JPS5883621A - Anti-inflammatory and analgesic gelatinous agent - Google Patents

Abstract

PURPOSE:The titled gelatinous agent, containing a ketoprofen ester as an active constituent, capable of exhibiting improved percutaneous absorption and anti- inflammatory effect, good stability and compatibility with a gelatinous substrate, and improved anti-inflammatory and analgesic action, and useful for treating blows, etc. CONSTITUTION:An anti-inflammatory and analgesic gelatinous agent containing a ketoprofen ester expressed by the formula (R is 1-6C lower alkyl, phenyl, pyridyl or lower alkyl substituted by 1-2 OH groups), e.g. ketoprofen ethyl ester, as an active consituent. The compound is mixed with a glycol, lower alcohol and/or water, a gelling agent, e.g. carboxyvinyl polymer, as a gelatinous base, and if desired a neutralizing agent or a nonionic surfactant to prepare the aimed gelatinous agent. The amount of the compound to be used is 0.5-10wt% for well expectable effects. The agent is useful for treating chronic rheumarthritis, osteoarthritis, Duplay's disease, fracture, sprain, and other inflammatory and painful diseases.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an anti-inflammatory analgesic gel containing ketoprofen ester as an active ingredient.

Ketoprofen represented by the formula (■) (wherein, R represents a lower alkyl group having a carbon number of Cx-Ca and a lower alkyl group substituted with 1 to 2 phenyl groups, pyridyl groups, or hydrophilic groups) Ester derivatives, specifically methyl, ethyl, and n-propyl of ketoprofen.

Impropyl, n-butyl, 2-hydroxydiethyl,
2-hydroxypropyl, 2,3-dihydroxypropyl, 2-hydroxyethoxyethyl, 2-pyriyoko
Represents esters such as 3-pyridylmethyl and benzyl.

It is a useful drug in the treatment of periarthritis, contusions, sprains, fractures, and other inflammatory pain disorders.

Conventional 1 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 preparations, their absorption is 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 by applying it topically. As seen in Patent Publication No. 81616, 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. However, the conventional drawbacks have not been overcome.

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 intensive 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 cateprofen 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, indometacin has the disadvantage of poor solubility in gel bases and easy crystal precipitation, whereas ketoprofen ester has good stability in gel bases and has a stable phase. The present invention was completed by discovering that the drug has excellent solubility and is therefore compatible with the gel base of the present invention, and that the present preparation also has excellent usability.

The gel agent of the present invention is a mixture of a ketoprofen ester and a glycol-like lower alcohol, water, or a mixture of a lower alcohol and water, a gelling agent, and if desired, a nonionic surfactant is added thereto. Manufactured by forcing.

In addition, a neutralizing agent may be appropriately blended with a gelling agent.More specifically, the glycols used in the present invention include glycol derivatives such as propylene glycol, butylene glycol, and propylene carbonate. As the lower alcohol, ethanol, isopropyl alcohol, etc. are preferable. 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. Further, it is preferable that the contents of these ingredients are mixed such that the glycol content is 40% by weight or less, the lower alcohol content is 60% by weight or less, and the water content is 55% by weight or less.

Examples of gelling agents include carboxyvinyl polymers, hydroxyethylcellulose, methylcellulose, carboxymethylcellulose, propylene glycol alginate, and the like.

Moreover, this gelling agent has a final concentration of 0.5 to 5jkiit%.
It is preferable to mix them so that

Incidentally, examples of the organic amine that neutralizes the carboxyvinyl polymer include triethanolamine, diisopropanolamine, and the like. Further, this neutralizing agent is preferably in the form of 0.1 to 1% by weight, so that the gel agent is around neutrality, that is, pH 4.
The pH may be adjusted to 7 to 7, preferably 4.5 to 6.

Furthermore, as nonionic surfactants, sorbitan sesquioleate, sorbitan trioleate, sorbitan monooleate, sorbitan monostearate, sorbitan monolaurate 1 monostearinated polyethylene glycol, polyoxyethylene sorbitan monooleate 1 monolauric acid Preferably, polyoxyethylene sorbicun, polyoxyethylene nonylphenyl ether, polyoxyethylene cetyl ether, polyoxyethylene lauryl ether or a mixture thereof is blended.

