JPWO2020013179A1 - Transdermal absorption composition with controlled release of minoxidil - Google Patents

Abstract

An object of the present invention is to provide a method for easily enhancing the transdermal absorbability of minoxidil without using prodrugs by organic synthesis. The present invention is a percutaneous absorption composition comprising an interaction of minoxidil and a lipophilic compound having a ketone group; the complex, a transdermal absorption control agent, and a lipophilic medium. As well as methods of controlling the release of the minoxidil from the complex into the skin.

Description

The present invention relates to a transdermal absorption composition in which the release of minoxidil in the skin is controlled, and a method for controlling minoxidil in 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 fat-solubility, 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 oily base material, 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. 2010-600500 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 minoxidil without using prodrugs by organic synthesis.

As a result of diligent research, the present inventors easily impart fat solubility to the minoxidil by forming a complex with a fat-soluble compound having a ketone group through an interaction. We have completed the present invention by finding that minoxidil can be easily released in the skin while the skin absorbability is enhanced.

That is, the present invention
(1) A complex formed through an interaction between minoxidil and a fat-soluble compound having a ketone group;
(2) The lipophilic 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 coumarin. , The complex described in (1) above;
(3) The complex according to (2) above, wherein the terpene having the ketone group is (+)-camphor or geranyl acetone;
(4) The complex according to (2) above, wherein the lignoid having a ketone group is a flavone;
(5) The complex according to (2) above, wherein the vanillyl having a ketone group is gingerol or shogaol;
(6) The complex according to (2) above, wherein the curcuminoid having a ketone group is curcumin;
(7) The complex according to (1) above, wherein the fat-soluble compound having a ketone group is methyl ethyl ketone, methyl isobutyl ketone, acetophenone, curcumin or vitamin K;
(8) A transdermal absorption composition containing the complex according to any one of (1) to (7) above, a transdermal absorption control agent, and a fat-soluble medium;
(9) The transdermal absorption composition according to (8) above, wherein the complex is dissolved in the fat-soluble medium;
(10) The composition according to (8) or (9) above, wherein the fat-soluble medium is a transdermal absorption-promoting fat-soluble medium;
(11) The composition according to (10) above, wherein the transdermal absorption-promoting fat-soluble medium is selected from the group consisting of isopropyl myristate, olive oil, cyclopentasiloxane, squalane, and limonene.
(12) A composition containing minoxidil, a fat-soluble compound having a ketone group, and a transdermal absorption control agent;
(13) The composition according to (12) above, further comprising a fat-soluble medium;
(14) The compositions according to (8) to (13) above, wherein the transdermal absorption control agent is alcohol;
(15) The composition according to (14) above, wherein the alcohol is selected from the group consisting of ethanol, geraniol, citronellol, and 1,2-hexanediol.
(16) Controlling the release of minoxidil from the complex into the skin, which comprises a step of dissolving the complex according to any one of (1) to (7) in a transdermal absorption control agent. Method;
(17) A method for releasing the minoxidil from the complex into the skin, which comprises a step of dissolving the complex according to any one of (1) to (7) in a transdermal absorption control agent;
(18) A method for releasing the minoxidil in the skin from a composition containing minoxidil, a fat-soluble compound having a ketone group, and a transdermal absorption control agent;
(19) A method for producing a complex formed through an interaction between minoxidil and a fat-soluble compound having a ketone group, which comprises a step of mixing minoxidil powder and a fat-soluble compound having a ketone group;
(20) A composition containing the minoxidil, the fat-soluble compound having a ketone group, and the transdermal absorption control agent, which comprises a step of mixing a minoxidil powder, a fat-soluble compound having a ketone group, and a transdermal absorption control agent. Manufacturing method of things;
(21) The complex according to (1) above, which comprises the fat-soluble compound having a ketone group in the essential oil;
(22) The complex according to (21) above, wherein the essential oil is camphor tree or sage;
Regarding.

In the complex of the present invention, minoxidil and a fat-soluble compound having a ketone group are complexed through an interaction, so that they can be uniformly dissolved (fat-soluble or oil-soluble) in a fat-soluble medium. As a result, the transdermal absorbability of the minoxidil can be improved, and after permeation into the stratum corneum, minoxidil can be released to exert a medicinal effect.
In addition, in the present invention, the release of minoxidil from the complex in the skin can be controlled by appropriately using a transdermal absorption control agent.

