Method for preparing novel PLGA nanocarrier

Abstract

The present invention relates to a method for preparing a novel PLGA nanocarrier and, particularly, to a method for preparing a PLGA nanocarrier that uses propylene carbonate as a solvent, instead of a biologically toxic organic solvent, and thus has high uniformity and excellent dispersibility, and is biologically safe, thus being suitable for use as a cosmetic composition.

Description

Method for manufacturing a novel PLGA nanocarrier

[0001] The present invention relates to a method for producing a novel PLGA nano-carrier, and more particularly, to a method for producing a PLGA nano-carrier that is safe for use in a cosmetic composition by using propylene carbonate as a solvent instead of a biotoxic organic solvent.

[0002] Functional cosmetics are products that claim to have skin whitening, wrinkle improvement, a smooth tan, or UV protection. Active ingredients such as vitamins A and C, which are used as raw materials in these products, become unstable when exposed to light, heat, and air. Their low absorption rate into the skin leads to lower efficacy relative to their cost. Research is underway to develop high-functional cosmetics that stabilize unstable substances used in cosmetics, protect the bioactive ingredients from external factors, and enhance skin affinity for easier absorption. In particular, active research is underway to develop safe and skin-friendly delivery systems that deliver precise and stable ingredients to the desired skin area. Research has been conducted using the biodegradable polymer PLGA. However, the residual hazards of organic solvents commonly used to dissolve PLGA, such as acetonitrile, acetone, THF, and DMSO, have limited its use in cosmetic compositions. Furthermore, the cosmetics market is currently emphasizing "eco-friendly cosmetics" that utilize more environmentally friendly ingredients. Therefore, recently, the use of organic solvents is being avoided not only in the raw material ingredients of cosmetics but also in the raw material processing stage.

[0003] Accordingly, the inventors of the present invention conducted research to develop a manufacturing method capable of manufacturing a nanocarrier that can be used in cosmetics without using an organic solvent, but at a level similar to that of existing nanocarriers, and in the process, by using propylene carbonate, a cosmetic solvent, as a solvent, they developed a method for manufacturing PLGA nanocarriers that can be safely used without worrying about the residual organic solvent having biotoxicity, thereby completing the present invention.

[0004] The purpose of the present invention is to provide a method for manufacturing a PLGA nano-carrier, a PLGA nano-carrier manufactured by the manufacturing method, and a cosmetic composition comprising the nano-carrier.

[0005] The technical problems of the present invention are not limited to the technical problems mentioned above, and other technical problems not mentioned will be clearly understood by those skilled in the art from the description below.

[0006] According to an embodiment of the present invention, a method for producing a PLGA nano-carrier is provided, comprising the steps of (S1) dissolving PLGA (Poly(lactic-co-glycolic acid)) in a propylene carbonate (PC) solvent to produce an organic phase; (S2) dissolving an emulsifier in purified water to produce an aqua phase; and (S3) mixing the organic phase and the aqua phase produced above so that the weight ratio of propylene carbonate / purified water is 0.01 to 0.39.

[0007] The manufacturing method according to the present invention is characterized in that it manufactures PLGA nanoparticles of uniform size by using propylene carbonate as a solvent instead of an organic solvent having biotoxicity and adjusting the content ratio of propylene carbonate / purified water to an optimal ratio, and the manufactured PLGA nano-carrier is safe for the body and can be stably maintained at high temperatures for a long period of time, and can be utilized as a cosmetic composition containing various functional raw materials.

[0008] In order to more fully understand the drawings cited in the detailed description of the present invention, a brief description of each drawing is provided.

[0009] Figure 1 is a diagram showing a TEM photograph of PLGA nanoparticles according to Example 1.

[0010] Figure 2 is a photograph of an aqueous solution in which a PLGA nano-carrier according to Example 1 is dispersed.

[0011] Figure 3 is a DLS graph of a PLGA nano-carrier according to Example 1.

[0012] Figure 4 is a DLS graph of a PLGA nano-carrier according to Example 2.

[0013] Figure 5 is a DLS graph of a PLGA nano-carrier according to Comparative Example 3.

