Composition containing polymeric hyaluronic acid microparticles

Abstract

The present specification discloses a composition containing polymeric hyaluronic acid microparticles. According to the present invention, the polymeric hyaluronic acid is micronized, so that the polymeric hyaluronic acid can easily permeate into the skin and can be stably contained in the dosage form without being subjected to low molecular weight. In addition, the micronized polymeric hyaluronic acid included in the composition of the present disclosure expands again in size after penetrating into the skin and being neutralized to adapt to the pH of the skin, and thus can provide excellent moisturizing and elasticity improving efficacy to the skin.

Description

Technical Field

[0001] This specification discloses a composition containing high-molecular-weight hyaluronic acid microparticles.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to Korean Patent Application No. 10-2022-0116111 filed on September 15, 2022 and Korean Patent No. 2022-0116133 filed on September 15, 2022, the entire contents of which are incorporated herein by reference. Background Art

[0004] Hyaluronic acid (HA) is a linear high molecular weight polysaccharide composed of alternating bonds of β-acetylglucosamine and β-glucuronic acid, which is distributed in connective tissues such as subcutaneous tissue and cartilage tissue in the human body. Hyaluronic acid has excellent biocompatibility and is known to have beneficial effects on the skin, such as enhancing skin moisturizing ability, maintaining skin elasticity, and improving skin barrier function. However, the structural stability of natural hyaluronic acid is poor and it is easily decomposed and cleared in the body, so research on stabilizing hyaluronic acid is already underway.

[0005] The molecular weight of hyaluronic acid varies depending on the length of the sugar chain. Low molecular weight hyaluronic acid easily penetrates the skin, but has a short retention time in the skin and poor water holding capacity, so it has low efficacy on the skin and has problems such as taste change and discoloration. High molecular weight hyaluronic acid has excellent moisturizing and regenerative abilities for the skin, but it is difficult to penetrate the skin. Therefore, when it is actually used in dosage forms, the effect of hyaluronic acid on the skin is limited unless it is directly administered into the skin through injections.

[0006] In addition, in the cosmetics industry or the pharmaceutical industry, when a skin external dosage form contains a functional substance that is difficult to penetrate or has low stability, a method of using synthetic surfactants to promote the skin absorption of the functional substance, or using synthetic polymer compounds or liposome nanoparticles such as polyethylene glycol as carriers to improve the skin permeability of the functional substance is widely used. However, as mentioned above, the amphiphilic enhancers used in the synthetic compounds or liposome nanoparticles are toxic to the human body, have allergen problems, are harmful to the environment, etc., and therefore, their use is recently curbed in the cosmetics industry and the pharmaceutical industry. Therefore, it is necessary to develop a carrier that is compatible with the human body and the environment and can effectively promote the percutaneous absorption of the functional substance. Summary of the invention

[0007] Technical issues

[0008] The problem to be solved by the present disclosure is to provide a composition containing high-molecular-weight hyaluronic acid that can easily penetrate the skin without being reduced in molecular weight or cross-linked, and a method for preparing the same.

[0009] The problem to be solved by the present disclosure is to provide a composition containing high molecular weight hyaluronic acid which is stable in a dosage form and a preparation method thereof.

[0010] The problem to be solved by the present disclosure is to provide a carrier composition for transdermal delivery of effective substances that is biocompatible and can easily penetrate the skin.

[0011] The problem to be solved by the present disclosure is to provide a composition for external use on the skin containing an effective substance and a carrier composition for transdermal delivery of the effective substance.

[0012] Technical Solution

[0013] In order to solve the above-mentioned problem, one embodiment of the present disclosure provides a composition, which includes: polymer hyaluronic acid or its salt particles; and an acidic pH regulator, wherein the acidic pH regulator is an organic acid or an inorganic acid, and the average particle size of the polymer hyaluronic acid or its salt particles is less than 100 nm, and the pH is greater than 3.0 and less than 5.0.

[0014] In addition, one embodiment of the present disclosure provides a preparation method, which is a preparation method of the composition, and the preparation method includes: adding an acidic pH regulator to a solution containing polymer hyaluronic acid or a salt thereof, thereby micronizing the polymer hyaluronic acid or a salt thereof, wherein the average particle size of the micronized polymer hyaluronic acid or a salt thereof particles is less than 100 nm, and the pH of the composition is greater than 3.0 and less than 5.0.

[0015] In addition, one embodiment of the present disclosure provides a carrier composition for transdermal delivery of functional substances, which includes: polymer hyaluronic acid or its salt particles; and an acidic pH regulator, wherein the acidic pH regulator is an organic acid or an inorganic acid, the average particle size of the polymer hyaluronic acid or its salt particles is less than 100 nm, the pH is greater than 3.0 and less than 5.0, and the functional substances are released at a pH of 5 to 7.

[0016] In addition, one embodiment of the present disclosure provides a composition for external skin application, comprising: an effective substance; and a carrier for transdermal delivery of the effective substance comprising the composition.

[0017] Effects of the Invention

[0018] One embodiment of the present disclosure can provide a composition containing hyaluronic acid microparticles that can easily penetrate the skin and stably be contained in a dosage form by micronizing a high molecular hyaluronic acid without being reduced in molecular weight. After the micronized high molecular hyaluronic acid according to one embodiment of the present disclosure penetrates into the skin and is neutralized to be suitable for the pH of the skin, the size expands again, thereby providing excellent moisturizing and elasticity improvement effects to the skin. In addition, according to one embodiment, a skin topical agent composition including an effective substance and a carrier for transdermal delivery of the effective substance including the composition, after penetrating into the skin to release the effective substance, the carrier itself can also provide useful effects to the skin, through which a dual functional can be displayed. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 is a graph comparing the particle sizes of a composition according to an embodiment of the present disclosure (Example 1) and Comparative Example 1.

[0020] Figure 2 is a graph comparing the particle sizes of the compositions according to one embodiment of the present disclosure (Examples 1 to 4) and Comparative Example 2.

[0021] Figure 3 This is a graph showing the molecular weight of high-molecular-weight hyaluronic acid microparticles contained in the composition of Comparative Example 1.

[0022] Figure 4 This is a graph showing the molecular weight of high-molecular-weight hyaluronic acid microparticles contained in a composition (Example 1) according to one example of the present disclosure.

[0023] Figure 5 This is a graph confirming the absorption depth into skin tissue of the composition (Example 1) according to one example of the present disclosure and Comparative Example 1.

[0024] Figure 6 is a diagram showing a schematic diagram of an efficacy substance transmission and release system of a carrier composition according to an embodiment of the present disclosure.

[0025] Figure 7 This is a graph confirming the absorption depth of the effective substance in the skin tissue of Example 5 and Comparative Example 3 according to one embodiment of the present disclosure. DETAILED DESCRIPTION

[0026] Hereinafter, preferred embodiments of the present disclosure are described in detail with reference to the accompanying drawings.

[0027] The embodiments of the present disclosure disclosed herein are only exemplified for the purpose of illustration, and the embodiments of the present disclosure can be implemented in various forms, and shall not be interpreted as limiting the present disclosure to the described embodiments. It is understandable that the present disclosure can make various deformations and can have various forms, so the embodiments are not intended to limit the present disclosure to any specific form, and all deformations, equivalents and even substitutes that do not depart from the thought and technical scope of the present disclosure belong to the protection scope of the present disclosure. Unless otherwise clearly defined in the context, the singular expression includes the plural expression. In this application, the terms such as "including" or "having" are intended to specify the existence of the features, numbers, steps, operations, constituent elements, parts or combinations thereof recorded in the specification, and do not exclude the existence or additional possibility of one or more other features, numbers, steps, operations, constituent elements, parts or combinations thereof.

[0028] One embodiment of the present disclosure can provide a composition, which includes: polymer hyaluronic acid or its salt particles; and an acidic pH regulator, wherein the acidic pH regulator is an organic acid or an inorganic acid, and the average particle size of the polymer hyaluronic acid or its salt particles is less than 100 nm, and the pH is greater than 3.0 and less than 5.0.