It is a figure which shows the minoxidil concentration in a pig skin. It is a figure which shows the minoxidil concentration in a receiver liquid. It is a figure which shows the minoxidil concentration in a pig skin. It is a figure which shows the minoxidil concentration in a receiver liquid.

In the complex of the present invention, minoxidil and a lipophilic compound having a ketone group are complexed through an interaction. Therefore, the complex of the present invention can have a chemical equilibrium relationship with minoxidil and the fat-soluble compound having the ketone group, and as a result, in the fat-soluble medium, it is fat-solubilized by solvation, cluster formation, or the like. While it can exist stably, it dissociates and releases minoxidil inside the skin, so that it can exert its medicinal effect.
The complex of the present invention may be complexed via an interaction that can be dissociated in water.

In the present invention, minoxidil may be used alone, or may be used in combination with any one or more water-soluble active ingredients.
Such a 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 pharmaceutical or cosmetic that can form a complex with a fat-soluble compound having a ketone group through an interaction. , Any water-soluble pharmaceutical or cosmetic active ingredient, such as amino acids, hydrophilic vitamins, sugars, peptides and other hydrophilic agents 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 has various interactions with the ketone group of a fat-soluble compound having a ketone group, such as ionic bond, hydrogen bond, bipolar interaction, van der Waals force, charge transfer interaction, π-. It can form π-interactions, hydrophobic interactions, solvations, reversible chemical bonds, and so on.

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, ascorbic sodium phosphate, ascorbic magnesium phosphate, ascorbic 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, since 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 zanamivir (Relenza), acyclovir, cytarabine ocphosphate, and fludarabine phosphate.

The fat-soluble 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 fat-soluble compound having a ketone group having 4 or more carbon atoms, for example, 4 to 50 carbon atoms 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.
Preferably, the ketone group of the present invention has both ends of − (C = O) − bonded to a carbon atom.

Examples of the terpen having a ketone group include geranylacetone, camphor, for example, (±) -camphor, (+)-camphor, and (-)-camphor, and carboxylic and capsantin, which satisfactorily lipophilicize minoxydil. Geranylacetone or (+)-camphor is preferable, and natural products such as essential oils containing the above compounds may be used. It is preferably camphor tree from the viewpoint of satisfactorily lipolytic 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 tree is a mixture of limonene (5-10%), α-pinene, myrcene and the like, with camphor as the main component (50-60%).
As an example, sage is a mixture of camphor as a main component (20 to 30%), Cis-thujone (15 to 20%), eucalyptus (10 to 15%), and the like.

Examples of the lignoid having a ketone group include flavones.

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 lipolytic minoxidil.

Examples of the aliphatic ketone and aromatic ketone include methyl ethyl ketone, methyl isobutyl ketone, acetophenone, curcumin and vitamin K.

In the present invention, the fat-soluble compound having a ketone group may be used alone or in combination of two or more.
The fat-soluble compound having a ketone group of the present invention is particularly preferably geranylacetone or (+)-camphor from the viewpoint of favorably fat-solubilizing minoxidil.

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 the transdermal absorption of the active ingredient of a water-soluble pharmaceutical or cosmetic. A transdermal absorption control agent having a hydroxyl group is preferable, and a monohydric or polyhydric alcohol is particularly preferably used because the complex of the present invention can be satisfactorily stabilized in a fat-soluble medium.
In the complex of the present invention, minoxidil, a fat-soluble compound having a ketone group, and a transdermal absorption control agent may be further complexed through an interaction. In such complexes, the release of minoxidil in the skin is better regulated.

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 alcohol, carbeol, and neomenthol, and preferred examples include methanol, ethanol, citronellol, and geraniol.

などの炭素数８〜１８の飽和アルコール；ならびにオレイルアルコール、リノレイルアルコール、及びリノレニルアルコールなどの炭素数８〜１８の不飽和アルコールなどが挙げられる。好ましくは、オクタノール、デカノール、ラウリルアルコール、ミリスチルアルコール、及びオレイルアルコールが挙げられ、より好ましくは、オレイルアルコールが挙げられる。Examples of the higher alcohols include octanol, nonanol, decanol, undecyl alcohol, lauryl alcohol, tridecyl alcohol, myristyl alcohol, pentadecyl alcohol, cetyl alcohol, heptadecyl alcohol, stearyl alcohol, and fine oxocol 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, lauryl alcohol, myristyl alcohol, and oleyl alcohol, and more preferably oleyl alcohol.

