CN117835966A

CN117835966A - Method for promoting skin penetration of water-soluble pharmaceutical agent

Info

Publication number: CN117835966A
Application number: CN202280056056.1A
Authority: CN
Inventors: 佐藤知子; 冈本亨; A·洛因德; 柳原茜; 八卷悟史; 秦英夫
Original assignee: Shiseido Co Ltd
Current assignee: Shiseido Co Ltd
Priority date: 2021-09-09
Filing date: 2022-09-02
Publication date: 2024-04-05
Also published as: WO2023037983A1; JPWO2023037983A1

Abstract

The subject matter of the present disclosure is to facilitate penetration of water-soluble agents into the skin. The method for promoting skin penetration of a water-soluble drug of the present disclosure comprises any one of the following steps (a), (b), (c) and steps (d 1) to (d 3): (a) preparing an emulsified composition comprising a water-soluble pharmaceutical agent; (b) Preparing an application type body repair skin forming agent comprising: a 1 st agent containing a crosslinking reactive component constituting the body repair film, and a 2 nd agent containing a catalyst for crosslinking the crosslinking reactive component; (c) Applying the emulsified composition to the skin to form a layer of emulsified composition; (d1) After the 1 st agent is applied to the emulsion composition layer to form the 1 st agent layer, the 2 nd agent is applied to the 1 st agent layer and crosslinked to form a body repair film; (d2) After the 2 nd agent is applied to the emulsion composition layer to form the 2 nd agent layer, the 1 st agent is applied to the 2 nd agent layer and crosslinked to form the body repair film; (d3) After the 1 st agent and the 2 nd agent are mixed to prepare a mixture, the mixture is applied to the emulsion composition layer and crosslinked to form the body repair film.

Description

Method for promoting skin penetration of water-soluble pharmaceutical agent

Technical Field

The present disclosure relates to a method for promoting skin penetration using a water-soluble drug of an applied body repair skin film forming agent.

Background

Coating agents are known which can be applied to a body surface to form a coating film capable of repairing wrinkles, flaws, and the like.

Patent document 1 discloses a composition for forming a layer in situ on the skin surface of a subject, which comprises 1 or more crosslinkable polymers, and artificial skin comprising a layer formed from the composition.

Patent document 2 describes that a water-soluble drug is a drug that does not easily penetrate the skin.

Prior art literature

Patent literature

Patent document 1: japanese patent application laid-open No. 2019-503396

Patent document 2: japanese patent laid-open No. 2020-121938

Disclosure of Invention

Problems to be solved by the invention

The water-soluble agent is generally an agent that is less likely to penetrate the skin than the oil-soluble agent. Among them, a water-soluble drug which is solidified at room temperature is less likely to penetrate into the skin because the drug is solidified with evaporation of water after the composition in which such drug is dissolved in water is applied to the skin.

Thus, the subject matter of the present disclosure is to facilitate penetration of water-soluble agents to the skin.

Means for solving the problems

Scheme 1

A method for promoting skin penetration of a water-soluble drug, which comprises the following steps (a), (b), (c) and any one selected from the steps (d 1) to (d 3):

(a) Preparing an emulsified composition comprising the water-soluble pharmaceutical agent;

(b) Preparing an application type body repair skin forming agent comprising: a 1 st agent containing a crosslinking reactive component constituting a body repair film, and a 2 nd agent containing a catalyst for crosslinking the crosslinking reactive component;

(c) The emulsion composition is applied to the skin to form an emulsion composition layer,

(d1) After the 1 st agent is applied to the emulsion composition layer to form a 1 st agent layer, the 2 nd agent is applied to the 1 st agent layer and crosslinked to form a body repair film;

(d2) After the 2 nd agent is applied to the emulsion composition layer to form a 2 nd agent layer, the 1 st agent is applied to the 2 nd agent layer and crosslinked to form a body repair film;

(d3) After the 1 st agent and the 2 nd agent are mixed to prepare a mixture, the mixture is applied to the emulsion composition layer and crosslinked to form a body repair film.

Scheme 2

The method of claim 1, wherein at least one of the 1 st agent and the 2 nd agent further comprises a water-soluble agent.

Scheme 3

The method according to claim 1 or 2, wherein the water-soluble drug is a water-soluble drug that is solid at room temperature.

Scheme 4

According to the method of claim 3, the water-soluble drug substance that is solid at room temperature is a crystalline water-soluble drug substance.

Scheme 5

The method according to scheme 4, wherein the crystalline water-soluble pharmaceutical agent is at least one selected from the group consisting of 4-methoxysalicylic acid, tranexamic acid, L-ascorbic acid, 4-methoxysalicylate, tranexamic acid salt, L-ascorbate, glycylglycine, nicotinamide, arbutin, L-ascorbyl glucoside, 1- (2-hydroxyethyl) -2-imidazolidinone, pyrimidinylpyrazole compounds represented by the following formula 1 and salts thereof,

in the formula (1) of the present invention,

R ¹ 、R ³ 、R ⁴ and R is ⁶ Each independently represents an alkyl group having 1 to 3 carbon atoms,

R ² and R is ⁵ Each independently represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.

Scheme 6

The method according to any one of claims 1 to 5, wherein the emulsion composition contains 0.1% by mass or more of the water-soluble drug.

Scheme 7

The method according to any one of claims 2 to 6, wherein at least one of the 1 st agent and the 2 nd agent further comprises a water-soluble drug, and wherein at least one of the 1 st agent and the 2 nd agent comprises 0.1% by mass or more of the water-soluble drug.

Scheme 8

The method according to any one of schemes 1 to 7, wherein the 1 st agent contains at least one selected from the group consisting of 1 st unsaturated organopolysiloxane and 1 st hydride-functional polysiloxane,

in the case where the 1 st agent contains only the 1 st unsaturated organopolysiloxane out of the 1 st unsaturated organopolysiloxane and the 1 st hydride-functional polysiloxane, the 2 nd agent contains the 2 nd hydride-functional polysiloxane,

in the case where the 1 st agent contains only the 1 st hydride-functional polysiloxane out of the 1 st unsaturated organopolysiloxane and the 1 st hydride-functional polysiloxane, the 2 nd agent contains the 2 nd unsaturated organopolysiloxane.

Scheme 9

The method according to claim 8, wherein the 1 st unsaturated organopolysiloxane and the 2 nd unsaturated organopolysiloxane are at least one selected from the group consisting of an organopolysiloxane having a vinyl group, an organopolysiloxane terminated with a vinyl group, and an organopolysiloxane having a branched chain terminated with a vinyl group.

Scheme 10

The method according to scheme 9, wherein the 1 st unsaturated organopolysiloxane and the 2 nd unsaturated organopolysiloxane are at least one selected from the group consisting of vinyl-terminated polydimethylsiloxane, vinyl-terminated diphenylsiloxane-dimethylsiloxane copolymer, vinyl-terminated polyphenylmethylsiloxane, vinyl-terminated vinylphenylsiloxane-phenylmethylsiloxane copolymer, vinyl-terminated trifluoropropylmethylsiloxane-dimethylsiloxane copolymer, vinyl-terminated diethylsiloxane-dimethylsiloxane copolymer, vinyl methylsiloxane-dimethylsiloxane copolymer, trimethylsiloxy-terminated vinylmethylsiloxane-dimethylsiloxane copolymer, silanol-terminated vinylmethylsiloxane-dimethylsiloxane copolymer, vinylmethylsiloxane homopolymer, vinyl T-structural polymer, vinyl Q-structural polymer, monovinyl-terminated polydimethylsiloxane, vinylmethylsiloxane terpolymer, and vinylmethoxysilane homopolymer.

Scheme 11

The method according to any one of the schemes 8 to 10, wherein the 1 st hydride-functional polysiloxane and the 2 nd hydride-functional polysiloxane are non-terminal and/or terminal hydrogenated organopolysiloxanes.

Scheme 12

The method according to scheme 11, wherein the 1 st hydride-functional polysiloxane and the 2 nd hydride-functional polysiloxane are at least one selected from the group consisting of hydride-terminated polydimethylsiloxane, hydride-terminated polyphenyl- (dimethylhydrosiloxy) siloxane, hydride-terminated methylhydrosiloxane-phenylmethylsiloxane copolymer, trimethylsiloxy-terminated methylhydrosiloxane-dimethylsiloxane copolymer, polymethylhydrosiloxane, trimethylsiloxy-terminated polyethylhydrosiloxane, triethylsiloxane, methylhydrosiloxane-phenyloctylmethylsiloxane copolymer, and methylhydrosiloxane-phenyloctylmethylsiloxane terpolymer.

Scheme 13

The method according to any one of schemes 1 to 12, wherein the catalyst is at least one selected from the group consisting of platinum carbonyl cyclovinylmethylsiloxane complex, platinum divinyl tetramethyldisiloxane complex, platinum cyclovinylmethylsiloxane complex, and platinum octaldehyde/octanol complex.

Scheme 14

The method according to any one of aspects 1 to 13, wherein at least one of the 1 st agent and the 2 nd agent contains at least one selected from the group consisting of a fiber, a pigment, a dye, a thickener, an ultraviolet absorber, and a reinforcing material.

Scheme 15

The method according to any one of claims 1 to 14, wherein the emulsified composition is an oil-in-water emulsified composition.

Scheme 16

The method according to any one of aspects 1 to 15, wherein at least one of the 1 st agent and the 2 nd agent is an emulsified composition.

ADVANTAGEOUS EFFECTS OF INVENTION

According to the present disclosure, the water-soluble agent can be made to easily permeate the skin.

Drawings

Fig. 1 is a diagram simulating the behavior of a water-soluble drug when a composition containing a water-soluble drug and moisture is applied to the skin, and the behavior of a water-soluble drug when an emulsion composition containing a water-soluble drug is applied to the skin to form an emulsion composition layer and then a body repair film is applied so as to cover the emulsion composition layer.

Detailed Description

Hereinafter, embodiments of the present disclosure will be described in detail. The present disclosure is not limited to the following embodiments, and can be implemented by various modifications within the scope of the invention.

The method for promoting skin penetration of a water-soluble drug of the present disclosure comprises any one of the following steps (a), (b), (c) and steps (d 1) to (d 3):

(a) Preparing an emulsified composition comprising a water-soluble pharmaceutical agent;

(b) Preparing an application type body repair skin forming agent, wherein the application type body repair skin forming agent comprises: a 1 st agent containing a crosslinking reactive component constituting a body repair film, and a 2 nd agent containing a catalyst for crosslinking the crosslinking reactive component;

(c) Applying the emulsified composition to the skin to form a layer of emulsified composition;

(d1) After the 1 st agent is applied to the emulsion composition layer to form the 1 st agent layer, the 2 nd agent is applied to the 1 st agent layer and crosslinked to form the body repair film;

(d2) After the 2 nd agent is applied to the emulsion composition layer to form the 2 nd agent layer, the 1 st agent is applied to the 2 nd agent layer and crosslinked to form the body repair film;

(d3) After the 1 st agent and the 2 nd agent are mixed to prepare a mixture, the mixture is applied to the emulsion composition layer and crosslinked to form the body repair film.

While not being limited by the principle, the principle of action of the skin permeation enhancement method of the present disclosure to facilitate permeation of a water-soluble agent into the skin is considered as follows.

