JPWO2019022249A1 - Transdermal composition with controlled release of minoxidil - Google Patents

Abstract

An object of the present invention is to provide a method for easily increasing the transdermal absorbability of minoxidil without using a prodrug by organic synthesis. The present invention includes a complex formed by a minoxidil and a fat-soluble compound having an aldehyde group through an interaction capable of dissociating in water; A transdermal composition; as well as a method of controlling the release of minoxidil in the skin from the complex.

Description

The present invention relates to a transdermal absorption composition with controlled release of minoxidil in the skin, and a method for controlling minoxidil in the skin.

In recent years, research on transdermal absorption technology in which an active ingredient is absorbed from the skin to induce it to directly act on the skin has been advanced.
In particular, for water-soluble drugs, it is difficult to penetrate into the stratum corneum, which has high fat-solubility, and one of the methods for increasing its transdermal absorbability is fat-solubilization (oil-solubilization) of water-soluble drugs. Has been. For example, a fat-solubilized site is introduced into a water-soluble drug by organic synthesis (prodrug formation), dissolved and dispersed in an oil-and-fat base material, and applied to the skin. After permeating the stratum corneum, the bond between the water-soluble drug and the fat-soluble site is cleaved 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 enclosed in liposomes, dissolved/dispersed in an oil/fat base material and applied to the skin. After permeating the stratum corneum, the liposome interface is disrupted by enzymes and the like inside the skin, and the water-soluble drug is released.

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

JP, 2013-241459, A International publication number WO2012/043701 JP, 2010-100650, A Patent No. 5680197 JP, 2010-6771, A

Prodrug formation is an excellent method for imparting lipophilicity to water-soluble drugs and increasing percutaneous absorption, but it is a complicated process for obtaining a manufacturing process for organic synthesis and approval for the manufacture and sale of drugs and quasi drugs. Is required.

On the other hand, as a drug that is converted into a prodrug or encapsulated in liposomes, for example, an artificial amino acid, tranexamic acid, inhibits melanin production by binding to the proteolytic enzyme plasmin and inhibiting activation in the epidermis. Is known to do. Utilizing this action, the whitening effect has recently been proclaimed, and has attracted attention as a raw material for cosmetics. However, there is a problem that tranexamic acid has low skin permeability.

It is an object of the present invention to provide a method for easily increasing the transdermal absorbability of minoxidil without using a prodrug by organic synthesis.

As a result of earnest research, the present inventors have found that minoxidil easily forms a complex with a fat-soluble compound having an aldehyde group through a reversible interaction that can be dissociated in water. The present invention has been completed by finding that minoxidil can be easily released in the skin while imparting lipophilicity to enhance its transdermal absorbability.

That is, the present invention is
(1) A complex formed by minoxidil and a fat-soluble compound having an aldehyde group through an interaction capable of dissociating in water;
(2) The fat-soluble compound having an aldehyde group, the terpene having an aldehyde group, a lignoid having an aldehyde group, and one or more selected from the group consisting of vanilloids having an aldehyde group, the complex according to (1);
(3) The complex according to (2) above, wherein the terpene having an aldehyde group is citral or citronellal;
(4) The complex according to (2), wherein the lignoid having an aldehyde group is cinnamaldehyde;
(5) The complex according to (2) above, wherein the vanilloid having an aldehyde group is vanillin;
(6) The complex according to (1), wherein the fat-soluble compound having an aldehyde group is dodecanal or 4-butoxybenzaldehyde;
(7) A percutaneous absorption composition containing the complex according to any one of (1) to (6), a percutaneous absorption control agent, and a fat-soluble medium;
(8) The transdermal absorption composition according to (7) above, wherein the complex is dissolved in the fat-soluble medium;
(9) The composition according to (7) or (8), wherein the fat-soluble medium is a percutaneous absorption-promoting fat-soluble medium;
(10) The composition according to (9), wherein the percutaneous absorption-promoting fat-soluble medium is one or more selected from the group consisting of isopropyl myristate, cyclopentasiloxane, squalane, and limonene;
(11) A composition comprising minoxidil, a fat-soluble compound having an aldehyde group, and a transdermal absorption controller;
(12) The composition according to (11) above, which further contains a fat-soluble medium;
(13) The composition according to the above (7) to (12), wherein the percutaneous absorption control agent is alcohol.
(14) The composition according to (13) above, wherein the alcohol is one or more selected from the group consisting of ethanol, geraniol, citronellol, and 1,2-hexanediol;
(15) Controlling the release of minoxidil in the skin from the complex, which comprises a step of dissolving the complex according to any one of (1) to (6) in a transdermal absorption controller. Method;
(16) A method of releasing the minoxidil from the complex in the skin, comprising a step of dissolving the complex according to any one of (1) to (6) in a transdermal absorption controller;
(17) A method of releasing minoxidil into the skin from a composition containing minoxidil, a fat-soluble compound having an aldehyde group, and a transdermal absorption controller;
(18) comprising a step of mixing a powder of minoxidil and a fat-soluble compound having an aldehyde group, a complex formed through an interaction capable of dissociating in water by the minoxidil and the fat-soluble compound having an aldehyde group Manufacturing method of;
(19) A step of mixing a powder of minoxidil, an oil-soluble compound having an aldehyde group, and a transdermal absorption controller, the composition containing the minoxidil, the oil-soluble compound having an aldehyde group, and the transdermal absorption controller. Manufacturing method of goods;
(20) The complex according to (1) above, wherein the essential oil contains a fat-soluble compound having the aldehyde group.
(21) The complex according to (20) above, wherein the essential oil is lemongrass or citronella;
Regarding

