JPS63230641A - Transcutaneous absorbefacient and external drug for skin containing said absorbefacient - Google Patents

Abstract

PURPOSE:To obtain a transcutaneous absorbefacient having excellent absorbefacient effect of drug active component and good safety and feeling to the skin, by using a nonionic surfactant, etc., containing N in the molecule and a nonionic surfactant free from nitrogen atom in the molecule as active components. CONSTITUTION:The objective agent contains (A) an N-containing nonionic surfactant (e.g. fatty acid alkanolamide or polyoxyethylene fatty acid alkanolamide), ampholytic surfactant (e.g. N,N-dimethyl-N-lauryl-N- carboxymethylammonium betaine), semi-polar surfactant (e.g. lauryl dimethylamine oxide) and cationic surfactant (e.g. fatty acid amine salt) and (B) a nonionic surfactant free from N in the molecule (e.g. sorbitan monooleate) as active components. The effect of the drug-active component such as predonisolone can be promoted by the use of the absorbefacient.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a transdermal absorption enhancer and a preparation for external use on the skin containing the transdermal absorption enhancer component. More specifically, one or more surfactants selected from the group consisting of nonionic surfactants, amphoteric surfactants, semipolar surfactants, and cationic surfactants each having a nitrogen atom in the molecule; The present invention relates to a transdermal absorption enhancer containing one or more nonionic surfactants without a nitrogen atom as an active ingredient, and a preparation for external use on the skin containing the transdermal absorption enhancer and a medicinal ingredient.

[Prior Art] Oral administration, injection, and the like have been widely used as methods for administering medicinal ingredients.

However, when administered orally, there are disadvantages such as insufficient absorption, temporary higher concentrations in the body than necessary in order to maintain the effect, and side effects such as gastrointestinal disorders and loss of appetite. was there. Furthermore, although absorption is rapid when administered by injection, a specialist such as a doctor is required.

In recent years, in order to improve such side effects and drawbacks, external preparations using transdermal administration methods have been developed. However, even with such external preparations, there are many cases where sufficient transdermal absorption is still not achieved, and the situation is far from satisfactory.

In other words, the surface of the skin is called the stratum corneum, which originally has a physiological function as a barrier to prevent foreign substances from entering the body. Merely adding medicinal ingredients to a drug does not provide sufficient transdermal absorption.

In order to improve this, various transdermal absorption enhancers have been proposed in recent years. For example, dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide, methyl decyl sulfoxide, etc. are known, but these cannot be said to be sufficient in terms of transdermal absorption promoting effect, safety, and usability.

[Problems to be Solved by the Invention] In view of the above-mentioned problems, the present inventors have developed a transdermal absorption enhancer i that is excellent in promoting transdermal absorption of medicinal ingredients and is also satisfactory in terms of safety and usability. As a result of intensive research, we have completed the present invention.

[Means for Solving the Problems] That is, the present invention provides a surfactant selected from the group consisting of a nonionic surfactant having a nitrogen atom in its molecule, an amphoteric surfactant, a semipolar surfactant, and a cationic surfactant. A transdermal absorption enhancer for medicinal ingredients, the active ingredients of which are one or more types of nonionic surfactants with or without nitrogen atoms in the molecule, and one or more nonionic surfactants with or without nitrogen atoms in the molecule, and the desired medicinal ingredients. This is an external preparation for skin, characterized by containing the above-mentioned transdermal absorption enhancer component.

Hereinafter, the configuration of the present invention will be explained in detail.

