Composition containing polymeric hyaluronic acid microparticles

Abstract

This specification discloses the composition that contains high molecular weight hyaluronic acid microparticles.In the present invention, by micronizing high molecular weight hyaluronic acid, even without the low molecular weight of high molecular weight hyaluronic acid, it can be easily penetrated into skin, and can be stably contained in preparation.In addition, the microparticulate high molecular weight hyaluronic acid that is contained in the composition of the present invention penetrates into skin, and then is neutralized according to the pH of skin, and then expands again in size, so that it can exert excellent moisturizing effect and elasticity improving effect on skin.

Description

[Technical Field]

[0001] Disclosed herein are compositions comprising polymeric hyaluronic acid microparticles.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority based on Korean Patent Application No. 10-2022-0116111, filed on September 15, 2022, and Korean Patent Application No. 2022-0116133, filed on September 15, 2022, the entire specifications of which are incorporated herein by reference. [Background technology]

[0003] Hyaluronic acid (HA; Hyaluronate) is a linear polymeric polysaccharide consisting of alternating bonds between β-acetylglucosamine and β-glucuronic acid, and is distributed in connective tissues such as subcutaneous tissue and cartilage in the human body. Hyaluronic acid has excellent biocompatibility and is known to have beneficial effects on the skin, such as promoting skin's moisturizing ability, maintaining skin elasticity, and improving the skin's barrier function. However, natural hyaluronic acid has poor structural stability and is easily degraded and excreted in the body, so research is being conducted to stabilize it.

[0004] The molecular weight of hyaluronic acid varies depending on the length of the sugar chain. Low-molecular-weight hyaluronic acid penetrates the skin easily, but its short residence time and poor water retention result in little effect on the skin, and problems such as changes in odor and discoloration occur. High-molecular-weight hyaluronic acid has excellent moisturizing and regenerative properties for the skin, but is difficult to penetrate into the skin. Unless it is administered directly to the skin by injection, there are limitations to the effects of hyaluronic acid on the skin when applied to actual formulations.

[0005] In addition, in the cosmetics and pharmaceutical industries, when incorporating poorly permeable or unstable active substances into topical skin preparations, methods such as using synthetic surfactants to promote dermal absorption of the active substance or using synthetic polymer compounds such as polyethylene glycol or liposome nanoparticles as transporters to increase the dermal permeability of the active substance are widely used. However, the amphiphilic enhancers used in these synthetic compounds and liposome nanoparticles have problems such as human toxicity, allergies, and environmental hazards, and the cosmetics and pharmaceutical industries have recently been avoiding their use. Therefore, there is a need to develop a transporter that is gentle on the human body and the environment and can effectively promote the percutaneous absorption of active substances. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Korean Patent Publication No. 10-2022-95126 [Patent Document 2] Korean Patent Registration No. 10-2430199 Summary of the Invention [Problem to be solved by the invention]

[0007] 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 depolymerized or crosslinked, and a method for producing the same.

[0008] The problem to be solved by the present disclosure is to provide a composition containing high molecular weight hyaluronic acid that is stable in a formulation, and a method for producing the same.

[0009] The problem to be solved by the present disclosure is to provide a carrier composition for transdermal delivery of an active substance that has excellent biocompatibility and is easily permeable to the skin.

[0010] The problem to be solved by the present disclosure is to provide an external skin preparation composition comprising an active substance and a carrier composition for transdermal delivery of the active substance. [Means for solving the problem]

[0011] In order to solve the above problems, one embodiment of the present disclosure provides a composition comprising polymeric 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 polymeric hyaluronic acid or its salt particles have an average particle size of 100 nm or less, and a pH of 3.0 or more but less than 5.0.

[0012] Furthermore, one embodiment of the present disclosure provides a method for producing the composition, which comprises the step of micronizing the polymeric hyaluronic acid or its salt by adding an acidic pH adjuster to a solution containing the polymeric hyaluronic acid or its salt, wherein the average particle size of the micronized polymeric hyaluronic acid or its salt particles is 100 nm or less, and the pH of the composition is 3.0 or more and less than 5.0.

[0013] Furthermore, one embodiment of the present disclosure provides a carrier composition for transdermal delivery of an active substance, which comprises particles of polymeric hyaluronic acid or a salt thereof and an acidic pH adjuster, wherein the acidic pH adjuster is an organic acid or an inorganic acid, the particles of polymeric hyaluronic acid or a salt thereof have an average particle size of 100 nm or less, and the pH is 3.0 or more but less than 5.0, and the active substance is released at a pH of 5 to 7.

[0014] Another embodiment of the present disclosure provides a skin topical composition comprising an active substance and a carrier for transdermal delivery of the active substance, the carrier comprising the composition. [Effects of the Invention]

[0015] One embodiment of the present disclosure provides a composition containing hyaluronic acid microparticles that can easily penetrate the skin without reducing the molecular weight of the high molecular weight hyaluronic acid and can be stably incorporated into a formulation by micronizing high molecular weight hyaluronic acid. After penetrating the skin, the micronized high molecular weight hyaluronic acid according to one embodiment of the present disclosure neutralizes to the skin's pH and expands again, thereby providing excellent moisturizing and elasticity-improving effects on the skin. Furthermore, a topical skin composition according to one embodiment, comprising an active substance and a transdermal delivery carrier for the active substance, comprising the composition, can exhibit dual functionality in that it penetrates the skin to release the active substance, and then the carrier itself can provide beneficial effects on the skin. [Brief explanation of the drawings]

[0016] [Figure 1] FIG. 1 is a diagram comparing particle sizes in a composition according to an example of the present disclosure (Example 1) and Comparative Example 1. [Figure 2] FIG. 2 is a diagram comparing particle sizes in a composition according to an example of the present disclosure (Examples 1 to 4) and Comparative Example 2. [Figure 3] FIG. 1 is a diagram showing the molecular weight of the polymeric hyaluronic acid microparticles contained in the composition of Comparative Example 1. [Figure 4] FIG. 1 is a diagram showing the molecular weight of polymeric hyaluronic acid microparticles contained in a composition according to one example of the present disclosure (Example 1). [Figure 5] FIG. 1 is a diagram confirming the depth of absorption in skin tissue of a composition according to an example of the present disclosure (Example 1) and Comparative Example 1. [Figure 6] 1 is a schematic diagram of a carrier composition active agent delivery and release system according to one embodiment of the present disclosure. [Figure 7] FIG. 10 is a diagram confirming the absorption depth in skin tissue of effective substances according to Example 5 and Comparative Example 3 according to an embodiment of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0017] Preferred embodiments of the present disclosure will now be described in detail with reference to the accompanying drawings.

