JP3313893B2 - Transdermal absorption enhancer and skin external preparation - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

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

[0002]

2. Description of the Related Art Drug treatment using a percutaneous administration route for inflammation and diseases on the skin close to the skin is more effective than the gastrointestinal administration such as oral administration or the intravascular administration such as intravenous injection. It has many advantages, such as being less susceptible to metabolism by, or having less side effects, and has been widely and more frequently used since ancient times. An example of successful drug treatment using such a transdermal administration route is a skin external preparation of indomethacin, etc., which by transdermal administration significantly reduces side effects such as stomach ulcer frequently occurring during oral administration.

[0003] However, since the skin is a defense mechanism for protecting the living body from the outside world, it is often difficult to transport the drug into the living body by transdermal administration. Very few at present.

Attempts have also been made to improve percutaneous absorption using a percutaneous absorption enhancer such as Aison. However, these percutaneous absorption enhancers are not suitable for safety, such as causing inflammation. The problem is so large that it has not been used for practical use.

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

[0006]

DISCLOSURE OF THE INVENTION The present invention has been made in view of the above, and is intended to provide a percutaneous absorption enhancer which is highly safe and has an excellent percutaneous absorption promoting action, and a skin external preparation containing the same. The task is to provide.

[0007]

Means for Solving the Problems In order to solve the above-mentioned problems, the present inventors have conducted screenings for various substances with the index of promoting transdermal absorption and safety as an index. The present inventors have found a strong transdermal absorption promoting action and high safety for phosphatidylserine to be used and completed the present invention.

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

[0009]

Embedded image

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

<1> Transdermal absorption enhancer 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 each independently represents a residue of a saturated or unsaturated fatty acid having 13 to 21 carbon atoms. And at least one of R ₁ and R ₂ is an acyl group comprising a residue of an unsaturated fatty acid.

By the esterification, the compound having 13 carbon atoms as described above is used.
Examples of the saturated fatty acid that becomes the acyl group of to 21 include:
Tridecanoic acid, myristic acid, palmitic acid, stearic acid, behenic acid and the like. Examples of the unsaturated fatty acid that becomes an acyl group having 13 to 21 carbon atoms by esterification include, for example, oleic acid, linoleic acid, linoleic acid, ascleic acid, petroselinic acid, and ritinoleic acid. Preferably, oleic acid, linoleic acid, linoleic acid and the like can be mentioned.

The phosphatidylserine represented by the above general formula (I) is a compound widely distributed in a living body. For example, bovine brain and chicken eggs are extracted with an organic solvent such as ether, tetrahydrofuran, chloroform or the like, and silica gel is extracted. 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 phosphatidylserine represented by the general formula (I) from bovine brain includes, for example,
Chloroform was added to the homogenate obtained by adding water to the bovine brain and homogenizing, and the mixture was sonicated. The phases were separated, and only the chloroform layer was taken out and purified by silica gel column chromatography and high-performance liquid chromatography equipped with an ODS column. Methods can be mentioned.

Of the phosphatidylserine represented by the above general formula (I) thus obtained, phosphatidylserine which has a high content in bovine brain and is 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, ie, an oleyl group, and dioleylphosphatidylserine, and R ₁ and R _{2 in} the general formula (I) are both the residue of linoleic acid. A compound which is an acyl group consisting of a group, ie, a linoleyl group, dilinoleyl phosphatidylserine can be mentioned.

When the phosphatidylserine represented by the above general formula (I) is incorporated into a skin external preparation together with a medicinal ingredient as a transdermal absorption enhancer, the percutaneous absorbability of the medicinal ingredient can be enhanced. Becomes possible. Further, the percutaneous absorption enhancer of the present invention comprising phosphatidylserine represented by the above general formula (I) can achieve a great effect by percutaneous absorption, but is hardly percutaneous when used alone. Particularly effective is an external preparation for skin containing the component as a medicinal component.

Further, as described above, the phosphatidylserine represented by the general formula (I), which is a transdermal absorption enhancer of the present invention, is a compound which is widely distributed in a living body, and therefore has high safety. Needless to say.

<2> External preparation for skin of the present invention The external preparation for skin of the present invention comprises a phosphatidylserine represented by the above general formula (I) as a transdermal absorption promoter together with a pharmaceutically active ingredient. is there. The amount of the transdermal absorption enhancer in the skin external preparation of the present invention is preferably 0.01 to 10% by weight, more preferably 1 to 5% by weight, based on the total amount of the skin external preparation. If the amount of the percutaneous absorption enhancer is less than 0.01% by weight, the effect of promoting percutaneous absorption may not be sufficiently obtained. If the amount exceeds 10% by weight, the combination of a medicinal ingredient and other optional ingredients may be obtained. The amount is limited, and the function, stability, feeling of use, etc. as an external preparation for skin may be impaired.

