JPH0331217A - Percutaneous absorption promoting composition and external preparation containing same composition - Google Patents

Abstract

PURPOSE:To obtain the title composition capable of synergistically enhancing skin permeation rate of a medicine by further blending combination system of 1-dodecylazacycloheptan-2-one and propylene glycol with a specific compound such as nicotic acid ester. CONSTITUTION:The percutaneous absorption promoting composition containing (A) 5-35wt.% 1-dodecylazacycloheptan-2-one, (B) 30-90wt.% propylene glycol and (C) 5-35 wt. one or two or more kind of compounds selected from nicotic acid ester, isonicotic acid ester, sebacic acid diester and N,N-diethyl-m-tolamide, preferably containing the ingredients A, B and C each in a weight ratio of 10-25%, 40-30% and 10-25%. The above-mentioned composition is effective on every type of water soluble medicine, fat soluble medicine or insoluble medicine and blended with an external preparation at an amount of 0.5-50wt.%, especially 5-40wt.%.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to a transdermal absorption promoting composition and an external preparation containing the same. For more details.

■ 1-)'f with dilazacyclohebutan-2-one.

■ Propylene glycol.

(2) One or more selected from the group consisting of nicotinic acid ester, isonicotinic acid ester, sebacic acid diester, and N,N-diethyl-m-)ylamide.

The present invention relates to a transdermal absorption promoting composition characterized by containing the same, and an external preparation containing the same.

(Prior Art) A transdermal absorption enhancer is a substance that reduces the barrier function of two epidermal tissues, particularly the stratum corneum, against drug absorption and increases the skin permeability of drugs.

Transdermal Thermal System
Since the new concept of apeutic System (TTS) was introduced.

There is an increasing need to develop excellent percutaneous absorption enhancers, and research on this topic is also active.

In other words, not only drugs with poor transdermal absorption, but also drugs that are considered to have relatively good transdermal absorption, and not only drugs for systemic treatment but also drugs for local treatment. However, increasing the permeation rate of the stratum corneum permeation process, which is considered to be the rate-limiting step in the transdermal absorption process, is the key to developing TTS formulations that aim to achieve accurate medicinal efficacy under precise administration control. This is because it is essential when designing.

Recently, two kinds of transdermal absorption enhancers have been reported, and 1-dodecyl azacyclohebutan-2-one [trade name: Eishin (Azone)] is a substance that shows particularly excellent transdermal permeability. , Nelson Company, USA. This compound is hereinafter referred to as Eishin] has attracted attention (Japanese Patent Publication No. 60-37092, JP-A No. 61-27966).
.

This patent document regarding Eishin describes the combination of Eishin and "propylene glycol as an inert carrier" in a drug, and JP-A-60-3 which was -1°
Publication No. 6422 discloses that this binary mixture of eisin and propylene glycol is a vehicle that can increase the penetration of drugs. Therefore, it is already known to incorporate propylene glycol in order to enhance the effect of promoting transdermal absorption of Eishin.

Regarding such a complex transdermal absorption promoting composition,
Arch, Derm, 118.474-477 (
1982) and Japanese Unexamined Patent Publication No. 61-33128.

As well as significantly increasing the skin permeation rate of.

Showing effects on both water-soluble and fat-soluble drugs.

It is excellent as a transdermal absorption enhancer due to its low toxicity. However, not only in the single system of Eishin, but also in the complex system represented by Eishin and propylene glycol,
It has not yet been shown to have a practical effect on promoting transdermal absorption of drugs.

An object of the present invention is to provide a composition that exhibits a synergistic transdermal absorption promoting effect compared to the effect observed in the eisin-propylene glycol complex system. Another object of the present invention is to provide an external preparation containing such a composition.

