JP6879734B2 - Skin penetration promoter - Google Patents

Description

The present invention relates to a skin penetration promoter of at least one compound selected from the group consisting of hydrophilic compounds and polymer compounds containing an aloe-derived ingredient as an active ingredient.

The present invention relates to a composition containing an aloe-derived component and at least one compound selected from the group consisting of hydrophilic compounds and polymer compounds.

The present invention relates to a method for promoting skin penetration of the compound, which comprises blending an aloe-derived component with at least one compound selected from the group consisting of a hydrophilic compound and a polymer compound.

The skin is roughly divided into the epidermis, dermis and subcutaneous tissue. Above all, the stratum corneum existing in the epidermis plays an important role as a barrier function, such as preventing excessive evaporation of water from the body and entry of foreign substances from the outside world. The stratum corneum of the skin, on the other hand, poses a major barrier to transdermal administration of the drug.

So far, skin penetration promoters for transdermally administering drugs to the stratum corneum of the skin, such as Azone, Azone derivatives, and pyrothiodecane, have been developed. However, many of these skin penetration promoters have the effect of penetrating into the skin by themselves, damaging the stratum corneum structure and increasing the permeability of the drug, and are examined in terms of skin irritation and toxicity. There is room for.

In addition, loosening the barrier property of the stratum corneum of the skin more than necessary leads to the uptake of harmful substances, allergens, pathogens and other harmful components to the human body into the skin and blood (easy uptake). There is also room for consideration.

Therefore, in the technique of transdermally administering a drug, particularly in the stratum corneum of the skin, a technique of delivering the drug (necessary component) to an appropriate site only when necessary is required.

So far, aloe plants such as aloe vera have been reported to have a skin penetration promoting effect.

Aloe plants are succulent plants native to Africa, and it is said that there are more than 300 varieties in the world. Among them, aloe vera (scientific name: Aloe vera), which is characterized by having thick leaves, has long been used in folk remedies for burns and cuts.

In addition, the translucent gel part from which the outer skin of aloe plants has been removed is used for food, and the juice (also called "aloe vera juice") is widely used as a moisturizer for external skin preparations and cosmetics, and is safe. This is a typical example of a highly sexual component.

Fox et al. Are investigating the effect of aloe vera on the skin permeability of ketoprofen, an anti-inflammatory agent. Fox et al. Report that the gel and mesophyll portion of aloe vera increase the intradermal amount and skin permeability (skin permeability) of ketoprofen (Non-Patent Document 1).

Cole et al. Are investigating the effects of aloe vera on various fat-soluble drugs with different molecular weights. Cole et al. Report that the larger the molecular weight of the drug, the more the penetration promoting effect of aloe vera is exerted (Non-Patent Document 2).

However, previous reports have evaluated the skin permeability of drugs and compounds by targeting drugs with a molecular weight of 500 or less and fat-soluble compounds that are relatively easy to penetrate into the skin. ..

Therefore, the action exerted by aloe plant-derived components such as aloe vera is still exerted on (i) hydrophilic compounds (water-soluble components, impervious components) and (ii) polymer compounds having a molecular weight of 500 or more. Not revealed.

Lizelle T. Fox, Minja Gerber, Jan L. du Preez, Jeanetta du Plessis and Josias H. Hamman, Journal of Pharmacy and Pharmacology, 67, pp. 96-106 Louise Cole, Charles Heard, International Journal of Pharmaceutics 333 (2007) 10-16

In the present invention, various hydrophilic compounds having different molecular weights are used to verify the skin penetration promoting effect of aloe plant-derived components.

The present invention comprises (i) a skin penetration promoter of at least one compound selected from the group consisting of a hydrophilic compound and a polymer compound containing an aloe-derived component as an active ingredient, and (ii) an aloe-derived component and hydrophilicity. Aloe is added to a composition containing at least one compound selected from the group consisting of a sex compound and a polymer compound, and (iii) at least one compound selected from the group consisting of a hydrophilic compound and a polymer compound. An object of the present invention is to provide a method for promoting skin penetration of the compound, which comprises blending a derived component.

In the present invention, various hydrophilic compounds having different molecular weights were used to verify the skin penetration promoting effect of aloe plant-derived components.

So far, animal excised skin has been used for evaluation of skin penetration promoters. On the other hand, in recent years, there are increasing opportunities for the three-dimensional cultured human epidermal model, which is reconstructed by culturing epidermal cells on a collagen membrane, to be used as a substitute skin.

In the present invention, using a three-dimensional cultured human epidermis model, fluorescein sodium (for example, molecular weight: 376) and fluorescently labeled hyaluronic acid (for example, molecular weight: 3,200, 5,800, 29,000, etc.) based on aloe plant-derived components (for example, aloe vera juice), etc. ) Penetration into the skin was evaluated.

Then, it was found that the permeability of various hydrophilic compounds having different molecular weights to the skin was improved by the addition of the aloe plant-derived component. In particular, in the case of fluorescently labeled hyaluronic acid, it was clarified that the amount of permeation into the skin increased 40 times or more when the aloe plant-derived component was added, as compared with the case where the aloe plant-derived component was not added. It was clarified that the permeation-promoting effect of aloe plant-derived components on sodium fluorescein increased 8.6-fold in intradermal permeation and 2.9-fold in skin permeation.

The present invention has been completed based on these findings, and includes the following embodiments.

(I) Skin penetration promoter Item 1.
An agent for promoting skin penetration of at least one compound selected from the group consisting of hydrophilic compounds and polymer compounds, which comprises an aloe-derived ingredient as an active ingredient.

