JPH07109229A - Percutaneous absorption prometer and dermal agent composition for external use - Google Patents

Abstract

PURPOSE:To obtain a percutaneous absorption promoter capable of promoting percutaneous absorption of a medicinal component in a dermal agent for external use in both a closed system and an open system and excellent in safety and stability. CONSTITUTION:A percutaneous absorption promoter composed of hydrogenated bisabol represented by the formula. The compound of the formula can be synthesized by hydrogenating natural alpha-bisabol. If 0.01 to 10wt.% compound of the formula is added to a dermal agent composition for external use containing a bioactive substance, a dermal agent composition for external use improved in the amount of the dermal medicinal component absorbed into the lower cutaneous tissue and in the amount of the systemically active component transferred into the systemic blood flow is prepared. In this composition, one of 5 to 60wt.% ethanol, 2 to 20wt.% water-soluble polyvalent alcohol (e.g. propylene glycol or glycerin), 0.01 to 2wt.% water-soluble polymer (e.g. PVA, xanthan gum or CMC) and 0.1 to 10wt.% nonionic surfactant (e.g. a polyoxyethylene sorbitan fatty acid ester) may be blended.

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, which contains a percutaneous absorption enhancer used to promote the percutaneous absorption of a medicinal component contained in the external preparation and the same. The present invention relates to a skin external preparation composition.

[0002]

2. Description of the Related Art In recent years, transdermal administration has attracted attention as a route of administration of physiologically active substances. This is because intravenous or oral administration is painful, causes gastrointestinal disorders, needs to be administered multiple times a day to maintain blood levels, and is metabolized by the first-pass effect in the liver. This is because transdermal administration can avoid these problems.

By the way, the skin has an excellent barrier property against the invasion of external chemical substances. Permeation resistance to external chemicals is strongest in the outer layer of the epidermis, the stratum corneum, and the underlying layer is relatively less resistant. Therefore, when transdermally administering a physiologically active substance, it is most important to penetrate the stratum corneum.

Therefore, for the purpose of enhancing the permeability of the stratum corneum,
Transdermal absorption enhancers such as lecithin, oleic acid, surfactants, AZON, and monoterpenes are being studied. Among these transdermal absorption enhancers, monoterpenes make it easier for both water-soluble and oil-soluble substances to permeate.The action is transient, and if the administration is discontinued, the barrier function of the stratum corneum is immediately restored. It is useful because it has advantages such as

Among the monoterpenes, structurally hydroxyl groups,
Hydrocarbon-based monoterpenes having no carboxyl group have been reported to be useful (Drug Design.
Nand Delivery, 4, 313, 198.
9 years). In addition, α- which is a sesquiterpene alcohol
It has been reported that bisabolol has a remarkable accelerating effect (International Journal).
of Pharmaceuticals, 70, 87.
1991).

However, since hydrocarbon type monoterpenes have high volatility, they are effective in closed-dose type dosage forms such as poultices, but they are applied to open-type skin-applied preparations such as creams, ointments and solutions. If, it does not show sufficient effect. In addition, naturally occurring terpene compounds such as limonene and α-bisabolol often have a double bond in the molecule, and it has been pointed out that their oxides are allergic (Contact Dermatitis,
26, 332, 1992), there is a problem with safety and stability.

Japanese Patent Publication No. 3-65323 discloses at least one alcohol component selected from aliphatic alcohols having 7 to 20 carbon atoms and a melting point of 40 ° C. or lower, monoterpene alcohols and sesquiterpene alcohols,
In addition, a base for external preparations and an external preparation containing dimethyl sulfoxide as an essential component are further disclosed in JP-A-3-63233.
Japanese Patent Laid-Open Publication No. 2003-242242 discloses an external preparation that has a molecular formula of terpenes (C ₅ H ₈ ) _n and has no oxygen atom in its molecular skeleton in order to promote percutaneous absorption of the external preparation that absorbs the contained drug component from the skin. Transdermal absorption enhancers have been proposed.

