WO2021132529A1

WO2021132529A1 - Water-containing transdermally absorptive composition

Info

Publication number: WO2021132529A1
Application number: PCT/JP2020/048607
Authority: WO
Inventors: 文靖小野; 隆典中村
Original assignee: 国立大学法人九州大学; 日産化学株式会社
Priority date: 2019-12-27
Filing date: 2020-12-24
Publication date: 2021-07-01
Also published as: JPWO2021132529A1

Abstract

The purpose of the present invention is to provide a method for increasing, in a simple manner, the transdermal absorption properties of a water-soluble active ingredient without forming a prodrug via organic synthesis.　The present invention relates to: a composition containing a water-soluble active ingredient, a compound having a ketone group, and water; a transdermally absorptive composition containing said composition, a transdermal-absorption control agent, and a liposoluble medium; and a method for causing the water-soluble active ingredient to permeate into the skin from the composition.

Description

Water-containing transdermal absorption composition

The present invention relates to a water-containing transdermal absorption composition that absorbs a water-soluble active ingredient into the skin, and a method for absorbing the water-soluble active ingredient into the skin.

In recent years, research on transdermal absorption technology that induces the active ingredient to be absorbed from the skin so as to act directly on the skin has been advanced.
In particular, water-soluble drugs have a problem that they do not easily penetrate into the stratum corneum, which has high lipophilicity, and one of the methods for improving the transdermal absorbability is fat-solubilization (oil-solubilization) of water-soluble drugs. Has been done. For example, a fat-soluble site is introduced into a water-soluble drug by organic synthesis (prodrugization), dissolved and dispersed in an oil-based substrate, and applied to the skin. After permeation into the stratum corneum, the bond between the water-soluble drug and the fat-soluble site is broken by an enzyme or the like inside the skin, and the water-soluble drug is released. Alternatively, an aqueous solution of a water-soluble drug is encapsulated in liposomes, dissolved and dispersed in an oil-based substrate, and applied to the skin. After permeation into the stratum corneum, the interface of the liposome is disrupted by enzymes or the like inside the skin, and the water-soluble drug is released.

Recently, it has been reported that a permeability enhancer (transdermal absorption promoter) such as terpene or higher alcohol is used to enhance the transdermal absorbability of a drug (Patent Documents 1 to 5).

Japanese Unexamined Patent Publication No. 2013-241459 International Publication No. WO2012 / 043701 Japanese Unexamined Patent Publication No. 2010-160500 Japanese Patent No. 5680197 JP-A-2010-6771

Prodrugization is an excellent method of imparting lipophilicity to water-soluble drugs and enhancing transdermal absorbability, but it is a complicated procedure for obtaining approval for the manufacture and sale of organic synthetic manufacturing processes and quasi-drugs. Is required.

On the other hand, as a drug to be prodrugized or encapsulated in liposomes, for example, tranexamic acid, which is an artificial amino acid, suppresses melanin production by binding to plasmin, which is a proteolytic enzyme, and inhibiting activation in the epidermis. It is known to do. In recent years, the whitening effect has been touted by utilizing this action, and it is attracting attention as a raw material for cosmetics. However, there is a problem that tranexamic acid has low skin permeability.

An object of the present invention is to provide a method for easily enhancing the transdermal absorbability of a water-soluble active ingredient without using prodrugs by organic synthesis.

As a result of diligent research, the present inventors have made it possible to easily combine the water-soluble active ingredient, the compound having a ketone group, and water in an appropriate ratio, thereby easily transdermally absorbing the water-soluble active ingredient. The present invention has been completed by finding that the water-soluble active ingredient can be easily released in the skin.