Water-soluble agents are generally agents that are less permeable to lipophilic skin than oil-soluble agents. In addition, the water used to dissolve the water-soluble drug is generally more volatile than the oil used to dissolve the oil-soluble drug. Therefore, when a composition containing a water-soluble drug and moisture is applied to the skin, as shown in fig. 1, it is considered that although a part of the water-soluble drug 11 dissolved in the moisture 10 can gradually permeate from the composition to the skin, most of the water-soluble drug is dried by evaporation of the moisture in the composition, becomes a solid-state water-soluble drug 12, and cannot permeate to the skin and stays on the skin surface.

The present inventors have found that if a body repair film (sometimes simply referred to as "film") is applied so as to cover an emulsified composition layer containing a water-soluble drug after the emulsified composition layer is formed by applying the emulsified composition to the skin, the permeability of the water-soluble drug to the skin can be improved.

It is considered that if the body repair film is applied so as to cover the emulsion composition layer containing the water-soluble drug, as shown in fig. 1, unlike the case of the composition containing the water 10 and the water-soluble drug 11, the emulsion composition layer 15 containing the water-soluble drug is covered and blocked by the film 16, and evaporation of the water in the emulsion composition layer 15 is reduced or suppressed, so that drying of the water-soluble drug can be reduced or suppressed, and as a result, the water-soluble drug can be continuously permeated into the skin.

In addition, in the emulsion composition layer, typically, an oil component is contained in addition to moisture and the water-soluble agent. As a result, as shown in fig. 1, it is considered that, unlike the case of the composition containing the water 10 and the water-soluble drug 11, the oil 13 in the emulsion composition layer 15 acts to close the vicinity of the end of the emulsion composition layer 15 even if the end of the emulsion composition layer 15 is not covered with the coating film 16, and thus drying of the water-soluble drug can be further reduced or suppressed.

The definitions of the terms in this disclosure are as follows.

In the present disclosure, the term "body repair film" refers to a film intended to have a natural skin appearance when formed on the skin of a subject. Here, the term "natural skin appearance" means that, when applied to skin, the body repair film exhibits properties similar to or the same as at least one selected from the group consisting of the appearance, feel, and texture of actual skin, for example, the skin subjected to the film treatment can exhibit physical properties (e.g., elasticity and hardness) of actual (e.g., as-is) skin.

In the present disclosure, "body repair" refers to a method of masking, covering or covering a defect of a subject's body or a defect of skin, visually and/or tactilely improving the defect of the body or skin, but does not include a method of performing surgery, treatment or diagnosis on a human. Here, the "defect of the body" may refer to, for example, a portion of the body of the subject perceived as a spot or injury by the subject, or a portion of the body of the subject perceived as a spot or injury by a practitioner such as a dermatologist, esthetic, or plastic surgeon. The "defect of the body" includes a defect of the skin, and slackening of soft tissues of the body (for example, slackening or slackening of the skin, slackening of the breast, buttocks, abdomen, palate, neck, and the like), and the like. Further, in the "defect of skin", these items of the skin of the subject person who feels a spot or a wound are included. Examples of defects in the skin include a port-mark or flame mole (e.g., simple hemangioma or positive flame mole), chloasma, wrinkles, spots, acne, black mole, scars, tattoos, moles, skin deformation, moles, sun exposure, aging, uneven skin color, loose skin, rough skin, excessive pigmentation, enlarged pores, telangiectasia, redness, shininess, cellulite, striae gravidarum, or reduced elasticity of the skin.

In the present disclosure, "viscosity" refers to a fluid that is deformed by either shear stress or tensile stressIs a measure of resistance of (a). For example, the viscosity of the 1 st and 2 nd agents in the spread type body repair film forming agent affects the thickness, ductility, and uniformity and/or consistency of the layer formed on the substrate. The viscosity may be referred to as dynamic viscosity (alias, absolute viscosity, representative units are Pa.s, poise, P, cP.) or kinematic viscosity (representative units are cm) ² S, st, cst. ) Reported as the dynamic viscosity, which is the dynamic viscosity divided by the density of the fluid being measured. The viscosity ranges of the components disclosed herein are generally provided by the suppliers of the components as units of kinematic viscosity (e.g., cst) measured using a rheometer or candelan-finsk (Cannon-Fenske) tube viscometer, but the viscosity of the fluid may also be measured using, for example, a rheometer (e.g., a linear shear rheometer or dynamic shear rheometer) or a viscometer (also known as a viscometer, such as a capillary viscometer or a rotary viscometer).

In the "crosslinking" in the present disclosure, a concept called "curing" is also generally included.

The term "water-soluble" in the present disclosure means that the octanol water partition coefficient at 25℃is 1.0 or less. Such an octanol water partition coefficient is preferably 0 or less, more preferably-1.0 or less. Here, the octanol water partition coefficient can be obtained by adding a chemical to a flask containing octanol and an aqueous buffer having pH7, and then shaking the flask, and calculating the chemical concentration of each phase from the following formula a:

octanol water partition coefficient=log ₁₀ (concentration of agent in octanol phase/concentration of agent in aqueous phase) … formula A

In the present disclosure, the term "body surface" refers to the skin surface of the body.

Method for promoting skin permeation of Water-soluble drug

(a) An emulsified composition containing a water-soluble pharmaceutical agent is prepared,

Here, the skin permeation promoting method of the water-soluble drug of the present disclosure can be used, for example, as a cosmetic or medical application, and such a method does not include a method of performing surgery, treatment, or diagnosis on a human.

In view of obtaining a uniform body repair film with little unevenness, a method of forming a body repair film by applying the 1 st agent to the emulsion composition layer to form the 1 st agent layer, and then applying the 2 nd agent to the 1 st agent layer to crosslink the 1 st agent layer is preferable. Here, regarding the 1 st agent, the 2 nd agent, and the water-soluble agent, the following materials can be used.

The steps (d 1) to (d 3) in this method may be performed 1 time, or the formed body repair film may be performed a plurality of times.

Furthermore, in several embodiments, the skin permeation enhancement method of the water-soluble pharmaceutical agents of the present disclosure may also be utilized as a cosmetic method. For example, the skin exposed to dryness may take up moisture unknowingly, and the moisture content of the horny layer on the skin surface may not be maintained. If the moisture content of the skin is insufficient, the moisturizing component (natural moisturizing factor: nature Moisturizing Factor (NMF)) generated by the skin itself cannot be smoothly generated. As a result, it is considered that the barrier function and the moisturizing function are lowered on the skin surface, and the skin is easily damaged, and thus the skin is damaged, and the skin is roughened by losing the moisture.

On the other hand, if a skin film formed of the coating-type body repair film forming agent (sometimes simply referred to as "forming agent") of the present disclosure is applied to the skin, the skin can be well moisturized by the sealing effect (effect of preventing moisture from escaping from the skin) by the film. As a result, for example, the function of generating moisture retention components generated by the skin itself is improved, and the disorder of metabolism in the stratum corneum is also improved, so that problems such as skin roughness are less likely to occur, and the cosmetic effect can be improved. In addition, the skin formed by the coating film forming agent for the body repair of the present disclosure can also improve the permeability of the water-soluble agent (e.g., moisturizer, whitening agent) to the skin, and thus can further improve the cosmetic effect (e.g., moisturizing effect, whitening effect) of the skin. The term "cosmetic method" refers to a method of applying the agent for forming a body repair film of the present disclosure to skin to form a body repair film, and of conditioning the skin to beautify the skin, or to beautify the skin, unlike a method of performing surgery, treatment, or diagnosis on a human being.

In several embodiments, at least one of the 1 st and 2 nd agents comprising the spreaded body repair film forming agent comprises a water soluble agent.

The components of the coating-type body repair film forming agent that constitute the body repair film have oleophilic properties similar to skin. Therefore, even if an oil-soluble drug is mixed with a coating film forming agent for a body repair capable of forming such a coating film, the water-soluble drug is not actively mixed. The present inventors have also found that if a body repair film is formed by mixing a water-soluble drug with at least one of the 1 st and 2 nd agents constituting such a forming agent, the permeability of the water-soluble drug to the skin can be further improved.

When the body repair film is formed by mixing the water-soluble drug with at least one of the 1 st and 2 nd agents, it is considered that the water-soluble drug exists in the film in a state of being enclosed in water droplets. As a result, unlike the case where the composition containing the water-soluble drug 11 and the water 10 is simply applied to the skin, as shown in fig. 1, it is considered that the water droplets containing the water-soluble drug are covered with the coating film and are blocked, and evaporation of the water in the water droplets is reduced or suppressed, so that drying of the water-soluble drug can be reduced or suppressed, and as a result, the water-soluble drug can be continuously permeated to the skin through the emulsified composition layer.

It is considered that although moisture is not generated in the film itself, since the emulsion composition layer containing moisture exists between the film and the skin, water droplets in the film are induced to move from the film inside to the skin side. As a result, it is considered that the water-soluble drug in the water droplets in the coating is not easily left in the coating and can permeate the skin.

As a method of applying the emulsion composition to the skin, and further, a method of applying the 1 st agent, the 2 nd agent, and the mixture of the 1 st agent and the 2 nd agent, there are no particular restrictions, and for example, a means of spreading with a finger or the like, spraying, transfer, and the like can be employed.

For example, when the 1 st agent and/or the 2 nd agent in the case of an emulsified composition or containing a water-soluble drug is separated into water and oil, it is preferable to oscillate these agents and force them into a two-phase system (oil-in-water or water-in-oil type) from the viewpoints of permeability of the water-soluble drug to the skin, crosslinking reactivity of the 1 st agent and the 2 nd agent, dispersibility of water droplets containing the water-soluble drug in the coating film, and the like.

Application site

The emulsified composition and the spread-on body repair skin film forming agent of the present disclosure may be applied on the surface of the skin in all parts of the body, i.e., at any location if on the body surface. For example, it can be suitably applied to the skin surface of the head, face (lips, eyes, nose, cheeks, forehead, etc.), neck, ear, hand, wrist, foot, chest, abdomen, back, buttocks, etc. Here, the skin also includes nails, etc., which are hardened by the change in the cuticle of the skin.

Emulsified composition

The emulsion compositions of the present disclosure comprise water-soluble agents, typically, can also comprise moisture, oil, and emulsifiers. The formulation of such an emulsion composition is not particularly limited, and may be in the form of an oil-in-water emulsion composition or a water-in-oil emulsion composition. Among them, the oil-in-water emulsion composition is preferable from the viewpoint of permeability of the water-soluble drug to the skin and the like. In the case where the 1 st agent and/or the 2 nd agent of the coating-type body repair film forming agent described later are in the form of an emulsion composition, the emulsion composition of the present disclosure applied to the skin may be referred to as a 1 st emulsion composition for distinction from these, and the emulsion composition of the 1 st agent and/or the 2 nd agent may be referred to as an emulsion composition different from the 1 st emulsion composition, or the emulsion composition of the 1 st agent may be referred to as a 2 nd emulsion composition, and the emulsion composition of the 2 nd agent may be referred to as a 3 rd emulsion composition.