[0029] In this specification, "hyaluronic acid" refers to a raw material that is an anionic natural polysaccharide and exists in the form of a salt and belongs to EWG grade 1. It is mainly produced and purified by microorganisms, exists in the connective tissue and extracellular matrix of the human body, and has a high water content due to anionic functional groups, so most of them are used as moisturizers. The molecular structure of hyaluronic acid can be represented by the following chemical formula 1, and the salt form of hyaluronic acid can be included in this specification.

[0030]

Chemical formula 1

[0031]

[0032] The x is 200 to 20000 mol.

[0033] In one embodiment of the present disclosure, the salt is not particularly limited and may be an acid addition salt, a base addition salt or an amino acid salt. For example, the salt may be an inorganic acid salt of hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, phosphate, etc.; an organic acid salt of citrate, oxalate, acetate, formates, propionates, benzoates, trifluoroacetates, maleates, tartrates, methanesulfonates, benzenesulfonates, p-toluenesulfonates, etc.; an inorganic base salt of sodium salt, potassium salt, calcium salt, magnesium salt, copper salt, zinc salt, aluminum salt, ammonium salt, etc.; an organic base salt of triethylammonium salt, triethanolammonium salt, pyridinium salt, diisopropylammonium salt, etc.; an amino acid salt of lysine salt, arginine salt, histidine salt, aspartate, glutamate, etc. As an embodiment, the salt may be sodium hyaluronate, potassium hyaluronate, hyaluronate acetate, ammonium hyaluronate or C12-13 Alkyl Glyceryl Hydrolyzed Hyaluronate. In the present disclosure, the weight average molecular weight of the polymer hyaluronic acid or its salt varies according to the length of the sugar chain. As an embodiment, the weight average molecular weight of the polymer hyaluronic acid or its salt may be 5 to 10000 kDa. Specifically, the weight average molecular weight of the polymer hyaluronic acid or its salt can be 5 kDa or more, 10 kDa or more, 100 kDa or more, 500 kDa or more, 1000 kDa or more, 1100 kDa or more, 1200 kDa or more, 1300 kDa or more, 1400 kDa or more, 1500 kDa or more, 1600 kDa or more, 1700 kDa or more, 1800 kDa or more, 1900 kDa or more, 2000 kDa or more, 2200 kDa or more, 2400 kDa or more, 2600 kDa or more, 2800 kDa or more, 2900 kDa or more, 3000 kDa or more, 4000 kDa or more or 5000 kDa or more, and can be 10000 kDa or less, 9000 kDa or less. kDa or less, 8000 kDa or less, 7000 kDa or less, 6000 kDa or less, 5000 kDa or less, 4500 kDa or less, 4000 kDa or less, 3900 kDa or less, 3800 kDa or less, 3700 kDa or less, 3600 kDa or less, 3500 kDa or less, 3400 kDa or less, 3300 kDa or less, 3200 kDa or less, 3100 kDa or less, 3000 kDa or less, 2500 kDa or less, 2000 kDa or less, 1900 kDa or less, 1800 kDa or less, 1700 kDa or less, 1600 kDa or less, 1500 kDa or less, 1000 kDa or less, 500 kDa or less, 100 kDa or less, or 10 kDa or less. More specifically, the weight average molecular weight of the high molecular weight hyaluronic acid or its salt may be 1000 to 5000 kDa.When the weight average molecular weight of the high molecular weight hyaluronic acid or its salt is less than 5 kDa, the moisturizing effect may be reduced, and when it exceeds 10000 kDa, the viscosity may be too high or the micronization may be limited, which may make it difficult to penetrate the skin.

[0034] In one embodiment of the present disclosure, by containing polymer hyaluronic acid particles and acidic pH regulator at the same time, while maintaining the molecular weight of polymer hyaluronic acid, the net charge (net charge) of the molecule of negatively charged hyaluronic acid can be adjusted by using the hydrogen cation of the acid in the acidic pH regulator, so that the polymer hyaluronic acid particles are micronized into nanometer size. In more specific terms, the hydrogen cation of the acidic pH regulator in the solution increases, and the negative charge of the polymer hyaluronic acid is neutralized, thereby reducing the charge density of the polymer hyaluronic acid. This makes the polymer chain of the polymer hyaluronic acid in the solution change from linear to spherical. That is, the radius of gyration (globular size) of the polymer chain is reduced, so that the average diameter of the particles can be reduced, so the probability of the hyaluronic acid in the polymer chain forming hydrogen bonds increases, and micronized hyaluronic acid of a smaller size can be prepared. Therefore, the composition according to one embodiment of the present disclosure makes it easy for the polymer hyaluronic acid particles to penetrate into the skin, showing an improved skin permeability and penetration depth, so that the polymer hyaluronic acid can be transported to the lower part of the stratum corneum when the skin is administered. In addition, according to one embodiment of the present disclosure, the micronized polymer hyaluronic acid particles show pH sensitivity, so after penetrating into the skin, without the need for an additional double-liquid formulation, they can also be neutralized in the pH of the skin, such as pH 5 to 7, more specifically in an environment of about pH 5 to 6, so that the size of the polymer hyaluronic acid particles expands again by more than 200%, more specifically by more than 200%, more than 210%, more than 250%, more than 300%, more than 350%, more than 400% or more than 450%. The micronized polymer hyaluronic acid particles can provide beneficial effects to the skin through the effect of self-swelling, such as the moisturizing effect in the skin and the effect of improving or preventing skin wrinkles, preventing skin elasticity reduction or improving elasticity, etc. Furthermore, the composition containing micronized polymer hyaluronic acid particles according to one embodiment of the present disclosure can maintain a stable dosage form even at high temperatures, thereby solving the problem of dosage form destruction and reduced viscosity caused by high temperature treatment during the aging process of the existing composition containing polymer hyaluronic acid in the productization process. In one embodiment, the composition can also provide a composition with excellent permeability in the skin and dosage form stability by micronizing the polymer hyaluronic acid without using polyols or solubilizers.

[0035] As an embodiment, the average particle size of the micronized polymer hyaluronic acid particles can be less than 100nm. In this specification, the particle size refers to the maximum diameter in the particle, and the average particle size refers to the average particle size of at least 90% of the particles distributed in the composition. Specifically, the average particle size of the particles, that is, the average particle size, can refer to the average value of the maximum diameter in the particles of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% of the particles distributed in the composition. More specifically, the average particle size can be greater than 0 nm, and less than 100 nm, less than 95 nm, less than 90 nm, less than 85 nm, less than 80 nm, less than 75 nm, less than 70 nm, less than 65 nm, less than 60 nm, less than 55 nm, less than 50 nm, less than 45 nm, less than 40 nm, less than 35 nm, less than 30 nm, less than 25 nm, less than 20 nm, less than 15 nm or less than 10 nm.

[0036] From the perspective of micronizing the polymer hyaluronic acid particles, the pH of the composition according to one embodiment may be 3.0 or more and less than 5.0. Specifically, the pH of the composition may be 3 or more, 3.1 or more, 3.2 or more, 3.3 or more, 3.4 or more, 3.5 or more, 3.6 or more, 3.7 or more, 3.8 or more, 3.9 or more, 4.0 or more, 4.1 or more, 4.2 or more, 4.3 or more, 4.4 or more, 4.5 or more, 4.6 or more, 4.7 or more, 4.8 or more, or 4.9 or more, and may be less than 5.0, 4.9 or less, 4.8 or less, 4.7 or less, 4.6 or less, 4.5 or less, 4.4 or less, 4.3 or less, 4.2 or less, 4.1 or less, 4.0 or less, 3.9 or less, 3.8 or less, 3.7 or less, 3.6 or less, 3.5 or less, 3.4 or less, 3.3 or less, 3.2 or less, or 3.1 or less. When the pH of the composition according to one embodiment is less than 3.0, it may irritate the skin and is not suitable for formulation as a cosmetic composition under the safety management standards for circulating cosmetics. When the pH is above 5.0, the high molecular weight hyaluronic acid particles may not be micronized to an average size of less than 100 nm.

[0037] In one embodiment, the acidic pH regulator can be an organic acid or an inorganic acid, and its type is not limited as long as the pH of the composition can be adjusted to 3.0 or more and less than 5.0. For example, the organic acid can include one or more selected from the group consisting of citric acid, phosphoric acid, fumaric acid, ascorbic acid, ferulic acid, succinic acid, lactic acid, hyaluronic acid, malic acid, butyric acid, formic acid, acetic acid, salicylic acid, glycolic acid, tartaric acid, and gluconolactone. For example, the inorganic acid can include one or more selected from the group consisting of carbonic acid, hydrochloric acid, nitric acid, and sulfuric acid.