Item 2.
The hydrophilic compound, octanol / water partition coefficient log K _ow is the compound having a negative value, dermal penetration enhancers of claim 1.

Item 3.
The skin penetration promoter according to claim 1, wherein the polymer compound is a compound having a molecular weight of 500 or more.

Item 4.
The hydrophilic compound and at least one compound selected from the group consisting of polymer compounds, octanol / water partition coefficient log K _ow indicates a negative value, a molecular weight of 500 or more compounds, according to claim 1 Skin penetration promoter.

Item 5.
The aloe consists of aloe vera, aloe aloe, aloe elu, aloe camerony, aloe kedongensis, aloe ferox, aloe africana, aloe andungensis and aloe tomentosa, and hybrids of aloe aloe and aloe vera. The skin penetration promoter according to any one of claims 1 to 4, which is at least one aloe plant selected from the group.

(II) Composition item 6.
A composition containing an aloe-derived component and at least one compound selected from the group consisting of hydrophilic compounds and polymer compounds.

Item 7.
The hydrophilic compound, octanol / water partition coefficient log K _ow is the compound having a negative value, the composition of claim 6.

Item 8.
The composition according to claim 6, wherein the polymer compound is a compound having a molecular weight of 500 or more.

Item 9.
The hydrophilic compound and at least one compound selected from the group consisting of polymer compounds, octanol / water partition coefficient log K _ow indicates a negative value, a molecular weight of 500 or more compounds, according to claim 6 Composition.

Item 10.
The aloe consists of aloe vera, aloe aloe, aloe elu, aloe camerony, aloe kedongensis, aloe ferox, aloe africana, aloe andungensis and aloe tomentosa, and hybrids of aloe aloe and aloe vera. The composition according to any one of claims 6 to 9, which is at least one aloe plant selected from the group.

Item 11.
The composition according to any one of claims 6 to 10, which is a skin penetration promoter of at least one compound selected from the group consisting of a hydrophilic compound and a polymer compound.

(III) Method for promoting skin penetration Item 12.
A method for promoting skin penetration of the compound, which comprises blending an aloe-derived component with at least one compound selected from the group consisting of a hydrophilic compound and a polymer compound.

Item 13.
The hydrophilic compound, octanol / water partition coefficient log K _ow is a compound having a negative value, the skin penetration enhancing method according to claim 12.

Item 14.
The method for promoting skin penetration according to claim 12, wherein the polymer compound is a compound having a molecular weight of 500 or more.

Item 15.
The hydrophilic compound and at least one compound selected from the group consisting of polymer compounds, octanol / water partition coefficient log K _ow indicates a negative value, a molecular weight of 500 or more compounds, according to claim 12 How to promote skin penetration.

Item 16.
The aloe consists of aloe vera, aloe aloe, aloe elu, aloe camerony, aloe kedongensis, aloe ferox, aloe africana, aloe andungensis and aloe tomentosa, and hybrids of aloe aloe and aloe vera. The method for promoting skin penetration according to any one of claims 12 to 15, which is at least one aloe plant selected from the group.

It was generally thought that compounds with a molecular weight of 500 or more would hardly penetrate even when applied to the skin. It was also thought that the effect of the aloe plant on promoting skin penetration of the compound was reduced at a molecular weight of around 500.

However, as a result of the evaluation test of the present invention, it is clear that the skin penetration promoting effect of aloe plant-derived components (for example, aloe vera juice) can be applied to hydrophilic polymer compounds having a molecular weight of 500 or more. It became.

Since the effect of the present invention is greatly attenuated by the pretreatment of the aloe plant-derived component, it is considered that the aloe plant-derived component promotes penetration by coexisting without causing irreversible damage to the skin. It was.

Furthermore, as a result of examining the active ingredient of the present invention, it was considered that more activity was observed in the low molecular weight fraction in the aloe plant-derived ingredient, and that the aromatic ingredient contributed to the activity.

From these results, the aloe plant-derived component acts as a penetration promoter for hydrophilic compounds and polymer compounds with poor transdermal permeability, and is suitable for improving the penetration of compounds targeting the skin. It was considered.

In the present invention, the aloe plant-derived component acts as a penetration promoter for hydrophilic compounds and polymer compounds having poor transdermal permeability, and is suitable for improving the penetration of compounds targeting the skin.

The present invention comprises (i) a skin penetration promoter of at least one compound selected from the group consisting of a hydrophilic compound and a polymer compound containing an aloe-derived component as an active ingredient, and (ii) an aloe-derived component and hydrophilicity. A composition containing at least one compound selected from the group consisting of a sex compound and a polymer compound, and (iii) aloe to at least one compound selected from the group consisting of a hydrophilic compound and a polymer compound. It is possible to provide a method for promoting skin penetration of the compound, which comprises blending a derived component.

It is a figure explaining the Example. It is a figure explaining the Example. AVG (aloe vera juice) and sodium fluorescein solution were added to the forearm of the subject from the stratum corneum side. The surface of the stratum corneum (skin surface) was observed using a fluorescence microscope, and the stratum corneum was peeled off and its fluorescence was observed. It is a figure explaining the Example.

(I) Skin Penetration Promoter and (II) Composition The skin penetration promoter of the present invention is at least one compound selected from the group consisting of hydrophilic compounds and polymer compounds containing an aloe-derived ingredient as an active ingredient. It is a skin penetration promoter.

The aloe-derived component acts as a permeation accelerator for hydrophilic compounds and polymer compounds having poor percutaneous permeability, and is suitable for improving the permeation of compounds targeting the inside of the skin.