[0018] The embodiments of the present disclosure disclosed herein are presented for illustrative purposes only. The embodiments of the present disclosure may be embodied in various forms and should not be construed as limited to the embodiments set forth herein. Because the present disclosure may be modified in various ways and take various forms, the embodiments are not intended to limit the disclosure to the particular disclosed form, but should be understood to include all modifications, equivalents, and alternatives falling within the spirit and scope of the present disclosure. The singular includes the plural unless otherwise specified. In this application, the terms "comprises," "having," and the like, indicate the presence of a stated feature, number, step, operation, component, part, or combination thereof, but do not exclude the presence or addition of one or more other features, number, step, operation, component, part, or combination thereof.

[0019] One embodiment of the present disclosure may provide a composition comprising polymeric 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 polymeric hyaluronic acid or its salt particles having an average particle size of 100 nm or less, and a pH of 3.0 or more and less than 5.0.

[0020] "Hyaluronic acid" as used herein is an anionic natural polysaccharide that exists in salt form and is a raw material that meets EWG grade 1. It is primarily produced and purified by microorganisms and is present in the connective tissues and extracellular matrix of the human body. Due to its high water content due to its anionic functional groups, it is widely used as a moisturizing agent. The molecular structure of hyaluronic acid can be represented by the following general formula (1), and in this specification, it is included in the form of hyaluronic acid salt.

[0021] [ka]

[0022] In the formula, x is 200 to 20,000 moles.

[0023] In one embodiment of the present disclosure, the salt may be, but is not limited to, an acid addition salt, a base addition salt, or an amino acid salt. For example, the salt may be an inorganic acid salt such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, or phosphate; an organic acid salt such as citrate, oxalate, acetate, formate, propionate, benzoate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, or paratoluenesulfonate; an inorganic base salt such as sodium salt, potassium salt, calcium salt, magnesium salt, copper salt, zinc salt, aluminum salt, or ammonium salt; an organic base salt such as triethylammonium salt, triethanolammonium salt, pyridinium salt, or diisopropylammonium salt; or an amino acid salt such as lysine salt, arginine salt, histidine salt, aspartate, or glutamate. In one embodiment, the salt may be sodium hyaluronate, potassium hyaluronate, acetate hyaluronate, ammonium hyaluronate, or C12-13 alkyl glyceryl hydrolyzed hyaluronate. In the present disclosure, the weight-average molecular weight of the polymeric hyaluronic acid or its salt varies depending on the length of the sugar chain, and in one embodiment, the weight-average molecular weight of the polymeric hyaluronic acid or its salt may be 5 to 10,000 kDa.Specifically, the weight average molecular weight of the polymeric hyaluronic acid or its salt is 5 kDa or more, 10 kDa or more, 100 kDa or more, 500 kDa or more, 1,000 kDa or more, 1,100 kDa or more, 1,200 kDa or more, 1,300 kDa or more, 1,400 kDa or more, 1,500 kDa or more, 1,600 kDa or more, 1,700 kDa or more. or more, 1,800kDa or more, 1,900kDa or more, 2,000kDa or more, 2,200kDa or more, 2,400kDa or more, 2,600kDa or more, 2,800kDa or more, 2,900kDa or more, 3,000kDa or more, 4,000kDa or more or 5,000kDa or more, and may be 10,000kDa or less, 9,000kDa or less Da or less, 8,000kDa or less, 7,000kDa or less, 6,000kDa or less, 5,000kDa or less, 4,500kDa or less, 4,000kDa or less, 3,900kDa or less, 3,800kDa or less, 3,700kDa or less, 3,600kDa or less, 3,500kDa or less, 3,400kDa or less, 3,300kDa or less, 3,2 The molecular weight of the polymeric hyaluronic acid or its salt may be 1,000 kDa or less, 3,100 kDa or less, 3,000 kDa or less, 2,500 kDa or less, 2,000 kDa or less, 1,900 kDa or less, 1,800 kDa or less, 1,700 kDa or less, 1,600 kDa or less, 1,500 kDa or less, 1,000 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 polymeric hyaluronic acid or its salt may be 1,000 to 5,000 kDa. If the weight-average molecular weight of the polymeric hyaluronic acid or its salt is less than 5 kDa, the moisturizing effect may be reduced, while if it exceeds 10,000 kDa, the viscosity may be excessively high or there may be limitations in the ability to atomize the polymeric hyaluronic acid, making it difficult to penetrate the skin.

[0024] In one embodiment of the present disclosure, polymeric hyaluroin acid particles are mixed with an acidic pH adjuster, thereby maintaining the molecular weight of the polymeric hyaluroin acid while controlling the intramolecular net charge of the hyaluronic acid, which is negatively charged by hydrogen cations from the acidic pH adjuster, thereby enabling the polymeric hyaluroin acid particles to be refined to nano-size. More specifically, the hydrogen cations from the acidic pH adjuster increase in the solution, neutralizing the negative charge of the polymeric hyaluronic acid and reducing the charge density of the polymeric hyaluronic acid. As a result, the polymeric hyaluronic acid polymer chains, which were linear in the solution, become spherical. In other words, the radius of gyration (global size) of the polymeric chains decreases, reducing the average diameter of the particles, thereby increasing the probability of hydrogen bonding of hyaluronic acid within the polymeric chains and enabling the production of hyaluronic acid that has been refined to a smaller size. Therefore, a composition according to one embodiment of the present disclosure facilitates the penetration of polymeric hyaluronic acid particles into the skin, improving skin permeability and penetration depth, thereby delivering polymeric hyaluronic acid to the lower part of the stratum corneum upon application to the skin. Furthermore, according to one embodiment of the present disclosure, the micronized polymeric hyaluronic acid particles are pH-sensitive, and thus, after penetrating the skin, they are neutralized in a skin pH environment (e.g., pH 5-7, more specifically, about pH 5-6) without the need for a separate two-part formulation, and the size of the polymeric hyaluronic acid particles increases by 200% or more, more specifically, 200% or more, 210% or more, 250% or more, 300% or more, 350% or more, 400% or more, or 450% or more. The micronized polymeric hyaluronic acid particles can provide beneficial skin benefits, such as moisturizing effects due to their self-swelling effect, and preventing or improving wrinkles and loss of skin elasticity. Furthermore, the composition containing micronized polymeric hyaluronic acid particles according to one embodiment of the present disclosure maintains a stable formulation even at high temperatures, thereby solving the problem that conventional compositions containing polymeric hyaluronic acid suffer from the breakdown of the formulation and the decrease in viscosity due to high temperature treatment during the maturation process for commercialization.In one embodiment, the composition is prepared by micronizing high molecular weight hyaluronic acid without using a polyhydric alcohol or a solubilizing agent, thereby providing a composition with excellent skin permeability and formulation stability.

[0025] In one embodiment, the average particle size of the micronized polymeric hyaluronic acid particles may be 100 nm or less. In this specification, the particle size refers to the maximum diameter of the particles, 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, i.e., the average particle size, refers to the average maximum diameter of at least 90% of the particles distributed in the composition, such as 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more. More specifically, the average particle size may 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.

