JPH083072A - Percutaneous absorbefacient and external agent for skin - Google Patents

Abstract

PURPOSE:To provide a percutaneous absorbefacient composed of a specific phosphatidyl-serine, having excellent safety and percutaneous absorbefacient action and useful as a compounding agent for external agent for skin. CONSTITUTION:This absorbefacient is composed of a compound of formula (R1 and R2 are each a 13-21C acyl and at least one of R1 and R2 is a group having unsaturated bond such as oleic acid residue, linoleic acid residue or linolenic acid residue), e.g. dioleylphosphatidyl-serine or dilinoleylphosphatidyl- serine. The compound of formula can be produced e.g. by extracting bovine brain or chicken egg with an organic solvent such as ether, THF or chloroform and purifying by (octadecyl)silica gel column chromatography, etc. The external agent for skin to be compounded with the absorbefacient contains anti- inflammatory analgesic agent, antimycotic agent, antibacterial agent, etc., as active component and the amount of the active component and the absorbefacient is 0.01-10wt.% each based on the total amount of the external agent.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a percutaneous absorption enhancer and a skin external preparation containing the same, and more particularly to a percutaneous absorption enhancer comprising phosphatidylserine and a skin external preparation containing the same.

[0002]

2. Description of the Related Art A drug treatment using a transdermal route of administration for inflammation near the skin or a disease on the skin is more effective than gastrointestinal administration such as oral administration or intravascular administration such as intravenous injection. It has been widely and more frequently used since ancient times because it has many advantages such as being less likely to be metabolized by or being less likely to cause side effects. Examples of successful drug treatments using such a transdermal administration route include a skin external preparation of indomethacin, which has significantly reduced side effects such as gastric ulcer frequently occurring during oral administration by transdermal administration.

However, since the skin is a defense mechanism that protects the living body from the outside world, it is often difficult to transport the drug into the living body by transdermal administration. Currently very few.

Further, attempts have been made to improve percutaneous absorption by using a percutaneous absorption enhancer such as Azone. However, these percutaneous absorption enhancers are considered to be a cause of inflammation because of their safety. However, it has not been used for actual use.

On the other hand, it is known that phosphatidylserine represented by the general formula (I) is widely distributed in the living body, but it is known that this compound has a transdermal absorption promoting action. However, no attempt has been made to increase the drug efficacy by incorporating this into an external preparation for skin.

[0006]

The present invention has been made from the above viewpoints, and provides a percutaneous absorption enhancer which is highly safe and has an excellent action for promoting percutaneous absorption, and a skin external preparation containing the same. The challenge is to provide.

[0007]

Means for Solving the Problems In order to solve the above-mentioned problems, the present inventor has repeatedly screened various substances with the action of promoting transdermal absorption and safety as a result, The present inventors have completed the present invention by discovering a strong dermal absorption promoting action and high safety of phosphatidylserine.

That is, the present invention is a transdermal absorption enhancer comprising phosphatidylserine represented by the following general formula (I) and a skin external preparation containing the same.

[0009]

Embedded image

However, in the formula (I), R ₁ and R ₂ each independently represent an acyl group having 13 to 21 carbon atoms, and R 1
_At least one of ₁ and R ₂ has an unsaturated bond. Less than,
The present invention will be described in detail.

<1> Transdermal Absorption Promoter of the Present Invention The transdermal absorption enhancer of the present invention comprises phosphatidylserine represented by the above general formula (I). Here, in the formula (I), R ₁ and R ₂ are acyl groups constituting the ester portion of the above-mentioned phosphatidylserine, and are each independently a residue of a saturated or unsaturated fatty acid having 13 to 21 carbon atoms. An acyl group consisting of a group, and at least one of R ₁ and R ₂ is an acyl group consisting of a residue of an unsaturated fatty acid.

