JPH0662401B2 - Ketoprofen-containing patch - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (a) Field of Industrial Application The present invention relates to a novel poultice composition containing ketoprofen as an active ingredient. Moreover, further fracture,
The present invention relates to a poultice of a novel composition having an antiphlogistic and analgesic effect, which is useful for treating diseases such as bruise and sprain.

(B) Conventional technology Ketoprofen is a non-steroidal anti-inflammatory drug having an excellent anti-inflammatory and analgesic action.

However, when this drug is used orally, it exhibits excellent drug efficacy by absorption in the gastrointestinal tract, but it has a large number of side effects on the gastrointestinal tract, and thus requires careful handling during use. Therefore, for the purpose of reducing such side effects, an external preparation that is a transdermal administration type, such as a gel agent (JP-A-58-83621) and a cream agent (JP-A-58-83622), has been conventionally used. And poultices (JP-A-58
-83623) has been studied. The patent application for the invention relating to the external preparation is made by the same applicant as the present application.

The conventional known poultice has a completely different composition from the composition of the present application to be described later, and it does not have the following necessary requirements that future poultices should have at all, or is insufficient. .

That is, the necessary requirements for future poultices are: (a) good water retention, water vapor is vaporized at an appropriate rate, (b) excellent shape retention, and no softening, sagging or stickiness. (b) Adhesion to the skin is good, and it can adapt to flexion parts such as joints (d) Good drug release from the base (e) Excellent drug effect (f) Persistence of drug effect (G) Excellent fast-acting effect (h) Excellent cooling effect and good sustainability (i) Less irritation to skin (j) Base and medicinal components However, it is stable and so on.

In particular, conventionally known poultices are completely insufficient in terms of drug release among the above-mentioned requirements, and it is necessary to contain ketoprofen in an amount of 0.5% by weight or more in order to exert a drug effect. It is said that. It is considered that this is because ketoprofen, which is a medicinal component, is less likely to diffuse and move in the base layer of the poultice, and the conventional poultices cannot overcome this drawback.

As described above, conventionally known poultices are not sufficient in terms of their properties, and there has been a demand for the development of poultices satisfying the above requirements.

(C) Problems to be Solved by the Invention The present invention aims to develop a ketoprofen-containing poultice that satisfies the requirements (a) to (j) described in the preceding paragraph.

Conventional gelatin-containing poultices become gel-like when they contain water, soften and have fluidity under the influence of external conditions such as temperature, and have stability and release of the drug or adhesiveness. The present invention aims at completion of a novel poultice composition which does not affect the above-mentioned effects even if a new thickener containing gelatin is used, although it has delicate effects.

Incidentally, by imparting excellent adhesiveness to the poultice of the present application, it enhances the sealing therapy for the skin, enhances hydration of the stratum corneum and promotes percutaneous absorption of the medicinal component, and further has a rapid-acting medicinal effect and It is also an objective to solve sustainability problems.

Also, the PKa of ketoprofen, which is a medicinal component, is 3.9, and the ionization or affinity becomes large when the base of the poultice is alkaline or neutral, and the release from the base and the skin absorption are poor, and a sufficient effect is obtained. Can't expect. Therefore, an object of the present invention is to provide a poultice which has ketoprofen incorporated in a base material in a stable and easily released state.

Furthermore, the present invention seeks to improve water retention and volatility with respect to ketoprofen-containing poultices, adhesiveness or stability of base and drug, and to solve various problems relating to the above properties caused by containing water. With the goal.

Further, the conventional poultices have not been able to impart elasticity to the plaster itself, and thus it has not been possible to apply it to the flexion of joints and the like. In addition, the adhesive force of the poultice itself is not so much considered because it is only pursued the compress effect, and therefore other adhesive plasters,
A method of holding with a holding aid such as an adhesive sheet has been adopted. The present invention provides a plaster having elasticity by imparting elasticity to the plaster itself and spreading it on a stretchable base cloth, and to provide a poultice that can be applied to a bent part of the body. It is intended. Furthermore, it is also an object to provide a poultice which has a self-adhesive property and which does not require a holding aid.

