JPH06279288A - Cataplasm - Google Patents

Abstract

PURPOSE:To obtain a cataplasm having excellent percutaneous absorption of piroxicam and excellent performances as a cataplasm. CONSTITUTION:A cataplasm comprises a hydrophilic plaster containing (a) 0.05-5wt.% of cataplasm, (b) 2-50wt.% of a water-soluble high polymer containing a carboxyl group in the molecule and/or its salt, (c) 0.01-1wt.% of aluminum complex of amino acid and (d) 20-90wt.% of water, having pH5.5-8.0.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a poultice having excellent percutaneous absorbability of piroxicam and various performances as a poultice.

[0002]

BACKGROUND OF THE INVENTION Piroxicam is useful as an anti-inflammatory and analgesic drug, and has been widely used clinically as an oral preparation, and also as a suppository and an ointment. However, with oral and suppository, peptic ulcer with perforation, gastrointestinal tract disorder such as hematemesis, melena, etc. ,vomiting,
It has been reported to cause side effects such as diarrhea and loose stools.

In order to avoid such side effects and efficiently supply the drug locally, it is preferable to deliver the drug transdermally without going through the digestive tract. Typical ointments and poultices are typical dosage forms for percutaneous absorption. However, in the case of an ointment, due to its nature, the dose is unavoidable, and there is a drawback that the agent adheres to clothes or the like after application and is lost from the skin. On the other hand, poultices are a good dosage form without such drawbacks. As a poultice containing piroxicam, lornoxicam, tenoxicam, piroxicam or sulindac is 1.0 to 3
0.0 wt% sodium polyacrylate, 0.01-
5.0% by weight of aluminum hydroxide, 30.0 to 90.
It has already been reported that it was blended with a base consisting of 0% by weight of purified water (JP-A-1-316314).

This poultice is said to be more effective than poultices containing a non-steroidal anti-inflammatory analgesic such as indomethacin, diclofenac, flurbiprofen and ketoprofen. However, the effect is not sufficient, and there is a problem with the physical properties as a poultice, and it cannot be used and is not yet provided to the clinical site. Further, simply adding piroxicam to the base of a conventional poultice cannot provide its effect sufficiently, and furthermore, the conditions required as a poultice are not provided. That is, for example, generally known is a technique of crosslinking a water-soluble polymer containing a carboxyl group in the molecule with an aluminum compound,
This technique is unsuitable for use in plasters of piroxicam-containing poultices having good transdermal absorbability. For example, when aluminum hydroxide is used as a cross-linking agent, there is a drawback that the progress of the cross-linking reaction is slow and the release paper or release film applied to the surface of the plaster cannot be peeled off during use and cannot be used in practice. When a non-woven fabric is used as the above, the plaster penetrates into the non-woven fabric, and in the extreme case, it leaks out from the back of the support, and there is a drawback that it does not form as a poultice. Further, aluminum potassium sulfate, dried aluminum potassium sulfate, aluminum ammonium sulfate, dried aluminum ammonium sulfate, aluminum chloride and the like are also known as a cross-linking agent, but since the produced paste lacks flexibility and hardness is too high, the adhesive part There is a drawback that it cannot follow the movement of the skin and falls off from the skin. Furthermore, potassium aluminum sulfate, dried aluminum potassium sulfate, aluminum ammonium sulfate, dried aluminum ammonium sulfate, and aluminum chloride are known as strong astringents, and as a component of a poultice continuously used for a long time, a point of skin irritating action. Is not preferable. Further, it has been proposed to use aluminum stearate as a cross-linking agent, but aluminum stearate has extremely low solubility in water, the cross-linking reaction does not proceed at all, and it does not form as a poultice. It was a thing.

[0005]

SUMMARY OF THE INVENTION It is therefore an object of the present invention to provide a piroxicam-containing poultice which has excellent transdermal absorbability of piroxicam and satisfies various conditions as a poultice.

