JPH08325149A - External preparation containing pridinol mesilate - Google Patents

Abstract

PURPOSE: To obtain a pridinol mesilate-containing external preparation excellent in percutaneous absorbability and useful as a skeletal muscle relaxant. CONSTITUTION: Pridinol mesilate is compounded with glycerol and benzylalcohol preferably in amounts of 1-50wt.% and 1-20wt.%, respectively. The external preparation is preferably formed into a plaster. The simultaneous use of the benzylalcohol and the glycerol as percutaneous absorption-promoting agents gives such the high percutaneous absorption of the pridinol mesilate as being not given by the simultaneous use of propylene glycol or 1,3-butylene glycol. When the glycerol is compounded in a large amount, the percutaneous absorption of the pridinol mesilate is lowered, while when compounded in a small amount, the dispersibility of the pridinol mesilate is deteriorated on the formation of the medicinal preparation to lower workability and uniformity. The external preparation is excellent in percutaneous absorbability, maintains an effective concentration in blood for a long time, can easily be used, and is little in side effects.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an external preparation containing pridinol mesylate, which contains pridinol mesylate, which is useful as a skeletal muscle relaxant, and has excellent transdermal absorbability.

[0002]

BACKGROUND ART In general, most drug administration methods for systemic action are oral administration and injection. Metabolism in the liver (first-pass effect) is unavoidable with oral administration, and administration with injection requires frequent administration of a drug with a short biological half-life, making it difficult to maintain the blood concentration of the drug. Therefore, a therapeutic system that administers a drug by permeating and absorbing it through the skin is drawing attention as a new drug administration method. In the case of transdermal administration, the aforementioned drawbacks are overcome, and the number of administrations is reduced and compliance is improved.
It has advantages such as easy discontinuation of administration.

Pridinol mesylate is 1,1-Diphenyl-3
-piperidinopropanol methanesulfonate (Molecular formula: C ₂₀
H ₂₅ NO.CH ₃ SO ₃ H), with a central name,
In particular, it is a medicinal substance which is commonly used as a muscular abnormal tone relieving agent having a main action on interneurons in the spinal cord. Pridinol mesylate is commonly used as an orally administered drug and an injectable drug, but the orally administered drug is usually required to be administered three times a day, and has anorexia, heartburn, stomach upset / stomach. Gastrointestinal disorders such as discomfort and side effects such as liver and renal dysfunction have become problems. On the other hand, injections have drawbacks in that they are accompanied by pain during administration and that side effects such as wobbling due to a rapid increase in blood concentration are likely to occur.

Therefore, recently, a percutaneous skeletal muscle relaxation agent in which a water-soluble polymer contains pridinol mesylate is used (Japanese Patent Laid-Open No. Hei 10 (1999) -242242).
6-336434), however, even with such a transdermal agent, the expected effective blood level cannot be maintained sufficiently, and further increase in blood level cannot be expected. In addition, since pridinol mesylate is contained at a saturation concentration or higher, crystal precipitation of pridinol mesylate occurs, which causes a decrease in tackiness and a deterioration in usability. Therefore, development of an external preparation containing pridinol mesylate, which has excellent transdermal absorbability, maintains an effective blood concentration for a long time, is easy to use, and has few side effects, has been desired.

[0005]

DISCLOSURE OF THE INVENTION As a result of intensive studies conducted under such circumstances, the present inventors have found that by combining glycerin and benzyl alcohol with pridinol mesylate, it has excellent transdermal absorbability and durability, and is used. We have succeeded in developing an external preparation containing pridinol mesylate that has an excellent feeling.
That is, the present invention provides a pridinol mesylate-containing external preparation containing pridinol mesylate, glycerin, benzyl alcohol and a base for external use, and the present invention further provides a preferred dosage form of the external preparation. Another object of the present invention is to provide a pridinol mesylate-containing external preparation which is a patch.