(1) Ingredients derived from aloe Aloe is not particularly limited, but it is approved for use in Japanese pharmacy or non-medicinal products, and it is safe to use and easy to cultivate. : Aloe vera), Kidachi aloe (scientific name: Aloe arborescens), aloe eru (scientific name: Aloe eru), aloe cameronii (scientific name: Aloe cameronii), aloe kedongensis (scientific name: Aloe kedongensis), aloe -At least selected from the group consisting of Ferrox (scientific name: Aloe ferox), Aloe Africana (scientific name: Aloe africana), Aloe andongensis (scientific name: Aloe andongensis) and Aloe tomentosa (scientific name: Aloe tomentosa). It is preferable to use one type of aloe plant.

As the aloe, a hybrid between species arbitrarily selected from the above species can be used. For example, as a hybrid, a hybrid between Kidachi aloe and aloe vera, and a hybrid between aloe ferox and aloe Africana can be used. Etc. can be used. As the aloe used in the present invention, it is particularly preferable to use aloe vera as the aloe containing the improved species of the above species.

The aloe-derived component acts as a permeation accelerator for hydrophilic compounds and polymer compounds having poor percutaneous permeability, and is suitable for improving the permeation of compounds targeting the inside of the skin.

As the aloe-derived component, the whole aloe plant may be used as it is. As the aloe-derived component, the exodermis of the aloe leaf may be used, or the jelly material inside the leaf may be used. These are used as aloe juice.

As the aloe, a plant body (for example, leaves, stems, roots, etc.) in a raw state (undried product), a dried product (dried product), or a frozen product (frozen product) can be used. It is also possible to use an undried, dried or frozen aloe plant that has been crushed to an appropriate size and pulverized.

As the aloe-derived component, the whole aloe plant may be used, and aloe extract may be used. Examples of the method for producing an aloe extract (extract) include, but are not limited to, a method of combining an extraction step and a separation step, and a method of further combining a fractionation step with the above method.

The particular species of aloe is of plant origin, is highly safe, and has the advantage that the aloe juice is easy to ingest or apply on a daily basis.

(2) a hydrophilic compound and at least one compound hydrophilic compound selected from the group consisting of polymer compound is preferably octanol / water partition coefficient log K _ow is a compound having a negative value.

Hydrophilic compounds generally have a property of poor transdermal permeability (non-permeable hydrophilic compounds).

The polymer compound is preferably a compound having a molecular weight of 500 or more.

At least one compound selected from the group consisting of the hydrophilic compound and the polymer compound preferably has an octanol / water partition coefficient logK _ow showing a negative value and a molecular weight of 500 or more.

By the action of the aloe-derived component as a penetration promoter, the permeability of these hydrophilic compounds and polymer compounds having poor percutaneous permeability is improved by targeting the inside of the skin.

Hydrophilic compound In the present invention, there is a hydrophilic compound as a compound whose penetration in the skin is promoted by an aloe-derived component. The hydrophilic compound is preferably a compound in which the octanol / water partition coefficient logK _ow shows a negative value (hereinafter, also referred to as “logK _ow”).

Log K _ow of hydrophilic compounds exhibit a negative value, about -0.01 or less, more preferably about -0.1 or less, still more preferably not more than about -1. Log K _ow of hydrophilic compounds may be Shimese a negative value, the lower limit is about -20.

Polymer Compound In the present invention, there is a polymer compound as a compound whose penetration in the skin is promoted by an aloe-derived component. The polymer compound is preferably a compound having a molecular weight of about 500 or more.

If the molecular formula is known, the molecular weight can be derived from the calculation using the atomic weight. If the molecular formula is unknown, measure by gel filtration chromatography using pullulan (molecular weight: 1,420 to 642,000, Showa Denko KK) as a standard substance.

For measurement, for example, GPC system [SD-8022 / DP-8020 / AS-8020 / CO-8020 / RI-8020] equipped with two TSKgel GMPWXL columns (7.8 mm x 30 cm, Tosoh Corporation) (Tosoh Co., Ltd.) Company) is used. Then, for example, analysis is performed with a developing solvent: 1 M NaNO ₃ aqueous solution, a flow velocity: 1.0 mL / min, a column temperature: 40 ° C., a detection: RI detector, and an injection volume: 100 μL.

The sample for analysis is prepared by diluting it with distilled water as appropriate and filtering it with a 0.5 μm filter.

The molecular weight of the polymer compound is preferably about 500 or more, more preferably about 1000 to 100,000, and even more preferably about 1 to 100,000.

The aloe-derived component, compound penetrates the skin is facilitated by the present invention, the aloe-derived components, as the compound penetrates the skin is promoted, log K _ow indicates a negative value, a molecular weight of 500 or more compounds Is preferable. In the present invention, the compound whose penetration is promoted in the skin by the aloe-derived component is preferably a hydrophilic polymer compound.

Description of logK _ow
Estimation of log K _ow leads calculated from the basic structure of the functional groups and molecules in the compound. The estimation of logK _ow can be calculated for low molecular weight compounds for which structural formulas can be drawn.

It cannot be calculated directly for high molecular weight components (proteins, etc.) whose structural formulas cannot be drawn due to their large molecular weight, and components (hyaluronic acid, heparinoids, etc.) that are described only by repeating structures such as [basic structure] n. Therefore, in those compounds, it is possible to calculate a log K _ow a component estimates an estimate therefrom.

Hyaluronic acid is a repeating structure of disaccharide units of D-glucuronic acid and N-acetyl-D-glucosamine. Hyaluronic acid is a log K _ow value of disaccharide units (-6.68, calculated by EPI-Suite), the log K _ow value of sodium hyaluronate can be estimated to <-6.68.

