JPS6341367B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a liquid preparation for external use that maintains the effect of its active ingredients, is free from stickiness, and has a good feeling of use. Conventionally, liquid preparations in which ingredients such as salicylic acid esters such as methyl salicylate and glycol salicylate, as well as menthol, camphor, nonylic acid vanillylamide, vitamin E, and diphenhydramine are dissolved in alcohol or alcohol-water, have been known as external anti-inflammatory analgesics. It is being This topical anti-inflammatory analgesic liquid has an excellent feeling of use, is easy to use, can be easily applied to hairy areas, joints, etc., and has a fast-acting effect (anti-inflammatory analgesic effect and cooling sensation) immediately after application. Moreover, compared to patches, it does not inhibit the physiological functions of the skin, causes fewer skin problems, and does not require heating or large-scale equipment for production, making it easy to manufacture. The problem is that the effects are temporary and do not last long. The present inventors conducted extensive research with the aim of prolonging the effects of the active ingredients without sacrificing the excellent usability and quick-acting properties of the liquid formulation, and found that water-lower alcohol was used as the main solvent. It has been found that the above object can be achieved by adding 0.05 to 1% (weight/volume %, the same applies hereinafter) of dibenzylidene sorbitol to a liquid preparation for external use. That is, dibenzylidene sorbitol is known as a gelling agent, and by solidifying an organic solvent using dibenzylidene sorbitol or gelling a lower alcohol using dibenzylidene sorbitol, a solid stick-type external anti-inflammatory analgesic agent can be obtained. However, it is known that dibenzylidene sorbitol requires 1.5 to gel and solidify.
% or more, and in order to dissolve more than 1.5% of dibenzylidene sorbitol in the lower alcohol, it must be heated at high temperature for a long time. In addition, this type of solid stick-type external anti-inflammatory analgesic agent that uses dibenzylidene sorbitol as a gelling agent has the problem that the lower alcohol evaporates during storage and use, causing the form to shrink significantly. It has been proposed to incorporate benzyl alcohol or ethylene glycol monoethyl ether as a solvent, but problems remain in terms of practicality.) Furthermore, there is also the disadvantage that the gel is brittle and easily crumbles during use. However, when dibenzylidene sorbitol is blended at 0.05 to 1% in a water-lower alcohol solvent, the solvent does not gel and remains in liquid form, resulting in the use of the above-mentioned solid stick-type topical anti-inflammatory analgesic of dibenzylidene sorbitol. In addition to having no disadvantages, when this liquid is applied to the skin, the benefits of the liquid are maintained, such as the effects are immediately apparent after application, and the effects of the active ingredients are sustained. be. In addition, this liquid formulation containing 0.05 to 1% dibenzylidene sorbitol forms a gel on the skin surface as the lower alcohol evaporates after application, but it is not sticky and does not impair the feeling of use, and the appearance after application. It does not impair. Therefore, by blending 0.05 to 1% dibenzylidene sorbitol into a topical liquid preparation containing water and lower alcohol as the main solvent and containing the active ingredient, it has both quick-acting and long-lasting properties.
The present inventors have discovered that a liquid preparation with excellent feel and ease of use can be obtained, leading to the present invention. The present invention will be explained in detail below. The external liquid preparation according to the present invention is used as an external anti-inflammatory analgesic agent, disinfectant bactericidal agent, antipruritic agent, insect repellent, etc., and is blended with appropriate active ingredients according to its use. For example, in the case of topical anti-inflammatory analgesics, salicylic acid esters such as methyl salicylate and glycol salicylate, anti-inflammatory analgesics such as glycyrrhetinic acid, and indomethacin, as well as menthol, camphor, peppermint oil, eucalyptus oil, borneol, vitamin E, capsaicin, and nonyl acid vanillylamide, benzyl nicotinate, diphenhydramine,
One or more components such as chlorpheniramine maleate may be blended. In this case, by using methyl salicylate and glycol salicylate in combination, immediate and sustained effects (transdermal absorption) can be achieved more reliably. In addition, in the case of external disinfectants, one or more of the following active ingredients may be used: zypcaine hydrochloride, benzethonium chloride, benzalkonium chloride, thimerosal, resorcinol salicylate, pentachlorphenol, etc. Methyl salicylate, menthol,
One or more of camphor, thymol, eucalyptus oil, diphenhydramine, chlorpheniramine maleate, chloral hydrate, etc. can be used. Furthermore, in the case of insect repellents, N,N-diethylamide, di-n-propylisocincomeronate,
One or more of bisbutylenetetrahydrofurfural, pyrethrin, N-octyl-bicycloheptenedicarboximide, trichlorocarbanilide, etc. may be blended. Although the amount of these active ingredients varies depending on the type of ingredient and purpose of use, it is generally between 0.1 and 20
%. In the present invention, the above-mentioned components are dissolved in a solvent mainly composed of water and lower alcohol, and ethanol and isopropanol can be suitably used as the lower alcohol. Further, the mixing ratio of water and lower alcohol is preferably 1:99 to 20:80 in terms of weight ratio. In this case, in the present invention,
In addition to water and lower alcohols, it is preferable to use dihydric alcohols such as ethylene glycol and propylene glycol in combination, so that dibenzylidene sorbitol smoothly gels after application. In other words, dibenzylidene sorbitol generally exhibits gelling ability when mixed with lower alcohols at a concentration of 1.5 to 5% and solidifies the lower alcohols, but gelation does not occur when blended with lower alcohols at 1% or less. When the lower alcohol volatilizes during coating, the lower alcohol concentration in the coated area decreases, and when the dibenzylidene sorbitol concentration relatively increases, gelation occurs. At this time, propylene glycol etc.