The nonionic surfactants having a nitrogen atom in the molecule include fatty acid alkanolamide, polyoxyethylene fatty acid amide, alkanolamine ester, polyoxyethylene alkylamine, etc., and the amphoteric surfactants include N, N, N, etc. -dimethyl-N-lauryl-N-carboxymethylammonium betaine, N,N-dimethyl-
Carboxybetaine such as N-oleyl-N-carboxymethylammonium betaine, 2-lauryl-N-carboxyethyl-N-hydroxyethylimidazolinium betaine, 2-lauryl-N-carboxymethyl-N-
Imidacillin derivatives such as hydroxyethylimidazolinium betaine, aminocarboxylic acid salts such as N-coconut-alkyl-β-aminopropionic acid sodium salt, N-coconut-coconut-β-iminodipropionic acid di-sodium salt, sulfobetaine, aminobetaine etc., and the semipolar surfactants include lauryldimethylamine oxide, bis-(2
-Hydroxyethyl) laurylamine oxide and other amine oxides are used as cationic surfactants.
Examples include fatty acid amine salts, alkyl quaternary ammonium salts, aromatic quaternary ammonium salts, pyridinium salts, and imidazolium salts. One or more types are arbitrarily selected from these.

On the other hand, examples of nonionic surfactants that do not have a nitrogen atom in the molecule include sorbitan monooleate, sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, and sorbitan sesquis Sorbitan fatty acid esters such as oleate, sorbitan trioleate, diglycerol venter-2-ethylhexylate sorbitan, diglycerol tetra-2-ethylhexylate sorbitan, monocottonseed oil fatty acid glycerin, monoerucic acid glycerin, sesquioleic acid glycerin, monostearic acid Glycerin, glycerin polyglycerin fatty acids such as glycerol monostearate malic acid, propylene glycol fatty acid esters such as propylene glycol monostearate, lipophilic nonionic surfactants such as hydrogenated castor oil derivatives, glycerin alkyl ethers, polyoxyethylene POE sorbitan fatty acid esters such as sorbitan monooleate (hereinafter referred to as POE), POE sorbitan monostearate, POE sorbitan monooleate, POE sorbitan tetraoleate, POE sorbitan monolaurate, POE sorbitan monooleate,
POE sorbitol fatty acid esters such as POE sorbitol bentaoleate and POE sorbitol monostearate; POE glycerol fatty acid esters such as POE glycerol monostearate, POE glycerol monoisostearate and POE glycerol triisostearate;
POE monooleate, POE distearate 1. P
POE fatty acid esters such as OE monodioleate, ethylene glycol distearate, POE lauryl ether, POE oleyl ether, POE stearyl ether, POE behenyl ether, POE 2-octyl dodecyl ether, POE cholestanol ether, etc.
OE alkyl ethers, POE alkylphenyl ethers such as POE octylphenyl ether, POE nonylphenyl ether, r'OE dinonylphenyl ether, Pluronic types such as Pluronic, POE-P
Or' cetyl ether, POE-POP2-decyltetradecyl ether, POE-P monobutyl ether,
POE-POP alkyl ethers such as POE-POP hydrogenated lanolin and POE-POP glycerin ether, fatty acid esters of glycerol or polyglycerol such as diglycerin monooleate, hexaglycerin stearate, and decaglycerin monolaurate, Tetronic, etc. Tetra POE/Tetra POP ethylenediamine condensates, POE castor oil, POE hydrogenated castor oil, POE hardened castor monoisostearate OE hardened castor triisostearate OE hardened castor castor maleic acid POE castor oil hardened castor oil Oil derivatives' POE beeswax and lanolin derivatives such as OE sorbit beeswax,
l'OE propylene glycol fatty acid ester, C:i
Examples include hydrophilic nonionic surfactants such as sugar fatty acid esters and POE nonylphenyl formaldehyde condensates.

One or more selected from the group consisting of nonionic surfactants, amphoteric surfactants, semipolar surfactants, and cationic surfactants having a nitrogen atom in the molecule;
The molecular ratio of one or more nonionic surfactants having no nitrogen atom in the molecule is 20:1 to 1:20, preferably 10:1 to 1:10.

The following are examples of medicinal ingredients whose efficacy can be enhanced by the use of the above-mentioned transdermal absorption enhancers.

