Microfluidic device for optimization of nanoparticle synthesis of poorly soluble drugs

Abstract

본 개시는 안정적으로 고형 지질 나노 입자를 생성할 수 있는, 난용성 약물의 나노입자 합성 최적화를 위한 마이크로플루이딕 장치에 관한 것으로, 유기상 물질이 저장된 제1 저장 용기; 수상 물질이 저장된 제2 저장 용기; 미세 유체칩; 상기 제1 저장 용기 및 상기 미세 유체칩의 제1 주입구에 연결된 제1 펌프; 상기 제2 저장 용기 및 상기 미세 유체칩의 제2 주입구에 연결된 제2 펌프; 상기 미세 유체칩의 배출구에 연결된 제3 저장 용기; 및 상기 제1 저장 용기, 상기 미세 유체칩 및 상기 제1 펌프 중 적어도 하나에 배치된 히터를 포함할 수 있다.

Description

Technology Field

[0001] The present disclosure relates to a microfluidic device. More specifically, the present disclosure relates to a microfluidic device for optimizing nanoparticle synthesis of poorly soluble drugs, capable of stably producing solid lipid nanoparticles. Background Technology

[0002] A microfluidic machine is equipment capable of producing nanoparticles with high reproducibility and drug encapsulation efficiency through the homogeneous flow and mixing of fluids. At this time, the nanoparticles may include liposomes, lipoplexes, lipid nanoparticles (LNP), and solid lipid nanoparticles (SLN).

[0003] Among these, solid lipid nanoparticles are attracting attention due to their unique low in vivo toxicity and the ability to solubilize poorly soluble substances; however, they have the disadvantage that if the temperature is not maintained above the melting point of lipids, the sample aggregates or particles of uniform size cannot be obtained. Prior art literature

[0004] Korean Patent Publication No. 10-2023-0174058 (Published December 27, 2023) The problem to be solved

[0005] The embodiments disclosed in this disclosure are intended to provide a microfluidic device for optimizing nanoparticle synthesis of poorly soluble drugs, capable of stably producing solid lipid nanoparticles.

[0006] The problems that this disclosure aims to solve are not limited to those mentioned above, and other unmentioned problems will be clearly understood by a person skilled in the art from the description below. means of solving the problem

[0007] A microfluidic device according to the present disclosure for achieving the above-described technical problem may include: a first storage container in which an organic phase material is stored; a second storage container in which an aqueous phase material is stored; a microfluidic chip; a first pump connected to a first inlet port of the first storage container and the microfluidic chip; a second pump connected to a second inlet port of the second storage container and the microfluidic chip; a third storage container connected to an outlet port of the microfluidic chip; and a heater disposed in at least one of the first storage container, the microfluidic chip, and the first pump.

[0008] In addition, the heater may be placed in at least one of the first pump and the microfluidic chip.

[0009] Additionally, the heater may include a first heater disposed in the first pump; and a second heater disposed in the microfluidic chip.

[0010] In addition, the first heater may be placed in the container of the first pump.

[0011] In addition, the first heater may be arranged to surround the outer surface of the container of the first pump.

[0012] In addition, the first heater may be detachably disposed on the first pump.

[0013] In addition, the second heater may be disposed on the lower surface of the microfluidic chip.

[0014] In addition, the first inlet, the second inlet, and the outlet may be disposed on the upper surface of the microfluidic chip.

[0015] In addition, the second heater may be further disposed on the upper surface of the microfluidic chip.

[0016] In addition, the second heater can be detachably disposed on the microfluidic chip.

[0017] In addition, the heater may further include a third heater disposed in the first storage container.

[0018] In addition, the third heater may be arranged to surround the outer surface of the first storage container.

[0019] In addition, the third heater may be detachably disposed in the first storage container.

[0020] In addition, the heater may include a film heater.

[0021] Additionally, it may further include a temperature sensor disposed in at least one of the first storage container, the microfluidic chip, and the first pump.

[0022] In addition, the temperature sensor and the heater may be placed in the first pump.

[0023] In addition, the temperature sensor and the heater can be placed on the microfluidic chip.

[0024] In addition, it may further include a temperature control module for controlling the temperature of the heater.