[0026] In view of the above-mentioned micronization of polymeric 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 is 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 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. If the pH of the composition according to one embodiment is less than 3.0, it may irritate the skin and may not be suitable for formulation as a cosmetic composition that complies with the Korean Cosmetic Safety Management Standards for Distribution.If the pH is more than 5.0, it may not be possible to atomize the polymeric hyaluronic acid particles to an average size of 100 nm or less.

[0027] In one embodiment, the acidic pH adjuster may be an organic acid or an inorganic acid, and the type thereof is not limited as long as it can adjust the pH of the composition to 3.0 or more and less than 5.0. For example, the organic acid may include at least one 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 includes at least one selected from the group consisting of carbonic acid, hydrochloric acid, nitric acid, sulfuric acid, and the like.

[0028] In one embodiment, the acidic pH adjuster may include a fruit extract containing the organic or inorganic acid, and may be used without limitation in skin care products for the purpose of lowering pH, regardless of whether it falls within the range. For example, the fruit extract may include at least one selected from the group consisting of bilberry fruit extract (VACCINIUM MYRTILLUS 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).

[0029] In one embodiment, the present disclosure includes an organic or inorganic acid in the form of an acid itself, rather than in the form of a salt. Therefore, unlike, for example, when a metal salt of an organic acid is included, the metal salt acts as a metal cation, the hydrogen cation of the acid interacts with the negative charge of the polymeric hyaluronic acid to adjust the pH of the composition to less than 5.0, thereby enabling the polymeric hyaluronic acid particles to be atomized to an average particle size of 100 nm or less.

[0030] In one embodiment, the weight ratio of the polymeric hyaluronic acid or its salt to the acidic pH adjuster may be 1:0.01 to 10. Specifically, the acidic pH adjuster is contained in an amount of 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, per 1 part by weight of the polymeric hyaluronic acid or its salt. The amount of the acidic pH adjuster is 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, relative to 1 part by weight of the polymeric hyaluronic acid or its salt. If the weight ratio of the acidic pH adjuster to the polymeric hyaluronic acid or its salt is outside the above range, the particles of the polymeric hyaluronic acid or its salt may not be micronized, or the pH may be too low, less than 3.0, which may irritate the skin.

[0031] In one embodiment, the content of the polymeric hyaluronic acid or its salt may be 0.1 to 10 wt % based on the total weight of the composition. For example, the content of the polymeric hyaluronic acid or its salt may be 0.1 wt % or more, 0.3 wt % or more, 0.5 wt % or more, 0.6 wt % or more, 0.7 wt % or more, 0.8 wt % or more, 0.9 wt % or more, 1.0 wt % or more, 1.1 wt % or more, 1.2 wt % or more, 1.3 wt % or more, 1.5 wt % or more, 1.7 wt % or more, 2 wt % or more, 3 wt % or more, 4 wt % or more, 5 wt % or more, or 6 wt % or more based on the total weight of the composition. The content is 10% 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 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.If the content is less than 0.1% by weight, the effect on skin is small, and if it exceeds 10% by weight, it will be contained in excess compared with the acidic pH adjuster, so the particles of polymeric hyaluronic acid or its salt will not be atomized, and the viscosity will be too high, making it difficult to make into a liquid.

[0032] In one embodiment, the content of the acidic pH adjuster may be 0.01 to 50 wt % relative to the total weight of the composition, for example, the content of the acidic pH adjuster may be 0.01 wt % or more, 0.05 wt % or more, 0.1 wt % or more, 0.2 wt % or more, 0.3 wt % or more, 0.4 wt % or more, 0.5 wt % or more, 0.6 wt % or more, 0.7 wt % or more, 0.8 wt % or more, 0.9 wt % or more, 1.0 wt % or more, 1.1 wt % or more, 1.2 wt % or more, 1.3 wt % or more, 1.4 wt % or more, 1.5 wt % or more, 2 wt % or more, 3 wt % or more, 4 wt % or more, 5 wt % or more, 10 wt % or more, 15 wt % or more, 20 wt % or more, 25 wt % or more, 30 wt % or more, 35 wt % or more, or The content is 40% by weight or more, or 45% by weight or more, and 50% by weight or less, 45% by weight or less, 35% by weight or less, 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, 1.5% by weight or less, 1.4% 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, 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, or 0.1% by weight or less. If the content is less than 0.01% by weight, the particles of high molecular weight hyaluronic acid or its salt will not be atomized, and if it exceeds 50% by weight, it may irritate the skin.

[0033] In one embodiment, the composition of the present disclosure may further comprise a sequestering agent. Sequestering agents, also known as chelating agents, are typically used to bind with and inactivate metal ions, such as calcium, magnesium, or copper, which can adversely affect the stability or properties of cosmetics and other products. When organic or inorganic acids are used as acidic pH adjusters in the form of metal salts, the inclusion of such a sequestering agent in the composition can result in the polymeric hyaluronic acid particles swelling and preventing them from being micronized, making them less likely to penetrate the skin. However, in one embodiment, the present disclosure includes an organic or inorganic acid in the form of a metal salt rather than the acid itself, thereby further adding a sequestering agent to improve product stability and usability, thereby preventing micronization and enabling the average particle size of polymeric hyaluronic acid particles to be reduced to 100 nm or less. Furthermore, by lowering the pH of the composition of the present disclosure to less than 5.0, the polymeric hyaluronic acid particles are atomized and allowed to penetrate the skin. As a result, the pH of the polymeric hyaluronic acid particles naturally rises to 5.5-6.0 due to the difference in acidity with the skin's natural pH, causing the particles to swell, thereby increasing the particle size without the need for administering additional components.

[0034] In one embodiment, the sequestering agent may include, but is not limited to, at least one of an alkali salt of EDTA (ethylenediaminetetraacetic acid) and an alkali salt of a phosphate compound. More specifically, the sequestering agent may include at least one selected from the group consisting of disodium EDTA (ethylenediaminetetraacetic acid), tetrasodium EDTA, trisodium ethylenediaminedisuccinate, sodium phosphate, monosodium phosphate, disodium phosphate, trisodium phosphate, sodium tripolyphosphate, sodium hexametaphosphate, sodium metaphosphate, sodium phytate, tetrasodium pyrophosphate, and sodium acid pyrophosphate. Furthermore, the content of the sequestering agent in one embodiment may be 0.01 to 1 wt % based on the total weight of the composition. Specifically, the content of the sequestering agent is 0.001 wt % or more, 0.005 wt % or more, 0.01 wt % or more, 0.02 wt % or more, 0.03 wt % or more, 0.04 wt % or more, 0.05 wt % or more, 0.1 wt % or more, 0.5 wt % or more, or 0.9 wt % or more, and 1 wt % or less, 0.9 wt % or less, 0.8 wt % or less, 0.7 wt % or less, 0.6 wt % or less, 0.5 wt % or less, 0.4 wt % or less, 0.3 wt % or less, 0.2 wt % or less, 0.1 wt % or less, 0.05 wt % or less, 0.04 wt % or less, 0.03 wt % or less, or 0.01 wt % or less, based on the total weight of the composition. If the content of the sequestering agent is less than 0.01% by weight, the chelating effect may be low, and if it exceeds 1% by weight, beneficial metal ions in skin cells may be chelated, which may have adverse effects on the skin.