[0014] Figure 6 is a particle photograph of a PLGA nano-carrier according to Example 1.

[0015] Figure 7 is a particle photograph of a PLGA nano-carrier according to Comparative Example 3.

[0016] Figure 8 is a DLS graph of a PLGA nano-carrier according to Comparative Example 4.

[0017] Figure 9 is a DLS graph of a PLGA nano-carrier according to Comparative Example 6.

[0018] Figure 10 is a DLS graph of a PLGA nano-carrier according to Comparative Example 7.

[0019] Figure 11 is a particle photograph of a PLGA nano-carrier according to Comparative Example 7.

[0020] According to an embodiment of the present invention, a method for producing a PLGA nano-carrier is provided, comprising the steps of (S1) dissolving PLGA (Poly(lactic-co-glycolic acid)) in a propylene carbonate (PC) solvent to produce an organic phase; (S2) dissolving an emulsifier in purified water to produce an aqua phase; and (S3) mixing the organic phase and the aqua phase produced above so that the weight ratio of propylene carbonate / purified water is 0.01 to 0.39.

[0021] According to another embodiment of the present invention, a PLGA nano-carrier manufactured by the above manufacturing method is provided.

[0022] According to another embodiment of the present invention, a cosmetic composition comprising the PLGA nano-carrier is provided.

[0023] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention pertains. In general, the nomenclature used herein is well known and commonly used in the art. In addition, when describing embodiments of the present invention, if a detailed description of a related known structure or function is judged to hinder the understanding of the embodiments of the present invention, a detailed description thereof will be omitted. In addition, although embodiments of the present invention will be described below, the technical idea of ​​the present invention is not limited or restricted thereto, and can be modified and implemented in various ways by those skilled in the art.

[0024] When a part in this specification is said to include a certain component, this does not exclude other components, unless otherwise specifically stated, but rather means that other components may be included. In this specification, the term "and / or" includes a combination of multiple related items or any one of multiple related items.

[0025]

[0026] According to an embodiment of the present invention, a method for producing a PLGA nano-carrier is provided, comprising the steps of (S1) dissolving PLGA (Poly(lactic-co-glycolic acid)) in a propylene carbonate (PC) solvent to produce an organic phase; (S2) dissolving an emulsifier in purified water to produce an aqua phase; and (S3) mixing the organic phase and the aqua phase produced above so that the weight ratio of propylene carbonate / purified water is 0.01 to 0.39.

[0027] The above step (S1) is a step for preparing an organic phase, which uses propylene carbonate as a solvent for dissolving PLGA, and may further include a functional raw material loaded on a nano-carrier.

[0028] In the present invention, PLGA is a material obtained by polymerizing poly(lactic acid) (PLA) and poly(glycolic acid) (PGA) monomers. In the copolymer, lactic acid is introduced into the tricarboxylic acid cycle and is metabolized and eliminated as CO2 and water, and glycolic acid is excreted in the urine in an unchanged state or introduced into the Krebs cycle and further eliminated as CO2 and water. It is characterized by biodegradability, biocompatibility, and high cell absorption rate.

[0029] In the present invention, propylene carbonate (PC) is known as a biodegradable material and a solvent that is safe for the body, and can be used in a cosmetic composition.

[0030] In the present invention, the functional raw material may be a substance for moisturizing, wrinkle improvement, anti-aging, UV protection, whitening, anti-pigmentation, skin soothing, sebum control or pore management, and may be, for example, at least one selected from the group consisting of niacinamide, betaine, adenosine, retinyl palmitate, idebenone, bisabolol, mulberry extract, arbutin, licorice extract, ascorbyl tetraisopalmitate, tocopheryl acetate, adenosine and polyethoxylated retinamide. In one embodiment of the present invention, tocopheryl acetate was used, but it may be selected without limitation depending on the purpose.

[0031] The above step (S2) is a step for manufacturing an emulsifier, which is made by dissolving an emulsifier in purified water, and may further include a preservative.

[0032] In the present invention, the emulsifier may be at least one selected from the group consisting of PVA (Polyvinyl alcohol), Poloxamer, and Polysorbate 60. In one embodiment of the present invention, PVA was used, but the present invention is not limited thereto.