Ketoprofen ester, which is the active ingredient of the present invention, is 0
．． The desired effect can be expected at 5 to 10% by weight.

The ketoprofen ester gel of the present invention - for example (4
) A gelling agent is added to water to swell it, while (B) the ketoprofen ester is added to the glycol m 7 #
obtained by dissolving in a mixture of coals, then adding (B) to (A) and adding an amine for gelation.

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 has excellent analgesic and anti-inflammatory properties when applied to the skin and as shown in the experimental examples described below. It has a therapeutic effect.

The transdermal absorption effect and anti-inflammatory effect of the gel of the present invention will be demonstrated through pharmacological experiments.

Experimental Example 1 Carrageenin - External anti-inflammatory effect on rat skin edema After removing hair from the back of male Wistar rats (4 weeks old) with grades 90-1109 using EVA cream [trade name: Tokyo Kawabe Seiyaku (manufactured by M)], a device was applied. used.

1% carrageenan (Bikunin A: manufactured by Pasco Φ International Company) - Physiological saline for injection and 0.1 m//5ite each of physiological saline! A patch test adhesive plaster (Small 5ize manufactured by Torii Pharmaceutical Co., Ltd.) adsorbed with 0.1 of each test compound was immediately applied to the former so as to be symmetrical with the dorsal column.

After 2.5 hours, 1% Bonta Pen Sky Blue (PS
E) - A physiological saline solution of 0.5 m//10.09 m was injected into the tail vein, and after another 30 minutes, the animals were exsanguinated to death.

Peel off the skin and immediately measure the thickness of the injection site within the ridge with a thickness meter [:
Mal Thickness Gauge Co., Ltd.
(manufactured by Ozaki Seisakusho; measuring pressure: 40 g), and the edema rate was determined using the following formula.

In addition, the product of the major axis and the minor axis of the dye leaching part is determined as the dye leaching area, and Harada et al.
M, Takeuchi, M, Fukao,
T., & Katagiri, K.

: J, Pharm, Pharmacol 23
．． Bontamin Sky Blue was extracted using the method of 218.1974) and measured using a spectrophotometer to determine the amount of leached pigment.

The test results are shown in Table 1.

Table 1 100~1% carrageenan solution was applied to each test compound for 3 hours immediately after the skin injection.

The two company seals each have P<0.05. P<0.01 indicates a significant difference.

The numbers in [ ] represent the inhibition rate relative to the control group.

Experimental Example 2-1 Acute toxicity ddY male and female mice weighing 19-26 g and body weight 102
1 group of male and female Wistar rats weighing ~130g
It was used as 0 animals.

The test compound (gel containing 1% ketoprofen ethyl ester) was the maximum amount that could be applied for both types.15
000η/yu was applied to the backs of the rats after hair removal using electric clippers, and mortality was examined up to 14 days later.

The test results are shown in Table 2.

Experimental Example 2-2 Acute toxicity ddY strain #1 male mouse weighing 19-26 g and body weight 10
Male and female Wistar rats weighing 2 to 130 g were used in groups of 10, and the test compound (gel containing 1% ketoprofen-2-hydroxyethyl) was applied in the maximum amount of 15,000 to 15,000 ml per group for both species. Yu was applied to the backs of the animals from which hair had been removed using an electric cleaner, and mortality was examined up to 14 days later.

The test results are shown in Table 3.

Experimental Example 3 Rat gastric mucosal damage effect body weight approx. 2009
A test compound was administered to a male Wistar strain after fasting for 24 hours with free access to water. The test compound was applied by applying 0.0% gel to the rat's back where the hair had been pricked with an electric razor.
1-Applied Nogunchi 7-7. ) adhesive plaster [Torii Pharmaceutical (
Co., Ltd.) Small 5ize), and also Keto,・
Solo-7ene bulk powder was suspended in 0.5%-tragacanth-7,·' gum physiological saline and administered orally. At 6 days after administration, the animals were sacrificed, the stomach was removed, an incision was made along the large tube, and the presence or absence of ulcers on the gastric mucosa was visually observed.) The ulcer incidence was calculated using the following formula.