[0035] In one embodiment, the composition is prepared by micronizing high molecular weight hyaluronic acid without using a polyhydric alcohol or a solubilizing agent, thereby providing a composition with excellent in vivo permeability and formulation stability.

[0036] In one embodiment, the viscosity or hardness of the composition may vary depending on the formulation of the composition. For example, but not limited to, the viscosity may be 0.001 to 50 Pa·s. For example, but not limited to, the hardness may be 10 to 200 N.

[0037] The present disclosure may also provide a method for producing a composition according to the above-mentioned embodiment, comprising the step of micronizing the polymeric hyaluronic acid or its salt by adding an acidic pH adjuster to a solution containing the polymeric hyaluronic acid or its salt, wherein the average particle size of the micronized polymeric hyaluronic acid or its salt particles is 100 nm or less, and the pH of the composition is 3.0 or more and less than 5.0.

[0038] In one embodiment, the method may further comprise the step of adding a sequestering agent to the solution during the step of atomizing the polymeric hyaluronic acid or its salt.

[0039] In one embodiment, the method may further comprise the step of dissolving the polymeric hyaluronic acid or its salt in a solution containing at least one of water and an organic solvent before the step of micronizing the polymeric hyaluronic acid or its salt.

[0040] In one embodiment, the step of atomizing the polymeric hyaluronic acid or its salt may further include stirring and dissolving the solution with a magnetic stirrer.

[0041] In one embodiment, the method may further comprise, after the step of micronizing the high molecular weight hyaluronic acid or its salt, a step of aging the composition at a temperature of 30 to 60° C. In this case, the aging time in one embodiment is not limited, but may be, for example, 5 to 20 hours.

[0042] In one embodiment, the composition may be used for moisturizing skin. In another embodiment, the composition may be used for preventing or improving loss of skin elasticity. In another embodiment, the composition may be used for preventing or improving the onset of wrinkles. Another embodiment of the present disclosure may provide a method for moisturizing skin, preventing or improving loss of skin elasticity, or preventing or improving the onset of wrinkles, comprising administering to the skin of a subject in need thereof an effective amount of a composition comprising polymeric hyaluronic acid or a salt thereof particles and an acidic pH adjuster, wherein the acidic pH adjuster is an organic acid or an inorganic acid, the polymeric hyaluronic acid or salt thereof particles having an average particle size of 100 nm or less, and the composition having a pH of 3.0 or more and less than 5.0. Another embodiment may provide use of polymeric hyaluronic acid or a salt thereof particles and an acidic pH adjuster for preparing a composition for moisturizing skin, preventing or improving loss of skin elasticity, or preventing or improving the onset of wrinkles. Another embodiment may provide a composition for moisturizing skin, preventing or improving loss of skin elasticity, or preventing or improving the onset of wrinkles, which includes polymeric hyaluronic acid or its salt particles and an acidic pH adjuster. Another embodiment may provide a non-therapeutic cosmetic use of polymeric hyaluronic acid or its salt particles and an acidic pH adjuster as active ingredients for moisturizing skin, preventing or improving loss of skin elasticity, or preventing or improving the onset of wrinkles. In this case, the acidic pH adjuster may be an organic acid or an inorganic acid, the polymeric hyaluronic acid or its salt particles may have an average particle size of 100 nm or less, and the pH of the composition may be 3.0 or more but less than 5.0.

[0043] In one embodiment, the composition may be a topical skin composition. In the present disclosure, the term "topical skin composition" refers to a formulation that is applied to the outside of the skin. In one embodiment, the topical skin composition may be applied directly by hand or using various application means such as a spatula, and may include various formulations of cosmetics, pharmaceuticals, quasi-drugs, etc.

[0044] Furthermore, the composition according to one embodiment of the present disclosure may be provided as a carrier composition for transdermal delivery of an active substance, which has pH sensitivity and releases the active substance at pH 5-7.

[0045] In the present disclosure, the term "pH sensitivity" refers to the change in the properties of a substance depending on the pH, and in the present disclosure, this means that the size and shape of polymeric hyaluronic acid particles, the properties of capturing or releasing active substances, etc. change depending on the pH.

[0046] In one embodiment, the carrier composition penetrates the skin in a form in which the active substance is physically trapped by charge interaction with the micronized polymeric hyaluronic acid particles, and then naturally expands in size in response to the pH of the skin, thereby effectively releasing and delivering the trapped active substance into the skin.The carrier composition facilitates the penetration of the polymeric hyaluronic acid particles into the skin, improving the skin permeability and penetration depth, and therefore, when administered to the skin, can promote the skin absorption of the active substance down to the lower part of the stratum corneum.

[0047] In view of the above, another embodiment of the present disclosure may provide a skin topical composition comprising an active substance and a carrier for transdermal delivery of the active substance containing the composition.

[0048] Another embodiment of the present disclosure may provide a use of the micronized polymeric hyaluronic acid or its salt particles for use in manufacturing a carrier composition for transdermal delivery of the active substance. Another embodiment may provide a method for transdermal delivery of an active substance, comprising entrapping an effective amount of an active substance in the micronized polymeric hyaluronic acid or its salt particles. Another embodiment may provide the micronized polymeric hyaluronic acid or its salt for use as a carrier for transdermal delivery of an active substance. Another embodiment may provide a use of the micronized polymeric hyaluronic acid or its salt as a carrier for transdermal delivery of an active substance. Another embodiment may provide a non-therapeutic use of the micronized polymeric hyaluronic acid or its salt as a carrier for transdermal delivery.

[0049] In one embodiment, the active substance may include any substance that has beneficial effects on the skin or the human body, regardless of the type of substance or its efficacy. In one embodiment, the active substance may be an unstable substance that is easily degraded, or a substance that is insoluble or poorly soluble in water and does not easily permeate the skin by itself. In one embodiment, the active substance may be an active substance commonly used in the cosmetic or pharmaceutical fields. In one embodiment, the active substance may include at least one of an organic acid and its derivatives. For example, the organic acid may include at least one 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. In one embodiment, examples of the organic acid derivative include 3-O-ethyl ascorbic acid, ascorbyl glucoside, and sodium ascorbyl phosphate.