[0025] In addition, the temperature control module can control the temperature of the heater based on the temperature from the temperature sensor, the glass transition temperature of the microfluidic chip, and the melting point of the organic material.

[0026] In addition, it may further include a control panel for controlling the first pump and the second pump. Effects of the invention

[0027] According to the means for solving the problem described above in the present disclosure, solid lipid nanoparticles can be stably produced. For example, solid lipid nanoparticles can be produced uniformly, stably, and reproducibly by preventing the sample from aggregating by applying heat to an organic material through a heater.

[0028] The effects of the present disclosure are not limited to those mentioned above, and other unmentioned effects will be clearly understood by a person skilled in the art from the description below. Brief explanation of the drawing

[0029] FIG. 1 is a schematic diagram of a microfluidic device for optimizing the synthesis of nanoparticles of a poorly soluble drug according to one embodiment. Figure 2 is a perspective view of the microfluidic chip of Figure 1. FIG. 3 is a drawing showing an actual product of a microfluidic device for optimizing the synthesis of nanoparticles of poorly soluble drugs according to one embodiment. Figure 4 is a diagram showing the microfluidic chip of Figure 3. Figure 5 is a diagram showing the microfluidic chip and the second heater of Figure 3. Figure 6 is a diagram illustrating the composition of organic phase materials and aqueous phase materials. Figure 7 is a diagram illustrating the size distribution of nanoparticles measured through a dynamic light scattering device. Figure 8 is a diagram illustrating the particle capture efficiency of curcumin according to curcumin concentration and flow rate ratio. Figure 9 is a diagram illustrating the release characteristics of curcumin according to the synthesis conditions of solid lipid nanoparticles. Figure 10 is a diagram illustrating the stability of solid lipid nanoparticles in water. Figure 11 is a diagram illustrating the stability of solid lipid nanoparticles in a culture medium. Specific details for implementing the invention

[0030] Throughout this disclosure, the same reference numerals denote the same components. This disclosure does not describe all elements of the embodiments, and general content in the art to which this disclosure pertains or content that overlaps between embodiments is omitted. The terms 'part, module, component, block' as used in the specification may be implemented in software or hardware, and depending on the embodiments, a plurality of 'parts, modules, components, blocks' may be implemented as a single component, or a single 'part, module, component, block' may include a plurality of components.

[0031] Throughout the specification, when a part is described as being "connected" to another part, this includes not only cases where they are directly connected but also cases where they are indirectly connected, and indirect connections include connections made via a wireless communication network.

[0032] Furthermore, when it is stated that a part "includes" a certain component, this means that, unless specifically stated otherwise, it does not exclude other components but may include additional components.

[0033] Throughout the specification, when it is stated that a component is located "on" another component, this includes not only cases where a component is in contact with another component, but also cases where another component exists between the two components.

[0034] Terms such as "first," "second," etc., are used to distinguish one component from another, and the components are not limited by the aforementioned terms.

[0035] Singular expressions include plural expressions unless there is an obvious exception in the context.

[0036] In each step, identification codes are used for convenience of explanation and do not describe the order of the steps; the steps may be performed differently from the specified order unless a specific order is clearly indicated in the context.

[0037] The operating principles and embodiments of the present disclosure will be described below with reference to the attached drawings.

[0038] FIG. 1 is a schematic diagram of a microfluidic device (1000) for optimizing the synthesis of nanoparticles of a poorly soluble drug according to one embodiment, and FIG. 2 is a perspective view of a microfluidic chip (300) of FIG. 1.

[0039] A microfluidic device (1000) according to one embodiment may include, as shown in FIG. 1, a microfluidic chip (300), a first storage container (101), a second storage container (102), a third storage container (103), a first pump (201), a second pump (202), a heater (601, 602), a control panel (800), and a temperature control module (700).

[0040] The first storage container (101) can store an organic phase material. The first storage container (101) can be connected to the first inlet (301) of the microfluidic chip (300) via the first pump (201). The first storage container (101) may include a syringe.

[0041] The second storage container (102) can store an aqueous phase material. The second storage container (102) can be connected to the second inlet (302) of the microfluidic chip (300) via the second pump (202). The second storage container (102) may include a syringe.

