JP2000297036A - Anti-inflammatory and analgesic agent for external use - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an anti-inflammatory and analgesic agent for external use, capable of accelerating the transport of at least one kind ingredient selected from indometacin, ketoprofen and flurbiprofen into blood, muscle and synovial fluid. SOLUTION: This agent contains (A) at least one non-steroidal anti- inflammatory agent selected from indometacin, ketoprofen and flurbiprofen, (B) capsaicin and/or nonylic acid vanillylamide and (C) a polyoxyethylenesorbitan fatty acid ester. It is desirable that the component C is polysorbate 80 and the agent is used as a patch.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an external anti-inflammatory drug and, more particularly, to a combination of at least one nonsteroidal anti-inflammatory drug selected from indomethacin, ketoprofen and flurbiprofen, with capsaicin and / or vanillyl amide nonylate. To dramatically improve the therapeutic effect on inflammation.

[0002]

2. Description of the Related Art Indomethacin, ketoprofen and flurbiprofen are widely used in the field of orthopedic surgery for internal use in the treatment of osteoarthritis, shoulder periarthritis, muscle pain, etc.
Excellent effects have been observed.

On the other hand, in recent years, in order to prevent gastrointestinal disorders which are a side effect of these components, liquid preparations containing these components,
Ointments and patches have been developed. (JP-A-53-81
616, JP-A-56-135414, 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 from the skin, and at present it is not possible to obtain a therapeutic effect higher than that of internal administration by topical administration, and the biggest issue was to improve the therapeutic effect by improving absorption from the skin. .

As a method for solving this problem, a method for improving the solubility of these components in a base (Japanese Patent Application Laid-Open No.
36411, JP-A-58-124716, JP-A-58-124
4713, JP-A-59-137412, JP-A-61-1
2614, JP-A-62-270524), and a method of blending a component that promotes absorption from the skin (JP-A-58-150).
508, JP-A-58-52216, JP-A-60-146
823, JP-A-61-172833, JP-A-61-19
4015), a method of appropriately moisturizing the skin to promote absorption (JP-A-56-51412, JP-A-59-2797).
8) are known. However, these methods also promote the transfer of indomethacin, ketoprofen and flurbiprofen to the epidermis, but not to blood, muscle and synovial fluid. is not.

[0005]

SUMMARY OF THE INVENTION The present invention provides an external anti-inflammatory analgesic capable of promoting the transfer of at least one component selected from indomethacin, ketoprofen and flurbiprofen into blood, muscle and synovial fluid. Things.

[0006]

The topical anti-inflammatory analgesic of the present invention comprises (A) at least one nonsteroidal anti-inflammatory drug selected from indomethacin, ketoprofen and flurbiprofen; (B) capsaicin and / or It is characterized by containing nonyl acid vanillyl amide and (C) polyoxyethylene sorbitan fatty acid ester. The component (c) can be polysorbate 80. The external antiphlogistic analgesic of the present invention can be used as a patch.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION The topical anti-inflammatory analgesic composition according to the present invention comprises: (A) at least one selected from indomethacin, ketoprofen and flurbiprofen, and (B) capsaicin and / or nonylate as bases for external use. It comprises vanillylamide and (C) a polyoxyethylene sorbitan fatty acid ester. In this case, a synthetic product is used as the nonylate vanillylamide, and a synthetic product, a crude drug extract, or a crude drug powder or a crude drug extract or a crude drug tincture containing capsaicin may be used as capsaicin. The amount of these components is preferably 0.001 to 0.1% by weight in the case of nonylate vanillylamide. In the case of capsaicin, 0.001 to 0.1% by weight for synthetic products and crude drug extracts, 0.5 to 10% by weight for crude drug powder containing capsaicin, and 0.01 for crude drug extracts
-1.0% by weight, and 0.1-10% by weight for herbal tincture. If the amount is less than the lower limit, the therapeutic effect of capsaicin and / or nonylate vanillylamide is little improved. If the amount exceeds the upper limit, skin irritation such as redness and itching of the skin occurs, which is not preferable. .

