KR20240037525A - Carrier composition for transdermal delivery of active substance comprising polymer hyaluronic acid nanoparticles - Google Patents

Abstract

The present specification discloses a carrier composition for transdermal delivery of an effective substance comprising high molecular weight hyaluronic acid microparticles. The carrier composition according to the present disclosure not only penetrates the skin easily and is stable, but also can deliver a small amount of the effective substance to the skin with a high skin absorption rate. The carrier composition may exhibit dual functionality in that it can provide useful effects to the skin by itself after penetrating into the skin and releasing effective substances.

Description

Carrier composition for transdermal delivery of active substance comprising polymer hyaluronic acid nanoparticles}

Disclosed herein is a carrier composition for transdermal delivery of an effective substance.

In the cosmetics or pharmaceutical industries, when external skin formulations contain active substances that are difficult to penetrate or have low stability, synthetic surfactants are used to promote skin absorption of the effective substances, or synthetic polymer compounds such as polyethylene glycol or liposomes are used. A method of increasing the skin penetration rate of effective substances by using nanoparticles as a carrier has been widely used. However, due to problems such as toxicity in the human body, allergen issues, and environmental hazards of the amphiphilic enhancers used in the above-mentioned synthetic compounds or liposome nanoparticles, the cosmetics and pharmaceutical industries are trying to avoid their use. Therefore, there is a need to develop a delivery system that is friendly to the human body and the environment and can effectively enhance transdermal absorption of effective substances.

KR 10-1971834 B1

The problem that the present disclosure aims to solve is to provide a carrier composition for transdermal delivery of an effective substance that is biocompatible and easily penetrates the skin.

The problem that the present disclosure aims to solve is to provide a composition for topical skin application containing an effective substance and a carrier composition for transdermal delivery of the effective substance.

In order to solve the above problem, an embodiment of the present disclosure,

High molecular weight hyaluronic acid or its salt particles; and an acidic pH adjusting agent,

The acidic pH adjuster is an organic acid or an inorganic acid,

The average particle diameter of the polymer hyaluronic acid or its salt particles is 100 nm or less,

pH is greater than 3.0 but less than 5.0,

Provided is a carrier composition for transdermal delivery of an effective substance, which has pH sensitivity.

In addition, an embodiment of the present disclosure is an effective substance; and a carrier composition for transdermal delivery of the effective substance.

The carrier composition according to one embodiment of the present disclosure is in the form of nano-sized fine particles, which not only easily and stably penetrates the skin, but also can deliver a small amount of effective substances to the skin with a high skin absorption rate. In addition, after penetrating into the skin, it is neutralized to match the skin pH, expands again in size, and releases the effective substance. The high molecular weight hyaluronic acid or its salt and the acidic pH adjuster itself contained in the carrier composition can provide useful effects on the skin. In that it can exhibit dual functionality.

Figure 1 is a schematic diagram showing an effective substance delivery and release system of a carrier composition according to an embodiment of the present disclosure.
Figure 2 is a diagram confirming the absorption depth of the effective substance in skin tissue according to Example 1 and Comparative Example 1 according to an embodiment of the present disclosure.

Hereinafter, preferred embodiments of the present disclosure will be described in detail with reference to the attached drawings.

The embodiments of the present disclosure disclosed in the text are merely illustrative for purposes of explanation, and the embodiments of the present disclosure may be implemented in various forms and should not be construed as being limited to the embodiments described in the text. The present disclosure can be subject to various changes and may take various forms. The embodiments are not intended to limit the present disclosure to a specific disclosure form, and all changes, equivalents, or substitutes included in the spirit and technical scope of the present disclosure are included. It should be understood as including. Singular expressions include plural expressions unless the context clearly dictates otherwise. In this application, terms such as “comprise” or “have” are intended to designate the presence of features, numbers, steps, operations, components, parts, or combinations thereof described in the specification, and one or more other features The presence or addition of elements, numbers, steps, operations, components, parts or combinations thereof is not excluded.

One example of the present disclosure is polymer 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 diameter of the polymer hyaluronic acid or its salt particles is 100 nm or less, the pH is 3.0 or more and less than 5.0, and has pH sensitivity, A carrier composition for transdermal delivery of an effective substance can be provided.

“Hyaluronic acid” in this specification refers to an anionic natural polysaccharide that exists in salt form and is a raw material corresponding to EWG grade 1, so it is known to be an excellent material in terms of environmental and biocompatibility. It is mainly produced and purified through microorganisms. It exists in the connective tissue and extracellular matrix of the human body, and has a high water content due to anionic functional groups, so it is widely used as a moisturizer. The molecular structure of hyaluronic acid can be represented by the following formula (1), and in this specification, hyaluronic acid may be included in the form of a salt.

[Formula 1]

The x is 200 to 20000 mol.