The emulsion composition of the present disclosure can be appropriately prepared by a conventional method using a known material such as a water-soluble drug, an oil component, an emulsifier, and water. The emulsion composition of the present disclosure may be appropriately mixed with any component of the coating type body repair film forming agent described later, for example, in the same manner as long as the effect of the present disclosure is not adversely affected.

Water-soluble medicine

As the water-soluble agent, there is no particular limitation, a water-soluble agent that is liquid or solid at room temperature can be used, but in the emulsion composition of the present disclosure, the use of a water-soluble agent that is solid at room temperature is advantageous. Such a water-soluble drug is solidified when dried, and thus has a problem of further reducing permeability into the skin. According to the body repair film obtained from the agent of the present disclosure, drying of such a water-soluble agent can be reduced or prevented, and as a result, the permeability of such an agent to the skin can be improved. The water-soluble agents may be used singly or in combination of two or more. The term "room temperature" as used herein means 0 to 35℃and preferably 20 to 30 ℃.

The water-soluble drug that is solid at room temperature may include a water-soluble drug that is amorphous (e.g., amorphous) and a water-soluble drug that is crystalline. The crystalline water-soluble drug has a problem that if the drug is dried and crystallized, the permeability into the skin is further reduced as compared with the amorphous water-soluble drug. According to the body repair film formed of the forming agent of the present disclosure, crystallization associated with drying of such crystalline water-soluble agent can be reduced or prevented, and as a result, permeability of such agent to the skin can be improved. In the present disclosure, the term "crystalline water-soluble drug" may typically refer to an ionic crystalline water-soluble drug.

Examples of such crystalline water-soluble pharmaceutical agents include, but are not particularly limited to, at least one selected from the group consisting of 4-methoxysalicylic acid, tranexamic acid, L-ascorbic acid, 4-methoxysalicylate, tranexamic acid salt, L-ascorbate, glycylglycine, nicotinamide (niacinamide), arbutin, L-ascorbyl glucoside, 1- (2-hydroxyethyl) -2-imidazolidone, and pyrimidinylpyrazole compounds represented by the following formula 1 and salts thereof. The salt form is not particularly limited, and examples thereof include forms of alkali metal salts (e.g., sodium salt, potassium salt, lithium salt), alkaline earth metal salts (e.g., magnesium salt, calcium salt), ammonium salts, amino acid salts, sulfate salts, hydrochloride salts, and the like:

in formula 1, R ¹ 、R ³ 、R ⁴ And R is ⁶ Each independently is an alkyl group having 1 to 3 carbon atoms, and R ² And R is ⁵ Each independently represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.

Among the above water-soluble drugs, 4-methoxysalicylic acid, tranexamic acid, 4-methoxysalicylate, tranexamic acid salt, and nicotinamide (コ) can suitably improve the permeability to the skin by a coating film formed by the forming agent of the present disclosure.

Furthermore, in several embodiments, the water-soluble agent that permeates into the skin via the skin film of the present disclosure may stay in the epidermis among the stratum corneum, epidermis, and dermis constituting the skin for a long period of time (e.g., 24 hours or more). As a result, the efficacy (for example, moisturizing effect and whitening effect) of the agent against the skin can be improved.

The mixing amount of the water-soluble drug is not particularly limited, and for example, the water-soluble drug may be mixed so as to be contained in an amount of 0.1 mass% or more, 0.5 mass% or more, or 1.0 mass% or more in the emulsified composition. The upper limit of the blending amount is not particularly limited, and may be, for example, 10 mass% or less, 8.0 mass% or less, 5.0 mass% or less, or 3.0 mass% or less.

Oil content

Examples of the oil component include liquid oils and fats, solid oils and fats, waxes, hydrocarbon oils, silicone oils, and polar oils. The oil component may be used singly or in combination of two or more.

The blending amount of the oil component is not particularly limited, and may be appropriately adjusted according to the type of the dosage form to be used, for example.

Emulsifying agent

As the emulsifier, for example, an anionic, cationic, amphoteric, or nonionic emulsifier can be used. The emulsifier may be used singly or in combination of two or more. Here, the emulsifier in the present disclosure means an agent having an emulsifying function (surface active property), and may generally contain an agent called a surfactant. The water-soluble drug does not contain an emulsifier.

Specifically, the emulsifier may be at least one selected from hydrocarbon-based surfactants, silicone-based surfactants, and amphiphilic powders.

Examples of the hydrocarbon surfactant include polyoxyethylene alkyl ether, polyoxyethylene sterol ether, polyoxyethylene fatty acid ester, polyoxyethylene polyol fatty acid ester, polyoxyethylene hardened castor oil, polyoxyethylene sorbitan fatty acid ester, glycol fatty acid ester, glycerin fatty acid ester, sorbitan fatty acid ester, sucrose fatty acid ester, and polyglycerin fatty acid ester.

Examples of the silicone surfactant include polyether-modified silicone and alkyl co-modified polyether-modified silicone.

The mixing amount of the emulsifier is not particularly limited, and may be, for example, 0.01 mass% or more, 0.05 mass% or more, 0.1 mass% or more, or 0.2 mass% or more with respect to the total amount of the emulsion composition from the viewpoint of emulsion stability or the like. The upper limit of the mixing amount of the emulsifier is not particularly limited, and may be, for example, 5 mass% or less, 4 mass% or less, 3 mass% or less, 2 mass% or less, or 1 mass% or less.

Water

As the water, there is no particular limitation, and for example, water used in cosmetics or quasi drugs can be used. For example, ion-exchanged water, distilled water, ultrapure water, and tap water may be used.

The mixing amount of water is not particularly limited, and may be appropriately adjusted according to the type of the dosage form to be used, for example.

Product dosage form of emulsified composition

The product form of the emulsion composition is not particularly limited, and examples thereof include cosmetics used in the field of cosmetics. Examples of the cosmetic materials include skin care cosmetics such as a cosmetic liquid, a lotion, and an emulsion, sunscreen cosmetics (sunscreens), foundation cosmetics, color cosmetics such as foundation, lip gloss, lipstick, eye shadow, and nail polish, and cosmetics in which 2 or more functions of these cosmetics are combined.

In several embodiments, the 1 st agent layer may be formed by applying the 1 st agent of the forming agent to the emulsion composition layer, and the 2 nd agent may be applied in a manner of covering the cosmetic after further applying the cosmetic on the 1 st agent layer; the 2 nd agent layer may be formed by applying the 2 nd agent of the forming agent to the emulsion composition layer, and the 1 st agent may be applied so as to cover the cosmetic after the cosmetic is further applied to the 2 nd agent layer; alternatively, after the body repair film is formed, a cosmetic may be applied to the film. In this case, the cosmetic may be a cosmetic of the above-described emulsified composition, or may be a cosmetic different from the above-described emulsified composition.

Coating type body repair film forming agent

The coating type body repair skin film forming agent of the present disclosure comprises: the agent 1 containing a crosslinking reactive component constituting the body repair film and the agent 2 containing a catalyst for crosslinking the crosslinking reactive component, and optionally, at least one of the agent 1 and the agent 2 may contain a water-soluble agent. The body repair film obtained by the forming agent having such a constitution can improve the permeability of the water-soluble drug to the skin. That is, the coating film forming agent for body repair of the present disclosure can be used as a water-soluble agent for skin permeation.

The permeability of a water-soluble drug to the skin can be evaluated by a permeability test described later using a standing-type (sometimes referred to as "vertical" or "longitudinal") Franz diffusion cell. After applying the emulsion composition containing the water-soluble agent to the skin, the forming agent of the present disclosure is applied to the emulsion composition layer, and when human skin is used as the membrane arranged in the diffusion cell, the intra-membrane concentration in the epidermis after 24 hours may be 7.5 μg/cm ² Above, 8.0 μg/cm ² Above, 10.0 μg/cm ² Above, 15.0. Mu.g/cm ² Above, 20.0 μg/cm ² Above, 25.0 μg/cm ² Above, 28.0 μg/cm ² Above, 30.0. Mu.g/cm ² Above, 40.0. Mu.g/cm ² Above, 50.0 μg/cm ² Above, 60.0 μg/cm ² Above, 70.0 μg/cm ² Above, 80.0 μg/cm ² Above, 90.0. Mu.g/cm ² Above, or 100.0 μg/cm ² The above. The upper limit of the concentration in the film is not particularly limited, and may be, for example, 300.0. Mu.g/cm ² Below, 250.0. Mu.g/cm ² Below, or 200.0. Mu.g/cm ² The following is given. Here, the "intra-membrane concentration" refers to the concentration of the water-soluble drug (intra-skin concentration) accumulated in skin tissue (e.g., epidermis and/or dermis) during the test.

Further, when human skin is used as a membrane disposed in a diffusion cell, for example, a ratio of an intra-membrane concentration after 24 hours in skin tissue (e.g., epidermis and/or dermis) in the case where the forming agent of the present disclosure is applied to an emulsified composition layer after the emulsified composition containing the same amount of the water-soluble agent is applied to the skin, to an intra-membrane concentration after 24 hours in skin tissue (e.g., epidermis and/or dermis) in the case where only the composition (e.g., non-emulsified composition) containing the water-soluble agent and water is applied to the skin may be 1.1 or more, 1.3 or more, 1.5 or more, 2.0 or more, 3.0 or more, 4.0 or 5.0 or more. The upper limit of such a ratio is not particularly limited, and may be, for example, 10 or less, 9.0 or less, or 8.0 or less.

When the simulated skin is used as the membrane disposed in the diffusion cell, the simulated skin is different from the human skin, and it is unclear which corresponds to the stratum corneum, epidermis, and dermis, and therefore the cumulative permeation amount can be evaluated. The term "cumulative permeation amount" as used herein refers to the concentration of a water-soluble drug in a receiving liquid that has passed through the simulated skin in the test. After applying the emulsion composition containing the water-soluble agent to the skin, the forming agent of the present disclosure is applied to the emulsion composition layer, and when the simulated skin is used as the membrane arranged in the diffusion cell, the cumulative permeation after 24 hours may exhibit 2.0 μg/cm ² Above, 2.5. Mu.g/cm ² Above, 3.0 μg/cm ² Above, 3.5. Mu.g/cm ² Above, or 4.0 μg/cm ² The above. The upper limit of the cumulative permeation amount is not particularly limited, and may be, for example, 20.0. Mu.g/cm ² Below, 15.0. Mu.g/cm ² Below, or 10.0. Mu.g/cm ² The following is given.

Further, when the simulated skin is used as the membrane disposed in the diffusion cell, for example, the ratio of the cumulative permeation quantity after 24 hours in the case where the forming agent of the present disclosure is applied to the emulsified composition layer after the emulsified composition containing the same amount of the water-soluble drug is applied to the simulated skin to the cumulative permeation quantity after 24 hours in the case where only the composition (for example, a non-emulsified composition) containing the water-soluble drug and water is applied to the simulated skin may be 1.1 or more, 1.3 or more, 1.5 or more, 1.7 or more, 2.0 or more, 2.3 or more, 2.5 or more, 2.7 or more, or 3.0 or more. The upper limit of such a ratio is not particularly limited, and may be, for example, 10 or less, 8.0 or less, or 5.0 or less.