[0008] The external anti-inflammatory analgesic composition of the present invention can be used in any form as long as it is an external preparation. However, in order to make the present invention more effective, a liquid preparation, a softening agent The use of a patch is preferred. These dosage forms can contain conventional bases and compounding components depending on the dosage form.

For example, in the case of solutions and ointments, solvents, oil components, glycols, surfactants, water-soluble polymers and the like are used as bases, and the solvents include water, ethanol, propyl alcohol and isopropyl alcohol. , Acetone, benzyl alcohol, etc., oil components include lanolin, hydrogenated oil, lecithin, plastibase, liquid paraffin, oleic acid, stearic acid, myristic acid, palmitic acid, beeswax, paraffin wax, microcrystalline wax, diisopropyl adipate, myristine Isopropyl acid, isopropyl sebacate, isopropyl palmitate, squalane, squalene, cetanol, stearyl alcohol, oleyl alcohol, hexadecyl alcohol, silicone oil, etc. Serine, propylene glycol,
Polyethylene glycol, polypropylene glycol and the like, as surfactants polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester,
Polyoxyethylene glycerin fatty acid ester, polyethylene glycol fatty acid ester, polyoxyethylene glycol ether, polyoxyethylene alkyl phenyl ether, polyoxyethylene polyoxypropylene alkyl ether: polyoxyethylene phytosterol, sorbitan fatty acid ester, glycerin fatty acid ester, etc. Examples of the hydrophilic polymer include carboxyvinyl polymer, sodium carboxymethylcellulose, polyvinyl alcohol, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, hydroxypropylmethylcellulose, and polyacrylic acid.

In the case of a patch, an adhesive polymer, a humectant, a curing agent, an inorganic powder, a surfactant and water are used. Examples of the adhesive polymer include polyacrylic acid and sodium polyacrylate. , Gelatin, pectin, polyvinylpyrrolidone, vinyl acetate copolymer, polyethylene oxide, methyl vinyl ether / maleic anhydride copolymer, sodium alginate, sodium carboxymethylcellulose, xanthan gum, gum arabic, gum tragacanth, etc., as humectants glycerin, sorbitol , Propylene glycol, polyethylene glycol, polypropylene glycol, etc., and curing agents such as aluminum potassium sulfate, magnesium aluminate silicate, aluminum hydroxide, magnesium aluminate 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 and the like; inorganic powders such as kaolin, silicic anhydride, zinc oxide and titanium oxide; surfactants other than the component (C) include polyoxyethylene hydrogenated castor oil and polyoxyethylene glycerin Fatty acid esters, polyethylene glycol fatty acid esters, polyoxyethylene glycol ethers, polyoxyethylene alkyl phenyl ethers, polyoxyethylene polyoxypropylene alkyl ethers, polyoxyethylene phytosterols, sorbitan fatty acid esters, glycerin fatty acid esters, and the like.

The topical anti-inflammatory analgesic composition of the present invention may further contain various adjuvants, for example, l-menthol, dl-camphor, tocopherol acetate, tobacco extract, and horse chestnut for the purpose of improving the efficacy and the feeling of use. For the purpose of stabilizing an active ingredient such as an extract or arnic tincture, various stabilizers, for example, sodium edetate, sodium sulfite, butylhydroxyanisole, butylhydroxytoluene and the like can be blended.

[0012]

EXAMPLES [Test Example 1] (A) at least one non-steroidal anti-inflammatory drug selected from indomethacin, ketoprofen and flurbiprofen, (B) capsaicin and / or nonylate vanillylamide, and (C) The anti-inflammatory effect of the patch containing composition (Table 1) was compared between the example in which polysorbate 80 was blended and the comparative example in which any one of the components (A), (B) and (C) was excluded.