In one embodiment of the present disclosure, the salt is not particularly limited, but may be an acid addition salt, a base addition salt, or an amino acid salt. For example, the salts include inorganic salts such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, and phosphate; Organic acid salts such as citrate, oxalate, acetate, formate, propionate, benzoate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, and p-toluenesulfonate; Inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt, copper salt, zinc salt, aluminum salt, and ammonium salt; Organic base salts such as triethylammonium salt, triethanolammonium salt, pyridinium salt, and diisopropylammonium salt; It may be an amino acid salt such as lysine salt, arginine salt, histidine salt, aspartate, or glutamate. As an example, the salt is sodium hyaluronic acid, potassium salt of hyaluronic acid, acetate of hyaluronic acid, ammonium salt of hyaluronic acid, or C12-13 Alkyl Glyceryl Hydrolyzed Hyaluronate. You can. 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. As an example, 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 high molecular weight hyaluronic acid or its salt is 5 kDa or more, 10 kDa or more, 100 kDa or more, 500 kDa or more, 1000 kDa or more, 1,100 kDa or more, 1,200 kDa or more, 1,300 kDa or more, 1,400 kDa or more, More than 1,500 kDa, more than 1,600 kDa, more than 1,700 kDa, more than 1,800 kDa, more than 1,900 kDa, more than 2,000 kDa, more than 2,200 kDa, more than 2,400 kDa, more than 2,600 kDa, more than 2,800 kDa, more than 2,900 kDa, more than 3,000 kDa, 4,0 00 kDa It may be above 5,000 kDa, 10,000 kDa or less, 9,000 kda or less, less than 8,000 kDa, less than 7,000 kDa, less than 6,000 kDa, less than 5,000 kDa, 4,500 kDa or less, 4,000 kda or less or less, 3,600 kDa or less, 3,500 kDa or less, 3,400 kDa or less, 3,300 kDa or less, 3,200 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, It may be 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. More specifically, the weight average molecular weight of the high molecular weight hyaluronic acid or its salt may be 1,000 to 5,000 kDa. If the weight average molecular weight of the polymer hyaluronic acid or its salt is less than 5 kDa, the moisturizing effect may be reduced, and if it is more than 10,000 kDa, it may have excessively high viscosity or have limitations in atomization, making skin penetration difficult.

In the present disclosure, the "pH sensitivity" refers to changes in the properties of a material depending on pH. In the present disclosure, the size and shape of the polymer hyaluronic acid particles and the characteristics of capturing or releasing the effective substance change depending on the pH. means that

One embodiment of the present disclosure includes polymer hyaluronic acid particles together with an acidic pH adjuster, thereby maintaining the molecular weight of the polymer hyaluronic acid and reducing the intramolecular net charge (net) of hyaluronic acid, where hydrogen cations due to the acid of the acidic pH adjuster are negatively charged. By adjusting the charge, the polymer hyaluronic acid particles can be atomized into nano-sized particles. In more detail, the hydrogen cations of the acidic pH adjuster increase in the solution and neutralize the negative charge of the polymer hyaluronic acid, thereby lowering the charge density of the polymer hyaluronic acid. As a result, the high molecular weight hyaluronic acid polymer chain changes from being linear in the solution to having a spherical shape. In other words, the radius of gyration (globular size) of the polymer chain can be reduced, which can reduce the average diameter of the particles, so the intramolecular hydrophobic interaction and intermolecular hydrogen bonding within the polymer chain work together to atomize to a smaller size. hyaluronic acid can be produced. As a result, the carrier composition according to an embodiment of the present disclosure facilitates the penetration of polymer hyaluronic acid particles into the skin and improves skin penetration rate and penetration depth, so that polymer hyaluronic acid can be delivered to the lower part of the stratum corneum when administered to the skin, thereby delivering the effective substance. It can promote skin absorption.

According to one embodiment of the present disclosure, the micronized polymer hyaluronic acid particles exhibit pH sensitivity, so after penetrating into the skin, the pH of the skin, for example, pH 5 to 7, more specifically, about pH, without a separate two-liquid formulation. As it is neutralized in an environment of 5 to 6, the size of the polymer hyaluronic acid particles increases again by 200% or more, more specifically, by 200% or more, 210% or more, 250% or more, 300% or more, 350% or more, 400% or more, or 450% or more. It can be expanded to more than %. Therefore, the carrier composition penetrates into the skin in a form in which the effective substance is physically captured by electrostatic interaction with the carrier composition, and then naturally expands in size in response to skin pH, effectively releasing the captured effective substance into the skin. and can be delivered.

Another embodiment of the present disclosure may provide a composition for external application to the skin including an effective substance and a carrier composition for transdermal delivery of the effective substance.

Another embodiment of the present disclosure may provide the use of the micronized polymeric hyaluronic acid or its salt particles for use in the production of a carrier composition for transdermal delivery of the effective substance. Another embodiment may provide a method of transdermal delivery of an effective substance comprising entrapped an effective amount of the effective substance in the micronized polymer hyaluronic acid or salt particles thereof. Another embodiment may provide the micronized polymer hyaluronic acid or a salt thereof as a carrier for transdermal delivery of an effective substance. Another embodiment may provide the use of the micronized polymer hyaluronic acid or its salt as a carrier for transdermal delivery of an effective substance. Another embodiment may provide a non-therapeutic use of the micronized polymer hyaluronic acid or a salt thereof as a carrier for transdermal delivery.