That is, the present invention
[1] A composition containing a water-soluble active ingredient, a compound having a ketone group, and water;
[2] The compound having a ketone group is selected from the group consisting of a terpene having a ketone group, a lignoid having a ketone group, a vanilloid having a ketone group, a curcuminoid having a ketone group, chromone, and a coumarin. The composition according to [1];
[3] The composition according to the above [2], wherein the terpene having the ketone group is (+)-camphor or geranyl acetone;
[4] The composition according to the above [1], wherein the compound having a ketone group is acetone, methyl ethyl ketone, methyl isobutyl ketone, acetophenone, curcumin or vitamin K;
[5] The composition according to any one of the above [1] to [4], wherein the water-soluble active ingredient is a compound having an amino group, a hydroxyl group, or a thiol group;
[6] The composition according to any one of the above [1] to [5], wherein the water-soluble active ingredient is minoxidil;
[7] A transdermal absorption composition containing the composition according to any one of the above [1] to [6], a transdermal absorption control agent, and a fat-soluble medium;
[8] The transdermal absorption composition according to the above [7], wherein the fat-soluble medium is a transdermal absorption-promoting fat-soluble medium;
[9] The transdermal absorption composition according to the above [8], wherein the transdermal absorption-promoting fat-soluble medium is selected from the group consisting of isopropyl myristate, cyclopentasiloxane, squalane, diethyl sebacate, and limonene. Stuff;
[10] The transdermal absorption composition according to any one of the above [7] to [9], which comprises 2 parts by volume or more of a compound having a ketone group with respect to 1 part by volume of a fat-soluble medium;
[11] The transdermal absorption composition according to any one of the above [7] to [10], wherein the transdermal absorption control agent is a monohydric or multivalent alcohol;
[12] The monohydric or polyhydric alcohols are methanol, ethanol, 2-propanol, geraniol, citronellol, glycerin, propylene glycol, butylene glycol, oleyl alcohol, cetanol, lauryl alcohol, stearyl alcohol, 2-hexyldecanol, and 1,2. -The transdermal absorption composition according to the above [11], which is selected from the group consisting of hexanediol.
[13] A method for permeating the water-soluble active ingredient into the skin, which comprises mixing a water-soluble active ingredient, a compound having a ketone group, a transdermal absorption control agent, a fat-soluble medium, and water.
Regarding.

The composition containing the water-soluble active ingredient of the present invention, the compound having a ketone group, and water can improve the transdermal absorbability of the water-soluble active ingredient, and further, after permeation into the stratum corneum, inside the skin. It is also possible to release the water-soluble active ingredient to exert a medicinal effect.
Further, in the above composition, the water-soluble active ingredient and the compound having the ketone group may form a complex through a reversible interaction that can dissociate in water. Since the complex formed in this way is complexed through an interaction in which the water-soluble active ingredient and the compound having a ketone group can be dissociated in water, it is uniformly dissolved in a fat-soluble medium ( It can be fat-soluble or oil-soluble), and as a result, the transdermal absorbability of the water-soluble active ingredient can be improved, and after permeation into the stratum corneum, the water-soluble active ingredient can be dissolved by water inside the skin. It can be expected that it can be released and exert a medicinal effect.

It is a figure which shows the minoxidil concentration in the skin of the pig (Yucatan Micro Pig; YMP) in Comparative Example 1 and Examples 1 to 3. It is a figure which shows the minoxidil concentration in the receiver liquid in Comparative Example 1 and Example 1-3.

In the composition containing the water-soluble active ingredient of the present invention, the compound having a ketone group, and water (hereinafter, also referred to as "composition (1) of the present invention"), the compound having the water-soluble active ingredient and the ketone group. And may form a complex. In the complex, the water-soluble active ingredient and the compound having a ketone group are complexed through an interaction that can be dissociated in water. Therefore, the complex can have a chemical equilibrium relationship with the water-soluble active ingredient and the compound having a ketone group, and as a result, the complex is lipophilic in a fat-soluble medium by solvation, cluster formation, or the like. While it can exist stably, it can be expected to exert its medicinal effect because it easily dissociates with the water contained therein and releases the water-soluble active ingredient.

The water-soluble active ingredient of the present invention is not particularly limited as long as it is an active ingredient such as a water-soluble drug or cosmetic, and any active ingredient of the water-soluble drug or cosmetic, for example, an amino acid, a hydrophilic vitamin, a sugar, or a peptide. Other hydrophilic agents and the like can be used.
Examples of such a water-soluble active ingredient of the present invention include those having an amino group, a hydroxyl group, or a thiol group. Each of these groups can dissociate with the ketone group of a compound having a ketone group in water, such as ionic bond, hydrogen bond, dipole interaction, van der Waals force, charge transfer interaction, π. It may form −π interactions, hydrophobic interactions, solvations, reversible chemical bonds, and the like.

The amino acids include, for example, artificial amino acids such as tranexamic acid; as well as alanine, arginine, aspartic acid, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan. , Tyrosine, and natural amino acids such as valine.

