KR20220033960A - 3D microfluidic reactor for improving encapsulation efficiency of drugs, and method of manufacturing uniform capsules by one-flow process - Google Patents

Abstract

The present invention relates to a three-dimensional (3D) microfluidic reactor. The 3D microfluidic reactor according to an embodiment of the present invention includes: a first fluid containing a drug and a solvent to precipitate drug particles by using a precipitation phenomenon caused by a difference in solubility; a first structure provided with a flow path structure so that a second fluid containing a first semi-solvent may be mixed continuously; and a second structure provided with a flow path structure so that a third fluid containing a carrier may be supplied to support the drug particles transferred from the first structure, wherein the first structure and the second structure fluidically communicate with each other to transfer the drug particles precipitated from the first structure toward the second structure with no delay. In this manner, the step of precipitating the drug particles and step of supporting the drug particles are carried out in a continuous one-flow process.

Description

3D microfluidic reactor for improving encapsulation efficiency of drugs, and method of manufacturing uniform capsules by one-flow process}

The present invention relates to a three-dimensional microfluidic reactor and a method for manufacturing a capsule containing uniformly sized drug particles using the same, and more particularly, hydrophilicity through a two-step three-dimensional fluid focusing effect based on continuous-flow A three-dimensional microfluidic reactor capable of uniformly controlling the size of drug particles and drug-polymer capsules, a method for manufacturing a capsule containing hydrophilic drug particles using the same, and a method for manufacturing by the batch process to improve drug loading efficiency Provided are a method and a sustained-release capsule in which hydrophilic drug particles of uniform size prepared therefrom are supported.

In the pharmaceutical and fine chemical industries, microfluidic reactors used for compound synthesis provide many advantages over conventional processes.

Specifically, the microfluidic reactor can secure rapid mass and heat transfer effects by providing a high surface area-to-volume ratio, and as a result, an improved effect can be obtained in terms of process safety.

In addition, microfluidic reactors can provide cost-effective advantages as they require relatively simple feasibility studies for scale-up. That is, when it is necessary to expand the design capacity of the microfluidic reactor, it is possible to increase the throughput by arranging a plurality of microfluidic reactor units required for design in parallel and simultaneously applying a higher flow rate. That is, since the microfluidic reactor does not require excessive testing and design for scale-up unlike the conventional batch process, it has the advantage of being able to easily achieve scale-up.

On the other hand, the nano-drug production method through the nano-precipitation method precipitates the drug particles by using a precipitation phenomenon caused by the difference in solubility of the drug in solvent and anti-solvent. In this regard, in the case of the conventional batch process-based precipitation reactor, there is a limit in manufacturing nanoparticles of a uniform size because the contact between a good solvent and an anti-solvent having high drug solubility is irregularly formed. In addition, there is a disadvantage in that the recrystallization phenomenon occurs by partially drying the drug particles after the nanoparticles are precipitated and before being supported on the carrier.

In this regard, the literature [Results in Pharma Sciences 2 (2012) 79-85] discloses a method for preparing protein-loaded PLGA nanoparticles using a flask, but when preparing a drug-polymer capsule by the method, As described above, due to recrystallization of the drug particles, the uniformity of the particles is deteriorated.

In order to solve this problem, it is necessary to develop a microfluidic reactor capable of producing uniform nano-drugs while securing advantageous effects in the process based on a microfluidic system.

In order to solve the above problems, an object of the present invention is to provide a three-dimensional microfluidic reactor for preventing recrystallization of drug particles and/or drug-polymer capsules.

Another object of the present invention is a first section in which the hydrophilic drug is granulated and precipitated, a second section in which the hydrophilic drug particles and a hydrophobic polymer compound are mixed, and a third section in which the hydrophilic drug particles are supported and encapsulated in a hydrophobic polymer compound are successively An object of the present invention is to provide a method for manufacturing a capsule in which hydrophilic drug particles of a uniform size are supported in a connected three-dimensional microfluidic reactor in a batch process.

Another object of the present invention is to provide a method for efficiently supporting hydrophilic drug particles on a hydrophobic high molecular compound carrier in the above-mentioned manufacturing method.

Another object of the present invention is to provide a sustained-release capsule carrying hydrophilic drug particles of uniform size prepared by the above-described capsule manufacturing method and/or a method for efficiently supporting hydrophilic drug particles on a hydrophobic polymeric compound carrier. will be.

According to one aspect of the present invention, a flow path such that a first fluid containing a drug and a solvent and a second fluid containing a first anti-solvent are continuously mixed in order to precipitate drug particles using a precipitation phenomenon due to a difference in solubility. A first structure having a structure and a second structure having a flow path structure to supply a third fluid including a carrier to support the drug particles delivered from the first structure, wherein the first structure and the The second structure is in fluid communication with each other so that the drug particles precipitated from the first structure are transferred to the second structure side without delay, whereby the precipitation process and the loading process of the drug particles are a continuous batch process, a three-dimensional microfluidic reactor provided

In this case, the first structure may include: a first channel connected to one side of the first concentrated space having a hexahedral shape to supply the first fluid to the first concentrated space; The second to fifth channels each connected to the four surfaces in contact with the one side of the first concentrated space and supplying the second fluid to the inner side of the first concentrated space, and the one side of the first concentrated space are opposite to each other It may include a sixth channel that is connected to the other side of the drug particles out of the first concentration space.

At this time, the three-dimensional microfluidic reactor may include a plurality of first structures to precipitate different drug particles, respectively, and the plurality of first structures may be connected to the second structure after they merge with each other.

At this time, the second structure is connected to one end of the first structure to cross and a seventh channel for supplying the third fluid and a seventh channel connected to one end of the seventh channel and having at least three bent portions It can include 8 channels.

At this time, in fluid communication with the second structure, a third structure having a flow path structure to supply a fourth fluid containing a second antisolvent for improving the loading efficiency of the particle drug on the carrier is further added. may include

In this case, the third structure may include: a ninth channel having one end connected to one end of the second structure and the other end connected to one side of the second concentration space having a hexahedral shape; The tenth to thirteenth channels each connected to the four surfaces in contact with the one side of the second concentrated space and supplying the fourth fluid to the inner side of the second concentrated space, and one side of the second concentrated space facing each other It may include a 14th channel that is connected to the other side and through which the drug particles encapsulated by the carrier flow out from the second concentration space.