[0038] As an embodiment, the acidic pH regulator may include a fruit extract, and the fruit extract includes the organic acid or the inorganic acid, whether or not within this range, as long as the purpose is to reduce the pH, it can be used in skin care products without restriction. For example, the fruit extract may include one or more selected from the group consisting of vaccinium myrtillus fruit extract (VACCINIUMMYRTILLUS FRUIT EXTRACT), sugarcane extract (SACCHARUM OFFICINARUM (SUGARCANE) EXTRACT), orange fruit extract (CITRUS AURANTIUM DULCIS (ORANGE) FRUIT EXTRACT) and lemon fruit extract (CITRUS LIMON (LEMON) FRUIT EXTRACT).

[0039] As one embodiment, the present disclosure includes an organic acid or an inorganic acid in the form of an acid itself rather than a salt. Therefore, unlike when a metal salt of an organic acid is included, in which the metal salt acts as a metal cation, the hydrogen cation of the acid interacts with the negative charge of the polymer hyaluronic acid, thereby adjusting the pH in the composition to less than 5.0, thereby micronizing the average diameter of the polymer hyaluronic acid particles to less than 100 nm.

[0040] In one embodiment, the weight ratio of the polymer hyaluronic acid or its salt to the acidic pH regulator can be 1: 0.01 to 10. Specifically, the acidic pH regulator can contain 0.01 parts by weight or more, 0.1 parts by weight or more, 0.2 parts by weight or more, 0.3 parts by weight or more, 0.4 parts by weight or more, 0.5 parts by weight or more, 0.6 parts by weight or more, 0.7 parts by weight or more, 0.8 parts by weight or more, 0.9 parts by weight or more, 1 part by weight or more, 1.1 parts by weight or more, 1.2 parts by weight or more, 1.3 parts by weight or more, 1.4 parts by weight or more, 1.5 parts by weight or more, 1.6 parts by weight or more, 1.7 parts by weight or more, 1.8 parts by weight or more, 1.9 parts by weight or more, 2 parts by weight or more, or 5 parts by weight or more, relative to 1 part by weight of the polymer hyaluronic acid or its salt. Relative to 1 part by weight of the polymer hyaluronic acid or its salt, it may contain 10 parts by weight or less, 9 parts by weight or less, 8 parts by weight or less, 7 parts by weight or less, 6 parts by weight or less, 5 parts by weight or less, 4 parts by weight or less, 3 parts by weight or less, 2 parts by weight or less, 1.9 parts by weight or less, 1.8 parts by weight or less, 1.7 parts by weight or less, 1.6 parts by weight or less, 1.5 parts by weight or less, 1.4 parts by weight or less, 1.3 parts by weight or less, 1.2 parts by weight or less, 1.1 parts by weight or less, 1 part by weight or less, 0.9 parts by weight or less, 0.8 parts by weight or less, 0.7 parts by weight or less, 0.6 parts by weight or less, 0.5 parts by weight or less, or 0.1 parts by weight or less. When the weight ratio of the acidic pH adjusting agent relative to the polymer hyaluronic acid or its salt exceeds the above range, the particles of the polymer hyaluronic acid or its salt may not be micronized, or the pH is too low to be less than 3.0, resulting in possible skin irritation.

[0041] In one embodiment, the content of the polymer hyaluronic acid or its salt can be 0.1 to 10 weight % based on the total weight of the composition. For example, the content of the polymer hyaluronic acid or its salt can be 0.1 weight % or more, 0.3 weight % or more, 0.5 weight % or more, 0.6 weight % or more, 0.7 weight % or more, 0.8 weight % or more, 0.9 weight % or more, 1.0 weight % or more, 1.1 weight % or more, 1.2 weight % or more, 1.3 weight % or more, 1.5 weight % or more, 1.7 weight % or more, 2 weight % or more, 3 weight % or more, 4 weight % or more, The content of the present invention is 5% by weight or more, 6% by weight or more, 7% by weight or more, 8% by weight or more or 9% by weight or more, and may be 10% by weight or less, 9% by weight or less, 8% by weight or less, 7% by weight or less, 6% by weight or less, 5% by weight or less, 4% by weight or less, 3% by weight or less, 2.5% by weight or less, 2% by weight or less, 1.5% by weight or less, 1.3% by weight or less, 1.2% by weight or less, 1.1% by weight or less, 1% by weight or less, 0.9% by weight or less or 0.8% by weight or less. When the content is less than 0.1% by weight, the effect on the skin may be minimal, and when it exceeds 10% by weight, the content is too much compared to the acidic pH adjuster, and the particles of the high molecular weight hyaluronic acid or its salt may not be micronized, and it may be difficult to prepare a liquid dosage form due to excessively high viscosity.

[0042] In one embodiment, the content of the acidic pH regulator can be 0.01 to 50 weight % based on the total weight of the composition. For example, the content of the acidic pH regulator can be 0.01 weight % or more, 0.05 weight % or more, 0.1 weight % or more, 0.2 weight % or more, 0.3 weight % or more, 0.4 weight % or more, 0.5 weight % or more, 0.6 weight % or more, 0.7 weight % or more, 0.8 weight % or more, 0.9 weight % or more, 1.0 weight % or more, 1.1 weight % or more, 1.2 weight % or more, 1.3 weight % or more, 1.4 weight % or more, 1.5 weight % or more, 2 weight % or more, 3 weight % or more, 4 weight % or more, 5 weight % or more, 10 weight % or more, 15 weight % or more, 20 weight % or more, 25 weight % or more, 30 weight % or more, 35 weight % or more, 40 weight % or more, 45 weight % or more, 50 ... %, 40 wt % or more, or 45 wt % or more, or 50 wt %, 45 wt %, 35 wt %, 30 wt %, 25 wt %, 20 wt %, 15 wt %, 10 wt %, 9 wt %, 8 wt %, 7 wt %, 6 wt %, 5 wt %, 4 wt %, 3 wt %, 2 wt %, 1.5 wt %, 1.4 wt %, 1.3 wt %, 1.2 wt %, 1.1 wt %, 1 wt %, 0.9 wt %, 0.8 wt %, 0.7 wt %, 0.6 wt %, 0.5 wt %, 0.4 wt % or 0.1 wt %. When the content is less than 0.01 wt %, the particles of the high molecular weight hyaluronic acid or its salt may not be micronized, and when it exceeds 50 wt %, it may irritate the skin.

[0043] As an embodiment, the composition of the present disclosure may also include a metal ion chelator. The metal ion chelator (sequestering agent) is also called a complexing agent (chelating agent), and is used to be combined with metal ions such as calcium, magnesium or copper that are usually adversely affected in the stability or properties of cosmetics and other products and inertized. In the micronization of high molecular hyaluronic acid particles, when organic acid or inorganic acid is used as acidic pH regulator in the form of metal salts, if the composition includes the above-mentioned metal ion chelator, the high molecular hyaluronic acid particles swell in the composition and cannot be micronized, so it is difficult to penetrate the skin, on the contrary, as an embodiment, the organic acid or inorganic acid included in the present disclosure is acid itself, rather than in the form of metal salts, so, even if a metal ion chelator is also included to improve the stability and use of the product, micronization will not be hindered, and the average diameter of the high molecular hyaluronic acid particles can be micronized to less than 100nm. In addition, the composition according to the present disclosure penetrates the skin by lowering the pH to less than 5.0 and micronizing the high-molecular hyaluronic acid particles. Therefore, due to the difference in acidity from the original pH of the skin, the pH of the high-molecular hyaluronic acid particles naturally increases to 5.5 to 6.0 and swells, thereby increasing the size of the particles without administering other ingredients.