In other words, steroidal anti-inflammatory agents such as prednisolone and dexamethacin, nonsteroidal anti-inflammatory agents such as indomethacin, flufenamic acid, and mefenamic acid, antihistamine agents such as chlorpheniramine, diphenhydramine, and promethacin, sulfamonomethoxine, and sulfamethizole. Sulfa drugs such as. Antibiotics such as penicillin, cephalosporin, erythromycin, tetracycline, chloramphenicol, streptomycin, antifungal agents such as naphthiomate, clotrimazole, anti-malignant agents such as 5-fluorouracil, cyclophosphamide, busulfan, actinomycin, etc. agents, morphine, codin, nalorufine, pentazocine, aspirin, acetanilide,
Analgesics such as aminopyrine, prostaglandin preparations,
hypnotics and sedatives such as barbital and thiobental;
Psychotropic agents such as chlorpromazine, reserpine, and chlordiazepoxide; antiparkinsonian agents such as chlorzoxazone and levodopa; inotropes such as dioquitoxin and digoxin; antiarrhythmic agents such as propyroinamide hydrochloride and propranol hydrochloride; antiarrhythmic agents such as diviridamol and amyl nitrite; Anginal drugs, antihypertensive drugs such as diazoxide, minoxidil, reserpine, and guanethidine nitrate, ultraviolet inhibitors such as para-aminobenzoate ester, hydroquinone, and vitamin C.
Esters, melanin production inhibitors such as parahydroxycinnamate, psoriasis P such as 8-methoxypsoralen
UVA treatment agents, vitamins such as vitamin Δ, vitamin E and vitamin C, hormones such as insulin, estradiol, and methyltestosterone, diagnostic agents, allergens for patch tests, insect repellents, insecticides, moisturizers, keratin softeners, and dyes. It is a medicinal ingredient in hair products, etc.

These medicinal ingredients are quickly absorbed into the skin by mixing them into the transdermal absorption enhancer of the present invention and applying the mixture to the skin. If the medicinal ingredient is intended for local action, it will penetrate deeply into the skin and exhibit excellent effects, whereas if the medicinal ingredient is intended for systemic action, it will be transferred into the bloodstream, so it will be equally effective. It has a great effect.

Naturally, it is used for humans, but it is also effective for other animals.

The amount of medicinal ingredients to be blended may be sufficient as long as it is sufficient to achieve the desired medicinal effect, and it varies depending on the type of medicinal ingredient, patient's weight, symptoms, etc. - Although it cannot be generalized, it is generally Transdermal absorption enhancer o, ooi per 1 weight
~50wt.

The above-mentioned transdermal absorption enhancer may be used as it is by appropriately mixing the medicinal ingredients, but in general, the components are mixed in an appropriate skin external preparation, taking into consideration the feeling of use and the preference for application.
For example, it is used by being incorporated into the base of cream preparations, ointment preparations, gel preparations, lotion preparations, emulsions, adhesive tapes, and the like.

In that case, the amount of each component to be blended will vary depending on the type of medicinal ingredient, etc., but the following range is generally the preferred range of the amount to be blended. That is, one or more surfactants selected from the group consisting of nonionic surfactants, amphoteric surfactants, semipolar surfactants, and cationic surfactants each having a nitrogen atom in the molecule, and one or more surfactants having a nitrogen atom in the molecule. The total compounding amount of one or more nonionic surfactants without 0.001 to 10% by weight, more preferably 0.01 to 5% by weight of the active ingredient in the external preparation. 001-10
% by weight, more preferably 0.01-5% by weight. In addition, one or more types selected from the group consisting of nonionic surfactants, amphoteric surfactants, semipolar surfactants, and cationic surfactants each having a nitrogen atom in the molecule, and a nitrogen atom in the molecule. Nonionic interface with and without.

The ratio of one or more activators is as described above, that is, the molecular ratio is 20:1 to 1:20. Preferably a ratio of 10:1 to 1:10 is applied as such.

