JP5099956B2 - New anti-inflammatory analgesic cataplasm - Google Patents

Description

The present invention relates to an anti-inflammatory analgesic poultice.
In detail, this invention relates to the dispersal type | formula poultice for anti-inflammatory analgesia which contains felbinac (4-biphenylacetic acid) and / or its pharmaceutically acceptable salt as an active ingredient.

Pap agents contain water in the adhesive base and have an excellent cooling effect. They have long been used for sprains and myalgia. In addition, anti-inflammatory agents such as ketoprofen and indomethacin are used as a base to suppress inflammation itself. What is dissolved in is known.
Among these anti-inflammatory agents, those having a carboxylic acid group in the molecule are known to form l-menthol and l-menthol ester, and a method using a fatty acid metal salt as a countermeasure against this esterification is patented. Although it is disclosed in Document 1, it cannot be said that Ferbinac's poultice is still sufficiently stable, and further stabilization of the main drug has been desired.
On the other hand, felbinac, which can exert an excellent effect as an anti-inflammatory agent, is very poorly soluble in water, alcohol and the like, and thus it has been difficult to formulate patches and the like.
In order to solve the problem, Patent Document 2 attempts to formulate felbinac as a poultice by adding crotamiton as an absorption aid in the adhesive base of the poultice, and Patent Document 3 discloses felbinac. (1%), polyethylene glycol isostearate (3%) and 5-methyl-2-pyrrolidone (5%) are disclosed as creams (dissolvable preparations), all of which have sufficient preparation stability No, it was not preferable.

Japanese Patent No. 3238409 Japanese Patent Laid-Open No. 3-193728 JP-A-11-199521

  The present invention has been made in view of the above-described situation, and an object of the present invention is to provide a felbinac-containing cataplasm containing an extremely effective formulation and having high practicality.

In order to achieve the above object, the present invention has the following configuration.
“Dispersed felbinac-containing cataplasm containing a felbinac and / or a pharmaceutically acceptable salt thereof, l-menthol, and a highly hydrophilic surfactant in an adhesive base.”

That is, the present inventors do not dissolve felbinac but disperse it in the adhesive base, so that l-menthol ester is not produced even if l-menthol is contained in the adhesive base. As a result of intensive research, we thought that it could be kept stable in the adhesive base. As a result, fervinac was further obtained by coexisting a highly hydrophilic surfactant in the adhesive base where felbinac and l-menthol coexisted. Was stably held in the adhesive base, and as a result, a cataplasm having good formulation stability and high practicality was obtained, and the present invention was completed.
In the present invention, it is one of the features that the ferbinac is not only dispersed but also uniformly dispersed.

  The present invention has a remarkable effect in that it provides a felbinac-containing cataplasm having an extremely good formulation stability and high practicality.

  The cataplasm of the present invention comprises felbinac and / or a pharmaceutically acceptable salt thereof, l-menthol, and a highly hydrophilic surfactant in an adhesive base. However, as a preferable thing of the highly hydrophilic surfactant used by this invention, a highly hydrophilic nonionic surfactant is mentioned, for example. Examples of the highly hydrophilic nonionic surfactant according to the present invention include nonionic surfactants having an HLB value of 10 or more. Specific examples of such highly hydrophilic nonionic surfactants include, for example, polyethylene glycol fatty acid esters (eg, polyethylene glycol monostearate (10)) and polyoxyethylene sorbitan fatty acid esters (eg, monooleic acid). Polyoxyethylene (20) sorbitan, etc.).

  In the cataplasm of the present invention, for the purpose of further improving dispersibility, it is also one of preferred embodiments that a dispersion solvent such as polyethylene glycol and polypropylene glycol is further contained in the adhesive base.