(D) Means for Solving the Problem The present invention provides a poultice containing a novel composition of ketoprofen, and further suitable water retention and volatility, adhesiveness or base, stability of drug. The present invention provides a poultice that comprises:

Incidentally, water retention and volatility in the above characteristics are involved in cooling action and its sustainability, fast-acting, drug release or skin irritation, and adhesiveness is drug release, drug efficacy, persistence of drug efficacy and fast-acting property, It is involved in water retention and volatility of water, and the stability of the base or drug is related to softening of the base, sagging or stickiness, release of drug, medicinal effect, retention of water or retention of drug. The invention is a composition in which optimum conditions are found in these characteristics.

The present invention is a plaster consisting of a "thickener", a "polyhydric alcohol", a "solvent", and "water", which is prepared by blending sodium polyacrylate, gelatin, polyvinyl alcohol and a methyl vinyl ether maleic anhydride copolymer. Main body component, or
The present invention relates to a poultice of a novel composition characterized in that "ketoprofen" is added as a medicinal component to a "main ingredient of plaster" obtained by further blending a "stabilizer" with the main ingredient of plaster. .

Further, each composition of the poultice of the present invention and its compounding ratio will be described in detail.

The present invention comprises 1 to 10 wt% of sodium polyacrylate, 1 to 20 wt% of gelatin, 1 to 10 wt% of polyvinyl alcohol, and 0.1 to 5 wt% of methyl vinyl ether maleic anhydride copolymer. "Thickener" and "polyhydric alcohol" 5-40% by weight, "solvent" 0.01-15
10% to 80% by weight of "water", the main ingredient of the plaster,
Alternatively, a "stabilizer" 0.01 is added to the main ingredients of these plasters.
The present invention relates to an anti-inflammatory and analgesic poultice, which comprises 0.1 to 10% by weight of "ketoprofen" as a medicinal component in a "paste main component" containing 10 to 10% by weight.

More specifically, sodium polyacrylate is 1 to 1
0% by weight, preferably 1 to 7% by weight, more preferably 2
-5% by weight, gelatin is 1-20% by weight, preferably 2-10% by weight, more preferably 2-6% by weight, polyvinyl alcohol is 1-10% by weight, preferably 1-7% by weight. , More preferably 2 to 5% by weight, methyl vinyl ether maleic anhydride copolymer is 0.1 to 5% by weight, preferably 0.5 to 4% by weight, more preferably 1 to 4% by weight, respectively. , Becomes a "thickener". Next, the "polyhydric alcohol" is used by selecting one kind or two or more kinds from glycerin, propylene glycol, sorbitol, ethylene glycol, diethylene glycol, polyethylene glycol, polypropylene glycol, 1,3-butylene glycol, etc., and blending them. The amount is 5-40% by weight, preferably 10-30% by weight, more preferably 20-30% by weight. The "solvent" is used by selecting one or more kinds from propylene carbonate, crotamiton, diisopropyl adipate, peppermint oil, polyethylene glycol, polyoxyethylene nonylphenyl ether, methyl salicylate, glycol salicylate, benzyl alcohol, etc. The amount is 0.01
-15 wt%, preferably 0.1-10 wt%, more preferably 0.2-6 wt%. "Water" is 10-80
%, Preferably 20 to 70% by weight, more preferably 40 to 60% by weight. Next, the “stabilizer” is polysorbate 80, sucrose fatty acid ester, benzophenone-based compound (for example, 2,2′-dihydroxy-4,
4'-dimethoxybenzophenone, 2-hydroxy-4
-Methoxybenzophenone, 2-hydroxy-4-n-
Octoxybenzophenone, 2,2'-dihydroxy-
4-methoxybenzophenone, 2-hydroxy-4-methoxybenzophenone-5-sulfonic acid, 4-phenylbenzophenone-2-carboxylic acid-isooctyl ester, 2-hydroxybenzophenone, 2,4-dihydroxybenzophenone, 2,2'- 4,4'-tetrahydroxybenzophenone, etc.), urea or the like, and one or more kinds of them are selected and used in an amount of 0.01 to 10% by weight, preferably 0.05 to 7% by weight, more preferably Is 0.1 to 5% by weight. Next, "ketoprofen", which is a medicinal component, is 0.1 to 10% by weight, preferably 0.1.
-5% by weight, more preferably 0.2-3% by weight. The poultice composition of the present invention has a pH value of 4.
It is prepared to have a pH value of 5 to 6.8, preferably 5 to 6.5.