The topical preparation for promoting transdermal absorption of medicinal ingredients according to the present invention includes:
In addition to the above-mentioned essential components, components that are commonly used in pharmaceuticals, quasi-drugs, cosmetics, etc. can be added.

These ingredients include polyhydric alcohols, oils, waxes, acids, alkalis, cationic surfactants, nonionic surfactants, anionic surfactants, amphoteric surfactants, powders, pigments, dyes, preservatives, and antioxidants. agent, ultraviolet absorber,
Examples include chelating agents, water-soluble polymers, montmorillonite, alcohols, solvents, fragrances, and the like.

[Examples] Next, the present invention will be specifically explained with reference to Examples, but the present invention is not limited only to these Examples.

Example 1 Cream (1) Dexamethacin 0.025%
(2) Propylene glycol 8.0 (3) Glycerin 5.0 (4) Liquid paraffin 1.0 (5) Diisopropyl adipate 3.0 (6) Fatty acid alkanolamide
1.8(7) Sorbitan monooleate 1.0
(8) Glycerin monofatty acid ester 1.5 (9) Preservative appropriate amount (10) Clay mineral (bentonite) 6.0 (11) Purified water
Residue [Production method] Add (1), (4), (8), and (9) to (5), and make 7
Heat to 0°C and mix to dissolve. This is referred to as composition (A).

Add and dissolve (6) and (7) to a part of (11), and then (
Add and mix 2) and (3). This is referred to as composition (B).

While maintaining the temperature at 70° C., composition (A) is gradually added while stirring composition (B), pre-emulsified, and then emulsified using a homomixer.

This was added while stirring to a mixture in which (10) had been added and dispersed in the remainder of (11), and the mixture was cooled to obtain a cream.

Comparative Example 1 Cream (1) Dexamethacin 0.025% (
2) Propylene glycol 8.0 (3) Glycerin 5.0 (4) Liquid paraffin 1.0 (5) Diisopropyl adipate 3.0 (6) Glycerin monofatty acid ester 1.5 (7) Preservative appropriate amount (8) Clay mineral (bentonite) 6.0 (9) Purified water
Residue [Manufacturing method] According to Example 1.

Test Example The creams prepared in Example 1 and Comparative Example 1 were compared for their vasoconstrictive effects.

That is, the creams prepared in Example 1 and Comparative Example 1, as well as the two creams that do not contain dexamethacin, were randomly assigned to the upper backs of 10 healthy male subjects. )
It was applied and sealed. After 4 hours, the bandage was peeled off, test t1 was removed, and the sample was left for another 4 hours before being evaluated.

Judgment criteria are: ``pronounced pallor'' (score 2), ``obvious pallor'' (score 1), and ``slight pallor'' (score 0.5) due to pallor caused by the vasoconstriction effect of steroids. ), rNo change" (score 0), and an average score was determined for each base side.

The results are shown in Table-1.

As is clear from the table, it can be seen that the cream of Example 1 has excellent vasoconstriction effect.

Example 2 Gel (1) Ondomethacin 1.0% (2
) Ethyl alcohol 50.0 (3) Carboxy vinyl polymer 1.2 (4) Polyoxyethylene (40 mole addition) Hydrogenated castor oil 1.5 (5) Lauric acid jetanolamide 1.5 (6) Lauryl dimethylamine oxide 1.0(7) Lauryl Betaine
0.5 (8) POE sorbitan monostearate 1.14 (9) POE fatty acid ester
0.2(10) diisopropanolamine
0.35 (11) Purified water
Residue [manufacturing method] (5) , (6) , (7) , (8L) (9) (1
After dissolving in 1), (3) is well dispersed. this,(
Add (1) and (4) to 2) and mix well. Furthermore, (10) was added to this mixture, and the mixture was thoroughly stirred and mixed to obtain a gel.