As an example, the effective substance may be included as long as it has a useful effect on the skin or the human body without being limited by the effect or type of substance. As an example, the effective substance may be a substance that is unstable and easily denatured, or may be a substance that is water-insoluble or poorly soluble and thus difficult to penetrate the skin. As an example, the effective substances may be effective substances commonly used in the cosmetics or pharmaceutical fields. As an example, the effective substance may include one or more of organic acids and their derivatives. For example, the organic acids include citric acid, phosphoric acid, fumaric acid, ascorbic acid, ferulic acid, succinic acid, and lactic acid. Lactic acid, Hyaluronic acid, Malic acid, Butyric acid, Formic acid, Acetic acid, Salicylic acid, It may include one or more selected from the group consisting of glycolic acid, tartaric acid, and gluconolactone. As an example, the organic acid derivative may include 3-O-ethyl ascorbic acid, ascorbyl glucoside, sodium ascorbyl phosphate, etc.

As an example, the effective substance may be included in an amount of 0.01 to 40% by weight based on the total weight of the external skin composition. Specifically, the effective substance is more than 0.01% by weight, more than 0.02% by weight, more than 0.03% by weight, more than 0.04% by weight, more than 0.05% by weight, more than 0.06% by weight, more than 0.07% by weight, more than 0.08% by weight, based on the total weight of the external skin composition. % 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 weight% or more % 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 weight% or more % or more, 15% by weight or more, 20% by weight or more, 25% by weight or more, or 29% by weight or more. As an example, the effective substance is 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, based on the total weight of the external skin composition. 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, It may be included in 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. Additionally, as an example, the weight ratio of the carrier composition to the total weight of the effective substance may vary depending on the type of the effective substance. For example, the weight ratio may be 1:0.01-100. Specifically, the weight ratio of the carrier composition to the total weight of the effective 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. , may be 10 or greater, 20 or greater, 30 or greater, 40 or greater, 50 or greater, 60 or greater, 70 or greater, 80 or greater, or 90 or greater, and may be 100 or lower, 90 or lower, 80 or lower, 70 or lower, 60 or lower, 50 or lower, or 40 or lower. , 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 too little of the effective substance is included, the desired effect of the effective substance may not be sufficiently achieved, and if the effective substance is excessively included, the content of the carrier composition may be relatively reduced, thereby reducing skin delivery efficiency.

A composition for external use for skin containing a carrier composition containing micronized polymer hyaluronic acid particles according to an embodiment of the present disclosure maintains a stable formulation even at high temperatures, so that compositions containing conventional polymer hyaluronic acid are prepared at high temperatures during the maturation process for commercialization. Treatment can solve the problem of the formulation breaking and viscosity decreasing. In one embodiment, a composition with excellent penetration into the skin and formulation stability can be provided through micronization of high molecular weight hyaluronic acid without polyhydric alcohol or solubilizer.

As an example, the average particle diameter of the micronized polymer hyaluronic acid particles may be 100 nm or less. In this specification, the average particle diameter of the particles refers to the largest diameter within the particles, and the average particle size refers to the average of the particle diameters of at least 90% or more of the particles distributed in the composition. Specifically, the average particle diameter of the particles distributed in the composition is at least 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more. It may mean the average value of the largest diameter within the particles of more than 99% of the particles. More specifically, the average particle diameter is 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. It may be 50 nm or less, 45 nm or less, 40 nm or less, 35 nm or less, 30 nm or less, 25 nm or less, 20 nm or less, 15 nm or less, or 10 nm or less.

From the viewpoint of atomizing the polymer hyaluronic acid particles as described above, 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, It can be 4.4 or higher, 4.5 or higher, 4.6 or higher, 4.7 or higher, 4.8 or higher, or 4.9 or higher, and can be less than 5.0, 4.9 or lower, 4.8 or lower, 4.7 or lower, 4.6 or lower, 4.5 or lower, 4.4 or lower, 4.3 or lower, 4.2 or lower, 4.1 or lower, It may be 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 if the pH is more than 5.0, the polymer hyaluronic acid particles may not be atomized to an average size of 100 nm or less.

In one embodiment, the acidic pH adjuster may be an organic acid or an inorganic acid, and the type 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 acids include citric acid, phosphoric acid, fumaric acid, ascorbic acid, ferulic acid, succinic acid, and lactic acid. Lactic acid, Hyaluronic acid, Malic acid, Butyric acid, Formic acid, Acetic acid, Salicylic acid, It may include one or more selected from the group consisting of glycolic acid, tartaric acid, and gluconolactone. For example, the inorganic acid may include one or more selected from the group consisting of carbonic acid, hydrochloric acid, nitric acid, and sulfuric acid.

As an example, the composition may further include 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 effective substance.