(Means for Solving the Problems) Therefore, the present inventors conducted intensive research on a composition for promoting transdermal absorption that meets the above-mentioned purpose. A composite system of 1,3-butylene glycol and Eisone cannot enhance the transdermal absorption promoting effect of Eisin, and a composite system of Eisin and isopropyl adipate, or a composite system of Eisin and ethylene glycol salicylate, etc. It was also confirmed that the absorption-promoting effect of Eishin was actually weakened. The latter finding is based on a report that the percutaneous absorption promoting effect of Eishin is diminished in the presence of lipophilic substances such as diethyl sebacate [S, Kondo et al.
al,,,J,Pharmacobio-Dyn,,
11.88-94 (1988) + especially page 92, left column, lines 12-15].

Under these circumstances, as a result of further intensive research, Eishin and
The combination of specific propylene glycol with diethyl sebacate itself and the same lipophilic substances nicotinic acid ester, isonicotinic acid ester, N,N-diethyl-m-)ylamide, which have been described as reducing the promoting effect of eicin. We have discovered that, quite unexpectedly, when using a specific formulation, the absorption promoting effect of Eishin is synergistically enhanced.

In other words, the present invention is ■ With Eishin.

■ Propylene glycol.

■ Nicotinic acid ester, isonicotinic acid ester, sebacic acid diester, and N,N-diethyl-m-)
The composition comprises a transdermal absorption promoting composition characterized by containing one or more kinds selected from the group consisting of polyamides, and an external preparation characterized by containing the composition and a drug. It is something.

Note that the percutaneous absorption promoting effect of the present invention was confirmed with dantrolene sodium, a skeletal muscle relaxant, and inderoxazine hydrochloride, a therapeutic agent for cerebrovascular disorders and head trauma.

Dantrolene sodium, unlike many other peripheral muscle relaxants, is a drug that exerts muscle relaxing effects by directly inhibiting calcium release during the excitation-contraction phase of the skeleton, without going through the nervous system.

Already in use. However, the current administration route is oral or injection, and nine different side effects have been reported because the drug's effects extend to the whole body other than the affected area. Therefore, systemic administration is not preferable for localized muscle tension diseases, and there has been a demand for the development of a TTS formulation that allows the drug to primarily migrate into the muscle, which is the diseased area. However, dantrolene sodium has extremely poor skin absorption.

When developing the TTS formulation, it was necessary to develop a strong transdermal absorption enhancer to significantly improve the skin permeability of dantrolene sodium.

Recently, however, an invention has been published that uses dantrolene sodium as an external preparation (Japanese Patent Application Laid-Open No. 1-12
No. 8928).

This publication describes specific alcohols of specific dicarboxylic acids, including eishin, isopropyl adipate, and diethyl sebacate, as absorption modifiers for preparing dantrolene sodium as an external preparation.

However, the publication describes nicotinic acid esters and isonicotinic acid esters that are essential to the present invention.

N,N-diethyl-m-)ylamide is not disclosed at all, and sebacic acid diester, which is essential to the present invention, is not specifically described, and isopropyl adipate does not attenuate or enhance the promoting effect. and 1,3-butylene glycol.
Considering the knowledge of those skilled in the art based on bio-Dyn, this does not suggest a composite system of sepacic acid diester toflobylene glycol and eisin.

In addition, Example 6 and other formulations in which almost no transdermal absorption of dantrolene sodium is observed are disclosed, which not only raises questions as to whether the invention of a topical dantrolene sodium preparation, especially a patch, is practical. However, only the Eisin-propylene glycol composite system has been confirmed to be effective, and the effects that it is said to have achieved are significantly different from those achieved by the present invention.

On the other hand, a percutaneous absorption topical preparation of inderoxazine or its salt for systemic application is known from Japanese Patent Laid-Open No. 1-68323 filed by the present applicant.

Makoto: Although the invention discloses the formulation of an external preparation that brings about a specific absorption-promoting effect, it does not disclose the use of Eishin, and its absorption-promoting effect is also different when compared to the effect of the present invention. was recognized.

