KR102499988B1 - 3D microfluidic reactor for improving encapsulation efficiency of drugs, and method of manufacturing uniform capsules by one-flow process - Google Patents

Abstract

A three-dimensional microfluidic reactor is disclosed. In the three-dimensional microfluidic reactor according to an embodiment of the present invention, a first fluid containing a drug and a solvent and a second fluid containing a first anti-solvent are used to precipitate drug particles using a precipitation phenomenon caused by a solubility difference. It includes a first structure having a flow path structure to continuously mix and a second structure having a flow path structure to supply a third fluid including a carrier to support drug particles delivered from the first structure, The 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 process of precipitating and supporting the drug particles is performed in a continuous batch 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 carrying uniformly sized drug particles using the same, and more particularly, to a hydrophilic through a two-step three-dimensional fluid focusing effect based on continuous-flow A three-dimensional microfluidic reactor capable of uniformly adjusting the size of drug particles and drug-polymer capsules, a method for manufacturing a capsule carrying hydrophilic drug particles using the same, and a manufacturing method using the batch process to improve drug loading efficiency A method and a sustained-release capsule loaded with uniformly sized hydrophilic drug particles prepared therefrom are provided.

Mainly in the pharmaceutical and fine chemical industries, microfluidic reactors used for the synthesis of compounds offer 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, since microfluidic reactors require relatively simple feasibility studies for scale-up, they can provide cost-effective advantages. That is, when it is necessary to expand the design capacity of the microfluidic reactor, the throughput can be increased by arranging a plurality of microfluidic reactor units required in design in parallel and simultaneously applying a higher flow rate. That is, the microfluidic reactor has the advantage of being able to easily achieve scale-up because it does not require excessive testing and design for scale-up, unlike conventional batch processes.

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

In this regard, a method for preparing protein-loaded PLGA nanoparticles using a flask is disclosed in [Results in Pharma Sciences 2 (2012) 79-85], but when a drug-polymer capsule is prepared by the method, As described above, recrystallization of the drug particles causes a problem in that the uniformity of the particles is reduced.

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

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 to continuously divide the first section in which the hydrophilic drug is granulated and precipitated, the second section in which the hydrophilic drug particles and the hydrophobic polymer compound are mixed, and the third section in which the hydrophilic drug particles are supported and encapsulated in the hydrophobic polymer compound are successively formed. It is to provide a method for manufacturing capsules carrying hydrophilic drug particles of uniform size in a connected three-dimensional microfluidic reactor in a batch process.

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

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

According to one aspect of the present invention, 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 caused by a solubility difference. It includes a first structure having a structure and a second structure having a flow path structure to supply a third fluid containing a carrier to support the drug particles delivered from the first structure, The second structure is in fluid communication with each other so that the drug particles precipitated from the first structure are transferred without delay to the second structure, so that the precipitation process and the loading process of the drug particles are a continuous batch process, a three-dimensional microfluidic reactor Provided.

At this time, the first structure includes: a first channel connected to one side of a first concentrating space having a hexahedral shape and supplying the first fluid to the first concentrating space; second to fifth channels connected to four surfaces of the first concentrating space contacting the one side surface and supplying the second fluid to the inside of the first concentrating space and opposing one side surface of the first concentrating space It may include a sixth channel connected to the other side of the chamber through which the drug particles are discharged from the first concentrating 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 joined to each other and then connected to the second structure.

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

At this time, a third structure that is in fluid communication with the second structure and has a flow path structure to supply a fourth fluid containing a second anti-solvent for improving the loading efficiency of the particulate drug to the carrier is further provided. can include

At this time, the third structure includes 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; Tenth to thirteenth channels connected to four surfaces of the second concentrating space contacting the one side surface and supplying the fourth fluid to the inside of the second concentrating space and opposing one side surface of the second concentrating space It may include a 14th channel connected to the other side of the chamber through which the drug particles encapsulated by the carrier are discharged from the second concentrating space.