At this time, in fluid communication with the second structure, a third structure having a flow path structure to supply a fourth fluid containing a second antisolvent for improving the loading efficiency of the particle drug on the carrier is further added. Including, wherein the first structure includes: a first channel connected to one side of the first concentrated space having a hexahedral shape to supply the first fluid to the first concentrated space; The second to fifth channels each connected to the four surfaces in contact with the one side of the first concentrated space and supplying the second fluid to the inner side of the first concentrated space, and the one side of the first concentrated space are opposite to each other and a sixth channel connected to the other side to drain the drug particles from the first concentration space, the second structure being connected to intersect one end of the six channels and supplying the third fluid and a seventh channel and an eighth channel connected to one end of the seventh channel and having at least three bent portions, wherein the third structure has one end connected to one end of the eighth channel and the other end has a hexahedral shape a ninth channel connected to one side of the second concentration space having a; The tenth to thirteenth channels each connected to the four surfaces in contact with the one side of the second concentrated space and supplying the fourth fluid to the inner side of the second concentrated space, and one side of the second concentrated space facing each other It may include a 14th channel that is connected to the other side and through which the drug particles encapsulated by the carrier flow out from the second concentration space.

In this case, the micro-reactor may be formed by stacking a plurality of flat-panel films each having a pattern etched by a laser.

According to another aspect of the present invention, there is provided a method for preparing a capsule in which hydrophilic drug particles of a uniform size are supported:

The first section for granulating and precipitating the hydrophilic drug, the second section for mixing the hydrophilic drug particles and the hydrophobic polymer compound, and the third section for encapsulating the hydrophilic drug particles by supporting the hydrophobic polymer compound are connected in a continuous batch process. In a fluid reactor,

a) precipitating the hydrophilic drug after granulating the hydrophilic drug by introducing an antisolvent for the hydrophilic drug in the three-dimensional and vertical four directions in a state in which the solution in which the hydrophilic drug is dissolved in the first section is horizontally flowed;

b) continuously mixing with the precipitated hydrophilic drug particles by introducing a solution in which the hydrophobic polymer compound is dissolved in the second section; and

c) In the third section, a solution in which the water-soluble polymer compound is dissolved is introduced in three-dimensional vertical four directions to support the hydrophilic drug particles on the hydrophobic polymer compound and encapsulate.

According to a preferred embodiment of the present invention, step a) may include separately granulating and precipitating two or more different hydrophilic drugs in the first section.

According to another preferred embodiment of the present invention, the hydrophilic drug may be one or more selected from the group consisting of alendronate, doxorubicin hydrochloride, varenicline, neomycin, and therapeutic peptides or proteins.

According to another preferred embodiment of the present invention, the anti-solvent for the hydrophilic drug in step a) may be at least one selected from the group consisting of acetonitrile, tetrahydrofuran, dimethyl sulfoxide and ethanol.

According to another preferred embodiment of the present invention, the hydrophobic polymer compound is polylactic acid, polylactide, polylactic-co-glycolic acid, polylactide-co-glycolide (PLGA), polyphosphazine, polyiminocarbonate , polyphosphoesters, polyanhydrides, polyorthoesters, copolymers of lactic acid and caprolactone, polycaprolactone, polyhydroxyvalate, polyhydroxybutyrate, polyamino acids, copolymers of lactic acid and amino acids, and these It may be selected from the group consisting of a mixture of

According to another preferred embodiment of the present invention, the water-soluble polymer compound in step c) may be a hydrophilic drug stabilizer to increase the efficiency of supporting the hydrophilic drug on the hydrophobic polymer compound.

According to another preferred embodiment of the present invention, the size of the hydrophilic drug particles is the flow rate of the solution in which the hydrophilic drug is dissolved in step a), the concentration of the hydrophilic drug in step a), and the solution in which the hydrophilic drug is dissolved in step a): It can be adjusted by using any one or more selected from the group consisting of the flow rate ratio of the anti-solvent as a variable.

According to another preferred embodiment of the present invention, the hydrophilic drug particles may have a uniform diameter of 10 nm to 1,000 nm.

According to another preferred embodiment of the present invention, the flow rate ratio of the solution in which the hydrophilic drug is dissolved and the antisolvent in the first section of step a) may be 1:2 to 1:12.

According to another preferred embodiment of the present invention, the hydrophilic drug is alendronate, the hydrophobic polymer compound is polylactic-co-glycolic acid, polylactide-co-glycolide (PLGA), and the water-soluble polymer compound is polyvinyl. It may be alcohol.

According to another preferred embodiment of the present invention, in order to increase the loading efficiency of alendronate, 0.1 wt% to 2.5 wt% of a polyvinyl alcohol solution may be used.

According to another preferred embodiment of the present invention, the loading ratio of alendronate may be at least 70% or more.

According to another preferred embodiment of the present invention, the manufacturing method may be performed in the three-dimensional microfluidic reactor described above.

According to another aspect of the present invention, there is provided a sustained-release capsule in which hydrophilic drug particles of uniform size prepared by the above-described capsule manufacturing method are supported.

According to another aspect of the present invention, there is provided a sustained-release capsule in which alendronate of uniform nano-particle size prepared by the above-described capsule manufacturing method is supported on polylactide-co-glycolide.

The three-dimensional microfluidic reactor according to the present invention and a method for manufacturing a capsule carrying hydrophilic drug particles using the same are based on continuous-flow, and through the three-dimensional fluid focusing effect in two steps, the hydrophilic drug particles and the drug-polymer capsule size can be uniformly controlled, and thus the prepared drug-polymer capsule is capable of continuously releasing the drug in the body in a sustained-release form for a long period of time, which is more effective in treating related diseases.

1 is a perspective view showing a three-dimensional microfluidic reactor according to an embodiment of the present invention.
2 is a perspective view showing only a portion adjacent to a fluid in a three-dimensional microfluidic reactor according to an embodiment of the present invention.
FIG. 3 is a cross-sectional view of a three-dimensional microfluidic reactor according to an embodiment of the present invention as viewed in the direction AA of FIG. 1 .
FIG. 4 is a cross-sectional view of a three-dimensional microfluidic reactor according to an embodiment of the present invention as viewed from the direction BB of FIG. 1 .
5 is a perspective view showing another example of a three-dimensional microfluidic reactor according to an embodiment of the present invention.
6 is an explanatory view for explaining a method of forming a three-dimensional microfluidic reactor according to an embodiment of the present invention.
7 is a schematic diagram illustrating a microfluidic reactor equipped with a single flow-based three-dimensional focusing structure made of a polyimide-based film. Here, in the first section, drug particles are formed and precipitated, in the second section, drug particles and a polymer compound used as a carrier are mixed, and in the third section, drug particles are supported on the polymer compound and encapsulated.
8 is a dynamic light scattering spectrophotometer (Dynamic Light Scattering) showing the size of drug particles according to the initial drug flow rate, initial drug concentration, and the solvent:antisolvent flow rate ratio, which are each condition of the drug particle formation and precipitation step in the first section of FIG. , DLS) and analyzed.
9 is a three-dimensional focusing effect according to the drug flow rate and solvent:anti-solvent flow rate ratio of the drug particleization and precipitation step made in the first section of FIG. 7 using computational fluid dynamics (CFD). will be.
10 is a three-dimensional microfluidic reactor (a), a flask (b), and a drug-polymer capsule prepared using each of the T-type device (c) is analyzed with a scanning electron microscope (Scanning Electron Microscope, SEM) is shown. .
11 shows a drug-polymer capsule prepared using a three-dimensional microfluidic reactor analyzed with a transmission electron microscope (TEM).
12 shows a comparison of drug loading efficiency according to PVA concentration during preparation of a drug-polymer capsule (ALS-PLGA capsule) using a three-dimensional microfluidic reactor.
13 shows a comparison of drug loading efficiency of drug-polymer capsules prepared using a three-dimensional microfluidic reactor (a), flask (b), and T-type device (c), respectively.