[0050] In one embodiment, the active substance may be contained in an amount of 0.01 to 40% by weight based on the total weight of the external skin preparation composition. Specifically, the active substance is contained in an amount of 0.01 wt % or more, 0.02 wt % or more, 0.03 wt % or more, 0.04 wt % or more, 0.05 wt % or more, 0.06 wt % or more, 0.07 wt % or more, 0.08 wt % or more, 0.09 wt % or more, 0.1 wt % or more, 0.2 wt % or more, 0.3 wt % or more, 0.4 wt % or more, 0.5 wt % or more, 0.6 wt % or more, 0.7 wt % or more, 0.8 wt % or more, 0.9 wt % or more, 1 wt % or more, 2 wt % or more, 3 wt % or more, 4 wt % or more, 5 wt % or more, 6 wt % or more, 7 wt % or more, 8 wt % or more, 9 wt % or more, 10 wt % or more, 15 wt % or more, 20 wt % or more, 25 wt % or more, or 29 wt % or more, based on the total weight of the topical skin composition. In one embodiment, the active ingredient is contained in an amount of 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, or 0.01% by weight or less, based on the total weight of the topical skin composition. In one embodiment, the weight ratio of the carrier composition to the total weight of the active substance may vary depending on the type of active substance. For example, the weight ratio may be 1:0.01 to 100. Specifically, the weight ratio of the carrier composition to the total weight of the active substance is 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 is 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.If the content of the active substance is too low, the intended efficacy of the active substance may not be fully exerted, and if the content of the active substance is too high, the content of the carrier composition may be relatively reduced, which may result in a decrease in skin delivery efficiency.

[0051] In one embodiment, the composition may further contain a basic pH adjuster in addition to the acidic pH adjuster to adjust the pH of the composition to 3.0 or more and less than 5.0 depending on the type and content of the active substance.

[0052] In one embodiment, the topical skin composition may be used for various purposes depending on the type of active substance. For example, the composition may be used for skin moisturizing. In one embodiment, the composition may be used for preventing or improving loss of skin elasticity. In one embodiment, the composition may be used for preventing or improving the onset of skin wrinkles. In one embodiment, the composition may be used for skin whitening. In one embodiment, the composition may be used for anti-inflammatory purposes. In one embodiment, the composition may be used for preventing, improving, or treating acne. Another embodiment of the present disclosure may provide a method for skin moisturizing, skin whitening, preventing or improving loss of skin elasticity, preventing or improving the onset of skin wrinkles, anti-inflammatory, or anti-acne, comprising administering an effective amount of a carrier composition having the active substance entrapped therein to the skin of a subject in need thereof. Another embodiment may provide use of the carrier composition having the active substance entrapped therein to prepare a topical skin composition for skin moisturizing, skin whitening, preventing or improving loss of skin elasticity, preventing or improving the onset of skin wrinkles, anti-inflammatory, or anti-acne. Another embodiment may provide a carrier composition having the active agent entrapped therein for use in a composition for moisturizing the skin, whitening the skin, preventing or improving loss of skin elasticity, preventing or improving the onset of wrinkles on the skin, anti-inflammatory or anti-acne. Another embodiment may provide a non-therapeutic cosmetic use of a carrier composition having the active agent entrapped therein as an active ingredient for moisturizing the skin, whitening the skin, preventing or improving loss of skin elasticity, preventing or improving the onset of wrinkles on the skin, anti-inflammatory or anti-acne.

[0053] In one embodiment, the composition may be a cosmetic composition. In one embodiment, the cosmetic composition may have the appearance of a cosmetically or dermatologically acceptable vehicle or base. For example, the composition may be provided in the form of a solution, gel, solid, a paste-free product, an emulsion obtained by dispersing an oil phase in an aqueous phase, a suspension, a microemulsion, microcapsules, microgranules, or ionic (liposome) and non-ionic vesicular dispersions, or in the form of a cream, lotion, emulsion, powder, ointment, spray, or stick concealer. These compositions may be prepared according to conventional methods in the art. The compositions according to the present disclosure may also be used in the form of a foam or an aerosol composition further comprising a compressed propellant.

[0054] The cosmetic composition according to an embodiment of the present disclosure is not particularly limited in its formulation and may be formulated into cosmetics such as ampoules, creams, softening lotions, astringent lotions, nourishing lotions, nourishing creams, gel creams, massage creams, serums, eye creams, eye essences, cleansing creams, cleansing foams, cleansing waters, cleansing tissues containing the cosmetic composition, packs, body lotions, body creams, body oils, and body essences. When the formulation according to an embodiment of the present disclosure is a paste, cream, or gel, the carrier may be animal fiber, plant fiber, wax, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silica, talc, or zinc oxide. When the formulation according to an embodiment of the present disclosure is a spray, the carrier may be lactose, talc, silica, aluminum hydroxide, calcium silicate, or polyamide powder, and may further include a propellant such as chlorofluorohydrocarbons, propane / butane, or dimethyl ether. When the formulation according to an embodiment of the present invention is a solution or emulsion, the carrier component may be a solvent, solvating agent, or emulsifier, such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyl glycol oil, glycerin aliphatic esters, polyethylene glycol, or fatty acid esters of sorbitan. When the formulation according to an embodiment of the present invention is a suspension, the carrier component may be a liquid diluent such as water, ethanol, or propylene glycol, a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester, or polyoxyethylene sorbitan ester, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, or tragacanth.When the formulation according to an embodiment of the present invention is a surfactant-containing cleanser, the carrier component may be fatty alcohol sulfate, fatty alcohol ether sulfate, sulfosuccinate monoester, isethionate, imidazolinium derivative, methyl taurate, sarcosinate, fatty acid amide ether sulfate, alkylamidobetaine, fatty alcohol, fatty acid glyceride, fatty acid diethanolamide, vegetable oil, lanolin derivative, or ethoxylated glycerin fatty acid ester.

[0055] The cosmetic composition according to an embodiment of the present disclosure may further include functional additives and ingredients commonly found in cosmetic compositions. The functional additives may include a component selected from the group consisting of water-soluble vitamins, oil-soluble vitamins, polymeric peptides, polymeric polysaccharides, sphingolipids, and seaweed extracts. Other ingredients may include oils and fats, moisturizers, emollients, neutralizers, surfactants, organic and inorganic pigments, organic powders, UV absorbers, preservatives, disinfectants, antioxidants, plant extracts, pH adjusters, alcohol, colorants, fragrances, blood circulation enhancers, cooling agents, antiperspirants, purified water, etc.