The esters of nicotinic acid ester, isonicotinic acid ester, and hisebacic acid diester that are further blended into the eisin-propylene glycol combination system specified in the present invention are esters composed of lower alkyl groups, aralkyl groups, etc. Specific examples of groups include linear or branched alkyl groups having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, and pentyl groups; examples of aralkyl groups include benzyl and phenethyl groups. Preferred examples include groups.

These nicotinic acid esters, isonicotinic acid esters,
Sebacic acid diester (hereinafter referred to as esters) and N
, N-diethyl-m-toluamide (hereinafter referred to as DEET) can be used alone or in an appropriate combination of two or more thereof.

The amount of each component used in the composition of the present invention is approximately 5 to 35% by weight, preferably approximately 1% by weight, based on the total amount of the composition.
0 to 25% by weight, propylene glycol about 30 to 90%, preferably about 40 to 80%, and esters or DEET about 5 to 35%, preferably about 10 to 25%.

The present invention also includes external preparations containing the above-mentioned composition and a drug, and examples of the external preparation include any of skin-applied preparations such as patches, ointments including gel ointments, and emulsions. However, it is preferable to use a patch as a formulation of TTS, which is easy to administer, can be controlled, and can be expected to have accurate medicinal efficacy.

The drug used in the external preparation of the present invention may be any drug whose transdermal absorption is significantly enhanced by the transdermal absorption promoting composition of the present invention.

Among other things, preparation of TTS as an appropriate dosage form is desired for the purpose of reducing side effects, sustaining drug efficacy, and avoiding inactivation due to first passage through the liver.

It is even more preferable if the drug is inherently inferior in transdermal absorption.

Therefore, the drug is local in its therapeutic purpose.

It doesn't matter if it's systemic. Also, water-soluble drugs.

It may be a fat-soluble drug or a poorly soluble drug.

Such drugs include (1) anti-inflammatory agents: '-fson, hydrocortiscin, petamethacin, dexamethacin, prednisolone;

Steroid anti-inflammatory drugs such as triamcinolone, fluorodinolone, its salts, and its derivatives, acetaminophen, phenacetin, indomethacin, flufenamic acid,
Mefenamic acid.

Diclofenac, Arclofenac, Clidanac,
Ibuprofen, fenoprofen, flurbiprofen, ketoprofen.

Fuenbufuen, thiaramide, naproxel 2ta Phenylbuzone, oxyphenpudazone.

Nonsteroidal anti-inflammatory agents such as piroxicam, its salts, and its derivatives, and other anti-inflammatory agents such as glycyrrhizin and glycyrrhetinic acid.

(2) Antibiotics chloramphenicol, tetracycline antibiotics,
penicillin antibiotics, cephalosporin antibiotics,
macrolide antibiotics, lincomycin antibiotics,
Antibiotics such as aminoglycoside antibiotics.

(3) Antifungal agents Antifungal agents such as tolnaftate, clotrimazole, griseofulvin, nystatin, amphotericin-B.

(4) Cardiovascular agents Circulatory agents such as vasodilators such as nitroglycerin, insorbide nitrate, trapidil, and nicorandil, and calcium antagonists such as nifedipine, nicardipine, nimodipine, nitrendipine and its salts.

(5) Antihistamines diphenhydramine, chlorpheniramine.

Antihistamines such as flemastine and its salts.

(6) Neuropsychiatric agents diazepam, chlordiazepoxide, nitrazepam, oxazepam, fludiazepam.

Neuropsychiatric drugs such as metazebam, chlorpromazine, haloperidol, fluphenazine, thioridazine, belphenazine and its salts.

(7) Muscle relaxants such as skeletal muscle relaxants such as dantrolene, bricinol and its salts.

(8) Antispasmodics Antispasmodics such as atropine, scopolamine, its salts, and its derivatives.

(9) Brain disorder improving agent Brain disorder improving agents such as inderoxazine and its salts.

Examples include.

These drugs are used in external preparations for shrub inventions.
It can be used as a combination drug as appropriate depending on the therapeutic purpose such as indication.