Hereinafter, with reference to the accompanying drawings, embodiments of the present invention will be described in detail so that those of ordinary skill in the art can easily carry out the present invention. The present invention may be embodied in many different forms and is not limited to the embodiments described herein. In order to clearly explain the present invention in the drawings, parts irrelevant to the description are omitted, and the same reference numerals are given to the same or similar components throughout the specification.

In the present specification, terms such as “comprise” or “have” are intended to designate that a feature, number, step, operation, component, part, or combination thereof described in the specification exists, but one or more other features It should be understood that this does not preclude the possibility of the presence or addition of numbers, steps, operations, components, parts, or combinations thereof.

The three-dimensional microfluidic reactor (10, hereinafter 'microfluidic reactor') according to an embodiment of the present invention precipitates drug particles using a precipitation phenomenon due to a difference in solubility, and supports the precipitated drug particles on a carrier It is a device that can continuously perform the process.

In particular, the microfluidic reactor 10 according to an embodiment of the present invention can omit a separate drying process between the precipitation process of drug particles and the loading process, thereby preventing recrystallization of drug particles that may be caused by drying It is a device that can Hereinafter, the main configuration and effects of the microfluidic reactor 10 will be described in more detail with reference to the drawings.

1 is a perspective view showing a three-dimensional microfluidic reactor according to an embodiment of the present invention. 2 is a perspective view showing only a portion adjacent to a fluid in a three-dimensional microfluidic reactor according to an embodiment of the present invention. 3 is a cross-sectional view of a three-dimensional microfluidic reactor according to an embodiment of the present invention as viewed from the direction A-A of FIG. 1 . 4 is a cross-sectional view of a three-dimensional microfluidic reactor according to an embodiment of the present invention as viewed from the direction B-B of FIG. 1 .

Referring to FIG. 1 , the microfluidic reactor 10 according to an embodiment of the present invention includes a first structure 30 , a second structure 50 , and a third structure 70 sequentially connected to each other.

First, the first structure 30 is a structure having a flow path so that the first fluid F1 and the second fluid F2 are continuously mixed in order to precipitate drug particles from the first fluid F1 containing the drug. .

As a specific example, referring to FIGS. 2 to 4 , the first structure 30 includes first to sixth channels ( 31 to 36) may be included. Hereinafter, in the present specification, in describing the channel, the channel is defined as a space structure having a hollow so that a fluid can move therein.

At this time, one end of the first channel 31 may be connected to the first surface 31 of the first concentration space 40 . In addition, a fluid pump P capable of supplying the first fluid F1, for example, a syringe pump capable of precisely controlling the flow of a small amount of fluid, may be connected to the other end of the first channel 31 . The first fluid F1 may be supplied to the first concentration space 40 from the outside of the microfluidic reactor 10 through the first channel 31 .

In this case, the first fluid F1 may include a drug to be granulated by subsequent precipitation and a solvent for dissolving the drug.

In addition, second to fifth channels 32 to 35 may be connected to the second to fifth surfaces 42 to 45 in contact with the first surface 41 of the first concentration space 40 , respectively. That is, the second to fifth channels 32 to 35 may be arranged to surround the first fluid F1 in a cross shape, as shown in FIGS. 3 and 4 .

At this time, the fluid pump P is connected to one side of the second channel to the fifth channel 32 to 35 as in the first channel 31 , so that the second fluid F2 is directed toward the first concentration space 40 . can be supplied.

In one embodiment of the present invention, the second fluid F2 is a fluid that can be mixed with the first fluid F1 to precipitate the drug particles, and may include a first antisolvent for the drug. Through this, when the first fluid F1 and the second fluid F2 are mixed in the first concentrated space 40, a difference in solubility between the solvent and the first anti-solvent included in the first fluid F1 occurs. do. As a result, it is possible to precipitate drug particles in a granular form from the drug. As described above, the precipitation method for precipitating particles using the difference in solubility is a known technique, and a detailed description thereof will be omitted.

In an embodiment of the present invention, as described above, the second to fifth channels 32 to 35 are arranged in a cross shape, and a first concentration space connected to the second to fifth channels 32 to 35 . The area of the side surfaces 42 to 45 of 40 may be formed to be the same as each other. Therefore, it is possible to apply a pressure of equal size up, down, left and right through the second fluid F2 with respect to the first fluid F1 introduced into the first concentrated space 40 . As a result, the microfluidic reactor 10 according to an embodiment of the present invention is uniformly without bias in any one direction with respect to the first fluid F1 moving in one direction (the y-direction relative to FIG. 3 ). Since the second fluid F2 can be mixed, drug particles having an overall uniform size can be precipitated.

Hereinafter, an effect that can be obtained by applying a fluid pressure of a uniform size in all directions to a fluid moving in one direction is defined as a 'three-dimensional fluid flow focusing effect'.

In an embodiment of the present invention, when the first concentration space 40 is used as a reference, the sixth channel 36 may be disposed on the other side of the first channel 31 . That is, referring to FIG. 3 , the sixth channel 36 may be connected to the sixth surface 46 of the first concentration space 40 .

At this time, the sixth channel 36 may function as a passage through which the first fluid F1 and the second fluid F2 mixed with each other in the first concentrated space 40 flow out of the first structure 30 . can Therefore, the drug particles in the form of particles precipitated as described above through the sixth channel 36 may also flow out together.

The microfluidic reactor 10 according to an embodiment of the present invention includes one end of the first structure 30 and a second structure 50 in fluid communication with each other.

At this time, the second structure 50 is provided with a flow path structure to supply the third fluid F3 including a carrier for supporting the drug particles delivered from the first structure 30, and to mix them with the drug particles. can do.