[0056] In one embodiment, the composition may be a pharmaceutical composition. When the composition according to one embodiment of the present disclosure is applied to a pharmaceutical product, the active ingredient used in one embodiment of the present disclosure may be added to a commonly used inorganic or organic carrier to form a semi-solid or liquid parenteral formulation. The pharmaceutical composition according to the present disclosure may be administered parenterally, rectally, topically, transdermally, intravenously, intramuscularly, intraperitoneally, subcutaneously, or the like. In one embodiment, the pharmaceutical composition may be a parenteral formulation, more specifically, a topical skin formulation. For example, the topical skin formulation may be an ointment, lotion, emulsion, gel, cream, spray, suspension, emulsion, patch, or other formulation, but is not limited to these. The active ingredient in the composition according to one embodiment of the present disclosure can be easily formulated according to conventional methods widely known in the art, and surfactants, excipients, colorants, spices, preservatives, stabilizers, buffers, suspending agents, and other commonly used adjuvants may be used as appropriate. The dosage of the active ingredient of the pharmaceutical composition according to one embodiment of the present disclosure will depend on the age, sex, and weight of the recipient, the condition and its severity, the route of administration, and the prescriber's discretion. Determination of the appropriate dosage based on these factors is within the skill of one of ordinary skill in the art. The daily dosage may be, for example, but is not limited to, 0.1 to 100 mg / kg / day, more specifically, 5 to 50 mg / kg / day.

[0057] In one embodiment, the composition may be a food composition. The food composition according to one embodiment of the present disclosure may be a liquid or solid formulation, such as a tablet, capsule, soft capsule, pill, granule, beverage (drinkable), diet bar, chocolate, caramel formulation, or confectionery formulation, and the formulation is not particularly limited. In addition to the active ingredient, the food composition according to one embodiment of the present disclosure may contain excipients, sugars, flavorings, colorants, oils and fats, proteins, etc. as needed.

[0058] [Embodiment] The present disclosure will be described in more detail below with reference to the following examples. However, the following examples are merely illustrative examples to aid in understanding the present disclosure, and are not intended to limit the scope of the present disclosure.

[0059] [Test Example 1] In order to confirm the microparticulation of the polymeric hyaluronic acid or its salt according to the present disclosure, Examples 1 to 4 having the compositions shown in Table 1 below were produced by the following method.

[0060] First, sodium hyaluronate (manufacturer: Hyundai Bioland, product name: Bio sodium hyaluronate, weight-average molecular weight: 1,500 kDa) was prepared as a polymeric hyaluronate. In Examples 1 to 4, 1,2-hexanediol and the sodium hyaluronate were dissolved in deionized water using a magnetic stirrer, and then the remaining ingredients were added. The mixture was mixed at high speed of 12,000 rpm using a homogenizer to induce particle atomization. The pH of the atomized solution was 3 to 4. The hyaluronic acid solution was placed in a chamber at 45°C, and then aged for 12 hours or more to stabilize the particles and physical properties, producing the final composition.

[0061] As comparative examples for comparing the effects of the examples, Comparative Example 1 containing only a solvent and sodium hyaluronate, and Comparative Example 2 containing trisodium citrate (pH 6.5), a type of conjugate base, i.e., a metal salt of an organic acid, as a pH adjuster, were produced in the same manner as in Examples 1 to 4.

[0062] [Table 1]

[0063] To compare the microparticulation of polymeric hyaluronic acid or its salt in Examples 1 to 4 with Comparative Examples 1 and 2, the average particle size of each composition was measured using a Zetasizer from Malvern Instruments, and the results are shown in Figures 1 and 2.

[0064] As a result, as shown in Figures 1 and 2, the particles of polymeric hyaluronate in Comparative Example 1, which is a polymeric hyaluronate aqueous solution without the addition of a pH adjuster, are distributed in the range of 100 to 1000 nm, and no decrease in particle size was observed, whereas the particles of polymeric hyaluronate in Examples 1 to 4, even when the type of acid was changed or a sequestering agent was added, all had sizes in the range of 10 to 100 nm, and it was confirmed that they were atomized to about 10% or less of those in Comparative Example 1. In the case of Comparative Example 2, the average particle diameter of polymeric hyaluronate was 100 nm or less, but by using a metal salt of an organic acid as a pH adjuster, there is a limit in that the particle size does not expand again after administration to the skin, as confirmed in Test Example 2 described below.

[0065] In addition, when the relative molecular weights of Example 1 and Comparative Example 1 were measured by gel chromatography (GPC) at the request of the Korea Polymer Testing Institute (Koptri), an accredited testing organization, it was found that the polymeric hyaluronates of Comparative Example 1 (Figure 3) and Example 1 (Figure 4) both showed the same peak at 17 minutes, indicating that they had the same maximum molecular weight. This result means that the polymeric hyaluronate of Example 1 was only micronized to a particle size of 100 nm or less, without any change in molecular weight.

[0066] [Test Example 2] Whether the micronized polymeric hyaluronic acid or its salt particles according to the present disclosure are administered to the skin and then neutralized by the pH of the skin, thereby expanding in size again, and whether the effects of polymeric hyaluronic acid salts, such as moisturizing or improving skin elasticity, can be provided to the skin, was confirmed by observing the change in size of the micronized polymeric hyaluronic acid or its salt particles in response to changes in pH, using Examples 1 to 4 and Comparative Example 2 produced in Test Example 1 as the subjects.

[0067] Specifically, a basic neutralizer (manufacturer: ANGUS, product name: Tromethamine) was added to each of Examples 1 to 4 and Comparative Example 2 produced in Test Example 1 to increase the pH of each composition to pH 6, the same as the pH of the skin, and then changes in particle behavior were confirmed using a Zetasizer (Malvern, UK) device.

[0068] As a result, as shown in the table below, in Examples 1 to 4, as the pH of the composition increased, the particle size increased again compared to before the pH was increased, but in Comparative Example 2, the change in particle size was minimal, and it was confirmed that the size actually decreased slightly.

[0069] [Table 2]

[0070] [Test Example 3] The viscosity of Examples 1 to 4 and Comparative Example 1 produced in Test Example 1 was measured to confirm changes in the physical properties of the composition according to the present disclosure.

[0071] The viscosity (Pa·s) was measured at 25°C using a rheometer (Malvern, UK) with a plate type CP 4 / 40 under the following conditions: an oscillation stress adjusted to 1 Pa, a frequency range of 0.1 to 10 Hz, a shear stress of 1 Pa, and a gap of 1 mm. The G' and G" values ​​were measured at 1 Hz, and the G' and G" measurement samples were standardized to disks with a diameter of 20 mm and a thickness of 1 mm.

[0072] As a result, as shown in the table below, in Examples 1 to 4, it can be confirmed that the physical properties of the composition are stabilized at a low viscosity, even though the hyaluronic acid solution was aged at 45°C for more than 12 hours during production.

[0073] [Table 3]

[0074] [Test Example 4] In order to confirm the increase in skin permeability due to the micronization of the polymeric hyaluronic acid or salt thereof particles according to the present disclosure, the following experiment was carried out.

