JPH05105628A - Antiinflammatory analgesic for external use - Google Patents

Abstract

PURPOSE:To provide an antiinflammatory analgesic for external use, improved in perctaneous absorption of a non-steroidal anti-inflammatory drug selected from indomethacin, ketoprofed and flurbiprofen, penetrating to a deep part of skin and showing a remarkably improved therapeutic effect. CONSTITUTION:As the essential components, (A) one or more non-steriodal antiinflammatory drugs selected from indomethacin, ketoprofen and flurbiprofen and (B) capsaicin and/or nonylic acid vanillyl amide are mixed respectively in an amount of (A)=0.1-5.0wt.% and (B)=0.001-0.1wt.% to obtain the objective antiinflammatory analgesic for external use, improved in the effect of the medicinal component (A) by promoting penetration of the medicinal component (A) into blood, muscle and synovial fluid and applicable as a medinine for external use, by any dosage form, e.g. liquid, ointment or plaster. In addition, a galnical extract, a galnical powder, a galnical essence or a galenical tincture other than synthesized capsaincin can also be used. As the blending ratio is the galenical powder: 0.1-10wt.%, the essence: 0.01-1.0wt.%, the tincture 0.1-10wt.% or in case of the other 0.01-0.1wt.%, respectively.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an anti-inflammatory agent for external use, and more specifically, it contains at least one nonsteroidal anti-inflammatory agent selected from indomethacin, ketoprofen and flurbiprofen, and capsaicin and / or vanillylamide nonylate. By doing so, it relates to a dramatic improvement in the therapeutic effect on inflammation.

[0002]

BACKGROUND OF THE INVENTION Indomethacin, ketoprofen and flurbiprofen are widely used by oral administration in the field of orthopedic surgery for the treatment of osteoarthritis, periarthritis of the shoulder, myalgia and the like, and excellent effects have been recognized.

On the other hand, in recent years, in order to prevent gastrointestinal disorders, which are the side effects of these ingredients, liquid preparations containing these ingredients,
Ointments and patches have been developed. (JP-A-53-81
616, JP-A-56-135414, and JP-A-57-35.
509, JP-A-58-83621, and JP-A-58-396.
16, JP-A-55-62013, JP-A-55-6201
4, JP-A-57-140711, JP-A-61-2752
12, JP-A-63-88125). However, these components are poorly absorbed through the skin, and it is the current situation that the therapeutic effect over oral administration has not been obtained by external administration, and the improvement of the therapeutic effect by improving the absorption through the skin has been the biggest issue. ..

As a method for solving this problem, a method of improving the solubility of these components in a base (Japanese Patent Laid-Open No. 56-
36411, JP-A-58-124716, JP-A-58-58
4713, JP-A-59-37412, JP-A-61-1.
2614, JP-A-62-270524), a method of blending a component that promotes absorption through the skin (JP-A-58-150).
508, JP-A-58-52216, and JP-A-60-146.
823, JP 61-172833, JP 61-19.
4015), and a method of accelerating absorption by appropriately stuffing the skin (JP-A-56-51412, JP-A-59-2797).
8) etc. are known. However, these methods also improve the effects of these drugs because they promote the transfer of indomethacin, ketoprofen and flurbiprofen to the epidermis, but not to blood, muscle and synovial fluid. is not.

[0005]

DISCLOSURE OF THE INVENTION The present invention aims to promote the transfer of at least one component selected from indomethacin, ketoprofen and flurbiprofen into blood, muscle and synovial fluid to promote the transfer of these drugs. It is intended to provide an external anti-inflammatory analgesic with improved effects.

[0006]

DISCLOSURE OF THE INVENTION The present inventors have conducted intensive research to promote the transfer of at least one component selected from indomethacin, ketoprofen and flurbiprofen into blood, muscle and synovial fluid. 0.1 at least one non-steroidal anti-inflammatory drug selected from :, indomethacin, ketoprofen and flurbiprofen
It was found that the above object can be achieved by blending 0.001 to 0.1% by weight of capsaicin and / or nonyl acid vanillylamide with respect to ˜5.0% by weight.

That is, the external anti-inflammatory analgesic of the present invention comprises at least one non-steroidal anti-inflammatory drug selected from indomethacin, ketoprofen and flurbiprofen in an amount of 0.1 to 5.0% by weight of capsaicin and / or. It is characterized in that 0.001-0.1% by weight of nonyl acid vanillyl amide is blended.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION The external anti-inflammatory and analgesic composition of the present invention comprises an external base and at least one selected from indomethacin, ketoprofen and flurbiprofen, and capsaicin and / or vanillylamide nonylate. In this case, a synthetic product is used as nonyl acid vanillylamide, but a synthetic product is used as capsaicin,
A crude drug extract may be used, or a crude drug powder containing capsaicin or a crude drug extract or a crude drug tincture may be used. Also,
In the case of nonyl acid vanillyl amide, these compounding amounts are 0.
001 to 0.1% by weight is preferable. In the case of capsaicin, 0.001-0.1% by weight of synthetic products and crude drug extracts, 0.5-10% by weight of crude drug powder containing capsaicin, 0.01-1.0% by weight of crude drug extract, The crude drug tincture is preferably 0.1 to 10% by weight. If the amount is less than this amount, the therapeutic effect of capsaicin and / or vanillyl nonyl acid is not improved, and if the amount is more than this amount, skin irritation such as redness and itchiness of the skin occurs, which is not preferable.