As an illustrative example, referring to FIG. 3 , the second structure 50 includes one end of the sixth channel 36 included in the first structure 30 and a seventh channel 51 connected to cross each other. can do. That is, the sixth channel 36 is connected to one side 52 of the seventh channel 51 in a fluid communication with each other, so that the sixth channel 36 and the seventh channel 51 are arranged to be perpendicular to each other. can

In one embodiment of the present invention, the third fluid F3 may be supplied to the inside of the microfluidic reactor 10 through the seventh channel 51 at one end connected to the fluid pump P. As shown in FIG. 3 , the supplied third fluid F3 may be mixed with the drug particles introduced from the sixth channel 36 and then flow in one direction.

At this time, the third fluid F3 may include a carrier for supporting the drug particles. Here, the carrier is for manufacturing a capsule in which the drug particles are supported, and may be formed in a spherical shape surrounding the drug particles when finally encapsulated via a third structure 70 to be described later.

Meanwhile, the second structure 50 may include an eighth channel 54 connected to the other end of the seventh channel 51 .

At this time, referring to FIG. 3 , the eighth channel 54 is connected to the seventh channel 51 , and a first bent part ( 55a). In addition, the eighth channel 54 may further include at least two bent portions 55b and 55c that change the extension direction in a bent form until they are connected to each other with a third structure 70 to be described later. As such, the eighth channel 54 has a plurality of bent portions 55a to 55c, so that the drug particles and the carrier are formed without extending the length of the microfluidic reactor 10 in the y-axis direction, based on FIG. 3 . It is possible to secure a channel length that can be sufficiently mixed. In addition, by an external force generated when the fluid flow is switched through the bent portions 55a to 55c, mixing of the drug particles and the carrier can be further promoted.

Although the figure shows that the eighth channel 54 has three bent portions 55a to 55c, an embodiment of the present invention is not limited thereto, and a larger number of bent portions may be provided. However, when a large number of bent portions are provided, there is a disadvantage in that it is not possible to provide a pressure of an appropriate size to the fluid due to pressure dissipation generated when the fluid flow is switched. Therefore, it is preferable to determine the number of bent parts in consideration of the capacity of the pump.

The microfluidic reactor 10 according to an embodiment of the present invention further includes one end of the second structure 50 and a third structure 70 in fluid communication with each other.

At this time, the third structure 70 supplies the fourth fluid F4 containing the second anti-solvent for improving the loading efficiency of the drug particles and the carrier mixed through the second structure 50 described above. A flow path structure may be provided.

Referring back to FIG. 2 , the third structure 70 may have a structure similar to that of the first structure.

Specifically, the third structure 70 is a space corresponding to the first concentrated space 40 of the first structure 30 , and may include a second concentrated space 80 formed in a hexahedral shape.

In addition, a ninth channel 71 having one end connected to the eighth channel 54 of the second structure 50 and each other may be connected to the first surface 81 of the second concentrated space 80 . Through this, the fluid in a state in which the drug particles and the carrier are mixed from the second structure 50 may be moved toward the second concentration space 80 .

And, as shown in FIGS. 3 and 4 , the first surface 81 of the second concentrated space 80 and the fourth surfaces 82 to 85 in contact with each other have tenth channels to thirteenth channels 72 to 75 . This can be connected. A fluid pump P may be connected to each end of the tenth to thirteenth channels 72 to 75 , similarly to the second to fifth channels 32 to 35 . Through this, the fourth fluid F4 may be supplied to the second concentration space 80 through the tenth to thirteenth channels 72 to 75 .

At this time, the fourth fluid F4 supplied through the tenth to thirteenth channels 72 to 75 is applied to the drug particles and the carrier moved through the ninth channel 71 in the second concentrated space 80 . By applying pressure to the capsule, the capsule containing the drug particles may be formed.

Specifically, the fourth fluid F4 may generate a three-dimensional fluid flow focusing effect in the same way as the second fluid F2 . Through this, by applying pressure to the drug particles and the carrier in all directions of the second concentrated space 80, it is possible to accelerate the loading of the drug particles to the carrier, and since the same pressure is applied in all directions, a more uniform sized drug capsules can be produced.

In one embodiment of the present invention, based on the second concentrated space 80, the other side of the ninth channel 71, specifically, the fourth channel 86 on the sixth surface 86 of the second concentrated space 80 (76) may be disposed. The drug particles encapsulated in the second concentration space 80 may be moved to the outside through the fourteenth channel 76 .

5 is a perspective view showing another example of a three-dimensional microfluidic reactor according to an embodiment of the present invention.

Referring to FIG. 5 , the microfluidic reactor 10 according to an embodiment of the present invention may include a plurality of first structures 30 and 30 ′.

At this time, the plurality of first structures 30 may precipitate different types of drug particles by supplying different types of first fluid F1 to third fluid F3, respectively. However, the plurality of first structures 30 and 30 ′ may have the same structure and function, except that only the type of drug to be supplied is different.

As shown in FIG. 5 so that the drug particles precipitated through the plurality of first structures 30 and 30' are mixed with each other, one end of each of the sixth channels 36 and 36' is gathered together in a form can be formed. In addition, a separate connection channel 37 may be introduced to connect the joined sixth channel 36 with the second structure 50 .

By providing the plurality of first structures 30 and 30 ′ as described above, it is possible to integrally support a single carrier after precipitating different materials having a difference in physical properties.

On the other hand, the structures of the first to third structures 30 , 50 and 70 described above are only one embodiment of the present invention, and the first to third structures 30 , 50 and 70 of various shapes are provided. It should be noted that can be applied.

6 is an explanatory view for explaining a method of forming a three-dimensional microfluidic reactor according to an embodiment of the present invention.

The microfluidic reactor 10 according to an embodiment of the present invention may be formed by laminating a plurality of flat films A1 to A8. At this time, the number of laminated flat films (A1 to A8) may be variously adopted according to the design.

In one embodiment of the present invention, the flat films (A1 to A8) may be formed of a polyimide (PI) film having excellent chemical resistance.

In this case, each of the flat films A1 to A8 may include patterns of different shapes to form a channel included in the first structure 30 to the third structure 70 during lamination. In this case, the pattern may be formed through laser etching. Through this, the microfluidic reactor 10 according to an embodiment of the present invention can easily form a complex flow path structure included in a microscopically sized reactor.

And, referring to FIG. 6 , each of the flat films A1 to A8 may include a plurality of alignment holes K. The flat films A1 to A8 may be more precisely aligned by the length member passing through the alignment hole K in common.

A second aspect of the present invention relates to a method for preparing a capsule carrying hydrophilic drug particles of uniform size, comprising:

The first section for granulating and precipitating the hydrophilic drug, the second section for mixing the hydrophilic drug particles and the hydrophobic polymer compound, and the third section for encapsulating the hydrophilic drug particles by supporting the hydrophobic polymer compound are connected in a continuous batch process. In a fluid reactor,

a) precipitating the hydrophilic drug after granulating the hydrophilic drug by introducing an antisolvent for the hydrophilic drug in the three-dimensional and vertical four directions in a state in which the solution in which the hydrophilic drug is dissolved in the first section is horizontally flowed;

b) continuously mixing with the precipitated hydrophilic drug particles by introducing a solution in which the hydrophobic polymer compound is dissolved in the second section; and

c) In the third section, a solution in which the water-soluble polymer compound is dissolved is introduced in three-dimensional vertical four directions to support the hydrophilic drug particles on the hydrophobic polymer compound and encapsulate.