[0044] As an embodiment, the metal ion chelating agent may include one or more of alkali salts of ethylenediaminetetraacetic acid (EDTA) and alkali salts of phosphate compounds, but its types are not limited thereto. More specifically, it may include one or more of the group consisting of disodium ethylenediaminetetraacetic acid, tetrasodium ethylenediaminetetraacetic acid, trisodium ethylenediamine disuccinate, sodium phosphate, monosodium phosphate, disodium phosphate, trisodium phosphate, sodium tripolyphosphate, sodium hexametaphosphate, sodium metaphosphate, sodium phytate, tetrasodium pyrophosphate and sodium acid pyrophosphate. In addition, according to an embodiment, the content of the metal ion chelating agent may be 0.01 to 1% by weight relative to the total weight of the composition. Specifically, the content of the metal ion chelating agent, relative to the total weight of the composition, can be 0.001% by weight or more, 0.005% by weight or more, 0.01% by weight or more, 0.02% by weight or more, 0.03% by weight or more, 0.04% by weight or more, 0.05% by weight or more, 0.1% by weight or more, 0.5% by weight or more, or 0.9% by weight or less, and can be 1% by weight or less, 0.9% by weight or less, 0.8% by weight or less, 0.7% by weight or less, 0.6% by weight or less, 0.5% by weight or less, 0.4% by weight or less, 0.3% by weight or less, 0.2% by weight or less, 0.1% by weight or less, 0.05% by weight or less, 0.04% by weight or less, 0.03% by weight or less, or 0.01% by weight or less. When the content of the metal ion chelating agent is less than 0.01 wt %, the chelating effect may be small, and when it exceeds 1 wt %, it may also chelate beneficial metal ions in skin cells, thereby causing negative effects on the skin.

[0045] In one embodiment, the composition can provide a composition with excellent in vivo permeability and dosage form stability by micronizing high molecular weight hyaluronic acid without using polyols or solubilizers.

[0046] In one embodiment, the viscosity or hardness of the composition may vary according to the dosage form of the composition. For example, the viscosity may be 0.001 to 50 Pa.s, but is not limited thereto. For example, the hardness may be 10 to 200 N, but is not limited thereto.

[0047] The present disclosure may provide a preparation method, which is a preparation method of the composition according to one embodiment above, the method comprising: adding an acidic pH regulator to a solution containing polymer hyaluronic acid or a salt thereof, thereby micronizing the polymer hyaluronic acid or a salt thereof, wherein the average particle size of the micronized polymer hyaluronic acid or a salt thereof particles is less than 100 nm, and the pH of the composition is greater than 3.0 and less than 5.0.

[0048] As an embodiment, in the step of micronizing the polymer hyaluronic acid or its salt, the method may further include: a step of adding a metal ion chelating agent to the solution.

[0049] As an embodiment, before the step of micronizing the polymer hyaluronic acid or its salt, the method may further include: a step of dissolving the polymer hyaluronic acid or its salt in a solution containing at least one of water and an organic solvent.

[0050] As an embodiment, the step of micronizing the high molecular weight hyaluronic acid or its salt may further include: using a magnetic stirrer to stir and dissolve the solution.

[0051] As an embodiment, after the step of micronizing the polymer hyaluronic acid or its salt, the method may further include: a step of aging the composition at a temperature of 30 to 60° C. At this time, the aging time according to an embodiment may be, for example, 5 to 20 hours, but is not limited thereto.

[0052] In one embodiment, the composition can be used for skin moisturizing. In one embodiment, the composition can be used to prevent skin elasticity from decreasing or improving elasticity. In one embodiment, the composition can be used to prevent skin wrinkle generation or improve skin wrinkles. Another embodiment of the present disclosure can provide a method for skin moisturizing, preventing skin elasticity from decreasing or improving elasticity, or preventing skin wrinkle generation or improving skin wrinkles, the method comprising: administering an effective amount of the composition to the skin of the desired object, the composition comprising polymer hyaluronic acid or its salt particles and an acidic pH regulator, the acidic pH regulator is an organic acid or an inorganic acid, the average particle size of the polymer hyaluronic acid or its salt particles is less than 100nm, and the pH of the composition is 3.0 or more and less than 5.0. Another embodiment can provide a use of polymer hyaluronic acid or its salt particles and an acidic pH regulator for preparing a composition for skin moisturizing, preventing skin elasticity from decreasing or improving elasticity, or preventing skin wrinkle generation or improving skin wrinkles. Another embodiment may provide a polymer hyaluronic acid or its salt particles and an acidic pH regulator for use in a composition for moisturizing the skin, preventing a decrease in skin elasticity or improving elasticity, or preventing the formation of skin wrinkles or improving skin wrinkles. Another embodiment may provide a polymer hyaluronic acid or its salt particles and an acidic pH regulator as non-therapeutic cosmetic uses of an active ingredient for moisturizing the skin, preventing a decrease in skin elasticity or improving elasticity, or preventing the formation of skin wrinkles or improving skin wrinkles. In this case, the acidic pH regulator is an organic acid or an inorganic acid, the average particle size of the polymer hyaluronic acid or its salt particles is less than 100 nm, and the pH of the composition is greater than 3.0 and less than 5.0.

[0053] In one embodiment, the composition may be a composition for external use on the skin. In the present disclosure, the "composition for external use on the skin" refers to a composition in a dosage form applied to the outside of the skin. As one embodiment, the composition for external use on the skin may be applied directly by hand or by various application means such as a spatula, and may include cosmetics, pharmaceuticals, quasi-drugs, etc. in various dosage forms.

[0054] In addition, the composition according to an embodiment of the present disclosure may be provided as a carrier composition for transdermal delivery of a functional substance having pH sensitivity for releasing the functional substance at pH 5 to 7.

[0055] In the present disclosure, the "pH sensitivity" refers to that the characteristics of a substance change with pH. In the present disclosure, it refers to that the size and shape of the polymer hyaluronic acid particles, the characteristics of capturing or releasing functional substances, etc. change with pH.

[0056] In one embodiment, the carrier composition can sense the pH of the skin after the functional substance is physically captured by the micronized high molecular weight hyaluronic acid through the charge interaction between the functional substance and the micronized high molecular weight hyaluronic acid, thereby effectively releasing and transmitting the captured functional substance into the skin while the size naturally expands. The carrier composition can make the high molecular weight hyaluronic acid easily penetrate into the skin, thereby improving the skin permeability and penetration depth, and thus can promote the absorption of the functional substance into the lower part of the stratum corneum of the skin when the drug is administered to the skin.

[0057] From this viewpoint, another embodiment of the present disclosure may provide a composition for external skin application, comprising: an effective substance; and a carrier for transdermal delivery of the effective substance comprising the composition.

[0058] Another embodiment of the present disclosure may provide a use of the micronized polymer hyaluronic acid or its salt particles for preparing a carrier composition for transdermal delivery of the functional substance. Another embodiment may provide a method for transdermal delivery of a functional substance, the method comprising: a step of causing the micronized polymer hyaluronic acid or its salt particles to capture an effective amount of the functional substance. Another embodiment may provide the micronized polymer hyaluronic acid or its salt for use as a carrier for transdermal delivery of a functional substance. Another embodiment may provide a use of the micronized polymer hyaluronic acid or its salt as a carrier for transdermal delivery of a functional substance. Another embodiment may provide a non-therapeutic use of the micronized polymer hyaluronic acid or its salt as a carrier for transdermal delivery.

[0059] As an embodiment, as long as it is a substance that has useful effects on the skin or human body, the functional substance includes all but not limited to the types of the effects and substances. As an embodiment, the functional substance can be an unstable and easily denatured substance, or a water-insoluble or poorly soluble substance that is difficult to penetrate through the skin. As an embodiment, the functional substance can be a functional substance conventionally used in the field of cosmetics or pharmacy. As an embodiment, the functional substance can include one or more of an organic acid and its derivatives. For example, the organic acid may include one or more selected from the group consisting of citric acid, phosphoric acid, fumaric acid, ascorbic acid, ferulic acid, succinic acid, lactic acid, hyaluronic acid, malic acid, butyric acid, formic acid, acetic acid, salicylic acid, glycolic acid, tartaric acid, and gluconolactone, etc. As an embodiment, the organic acid derivative may include 3-O-ethyl ascorbic acid, ascorbyl glucoside, sodium ascorbyl phosphate, etc.