In the complex of the present invention, minoxidil and a fat-soluble compound having an aldehyde group are complexed via an interaction capable of dissociating in water, and therefore, the complex is uniformly dissolved in the fat-soluble medium (lipid-solubilized or oil-solubilized). As a result, the transdermal absorbability of the minoxidil can be improved, and after passing through the stratum corneum, minoxidil can be released by water in the skin to exert a medicinal effect.
Further, in the present invention, the release of minoxidil from the complex in the skin can be controlled by appropriately using a percutaneous absorption control agent.

It is a figure which shows the amount of minoxidil in pig skin when changing a fat-soluble medium. It is a figure which shows the amount of minoxidil in a receiver liquid when changing a fat-soluble medium. It is a figure which shows the amount of minoxidil in pig skin when changing the amount of citral. It is a figure which shows the amount of minoxidil in a receiver liquid when changing the amount of citral. It is a figure which shows the amount of minoxidil in pig skin when changing the amount of minoxidil. It is a figure which shows the amount of minoxidil in a receiver liquid when changing the amount of minoxidil. It is a figure which shows the amount of minoxidil in pig skin per 1 piece of tapes. It is a figure which shows the amount of minoxidil in pig skin and a receiver liquid. It is a figure which shows the amount of various aldehydes in pig skin per piece of tape. It is a figure which shows the amount of various aldehydes in a pig skin and a receiver liquid.

In the complex of the present invention, minoxidil and a fat-soluble compound having an aldehyde group are complexed via an interaction capable of dissociating in water. Therefore, the complex of the present invention can be in a chemical equilibrium relationship with the fat-soluble compound having minoxidil and the aldehyde group, and as a result, it is fat-solubilized by solvation or cluster formation in the fat-soluble medium. On the other hand, it can exist stably, but inside the skin, it is easily dissociated by water contained therein to release minoxidil, so that it can exert a drug effect.

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 may be an active ingredient such as a water-soluble drug or cosmetic which is capable of forming a complex with a fat-soluble compound having an aldehyde group through an interaction capable of dissociating in water. There is no particular limitation, and any water-soluble active ingredient of pharmaceuticals or cosmetics, such as amino acids, hydrophilic vitamins, sugars, peptides and other hydrophilic drugs can be used.
Examples of such water-soluble active ingredients of the present invention include those having an amino group, a hydroxyl group, or a thiol group. These groups are, respectively, an interaction capable of dissociating in water with the aldehyde group of the fat-soluble compound having an aldehyde group, for example, an ionic bond, a hydrogen bond, a dipole interaction, a Van der Waals force, a charge transfer interaction. , Π-π interaction, hydrophobic interaction, solvation, and reversible chemical bond can be formed.

Examples of the amino acid include artificial amino acids such as tranexamic acid; and alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan. , Natural amino acids such as tyrosine, and valine.

Examples of the hydrophilic vitamins include ascorbic acid, sodium ascorbyl phosphate, magnesium ascorbyl 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 peptides include known peptides as well as peptides having a specific effect (for example, since they are recognized by human T cells, a therapeutic effect on pollinosis is expected). Specific examples are peptide A (amino acid sequence: QFAKLGTGFTLMG) and peptide B (amino acid sequence: SMKVTVAFNQFGP).

