JP2002302438A - Patch containing felbinac - Google Patents

Abstract

PROBLEM TO BE SOLVED: To prepare a patch having high transdermal absorptivity of felbinac and excellent adhesion. SOLUTION: This patch contains the felbinac, water, a lower alkanolamine, and a dialkylolamide of a fatty acid.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an anti-inflammatory analgesic patch containing felbinac as an active ingredient, and more particularly to a felbinac-containing patch having high transdermal absorbability and excellent adhesiveness of felbinac.

[0002]

BACKGROUND OF THE INVENTION Felbinac is an active metabolite of the oral non-steroidal anti-inflammatory analgesic fenbufen, and is known to exert a strong anti-inflammatory and analgesic action. However, since it has side effects on the digestive tract, its use is restricted for reasons such as fear of gastrointestinal ulcers.

[0003] For some time, attempts have been made to transdermally administer this drug to maintain its efficacy while avoiding side effects. For example, JP-A-59-222409 discloses that
Transdermal administration as an anti-inflammatory analgesic gel ointment is described. In this publication, felbinac is also described as a phenylacetic acid derivative-type anti-inflammatory analgesic, but because of the gel ointment, it was difficult to administer the drug quantitatively. Therefore,
JP-A-1-85913 describes an anti-inflammatory and analgesic patch capable of quantitatively administering felbinac. In this publication, an alkali and a water-soluble organic amine are contained as an active ingredient to ensure the solubility of felbinac.In this patch composition, although felbinac is uniformly dispersed, It is not completely dissolved and no transdermal absorbability has been obtained to ensure the efficacy of Felbinac. JP-A-3-193728 discloses a patch containing crotamiton as an absorption aid for felbinac. However, even with these techniques, the development of an external preparation excellent in transdermal absorbability and excellent adhesiveness of felbinac has not been successful.

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to provide a patch which has high transdermal absorbability of felbinac and excellent tackiness in view of the above-mentioned circumstances.

[0005]

Means for Solving the Problems As a result of diligent studies, the present inventors have found that by adding water, lower alkanolamine and fatty acid dialkylolamide to felbinac, transdermal absorption and adhesiveness are improved. A formulation has been obtained and found to achieve said purpose. That is, the present invention is a patch characterized by containing felbinac, water, lower alkanolamine, and fatty acid dialkylolamide.

[0006]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The patch of the present invention is characterized by containing, as essential components, felbinac, water, lower alkanolamine and fatty acid dialkylolamide. The lower alkanolamine to be incorporated in the patch of the present invention is a mono-, di- or tri-lower alkanolamine, wherein the lower alkanol is generally an alkanol having 1 to 4 carbon atoms. These lower alkanolamines can be used alone or in combination.

Preferred lower alkanolamines include monomethanolamine, monoethanolamine, monopropanolamine, monoisopropanolamine,
Dimethanolamine, diethanolamine, dipropanolamine, diisopropanolamine, dibutanolamine, diisobutanolamine, di-sec-butanolamine, trimethanolamine, triethanolamine, tripropanolamine, triisopropanolamine, tributanolamine, tributanolamine Isobutanolamine and tri-sec-butanolamine.
Among them, particularly preferred are diisopropanolamine and triethanolamine.

The fatty acid dialkylolamide compounded in the patch of the present invention is a compound obtained by condensing a fatty acid and dialkylolamide, and the fatty acid portion includes coconut oil fatty acid and palm kernel oil fatty acid. , Palmitic acid, myristic acid, stearic acid, lauric acid, oleic acid, linoleic acid, isostearic acid, capric acid, caprylic acid, and the like. Amines. These fatty acid dialkylolamides can be used alone or in combination.

Preferred fatty acid dialkylolamides include coconut oil fatty acid diethanolamide, palm kernel oil fatty acid diethanolamide, stearic acid diethanolamide, lauric acid diethanolamide, oleic acid diethanolamide, linoleic acid diethanolamide and isostearic acid diethanolamide. No. Of these, particularly preferred are coconut oil fatty acid diethanolamide and lauric acid diethanolamide.

The amount of felbinac to be added to the patch of the present invention may be an amount which can provide the desired effect depending on the purpose, but is generally 0% based on the total weight of the patch composition. It is preferable to mix it so that it is about 0.1 to 5.0% by weight, and it is particularly preferable to mix it within the range of 0.2 to 2.5% by weight. When the blending amount of felbinac is 0.
If the amount is less than 1% by weight, a sufficient pharmacological effect cannot be expected. If the amount is more than 5.0% by weight, a problem of irritation to the skin occurs.