The medicinal component incorporated in the external preparation for skin of the present invention is not particularly limited as long as it is a component used as an active ingredient in the external preparation for skin.
Examples include antifungal agents, bactericides, antiviral agents and the like. Of these medicinal components, in the present invention, anti-inflammatory analgesics, antifungal agents, bactericides and the like can be mentioned as preferable medicinal components, and these various medicinal components can be used alone or as necessary. Accordingly, two or more kinds of components can be used in combination. Furthermore, an antiphlogistic analgesic can be said to be the most preferred active ingredient in the present invention. This is because, among the above medicinal ingredients, the site of action of the anti-inflammatory analgesic is the deepest, and the most excellent transdermal absorption is required.

Examples of the above antiphlogistic 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 are steroidal or non-steroidal compounds such as betamethasone, dexamethasone, triamsilonone, triamsilonone acetonide, flumethasone, fluocinonide, beclomethasone, fluocinolone, fluoxycortide, mometasone, clobetasone, clobetasol, and derivatives thereof. Can be. Of these, the most preferred anti-inflammatory analgesics are indomethacin and its derivatives, which have significant side effects by administration routes other than transdermal absorption and have insufficient transdermal absorption.

The derivatives of the various compounds listed as the above-mentioned antiphlogistic analgesic are not particularly limited as long as the effects of the present invention are not impaired.
Examples thereof include salts of acids or bases, esters, ketals, acetals, and hemiacetals. These derivatives can be easily obtained by treating the above various compounds by a conventional method.

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

Examples of the above antifungal agents include tolnaftate, clotrimazole, haloprosin, tricomycin, pesimilon, pyrrolnitrin, nystatin,
Exalamide, miconazole nitrate, econazole nitrate,
Preferred are isoconazole nitrate, bifonazole, terbinafine and the like and derivatives thereof.

The derivatives of the various compounds mentioned as the above-mentioned antifungal agents are not particularly limited as long as the effects of the present invention are not impaired.
Examples thereof include salts of acids or bases, esters, ketals, acetals, and hemiacetals. These derivatives can be easily obtained by treating the above various compounds by a conventional method.

In the external preparation for skin of the present invention, one kind selected from the above-mentioned various compounds and various derivatives of these compounds may be used alone or as a combination of two or more kinds as antifungal agents. It is. The amount of the antifungal agent in the external preparation for skin of the present invention varies greatly depending on the kind of the antifungal agent to be added, but is generally preferably 0.01 to 10% by weight, more preferably 0.01 to 10% by weight based on the total amount of the external preparation for skin. Is 0.1 to 5% by weight.

Examples of the above bactericides include hexachlorophen, resorcin, crystal violet, benzethonium chloride, benzalkonium chloride, chlorhexidine gluconate, and the like. Can be blended. The compounding amount is 0.01 to 10% by weight based on the total amount of the external preparation for skin.
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 added to the external preparation for skin. Such optional components are not particularly limited as long as they are components used in external preparations for the skin. For example, lower alcohols such as ethanol and isopropanol, thickeners, fats and oils, higher alcohols, higher fatty acids , Surfactants, preservatives, antioxidants, UV absorbers,
Examples include coloring agents, fragrances, water-soluble polymers, powders, and adhesives.

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

As for the dosage 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 Dioleyl phosphatidylserine and dilinoleyl phosphatidylserine 5 L of purified water was added to 5 kg of bovine brain and homogenized to prepare a homogenate. 5 L to the obtained homogenate
Was added and sonicated, followed by separation.
From this, only the chloroform layer was collected and taken out, and silica gel column chromatography (chloroform: methanol = 1: 0 → chloroform: methanol = 1: 1).
And 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 was directly used as a transdermal absorption enhancer 1
And as a transdermal absorption enhancer 2, it was used in the following examples of skin external preparations.

<Evaluation of the transdermal absorption enhancer of the present invention> As the transdermal absorption enhancer of the present invention, dioleylphosphatidylserine (transdermal absorption enhancer 1) obtained in Example 1 and dirino By using rail phosphatidylserine (transdermal absorption enhancer 2), the transdermal absorption rate and amount of indomethacin, which is an anti-inflammatory analgesic, were examined to determine the degree to which the transdermal absorption was promoted, and the transdermal absorption promoting action was evaluated.

A percutaneous absorption test was performed using a diffusion cell having a structure in which a membrane can be mounted at the center of the cell and a liquid can be injected vertically in contact with the membrane with the membrane interposed therebetween. A back skin of a male guinea pig is attached to the above diffusion cell, and propylene containing 1% by weight of each of indomethacin and a transdermal absorption enhancer 1 obtained in Example 1 as a test solution is placed above the cell with the skin interposed therebetween. Apply 1 mL of the glycol solution on the skin, and put the pH below the cell
The phosphate buffered saline of 7.4 was put into 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. In addition, a rotor was put together with the receptor liquid in the lower part of the cell into which the receptor liquid was charged, and the receptor liquid was continuously stirred using a magnetic stirrer during the experiment.

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

From the obtained measured values of indomethacin concentration,
The transdermal absorption rate of indomethacin and the transdermal absorption amount up to 24 hours after the start of the test were determined. As a control, a 1% by weight propylene glycol solution of indomethacin was used. Table 1 shows the results.