Examples of the hydrophilic drug include zanamivir (relenza), acyclovir, cytarabine ocfosfate, and fludarabine phosphate.

The fat-soluble compound having an aldehyde group of the present invention is not particularly limited as long as it is a fat-soluble compound containing at least one aldehyde group, and any compound containing an aliphatic aldehyde or an aromatic aldehyde can be used. .. Among them, terpenes having an aldehyde group, lignoides having an aldehyde group, vanilloids having an aldehyde group, and the like are preferable from the viewpoint of natural origin and safety.

Examples of the terpene having an aldehyde group include citral, citronellal, cyclocitral, safranal, ferrandral, perylaldehyde, tagetone, and retinal, and from the viewpoint of satisfactorily fat-solubilizing minoxidil, citral and citronellal are preferable, Further, a natural product such as an essential oil containing the above compound (essential oil) may be used. Lemongrass or citronella is preferable from the viewpoint of satisfactorily fat-solubilizing 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 an aldehyde group of the present invention is contained.
Lemongrass is, for example, a mixture of citral (50 to 80%) as a main component and geraniol (3 to 10%), farnesol, nerol, citronellol and myrcene.
As an example, citronella is a mixture of geraniol as a main component (10 to 60%), citronellol (3 to 10%), citronellal (1 to 30%) and the like.

As the lignoid having an aldehyde group, cinnamaldehyde is preferable from the viewpoint of satisfactorily fat-solubilizing minoxidil.

As the vanilloid having an aldehyde group, vanillin is preferable from the viewpoint of satisfactorily fat-solubilizing minoxidil.

As the above-mentioned aliphatic aldehyde or aromatic aldehyde, dodecanaal or 4-butoxybenzaldehyde is also preferable from the viewpoint of satisfactorily fat-solubilizing minoxidil.

In the present invention, the fat-soluble compound having an aldehyde group may be used alone or in combination of two or more kinds.
The fat-soluble compound having an aldehyde group of the present invention is particularly preferably citral or citronellal from the viewpoint of satisfactorily fat-solubilizing minoxidil.

The percutaneous absorption control agent of the present invention is not particularly limited as long as it is conventionally used for controlling percutaneous absorption of an active ingredient of a water-soluble drug or cosmetic in the field of medicines and cosmetics, particularly external skin preparations. From the viewpoint that the complex of the present invention can be satisfactorily stabilized in a fat-soluble medium, a transdermal absorption controller having a hydroxyl group is preferable, and a monohydric or polyhydric alcohol is particularly preferably used.
The complex of the present invention may be a complex of minoxidil, a lipid-soluble compound having an aldehyde group, and a transdermal absorption controller through an interaction capable of dissociating in water. With such a complex, the release of minoxidil in the skin is better controlled.

Examples of the monohydric alcohol include lower alcohols such as methanol, ethanol, 1-propanol, and 2-propanol; higher alcohols; and nerolidol, geraniol, menthol, borneol, isoborneol, nerol, citronellol, fentyl. Examples thereof include terpenes having a hydroxyl group such as alcohol, carveol, and neomenthol, and preferably methanol, ethanol, citronellol, and geraniol.

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 oxochol 180 (FO180). :

And saturated alcohols having 8 to 18 carbon atoms; and oleyl alcohol, linoleyl alcohol, and unsaturated alcohols having 8 to 18 carbon atoms such as linolenyl alcohol. Preferable examples include octanol, decanol, lauryl alcohol, myristyl alcohol, and oleyl alcohol, and more preferable examples include oleyl alcohol.

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

The complex of the present invention can be simply prepared by mixing the minoxidil and the fat-soluble compound having the aldehyde group, and heating and cooling for a certain period of time if necessary. From the viewpoint that the complex can be satisfactorily obtained, it is preferable to add and mix the percutaneous absorption controlling agent of the present invention, particularly the liquid percutaneous absorption controlling agent. In addition, it is preferable that the percutaneous absorption control agent of the present invention is in a liquid state 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 the preparation of the percutaneous absorption composition of the present invention.
When minoxidil is solid (preferably crystalline), it is preferable to mix it in powder form in order to obtain the complex of the present invention well. Examples of the method for making powder include a method by dry pulverization. The conditions for dry crushing are not particularly limited as long as minoxidil can be crushed into small pieces, but it is preferable to use a crusher such as a mortar, a ball mill, a homogenizer, a cutter mill, and a hammer mill. Further, the crushing time, the processing pressure, etc. are appropriately adjusted according to the hardness of minoxidil to be crushed.
It is desirable that the powder obtained by the above method is further sieved in order to make the particle diameter 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 and the fat-soluble compound having an aldehyde group varies depending on the type of these substances used, but is 1:1 to 100, preferably 1:10 to 50.
When the percutaneous absorption control agent is also mixed, the mixing ratio of the minoxidil, the fat-soluble compound having an aldehyde group, and the percutaneous absorption control agent varies depending on the type of these substances used, but is 1:1. ˜100:1 to 100, preferably 1:1 to 100:10 to 50, and more preferably 1:10 to 50:10 to 50.
The composition ratio (molar ratio) of the fat-soluble compound having the minoxidil and the aldehyde group, which constitutes the complex of the present invention, is 1 to 100:100 to 1, and more preferably 1 to 10:10 to 1. is there.

