JP3091285B2 - External anti-inflammatory analgesic - Google Patents

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 analgesic, and more particularly to a combination of at least one non-steroidal anti-inflammatory drug selected from indomethacin, ketoprofen and flurbiprofen, with capsaicin and / or nonylate vanillylamide. 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 in the treatment of osteoarthritis, shoulder periarthritis, muscle pain and the like, and their excellent effects have been recognized.

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 improvement of the therapeutic effect by improving absorption from the skin was the biggest issue. .

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 for the transfer of at least one component selected from indomethacin, ketoprofen and flurbiprofen into blood, muscle and synovial fluid by promoting the transfer of these drugs. It is intended to provide an external anti-inflammatory analgesic with improved effects.

[0006]

Means for Solving the Problems The present inventors have developed a skin comprising at least one nonsteroidal anti-inflammatory drug selected from indomethacin, ketoprofen and flurbiprofen.
Intensive search to promote absorption and translocation into blood, muscle and synovial fluid resulted in capsaicin and vanillyl nonylate.
Amide and non-steroidal anti-inflammatory drugs for skin absorption and deep skin
It has been found that there is a transition promotion and sustaining effect.

The present invention provides an indomethacin comprising at least one of capsaicin and nonylate vanillylamide.
, Ketoprofen and flurbiprofen
At least one nonsteroidal anti-inflammatory agent for promoting skin absorption and deep skin penetration. Further, the present invention provides 0.1 to 5.0% by weight of at least one nonsteroidal anti-inflammatory agent selected from indomethacin, ketoprofen and flurbiprofen , and capsaicin ,
Providing external anti-inflammatory analgesic agent characterized in that it contains 0.001 to 0.1 wt% wherein a nonsteroidal anti-inflammatory agents of the skin absorbing and skin deep migration promoting sustained agent. (A) indomethacin, ketoprofen and furul
At least one non-steroi selected from biprofen
De antiinflammatory agents, (B) low capsaicin and vanillylamide nonylate
Skin absorption of at least one component (A), deep skin
Migration promoting sustained agent, and (C) dl-camphor and / or tocopherol acetate
And providing an external anti-inflammatory analgesic characterized by containing
You. In addition, (A) indomethacin, ketoprofen and
At least one non-sterol selected from lurbiprofen;
(B) low levels of capsaicin and nonylate vanillylamide
Skin absorption of at least one component (A), deep skin
A patch characterized by containing a transition promoting and stabilizing agent, and (C) castor oil.
provide.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION The external anti-inflammatory and analgesic composition according to the present invention is obtained by mixing at least one selected from indomethacin, ketoprofen and flurbiprofen with capsaicin and / or nonylate vanillylamide in an external base. In this case, a synthetic product is used as nonylate vanillylamide, but a synthetic product is used as capsaicin.
A crude drug extract, a crude drug powder or a crude drug extract or a crude drug tincture containing capsaicin may be used. Also,
In the case of nonylate vanillylamide, the amount of these components is 0.1.
001 to 0.1% by weight is preferred. 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, 0.01 to 1.0% by weight for crude drug extracts, 0.1 to 10% by weight is preferred for crude drug tincture. If the amount is less than the above, the therapeutic effect of capsaicin and / or nonylyl vanillylamide is little improved, and if the amount is more than the above, skin irritation such as redness and itching of the skin occurs, which is not preferable.

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, an ointment, 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 silicate aluminate, aluminum hydroxide, magnesium magnesium hydroxide, 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 .; kaolin, silicic anhydride, zinc oxide, titanium oxide, etc. as inorganic powders; polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene glycerin as surfactants Examples include fatty acid esters, polyethylene glycol fatty acid esters, polyoxyethylene glycol ether, polyoxyethylene alkyl phenyl ether, polyoxyethylene polyoxypropylene alkyl ether, polyoxyethylene phytosterol, sorbitan fatty acid esters, glycerin fatty acid esters, and the like.

The topical anti-inflammatory analgesic composition of the present invention further contains various adjuvants such as l-menthol, dl-camphor, tocopherol acetate, oak extract, and sea chirney 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.

[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 into deep skin, an external anti-inflammatory analgesic with significantly improved therapeutic effect can be obtained. . 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.

[0014]

【Example】

Example 1 A product of the present invention containing at least one nonsteroidal anti-inflammatory drug selected from indomethacin, ketoprofen and flurbiprofen and capsaicin and / or vanillyl amide nonylate, and capsaicin and / or
Alternatively, the anti-inflammatory effects of a comparative product excluding nonylate vanillylamide were compared for a liquid composition (Table 1), a gel ointment composition (Table 2), and a patch composition (Table 3).

[0015]

[Table 1]

[0016]

[Table 2]

[0017]

[Table 3]

The test method was as follows: test drug (0.2 ml of liquid agent, 0.2 g of ointment, 3 × 3.5 c for poultice)
m) was administered to male Wistar rats (Charles River Japan), 6-week-old right foot, and 1 hour later, 1% carrageenin (LAMBA CARRAGEENIN, Min.)
0.1 ml of sei Rikagaku Co) solution was injected subcutaneously into the right foot and immediately thereafter, a volume measuring device (Ugo B) was used.
asile). 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 t hour 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 4 and 5. As is clear from Tables 4 and 5, it was confirmed that the combination of capsaicin or nonylate vanillylamide improved the anti-inflammatory effect of indomethacin, ketoprofen or flurbiprofen in any of the dosage forms.

