JPH0624965A - Tenidap-containing fomentation - Google Patents

Abstract

PURPOSE:To obtain a fomentation containing tenidap or its salt as a pharmacodynamically effective ingredient, having good percutaneous absorption and excellent in external antiphlogistic sedative action and antirheumatic action. CONSTITUTION:This fomentation contains tenidap having nonsteroidal antiphlogistic sedative action and antirheumatic action or its salt as a pharmacodynamically effective ingredient. A fomentation base used for preparing the fomentation consists of a water soluble thickener, a humectant and water. The objective fomentation is prepared by blending a fomentation base obtained by blending a dissolving agent or absorption promoter into the fomentation with tenidap or its salt as a pharmacodynamical ingredient.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a ship agent having good transdermal absorbability, containing tenidap (generic name) or its salt having a nonsteroidal anti-inflammatory and anti-rheumatic action as a medicinal component. It is related to ship agents.

[0002]

BACKGROUND OF THE INVENTION The compound which is the medicinal ingredient of the present invention is called tenidap as a general name, and its official chemical name is 5-chloro-2,3-dihydro-2-oxo-3- ( 2-thienylcarbonyl) -1H-indole-1-carboxamide (alias: 5-chloro-3-
(2-thenoyl) -2-oxindole-1-carboxamide). This tenidap was first synthesized by Pfizer Inc. in the United States, has a remarkable inhibitory action on 5-lipoxygenase, an inhibitory action on interleukin-1, and the like, and is currently under clinical trial as an antiarthritic drug. This tenidap is already disclosed as a basic patent in US Pat. No. 4,556,672.

Further, JP-A-60-209564 discloses it as an analgesic anti-inflammatory agent.
Japanese Patent Publication No. 209565 discloses tenidap and a method for manufacturing the same. Also, JP-A-63-201184
JP-A No. 1-311022 discloses tenidap as an interleukin-1 biosynthesis inhibitor, and JP-A No. 1-311022 discloses tenidap that suppresses T cell function. Further, these prior patents only mention that tenidap can be applied as an oral preparation, an injection, or a local preparation such as a solution, lotion, ointment, cream, gel, suppository, etc. There is no disclosure about the agent, and there is no description suggesting it. Furthermore, not to mention the ship agent containing tenidap, there is no description about the specific formulation at all.

[0004]

As described above, no attention has been paid to the shipping agent containing tenidap as a medicinal component, and no study has been made at all. Also, of course, it has not been put to practical use. Therefore, it was quite unpredictable whether tenidap could be used as a medicinal ingredient of a ship agent and could develop a good ship agent. Therefore, the present inventors were interested in tenidap having a remarkable anti-inflammatory and analgesic action and anti-rheumatic action, and variously studied to put it into practical use as a ship agent. Surprisingly, the melting point of tenidap is high and it is difficult to dissolve in the ship base. It is not dissolved in, but is taken up in the crystalline state, and the physical point such as compatibility with the base and drug stability,
In addition, it was revealed that there is a problem in the release of the drug from the base and the manifestation of the drug effect due to the decrease in the transdermal absorbability. Therefore, it was found that the development of the ship agent containing tenidap is difficult unless the problems such as the formulation design of the ship agent and the manifestation of drug efficacy are overcome.

[0005] Therefore, the purpose of the present inventors is to solve the above-mentioned problems. Specifically, a ship base consisting of a water-soluble polymer, a moisturizer, and water, a study of its compounding formulation, and tenidup are proposed. Examination of dissolution agent for dissolution, examination of absorption enhancer for accelerating percutaneous absorption and release of medicinal component from base ingredient, other excipients, stimulants, p
The purpose of the present invention is to provide an anti-inflammatory analgesic ship agent containing tenidap by intensively conducting research on a compounding base such as an H regulator.

[0006]

[Means for Solving the Problems] The inventors of the present invention have conducted extensive studies to solve the above-mentioned problems, and found that they were dissolved in a ship base consisting of a water-soluble polymer, a moisturizer and water, or dissolved in these ship bases. Agent or absorption enhancer, and further, an appropriate excipient, stimulant, pH adjuster, etc. are added to the ship base, and tenidap (hereinafter, collectively referred to as a salt-forming compound), which is a medicinal component, is added. It has been completed by discovering the development of an optimal ship agent.