The amount of the drug to be blended varies depending on the type and amount of the absorption-promoting composition of the present invention used, but it is approximately 0.1 to 5% by weight based on the total formulation.

It is preferably about 0.5 to 3% by weight, and in the case of IJum, it has been confirmed that when it is about 1.5% by weight or more, the transdermal absorption of the drug by the absorption-promoting composition of the present invention is further enhanced. approximately 1.5 to 3% by weight is still preferred.

The transdermal absorption promoting composition consisting of eishin, propylene glycol, and esters or DEET to be added to the external preparation of the present invention has the composition and blending ratio as described above.

The proportion of the composition used in the external preparation depends on the form of the external preparation,
It is preferably about 0.5 to 50% by weight, particularly about 5 to 40% by weight, based on the total amount of the drug, depending on the type and amount of the drug and base used.

In addition to the above-mentioned absorption-promoting composition, the external preparation of the present invention also contains:
It is possible to further add two conventionally known percutaneous absorption enhancers within a range that does not impair the percutaneous absorption promoting effect of the present invention. Examples of such percutaneous absorption enhancers include dimethyl sulfoxide, dimethylacetamide, dimethylformamide, lactic acid, and ureas.

Furthermore, each component of the transdermal absorption promoting composition of the present invention does not have to be added at the same time when preparing an external preparation, but it is sufficient that the components of the composition are contained in the external preparation.

Among external preparations, for example, patches usually have two layers: a support and a pressure-sensitive adhesive layer capable of releasing the drug (in the case where the drug is mixed into the pressure-sensitive adhesive layer, there are nine separate layers).

(e.g., they may contain special forms of drug release).

and a release film that protects this pressure-sensitive adhesive layer.

For the sake of simplicity, if a patch with a drug-incorporated pressure-sensitive adhesive layer is described, the pressure-sensitive adhesive layer will be described as follows.

A therapeutic drug, a patch base, and the percutaneous absorption promoting composition of the present invention are mixed to form a plaster.

The patch base can homogeneously mix the drug, has pressure-sensitive adhesive properties at room temperature, releases the drug when applied, and does not impair the transdermal absorption of the drug promoted by the absorption-promoting composition of the present invention. Any base may be used, including all general adhesive bases other than bases that reduce the effect of eisin-propylene glycol esters or DEET.

Specific examples of adhesive components include natural rubber, styrene-butadiene rubber (SBR), polyisoprene rubber, polyisobutylene rubber, and styrene-inprene-styrene block copolymer (SIS).

Styrene-butadiene-styrene block copolymer (S
BS), silicone rubber (organopolysiloxane rubber)
y Acrylic copolymers such as (meth)acrylic acid-(meth)acrylic ester copolymers, hydrophilic polymers such as sodium polyacrylate, carboxymethylcellulose (CMC), sodium carboxymethylcellulose (CMCNa), and polyvinyl alcohol. (PV
A), polyvinylpyrrolidine (pvp), methyl vinyl ether maleic anhydride copolymer, sodium alginate, alginate propylene glycol ester, pectin, xanthan gum, xanthan gum, locust pea gum, guar gum, alapiano galactan, sodium hyaluronate, etc. .

Rubber and the like can be used as latex emulsions. Moreover, these adhesive components and hydrophilic polymers can be used in appropriate combinations.

Ingredients that can be added to these as needed are:

Sludge agent such as gelatin] Powder excipients such as kaolin, bentonite, zinc oxide, titanium oxide; Finton O (
Petroleum resins, rosin, hydrogenated rosin, such as product name 9 (aliphatic type, manufactured by Nippon Zeon Co., Ltd.), Alcon ■ (product name, manufactured by Arayo Kagaku Co., Ltd., alicyclic type).

Tackifier components such as resins such as ester gum; higher fatty acid esters such as polybutene, liquid paraffin, and inpropyl myristate; softeners such as silicone oil and various vegetable oils; glyceryl fatty acid esters such as glyceryl monostearate, polyoxyethylene Sorbitan monolaurate (for example, Nikko Chemicals: TL-10).