As an example, the acidic pH adjuster may include a fruit extract containing the organic acid or inorganic acid, and can be used without limitation for the purpose of lowering the pH of skin care products, whether or not it falls within the scope thereof. For example, the fruit extract includes VACCINIUM MYRTILLUS FRUIT EXTRACT, SACCHARUM OFFICINARUM ( SUGARCANE) EXTRACT, and Citrus Aurantium Dulcis (Orange). It may include one or more selected from the group consisting of fruit extract ( CITRUS AURANTIUM DULCIS (ORANGE) FRUIT EXTRACT) and citrus limon (lemon) fruit extract ( CITRUS LIMON (LEMON) FRUIT EXTRACT).

As an example, the present disclosure includes the acid itself rather than the salt form of an organic acid or an inorganic acid, so, for example, when a metal salt of an organic acid is included, unlike the metal salt acting as a metal cation, the hydrogen cation of the acid acts as a negative charge of the polymer hyaluronic acid. By acting with, the pH in the composition can be adjusted to less than 5.0, and thus the average diameter of the polymer hyaluronic acid particles can be atomized to 100 nm or less.

In one embodiment, the weight ratio of the polymer hyaluronic acid or its salt and the acidic pH adjuster may be 1:0.01 to 10. Specifically, the acidic pH adjuster is used in an amount of 0.01 parts by weight or more, 0.1 parts by weight, 0.2 parts by weight, 0.3 parts by weight, 0.4 parts by weight or more, 0.5 parts by weight or more, based on 1 part by weight of the polymer hyaluronic acid or its salt. 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, It may contain more than 1.6 parts by weight, more than 1.7 parts by weight, more than 1.8 parts by weight, more than 1.9 parts by weight, more than 2 parts by weight, or more than 5 parts by weight, and less than 10 parts by weight based on 1 part by weight of the polymer hyaluronic acid or its salt. , 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. , may be included in 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. 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 atomized or the pH may be too low to less than 3.0, which may cause skin irritation.

In one embodiment, the content of the high molecular weight hyaluronic acid or its salt may be 0.1 to 10% by weight based on the total weight of the external skin composition. For example, the content of the high molecular weight hyaluronic acid or its salt is 0.1% by weight or more, 0.3% 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, based on the total weight of the external skin composition. 0.9% by weight or more, 1.0% by weight or more, 1.1% by weight or more, 1.2% by weight or more, 1.3% by weight or more, 1.5% by weight or more, 1.7% by weight or more, 2% by weight or more, 3% by weight or more, 4% by weight or more, It may be at least 5% by weight, at least 6% by weight, at least 7% by weight, at least 8% by weight, or at least 9% by weight, and at most 10% by weight, at most 9% by weight, at most 8% by weight, at most 7% by weight, and at most 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. It may be 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 the skin may be minimal, and if it is more than 10% by weight, the content is excessive compared to the acidic pH adjuster, so the particles of the high molecular weight hyaluronic acid or its salt may not be atomized, and the viscosity may be too high to be in liquid form. Manufacturing it into a dosage form can be difficult.

In one embodiment, the content of the acidic pH adjuster may be 0.01 to 50% by weight based on the total weight of the external skin composition. For example, the content of the acidic pH regulator is 0.01% by weight, 0.05% by weight, 0.1% by weight, 0.2% by weight, 0.3% by weight, 0.4% by weight, 0.5% by weight, based on the total weight of the external skin composition. % 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, 1.0% by weight or more, 1.1% by weight or more, 1.2% by weight or more, 1.3% by weight or more, 1.4% by weight or more, 1.5 weight% or more % or more, 2% by weight or more, 3% by weight or more, 4% by weight or more, 5% by weight or more, 10% by weight or more, 15% by weight or more, 20% by weight or more, 25% by weight or more, 30% by weight or more, 35% by weight or more % or more, 40 weight% or more, or 45 weight% or more, and may be 50 weight% or less, 45 weight% or less, 35 weight% or less, 30 weight% or less, 25 weight% or less, 20 weight% or less, 15 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, It may be 0.4% by weight or less or 0.1% by weight or less. If the content is less than 0.01% by weight, particles of high molecular weight hyaluronic acid or its salt may not be atomized, and if it is more than 50% by weight, skin irritation may occur.

As an example, the composition for external application for skin of the present disclosure may further include a metal ion sequestering agent. The metal ion sequestering agent is also called a chelating agent and is usually used to bind and inactivate metallic ions such as calcium, magnesium or copper that adversely affect the stability or properties of products such as cosmetics. . When using an organic acid or inorganic acid in the form of a metal salt, etc. as an acidic pH adjuster for the micronization of polymer hyaluronic acid particles, if the composition contains a metal ion sequestering agent as described above, the polymer hyaluronic acid particles swell within the composition, preventing micronization. Therefore, while it is difficult to penetrate the skin, the present disclosure, as an example, contains the acid itself rather than the form of an organic or inorganic acid such as a metal salt, so even if a metal ion sequestering agent is further included to improve the stability and usability of the product, the atomization is possible. Since it is not inhibited, it is possible to micronize the average diameter of polymer hyaluronic acid particles to 100 nm or less. In addition, the composition according to the present disclosure lowers the pH to less than 5.0 to micronize the polymer hyaluronic acid particles to penetrate the skin, so the pH of the polymer hyaluronic acid particles naturally increases to 5.5 to 6.0 due to the difference in acidity from the skin's original pH, causing swelling. Thus, the size of the particles can be increased without the administration of additional ingredients.