Among the former, the combination of sesquiterpene alcohols and dimethylsulfoxide exhibits some promoting effect even when used in an open system, but skin irritation due to dimethylsulfoxide poses a problem.

The latter invention, when using monoterpenes and sesquiterpenes, has an effect in a closed system as in the above-mentioned paper, but has little effect in an open system. In addition, the compounds of diterpenes and above are not so remarkable in volatility, but have no transdermal absorption promoting effect. Further, in any of the inventions, there is a problem in safety of the above-mentioned terpene oxide.

[0010]

Means for Solving the Problems As a result of intensive studies in view of such circumstances, the compound represented by the following structural formula (I) is excellent as a percutaneous absorption promoter for closed and open type external preparations, It was found that having no double bond in the inside provides better safety and stability, and completed the present invention.

[0011]

[Chemical 4]

That is, the present invention is a skin external preparation composition containing a percutaneous absorption enhancer comprising a compound represented by the following structural formula (I) and a physiologically active substance, which is represented by the structural formula (I). A skin external preparation composition containing a compound, and a skin external preparation composition containing a physiologically active substance, which comprises ethanol, a water-soluble polyhydric alcohol, a water-soluble polymer, and a nonionic surfactant. A skin external preparation composition comprising one or more compounds selected from the group consisting of and a compound represented by the structural formula (I).

[0013]

[Chemical 5]

The details of the configuration of the present invention will be described below. The physiologically active substance used in the present invention is roughly classified into a drug for skin application and a drug for systemic action, and its compounding amount is such that local effect and systemic effect are exhibited, respectively.

The present invention provides a percutaneous absorption enhancer for increasing the skin permeation rate of various physiologically active substances, and by using the percutaneous absorption enhancer of the present invention, it is possible to improve the skin lower tissue. There is an increase in the amount of skin application drug absorbed and the amount of systemic drug that migrates into the systemic bloodstream.

The physiologically active substances used in the present invention include antibacterial agents, antifungal agents, acne therapeutic agents, lincomycin, tetracycline, erythromycin, penicillin G, cephalexin, chlorhexidine, streptomycin, amphotericin B and other antiviral agents, 5 -Anti-metabolites such as fluorouracil, 6-mercaptopurine and methotrexate, cortisone acetate, betamethasone valerate, steroidal anti-inflammatory agents such as hydrocortisone cyclopentyl propionate, indomethacin, ibuprofen, mefenamic acid, sodium glycyrrhizinate, potassium glycyrrhetinate Non-steroidal anti-inflammatory drugs, etc., local anesthetics such as dibucaine, procaine, lidocaine, estradiol, testosterone, ethinyl estradiol, proge Hormone and its derivatives and hydroquinone, such as cyproterone, arbutin, ascorbic acid, phosphoric acid ester magnesium salt of ascorbic acid,
Other skin application substances such as diisopropylamine dichloroacetate, γ-aminobutyric acid, tocopherol, tocopherol nicotinate, and tocopherol acetate can be used.

The percutaneous absorption enhancer of the present invention comprises the compound represented by the structural formula (I), and the extraction method, the production method and the like are not particularly limited. Further, although the compound has stereoisomers, any one of them may be used alone or a mixture of two or more kinds may be used. As a method for producing the compound, for example, commercially available, naturally-occurring α-bisabolol is hydrogenated [Ha
shidoko, Z. Natureforsch. , C:
Biosci. , Volume 46 (5-6), 349-356.
Page, 1991]. Hereinafter, the compound obtained by hydrogenating α-bisabolol is referred to as hydrogenated bisabolol.

The compounding amount of the compound represented by the structural formula (I) in the external preparation for skin of the present invention varies depending on the drug and the formulation and is not particularly limited, but is 0 based on the total amount of the final composition. It is preferable to add about 0.01 to 10% by weight.