Polyoxyethylene sorbitan monostearate (for example, Nikko Chemicals: TS-10) Natonopolyoxyethylene lupitan fatty acid ester.

Sorbitan monostearate (Nikko Chemicals: 5
Surfactants such as sorbitan fatty acid esters such as S-10); methylparaben, ethylparapen, propylparaben, phthylhalachen, sorbic acid, salts of sorbic acid, butylhydroxyanisole (BHA), dibutylhydroxytoluene (BIT), nordihydroguay Aretic acid.

Preservatives and oxidation (aging) inhibitors such as guaiacol esters; pH adjusters such as organic acids such as acetic acid, succinic acid, citric acid, malic acid, fumaric acid, maleic acid, and tartaric acid (themselves useful as patch bases) astringents such as salts that produce trivalent metal ions such as aluminum chloride, aluminum sulfate, alum, and aluminum allantoinate; humectants such as alkaline earth metal salts; flavoring agents such as menthol; Solvent; water etc. are mentioned.

In addition, examples of moisturizing agents include polyhydric alcohols such as mannitol, sorbitol, glycerin, diglycerin, triglycerin, and propylene glycol.
When 3-butylene glycol is used in place of propylene glycol in the absorption-promoting composition of the present invention, the percutaneous absorption-promoting effect is conversely reduced. Therefore, polyhydric alcohol is used as a moisturizing agent, and 1,3-butylene glycol in polyhydric alcohol does not preclude its use as a moisturizing agent as long as it does not impair the absorption promoting effect of the present invention. Rather, it is preferable not to use it. Polyhydric alcohols also include those that serve as solvents for drugs.

These bases are appropriately determined in consideration of the amount of the drug and the percutaneous absorption promoting composition to be used and the percutaneous absorption promoting effect. Specifically, the amount of these bases used differs between poultices and patches such as tapes, but the amount of these bases used is approximately 45 to 99.4% by weight (propylene glycol) based on the entire preparation (paste). ), preferably about 57 to 94.5% by weight.

In addition, as a solvent for dantrolene sodium, macrogol (PEG) 400. N-methyl-2-pyrrolidone, ethylene glycol, propylene glycol/I/ in a coexistence system with PEG, serine, diglycerin, triglycerin, and water (normal water and purified water).

The solvent is drug specific and is typically, but not limited to, the macrogol (PEG) mentioned above.

N-methyl-2-pyrrolidone, propylene glycol,
In addition to glycerin, organic solvents such as ethanol, isopropanol, benzine alcohol, phenethyl alcohol, crotamiton, water, or a mixed solvent thereof may be used.

In order to manufacture the patch of the present invention, a drug and a base are required.

Each component of the composition for promoting transdermal absorption is kneaded uniformly.

The mixture is spread on a support and dried if necessary.

Attach release film and cut to appropriate size.

Pack it.

When kneading and manufacturing a uniform paste, 1) A chemical used to facilitate the mechanical kneading operation.

Taking into consideration the physicochemical properties of the base and each component of the transdermal absorption promoting composition, it is free to appropriately set the order of addition and kneading, or to perform heating and ultrasonic treatment.

When producing bag or tape formulations using the emulsion method, adhesive components such as rubber are prepared in advance as a latex emulsion.

It can be added and kneaded.

Spreading is carried out according to a conventional method, such as by maintaining the prepared paste on a support or a release film at an appropriate temperature or by heating it to uniformly apply the paste to a predetermined thickness.

Drying is performed when producing tape formulations with low water content by a solvent method or an emulsion method, and the solvent or water is volatilized.

Next, when the paste is spread on a support, a release film is laminated onto the paste, and when the paste is spread on the release film, a support is laminated onto the spread plaster.

As the support, cloth, nonwoven fabric, plastic film, etc. are used, and flannelette and nonwoven fabric are particularly preferred.