[0075] First, Fitzpatrick type II skin tissue (manufacturer: Genoskin, product name: NativeSkin) biopsied from the abdomen of a 33-year-old woman was supplied by the manufacturer, and Example 1 and Comparative Example 1 produced in Test Example 1 were applied to the skin tissue. Tape discs (manufacturer: Cuderm, product name: D100, diameter: 22 mm) were attached to the skin tissue, and then pressure was applied to the skin tissue at a force of 225 gr. / sq.cm using a D-squame pressure device, after which the tape discs were peeled off. A total of 10 tape discs were peeled off sequentially at approximately 3-minute intervals, and the tape disc samples were stored in a freezer.

[0076] Using a desorption electrospray ionization (DESI) mass spectrometer (manufacturer: Waters, product name: 2D DESI stage & XEVO G2-XS QTof), the penetration of each composition was confirmed at each time from the tape disk sample stored in the freezer. At that time, DESI-MS spectra were acquired using a 2D DESI stage and XEVO G2-XS QTof (Waters, Milford, USA). The spray solvent was 98% methanol + 0.1% formic acid, the flow rate was 2 μL / min, and the spray gas inlet pressure was set to 0.5 MPa. 100 × 100 μm sections were removed from the tape-stripped tape disk sample. 2 The area of ​​the ion beam was measured. In the cation mode, the measured mass range was 50–1,000 m / z. MS imaging data were acquired using MassLynx 4.2 (Waters, USA) and visualized using HDI (High Definition Imaging) 1.5 software (Waters).

[0077] As a result, as shown in FIG. 5, in the case of Comparative Example 1, the size of the polymeric hyaluronate particles was large, so no particles were observed to have penetrated the stratum corneum, whereas in Example 1 according to one embodiment of the present disclosure, deep penetration up to the tenth order was confirmed due to the microparticulation of the polymeric hyaluronate.

[0078] [Example 5] A carrier composition for transdermal delivery of an active substance according to one embodiment of the present disclosure and a composition containing the active substance were prepared by the following method.

[0079] First, sodium hyaluronate (manufacturer: Hyundai Bioland, product name: Bio sodium hyaluronate, weight-average molecular weight: 1,500 kDa) was prepared as a polymeric hyaluronate. 1,2-Hexanediol and the sodium hyaluronate were dissolved in deionized water using a magnetic stirrer. The remaining ingredients listed in Table 4 below were added, and the mixture was mixed at high speed of 12,000 rpm using a homogenizer to atomize the particles to an average particle size of 100 nm or less. The pH of the atomized solution was 3-4. The hyaluronic acid solution was placed in a chamber at 45°C, and then aged for at least 12 hours to stabilize the particles and physical properties, producing the final composition.

[0080] Comparative Example 3 As a comparative example for comparing the effects of the examples, Comparative Example 3 was prepared using the same composition and method as in Example 5, except that sodium hyaluronate was not included.

[0081] [Table 4]

[0082] [Test Example 5] In order to confirm the transdermal delivery effect of the carrier composition of the present disclosure on the active substance, the amount of skin absorption of ascorbic acid, which is the active substance of Example 5 and Comparative Example 3, was measured by the following method and then compared.

[0083] The amount of ascorbic acid absorbed was measured using a Franz diffusion cell. A membrane (Isopore, Merck Millipore, USA) was fixed between the donor and receptor phases, and the contact area with the receptor phase was approximately 1.767 cm.2 The receptor phase was phosphate buffered saline (PBS, 7 mL), and the mixture was stirred at 600 rpm at 32°C. After 1 and 3 hours, the receptor phase was sampled and the amount of ascorbic acid was quantified by HPLC (high-performance liquid chromatography). For HPLC analysis, Mightysil RP-18 GP 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. Detection was performed at a wavelength of 254 nm and a flow rate of 1 mL / min, and the concentration was calculated from the area of ​​the resulting peak according to Non-Patent Document 1. The document is incorporated herein by reference in its entirety.

[0084] [Table 5]

[0085] As a result, in the case of Comparative Example 3, which is a composition containing an active substance without the carrier composition of the present disclosure, the amount of ascorbic acid absorbed into the skin tissue was extremely small and not detected, whereas in Example 5, it was confirmed that the carrier composition containing micronized polymeric hyaluronate effectively delivered ascorbic acid to the skin tissue, resulting in a high absorption amount.

[0086] [Test Example 6] In order to confirm the transdermal delivery effect of the active substance by the carrier composition according to the present disclosure, the penetration depth of the active substance into the skin was confirmed by the following method.

[0087] First, Fitzpatrick type II skin tissue (manufacturer: Genoskin, product name: NativeSkin) biopsied from the abdomen of a 33-year-old woman was supplied by the manufacturer, and Example 5 and Comparative Example 3 were applied to the skin tissue. Tape discs (manufacturer: Cuderm, product name: D100, diameter: 22 mm) were attached to the skin tissue, and then pressure was applied to the skin tissue at a force of 225 gr. / sq.cm using a D-squame pressure device, after which the tape discs were peeled off. A total of 10 tape discs were peeled off sequentially at approximately 3-minute intervals, and the tape disc samples were stored in a freezer.

[0088] Using a desorption electrospray ionization (DESI) mass spectrometer (manufacturer: Waters, product name: 2D DESI stage & XEVO G2-XS QTof), the penetration of each composition was confirmed at each time from the tape disk sample stored in the freezer. At that time, DESI-MS spectra were acquired using a 2D DESI stage and XEVO G2-XS QTof (Waters, Milford, USA). The spray solvent was 98% methanol + 0.1% formic acid, the flow rate was 2 μL / min, and the spray gas inlet pressure was set to 0.5 MPa. A 100 × 100 μm sample was taken from the tape-peeled tape disk sample. 2 The area of ​​the ion beam was measured. In the cation mode, the measured mass range was 50–1,000 m / z. MS imaging data were acquired using MassLynx 4.2 (Waters, USA) and visualized using HDI (High Definition Imaging) 1.5 software (Waters).

[0089] As a result, as shown in FIG. 7, in the case of Comparative Example 3, which is a composition containing an active substance without the carrier composition of the present disclosure, no active substance was observed to have penetrated into the stratum corneum, whereas in Example 5, it was confirmed that the active substance had penetrated deep into the stratum corneum up to the 10th tape peeling using a carrier composition containing micronized polymeric hyaluronate.

[0090] The present disclosure can provide the following embodiments as examples.

[0091] A first embodiment may provide a composition comprising particles of polymeric hyaluronic acid or its salt and an acidic pH adjuster, wherein the acidic pH adjuster is an organic acid or an inorganic acid, the particles of polymeric hyaluronic acid or its salt having an average particle size of 100 nm or less, and a pH of 3.0 or more but less than 5.0.

[0092] The second embodiment may provide a composition according to the first embodiment, further comprising a sequestering agent.

[0093] A third embodiment may provide a composition according to the first or second embodiment, wherein the sequestering agent is at least one of an alkali salt of EDTA (ethylene-diamine-tetraacetic acid) and an alkali salt of a phosphate compound.