Examples of the hydrophilic vitamin include ascorbic acid, ascorbyl sodium phosphate, ascorbyl magnesium phosphate, ascorbyl glucoside, ethyl ascorbic acid, and vitamins B1, B2, B4, B5, B6, B7, and B12.

Examples of the sugar include glucose, trehalose, dextran, pullulan, cyclodextrin, mannitol, glucosamine, galactosamine, raffinose, mannan, and pectin.

Examples of the peptide include known peptides and peptides having a specific effect (for example, because it is recognized by human T cells, it is expected to have a therapeutic effect on pollinosis, etc.). Specific examples are peptide A (amino acid sequence: QFAKLTGFTLMG) and peptide B (amino acid sequence: SMKVTVAFNQFGP).

Examples of the hydrophilic agent include minoxidil, zanamivir (Relenza), acyclovir, cytarabine ocphosphate, and fludarabine phosphate. Minoxidil is preferred. As a product containing minoxidil, Ligro (registered trademark) EX5 (manufactured by Rohto Pharmaceutical Co., Ltd.) is exemplified.

In the present invention, the above-mentioned water-soluble active ingredient may be used alone or in combination of two or more.

The compound having a ketone group of the present invention is not particularly limited as long as it is a fat-soluble compound containing at least one ketone group, and any compound including an aliphatic ketone or an aromatic ketone can be used. Among them, a compound having a ketone group having 3 or more carbon atoms, for example, 3 to 50, particularly 4 to 50, is preferable. Further, from the viewpoint of natural origin and safety, terpenes having a ketone group, lignoids having a ketone group, vanilloids having a ketone group, curcuminoids having a ketone group, chromone having a ketone group, coumarin and the like are more preferable.
In the present invention, the ketone group means a group represented by-(C = O)-(both ends are not bonded to a hydrogen atom). In addition, the tautomeric form, the enol type: = C (OH)-can also be included in the ketone group in the present invention. Further, an ester in which one of both ends is bonded to an oxygen atom and the other one is bonded to a carbon atom, preferably isopropyl myristate (IPM), may also be included in the compound having a ketone group in the present invention.
Preferably, the ketone group of the present invention has both ends of − (C = O) − bonded to a carbon atom.

Examples of the terpene having a ketone group include geranylacetone, camphor, for example (±) -camphor, (+)-camphor, and (-)-camphor, and carboxylic and capsantin, and water-soluble active ingredients, particularly. Geranylacetone or (+)-camphor is preferable from the viewpoint of favorably fat-solubilizing minoxydil, and natural products such as essential oils containing the above compounds may be used. It is preferably camphor tree from the viewpoint of satisfactorily lipophilicizing a water-soluble active ingredient, particularly minoxidil.
Essential oil is a general term for volatile organic substances produced by plants, and is generally a mixture of many compounds. It is not particularly limited, and it can be carried out as long as the terpene having the ketone group of the present invention is included.
As an example, camphor is a mixture of limonene (5 to 10%), α-pinene, myrcene and the like, with camphor as the main component (50 to 60%).
As an example, sage is a mixture of camphor as the main ingredient (20 to 30%), Cis-thujone (15 to 20%), eucalyptus (10 to 15%), and the like.

Examples of the lignoid having a ketone group include flavone.

Examples of the vanillyl having a ketone group include gingerol and shogaol.

Examples of the curcuminoid having a ketone group include curcumin, demethoxycurcumin, bisdemethoxycurcumin, and the like, and curcumin is preferable from the viewpoint of satisfactorily lipophilicizing a water-soluble active ingredient, particularly minoxidil.

The compound having a ketone group of the present invention is particularly preferably geranylacetone or (+)-camphor from the viewpoint of satisfactorily lipophilicizing a water-soluble active ingredient, particularly minoxidil.
In addition, the compound having a ketone group of the present invention is particularly suitable for acetone, methyl ethyl ketone, and methyl isobutyl ketone (4-) from the viewpoint of satisfactorily lipophilicizing water-soluble active ingredients, particularly minoxidyl, and enhancing transdermal absorbability. Methyl-2-pentanone), acetophenone, curcumin or vitamin K is preferred, with methyl isobutyl ketone being particularly preferred.

In the present invention, the above-mentioned compound having a ketone group may be used alone or in combination of two or more.