Furthermore, in addition to the above essential components, if necessary, the following will be described.
Optional ingredients such as kaolin, zinc white, titanium, talc, bentonite,
"Filler" such as aluminum hydrosilicate, citric acid, acetic acid, malic acid, salicylic acid, succinic acid, etc.
"PH adjusting agents", "preservatives such as thymol, methylparaben, ethylparaben
Agent ", l-menthol, camphor, eucalyptus oil, capsicum
Kiss, vitamin E, nonyl acid vanillyl amide, nicotine
Acid benzyl ester, turpentine, diphenhydramid
, Capsaicin, chlorpheniramine maleate, gu
Lycyrrhizic acid, glycyrrhetinic acid, platonin, ben
Jill alcohol, funnel extract, buckwheat flour, common oil
“Medical benefits such as horse chestnut extract and benradonna extract
Agent ", ascorbic acid, stearic acid ester, dibutyl hydrate
Roxytoluene, butylhydroxyanisole, gallic
Acid ester, vitamin E, disodium edetate, etc.
"Antioxidant", Polyoxyethylene sorbitan monostearate, Poly
Polio such as oxyethylene sorbitan monopalmitate
Xyethylene sorbitan fatty acid ester or sorbita
Sodium monostearate, sorbitan sesquioleate, etc.
"Emulsifiers" such as rubitan fatty acid esters, calcium chloride, calcium carbonate, magnesium chloride, etc.
Alkaline earth metal, Kali Ming van, Ammonia Ming van,
Aluminum compounds such as aluminum hydroxide, formali
, Glyoxazole, glutaraldehyde, dialde
Aldehydes such as hydrostarch, epoxy compounds, iso
"Crosslinking agents" such as cyanate compounds, or Azone 1 type of component consisting of "absorption promoter" or
By mixing two or more types, the characteristics of poultices are further improved.
It can be improved.

The compounding composition of the present invention described in detail above is a completely novel one, and is not described at all in the publicly known documents relating to ketoprofen-containing poultices, and there is no disclosure suggesting it. Further, there is no example invented with the ketoprofen-containing poultice aiming at the effect to be described later, and the compounding composition and effect are the first things the present inventor could achieve.

Next, the method for producing the poultice of the present invention will be described.

First, (A) ketoprofen, which is a medicinal component, and a stabilizer are mixed and dissolved with a solubilizer to make them uniform.

Separately, the thickening agent (B) is mixed and dispersed in a polyhydric alcohol and water, and a filler is added to obtain a uniform kneaded product.

Next, add (A) to (B) and mix uniformly pH value 4.5-
A kneaded product having 6.8 is obtained.

This kneaded product is spread-coated on a support by a usual method, and then a release coating is applied thereon.

Non-stretchable or stretchable woven fabric, knitted fabric, non-woven fabric,
Nonwoven paper is used. In addition, since the poultice of the present invention has a high adhesive strength, even if it is spread on a stretchable base cloth, it can be sufficiently applied as a stretchable poultice to the bent part of the body and the like. is there. The release coating may be polyethylene, polypropylene or release paper.

The order of mixing each base, medicinal component or other component in the above production method is only one example, and the present invention is not limited to this mixing order.

(E) Action The poultice of the present invention has a suitable action as a poultice in physicochemical properties such as water retention, volatility, adhesiveness or stability of base and drug, and side effects such as skin irritation It has the property of being small.

The function of the poultice of the present invention will be described below with reference to test examples.

Test Example 1 External anti-inflammatory effect on carrageenin-induced skin edema of rat Wistar male rats (4 weeks old) weighing about 100 g were hair-removed with Everclaim [trade name: manufactured by Tokyo Tanabe Seiyaku Co., Ltd.] and then overnight. I used it.

A test compound of 2 × 2 cm square was applied to one side of the rat's back for 6 hours, then peeled off and immediately 1% carrageenin (Pykunin A: Pasco International Company) was applied to the same site.
0.1 ml / well of physiological saline and physiological saline on the other side
Each site was injected intradermally so that the spinal column was symmetrical. The rat was exsanguinated to death 3 hours after the injection of the inflammatory agent, the skin was peeled off, and the edema rate was calculated by the following formula.

The test results are shown in Table 1.