[0020]

[Table 4]

[0021]

[Table 5] ─────────────────────────────────── Suppression rate (%: average value of n = 5) ) Test drug body weight (g) 1 hour 2 hours 4 hours 6 hours ─────────────────────────────── ──── Present product 1 171.2 30.2 40.6 44.4 28.3 Comparative product 1 173.5 26.0 33.3 35.1 17.6 Present product 2 169.2 37.7 46.1 47.0 35.7 Comparative product 2 171.3 23.4 35.9 40.6 27.8 Present product 3 175.2 34.4 47.0 44.1 34.7 Comparative product 3 174.1 20.1 29.5 31.7 21.9 Inventive product 4 172.1 18.5 42.8 44.9 31.2 Comparative product 4 169.8 14.6 33.1 34.5 19.6 Inventive product 5 173.4 31.8 50.4 49.6 38.8 Comparative product 5 172.6 21.4 38.3 42.4 29.3 Inventive product 6 168.9 35.7 49.3 48.2 37.7 Comparative product 6 170.1 18.5 35.1 33.7 24.8 Inventive product 7 174.0 41.9 49.0 50.0 40.7 Comparative product 7 173.1 37.3 42.2 39.3 26.4 Inventive product 8 171.9 45.1 51.7 54.3 46.2 Comparative product 8 169.0 34.7 47.8 43.4 29.4 Present product 9 172.9 39.0 52.0 56.2 45.1 Comparative product 9 171.3 28.9 46.4 41.5 27.0 ───────────────────────────────── ──

[0022]

Embodiment 2 Comparative products 1 to 9 of the above-mentioned embodiment 1 and the present invention product 1
9 to the back of a hairless rat (Saitama experimental animal, male, 7 weeks old) (0.1 ml of solution was applied in a 3 cm diameter circle, 0.1 g of ointment was applied in a 3 cm diameter circle, pap) After 3 hours, whole blood was collected, serum was separated, and the serum concentration of each active ingredient was measured by HPLC.

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

[0024]

[Table 6]

Examples of the preparation according to the present invention will be described below. These examples were extremely good with respect to all the comparative examples shown below, with respect to the excellent therapeutic effect associated with the improvement in the deep migration of the drug.

Example 3 and Comparative Example 4 The composition shown in Table 7 below was prepared and used as an external anti-inflammatory and analgesic solution. The evaluation was performed according to the evaluation methods of Examples 1 and 2. Table 8 shows the results.

[0027]

Table 7 配合 Composition (% by weight) Example 3 Comparative Example 3 ────────────────────────────────── Ketoprofen 2.5 2.5 Vanillyl nonylate 0.008 --- l -Menthol 3.0 3.0 Tocopherol acetate 1.0 1.0 POE (10) monolaurate 3.0 3.0 Diisopropyl adipate 5.0 5.0 Purified water 30.0 30.0 Ethanol 20.0 20.0 Isopropanol 35.492 35.5 ───────────────────────────────────Dissolve ketoprofen in ethanol Thereafter, the components were 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.
Table 10 shows the results.

[0030]

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

[0031]

[Table 10]

Example 5 and Comparative Example 5 The 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.
Table 12 shows the results.

[0033]

[Table 11] Ketoprofen is dissolved in propylene glycol, and the pepper extract is heated and dissolved in purified water. Next, the other components are
Heated, added ketoprofen and pepper extract solution to the dissolved solution, after emulsification kneading, defoaming, cooling,
An external anti-inflammatory analgesic cream of the present invention was obtained.

[0034]

[Table 12]

Example 6 and Comparative Example 6 The formulations shown in Table 13 below were prepared and used as patches. The evaluation was performed according to the evaluation methods of Examples 1 and 2. About the result,
It is shown in Table 14.

[0035]

[Table 13] Dissolve indomethacin, 1-menthol, dl-camphor, castor oil and POE (10) nonylphenyl ether. Next, dissolve the other ingredients, was dispersed, added indomethacin solution, those kneaded, and spread so that on the polyester nonwoven fabric 1 m ² per the 1000 g, was patch of the present invention.

[0036]

[Table 14]

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61K 47/16 A61K 47/16 A61P 25/04 A61P 25/04 29/00 29/00 (58) Fields surveyed (Int.Cl. . ^7, DB name) A61K 31/405 A61K 9/70 A61K 31/165 A61K 31/19 A61K 35/78 A61K 47/16

Claims (4)

(57) [Claims] 1. Indomethacin, keto comprising at least one of capsaicin and nonylate vanillylamide
Less selected from profen and flurbiprofen
Both are a type of non-steroidal anti-inflammatory agent that promotes absorption and deep penetration of skin into the skin. 2. The method according to claim 1 , wherein 0.1 to 5.0% by weight of at least one nonsteroidal anti-inflammatory drug selected from indomethacin, ketoprofen and flurbiprofen , and capsaicin are added to the nonsteroidal anti-inflammatory agent . An external anti-inflammatory analgesic, comprising 0.001 to 0.1% by weight as an agent for promoting the absorption of the anti-inflammatory agent into the skin and deep skin transfer. (A) Indomethacin, ketoprofen
And at least one member selected from flurbiprofen
Non-steroidal anti-inflammatory drugs, (B) low amounts of capsaicin and nonylate vanillylamide
Skin absorption of at least one component (A), deep skin
Transition promoting and sustaining agent, (C) dl-camphor and / or tocopherol acetate
An external anti-inflammatory analgesic, comprising: (A) Indomethacin, ketoprofen
And at least one member selected from flurbiprofen
Non-steroidal anti-inflammatory drugs, (B) low amounts of capsaicin and nonylate vanillylamide
Skin absorption of at least one component (A), deep skin
Transition promoting and sustaining agent, (C) A patch comprising castor oil.