The transdermal absorption control agent of the present invention is not particularly limited as long as it is commonly used in the field of pharmaceuticals and cosmetics, particularly skin external preparations, for controlling transdermal absorption of active ingredients of water-soluble pharmaceuticals or cosmetics. Percutaneous absorption control having a hydroxyl group from the viewpoint that the composition (1) of the present invention can be well stabilized in a fat-soluble medium and the release of a water-soluble active ingredient in the skin can be better controlled. Agents are preferred, and monohydric or polyhydric alcohols are particularly preferred.
The complex of the present invention may be complexed with a water-soluble active ingredient, a compound having a ketone group, and a transdermal absorption control agent via an interaction capable of dissociating in water. In such complexes, the release of water-soluble active ingredients in the skin is better controlled.

The monohydric alcohols include, for example, lower alcohols such as methanol, ethanol, 1-propanol, and 2-propanol; higher alcohols; and nerolidol, geraniol, menthol, borneol, isoborneol, nerol, citronellol, fentyl. Examples include terpenes having a hydroxyl group such as alcohols, carbeols, and neomenthols, preferably methanol, ethanol, 2-propanol, citronellol, and geraniol, and more preferably ethanol.

Examples of the higher alcohols include octanol, nonanol, decanol, undecyl alcohol, lauryl alcohol, tridecyl alcohol, myristyl alcohol, pentadecyl alcohol, cetyl alcohol (cetyl alcohol), 2-hexyldecanol, heptadecyl alcohol, stearyl alcohol, and Fine oxohol 180 (FO180):

Such as saturated alcohols having 8 to 18 carbon atoms; and unsaturated alcohols having 8 to 18 carbon atoms such as oleyl alcohol, linoleil alcohol, and linolenyl alcohol. Preferred examples include octanol, decanol, cetanol, lauryl alcohol, myristyl alcohol, stearyl alcohol, 2-hexyl decanol, and oleyl alcohol, and more preferably oleyl alcohol, cetanol, lauryl alcohol, stearyl alcohol, and 2-hexyl decanol. Be done.

Examples of the polyhydric alcohol include ethylene glycol, propylene glycol, 1,3-propanediol, butylene glycol (eg, 1,2-butanediol, 1,3-butanediol, 1,4-butanediol, or 2). , 3-Butanediol), 1,5-pentanediol, 1,2-hexanediol, glycerin, dipropylene glycol, diethylene glycol, triethylene glycol, polyethylene glycol 400 and the like, preferably glycerin, propylene glycol, etc. Butylene glycol such as 1,3-butanediol and 1,2-hexanediol, particularly preferably propylene glycol and 1,3-butanediol can be mentioned.

The composition (1) of the present invention can be easily prepared by mixing the water-soluble active ingredient, the compound having a ketone group, and water, and heating and cooling for a certain period of time, if necessary. it can. From the viewpoint that the composition (1) of the present invention can be obtained satisfactorily, it is preferable to add and mix the percutaneous absorption control agent of the present invention, particularly the liquid percutaneous absorption control agent. Further, the transdermal absorption control agent of the present invention is preferably liquid in that the obtained composition (1) can be stably dissolved. In this case, the solution of the percutaneous absorption control agent in which the obtained composition (1) is dissolved can be used for preparing the percutaneous absorption composition of the present invention.
When the water-soluble active ingredient is a solid (preferably a crystal), it is preferable to mix it as a powder in order to obtain the composition (1) of the present invention satisfactorily. Examples of the method of powdering include a method of dry pulverization. The conditions for dry crushing are not particularly limited as long as the water-soluble active ingredient can be crushed into small pieces, but it is desirable to use a crusher such as a mortar, a ball mill, a homogenizer, a cutter mill, or a hammer mill. Further, the crushing time, the processing pressure, and the like are appropriately adjusted according to the hardness of the water-soluble active ingredient to be crushed.
It is desirable that the powder obtained by the above method be further sieved in order to make the particle size uniform. The sieve is preferably 500 μm or less, more preferably 200 μm or less, and particularly preferably 100 μm or less.