[0033] The above emulsifier may be included in a ratio of 0.05 to 5 parts by weight per 100 parts by weight of purified water. If the ratio of the emulsifier is less than 0.05 parts by weight, the stabilization effect of the nano-carrier is not achieved, resulting in a high PDI and excessively large particle size. If the ratio of the emulsifier exceeds 5 parts by weight, the emulsifiers may gel together, hindering the formation of nano-particles. In addition, the viscosity may be high, reducing ease of use.

[0034] In the present invention, the preservative may be at least one selected from the group consisting of 1,2-hexanediol, phenoxyethanol, ethylhexylglycerin, benzyl alcohol, p-hydroxybenzoic acid, and sodium lauroyl sarcosinate, but is not limited thereto.

[0035] The above step (S3) is a step of mixing an organic phase and an aqueous phase, and is characterized in that the mixing is performed so that the content ratio (weight ratio) of propylene carbonate / purified water is 0.01 to 0.39. When the two solvents (solvents) of the organic phase and the aqueous phase are mixed, the actual volume affects the formation of nanoparticles. The propylene carbonate according to the present invention has good solubility in PLGA, but its miscibility with water is lower than that of other organic solvents. Therefore, in order to stably form a nano-carrier, it is essential to set an optimal ratio (content ratio) between solvents. When the above propylene carbonate / purified water content ratio (Weight ratio) is less than 0.01, there is a problem that the yield and concentration of nanoparticles are too low. When the above propylene carbonate / purified water content ratio (Weight ratio) exceeds 0.4, the high ratio of propylene carbonate causes the solubility in water to decrease, so that undissolved propylene carbonate droplets exist in a dispersed form to form multipicks, and there is a problem that the particle size is large and not uniform and the particle formation yield is low. Specifically, a mixing device using a stirring homogenizer including a microchannel or an Agi mixer can be used to mix the oil phase and the water phase, and any system that can mix the water phase and the oil phase can be utilized without limitation thereto. For example, it can be performed by a method of stirring the water phase using an Agi mixer and adding the oil phase, or a method of adding the oil phase to the water phase while mixing by placing a stirring magnet (stirring bar) on a stirrer.

[0036] According to another embodiment of the present invention, a PLGA nano-carrier manufactured by the above manufacturing method is provided.

[0037] In the present invention, the nano-carrier means a particle having a nano-size, and may be a nano-particle commonly used in the art to easily deliver an effective ingredient (functional raw material) to a target.

[0038] In the present invention, the PLGA nano-carrier may have a size of 50 to 350 nm, specifically 100 to 200 mm, but is not limited thereto. In addition, the PLGA nano-carrier is stably maintained for a long period of time at room temperature and body temperature, specifically 25 to 50°C, and thus can be stored for a long period of time.

[0039]

[0040] According to another embodiment of the present invention, a cosmetic composition comprising the PLGA nano-carrier is provided.

[0041] The cosmetic composition of the present invention may be applied directly to the skin, and the area of ​​application thereof is not limited.

[0042] The cosmetic composition of the present invention can be used for moisturizing, wrinkle improvement, anti-aging, UV protection, whitening, anti-pigmentation, skin soothing, sebum control, or pore management, depending on the characteristics of the functional raw material contained therein.

[0043] In addition to the above components, the cosmetic composition according to the present invention may further include components included in general cosmetic compositions, such as preservatives, functional ingredients, ion sequestering agents, bactericidal agents, pH regulators, antioxidants, alcohols, plant extracts, fragrances, cooling agents, and additives. The blending amounts of the above components are not particularly limited, and can be easily selected by those skilled in the art within a range that does not impair the purpose and effects of the present invention.

[0044] The cosmetic composition according to the present invention can be manufactured into any formulation commonly manufactured in the art, and for example, can be formulated into a solution, suspension, emulsion, paste, gel, cream, lotion, serum, essence, powder, soap, surfactant-containing cleansing, oil, spray, bead capsule and pack, and specifically, can be formulated into a cream, lotion, serum, essence, pack or bead capsule, but is not limited thereto.