The tenidap-containing ship agent of the present invention will be described in detail below. First of all, tenidap, which is a medicinal ingredient used in the present invention, naturally includes pharmaceutically acceptable salts. The salt may be basic because tenidap is an acidic compound. For example, ammonia, organic amine, alkali metal hydroxide, alkali metal carbonate, alkali metal hydride, alkali metal alkoxide, alkaline earth metal hydroxide, alkaline earth metal carbonate, alkaline earth metal hydride and alkaline earth metal. It means a salt formed by a metal alkoxide or the like. Among them, specific salts include sodium, potassium, ammonium, ethanolamine, diethanolamine, triethanolamine and the like. Further, in particular, in the case of the sodium salt, a hydrate or an anhydride thereof is naturally included. The compounding ratio of tenidap as a medicinal component is 0.01 to 100% by weight of the ship agent.
The content is 10% by weight, preferably 0.05 to 7% by weight, more preferably 0.1 to 5% by weight, and the mixing ratio of these has a great influence on the manifestation of drug effect.

Next, the water-soluble polymer is selected from natural polymers, semi-synthetic polymers or synthetic polymers. Examples of natural polymers are gelatin, hyaluronic acid or its salts, collagen, xanthan gum, acacia. Examples include gum, guar gum, carrageenan, alginic acid, sodium alginate, agar, gum arabic, tragacanth gum, karaya gum, pectin, starch and the like.

Examples of the semi-synthetic polymer include methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, soluble starch, carboxymethyl starch and dialdehyde starch.

As the synthetic polymer, polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl methacrylate, polyacrylic acid, sodium polyacrylate, polyacrylic acid copolymer (carboxyvinyl polymer etc.), polyethylene oxide, methyl vinyl ether-maleic anhydride. Examples thereof include acid copolymers and isobutylene-maleic anhydride copolymers. Further, of course, these water-soluble polymers include those treated with a known crosslinking agent or polymerization agent.

These water-soluble polymers can be blended alone or in combination of two or more depending on the formulation, and the blending amount is 1
Is 45% by weight, preferably 2 to 35% by weight, more preferably 3 to 20% by weight, and the improvement and retention of water retention of water or stability or transdermal ( Skin) Adhesiveness, drug release from the base, absorption through the skin, stickiness and sagging in the base,
It is greatly improved in pain at the time of peeling and stiffness after the base.

As the moisturizer, glycerin, propylene glycol, sorbitol, ethylene glycol,
One kind or two or more kinds are blended from diethylene glycol, polyethylene glycol, polypropylene glycol, 1,3-butylene glycol and the like. Moreover, the compounding quantity is 5
-60% by weight, preferably 7-50% by weight, more preferably 10-45% by weight, and is used to maintain an appropriate moist state of the ship agent, to maintain cooling for a long time, to volatilize water or to have a medicinal component. The release property and transdermal absorbability from the base are improved.

Also, water that is indispensable as a ship base is 3 to
70% by weight, preferably 10 to 65% by weight, more preferably 20 to 60% by weight, and the stability of the ship base, the cooling effect, the release of the medicinally active ingredient from the base, and the amount of water are dependent on the proportion of water. The skin absorbability is improved.

Further, in the ship agent of the present invention, the drug is completely dissolved by properly adding a solubilizer or an absorption promoter, and the effect of uniform dispersion in the base and the influence of the drug taken up by the base. A good ship agent can be obtained, which shows a relieving effect on the inhibition of the release property, a promotion of transdermal absorption, or a sustained effect of the drug effect.

