KR-20260066720-A - Method for manufacturing nanoparticles

Abstract

[Project] To provide a method for manufacturing nanoparticles that enables the convenient production of desired nanoparticles using a microfluidic device. [Solution] A method for manufacturing nanoparticles according to the present invention comprises a process of introducing a first liquid containing at least one material into a mixing channel (20) through a first fluid inlet channel (10a) of a microfluidic device (1a), and simultaneously introducing a second liquid into the mixing channel (20) through a second fluid inlet channel (10b) and a third fluid inlet channel (10c) on both sides of the first fluid inlet channel (10a). The Reynolds number in the mixing channel (20) is set to a value greater than or equal to a predetermined value, and the flow of the first liquid in the mixing channel (20) is asymmetrical so that the flow of the first liquid immediately after entering the mixing channel (20) through the first fluid inlet channel (10a) is biased toward one of the two side walls of the mixing channel (20).

Inventors

• 타카타 코지
• 무라카미 타츠야
• 하시오카 신기

Assignees

• 토야마켄
• 고리쓰다이가쿠호진 도야마켄리쓰다이가쿠
• 니폰 제온 가부시키가이샤

Dates

Publication Date

20260512

Application Date

20240906

Priority Date

20230908

Claims (11)

1. A process having to introduce a first liquid containing at least one material into a mixing channel through a first fluid inlet channel of a microfluidic device, and simultaneously introduce a second liquid into the mixing channel through a second fluid inlet channel and a third fluid inlet channel on both sides of the first fluid inlet channel, A method for manufacturing nanoparticles, wherein the Reynolds number in the mixing channel is set to a value greater than or equal to a predetermined value, and the flow of the first liquid in the mixing channel is asymmetrical so that the flow of the first liquid immediately after entering the mixing channel through the first fluid inlet channel is directed toward one of the two side walls of the mixing channel.
2. In paragraph 1, A method for manufacturing nanoparticles having a Reynolds number of 151 or higher.
3. In paragraph 2, A method for manufacturing nanoparticles having a Reynolds number of 281 or higher.
4. In any one of paragraphs 1 through 3, The gap between the first fluid inlet channel and the second fluid inlet channel is greater than the horizontal width of each of the first fluid inlet channel, the second fluid inlet channel, and the third fluid inlet channel, and A method for manufacturing nanoparticles, wherein the gap between the first fluid inlet channel and the third fluid inlet channel is greater than the width of each of the first fluid inlet channel, the second fluid inlet channel, and the third fluid inlet channel.
5. In any one of paragraphs 1 through 3, A method for manufacturing nanoparticles, further comprising a process of discharging the first liquid and the second liquid from the mixing channel through a fluid outlet channel located downstream of the mixing channel.
6. In paragraph 5, A method for manufacturing nanoparticles, wherein the fluid outlet channel is composed of a single fluid outlet channel having a width narrower than the width of the mixing channel.
7. In any one of paragraphs 1 through 3, A method for manufacturing nanoparticles, wherein the temperature of the above-mentioned mixing channel is 45℃ or higher.
8. In any one of paragraphs 1 through 3, A method for manufacturing nanoparticles, wherein the temperature of the above-mentioned mixing channel is above room temperature.
9. In any one of paragraphs 1 through 3, A method for manufacturing nanoparticles in which at least one of the above materials comprises lipids.
10. In any one of paragraphs 1 through 3, A method for manufacturing nanoparticles, wherein the second liquid is an aqueous solvent and comprises at least one water-soluble material.
11. In Paragraph 10, A method for manufacturing nanoparticles, wherein at least one of the above-mentioned water-soluble materials comprises at least one of a protein and a peptide.

