JPH0228570B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to an anti-inflammatory analgesic gel containing ketoprofen ester as an active ingredient. Ketoprofen ester has the formula () (In the formula, R represents a lower alkyl group having a carbon number of C ₁ to C ₆ and a lower alkyl group substituted with 1 to 2 phenyl groups, pyridyl groups, or hydroxyl groups.) Specifically, ketoprofen is methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-hydroxyethyl, 2-hydroxypropyl, 2,3-dihydroxypropyl, 2-hydroxyethoxyethyl, 2-pyridylmethyl, 3- Represents esters such as pyridylmethyl and benzyl. The compound represented by the general formula () has excellent anti-inflammatory and analgesic effects, and is effective against rheumatoid arthritis,
It is a useful drug in the treatment of osteoarthritis, shoulder periarthritis, contusions, sprains, fractures, and other inflammatory and painful diseases. Conventionally, it has been generally known that non-steroidal anti-inflammatory analgesics have poor percutaneous absorption compared to other anti-inflammatory analgesics, and although there have been some examples of them being used as external agents, their absorption has been limited. None of the effects are satisfactory. An example of an anti-inflammatory analgesic ointment containing indomethacin was developed as a therapeutic agent for inflammatory diseases with the aim of reducing side effects such as gastrointestinal disorders when applied topically. 53−81616
As seen in the patent publication, this example also has many clinical problems in terms of therapeutic efficacy due to poor drug release from the ointment base (gel base), resulting in poor transdermal absorption. It has not been possible to overcome the traditional drawbacks. For the reasons detailed above, there is currently a demand for the development of external anti-inflammatory analgesics that have excellent transdermal absorption and excellent medicinal efficacy. Therefore, the present inventors conducted extensive research in search of a topical anti-inflammatory analgesic that could meet the above requirements, and as a result, the gel of the present invention, which is characterized by containing a ketoprofen ester, was found to be a gel containing indomethacin. It was found that the transdermal absorption and anti-inflammatory effect were very superior compared to other preparations such as . Furthermore,
In terms of formulation, indometacin had the disadvantage of poor solubility in gel bases and easy precipitation of crystals, whereas ketoprofen esters have good stability and compatibility with gel bases. The present invention was completed by discovering that the drug is compatible with the gel base of the present invention, and that the usability of this preparation is also excellent. The gel agent of the present invention is a composition comprising a ketoprofen ester, a glycol, a lower alcohol, water, or a mixture of a lower alcohol and water, a gelling agent, and, if desired, a nonionic surfactant added thereto. Manufactured by gelation. Note that a neutralizing agent may be appropriately added depending on the gelling agent. More specifically, the glycols used in the present invention include propylene glycol, butylene glycol, and glycol derivatives such as propylene carbonate, and the lower alcohols include ethanol, isopropyl alcohol, and the like.
Note that lower alcohols are usually used mixed with water, but there are cases where they are not mixed at all due to other formulations, and in this case, water is mixed alone. or,
The content of these is 40% by weight or less of glycol,
It is preferable to mix so that the lower alcohol content is 60% by weight or less and the water content is 55% by weight or less. Next, examples of the gelling agent include carboxyvinyl polymer, hydroxyethyl cellulose, methyl cellulose, carboxymethyl cellulose, alginate propylene glycol ester, and the like. The gelling agent is preferably blended so that the final concentration is 0.5 to 5% by weight. Incidentally, examples of the organic amine that neutralizes the carboxyvinyl polymer include triethanolamine, diisopropanolamine, and the like. Further, it is preferable to blend this neutralizing agent in an amount of 0.1 to 1% by weight, so that the gel agent is near neutral, that is, PH4 to 7, preferably PH4.5.
It should be adjusted so that it becomes ~6. Furthermore, nonionic surfactants include sorbitan sesquioleate, sorbitan trioleate, sorbitan monooleate, sorbitan monostearate, sorbitan monolaurate, polyethylene glycol monostearate, polyoxyethylene sorbitan monooleate, and monolauric acid. Preferably, polyoxyethylene sorbitan, polyoxyethylene nonylphenyl ether, polyoxyethylene cetyl ether, polyoxyethylene lauryl ether or a mixture thereof is blended. The effect of ketoprofen ester, which is the active ingredient of the present invention, can be expected to be sufficient at 0.5 to 10% by weight. The ketoprofen ester gel of the present invention can be prepared by, for example, (A) adding a gelling agent to water to swell it, while (B) dissolving the ketoprofen ester in a mixture of glycols and lower alcohol; It can be obtained by adding (A) to (A) and adding an amine to form a gel.
Incidentally, the gel of the present invention can be obtained even if the order of blending the compounds is slightly changed in the above method. The gel 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 is an excellent analgesic and anti-inflammatory treatment as shown in the experimental examples below. It is effective. The transdermal absorption effect and anti-inflammatory effect of the gel of the present invention will be shown below through pharmacological experiments. Experimental Example 1 Carrageenin - Topical anti-inflammatory effect on rat skin edema 90-110g Wistar male rats (4 weeks old)
Eva Cream [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 International Company) - Physiological saline for injection and physiological saline were injected intradermally at 0.1 ml/site each in a dorsal column symmetrical manner, and the former was tested. A patch test adhesive plaster (Small size, manufactured by Torii Pharmaceutical Co., Ltd.) adsorbed with 0.1 ml of each compound was immediately applied. After 2.5 hours, 0.5 ml/100 g of 1% Pontamine Sky Blue (PSB)-physiological saline was injected through the tail vein, and 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] 〓 The numbers in 〓 represent the inhibition rate relative to the control group.
Experimental example 2-1 Acute toxicity ddY male and female mice weighing 19-26g and body weight 102
~130g Wistar male and female rats
A group of 10 animals were used. The test compound (gel containing 1% ketoprophen ethyl ester) was applied to the back of the hair removed with an electric clipper at the maximum application amount of 15,000 mg/kg for both types, and mortality was examined up to 14 days later. Ta. The test results are shown in Table 2.

