JPH01128923A - Skeletal muscle relaxing external preparation - Google Patents

Abstract

PURPOSE:To obtain a skeletal muscle external preparation containing dantrolene sodium as active ingredient, useful in treatment of muscle fatigue, preoperative muscle relax, etc., and having reduced side effect. CONSTITUTION:Dantrolene sodium which is an active ingredient is blended with a 6-24C higher alcohol and/or higher fatty acid, glycols, nonionic surfactant, absorption regulator, etc., and formulated according to ordinary method to provide the aimed product capable of preparing in a form of cream agent, ointment, gel agent, pack agent, liquid medicine, tape agent, water-containing cataplasm, etc. When dantrolene sodium is used together with absorption regulator, even small amount of dantrolene sodium can be administered into a muscle. As the absorption regulator 1-dodecylhexahydro-2H-azepin-2-one, etc., is examplified.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a topical skeletal muscle relaxing agent, and more specifically, contains dantrolene sodium (1-((5-()) as an active ingredient.
The present invention relates to an external skeletal muscle relaxing preparation containing P-nitrophenyl)furfurylidene]amino)hydantoin sodium hydrate).

[Conventional technology and problems]

Skeletal muscle relaxants currently used are mainly classified into central muscle relaxants and peripheral muscle relaxants.

Dantrolene sodium is a peripheral skeletal muscle relaxant that directly acts on the processes following excitation-contraction coupling, so it induces skeletal muscle relaxation through direct muscle action without going through the nervous system like many peripheral muscle relaxants. let

However, intravenous injection involves a high incidence of side effects since the drug is administered throughout the body, and oral administration is not a perfect method of administration because absorption from the gastrointestinal tract is poor.

[Means for solving problems]

Therefore, the present inventors discovered that dantrolene sodium acts directly on skeletal muscles and causes them to relax, so local application may significantly reduce side effects.
Furthermore, based on this knowledge, the inventors have discovered that by using dantrolene sodium in combination with a transdermal absorption regulator, an effective amount of dantrolene sodium can be intramuscularly administered even in a smaller amount, thereby completing the present invention.

The external preparation for skeletal muscle relaxation according to the present invention contains dantrolene sodium as an active ingredient, and is a variety of transdermal absorption preparations for the purpose of treating muscle fatigue, preoperative muscle relaxation, and the like.

The formulation of the present invention can be in the form of a cream, ointment (including gel), pack, liquid, tape, or water-containing patch, and is particularly suitable for use as a tape or water-containing patch. By doing so, the drug effect can be sustained.

The formulation of the present invention can contain a transdermal absorption regulator as required, and the absorption regulators include C1 to C5 alcohol ester of 04 to C14 monocarboxylic acid and C1 to C5 alcohol ester of 04 to C14 monocarboxylic acid.
4~C engineering. or derivatives of 1-dodecylhexahydro-2H-azepin-2-one (hereinafter abbreviated as Az) and Az'. can be used.

〔Example〕

Next, preferred embodiments of the present invention will be shown.

Example 1 20.0 parts of propylene glycol and 58.0 parts of purified water are mixed with 2.0 parts of dantrolene sodium and dissolved by heating to 80°C. Separately, 5.0 parts of cetanol, 6.0 parts of stearic acid, 4.0 parts of glyceryl monostearate and 5.0 parts of Az are mixed and heated to 80°C to dissolve.

The above-mentioned dantrolene sodium solution was added to this, and the mixture was uniformly emulsified using a homomixer while being left to cool in a greenhouse to obtain a cream.

Example 2 Dantrolene sodium 2.0 parts, Az 5.0 parts, Tw
Mix and stir 3.0 parts of een20 until uniform. on the other hand,
After stirring and swelling 1.0 part of Carboball 940 in 23.0 parts of purified water, 0.5 part of diisopropanolamine is added to gel it.

20.0 parts of propylene glycol and the above-mentioned dantrolene sodium solution were added to this, and the mixture was sufficiently stirred until the whole was homogeneous to obtain a gel ointment.

Example 3 62.0 parts of propylene glycol, 25.0 parts of stearyl alcohol, and 5.0 parts of stearic acid are heated and dissolved at 80°C to obtain a homogeneous mixture. To this, 1.0 part of dantrolene sodium and 5.0 parts of Az were added, mixed and stirred to make the mixture uniform, and then cooled to room temperature to obtain a lyogel.

Example 4 After 2.0 parts of dantrolene sodium was added to 50.0 parts of propylene glycol and dissolved, 5.0 parts of Az, 20.0 parts of ethanol, and 23.0 parts of purified water were added to prepare a solution.

Example 5 A dispersion of 5.0 parts of sodium polyacrylate, 0.15 parts of aluminum hydroxide gel, 5.0 parts of sodium carboxymethylcellulose, and 2.0 parts of dantrolene sodium was suspended in 30.0 parts of concentrated glycerin. and warm it to 45-55°C. After adding and mixing 5.0 parts of Az to this, 4.0 parts of gelatin was added to 49.15 parts of purified water.
Add a solution prepared by heating and dissolving 0 parts of tartaric acid and 2.2 parts of tartaric acid at 50 to 55°C, and mix well. This poultice composition was spread evenly on a nonwoven fabric, a poly film was attached to the surface, and the composition was cut into an appropriate size to prepare a poultice.