[0042] The third storage container (103) can store material discharged from the microfluidic chip (300). For example, the third storage container (103) can store material produced by synthesizing (or mixing) organic material from the aforementioned first storage container (101) and aqueous material from the second storage container (102) together. The third storage container (103) can be connected to the outlet (303) of the microfluidic chip (300). The third storage container (103) may include a syringe.

[0043] The first pump (201) may be connected to the first storage container (101) and the microfluidic chip (300). For example, one side of the first pump (201) may be connected to the first storage container (101) through the fourth tube (404), and the other side of the first pump (201) may be connected to the first inlet (301) of the microfluidic chip (300) through the first tube (401). The first pump (201) may pump an aqueous substance from the first storage container (101), store it in the container of the first pump (201), and then pump the aqueous substance stored in the container to provide it to the first inlet (301) of the microfluidic chip (300). The second pump (202) may include a syringe pump.

[0044] The second pump (202) may be connected to the second storage container (102) and the microfluidic chip (300). For example, one side of the second pump (202) may be connected to the second storage container (102) through the fifth tube (405), and the other side of the second pump (202) may be connected to the second inlet (302) of the microfluidic chip (300) through the second tube (402). The second pump (202) may pump an aqueous substance from the second storage container (102), store it in the container of the second pump (202), and then pump the aqueous substance stored in the container to provide it to the second inlet (302) of the microfluidic chip (300). The second pump (202) may include a syringe pump.

[0045] The third storage container (103) can store synthetic material discharged from the microfluidic chip (300). The third storage container (103) can be connected to the outlet (303) of the microfluidic chip (300). For example, the third storage container (103) can be connected to the outlet (303) of the microfluidic chip (300) through the third tube (403).

[0046] The microfluidic chip (300) can produce a synthetic material by mixing an organic material supplied through a first inlet (301) and an aqueous material supplied through a second inlet (302), and discharge the synthetic material through an outlet (303). As shown in FIGS. 1 and 2, this microfluidic chip (300) may include a main body (350), a first inlet (301), a second inlet (302), an outlet (303), a first flow path (311), a second flow path (312), and a third flow path (313).

[0047] The main body (350) can form the exterior of the microfluidic chip (300). A first inlet (301), a second inlet (302), and an outlet (303) may be disposed on the outside of the main body (350), and a first flow path (311), a second flow path (312), and a third flow path (313) may be formed inside the main body (350). The main body (350) may be made of a transparent material.

[0048] The first inlet (301) can be connected to the first pump (201). For example, the first inlet (301) can be connected to the first pump (201) through the first tube (401).

[0049] The second inlet (302) can be connected to the second pump (202). For example, the second inlet (302) can be connected to the second pump (202) through the second tube (402).

[0050] The outlet (303) can be connected to the third storage container (103). For example, the outlet (303) can be connected to the third storage container (103) through the third tube (403).

[0051] The first flow path (311) can be connected to the first inlet (301), the second flow path (312), and the outlet (303). For example, one side of the first flow path (311) may be connected to the first inlet (301), and the other side of the first flow path (311) may be connected to the connection between the outlet (303) and the second flow path (312).

[0052] The second flow path (312) can be connected to the second inlet (302), the first flow path (311), and the outlet (303). For example, one side of the second flow path (312) may be connected to the second inlet (302), and the other side of the second flow path (312) may be connected to the connection between the outlet (303) and the first flow path (311).

[0053] The third Euro (313) can be connected to a connection part and an outlet (303) where the other side of the first Euro (311) and the other side of the second Euro (312) are connected to each other. For example, one side of the third Euro (313) can be connected to a connection part where the other side of the first Euro (311) and the other side of the second Euro (312) are connected to each other, and the other side of the third Euro (313) can be connected to an outlet (303).