At this time, a third structure that is in fluid communication with the second structure and has a flow path structure to supply a fourth fluid containing a second anti-solvent for improving the loading efficiency of the particulate drug to the carrier is further provided. wherein the first structure includes: a first channel connected to one side of a first concentrating space having a hexahedral shape and supplying the first fluid to the first concentrating space; second to fifth channels connected to four surfaces of the first concentrating space contacting the one side surface and supplying the second fluid to the inside of the first concentrating space and opposing one side surface of the first concentrating space and a sixth channel connected to the other side of the structure through which the drug particles flow out from the first concentration space, and the second structure is connected to cross one end of the six channels and supplies the third fluid. 7 channels and an 8th channel connected to one end of the 7th channel and having at least three bent parts, wherein the third structure has one end connected to one end of the 8th channel and the other end in a hexahedral shape. a ninth channel connected to one side of the second concentration space having Tenth to thirteenth channels connected to four surfaces of the second concentrating space contacting the one side surface and supplying the fourth fluid to the inside of the second concentrating space and opposing one side surface of the second concentrating space It may include a 14th channel connected to the other side of the chamber through which the drug particles encapsulated by the carrier are discharged from the second concentrating space.

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

According to another aspect of the present invention, there is provided a method for manufacturing a capsule carrying hydrophilic drug particles of uniform size:

A three-dimensional microstructure in which the first section in which the hydrophilic drug is granulated and precipitated, the second section in which the hydrophilic drug particles and the hydrophobic polymer compound are mixed, and the third section in which the hydrophilic drug particles are supported and encapsulated in the hydrophobic polymer compound are connected in a continuous batch process. in a fluid reactor,

a) injecting an anti-solvent for the hydrophilic drug in four three-dimensional vertical directions in a state in which the solution in which the hydrophilic drug is dissolved is horizontally flowing in the first section to make the hydrophilic drug into particles and then to precipitate;

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

c) encapsulating the hydrophilic drug particles by supporting them in the hydrophobic polymer compound by injecting the solution in which the water-soluble polymer compound is dissolved in the third section in four three-dimensional vertical directions.

According to a preferred embodiment of the present invention, step a) may include individually 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 at least one 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, and 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 mixtures of.

According to another preferred embodiment of the present invention, the water-soluble polymer compound in step c) may be a hydrophilic drug stabilizer for increasing the efficiency of loading the hydrophilic drug in 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 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: It may be adjusted by using at least one 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 anti-solvent 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 high molecular compound is polylactic-co-glycolic acid or polylactide-co-glycolide (PLGA), and the water-soluble high molecular compound is polyvinyl It can be alcohol.

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

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 above-described three-dimensional microfluidic reactor.

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

According to another aspect of the present invention, a sustained-release capsule containing polylactide-co-glycolide containing alendronate having a uniform nanoparticle size prepared by the above-described capsule manufacturing method is provided.

The three-dimensional microfluidic reactor according to the present invention and the method for manufacturing a capsule carrying hydrophilic drug particles using the same are based on continuous-flow and the size of hydrophilic drug particles and drug-polymer capsules through a two-step three-dimensional fluid convergence effect can be uniformly controlled, and the drug-polymer capsule prepared according to this method can continuously release the drug in the body for a long time in a sustained release form, and 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 from the direction AA of FIG. 1 as a reference.
FIG. 4 is a cross-sectional view of a three-dimensional microfluidic reactor according to an embodiment of the present invention as viewed in the BB direction of FIG. 1 as a reference.
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 showing a microfluidic reactor having a single flow-based three-dimensional focusing structure (3D flow focusing) made of a polyimide-based film. Here, in the first section, drug particles are formed and precipitated, in the second section, the drug particles and the polymer compound used as the carrier are mixed, and in the third section, the drug particles are supported in the polymer compound and encapsulated.
FIG. 8 shows the size of drug particles according to the initial drug flow rate, initial drug concentration, and flow rate ratio of solvent:anti-solvent, which are each condition of the drug particleization and precipitation steps in the first section of FIG. , DLS).
FIG. 9 shows the three-dimensional focusing effect according to the drug flow rate and the solvent:anti-solvent flow rate ratio in the drug particleization and precipitation steps in the first section of FIG. 7 calculated using computational fluid dynamics (CFD). will be.
FIG. 10 shows a drug-polymer capsule prepared using a three-dimensional microfluidic reactor (a), a flask (b), and a T-shaped device (c), respectively, analyzed by a scanning electron microscope (SEM). .
11 shows a drug-polymer capsule prepared using a three-dimensional microfluidic reactor analyzed by a transmission electron microscope (TEM).
12 shows a comparison of drug loading efficiency according to PVA concentration in the manufacture of a drug-polymer capsule (ALS-PLGA capsule) using a three-dimensional microfluidic reactor.
13 shows a comparison of drug loading efficiencies of drug-polymer capsules prepared using a three-dimensional microfluidic reactor (a), a flask (b), and a T-shaped device (c), respectively.