It is preferable that the lower alkanolamine is compounded in such an amount that the total amount is about 0.1 to 10.0% by weight based on the total weight of the patch composition of the present invention. It is particularly preferable that the compounding agent be contained in the range of 0.5 to 5.0% by weight. When the amount of the lower alkanolamine is less than 0.1% by weight, the solubility of felbinac decreases, and when the amount is more than 10.0% by weight, the stability of felbinac decreases.

The patch of the present invention contains a very small amount of a fatty acid dialkyrolamide. That is, the amount of the fatty acid dialkyrolamide is preferably such that the total is about 0.01 to 1.0% by weight based on the total weight of the patch composition of the present invention. .0
It is particularly preferable to mix within the range of 5 to 0.5% by weight. When the amount of the fatty acid dialkyrolamide is less than 0.01% by weight, the transdermal absorbability of felbinac decreases, and when it exceeds 1.0% by weight, the adhesiveness decreases.

Thus, according to a preferred embodiment of the patch of the present invention, the compounding amounts of the above components are about 0.1 to 5.0% by weight of felbinac and about 20 to 80% by weight of water, respectively.
About 0.1 to 10.0% by weight of a lower alkanolamine and about 0.01 to 1% of a fatty acid dialkylolamide.
It is about 0% by weight. The pH of the patch of the present invention is pH 6
To 8, and particularly preferably pH 6.5 to 7.5. When the pH is lower than 6, there is a problem that felbinac precipitates as crystals in the preparation, and when the pH is higher than 8, there is a problem that felbinac becomes unstable. The pH of the preparation may be adjusted by adding a pH adjuster described below.

The composition used in the patch of the present invention can be prepared by mixing and formulating felbinac, water and other components according to a conventional method. For example, a lower alkanolamine, a fatty acid dialkyrolamide and felbinac are added to purified water to prepare an aqueous solution of felbinac, and if necessary, a pH adjuster, a wetting agent,
It can be prepared by adding a water-soluble polymer, a stabilizer, a surfactant, a curing agent, a preservative, and the like. By adding these pharmaceutically acceptable additives, the percutaneous absorbability and adhesiveness in the formulation of felbinac can be further increased, and the solubility can be improved. Examples of these additives include, for example, the following.

PH adjusters: citric acid, sodium citrate, gluconic acid, succinic acid, acetic acid, sodium acetate, tartaric acid, sodium tartrate, lactic acid, calcium lactate, sodium lactate, boric acid, ammonium borate, maleic acid, apple Acids and the like.

Wetting agent: glycerin, light silicic anhydride, D
-Sorbitol, 1,3-butylene glycol, propylene glycol, dipropylene glycol, macrogol, water candy, liquid paraffin and the like.

Water-soluble polymer: polyacrylic acid or a salt thereof, partially neutralized polyacrylic acid, carboxyvinyl polymer or a salt thereof, carboxymethylcellulose or a salt thereof, alginic acid or a salt thereof, propylene glycol alginate, chitosan, hydroxypropyl Cellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, ethylcellulose, methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, N-vinylacetamide polymer, polyvinyl methacrylate, pluronic, gelatin, methylvinyl ether maleic anhydride copolymer, soluble starch, pullulan, methyl acrylate, Acrylic acid-2
-Ethylhexyl copolymer and the like.

Stabilizers: ascorbic acid, sodium edetate, oxybenzone, hydrous silicon dioxide, xanthan gum, xylitol, dibutylhydroxytoluene,
Butylhydroxyanisole, aluminum stearate, magnesium stearate, sodium metaphosphate and the like.

Surfactants: lecithin, lecithin derivatives,
Propylene glycol fatty acid ester, glycerin fatty acid ester, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyethylene glycol fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ether, polysorbate and the like.

Hardening agents: aluminum magnesium silicate, sodium magnesium silicate, magnesium aluminate metasilicate, magnesium aluminate hydroxide, aluminum hydroxide, aluminum hydroxide gel, dihydroxyaluminum amino acetate and the like.

Preservatives: parabens such as methylparaben, ethylparaben, propylparaben, butylparaben, benzyl alcohol, benzalkonium chloride, benzethonium chloride, chlorobutanol and the like.

Thus, the patch of the present invention was obtained by sufficiently mixing the patch composition obtained by adding the necessary additives to felbinac, water, lower alkanolamine and fatty acid dialkylolamide as described above. Thereafter, it is prepared by spreading on a support and coating the plaster surface with a plastic film. The support of the adhesive patch is not particularly limited, and for example, a film or sheet of polyolefin, polyester, polypropylene, polyvinylidene chloride, polyurethane, polyvinyl alcohol, polyamide, cotton, wool, or the like, knit, nonwoven fabric or a laminated film thereof is used. No. The patch of the present invention thus obtained has good absorption of the active ingredient, felbinac, from the skin and also has excellent adhesiveness, and a desired drug effect can be expected by appropriately applying the patch to the affected area.