By esterification, the number of carbon atoms as described above is 13
Examples of the saturated fatty acid to be the acyl group of ~ 21 include, for example,
Examples thereof include tridecanoic acid, myristic acid, palmitic acid, stearic acid and behenic acid. In addition, examples of the unsaturated fatty acid that becomes an acyl group having 13 to 21 carbon atoms by esterification include oleic acid, linoleic acid, linoleic acid, ascleic acid, petroselinic acid, and lithinoleic acid. Preferably, oleic acid, linoleic acid, linoleic acid, etc. can be mentioned.

The phosphatidylserine represented by the above general formula (I) is a compound widely distributed in the living body. For example, beef brain and hen's egg are extracted with an organic solvent such as ether, tetrahydrofuran, chloroform, and silica gel. It can be easily obtained by purification by ordinary means such as column chromatography or octadecyl silica gel column chromatography.

The method for extracting and purifying the phosphatidylserine represented by the general formula (I) from bovine brain is, for example,
Chloroform was added to the homogenate obtained by adding water to bovine brain and homogenizing the mixture, followed by sonication. Then, the mixture was separated, and the chloroform layer was taken out and purified by silica gel column chromatography and high performance liquid chromatography equipped with an ODS column. A method can be mentioned.

Among the phosphatidylserines represented by the above general formula (I) thus obtained, phosphatidylserine having a high content in bovine brain and being easily available is represented by the general formula (I). Wherein R ₁ and R ₂ are both an acyl group consisting of a residue of oleic acid, that is, an oleyl group, dioleylphosphatidylserine, and R ₁ and R _{2 in} the general formula (I) are both linoleic acid residues. The compound dilinoleylphosphatidylserine which is an acyl group consisting of a group, that is, a linoleyl group can be mentioned.

When such a phosphatidylserine represented by the above general formula (I) is used as a transdermal absorption enhancer together with a medicinal component in an external skin preparation, the transdermal absorbability of the medicinal component is enhanced. Is possible. Further, the percutaneous absorption enhancer of the present invention comprising phosphatidylserine represented by the above general formula (I) can exert a large effect by being percutaneously absorbed, but is hardly percutaneously absorbed by itself. The effect can be exerted particularly in the external preparation for skin in which the component is blended as a medicinal component.

Further, as described above, the phosphatidylserine represented by the above-mentioned general formula (I), which is the percutaneous absorption enhancer of the present invention, is a compound widely distributed in the living body, so that it is highly safe. Needless to say.

<2> External preparation for skin of the present invention The external preparation for skin according to the present invention contains a phosphatidylserine represented by the above general formula (I) as a transdermal absorption enhancer together with a medicinal component. is there. The compounding amount of the percutaneous absorption enhancer in the external preparation for skin of the present invention is preferably 0.01 to 10% by weight, and more preferably 1 to 5% by weight based on the total amount of the external preparation for skin. If the blending amount of the transdermal absorption promoter is less than 0.01% by weight, the transdermal absorption promoting action may not be sufficiently obtained, and if it is blended over 10% by weight, the medicinal component and other optional components are blended. The amount is limited, and the function, stability, and feeling of use as a skin external preparation may be impaired.

The medicinal ingredient to be incorporated in the external preparation for skin of the present invention is not particularly limited as long as it is a component used as a medicinal ingredient in the external preparation for skin. For example, an anti-inflammatory analgesic,
Examples thereof include antifungal agents, bactericides, antiviral agents, and the like. Among these medicinal components, in the present invention, antiphlogistic analgesics, antifungal agents, bactericides and the like can be mentioned as preferable medicinal components, and these various medicinal components can also be used alone or as necessary. It is also possible to use two or more kinds of components in combination according to the necessity. Furthermore, the anti-inflammatory analgesic can be said to be the most preferable medicinal component in the present invention. This is because, among the above medicinal components, the site of action of the anti-inflammatory analgesic is the deepest and the highest transdermal absorbability is required.