[0006]

In view of such circumstances, the present inventors have conducted earnest research on the percutaneous absorbability of piroxicam and various performances of poultices, and as a result, blended piroxicam with a hydrophilic base, By using a plaster having a pH of 5.5 to 8.0, the transdermal absorbability can be enhanced, and the hydrophilic base is water-soluble having a carboxyl group in the molecule of 2 to 50% by weight. Polymeric substances and / or salts thereof, 0.
0 1 to 1 wt% amino acid aluminum complex and 20 to
By containing 90% by weight of water, all the ideal properties that a poultice should have such as moderate internal cohesive force and viscoelasticity of the plaster, strong adhesion to the skin and good stability of the main drug over time are included. It was found that a piroxicam poultice having good physical properties provided was obtained, and the present invention was completed.

That is, the present invention provides the following component (a),
(B), (c) and (d): (a) Piroxicam 0.05-5 wt%, (b) Water-soluble polymeric substance having a carboxyl group in the molecule and / or its salt 2-50 wt%, (C) Amino acid aluminum complex 0.01 to 1% by weight, (d) Water 20 to 90% by weight, and a patch containing a hydrophilic plaster having a pH of 5.5 to 8.0.

The active ingredient piroxicam (a) used in the present invention is contained in the plaster in an amount of 0.05 to 5% by weight (hereinafter, simply referred to as "%"), particularly 0.1 to 2%. Is preferred. If the amount is less than 0.05%, the effect is insufficient, and if the amount exceeds 5%, the effect is not improved so much.

The water-soluble polymeric substance having a carboxyl group in the component (b) and / or its salt used in the present invention is a water-soluble polymeric substance having a carboxyl group in the molecule, whether natural, synthetic or semi-synthetic. There is no particular limitation as long as it is a high-molecular substance and / or a salt thereof, and specific examples include sodium alginate, polyacrylic acid, sodium polyacrylate, carboxyvinyl polymer, sodium carboxymethylcellulose, gelatin and the like. The component (b) is contained in the plaster in an amount of 2 to 50%, especially 4 to 25%.
It is preferable to contain it. If this amount is less than 2%, the plaster will be brittle, and if it exceeds 50%, the hardness of the plaster will be too high and the adhesion to the skin will decrease, which is not preferable.

Examples of the amino acid aluminum complex as the component (c) include N-acetyl-L-glutamine aluminum complex and dihydroxyaluminum aminoacetate. The component (c) is 0.01 in the paste.
The content is preferably ˜1%, and particularly preferably 0.02 to 0.4%. If the content is less than 0.01%, the plaster will be brittle, and if it exceeds 1%, the hardness of the plaster will be too high and the adhesion to the skin will be reduced, which is not preferable.

Water (d) is contained in an amount of 20 to 90%, preferably 25 to 80%. If this amount is less than 20%, the plaster will lack flexibility, and if it exceeds 90%, the plaster will be fragile, which is not preferable.

The plaster of the poultice of the present invention may contain, in addition to the above-mentioned essential components, components used in ordinary plasters, if necessary. Examples of such optional components include known surfactants, absorption promoters, preservatives, adhesives, antioxidants, moisturizers, inorganic powders, coloring agents, and fragrances.

In the present invention, the pH of the plaster is 5.5 to 5.
It should be 8.0. When the pH is less than 5.5, the transdermal absorbability is not sufficient, and when it exceeds 8.0, it is not preferable considering that it is continuously applied in terms of skin irritation. this
A pharmaceutically acceptable acid, alkali or the like can be used to adjust the pH.

The plaster of the poultice of the present invention is produced by mixing and stirring the above components by a conventional method. The poultice of the present invention can be obtained by supporting the obtained plaster on a support. The support used here is not particularly limited as long as it is a flexible woven fabric, non-woven fabric, film or sheet, and for example, a fiber such as rayon, polyester, polyolefin or urethane is woven or non-woven fabric, or a polymer film. , A foam sheet, etc., but a support having elasticity in all directions is preferable.
An anchor coat may be applied to these if necessary.
The method of supporting on the support is not particularly limited, but the prepared plaster is spread on the support and the surface thereof is covered with a protective film, or the plaster is spread on the protective film, and then A method of attaching the support is exemplified. The poultice thus obtained can be stored in an airtight container or the like if necessary.

[0015]

The poultice of the present invention is excellent in the percutaneous absorbability of piroxicam and various properties as a poultice.

