JPS63287721A - Anti-inflammatory analgesic gel agent - Google Patents

Abstract

PURPOSE:To obtain the titled anti-inflammatory analgesic gel agent capable of being percutaneously administered, useful for treating various inflammatory diseases, containing mefenamic acid as an active ingredient. CONSTITUTION:A gel base comprising (A) a glycol, (B) a lower alcohol, (C) a ketone, water and a gelatinizing agent, containing mefenamic acid as an active ingredient of anti-inflammatory analgesic gelatinizing agent. Mefenamic acid is a compound named N-(2,3-xylyl)anthranilic acid (chemical name) useful for various inflammatory diseases. The ratio of the compound blended as the active ingredient is 0.5-5wt.%, preferably 1-3wt.% and the effects can be sufficiently shown. The blending ratio of the gel base is preferably 5 <=60wt.% component A, 50wt.% component B, <=40wt.% component C and <=20wt.% water.

Description

Detailed Description of the Invention (Field of Industrial Application) The present invention relates to an anti-inflammatory analgesic gel containing mefenamic acid as an active ingredient, and more specifically to mefenamic acid, which is useful for the treatment of various inflammatory diseases and can be administered transdermally. This invention relates to an acid-containing anti-inflammatory analgesic gel.

(Prior art) Mefenamic acid is N-(2,3-xylyl)anthranilic acid (molecular formula 'C+sH+5N (h: molecular weight: 241
．． It is a non-steroidal anti-inflammatory analgesic with the chemical name 28), and is widely used for various inflammatory diseases such as low back pain, osteoarthritis, chronic rheumatoid arthritis, and neuralgia. Up until now, mefenamic acid has generally been administered orally in the form of tablets, powders, syrups, or capsules.

(Problem to be solved by the invention) However, when mefenamic acid is used repeatedly, gastrointestinal, liver and
It causes kidney damage and its use is restricted in some patients. Therefore, there has been a desire for a treatment method by transdermal administration that can reduce the occurrence of these side effects, provide sustained efficacy, ease of administration, and provide direct effects on local affected areas.

Furthermore, as is well known, mefenamic acid has a low solubility in water among non-steroidal anti-inflammatory analgesics, and very few mefenamic acids exhibit high solubility in bases that can be used in external preparations. In addition, since the stability depends on the selection of the base, it is also difficult to combine bases.

In addition, mefenamic acid has anti-inflammatory properties compared to indomethacin.
The analgesic effect is weak (therefore, even when administered orally, a single dose of indomethacin is 25 mg, whereas that of mefenamic acid is 250 mg. Furthermore, mefenamic acid itself has poor transdermal absorption, and is mixed and dispersed in an ointment base. However, this method has the disadvantage that the absorption rate is significantly lower than that when administered orally.

An object of the present invention is to eliminate the above-mentioned drawbacks, and to provide a mefenamic acid-containing gel that exhibits excellent anti-inflammatory and analgesic therapeutic effects when administered transdermally.

(Means for Solving the Problem) As a result of intensive research aimed at achieving the above-mentioned purpose, the present inventors found that mefenamic acid, which had been thought to have a weaker anti-inflammatory effect than indomethacin when administered orally, surprisingly It was discovered that when incorporated into the gel base of the present invention, it exhibits an excellent anti-inflammatory effect, and the present invention was completed.

The base of the anti-inflammatory and analgesic gel of the present invention consists of glycols, lower alcohols, ketones, water, and a gelling agent. If desired, a pH adjuster, an absorption enhancer, a surfactant, etc. may be added to the base.

Preferred glycols used in the present invention include propylene glycol, 1,3-butylene glycol, and polyethylene glycol; preferred lower alcohols include ethanol and isopropanol; and preferred ketones include acetone and methyl ethyl ketone. Note that ketones may not be included at all due to other formulations. Moreover, it is preferable to blend these contents so that glycols are 60% by weight or less, lower alcohols are 50% by weight or less, ketones are 40% by weight or less, and water is 20% by weight or less. Next, as a gelling agent, carboxyvinyl polymer,
Examples include hydroxyethylcellulose, methylcellulose, carboxymethylcellulose, and the like. Furthermore, this gelling agent is preferably blended so that the final concentration is 0.5 to 5% by weight. Further, a PU regulator, an absorption enhancer, a surfactant, etc. can be added if desired. pH8l
Examples of the stabilizer include triethanolamine, diisopropanolamine, diphenvidramine, and the like. pH
The gel agent may be adjusted to be around neutral, that is, pH 5 to 7, preferably pH 5.5 to 6.5.

Next, as absorption enhancers, fatty acid esters such as diethyl sebacate and diisopropyl adipate, polyhydric alcohol medium chain fatty acid esters such as ethylene glycol caprylate and propylene glycol monocabrilate, pyrrolidone carboxylic acid, N-methyl-2 - Pyrrolidone derivatives such as pyrrolidone, crotamiton, propylene carbonate, and the like.

Furthermore, examples of the surfactant include nonionic surfactants such as polyoxyethylene nonylphenyl ether, polyoxyethylene octylphenyl ether, polyoxyethylene lauryl ether, sorbitan monolaurate, sorbitan monooleate, etc., or mixtures thereof.

Examples of anionic surfactants include sodium lauryl sulfate, sodium di-2-ethylhexyl sulfosuccinate, and sodium polyoxyethylene oleyl ether phosphate.

The blending ratio of mefenamic acid, which is the active ingredient of the present invention, is 0.
The effect is sufficiently exhibited at 5 to 5% by weight, preferably 1 to 3% by weight.

The method for preparing a gel agent using the gel base of the present invention is not particularly limited, and any conventional method can be used.

(Example) The present invention will be explained in more detail with reference to Examples and Comparative Examples below.