In the present invention, by appropriately using the above-mentioned percutaneous absorption control agent, particularly monohydric or polyhydric alcohol, for example, depending on the type and amount of use of these percutaneous absorption control agents, The release of minoxidil from the complex of the invention can be controlled. For example, by increasing the lipid solubility of the percutaneous absorption control agent (for example, by increasing the carbon number), the release of minoxidil of the present invention can be delayed, and the lipid solubility of the percutaneous absorption control agent is decreased. The release of the minoxidil of the present invention can be promoted by doing so (for example, by reducing the carbon number). The present invention also relates to a method for controlling the release of minoxidil in the skin from the complex, which comprises the step of dissolving the complex of the present invention in a percutaneous absorption control agent. The present invention also relates to the use of a percutaneous absorption control agent for controlling the release of minoxidil in the skin from the complex of the present invention.

In the present invention, the above percutaneous absorption control agents may be used alone or in combination of two or more kinds.

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

Isopropyl myristate (IPM), squalane, squalane, squalene, silicone oil, jojoba oil, almond oil, olive oil, horse oil, mineral oil and the like can be used, preferably isopropyl myristate (IPM), cyclopenta Siloxane, squalane, limonene (especially R-(+)-limonene) can be used.
In the present invention, the fat-soluble medium may be used alone or in combination of two or more kinds.

The percutaneous absorption composition of the present invention can be prepared by mixing the solution of the percutaneous 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 controller. From this viewpoint, for example, when the fat-soluble medium is squalane, geraniol or citronellol is preferable as the percutaneous absorption control agent, and when the fat-soluble medium is IPM, ethanol or 1,2-hexanediol is preferable as the percutaneous absorption control agent. When the fat-soluble medium is KF995, geraniol or citronellol is preferable as the transdermal absorption controller.

When the percutaneous absorption composition of the present invention is used as a medicine or a cosmetic, it may be used as such, but it may also be used as a conventional pharmaceutical preparation, especially as 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, disintegrators, emulsifiers, stabilizers, flavors, diluents, etc. as long as the effects of the present invention are not impaired. The additive may be included.
The external preparation for skin of the present invention may contain components that can be usually added to the external preparation for skin, as long as the effects of the present invention are not impaired. Such components include glycerin, polyhydric alcohols such as propylene glycol, liquid paraffin, squalane, higher fatty acids, oils such as higher alcohols, citric acid, organic acids such as lactic acid, caustic soda, alkalis such as triethanolamine, Cationic surfactant, amphoteric surfactant, nonionic surfactant, powder, pigment, dye, antiseptic and fungicide, resin, pH adjusting agent, antioxidant, ultraviolet absorber, chelating agent, thickener, Moisturizers, alcohol, water, fragrances, etc. are exemplified.
The present invention also relates to a method for transdermal administration of said minoxidil, 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 transdermally administering said minoxidil.

Further, the composition of the present invention may be a composition containing the minoxidil, the fat-soluble compound having an aldehyde group, and the transdermal absorption controller, 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 said 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 said minoxidil.

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

1. Reagents and Equipment The reagents used in the examples are shown below.
Squalane (first grade), citronellol (first grade), ethanol (special grade), isopropyl myristate (IPM) (special grade), 1×PBS, 1-dodecanal, cinnamaldehyde (special grade), (R)-(+)-limonene (first grade) ) And ammonium formate (special grade) were obtained from Wako Pure Chemical Industries, Ltd. Minoxidil, vanillin, (−)-citronellal, citral (cis-and trans-mixture), geraniol, 4-butoxybenzaldehyde and minoxidil were obtained from Tokyo Chemical Industry Co., Ltd. Acetonitrile (for high performance liquid chromatography) and methanol (for high performance liquid chromatography) were obtained from Kanto Chemical Co., Inc. KF995 was obtained from Shin-Etsu Silicone Co., Ltd.
The apparatus used for the analysis is shown below.
Liquid chromatograph mass spectrometer (LC/MS)
Equipment: e2695 (LC part), 2489 (UV-Vis detector), 3100 Mass Detector, Nippon Waters Co., Ltd. high performance liquid chromatography (HPLC)
Equipment: 1200 series, manufactured by Agilent Technology Co., Ltd.