[Table] Experimental example 2-2 Acute toxicity ddY male and female mice weighing 19-26g and body weight 102
~130g Wistar male and female rats
A group of 10 animals were used. The test compound (gel containing 1% ketoprophen-2-hydroxyethyl) was applied to the back of the hair removed with electric clippers at the maximum amount of 15,000 mg/Kg for both species, and death was maintained for up to 14 days. Examined. The test results are shown in Table 3.

[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. To apply the test compound, a patch test bandage (Small size, Torii Pharmaceutical Co., Ltd.) containing 0.1 ml of gel was applied to the back of a rat whose hair had been shaved with an electric razor, and the bulk ketoprofen powder was 0.5% - gum tragacanth physiological saline. It was suspended in water and administered orally. 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 4.

[Table] Experimental Example 4 Patch test on healthy men A patch test was conducted on 22 healthy men according to the method of Kawamura et al. (Taro Kawamura et al.: Journal of the Japanese Dermatological Society 80 , 301, 1969). That is, a patch test adhesive plaster [manufactured by Torii Pharmaceutical Co., Ltd.] with 0.1 ml of the test compound applied
Small size] was pasted on the inside of the subject's upper arm for 24 hours. 30 minutes and 24 hours after peeling, skin findings at the patched area were visually evaluated according to the criteria below.

【table】 The test results are shown in Table 5.