[0023]

The present invention will be further described with reference to the following examples and comparative examples.
Although the present invention will be described in detail, the present invention
Not promised.Example 1  Manufacture of patch: invention product and ratio in the composition shown below
A patch of a comparative product was prepared. In the composition, Table 1 shows the invention and Table 1
2 indicates a comparative product.

[0024]

[Table 1]

[0025]

[Table 2]

(Invention 1) Felbinac, coconut oil fatty acid diethanolamide, diisopropanolamine and purified water were mixed in the amounts shown in Invention 1 in Table 1 to obtain a felbinac solution (solution A). ). Next, the polyacrylic acid copolymer in an amount according to the blending ratio shown in Table 1 was dissolved in purified water to obtain a polyacrylic acid copolymer solution (B
liquid). Separately, gelatin in an amount according to the compounding ratio shown in Table 1,
Polyvinyl alcohol, methyl paraben and propyl paraben were dissolved in warm water to obtain a gelatin solution (C
liquid). The solution A, solution B, D-sorbitol and sodium edetate were mixed with stirring, and a solution in which polyacrylic acid partially neutralized product, tartaric acid, magnesium aluminate metasilicate and glycerin were added, and further, solution C was further added. In addition, a uniform plaster was obtained. Spread the obtained plaster on a non-woven fabric,
It was covered with a plastic film and cut into a predetermined size to obtain a patch.

(Inventive product 2) According to the compounding ratio shown in Inventive product 2 in Table 1, a patch was obtained in the same manner as in the production of Inventive product 1.

(Invention product 3) A patch was obtained in the same manner as in the production of invention product 1 according to the compounding ratio shown in invention product 3 in Table 1.

(Invention product 4) Felbinac, lauric acid diethanolamide, diisopropanolamine and purified water were mixed in amounts according to the compounding ratio shown in Invention product 4 in Table 1.
A solution of felbinac was obtained (Solution A). Thereafter, a patch was obtained in the same manner as in the production of the invention product 1.

(Comparative product 1) Felbinac, diisopropanolamine and purified water were mixed in amounts according to the mixing ratio shown in Comparative product 1 in Table 2 to obtain a solution of felbinac (A).
liquid). Thereafter, a patch was obtained in the same manner as in the production of the invention product 1.

(Comparative product 2) According to the compounding ratio shown in Comparative product 2 in Table 2, the same operation as in the production of invention product 1 was performed, and sodium tartrate was partially neutralized with polyacrylic acid, tartaric acid, and aluminate metasilicate. A patch was obtained by adding the liquid in which magnesium and glycerin were dispersed.

(Comparative product 3) Felbinac, diisopropanolamine and crotamiton were mixed in amounts according to the compounding ratio shown in Comparative product 3 in Table 2 to obtain a solution of felbinac (solution A). Thereafter, a patch was obtained in the same manner as in the production of the invention product 1.

[0033]Example 2  Absorbency test of patches: products 1 to 4 of the present invention obtained in Example 1
Skin permeation experiments were performed on the patches
And evaluation of transdermal absorbability. (1) Skin permeation test device For the skin permeation test, a side-by-side
A side diffusion cell was used. Figure 1 shows a symmetric pair
The cell (1 in FIG. 1) on the receptor side of the apparatus is shown. The cell
The effective area of the opening (2 in FIG. 1) is 0.64 cm.²,
The effective volume of the cell was 5.0 mL. Water of the device
ー Circulate the jacket with a silicone tube into a circulating water bath
Connect (6 in Fig. 1) and keep the solution temperature in the cell at 37 ° C.
Was. The inside of the cell is a magnetic stirrer (Fig. 1).
5) With continuous stirring at 1200 rpm
Was.

(2) Preparation of Skin Sample An intact back skin of a 7 to 10-week-old female hairless mouse (Hr / Kud strain) was cut out, and the attached fat was removed with dissecting scissors.

(3) Procedure for skin permeation test of drug from patch The skin of the hairless mouse (3 in FIG. 1) collected above was covered with the opening of the cell on the receptor side of the side-by-side diffusion cell. Attach, 1.5cm x 1.5 on it
The patch (4 in FIG. 1) cut into cm was adhered, and the other cell was overlaid so that the openings would fit together, and both cells were fixed. 5 mL of an isotonic phosphate buffer solution was added to the cell on the receptor side, the addition time was set to 0 o'clock, the temperature was kept constant at 37 ° C, and 100 µL of a sample was collected at regular time intervals. Was determined, and the cumulative amount of drug permeated through the skin was determined for each sample collection time. After the sample was collected, the same amount of isotonic phosphate buffer was immediately added to the receptor cell in order to maintain the liquid volume in the receptor cell.