It is clear from Table 1 that the poultice of the present invention shows a remarkable anti-inflammatory action even if the content of ketoprofen, which is a medicinal component, is small.

The poultice of Example 1 of the present invention (ketoprofen 0.
3% content) and the poultice of Comparative Example 3 (1% ketoprofen
Content) is almost the same regardless of the content of ketoprofen, suggesting that the poultice of the present invention has a high drug-releasing and skin-absorbing action. Is.

Test Example 2 Stability Test Over Time The change in ketoprofen content of Examples 1, 4, 5, 6 and Comparative Examples 1, 2, 3, 4 with time was examined by the residual ratio with respect to the initial content value.

As is clear from the results of Table 2, the poultice of the present invention whose pH value was adjusted to 7 or less for stabilization was compared with the poultice of the comparative example having a pH value of about 7 in which no stabilization was attempted, and the residual rate of ketoprofen. Was found to be very high.

That is, it shows that the poultice of the present invention has a high stability over time.

Test Example 3 Light stability test Examples 1, 2, 3 and Comparative Examples 1, 2, 3, 4 were exposed to direct sunlight for 4 hours and 8 hours, and the residual rate of ketoprofen at that time was examined.

As is apparent from the results of Table 3, the poultice of the present invention containing a benzophenone-based light stabilizer as a stabilizer is
It was found that the residual rate of ketoprofen was much higher than that of the poultice of Comparative Example containing no stabilizer. That is,
It is shown that the poultice of the present invention has a high light stability effect.

Test Example 4 Adhesiveness Test The adhesiveness was evaluated using Examples 1, 10, 12 and Comparative Examples 1, 2, 3. (The higher the value, the greater the tackiness.) As is clear from the results in Table 4, the poultice of the present invention shows a remarkable adhesive force to the poultice of Comparative Example.

Test Example 5 Adhesion, coolness, persistence of plaster on skin, moisturizing and test for sagging of plaster Sticking by 50 subjects using Examples 1, 2, 3 and Comparative Examples 1, 2, 4 The test was conducted.

[Test method] 1) Adhesion Each sample was adjusted to a size of 10 x 14 cm, and the application site was applied on the outside of the forearm for 8 hours, and the degree of adhesion of the product to the skin at that time was scored according to the following procedure and adhered. It was sex.

(Score) 3 ... No peeling at all 2 ... Partly peeled off 1 ... Dropped in the middle 2) Cool sensation
The strength of coldness and its persistence are scored according to the following procedure,
They each showed a fast-acting effect, a cold sensation, and sustainability.

a. Fast-acting (score) within 3 ... 5 minutes 2 ... within 5-10 minutes 1 ... 10 minutes or more b. Strength of cold feeling (score) 3 ... strong 2 ... normal 1 ... weak c. Persistence (score) 3 ... feels long 2 ... normal 1 ... short 3) Persistence of the plaster on the skin In the sticking test carried out in the same manner as the adhesiveness test, the plaster was detected on the skin. The residual property was evaluated by scoring according to the following procedure.

(Score) 3 ... Not left 2 ... A little left 1 ... Significantly left 4) Moisture retention In the pasting test conducted in the manner of the adhesion test, the moisture retention was scored and evaluated in the following manner. did.

(Score) 3 ... Contains a large amount of water even after use and has a sufficient cooling action 2 ... Reduces the water content in the plaster and reduces the cooling action 1 ... It becomes a dry state and does not have a cooling action. 5) Drip and tackiness of the plaster body In the sticking test conducted as a necessary part of the adhesion test, the sagging and tackiness of the plaster body were scored and evaluated in the following manner. .

(Score) 3 ... No sagging or stickiness 2 ... Softening of plaster and partial sagging or stickiness 1 ... Sagging or sticking on plaster due to body temperature or perspiration during use 6 ) Skin irritation The skin irritation was evaluated according to the following procedure in the patch test conducted according to the procedure of the adhesion test.

+: Clear redness ±: faint redness --- no change It is clear that each of the above-mentioned tests shows a significant difference in each action as compared with the comparative example. is there.

(F) Example Example 1 (A) 1.0 part by weight of peppermint oil and 0.3 part by weight of ketoprofen, 0.5 part by weight of polyethylene glycol monostearate, 0.1 part by weight of thymol, and dibutylhydroxy on a water bath. 3.0 parts by weight of toluene, 2-hydroxy-4
Mix 0.5 parts by weight of methoxybenzophenone with heating to make a uniform solution.