[0045]

[0046] Hereinafter, examples and experimental examples are presented to explain the present invention more specifically, but the present invention is not limited thereto.

[0047]

[0048] Manufacturing Example. Preparation of PLGA nanocarriers as cosmetic compositions.

[0049] The inventors of the present invention used propylene carbonate as a solvent to replace the organic solvents previously used in order to apply PLGA nano-carriers to cosmetic compositions.

[0050] More specifically, PLGA (Poly(lactic-co-glycolic acid)) was dissolved in a propylene carbonate (PC) solvent to prepare an organic phase. Functional raw materials can be included at this time. Next, PVA was dissolved in purified water at 70-80℃ to prepare an aqueous phase. Next, the organic phase and the aqueous phase prepared above were each injected into a microchannel where the two fluids can be mixed using a syringe pump so that the weight ratio of propylene carbonate / purified water was 0.01 to 0.39, thereby preparing a PLGA nanocarrier. At this time, there is no limitation on the shape and size of the microchannel, and any system that can mix the two fluids, the oil phase and the aqueous phase, can be used. In the above method, it is possible to prepare a uniform nanocarrier without using an organic solvent for a certain weight ratio.

[0051]

[0052] Experimental Example 1. Comparative Experiment According to the Content Ratio of Propylene Carbonate / Purified Water

[0053] Propylene carbonate, used as a solvent, exhibits good solubility for PLGA but has lower miscibility with water than other organic solvents. Therefore, the ratio between solvents (weight ratio) is crucial for stable formation of nanocarriers. Accordingly, the weight ratio of propylene carbonate to purified water was adjusted to find optimal conditions.

[0054]

[0055] 1-1. Preparation of Examples 1 to 4 and Comparative Examples 1 to 3

[0056] Using the same method as the above manufacturing example, PLGA nano-carriers according to Examples 1 to 4 were manufactured by adjusting the content ratio (weight ratio) of propylene carbonate / purified water to 0.01 to 0.33 as shown in Table 1 below. The unit of the component content in Table 1 below is weight%.

[0057]

[0058]

[0059] 1-2. Preparation of Comparative Examples 1 to 3

[0060] Using the same method as the manufacturing example above, PLGA nano-carriers according to Comparative Examples 1 to 3 were manufactured by adjusting the content ratio (weight ratio) of propylene carbonate / purified water to 0.4 to 1, as shown in Table 2 below. The unit of the component content in Table 2 below is weight%.

[0061]

[0062]

[0063] 1-3. TEM and aqueous solution observation

[0064] TEM analysis images and aqueous solution images of the PLGA nanocarrier according to Example 1 are shown in FIGS. 1 and 2.

[0065] As shown in Fig. 1, it was confirmed that the PLGA nano-carrier according to Example 1 was composed of uniform spherical nanoparticles. In addition, as shown in Fig. 2, it was confirmed that PLGA was well dissolved in the solvent propylene carbonate and evenly dispersed in the aqueous solution.

[0066]

[0067] 1-4. Particle size and PDI measurement

[0068] The particle size of the PLGA nanocarriers of Examples 1 to 4 was measured using Zeta Sizer. More specifically, the nanocarrier suspension was placed in a cell of the Zetasizer, a diffusion light scattering device, and the particle distribution was confirmed. As a result, it was confirmed that uniform spherical nanoparticles were formed with an average volume-based particle diameter of 50 to 200 nm and a PDI of 0.3 or less. In particular, when the content ratio of propylene carbonate / purified water was 0.33 (Example 2), it was confirmed that the best type of nanoparticles were formed as a single peak. In addition, when the content ratio of propylene carbonate / purified water was 0.01 as in Example 4, uniform spherical nanoparticles were formed, but the yield and concentration were minimized. Therefore, it was confirmed that it was difficult to form the desired nanoparticles when the content ratio was less than 0.01, and thus the minimum value of the content ratio of propylene carbonate / purified water was determined.