Examples of the above anti-inflammatory analgesics include indomethacin, methyl salicylate, diclofenac sodium, flufenamic acid, bufexamac, ibuprofen, zaltoprofen, naproxen, flurbiprofen, flurbiprofen axetil, fenbufen, mefenamic acid, Piroxicam, ampiroxicam,
Tenoxicam, felbinac, tocoretinate, hydrocortisone, prednisolone, methylprednisolone,
Preferred examples include steroidal or nonsteroidal compounds such as betamethasone, dexamethasone, triamsilonone, triamsilonone acetonide, flumethasone, fluocinonide, beclomethasone, fluocinolone, fluoxycortide, mometasone, clobetasone, and clobetasol, and derivatives thereof. You can Further, of these, the most preferable anti-inflammatory and analgesic agents are indomethacin and its derivatives, which have large side effects by administration routes other than percutaneous absorption and have insufficient transdermal absorbability.

Derivatives of the various compounds listed as the above anti-inflammatory analgesics are not particularly limited as long as they do not impair the effects of the present invention, for example, physiologically acceptable.
Examples thereof include acid or base salts, esters, ketals, acetals and hemiacetals. These derivatives can be easily obtained by treating the above-mentioned various compounds by a conventional method.

In the external preparation for skin of the present invention, as an anti-inflammatory analgesic, one kind selected from the above various compounds and various derivatives of these compounds may be used alone, or two or more kinds may be used in combination. Is. Further, the compounding amount of the anti-inflammatory analgesic in the external preparation for skin of the present invention largely varies depending on the type of the anti-inflammatory analgesic to be mixed, but is generally 0.01 to 10% by weight, and more preferably the total amount of the external skin preparation. Is 0.1 to 5% by weight.

Examples of the above-mentioned antifungal agents include tolnaftate, clotrimazole, haloprozin, trichomycin, pesimilone, pyrrolenitrin, nystatin,
Exaramide, miconazole nitrate, econazole nitrate,
Preferable examples include isoconazole nitrate, bifonazole, terbinafine and the like and derivatives thereof.

Derivatives of the various compounds listed as the above antifungal agents are not particularly limited as long as they do not impair the effects of the present invention, and for example, physiologically acceptable,
Examples thereof include acid or base salts, esters, ketals, acetals and hemiacetals. These derivatives can be easily obtained by treating the above-mentioned various compounds by a conventional method.

In the external preparation for skin of the present invention, as an antifungal agent, one kind selected from the above-mentioned various compounds and various derivatives of these compounds may be used alone, or two or more kinds may be used in combination. Is. Further, the compounding amount of the antifungal agent in the external preparation for skin of the present invention largely varies depending on the type of the antifungal agent to be mixed, but is generally 0.01 to 10% by weight, and more preferably about the total amount of the external preparation for skin. Is 0.1 to 5% by weight.

Examples of the bactericide include hexachlorophene, resorcin, crystal violet, benzethonium chloride, benzalkonium chloride, chlorhexidine gluconate and the like, and one or more of them may be applied to the skin external preparation of the present invention. Can be blended with. The blending amount is 0.01 to 10% by weight based on the total amount of the external preparation for skin.
Is preferable, and more preferably 0.1 to 5% by weight.

The external preparation for skin of the present invention may contain, in addition to the above-mentioned components, optional components usually contained in external preparations for skin. Such an optional component is not particularly limited as long as it is a component used in the external preparation for skin, for example, lower alcohols such as ethanol and isopropanol, thickeners, oils and fats, higher alcohols and higher fatty acids. , Surfactants, preservatives, antioxidants, UV absorbers,
Colorants, fragrances, water-soluble polymers, powders, adhesives and the like can be mentioned.

The dosage form of the external preparation for skin of the present invention is not particularly limited, and it is usually used as an external preparation for skin such as lotion, aqueous gel, oily gel, cream, emulsion, stick and powder. Dosage forms that have been mentioned. Further, it may be used as a patch to be applied after being spread on a cloth or a polymer sheet.

Regarding the dose of the external preparation for skin of the present invention, an appropriate amount may be administered several times a day to the affected area or the vicinity of the affected area.

[0030]

Embodiments of the present invention will be described below. First, examples of the transdermal absorption enhancer of the present invention will be described.