In several embodiments, the application performance of the application type body repair film forming agent can be evaluated by using the viscosity of B-type viscometer (doctor solution Pu co). The viscosity of the 1 st agent and the 2 nd agent in the coating-type body repair film-forming agent of the present disclosure, as measured under the conditions of 60 revolutions per minute (rotor No.3 or No. 4), may be, for example, 100mpa·s or more, 500mpa·s or more, 1,000mpa·s or more, 2,000mpa·s or more, 5,000mpa·s or more, 7,500mpa·s or more, 10,000mpa·s or more, or 15,000mpa·s or more, and may be 1,000,000mpa·s or less, 750,000mpa·s or less, 500,000mpa·s or less, 250,000mpa·s or less, 200,000mpa·s or less, 175,000mpa·s or less, 150,000mpa·s or less, 125,000mpa·s or less, or 80,000mpa·s or less, as measured at 25 ℃. Among them, the 1 st agent and the 2 nd agent of the coating film forming agent for body repair preferably have a viscosity of 20,000mpa·s or less, 15,000mpa·s or less, or 10,000mpa·s or less, preferably a viscosity of 3,000mpa·s or more, 5,000mpa·s or more, or 7,000mpa·s or more, immediately after the preparation, from the viewpoints of smooth coating performance, suppression of liquid dripping from the skin, and the like.

In several embodiments, from the viewpoints of smooth application performance, suppression of liquid dripping from the skin, and the like, the viscosity after 2 weeks of the 1 st agent and the 2 nd agent in the application-type body repair film forming agent of the present disclosure measured under the conditions of 25 ℃, 60 revolutions per minute (rotor No. 3) is preferably 50,000mpa·s or less, 30,000mpa·s or less, or 15,000mpa·s or less, preferably 5,000mpa·s or more, 7,000mpa·s or more, or 10,000mpa·s or more.

Dose 1

The coating-type body repair film forming agent of the present disclosure includes a 1 st agent including a crosslinking-reactive component constituting a body repair film. The crosslinking reactive component is not particularly limited, and examples thereof include at least one selected from the group consisting of the 1 st unsaturated organopolysiloxane and the 1 st hydride functional polysiloxane. However, in the case where the 1 st agent contains only the 1 st unsaturated organopolysiloxane out of the 1 st unsaturated organopolysiloxane and the 1 st hydride-functional polysiloxane, the 2 nd agent in the forming agent of the present disclosure contains the 2 nd hydride-functional polysiloxane described later, and in the case where the 1 st agent contains only the 1 st hydride-functional polysiloxane out of the 1 st unsaturated organopolysiloxane and the 1 st hydride-functional polysiloxane, the 2 nd agent contains the 2 nd unsaturated organopolysiloxane.

The dosage form of the 1 st agent is not particularly limited, and may be, for example, a single-phase system composed of an oil phase, a non-emulsified oil-in-water or water-in-oil two-phase system, or a two-phase system composed of an oil-in-water emulsion composition or a water-in-oil emulsion composition. Here, the single-phase system composed of an oil phase is typically in an anhydrous state. In the present disclosure, "anhydrous" means that water is not included in the composition, but that the content of water is a low amount, that is, 10 mass% or less, 5 mass% or less, 2 mass% or less, 1 mass% or less, or 0.1 mass% or less. The non-emulsified two-phase system may include a water-in-oil type composition in which water droplets are forcibly dispersed in a dispersion medium containing oil or an oil-in-water type composition in which oil droplets are forcibly dispersed in a dispersion medium containing water by shaking a liquid in a state of being separated into water and oil.

Among such dosage forms, the 1 st agent is advantageous from the viewpoints of long-term storage property, drying property after application to the emulsion composition layer, crosslinking property, and the like, and the 1 st agent is a single-phase system composed of an oil phase in an anhydrous state. When the 1 st agent contains a water-soluble drug, the composition is preferably a two-phase system composed of an oil-in-water type or water-in-oil type emulsion composition, and more preferably a water-in-oil type emulsion composition, from the viewpoints of the crosslinking reactivity after the 1 st agent is applied to the emulsion composition layer, the dispersibility of water droplets containing the water-soluble drug in the coating film, the permeability of such water-soluble drug to the skin, and the like.

These formulations can be appropriately prepared by a conventional method using a crosslinking reactive component and a known material such as an oil component, an emulsifier, and water, as described above.

Since the 1 st agent is applied to the emulsion composition layer by, for example, application, it is preferable to have a glass transition temperature of not more than body temperature from the viewpoint of application performance. For example, the glass transition temperature may be 37 ℃ or less, 25 ℃ or less, 10 ℃ or less, or 0 ℃ or less. The lower limit of the glass transition temperature is not particularly limited, and may be, for example, -30 ℃ or higher, -20 ℃ or higher, or-10 ℃ or higher. The "glass transition temperature" herein means a temperature at which transition from a solid state to a liquid state occurs, and can be measured, for example, using a Differential Scanning Calorimeter (DSC) according to ASTM D3418-03.

(1 st unsaturated organopolysiloxane)

The 1 st unsaturated organopolysiloxane is not particularly limited, and examples thereof include one or more organopolysiloxanes having at least 2 carbon-carbon double bonds or at least 1 carbon-carbon triple bond in the molecule. As such an unsaturated organopolysiloxane, there can be preferably mentioned one or more organopolysiloxanes having an average of at least 2 alkenyl functional groups and a viscosity of 10,000 to 2,000,000cst at 25 ℃. Here, in the present disclosure, "carbon-carbon double bond" and "carbon-carbon triple bond" are sometimes simply referred to as "double bond" and "triple bond". The 1 st unsaturated organopolysiloxane may be used singly or in combination of two or more kinds.

Such organopolysiloxanes may contain double or triple bonds in terminal units of the polymer, in non-terminal monomer units of the polymer, or combinations thereof, with non-terminal monomer units of the polymer being preferred.

In certain embodiments, the monomer units containing double bonds in the organopolysiloxane may be on average 40 monomer units or more, 200 monomer units or more, 400 monomer units or more, 1,000 monomer units or more, or 2,000 monomer units or more apart.

In one embodiment, the amount of the monomer unit containing a double bond or a triple bond of the organopolysiloxane having a double bond or a triple bond may be, for example, 0.01 mass% or more or 0.03 mass% or more, and may be 2 mass% or less or 0.6 mass% or less.

In one embodiment, the organopolysiloxane having double or triple bonds may have a vinyl equivalent weight of, for example, 0.005 or more or 0.01 or more, and may have a vinyl equivalent weight of 0.5 or less or 0.25 or less per 1 kg. The approximate molar amount of double or triple bonds in the organopolysiloxane can be calculated based on the average molecular weight of the organopolysiloxane. The average molecular weight or molecular mass of each component disclosed in the present specification is generally provided by the supplier of each component and may be expressed in units of daltons (Da) or g/mol equivalent thereto.

In one embodiment, the 1 st unsaturated organopolysiloxane can have a viscosity of 10,000 to 2,000,000cst at 25 ℃. The lower limit of the viscosity is preferably 20,000cst or more, 40,000cst or more, 60,000cst or more, 80,000cst or more, or 100,000cst or more, more preferably 125,000cst or more, or 150,000cst or more. The upper limit of the viscosity is preferably 1,000,000cst or less, 500,000cst or less, 450,000cst or less, 400,000cst or less, 350,000cst or less, 300,000cst or less, or 250,000cst or less, more preferably 200,000cst or less, or 180,000cst or less, and even more preferably 165,000cst or less.

In one embodiment, the 1 st unsaturated organopolysiloxane may have an average molecular weight of 60,000Da to 500,000 Da. The lower limit of the average molecular weight is preferably 72,000Da or more, 84,000Da or more, 96,000Da or more, or 100,000Da or more, more preferably 140,000Da or more, or 150,000Da or more. The upper limit of the average molecular weight is preferably 200,000Da or less, 190,000Da or less, 180,000Da or less, or 170,000Da or less, more preferably 160,000Da or less, and still more preferably 155,000Da or less.

As the 1 st unsaturated organopolysiloxane, for example, at least one unsaturated organopolysiloxane selected from the group consisting of an organopolysiloxane having a vinyl group, an organopolysiloxane terminated with a vinyl group, and an organopolysiloxane having a branched chain terminated with a vinyl group can be used.

Specifically, examples thereof include vinyl-terminated polydimethylsiloxane, vinyl-terminated diphenylsiloxane-dimethylsiloxane copolymer, vinyl-terminated polyphenylmethylsiloxane, vinyl-terminated vinylphenylmethylsiloxane-phenylmethylsiloxane copolymer, vinyl-terminated trifluoropropylmethylsiloxane-dimethylsiloxane copolymer, vinyl-terminated diethylsiloxane-dimethylsiloxane copolymer, vinyl-methylsiloxane-dimethylsiloxane copolymer, trimethylsiloxy-terminated vinylmethylsiloxane-dimethylsiloxane copolymer, silanol-terminated vinylmethylsiloxane-dimethylsiloxane copolymer, vinylmethylsiloxane homopolymer, vinyl T-structure polymer, vinyl Q-structure polymer, monovinyl-terminated polydimethylsiloxane, vinyl methylsiloxane terpolymer, and vinylmethoxysilane homopolymer. The 1 st unsaturated organopolysiloxane may be used singly or in combination of two or more kinds. Among them, vinyl-terminated polydimethylsiloxane is preferable, and vinyl polydimethylsiloxane (divinyl polydimethylsiloxane) is more preferable. In the present disclosure, "terminal" refers to either one terminal or both terminals. In the case of distinguishing them, for example, it may be expressed as "vinyl single terminal", "vinyl both terminals".

The blending amount of the 1 st unsaturated organopolysiloxane in the 1 st agent is not particularly limited as long as it is appropriately adjusted according to the required film properties and the like. For example, the amount of the 1 st unsaturated organopolysiloxane to be blended may be 5 mass% or more, 10 mass% or more, 20 mass% or more, 30 mass% or more, 35 mass% or more, or 40 mass% or more, or 90 mass% or less, 80 mass% or less, 70 mass% or less, 60 mass% or less, 50 mass% or less, or 45 mass% or less, based on the entire 1 st agent.

(1. Hydride functional polysiloxanes)

The 1 st hydride functional polysiloxane is not particularly limited, and examples thereof include compounds of the following formula 2. The 1 st hydride functional polysiloxane may be used singly or in combination of two or more kinds:

in formula 2, R ^1b 、R ^2b 、R ^3b 、R ^4b 、R ^5b 、R ^6b 、R ^7b 、R ^8b 、R ^9b And R is ^10b Each independently selected from hydrogen, C _1-20 Alkyl, C _2-20 Alkenyl, C _5-10 Aryl, hydroxy, or C _1-20 Alkoxy, m and n are each independently integers from 10 to 6,000. Wherein R is ^1b 、R ^2b 、R ^3b 、R ^4b 、R ^5b 、R ^6b 、R ^7b 、R ^8b 、R ^9b And R is ^10b At least 1 of which is hydrogen.

In several embodiments, R ^1b 、R ^2b 、R ^3b 、R ^4b 、R ^5b 、R ^6b 、R ^7b 、R ^8b 、R ^9b And R is ^10b At least 1 of them being hydrogen and the remainder being C _1-20 An alkyl group.