[0016]

The present invention will be described in more detail below with reference to examples, but the present invention is not limited thereto. Example 1 As shown in Table 1 below, plasters having various pHs were prepared. That is, 0.25 g of piroxicam is added to 15 g of concentrated glycerin and stirred. To this, 4 g of sodium carboxymethyl cellulose (Daicel CMC1340 (Daicel Chemical Industry Co., Ltd.)), 5 g of sodium polyacrylate (Aronbis SS (Nippon Pure Chemical Co., Ltd.)), and 0.1 g of aluminum glycinate were added and stirred uniformly ( A). On the other hand, 1 g of gelatin was added to 50 g of purified water that had been heated to 60 ° C in advance.
g, polyoxyethylene (10) hydrogenated castor oil 1 g, and sodium edetate 0.05 g are dissolved (B). A dispersion of kaolin (4 g) in the remaining purified water, tartaric acid in the amounts shown in Table 1, and the ingredients (A) and (B) described above were added and the mixture was stirred with a stirrer until uniform, and a piroxicam-containing poultice plaster. Got the body A non-woven fabric consisting of polyester, polypropylene and rayon fibers with a basis weight of 75 g per 1 m ² .
Spread this plaster to 0.1 g / cm ² , cover the surface with a polyester film, and piroxicam to 0.25
Piroxicam poultices a to e of the present invention containing mg / cm ²
Got

[0017]

[Table 1]

Example 2 15 g of concentrated glycerin, 0.25 g of piroxicam, sodium carboxymethyl cellulose (serogen F-SH
(Daiichi Kogyo Seiyaku Co., Ltd.) 5 g, sodium polyacrylate (Aronbis SS (Nippon Pure Chemicals Co., Ltd.)) 5 g, N-
0.15 g of acetyl-L-glutamine aluminum is added and stirred uniformly (A). 1 g of gelatin was dissolved in 67.57 g of heated purified water, and 4 g of kaolin, 1 g of tartaric acid, 1 of polyoxyethylene (10) monooleate
g, 0.03 g of sodium edetate and the above (A) were added and stirred with a stirrer until uniform to obtain a plaster of a poultice containing piroxicam. Polyester, This plaster in basis weight of the nonwoven fabric of 1 m ² per 100g consisting of rayon fibers are spread so that 0.1 g / cm ^2, covering the surface with a polypropylene film, piroxicam 0.25mg
A piroxicam poultice of the present invention containing / cm ² was obtained.

Example 3 0.5 g of piroxicam was added to 20 g of concentrated glycerin, the mixture was stirred, and sodium carboxymethyl cellulose (Daicel CMC1240 (Daicel Chemical Industry Co., Ltd.)) 3 was added.
g, sodium polyacrylate (Panakayak CP (Nippon Kayaku Co., Ltd.)) 5 g, aluminum glycinate 0.1
Add g and stir uniformly (A). On the other hand, 4 g of kaolin is uniformly dispersed in 10 g of D-sorbitol solution (B). 1 g of gelatin was dissolved in 51.85 g of heated purified water, 3.5 g of 10% polyacrylic acid aqueous solution (Jerimer AC10H (Nippon Pure Chemicals)), and 1 part of polysorbate 80 were dissolved.
g, 0.05 g of sodium edetate and the above (A) and (B) were added and stirred until uniform with a stirrer to obtain a plaster of a poultice containing piroxicam. This plaster nonwoven having a mass per unit area of 1 m ² per 120g of polyester fibers are spread so that 0.1 g / cm ^2, covering the surface with a polypropylene film, piroxicam 0.5 mg /
A piroxicam poultice of the present invention containing cm ² was obtained.