As the solubilizer, oleic acid, propylene carbonate, methyl salicylate, glycol benzyl alcohol salicylate, polyethylene glycol, dimethylsulfoxide, isopropyl myristate, horse oil, crotamiton, oleyl alcohol, peppermint oil, eucalyptus oil,
1-limonene, d-limonene, dl-limonene or other essential oils, or surfactants (eg, glycerin fatty acid ester, sorbitan fatty acid ester, propylene glycol fatty acid ester, polysorbate 80 (trade name), polyoxyethylene (POE and Abbreviated) hydrogenated castor oil, POE sorbitan monolaurate, POE nonyl phenyl ether, POE lauryl ether, POE
(40) stearate, POE (20) monostearate, lauric acid diethanolamide, sodium lauryl sulfate, lauromacrogol, polyethylene glycol monostearate) and the like. Further, as an absorption enhancer, diisopropyl adipate, polyethylene glycol, lecithin, dimethyl sulfoxide, isopropyl myristate, squalane, squalene, horse oil, crotamiton, azone, 1- [2- (decylthio) ethyl]
Azacyclopentan-2-one (abbreviated as HPE-101), l-menthone, l-menthol, peppermint oil, eucalyptus oil, l-limonene, d-limonene, dl-limonene or other essential oil, or surfactant. Further, other known absorption enhancers are used.

The above-mentioned solubilizers or absorption promoters may be added individually or in combination as appropriate to form 0.01 to 10% by weight, preferably 0.1 to 7% by weight, more preferably 0.1% by weight.
It is used within the range of 3 to 5% by weight. In particular, when a solubilizer and an absorption promoter are used in combination, a good ship agent can be obtained. Further, if necessary, an excipient, a stimulant alleviating agent, a medicinal effect auxiliary agent, a pH adjusting agent and the like can be added.

First, as excipients, kaolin, zinc white,
Fillers such as titanium, talc, bentonite and hydrous aluminum silicate. Preservatives such as thymol, methylparaben, benzalkonium chloride, ethylparaben. Antioxidants such as ascorbic acid, stearic acid ester, disodium edetate, dibutylhydroxytoluene, butylhydroxyanisole and gallic acid ester. Emulsifiers such as sorbitan fatty acid ester, glycerin fatty acid ester, polyethylene glycol fatty acid ester, polyoxyethylene sorbitan fatty acid ester and polyoxyethylene alkyl ether. Phenyl salicylate, glycol salicylate, methyl para-aminobenzoate, 2-hydroxy-4
-Methoxybenzophenone, 2,2'-dihydroxy-
An ultraviolet absorber such as 4,4′-dimethoxybenzophenone and 2-hydroxy-4-methoxybenzophenone-5-sulfonic acid. Alkaline earth metals such as calcium chloride, calcium carbonate, magnesium chloride, aluminum compounds such as potassium carbonate, ammonium carbonate, aluminum hydroxide, aldehydes such as formalin, glyoxazole, glutaraldehyde and dialdehyde starch, epoxy compounds, A crosslinking agent or a polymerizing agent such as an isocyanate compound. Included are tackifiers such as polybutene, natural latex, vinyl acetate emulsion, polyacrylic ester emulsion, etc., and one or more of these various excipients are appropriately blended to develop a superior ship agent. be able to.

Antihistamines such as diphenhydramine hydrochloride, diphenhydramine tannate, dl-chlorpheniramine maleate, d-chlorpheniramine maleate and chlorpheniramine maleate for the purpose of alleviating the skin irritation of the ship agent. Antiallergic agents such as amlexanox, ibucilast, azelastine, oxatomide, sodium cromoglycate, tazanolast, terfenadine, tranilast, ketotifen fumarate, and lepirinast, or steroids. In addition, side effects on the skin can be suppressed by appropriately blending stimulants such as glycyrrhizinic acid, glycyrrhetinic acid, cyclodextrins such as α, β and γ, or compounds derived from cyclodextrin.

As a medicinal effect auxiliary agent, l-menthol,
Camphor, eucalyptus oil, capsicum extract, capsaicin, vitamin E, platonin, fungus extract, buckwheat flour powder, horse chestnut extract, belladonna extract, vanillyl amide nonylate, turpentine oil, benzyl nicotinate and the like can be appropriately added.

Further, as a pH adjusting agent, citric acid, acetic acid,
PH of ship agents for organic acids such as malic acid, succinic acid and tartaric acid, and water-soluble organic amines such as triethanolamine, diisopropanolamine and diethanolamine
4 to 9, preferably 4.5 to 7, and more preferably 5 to
Relaxing skin irritation by adjusting the range to 6.5
It is possible to improve the drug release from the base, the transdermal absorbability, the stability of the base, or the maintenance of the adhesiveness. still,
The compounding amount of the pH adjusting agent is used according to the concentration of PH.