In several embodiments, R ^1b 、R ^2b 、R ^3b 、R ^4b 、R ^5b 、R ^6b 、R ^7b 、R ^8b 、R ^9b And R is ^10b Is hydrogen (e.g., 2 Si-H units per molecule of the functionalized hydride polysiloxane).

In other embodiments, R ^1b 、R ^2b 、R ^3b 、R ^4b 、R ^5b 、R ^6b 、R ^7b 、R ^8b 、R ^9b And R is ^10b Is hydrogen (e.g.,the functionalized hydride polysiloxane has 3 Si-H units per molecule).

In several embodiments, R ^1b 、R ^2b 、R ^3b 、R ^4b 、R ^5b 、R ^6b 、R ^7b 、R ^8b 、R ^9b And R is ^10b At least 2 of which are hydrogen (e.g., 2 Si-H units per molecule of the functionalized hydride polysiloxane), the remainder being C _1-20 An alkyl group.

In other embodiments, R ^1b 、R ^2b 、R ^3b 、R ^4b 、R ^5b 、R ^6b 、R ^7b 、R ^8b 、R ^9b And R is ^10b At least 3 of which are hydrogen (e.g., 3 Si-H units per molecule of the functionalized hydride polysiloxane), the remainder being C _1-20 An alkyl group.

In several embodiments, R ^4b 、R ^5b 、R ^9b And R is ^10b At least 2 of which are hydrogen (e.g., 2 Si-H units per molecule of the functionalized hydride polysiloxane), the remainder being C _1-20 An alkyl group.

In other embodiments, R ^4b 、R ^5b 、R ^9b And R is ^10b At least 3 of which are hydrogen (e.g., 3 Si-H units per molecule of the functionalized hydride polysiloxane), the remainder being C _1-20 An alkyl group.

In several embodiments, the sum of m and n is an integer from 10 to 1,300, 10 to 1,100, 10 to 600, 15 to 500, 15 to 400, 20 to 300, 20 to 200, 25 to 100, 25 to 75, 30 to 50, or 40 to 45.

In several embodiments, as the 1 st hydride-functional polysiloxane, there may be mentioned organopolysiloxanes which are hydrogenated at the non-terminal and/or terminal, there may be mentioned one or more organopolysiloxanes which are composed of one or more organopolysiloxanes having at least 2 Si-H units in the molecule, preferably one or more organopolysiloxanes which have an average of at least 2 Si-H units and a viscosity of from 2 to 100,000cst at 25 ℃.

In certain embodiments, the organopolysiloxane having Si-H units can be in terminal units of the polymer, non-terminal units of the polymerSuch Si-H units are contained in the bulk unit, or in a combination thereof. Among them, si-H units are preferably contained in non-terminal monomer units of the polymer. The 1 st hydride functional polysiloxane in this case may be terminated by an alkyl group. For example, in formula 2, R ^2b And R is ^7b Either or both of them may be C _1-20 An alkyl group.

In one embodiment, in formula 2, R ^1b 、R ^2b 、R ^3b 、R ^6b 、R ^7b And R is ^8b In which 1, 2, 3, 4, 5 or 6 may be C _1-20 An alkyl group.

In one embodiment, R ^1b 、R ^2b 、R ^3b 、R ^4b 、R ^5b 、R ^6b 、R ^7b 、R ^8b And R is ^10b Respectively C _1-20 Alkyl radicals, e.g. C ₁ Alkyl (e.g., methyl), R ^9b May be hydrogen.

In one embodiment, R ^1b 、R ^2b 、R ^3b 、R ^4b 、R ^5b 、R ^6b 、R ^7b 、R ^8b And R is ^9b Respectively C _1-20 Alkyl radicals, e.g. C ₁ Alkyl (e.g., methyl), R ^10b May be hydrogen.

In one embodiment, the Si-H containing monomer units in the organopolysiloxane may be on average 1 monomer unit or more, 2 monomer units or more, 5 monomer units or more, 10 monomer units or more, 20 monomer units or more, 40 monomer units or more, 200 monomer units or more, 400 monomer units or more, 1,000 monomer units or more, or 2,000 monomer units or more apart.

In one embodiment, the amount of si—h containing monomer units of the organopolysiloxane having si—h units may be 0.003 mass% or more, 0.01 mass% or more, 0.1 mass% or more, 1 mass% or more, 3 mass% or more, 5 mass% or more, 10 mass% or more, 20 mass% or more, or 26 mass% or more, and further may be 50 mass% or less, 45 mass% or less, 40 mass% or less, 35 mass% or less, 30 mass% or less, or 27 mass% or less.

In one embodiment, the organopolysiloxane having Si-H units may have a Si-H content of 0.1mmol/g or more, 0.5mmol/g or more, 1mmol/g or more, 2mmol/g or more, 3mmol/g or more, or 4mmol/g or more, and may be 20mmol/g or less, 10mmol/g or less, 9mmol/g or less, 8mmol/g or less, 7mmol/g or less, 6mmol/g or less, or 5mmol/g or less. The approximate molar amount of Si-H units in the organopolysiloxane can be calculated based on the average molecular weight of the organopolysiloxane.

In one embodiment, the 1 st hydride functional polysiloxane can have a viscosity of 2 to 500,000cst at 25 ℃. The lower limit of the viscosity is preferably 3cst or more, 4cst or more, 5cst or more, 10cst or more, 12cst or more, 15cst or more, 20cst or more, 25cst or more, or 30cst or more, more preferably 40cst or more. The upper limit of the viscosity is preferably 200,000cst or less, 100,000cst or less, 50,000cst or less, 20,000cst or less, 10,000cst or less, 5,000cst or less, 2,000cst or less, or 1,000cst or less, more preferably 500cst or less. The viscosity of the hydride-functional polysiloxane is particularly preferably in the range of 45 to 100cst or 45 to 50cst at 25 ℃.

In certain embodiments, the hydride functional polysiloxane can have an average molecular weight of 400 to 500,000 Da. The lower limit of the average molecular weight is preferably 500Da or more, 800Da or more, 900Da or more, 1,000Da or more, 1,200Da or more, 1,400Da or more, 1,600Da or more, 1,800Da or more, 2,000Da or more, or 2,200Da or more, more preferably 2,300Da or more. The upper limit of the average molecular weight is preferably 250,000Da or less, 140,000Da or less, 100,000Da or less, 72,000Da or less, 62,700Da or less, 60,000Da or less, 50,000Da or less, 49,500Da or less, 36,000Da or less, 28,000Da or less, 25,000Da or less, 20,000Da or less, 15,000Da or less, 10,000Da or less, 5,000Da or less, or 4,000Da or less, more preferably 2,500Da or less.

The 1 st hydride-functional polysiloxane is not limited to, and for example, at least one selected from the group consisting of hydride-terminated polydimethylsiloxane, hydride-terminated polyphenyl- (dimethylhydrosiloxy) siloxane, hydride-terminated methylhydrosiloxane-phenylmethylsiloxane copolymer, trimethylsiloxy-terminated methylhydrosiloxane-dimethylsiloxane copolymer, polymethylhydrosiloxane, trimethylsiloxy-terminated polyethylhydrosiloxane, triethylsiloxane, methylhydrosiloxane-phenyloctylmethylsiloxane copolymer, and methylhydrosiloxane-phenyloctylmethylsiloxane terpolymer may be employed. Among them, hydride terminal polydimethylsiloxane is preferable, and hydrogenated polydimethylsiloxane is more preferable.

The blending amount of the 1 st hydride functional polysiloxane in the 1 st agent is not particularly limited as long as it is appropriately adjusted according to the required film properties and the like. For example, the amount of the 1 st hydride-functional polysiloxane to be blended may be 1 mass% or more, 3 mass% or more, or 5 mass% or more, 75 mass% or less, 60 mass% or less, 50 mass% or less, 40 mass% or less, 30 mass% or less, 20 mass% or less, or 10 mass% or less, based on the entire 1 st agent.

(other polymers)

Agent 1 may optionally comprise other polymers besides the 1 st unsaturated organopolysiloxane and the 1 st hydride functional polysiloxane. Other polymers may be used singly or in combination of two or more.

In one embodiment, the other polymer may have a viscosity of 0.7cst to 50,000cst at 25 ℃. The lower limit of the viscosity may be 1cst or more, 6cst or more, 10cst or more, 20cst or more, 50cst or more, 100cst or more, 200cst or more, 300cst or more, 400cst or more, 750cst or more, 1,000cst or more, 1,500cst or more, 2,000cst or more, 2,500cst or more, 3,000cst or more, 3,500cst or more, or 4000cst or more. The upper limit of the viscosity may be 45,000cst or less, 40,000cst or less, 35,000cst or less, 30,000cst or less, 25,000cst or less, 20,000cst or less, 15,000cst or less, 12,000cst or less, 10,000cst or less, 5,000cst or less, 4,000cst or less, 2,000cst or less, 1,500cst or less, or 1,000cst or less.

In certain embodiments, the other polymers may have an average molecular weight of 180Da to 80,000 Da. The lower limit of the average molecular weight may be 500Da or more, 800Da or more, 1,500Da or more, 3,000Da or more, 6,000Da or more, 9,400Da or more, 10,000Da or more, 15,000Da or more, 20,000Da or more, 30,000Da or more, 40,000Da or more, 50,000Da or more, 55,000Da or more, 60,000Da or more, or 62,000Da or more. The upper limit of the average molecular weight may be 75,000Da or less, 70,000Da or less, 65,000Da or less, or 63,000Da or less.

As the other polymer, there may be preferably mentioned one or more organopolysiloxanes having an average of at least 1 alkenyl functional group and a viscosity of 0.7 to 50,000cst at 25 ℃.

Specifically, as the other polymer, for example, a polymer selected from the group consisting of vinyl-terminated polydimethylsiloxane, vinyl-terminated diphenylsiloxane-dimethylsiloxane copolymer, vinyl-terminated polyphenylmethylsiloxane, vinyl-terminated vinylphenylsiloxane-phenylmethylsiloxane copolymer, vinyl-terminated trifluoropropylmethylsiloxane-dimethylsiloxane copolymer, vinyl-terminated diethylsiloxane-dimethylsiloxane copolymer, vinyl methylsiloxane-dimethylsiloxane copolymer, trimethylsiloxy-terminated vinylmethylsiloxane-dimethylsiloxane copolymer, silanol-terminated vinylmethylsiloxane-dimethylsiloxane copolymer, vinyl-terminated vinylrubber, vinylmethylsiloxane homopolymer, vinyl T-structured polymer, vinyl Q-structured polymer, unsaturated organic polymer (for example, unsaturated fatty alcohol, unsaturated fatty acid, unsaturated fatty ester, unsaturated fatty amide, unsaturated fatty urethane, unsaturated fatty urea, ceramide, crocetin, lecithin, and sphingosine), monovinyl-terminated polydimethylsiloxane, vinylmethylsiloxane homopolymer, vinylmethylsiloxane copolymer, monovinylmethylsiloxane, monovinylsiloxane, and at least one-terminated polysiloxane, and at least one of vinyl-terminated polysiloxane may be employed. Among them, vinyl-terminated polydimethylsiloxane is preferable, and divinyl polydimethylsiloxane and 1, 3-divinyl tetramethyl disiloxane are more preferable.