[0060] As an example, the functional substance may be contained in an amount of 0.01 to 40% by weight relative to the total weight of the skin external preparation composition. Specifically, the effective substance may contain 0.01% by weight or more, 0.02% by weight or more, 0.03% by weight or more, 0.04% by weight or more, 0.05% by weight or more, 0.06% by weight or more, 0.07% by weight or more, 0.08% by weight or more, 0.09% by weight or more, 0.1% by weight or more, 0.2% by weight or more, 0.3% by weight or more, 0.4% by weight or more, 0.5% by weight or more, 0.6% by weight or more, 0.7% by weight or more, 0.8% by weight or more, 0.9% by weight or more, 1% by weight or more, 2% by weight or more, 3% by weight or more, 4% by weight or more, 5% by weight or more, 6% by weight or more, 7% by weight or more, 8% by weight or more, 9% by weight or more, 10% by weight or more, 15% by weight or more, 20% by weight or more, 25% by weight or more, or 29% by weight or more. As one embodiment, the functional substance may contain 30% by weight or less, 25% by weight or less, 20% by weight or less, 15% by weight or less, 10% by weight or less, 9% by weight or less, 8% by weight or less, 7% by weight or less, 6% by weight or less, 5% by weight or less, 4% by weight or less, 3% by weight or less, 2% by weight or less, 1% by weight or less, 0.9% by weight or less, 0.8% by weight or less, 0.7% by weight or less, 0.6% by weight or less, 0.5% by weight or less, 0.4% by weight or less, 0.3% by weight or less, 0.2% by weight or less, 0.1% by weight or less, 0.09% by weight or less, 0.08% by weight or less, 0.07% by weight or less, 0.06% by weight or less, 0.05% by weight or less, 0.04% by weight or less, 0.03% by weight or less, 0.02% by weight or less, relative to the total weight of the skin external preparation composition. In addition, as an embodiment, the weight ratio of the carrier composition relative to the total weight of the functional substance may be different depending on the type of the functional substance. For example, the weight ratio may be 1:0.01-100. Specifically, the weight ratio of the carrier composition relative to the total weight of the functional substance may be 1:0.01 or more, 0.1 or more, 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 20 or more, 30 or more, 40 or more, 50 or more, 60 or more, 70 or more, 80 or more, or 90 or more, and may be 100 or less, 90 or less, 80 or less, 70 or less, 60 or less, 50 or less, 40 or less, 30 or less, 20 or less, 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less.When too little effective substance is contained, the desired effect of the effective substance may not be fully manifested. When too much effective substance is contained, the content of the carrier composition is relatively reduced, which may reduce the skin delivery efficiency.

[0061] As an example, the composition may further contain an alkaline pH adjuster in addition to the acidic pH adjuster to adjust the pH of the composition to be greater than 3.0 and less than 5.0 according to the type and content of the functional substance.

[0062] In addition, in one embodiment, the skin topical composition can be provided for multiple purposes according to the type of functional ingredients. For example, the composition can be used for skin moisturizing. In one embodiment, the composition can be used to prevent skin elasticity reduction or improve elasticity. In one embodiment, the composition can be used to prevent skin wrinkle generation or improve skin wrinkles. In one embodiment, the composition can be used for skin whitening. In one embodiment, the composition can be used for anti-inflammation. In one embodiment, the composition can be used to prevent, improve or treat acne. Another embodiment of the present disclosure can provide a method for skin moisturizing, skin whitening, preventing skin elasticity reduction or improving elasticity, preventing skin wrinkle generation or improving wrinkles, anti-inflammation or anti-acne, the method comprising: a step of administering an effective amount of a carrier composition to the skin of the desired object, the carrier composition capturing the above-mentioned functional substances. Another embodiment can provide a use of a carrier composition for preparing a skin topical composition for skin moisturizing, skin whitening, preventing skin elasticity reduction or improving elasticity, preventing skin wrinkle generation or improving wrinkles, anti-inflammation or anti-acne, capturing the above-mentioned functional substances. Another embodiment may provide a carrier composition for capturing the above-mentioned functional substances, which is applied to a composition for skin moisturizing, skin whitening, preventing skin elasticity reduction or improving elasticity, preventing skin wrinkle formation or improving wrinkles, anti-inflammation or anti-acne. Another embodiment may provide a carrier composition for capturing the above-mentioned functional substances as a non-therapeutic cosmetic use of an active ingredient for skin moisturizing, skin whitening, preventing skin elasticity reduction or improving elasticity, preventing skin wrinkle formation or improving wrinkles, anti-inflammation or anti-acne.

[0063] In one embodiment, the composition may be a cosmetic composition. In one embodiment, the cosmetic composition may include a cosmetic or dermatologically acceptable medium or matrix. For example, it may be provided as a solution, gel, solid, pasty anhydrous product, an emulsion, suspension, microemulsion, microcapsule, microgranule ball or ionic (liposome) and non-ionic vesicle dispersant obtained by dispersing the oil phase into the aqueous phase, or the form of a cream, toner, lotion, powder, ointment, spray or concealer stick. These compositions can be prepared according to conventional methods in the art. The composition according to the present disclosure can also be used in the form of a foam or an aerosol composition further containing a compressed propellant.

[0064] The dosage form of the cosmetic composition according to one embodiment of the present disclosure is not particularly limited, for example, it can be made into an ampoule, cream, skin softening lotion, astringent lotion, nutritional lotion, nutritional cream, gel cream, massage cream, essence, eye cream, eye essence, cleansing cream, cleansing foam, cleansing water, cleansing towel containing the cosmetic composition, facial mask, body lotion, body cream, body oil and body essence. When the dosage form according to one embodiment of the present disclosure is a paste, cream or gel, animal fiber, plant fiber, wax, paraffin, starch, tragacanth gum, cellulose derivatives, polyethylene glycol, silicon, bentonite, silicon dioxide, talc or zinc oxide can be used as a carrier component. When the dosage form according to one embodiment of the present disclosure is a spray, lactose, talc, silicon dioxide, aluminum hydroxide, calcium silicate or polyamide powder can be used as a carrier component, and a propellant such as chlorofluorocarbon, propane / butane or dimethyl ether can be further contained. When the dosage form according to one embodiment of the present disclosure is a solution or an emulsion, a solvent, a solvating agent or an emulsifying agent is used as a carrier component, such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol oil, glycerol fatty acid ester, polyethylene glycol or fatty acid ester of sorbitan. When the dosage form according to one embodiment of the present disclosure is a suspension, a liquid diluent such as water, ethanol or propylene glycol, a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar or tragacanth gum, etc. can be used as a carrier component. When the dosage form according to one embodiment of the present disclosure is a facial cleanser containing a surfactant, fatty alcohol sulfates, fatty alcohol ether sulfates, sulfosuccinic acid monoesters, hydroxyethyl sulfonates, imidazoline derivatives, methyl taurates, sarcosinates, fatty acid amide ether sulfates, alkylamide betaines, fatty alcohols, fatty acid glycerides, fatty acid diethanolamides, vegetable oils, lanolin derivatives or ethoxylated glyceryl fatty acid esters, etc. can be used as carrier ingredients.

[0065] The cosmetic composition according to one embodiment of the present disclosure may also include functional additives and ingredients contained in a common cosmetic composition. As the functional additive, it may include ingredients selected from the group consisting of water-soluble vitamins, oil-soluble vitamins, polymer peptides, polymer polysaccharides, sphingolipids and seaweed extracts. In addition, the blending ingredients included may be oil components, moisturizers, emollients, neutralizers, surfactants, organic pigments and inorganic pigments, organic powders, ultraviolet absorbers, preservatives, bactericides, antioxidants, plant extracts, pH regulators, alcohols, pigments, spices, blood circulation promoters, cooling agents, antiperspirants, purified water, etc.