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

In this specification, terms such as "include" or "have" are intended to designate that there is a feature, number, step, operation, component, part, or combination thereof described in the specification, but one or more other features It should be understood that the presence or addition of numbers, steps, operations, components, parts, or combinations thereof is not precluded.

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

In particular, the microfluidic reactor 10 according to an embodiment of the present invention can omit a separate drying process between the precipitation process and the loading process of the drug particles, thereby preventing recrystallization of the drug particles that may occur due to drying. It is a device that can Hereinafter, the main components 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. FIG. 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 as a reference. FIG. 4 is a cross-sectional view of a 3-dimensional microfluidic reactor according to an embodiment of the present invention as viewed in the B-B direction of FIG. 1 as a reference.

Referring to FIG. 1 , a 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 the 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 (connected to each side surface 41 to 46 of the first concentration space 40 formed in a hexahedral shape). 31 to 36). Hereinafter, in the present specification, in describing the channel, the channel is defined as a space structure having a hollow so that 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 . 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 from the outside of the microfluidic reactor 10 to the first concentration space 40 through the first channel 31 as described above.

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

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

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

In one embodiment of the present invention, the second fluid (F2) is a fluid capable of precipitating the drug particles by being mixed with the first fluid (F1), and may include a first anti-solvent for the drug. Through this, when the first fluid F1 and the second fluid F2 are mixed in the first concentration space 40, a solubility difference between the solvent included in the first fluid F1 and the first anti-solvent occurs. do. As a result, it is possible to precipitate drug particles in particulate form from the drug. Precipitation, which precipitates particles using the difference in solubility, is a well-known technique, so a detailed description thereof will be omitted.

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

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

In one embodiment of the present invention, a sixth channel 36 may be disposed on the other side of the first channel 31 with respect to the first concentration space 40 . 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 functions as a passage through which the first fluid F1 and the second fluid F2 mixed with each other in the first concentration space 40 flow out of the first structure 30. can Therefore, drug particles in the form of particles that are precipitated as described above may flow out together through the sixth channel 36 .

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 carrying the drug particles delivered from the first structure 30 and to mix it with the drug particles. can do.

As an illustrative example, referring to FIG. 3 , the second structure 50 includes a seventh channel 51 connected to one end of the sixth channel 36 included in the first structure 30 so as 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 form capable of fluid communication with each other, so that the sixth channel 36 and the seventh channel 51 are disposed perpendicular to each other. can

In one embodiment of the present invention, the third fluid F3 may be supplied into the microfluidic reactor 10 through the seventh channel 51, one end of which is connected to the fluid pump P. As shown in FIG. 3 , the third fluid F3 supplied in this way may flow in one direction after being mixed with the drug particles introduced from the sixth channel 36 .

At this time, the third fluid (F3) may include a carrier for carrying 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 enclosing the drug particles when they are 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 portion that changes the extension direction from one end of the seventh channel 51 to a bent form ( 55a) may be included. In addition, the eighth channel 54 may further include at least two bent portions 55b and 55c that change an extension direction in a bent form until connected to a third structure 70 to be described later. As such, since the eighth channel 54 has a plurality of bent parts 55a to 55c, based on FIG. 3, the drug particles and the carrier can be formed without extending the length of the microfluidic reactor 10 in the y-axis direction. It is possible to secure a channel length that can be sufficiently mixed. In addition, mixing of the drug particles and the carrier may be more promoted by an external force generated when the fluid flow is switched through the bent parts 55a to 55c.