Example 6 35.0 parts of styrene-butadiene rubber, 20 parts of natural rosin
．． 0 parts, poly 11213.0 parts, liquid paraffin 15.
0 parts and 15.0 parts of zinc oxide were heated and melted (150°C) under an inert gas and mixed, and after cooling to about 70°C, 1. Combined with dantrolene sodium and thoroughly combined,
Obtain a homogeneous plaster mixture. Then, this was spread on a nonwoven fabric using a calendar roll at a temperature of about 60 to 65°C.

A sample was obtained by rapid cooling.

Next, an experiment was conducted to determine the level of intramuscular dantrolene sodium concentration when gels containing dantrolene sodium at the ratios shown in Table 1 were topically applied.

Table 61 Experimental method Male rats weighing 100 to 120 g were depilated the day before the experiment using clippers and depilatory cream. 200 μl of each test drug was applied to a fixed area on the back of each animal, and in order to prevent drug leakage, the upper part was covered with a vinyl sheet and fixed with an elastic bandage.

30 minutes and 2.6.10 hours after application, the animals in each treatment group were taken and bled. After wiping off the applied drug thoroughly, the muscle directly below was removed.

I used it as a sample.

The specimen was homogenized with methanol and heated to 3°000
The mixture was centrifuged for one portion at Xg, and the upper layer was used as a sample. Note that dantrolene sodium was quantified using high performance liquid chromatography (HPLC).

The experimental results are shown in Table 2 and Figure.

Table 2 Topical application of gel containing dantrolene sodium (200 m
g/rat) Intramuscular dantrolene sodium 1ff at L/ta! ! Degree of intramuscular strain (ngEq/g v, L,) (average measurement error) 0.5 2 6
10DAN+5XAz 228.37±
84.10194.33±211.04 165.87
±16.27 162.18±88.380^N-al
one 91. +1±19.44 77.29±5
．． 08 81.33±4.14 215.45±12
0.86 [Effects of the Invention] The skeletal muscle relaxing topical preparation of the present invention can significantly reduce side effects by one local application because dantrolene sodium as its active ingredient acts directly on skeletal muscles to relax them. be.

That is, as is clear from Table 2 and Figures.

When only 2% dantrolene sodium gel was applied, the maximum muscle concentration was 214.45 after 10 hours of application.
ng Eq/g w, t, and it was shown that dantrolene sodium is absorbed transdermally and transferred into tissues even when suspended in a gel base.

However, when using a gel containing Az, an absorption regulator, the maximum muscle white density was 228 after 30 minutes of application.
．． 37 ng Eq/g w,t, which was larger than when Az was not used.

This means that the absorption modifier Az clearly enhances the transdermal absorption effect of dantrolene sodium.

In addition, looking at the time course of the 2% dantrolene sodium + 5% Az gel administration group, after reaching the maximum value 30 minutes after application, the muscle white concentration was sustained and remained relatively stable and high. Shown.

[Brief explanation of the drawing]

The drawings are diagrams showing experimental results of the formulation of the present invention. Patent amount: Applicant Mikasa Pharmaceutical Co., Ltd. Muscle white density (ng Eq / gν, t,);
Gigiro, Roro
b + q = Writ of amendment to wrongful procedure (voluntary) December 70, 1988 Director General of the Patent Office Kunihiko Ogawa 1, Indication of the case Patent Application No. 1982-285003 2, Title of the invention: Skeletal muscle relaxant topical agent 3, Relationship with the case of the person making the amendment Patent applicant Mikasa Pharmaceutical Co., Ltd. Representative Murao Ogata 4, Agent 2-11-201 Kamishinjo, Nakahara-ku, Yozaki City, Kanagawa Prefecture, page 5, line 4 of the specification, Correct "pack agent" to "poultice agent".

Claims (1)

[Scope of Claims] 1. A topical skeletal muscle relaxing preparation containing dantrolene sodium as an active ingredient. 2. Dantrolene sodium and C_6 to C_2_4 higher alcohols and/or higher fatty acids, glycols,
The external preparation for skeletal muscle relaxation according to claim 1, which is an ointment containing a nonionic surfactant and an absorption modifier. 3. The skeleton according to claim 1, which is a gel ointment containing dantrolene sodium, a gelling agent, a glycol, a lower alcohol and/or water, a neutralizing agent, a nonionic surfactant, and an absorption modifier. Topical muscle relaxant. 4. Dantrolene sodium, glycols, lower alcohols and/or water, neutralizing agent, nonionic surfactant,
The external preparation for skeletal muscle relaxation according to claim 1, which is a liquid preparation containing an absorption modifier. 5. The external skeletal muscle relaxing preparation according to claim 1, which is a poultice containing dantrolene sodium, glycols, water-soluble polymers, organic acids, inorganic powders, and absorption modifiers. 6. Dantrolene sodium, adhesive, tackifier,
The external skeletal muscle relaxing preparation according to claim 1, which is a tape preparation containing a softening agent and an excipient. 7. As the absorption modifier, a compound selected from the group consisting of C_1 to C_5 alcohol esters of C_4 to C_1_4 monocarboxylic acids and C_1 to C_3 alcohol diesters of C_4 to C_1_0 dicarboxylic acids is used. Any one of the range items 2 to 5
The topical skeletal muscle relaxing agent described in . 8. Claims 2 to 5 in which derivatives of 1-dodecylhexahydro-2H-azepin-2-one and 1-dodecylhexahydro-2H-azepin-2one are used as the absorption modifier. The external skeletal muscle relaxing agent according to any one of the above.