[0094] 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 polymeric hyaluronic acid or a salt thereof is 5 to 10,000 kDa.

[0095] A fifth embodiment may provide a composition according to any one of the first to fourth embodiments, wherein the weight ratio of the polymeric hyaluronic acid or a salt thereof to the acidic pH adjuster is 1:0.01-10.

[0096] The sixth embodiment may provide a composition according to any one of the first to fifth embodiments, wherein the polymeric hyaluronic acid or a salt thereof is contained in an amount of 0.1 to 10% by weight relative to the total weight of the composition.

[0097] The 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 wt % relative to the total weight of the composition.

[0098] Embodiment 8-1 may provide a composition in any one of Embodiments 1 to 7, wherein the organic acid is at least one 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.

[0099] Embodiment 8-2 may provide a composition in any one of embodiments 1 to 8-1, wherein the inorganic acid is at least one selected from the group consisting of carbonic acid, hydrochloric acid, nitric acid, and sulfuric acid.

[0100] A ninth embodiment may provide a composition according to any one of the first to eighth embodiments, wherein the composition is a skin external preparation composition.

[0101] A tenth embodiment may provide a composition according to any one of the first to ninth embodiments, wherein the composition is for moisturizing skin.

[0102] An eleventh embodiment may provide a composition according to any one of the first to tenth embodiments, wherein the composition is for preventing or improving loss of skin elasticity.

[0103] A twelfth embodiment may provide the composition of any one of the first to eleventh embodiments, wherein the composition is a cosmetic composition.

[0104] A thirteenth embodiment may provide the composition of any one of the first to twelfth embodiments, wherein the composition is a food composition.

[0105] A fourteenth embodiment may provide a composition according to any one of the first to thirteenth embodiments, wherein the composition is a pharmaceutical composition.

[0106] The fifteenth embodiment may provide a method for producing the composition of any one of the first to fourteenth embodiments, which comprises a step of micronizing the polymeric hyaluronic acid or its salt by adding an acidic pH adjuster to a solution containing the polymeric hyaluronic acid or its salt, wherein the average particle size of the micronized polymeric hyaluronic acid or its salt particles is 100 nm or less, and the pH of the composition is 3.0 or more and less than 5.0.

[0107] The sixteenth embodiment may provide a manufacturing method according to the fifteenth embodiment, wherein the step of micronizing the high molecular weight hyaluronic acid or its salt further comprises the step of adding a sequestering agent to the solution.

[0108] 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 active substance, and the composition releases the active substance at a pH of 5 to 7.

[0109] An eighteenth embodiment may provide a skin topical composition comprising an active substance and a carrier for transdermal delivery of the active substance, the carrier comprising a composition according to any one of the first to fourteenth embodiments.

[0110] The 19th embodiment may provide an external skin preparation composition in the 18th embodiment, wherein the external skin preparation composition contains an active substance in an amount of 0.01 to 40% by weight relative to the total weight of the external skin preparation composition.

[0111] The twentieth embodiment may provide a skin topical preparation composition according to the eighteenth or nineteenth embodiment, in which the active substance is physically entrapped in the carrier composition.

[0112] A 21st embodiment may provide an external skin preparation composition according to any one of the 18th to 20th embodiments, wherein the external skin preparation composition is for moisturizing the skin.

[0113] The 22nd embodiment may provide an external skin preparation composition in the 18th to 21st embodiments, wherein the external skin preparation composition is for preventing or improving a decrease in skin elasticity.

[0114] A 23rd embodiment may provide an external skin preparation composition according to any one of the 18th to 22nd embodiments, wherein the external skin preparation composition is for skin whitening.

[0115] A 24th embodiment may provide an external skin preparation composition according to any one of the 18th to 23rd embodiments, wherein the external skin preparation composition is a cosmetic composition.

[0116] A 25th embodiment may provide an external skin preparation composition according to any one of the 18th to 24th embodiments, wherein the external skin preparation composition is a pharmaceutical composition.

Claims

1. The composition comprises polymeric hyaluronic acid or salt particles thereof and an acidic pH adjuster, the acidic pH adjuster is an organic acid or an inorganic acid, The polymeric hyaluronic acid or salt thereof has an average particle size of 100 nm or less, A composition having a pH of 3.0 or greater but less than 5.

0.

2. The composition of claim 1 further comprising a sequestering agent.

3. 3. The composition according to claim 2, wherein the sequestering agent is at least one of an alkali salt of ethylene-diamine-tetraacetic acid (EDTA) and an alkali salt of a phosphate compound.

4. The composition according to claim 1, wherein the weight-average molecular weight of the polymeric hyaluronic acid or its salt is 5 to 10,000 kDa.

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

6. The composition according to claim 1, wherein the polymeric hyaluronic acid or its salt is contained in an amount of 0.1 to 10% by weight based on the total weight of the composition.

7. The composition of claim 1, wherein the acidic pH adjuster is present in an amount of 0.01 to 50% by weight based on the total weight of the composition.

8. The organic acid may be 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, or tartaric acid. at least one selected from the group consisting of hydroxybenzoates, ... The composition according to claim 1 , wherein the inorganic acid is at least one 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 skin topical composition.

10. The composition of claim 1 , wherein the composition is for moisturizing skin.

11. The composition according to claim 1, wherein the composition is for preventing or improving loss of skin elasticity.

12. The composition of claim 1 , wherein the composition is a cosmetic composition.

13. The composition of claim 1 , wherein the composition is a food composition.

14. The composition of claim 1 , wherein the composition is a pharmaceutical composition.

15. A method for producing the composition according to any one of claims 1 to 14, comprising the steps of: The method comprises the step of adding an acidic pH adjuster to a solution containing high molecular weight hyaluronic acid or a salt thereof to atomize the high molecular weight hyaluronic acid or a salt thereof, The average particle size of the micronized polymeric hyaluronic acid or its salt particles is 100 nm or less, The method for producing the composition, wherein the pH of the composition is 3.0 or more and less than 5.

0.

16. 16. The method of claim 15, wherein the step of micronizing the polymeric hyaluronic acid or salt thereof further comprises adding a sequestering 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 active substance, and the composition releases the active substance at a pH of 5 to 7.

18. an active substance; A carrier for transdermal delivery of the active substance comprising the composition of any one of claims 1 to 8; A skin topical composition comprising:

19. The external skin preparation composition according to claim 18, wherein the external skin preparation composition contains the active substance in an amount of 0.01 to 40% by weight based on the total weight of the external skin preparation composition.

20. 20. The topical skin composition of claim 18, wherein the active ingredient is physically entrapped in the carrier composition.

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

22. The external skin preparation composition according to claim 18, which is for preventing or improving a decrease in skin elasticity.

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

24. The topical skin composition according to claim 18, wherein the topical skin composition is a cosmetic composition.

25. The external skin preparation composition according to claim 18, wherein the external skin preparation composition is a pharmaceutical composition.

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