Heparinoids are compounds in which the repeating structure of the disaccharide units of D-glucuronic acid and N-acetyl-D-galactosamine is polysulfated. Heparinoid from log K _ow value of disaccharide units sulfated (-16.60, calculated by EPI-Suite), <- can be estimated that 16.60.

The protein is thought to depend on the _{amino acid logK ow.} Protein, an estimate of the log K _ow of amino acids calculated in EPI-Suite, determines the water level of cosmetic ingredients, such as type 1 collagen and elastin.

Hyaluronic acid is a high-molecular-weight polysaccharide in which glucuronic acid and N-acetylglucosamine are repeatedly and alternately bonded in a straight chain, and is a type of glycosaminoglycan (mucopolysaccharide) that is abundant in the skin, joints, eyes, and the like.

Due to its excellent water retention effect, it is used as a moisturizer in many cosmetics.

However, since hyaluronic acid has a large molecular weight of several millions, it hardly penetrates into the skin even when applied, and its moisturizing effect remains on the skin surface and is exhibited by holding water.

In recent years, an approach to increase the penetration of moisturizing ingredients into the skin and moisturize from the inside of the skin has been studied. Hyaluronic acid is hydrolyzed to a molecular weight of about 2,000 to 10,000 to reduce the molecular weight and penetrate into the skin. Is being considered.

However, it is generally considered that components having a molecular weight of more than 500 hardly permeate or permeate the skin, and there is room for study on the permeability of hydrolyzed hyaluronic acid having a low molecular weight.

According to the present invention, when the aloe-derived component acts as a penetration accelerator, the permeability of these hydrophilic compounds and polymer compounds having poor percutaneous permeability is improved by targeting the inside of the skin.

(3) Skin Penetration Promoter of At least One Compound Selected from the Group Consisting of Hydrophilic Compounds and Polymer Compounds Containing Aloe-Derived Ingredients In the present invention, the aloe-derived ingredients are transdermally permeable. It acts as a penetration promoter for scarce hydrophilic compounds and high molecular compounds, and is suitable for improving the penetration of compounds targeting the skin.

As one aspect of the skin penetration promoter of the present invention, there is a skin penetration promoter (composition) containing an aloe-derived component and at least one compound selected from the group consisting of a hydrophilic compound and a polymer compound. be able to. Since this composition contains an aloe-derived component, it functions as a skin penetration promoter for at least one compound selected from the group consisting of hydrophilic compounds and polymer compounds.

The blending ratio of the aloe-derived component in the skin penetration promoter (composition) of the present invention is not limited as long as the effect of the present invention is exhibited. For example, the skin penetration promoter (composition) preferably contains about 1 to 100% by weight, more preferably about 10 to 90% by weight, of the aloe-derived component.

For example, when a compound is dissolved in raw aloe juice (as is) and used, the aloe-derived component is approximately 100% by weight in the skin penetration promoter (composition).

Blending ratio of aloe-derived component and at least one compound selected from the group consisting of hydrophilic compound and polymer compound In the skin penetration promoter (composition) of the present invention, the aloe-derived component, hydrophilic compound and polymer The blending ratio with at least one compound selected from the group consisting of compounds can promote the penetration of at least one compound selected from the group consisting of hydrophilic compounds and polymer compounds into the skin due to the aloe-derived component. It is preferable to adjust in the range.

The blending ratio of the aloe-derived component and at least one compound selected from the group consisting of the hydrophilic compound and the polymer compound is composed of the hydrophilic compound and the polymer compound when the aloe-derived component is 1 part by weight. It is preferable to blend at least one compound selected from the group in an amount of about 0.0001 to 100 parts by weight. That is, it is preferable to adjust at least one compound selected from the group consisting of aloe-derived components: hydrophilic compounds and polymer compounds = 1: 0.0001 to 100 (weight ratio).

For example, when 0.01 g of a compound is dissolved in 100 g of raw aloe juice (as is) and used, the weight ratio is 1: 0.0001. Further, when 0.1 g of the dried aloe juice and 10 g of the compound are dissolved in 100 g of a solvent and used, the weight ratio is 1: 100. Further, in the following examples, as an example, 500 μg of the compound was dissolved in 1 mL (= 1 g) of raw aloe juice for the test. This means that 0.05 g of the compound was dissolved in 100 g of the raw aloe juice (weight ratio = raw aloe juice 1: compound 0.0005).

Whether or not the aloe-derived component can promote the penetration of at least one compound selected from the group consisting of hydrophilic compounds and polymer compounds into the skin is referred to the test example described later.

Using a human epidermis model, it comprises a composition (combination group) in which an aloe-derived component is blended with at least one compound selected from the group consisting of a hydrophilic compound and a polymer compound, and a hydrophilic compound and a polymer compound. By measuring the degree of penetration of at least one compound selected from the group consisting of hydrophilic compounds and polymer compounds into the skin with at least one compound selected from the group alone (single group), Can be contrasted.

In the skin penetration promoter (composition) of the present invention of the present invention, the blending ratio of the aloe-derived component and at least one compound selected from the group consisting of hydrophilic compounds and polymer compounds is set.
Aloe-derived component: As at least one compound selected from the group consisting of hydrophilic compounds and polymer compounds,
1: 0.0001 to 100 (weight ratio), 1: 0.0001 to 80 (weight ratio), 1: 0.0001 to 60 (weight ratio),
1: 0.0001 to 40 (weight ratio), 1: 0.0001 to 20 (weight ratio), 1: 0.0001 to 10 (weight ratio),
Is preferable in this order.