[0054] Heaters (601, 602) can provide heat to at least one of a first storage container (101), a second storage container (102), a third storage container (103), a first pump (201), a second pump (202), and a microfluidic chip (300). To this end, according to one embodiment, heaters (601, 602) may be placed in at least one of a first storage container (101), a second storage container (102), a third storage container (103), a first pump (201), a second pump (202), and a microfluidic chip (300). For example, as shown in FIGS. 1 and 2, a first heater (601) may be placed in the first pump (201), and a second heater (602) may be placed in the microfluidic chip (300). As a specific example, the first heater (601) may be positioned on the outer surface of the container of the first pump (201) to surround the container of the first pump (201), and the second heater (602) may be positioned on the lower surface of the microfluid chip (300). Here, the lower surface of the microfluid chip (300) may be a surface located opposite to the upper surface (e.g., the upper surface of the main body (350)) where the first inlet (301), the second inlet (302), and the outlet (303) are positioned. In other words, the second heater (602) may be positioned on the lower surface of the main body (350) of the microfluid chip (300).

[0055] Heat from the first heater (601) can be provided to the organic material stored in the container of the first pump (201) to heat the organic material in the container of the first pump (201), and heat from the second heater (602) can be provided to the organic material in the flow paths (311, 312, 313) of the microfluid chip (300) to heat the organic material in the microfluid chip (300).

[0056] The heaters (601, 602) may have the form of a thin film. For example, at least one of the first heater (601) and the second heater (602) may include a film heater.

[0057] A temperature sensor (500) may be placed on at least one of the components to which a heater (601, 602) is attached. For example, the temperature sensor (500) may be placed on a first pump (201) to which a first heater (601) is attached. In this case, the temperature sensor (500) can detect the temperature of the first pump (201). For example, the temperature sensor (500) can detect the temperature of an organic material stored in a container of the first pump (201).

[0058] The temperature control module (700) can control the temperature of the heaters (601, 602). For example, the temperature control module (700) can control the temperature of the first heater (601) and the temperature of the second heater (602), respectively. At this time, the temperature control module (700) can control the temperature of the first heater (601) and the temperature of the second heater (602) based on temperature information from the temperature sensor (500). For example, the temperature control module (700) can control the first heater (601) and the second heater (602) based on temperature information from the aforementioned temperature sensor (500) so that the temperature of the first heater (601) and the temperature of the second heater (602) can be maintained at a preset target temperature, respectively. In other words, when the detected temperature from the temperature sensor (500) is lower than the target temperature, the temperature sensor (500) module may increase the output of each of the first heater (601) and the second heater (602) so that the first heater (601) and the second heater (602) each provide heat at a temperature higher than the current temperature. Meanwhile, when the detected temperature from the temperature sensor (500) is higher than the target temperature, the temperature sensor (500) module may decrease the output of each of the first heater (601) and the second heater (602) so that the first heater (601) and the second heater (602) each provide heat at a temperature lower than the current temperature. Here, the current temperature may be the most recent temperature measured by the temperature sensor (500).

[0059] The aforementioned target temperature may be a temperature higher than the melting point of the organic material. This target temperature may be set based on the glass transition temperature of the organic material. In this case, the glass transition temperature of the organic material may be controlled according to the material of the microfluidic chip (300). For example, since the glass transition temperature of the organic material may vary depending on the material of the microfluidic chip (300), the target temperature may be appropriately controlled through the temperature control module (700) in consideration of this. Through the control of this target temperature, the temperature of the heaters (601, 602) may be controlled, and accordingly, the temperature of the organic material may be controlled to be higher than the melting point of the organic material. The temperature control range may be controlled according to the detectable range of the temperature sensor (500).

[0060] When preparing a sample of an organic phase material, the organic phase containing solid lipid particles is placed into a syringe in which a heater (601, 602) is operated, and the operating temperature (e.g., target temperature) can be determined by taking into account the melting point of the sample used and the glass transition temperature of the microfluidic chip (300) used.

[0061] The control panel (800) can control the first pump (201) and the second pump (202). For example, the control panel (800) can control the flow rate and total flow rate of organic matter and aqueous matter supplied to the microfluidic chip (300) by controlling the first pump (201) and the second pump (202). In other words, the control panel (800) can control the flow rate and total flow rate of organic matter and the flow rate and total flow rate of aqueous matter. The control panel (800) may include a screen that displays the flow rate and total flow rate of each of the aforementioned substances. Additionally, a user interface capable of controlling the first pump (201) and the second pump (202) may be displayed on the screen of the control panel.