[0036]

[Table 1]

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

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

[0039]

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

[0040]

[Table 2]

[0041]

Example 12 Stick Preparation The components shown in Table 3 were heated and dissolved, followed by cooling and molding to obtain a stick preparation.

[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 the B component was gradually added to the A component while stirring, followed by cooling to obtain a cream. Similarly, a cream of a comparative example containing no transdermal absorption enhancer of the present invention was produced.

[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, and the degree to which indomethacin, which is a medicinal component, was absorbed percutaneously and exhibited an anti-inflammatory effect. Was evaluated.

Ten panelists selected from patients with arthritis were arbitrarily divided into two groups, A and B, each of which consisted of five persons. In group A, the cream of Example 13 was compared for the first week and compared for the next week. The cream of Example 1 was used, the group B received the cream of Comparative Example 1 for the first week, and the cream of Example 13 for the next week. Asked if the pain was relieved. Table 5 shows the results.

[0047]

[Table 5]

From this, it can be seen that the cream of Example 13 has a higher effect of relieving pain irrespective of the order of use. This is because the cream of Example 13 percutaneously absorbs more of the anti-inflammatory analgesic by the action of the transdermal absorption enhancer of the present invention. Furthermore, in the above-mentioned actual use test, no undesired symptoms such as eczema and rash were observed, which confirmed that the transdermal absorption enhancer of the present invention is excellent in safety.

[0049]

EFFECT OF THE INVENTION The transdermal absorption enhancer of the present invention has high safety and furthermore has excellent transdermal absorption promoting action. In addition, the external preparation for skin containing the transdermal absorption enhancer of the present invention can be used continuously for a long period of time and has excellent medicinal effects because the active ingredient is well absorbed through the skin.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61K 31/135 A61K 31/135 31/14 31/14 31/155 31/155 31/16 31/16 31/165 31/165 31/19 31/19 31/27 31/27 31/40 31/40 31/405 31/405 31/415 31/415 31/54 31/54 31/573 31/573 31/58 31/58 31 / 60 31/60 45/00 45/00 A61P 17/00 101 A61P 17/00 101 29/00 29/00 31/10 31/10 // C07F 9/10 C07F 9/10 B (58) Field surveyed ( Int.Cl. ⁷ , DB name) A61K 47/24 A61K 9/00 A61K 31/05 A61K 31/055 A61K 31/085 A61K 31/135 A61K 31/14 A61K 31/155 A61K 31/16 A61K 31/165 A61K 31/19 A61K 31/27 A61K 31/40 A61K 31/405 A61K 31/415 A61K 31/54 A61K 31/573 A61K 31/58 A61K 31/60 A61K 45/00 A61P 17/00 101 A61P 29/00 A61P 31 / 10 C07F 9/10

Claims (15)

(57) [Claims] 1. A transdermal absorption enhancer containing phosphatidylserine, wherein all of the phosphatidylserine contained in the transdermal absorption enhancer is represented by the following general formula (I). , A transdermal absorption enhancer. 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. In the general formula (I), R ₁ and R ₂
The percutaneous absorption enhancer according to claim 1, wherein both have an unsaturated bond. 3. The transdermal 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. 4. An external preparation for skin containing the transdermal absorption enhancer according to any one of claims 1 to 3 (provided that the general formula (I)
Phosphatids other than phosphatidylserine represented by
Except for those containing gillserine in external preparations for skin). 5. The external preparation for skin according to claim 4, further comprising an anti-inflammatory analgesic agent as a medicinal component. 6. The method of claim 1, wherein the anti-inflammatory agent 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 5, which is selected from dexamethasone, triamsilonone, triamsilonone acetonide, flumethasone, fluocinonide, beclomethasone, fluocinolone, fluoxycortide, mometasone, clobetasone, clobetasol and derivatives thereof. . 7. The skin external preparation according to claim 6, wherein the derivative is selected from a salt, an ester, a ketal, an acetal, and a hemiacetal. 8. The skin according to claim 5, wherein the content of the antiphlogistic analgesic is 0.01 to 10% by weight based on the total amount of the external preparation for skin. External preparation. 9. The external preparation for skin according to claim 4, further comprising an antifungal agent as a medicinal ingredient. 10. The method according to claim 1, wherein the antifungal agent is selected from tolnaftate, clotrimazole, haloprosin, tricomycin, pesimilone, pyrrolnitrin, nystatin, exalamide, miconazole nitrate, econazole nitrate, isoconazole nitrate, bifonazole and terbinafine. The external preparation for skin according to claim 9, which is used. 11. The external preparation for skin according to claim 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. 12. The external preparation for skin according to claim 4, wherein
An external preparation for skin, comprising a bactericide as a medicinal ingredient. 13. The fungicide according to claim 13, wherein the disinfectant is hexachlorophene,
13. The external preparation for skin according to claim 12, which is selected from resorcin, crystal violet, benzethonium chloride, benzalkonium chloride, and chlorhexidine gluconate. 14. The external preparation for skin according to claim 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. 15. The method according to claim 4, wherein the content of the transdermal absorption enhancer is 0.01 to 10% by weight based on the total amount of the external preparation for skin. External preparation for skin.