At this blending ratio, the aloe-derived component acts as a penetration promoter for the skin with respect to hydrophilic compounds and polymer compounds having poor transdermal permeability, and is suitable for improving the penetration of compounds targeting the skin.

Form of Skin Penetration Promoter (Composition) The skin penetration promoter (composition) targeted by the present invention contains at least an aloe-derived component, a hydrophilic compound, a polymer compound and the like as components, and has the effect of the present invention. Based on this, any product may be used as long as it can enjoy the advantage of suppressing deterioration of product quality, particularly appearance. To that extent, the form, mode of use, and use of the pharmaceutical product are not particularly limited.

The form of the skin penetration enhancer (composition) (including the form of a pharmaceutical product) of the present invention of the present invention is not particularly limited, and includes both a parenteral administration form and an oral administration form.

A parenteral administration form is preferable, and examples thereof include injections, infusions, and transdermal absorbents.

As the transdermal absorbent, it can be an external preparation such as an ointment, a gel, a paste, a cream, a lotion, a spray, a solution, or a suspension. In addition, when an injection is used, a method such as local injection, intraperitoneal administration, selective intravenous injection, intravenous injection, subcutaneous injection, or organ perfusate injection can be selected.

When the skin penetration promoter (composition) of the present invention of the present invention is used as an external preparation, lower alcohol and water can be used as the base. Examples of the lower alcohol include alcohols having 1 to 7 carbon atoms such as methanol; ethanol; n-propyl alcohol, isopropyl alcohol; 1,3-butyl alcohol, sec-butyl alcohol, isobutyl alcohol, tert-butyl alcohol; and benzyl alcohol. can do.

When used as an external preparation, its pH is preferably in the range of 4 to 8 for the reason of reducing irritation to the skin. The pH adjustment can be performed using a basic substance or an acidic substance. Examples of the basic substance include inorganic bases such as sodium hydroxide and potassium hydroxide; organic amines such as triethanolamine and diisopropanolamine; and basic amino acids such as arginine, lysine and ornithine. Examples of acidic substances include inorganic acids such as hydrochloric acid, nitric acid, metasulfonic acid, sulfuric acid, p-toluenesulfonic acid, phosphoric acid, citric acid, malic acid, tartaric acid, and succinic acid, and organic acids.

When used as an external preparation, it is also possible to add a medicinal aid as another ingredient. As medicinal aids, cooling agents such as camphor, terepine oil, peppermint oil, menthol and its derivatives, eucalyptus oil, and menthyl lactate; local stimulants such as vanillylamide nonanoic acid and capsaicin; anti-inflammatory agents such as glycyrrhizinic acid; diphenyl Antihistamines such as imidazole, diphenhydramine and its salts, chlorpheniramine maleate; blood circulation promoters such as tocopherol acetate and benzyl nicotinate; , Sansho extract, menthol extract and other crude drugs. In addition to the above-mentioned ingredients, appropriate additives used in ordinary skin external preparations such as active ingredients, preservatives, preservatives, antioxidants, stabilizers, etc. that can be used in combination can be appropriately used.

The skin penetration promoter (composition) of the present invention is prepared as an external preparation and can be locally administered externally. The dose of the skin penetration promoter (composition) of the present invention of the present invention of the present invention varies depending on the age, sex, etc. of the subject and cannot be uniformly specified.

The skin penetration promoter (composition) of the present invention acts as a skin penetration promoter for hydrophilic compounds and polymer compounds having poor percutaneous permeability due to aloe-derived components, and is a compound targeting the inside of the skin. It would be good if we could improve the penetration of. The dose of the skin penetration promoter (composition) of the present invention is, in addition to the content of the aloe-derived component, the type of at least one compound selected from the group consisting of the target hydrophilic compound and the polymer compound. Adjust as appropriate.

The skin penetration promoter (composition) of the present invention can be applied to cosmetics (cosmetics). As cosmetics, lotions, milky lotions such as lotions, creams, gels and the like are preferable. Application to cosmetics such as solid cosmetics, liquid cosmetics, paste cosmetics, powder cosmetics, jelly cosmetics, gel cosmetics, paste cosmetics, spray cosmetics, etc. Is possible.

In the skin penetration promoter (composition) of the present invention, the aloe-derived component is a hydrophilic compound and high in the application as a skin penetration promoter of at least one compound selected from the group consisting of a hydrophilic compound and a polymer compound. It was discovered by discovering an unknown attribute that promotes penetration of at least one compound selected from the group consisting of molecular compounds into the skin. Further, the use found by the attribute is a new use different from the conventionally known use for the composition containing the aloe-derived component.

(III) Skin Penetration Promotion Method The skin penetration promotion method of the present invention can be carried out by using an aloe-derived component in combination with at least one compound selected from the group consisting of hydrophilic compounds and polymer compounds. .. The aloe-derived component promotes the penetration of hydrophilic compounds and polymer compounds having poor percutaneous permeability into the skin, and improves the penetration by targeting the inside of the skin.

For at least one compound selected from the group consisting of aloe-derived components and hydrophilic compounds and polymer compounds to be used, the content described in (I) and (II) above may be used as the blending ratio thereof. it can.

Hereinafter, the present invention and its effects will be described more clearly with reference to Test Examples and Examples.

However, the present invention is not limited to such test examples and examples.