In the drawing, the eighth channel 54 is illustrated as having three bent parts 55a to 55c, but one embodiment of the present invention is not limited thereto, and may have a greater number of bent parts. However, when a large number of bent parts are provided, there is a disadvantage in that an appropriate pressure cannot be provided 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 a third structure 70 in fluid communication with one end of the second structure 50 .

At this time, the third structure 70 supplies the fourth fluid F4 containing the second anti-solvent for improving the carrying efficiency of the mixed drug particles and the carrier through the above-described second structure 50. 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 concentration space 40 of the first structure 30 and may include a second concentration 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 may be connected to the first surface 81 of the second concentration space 80 . Through this, the fluid in a state in which the drug particles and the carrier are mixed can be moved from the second structure 50 toward the second concentration space 80 .

And, as shown in FIGS. 3 and 4, the 10th to 13th channels 72 to 75 are provided on the four surfaces 82 to 85 in contact with the first surface 81 of the second concentration space 80. this can be connected. Like the second to fifth channels 32 to 35, a fluid pump P may be connected to each end of the 10th to 13th channels 72 to 75. Through this, the fourth fluid F4 can be supplied toward the second concentration space 80 through the tenth to thirteenth channels 72 to 75 .

At this time, the fourth fluid (F4) supplied through the 10th to 13th channels (72 to 75) is applied to the drug particles and carriers moved through the ninth channel (71) in the second concentration space (80). Pressure may be applied to form a capsule containing drug particles.

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

In one embodiment of the present invention, on the other side of the ninth channel 71 with respect to the second concentration space 80, specifically, the 14th channel on the sixth surface 86 of the second concentration space 80 (76) can be arranged. 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. However, the plurality of first structures 30 and 30' may have the same structure and function, except for the type of drug supplied.

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

By providing the plurality of first structures 30 and 30' in this way, it is possible to integrally support different types of materials having different physical properties on a single carrier after precipitating them respectively.

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 various types of first to third structures 30, 50 and 70 It should be noted that may apply.

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 stacking 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 having different shapes to form channels included in the first structures 30 to the third structures 70 when stacked. 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 micro-sized reactor.

Also, referring to FIG. 6 , each of the flat films A1 to A8 may have a plurality of alignment holes K. The flat films A1 to A8 may be more precisely aligned by the length member commonly penetrating the alignment hole K.

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

A three-dimensional microstructure in which the first section in which the hydrophilic drug is granulated and precipitated, the second section in which the hydrophilic drug particles and the hydrophobic polymer compound are mixed, and the third section in which the hydrophilic drug particles are supported and encapsulated in the hydrophobic polymer compound are connected in a continuous batch process. in a fluid reactor,

a) injecting an anti-solvent for the hydrophilic drug in four three-dimensional vertical directions in a state in which the solution in which the hydrophilic drug is dissolved is horizontally flowing in the first section to make the hydrophilic drug into particles and then to precipitate;

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

c) encapsulating the hydrophilic drug particles by supporting them in the hydrophobic polymer compound by injecting the solution in which the water-soluble polymer compound is dissolved in the third section in four three-dimensional vertical directions.

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 controlled and precipitated through a three-dimensional fluid convergence effect. ) step proceeds.

In the production method of the present invention, step a) may include individually 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 at least one 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, dimethylsulfoxide and ethanol. However, as long as it can act as an anti-solvent for hydrophilic drugs, it can be used without limitation.

As confirmed in Figure 6, as the drug concentration decreases in each initial drug flow rate condition (0.1 ml / min, 0.3 ml / min, and 0.5 ml / min), the drug particle size decreases, 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 a group consisting of 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 flow rate ratio of the solution in which the hydrophilic drug is dissolved in step a):antisolvent Since any one or more selected from can be adjusted as a variable, by adjusting each of the above conditions according to the size of the drug particle to be produced, a uniform size having a diameter of various sizes, for example, 10 to 1,000 nm Nanoparticle drugs can be prepared.

