JPH0228571B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula () (wherein, R represents a hydrogen atom, a lower alkyl group, a pyridyl group, an aryl group, or a lower alkyl group substituted with 1 to 2 hydroxyl groups)
The present invention relates to an anti-inflammatory and analgesic gel cream containing a (m-benzoylphenyl)propionic acid derivative as an active ingredient. 2-(m-benzoylphenyl)propionic acid derivatives represented by the general formula (), such as ketoprofen and ketoprofen ester, are non-steroidal anti-inflammatory and analgesic agents with excellent anti-inflammatory and analgesic effects. It is a drug useful in the treatment of rheumatoid arthritis, osteoarthritis, shoulder periarthritis, contusions, sprains, fractures, and other inflammatory and painful diseases. Specifically, the compounds represented by the general formula () are 2-(m-benzoylphenyl)propionic acid and methyl, ethyl, n-propyl, isopropyl, n-2-(m-benzoylphenyl)propionic acid. Represents esters such as butyl, n-pentyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 2-hydroxyethoxyethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, benzyl, etc. . Conventionally, non-steroidal anti-inflammatory analgesics have been commonly used by oral administration in the form of capsules, tablets, etc., and have shown excellent clinical results. However, on the other hand, side effects such as gastrointestinal, hepatic, and renal damage due to continuous oral administration of these drugs have become a problem, and efforts have been made to develop suppositories and other formulations to reduce such side effects. However, satisfactory results have not yet been obtained. In particular, it is generally known that non-steroidal anti-inflammatory analgesics have poor percutaneous absorption compared to other anti-inflammatory analgesics, and although there are some examples of them being used as external agents, their absorption is limited. None of the effects are satisfactory. Furthermore, there are very few external preparations that are sufficiently useful in terms of local efficacy and safety. For the reasons detailed above, there is currently a demand for the development of external anti-inflammatory analgesics that have excellent transdermal absorption, excellent medicinal efficacy, and even higher safety. Therefore, as a result of extensive research in search of a topical anti-inflammatory analgesic that can meet the above requirements, the present inventors have found a drug containing a 2-(m-benzoylphenyl)propionic acid derivative represented by the general formula (). It is already known that the gel-like cream of the present invention, which is characterized by the above, not only exhibits the same anti-inflammatory effect as when used internally, but also completely eliminates side effects and is safer when used internally. The present invention was completed based on the discovery that it has superior analgesic and anti-inflammatory effects compared to other preparations such as Buch Examack-containing cream. The gel-like cream of the present invention is produced by homogeneously emulsifying a mixture of a compound represented by the general formula (), higher fatty acid esters, lower alcohol, emulsifier, and preservative, gelling agent, and water to produce higher fatty acid diethanolamide. Alternatively, it is manufactured by blending amines, inorganic alkalis, etc. Incidentally, an absorption enhancer, a humectant, etc. may be added if desired. More specifically, the higher fatty acid esters used in the present invention include isopropyl myristate, isopropyl palmitate, diethyl sebacate, hexyl laurate, and cetyl isooctanoate, the lower alcohols include ethanol and isopropanol, and the emulsifiers include ethanol and isopropanol. is polyoxyethylene alkyl ether (e.g. lauryl ether, cetyl ether, stearyl ether, oleyl ether, etc.) and polyethylene glycol,
Fatty acid esters (eg monolaurate, monostearate, monooleate, etc.) are preferred. As the preservative, paraoxybenzoic acid ester is preferred. In addition, these contents are higher fatty acid esters.
25% by weight or less, lower alcohol 40% by weight or less,
It is preferable to mix the emulsifier in an amount of 5% by weight or less and the preservative in an amount of 0.5% by weight or less. Next, as a gelling agent, a carboxyvinyl polymer can be mentioned, and the content of the gelling agent is preferably 0.5 to 5% by weight. In addition, in order to give the cream containing carboxyvinyl polymer gel properties, coconut oil fatty acid diethanolamide, lauric acid diethanolamide, triethanolamine,
diisopropanolamine, sodium hydroxide,
Add a water-soluble basic substance such as potassium hydroxide. The amount added is preferably 0.1 to 10% by weight, and the pH
The pH may be adjusted to 4 to 8, preferably 4.5 to 6.5. Next, absorption enhancers include propylene carbonate, diisopropyl adipate, and the like. Further, examples of humectants include glycerin, propylene glycol, sorbitol, and the like. The compound represented by the general formula (), which is the active ingredient of the present invention, can be expected to be sufficiently effective at 0.5 to 10% by weight. The gel cream of the present invention can be prepared by dissolving, for example, (A) a compound represented by the general formula () in a mixture of higher fatty acid ester and lower alcohol, and further adding a preservative and an emulsifier. On the other hand, (B) is obtained by adding a gelling agent to water to swell it, then adding (B) to (A) and uniformly emulsifying it with a homomixer, and after emulsifying, adding a water-soluble basic substance to gel it. It will be done. In the above method, the gel cream of the present invention can be obtained even if the order of blending the compounds is slightly changed. The gel-like cream of the present invention produced as described above is stable even when stored for a long period of time, and when applied to the skin, it has excellent analgesic and anti-inflammatory properties as shown in the experimental examples below. It has a therapeutic effect. The anti-inflammatory effect of the compound represented by the general formula () when applied to the gel cream of the present invention will be shown below through pharmacological experiments. Experimental Example 1 Carrageenin - External anti-inflammatory effect on rat skin edema 90-110g Wistar male rats (4 weeks old)
Evaclaim [Product name: Tokyo Tanabe Pharmaceutical Co., Ltd.]
After removing the hair with a product manufactured by J.D. Co., Ltd., I left it overnight and used it. 1% carrageenan (Pycnin A: manufactured by Pasco Isoternal Company) - Physiological saline solution for injection and physiological saline solution were injected intradermally at 0.1 ml/site each in dorsal column symmetry, and the former was administered as a test subject. A patch test bandage (Small size, manufactured by Torii Pharmaceutical Co., Ltd.) containing 0.1 ml of each drug was applied immediately.
1% Pontamine Sky Blue (PSB) after 2.5 hours
- Inject 0.5ml/100g of physiological saline through the tail vein,
After another 30 minutes, the animals were exsanguinated to death. Peel the skin and immediately measure the thickness of the intradermal injection site with a dial.
Thickness gauge manufactured by Ozaki Seisakusho Co., Ltd.: Measuring pressure 40g]
The edema rate was determined using the following formula. Edema rate (%) = Thickness of the carrageenin injection site - Thickness of the physiological saline injection site / Thickness of the physiological saline injection site x 100 In addition, the product of the major axis and the minor axis of the pigment exudation area is determined as the pigment exudation area. et al (Harada, M.,
Takeuchi, M. Fukao, T. & Katagiri, K.: J.
Pharm. Pharmacol 23 , 218, 1971) was used to extract Pontamine Sky Blue, and the amount of leached pigment was determined by measuring with a spectrophotometer. The test results are shown in Table 1.