The external anti-inflammatory and analgesic composition of the present invention can be used in any dosage form as long as it is an external preparation, but in order to make the present invention more effective, a liquid agent, an ointment, The use of patches is preferred. These dosage forms may contain conventional bases and compounding ingredients depending on the dosage form.

In the case of liquids and ointments, for example, a solvent as a base, an oil component, glycols, a surfactant, a water-soluble polymer and the like are used, and the solvent is water, ethanol, propyl alcohol, isopropyl alcohol. , Acetone, benzyl alcohol, etc. as the oil component, lanolin, hydrogenated oil, lecithin, plastibase, liquid paraffin, oleic acid, stearic acid, myristic acid, palmitic acid, beeswax, paraffin wax, microcrystalline wax, diisopropyl adipate, myristin Isopropyl acid, isopropyl sebacate, isopropyl palmitate, squalane, squalene, cetanol, stearyl alcohol, oleyl alcohol, hexadecyl alcohol, silicone oil, etc. are the glycols. Serine, propylene glycol,
Polyethylene glycol, polypropylene glycol, etc., as the surfactant, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester,
Polyoxyethylene glycerin fatty acid ester, polyethylene glycol fatty acid ester, polyoxyethylene glycol ether, polyoxyethylene alkylphenyl ether, polyoxyethylene polyoxypropylene alkyl ether, polyoxyethylene phytosterol, sorbitan fatty acid ester, glycerin fatty acid ester, etc. Examples of the polymer include carboxyvinyl polymer, sodium carboxymethylcellulose, polyvinyl alcohol, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, hydroxypropylmethylcellulose, polyacrylic acid and the like.

Further, in the case of the patch, an adhesive polymer, a moisturizer, a curing agent, an inorganic powder, a surfactant, water and the like are used, and the adhesive polymer is polyacrylic acid, sodium polyacrylate. , Gelatin, pectin, polyvinylpyrrolidone, vinyl acetate copolymer, polyethylene oxide, methyl vinyl ether / maleic anhydride copolymer, sodium alginate, sodium carboxymethyl cellulose, xanthan gum, gum arabic, tragacanth gum, etc. as humectants, glycerin, sorbitol , Propylene glycol, polyethylene glycol, polypropylene glycol, etc. as the curing agent, potassium aluminum sulfate, magnesium aluminate silicate, aluminum hydroxide, magnesium alumina hydroxide, metasilicate Magnesium Min acid, synthetic hydrotalcite, dihydroxy aluminum aminoacetate, triglycidyl isocyanate, polyethylene glycol diglycidyl ether, ethylene glycol diglycidyl ether, glycerol diglycidyl ether,
Triglycerin diglycidyl ether, etc., inorganic powders such as kaolin, silicic acid anhydride, zinc oxide, titanium oxide, etc., and surfactants such as polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene glycerin. Examples thereof include fatty acid ester, polyethylene glycol fatty acid ester, polyoxyethylene glycol ether, polyoxyethylene alkylphenyl ether, polyoxyethylene polyoxypropylene alkyl ether, polyoxyethylene phytosterol, sorbitan fatty acid ester, and glycerin fatty acid ester.

Further, the external anti-inflammatory and analgesic composition of the present invention has various adjuvants such as l-menthol, dl-camphor, tocopherol acetate, psyllium extract, horse chestnut flea for the purpose of improving efficacy and feeling of use. Various stabilizers such as sodium edetate, sodium sulfite, butylhydroxyanisole, and butylhydroxytoluene can be added for the purpose of stabilizing active ingredients such as extracts and arnica tincture.

[0013]

According to the present invention, indomethacin,
By increasing the absorption of at least one non-steroidal anti-inflammatory drug selected from ketoprofen and flurbiprofen from the skin and migrating into the deep skin, an external anti-inflammatory analgesic with dramatically improved therapeutic effect can be obtained. .. Furthermore, the present invention is a technique that can be applied to all dosage forms of external preparations, and is widely used for solutions, ointments, patches and the like.

[0014]

【Example】

Example 1 The product of the present invention containing at least one non-steroidal anti-inflammatory agent selected from indomethacin, ketoprofen and flurbiprofen and capsaicin and / or vanillylamide nonylate, and capsaicin and / or
Alternatively, the anti-inflammatory effect was compared for the liquid formulation composition (Table 1), gel ointment formulation composition (Table 2), and patch formulation composition (Table 3) for the comparative product excluding nonyl acid vanillyl amide.