[0069] Meanwhile, the particle size of the PLGA nano-carriers of Comparative Examples 1 to 3, in which the content ratio of propylene carbonate / purified water was 0.40 or higher, was measured, and it was confirmed that the particle size was large and non-uniform, and the PDI was relatively high. This is believed to be the result of low solubility in water due to the high ratio of propylene carbonate, and undissolved propylene carbonate droplets existed in a dispersed form, so that when checking the DLS particle distribution, multi-peaks were observed in the particle distribution graph, and it was confirmed that the particle formation yield was low.

[0070] More specifically, the particle size and PDI of the PLGA nano-carriers according to Examples 1 to 2 and Comparative Example 3 are measured and shown in Table 3. In addition, the DLS graphs of each nano-carrier are shown in FIGS. 3 to 5, the particle photograph of Example 1 is shown in FIG. 6, and the particle photograph of Comparative Example 3 is shown in FIG. 7.

[0071]

[0072]

[0073] As shown in Table 3 and Figures 3 to 7, the particle size of the PLGA nano-carriers according to Examples 1 to 2 of the present invention was uniform at approximately 100 to 200 nm, whereas the PLGA nano-carriers according to Comparative Example 3 had large and non-uniform particle sizes, making them unsuitable for use in future cosmetic compositions. Therefore, when manufacturing PLGA nano-carriers using propylene carbonate, it was confirmed that the optimal content ratio of propylene carbonate / purified water was 0.01 to 0.39.

[0074]

[0075] Experimental Example 2. Comparative Experiment According to PLGA Solvent

[0076] In order to compare the effect of PLGA solvent on the stable formation of nanoparticles, PLGA nanocarriers according to Comparative Examples 4 to 6 were prepared using triethyl carbonate, acetonitrile, or acetone instead of propylene carbonate used in Example 1, as shown in Table 4, and the particle size was measured. The unit of the component contents in Table 4 below is weight%.

[0077]

[0078]

[0079] In addition, the particle size and PDI measurement results of the PLGA nano-carrier according to Comparative Example 4 are shown in Table 5, and the DLS graph is shown in Fig. 8.

[0080]

[0081]

[0082] As shown in Table 5 and Fig. 8, the PLGA nano-carrier of Comparative Example 4 had a problem in that the polarity of the solvent was low, resulting in low PLGA solubility, and thus the particle distribution was wide and nanoparticles were not formed evenly. The PLGA nano-carrier of Comparative Example 5 also showed similar results.

[0083] In addition, the DLS graph of the PLGA nano-carrier according to Comparative Example 6 is shown in Fig. 9. As shown in Fig. 9, in the case of the PLGA nano-carrier of Comparative Example 6 using acetone as a solvent, nanoparticles of a similar level as those of the PLGA nano-carrier according to Example 1 were formed, but as disclosed in Table 6 below, residual solvent (acetone) was detected, confirming that it is unsuitable for use as a cosmetic composition.

[0084]

[0085]

[0086] Experimental Example 3. Comparative Experiment According to the Limited Ratio of PVA to Purified Water

[0087] In order to compare the effect of the ratio of PVA on the stable formation of nanoparticles, PLGA nanocarriers according to Comparative Examples 7 and 8 were manufactured by adjusting the ratio of PVA to purified water, as shown in Table 7, and the particle size was measured.

[0088]

[0089]

[0090] In addition, the particle size and PDI measurement results of the PLGA nano-carrier according to Comparative Example 7 are shown in Table 8, the DLS graph is shown in Fig. 10, and the particle photograph is shown in Fig. 11.

[0091]

[0092]

[0093] As shown in Table 8 and Figures 10 to 11, when the ratio of PVA is very low, such as 0.01, the stabilization effect of the nano-carrier is not achieved, resulting in high PDI and large particle size, making it unsuitable for use as a cosmetic composition. In addition, when the ratio of PVA is high, such as 6 (Comparative Example 8), it was confirmed that the viscosity is high, reducing the ease of experimentation. Therefore, it was confirmed that the ratio of PVA to purified water is an important factor in the stable formation of nanoparticles.

[0094]

[0095] Experimental Example 4. Confirmation of long-term and high-temperature stability

[0096] To confirm the long-term stability and high-temperature stability of the PLGA nanocarrier according to the present invention, the particles were observed after storage at 40°C for 2 weeks, 50°C for 1 week, and 25°C for 3 months. The results are shown in Table 9.