In the manufacturing method of the present invention, the first section of the three-dimensional microfluidic reactor is a section in which the hydrophilic drug is granulated and precipitated, and the size of the hydrophilic drug particles is uniformly adjusted through the three-dimensional fluid focusing effect to precipitate a ) step proceeds.

In the manufacturing method of the present invention, step a) may include separately granulating and precipitating two or more different hydrophilic drugs in the first section.

According to another preferred embodiment of the present invention, the hydrophilic drug may be one or more selected from the group consisting of alendronate, doxorubicin hydrochloride, varenicline, neomycin, and therapeutic peptides or proteins, but is not limited thereto.

According to another preferred embodiment of the present invention, the anti-solvent for the hydrophilic drug in step a) is at least one selected from the group consisting of acetonitrile (ACN), tetrahydrofuran, dimethyl sulfoxide and ethanol. However, as long as it can act as an anti-solvent to a hydrophilic drug, it can be used without limitation.

As can be seen in FIG. 6 , the lower the drug concentration in each initial drug flow rate condition (0.1 ml/min, 0.3 ml/min and 0.5 ml/min), the smaller the drug particle size, and each drug concentration condition (5 mg/min) mL, 10 mg/mL and 23.3 mg/mL), the larger the initial drug flow rate, the smaller the drug particle size. In addition, as the flow rate ratio of solvent:antisolvent increases, the particle size of the drug decreases.

As such, the size of the hydrophilic drug particles is the flow rate of the solution in which the hydrophilic drug in step a) is dissolved, the concentration of the hydrophilic drug in step a) and the solution in which the hydrophilic drug in step a) is dissolved: a group consisting of a flow rate ratio Since it can be adjusted by using any one or more selected from Nanoparticle drugs can be prepared.

According to another preferred embodiment of the present invention, the flow rate ratio of the solution in which the hydrophilic drug is dissolved and the antisolvent to the hydrophilic drug in the first section of step a) may be 1:2 to 1:12, preferably preferably 1:2 to 1:10, most preferably 1:2 to 1:8. At this time, as confirmed in FIG. 9, when the flow rate of the anti-solvent is further increased at the solvent: anti-solvent flow rate ratio of 1:12, the three-dimensional focusing effect is reduced and the focusing is broken, so the solvent: anti-solvent flow rate It is important that the ratio does not deviate from the above range.

In the manufacturing method of the present invention, the second section of the three-dimensional microfluidic reactor is a section for mixing the hydrophilic drug particles and the hydrophobic polymer compound, and a hydrophobic polymer compound serving as a carrier for the hydrophilic drug particles precipitated in the first section Step b) of this continuous mixing proceeds. Recrystallization of drug particles can be prevented through such a continuous batch process, and as a result, drug particles having a uniform size can be manufactured.

According to a preferred embodiment of the present invention, the hydrophobic polymer of step b) is polylactic acid, polylactide, polylactic-co-glycolic acid, polylactide-co-glycolide (PLGA), polyphosphazine, Polyiminocarbonate, polyphosphoester, polyanhydride, polyorthoester, copolymer of lactic acid and caprolactone, polycaprolactone, polyhydroxyvalate, polyhydroxybutyrate, polyamino acid, lactic acid and amino acid It may be selected from the group consisting of coalescing and mixtures thereof, but any hydrophobic polymer compound known to be suitable for supporting hydrophilic drug particles may be used without limitation.

In the production method of the present invention, the third section of the three-dimensional microfluidic reactor is a section in which hydrophilic drug particles are supported on a hydrophobic polymer compound and encapsulated, and in the second section, the hydrophilic drug particles and the hydrophilic polymer compound are mixed with the hydrophilic drug. Step c) of preparing a drug-polymer capsule of a uniform size by injecting a water-soluble polymer compound in a three-dimensional focus to increase the loading efficiency of the drug is performed.

According to a preferred embodiment of the present invention, the water-soluble polymer compound of step c) may be a hydrophilic drug stabilizer to increase the efficiency of loading the hydrophilic drug on the hydrophobic polymer compound, for example, poloxamer 407 (pluronic f127, f108), polysorbate 20, polyvinyl alcohol (PVA), or Tween 20, but is not limited thereto.

In the preparation method of the present invention, the size of the drug-polymer capsule precipitated in the third section is the concentration of the hydrophobic polymer compound in the second section, the flow rate of the solution in which the hydrophobic polymer compound is dissolved, and the concentration of the water-soluble polymer compound in the third section A uniform diameter of 0.1 μm to 2 μm can be prepared by using the flow rate of the solution in which the water-soluble polymer is dissolved and the water-soluble polymer compound as a variable.

According to another preferred embodiment of the present invention, the hydrophilic drug is alendronate, the hydrophobic polymer compound is polylactic-co-glycolic acid, polylactide-co-glycolide (PLGA), and the water-soluble polymer compound is polyvinyl alcohol In the case of , 0.1 wt% to 2.5 wt% of a polyvinyl alcohol solution may be used in order to increase the loading efficiency of alendronate, and more preferably 0.1 wt% to 2.5 wt% of a polyvinyl alcohol solution may be used.

According to a preferred embodiment of the present invention, as shown in FIGS. 12 and 13, when a drug-polymer capsule is prepared with a three-dimensional microfluidic reactor according to the present invention using a 2 wt% polyvinyl alcohol solution, a maximum of 97 It was confirmed that the drug loading efficiency can be increased up to %.

Accordingly, the loading rate of alendronate according to the preparation method of the present invention is, for example, 50% or more, preferably, for example, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or greater, and most preferably up to 97% or greater.

According to another preferred embodiment of the present invention, the manufacturing method may be performed in the three-dimensional microfluidic reactor described above.

Furthermore, a third aspect of the present invention relates to a sustained-release capsule in which hydrophilic drug particles of uniform size prepared by the above-described capsule manufacturing method are supported.

In the third aspect of the present invention, the sustained-release capsule in which uniformly sized hydrophilic drug particles are supported may be in the form of a sustained-release capsule in which nano-sized alendronate is supported on polylactide-co-glycolide.

Hereinafter, the present invention will be described in more detail through examples. However, since the present invention can have various changes and can have various forms, the specific examples and descriptions described below are only for helping the understanding of the present invention, and the present invention is limited to specific disclosed forms it's not meant to be It should be understood that the scope of the present invention includes all modifications, equivalents and substitutes included in the spirit and scope of the present invention.