The mixing ratio (weight ratio) of the water-soluble active ingredient and the compound having a ketone group varies depending on the type of these substances used, but is 1: 0.1 to 100, preferably 1: 0.5 to. It is 50, more preferably 1: 1 to 5.
When the transdermal absorption control agent is also mixed, the mixing ratio (weight ratio) of the water-soluble active ingredient, the compound having a ketone group, and the transdermal absorption control agent differs depending on the type of these substances used. However, it is 1: 0.1 to 100: 1 to 100, preferably 1: 0.5 to 50: 2 to 95, and more preferably 1: 1 to 5: 5 to 95.
The composition ratio (molar ratio) of the water-soluble active ingredient and the compound having a ketone group constituting the composition (1) of the present invention is 1 to 100: 100 to 1, more preferably 1 to 10 :. It is 10 to 1.

In the present invention, by appropriately using the above-mentioned transdermal absorption control agent, particularly monovalent or polyhydric alcohol, for example, depending on the type and amount of these transdermal absorption control agents, in the skin after percutaneous absorption. The release of the water-soluble active ingredient from the composition (1) of the present invention can be controlled. For example, by increasing the fat solubility of the transdermal absorption control agent (for example, by increasing the number of carbon atoms), the release of the water-soluble active ingredient of the present invention can be delayed, and the fat of the transdermal absorption control agent can be delayed. By reducing the solubility (for example, by reducing the number of carbon atoms), the release of the water-soluble active ingredient of the present invention can be promoted. The present invention also comprises a method for controlling the release of a water-soluble active ingredient from the composition (1) into the skin, which comprises a step of dissolving the composition (1) of the present invention in a transdermal absorption control agent. Related. The present invention also relates to the use of a transdermal absorption control agent for controlling the release of the water-soluble active ingredient from the composition (1) of the present invention into the skin.

In the present invention, the above-mentioned transdermal absorption control agent may be used alone or in combination of two or more.

The fat-soluble medium of the present invention is not particularly limited as long as it is a fat-soluble medium commonly used as a base material in the fields of pharmaceuticals and cosmetics, particularly skin external preparations, and a percutaneous absorption-promoting fat-soluble medium is preferably used. Can be used.
The transdermal absorption-promoting fat-soluble medium is particularly limited as long as it is commonly used in the field of pharmaceuticals and cosmetics, especially external preparations for skin, to promote transdermal absorption of active ingredients of water-soluble pharmaceuticals or cosmetics. For example, limonene (eg, d-limonene ((+)-limonene), especially R- (+)-limonene), cyclopentasiloxane (KF995):

Isopropyl myristate (IPM), squalene, squalene, squalene, silicon oil, jojoba oil, almond oil, olive oil, horse oil, diethyl sebacate, mineral oil and the like can be used, preferably isopropyl myristate (IPM). ), Cyclopentasiloxane, squalene, limonene (particularly R- (+)-lymonen), and diethyl sebacate can be used, more preferably isopropyl myristate (IPM).
In the present invention, the fat-soluble medium may be used alone or in combination of two or more.

The transdermal absorption composition of the present invention can be prepared by mixing the solution of the transdermal absorption control agent in which the composition (1) of the present invention obtained above is dissolved and the fat-soluble medium. ..
Alternatively, it can be prepared by mixing a solution of the transdermal absorption control agent in which the water-soluble active ingredient and the compound having a ketone group are dissolved, and the fat-soluble medium, and adding water to the solution.

The mixing ratio of the fat-soluble medium and the compound having a ketone group varies depending on the type of these substances used, but for example, 1 part by volume or more of the compound having a ketone group is added to 1 part by volume of the fat-soluble medium. It is preferably 2 parts by volume or more, more preferably 2 to 500 parts by volume, still more preferably 10 to 200 parts by volume, and most preferably 50 to 150 parts by volume.

The composition (1) of the present invention can exhibit good solubility in a fat-soluble medium by using an appropriate transdermal absorption control agent. From this point of view, for example, when the fat-soluble medium is squalane, gelaniol or citronellol is preferable as the transdermal absorption control agent, and when the fat-soluble medium is IPM, ethanol, 1,2-hexanediol or propylene is used as the transdermal absorption control agent. A combination of glycol or 1,3-butanediol, particularly ethanol, propylene glycol, and 1,3-butanediol is preferred, and when the fat-soluble medium is KF995, geraniol or citronellol is preferred as the transdermal absorption control agent.

Although the transdermal absorption composition of the present invention contains water, it preferably contains 1 wt% or more, particularly 5 wt% or more, based on the total weight of the composition, in that it dissolves more water-soluble active ingredients more uniformly. Is preferable, and 10 wt% or more is particularly preferable. Further, from the viewpoint of suppressing phase separation, it is preferably contained in an amount of 70 wt% or less, particularly preferably 50 wt% or less, and particularly preferably 30 wt% or less, based on the total weight of the composition.