According to another preferred embodiment of the present invention, in the first section of step a), the flow rate ratio of the solution in which the hydrophilic drug is dissolved and the anti-solvent to the hydrophilic drug may be 1:2 to 1:12, preferably Preferably it may be 1:2 to 1:10, and most preferably 1:2 to 1:8. At this time, as confirmed in FIG. 9 , when the flow rate of the antisolvent is further increased at the solvent:antisolvent flow rate ratio of 1:12, the 3D convergence effect decreases and the focusing is broken, so the solvent:antisolvent flow rate It is important that the ratio does not deviate from the above range.

In the production method of the present invention, the second section of the three-dimensional microfluidic reactor is a section for mixing hydrophilic drug particles and a hydrophobic polymer compound, and the hydrophobic polymer compound serves as a carrier for the hydrophilic drug particles precipitated in the first section. Step b) of this continuous mixing proceeds. Through such a continuous batch process, recrystallization of drug particles can be prevented, 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 compound in step b) is polylactic acid, polylactide, polylactic-co-glycolic acid, polylactide-co-glycolide (PLGA), polyphosphazine, Polyiminocarbonates, polyphosphoesters, polyanhydrides, polyorthoesters, copolymers of lactic acid and caprolactone, polycaprolactone, polyhydroxyvalate, polyhydroxybutyrate, polyamino acids, copolymers of lactic acid and amino acids. It may be selected from the group consisting of polymers and mixtures thereof, but any hydrophobic high molecular compound known to be suitable for carrying hydrophilic drug particles may be used without limitation.

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

According to a preferred embodiment of the present invention, the water-soluble polymer compound in step c) may be a hydrophilic drug stabilizer for increasing the efficiency of loading the hydrophilic drug in 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 determined by 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. It can be prepared with a uniform diameter of 0.1 μm to 2 μm by setting the flow rate of the solution in which the polymer and the water-soluble polymer compound are dissolved as variables.

According to another preferred embodiment of the present invention, the hydrophilic drug is alendronate, the hydrophobic polymer compound is polylactic-co-glycolic acid or polylactide-co-glycolide (PLGA), and the water-soluble polymer compound is polyvinyl alcohol. In the case of , in order to increase the loading efficiency of alendronate, a polyvinyl alcohol solution of 0.1 wt% to 2.5 wt% may be used, and more preferably, a polyvinyl alcohol solution of 0.1 wt% to 2.5 wt% 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 the three-dimensional microfluidic reactor according to the present invention using a 2% by weight polyvinyl alcohol solution, up to 97 It was confirmed that the loading efficiency of the drug can be increased up to %.

Therefore, the loading rate of alendronate according to the production 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 It may be 95% or more, and most preferably up to 97% or more.

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

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

In the third aspect of the present invention, the sustained-release capsule loaded with uniformly sized hydrophilic drug particles may be in the form of a sustained-release capsule loaded with nanoparticle-sized alendronate in polylactide-co-glycolide.

Hereinafter, the present invention will be described in more detail through examples. However, the present invention can be made with various changes and can have various forms, and the specific embodiments and descriptions described below are only intended to aid understanding of the present invention, and the present invention is limited to specific disclosure forms. It's not something I want to do. 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 carrying hydrophilic drug particles of uniform size

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

1-1. Setting up a computational fluid dynamics simulation

The fluid flow inside the microchannel can be described by the incompressible Navier-Stokes equation together with the equation of conservation of mass. Assuming a steady state, the governing equations for fluid flow can be simplified.

[Navier-Stokes equation]

[mass conservation formula]

In the above equation, ρ is the fluid density, ν is the fluid linear velocity, p is the pressure, μ is the fluid dynamic viscosity, and g is the gravitational acceleration. The boundary condition applied in the overall governing equation was set to the non-slip condition, and therefore, the flow velocity at all channel interfaces (fluid inlet and outlet, channel surface) where the fluidized layer exists was set to zero. The equations were discretized based on the finite volume method and the commercially available numerical software FLUENT 2019 R2 (ANSYS, INC.) was used for numerical simulations. 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 as carrier solvents.

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. At this time, acetonitrile (ACN) was used as an anti-solvent for the hydrophilic drug in the first section of the three-dimensional microfluidic reactor.