Preparation of capsules in which hydrophilic drug particles of uniform size are supported

In this example, in order to confirm the possibility of producing a capsule containing hydrophilic drug particles of a uniform size using the three-dimensional microfluidic reactor of FIG. (Poly (Lactic-co-glycolic acid), PLGA) was prepared in the form of a supported capsule.

1-1. Computational Fluid Dynamics Simulation Setup

The fluid flow inside the microchannel can be explained by the incompressible Navier-stokes equation along with the conservation of mass equation. Assuming steady state, the governing equations for fluid flow can be simplified.

[Navier-Stokes expression]

[Conservation of mass formula]

where ρ is the fluid density, ν is the fluid linear velocity, p is the pressure, μ is the fluid kinematic viscosity, and g is the gravitational acceleration. The boundary condition applied in the overall governing equation was set as the non-slip condition, so the flow velocity at all channel interfaces (inlet and outlet of fluid, channel surface) where the fluidized bed exists was set to zero. The equation was discretized based on the finite volume method, and the commercially available numerical software FLUENT 2019 R2 (ANSYS, INC.) was used for numerical simulation. As a carrier solvent, the physical properties of water (998 kg m ^-3,0.00089 kgm ^-1 s ^-1 ) and acetonitrile (786 kg m ^-3,0.00082 kgm ^-1 s ^-1 ) at 25° C. were used.

1-2. Manufacture of alendronate@PLGA

As shown in the schematic diagram of FIG. 7, drug-polymer capsules were prepared under the conditions of Table 1 using the three-dimensional microfluidic reactor of the present invention. In this case, acetonitrile (ACN) was used as an anti-solvent for the hydrophilic drug in the first section of the three-dimensional microfluidic reactor.

Drugs/Polymers density menstruum flow rate alendronate 5 to 23.3 mg/mL Purified water 0.1-0.5 mL/min PLGA 1 to 10 wt% ACN 0.1 to 1 mL/min PVA 0.1 to 1% by weight Purified water -

Identification of drug particle size according to changes in initial drug flow rate, drug concentration, and solvent-antisolvent flow rate ratio

In this embodiment, in the production of a capsule carrying hydrophilic drug particles using the three-dimensional microfluidic reactor of the present invention, 1) initial drug flow rate, 2) drug concentration, and 3) solvent: antisolvent flow rate ratio change The size of the drug particles was confirmed.

Capsules were prepared in the same manner as in Example 1-2. At this time, the initial drug flow rate was set to 0.1 ml/min, 0.3 ml/min, and 0.5 ml/min, respectively, and the drug concentration was set to 5 mg/mL, 10 mg/mL and 23.3 mg/mL, respectively, under each initial drug flow rate condition. While controlling, the solvent:anti-solvent flow rate ratios at each drug concentration were changed to 1:2, 1:6, and 1:12, respectively, and the size of the drug particles prepared according to each condition was measured using a dynamic light scattering spectrophotometer (DLS). analyzed.

As a result, as confirmed in FIG. 8 , the drug particle size decreased as the drug concentration decreased in each initial drug flow rate condition (0.1 ml/min, 0.3 ml/min, and 0.5 ml/min), and each drug concentration condition (5 mg/mL, 10 mg/mL, and 23.3 mg/mL), the drug particle size decreased as the initial drug flow rate increased. In addition, as the flow rate ratio of solvent:antisolvent increased, the particle size of the drug decreased. According to each of the above conditions, it was confirmed that nanoparticles of various sizes can be prepared by adjusting the size of the drug particles to a diameter of 50 to 410 nm.

Therefore, depending on the type of drug, the target location of the drug, the drug concentration to be delivered, etc., 1) the initial drug flow rate, 2) the drug concentration, and 3) the solvent:antisolvent flow rate ratio is adjusted to have a diameter of several tens of nanometers to several thousand nanometers. It is possible to prepare drug particles having

Confirmation of 3D focusing effect according to the change of initial drug flow rate and solvent-antisolvent flow rate ratio

In the production of capsules loaded with hydrophilic drug particles using the three-dimensional microfluidic reactor of the present invention, to confirm the three-dimensional focused flow change according to the condition of the initial drug flow rate and the solvent-anti-solvent flow rate ratio in the first step The flow cross-section was confirmed using computational fluid dynamics (CFD). At this time, the initial drug flow rate was set to 0.1 ml/min, 0.3 ml/min, and 0.5 ml/min, respectively, while the drug concentration was kept constant at 10 mg/mL, and the solvent:anti-solvent was The flow rate ratios were changed to 1:2, 1:6 and 1:12, respectively. According to the degree of mixing in the three-dimensional focused flow, the flow pattern is represented by color as 0 (blue, completely mixed)-1 (red, completely unmixed).

As can be seen in FIG. 9 , when the solvent:anti-solvent flow rate ratio was increased from 1:2 to 1:6, the mixing degree and the three-dimensional focusing effect were increased, but the solvent:antisolvent flow rate ratio was changed to 1:12. When increasing, the 3D focusing effect was reduced, and thus the focusing was broken. This phenomenon was the same even when the initial drug flow rate conditions were changed. Therefore, it is important to control the flow rate ratio of the solvent:antisolvent in order to properly mix the solvent and the antisolvent and to exhibit an optimal three-dimensional focused flow effect, and the most preferable solvent:antisolvent flow rate ratio is 1:2 to 1: 8 was confirmed.

Quality Comparison of Drug-Polymer Capsules Made with Flask, T-Type Device and 3D Microfluidic Reactor

In this example, the drug-polymer capsules prepared using the three-dimensional microfluidic reactor of the present invention and the conventionally known drug-polymer capsules prepared by the flask manufacturing method and the manufacturing method using the T-type device The quality of drug-polymer capsules was compared.

The concentrations of alendronate, PLGA and PVA in each preparation method were matched as shown in Table 2.

Drugs/Polymers density alendronate 10 mg/mL PLGA 2% by weight PVA 1% by weight

4-1. Manufacturing method using three-dimensional microfluidic reactor (in one-flow)

The initial flow rate of the alendronate-dissolved solution in the first section of the three-dimensional microfluidic reactor prepared in Example 1 was 0.3 mL/min, and the alendronate-dissolved solution in the second section: the flow rate ratio of acetonitrile was 1:6 , a drug-polymer capsule was prepared by setting the flow rate ratio of PVA-dissolved solution: PLGA-dissolved acetonitrile to 1:2 in the third section.