When used as a medicine or cosmetic, the transdermal composition of the present invention may be used by itself, or may be used as a conventional pharmaceutical preparation, particularly a skin external preparation, or a cosmetic. The pharmaceutical preparation or cosmetic is acceptable in the field of pharmaceuticals and cosmetics such as excipients, lubricants, binders, disintegrants, emulsifiers, stabilizers, flavoring agents and diluents as long as the effects of the present invention are not impaired. It may contain an additive to be added.
The external preparation for skin of the present invention can contain components that can be usually blended in the external preparation for skin, as long as the effects of the present invention are not impaired. Such components include polyhydric alcohols such as glycerin and propylene glycol, oils such as liquid paraffins, squalanes, higher fatty acids and higher alcohols, organic acids such as citric acid, lactic acid and tartrate, and inorganic acids such as hydrochloric acid and phosphoric acid. , Citric acid, alkalis such as triethanolamine, cationic surfactant, amphoteric surfactant, nonionic surfactant, powder, pigment, dye, antiseptic and antifungal agent, resin, pH adjuster, antioxidant, Examples include UV absorbers, chelating agents, thickeners, moisturizers, alcohols, water, fragrances and the like. It is preferably tartaric acid or phosphoric acid.

The transdermal absorption composition of the present invention preferably contains ethanol, propylene glycol, and 1,3-butanediol as a transdermal absorption control agent; and tartrate acid, and more preferably minoxydil as a water-soluble active ingredient; a ketone group. Methylisobutylketone as a compound having; ethanol, propylene glycol, and 1,3-butanediol as a transdermal absorption control agent; and tartrate acid.

The present invention also relates to a method for transdermally administering the water-soluble active ingredient, which comprises applying the transdermal absorption composition of the present invention to the skin. The present invention also relates to the use of the transdermal absorption composition of the present invention for percutaneously administering the water-soluble active ingredient.

Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.

1. 1. Reagents and Equipment The reagents used in the examples are shown below.
Ligro® EX5 was obtained from Rohto Pharmaceutical Co., Ltd. Isopropyl myristate (IPM) (special grade), ammonium formate (special grade), 1 × PBS, and ethanol for disinfection were obtained from Fujifilm Wako Pure Chemical Industries, Ltd. 4-Methyl-2-pentanone (MIK) was obtained from Tokyo Chemical Industry Co., Ltd. Acetonitrile (for high performance liquid chromatography) was obtained from Kanto Chemical Co., Inc.
Ligro (registered trademark) EX5 contains 5 g of minoxidil as an active ingredient in 100 mL, and also contains ethanol, propylene glycol, 1,3-butylene glycol (1,3-butanediol), tartaric acid, and water. ..
The equipment used for the analysis is shown below.
Liquid chromatograph mass spectrometer (LC / MS)
Equipment: e2695 (LC part), 2489 (UV-Vis detector), 3100 MassDetector, manufactured by Japan Waters Corp. Column: Shоdex Asahipak NH2P-40 2D (2.0 mm ID x 150 mm)

2. Preparation Example of Transdermal Absorption Composition Containing Minoxidil Add IPM and / or MIK To a 6 mL screw cap sample tube, add Ligro® EX5 and IPM and / or MIK in the amounts shown in Table 1. Mixing was performed with a vortex mixer to prepare transdermal absorption compositions of Comparative Example 1, Example 1, Example 2, and Example 3.
The preparation conditions are shown in Table 1.

3. 3. Transdermal Absorption Test of Minoxidil Oil Soluble Solution The stratum corneum is hydrophobic and becomes hydrophilic as it goes deeper. That is, adding oil can be an effective means to break through the barrier of the stratum corneum. Therefore, a transdermal absorbability test was conducted to determine whether or not minoxidil was absorbed more than the commercially available product by adding oil to the commercially available product, Ligro.
The transdermal absorption compositions used in this experiment are Comparative Example 1, Example 1, Example 2, and Example 3 shown in Table 1 above.
The transdermal absorbability test was performed as follows. As a transdermal absorption test, porcine skin (Yucatan Microlо Pig (manufactured by Charles River Laboratories, Japan)) was used. 5 mL of a stirrer and an aqueous PBS solution was added to the receiver phase of Franzcel, the pig skin was sandwiched above the aqueous PBS solution, and water at 37 ° C. was flowed through the water jacket of Franzcel. The receiver phase was agitated and 200 μL of Comparative Example 1, Example 1, Example 2 and Example 3 was placed on the porcine skin. After 24 hours, the methanol extract of pig skin and the PBS aqueous solution of the receiver phase were sampled, and the amount of minoxidil was quantified by LC-MS. The conditions for LC-MS are as follows.
Column temperature: 30 ° C., detection mass (m / z): 210, eluent: 10 mM ammonium formate / acetonitrile (10/90, vоl / vоl), flow velocity: 0.2 mL
The results are shown in FIGS. 1 and 2.