The present invention will be described in detail below. Generally, glycols such as glycerin, propylene glycol, ethylene glycol, and 1,3-butylene glycol are used as external preparations as stabilizers, plasticizers, solubilizers, wetting agents, softeners, adhesives, excipients, dispersions. Agents, moisture barriers, preservatives, solvents,
It is formulated for a wide range of uses such as dissolving agents,
It is an important ingredient in drug product development. Particularly, in the patch, glycols are considered to be essential components. Among these glycols, propylene glycol and 1,3-butylene glycol have the effect of promoting the percutaneous absorption of drugs in addition to the above-mentioned compounding purposes, and when combined with other transdermal absorption promoters, further percutaneous absorption is achieved. Although it has been reported to have an effect of enhancing the promoting effect, that is, a combined effect (BWBarr
y, Journal of Controlled Release, 6 (1987) 85-97, etc.), it is considered that glycerin cannot be expected to have a transdermal absorption promoting effect and a concomitant effect even with the same type of glycols. There is no report that such an effect was obtained.

In the present invention, the percutaneous absorption accelerating property of pridinol mesylate is particularly recognized when it is used in combination with propylene glycol or 1,3-butylene glycol, which is generally said to be highly effective in combination with a transdermal absorption promoter. Despite this, it was discovered that the combined use of glycerin, which is considered to have a low combined effect, exerts an unexpectedly high absorption promoting effect. That is, the present invention, by the combined use of benzyl alcohol and glycerin is a percutaneous absorption enhancer, high transdermal absorbability of pridinol mesylate, which cannot be obtained in combination with propylene glycol or 1,3-butylene glycol. It has been found that it can be obtained.

The proportion of glycerin in the external preparation according to the present invention is 1 to 50% by weight (hereinafter referred to simply as%), preferably 5 to 30%, more preferably 10 to 25%. Is compounded in. When the amount of glycerin added is large, the percutaneous absorbability of pridinol mesylate tends to decrease. On the other hand, when the blending amount is too small, the dispersibility of the powder component is poor at the time of formulation, resulting in a problem that workability and uniformity are lacking. In addition, when the dosage form is a patch, the plasticity is poor, so that a patch with a good feeling of use cannot be obtained. In addition, glycerin is a substance having the advantage of being less irritating than other glycols.

On the other hand, the mixing ratio of benzyl alcohol is
The content is 0.1 to 50%, preferably 1 to 20%, more preferably 5 to 10%. When the blending amount of benzyl alcohol increases, phase separation of benzyl alcohol itself,
Embossment is likely to occur. On the other hand, if the blending amount is too small, the homogeneity of pridinol mesylate will be deteriorated and the transdermal absorbability will be decreased, such being undesirable. It is also considered that benzyl alcohol acts as a solubilizing agent and evenly dissolves and disperses pridinol mesylate in the preparation to suppress the precipitation of crystals.

In the external preparation according to the present invention, other commonly used absorption enhancers include eucalyptus oil, propylene glycol monocaprylate, peppermint oil, diisopropyl adipate, lauryl alcohol, isopropyl myristate, oleic acid and the like. It can also be blended. The higher the pH is, the better the transdermal absorbability of pridinol mesylate is, but the pH of the preparation is adjusted within the range of pH 5 to 8 in consideration of the transdermal absorbability of pridinol mesylate and the convenience of formulation. Preferably.

The external preparation according to the present invention can be formulated into a dosage form generally known as an external preparation. The dosage forms of such preparations include patches, patches, tapes,
Examples include ointments, gels, creams, liquids and the like.

The external base to be added to the external preparation according to the present invention is not particularly limited, and examples thereof include commonly used water-soluble polymers, surfactants, stabilizers and pH adjusters. it can. As the water-soluble polymer, for example, polyacrylic acid, sodium polyacrylate, carboxyvinyl polymer, carmellose sodium, polyvinyl alcohol, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, alginic acid, sodium alginate, gelatin,
Any of methyl vinyl ether / maleic anhydride copolymer and the like can be used.

Examples of the surfactant include polyoxyethylene sorbitan fatty acid ester, sorbitan fatty acid ester, polyoxyethylene alkyl phenyl ether and the like. Examples of the stabilizer include sodium bisulfite, L-ascorbic acid, sodium ascorbate, butylhydroxyanisole,
Butyl hydroxytoluene, propyl gallate, tocopherol acetate, dl-α-tocopherol, sodium bisulfite and the like can be mentioned.

Examples of the pH adjusting agent include diisopropanolamine, diethanolamine, triethanolamine, citric acid and tartaric acid. As the dosage form of the external preparation according to the present invention, the patch is the most preferred dosage form because of the absorbability (persistence) of the drug, the safety, the ease of use, and the like. For such patches, in addition to the above-mentioned respective bases, commonly used crosslinking agents, fillers and the like are appropriately used.