As components other than the above in the cataplasm of the present invention, general components usually used in cataplasms, that is, thickeners, wetting agents (humectants), fillers (excipients), absorption promoters, antiseptics Agents, antioxidants, general stabilizers in this type of formulation, and the like.
Examples of thickeners include, for example, synthetic water-soluble polymers such as sodium polyacrylate, polyacrylic acid, polyvinyl alcohol, and polyvinylpyrrolidone, natural polymer derivatives such as carboxymethylcellulose Na, methylcellulose, and hydroxymethylcellulose, starch, gelatin And natural products.
Examples of the wetting agent (humectant) include polyhydric alcohols such as glycerin, propylene glycol, 1,3-butylene glycol, and sorbitol.
Examples of the filler (excipient) include inorganic substances such as kaolin, zinc white, titanium oxide, talc, bentonite, hydrous aluminum silicate, and magnesium metasilicate aluminate. In the case of titanium oxide, it can be used not only as a filler (excipient) but also for the purpose of dispersing powder, so even when other inorganic substances are used as the filler (excipient). Further, it is one of preferred embodiments to further contain titanium oxide as necessary.
Examples of the absorption promoter include alcohols such as ethanol, propanol, pentanol, hexanol, octanol, decanol, and benzyl alcohol, and polyhydric alcohols such as polyethylene glycol, propylene glycol, ethylene glycol, diethylene glycol, dipropylene glycol, and glycerin. And fatty acid esters such as isostearic acid and lauric acid, and fatty acid esters such as isopropyl myristate, octyldodecyl myristate, and isopropyl palmitate.
Examples of preservatives, antioxidants, and other stabilizers include thymol, methyl paraoxybenzoate (methylparaben), ethyl paraoxybenzoate (ethylparaben), ascorbic acid, butylhydroxyanisole, dibutylhydroxytoluene, vitamin E. Edetate disodium, tartaric acid and the like.

  The felbinac-containing poultice of the present invention is characterized in that it is a dispersion-type felbinac-containing poultice, so that a dissolving agent for the purpose of dissolving felbinac is not necessary. This is because if felbinac is dissolved, it does not become a dispersible felbinac-containing cataplasm.

  The dispersible felbinac-containing cataplasm of the present invention comprises felbinac and / or a pharmaceutically acceptable salt thereof, l-menthol and a highly hydrophilic surfactant, and if necessary, a dispersion of polyethylene glycol or the like. A dispersion aid for powders such as a solvent and titanium oxide, and a thickener, a wetting agent (humectant), a filler (excipient), an absorption accelerator, a preservative, It can be easily obtained by spreading and applying an adhesive base containing a necessary amount of at least one of an antioxidant, a stabilizer and the like on a suitable support such as a nonwoven fabric or a knitted fabric. I can do it.

EXAMPLES Hereinafter, although an Example demonstrates this invention more concretely, this invention is not limited at all by these Examples.

Examples 1 and 2
After adding highly hydrophilic nonionic surfactant to purified water (warm water) and stirring, titanium oxide, synthetic aluminum silicate and felbinac were added and stirred and dispersed.
Next, gelatin, disodium edetate, glycerin, polyvinyl alcohol, isopropyl myristate, l-menthol, tartaric acid, magnesium aluminate metasilicate, partially neutralized polyacrylic acid and polyacrylic acid were added to the dispersion. It stirred until it melt | dissolved and disperse | distributed uniformly and the adhesive base for cataplasms of this invention was prepared. Table 1 shows the amount of each component added, the dispersibility of the obtained adhesive base, and the ratio of the produced ester.

Comparative Examples 1 and 2
In Examples 1 and 2, the cataplasm of Comparative Examples 1 and 2 was the same as in Examples 1 and 2 except that a non-ionic surfactant with low hydrophilicity was used instead of the non-ionic surfactant with high hydrophilicity. An adhesive base was prepared. Table 1 shows the added amount of each component, the dispersibility of the obtained adhesive base, and the ratio of the produced ester.

Example 3
Felbinac was dispersed in polyethylene glycol 400 and a highly hydrophilic nonionic surfactant.
Next, in purified water (hot water), titanium oxide, synthetic aluminum silicate, gelatin, edetate disodium, glycerin, polyvinyl alcohol, isopropyl myristate, l-menthol, tartaric acid, magnesium metasilicate aluminate, polyacrylic acid A Japanese product and polyacrylic acid were added, and the mixture was sufficiently dissolved and stirred until uniformly dispersed to prepare an adhesive base for cataplasms of the present invention. Table 1 also shows the amount of each component added, the dispersibility of the obtained adhesive base, and the ratio of the produced fervinac-menthol ester.

Comparative Example 3
Felbinac and l-menthol were dissolved in N-methyl-2-pyrrolidone.
Next, purified water (warm water), titanium oxide, synthetic aluminum silicate, gelatin, edetate disodium, glycerin, polyvinyl alcohol, tartaric acid, magnesium metasilicate magnesium aluminate, polyacrylic acid partial neutralized product, polyacrylic acid and this The surfactant according to the invention was added and sufficiently stirred to prepare an adhesive base for a cataplasm of Comparative Example 3. Table 1 also shows the amount of each component added, the dispersibility of the obtained adhesive base, and the ratio of the produced fervinac-menthol ester.