Examples of the polyhydric alcohol include ethylene glycol, propylene glycol, 1,3-propanediol, 1,2-butanediol, 1,3-butanediol, 1,4-butanediol, and 2,3-butanediol. Examples thereof include 1,5-pentanediol, 1,2-hexanediol, glycerin, dipropylene glycol, diethylene glycol, triethylene glycol, polyethylene glycol 400 and the like, and propylene glycol and 1,2-hexanediol are preferable. ..

The complex of the present invention can be easily prepared by mixing the minoxidil with the fat-soluble compound having a ketone group, heating and cooling for a certain period of time, if necessary. It is preferable to add and mix the percutaneous absorption control agent of the present invention, particularly the liquid percutaneous absorption control agent, from the viewpoint of obtaining a good complex. Further, the transdermal absorption control agent of the present invention is preferably liquid in that the obtained complex can be stably dissolved. In this case, the solution of the percutaneous absorption control agent in which the obtained complex is dissolved can be used for preparing the percutaneous absorption composition of the present invention.
When minoxidil is a solid (preferably crystalline), it is preferably mixed as a powder in order to obtain a good complex of the present invention. Examples of the method of powdering include a method of dry pulverization. The conditions for dry crushing are not particularly limited as long as minoxidil 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 minoxidil 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 of the minoxidil to the fat-soluble compound having a ketone group varies depending on the type of these substances used, but is 1: 1 to 100, preferably 1: 10 to 50.
When the transdermal absorption control agent is also mixed, the mixing ratio of the minoxidil, the fat-soluble compound having a ketone group, and the transdermal absorption control agent varies depending on the type of these substances used, but is 1: 1. ~ 100: 1-100, preferably 1: 1-100: 10-50, more preferably 1: 10-50: 10-50.
The composition ratio (molar ratio) of the minoxidil and the fat-soluble compound having a ketone group constituting the complex of the present invention is 1 to 100: 100 to 1, more preferably 1 to 10: 10 to 1. be.

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. It is possible to control the release of minoxidil from the complex of the present invention. 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 minoxidil of the present invention can be delayed, and the fat solubility of the transdermal absorption control agent is lowered. By allowing (for example, by reducing the number of carbon atoms), the release of minoxidil of the present invention can be promoted. The present invention also relates to a method for controlling the release of minoxidil from the complex into the skin, which comprises a step of dissolving the complex of the present invention in a transdermal absorption control agent. The present invention also relates to the use of a transdermal absorption control agent to control the release of minoxidil from the complex of the present invention into the skin.

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

ミリスチン酸イソプロピル（ＩＰＭ）、スクアラン、スクワラン、スクワレン、シリコンオイル、ホホバオイル、アーモンドオイル、オリーブオイル、馬油、及びミネラルオイルなどを使用することができ、好ましくはミリスチン酸イソプロピル（ＩＰＭ）、オリーブオイル、シクロペンタシロキサン、スクアラン、リモネンを使用することができる。
本発明では、前記の脂溶性媒体を、単独で使用してもよいし、２種以上を組み合わせて使用してもよい。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 medicines and cosmetics, especially external preparations for skin, to promote transdermal absorption of active ingredients of water-soluble medicines or cosmetics. For example, limonene (eg, d-limonene), cyclopentasiloxane (KF995):

Isopropyl myristate (IPM), squalane, squalene, squalene, silicon oil, jojoba oil, almond oil, olive oil, horse oil, mineral oil and the like can be used, preferably isopropyl myristate (IPM), olive oil. , Cyclopentasiloxane, squalane, limonene can be used.
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 complex obtained above is dissolved and the fat-soluble medium.

The complex 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, geraniol or citronellol is preferable as the transdermal absorption control agent, and when the fat-soluble medium is IPM, ethanol or 1,2-hexanediol is preferable as the transdermal absorption control agent. When the fat-soluble medium is KF995, geraniol or citronellol is preferable as the transdermal absorption control agent.