Comparative Example 2 (1) Indomethacin i, o% (2
) Ethyl alcohol 50.0 (3) Carboxyvinyl polymer 1.2 (4) Polyoxyethylene (40 mole addition) Hydrogenated castor oil 1.5 (5) Diisopropaturamine 0.35 (6) Purified water
Residue [Manufacturing method] According to Example 2.

Comparative Example 3 Commercially available soft IF (gel-like external preparation) containing 1% indomethacin.

Trial Example The efficacy of the above gel base was investigated and compared using a carrageenan edema inhibition rate test.

That is, 5 male Wistar rats aged 6 weeks old were made into one group, and the volume of the right hind limb of the rats in each group was first measured using a rat hind limb paw edema volume measuring device KM-357 (Natsume Seisaku rupture). Measure and then apply 0.2 g of the sample to the right hind paw of the rat. Two hours later, 0.05ml of 1% carrageenan sodium salt was subcutaneously injected into the same site, and 3 hours after injection of carrageenan sodium salt, the volume of the right hind paw was measured, and the difference between the volume of the right hind paw before sample application was determined as the paw edema volume. The foot edema suppression rate was calculated using the following formula.

However, ■c and Vt indicate the average foot edema volume of the control group (no test sample applied) and the test sample applied group, respectively.

The above test results are shown in Table-2.

As is clear from the table, it can be seen that the gel base of Example 2 has an excellent effect of inhibiting carrageenan edema.

Example 3 (1) Hydroquinone 1.0%
(2) Distearyldimethylammonium chloride 0.5 (3) Triglycerol monolaurate 1.5 (4) Purified water
Residue [Production method] (After dissolving 2L (3) in (4), add (1),
Stir well to dissolve and use as a sample.

Comparative Example 4 (1) Hydroquinone 1.0%
(2) Purified water remainder [Production method] ° According to Example 3.

Comparative Example 5 (1) Hydroquinone 1.0% (2
) Urea 5.0 (3) Purified water Residue [Production method] According to Example 3.

Test Example Sample 1001 was applied to the back skin of three hairless mice in a group using a Torii batch test adhesive plaster (diameter 1.6 cm). A sponge was placed on top of the bandage and then covered with a thin rubber film so that the bandage adhered tightly. Immediately after application, the sample was placed in a sealed plastic container, and air was blown thereto to absorb exhaled carbon dioxide into the 50% methanol solution of monoethanolamine.

After application, remove the bandage from the application area 24 and 48 hours later,
The activity in the plaster was measured. The applied area was then stripped 8 times with cellophane tape, and the activity in the stratum corneum adhered to the cellophane tape was measured.

Thereafter, the animal's skin was peeled off from the area where the layer killing was applied, and the activity in the skin was measured. The remaining whole body was homogenized in a blender by adding 30 g of 0.5N aqueous sodium hydroxide solution, and a certain amount of this was collected to measure the activity. In addition, feces and urine that had been excreted within the required time were collected and their activity was measured.

Here, the sum of the amount of exhalation excreted, the amount of feces/urine excreted, and the amount stored in the body was defined as the amount of percutaneous absorption in the body.

The above test results are shown in Table-3.

Table 3 [Effects of the Invention] The transdermal absorption enhancer and skin external preparation according to the present invention are transdermal absorption enhancers that are excellent in the effect of promoting transdermal absorption of medicinal ingredients, and are safe and have a good feel when used. .

Claims (1)

[Claims] 1. A nonionic surfactant having a nitrogen atom in its molecule;
One or more types selected from the group consisting of amphoteric surfactants, semipolar surfactants, and cationic surfactants, and one or more types of nonionic surfactants that do not have a nitrogen atom in the molecule. A transdermal absorption enhancer for medicinal ingredients containing as an active ingredient. 2. A medicinal ingredient, one or more selected from the group consisting of a nonionic surfactant having a nitrogen atom in the molecule, an amphoteric surfactant, a semipolar surfactant, and a cationic surfactant, and a molecule. 1. A preparation for external use on the skin, characterized in that it contains one or more nonionic surfactants that do not contain nitrogen atoms.