics of usable co-solvents including diethyl ether are summarized in Table 6, and examples using various co-solvents are summarized in Table 7.

[0152] menstruum Boiling point (°C) Relative polarity Solubility (water, g / mL) Vapor pressure (20→, hPa) methylene chloride 39.8 0.309 1.32 475 diethyl ether 34.6 0.117 7.5 587 Pentane 36.1 - 0.0039 573

[0153] (1) Preparation of microparticles containing donepezil

[0154] [Example 8]

[0155] 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 each microchannel to form microparticles at the intersection of the oil phase and the aqueous phase, which were then collected from the aqueous phase (10°C). The aqueous phase solution was a 0.25% (w / v) PVA solution. The prepared 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 prepared microparticles were sieved and freeze-dried to complete the preparation of dried microparticles.

[0156] [Example 9]

[0157] 0.98264g of donepezil, 1.0g of DL-lactide / glycolide copolymer, and 3.0g of lactide copolymer were dissolved in a mixture of 6.0g of dichloromethane and 4.5g of diethyl ether, and the preparation method was the same as in Example 8.

[0158] [Example 10]

[0159] 0.98264g of donepezil, 1.0g of DL-lactide / glycolide copolymer, and 3.0g of lactide copolymer were dissolved in a mixture of 8.0g of dichloromethane and 3.0g of pentane, and the preparation method was the same as in Example 8.

[0160] [Example 11]

[0161] 0.98264g of donepezil, 1.0g of DL-lactide / glycolide copolymer, and 3.0g of lactide copolymer were dissolved in a mixture of 6.0g of dichloromethane and 4.5g of methyl-t-butyl ether, and the preparation method was the same as in Example 8.

[0162] Example 8 Example 9 Example 10 Example 11 Donepezil 0.98264 g 0.98264 g 0.98264 g 0.98264 g 75 / 25 DL-lactide / glycolide copolymer 1.0 g 1.0 g 1.0 g 1.0 g Lactid copolymer 3.0 g 3.0 g 3.0 g 3.0 g dichloromethane 22.667 g 6.0 g 8.0 g 6.0 g diethyl ether - 4.5 g - - Pentane - - 3.0 g - methyl-t-butyl ether - - - 4.5 g

[0163] (2) Comparison of encapsulation rate of donepezil microparticles and residual organic solvent according to the type of co-solvent

[0164] Encapsulation rate (%) Residual organic solvent (ppm) note Example 8 105.95 Dichloromethane: 3,744.1 - Example 9 106.38 Dichloromethane: 440.4 Diethyl ether: 4,050.4 - Example 10 88.83 Dichloromethane: 435.4-pentane: 25,537.9 - Example 11 82.04 Dichloromethane: 42.6 Methyl-t-butyl ether: 7,537.7 porous

[0165] When comparing Example 8 and Example 9, the amount of dichloromethane used was reduced due to the use of diethyl ether as a co-solvent, so the residual dichloromethane solvent was lower in Example 9, which used diethyl ether under the same drying conditions.

[0166] In addition, in the case of Example 10, the residual solvent of pentane used as a co-solvent was measured to be very high, which may be because although the boiling point of pentane is lower than that of diethyl ether, its solubility in water is poor, so pentane could not be removed to the outside through water.

[0167] In the case of Example 11, although the boiling point of methyl-t-butyl ether is higher than that of pentane, its solubility in water is higher than that of pentane, so it appears that residual solvent was removed. However, since the boiling point is 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 had holes.

[0169] [Experimental Example 5] Evaluation of Increase in Polymer Ratio of Oil Phase Solution Due to Use of Co-solvent

[0170] When preparing the oil phase solution, the use of a co-solvent lowers the viscosity, making it possible to dissolve and manufacture polymers at higher concentrations compared to using dichloromethane as a sole solvent.

[0172] (1) Preparation of microparticles containing donepezil

[0173] Example 8 Example 12 Example 13 Example 14 Example 15 Example 16 Donepezil 0.98264 g - 0.98264 g 0.98264 g 0.98264 g 0.98264 g 75 / 25 DL-lactide / glycolide copolymer 1.0 g 1.0 g 1.0 g 1.0 g 1.0 g 1.0 g Lactid copolymer 3.0 g 3.0 g 3.0 g 3.0 g 3.0 g 3.0 g dichloromethane 22.667 g 22.667 g 6.0 g 10.5 g 6.0 g 4.0 g diethyl ether - - - - 4.5 g 3.0 g

[0174] [Example 12]

[0175] 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, and the preparation method was the same as in Example 8.

[0176] [Example 13]

[0177] 0.98264g of donepezil, 1.0g of DL-lactide / glycolide copolymer, and 3.0g of lactide copolymer were mixed and dissolved in 6.0g of dichloromethane, and the preparation method was the same as in Example 8.

[0178] [Example 14]

[0179] 0.98264g of donepezil, 1.0g of DL-lactide / glycolide copolymer, and 3.0g of lactide copolymer were mixed and dissolved in 10.5g of dichloromethane, and the preparation method was the same as in Example 8.

[0180] [Example 15]

[0181] 0.98264g of donepezil, 1.0g of DL-lactide / glycolide copolymer, and 3.0g of lactide copolymer were mixed and dissolved in 6.0g of dichloromethane and 4.5g of diethyl ether, and the preparation method was the same as in Example 8.

[0182] [Example 16]

[0183] 0.98264g of donepezil, 1.0g of DL-lactide / glycolide copolymer, and 3.0g of lactide copolymer were dissolved in a mixture of 4.0g of dichloromethane and 3.0g of diethyl ether, and the preparation method was the same as in Example 8.