(B) Next, 40.6 parts by weight of purified water, 6 parts by weight of gelatin,
3.5 parts by weight of polyvinyl alcohol and 5 parts by weight of kaolin are put in a mixer and dissolved at about 50 ° C. to obtain a uniform dispersion.

To this, 25 parts by weight of glycerin prepared beforehand, a dispersion of 2 parts by weight of sodium polyacrylate, 10 parts by weight of purified water, and a solution of 2.5 parts by weight of methoxyethylene maleic anhydride copolymer were added and stirred. Mix to obtain a uniform kneaded product.

Next, (A) is added to this kneaded product and stirred to obtain a uniform kneaded product. This was applied to a predetermined non-woven fabric to a thickness of about 1 mm using a spreading machine, then covered with a polypropylene film and cut into a predetermined size to obtain a product.

Examples 2 to 6 Production was carried out according to the method of Example 1. The results are shown in Table 6.

Example 7 (A) On a water bath, 0.2 part by weight of crotamiton and 0.2 part by weight of ketoprofen, 1.0 part by weight of polyethylene glycol monostearate, 5.0 parts by weight of dibutylhydroxytoluene, 2-hydroxy-4-. 0.1 parts by weight of methoxybenzophenone is heated and mixed to prepare a uniform solution.

(B) Next, 62.6 parts by weight of purified water, 6 parts by weight of gelatin,
Polyvinyl alcohol 2.0 parts by weight, titanium oxide 1.0
Part by weight is put in a mixer and dissolved at about 50 ° C. to obtain a uniform dispersion.

15 parts by weight of glycerin prepared in advance, 2 parts by weight of sodium polyacrylate, 4.0 parts by weight of purified water, and 1.0 part by weight of a solution of methoxyethylene maleic anhydride copolymer were added to the solution. Charge, stir and mix to obtain a uniform kneaded product.

This kneaded product was stirred, mixed and coated in the same manner as in Example 1 to obtain a product.

Example 8 (A) 1.0 parts by weight of crotamiton and 0.5 parts by weight of ketoprofen on a water bath, 3.0 parts by weight of polyoxyethylene hydrogenated castor oil, 0.5 parts by weight of dibutylhydroxytoluene, 2-hydroxy-4 0.5 parts by weight of methoxybenzophenone and 0.5 parts by weight of thymol are heated and mixed to prepare a uniform solution.

(B) Next, 46 parts by weight of purified water, 4 parts by weight of gelatin, 2.0 parts by weight of polyvinyl alcohol, and 10 parts by weight of zinc white are put in a mixer and dissolved at about 50 ° C. to obtain a uniform dispersion liquid.

25 parts by weight of polyethylene glycol, 2 parts by weight of sodium polyacrylate prepared in advance, 4.0 parts by weight of purified water, and 1.0 part by weight of methoxyethylene maleic anhydride copolymer dissolved solution. Is added and mixed by stirring to obtain a uniform kneaded product.

This kneaded product was stirred, mixed and coated in the same manner as in Example 1 to give a product.

Examples 9 to 17 Each additive was adjusted according to the method of Examples 1 to 8,
The mixture was mixed to prepare a kneaded product, which was then applied to obtain a product. The results are shown in Table 6.

Comparative Example 1 (A) 1.0 parts by weight of crotamiton and 0.3 parts by weight of ketoprofen were heated, mixed and stirred on a water bath to obtain a uniform solution.

(B) Purified water (45.2 parts by weight), sorbitol (10 parts by weight), gelatin (5 parts by weight) and kaolin (7 parts by weight) were placed in a mixer and dissolved at about 50 ° C. to obtain a uniform dispersion liquid.

A dispersion of 25 parts by weight of glycerin, 3.0 parts by weight of sodium polyacrylate, and 3.5 parts by weight of carboxymethyl cellulose, which had been prepared in advance, was added to this and mixed by stirring to obtain a uniform kneaded product.

Next, this kneaded product is put into (A) and stirred to obtain a uniform kneaded product. This was applied to a predetermined non-woven fabric to a thickness of 1 mm using a spreading machine, then covered with a polypropylene film and cut into a predetermined size to obtain a product.