The blending amount of the other polymer in the 1 st agent is not particularly limited as long as it is appropriately adjusted according to the required film properties and the like. For example, the amount of the other polymer to be blended may be 0.01 mass% or more, 0.1 mass% or more, 0.3 mass% or more, or 0.5 mass% or more, and may be 20 mass% or less, 15 mass% or less, or 10 mass% or less, based on the entire 1 st agent.

Unsaturated organopolysiloxane 1, hydride-functional polysiloxane 1, ratio of functional groups in other polymers

In one embodiment, the molar ratio of Si-H functional groups derived from the 1 st hydride functional polysiloxane to alkenyl functional groups derived from the 1 st unsaturated organopolysiloxane is preferably from 60:1 to 1:5, more preferably from 45:1 to 15:1.

In one embodiment, the molar ratio of Si-H functional groups derived from the 1 st hydride-functional polysiloxane to alkenyl functional groups derived from other polymers is preferably from 60:1 to 1:5, more preferably from 45:1 to 15:1.

In one embodiment, the molar ratio of alkenyl functionality derived from the 1 st unsaturated organopolysiloxane to alkenyl functionality derived from other polymers is preferably from 100:1 to 1:100, more preferably from 10:1 to 1:10.

Dose 2

The 2 nd agent constituting the coating film forming agent for a body repair of the present disclosure contains a catalyst for crosslinking the crosslinking-reactive component in the 1 st agent.

(catalyst)

The catalyst is not particularly limited, and examples thereof include any substances capable of causing, promoting, or initiating a physical and/or chemical crosslinking reaction with respect to an unsaturated organopolysiloxane and a hydride-functional polysiloxane that are crosslinking-reactive components constituting a body repair film. The catalyst may or may not undergo permanent physical and/or chemical changes during or at the end of the process.

The catalyst is not limited to the following, and examples thereof include metal catalysts which can initiate and/or promote crosslinking at a temperature of or below body temperature, for example, metal catalysts of group VIII such as platinum catalysts, rhodium catalysts, palladium catalysts, cobalt catalysts, nickel catalysts, ruthenium catalysts, osmium catalysts, and iridium catalysts, and metal catalysts of group IVA such as germanium catalysts and tin catalysts. Among them, a platinum catalyst, a rhodium catalyst, or a tin catalyst is preferable. The catalyst may be used singly or in combination of two or more.

As platinum catalysts there may be mentioned, for example, platinum catalysts selected from the group consisting of platinum carbonyl cyclovinylmethylsiloxane complexes, platinum divinyl tetramethyldisiloxane complexes, platinum cyclovinylmethylsiloxane complexes, platinum octaldehyde/octanol complexes, and other Pt (0) catalysts such as, for example, carbster catalysts, platinum-alcohol complexes, platinum-alkoxide complexes, platinum-ether complexes, platinum-aldehyde complexes, platinum-ketone complexes, platinum-halogen complexes, platinum-sulfur complexes, platinum-nitrogen complexes, platinum-phosphorus complexes, platinum-carbon double bond complexes, platinum carbon triple bond complexes, platinum-imide complexes, platinum-amide complexes, platinum-ester complexes, platinum-phosphate complexes, platinum-thiol complexes, platinum lone pair complexes, platinum-aromatic complexes, platinum pi-electron complexes, and combinations thereof. Among them, at least one of platinum carbonyl cyclovinylmethylsiloxane complex, platinum divinyl tetramethyl disiloxane complex, platinum cyclovinylmethylsiloxane complex, and platinum octaldehyde/octanol complex is preferable.

Examples of the rhodium catalyst include rhodium tri (dibutyl sulfide) trichloride and rhodium trichloride hydrate.

Examples of the tin catalyst include tin (II) octoate, tin (II) neodecanoate, dibutyltin diisooctylmaleate, tin di-n-butylbis (2, 4-glutarate), tin di-n-butylbutoxychloride, dibutyltin dilaurate, dimethyltin dineodecanoate, tin dimethylhydroxy (oleate), and tin (II) oleate.

Among these catalysts, platinum catalysts are more preferable, and platinum divinyl tetramethyl disiloxane complex is particularly preferable.

The mixing amount of the catalyst in the 2 nd agent is not particularly limited as long as it is appropriately adjusted according to the required film properties and the like. For example, the amount of the catalyst to be mixed may be 0.001 mass% or more, 0.005 mass% or more, or 0.010 mass% or more, or 1.0 mass% or less, 0.10 mass% or less, or 0.050 mass% or less, based on the total amount of the 2 nd agent.

Dosage form of 2 nd dose

The dosage form of the 2 nd agent of the present disclosure is not particularly limited, and may be, for example, a single-phase system composed of an oil phase in an anhydrous form, a two-phase system composed of a non-emulsified oil-in-water or water-in-oil type, or a two-phase system composed of an oil-in-water emulsion composition or a water-in-oil emulsion composition. Among them, a two-phase system composed of an oil-in-water type or water-in-oil type emulsion composition is preferable from the viewpoints of the crosslinking reactivity with the 1 st agent, the permeability of the water-soluble drug to the skin, and the like.

These formulations can be appropriately prepared by a conventional method using a catalyst and known materials such as any of the above-mentioned oil components, emulsifiers, and water.

As the silicone oil that can be mixed in the oil component of the 2 nd agent, for example, chain silicones such as dimethylpolysiloxane (polydimethylsiloxane), methylphenylpolysiloxane, methyl hydrogen-containing polysiloxane, and the like can be used; and cyclic silicones such as octamethyl cyclotetrasiloxane, decamethyl cyclopentasiloxane, and dodecamethyl cyclohexasiloxane. Further, as the silicone oil, the 1 st unsaturated organopolysiloxane and the 1 st hydride functional polysiloxane which can be used in the 1 st agent described above can be used. The unsaturated organopolysiloxane and the hydride-functional polysiloxane in the 2 nd agent may be referred to as an unsaturated organopolysiloxane and a hydride-functional polysiloxane in the 2 nd agent in order to distinguish them from the 1 st unsaturated organopolysiloxane and the 1 st hydride-functional polysiloxane in the 1 st agent.

(other polymers)

Agent 2 may be similarly compounded with the other polymers described above that can be compounded with agent 1.

In the case where the 2 nd unsaturated organopolysiloxane and the other polymer are used in the 2 nd agent, the same ratio of the functional groups as in the above-mentioned 1 st unsaturated organopolysiloxane and the other polymer can be used.

Arbitrary composition

The coating-type body repair film forming agent of the present disclosure may appropriately blend various components with respect to the 1 st agent and/or the 2 nd agent within a range that does not adversely affect the effects of the present disclosure.

Examples of the optional components include, but are not limited to, the water-soluble drugs, touch modifiers, adhesion modifiers, ductility enhancers, diluents, adhesion modifiers, emulsifiers (surfactants) other than the above, solvents, humectants, stock materials, fibers, pigments, dyes, components for thickening aqueous or oil phases (thickeners), protective colloids, reinforcing materials (fillers), skin permeation enhancers, optical modifiers, scattering agents, adsorbents, magnetic materials, gas transport modifiers, liquid transport modifiers, pH modifiers, sensitization modifiers, and aesthetic modifiers. Any of the components may be used singly or in combination. The water-soluble component among the optional components may be contained in the water-soluble pharmaceutical agent.

In the case where at least one of the 1 st and 2 nd agents contains a water-soluble drug, the water-soluble drug may be mixed so as to contain 0.1 mass% or more, 0.5 mass% or more, or 1.0 mass% or more in at least one of the 1 st and 2 nd agents. The upper limit of the blending amount is not particularly limited, and may be, for example, 10 mass% or less, 8.0 mass% or less, 5.0 mass% or less, or 3.0 mass% or less. Here, from the viewpoint of permeability of the water-soluble drug from the coating film to the skin, the water-soluble drug is preferably blended in the 1 st agent which can become the main component constituting the coating film.

In addition, in the case of the optical fiber,examples thereof include cosmetics such as moisturizers, ultraviolet absorbers, skin protectants, skin tranquilizers, skin lightening agents, skin luster agents, skin softeners, skin smoothening agents, skin bleaching agents, skin exfoliating agents, skin tightening agents, cosmetics, vitamins, antioxidants, cell signal transduction agents, cell regulators, cell interaction agents, skin sun agents, anti-aging agents, wrinkle inhibitors, speckle lightening agents, alpha-hydroxy acids, beta-hydroxy acids, and ceramides; examples thereof include therapeutic agents such as pain reliever, analgesic, antipruritic, anti-acne agent (e.g., β -hydroxy acid, salicylic acid, benzoyl peroxide), anti-inflammatory agent, antihistamine, corticosteroid, NSAID (non-steroidal anti-inflammatory), antiseptic, antibiotic, antibacterial, antifungal, antiviral, antiallergic, anti-irritant, insect repellent, phototherapy, blood coagulant, antitumor, immune system enhancer, immune system inhibitor, coal tar, anthralin, fluocinolone acetonide, methotrexate, cyclosporine, pimecrolimus, tacrolimus, azathioprine, fluorouracil, ceramide, anti-irritant, and skin cooling compound; further, for example, antioxidants, vitamins, vitamin D can be mentioned ₃ Analogues, retinoids, minerals, mineral oils, petrolatum, fatty acids, plant extracts, polypeptides, antibodies, proteins, sugars, humectants, and emollients.

Examples of the reinforcing material include materials selected from carbon (e.g., graphene), silver, mica, zinc sulfide, zinc oxide, titanium dioxide, aluminum oxide, clay (e.g., kaolin), chalk, talc, calcite (e.g., calcium carbonate (CaCO) ₃ ) At least one of magnesium carbonate, barium sulfate, zirconium dioxide, a polymer (e.g., nylon) or polymer beads formed from the polymer, silica (e.g., fumed silica, silicic acid, or anhydrous silica), aluminum silicate, and calcium silicate, which may be subjected to a surface treatment. Such a reinforcing material can improve physical properties (for example, strength) of the body repair film, and can also function as a viscosity modifier. Among them, the reinforcing material is preferably one obtained by the following methodThe surface-treated silica may be, for example, a silica treated with a surface-treating agent such as hexamethyldisilazane, polydimethylsiloxane, hexadecylsilane, or methacrylic silane. In addition, fumed silica is also preferable, and fumed silica surface-treated with hexamethyldisilazane or the like can be suitably used.

In one embodiment, the reinforcing material may have a thickness of 50 to 500m ² Specific surface area per gram. The specific surface area of the reinforcing material is preferably 100 to 350m ² Preferably from 135 to 250m ² And/g. Here, the specific surface area of the reinforcing material can be calculated using the BET method.

In one embodiment, the reinforcing material may have an area equivalent particle size of 1nm to 20 μm. The area equivalent particle diameter of the reinforcing material is preferably 2nm to 1. Mu.m, more preferably 5nm to 50nm. Here, the area equivalent particle diameter of the reinforcing material may be, for example, a particle diameter in the case of converting into a particle having a circular shape with the same area as the projected area of the reinforcing material particles observed by a transmission electron microscope. The area equivalent particle diameter may be defined as an average value of 10 or more particles.