[0066] In one embodiment, the composition can be a pharmaceutical composition. When the composition according to one embodiment of the present disclosure is applied to pharmaceuticals, a non-oral agent in a semi-solid or liquid form can be formulated by adding a commonly used inorganic carrier or organic carrier to the active ingredient used in one embodiment of the present disclosure. The pharmaceutical composition according to the present disclosure can be administered by non-oral, rectal, local, transdermal, intravenous, intramuscular, intraperitoneal, subcutaneous and other routes. As one embodiment, the pharmaceutical composition can be a non-oral agent, more specifically a skin topical agent. For example, the skin topical agent can be an ointment, a toner, an emulsion, a gel, a cream, a spray, a suspension, an oil, a patch and other dosage forms, but is not limited thereto. The composition according to one embodiment of the present disclosure can be implemented according to conventional methods known in the art, so that the active ingredient can be easily formulated, and at this time, a surfactant, an excipient, a colorant, a fragrance, a preservative, a stabilizer, a buffer, a suspending agent, and other commonly used adjuvants can be appropriately used. The dosage of the active ingredient of the pharmaceutical composition according to one embodiment of the present disclosure may vary according to the age, sex, weight, pathological state and severity of the subject to be administered, the route of administration or the judgment of the prescriber. It is within the level of those skilled in the art to determine the appropriate dosage based on these factors, and the daily dosage may be, for example, 0.1 mg / kg / day to 100 mg / kg / day, more specifically 5 mg / kg / day to 50 mg / kg / day, but is not limited thereto.

[0067] In one embodiment, the composition may be a food composition. The food composition according to one embodiment of the present disclosure may be in the form of a liquid or solid state, and may be a tablet, capsule, soft capsule, pill, granule, beverage (drink), fat-reducing bar, chocolate, caramel dosage form or biscuit dosage form, and its dosage form is not particularly limited. In addition to the active ingredient, the food composition according to one embodiment of the present disclosure may also contain an appropriate amount of excipients, sugars, spices, pigments, oils, proteins, etc. as needed. DETAILED DESCRIPTION

[0069] Hereinafter, the present disclosure will be described in more detail by the following examples. However, the purpose of providing the following examples is only to illustrate to help understand the present disclosure, and the category and scope of the present disclosure are not limited thereto.

[0070] [Test Example 1]

[0071] In order to confirm the micronization of the high molecular weight hyaluronic acid or its salt according to the present disclosure, as an example, Examples 1 to 4 having the components shown in Table 1 below were prepared by the following method.

[0072] First, as a high molecular weight hyaluronate, sodium hyaluronate (manufacturer: Hyundai Biolande, product name: Biosodium hyaluronate, weight average molecular weight: 1500KDa) is prepared. In Examples 1 to 4, 1,2-hexanediol and the sodium hyaluronate are dissolved in deionized water using a magnetic stirrer, and then the remaining ingredients are added and stirred at a high speed of 12000rpm using a homogenizer to induce micronization of the particles. At this time, the pH range of the micronized solution is 3 to 4. After the hyaluronic acid solution is placed in a chamber at 45°C, the particles and physical properties are stabilized through a maturation process for more than 12 hours to prepare the final composition.

[0073] As comparative examples for comparing the effects of the embodiments, Comparative Example 1 containing only a solvent and sodium hyaluronate and Comparative Example 2 containing a metal salt of an organic acid using trisodium citrate (pH 6.5), which is a conjugate base, as a pH adjuster were prepared in the same manner as in Embodiments 1 to 4.

[0074]

Table 1

[0075] Element Example 1 Example 2 Example 3 Example 4 Comparative Example 1 Comparative Example 2 Deionized water Up to 100 Up to 100 Up to 100 Up to 100 Up to 100 Up to 100 1,2-Hexanediol 1.2 1.2 1.2 1.2 1.2 1.2 Sodium Hyaluronate 0.8 0.8 0.8 0.8 0.8 0.8 ascorbic acid 0.9 - - 0.9 - - Succinic acid - 1.5 - - - - Citric acid - - 0.4 - - - Trisodium Citrate - - - - - 0.5 Disodium EDTA - - - 0.03 - -

[0076] (weight%)

[0077] In order to compare the micronization of the polymer hyaluronic acid or its salt in Examples 1 to 4 and Comparative Examples 1 and 2, the average particle size of each composition was measured using a Zetasizer instrument from Malvern Panalytical, and Figure 1 and Figure 2 It is shown in .

[0078] The results, such as Figure 1 and Figure 2As shown, in Comparative Example 1, which is a high molecular hyaluronic acid aqueous solution without adding a pH adjuster, the high molecular hyaluronate particles are distributed in the range of 100 nm to 1000 nm and the particle size does not decrease, but the high molecular hyaluronate particles of Examples 1 to 4 are also distributed in the range of 10 to 100 nm in the case of changing the acid type and adding a metal ion chelating agent, so it can be confirmed that the degree of micronization is about 10% or less of Comparative Example 1. In Comparative Example 2, the average particle size of the high molecular hyaluronate is less than 100 nm, but since a metal salt of an organic acid is used as a pH adjuster, as confirmed in Experimental Example 2 described later, it has the limitation that the particle size does not expand again after skin administration.

[0079] In addition, the relative molecular weight of Example 1 and Comparative Example 1 was measured by gel chromatography (GPC) using the recognized testing organization, Korea Polymer Testing Institute (Koptri). The results showed that Comparative Example 1 ( Figure 3 ) and Example 1 ( Figure 4 ) all showed the same peak at about 17 minutes, indicating the same maximum molecular weight. The above results mean that in Example 1, the molecular weight of the high molecular weight hyaluronate did not change, only the particle size of the high molecular weight hyaluronate was micronized to less than 100 nm.

[0080] [Test Example 2]

[0081] Examples 1 to 4 and Comparative Example 2 prepared in the Test Example 1 were used as objects to measure the change in the particle size of the micronized polymer hyaluronic acid or its salt with pH, ​​so as to confirm whether the micronized polymer hyaluronic acid or its salt particles according to the present disclosure are neutralized and expanded again at the pH of the skin after being administered into the skin, and whether the polymer hyaluronate provides skin moisturizing or skin elasticity improvement effects to the skin.

[0082] Specifically, an alkaline neutralizer (manufacturer: ANGUS, product name: Tromethamine) was added to each of Examples 1 to 4 and Comparative Example 2 prepared in the Test Example 1 to increase the pH of each composition to pH 6, which is the same as the skin pH, and then the particle movement change was confirmed using a Zetasizer instrument (Malvern, UK).

[0083] As shown in the table below, it can be confirmed that in Examples 1 to 4, the particle size increased again as the pH of the composition increased compared to before the pH increase, but the particle size of Comparative Example 2 changed little or even decreased slightly.

[0084]

Table 2

[0085] Example 1 Example 2 Example 3 Example 4 Comparative Example 2 Average particle size increase rate (%) 460％ 390％ 210％ 250％ -10％

[0086] [Test Example 3]

[0087] Examples 1 to 4 and Comparative Example 1 prepared in Test Example 1 were used as objects to perform viscosity measurement to confirm changes in physical properties of the composition according to the present disclosure.

[0088] At this time, in the measurement of viscosity (Pa.s), a rheometer (Malvern Panalytical, UK) was used, and the plate type (Plate type) CP 4 / 40 was used at 25°C, the oscillation stress (oscillation stress) was adjusted to 1Pa, the frequency range (frequency range) was 0.1-10Hz, the shear stress (Shear stress) was 1Pa, and the gap (gap) was 1mm. Among them, the G' and G" values ​​at 1Hz were measured, and the specifications of the G' and G" measurement samples were unified into a disk shape with a diameter of 20mm and a thickness of 1mm.

[0089] As a result, as shown in the following table, it was confirmed that in Examples 1 to 4, even if the hyaluronic acid solution was aged at 45° C. for 12 hours or more during preparation, the physical properties of the composition were stable at a low viscosity.

[0090]

Table 3

[0091] Example 1 Example 2 Example 3 Example 4 Comparative Example 1 Viscosity(Pa.s) 0.023 0.025 0.018 0.022 0.306

[0092] [Test Example 4]

[0093] In order to confirm the improvement of skin permeability under micronization of the high molecular weight hyaluronic acid or its salt particles according to the present disclosure, the following experiment was conducted.

[0094] First, skin tissue of Fitzpatrick skin type II (manufacturer: Genoskin, product name: NativeSkin) obtained from a 33-year-old female abdominal biopsy was obtained through the manufacturer, and Example 1 and Comparative Example 1 prepared in Test Example 1 were applied to the skin tissue respectively. After a tape sampling disc (manufacturer: Cuderm, product name: D100, diameter: 22 mm) was attached to the skin tissue, a D-squame pressure instrument was used to press with a force of 225 gr. / sq.cm, and then the tape sampling disc was removed. A total of 10 tape sampling discs were removed in sequence at intervals of about 3 minutes, and the tape sampling disc samples were stored in a freezer.