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

Determination 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 manufacture of capsules 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.

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

As a result, as confirmed in FIG. 8, the drug particle size decreased as the drug concentration decreased at 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 ml / min) mg/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 solvent:antisolvent flow rate ratio increased, the drug particle size decreased. According to each of the above conditions, it was confirmed that nanoparticle drugs of various sizes could 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 flow rate ratio of the solvent:antisolvent are adjusted to form tens of nanometers to several thousand nanometers in diameter. It is possible to prepare drug particles with

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

In the manufacture of capsules carrying hydrophilic drug particles using the three-dimensional microfluidic reactor of the present invention, in order to confirm the change in the three-dimensional focused flow according to the initial drug flow rate and the solvent-anti-solvent flow rate ratio condition in the first step A cross-section of the flow was identified 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 ratio was set at each initial drug flow rate condition. The flow rate ratio was changed to 1:2, 1:6 and 1:12, respectively. According to the degree of mixing in the three-dimensional focused flow, the flow patterns are color coded from 0 (blue, perfectly mixed) to 1 (red, completely unmixed).

As confirmed in FIG. 9, when the flow rate ratio of solvent:antisolvent was increased from 1:2 to 1:6, the degree of mixing and the 3D focusing effect increased, but the flow rate ratio of solvent:antisolvent was increased to 1:12. In the case of increasing the 3D convergence effect, the phenomenon of breaking the focusing occurred. This phenomenon was the same even when the initial drug flow rate condition was changed. Therefore, it is important to control the solvent:antisolvent flow rate ratio in order to properly mix the solvent and antisolvent and exhibit the optimal three-dimensional focused flow effect. The most preferable solvent:antisolvent flow rate ratio is 1:2 to 1:1:2. 8 was confirmed.

Comparison of the quality of drug-polymer capsules prepared with flasks, T-shaped devices and 3-dimensional microfluidic reactors

In this embodiment, each drug-polymer capsule prepared using the three-dimensional microfluidic reactor of the present invention and the flask manufacturing method, which is a manufacturing method of conventionally known drug-polymer capsules, and the manufacturing method using a 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.

drug/polymer density alendronate 10 mg/mL PLGA 2% by weight PVA 1% by weight

4-1. Manufacturing method using a 3-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 flow rate ratio of the alendronate-dissolved solution:acetonitrile was 1:6 in the second section. , In the third section, a drug-polymer capsule was prepared by setting the flow rate ratio of PVA-dissolved solution:PLGA-dissolved acetonitrile to 1:2.

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

The flask-based preparation 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, 3 mL of purified water as a solvent for alendronate, 18 mL of acetonitrile as an anti-solvent for alendronate, 9.5 mL of acetonitrile as a solvent for PLGA, and PVA Purified water as a solvent was adjusted to an amount of 1.9 mL.

4-3. Manufacturing method using T-shaped device

The manufacturing method using the T-shaped 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 is dissolved is 0.3 mL/min, in the second section, the flow rate ratio of the solution in which alendronate is dissolved: acetonitrile is 1:6, and in the third section, the PVA dissolved solution 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 were observed with a scanning electron microscope. As confirmed in FIG. 10, all of the drug-polymer capsules were manufactured in a spherical shape. 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 size 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, which can induce sustained release.

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 to 50 μm (preferably 0.6 to 15 μm)

As shown in Table 3, the size of the drug-polymer capsules prepared by the methods of Example 4-2 (flask) and Example 4-3 (T-shaped device) was similar to that of Example 4-1 (three-dimensional microfluidic reactor). ), showing a wider range than the size of the drug-polymer capsule prepared by the method, it was confirmed that the uniformity was poor.

Accordingly, the highest quality drug-polymer capsules could be 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 manufacturing 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 confirming 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), as shown in FIG. 11, it was confirmed that alendronate was properly loaded into PLGA. did

Therefore, it was confirmed that the manufacturing method using the three-dimensional microfluidic reactor of Example 4-1 was most effective in manufacturing 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 was dissolved in the second section (PLGA/drug mixture) of the three-dimensional microfluidic reactor, and the concentration of PVA and PVA dissolved in the third section (drug/polymer encapsulation) If the flow rate of purified water is controlled, the size of capsule particles up to about 2 μm can be selectively and reproducibly produced.