The mixing amount of the reinforcing material may be, for example, 0.001 mass% or more, 0.01 mass% or more, 0.1 mass% or more, 0.5 mass% or more, 1 mass% or more, 3 mass% or more, or 5 mass% or more, 25 mass% or less, 15 mass% or less, or 10 mass% or less, with respect to the entire amount of the 1 st or 2 nd agent.

From the viewpoint of the reinforcement of the body repair film, the total amount of the 1 st and 2 nd unsaturated organopolysiloxane, the 1 st and 2 nd hydride-functional polysiloxane, and other polymers, and the mass ratio to the reinforcing material may be 100:1 to 1:1, preferably 50:1 to 2:1, more preferably 15:1 to 3:1, still more preferably 10:1 to 4:1, and particularly preferably 5:1 to 9:1.

At least one selected from pigments, dyes and reinforcing materials among the arbitrary components is preferably blended in the 1 st agent. In particular, in the case of pigments and dyes, if the 2 nd agent is applied to the application surface of the 1 st agent when they are mixed in the 2 nd agent, the pigments or dyes are likely to be localized in the middle thereof and color unevenness may occur. From the viewpoint of suppressing color unevenness, it is advantageous that the pigment and the dye are compounded in the 1 st agent. In addition, in the 2 nd agent, pigments, dyes and reinforcing materials may be blended in such a range that color unevenness does not occur, but they are advantageously not contained in the 2 nd agent.

Kit comprising coating-type body repair coating forming agent

The coating-type body repair film forming agent of the present disclosure may be provided as a kit having the 1 st agent and the 2 nd agent described above constituting such a forming agent. The kit may further include the above-described emulsion composition in addition to the 1 st and 2 nd agents, and further may include any member for facilitating application of the 1 st agent or the like, for example.

Examples of the optional member include instructions for use, brushes, cotton sticks, cutters, scissors, a cleaning agent for removing a body repair film from a body surface, a mirror, and the like. Here, the "instruction manual" may include, for example, a general instruction manual in which instructions are attached in the form of a book in the kit, and may include a substance in which instructions for use are printed on a packaging container for housing the kit, a packaging container such as a tube for injecting the 1 st dose, or the like.

In one embodiment, in order to prevent contact between the 1 st and 2 nd agents, the agents may be contained in separate containers, or may be contained in each of 2 or more containers. The encapsulated agents may be applied 1 at 1 time or may be mixed together before or at the time of use.

Body repair coating

Thickness

The thickness of the body repair film prepared by using the coating-type body repair film forming agent of the present disclosure is not particularly limited, and may be appropriately adjusted in consideration of, for example, air permeability, invisibility, compressibility, and sealing to the skin. The thickness of the body repair film may be, for example, 0.5 μm or more, 1 μm or more, 10 μm or more, 30 μm or more, or 40 μm or more. The upper limit of the thickness is not particularly limited, and may be, for example, 150 μm or less, 100 μm or less, 90 μm or less, 80 μm or less, 70 μm or less, 60 μm or less, or 50 μm or less. The thickness may be defined as an average value calculated by measuring the thickness of an arbitrary portion of the body repair film 5 times using a high-precision digital micrometer (MDH-25 MB, manufactured by the company chemical company).

Performance

The body repair film prepared from the coating-type body repair film forming agent of the present disclosure can provide excellent results for various performances as shown below, for example.

(adhesive force)

In several embodiments, the resulting body repair film may exhibit good adhesion to a body surface. Such adhesion can be evaluated by replacing the adhesion of the body repair film applied to the polypropylene sheet. The adhesive force of the body repair film on the polypropylene sheet may be 2N/m or more, 5N/m or more, 8N/m or more, 10N/m or more, or 15N/m or more. The upper limit of the adhesive force is not particularly limited, and may be, for example, 200N/m or less, 100N/m or less, 80N/m or less, 50N/m or less, or 30N/m or less from the viewpoint of peelability of the skin or the like. Here, the adhesion force can be measured by the peel adhesion test according to ASTM C794 using a fin device.

(tensile Strength)

In several embodiments, the resulting body repair film may exhibit good tensile strength. The tensile strength of the body repair film may be 0.05MPa or more, 0.10MPa or more, 0.20MPa or more, or 0.50MPa or more. The upper limit of the tensile strength is not particularly limited, and may be, for example, 5.0MPa or less, 3.0MPa or less, 2.0MPa or less, or 1.0MPa or less. The tensile strength can be measured by an extension tensile test according to ASTM D5083 using a fin device.

(elongation at break)

In several embodiments, the resulting body repair film may exhibit good elongation at break. The elongation at break of the body repair film may be 25% or more, 50% or more, 100% or more, 200% or more, or 400% or more. The upper limit value of the elongation at break is not particularly limited, and may be, for example, 1,500% or less, 1,200% or less, 1,000% or less, 800% or less, or 600% or less. The elongation at break can be measured by an elongation tensile test according to ASTM D5083 using a bilrun device.

(resistance to cracking)

In several embodiments, the resulting body repair film may exhibit good crack resistance. Such performance can be evaluated, for example, by the presence or absence of cracking of the body repair film upon peeling from the skin. The rupture of the body repair film may be 15% or less, 10% or less, or 5% or less of the whole body. The lower limit of the fracture is not particularly limited, and may be, for example, 0% or more than 0%.

(oxygen transmittance)

In several embodiments, the resulting body repair film may exhibit good oxygen transmission. As the oxygen permeability of the body repair film, the film thickness of 300 μm can reach 5X 10 ^-9 cm ³ /(cm ² S) or more, 5×10 ^-7 cm ³ /(cm ² S) or more, or 5X 10 ^-5 cm ³ /(cm ² S) above. The upper limit of the oxygen permeability is not particularly limited, and may be, for example, 5cm ³ /(cm ² S) or less, 0.5cm ³ /(cm ² S) or below, 5×10 ^-2 cm ³ /(cm ² S) or below, 5×10 ^-3 cm ³ /(cm ² S) or less, or 5X 10 ^-4 cm ³ /(cm ² S) is as follows. The oxygen permeability can be measured by using an apparatus of the type コ according to the oxygen permeability test of plastic films and sheets of ASTM F2622.

(Water vapor Transmission Rate)

In several embodiments, the resulting body repair film may exhibit good water vapor transmission rates. The water vapor permeability of the body repair film was 1X 10 in the body repair film having a thickness of 300. Mu.m ^-9 cm ³ /(cm ² S) or more, 1×10 ^-8 cm ³ /(cm ² S) or more, or 1×10 ^-7 cm ³ /(cm ² S) above. The upper limit of the water vapor permeability is not particularly limited, and may be, for example, 1.5X10 ^-1 cm ³ /(cm ² S) or below, 1.5X10 ^-2 cm ³ /(cm ² S) is 1×10 ^-4 cm ³ /(cm ² S) is 1×10 ^-5 cm ³ /(cm ² S) or 1×10 ^-6 cm ³ /(cm ² S) is as follows. The water vapor permeability can be measured by the water vapor permeability test of plastic films and sheets according to ASTM F1249 using a コ n device.

Examples

The present invention will be described in further detail with reference to examples, but the present invention is not limited to these examples.

Evaluation test

The following permeability test was performed using each test sample obtained by the following production method, and the results are summarized in tables 1 to 3. Here, "O/W" and "W/O" in the tables refer to "oil-in-water type emulsion composition" and "water-in-oil type emulsion composition", and "cumulative transmission amount ratio" refers to the ratio of the cumulative transmission amount in the examples in the same table to the cumulative transmission amount in the comparative examples in the table.

Permeability test

The cumulative permeation amount of the water-soluble drug into simulated skin after 24 hours was measured by the following conditions and methods using a stationary Franz diffusion cell and simulated skin.

(test conditions)

Type of cell: standing Franz diffusion cell コ (manufactured by Franz corporation)

Volume of the receiving well: 9.6mL

Simulated skin area as subject: 1.77cm ²

Type of simulated skin: start-M (Artificial membrane simulating skin available from Merck KGaA Co., ltd.)

Receiving liquid: phosphate Buffered Saline (PBS)

(test method)

The receiving solution was prepared at an appropriate pH, and the solution was filtered through a ZapCap CR 0.2 μm membrane while evacuating the solution.

The diffusion cell was assembled according to the following (1) to (9). In the test of the receiving liquid, the liquid was continuously stirred with a stirrer using a stirring block heater maintained at 32±0.5℃:

(1) The simulated skin is removed from the package and placed in a counter of a biosafety cabinet. The simulated skin was gently beaten with dust free paper to dry, then sprayed with fresh PBS, and gently beaten again to dry. This process was repeated 3 more times, removing residues present on the simulated skin.

(2) Then, the receiving hole is filled with the degassed receiving liquid. A teflon (trademark) -coated stirring tool was placed in each receiving hole.

(3) The simulated skin was investigated using only the portions with uniform thickness and no macroscopic lesions on the surface.

(4) The simulated skin was cut to about 2cm square.

(5) The cut simulated skin piece was placed in the center of the supply tank.

(6) The simulated skin was again centered with the edges completely flat. The feed holes and the receiving holes are then aligned and clamped together with a spring clamp.

(7) If necessary, an additional receiving liquid is added. The presence of air bubbles is removed by inverting the cell and air is displaced along the sample port.

(8) Then, the diffusion cell was placed in a stirred dry block heater and rehydrated from the receiving liquid for 20 minutes in advance. The block heater was maintained at 32 ℃.+ -. 0.5 ℃ throughout the test while continuously stirring.

(9) After 20 minutes, the surface of the simulated skin was investigated. When the simulated skin is wet, the simulated skin is considered to be damaged and discarded.

The cells were assembled and after 20 minutes of hydration of the simulated skin, tritiated water tests were performed to evaluate the barrier integrity of each simulated skin segment prior to application of the test sample to the simulated skin. The simulated skin barrier integrity was evaluated according to the following (a) - (i). In addition, regarding simulated skin barrier integrity, it is detailed in Tioga Research SOP lab.011:

(a) A150. Mu.l aliquot of tritiated water (25. Mu. Ci water/10 ml water spiked) was added to the feed well of each diffusion cell.

(b) After 5 minutes tritiated water from the supply hole was removed and the simulated skin was gently tapped using dust free paper to dry.

(c) After removal of the tritiated feed solution, the receiving wells were stirred for a further 1 hour.

(d) After stirring for 1 hour, 300 μl aliquots were taken from each receiving well. The remaining stock was discarded and exchanged with fresh PBS (simulated skin barrier integrity test used only PBS in the stock).

(e) 600 μl of scintillation fluid (Ultima Gold XR) was added to each sample aliquot.

(f) The tritium content of the recipient well aliquots was then determined using a Liquid Scintillation Counter (LSC).

(g) After the LSC analysis is completed, the results are analyzed. Any diffusion cell exhibiting an abnormally high tritiated water flux was discarded.

(h) The diffusion cells were then displaced a second time according to tritiated water flux. Then, the diffusion cells were assigned in such a way that each test sample was assigned to a diffusion cell having an almost equivalent average tritiated water flux value.

(i) After the completion of the simulated skin barrier integrity test, the entire volume of the receiving chamber was exchanged with the receiving liquid.