The ethanol used in the present invention may be ethanol normally used in pharmaceuticals or cosmetics, and the manufacturing method such as synthesis or fermentation method is not particularly limited.

The content thereof is preferably 5 to 60% by weight based on the weight of the final composition.

Examples of the water-soluble polyhydric alcohol used in the present invention include propylene glycol, glycerin, 1,3-butylene glycol, diglycerin, polyglycerin, dipropylene glycol, sorbitol and maltitol.

The content thereof is preferably 2 to 20% by weight based on the weight of the final composition.

Examples of the water-soluble polymer used in the present invention include polyvinyl alcohol, xanthan gum,
Examples thereof include carboxyvinyl polymer, carboxycellulose, hydroxypropyl cellulose, sodium polyacrylate and the like.

The content thereof is preferably 0.01 to 2% by weight based on the weight of the final composition.

Examples of the nonionic surfactant used in the present invention include polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, and other polyoxyethylene sorbitan fatty acid esters, sorbitan monooleate, and sorbitan sesqui. Sorbitan fatty acid esters such as oleate, polyoxyethylene hydrogenated castor oil, polyoxyethylene oleyl ether, polyoxyethylene alkyl ethers such as polyoxyethylene stearyl ether, glycerin monostearate, glycerin monooleate, polyglycerin monooleate Glycerin esters such as ates, propylene glycol monolaurate, propylene glycol fatty acid esters such as propylene glycol monostearate, polyethylene Polyethylene glycol fatty acid esters such as recall monolaurate and polyethylene glycol dioleate, polyoxyethylene polyoxypropylene alkyl ethers such as polyoxyethylene polyoxypropylene cetyl ether, polyoxyethylene polyoxypropylene behenyl ether, and polyoxyethylene Examples thereof include polyoxyethylene alkylphenyl ethers such as nonyl phenyl ether and polyoxyethylene octyl phenyl ether.

The compounding amount thereof is preferably 0.1 to 10% by weight based on the weight of the final composition.

Further, by combining ethanol, a nonionic surfactant and a water-soluble polyhydric alcohol in combination, a stable and excellent preparation for percutaneous absorption can be obtained.

In addition to the essential components, the external preparation for skin of the present invention appropriately contains a base, a preservative, a perfume, a coloring agent and the like according to each preparation within a range not impairing the effects of the present invention. be able to.

Examples of the form of the external preparation for skin of the present invention include ointments, creams, liniments, poultices, aerosols, emulsions, lotions, packs and bath salts.

[0030]

The present invention will be described in more detail with reference to the following examples. Unless otherwise specified,% indications below are
Indicates weight percent.

The transdermal absorbability test, safety test and storage stability test in the examples are as follows.

(1) Percutaneous Absorption Test A hairless rat (male: 150-
180 g) abdominal skin, upper cell (open system)
A skin external preparation composition (10 mg / cm ² ) is added to the lower cell, and physiological saline (1.0% polyoxyethylenesorbitan monooleate-containing physiological saline is used when the physiologically active substance is oil-soluble) in the lower cell (17 0.5 ml), and physiological saline was sampled from the lower cell over time, the concentration of the physiologically active substance transferred to the lower cell was quantified, and the transfer rate from the upper cell (%)
I asked.

(2) Safety test The presence or absence of photosensitization was determined by the adjuvant strip method using Hartley guinea pigs.

(3) Storage stability test Samples were stored in a constant temperature layer at 5 ° C. and 40 ° C. for 1 month, and the changes in color and odor of both samples were compared.

The hydrogenated bisabolol used in this example is H
Ashidoko et al. [Z. Natureforsc
h. , C: Biosci. , Volume 46 (5-6), 34
9-356, 1991].

Example 1

[0037]

[Table 1]

An ointment having the above composition was prepared according to a conventional method, and a percutaneous absorption test was conducted.