Examples of the cross-linking agent include aluminum compounds such as aluminum hydroxide, salts of inorganic or organic acids such as aluminum stearate, double salts such as aluminum alum, inorganic aluminum complex salts and organic aluminum chelate compounds. Is mentioned. Examples of the filler include kaolin, titanium oxide, zinc oxide, silicic acid anhydride and the like. If desired, the external preparation of the present invention may further contain a thickener, a tackifier, an antiseptic, a flavoring agent, a coloring agent and the like.

The present invention will be specifically described below with reference to examples, but the present invention is not limited to the following examples unless the gist thereof is changed.

Examples 1 and 2 (patch)

[Table 1] Table 1

(A) (1) to (6) are mixed well with a stirrer, and (7) in which (8) is dissolved is added and mixed well. (B) Dissolve (9) to (11) in (12). (C) Add (B) to (A) and stir and mix uniformly. (D) This plaster is spread on a non-woven fabric and covered with a polyester film to obtain a patch.

Example 3 (gel agent) (A) Swell (4) into (6). (B) Dissolve (1) in (2) and (3). (C) Add (A) and (5) to (B) and stir until the whole becomes uniform to obtain a gel agent.

Example 4 (solution) (A) (1) to (5) are uniformly dissolved and mixed to obtain a liquid agent.

Comparative Example 1 and Comparative Example 2 (patch)

[Table 2] Table 2

(A) Add (2) and (3) to (1) and dissolve. (B) Add (4) to (10) to (A) and mix evenly. (C) This plaster is spread on a non-woven fabric and covered with a polyester film to obtain a patch.

Comparative Example 3 (gel agent) (A) Swell (3) into (5). (B) Dissolve (1) in (2). (C) Add (A) and (4) to (B) and stir until the whole becomes uniform to obtain a gel agent.

Comparative Example 4 (gel agent) (A) Swell (3) into (5). (B) Dissolve (1) in (2). (C) Add (A) and (4) to (B) and stir until the whole becomes uniform.

Comparative Example 5 (liquid agent) (A) (1) to (5) are uniformly dissolved and mixed.

Comparative Example 6 (liquid agent) (A) (1) to (5) are uniformly dissolved and mixed.

Test Example 1 Experimental method: The patch prepared by the method described in Example 2, Comparative Example 1 and Comparative Example 2 was sealed with an aluminum laminate packaging material, and stored in a constant temperature bath at 60 ° C. for 2 weeks. The appearance change of the plaster surface was observed. Table 3 shows the results. Results: Crystallization of pridinol mesylate was observed in the patches of Comparative Example 1 and Comparative Example 2, but no precipitation of crystals was observed in the patch of Example 2 of the present invention. .

[0028]

[Table 3] Table 3

Test Example 2 Each patch prepared by the method described in Example 1, Example 2, Comparative Example 1 and Comparative Example 2 was subjected to a skin permeation comparison test by the following experimental method. The result is shown in FIG. Experimental method: On the day before the experiment, the hair on the back of female hairless rats (average weight: 135 g), 7 weeks old, was shaved with an electric clipper. After cervical dislocation of the hairless rat from which hair had been removed the day before,
The dorsal skin was removed. The excised skin was fixed to a Franz diffusion cell (diameter: 2 cm), and the patch of Examples 1 and 2 and Comparative Examples 1 and 2 (about 1.3 mg of prizinol mesylate (Example 1, Comparative Example 1) on the donor side, respectively. ) And about 2.7
mg (Example 2, Comparative Example 2)) was applied and the receptor side was filled with physiological saline. 37 ° C on the receptor side during the experiment
Was maintained, and the mixture was stirred with a magnetic stirrer. A fixed amount was sampled from the receptor side at predetermined time intervals, and the amount of permeated pridinol mesylate was measured using high performance liquid chromatography.

Results: As is clear from FIG. 1, the product of the present invention showed an increase in permeability with an increase in the drug concentration, and a higher transdermal absorbability was observed as compared with those of the comparative examples. . On the other hand, in the comparative example, the saturation concentration was already reached at the drug concentration of 0.5% (Comparative Example 1), so that even if the drug concentration was 1.0% (Comparative Example 2), the permeability was further increased. Is not seen,
The transdermal absorbability was lower than that of the product of the present invention.