The skin barrier integrity test is ended and, with the cells properly sorted, it can be said that preparation is made for applying the test sample to the simulated skin. The supply cell is first removed from the diffusion cell. This step is necessary to enable proper application of the test sample over the exposed surface portion. Next, will have a thickness of about 1.77cm ² The plastic washing device of the opening part is arranged on the simulated skin in a way that the opening part and the receiving chamber are arranged in a row. Then, a single application protocol was used for this test. For example, in the case of a test sample to which an emulsion composition (e.g., oil-in-water emulsion, water-in-oil cream) containing a water-soluble agent is administered, the emulsion composition is added at 2mg/cm ² Is applied to simulated skin, and is stretched over the simulated skin surface using a glass rod (note that the test sample stays within the confines of the plastic gasket). In the case of applying a test sample containing the 1 st agent and the 2 nd agent of the coating type body repair film forming agent to the emulsion composition layer, the 1 st agent was added at a concentration of 5.5mg/cm ² Is applied to the emulsion composition layer, and is stretched by a glass rod to form a 1 st dose layer, and then a 2 nd dose is applied at a concentration of 5.5mg/cm ² Is applied to the 1 st dose layer. In order to confirm the amount of the test sample remaining after the extension during the whole application of the test sample, the weight of the diffusion cell was measured before and after each application step.

At 1, 2, 4, 6, 20, and 24 hours, 300 μl of the sample was aliquoted and withdrawn from the receiving well using a calibrated Hamilton-type syringe. A new receiving medium was added and 300. Mu.l of sample aliquots were exchanged. The samples were then filtered using a 0.2 μm GHP membrane filter plate.

The sample aliquots were analyzed by an Agilent G6120 HPLC system with LC-MS detector to quantify the cumulative penetration of the water-soluble drug into simulated skin after 24 hours. The sample is stored in a cold storage at 4-8deg.C before analysis, thereby preventing undesired decomposition of the water-soluble drug.

Examples 1 to 2 and comparative examples 1 to 2

The test samples of examples 1 to 2 and comparative examples 1 to 2 were prepared in the following manner.

Comparative example 1

The aqueous phase portion was prepared by uniformly mixing 77.8 parts by mass of ion-exchanged water, 5 parts by mass of 1, 3-butanediol as a humectant, 5 parts by mass of dipropylene glycol, 5 parts by mass of glycerin, 0.2 parts by mass of sodium stearoylmethyl taurate as a surfactant, and 1 part by mass of 4-methoxysalicylic acid potassium salt as a water-soluble drug, and then 3 parts by mass of liquid paraffin as an oil component, 2 parts by mass of pentaerythritol tetraethyl caproate, and 1 part by mass of hydrogenated palm oil were added to the aqueous phase portion, followed by uniformly mixing to prepare an oil-in-water emulsion composition (emulsion) of comparative example 1.

Example 1

In example 1, after the emulsion composition of comparative example 1 was applied to the simulated skin to form an emulsion composition layer, the following 1 st agent was applied to the emulsion composition layer to form a 1 st agent layer, and the following 2 nd agent was applied to the 1 st agent layer.

(agent 1)

The 1 st agent was prepared by uniformly mixing 53 parts by mass of divinyl polydimethylsiloxane as 165,000cst of the 1 st unsaturated organopolysiloxane, 13 parts by mass of hydrogenated polydimethylsiloxane as 45cst of the 1 st hydride functional polysiloxane, 9 parts by mass of silylated silica as a reinforcing material, and 25 parts by mass of a mixture of polydimethylsiloxane and trisiloxane as an oil component.

(agent 2)

The water phase was prepared by uniformly mixing 65.5 parts by mass of ion-exchanged water, 20 parts by mass of glycerin as a humectant, and 10 parts by mass of ethanol. Next, 2 parts by mass of divinyl polydimethylsiloxane as an oil component, 1 part by mass of PEG-12 polydimethylsiloxane as a surfactant, and 1.5 parts by mass of a mixture of vinyl polydimethylsiloxane, divinyl disiloxane, and a platinum catalyst as a catalyst were uniformly mixed to prepare an oil phase portion. The oil phase was added to the water phase, and the mixture was uniformly mixed to prepare the 2 nd agent of the oil-in-water emulsion composition.

TABLE 1

TABLE 1 (use of 4-methoxysalicylic acid potassium salt as water-soluble pharmaceutical agent)

< results >

From the results of table 1, it was confirmed that when a body repair film is formed by applying a body repair film forming agent to a layer of such an emulsion composition, the permeability of the water-soluble agent to the skin is improved, as compared with the simple application of an oil-in-water emulsion composition containing the water-soluble agent to the skin.

Comparative example 2 ]

After 10 parts by mass of dimethylpolysiloxane (1.5 CS) as an oil component, 1 part by mass of methylpolysiloxane and 1.2 parts by mass of polyether-modified silicone as a surfactant were uniformly mixed to prepare an oil phase portion, an aqueous phase portion prepared by uniformly mixing 76.8 parts by mass of ion-exchanged water, 5 parts by mass of glycerin as a humectant, 5 parts by mass of dipropylene glycol, and 1 part by mass of 4-methoxysalicylic acid potassium salt as a water-soluble drug was added to the oil phase portion, and the mixture was uniformly mixed to prepare a water-in-oil emulsion composition (cream) of comparative example 2.

Example 2]

In example 2, after the emulsion composition of comparative example 2 was applied to the simulated skin to form an emulsion composition layer, the 1 st agent of example 1 was applied to the emulsion composition layer to form a 1 st agent layer, and then the 2 nd agent of example 1 was applied to the 1 st agent layer.

TABLE 2

TABLE 2 (use of 4-methoxysalicylic acid potassium salt as water-soluble pharmaceutical agent)

< results >

From the results of table 2, it was confirmed that, in the case of the water-in-oil emulsion composition, when the body repair coating is formed by applying the body repair coating forming agent to the layer of the emulsion composition, the permeability of the water-soluble agent to the skin is also improved.

Description of symbols

10. Moisture content

11. Water-soluble pharmaceutical agent

12. Solid water-soluble pharmaceutical agent

13. Oil component (oil phase)

14. Moisture (Water phase)

15. Emulsifying composition layer

16. Body repair film

Claims

1. A method for promoting skin penetration of a water-soluble drug, which comprises the following steps (a), (b), (c) and any one selected from the steps (d 1) to (d 3):

(c) Applying the emulsified composition to skin to form a layer of emulsified composition;

2. The method of claim 1, at least one of the 1 st and 2 nd agents further comprising a water-soluble agent.

3. The method of claim 1 or 2, wherein the water-soluble pharmaceutical agent is a water-soluble pharmaceutical agent that is solid at room temperature.

4. The method of claim 3, wherein the water-soluble pharmaceutical agent that is solid at room temperature is a crystalline water-soluble pharmaceutical agent.

5. The method according to claim 4, wherein the crystalline water-soluble pharmaceutical agent is at least one selected from the group consisting of 4-methoxysalicylic acid, tranexamic acid, L-ascorbic acid, 4-methoxysalicylate, tranexamic acid salt, L-ascorbate, glycylglycine, nicotinamide, arbutin, L-ascorbyl glucoside, 1- (2-hydroxyethyl) -2-imidazolidinone, and pyrimidinylpyrazole compounds represented by the following formula 1 and salts thereof,

In the formula (1) of the present invention,

6. The method according to any one of claims 1 to 5, wherein the emulsion composition contains 0.1% by mass or more of the water-soluble drug.

7. The method according to any one of claims 2 to 6, wherein at least one of the 1 st agent and the 2 nd agent further comprises a water-soluble drug, and wherein at least one of the 1 st agent and the 2 nd agent comprises 0.1% by mass or more of the water-soluble drug.

8. The method according to any one of claims 1 to 7, wherein the 1 st agent comprises at least one selected from the group consisting of 1 st unsaturated organopolysiloxane and 1 st hydride-functional polysiloxane,

in the case where the 1 st agent contains only the 1 st unsaturated organopolysiloxane, out of the 1 st unsaturated organopolysiloxane and the 1 st hydride-functional polysiloxane, the 2 nd agent contains the 2 nd hydride-functional polysiloxane,

in the case where the 1 st agent contains only the 1 st hydride-functional polysiloxane among the 1 st unsaturated organopolysiloxane and the 1 st hydride-functional polysiloxane, the 2 nd agent contains the 2 nd unsaturated organopolysiloxane.

9. The method according to claim 8, wherein the 1 st unsaturated organopolysiloxane and the 2 nd unsaturated organopolysiloxane are at least one selected from the group consisting of an organopolysiloxane having a vinyl group, an organopolysiloxane terminated with a vinyl group, and an organopolysiloxane having a branched chain that is vinyl-ized.

10. The method of claim 9, the 1 st unsaturated organopolysiloxane and the 2 nd unsaturated organopolysiloxane being at least one selected from the group consisting of vinyl-terminated polydimethylsiloxane, vinyl-terminated diphenylsiloxane-dimethylsiloxane copolymer, vinyl-terminated polyphenylmethylsiloxane, vinyl-terminated vinylphenylsiloxane-phenylmethylsiloxane copolymer, vinyl-terminated trifluoropropylmethylsiloxane-dimethylsiloxane copolymer, vinyl-terminated diethylsiloxane-dimethylsiloxane copolymer, vinyl methylsiloxane-dimethylsiloxane copolymer, trimethylsiloxy-terminated vinylmethylsiloxane-dimethylsiloxane copolymer, silanol-terminated vinylmethylsiloxane-dimethylsiloxane copolymer, vinylmethylsiloxane homopolymer, vinyl T-structural polymer, vinyl Q-structural polymer, monovinyl-terminated polydimethylsiloxane, vinylmethylsiloxane terpolymer, and vinylmethoxysilane homopolymer.

11. The method according to any one of claims 8 to 10, the 1 st hydride functional polysiloxane and the 2 nd hydride functional polysiloxane being non-terminal and/or terminal hydrogenated organopolysiloxanes.

12. The method of claim 11, the 1 st hydride-functional polysiloxane and the 2 nd hydride-functional polysiloxane are at least one selected from the group consisting of hydride-terminated polydimethylsiloxane, hydride-terminated polyphenyl- (dimethylhydrosiloxy) siloxane, hydride-terminated methylhydrosiloxane-phenylmethylsiloxane copolymer, trimethylsiloxy-terminated methylhydrosiloxane-dimethylsiloxane copolymer, polymethylhydrosiloxane, trimethylsiloxy-terminated polyethylhydrosiloxane, triethylsiloxane, methylhydrosiloxane-phenyloctylmethylsiloxane copolymer, and methylhydrosiloxane-phenyloctylmethylsiloxane terpolymer.

13. The method of any one of claims 1-12, the catalyst is at least one selected from the group consisting of platinum carbonyl cyclovinylmethylsiloxane coordination compounds, platinum divinyl tetramethyldisiloxane coordination compounds, platinum cyclovinylmethylsiloxane coordination compounds, and platinum octal/octanol coordination compounds.

14. The method of any one of claims 1-13, at least one of the 1 st agent and the 2 nd agent comprising at least one selected from fibers, pigments, dyes, thickeners, ultraviolet absorbers, and reinforcing materials.

15. The method of any one of claims 1-14, wherein the emulsified composition is an oil-in-water emulsified composition.

16. The method of any one of claims 1-15, at least one of the 1 st and 2 nd agents being an emulsified composition.