Establishment of conditions to improve the loading efficiency of alendronate

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

5-1. Optimization of PVA concentration

Drug-polymer capsules were prepared under the same conditions as in the preparation method using the three-dimensional microfluidic reactor of Example 4-1, but the concentrations of PVA (dissolved in PLGA anti-solvent) were 0.5% by weight, 1% by weight, and 2% by weight, respectively. The loading efficiency of alendronate according to the PVA concentration was evaluated by varying the weight%. 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 re-dispersed in DCM to remove all remaining polymer. Thereafter, the remaining hydrophilic drug is dispersed in 1 mL of purified water, and then the absorbance is measured through UV-vis to calculate the amount of the hydrophilic drug through the existing hydrophilic drug calibration curve graph. Subsequently, loading efficiency was confirmed by comparing the concentration of the hydrophilic drug consumed through the microfluid and the concentration of the hydrophilic drug measured through the Uv-vis.

As confirmed in FIG. 12, the loading efficiency of alendronate increased as the concentration of PVA increased. Accordingly, the optimal PVA concentration for maximizing the loading efficiency of alendronate was selected as 2% by weight.

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

In order to compare alendronate loading efficiency according to the difference in manufacturing method, after matching the concentration of PVA to 2% by weight, Example 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 way as in the -shaped device).

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

Claims (23)

A first structure having a flow path structure so 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 caused by a difference in solubility, and
A second structure having a flow path structure to supply a third fluid containing a carrier to carry the drug particles delivered from the first structure,
The first structure,
a first channel connected to one side of a first concentrating space having a hexahedral shape and supplying the first fluid to the first concentrating space;
second to fifth channels connected to four surfaces of the first concentrating space that are in contact with the one side and supplying the second fluid to the inside of the first concentrating space; and
A sixth channel connected to one side of the first concentrating space and the opposite side of the first concentrating space through which the drug particles are discharged from the first concentrating space;
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 supporting process of the drug particles are a continuous batch process. 3D microfluidic reactor. delete According to claim 1,
The three-dimensional microfluidic reactor includes 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. According to claim 1,
The second structure,
A seventh channel connected to cross one end of the first structure and supplying the third fluid; and
A three-dimensional microfluidic reactor comprising an eighth channel connected to one end of the seventh channel and having at least three bent portions. According to claim 1,
A third structure that is in fluid communication with the second structure and has a flow path structure to supply a fourth fluid containing a second anti-solvent for improving the loading efficiency of the particulate drug to the carrier, 3D microfluidic reactor. According to 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 connected to four surfaces of the second concentrating space that are in contact with the one side and supplying the fourth fluid to the inside of the second concentrating space; and
A three-dimensional microfluidic reactor comprising a 14th channel connected to one side of the second concentrating space and the other side opposite to the second concentrating space through which the drug particles encapsulated by the carrier flow out from the second concentrating space. According to claim 1,
A third structure that is in fluid communication with the second structure and has a flow path structure to supply a fourth fluid containing a second anti-solvent for improving the loading efficiency of the particulate drug to the carrier;
The first structure,
a first channel connected to one side of a first concentrating space having a hexahedral shape and supplying the first fluid to the first concentrating space; second to fifth channels connected to four surfaces of the first concentrating space contacting the one side surface and supplying the second fluid to the inside of the first concentrating space and opposing one side surface of the first concentrating space And a sixth channel connected to the other side of the first concentration space through which the drug particles flow out,
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 parts,
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 a second concentration space having a hexahedral shape; Tenth to thirteenth channels connected to four surfaces of the second concentrating space contacting the one side surface and supplying the fourth fluid to the inside of the second concentrating space and opposing one side surface of the second concentrating space and a 14th channel through which the drug particles encapsulated by the carrier are discharged from the second concentrating space connected to the other side of the reactor. The method according to any one of claims 1 and 3 to 7,
The microfluidic reactor is formed by stacking a plurality of flat films each having a pattern etched by a laser, a three-dimensional microfluidic reactor. delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete

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