[0095] Using a desorption electrospray ionization (DESI) mass spectrometer (manufacturer: Waters, product name: 2D DESIstage & XEVO G2-XS QTof), the penetration of each composition in each sequence was confirmed through the tape sampling tray sample stored in the freezer. At this time, the DESI-MS spectrum was obtained using the 2D DESI platform and XEVO G2-XS QTof (Waters, Milford, USA). The nebulization solvent was 98% methanol + 0.1% formic acid, the flow rate was 2μL / min, and the nebulization gas inlet pressure was set to 0.5MPa. 100×100μm was measured from the tape sampling tray sample peeled from the above tape 2 The mass range was 50-1000 m / z in positive ion mode. MassLynx 4.2 (Waters, USA) was used to acquire MS imaging data and HDI (High Definition Imaging) 1.5 software (Waters) was used for visualization.

[0096] The results, such as Figure 5 As shown, in Comparative Example 1, since the particle size of the polymer hyaluronate is large, no particles are confirmed to penetrate into the stratum corneum. In contrast, in Example 1 according to one embodiment of the present disclosure, it is confirmed that the polymer hyaluronate is micronized and penetrated to the tenth depth.

[0097] [Example 5]

[0098] The carrier composition and the composition including the functional substance for transdermal delivery of the functional substance according to one embodiment of the present disclosure were prepared by the following method.

[0099] First, as a high molecular weight hyaluronate, sodium hyaluronate (manufacturer: Hyundai Biolande, product name: Biosodium hyaluronate, weight average molecular weight: 1500KDa) is prepared. 1,2-Hexanediol and the sodium hyaluronate are dissolved in deionized water using a magnetic stirrer. The remaining components in Table 4 below are added, and the particles are micronized to an average particle size of less than 100nm with a homogenizer at a high speed of 12000rpm. At this time, the pH range of the micronized solution is 3 to 4. After the hyaluronic acid solution is added to a chamber at 45°C, the particles and physical properties are stabilized through a maturation process for more than 12 hours to prepare the final composition.

[0100] [Comparative Example 3]

[0101] As a comparative example for comparing the effects of the examples, Comparative Example 3 was prepared by the same components and method as Example 5 except that sodium hyaluronate was not included.

[0102]

Table 4

[0103] Element Example 5 Comparative Example 3 Solvents Deionized water Up to 100 Up to 100 Hyaluronate Sodium Hyaluronate 0.6 - Metal ion chelators Sodium metaphosphate 0.08 0.08 Effective substances ascorbic acid 0.5 0.5 Stabilizer caffeine 0.17 0.17 Stabilizer Mannitol 0.1 0.1 preservative 1,2-Hexanediol 1.2 1.2 Alkaline pH adjuster Tromethamine 0.3 0.3 Acidic pH Adjuster Succinic acid 0.5 0.5

[0104] (weight%)

[0105] [Test Example 5]

[0106] In order to confirm the transdermal delivery effect of the effective substance based on the carrier composition according to the present disclosure, the skin absorption amount of ascorbic acid as each effective substance of Example 5 and Comparative Example 3 was measured by the following method and then compared.

[0107] The absorption of ascorbic acid was determined using a Franz diffusion cell. A membrane (Isopore, Merck Milipore, USA) was fixed between the donor and receptor phases, at which point the area in contact with the receptor phase was approximately 1.767 cm 2 . PBS (phosphate buffer saline, 7 mL) was used as the acceptor phase, and stirring was continued at a fixed speed of 600 rpm while maintaining 32°C. After 1 hour and 3 hours, the acceptor phase was taken out, and the amount of ascorbic acid was quantified using HPLC (high-performance liquid chromatography). In the HPLC analysis, Mightysil RP-18GP 250-4.6 (5 μm) was used as the stationary phase, and a mixture of 1% CH3COOH: methanol (90:10, v / v) was used as the mobile phase. The detection wavelength was 254 nm, the flow rate was 1 mL / min, and the concentration was calculated from the area of ​​the peak obtained according to the reference "Snezana S Mitic, Danijela A Kostic, Danijela CNaskovic-Dokic, Milan N Mitic, Rapid and Reliable HPLC Method for the Determination of Vitamin C in Pharmaceutical Samples, Tropical Journal of Pharmaceutical Research February 2011; 10(1): 105-111". The entire contents of the reference are incorporated herein by reference.

[0108]

Table 5

[0109] After 1 hour After 3 hours Example 5 59.64 μg / mL 87.87 μg / mL Comparative Example 3 0μg / mL 0μg / mL

[0110] As a result, it was confirmed that in Comparative Example 3, which is a composition including an effective substance but no carrier composition, the amount of ascorbic acid absorbed by the skin tissue was extremely small and no ascorbic acid was confirmed. In contrast, in Example 5, ascorbic acid was effectively transported into the skin tissue by a carrier composition including micronized high-molecular hyaluronate, thereby showing a high absorption amount.

[0111] [Test Example 6]

[0112] In order to confirm the transdermal delivery effect of the effective substance based on the carrier composition according to the present disclosure, the following experiment was used to confirm the penetration depth of the effective substance into the skin.

[0113] First, skin tissue of Fitzpatrick skin type II obtained from abdominal biopsy of a 33-year-old female (manufacturer: Genoskin, product name: NativeSkin) was obtained by the manufacturer, and Example 5 and Comparative Example 3 were applied to the skin tissue, respectively. After a tape sampling disk (manufacturer: Cuderm, product name: D100, diameter: 22 mm) was attached to the skin tissue, a D-squame pressure instrument was used to press with a force of 225 gr. / sq.cm, and then the tape sampling disk was removed. A total of 10 tape sampling disks were removed in sequence at intervals of about 3 minutes, and the tape sampling disk samples were stored in a freezer.

[0114] Using a desorption electrospray ionization (DESI) mass spectrometer (manufacturer: Waters, product name: 2D DESI stage & XEVO G2-XS QTof), the penetration of each composition in each sequence was confirmed through the tape sampling disk sample stored in the freezer. At this time, the DESI-MS spectrum was acquired using the 2D DESI platform and XEVO G2-XS QTof (Waters, Milford, USA). The nebulization solvent was 98% methanol + 0.1% formic acid, the flow rate was 2 μL / min n, and the nebulization gas inlet pressure was set to 0.5 MPa. 100×100 μm was measured from the tape sampling disk sample peeled from the above tape 2 The mass range was 50-1000 m / z in positive ion mode. MassLynx 4.2 (Waters, USA) was used to acquire MS imaging data and HDI (High Definition Imaging) 1.5 software (Waters) was used for visualization.

[0115] The results, such as Figure 7As shown, it was confirmed that the effective substance in Comparative Example 3, which is a composition including an effective substance but no carrier composition, did not penetrate into the stratum corneum. On the contrary, in Example 5, the effective substance penetrated to the depth of the tenth tape peeling due to the carrier composition including micronized high molecular weight hyaluronate.

[0116] As an embodiment, the present disclosure may provide the following implementation forms.

[0117] The first embodiment can provide a composition, which includes: high molecular weight hyaluronic acid or its salt particles; and an acidic pH adjuster, wherein the acidic pH adjuster is an organic acid or an inorganic acid, the average particle size of the high molecular weight hyaluronic acid or its salt particles is less than 100 nm, and the pH is greater than 3.0 and less than 5.0.

[0118] A second embodiment can provide a composition according to the first embodiment, further comprising a metal ion chelating agent.

[0119] A third embodiment may provide a composition according to the first embodiment or the second embodiment, wherein the metal ion chelating agent is one or more of an alkali salt of ethylenediaminetetraacetic acid (EDTA) and an alkali salt of a phosphate compound.

[0120] A fourth embodiment may provide a composition according to any one of the first to third embodiments, wherein the weight average molecular weight of the polymer hyaluronic acid or a salt thereof is 5 to 10000 kDa.