[0062] According to one embodiment, since the first pump (201) where the sample (e.g., organic material) stays the longest and the microfluidic chip (300) where direct mixing of the sample takes place can be heated, the sample can be mixed homogeneously without hardening. Therefore, when manufacturing solid lipid nanoparticles (SLN) using the microfluidic chip (300), the sample does not aggregate, so solid nanoparticles of uniform particle size can be produced.

[0063] Meanwhile, the microfluidic device (1000) of one embodiment may further include a third heater disposed in the first storage container (101). For example, the heater may include a first heater (601), a second heater (602), and a third heater. In this case, the third heater may be disposed on the outer surface of the first storage container (101) so as to surround the first storage container (101). The third heater may include a film heater. The third heater may be controlled by the aforementioned temperature control module (700).

[0064] The temperature conditions of each heater mounted on the first pump (201) and the microfluidic chip (300) are the same, and the temperature of the heater can be set according to the melting temperature of the oil phase nanoparticles used.

[0065] When controlling the temperature, it is important to ensure that the temperature does not drop below the standard melting temperature of the particles. However, it is acceptable for the heater temperature to rise high enough to reach the target temperature.

[0066] When maintaining the internal temperature of the microfluidic chip (300), there is difficulty in measuring the internal temperature of the microfluidic chip (300). Therefore, the temperature difference between the inside of the microfluidic chip (300) and the outside of the microfluidic chip (300) is initially measured to generate preliminary data, and by controlling the temperature of the heater based on the preliminary data, a continuously uniform temperature can be maintained inside the microfluidic chip (300).

[0067] A certain range of bumpers can be formed for the temperature difference between the inside and outside of the microfluidic chip (300) so that the temperature above the melting point of the particles can be maintained.

[0068] When controlling the temperature based on the difference between the internal temperature and the external temperature of the microfluidic chip (300), the conductivity of the microfluidic chip (300) (e.g., glass transition temperature) may vary depending on time and conditions, and the temperature may be maintained depending on the conditions.

[0069] In a microfluidic system, setting the heating location to three places—a device where the material is stored as nanoparticles (e.g., a first storage container (101)), a syringe (e.g., a container of the first pump (201)) and a microfluidic chip (300)—may be most efficient when mixing nanoparticles.

[0070] In the combined structure of the film heater (e.g., 602) of the microfluidic chip (300), a heater may be disposed on the lower surface and the upper surface of the microfluidic chip (300), respectively.

[0071] The second heater (602) can be detachably coupled to the first pump (201).

[0072] The second heater (602) can be detachably coupled to the microfluidic chip (300).

[0073] The temperature sensor (500) may be placed in the first pump (201) and the microfluidic chip (300), respectively.

[0074] It is also possible to control the first heater (601) of the first pump (201) and the first heater (601) of the microfluid chip (300) in the same way by measuring only the temperature of the material remaining on the first pump (201) side without measuring the temperature of the microfluid chip (300).

[0075] FIG. 3 is a drawing showing an actual product of a microfluidic device (1000) for optimizing the synthesis of nanoparticles of a poorly soluble drug according to one embodiment, FIG. 4 is a drawing showing the microfluidic chip (300) of FIG. 3, and FIG. 5 is a drawing showing the microfluidic chip (300) of FIG. 3 and a second heater (602).

[0076] Since the microfluidic device (1000) of FIGS. 3 to 5 is substantially the same as the microfluidic device (1000) of FIGS. 1 and 2 described above, the description of the components of the microfluidic device (1000) of FIGS. 3 to 5 refers to the description of the components of the microfluidic device (1000) of FIGS. 1 and 2.

[0077] Meanwhile, the microfluidic device (1000) of FIGS. 3 to 5 may further include a first fixing member (111), a second fixing member (112), and a third fixing member (113), as shown in FIG. 3. A first storage container (101) may be placed on the first fixing member (111), a second storage container (102) may be placed on the second fixing member (112), and a third storage container (103) may be placed on the third fixing member (113).

[0078] Additionally, as shown in FIG. 5, the second heater (602) may include a film (621) and a heating wire (622) that provides heat. The heating wire (622) may be placed within the film (621). The aforementioned first heater (601) and third heater may each have the same configuration as the second heater (602) shown in FIG. 5.