4-2. Flask (in batch) based manufacturing method

The flask-based manufacturing method was performed in the same manner as described in [Results in Pharma Sciences 2 (2012) 79-85]. However, considering the type of hydrophilic drug, the difference in molecular weight of PLGA, and the flow rate, purified water as a solvent of alendronate is 3 mL, acetonitrile as an antisolvent of alendronate is 18 mL, acetonitrile as a solvent of PLGA is 9.5 mL, PVA Purified water as a solvent of was adjusted to an amount of 1.9 mL.

4-3. Manufacturing method using T-shaped device

The manufacturing method using a T-type device (Upchurch Scientific. Co.) was performed under the same conditions as the manufacturing method using the three-dimensional microfluidic reactor of Example 4-1.

Specifically, in the first section, the initial flow rate of the solution in which alendronate was dissolved was 0.3 mL/min, in the second section, the flow rate ratio of the solution in which alendronate was dissolved: acetonitrile was 1:6, and in the third section, PVA was dissolved. A drug-polymer capsule was prepared by setting the flow rate ratio of solution: acetonitrile in which PLGA was dissolved to 1:2.

4-4. Comparison of quality of drug-polymer capsules according to each manufacturing method

The shape and size distribution of the drug-polymer capsules prepared in Examples 4-1 to 4-3, respectively, were observed with a scanning electron microscope. As can be seen in FIG. 10 , the drug-polymer capsules were all spherical. The size distribution of the drug polymer prepared in the flask showed a size difference of more than 70%, and the method using the T-shaped device showed a more uniform difference of more than 48%. This leads to non-uniform drug release. However, the distribution of drug polymer capsules prepared in a three-dimensional microfluidic reactor (in one-flow) has a size distribution of 15% or less, so that sustained release can be induced.

In addition, the size of the drug-polymer capsule according to each manufacturing method is shown in Table 3.

Manufacturing method Drug-polymer capsule size Example 4-1 0.1 to 10 μm (preferably 0.1 to 1 μm) Example 4-2 0.1 to 100 μm (preferably 0.6 to 45 μm) Example 4-3 0.1-50 μm (preferably 0.6-15 μm)

As shown in Table 3, the size of the drug-polymer capsules prepared by the method of Example 4-2 (flask) and Example 4-3 (T-shaped device) is Example 4-1 (three-dimensional microfluidic reactor). ) showed a wider range than the size of the drug-polymer capsule prepared by the method of ), confirming that the uniformity was inferior.

Accordingly, the highest quality drug-polymer capsules were obtained in the manufacturing method using the three-dimensional microfluidic reactor of Example 4-1. The quality of the drug-polymer capsules prepared in each preparation method was evaluated as Example 4-2 (flask) < Example 4-3 (T-shaped device) < Example 4-1 (three-dimensional microfluidic reactor).

As a result of checking the drug-polymer capsule obtained in the manufacturing method using the three-dimensional microfluidic reactor of Example 4-1 with a transmission electron microscope (TEM), it was confirmed that alendronate was properly loaded in PLGA, as shown in FIG. 11 . did

Therefore, it was confirmed that the manufacturing method using the three-dimensional microfluidic reactor of Example 4-1 is the most effective in order to prepare a high-quality drug-polymer capsule having a uniform drug particle size. At this time, the concentration of PLGA and the flow rate of acetonitrile in which PLGA is dissolved in the second section (PLGA/drug mixture) of the three-dimensional microfluidic reactor, and the concentration of PVA and the concentration of PVA in the third section (drug/polymer encapsulation) If the flow rate of purified water is controlled, the size of the capsule particles down to about 2 μm can be selectively prepared with reproducibility.

Establishment of conditions to improve the loading efficiency of alendronate

In order to effectively support the hydrophilic drug alendronate on the hydrophobic polymer compound PLGA, in the third section of the preparation method of Example 1, PVA is used as a stabilizer for alendronate. Therefore, in this example, it was attempted to derive an optimal PVA concentration for improving the loading efficiency of alendronate.

5-1. Optimization of PVA concentration

Drug-polymer capsules were prepared under the same conditions as the manufacturing method using the three-dimensional microfluidic reactor of Example 4-1, but the concentrations of PVA (dissolved in the antisolvent of PLGA) were 0.5 wt%, 1 wt%, and 2 By weight %, the loading efficiency of alendronate according to the PVA concentration was evaluated. The loading efficiency was evaluated in the following way.

The polymer portion of the prepared drug-polymer capsule is selectively dispersed and dissolved in a solvent (DCM), centrifuged at 13000 rpm for 15 minutes, and then redispersed in DCM to remove all remaining polymer. Then, the remaining hydrophilic drug is dispersed in 1 mL of purified water, and the absorbance is measured through UV-vis to calculate the amount of the hydrophilic drug through the existing hydrophilic drug calibration curve graph. Thereafter, the loading efficiency was confirmed by comparing the concentration of the hydrophilic drug consumed through the microfluid and the hydrophilic drug measured through the UV-vis.

12 , as the concentration of PVA increased, the loading efficiency of alendronate increased. Accordingly, the optimal PVA concentration for maximizing the loading efficiency of alendronate was selected to be 2 wt%.

5-2. Comparison of the loading efficiency of alendronate according to each manufacturing method

In order to compare the alendronate loading efficiency according to the manufacturing method difference, after matching the concentration of PVA to 2 wt%, Examples 4-1 (three-dimensional microfluidic reactor), 4-2 (flask) and 4-3 (T - The loading rate of alendronate was confirmed in the drug-polymer capsules prepared in the same manner as the -shaped device).

As a result, as confirmed in FIG. 13 , the manufacturing method using the three-dimensional microfluidic reactor of Example 4-1 showed a drug loading efficiency of 96 ± 18%, significantly higher drug loading efficiency than the other two manufacturing methods. showed

Claims (23)