When a higher alcohol is used in combination, the lower alcohol evaporates and gelation occurs more smoothly. In addition, when dihydric alcohol is used as an active ingredient, such as nonylic acid vanillylamide, capsaicin, capsicum extract, arnica tincture, or other thermal stimulants (redness agents, blood circulation promoters), the effect of the dihydric alcohol can be enhanced. Pull it out to ensure that the warm sensation lasts for a long time. In addition, when using dihydric alcohol together with water and lower alcohol,
The ratio by weight is preferably 5-15 water: 90-65 lower alcohol: 5-15 dihydric alcohol. Furthermore, as a dihydric alcohol,
It feels less sticky when used, does not cause the inconvenience of whiteness and dryness at the application site, is highly safe for the human body, and has a certain antifungal effect and fermentation inhibitory effect on the same level as ethanol.
Propylene glycol is most preferred because it is effective in killing streptococci in the air at a concentration of 1 to 2 ppm. In addition, in the present invention, the heating conditions are relaxed,
For the purpose of simplifying production, 0 to 10% of higher alcohols such as 2-octyluntecanol and cellosolves such as methyl cellosolve may be blended if necessary. The liquid preparation of the present invention uses water, a lower alcohol, more preferably a dihydric alcohol as a solvent, and dibenzylidene sorbitol is blended into the liquid preparation containing the above-mentioned active ingredient. More gel all D,
A product commercially available under the name Gelol T can be used. The blending amount of dibenzylidene sorbitol is 0.05 to 1%, preferably 0.1 to 0.7% of the total amount, which allows the base to be kept in a liquid state without solidifying, and does not cause stickiness. You can maintain a good usability,
Moreover, it is possible to measure the duration of the effect of the active ingredient. On the other hand, if the amount of dibenzylidene sorbitol blended is too small, the above-mentioned effects will not be achieved sufficiently, and if the amount of dibenzylidene sorbitol blended is too large, it will not become a liquid formulation but will turn into a gel.
They have no merit as liquid preparations, and neither of them can achieve the purpose of the present invention. In the present invention, in addition to the above-mentioned components, polyvinylpyrrolidone, ethylcellulose, methylcellulose, hydroxypropylcellulose,
It is also possible to blend polymer compounds such as polyvinylpyrrolidone vinyl acetate copolymer, soluble nylon, acrylic resin, etc. in an amount of about 0 to 5% of the total amount. In this case, in the present invention, the sticky feeling of the above-mentioned polymer compound can be suppressed by the action of dibenzylidene sorbitol. There are no particular restrictions on the method for producing the liquid preparation of the present invention, but in general, dibenzylidene sorbitol is first dissolved in a solvent, and in particular, a dihydric alcohol such as propylene glycol or a higher alcohol such as 2-octylundecanol is used. In such cases, a method may be adopted in which the ingredients are heated and dissolved, a lower alcohol and water are added thereto, and then the desired ingredients such as active ingredients are added thereto. Therefore, the external liquid preparation according to the present invention uses water-lower alcohol as the main solvent and contains dibenzylidene sorbitol at a ratio of 0.05 to 1% in the external liquid preparation containing the active ingredient, so that the dosage form is improved. It is liquid, so it is easy to use and can be applied anywhere.It is fast-acting and the effect of the active ingredient is reliably long-lasting.It is also non-sticky and has a good feeling of use. It is something.
Furthermore, according to the present invention, when a cooling stimulant such as menthol is blended, the refreshing feeling is sustained. EXAMPLES Hereinafter, the present invention will be specifically explained by showing Examples and Comparative Examples. In addition, in the following examples, parts indicate parts by weight. [Example 1] 0.5 part of dibenzylidene sorbitol is heated and dissolved in 10 parts of propylene glycol, and then 75 parts of ethanol and 15 parts of water are added. Add and dissolve 5.0 g of methyl salicylate and 5.0 g of l-menthol to make a total volume of 100 ml. [Comparative Example 1] 5.0 g of methyl salicylate in a solvent consisting of 75 parts of ethanol, 10 parts of propylene glycol, and 15 parts of water.
Add and dissolve 5.0 g of l-menthol to make a total volume of 100 ml. Next, a certain amount of the external anti-inflammatory analgesic solution of Example 1 and Comparative Example 1 was applied to the inside of a person's lower arm, and the refreshing feeling over time was tested using an absolute evaluation of paired comparison. The results are shown in Figure 1. The results are shown as the average value and standard deviation of the seven panelists. Further, FIG. 1A shows the results of Example 1, B shows the results of Comparative Example 1, and the evaluation criteria (vertical axis in FIG. 1) are as follows. 5: Extremely strong cooling sensation 4: 〃 Strong 3: 〃 Yes 2: 〃 Weak 1: 〃 Extremely weak 0: 〃 Not at all From the results shown in Figure 1, the liquid formulation of Example 1 was the same as Comparative Example 1.
It can be seen that the refreshing feeling is stronger and lasts longer than that of the liquid formulation (the results 2 hours after application are P≦0.05 in a t-test: paired difference test, and there is a significant difference). [Example 2, Comparative Example 2] An anti-inflammatory analgesic liquid for external use having the formulation shown in the table below was prepared in the same manner as in Example 1 and Comparative Example 1.