[0097]

[0098]

[0099] As shown in Table 9, the PLGA nanocarrier according to Comparative Example 7 showed an aggregation reaction under all conditions, while the PLGA nanocarriers according to Examples 1 to 4 were confirmed to remain stable over a wide temperature range for a long period of time.

[0100]

[0101] Experimental Example 5. Analysis of functional raw material loading efficiency

[0102] In order to utilize the PLGA nano-carrier according to the present invention in a cosmetic composition, the loading efficiency for tocopheryl acetate, a functional raw material suitable for cosmetic compositions, was analyzed. More specifically, the obtained nano-carrier suspension was centrifuged at approximately 5000 rpm using a 10000 da Amicon centrifuge filter, and the filtered lower layer was analyzed by HPLC to determine the amount of free active ingredient that was not loaded.

[0103]

[0104] The results are shown in Table 10.

[0105]

[0106]

[0107] As shown in Table 10, the loading efficiency of the PLGA nano-carrier according to Example 1 for tocopheryl acetate was confirmed to be excellent, reaching approximately 90%, thereby confirming its high potential for use as a cosmetic composition.

[0108]

[0109] In summary, it was confirmed that when PLGA nano-carriers are manufactured by reacting propylene carbonate as an organic solvent with distilled water as an aqueous solvent at an optimal content ratio, functional raw materials can be stably loaded, and nanoparticles of uniform size can be manufactured. In addition, there is no residual organic solvent with biotoxicity, so it can be used as a safe raw material in cosmetic compositions.

[0110]

[0111] While specific aspects of the present invention have been described in detail above, it will be apparent to those skilled in the art that these specific descriptions merely represent preferred embodiments and are not intended to limit the scope of the present invention. Therefore, the substantial scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. (S1) A step of preparing an organic phase by dissolving PLGA (Poly(lactic-co-glycolic acid)) in a propylene carbonate (PC) solvent; (S2) A step of preparing an aqua phase by dissolving an emulsifier in purified water; and (S3) A step of mixing the organic phase and the aqua phase manufactured above so that the weight ratio of propylene carbonate / purified water is 0.01 to 0.

39. Method for manufacturing PLGA nano-carriers.

2. In paragraph 1, A method for manufacturing a PLGA nano-carrier, wherein the organic phase in the above (S1) further includes a functional raw material.

3. In paragraph 2, A method for producing a PLGA nano-carrier, wherein the functional raw material is at least one selected from the group consisting of niacinamide, betaine, adenosine, retinyl palmitate, idebenone, bisabolol, mulberry extract, arbutin, licorice extract, ascorbyl tetraisopalmitate, tocopheryl acetate, adenosine, and polyethoxylated retinamide.

4. In paragraph 1, A method for producing a PLGA nano-carrier, wherein the emulsifier in the above (S2) is at least one selected from the group consisting of PVA (polyvinyl alcohol), poloxamer, and polysorbate 60.

5. In paragraph 1, A method for producing a PLGA nano-carrier, wherein the emulsifier in the above (S2) is included in a ratio of 0.05 to 5 parts by weight per 100 parts by weight of purified water.

6. In paragraph 1, A method for producing a PLGA nano-carrier, wherein the award in the above (S2) further includes a preservative.

7. In paragraph 6, A method for producing a PLGA nano-carrier, wherein the above preservative is at least one selected from the group consisting of 1,2-hexanediol, phenoxyethanol, ethylhexylglycerin, benzyl alcohol, p-hydroxybenzoic acid, and sodium lauroyl sarcosinate.

8. A PLGA nano-carrier manufactured by a manufacturing method according to any one of claims 1 to 7.

9. In the 8th paragraph, the PLGA nano-carrier has a size of 50 to 200 nm.

10. A cosmetic composition comprising a PLGA nano-carrier according to claim 9.

11. A cosmetic composition according to claim 10, wherein the cosmetic composition does not contain at least one of acetonitrile, acetone, THF (Tetrahydrofuran), and DMSO (Dimethyl sulfoxide).

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