Comparative Examples 2 to 4 Production was performed according to the method of Comparative Example 1. The results are shown in Table 6.

(G) Effect The present invention provides a novel poultice composition containing ketoprofen.

Due to this novel composition, the poultice of the present invention has a remarkable action as described above, and from the action, the following excellent effects are exhibited.

(1) The poultice of the present invention has a remarkable anti-inflammatory effect even if the content of ketoprofen, which is a medicinal component, is small.
This clearly shows how excellent the ketoprofen releasing property from the poultice of the present invention is, and it can be said that the poultice of the present invention has a sufficient pharmacological effect.

Further, the physicochemical properties do not require a large amount of expensive ketoprofen to be shared, which is very economical and contributes to a low product cost.

(2) The poultice of the present invention has a very excellent effect on the stability over time and the light stability as described above. The main reason for this is that the present inventor considers that the PAP base is weakly acidic or that a stabilizer is blended.

Due to this action, the poultice of the present invention can be stored for a long period of time and has the effect of high stability in use.

(3) The poultice of the present invention has excellent adhesive strength. The present inventor has considered that this property is due to the thickener in the poultice of the present invention, which results in favorable results in drug release, cooling sensation, rapid action, sustainability, adhesion, and water retention. I'm giving.

In addition, when it is applied to the skin, it shows a strong adhesive force, and it also has an adhesive force without the need to use other holding aids. Furthermore, it does not easily come off or peel off, and as a poultice It has an optimal function. Further, due to this excellent adhesive strength, the poultice of the present invention has sufficient elasticity, and therefore, by spreading this on an elastic base cloth, it is possible to apply elasticity to joints and other bending parts. Since it is possible to obtain a poultice and to bind it to the affected area, it has various effects such as the anti-inflammatory and analgesic effect and the ability to fix and maintain it.

(4) The poultice of the present invention shows excellent evaluation in adhesiveness, cooling sensation, persistence of the plaster on the skin, moisturizing property, sagging or stickiness of the plaster, and a patch test for skin irritation. It can be said that this is one which can sufficiently satisfy the requirements for a poultice and has an optimum effect in use.

All of the above-mentioned effects are entirely derived from the novel blended composition of the present invention, which is a novel finding first discovered by the present inventors.

As described in detail above, the poultice of the present invention has a very outstanding effect as an anti-inflammatory analgesic poultice for the purpose of treating neuralgia, stiff shoulder, bruise, sprain, or muscle pain,
It is a very useful industrial product as a medical product.

Claims (4)

[Claims] 1. A plaster main component containing a thickener comprising poly (sodium acrylate), gelatin, polyvinyl alcohol and methyl vinyl ether maleic anhydride copolymer, a polyhydric alcohol, a solubilizer and water as a medicinal component. A ketoprofen-containing poultice containing ketoprofen. 2. Polysodium acrylate 1 to 10% by weight, gelatin 1 to 20% by weight, polyvinyl alcohol 1 to 10
Wt% and methyl vinyl ether maleic anhydride copolymer 0.1 to 5 wt% thickener, polyhydric alcohol 5 to 40 wt%, solubilizer 0.01 to 15 wt%, water 10
The ketoprofen-containing poultice according to claim 1, wherein 0.1 to 5% by weight of ketoprofen is contained as a medicinal component in the main ingredient of the plaster containing -80% by weight. 3. A thickener, a polyhydric alcohol, a solubilizer, which comprises sodium polyacrylate, gelatin, polyvinyl alcohol and a methyl vinyl ether maleic anhydride copolymer.
A ketoprofen-containing poultice, which comprises ketoprofen as a medicinal component in the main ingredient of a plaster containing water and a stabilizer. 4. Sodium polyacrylate 1 to 10% by weight, gelatin 1 to 20% by weight, polyvinyl alcohol 1 to 10
Wt% and methyl vinyl ether maleic anhydride copolymer 0.1 to 5 wt% thickener, polyhydric alcohol 5 to 40 wt%, solubilizer 0.01 to 15 wt%, water 10
4. 80% by weight and 0.01-10% by weight of a stabilizer are added to the plaster main component, and 0.1 to 5% by weight of ketoprofen is contained as a medicinal component. Ketoprofen-containing poultice.