[Table] Experimental Example 2 Anti-inflammatory effect of topical application on rat footpad edema due to bone fracture Male Wistar rats weighing around 130g (5 weeks old)
A group of 8 animals was used. Carefully rub 100 mg of the test drug into the left leg.
The application site was wrapped in saran wrap to prevent rats from licking it. In addition, there is a disposable beaker (DB-1) on the head.
for Automatic Blood Cell Counter：TOA
(manufactured by Medical Electrouics Co., Ltd.) and fixed with rubber. After 3 hours, the rat was anesthetized with ether, and the leg region to which the test drug was applied was pinched using forceps equipped with a rubber tube to induce a linear fracture in the metatarsal bone. Immediately thereafter, 100 mg of the test drug was applied to the same area again, and the same treatment was performed. Judgment was made 3 hours after the fracture, and the edema rate was calculated by measuring the foot volume before and 3 hours after the fracture using Fujihira's method (Eiichi Fujihira: Applied Pharmacology 5, 119-, 1971).
Statistical processing was performed using student-test (Kimichi Sugimoto: Illustrated Medical Statistics: Igaku Shoin 1968). The test results are shown in Table 2.

【table】

[Table] Experimental Example 3: Damage to gastric mucosa in rats Male Wistar rats weighing approximately 200 g were given free access to water and fasted for 24 hours, after which the test compound was administered. The test compound was applied by applying 0.1 ml of the gel-like cream preparation to the back of rats that had been shaved with an electric razor.
A patch test bandage was applied, and the bulk ketoprofen powder was suspended in 0.5% gum tragacanth saline and orally administered. Six hours after administration, the animals were sacrificed, the stomach was removed, an incision was made along the large bay, and the presence or absence of ulcers on the gastric mucosa was visually observed, and the ulcer incidence was calculated using the following formula. Ulcer incidence (%) = Number of animals with ulcers/Number of animals subjected to experiment x 100 The test results are shown in Table 3.