As an example, the type of the metal ion sequestering agent is not limited, but may include, for example, one or more of an alkali salt of EDTA (ethylene-diamine-tetraacetic acid) and an alkali salt of a phosphate-based compound. . More specifically, disodium EDTA (ethylene-diamine-tetraacetic acid), tetrasodium EDTA, trisodium ethylenediamine disuccinate, sodium phosphate, monosodium phosphate, disodium phosphate, trisodium phosphate, sodium tripolyphosphate, sodium It may include one or more selected from the group consisting of hexametaphosphate, sodium metaphosphate, sodium phytate, tetrasodium pyrophosphate, and sodium acid pyrophosphate. Additionally, the content of the metal ion sequestering agent according to one embodiment may be 0.01 to 1% by weight based on the total weight of the external skin composition. Specifically, the content of the metal ion sequestering agent is 0.001% by weight, 0.005% by weight, 0.01% by weight, 0.02% by weight, 0.03% by weight, 0.04% by weight, 0.05% by weight, based on the total weight of the external skin composition. % or more, 0.1 weight% or more, 0.5 weight% or more, or 0.9 weight% or more, and may be 1 weight% or less, 0.9 weight% or less, 0.8 weight% or less, 0.7 weight% or less, 0.6 weight% or less, 0.5 weight% or less, It may be 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. If the content of the metal ion sequestering agent is less than 0.01% by weight, the chelating effect may be small, and if it is more than 1% by weight, it may chelate even beneficial metal ions in skin cells, resulting in a negative effect on the skin.

In one embodiment, the composition for topical skin application can provide a composition with excellent body penetration and formulation stability of the effective substance through micronization of high molecular weight hyaluronic acid without polyhydric alcohol or solubilizer.

In one embodiment, the viscosity or hardness of the external skin composition may vary depending on the formulation 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.

In one embodiment, the composition for external application for skin may be provided for various purposes depending on the type of effective ingredient. For example, the composition may be for moisturizing the skin. In one embodiment, the composition may be used to prevent loss of skin elasticity or improve skin elasticity. In one embodiment, the composition may be used to prevent skin wrinkles or improve wrinkles. In one embodiment, the composition may be used for skin whitening. In one embodiment, the composition may be anti-inflammatory. In one embodiment, the composition may be for preventing, improving, or treating acne. Another embodiment of the present disclosure includes administering an effective amount of a carrier composition containing the above-mentioned effective substances to the skin of a subject in need thereof, for moisturizing the skin, whitening the skin, preventing loss of skin elasticity or improving elasticity, and creating skin wrinkles. It can provide methods for prevention or wrinkle improvement, anti-inflammatory or anti-acne. Another embodiment is a carrier containing the above-mentioned effective substances for producing a skin external composition for moisturizing the skin, whitening the skin, preventing loss of skin elasticity or improving elasticity, preventing the formation of skin wrinkles or improving wrinkles, and anti-inflammatory or anti-acne. The use of the composition can be provided. Another embodiment provides a carrier composition containing the above-mentioned effective substances for use in a composition for moisturizing the skin, whitening the skin, preventing loss of skin elasticity or improving elasticity, preventing the formation of skin wrinkles or improving wrinkles, and anti-inflammatory or anti-acne. can do. Another example is a non-therapeutic carrier composition containing the above-mentioned effective substances as active ingredients for skin moisturizing, skin whitening, preventing loss of skin elasticity or improving elasticity, preventing skin wrinkle formation or improving wrinkles, and anti-inflammatory or anti-acne. It can be used for cosmetic purposes.

In the present disclosure, the 'composition for external application to the skin' refers to a composition in a formulation that is applied outside the skin. As an example, the composition for topical skin application may be applied directly by hand or using various application means such as a spatula, and may include cosmetics, pharmaceuticals, quasi-drugs, etc. of various formulations.

In one embodiment, the external skin composition may be a cosmetic composition. In one embodiment, the external form of the cosmetic composition may contain a cosmetically or dermatologically acceptable medium or base. For example, in the form of solutions, gels, solids, pasty anhydrous products, emulsions obtained by dispersing the oil phase in the water phase, suspensions, microemulsions, microcapsules, microgranules or vesicular dispersions of ionic (liposomes) and non-ionic types. , or may be provided in the form of a cream, skin, 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 in the form of an aerosol composition further containing a compressed propellant.