[0031]

Example 1 Dioleylphosphatidylserine and dilinoleylphosphatidylserine 5 kg of bovine brain was mixed with 5 L of purified water to prepare a homogenate. 5 L to the obtained homogenate
Chloroform was added to sonicate, and the layers were separated.
From this, only the chloroform layer was collected and taken out, and silica gel column chromatography (chloroform: methanol = 1: 0 → chloroform: methanol = 1: 1).
Then, the product was purified by high performance liquid chromatography (55% acetonitrile aqueous solution) equipped with an ODS column to obtain 1.964 g of dioleylphosphatidylserine and 0.893 g of dilinoleylphosphatidylserine. Each of these is as it is, percutaneous absorption enhancer 1
Further, as a percutaneous absorption enhancer 2, it was used in the following examples of skin external preparations.

<Evaluation of Transdermal Absorption Promoter of the Present Invention> As the transdermal absorption enhancer of the present invention, dioleylphosphatidylserine (transdermal absorption enhancer 1) obtained in Example 1 above and dirino Using the rail phosphatidylserine (transdermal absorption enhancer 2), the percutaneous absorption rate and amount of indomethacin, which is an anti-inflammatory analgesic, were investigated, and the degree of promotion was evaluated.

A percutaneous absorption test was conducted using a diffusion cell having a structure in which a membrane can be attached to the center of the cell and a liquid can be charged in a state of contacting with the membrane above and below the membrane. A male guinea pig dorsal skin was attached to the diffusion cell, and propylene containing 1 wt% each of indomethacin as a test solution and the transdermal absorption enhancer 1 obtained in Example 1 was placed on the upper part of the cell across the skin. Apply 1 mL of glycol solution on the skin, and use pH as a receptor solution at the bottom of the cell.
The phosphate buffered saline solution of 7.4 was added to a position in contact with the back skin of the guinea pig, and the entire diffusion cell was put in a constant temperature water layer at 37 ° C. A rotor was placed together with the receptor solution in the lower part of the cell containing the receptor solution, and the receptor solution was continuously stirred using a magnetic stirrer during the experiment.

The receptor solution was sampled from the diffusion cell at regular intervals, and the concentration of indomethacin in the receptor solution was measured by high performance liquid chromatography. Further, in the same manner as above, an experiment was conducted on the percutaneous absorption enhancer 2 obtained in Example 1.

From the obtained indomethacin concentration measurement value,
The transdermal absorption rate of indomethacin and the transdermal absorption amount from 24 hours after the start of the test were determined. A 1 wt% propylene glycol solution of indomethacin was used as a control. The results are shown in Table 1.

[0036]

[Table 1]

From these results, it is clear that the transdermal absorption enhancers obtained in Example 1 both accelerate the transdermal absorption rate of indomethacin and increase the transdermal absorption amount. It can be said that the action is excellent.

Next, examples of the external preparation for skin of the present invention containing the percutaneous absorption enhancer obtained in Example 1 will be described. In addition, all compounding amounts used below are parts by weight.

[0039]

Examples 2 to 11 Lotion Agents The components shown in Table 2 were dissolved by heating and cooled to obtain lotion agents.

[0040]

[Table 2]

[0041]

Example 12 Stick Agent The components shown in Table 3 were dissolved by heating and cooled to obtain a stick agent.

[0042]

[Table 3]

[0043]

Example 13 Cream A component and B component shown in Table 4 were separately heated and dissolved at 80 ° C., and component B was gradually added to component A with stirring and cooled to obtain a cream. Also, a cream of Comparative Example containing no percutaneous absorption enhancer of the present invention was produced in the same manner.

[0044]

[Table 4]

<Evaluation of the external preparation for skin of the present invention> The creams obtained in Example 13 and Comparative Example 1 were subjected to a practical use test to the extent that indomethacin, which is a medicinal component, is transdermally absorbed and exhibits an anti-inflammatory effect. Was evaluated.

Ten panelists selected from arthritis patients were arbitrarily divided into 5 groups of 5 groups A and B. Group A was compared with the cream of Example 13 for the first week and compared for the next week. Using the cream of Example 1, the group B was asked to use the cream of Comparative Example 1 for the first week and the cream of Example 13 for the next week, and which cream was then used in the questionnaire. I asked if the pain was alleviated. The results are shown in Table 5.