[0184] (2) Comparison of viscosity of oil phase solution according to co-solvent ratio and verification of feasibility of manufacture

[0185] Solid content ratio (%) Viscosity (cp) Manufacturability Example 8 18.02 10.9 possible Example 12 15.00 11.0 possible Example 13 45.37 399.9 impossibility Example 14 32.18 53.4 impossibility Example 15 32.18 28.6 possible Example 16 41.58 109.0 possible

[0186] Compared to Example 8, the viscosity of Example 12, a placebo solution in which the main component is not dissolved, is similar, which means that the main component does not have a significant effect on the viscosity.

[0187] In addition, through Examples 13 and 14, it was confirmed that it is impossible to prepare a high-concentration oil-phase solution with a solid content ratio exceeding 30% using dichloromethane as a single solvent.

[0188] However, in the case of Examples 15 and 16 using the co-solvent diethyl ether, it can be confirmed that microparticles can be manufactured without problems and have lower viscosity compared to the dichloromethane single solvent group with the same solid content ratio, even though the solid content ratio exceeds 30%.

[0189] Depending on the viscosity or density of the organic solution for microparticle production, the uniformity of the microparticles was evaluated, as well as how much the production time could be shortened and how efficiently residual organic solvent could be removed, thereby assessing whether the production of microparticles could be easily performed.

[0190] From the foregoing description, a person skilled in the art to which the present invention pertains will understand that the present invention may be implemented in other specific forms without altering its technical concept or essential features. In this regard, the embodiments described above should be understood as illustrative in all respects and not restrictive. The scope of the present invention should be interpreted as including all modifications or variations derived from the meaning and scope of the claims set forth below and their equivalents, rather than from the detailed description above.

Claims

Claim 1 A method for manufacturing microparticles containing a poorly soluble drug, comprising: 1) a step of 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) a step of preparing an aqueous solution by dissolving a surfactant in water; and 3) a step of manufacturing microparticles using the oil phase solution and the aqueous solution, wherein the mixed solvent comprises a first solvent and a co-solvent, the first solvent is dichloromethane, and the co-solvent is diethyl ether. Claim 2 delete Claim 3 In claim 1, the co-solvent has a density of 1.3 g / cm³ 3 Method for manufacturing microparticles containing a drug with poor soluble properties. Claim 4 A method for manufacturing microparticles according to claim 1, wherein the co-solvent comprises a poorly soluble drug having a polarity index of 3 or less. Claim 5 In claim 1, the method for manufacturing microparticles comprising a poorly soluble drug having a boiling point of 50°C or lower, wherein the co-solvent is a method for manufacturing microparticles. Claim 6 In paragraph 1, the above common medium has a degree of acceptance of 2 20 to 8 20 Method for preparing microparticles containing a poorly soluble drug g / 100g water. Claim 7 A method for manufacturing microparticles containing a poorly soluble drug, wherein, in claim 1, the first solvent and the co-solvent are included in a weight ratio of 1:0.5 to 1:

10. Claim 8 In claim 1, the poorly soluble drug is Naltrexone, Donepezil, Finasteride, Aripiprazole, Olanzapine, Palonosetron, Minocycline, Memantine, Alendronate, Deoxycholate, Risedronate, Ibandronate, Zoledronate, Liraglutide, Exenatide, Lanreotide, Octreotide, Deslorelin, Leuprorelin, Goserelin, Triptorelin, or Method for manufacturing microparticles containing a poorly soluble drug, dutasteride. Claim 9 A method for manufacturing microparticles containing a poorly soluble drug according to claim 1, wherein the poorly soluble drug and the mixed solvent of step 1) are mixed in a weight ratio of 1:7 to 1:

30. Claim 10 A method for manufacturing microparticles containing a poorly soluble drug according to claim 1, wherein the poorly soluble drug and the biodegradable polymer of step 1) are included in a weight ratio of 1:0.5 to 1:

10. Claim 11 A method for preparing microparticles comprising a poorly soluble drug selected from the group consisting of polylactide, polylactic acid, polylactide-co-glycolide, polylactic-co-glycolic acid, polyphosphazine, polyiminocarbonate, polyphosphoester, polyanhydride, polyorthoester, polycaprolactone, polyhydroxyvalrate, polyhydroxybutyrate, polyamino acid, and combinations thereof, wherein the biodegradable polymer comprises a poorly soluble drug. Claim 12 A method for preparing microparticles according to claim 1, wherein the surfactant comprises a poorly soluble drug 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 ester, polyoxyethylene castor oil derivative, sodium stearate, esteramine, linear diamine, patiamine, and combinations thereof. Claim 13 In claim 1, the above step 3) is a method for producing microparticles containing a poorly soluble drug by using an oil phase solution and an aqueous solution to produce microparticles by an emulsion method, a porous membrane method, a spray drying method, or a microfluidic method. Claim 14 A method for manufacturing microparticles containing a poorly soluble drug according to claim 1, further comprising the step of removing residual organic solvent within the microparticles manufactured in step 3). Claim 15 A method for preparing microparticles containing a poorly soluble drug, wherein, in claim 14, the step of removing the residual organic solvent is to remove the residual organic solvent by placing microparticles containing the residual organic solvent into an aqueous solution and stirring. Claim 16 A method for manufacturing microparticles containing a poorly soluble drug according to claim 15, wherein the stirring process comprises: a first stirring step of stirring at 200 to 400 rpm for 30 minutes to 2 hours at 10°C to 20°C; a second stirring step of stirring at 200 to 400 rpm for 30 minutes to 2 hours at 25°C to 35°C; and a third stirring step of stirring at 200 to 400 rpm for 30 minutes to 2 hours at 45°C to 55°C. Claim 17 delete Claim 18 delete

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