(4) Results of Skin Permeation Experiment The results of measurement of the cumulative skin permeation amount of felbinac from the patch stuck to the hairless mouse skin are shown. Values are means ± SEM. D. (N = 3). FIG. 2 shows the results of Invention products 1 to 4 and Comparative product 1. FIG. 3 shows the results of Invention product 2 and Comparative products 1 to 3. Invention products 1 to 3 in FIG. 2 are formulations in which coconut oil fatty acid diethanolamide is added and the amount of addition is changed, and invention product 4 is a formulation in which lauric acid diethanolamide is added. Comparative product 1 is a formulation without the addition of fatty acid dialkylolamide. Invention 1
In Nos. 3 to 3, it was confirmed that the cumulative skin permeation amount of felbinac increased in proportion to the amount of coconut oil fatty acid diethanolamide added. In addition, from the results of Invention product 4, the same cumulative skin permeation amount of felbinac was obtained by addition of lauric acid diethanolamide. Comparison of invention products 1 to 4 and comparative product 1 confirmed that the addition of fatty acid dialkyrolamide increased the cumulative skin permeation amount of felbinac. Inventive product 2 in FIG. 3 is 0.5 parts by weight of coconut oil fatty acid diethanolamide, Comparative product 2 is 0.5 parts by weight of sodium tartrate, and Comparative product 3 is 0.5 parts by weight of crotamiton.
Comparative product 1 is a prescription in which parts by weight were added, and the comparative product 1 was a prescription without addition. Comparative product 2 gave only the same results as comparative product 1. The comparative product 3 had a cumulative skin permeation amount of felbinac approximately three times that of the comparative product 1. In addition, the invention product 2 provided about twice the accumulated skin permeation amount of felbinac as compared with the comparative product 3, and it was confirmed that the addition of the fatty acid dialkyrolamide increased the accumulated skin permeation amount of felbinac. From the above results, it has been clarified that a preparation excellent in transdermal absorbability can be obtained by adding the fatty acid dialkyrolamide.

[0037]Example 3  Adhesive strength test of patch: products 1 to 4 of the present invention obtained in Example 1
And the patch of Comparative Product 3 at 40 ° C and 75% RH.
Store for 6 months in a warm layer and evaluate the adhesive strength and its stability.
Was.

(1) Test Method for Adhesive Strength A test was conducted according to the adhesive force test method described in the Pharmaceutical Manufacturing Guidelines (1998 edition, P99).

(2) Adhesive strength test procedure The liner of the preparation was peeled off, and the adhesive side of the preparation was placed on an inclined surface of 30 degrees with respect to the horizontal with the adhesive side of the preparation facing upward.
The cm portion was covered with a suitable paper, leaving a 5 cm adhesive surface in the center. The steel ball was rolled from the upper part of the slope to the adhesive surface of the preparation, and the number of the steel ball stopping at the adhesive surface and the stop time were judged.

(3) Results of Adhesion Test Table 3 shows the results of the adhesion test according to the adhesion test procedure. According to the Pharmaceutical Manufacturing Guidelines, it is said that when the steel ball of No. 4 or more stops, the adhesive strength is good. Inventive products 1 to 4 to which fatty acid dialkyrolamide was added were all ball Nos. It showed good adhesion of 4 or more. However, when the amount of fatty acid dialkylolamide increases, the tendency of the adhesiveness to decrease is recognized, and the addition of a large amount of fatty acid dialkylolamide should be avoided. On the other hand, Comparative Example 3 in which 0.5 part by weight of crotamiton was added,
After one month, the ball No. No more than 4 stop results were obtained. From the above results, it was revealed that the patch of the present invention was a preparation excellent in adhesiveness.

[0041]

[Table 3]

[0042]

According to the present invention, it is possible to obtain a patch containing felbinac, which is excellent in percutaneous absorption of felbinac and excellent in adhesiveness.

[Brief description of the drawings]

FIG. 1 is a side sectional view schematically showing a diffusion cell, a skin sample, and a patch sample used in a skin permeation test of the patch.

FIG. 2 shows an example of the results of a skin permeation experiment measured on the present invention and a comparative sample of an attachment.

FIG. 3 shows another example of the results of skin permeation experiments measured on the present invention and a patch sample for comparison.

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Claims (1)

[Claims] 1. A patch containing felbinac, water, lower alkanolamine, and fatty acid dialkylolamide.