Example 4 1 g of polyethylene glycol monolaurate, 3 g of propylene glycol and 1 g of castor oil and 1 g of piroxicam
And stir. To this solution, 25 g of concentrated glycerin, sodium carboxymethyl cellulose (Daicell CMC12
60 (Daicel Chemical Industry Co., Ltd.) 5 g, sodium polyacrylate (Aronbis M (Nippon Pure Chemical Co., Ltd.)) 5
g, N-acetyl-L-glutamine aluminum 0.3
Add g and stir uniformly (A). Lactic acid 1g and purified water 5
7.7 g and (A) were added and stirred with a stirrer until uniform to obtain a plaster of a poultice containing piroxicam. Was spread as plaster prepared above to the nonwoven fabric side to support laminated urethane film basis weight of the nonwoven fabric of 1 m ² per 20g made of rayon fiber is 0.01 g / cm ^2, the surface with a polyester film A piroxicam poultice of the present invention containing 0.1 mg / cm ² of piroxicam was obtained.

Example 5 20 g of concentrated glycerin, 3 g of sodium carboxymethylcellulose (Daicel CMC2200 (Daicel Chemical Industry Co., Ltd.)), 4 g of sodium polyacrylate (Aronbis MS (Nippon Pure Chemicals)), 0.2 g of acetylglutamine aluminum. (A) Gelatin (1 g) and polyvinyl alcohol (EG-05 (Nippon Gosei Kogyo Co., Ltd.)) (2 g) are dissolved in warm purified water (44.47 g) (B). Polyethylene glycol 0.5g, medium chain fatty acid triglyceride (O
0.5 g of DO (Nisshin Oil Co., Ltd.) with piroxicam.
Add 25 g and stir uniformly (C). Kaolin (4 g), tartaric acid (0.08 g), D-sorbitol (20 g) and the above (A), (B) and (C) were added and the mixture was stirred with a stirrer until uniform to give a plaster of a poultice containing piroxicam. The present invention comprising polypropylene fiber spread on a non-woven fabric having a basis weight of 80 g per 1 m ² such that the paste has a weight of 0.1 g / cm ² , covered with a polypropylene film, and containing 0.25 mg / cm ^{2 of} piroxicam. To obtain a piroxicam patch.

Example 6 20 g of concentrated glycerin, 3 g of sodium polyacrylate (Aronbis MS (Nippon Pure Chemicals Co., Ltd.)), 4 sodium carboxymethyl cellulose (Daicel CMC1340) 4
g and 0.15 g of aluminum glycinate are added and stirred uniformly (A). 1 g of gelatin and 2 g of polyvinyl alcohol (EG-05 (Nippon Gosei Kogyo Co., Ltd.)) are dissolved in 42.54 g of warm purified water (B). 0.5 g of 1-menthol was added to 0.5 g of heated polyethylene glycol monolaurate and 2 g of medium-chain fatty acid triglyceride (ODO (Nisshin Oil Co., Ltd.)), and 0.25 g of piroxicam was further added and stirred uniformly. (C). Kaolin 4
g, 0.06 g of tartaric acid, 20 g of D-sorbitol liquid, and the above (A), (B) and (C) were stirred with a stirrer until uniform, to give a plaster of a poultice containing piroxicam. 1m made of polyester and polypropylene fibers
0.1 g of this plaster on 100 g of non-woven fabric per ²
/ Cm ² and then spread so that cover the surface with a polypropylene film, to obtain a pyro carboxymethyl cam cataplasm of the present invention piroxicam a 0.25 mg / cm ² containing.

Example 7 20 g of concentrated glycerin, 5 g of sodium polyacrylate (Aronbis MS (Nippon Pure Chemicals)), 3 sodium carboxymethylcellulose (Daicel CMC1340) 3
g and 0.15 g of aluminum glycinate are added and stirred uniformly (A). 1 g of gelatin and 2 g of polyvinyl alcohol (EG-05 (Nippon Gosei Kogyo KK)) are dissolved in 42.45 g of warm purified water (B). 0.5 g of heated polyoxyethylene (9) lauryl ether, medium-chain fatty acid triglyceride (ODO (Nisshin Oil Co., Ltd.)) 1
0.5 g of 1-menthol is added to and dissolved therein, and 0.25 g of piroxicam is further added and the mixture is stirred uniformly (C). Kaolin 4 g, tartaric acid 0.1 g, D-sorbitol liquid 20 g,
0.05 g of sodium edetate and the above (A), (B) and (C) were stirred with a stirrer until uniform, to obtain a plaster of a poultice containing piroxicam.