Description

Method for manufacturing nanoparticles The present invention relates to a method for manufacturing nanoparticles using a microfluidic device. A method for manufacturing nanoparticles that can be used as carriers in a drug delivery system (DDS) or as pharmaceuticals is known to be manufactured using a microfluidic device. For example, Patent Document 1 describes a technique for chemically synthesizing reconstituted HDL (rHDL) with a size (around 10 nm) similar to that of natural high-density lipoprotein (HDL) by mixing a first liquid containing a phospholipid (DMPC: dimyristoyl phosphatidylcholine) and a second liquid containing apolipoprotein A-I (apoA-I) using a microfluidic device. In the method for manufacturing nanoparticles of Patent Document 1, a microfluidic device having three fluid inlet channels (a central fluid inlet channel and fluid inlet channels on both sides thereof) and a mixing channel where these fluid inlet channels merge is used to manufacture rHDL. In this microfluidic device, a first liquid is introduced into the central fluid inlet channel, and a second liquid is introduced into the fluid inlet channels on both sides thereof. It is believed that the first liquid flows into the mixing channel through the central fluid inlet channel, and the second liquid flows into the mixing channel through the fluid inlet channels on both sides. It is thought that the first liquid and the second liquid form a microvortex (micro-vortex) in the mixing channel that is symmetric (mirror-symmetric) with respect to the central fluid inlet channel, thereby rapidly mixing the DMPC contained in the first liquid and the apolipoprotein A-I contained in the second liquid, and reconstructing rHDL. In recent years, rHDL (DSPC-rHDL) using DSPC (distearoyl phosphatidylcholine) as a phospholipid has been found to be promising as a carrier in drug delivery systems or as a pharmaceutical product. Cholic acid dialysis has been known as a technique for reconstructing DSPC-rHDL. However, cholic acid dialysis has problems such as requiring labor and time for tasks like removing cholic acid by dialysis, and toxicity caused by residual cholic acid. Accordingly, the inventors attempted to reconstitute DSPC-rHDL according to the method for manufacturing nanoparticles of Patent Document 1. However, DSPC-rHDL could not be reconstituted using the method for manufacturing nanoparticles of Patent Document 1, and it was suggested that the mixing efficiency of the first liquid and the second liquid in the mixing channel was insufficient as the cause. In addition, phospholipids with high phase transition temperatures, such as DSPC or HSPC (hydrogenated soy phosphatidylcholine), are thought to undergo rapid self-assembly when the first liquid and the second liquid are mixed, and it is considered impossible or difficult to reconstitute rHDL using the nanoparticle manufacturing method of Patent Document 1. Therefore, there is a need for a technology that can manufacture various nanoparticles (rHDL, liposomes, lipid nanoparticles, polymer nanoparticles, polymer lipid hybrids, etc.) that can be used as carriers in drug delivery systems, pharmaceuticals, cosmetics, or non-pharmaceutical products using a microfluidic device. FIG. 1 is an exploded perspective view of a microfluidic device, etc., used in a method for manufacturing nanoparticles according to one embodiment of the present invention. Figure 2 is a plan view of the microfluidic device shown in Figure 1. Figure 3 is a diagram showing the microfluidic device shown in Figure 1 immersed in a constant temperature water bath. FIG. 4a is a conceptual diagram showing the flow state of a first liquid and a second liquid flowing through a mixing channel when the Reynolds number in the mixing channel is greater than or equal to a first predetermined value in the microfluidic device shown in FIG. 2. FIG. 4b is a conceptual diagram showing the flow state of a first liquid and a second liquid flowing through a mixing channel when the Reynolds number in the mixing channel is greater than or equal to a second predetermined value in the microfluidic device shown in FIG. 2. FIG. 4c is a conceptual diagram showing the flow state of a first liquid and a second liquid flowing through a mixing channel when the Reynolds number in the mixing channel is less than a first predetermined value in the microfluidic device shown in FIG. 2. Figure 5a is a photograph showing the state of the first liquid and the second liquid flowing through the mixing channel when the Reynolds number in the mixing channel is about 151. FIG. 5b is a photograph showing the state of the first liquid and the second liquid flowing through the mixing channel when the Reynolds number in the mixing channel is about 173. FIG. 5c is a photograph showing the state of the first liquid and the second liquid flowing through the mixing channel when the Reynolds number in the mixing channel is about 281. FIG. 5d is a photograph showing the sta