[0121] A fifth embodiment may provide a composition according to any one of the first to fourth embodiments, wherein the weight ratio of the polymer hyaluronic acid or a salt thereof to the acidic pH adjuster is 1:0.01 to 10.

[0122] A sixth embodiment may provide a composition according to any one of the first to fifth embodiments, wherein the polymer hyaluronic acid or a salt thereof is contained in an amount of 0.1 to 10% by weight based on the total weight of the composition.

[0123] A seventh embodiment may provide a composition according to any one of the first to sixth embodiments, wherein the acidic pH adjuster is contained in an amount of 0.01 to 50% by weight based on the total weight of the composition.

[0124] The 8th embodiment can provide a composition according to any one of the first embodiment to the seventh embodiment, wherein the organic acid is one or more selected from the group consisting of citric acid, phosphoric acid, fumaric acid, ascorbic acid, ferulic acid, succinic acid, lactic acid, hyaluronic acid, malic acid, butyric acid, formic acid, acetic acid, salicylic acid, glycolic acid, tartaric acid and gluconolactone.

[0125] Embodiment 8-2 may provide a composition according to any one of Embodiment 1 to Embodiment 8-1, wherein the inorganic acid is one or more selected from the group consisting of carbonic acid, hydrochloric acid, nitric acid, and sulfuric acid.

[0126] A ninth embodiment can provide a composition according to any one of the first to eighth embodiments, wherein the composition is a composition for external use on skin.

[0127] A tenth embodiment can provide a composition according to any one of the first to ninth embodiments, wherein the composition is used for moisturizing the skin.

[0128] The eleventh embodiment can provide a composition according to any one of the first to tenth embodiments, wherein the composition is used for preventing a decrease in skin elasticity or improving elasticity.

[0129] A twelfth embodiment can provide a composition according to any one of the first to eleventh embodiments, wherein the composition is a cosmetic composition.

[0130] A 13th embodiment can provide a composition according to any one of the first to 12th embodiments, wherein the composition is a food composition.

[0131] A fourteenth embodiment can provide a composition according to any one of the first to thirteenth embodiments, wherein the composition is a pharmaceutical composition.

[0132] The 15th embodiment can provide a preparation method, which is a preparation method for any one of the compositions in the 1st to 14th embodiments, the method comprising: adding an acidic pH regulator to a solution containing a polymer hyaluronic acid or a salt thereof, thereby micronizing the polymer hyaluronic acid or a salt thereof, wherein the average particle size of the micronized polymer hyaluronic acid or a salt thereof particles is less than 100 nm, and the pH of the composition is greater than 3.0 and less than 5.0.

[0133] A sixteenth embodiment may provide a preparation method according to the fifteenth embodiment, wherein the step of micronizing the polymer hyaluronic acid or its salt further comprises: a step of adding a metal ion chelating agent to the solution.

[0134] A seventeenth embodiment may provide a composition according to any one of the first to fourteenth embodiments, wherein the composition is a carrier composition for transdermal delivery of an effective substance, and the composition releases the effective substance at a pH of 5 to 7.

[0135] The eighteenth embodiment may provide a composition for external use on skin, comprising: an effective substance; and a carrier for transdermal delivery of the effective substance comprising the composition according to any one of the first to fourteenth embodiments.

[0136] A nineteenth embodiment may provide a composition for external use on skin according to the eighteenth embodiment, wherein the composition for external use on skin contains 0.01 wt % to 40 wt % of the active ingredient based on the total weight of the composition for external use on skin.

[0137] A 20th embodiment can provide a skin external preparation composition according to the 18th embodiment or the 19th embodiment, wherein the carrier composition physically captures the effective substance.

[0138] According to a 21st embodiment, there can be provided a composition for external use on skin, wherein the composition for external use on skin is used for moisturizing the skin according to any one of the 18th to 20th embodiments.

[0139] According to a 22nd embodiment, there can be provided a composition for external use on skin, which is used for preventing a decrease in skin elasticity or improving skin elasticity according to any one of the 18th to 21st embodiments.

[0140] According to a 23rd embodiment, there can be provided a composition for external use on skin, wherein the composition for external use on skin is used for skin whitening according to any one of the 18th to 22nd embodiments.

[0141] According to a 24th embodiment, there is provided a composition for external use on skin according to any one of the 18th to 23rd embodiments, wherein the composition for external use on skin is a cosmetic composition.

[0142] According to a 25th embodiment, there is provided a composition for external use on skin, wherein the composition for external use on skin is a pharmaceutical composition according to any one of the 18th to 24th embodiments.

Claims

1. A composition comprising: High molecular weight hyaluronic acid or its salt particles; and Acidic pH adjuster, The acidic pH regulator is an organic acid or an inorganic acid. The average particle size of the polymer hyaluronic acid or its salt particles is less than 100 nm. The pH is 3.0 or more and less than 5.

0.

2. The composition according to claim 1, wherein Also included are metal ion chelators.

3. The composition according to claim 2, wherein The metal ion chelating agent is one or more of an alkali salt of EDTA and an alkali salt of a phosphate compound.

4. The composition according to claim 1, wherein The weight average molecular weight of the high molecular weight hyaluronic acid or its salt is 5 to 10000 kDa.

5. The composition according to claim 1, wherein The weight ratio of the polymer hyaluronic acid or its salt to the acidic pH regulator is 1:0.01 to 10.

6. The composition according to claim 1, wherein The polymer hyaluronic acid or its salt contains 0.1 to 10 weight % relative to the total weight of the composition.

7. The composition according to claim 1, wherein The acidic pH adjuster is contained in an amount of 0.01 to 50 wt % relative to the total weight of the composition.

8. The composition according to claim 1, wherein The organic acid is one or more selected from the group consisting of citric acid, phosphoric acid, fumaric acid, ascorbic acid, ferulic acid, succinic acid, lactic acid, hyaluronic acid, malic acid, butyric acid, formic acid, acetic acid, salicylic acid, glycolic acid, tartaric acid and gluconolactone, The inorganic acid is one or more selected from the group consisting of carbonic acid, hydrochloric acid, nitric acid, and sulfuric acid.

9. The composition according to claim 1, wherein The composition is a composition for external use on the skin.

10. The composition according to claim 1, wherein The composition is used for skin moisturizing.

11. The composition according to claim 1, wherein The composition is used to prevent the reduction of skin elasticity or to improve elasticity.

12. The composition according to claim 1, wherein The composition is a cosmetic composition.

13. The composition according to claim 1, wherein The composition is a food composition.

14. The composition according to claim 1, wherein The composition is a pharmaceutical composition.

15. A preparation method, as a preparation method of the composition according to any one of claims 1 to 14, the method comprising: a step of adding an acidic pH adjusting agent to a solution containing high molecular weight hyaluronic acid or a salt thereof to micronize the high molecular weight hyaluronic acid or a salt thereof, The average particle size of the micronized high molecular weight hyaluronic acid or its salt particles is less than 100 nm. The pH of the composition is 3.0 or more and less than 5.

0.

16. The preparation method according to claim 15, wherein: The step of micronizing the polymer hyaluronic acid or its salt further comprises: The step of adding a metal ion chelating agent to the solution.

17. The composition according to any one of claims 1 to 8, wherein The composition is a carrier composition for transdermal delivery of an effective substance, and the composition releases the effective substance at a pH of 5 to 7.

18. A composition for external use on skin, comprising: Effective substances; and A carrier for transdermal delivery of the efficacy substance comprising the composition according to any one of claims 1 to 8.

19. The composition for external use on skin according to claim 18, wherein The skin external preparation composition contains 0.01 wt % to 40 wt % of the effective substance relative to the total weight of the skin external preparation composition.

20. The composition for external use on skin according to claim 18, wherein The carrier composition physically captures the efficacy substance.

21. The composition for external use on skin according to claim 18, wherein The skin external preparation composition is used for skin moisturizing.

22. The composition for external use on skin according to claim 18, wherein The skin external preparation composition is used to prevent reduction in skin elasticity or to improve elasticity.

23. The composition for external use on skin according to claim 18, wherein The skin external preparation composition is used for skin whitening.

24. The composition for external use on skin according to claim 18, wherein The skin external application composition is a cosmetic composition.

25. The composition for external use on skin according to claim 18, wherein The skin external application composition is a pharmaceutical composition.

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