Further, as the release film, cellophane or polyethylene film that has been subjected to release treatment is preferably used.

Other external preparations 9 For example, ointments based on macrogol, etc.
Gels (hydrogel or hydrophilic gel ointment) based on carboxyvinyl polymers, emulsions based on water, oily components, and emulsifiers can also be formulated according to conventional methods.

(Effects of the Invention) The composition of the present invention synergistically increases the skin permeation rate of drugs compared to conventionally known eisin-propylene glycol complex promoters. Therefore.

Practical TTS can be achieved by making a patch using this composition.
It becomes possible to formulate a formulation of

In particular, one aspect of the present invention is the synergistic effect of promoting percutaneous absorption.

Even if 1,3-butylene glycol is used in place of propylene glycol, or isopropyl adipate or ethylene glycol salicylate is used as an ester, this cannot be achieved, and in fact, it may be reduced. On the contrary, this is a completely unexpected effect.

Such synergistic effect was confirmed by the following test method.

Experiment 1. Skin permeability test of dantrolene sodium (in vitro) (Preparation of sample solution) Comparative example 1゜Two parts of dantrolene sodium was added to Macrogol 40048
The sample solution was dissolved by heating at 60° C., then returned to room temperature, 50 parts of propylene glycol was added thereto, and mixed well to obtain a sample solution.

Comparative Example 2 A sample solution was prepared in the same manner as in Comparative Example 1 except that 38 parts of macrogol 400 and 40 parts of propylene glycol were added and mixed, and then 20 parts of n-butyl isonicotinate was added and mixed. Obtained.

Comparative Example 3 In place of 20 parts of n-butyl isonicotinate, Eishin 2
A sample solution was obtained in the same manner as in Comparative Example 2 except that the sample solution was 0 parts.

Experimental method The abdominal skin of male Hartley guinea pigs, which had been shaved the day before, was removed and
z) After mounting in the type diffusion cell, a sample solution of dantrolene sodium and a dantrolene sodium solution of the present invention prepared in the same manner were respectively added to the donor side. An isotonic 10 mM potassium dihydrogen phosphate solution was used on the receptor side, and the cell temperature was 37°C. The receptor solution was collected over time, and the concentration of dantrolene sodium in the sample solution and the example solution was measured by high performance liquid chromatography (HP
The cumulative skin permeation amount of dantrolene sodium (DN) after 32 hours (unit * ng/sq-c) was measured by LC).
m ) was determined, and the transmittance (the magnification of the example when Comparative Example 3 is set to 1) was determined.

The experimental results are shown in the table below.

As is clear from the above experiments, the propylene glycol single system without the addition of Eishin and hisesters, the propylene glycol ester complex system without the addition of Eishin, and the Eisin-propylene glycol complex system without the addition of esters (Table 1) Although not shown, the Eisin-propylene glycol complex of Comparative Example 3 exhibits the most skin permeation effect among the Eishin single system without propylene glycol processing and the Eisin-ester complex system that have almost no cumulative permeation amount of Darontrene sodium. The transdermal absorption enhancer of the present invention exhibited an unexpectedly remarkable effect on promoting transdermal absorption compared to other systems, and this effect was noticeable even in water-containing systems, so it was used in water-containing systems such as poultices. Although not shown in the table, methyl isonicotinate and benzyl nicotinate also showed similar results.

Experimental example 2. Skin permeation test of inderoxazine hydrochloride (
In Vitro) Inderoxazine hydrochloride was used as the drug, and ethanol was used as the solvent for inderoxazine hydrochloride, and the amounts of each were set to amounts suitable for this system.

The preparation and test were conducted in the same manner as in Experimental Example 1, except that the amount of skin permeation was determined over a cumulative 8 hours. In addition, Comparative Examples 4 to 7 were prepared in the same manner as in Example 7 described later using the amounts shown in the table below.

The results are shown in the table below.