Test Example 3. The absorption kinetics of each patch prepared by the method described in Example 2 and Comparative Example 2 was measured. Experimental method: On the day before the experiment, the back hair of female hairless rats (average weight 136.5 g) at 8 weeks of age was shaved with an electric clipper, and further fasted. One patch (4 × 2.5 cm) of Example 2 and Comparative Example 2 (about 7 mg as pridinol mesylate) was applied to the right side of the rat dorsal skin that had been hair-removed the day before, avoiding the midline and fixed on it. It was fixed with an adhesive tape for use, and a surgical tape (3M) was attached and fixed so as to further wrap around the trunk. 4 hours after the administration of the drug, 4 ml of blood was collected from the inferior abdominal vena cava under ether anesthesia. Centrifuge blood (3000r
(pm, 20 minutes), 0.75 ml of serum was taken, made alkaline with sodium hydroxide, and pridinol mesylate was extracted with petroleum ether, and then the concentration in serum was measured by high performance liquid chromatography.

Results: Table 4 shows the measured values showing the pharmacokinetics. The patch of the present invention maintained a stable blood concentration of pridinol mesylate until 16 hours later, and had higher Cmax and AUC than Comparative Example 2 due to the effect of the absorption enhancer, and had high transdermal absorbability. Admitted.

[0033]

[Table 4] Table 4 (Note) Tmax: Time to reach maximum blood concentration Cmax: Maximum blood concentration AUC: Area under the blood concentration time curve

Test Example 4. With respect to each gel preparation prepared by the method described in Example 3, Comparative Example 3 and Comparative Example 4, a skin permeability comparison test was performed by the method described in Test Example 2. At the same time, the external appearance was observed and the feelings of rubbing were compared. The results of the skin permeability test are shown in FIG. Results: As is clear from FIG. 2, glycerin of Comparative Example 4 alone was inferior in transdermal absorbability, and benzyl alcohol of Comparative Example 3 alone showed an enhancing effect, but the glycerin prepared in Comparative Example 4 was used in combination. It was confirmed that the invention product maintains high transdermal absorbability. In addition, as a result of observing the appearance and comparing the feeling of application, in Comparative Example 3, benzyl alcohol was seen to stand out and the feeling of application was poor, but the product of the present invention (Example 3)
By incorporating glycerin, the dispersibility of benzyl alcohol was improved, and no protrusion of benzyl alcohol was observed, and an improvement in the feeling of application was observed.

Test Example 5. For each liquid preparation prepared by the method described in Example 4, Comparative Example 5 and Comparative Example 6, Test Example 2
A comparative test of skin permeability was performed by the method described in 1.
The result is shown in FIG. Results: As is clear from FIG. 3, the liquid preparation of the present invention prepared by combining benzyl alcohol and glycerin contains propylene glycol, which is generally said to have a transdermal absorption-promoting action as shown in Comparative Example. An extremely high transdermal absorbability was observed as compared with the liquid preparation in combination with 1,3-butylene glycol.

[Brief description of drawings]

FIG. 1 is a graph showing changes in skin permeation amount between Examples 1 and 2 according to the present invention and Comparative Examples 1 and 2.

FIG. 2 is a diagram of Example 3 according to the present invention and Comparative Examples 3 and 2;
It is a graph which shows the skin permeation amount after 2 hours.

FIG. 3 is a diagram of Example 4 according to the present invention and Comparative examples 5 and 6;
It is a graph which shows the skin permeation amount after 2 hours.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Reference number within the agency FI Technical indication location A61K 9/70 363 A61K 9/70 363 47/10 47/10 GE (72) Inventor Keizo Mizuno 870 Kamiirai, Tokorozawa, Saitama Prefecture AXIS Kotesashi 101 Room

Claims (3)

[Claims] 1. An external preparation containing pridinol mesylate, which comprises pridinol mesylate, glycerin, benzyl alcohol, and a base for external use. 2. The external preparation according to claim 1, wherein the glycerin is 5 to 30% by weight and the benzyl alcohol is 1 to 20% by weight. 3. The external preparation according to claim 1, wherein the dosage form of the external preparation is a patch.