[0079] Hereinafter, with reference to FIGS. 6, 7, 8, 9, 10, and 11, a method for manufacturing solid lipid nanoparticles (SLN) using a microfluidic device (1000) according to one embodiment (e.g., the microfluidic device (1000) of FIGS. 3 to 5) is described as follows. For example, after attaching a temperature control module (700) to the microfluidic device (1000), solid lipid nanoparticles were synthesized using curcumin (Cur), a sparingly soluble substance, and cetyl palmitate, a solid lipid, to verify whether solid lipid nanoparticles could be synthesized as designed. At this time, in order to verify whether synthesis proceeds well under various conditions, the curcumin content and the flow rate ratio (FRR) conditions between the organic phase substance and the aqueous phase substance were varied, and the preparation of the sample was set as shown in FIG. 6.

[0080] FIG. 6 is a diagram (6000) for explaining the composition of organic phase materials and aqueous phase materials, FIG. 7 is a diagram (700) for explaining the size distribution of nanoparticles measured through a Dynamic Light Scattering (DLS) device, FIG. 8 is a diagram (8000) for explaining the capture efficiency of curcumin within particles according to curcumin concentration and flow rate ratio, FIG. 9 is a diagram (9000) for explaining the release characteristics of curcumin according to the synthesis conditions of solid lipid nanoparticles, FIG. 10 is a diagram (10000) for explaining the stability of solid lipid nanoparticles in the aqueous phase, and FIG. 11 is a diagram (11000) for explaining the stability of solid lipid nanoparticles in the medium.

[0081] For example, an organic phase material may be stored in a first storage container (101) and a first pump (201) (e.g., a first pump (201) equipped with a first heater (601) and a temperature sensor (500)). The organic phase material may include 1 ml of ethanol (EtOH), 10 mg of cetyl palmitate (e.g., a sparingly soluble substance), 3 mg of C18-PEG2000, and 5 mg of curcumin (e.g., a solid lipid), as shown in FIG. 6. For example, the organic phase material may be a mixture of 1 ml of ethanol (EtOH), 10 mg of cetyl palmitate (e.g., a sparingly soluble substance), 3 mg of C18-PEG2000, and 5 mg of curcumin (e.g., a solid lipid).

[0082] An aqueous phase material may be stored in the second storage container (102) and the second pump (202). The aqueous phase material may include 3 ml of pure water (DI (Deionized) water) and a surfactant (Tween 20), as shown in FIG. 6. For example, the aqueous phase material may be a mixture of 3 ml of pure water (DI (Deionized) water) and a surfactant (Tween 20).

[0083] The organic phase material and the aqueous phase material as shown in FIG. 6 can be synthesized into solid lipid nanoparticles by mixing them in a microfluidic chip (300) (e.g., a microfluidic chip (300) with a second heater (602) attached). The synthesized solid lipid nanoparticles can be discharged into a third storage container (103).

[0084] The characteristics of the solid lipid nanoparticles synthesized through the first pump (201) with the first heater (601) attached and the microfluidic chip (300) with the second heater (602) attached are as follows.

[0085] First, to confirm the completeness of the prepared solid lipid nanoparticles, the size, polydispersity, and encapsulation efficiency were measured. Here, particle size and polydispersity were confirmed using a DLS (Zetasizer, Malvern) device, and to measure encapsulation efficiency, absorbance was measured at 425 nm, the maximum absorption wavelength of curcumin, using a Microplate Reader (Synergy, Bio Tek), and then the concentration was calculated.

[0086] Figure 7 shows the distribution of nanoparticle sizes (e.g., particle diameter) measured through a DLS device.