Next, a method for producing the tenidap-containing ship agent of the present invention will be described. First, (A) tenidap is mixed with a dissolving agent as needed to make it uniform. Next, (B) the water-soluble polymer is mixed and dispersed in water and a humectant, and an excipient and other additives are added as necessary to obtain a uniform kneaded product. Next, (A) is added to (B) and mixed to obtain a uniform kneaded product. This kneaded product is spread on a support by a usual method, and then a release coating is laminated thereon. As the support, non-stretchable or stretchable woven fabric, knitted fabric, non-woven fabric, non-woven paper and the like can be used. The release coating can be appropriately selected from plastic films such as polyethylene, polypropylene or polyester and release paper. In addition, the order of mixing each preparation, medicinal component or other component in the above-mentioned manufacturing method is only one example, and the present invention is not limited to this mixing order.

[0022]

EXAMPLES Next, examples for formulating the ship agent of the present invention will be shown, but the formulation is not necessarily limited to the following. Example 1 Purified water (47.0 parts), gelatin (6 parts), polyvinyl alcohol (3.0 parts) and kaolin (5 parts) were placed in a mixer and heated to about 50 ° C.
To obtain a uniform dispersion. Next, 23 parts of glycerin prepared beforehand, a dispersion of 3 parts of sodium polyacrylate, 10 parts of purified water, and a solution of 2.5 parts of polyacrylic acid were added and mixed by stirring to obtain a uniform kneaded product. . To this, 0.5 part of tenidap is added, mixed and dissolved to obtain a uniform kneaded product. 10 per 140 cm ² using a spreading machine
It was applied to a predetermined non-woven fabric so as to have g, then covered with a polypropylene film, and cut into a predetermined size to obtain a product.

Example 2 Purified water (44.7 parts), gelatin (5 parts), polyvinyl alcohol (4.5 parts) and kaolin (4 parts) were placed in a mixer and heated to about 50 ° C.
To obtain a uniform dispersion. Next, 23 parts of glycerin prepared in advance, a dispersion of 4 parts of sodium polyacrylate, 10 parts of purified water, and a solution of 2.5 parts of polyacrylic acid were added and mixed by stirring to obtain a uniform kneaded product. . To this, 0.3 part of tenidap, 1 part of crotamiton and 1 part of d-limonene are added, mixed and dissolved to obtain a uniform kneaded product. This was applied to a predetermined non-woven fabric using a spreading machine so as to have a weight of 10 g per 140 cm ² , then covered with a polypropylene film, and cut into a predetermined size to obtain a product.

Example 3 42 parts of purified water, 5 parts of gelatin, 3.5 parts of polyvinyl alcohol and 5 parts of kaolin were put in a mixer and dissolved at about 50 ° C. to obtain a uniform dispersion. Next, 26 parts of glycerin prepared beforehand, a dispersion of 3 parts of sodium polyacrylate, 10 parts of purified water, and a solution of 2.5 parts of polyacrylic acid were added and mixed by stirring to obtain a uniform kneaded product. . to this,
1 part of tenidap, 1 part of crotamiton and 1 part of peppermint oil are put in, mixed and dissolved to obtain a uniform kneaded product. This was applied to a predetermined non-woven fabric using a spreading machine so as to have a weight of 10 g per 140 cm ² , then covered with a polypropylene film, and cut into a predetermined size to obtain a product.

Example 4 Purified water (43.5 parts), gelatin (6 parts), polyvinyl alcohol (3.5 parts) and kaolin (5 parts) were placed in a mixer and heated to about 50 ° C.
To obtain a uniform dispersion. Next, 23 parts of glycerin prepared beforehand, a dispersion of 3 parts of sodium polyacrylate, 10 parts of purified water, and a solution of 2.5 parts of polyacrylic acid were added and mixed by stirring to obtain a uniform kneaded product. . To this, 0.5 part of tenidap, 2 parts of crotamiton and 1 part of eucalyptus oil are added, mixed and dissolved to obtain a uniform kneaded product. This was applied to a predetermined non-woven fabric using a spreading machine so as to have a weight of 10 g per 140 cm ² , then covered with a polypropylene film, and cut into a predetermined size to obtain a product.

Examples 5 to 15 Production was carried out according to the methods of Examples 1 to 4. The results are shown in Table 1.