<Experimental method>
(1) Preparation of aloe vera juice We obtained 5 samples of aloe vera leaves from Okinawa prefecture (M1 to M5, outdoor cultivated products) and 5 samples of aloe vera leaves from Shizuoka prefecture (S to S5, house cultivated products) (August 2016). Collected from Monday to October).

After washing the surface of each leaf, the outer skin was removed and the mesophyll part was taken out. This was mixed to obtain a juice-like aloe vera juice.

Brix (Brixmeter RA-410, Kyoto Electronics Co., Ltd.) and viscosity (Brookfield type rotational viscometer LVDV-II + Pro (adapter for small amount sample), Brookfield Co., Ltd.) were measured for the obtained aloe vera juice.

The viscosities were measured at a temperature of 25 ° C., and M1 to M5 and S1 were measured at rotor No. 18 and a rotation speed of 60 r / min. S2 and S3 were measured at rotor No. 18 and a rotation speed of 60 r / min. S4 and S5 were measured at rotor No. 63 and rotation speed 60 r / min.

The molecular weight distribution of aloe vera juice was analyzed by gel filtration chromatography using pullulan (molecular weight: 1,420 to 642,000, Showa Denko KK) as a standard substance. For measurement, GPC system [SD-8022 / DP-8020 / AS-8020 / CO-8020 / RI-8020] equipped with two TSKgel GMPWXL columns (7.8 mm x 30 cm, Tosoh Corporation) (Tosoh Corporation) ) Was used. Then, the analysis was performed with a developing solvent: 1 M NaNO ₃ aqueous solution, a flow velocity: 1.0 mL / min, a column temperature: 40 ° C., a detection: RI detector, and an injection volume: 100 μL.

Specimens for analysis were prepared by diluting each aloe vera juice 5 times with distilled water and filtering with a 0.5 μm filter.

(2) Examination of skin penetration promoting effect on sodium fluorescein
Using a three-dimensional cultured human epidermis model EpisSkin ^TM (SkinEthic), the skin penetration promoting effect on sodium fluorescein (molecular weight: 376.28, Wako Pure Chemical Industries, Ltd.) was examined.

EpisSkin ^TM -Large (surface area 1.07 cm ² ) was cultured overnight (37 ° C, 5% CO ₂ ) in the maintenance medium included in the kit, and then transferred to a 12-well plate containing 2 mL of medium as a receptor-side solution. .. Next, using distilled water or aloe vera juice (M-2 or S-2), add 150 μL of sodium fluorescein solution prepared to 500 μg / mL from the stratum corneum side, and incubate for 3 hours (37 ° C, 5% CO). ₂ ) After removing the sodium fluorescein solution on the stratum corneum side, the surface of the stratum corneum was washed 5 times with 500 μL of distilled water, and the epidermis model was collected.

In the example, 500 μg of the compound was dissolved in 1 mL (= 1 g) of raw aloe juice for the test. This means that 0.05 g of the compound was dissolved in 100 g of the raw aloe juice (weight ratio = raw aloe juice 1: compound 0.0005).

The collected epidermis model was finely chopped with scissors and extracted with 1 mL of distilled water by shaking for 3 hours. After centrifugation (room temperature, 14000 rpm, 10 min), the fluorescence intensity in the supernatant was measured with an EnSight ^TM multi-plate reader (PerkinElmer) (Ex 494 nm / Em 520 nm), and fluorescein permeated into the skin. The amount was calculated.

By measuring the fluorescence intensity in the medium, the amount of fluorescein that passed through the epidermis model was calculated.

(3) Examination of skin penetration promoting effect on calcein sodium
^{The permeability to EpisSkin TM-} Large (1 to 20 hours) was examined using 500 μg / mL sodium calcein (molecular weight: 666.50).

Fluorescence intensity was ^{measured with an EnSight TM} multi-plate reader (Ex 494 nm / Em 520 nm).

For the aloe vera juice, in consideration of antiseptic properties, the aloe vera juice produced in Shizuoka Prefecture is filtered through filter paper (No. 2, ADVANTEC) and sterilized by heating at 80 ° C for 30 minutes (hereinafter referred to as "AVG"). There was.

(4) Examination of skin penetration promoting effect on fluorescently labeled sodium hyaluronate
^{Permeability to EpisSkin TM-} Large (3 hours) was examined using three types of fluorescein amine-labeled sodium hyaluronate (all from PG Research).

Molecular weight 3,200 Da: Hereinafter referred to as "fHA3.2".

Molecular weight 5,800 Da: Hereinafter referred to as "fHA5.8".

Molecular weight 29,000 Da: Hereinafter referred to as "fHA29".

(5) Evaluation of permeability of fluorescently labeled hyaluronic acid to a three-dimensional cultured human epidermis model pretreated with aloe vera juice 150 μL of AVG (aloe vera juice) was added in advance ^{from the stratum corneum side of EpisSkin TM -Large and cultured for 1 hour (37 ° C).} , 5% CO ₂ ). After removing the AVG, the surface of the stratum corneum was washed 5 times with 500 μL of distilled water. Next, 150 μL of fHA3.2 solution prepared to 500 μg / mL using distilled water was added from the stratum corneum side, and the cells were cultured for 1 hour (37 ° C., 5% CO ₂ ). Then, the same procedure as described above was performed to measure the intradermal permeation amount of fHA3.2.

For comparison, we also examined a pretreatment using distilled water instead of AVG, and then using distilled water or AVG to add an fHA3.2 solution prepared at 500 μg / mL from the stratum corneum side. ..

(6) Search for active ingredients in aloe vera juice
5 mL of AVG was applied to a microfiltration membrane Amicon Ultra-4 (Millipore) with a molecular weight of 3,000 exclusion, and fractionated into high molecular weight AVG (hereinafter AVG-H) and low molecular weight AVG (hereinafter AVG-L).