Comparative Example 1

[0040]

[Table 2]

A comparative ointment having the above composition was prepared according to a conventional method, and a percutaneous absorption test was conducted.

Comparative Example 2

[0043]

[Table 3]

A comparative ointment having the above composition was prepared by a conventional method, and a percutaneous absorption test was conducted.

Comparative Example 3

[0046]

[Table 4]

A comparative ointment having the above composition was prepared according to a conventional method, and a percutaneous absorption test was conducted.

Table 5 shows the results of the transdermal absorbability test of Example 1 and Comparative Examples 1 to 3.

[0049]

[Table 5]

As is clear from the results in Table 5, Example 1 using the hydrogenated bisabolol of the present invention was most excellent in the migration rate of indomethacin. Comparative Example 1 using α-bisabolol has a large lag time and takes a long time until the effect is exhibited. In addition, Comparative Example 2 using limonene is effective in the initial stage but does not last. Comparative Example 3 containing no accelerator is
The permeability of indomethacin was significantly poor.

As a result of the storage stability test, Example 1 and Comparative Example 3 showed no change in odor and color in comparison with storage at 5 ° C. and 40 ° C. On the other hand, in Comparative Examples 1 and 2 containing the unsaturated compounds α-bisabolol and limonene, coloring and odor were observed. Further, also in the result of the safety test, Comparative Examples 1 and 2 in which limonene and α-bisabolol were blended showed suspicious results.

Example 2

[0053]

[Table 6]

An aqueous 5-fluorouracil (5-FU) solution containing the hydrogenated bisabolol of the present invention having the above composition was prepared, and the transdermal absorbability test was carried out. As Comparative Example 4, a 1% 5-FU aqueous solution containing no hydrogenated bisabolol was used.

[0055]

[Table 7]

As is clear from the results in Table 7, Example 2 containing the hydrogenated bisabolol of the present invention has a significantly higher transfer rate of 5-FU at each time than Comparative Example 4.

Example 3 Hydrocortisone (0.03 g) was added to hydrogenated bisabolol 1.
It was dispersed and dissolved in 97 g and further dispersed in 1.0 g of glycerin to prepare a 1% solution of hydrocortisone. The above-mentioned percutaneous absorbability test was carried out on 100 mg of this solution and a commercially available hydrocortisone preparation (hydrocortisone content 1%). The results are shown in Table 8.

[0058]

[Table 8]

As is clear from the results in Table 8, the hydrocortisone glycerin solution containing the hydrogenated bisabolol of the present invention had a superior hydrocortisone transfer rate as compared with the commercially available cream.

Example 4 Lotion

[0061]

[Table 9]

The lotion of the present invention having the above composition was prepared by a conventional method, and a percutaneous absorption test was conducted.

Example 5 Lotion

[0064]

[Table 10]

The lotion of the present invention having the above composition was prepared by a conventional method, and a percutaneous absorption test was conducted.

Example 6 Lotion

[0067]

[Table 11]

The lotion of the present invention having the above composition was prepared by a conventional method, and a percutaneous absorption test was conducted.

Example 7 Lotion

[0070]

[Table 12]

The lotion of the present invention having the above composition was prepared by a conventional method, and a percutaneous absorption test was conducted.

A lotion for comparison having the above composition was prepared by a conventional method, and a percutaneous absorption test was conducted.

Comparative Example 5 Lotion

[0074]

[Table 13]

A lotion for comparison having the above composition was prepared by a conventional method, and a percutaneous absorption test was conducted.

Comparative Example 6 Lotion

[0077]

[Table 14]

A lotion for comparison having the above composition was prepared by a conventional method, and a percutaneous absorption test was conducted.

Comparative Example 7 Lotion

[0080]

[Table 15]

A lotion for comparison having the above composition was prepared by a conventional method, and a percutaneous absorption test was conducted.