[0087] Figure 8 shows the average diameter (Size), polydisperse index (PDI), and intraparticle capture efficiency (EE) of solid lipid nanoparticles when the curcumin concentration is 3 mg / mL and the flow rate ratio (FRR) between the organic phase and the aqueous phase is 1:3, the average diameter (Size), polydisperse index (PDI), and intraparticle capture efficiency (EE) of solid lipid nanoparticles when the curcumin concentration is 3 mg / mL and the flow rate ratio (FRR) between the organic phase and the aqueous phase is 1:5, the average diameter (Size), polydisperse index (PDI), and intraparticle capture efficiency (EE) of solid lipid nanoparticles when the curcumin concentration is 5 mg / mL and the flow rate ratio (FRR) between the organic phase and the aqueous phase is 1:3, and The average diameter (Size), particle dispersion (PDI), and particle capture efficiency (EE) of solid lipid nanoparticles are shown, respectively, when the curcumin concentration is 5 mg / mL and the flow rate ratio (FRR) between the organic phase and the aqueous phase is 1:5.

[0088] Figure 9 shows a graph of curcumin release characteristics (C11) under a first condition where the concentration of curcumin is 3 mg / mL, the solubilization of the surfactant (Tween 20) is 2%, and the flow rate ratio (FRR) between the organic phase and the aqueous phase is 1:3; a graph of curcumin release characteristics (C22) under a second condition where the concentration of curcumin is 5 mg / mL, the solubilization of the surfactant (Tween 20) is 2%, and the flow rate ratio (FRR) between the organic phase and the aqueous phase is 1:3; and a graph of curcumin release characteristics (C33) under a third condition where the concentration of curcumin is 5 mg / mL, the solubilization of the surfactant (Tween 20) is 2%, and the flow rate ratio (FRR) between the organic phase and the aqueous phase is 1:5.

[0089] For example, Figure 9 shows a graph of the characteristics of curcumin release over time from solid lipid nanoparticles synthesized under each condition.

[0090] Under condition 1, the drug was initially released at about 50% for 8 hours, and then sustained-released for 6 days.

[0091] Under conditions 2 and 3, the drug exhibited a sustained-release form overall.

[0092] Figure 10 shows a graph (CV1) representing the size of solid lipid nanoparticles over time when stored in water, prepared under a first condition where the curcumin concentration is 3 mg / mL and the flow rate ratio (FRR) between the organic phase and the aqueous phase is 1:3; a graph (CV2) representing the size of solid lipid nanoparticles over time when stored in water, prepared under a second condition where the curcumin concentration is 3 mg / mL and the flow rate ratio (FRR) between the organic phase and the aqueous phase is 1:5; a graph (CV3) representing the size of solid lipid nanoparticles over time when stored in water, prepared under a third condition where the curcumin concentration is 5 mg / mL and the flow rate ratio (FRR) between the organic phase and the aqueous phase is 1:3; and a graph where the curcumin concentration is 5 mg / mL and the organic phase A graph (CV4) showing the size of solid lipid nanoparticles over time when solid lipid nanoparticles prepared under the fourth condition, where the flow rate ratio (FRR) between the organic phase and the aqueous phase is 1:5, are stored in water, and a graph (CV5) showing the size of solid lipid nanoparticles over time when solid lipid nanoparticles prepared under the fifth condition, where the concentration of curcumin is 7 mg / mL and the flow rate ratio (FRR) between the organic phase and the aqueous phase is 1:5, are stored in water.

[0093] Figure 11 shows a graph (CV11) representing the size of solid lipid nanoparticles over time when stored in a culture medium, prepared under a first condition where the curcumin concentration is 3 mg / mL and the flow rate ratio (FRR) between the organic phase and the aqueous phase is 1:3; a graph (CV22) representing the size of solid lipid nanoparticles over time when stored in a culture medium, prepared under a second condition where the curcumin concentration is 3 mg / mL and the flow rate ratio (FRR) between the organic phase and the aqueous phase is 1:5; a graph (CV33) representing the size of solid lipid nanoparticles over time when stored in a culture medium, prepared under a third condition where the curcumin concentration is 5 mg / mL and the flow rate ratio (FRR) between the organic phase and the aqueous phase is 1:3; and a graph where the curcumin concentration is 5 mg / mL and, A graph (CV44) showing the size of solid lipid nanoparticles over time when solid lipid nanoparticles prepared under the fourth condition, where the flow rate ratio (FRR) between the organic phase material and the aqueous phase material is 1:5, are stored in a medium, and a graph (CV55) showing the size of solid lipid nanoparticles over time when solid lipid nanoparticles prepared under the fifth condition, where the concentration of curcumin is 7 mg / mL and the flow rate ratio (FRR) between the organic phase material and the aqueous phase material is 1:5, are stored in a medium.