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, liquid paraffins, squalanes, higher fatty acids, oils such as higher alcohols, organic acids such as citric acid and lactic acid, alkalis such as caustic soda and triethanolamine. Cationic surfactants, amphoteric surfactants, nonionic surfactants, powders, pigments, dyes, antiseptic and anti-mold agents, resins, pH adjusters, antioxidants, UV absorbers, chelating agents, thickeners, Moisturizers, alcohols, water, fragrances and the like are exemplified.
The present invention also relates to a method for transdermally administering the minoxidil, which comprises applying the transdermal 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 minoxidil.

Further, the composition of the present invention may be a composition containing the minoxidil, the fat-soluble compound having a ketone group, and the transdermal absorption control agent, and is preferably a transdermal absorption composition.
The composition of the present invention may further contain the fat-soluble medium.
The present invention also relates to a method for transdermal administration of the minoxidil, which comprises applying the composition of the present invention to the skin. The present invention also relates to the use of the composition of the present invention for transdermal administration of the minoxidil.

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.
Ethanol (special grade), isopropyl myristate (IPM) (special grade), ammonium formate (special grade), olive oil, and 1 × PBS were obtained from Wako Pure Chemical Industries, Ltd. Minoxidil, geranyl acetone, and (+)-camphor were obtained from Tokyo Chemical Industry Co., Ltd. Acetonitrile (for high performance liquid chromatography) was obtained from Kanto Chemical Co., Inc.
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: Shodex Asahipak NH2P-40 2D (2.0 mm ID x 150 mm)

2. Preparation Example of Percutaneous Collection and Absorption Composition Containing Minoxidil Add Aliphatic Ketone To a 6 mL screw cap sample tube, add 40 mg of minoxidil, 200 mg of the aliphatic ketone shown in Table 1, and 2 mL of ethanol, and stir at room temperature for 1 hour. did. After 1 hour, 2 mL of isopropyl myristate (IPM) was added to the obtained uniform ethanol solution to prepare transdermal absorption compositions of Comparative Example 1 and Examples 1 and 2.
The preparation conditions are shown in Table 1.

3. 3. Transdermal absorption test of minoxidil oil-dissolved solution (1)
The stratum corneum is hydrophobic and becomes hydrophilic as it goes deeper. That is, oil solubilization is an effective means for breaking through the barrier of the stratum corneum. Therefore, a transdermal absorbability test was conducted to determine whether or not minoxidil was released in an aqueous PBS solution after breaking through the skin barrier using an oil-soluble solution of minoxidil.
The transdermal absorption compositions used in this experiment are Comparative Example 1, Example 1, and Example 2 shown in Table 1 above.
The transdermal absorbability test was performed as follows. Pig skin (Yucatan Micro Pig (manufactured by Charles River Laboratories, Japan)) was used as a transdermal absorption test. A stir bar and 5 mL of a PBS aqueous solution were added to the receiver phase of Franzcel, the pig skin was sandwiched over the PBS aqueous 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 and Example 2 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 rate: 0.2 mL
The results are shown in FIGS. 1 and 2.

As a result, the amount of minoxidil in porcine skin was detected to be about 54 times higher with the addition of geranyl acetone (Example 1) and about 30 times higher with the addition of (+)-camphor (Example 2) as compared with Comparative Example 1. Was done. Further, in the receiver solution, while Comparative Example 1 was below the detection limit, both the addition of geranyl acetone (Example 1) and the addition of (+)-camphor (Example 2) showed transdermal absorbability. The result was.
From these results, it was shown that the minoxidil oil-dissolved solution to which an aliphatic ketone was added promotes transdermal absorbability and is promising as a material for a transdermal drug delivery system (DDS).

4. Preparation Example of Percutaneous Collection and Absorption Composition Containing Minoxidil Using IPM and Olive Oil as Oily Base Material Minoxidil 42.5 mg, (+)-Camfer 42.5 mg, and Ethanol 2000 mg were added to a 6 mL screw cap sample tube. In addition, the mixture was stirred at room temperature for 30 minutes. After 30 minutes, 1850 mg of IPM and 200 mg of olive oil were added to the obtained uniform ethanol solution to prepare a transdermal absorption composition of Example 3 [minoxidil (1%) oil-dissolved solution].