[Table] Shows that.
The results of the above pharmacological experiments show that the gel of the present invention has excellent skin absorption, is very effective medicinally, and
It was found to be a highly safe drug. The present invention will be specifically explained below with reference to Examples, but the present invention is not limited only to the Examples. Example 1 Carboxyvinyl polymer [Carbopol 940
(manufactured by Gutsudoritsuchi Chemical Co., Ltd.)] were swollen in 26 parts of water. On the other hand, 10 parts of propylene carbonate and 5 parts of propylene glycol were mixed, and 1 part of ketoprophen ethyl ester was mixed therewith. Next, 2 parts of hydroxypropyl cellulose dissolved in a mixture of 34 parts of ethanol and 10 parts of isopropanol was added to the water-swollen carboxyvinyl polymer and stirred until completely hydrated. After mixing the above-mentioned mixture of propylene carbonate and propylene glycol mixed with ketoprophen ethyl ester, a solution of 0.3 parts of diisopropanolamine dissolved in 9.7 parts of water is added, and the mixture is thoroughly stirred until the whole is homogeneous. An anti-inflammatory analgesic gel was obtained. Example 2 Carboxyvinyl polymer [Hibis Wako
104 (manufactured by Wako Pure Chemical Industries, Ltd.)] were swollen in 26 parts of water. On the other hand, 10 parts of propylene carbonate and 5 parts of propylene glycol were mixed, and 1 part of ketoprofen-2-hydroxyethyl ester was mixed therewith. Next, 2 parts of hydroxypropyl cellulose dissolved in a mixture of 34 parts of ethanol and 10 parts of isopropanol was added to the water-swollen carboxyvinyl polymer and stirred until completely hydrated. After mixing the above-mentioned mixture of propylene carbonate and propylene glycol mixed with ketoprophen-2-hydroxyethyl ester, a solution of 0.3 parts of diisopropanolamine dissolved in 9.7 parts of water was added, and the mixture was thoroughly mixed until the whole was homogeneous. The mixture was stirred to obtain an anti-inflammatory analgesic gel. Example 3 2.5 parts of carboxyvinyl polymer (same as in Example 1) were swollen in 30 parts of water. On the other hand, 15 parts of ethanol and 5 parts of propylene glycol were mixed, and 3 parts of ketoprophen ethyl ester was mixed therewith. Next, hydroxypropyl cellulose 2
1 part dissolved in 35 parts of isopropanol was added to the water-swollen carboxyvinyl polymer and stirred until completely hydrated. After mixing the above-mentioned mixture of ethanol and propylene glycol mixed with ketoprophen ethyl ester, a solution of 0.3 parts of diisopropanolamine dissolved in 7.2 parts of water was added, and the mixture was thoroughly stirred until the whole was homogeneous. An anti-inflammatory analgesic gel was obtained. Example 4 1.5 parts of carboxyvinyl polymer (same as in Example 2) was swollen in 30 parts of water. On the other hand, mix 15 parts of propylene carbonate and 5 parts of propylene glycol, and add 1 part of ketoprophen ethyl ester.
parts were mixed. Next, 2 parts of hydroxypropyl cellulose dissolved in 35 parts of isopropanol was added to the water-swollen carboxyvinyl polymer and stirred until completely hydrated. After mixing the above-mentioned mixture of propylene carbonate and propylene glycol mixed with ketoprophen ethyl ester, a solution of 0.3 parts of diisopropanolamine dissolved in 10.2 parts of water is added, and the mixture is thoroughly stirred until the whole is homogeneous. An anti-inflammatory analgesic gel was obtained. Example 5 2 parts of carboxyvinyl polymer (same as in Example 1) were swollen in 39.7 parts of water. On the other hand, 40 parts of ethanol and 5 parts of 1,3-butylene glycol
3 parts of ketoprophen ethyl ester were mixed therewith. This was added to the water-swollen carboxyvinyl polymer described above and stirred until completely hydrated. Next, add 0.3 parts of diisopropanolamine dissolved in 10 parts of water,
The mixture was sufficiently stirred until the whole was homogeneous to obtain an anti-inflammatory analgesic gel. Example 6 1.5 parts of carboxyvinyl polymer (same as in Example 1) was swollen in 37.7 parts of water. Meanwhile, 40 parts of ethanol, 2 parts of diisopropyl adipate and 5 parts of 1,3-butylene glycol were mixed,
Two parts of ketoprophen ethyl ester were mixed with this. This was added to the water-swollen carboxyvinyl polymer described above and stirred until completely hydrated. Next, a solution of 0.1 part of diisopropanolamine dissolved in 10.5 parts of water was added and thoroughly stirred until the whole was homogeneous to obtain an anti-inflammatory and analgesic gel.

Claims (1)

[Claims] 1. An anti-inflammatory and analgesic gel comprising ketoprofen ester as an active ingredient, glycols, lower alcohol and/or water as a gel base, and a gelling agent.