Compared with Comparative Example 1, in Example 1, Example 2, and Example 3, a large amount of minoxidil was detected in the porcine skin and in the receiver liquid. In particular, in Example 3 in which both IPM and MIK were added, the minoxidil concentration in the pig skin was about 25 times, the minoxidil concentration in the receiver liquid was 15 times, and Example 1 and the embodiment in which IPM and MIK were added alone. It showed much higher transdermal absorbability than Example 2.
From these results, it was found that the addition of IPM or MIK to a commercially available product promotes transdermal absorbability. In particular, the co-addition of IPM and MIK dramatically promoted transdermal absorption, indicating that it is promising as a material for a transdermal drug delivery system (DDS).

Although the composition (1) of the present invention contains water, it improves the transdermal absorbability of the water-soluble active ingredient, increases the content in the skin, and releases the water-soluble active ingredient inside the skin. Therefore, the transdermal composition of the present invention containing the composition (1) of the present invention can be used for external preparations for skin, for example, pharmaceuticals and cosmetics used for external treatment for skin. can do.
In addition, by appropriately using a transdermal absorption control agent, the release of the water-soluble active ingredient from the composition (1) of the present invention inside the skin is controlled, so that it can be used in a drug delivery system.
That is, the composition (1) of the present invention can be used as a raw material for the production of external preparations for skin, for example, pharmaceuticals, cosmetics, or drug delivery systems used for external skin therapy.

Claims

A composition containing a water-soluble active ingredient, a compound having a ketone group, and water.
The compound according to claim 1, wherein the compound having a ketone group is selected from the group consisting of a terpene having a ketone group, a lignoid having a ketone group, a vanilloid having a ketone group, a curcuminoid having a ketone group, chromone, and a coumarin. Composition.
The composition according to claim 2, wherein the terpene having the ketone group is (+)-camphor or geranyl acetone.
The composition according to claim 1, wherein the compound having a ketone group is acetone, methyl ethyl ketone, methyl isobutyl ketone, acetophenone, curcumin or vitamin K.
The composition according to any one of claims 1 to 4, wherein the water-soluble active ingredient is a compound having an amino group, a hydroxyl group, or a thiol group.
The composition according to any one of claims 1 to 5, wherein the water-soluble active ingredient is minoxidil.
A transdermal absorption composition containing the composition according to any one of claims 1 to 6, a transdermal absorption control agent, and a fat-soluble medium.
The transdermal absorption composition according to claim 7, wherein the fat-soluble medium is a transdermal absorption-promoting fat-soluble medium.
The transdermal absorption composition according to claim 8, wherein the transdermal absorption-promoting fat-soluble medium is selected from the group consisting of isopropyl myristate, cyclopentasiloxane, squalane, diethyl sebacate, and limonene.
The transdermal absorption composition according to any one of claims 7 to 9, which contains 2 parts by volume or more of a compound having a ketone group with respect to 1 part by volume of a fat-soluble medium.
The transdermal absorption composition according to any one of claims 7 to 10, wherein the transdermal absorption control agent is a monohydric or polyhydric alcohol.
The monohydric or polyhydric alcohols are methanol, ethanol, 2-propanol, geraniol, citronellol, glycerin, propylene glycol, butylene glycol, oleyl alcohol, cetanol, lauryl alcohol, stearyl alcohol, 2-hexyldecanol, and 1,2-hexanediol. The transdermal absorption composition according to claim 11, which is selected from the group consisting of one or more.
A method for permeating the water-soluble active ingredient into the skin, which comprises mixing a water-soluble active ingredient, a compound having a ketone group, a transdermal absorption control agent, a fat-soluble medium, and water.