5. Transdermal absorption test of minoxidil oil-dissolved solution (2)
The transdermal absorption compositions used in this experiment are Commercial Product 1 (Reup x 5 Plus, Taisho Pharmaceutical Co., Ltd.) containing minoxidil at a concentration of 5%, and Example 3.
The transdermal absorbability test was performed as follows. Pig skin (Yucatan Micro Pig (manufactured by Charles River Laboratories, Japan)) was used as a transdermal absorption test. A stir bar and 5 mL of a PBS aqueous solution were added to the receiver phase of Franzcel, the pig skin was sandwiched over the PBS aqueous solution, and water at 37 ° C. was flowed through the water jacket of Franzcel. The receiver phase was agitated and 200 μL of Commercial Product 1 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 rate: 0.2 mL
The results are shown in FIGS. 3 and 4.

As a result, the amount of minoxidil in the porcine skin was detected about 9.7 times higher in Example 3 as compared with the commercially available product 1. In addition, the amount of minoxidil in the receiver liquid was detected about 27.9 times higher in Example 3.
Since the commercially available product 1 contains 5% minoxidil, the transdermal absorption composition of Example 3 [minoxidil (1%) oil-dissolved solution] used in this experiment promotes transdermal absorbability and transdermally. It has been shown to be promising as a skin drug delivery system (DDS) material.

Since the complex of the present invention can improve the transdermal absorbability of minoxidil, increase the content in the skin, and release minoxidil inside the skin to exert a medicinal effect, such a complex. The transdermal composition of the present invention containing the above can be used for external preparations for skin, for example, pharmaceuticals and cosmetics used for external treatment for skin.
In addition, by appropriately using a transdermal absorption control agent, the release of minoxidil from the complex of the present invention inside the skin is controlled, so that it can be used in a drug delivery system.

Claims (22)

A complex formed through an interaction between minoxidil and a fat-soluble compound having a ketone group. The claim that the fat-soluble 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. 1 The complex according to 1. The complex according to claim 2, wherein the terpene having a ketone group is (+)-camphor or geranyl acetone. The complex according to claim 2, wherein the lignoid having a ketone group is a flavone. The complex according to claim 2, wherein the vanillyl having a ketone group is gingerol or shogaol. The complex according to claim 2, wherein the curcuminoid having a ketone group is curcumin. The complex according to claim 1, wherein the fat-soluble compound having a ketone group is methyl ethyl ketone, methyl isobutyl ketone, acetophenone, curcumin or vitamin K. A transdermal absorption composition comprising the complex according to any one of claims 1 to 7, a transdermal absorption control agent, and a fat-soluble medium. The transdermal absorption composition according to claim 8, wherein the complex is dissolved in the fat-soluble medium. The composition according to claim 8 or 9, wherein the fat-soluble medium is a transdermal absorption-promoting fat-soluble medium. The composition according to claim 10, wherein the transdermal absorption-promoting fat-soluble medium is selected from the group consisting of isopropyl myristate, olive oil, cyclopentasiloxane, squalane, and limonene. A composition comprising minoxidil, a fat-soluble compound having a ketone group, and a transdermal absorption control agent. 12. The composition of claim 12, further comprising a fat-soluble medium. The compositions according to claims 8 to 13, wherein the transdermal absorption control agent is alcohol. The composition according to claim 14, wherein the alcohol is selected from the group consisting of ethanol, geraniol, citronellol, and 1,2-hexanediol. A method for controlling the release of minoxidil from the complex into the skin, which comprises a step of dissolving the complex according to any one of claims 1 to 7 in a transdermal absorption control agent. A method for releasing the minoxidil from the complex into the skin, which comprises a step of dissolving the complex according to any one of claims 1 to 7 in a transdermal absorption control agent. A method for releasing the minoxidil in the skin from a composition containing minoxidil, a fat-soluble compound having a ketone group, and a transdermal absorption control agent. A method for producing a complex formed through an interaction between minoxidil and a fat-soluble compound having a ketone group, which comprises a step of mixing minoxidil powder and a fat-soluble compound having a ketone group. Production of a composition containing the minoxidil, the fat-soluble compound having a ketone group, and the transdermal absorption control agent, which comprises a step of mixing a minoxidil powder, a fat-soluble compound having a ketone group, and a transdermal absorption control agent. Method. The complex according to claim 1, wherein the essential oil contains the fat-soluble compound having a ketone group. The complex according to claim 21, wherein the essential oil is camphor tree or sage.

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