[0047]

[Table 5]

From this, it is understood that the cream of Example 13 has a higher action of relieving pain regardless of the order of use. This is because the cream of Example 13 is more transdermally absorbed by the anti-inflammatory analgesic due to the action of the percutaneous absorption enhancer of the present invention. Further, in the above practical use test, no unfavorable symptoms such as eczema and rash were observed, which proves that the transdermal absorption enhancer of the present invention has excellent safety.

[0049]

The percutaneous absorption enhancer of the present invention is highly safe and has an excellent percutaneous absorption promoting action. In addition, the external preparation for skin containing the percutaneous absorption enhancer of the present invention can be continuously used for a long period of time, and since the medicinal component is well transdermally absorbed, it can exhibit excellent medicinal effects.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 31/135 9455-4C 31/14 9455-4C 31/155 9455-4C 31/16 9455-4C 31/165 9455-4C 31/19 9455-4C 31/27 ADZ 9455-4C 31/40 31/405 AAH 31/415 31/54 31/57 31/58 31/60 ADZ 31/71 45/00 ABE / / C07F 9/10 B 9155-4H

Claims (14)

[Claims] 1. A transdermal absorption enhancer comprising phosphatidylserine represented by the following general formula (I). Embedded image However, in the formula (I), R ₁ and R ₂ each independently represent an acyl group having 13 to 21 carbon atoms, and at least one of R ₁ and R ₂ has an unsaturated bond. 2. The percutaneous absorption enhancer according to claim 1, wherein the acyl group having an unsaturated bond is selected from residues of oleic acid, linoleic acid and linoleic acid. 3. A skin external preparation containing the percutaneous absorption enhancer according to claim 1 or 2. 4. The external preparation for skin according to claim 3, which contains an anti-inflammatory analgesic as a medicinal component. 5. The anti-inflammatory analgesic is indomethacin, methyl salicylate, diclofenac sodium, flufenamic acid, bufexamac, ibuprofen, zaltoprofen, naproxen, flurbiprofen, flurbiprofen axetil, fenbufen, mefenamic acid, piroxicam. , Ampiroxicam, tenoxicam,
Felbinac, tocoretinate, hydrocortisone, prednisolone, methylprednisolone, betamethasone,
The external preparation for skin according to claim 4, which is selected from dexamethasone, triamsilonone, triamsilonone acetonide, flumethasone, fluocinonide, beclomethasone, fluocinolone, fluoxycortide, mometasone, clobetasone, clobetasol and derivatives thereof. . 6. The external preparation for skin according to claim 5, wherein the derivative is selected from salts, esters, ketals, acetals and hemiacetals. 7. The skin according to any one of claims 4 to 6, wherein the content of the anti-inflammatory analgesic is 0.01 to 10% by weight based on the total amount of the skin external preparation. Topical agent. 8. The external preparation for skin according to claim 3, which contains an antifungal agent as a medicinal component. 9. The antifungal agent is tolnaftate, clotrimazole, haloprozin, tricomycin, pesimilone, pyrrolenitrin, nystatin, exaramide,
The external preparation for skin according to claim 8, which is selected from miconazole nitrate, econazole nitrate, isoconazole nitrate, bifonazole and terbinafine. 10. The external preparation for skin according to claim 8 or 9, wherein the content of the antifungal agent is 0.01 to 10% by weight based on the total amount of the external preparation for skin. 11. The external preparation for skin according to claim 3,
A skin external preparation characterized by containing a bactericide as a medicinal component. 12. The bactericide is hexachlorophene,
The external preparation for skin according to claim 11, which is selected from resorcin, crystal violet, benzethonium chloride, benzalkonium chloride, and chlorhexidine gluconate. 13. The external preparation for skin according to claim 11 or 12, wherein the content of the bactericide is 0.01 to 10% by weight based on the total amount of the external preparation for skin. 14. The external preparation for skin according to claim 3, wherein the content of the percutaneous absorption enhancer is 0.01 to 10% by weight based on the total amount of the external preparation for skin.