[Table] Experimental example 4 Acute toxicity DDY male and female mice weighing 19-26g and body weight
Male and female Wistar rats weighing 102 to 130 g were used in groups of 10 each. The test compound (gel-like cream preparation containing 3% ketoprofen) was applied to the backs of both species after hair removal using electric clippers at the maximum amount of 15,000 mg/kg, and mortality was examined up to 14 days later. The test results are shown in Table 4.

[Table] From the results of the above pharmacological experiments, it was found that the emulsion-based gel cream of the present invention is a useful preparation as an anti-inflammatory analgesic for external use, and is also highly safe. The present invention will be specifically explained below with reference to Examples, but the present invention is not limited only to the Examples. In the following description, parts mean parts by weight. Example 1 Carboxyvinyl polymer [Carbopol 940
(manufactured by Gutsudoritsuchi Chemical Co.)] 1 part was swollen in 66.8 parts of water. On the other hand, isopropyl myristate 10
and 5 parts of ethanol, and dissolved 3 parts of ketoprofen in this, and then added polyethylene glycol monostearate [Nitsukol MYS-40
(manufactured by Nikko Chemicals)] and 0.2 parts of methyl paraoxybenzoate were mixed. This is added to the water-swollen carboxyvinyl polymer and uniformly emulsified using a homomixer. After emulsification, a solution of 3 parts of coconut oil fatty acid diethanolamide dissolved in 10 parts of water was added and thoroughly stirred until the whole was homogeneous to obtain an anti-inflammatory and analgesic gel cream. Example 2 Carboxyvinyl polymer [Hibis Wako
104 (manufactured by Wako Pure Chemical Industries, Ltd.)] was swollen in 55.7 parts of water. Separately, 10 parts of isopropyl palmitate and 10 parts of diethyl sebacate were mixed, 1 part of ketoprofen was dissolved therein, and then 2 parts of polyoxyethylene cetyl ether [Nitsukol BC-20TX (manufactured by Nikko Chemicals)], carbonic acid 10 parts of propylene,
0.2 part of methyl paraoxybenzoate was mixed. This is added to the water-swollen carboxyvinyl polymer and uniformly emulsified using a homomixer.
After emulsification, a solution of 0.1 part of sodium hydroxide dissolved in 10 parts of water was added and thoroughly stirred until the whole was homogeneous to obtain an anti-inflammatory and analgesic gel cream. Example 3 1.5 parts of carboxyvinyl polymer (same as in Example 1) was swollen in 66.3 parts of water. On the other hand, 10 parts of cetyl isooctanoate [Nitsukol CIO-P (manufactured by Nikko Chemicals Co., Ltd.)] and 5 parts of ethanol were mixed, 3 parts of ketoprophene ethyl ester were mixed therein, and then polyethylene glycol monostearate [Nitsukol MYS -40 (manufactured by Nikko Chemicals)] and 0.2 parts of methyl paraoxybenzoate were mixed. This is added to the water-swollen carboxyvinyl polymer and uniformly emulsified using a homomixer. After emulsification, 3 parts of coconut oil fatty acid diethanolamide dissolved in 10 parts of water was added,
The mixture was sufficiently stirred until the whole was homogeneous to obtain an anti-inflammatory and analgesic gel cream. Example 4 1 part of carboxyvinyl polymer (same as in Example 2) was swollen in 58.7 parts of water. On the other hand, 10 parts of isopropyl myristate and 5 parts of diethyl sebacate were mixed, 3 parts of ketoprofen hydroxyethyl ester was mixed therewith, and then polyoxyethylene cetyl ether [Nitsukol BC-
25TX (manufactured by Nikko Chemicals)], 10 parts of propylene carbonate, and 0.2 parts of methyl paraoxybenzoate were mixed. This is added to the water-swollen carboxyvinyl polymer and uniformly emulsified using a homomixer. After emulsification, add 0.1 part of sodium hydroxide to water.
10 parts of the solution was added and thoroughly stirred until the whole was homogeneous to obtain an anti-inflammatory and analgesic gel cream.

Claims (1)

[Claims] 1 Emulsion base consisting of higher fatty acid esters, emulsifiers, preservatives, gelling agents, water-soluble basic substances, water and/or lower alcohols, and 2-(m-benzoylphenyl)propionic acid derivatives as active ingredients. Anti-inflammatory analgesic gel cream containing.