The cosmetic composition according to an embodiment of the present disclosure is not particularly limited in its formulation, for example, ampoule, cream, softening lotion, astringent lotion, nourishing lotion, nourishing cream, gel cream, massage cream, essence, eye It can be formulated into cosmetics such as cream, eye essence, cleansing cream, cleansing foam, cleansing water, cleansing tissue containing the cosmetic composition, pack, body lotion, body cream, body oil, and body essence. When the formulation according to an embodiment of the present disclosure is a paste, cream, or gel, animal fiber, vegetable fiber, wax, paraffin, starch, tracant, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc, or oxidation is used as the carrier ingredient. Zinc, etc. may be used. When the formulation according to an embodiment of the present disclosure is a spray, lactose, talc, silica, aluminum hydroxide, calcium silicate, or polyamide powder may be used as the carrier component, and additionally, chlorofluorohydrocarbon, propane/butane Alternatively, it may include a propellant such as dimethyl ether. When the formulation according to an embodiment of the present disclosure is a solution or emulsion, a solvent, solvating agent, or emulsifying agent is used as a carrier component, such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, and benzyl benzoate. , propylene glycol, 1,3-butyl glycol oil, glycerol fatty esters, polyethylene glycol or fatty acid esters of sorbitan. When the formulation according to an embodiment of the present disclosure is a suspension, the carrier component includes water, a liquid diluent such as ethanol or propylene glycol, and a suspension such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester, and polyoxyethylene sorbitan ester. Agents such as microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, or tracant can be used. When the formulation according to an embodiment of the present disclosure is a surfactant-containing cleansing agent, aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, sulfosuccinic acid monoester, isethionate, imidazolinium derivative, methyl taurate, and sarcomeric are used as carrier ingredients. Sinate, fatty acid amide ether sulfate, alkylamidobetaine, fatty alcohol, fatty acid glyceride, fatty acid diethanolamide, vegetable oil, linoline derivative, or ethoxylated glycerol fatty acid ester can be used.

The cosmetic composition according to an embodiment of the present disclosure may additionally include functional additives and components included in general cosmetic compositions. The functional additive may include ingredients selected from the group consisting of water-soluble vitamins, oil-soluble vitamins, polymer peptides, polymer polysaccharides, sphingolipids, and seaweed extract. Other ingredients included include oils and fats, moisturizers, emollients, neutralizers, surfactants, organic and inorganic pigments, organic powders, ultraviolet absorbers, preservatives, disinfectants, antioxidants, plant extracts, pH adjusters, alcohol, colorants, and fragrances. , blood circulation promoters, cooling agents, antiperspirants, purified water, etc.

In one embodiment, the composition for topical skin application may be a pharmaceutical composition. When applying the composition according to an embodiment of the present disclosure to a pharmaceutical, it can be formulated as a parenteral administration in a semi-solid or liquid form by adding an inorganic or organic carrier commonly used in the active ingredient used in an embodiment of the present disclosure. The pharmaceutical composition according to the present disclosure may be administered parenterally, rectally, topically, transdermally, intravenously, intramuscularly, intraperitoneally, subcutaneously, etc. As an example, the pharmaceutical composition may be a parenteral agent, more specifically, a topical skin agent. For example, the external skin preparation may be in the form of ointment, skin, lotion, gel, cream, spray, suspension, emulsion, patch, etc., but is not limited thereto. The composition according to an embodiment of the present disclosure can be easily formulated with active ingredients by carrying out a conventional method widely known in the art, wherein surfactants, excipients, colorants, spices, preservatives, stabilizers, buffers, Suspensions and other commonly used adjuvants can be used appropriately. The administered dose of the active ingredient of the pharmaceutical composition according to an embodiment of the present disclosure will vary depending on the age, gender, weight, pathological condition and severity of the subject, administration route, or the judgment of the prescriber. Determination of an appropriate dosage based on these factors is within the level of one skilled in the art, 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. /It may be work, but is not limited to this.

Hereinafter, the present disclosure will be described in more detail through the following examples. However, the following examples are provided only for illustrative purposes to aid understanding of the present disclosure, and the scope and scope of the present disclosure are not limited thereto.

[Manufacturing example]

A carrier composition for transdermal delivery of an effective substance and a composition containing the effective substance according to an embodiment of the present disclosure were prepared by the following method.

First, sodium hyaluronate (manufacturer: Hyundai Bioland, product name: Bio sodium hyaluronate, weight average molecular weight: 1,500 KDa) was prepared as a high molecular weight hyaluronic acid salt. 1,2-hexanediol and the sodium hyaluronate were dissolved in deionized water using a magnetic stirrer. The remaining ingredients in Table 1 below were added and mixed with a homogenizer at a high speed of 12000 rpm to atomize the particles to an average particle diameter of 100 nm or less. At this time, the pH range of the micronized solution was 3 to 4. The hyaluronic acid solution was placed in a 45°C chamber, and then the particles and physical properties were stabilized through a maturation process for more than 12 hours to prepare the final composition.