Example 1 1 g of mefenamic acid was completely dissolved in a mixture of 10 g of propylene carbonate, 35 g of polyethylene glycol (average molecular weight: 200), and 1 g of carboxyvinyl polymer [Carbopol 940 (manufactured by Gutdrich Chemical Co., Ltd.)] was dissolved.
Add purified water Log to the mixture to swell it, mix uniformly, and add triisopropanolamine 0 to the mixture.
．． A solution of 3 g in 10 g of ethanol was added, and isoprobanol was added to make 100 g, and the mixture was stirred until the whole was sufficiently uniform to obtain an anti-inflammatory analgesic gel.

Example 2 2 g of mefenamic acid was completely dissolved in a mixture of 5 g of propylene carbonate, 5 g of crotamiton, 40 g of 1.3-butylene glycol, and 10 g of methyl ethyl ketone, and 1 g of carboxyvinyl polymer [Hibis Wako-104 (manufactured by Wako Pure Chemical Industries, Ltd.)] was dissolved. Add 10 g of purified water to the mixture to swell it and mix uniformly. To the mixture, add 1 g of diisopropanolamine dissolved in ethanol Log, and then add ethanol to make 100 g. An anti-inflammatory and analgesic gel was obtained by stirring until the mixture became sufficiently uniform.

Example 3 Mefenamic acid 2gfcN-methyl-2-pyrrolidone 5g
, polyoxyethylene nonylphenyl ether [Nisocol NP-18TX (manufactured by Nikko Chemical Co., Ltd.)] 2 g, polyethylene glycol (average molecular weight: 400) 35 g,
Completely dissolve in a mixture of 20 g of isopropanol, add this to 1 g of carboxyvinyl polymer [Carboball 940 (manufactured by Guntolinoch Chemical Co., Ltd.)] and swell with 10 g of purified water, and mix uniformly. A solution of 0.3 g of triisopropanol amine dissolved in 24.7 g of isopropanol was added to the mixture, and the mixture was stirred until the whole was sufficiently homogeneous to obtain an anti-inflammatory and analgesic gel.

Example 4 2.5 g of mefenamic acid was completely dissolved in a mixture of 3 g of crotamiton, 5 g of propylene carbonate, 381 isopropyl myristate, 10 g of methyl ethyl ketone, and 20 g of polyethylene glycol (average molecular weight: 400). (manufactured by Yakuko Kogyo)] Add 10 g of purified water and 10 g of propylene glycol to 1 g to swell and mix uniformly.
．． A solution of 2 g in 10 g of ethanol was added, and isopropanol was added to make 100 g. The mixture was stirred until the whole was sufficiently uniform to obtain an anti-inflammatory analgesic gel.

Reference Example 1 - Indomethacin Gel Ointment (1%) A mixture of 1 g of indomethacin, 10 g of propylene carbonate, 35 g of polyethylene glycol (average molecular weight: 200) was completely dissolved, and 10 g of purified water was added to a mixture of carboxyvinyl polymer [Carboball 940 (Good Lynch)]. (manufactured by Chemical Co., Ltd.)] was added to the swollen product, and in the same manner as in Example 1, a gel ointment of Reference Example (2) was obtained.

Reference example 2 Mefenamic acid parent ointment (1%) Add 99 g of hydrophilic ointment to 1 g of mefenamic acid, and add plating with sodium hydroxide.
The lI 6.5 was thoroughly stirred to obtain the ointment of Reference Example 2.

In order to evaluate the obtained gel, a topical anti-inflammatory effect test on rat footprint edema due to bone fracture and a topical anti-inflammatory effect test on carrageenan-rat footprint edema were conducted.

Wistar male rat (5 weeks old, weight 90-100
g) was used. To the left leg Example 1, Example 2
) 1 each of the gel of Reference Example 1 and the ointment of Reference Example 2
00 mg was applied. After 3 hours, the rat was anesthetized with ether, and the adapted leg region was pinched using Kosohel forceps equipped with a rubber tube to induce a linear fracture in the metatarsal bone.

Immediately thereafter, the same site was applied with "LOOMGT" again and the same treatment was performed. Judgment was made 3 hours later, and the constant volume was measured before the fracture and 3 hours after the fracture to determine the edema rate. As a control, gel A group was established in which no ointment or ointment was applied, and the edema suppression rate for this group was calculated, and the results are shown in Table 1.

Table 1 Wistar male rats (6 weeks old, weight 130-150
g) was used. After measuring the left hind paw volume in advance, the gel of Example 1 and Example 2) and the ointment of Reference Example 2 were applied to the left hind paw of the rat twice, 2 hours and 1 hour before the injection of the inflammatory agent. 100 mg of each agent was applied. 0.1 mj of 1% carrageenan solution as an inflammatory agent! was subcutaneously injected into the left hind leg, and 1, 3, and 5 hours later, the stepping volume of the left hind leg was measured, and the edema rate was calculated from the value before the injection of the inflammatory agent. As a control, a group to which no gel or ointment was applied was provided, and the edema suppression rate for this group was calculated as described above, and the results are shown in Table 2.

Table 2 (Effects of the Invention) As described above, the anti-inflammatory and analgesic gel of the present invention has excellent anti-inflammatory and analgesic therapeutic effects when administered transdermally, and therefore is extremely useful as an anti-inflammatory and analgesic gel. It is a medicine,
Its practical value is extremely great.

Claims (3)

[Claims] (1) An anti-inflammatory analgesic gel containing mefenamic acid as an active ingredient. (2) An anti-inflammatory and analgesic gel according to claim (1), in which the gel base comprises glycols, lower alcohols, water, and a gelling agent. (3) In the gel according to claim (1), the gel base is glycols, lower alcohols, ketones,
An anti-inflammatory analgesic gel consisting of water and a gelling agent.