[0082]

[Table 16]

As is clear from the results shown in Table 16, the indomethacin transfer rate was excellent in the examples in which the hydrogenated bisabolol of the present invention was blended. Examples 4 to 7> Comparative Examples 5 to 6
>> In order of Comparative Example 7.

As a result of the storage stability test, Examples 4 to 7 and Comparative Example 7 showed no change in odor and color in comparison with storage at 5 ° C. and 40 ° C. On the other hand, in Comparative Examples 5 and 6 in which the unsaturated compounds α-bisabolol and limonene were mixed, coloring and odor were observed. From the above results, it can be seen that the examples of the present invention are formulations that are effective for skin permeation in the indomethacin open system and are excellent in stability.

Example 8 Cream

[0086]

[Table 17]

A cream containing the hydrogenated bisabolol of the present invention having the above composition, a nonionic surfactant and a water-soluble polyhydric alcohol was prepared by a conventional method, and the transdermal absorbability test was carried out.

Comparative Example 8 Cream

[0089]

[Table 18]

A comparative cream having the above composition and containing no hydrogenated visaborol was prepared by a conventional method, and the transdermal absorbability test was carried out.

[0091]

[Table 19]

As is clear from the results in Table 20, Example 8 of the present invention has a significantly higher transfer rate of 5-FU at each time than Comparative Example 8 in which no accelerator is added.

Example 9 Hydrocortisone (0.03 g) was added to hydrogenated bisabolol 1.
It was dispersed and dissolved in 97 g, and further dispersed in a preparation consisting of 0.1 g of polyoxyethylene sorbitan monooleate and 0.9 g of petrolatum to prepare a 1% solution of hydrocortisone. The above-mentioned percutaneous absorbability test was carried out on 100 mg of this solution and a commercially available hydrocortisone preparation (hydrocortisone content 1%). The results are shown in Table 20.

[0094]

[Table 20]

As is clear from the results shown in Table 20, Example 9 containing the hydrogenated bisabolol of the present invention had an excellent hydrocortisone transfer rate as compared with the commercially available cream.

Example 10 Hydrophilic ointment

[0097]

[Table 21]

A tetracycline-containing hydrophilic ointment of the present invention having the above composition was prepared, and the above-mentioned percutaneous absorption test was carried out. As a result, the skin permeation was remarkably higher than that of the same preparation without the addition of hydrogenated bisabolol. Was excellent.

Example 11 Lotion

[0100]

[Table 22]

According to a conventional method having the above composition, a lotion containing the hydrogenated bisabolol of the present invention, ethanol, a nonionic surfactant and a water-soluble polymer was mixed and prepared, and the percutaneous absorption test was conducted. As a result, the skin permeability of tocopherol nicotinate and dipotassium glycyrrhizinate was improved by the effect of hydrogenated bisabolol.

Example 12 Hair nourishing agent

[0103]

[Table 23]

A hair nourishing agent containing the hydrogenated bisabolol of the present invention, ethanol, a nonionic surfactant and a water-soluble polyhydric alcohol was blended according to a conventional method having the above composition, and the transdermal absorption test was carried out. As a result, the skin permeability of tocopherol acetate and diisopropylamine dichloroacetate was improved by the effect of hydrogenated bisabolol.

[0105]

As described above, it is clear that the percutaneous absorption enhancer and the external skin preparation composition of the present invention improve the skin permeability of a wide range of physiologically active substances.

Claims (3)

[Claims] 1. A percutaneous absorption enhancer comprising a compound represented by the following structural formula (I). [Chemical 1] 2. A skin external preparation composition containing a physiologically active substance, which comprises a compound represented by the following structural formula (I). [Chemical 2] 3. A skin external preparation composition containing a physiologically active substance, which comprises one or more compounds selected from the group consisting of ethanol, water-soluble polyhydric alcohols, water-soluble polymers, and nonionic surfactants. And a compound represented by the following structural formula (I): [Chemical 3]