2. Preparation Example of Transdermal Absorption Composition Containing Minoxidil Oil-Solubilized with Aromatic Aldehyde or Aliphatic Aldehyde To a 4 mL screw cap sample tube, 50 mg of minoxidil, 200 mg of each aldehyde shown in Table 1, and 2 mL of ethanol were added, and the mixture was heated at 80°C. It was heated at. After heating, 0.5 mL of the obtained homogenized ethanol solution was added to a separately prepared 4 mL screw cap sample tube, and 0.5 mL of isopropyl myristate (IPM) was added thereto to prepare Comparative Example 1 and Examples 1 to 1. The transdermal absorption composition of 6 was prepared.
The presence or absence of oil solubilization was confirmed by observing the dispersion state of these Examples and Comparative Examples 1 hour after the addition of IPM. The results are shown in Table 1.

From the results in Table 1, it was found that the time for preparing a homogeneous ethanol solution of minoxidil can be shortened by adding various aldehydes. In addition, in Comparative Example 1 in which no aldehyde was added, precipitation was observed after preparation of the ethanol solution, whereas in Examples 1 to 6 in which various aldehydes were added, no precipitation was observed, and even when mixed with IPM. A homogeneous solution could be prepared.

3. Solubility test of minoxidil ethanol solution prepared by stirring at room temperature in various fat-soluble media Minoxidil 40 mg, vanillin 200 mg, and ethanol 2 mL were added to a 4 mL screw cap sample tube, and the mixture was stirred at room temperature for 2 hours. After stirring, 0.5 mL of the resulting homogenized ethanolic solution of minoxidil was added to four 4 mL screw cap sample tubes separately prepared, and isopropyl myristate (IPM) and cyclopentasiloxane ( KF995) and (R)-(+)-limonene (0.5 mL each) were added and mixed with a vortex mixer to prepare transdermal absorption compositions of Examples 7 to 9.
The presence or absence of oil solubilization was confirmed by observing the dispersion state of these Examples after 1 hour of mixing. The results are shown in Table 2.

From the results in Table 2, it was found that a homogeneous ethanol solution of minoxidil can be prepared by stirring at room temperature. Further, it was found that the prepared vanillin-added minoxidil-containing ethanol solution can be prepared as a colorless transparent solution by mixing with various fat-soluble media.

4. Transdermal absorbability test of minoxidil oil-solubilized solution 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, an oil-solubilized solution of minoxidil was used to conduct a percutaneous absorption test on whether or not minoxidil is released in an aqueous PBS solution after breaking through the skin barrier.
The percutaneous absorption composition used in this experiment was citral (40 mg) in minoxidil (40 mg) using a 50% ethanol solution of minoxidil (comparative example 2) in which ethanol (2 mL) and water (2 mL) were added to minoxidil (40 mg). 200 mg), ethanol (2 mL), and IPM (2 mL) oil-solubilized solution (Example 10), and minoxidil (40 mg) vanillin (200 mg), ethanol (2 mL), and IPM (2 mL) oil-solubilized solution. (Example 11) was prepared and their transdermal absorbability was evaluated by the following transdermal absorbability test.
The transdermal absorption test was conducted as follows. Pig skin (Yucatan Micro Pig (manufactured by Charles River Japan)) was used for the transdermal absorption test. A stirrer and 5 mL of a PBS aqueous solution were added to the receiver phase of the Franz cell, the pig skin was sandwiched between the PBS aqueous solution upper portions, and water at 37° C. was poured into the water jacket section of the Franz cell. 200 μL of a 50% aqueous solution of minoxidil in ethanol (Comparative Example 2) or 200 μL of an ethanol/IPM solution (Examples 10 and 11) in which citral or vanillin was added to minoxidil was placed on the pig skin, and the receiver phase was stirred. After 24 hours, a methanol extract of pig skin and a PBS aqueous solution of a receiver phase were sampled, and the amount of minoxidil was quantified by LC/MS. The LC/MS measurement conditions are as follows. Shodex Asahipak NH2P-40 2D (2.0 mm ID x 150 mm) was used for the column, and the column temperature was set to 30°C. As the eluent, 10 mM ammonium formate/acetonitrile (10/90, v/v/l) was used, and the flow rate was set to 0.2 mL/min. The detected mass number was 210. The results are shown in Table 3.