Comparative Example 4
Felbinac and l-menthol were dissolved in crotamiton.
Next, purified water (warm water), titanium oxide, synthetic aluminum silicate, gelatin, edetate disodium, glycerin, polyvinyl alcohol, tartaric acid, magnesium metasilicate magnesium aluminate, polyacrylic acid partial neutralized product, polyacrylic acid and this The surfactant according to the invention was added and sufficiently stirred to prepare an adhesive base for cataplasm of Comparative Example 4. Table 1 also shows the amount of each component added, the dispersibility of the obtained adhesive base, and the ratio of the produced fervinac-menthol ester.

  In addition, the measuring method of ester body content used as the group for calculating the value of the ratio of the produced fervinac menthol ester body in a table | surface is as follows.

Quantitative determination of fervinac-menthol ester in the preparation 35 cm ^{2 of} a poultice preparation prepared by spreading and applying each adhesive base on a nonwoven fabric was cut out, and the mass was measured to obtain the initial mass. This was put in 70 mL of methanol and extracted by shaking for 30 minutes, and then methanol was added to the extract to make exactly 100 mL. 3 mL of mobile phase was added to 3 mL of this solution to obtain a sample solution.
Separately, 20 mg of fervinac-menthol ester was weighed and dissolved in methanol to make 100 mL. Methanol was further added to 1 mL of this solution to make exactly 100 mL.
3 mL of mobile phase was added to 3 mL of this solution to obtain a standard solution.
The sample solution and the standard solution were filtered through a HPLC filter, and then 20 μL of each solution was tested by the liquid chromatograph method under the following conditions.
<Test conditions>
Detector: UV absorptiometer (measurement wavelength: 254 nm)
Force ram: A stainless tube having an inner diameter of about 4 mm and a length of 15 to 30 cm filled with octadecylsilylated silica gel for liquid chromatograph of 5 to 10 μm.
Power ram temperature: constant temperature around 40 ° C. Mobile phase: acetonitrile / diluted phosphoric acid (1 → 1000) = 9/1
Flow rate: 1.0 mL / min.

[Discussion]
The poultice preparations of the present invention prepared by spreading and applying the adhesive bases obtained in Examples 1, 2 and 3 to nonwoven fabrics, respectively, are clear from the values of the ratio of ester bodies in Table 1. Compared with the cataplasm preparation prepared by spreading and applying the adhesive bases obtained in Comparative Examples 1, 2, 3 and 4 to nonwoven fabrics, the formulation stability was remarkably superior. The effectiveness of the disperse felbinac-containing cataplasm of the present invention in which a highly hydrophilic surfactant was contained in the adhesive base in which menthol coexists was confirmed.
In Comparative Example 1 and Comparative Example 2 using a non-ionic surfactant with low hydrophilicity, the value of the ratio of the ester is the same as Example 3 of the present invention using a non-ionic surfactant with high hydrophilicity. Although there is no change, dispersibility is extremely poor and formulation is difficult, and even if it is forcibly formulated in this state, skin irritation is strong and unpractical.
In Comparative Examples 3 and 4, N-methyl-2-pyrrolidone and crotamiton, which are felbinac solubilizers, coexist in the amounts necessary for dissolution, respectively. Therefore, the highly hydrophilic surfactant according to the present invention is used. Even if it coexists, it does not become a dispersion type, the former is in a semi-dissolved state and the latter is in a dissolved state, and both of them are inevitably poor in formulation stability.

  The present invention provides an antiphlogistic analgesic felbinac-containing cataplasm having a very good effect on formulation stability and high practicality, and it contributes greatly to this business.

Claims (5)

HLB value selected from the group consisting of felbinac and / or a pharmaceutically acceptable salt thereof (except when it contains ipriflavone) , l-menthol, and polyethylene glycol fatty acid ester and polyoxyethylene sorbitan fatty acid ester A disperse felbinac-containing cataplasm containing 10 or more nonionic surfactants in an adhesive base.   The disperse felbinac-containing poultice according to claim 1, wherein an absorption accelerator is further contained in the adhesive base.   The dispersion type felbinac-containing poultice according to claim 1 or 2, wherein the adhesive base contains a thickener selected from the group consisting of polyvinyl alcohol, polyacrylic acid, and gelatin.   The disperse felbinac-containing poultice according to any one of claims 1 to 3, further comprising polyethylene glycol in the adhesive base.   The disperse felbinac-containing poultice according to any one of claims 1 to 4, further comprising titanium oxide in the adhesive base.