After adjusting the total amount of the obtained fraction to 5 mL, the percutaneous permeation promoting effect on fHA3.2 was examined by the same method as in (2) above.

Aloe vera leaf water (Katakura Agribio) obtained by cryogenic distillation of aloe vera mesophyll was also evaluated in the same manner.

<Experimental results>
The Brix content of Okinawan aloe vera juice (M1 to M5) was 0.76 ± 0.02%. The Brix of aloe vera juice (S1 to S5) produced in Shizuoka Prefecture was 0.90 ± 0.08%. Brix was produced in Shizuoka prefecture and showed a slightly higher value.

In addition, regarding the viscosity, the ones produced in Shizuoka Prefecture (S1 to S5) showed high values (Table 4).

Okinawa Prefecture Aloe Vera Juice: 13 ± 2 mPa ・ s
Aloe vera juice from Shizuoka prefecture: 141 ± 106 mPa ・ s
The aloe vera produced in Shizuoka Prefecture collected this time was cultivated in the house by a water-reducing farming method that minimized watering, and it is thought that this increased the component content and viscosity in the mesophyll.

Next, the molecular weight distribution of aloe vera juice prepared from Okinawa prefecture (M2) and Shizuoka prefecture (S2) as representatives of each production area was analyzed.

Four major peaks were observed in each case, and it was calculated that peak 1 has a molecular weight of 1 million or more, peak 2 has a molecular weight of about 1,800, and peaks 3 and 4 have a molecular weight of 1,000 or less (Fig. 1: Distribution of molecular weight of). Aloe vera gel).

Next, the skin penetration promoting effect of sodium fluorescein on aloe vera juice (M2 and S2) was examined.

As a result, both the amount of intradermal permeation and the amount of skin permeation increased, and the promoting effects were observed to be 8.09 times and 2.89 times, respectively, for Okinawa prefecture (M2) and 8.59 times and 2.88 times, respectively for Shizuoka prefecture (S2). (Table 5).

Next, the skin penetration promoting effect on calcein sodium was examined for AVG (aloe vera juice) prepared by filtering and sterilizing aloe vera juice produced in Shizuoka prefecture.

When the amount of calcein in the permeate was measured, both distilled water and AVG were confirmed to increase with time, and showed high values in AVG over 1 to 20 hours (Table 6). As a result of measuring the intradermal permeation amount after 20 hours, it was 10.87 ± 0.83 μg in distilled water and 17.48 ± 0.47 μg in AVG.

Next, the effect of fluorescently labeled hyaluronic acid (fHA3.2) on permeability was examined (Table 7).

The permeation amount in the skin with distilled water was 0.18 ± 0.02 μg, while that with AVG was 7.64 ± 0.38 μg, confirming a 42.9-fold permeation promoting effect.

On the other hand, the amount of intradermal permeation when a mixed solution of ethanol and polyethylene glycol, which has been known as a skin permeation accelerator, was used was 0.25 ± 0.02 μg (1.39 times) at each 30% concentration. The amount was 6.62 ± 0.60 μg (38.0 times) in the 2% cyclohexane-1,4-dicarboxylic acid bisethoxydiglycol aqueous solution (Neosolue ^{TM-Aqulio, Nippon Fine Chemical Co., Ltd.).} From this, it was clarified that AVG exerts a superior effect on fluorescently labeled hyaluronic acid over existing skin penetration promoters.

The amount of skin permeation was less than the detection sensitivity (0.02 μg) in all the samples, and it was considered that the permeated fHA3.2 did not permeate the skin and remained in the skin.

Next, fHA5.8 and fHA29, which have large molecular weights, were evaluated in the same manner.

As a result, the permeation amount in the skin with distilled water was 0.04 ± 0.01 μg and 0.03 ± 0.00 μg, respectively, while that of AVG was 8.41 ± 0.52 μg and 4.62 ± 0.14 μg, respectively. It was confirmed that these fluorescently labeled hyaluronic acids also had a penetration promoting effect of 234.5 times and 161.0 times, respectively (Table 7).

From the above results, it was clarified that aloe vera juice (AVG) acts as an excellent permeation accelerator for hydrophilic compounds.

Next, for the purpose of clarifying the characteristics of the skin penetration promoting effect of aloe vera juice, the intradermal permeability of fHA3.2 was evaluated after pretreating a three-dimensional cultured human epidermis model with AVG in advance.

The promoting effect was 1.88 times.

On the other hand, when AVG was allowed to coexist with fHA3.2 after pretreatment with distilled water, a 10.97-fold promotion of permeation was observed (Table 8).

Since the permeation promoting effect is greatly attenuated by the pretreatment of AVG, it is considered that aloe vera juice promotes permeation by coexisting without causing irreversible damage to the skin.

We also examined the effect of fHA3.2 on the permeability of aloe vera juice fractions.

Aggregation of activity was observed in the low molecular weight fraction AVG-L (Table 9). From this, it was considered that the components having a molecular weight of 3,000 or less in AVG contributed to the activity.

Furthermore, the aloe vera leaf water obtained by cryogenic distillation of aloe vera mesophyll was also examined.

It was confirmed that the permeation was promoted 17.04 times that of distilled water. From this, it was clarified that a part of the aromatic distillation component also contributes to the activity.

The donor chamber of the Franz-type diffusion cell was fixed to the forearms of 5 subjects with double-sided tape, and 500 μL of sodium fluorescein solution prepared at 1 mg / mL using distilled water or AVG was added from the stratum corneum side.