[0094] That is, to confirm the stability of the manufactured solid lipid nanoparticles, the solid lipid nanoparticles were diluted in PBS (phosphate buffered saline) and cell medium, and the change in particle size was observed for two weeks. This was done to confirm colloidal stability, as a decrease in particle stability would result in particle aggregation. As a result of the measurement, as shown in Figures 10 and 11, no significant change in particle size was observed over two weeks.

[0095] In this way, the microfluidic device (1000) of one embodiment can produce solid lipid nanoparticles uniformly, stably, and reproducibly. In addition, the solid lipid nanoparticles produced using the microfluidic device (1000) according to one embodiment showed excellent results in terms of polydispersity and encapsulation efficiency compared to the conventional bulk method, which may be applied in the pharmaceutical and cosmetics industries in the future.

[0096] Meanwhile, in one embodiment, cetyl palmitate, a type of solid lipid, was used, but various polymers and lipids such as PLGA and Stearic Acid can be used. This means that various particles can be manufactured by using materials that can solidify during manufacturing, such as microspheres and emulsifiers, in addition to solid lipid nanoparticles (SLN). Thus, the microfluidic device (1000) of one embodiment can be applied to the pharmaceutical and cosmetic industries to improve the quality of particles.

[0097] As described above, the disclosed embodiments have been explained with reference to the attached drawings. Those skilled in the art will understand that the present disclosure may be practiced in forms different from the disclosed embodiments without changing the technical spirit or essential features of the present disclosure. The disclosed embodiments are illustrative and should not be interpreted restrictively. Explanation of the symbols

[0098] 1000: Microfluidic device 101: First storage container 102: Second storage container 103: Third storage container 201: First pump 202: Second pump 300: Microfluidic Chip 301: First injection port 302: Second injection port 303: Outlet 401: 1st tube 402: Tube 2 403: 3rd tube 404: Tube 4 405: Tube 5 311: First Euro 312: Second Euro 313: The 3rd Euro 350: Main unit 601: 1st Heater 602: 2nd Heater 500: Temperature sensor 800: Control Panel 700: Temperature control module

Claims

Claim 1 A microfluidic device for optimizing nanoparticle synthesis of a poorly soluble drug, comprising: a first storage container in which an organic phase material is stored; a second storage container in which an aqueous phase material is stored; a microfluidic chip including a first inlet, a second inlet, and an outlet; a first pump connected between the first storage container and the first inlet of the microfluidic chip to supply the organic phase material; a second pump connected between the second storage container and the second inlet of the microfluidic chip to supply the aqueous phase material; a third storage container connected to the outlet of the microfluidic chip; a heater disposed in each of the first pump and the microfluidic chip; a temperature sensor disposed in at least one of the first pump and the microfluidic chip; and a temperature control module that controls the temperature of the heater based on the temperature measured by the temperature sensor, the glass transition temperature of the microfluidic chip, and the melting point of the organic phase material. Claim 2 delete Claim 3 A microfluidic device for optimizing nanoparticle synthesis of poorly soluble drugs, wherein the heater comprises: a first heater disposed in the first pump; and a second heater disposed in the microfluidic chip. Claim 4 In claim 3, the first heater is a microfluidic device for optimizing the synthesis of nanoparticles of a poorly soluble drug, disposed in the container of the first pump. Claim 5 In claim 4, the first heater is positioned to surround the outer surface of the container of the first pump, a microfluidic device for optimizing the synthesis of nanoparticles of a poorly soluble drug. Claim 6 In claim 3, the first heater is detachably disposed of in the first pump, a microfluidic device for optimizing the synthesis of nanoparticles of a poorly soluble drug. Claim 7 In claim 3, the second heater is disposed on the lower surface of the microfluidic chip, a microfluidic device for optimizing the synthesis of nanoparticles of poorly soluble drugs. Claim 8 delete Claim 9 delete Claim 10 A microfluidic device for optimizing nanoparticle synthesis of poorly soluble drugs, further comprising a control panel for controlling the first pump and the second pump in claim 1.

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