The test results are shown in Table 4.

Experimental Example 4 Patch test on healthy men A patch test was performed on 22 healthy men using the method of Izai et al. (Aobe et al. = 1:
The procedure was carried out in accordance with J Skin Society Journal, 301.1969). That is, a patch test adhesive plaster [Small 5ize manufactured by Torii Pharmaceutical Co., Ltd.] to which the test compound was applied to 0.1 -
] was occlusively 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 following criteria.

The test results are shown in Table 5. ○ Table 5 The i mark indicates that there is a significant difference between the two with P < 0.01.

/ From the results of the above pharmacological experiments, it was found that the gel of the present invention has excellent skin absorption, is very effective medicinally, and is a highly safe drug.O The following examples are given to demonstrate the present invention. will be specifically described, but these are not limited to examples only.

Example 1 2 parts of carboxyvinyl polymer [Carboball 940 (manufactured by Gudrich Chemical Co., Ltd.)] was swollen in 26 parts of water. Meanwhile, 10 parts of propylene carbonate and 5 parts of propylene glycol were mixed, and 1 part of ketoprofen ethyl ester was mixed with the mixture.
parts were mixed. Next, 2 parts of dihydroxybrobyl 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 propylene carbonate mixed with the ketopro7ene ethyl ester and the propylene glycol-luno mixture, a solution of 0.3 parts of di-isopropanolamine dissolved in 9 parts and 7 parts of water was added. The mixture was sufficiently stirred until the whole was homogeneous to obtain an anti-inflammatory analgesic gel.

Example 2 Carboxyvinyl polymer [Hivis Wako 104 (
(manufactured by Wako Tsumugi Kogyo Co., Ltd.)] was swollen in 26 parts of water. On the other hand, 10 parts of propylene carbonate and 5 parts of propylene glycol
To this was added 1 part tt 7M of ketopro7ene-2-hydroxyethyl ester. 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. This is combined with the above-mentioned ketoprofen.
After completely mixing the mixture of propylene carbonate and propylene glycol containing 2- and droxyethyl ester, a solution of 20.3 parts of diisopropanonylamine dissolved in 9.7 parts of water was added, and the whole mixture was uniformly mixed. Example 3 Carboxyvinyl polymer (same as Example 1) 2
．． 5 parts were swollen in 30 parts of water. On the other hand, ethanol 15
1 part and 5 parts of propylene glycol, and 3 parts of ketoprofen ethyl ester were mixed therewith. 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. Mix the above ketopro7-entigle ester with the dough, mix the mixture of propylene carbonate and propylene glycol, and then add 9.3 parts of diisopropanolamine to 7.2 parts of water.
The solution was added to the mixture and thoroughly stirred until the whole was homogeneous to obtain an anti-inflammatory and analgesic gel.

Example 4 Carpoxyvinyl polymer (same as in Example 2)
1.5 parts were swollen in 30 parts of water. On the other hand, 15 parts of propylene carbonate and 5 parts of propylene glycol were mixed together, and 1 part of ketoprofen ethyl ester was mixed therewith. 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. To this, the ketoprofen ethyl ester was mixed. After mixing the mixture of propylene carbonate and propylene glycol, 0.3 parts of diisopropanol was added to 1 part of water.
A solution of 0 parts and 2 parts was added thereto and thoroughly stirred until the whole was homogeneous to obtain an anti-inflammatory and analgesic gel.

Claims (1)

[Claims] 1. An anti-inflammatory analgesic gel containing ketoprofen ester as an active ingredient. The anti-inflammatory and analgesic gel according to claim 1, which comprises ketoprofen ester as two effective acid components, glycols, lower alcohols and/or water as a gel base, and a gelling agent. 3. The anti-inflammatory and analgesic gel according to claim 1, comprising ketoprofen ester as an effective acid component, and glycols, lower alcohols and/or water as a gel base, a gelling agent, a neutralizing agent, and a nonionic surfactant. agent.