After 15 minutes, the fluorescein sodium solution on the stratum corneum side was removed, the surface of the stratum corneum was washed 5 times with 1 mL of distilled water, and the skin surface was observed with a fluorescence microscope (Fig. 2, Table 10).

Next, the stratum corneum was peeled off by the tape stripping method (10 sheets), and the fluorescence on the tape was observed (Fig. 3).

<Experimental consideration>
It was found that aloe vera juice significantly improved the permeability of fluorescently labeled hyaluronic acid (molecular weight: 3,200 to 29,000) into the epidermis.

This indicates that by applying hydrolyzed hyaluronic acid or the like together with aloe vera, the penetration into the skin is enhanced, and a moisturizing effect can be expected from both the inside and the outside of the skin.

Furthermore, since aloe vera itself is involved in moisturizing, synergistic moisturizing effects can be expected for both.

According to the present invention, the transdermal permeability of a polymer compound such as hydrolyzed hyaluronic acid can be improved. In the present invention, a component derived from aloe (aloe vera, etc.), which has been used for the treatment of wounds and burns for a long time and which itself acts as an excellent moisturizer, can be used.

Claims (7)

An agent for promoting skin penetration of at least one compound selected from the group consisting of hydrophilic compounds and polymer compounds containing an aloe-derived ingredient as an active ingredient.
The aloe-derived component is an aloe extract or aloe juice.
The hydrophilic compound and at least one compound selected from the group consisting of polymer compounds, octanol / water partition coefficient log K _ow indicates a negative value, a molecular weight of 500 or more compounds (where greater than average 6,000 Daltons A skin penetration promoter ( excluding collagen having a molecular weight) (however,
Comprising an agent which is delivered mixed ethoxylated oils, and the ethoxylated oil, a transdermal delivery system wherein the ethoxylated oil, characterized in that it comprises ethoxylated / molecule of 10 to 19, and,
(I) Arginine and / or one or more derivatives thereof; (ii) Black pepper extract and / or one or more components or derivatives thereof; and (iii) Peppermint extract and / or one or more components or derivatives thereof. Except for locally administrable vasodilators containing derivatives). The aloe consists of aloe vera, aloe aloe, aloe elu, aloe camerony, aloe kedongensis, aloe ferox, aloe africana, aloe andungensis and aloe tomentosa, and hybrids of aloe aloe and aloe vera. The skin penetration enhancer according to claim 1, which is at least one aloe plant selected from the group. A composition containing an aloe-derived component and at least one compound selected from the group consisting of hydrophilic compounds and polymer compounds.
The aloe-derived component is an aloe extract or aloe juice.
The hydrophilic compound and at least one compound selected from the group consisting of polymer compounds, octanol / water partition coefficient log K _ow indicates a negative value, a molecular weight of 500 or more compounds (where greater than average 6,000 Daltons (Excluding collagen having a molecular weight)
A composition containing a lower alcohol and / or water as a base (provided that this is a composition.
Ethoxylated oils, and includes a delivered agent is mixed with the ethoxylated oil, a transdermal delivery system, wherein the ethoxylated oil comprises ethoxylated / molecule 10 to 19,
(I) Arginine and / or one or more derivatives thereof; (ii) Black pepper extract and / or one or more components or derivatives thereof; and (iii) Peppermint extract and / or one or more components or derivatives thereof. Topically administrable vasodilators containing derivatives,
Cosmetics characterized by blending one or more of aloe extract, ginseng extract, rose extract, hyaluronic acid or a salt thereof, allantin, and ginseng extract, and
Ginseng without shredding, as it is or after extraction, ginseng in the state of leaving the shape, aloe extract, ginseng extract, rose extract, hyaluronic acid or its salt, one or more kinds of allantin And cosmetics in a container with a transparent formulation containing ginseng extract). The aloe consists of aloe vera, aloe aloe, aloe elu, aloe camerony, aloe kedongensis, aloe ferox, aloe africana, aloe andungensis and aloe tomentosa, and hybrids of aloe aloe and aloe vera. The composition according to claim 3, which is at least one aloe plant selected from the group. The composition according to claim 3 or 4, which is a skin penetration promoter of at least one compound selected from the group consisting of a hydrophilic compound and a polymer compound. The aloe-derived component is blended with at least one compound selected from the group consisting of hydrophilic compounds and polymer compounds (however, as a blending compound).
Comprising an agent which is delivered mixed ethoxylated oils, and the ethoxylated oil, a transdermal delivery system wherein the ethoxylated oil, characterized in that it comprises ethoxylated / molecule of 10 to 19, and,
(I) Arginine and / or one or more derivatives thereof; (ii) Black pepper extract and / or one or more components or derivatives thereof; and (iii) Peppermint extract and / or one or more components or derivatives thereof. (Excluding locally administrable vasodilators containing derivatives)
The aloe-derived component is an aloe extract or aloe juice.
The hydrophilic compound and at least one compound selected from the group consisting of polymer compounds, octanol / water partition coefficient log K _ow indicates a negative value, a molecular weight of 500 or more compounds (where greater than average 6,000 Daltons A method for promoting skin penetration of the compound, which is ( excluding collagen having a molecular weight). The aloe consists of aloe vera, aloe aloe, aloe elu, aloe camerony, aloe kedongensis, aloe ferox, aloe africana, aloe andungensis and aloe tomentosa, and hybrids of aloe aloe and aloe vera. The method for promoting skin penetration according to claim 6, which is at least one aloe plant selected from the group.

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