As a result, the amount of minoxidil in pig skin was about 22 times that of citral addition (Example 10) and about 19 times that of vanillin addition (Example 11), as compared to the 50% ethanol aqueous solution of minoxidil (Comparative Example 2). In the receiver solution, the citral addition (Example 10) was about 51 times, and the vanillin addition (Example 11) was about 53 times.
From these results, it was shown that the minoxidil oil-solubilized solution added with aldehyde promotes percutaneous absorption and is promising as a transdermal drug delivery system (DDS) material.

5. Effects of various fat-soluble media on percutaneous absorption We examined how the types of fat-soluble media affect percutaneous absorption.
The transdermal absorption composition used in this experiment was prepared as follows. 40 mg of minoxidil, 200 mg of citral and 2 mL of ethanol were added to the sample tube, and the mixture was stirred at room temperature for 1 hour. After 1 hour, 2 mL of the solvent shown in Table 4 was added to the prepared ethanol solution and shaken with a vortex mixer to prepare transdermal absorption compositions of Comparative Example 3 and Examples 12-14.

The transdermal absorption test was conducted as follows. Pig skin (Yucatan Micro Pig (manufactured by Charles River Japan)) was used for the transdermal absorption test. A stirrer and 5 mL of a PBS aqueous solution were added to the receiver phase of the Franz cell, the pig skin was sandwiched between the PBS aqueous solution upper portions, and water at 37° C. was poured into the water jacket of the Franz cell. Comparative Example 3 and Examples 12-14 (200 μL) shown in Table 4 were placed on porcine skin and the receiver phase was stirred. After 24 hours, a methanol extract of pig skin and a PBS aqueous solution of a receiver phase were sampled, and the amount of minoxidil was quantified by LC/MS. The LC/MS measurement conditions are as follows. Shodex Asahipak NH2P-40 2D (2.0 mm I.D. x 150 mm) was used for the column, and the column temperature was set to 30°C. As the eluent, 10 mM ammonium formate/acetonitrile (10/90, v/v/l) was used, and the flow rate was set to 0.2 mL/min. The detected mass number was 210. The results are shown in Figures 1 and 2.

As a result, as compared with Comparative Example 3 containing no fat-soluble medium, the solution to which the fat-soluble medium IPM (Example 12), KF995 (Example 13), and limonene (Example 14) was added was The transdermal absorbability was improved both in pig skin and in receiver solution. From this, it was found that the solution using the fat-soluble medium improves the transdermal absorbability.

6. Evaluation of percutaneous absorbability when the amount of citral was changed The percutaneous absorbability when the amount of citral used as a fat-soluble compound having an aldehyde group was changed was evaluated.
The transdermal absorption composition used in this experiment was prepared as follows. 40 mg of minoxidil, the amount of citral shown in Table 5, and 2 mL of ethanol were added to a sample tube, and the mixture was stirred at room temperature for 1 hour. After 1 hour, 2 mL of IPM was added to the prepared ethanol solution, and the mixture was shaken with a vortex mixer to prepare transdermal absorption compositions of Examples 15 and 16.

The transdermal absorption test was conducted as follows. Pig skin (Yucatan Micro Pig (manufactured by Charles River Japan)) was used for the transdermal absorption test. A stirring bar and 5 mL of a PBS aqueous solution were added to the receiver phase of the Franz cell, pig skin was sandwiched between the PBS aqueous solution upper portions, and water at 37° C. was poured into the water jacket of the Franz cell. Comparative Example 4 and Examples 15 and 16 (200 μL) shown in Table 5 were placed on pig skin and the receiver phase was stirred. After 24 hours, a methanol extract of pig skin and a PBS aqueous solution of the receiver phase were sampled, and the amount of minoxidil was quantified by LC/MS. The LC/MS measurement conditions are as follows. Shodex Asahipak NH2P-40 2D (2.0 mm I.D. x 150 mm) was used for the column, and the column temperature was set to 30°C. As the eluent, 10 mM ammonium formate/acetonitrile (10/90, v/v/l) was used, and the flow rate was set to 0.2 mL/min. The detected mass number was 210. The results are shown in Figures 3 and 4.