[0015]

[Table 1]

[0016]

[Table 2]

[0017]

[Table 3]

The test method was as follows: test drug (0.2 ml for liquid, 0.2 g for ointment, 3 × 3.5 c for poultice)
m) was administered to the right foot of a 6-week-old male Wistar rat (Charles River Japan), and 1 hour later, 1% carrageenin (LAMBA CARRAGEENIN, Min
sei Rikagaku Co) solution (0.1 ml) was subcutaneously injected into the right leg, and immediately thereafter, a volumetric measuring device (Ugo B
It was measured by Asile Inc.). The same operation was performed after 2, 4, and 6 hours, and the edema rate and the inhibition rate were calculated from the following formulas. In the case of a poultice, it is necessary to peel off and measure the volume every time, and it is difficult to repeatedly use the same drug. Therefore, a new drug was applied every time. Edema rate E (%) = (Vt−Vn) / Vn × 100 Vt; footpad volume t time after carrageenin injection Vn: footpad volume immediately after carrageenin injection Suppression rate I (%) = (Ec−Et) / Ec × 100 Et: Edema rate after t hours of the test drug group Ec: Edema rate after t hours of the control group

The evaluation results are shown in Tables 4 and 5. As is clear from Tables 4 and 5, it was confirmed that in any of the dosage forms, the anti-inflammatory effect of indomethacin, ketoprofen or flurbiprofen was improved by the incorporation of capsaicin or nonyl vanillylamide.

[0020]

[Table 4]

[0021]

[Table 5]

[0022]

[Example 2] Comparative products 1 to 9 of the above Example 1 and the product 1 of the present invention
~ 9 is administered to the back of hairless rats (Saitama experimental animal, male, 7 weeks old) (0.1 ml of the solution is applied in a circle with a diameter of 3 cm, 0.1 g of ointment is applied in a circle with a diameter of 3 cm, and a pap is applied. (3 x 2 cm of the agent was attached), whole blood was collected 4 hours later, serum was separated, and the serum concentration of each active ingredient was measured by the HPLC method.

The results are shown in Table 6. As is clear from Table 6, in the product of the present invention containing capsaicin or nonyl acid vanillylamide, the serum concentration was higher than that of the comparative product, and it was confirmed that indomethacin, ketoprofen or flurbiprofen migrated to the deep part. Was done.

[0024]

[Table 6]

The following are examples of the formulation of the present invention. With regard to the excellent therapeutic effect associated with the improvement of the drug deep migration, these examples were extremely good as compared with all the comparative examples shown below.

Example 3 and Comparative Example 4 The compounding compositions shown in Table 7 below were prepared to be external anti-inflammatory analgesic solutions. The evaluation was performed according to the evaluation methods of Examples 1 and 2. The results are shown in Table 8.

[0027]

[Table 7] After dissolving indomethacin in ethanol, each component was sequentially dissolved to give an external anti-inflammatory analgesic solution containing ketoprofen.

[0028]

[Table 8]

Example 4 and Comparative Example 4 The composition shown in Table 9 below was prepared to give an external anti-inflammatory analgesic gel ointment. The evaluation was performed according to the evaluation methods of Examples 1 and 2.
The results are shown in Table 10.

[0030]

[Table 9] Take a portion of ethanol and dissolve flurbiprofen, 1-menthol, dl-camphor and capsaicin. Next, the carboxyvinyl polymer is dissolved in ethanol and propylene glycol to prepare a solution of hydroxyethyl cellulose in purified water and a mixed polymer solution. After mixing this polymer solution and the above-mentioned active ingredient solution, triethanolamine was added thereto to obtain the external anti-inflammatory analgesic gel ointment of the present invention.

[0031]

[Table 10]

Example 5 and Comparative Example 5 The blending composition shown in Table 11 below was prepared to give an external anti-inflammatory analgesic cream. The evaluation was performed according to the evaluation methods of Examples 1 and 2.
The results are shown in Table 12.

[0033]

[Table 11] Ketoprofen is dissolved in propylene glycol, and the capsicum extract is dissolved in purified water by heating. Next, add the other ingredients to 80 °
Heat to, and add the ketoprofen and capsicum extract solution to the dissolved solution, after emulsification and kneading, defoaming, cooling,
The external anti-inflammatory analgesic cream of the present invention was used.

[0034]

[Table 12]

Example 6 and Comparative Example 6 A patch composition was prepared by preparing the compounding composition shown in Table 13 below. The evaluation was performed according to the evaluation methods of Examples 1 and 2. About the result
It shows in Table 14.

[0035]

[Table 13] Dissolve indomethacin, 1-menthol, dl-camphor, castor oil and POE (10) nonylphenyl ether. Next, after dissolving and dispersing other components, an indomethacin solution was added and kneaded, and the resulting mixture was spread on a polyester non-woven fabric so as to be 1000 g per 1 m ² to obtain a patch of the present invention.

[0036]

[Table 14]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI Technical display location A61K 35/78 C 7180-4C 47/16 E 7329-4C

Claims (1)

[Claims] 1. 0.1 to 5.0% by weight of at least one non-steroidal anti-inflammatory agent selected from indomethacin, ketoprofen and flurbiprofen and 0.001 to 0.001 of capsaicin and / or nonyl vanillylamide.
An anti-inflammatory agent for external use characterized by containing 0.1% by weight.