As a comparative example to compare the effects of the above examples, Comparative Example 1 was prepared with the same composition and method as Example 1, except that it did not contain sodium hyaluronate.

ingredient Example 1 Comparative Example 1 menstruum deionized water To 100 To 100 Hyaluronate Sodium Hyaluronate 0.6 - Metal ion sequestrant Sodium metaphosphate 0.08 0.08 Effective substance ascorbic acid 0.5 0.5 stabilizer Caffeine 0.17 0.17 stabilizer Mannitol 0.1 0.1 antiseptic 1,2-hexanediol 1.2 1.2 Basic PH regulator Tromethamine 0.3 0.3 acid pH regulator Succinic acid 0.5 0.5

(weight%)

[Test Example 1]

In order to confirm the transdermal delivery effect of the effective substance by the carrier composition according to the present disclosure, the skin absorption amount of each effective substance, ascorbic acid, of Example 1 and Comparative Example 1 prepared in the above Preparation Example was measured and compared by the following method. did.

The absorption of ascorbic acid was measured using a Franz diffusion cell. A membrane (Isopore, Merck Milipore, USA) was fixed between the donor and receptor phases, and the area in contact with the receptor phase was about 1.767 cm2. PBS (phosphate buffer saline, 7 mL) was used on the receptor, and the mixture was kept at 32°C and continuously stirred at 600 rpm. After 1 hour and 3 hours, the receptor phase was collected and the amount of ascorbic acid was quantified using high-performance liquid chromatography (HPLC). During HPLC analysis, Mightysil RP-18 GP 250-4.6 (5㎛) was used as a stationary phase, and a mixture of 1% CH ₃ COOH:methanol (90:10, v/v) was used as a mobile phase. Detection was performed at a wavelength of 254 nm and a flow rate of 1 mL/min, and the concentration was determined from the area of the obtained peak according to the reference "Snezana S Mitic, Danijela A Kostic, Danijela C Naskovic-Dokic, Milan N Mitic, Rapid and Reliable HPLC Method for the Determination of It was calculated according to “Vitamin C in Pharmaceutical Samples, Tropical Journal of Pharmaceutical Research February 2011; 10 (1): 105-111.” This document is incorporated herein by reference in its entirety.

After 1 hour After 3 hours Example 1 59.64 μg/mL 87.87 μg/mL Comparative Example 1 0 μg/mL 0 μg/mL

As a result, in the case of Comparative Example 1, which is a composition containing an effective substance without the carrier composition of the present disclosure, the amount of ascorbic acid absorbed into the skin tissue was extremely small and could not be confirmed, whereas Example 1 contained a micronized polymer hyaluronic acid salt. It was confirmed that ascorbic acid was effectively delivered into skin tissue by the carrier composition, showing a high absorption amount.

[Test Example 2]

In order to confirm the effect of transdermal delivery of the effective substance by the carrier composition according to the present disclosure, the penetration depth of the effective substance into the skin was confirmed by the following method.

First, Fitzpatric type II skin tissue (manufacturer: Genoskin, product name: NativeSkin) biopsied from the abdomen of a 33-year-old woman was supplied from the manufacturer, and Example 1 and Comparative Example 1 were applied to the skin tissue. Each was applied. After attaching a tape disk (manufacturer: Cuderm, product name: D100, diameter: 22mm) to the skin tissue, press it with a force of 225 gr./sq.cm using a D-squame pressure device, and then tape. The disk was removed. A total of 10 tape discs were sequentially removed at approximately 3-minute intervals, and the tape disc samples were stored in a freezer.

Desorption electrospray ionization (DESI) mass spectrometry (manufacturer: Waters, product name: 2D DESI stage & At this time, DESI-MS spectra were acquired using a 2D DESI stage and XEVO G2-XS QTof (Waters, Milford, USA). The nebulizing solvent was 98% methanol + 0.1% formic acid, the flow rate was 2 μL/min, and the nebulizing gas inlet pressure was set at 0.5 MPa. An area of 100 Х 100 μm ² was measured from the tape-stripped tape disc sample. A mass range from 50 to 1,000 m/z was measured in positive ion mode. MS imaging data were acquired using MassLynx 4.2 (Waters, USA) and visualized using High Definition Imaging (HDI) 1.5 software (Waters).

As a result, as shown in Figure 2, in the case of Comparative Example 1, which is a composition containing an effective substance without the carrier composition of the present disclosure, no effective substance penetrated into the stratum corneum was confirmed, whereas Example 1 contained a micronized polymer hyaluronic acid salt. It was confirmed that the effective substance was deeply penetrated up to 10 times of tape stripping by the carrier composition contained therein.

The present disclosure may provide the following embodiments as one example.

The first embodiment includes polymer 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 diameter of the polymer hyaluronic acid or its salt particles is 100 nm or less, the pH is 3.0 or more and less than 5.0, and has pH sensitivity, A carrier composition for transdermal delivery of an effective substance can be provided.

The second embodiment may provide a carrier composition, in which, according to the first embodiment, the composition releases an effective substance at pH 5 to 7.

The third embodiment can provide a carrier composition in the first or second embodiment, wherein the weight ratio of the polymer hyaluronic acid or its salt and the acidic pH adjuster is 1:0.01 to 10.