As a result, when compared with Comparative Example 4 in which the additive amount of the fat-soluble medium was not included, both when the citral addition amount was 200 mg (Example 15) and when the citral addition amount was 1000 mg (Example 16) The transdermal absorbability was improved. Comparing Example 15 and Example 16, the release ability of minoxidil in porcine skin of Example 16 is low with the decrease of the solution concentration, while the amount of minoxidil in the receiver solution is high in Example 16. Became. This can be considered that the addition of citral promotes penetration into deep skin.

7. Evaluation of transdermal absorbability when minoxidil amount was changed. Transdermal absorbability when minoxidil amount was changed was evaluated.
The transdermal absorption composition used in this experiment was prepared as follows. The amounts of minoxidil, 200 mg of citral, and 2 mL of ethanol shown in Table 6 were added to a sample tube, and the mixture was stirred at room temperature for 1 hour. After 1 hour, 2 mL of IPM was added to the prepared ethanol solution and shaken with a vortex mixer to prepare transdermal absorption compositions of Examples 17 to 19.

The transdermal absorption test was conducted as follows. Pig skin (Yucatan Micro Pig (manufactured by Charles River Japan)) was used for the transdermal absorption test. A stirring bar and 5 mL of a PBS aqueous solution were added to the receiver phase of the Franz cell, pig skin was sandwiched between the PBS aqueous solution upper portions, and water at 37° C. was poured into the water jacket of the Franz cell. Examples 17-19 (200 μL) shown in Table 6 were placed on pig skin and the receiver phase was agitated. After 24 hours, a methanol extract of pig skin and a PBS aqueous solution of the receiver phase were sampled, and the amount of minoxidil was quantified by LC/MS. The LC/MS measurement conditions are as follows. Shodex Asahipak NH2P-40 2D (2.0 mm I.D. x 150 mm) was used for the column, and the column temperature was set to 30°C. As the eluent, 10 mM ammonium formate/acetonitrile (10/90, v/v/l) was used, and the flow rate was set to 0.2 mL/min. The detected mass number was 210. The results are shown in Figures 5 and 6.

As a result, it was found that the transdermal absorbability was improved in the pig skin and the receiver solution in proportion to the amount of minoxidil.

8. Tape Stripping Method Test The tape stripping method was used to evaluate where the various aldehydes used as fat-soluble compounds having minoxidil and aldehyde groups are scattered.
The transdermal absorption composition used in this experiment was prepared as follows. 40 mg of minoxidil, 200 mg of each aldehyde shown in Table 7, and 2 mL of ethanol were added to a sample tube, and the mixture was stirred at room temperature for 1 hour. After 1 hour, 2 mL of IPM was added to the prepared ethanol solution and shaken with a vortex mixer to prepare transdermal absorption compositions of Examples 20 and 21.

The transdermal absorption test was conducted as follows. Pig skin (Yucatan Micro Pig (manufactured by Charles River Japan)) was used for the transdermal absorption test. A stirrer and 5 mL of a PBS aqueous solution were added to the receiver phase of the Franz cell, the pig skin was sandwiched between the PBS aqueous solution upper portions, and water at 37°C was flown through the water jacket of the Franz cell. Comparative Example 5 and Examples 20 and 21 (200 μL) shown in Table 7 were placed on pig skin and the receiver phase was stirred. After 24 hours, the surface of pig skin was washed with 80% ethanol, and then tape stripping was performed from the skin surface (the tape used was Nichiban Co., Ltd. plant-based Sellotape (registered trademark) (18 mm×35 m)). Samples were placed in microtubes in the categories shown in Table 8, and methanol was added to extract each component. The methanol extract and the PBS aqueous solution of the receiver phase were sampled, and the amount of minoxidil was quantified by LC/MS and various aldehydes were quantified by HPLC. The LC/MS measurement conditions are as follows. Shodex Asahipak NH2P-40 2D (2.0 mm ID x 150 mm) was used for the column, and the column temperature was set to 30°C. As the eluent, 10 mM ammonium formate/acetonitrile (10/90, v/v/l) was used, and the flow rate was set to 0.2 mL/min. The detected mass number was 210. The HPLC measurement conditions are as follows. GL Sciences Intersil ODS-4 5 mm (4.6 x 250 mm) was used for the column, and the column temperature was set to 40°C. Methanol/water (60/40, v/l/v) was used as the eluent, and the flow rate was set to 1 mL/min. The detection wavelength was 240 nm for citral and 310 nm for vanillin. The results are shown in FIGS.