As is clear from this table, the transdermal absorption promoting composition of the present invention exhibits a remarkable effect compared to the glopylene glycol single system and the Eisin-propylene composite system. Although not shown in the table, ethyl innicotinate, isonicotinic acid n
Similar effects were observed for n-butyl -phthyluninicotinate.

Experiment 3. Dantrolene sodium gel formulation guinea pig skin permeability test (in vitro) Cole 20g
Mix well and add 120 g of Macrogol 400 solution of 5% concentration dantrolene sodium little by little while stirring. Next, add 5 g of Eisin and mix well to prepare a sample.

(Experimental method) Sample gel (
Comparative Example 8), using the gel formulations of Examples 9 and 10, 24
Cumulative skin permeation amount of dantrolene after hours (ng/crn2
), except that the transmittance was determined when Comparative Example 8 was set to 1.
The method was the same as in Experiment 1.

The experimental results are shown in the table below.

Table 3 Guinea pig skin permeability of dantrolene sodium in propylene glycol-containing aqueous gel base system (
(in vitro) As is clear from this table, compared to the Azon-globylene glycol complex system that does not contain esters or DEET, the transdermal system of the present invention that contains esters such as n-butyl isonicotinate and DEET A gel preparation containing an absorption-promoting composition exhibits a synergistically high transdermal absorption-promoting effect of dantrolene sodium.

Experiment 4. Rat muscle white density measurement Rat muscle density measurement method Hind limbs and 6c of male Wistar rats shaved the day before
A poultice (Example 12) cut into pieces of m" was applied, and the muscle immediately below was removed at 3.6, 12.18 and 24 hours later.

It was used as a specimen.

The specimen was homogenized with methanol and then centrifuged.
After drying the supernatant under reduced pressure and extracting with aqueous acetonitrile,
The amount of dantrolene sodium was measured by high performance liquid chromatography (HPLC).

The results are shown in the table below.

Table 1 Rat time after application of poultice (Example 12)
Intramuscular concentration (ng/g muscle) 567 986 12 685 18 259 24 232 As is clear from this table, in the poultices with poorer dispersibility than the gel preparations, dantrolene Sodium is delivered to the muscles and its intramuscular concentrations are extremely high.

(Example) The present invention will be explained in more detail below with reference to Examples.

Example 1: Dissolve 2 parts of dantrolene sodium in Macrogol 400 by heating at 60°C, return to room temperature, and add 50 parts of propylene glycol to the solution (mix).

In addition to this, 10 parts of Eisin, 10 parts of ethyl isonicotinate
After addition, the mixture was thoroughly mixed to obtain a solution (total amount: 100 g).

Example 2 A solution was obtained in the same manner as in Example 1, except that n-butyl isonicotinate was used in place of ethyl isonicotinate.

Example 3 A solution was obtained in the same manner as in Example 1 except that n-butyl nicotinate was used instead of ethyl isonicotinate.

Example 4 A solution was obtained in the same manner as in Example 1, except that diethyl sebacate was used in place of ethyl isonicotinate.

Example 5゜ 2 parts of Dantrolene Sodium, 10 parts of Eishin.

Mix 10 parts of ethyl isonicotinate, add 50 parts of globylene glycol, 25 parts of purified water, and 60 parts of
(Span 60, product name, manufactured by Kao Atlas) 3
of the mixture was added and uniformly emulsified to obtain a milky lotion.

Example 6 A solution was obtained in the same manner as in Example 2, except that 40 parts of propylene glycol and 38 parts of polyethylene glycol were used.

Example 7 5 parts of inderoxazine hydrochloride were dissolved in 5 parts of propylene glycol by heating, then 5 parts of Eisin and 50 parts of diethyl sepacate were added, and 35 parts of ethanol was added thereto and mixed well to form a solution ( A total amount of 100 g) was obtained.

Example 8 A solution was obtained in the same manner as in Example 7, except that 30 parts of ethanol and 10 parts of Eishin were used.