[Example 3]

A topical anti-inflammatory analgesic solution having the following formulation was prepared in the same manner as in Example 1. Active ingredients Methyl salicylate 3.5g Glycol salicylate 1.8〃 L-menthol 5.0〃 Nonylic acid vanillylamide 0.015〃 Solvent Ethanol 85 parts Propylene glycol 10〃 Water 5 parts Dibenzylidene sorbitol (Gelol D)
0.45 [Example 4] Active ingredients Methyl salicylate 3.5 g Glycol salicylate 1.8 l-menthol 5.0 Glycyrrhetinic acid 0.1 Vitamin E 0.5 Solvent 2-octyluntecanol 5 parts Ethanol 75 parts Propylene glycol 10 Water 10 Dibenzylidene sorbitol 0.6〃 Dibenzylidene sorbitol was heated and dissolved in 2-octylundecanol (NJCOL-200) and propylene glycol, and ethanol and water were added to this, and the above active ingredient was added to the solution to make a total volume of 100.
A topical anti-inflammatory and analgesic solution was prepared by making the volume into ml. [Example 5] In the same manner as in Example 1, an external anti-inflammatory analgesic solution having the following formulation was prepared. Active ingredients Methyl salicylate 3.0g Glycol salicylate 3.0 L-menthol 5.0 dl-camphor 2.0 Nonylic acid vanillylamide 0.01 Solvent Ethanol 80 parts Propylene glycol 5 Water 15 Dibenzylidene sorbitol 0.2 [Example 6] Implementation Example 1 A topical antibacterial wound medicine with the following formulation was prepared using the same manufacturing method. Active ingredients Zipcaine hydrochloride 0.1g Naphazoline hydrochloride 0.1g Chlorpheniramine maleate 0.2〃 Benzethonium chloride 0.1〃 Solvent Ethanol 80 parts Propylene glycol 10〃 Water 10〃 Dibenzylidene sorbitol 0.5〃 [Example 7] Same as Example 1 An antipruritic agent with the following formulation was prepared. Active ingredients l-menthol 1.5g Diphenhydramine 0.5〃 Glycyrrhetinic acid 0.5〃 Chloral hydrate 1.0〃 Solvent Ethanol 80 parts Propylene glycol 10〃 Water 10〃 Dibenzylidene sorbitol 0.6 parts [Example 8] Same as Example 1 An insect repellent with the following formulation was prepared. Active ingredient N,N-diethylamide 3.0g Bisethylenetetrahydrofurfural
0.5〃 Butoxide 1.0〃 Di-n-propylisocincoronate 0.5〃 Solvent Ethanol 85 parts Propylene glycol 10〃 Water 5〃 Dibenzylidene sorbitol 0.7〃 The liquid preparations of Examples 3 to 8 all maintain the effects of the active ingredients. It is something to do.

[Brief explanation of the drawing]

Figure 1 is a graph showing the change in cooling sensation over time depending on the presence or absence of dibenzylidene sorbitol.
The figure is a graph showing the residual rate of salicylic acid ester on the skin over time depending on the presence or absence of dibenzylidene sorbitol.

Claims (1)

[Scope of Claims] 1. A liquid preparation for external use, which contains water and a lower alcohol as main solvents, and contains 0.05 to 1% by weight/volume of dibenzylidene sorbitol to the liquid preparation for external use containing an active ingredient. 2. The external liquid preparation according to claim 1, which contains a dihydric alcohol. 3. The liquid preparation for external use according to claim 2, wherein the weight ratio of water, lower alcohol, and dihydric alcohol is 5 to 15:90 to 65:5 to 15. 4. The external liquid preparation according to claim 2 or 3, wherein the dihydric alcohol is propylene glycol. 5. The external liquid preparation according to any one of claims 1 to 4, wherein the lower alcohol is ethanol or isopropanol. 6. The external liquid preparation according to any one of claims 1 to 5, wherein the active ingredient is an anti-inflammatory analgesic. 7. The external liquid preparation according to claim 6, which uses methyl salicylate and glycol salicylate together as an anti-inflammatory analgesic. 8. The external liquid preparation according to any one of claims 1 to 7, which contains a film-forming polymer compound in an amount of 0.1 to 10% by weight/volume based on the total weight/volume.