[0027]

[Table 1]

Next, specific effects of the present invention will be described in detail with reference to test examples. Test Example 1 Skin Permeation Test Using Hairless Mouse The exfoliated skin of the hairless mouse was attached so that the keratinous phase side is the donor phase and the dermal side is the receptor phase, and φ1 cm
Example 1, Example 2, Example 3, and Example 4 punched into
And Example 6 was stuck on the stratum corneum side. A pH 7.4 phosphate buffer solution was added to the receptor phase as a receptor solution. After 4, 8, 12, and 24 hours, the receptor liquid was sampled, the amount of drug permeation was quantified by HPLC, and the skin permeability was determined by the following formula. Skin permeation rate = skin permeation rate / initial content × 100 HPLC conditions: mobile phase 0.2% acetic acid / water: acetonitrile (55:45) absorption wavelength 254 nm column TSKgel ODS-80TM flow rate 1.0 ml / min Examples 1 to 4 and 6 according to the invention all have a range of about 3% in 4 hours and 5 to 8% in 8 hours,
10 to 15% range in 12 hours, 20 to 25 in 24 hours
It showed skin permeability in the range of%, and was proved to be excellent in skin permeability by hairless mice.

Test Example 2 Human Percutaneous Absorption Test Samples of Example 1, Example 2, Example 3, Example 4 and Example 6 punched out by 3 × 3 cm ² on the upper back of 6 healthy volunteers Was attached, and after 16 hours, the remaining amount of tenidap was quantified by HPLC. Quantitative method: The collected sample is subjected to reflux extraction with 70 ml of methanol for 2 hours. A sample for HPLC was prepared by extracting 100 ml of methanol after the extraction. HPLC conditions: mobile phase 0.2% acetic acid / water: acetonitrile (55:45) absorption wavelength 254 nm column TSKgel ODS-80TM flow rate 1.0 ml / min human absorption rate: (1-residual amount / initial content) x 100 (above The human absorptivity was determined from the formula) In the test results, Examples 1 to 4 and 6 according to the present invention each showed a good absorptivity within the range of 10 to 15%.

Test Example 3 Analgesic test in rats (experimental method) Randall and Selitto method: body weight 15
A group of 8 Wistar rats weighing about 0 g was used. The test drug (5 × 4 cm) was applied to the right hind leg, and the drug was removed 4 hours after that. Immediately after that, yeast solution (20%, 0.1 ml) was injected subcutaneously in the hind footpad of the application site as an inflammatory agent.
The pain threshold after time was measured. The drug effect was expressed as the rate of increase relative to the control group threshold. (Experimental results) The external analgesic effect of each test drug was examined against the decrease in pain threshold value 3 hours after the administration of yeast. The results are shown in Table 2. In Examples 2, 3, 4 and 6 of the test drug, a remarkable analgesic effect was observed as compared with the control, and the pain threshold value was increased.

[0031]

[Table 2]

[0032]

The ship agent of the present invention has the following excellent characteristics. a) Excellent drug release from the base. b) Good adhesion to the skin (skin). c) Less irritating to the skin (skin). d) The patch itself has excellent shape retention and is free from sagging, softening or stickiness. e) It has excellent absorbability to the skin (skin). f) It is excellent in water retention and has a long cooling duration, so it has an excellent cooling sensation. g) Remarkable anti-inflammatory / analgesic activity. h) Long-lasting medicinal effect and excellent long-lasting effect. As described above, the ship agent of the present invention has excellent actions and effects, so that an excellent anti-inflammatory and analgesic ship agent for external use can be provided. In addition, this ship agent is shown below for rheumatoid arthritis, osteoarthritis, low back pain, shoulder periarthritis, bruise, sprain, bone fracture, cancer pain, myalgia, peritenitis, tendon / tendonitis, humerus on the humerus. It is a pharmaceutical preparation useful for treating diseases such as condyleitis, swelling / pain after trauma, and gout.

Claims (2)

[Claims] 1. A ship agent containing tenidap or a salt thereof as a medicinal component. 2. The ship agent according to claim 1, wherein a base component consisting of a water-soluble polymer, a moisturizer and water contains tenidap or a salt thereof as a medicinal component.