Example 9. (Gel) 50 g of 1% Carbopo/9934 (trade name: carboxyvinyl polymer manufactured by Gutdrich Chemical Co.) and 20 g of propylene glycol were mixed well, and to this was added 20 g of a 5% concentration of dantrolene sodium in Macrogol 400 solution.
Add it little by little while stirring. Next, 5 g of Eisin and 5 g of n-butyl isonicotinate were added and mixed well to obtain a gel preparation.

Example 10. (Gel) A gel preparation was obtained in the same manner as in Example 10, except that n-butyl isonicotinate was replaced with DEET.

Example 11. (Poultice) 30 parts of gelatin and 5 parts of citric acid were dissolved and kneaded in a mixed solution of 179 parts of purified water and 40 parts of concentrated glycerin.

A solution of 20 parts of propylene glycol and 2.5 parts of preservative is added to this. Additionally, 20 parts of Eishin, 20 parts of ethyl isonicotinate, and 3.5 parts of preservative.

Add a mixture of 30 parts of surfactant (Tween 60:15 parts, Su-Kun 060:15 parts) and a dispersion of 6 parts of zinc oxide and 20 parts of purified water (knead to form a paste). Then, a mixture of 10 parts of sodium carboxymethyl cellulose and 30 g of sodium polyacrylate dispersed in 139 parts of propylene glycol was added and kneaded thoroughly. Furthermore, methyl vinyl ether/maleic anhydride copolymer (GAF product) was added. A solution prepared by dissolving 5 parts of dantrolene sodium in 60 parts of purified water is added and kneaded. Then, 80 parts of Eisin and 80 parts of ethyl isonicotinate are added. 20 parts of dantrolene sodium is added to Macrogol 400 2
5 parts of propylene glycol and 25 parts of propylene glycol, a solution heated at 60° C. is added and kneaded. Finally, a mixture of 120 parts of natural rubber latex and 20 parts of concentrated glycerin is added and kneaded uniformly at 60°C, then spread on flannel, a plastic film is pasted on the surface and cut into a predetermined size. .

Example 12. (Bag agent) 30 parts of gelatin and 5 parts of citric acid were dissolved and kneaded with 133 parts of purified water, 50 parts of concentrated glycerin, and 40 parts of propylene glycol, and 20 parts of propylene glycol and 2.5 parts of preservative were added thereto. Add dissolved solution. Additionally, 20 parts of Eishin, 20 parts of ethyl innicotinate, and 3 parts of preservative.
．． 5 parts, 65 parts of surfactant (15 parts of Tween 60°, 50 parts of Span 60°), a mixture of a dispersion of 6 parts of zinc oxide, and 20 parts of purified water were added and kneaded well to form a paste. I got it. Next, Karboyamenya. -7 Natoriu, □.

After adding a mixture of 30 g of sodium polyacrylate dispersed in 140 parts of propylene glycol, the mixture was kneaded.

Next, 80 parts of Eishin, 80 parts of ethyl isonicotinate,
20 parts of dantrolene sodium is mixed with 80 parts of propylene glycol and kneaded uniformly.

Furthermore, a solution prepared by dissolving 5 parts of methyl vinyl ether/maleic anhydride copolymer (GAF Co., Ltd. product name: Gangretzan in 60 parts of purified water) was added and kneaded, and then spread on a flannel and coated on its surface. Laminate plastic film and cut to desired size.

Claims (1)

[Scope of Claims] [1] (1) 1-dodecyl azacycloheptan-2-one, (2) propylene glycol, (3) nicotinic acid ester, isonicotinic acid ester,
1. A longitudinal absorption promoting composition comprising one or more selected from the group consisting of sebacic acid diester and N,N-diethyl-m-toluamide. [2] Drug, (1) 1-dodecyl azacycloheptan-2-one, (2) Propylene glycol, (3) Nicotinic acid ester, isonicotinic acid ester,
1. An external preparation which significantly promotes transdermal absorption of a drug, characterized by containing one or more selected from the group consisting of sebacic acid diester and N,N-diethyl-m-toluamide.