Regarding the amount of permeation of minoxidil, from Fig. 7 and Fig. 8, more minoxidil was detected in the lower portion of the stratum corneum when citral was added (Example 20). On the other hand, when vanillin was added (Example 21), minoxidil was detected from the upper part of the stratum corneum. Regarding the amount of permeation of aldehyde, from FIGS. 9 and 10, citral (Example 20) was not detected in the stratum corneum or the receiver liquid, but was detected in the layer below the stratum corneum. On the other hand, vanillin (Example 21) was detected not only under the stratum corneum but also in the stratum corneum and the receiver liquid.

From the above results, since citral was detected in the lower part of the stratum corneum when citral was added, it can be considered that the structure of the minoxidil-citral complex collapses in the lower part of the stratum corneum and releases minoxidil. On the other hand, when vanillin was added, since vanillin was detected in a wide range from the stratum corneum to the receiver, it can be considered that the minoxidil-vanillin complex collapses from the upper portion of the stratum corneum and releases minoxidil. This experiment revealed that citral and vanillin have different skin permeation capacities for minoxidil.

The complex of the present invention improves the transdermal absorbability of minoxidil, increases the content in the skin, and also releases minoxidil due to water and acidic conditions inside the skin, which can exert a medicinal effect, The percutaneous absorption composition of the present invention containing such a complex can be applied to a skin external preparation, for example, a drug or cosmetic used for skin external therapy.
Further, by appropriately using a percutaneous absorption control agent, the release of minoxidil from the complex of the present invention inside the skin is controlled, and thus it can be used for a drug delivery system.

Claims (21)

A complex formed by minoxidil and a fat-soluble compound having an aldehyde group through an interaction capable of dissociating in water. The complex according to claim 1, wherein the fat-soluble compound having an aldehyde group is selected from the group consisting of a terpene having an aldehyde group, a lignoid having an aldehyde group, and a vanilloid having an aldehyde group. The complex according to claim 2, wherein the terpene having an aldehyde group is citral or citronellal. The complex according to claim 2, wherein the lignoid having an aldehyde group is cinnamaldehyde. The complex according to claim 2, wherein the vanilloid having an aldehyde group is vanillin. The complex according to claim 1, wherein the fat-soluble compound having an aldehyde group is dodecanal or 4-butoxybenzaldehyde. A percutaneous absorption composition comprising the complex according to any one of claims 1 to 6, a percutaneous absorption control agent, and a fat-soluble medium. The transdermal absorption composition according to claim 7, wherein the complex is dissolved in the fat-soluble medium. The composition according to claim 7 or 8, wherein the fat-soluble medium is a transdermal absorption-promoting fat-soluble medium. The composition according to claim 9, wherein the percutaneous absorption-promoting fat-soluble medium is selected from the group consisting of isopropyl myristate, cyclopentasiloxane, squalane, and limonene. A composition comprising minoxidil, a fat-soluble compound having an aldehyde group, and a transdermal absorption controller. The composition according to claim 11, further comprising a fat-soluble medium. The composition according to claim 7, wherein the percutaneous absorption control agent is alcohol. 14. The composition of claim 13, wherein the alcohol is one or more selected from the group consisting of ethanol, geraniol, citronellol, and 1,2-hexanediol. A method for controlling the release of minoxidil in the skin from the complex, which comprises the step of dissolving the complex according to any one of claims 1 to 6 in a percutaneous absorption control agent. A method for releasing the minoxidil from the complex in the skin, which comprises the step of dissolving the complex according to any one of claims 1 to 6 in a percutaneous absorption control agent. A method of releasing minoxidil in the skin from a composition containing minoxidil, a fat-soluble compound having an aldehyde group, and a transdermal absorption controller. A method for producing a complex, which comprises the step of mixing a powder of minoxidil and a fat-soluble compound having an aldehyde group, through an interaction capable of dissociating in water by the minoxidil and the fat-soluble compound having an aldehyde group. .. Production of a composition containing the minoxidil, the fat-soluble compound having an aldehyde group, and the transdermal absorption controller, including a step of mixing a powder of minoxidil, a fat-soluble compound having an aldehyde group, and a transdermal absorption controller. Method. The complex according to claim 1, wherein the essential oil contains a fat-soluble compound having the aldehyde group. 21. The complex of claim 20, wherein the essential oil is lemongrass or citronella.