A first structure having a flow path structure such that a first fluid containing a drug and a solvent and a second fluid containing a first anti-solvent are continuously mixed in order to precipitate drug particles by using a precipitation phenomenon due to a difference in solubility; and
and a second structure having a flow path structure to supply a third fluid including a carrier to support the drug particles delivered from the first structure,
The first structure and the second structure are in fluid communication with each other so that the drug particles precipitated from the first structure are transferred to the second structure side without delay, so that the precipitation process and the loading process of the drug particles are made in a continuous batch process, 3D microfluidic reactor. The method of claim 1,
The first structure,
a first channel connected to one side of the first concentrated space having a hexahedral shape to supply the first fluid to the first concentrated space;
second to fifth channels connected to the four surfaces in contact with the one side of the first concentrated space and supplying the second fluid to the inner side of the first concentrated space; and
A three-dimensional microfluidic reactor comprising a sixth channel connected to the other side opposite to one side of the first concentrated space through which the drug particles are discharged from the first concentrated space. The method of claim 1,
The three-dimensional microfluidic reactor comprises a plurality of first structures to precipitate different drug particles, respectively, and the plurality of first structures are joined to each other and then connected to the second structure. The method of claim 1,
The second structure,
a seventh channel connected to cross one end of the first structure and supplying the third fluid; and
and an eighth channel connected to one end of the seventh channel and having at least three bent portions. The method of claim 1,
Further comprising a third structure in fluid communication with the second structure and having a flow path structure to supply a fourth fluid containing a second anti-solvent for improving the loading efficiency of the particle drug on the carrier, 3D microfluidic reactor. 6. The method of claim 5,
The third structure,
a ninth channel having one end connected to one end of the second structure and the other end connected to one side of the second concentration space having a hexahedral shape;
10th to 13th channels respectively connected to the four surfaces in contact with the one side of the second concentrated space to supply the fourth fluid to the inner side of the second concentrated space; and
A three-dimensional microfluidic reactor comprising a 14th channel connected to the other side opposite to one side of the second concentrated space through which the drug particles encapsulated by the carrier flow out from the second concentrated space. The method of claim 1,
Further comprising a third structure in fluid communication with the second structure and having a flow path structure to supply a fourth fluid containing a second anti-solvent for improving the loading efficiency of the particle drug on the carrier,
The first structure,
a first channel connected to one side of the first concentrated space having a hexahedral shape to supply the first fluid to the first concentrated space; Second to fifth channels each connected to the four surfaces in contact with the one side of the first concentrated space and supplying the second fluid to the inner side of the first concentrated space, and one side of the first concentrated space facing each other and a sixth channel through which the drug particles are discharged from the first concentration space by being connected to the other side of the
The second structure,
a seventh channel connected to cross one end of the six channels and supplying the third fluid; and an eighth channel connected to one end of the seventh channel and having at least three bent portions,
The third structure,
a ninth channel having one end connected to one end of the eighth channel and the other end connected to one side of the second concentration space having a hexahedral shape; The tenth to thirteenth channels each connected to the four surfaces in contact with the one side of the second concentrated space and supplying the fourth fluid to the inner side of the second concentrated space, and one side of the second concentrated space facing each other A three-dimensional microfluidic reactor comprising a fourteenth channel connected to the other side of the body through which the drug particles encapsulated by the carrier flow out from the second concentration space. 8. The method according to any one of claims 1 to 7,
The micro-reactor is a three-dimensional microfluidic reactor formed by stacking a plurality of flat-panel films each pattern etched by a laser. A three-dimensional microfluidic reactor continuously connected with a first section for granulating and precipitating a hydrophilic drug, a second section for mixing the hydrophilic drug particles and a hydrophobic polymer compound, and a third section for encapsulating the hydrophilic drug particles by supporting the hydrophobic polymer compound at,
a) in the first section, in a state in which the solution in which the hydrophilic drug is dissolved is horizontally flowed, and an anti-solvent for the hydrophilic drug is added in three-dimensional and vertical four directions to granulate the hydrophilic drug and then to precipitate;
b) continuously mixing with the precipitated hydrophilic drug particles by introducing a solution in which the hydrophobic polymer compound is dissolved in the second section; and
c) encapsulating a solution in which the water-soluble polymer compound is dissolved in the third section by supporting the hydrophilic drug particles in the hydrophobic polymer compound by introducing the solution in three-dimensional vertical and four directions;
A method for producing a capsule in which hydrophilic drug particles of uniform size are supported, comprising: 10. The method of claim 9, wherein step a) comprises individually granulating and precipitating two or more different hydrophilic drugs in the first section. The method according to claim 9, wherein the hydrophilic drug is at least one selected from the group consisting of alendronate, doxorubicin hydrochloride, varenicline, neomycin, and therapeutic peptides or proteins. method. 10. The method of claim 9, wherein the anti-solvent for the hydrophilic drug in step a) is at least one selected from the group consisting of acetonitrile, tetrahydrofuran, dimethyl sulfoxide and ethanol, and hydrophilic drug particles of uniform size are supported. A method of manufacturing the capsules. The method of claim 9, wherein the hydrophobic polymer in step b) is polylactic acid, polylactide, polylactic-co-glycolic acid, polylactide-co-glycolide (PLGA), polyphosphazine, polyiminocarbonate, poly Phosphoesters, polyanhydrides, polyorthoesters, copolymers of lactic acid and caprolactone, polycaprolactone, polyhydroxyvalate, polyhydroxybutyrate, polyamino acids, copolymers of lactic acid and amino acids, and mixtures thereof A method of manufacturing a capsule in which hydrophilic drug particles of a uniform size are supported, which is a hydrophobic polymer compound selected from the group consisting of. 10. The method of claim 9, wherein the water-soluble polymer compound in step c) is a hydrophilic drug stabilizer to increase the efficiency of loading the hydrophilic drug on the hydrophobic polymer compound. 10. The method of claim 9, wherein the size of the hydrophilic drug particles is determined by the flow rate of the solution in which the hydrophilic drug in step a) is dissolved, the concentration of the hydrophilic drug in step a) and the solution in which the hydrophilic drug in step a) is dissolved: antisolvent for the hydrophilic drug A method of manufacturing a capsule in which hydrophilic drug particles of a uniform size are supported, which are controlled by using any one or more selected from the group consisting of a flow rate ratio of The method according to claim 15, wherein the hydrophilic drug particles have a uniform diameter of 10 nm to 1,000 nm, and the hydrophilic drug particles of a uniform size are supported on the capsule manufacturing method. 10. The method of claim 9, wherein in the first section of step a), the flow rate ratio of the solution in which the hydrophilic drug is dissolved and the antisolvent is 1:2 to 1:12. manufacturing method. 10. The method of claim 9, wherein the hydrophilic drug is alendronate, the hydrophobic high molecular compound is polylactic-co-glycolic acid, polylactide-co-glycolide (PLGA), and the water-soluble high molecular compound is polyvinyl alcohol. A method of manufacturing a capsule in which hydrophilic drug particles of a size are supported. The method of claim 18, wherein 0.1 to 2.5 wt% of a polyvinyl alcohol solution is used in order to increase the loading efficiency of alendronate. The method according to claim 19, wherein the alendronate loading ratio is at least 70% or more, and the hydrophilic drug particles of uniform size are supported on the capsule manufacturing method. [Claim 10] The method of claim 9, wherein the manufacturing method is performed in the three-dimensional microfluidic reactor of claim 1, wherein the hydrophilic drug particles of a uniform size are supported. 22. A sustained-release capsule in which hydrophilic drug particles of uniform size prepared by the method of any one of claims 9 to 21 are supported. 22. A sustained-release capsule in which alendronate of uniform nano-particle size prepared by the method according to any one of claims 9 to 21 is supported on polylactide-co-glycolide.

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