[0013]

[Table 1]

The test method was as follows. A test drug (0.2 g of ointment was applied, and 3 × 3.5 cm of cataplasm was applied) was administered to male Wistar rats (Charles River Japan), 6-week-old right foot. After 1 hour, 1% carrageenin (LAMBA CARRAGEENI
(N, Minsei Rikagaku Co) solution was injected subcutaneously into the right foot and immediately measured with a volumetric device (Ugo Basile). The same operation was performed after 2, 4 and 6 hours, and the edema rate and the inhibition rate were calculated from the following equations. In the case of a poultice, it was necessary to peel off the volume at each time and measure the volume, and it was difficult to repeatedly use the same drug. Therefore, a new drug was applied at each time. Edema rate E (%) = (Vt−Vn) / Vn × 100 Vt: Footpad volume at time t after carrageenin injection Vn: Footpad volume immediately after carrageenin injection Inhibition rate I (%) = (Ec−Et) / Ec × 100 Et: Edema rate after t hours of test drug group Ec: Edema rate after t hours of control group

The evaluation results are shown in Tables 2 and 3. As is clear from Tables 2 and 3, it was confirmed that the combination of capsaicin or nonylate vanillylamide improved the anti-inflammatory effect of indomethacin, ketoprofen or flurbiprofen.

[0016]

[Table 2]

[0017]

[Table 3]

Test Example 2 Examples 1-3 of Test Example 1 above
And Comparative Examples 1 to 3 using hairless rats (Saitama experimental animal, male,
7 weeks old) (0.1 g of ointment was applied in a circle of 3 cm in diameter, 3 × 2 cm of cataplasm was applied), 4 hours later, whole blood was collected, serum was separated, and each sample was separated by HPLC. The serum concentration of the active ingredient was measured.

The results are shown in Table 4. As is clear from Table 4, in the product containing capsaicin or nonylate vanillylamide, the serum concentration was high, and it was confirmed that indomethacin, ketoprofen or flurbiprofen migrated deep into the skin.

[0020]

[Table 4]

Examples and comparative examples of the preparation of the present invention are shown below. In the examples, an excellent therapeutic effect was observed with an improvement in the deep migration of the drug.

Example 4 and Comparative Example 4 The composition shown in Table 5 below was prepared to give an external anti-inflammatory analgesic cream. Evaluation was performed according to the evaluation methods of Test Examples 1 and 2. Table 6 for results
Shown in

[0023]

[Table 5] Ketoprofen is dissolved in propylene glycol, and the pepper extract is heated and dissolved in purified water. Next, the other components are heated to 80 ° C.
Heated, added to the dissolved solution ketoprofen and pepper extract solution, after emulsification kneading, defoaming, cooling,
An external anti-inflammatory analgesic cream was used.

[0024]

[Table 6]

Comparative Examples 5 and 6 The compositions shown in Table 7 below were prepared and used as patches. Evaluation was performed according to the evaluation methods of Test Examples 1 and 2. Table 8 shows the results.

[0026]

[Table 7] Dissolve indomethacin, 1-menthol, dl-camphor, castor oil and POE (10) nonylphenyl ether. Next, after dissolving and dispersing the other components, the indomethacin solution was added and kneaded, and the mixture was spread on a polyester nonwoven fabric so as to be 1000 g per 1 m ² ,
It was a patch.

[0027]

[Table 8]

[0028]

According to the present invention, indomethacin,
An external antiphlogistic analgesic can be obtained in which the absorption of at least one non-steroidal anti-inflammatory drug selected from ketoprofen and flurbiprofen from the skin and transfer into deep skin are enhanced, and the therapeutic effect is dramatically improved. Further, the present invention is a technique applicable to all dosage forms of external preparations, and is widely used for liquid preparations, ointments, patches and the like.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 29/00 A61P 29/00

Claims (3)

[Claims] 1. A non-steroidal anti-inflammatory agent selected from the group consisting of (A) indomethacin, ketoprofen and flurbiprofen, (B) capsaicin and / or vanillyl amide nonylate, and (C) polyoxyethylene sorbitan fatty acid ester And a topical anti-inflammatory analgesic comprising: 2. The external anti-inflammatory analgesic according to claim 1, wherein (c) is polysorbate 80. 3. A patch according to claim 1, wherein the patch is a patch.
Or an external anti-inflammatory analgesic according to 2.