The fourth embodiment can provide the carrier composition according to any one of the first to third embodiments, wherein the high molecular weight hyaluronic acid or its salt has a weight average molecular weight of 5 to 10,000 kDa.

Embodiment 5-1 is according to any one of embodiments 1 to 4, wherein the organic acid is citric acid, phosphoric acid, fumaric acid, ascorbic acid, or ferulic acid. Ferulic acid, Succinic acid, Lactic acid, Hyaluronic acid, Malic acid, Butyric acid, Formic acid , a carrier composition that is one or more selected from the group consisting of acetic acid, salicylic acid, glycolic acid, tartaric acid, and gluconolactone can be provided. .

Embodiment 5-2 may provide the carrier composition according to any one of embodiments 1 to 4, wherein the inorganic acid is at least one selected from the group consisting of carbonic acid, hydrochloric acid, nitric acid, and sulfuric acid.

The sixth embodiment can provide the carrier composition according to any one of the first to fifth embodiments, wherein the carrier composition is for promoting skin absorption of an effective substance.

The seventh embodiment is an effective substance; and a carrier composition for transdermal delivery of an effective substance according to any one of the first to sixth embodiments. It is possible to provide a composition for external application to the skin including a.

The eighth embodiment may provide a composition for external application for skin, in the seventh embodiment, wherein the composition for external application for skin includes an effective substance in an amount of 0.01% by weight to 40% by weight based on the total weight of the composition for external application for skin.

The ninth embodiment may provide a composition for external application for skin, in the seventh or eighth embodiment, wherein the weight ratio of the carrier composition to the total weight of the effective substance is 1:0.01-100.

The tenth embodiment can provide the composition for topical skin application according to any one of the seventh to ninth embodiments, wherein the effective substance is physically captured with the carrier composition.

An 11th embodiment can provide the skin composition according to any one of the 7th to 10th embodiments, wherein the skin external composition is for skin moisturizing.

The twelfth embodiment may provide a composition for external application for skin according to any one of the seventh to eleventh embodiments, wherein the composition for external application for skin is for preventing a decrease in skin elasticity or improving elasticity.

The thirteenth embodiment can provide the composition for external application for skin according to any one of the seventh to twelfth embodiments, wherein the composition for external application for skin is for skin whitening.

The fourteenth embodiment can provide the composition for external application for skin according to any one of the seventh to thirteenth embodiments, wherein the composition for external application for skin is a cosmetic composition.

The fifteenth embodiment can provide the composition for external application for skin according to any one of the seventh to fourteenth embodiments, wherein the composition for external application for skin is a pharmaceutical composition.

Claims (15)

High molecular weight hyaluronic acid or its salt particles; and an acidic pH adjusting agent,
The acidic pH adjuster is an organic acid or an inorganic acid,
The average particle diameter of the polymer hyaluronic acid or its salt particles is 100 nm or less,
pH is greater than 3.0 but less than 5.0,
A carrier composition for transdermal delivery of an effective substance having pH sensitivity. The carrier composition of claim 1, wherein the composition releases the effective substance at pH 5 to 7. The carrier composition according to claim 1, wherein the weight ratio of the polymeric hyaluronic acid or its salt and the acidic pH adjuster is 1:0.01 to 10. According to paragraph 1,
A carrier composition wherein the high molecular weight hyaluronic acid or its salt has a weight average molecular weight of 5 to 10,000 kDa. The method of claim 1, wherein the organic acids include citric acid, phosphoric acid, fumaric acid, ascorbic acid, ferulic acid, succinic acid, and lactic acid. Lactic acid, Hyaluronic acid, Malic acid, Butyric acid, Formic acid, Acetic acid, Salicylic acid, At least one selected from the group consisting of glycolic acid, tartaric acid, and gluconolactone,
The carrier composition wherein the inorganic acid is at least one selected from the group consisting of carbonic acid, hydrochloric acid, nitric acid, and sulfuric acid. The carrier composition of claim 1, wherein the carrier composition promotes skin absorption of the effective substance. Effective substance; and
A carrier composition for transdermal delivery of the effective substance according to any one of claims 1 to 6;
A composition for external application to the skin containing a. The composition for external application for skin according to claim 7, wherein the composition for external application for skin contains the effective substance in an amount of 0.01% by weight to 40% by weight based on the total weight of the composition for external application for skin. The composition for external application for skin according to claim 7, wherein the weight ratio of the carrier composition to the total weight of the effective substance is 1:0.01-100. The composition for external application for skin according to claim 7, wherein the effective substance is physically captured with the carrier composition. The composition for external application for skin according to claim 7, wherein the composition for external application for skin is for moisturizing the skin. The composition for external application for skin according to claim 7, wherein the composition for external application for skin is used to prevent loss of skin elasticity or improve elasticity. The composition for external application for skin according to claim 7, wherein the composition for external application for skin is for skin whitening. The composition for external application for skin according to claim 7, wherein the composition for external application for skin is a cosmetic composition. The composition for external application for skin according to claim 7, wherein the composition for external application for skin is a pharmaceutical composition.