[0024] This plaster nonwoven having a basis weight of polyester and made of polypropylene fiber 1 m ² per 80g is spread so that 0.1 g / cm ^2, covering the surface with a polypropylene film, piroxicam 0.25 mg / cm ²
The contained piroxicam patch of the present invention was obtained.

Example 8 Aluminum glycinate 0.15 in the formulation of Example 7
Instead of g, 0.15 g of aluminum glycinate and 0.30 g of acetylglutamine aluminum having the same aluminum equivalent were added, and the total amount was 100 g with purified water.
In the same manner as in Example 7, except that the piroxicam poultice of Example 8 containing 0.25 mg / cm ² of piroxicam was obtained.

Example 9 3 g of carboxyvinyl polymer (Hibiswako 104 (Wako Pure Chemical Industries, Ltd.)) was added to 40 g of warm purified water with vigorous stirring to homogenize (A). Concentrated glycerin 15
g to sodium polyacrylate 5g, N-acetyl-L
-Add 0.3 g of glutamine aluminum complex and stir uniformly (A). Polyethylene glycol laurate 0.
0.5 g of 1-menthol, 0.3 g of castor oil, 0.25 g of piroxicam, methyl paraoxybenzoate 0.
Add 05 g and propyl paraoxybenzoate 0.02 g and stir uniformly (B). 2 g of gelatin and 1 g of polyvinyl alcohol EG-05 (Nippon Gosei Co., Ltd.) are dissolved in 17.08 g of warm purified water (C). 15 g of the D-sorbitol solution, (A), (B) and (C) were stirred with a stirrer until uniform, and a plaster of a poultice containing piroxicam was obtained.

[0027] This plaster nonwoven having a mass per unit area of 1 m ² per 65g of polypropylene fibers are spread so that 0.1 g / cm ^2, covering the surface with a polypropylene film, piroxicam and 0.25 mg / cm ² containing A piroxicam patch of the present invention was obtained.

COMPARATIVE EXAMPLE 1 1.85 g of tartaric acid and 6 parts of purified water having the composition shown in Table 1.
The piroxicam poultice of Comparative Example 1 containing 0.25 mg / cm ² of piroxicam was obtained by the same production method as in Example 1 except that the amount was 7.75 g. The pH of the plaster was 5.2.

Comparative Example 2 0.15 aluminum glycinate in the formulation of Example 7
Instead of g, 0.15 g of aluminum glycinate and aluminum hydroxide having an equivalent aluminum equivalent of 0.0
9 g was added so that the total amount was 100 g with purified water, and otherwise piroxicam was added to 0.1 g by the same production method as in Example 7.
A piroxicam poultice of Comparative Example ² containing 25 mg / cm ² was obtained.

Comparative Example 3 0.15 aluminum glycinate in the formulation of Example 7
Instead of g, 0.15 g of aluminum glycinate and 0.29 g of dried aluminum potassium sulfate having an equivalent aluminum equivalent were added so that the total amount became 100 g with purified water, and otherwise the same production method as in Example 7. A piroxicam poultice of Comparative Example 3 containing 0.25 mg / cm ² of piroxicam was obtained.

Test Example 1 Male guinea pigs (Hartley system, 5 weeks old, body weight 3) shaved with the piroxicam poultice of the present invention produced in a to e of Example 1 and the piroxicam poultice produced in Comparative Example 1
(00-350 g) on the back (30 cm ² ) and blood was collected from the cannula inserted into the jugular vein before administration and 2, 4, 6 and 8 hours after administration, and the piroxicam concentration in plasma was measured by high performance liquid chromatogram. It was quantified and the change in plasma concentration of piroxicam was observed. The result is shown in FIG. As is clear from FIG. 1, in the transdermal absorbability of piroxicam from the piroxicam poultice, Comparative Example 1 in which the pH of the plaster was 5.2 showed only the plasma concentration of 0.01 μg / ml or less as the measurement limit. Compared with the above, the piroxicam concentration in plasma was clearly higher in the sample of Example 1 in which the pH of the plaster was 5.5 or more, and therefore, the transdermal absorbability was good when the pH of the plaster was 5.5 or more. It can be seen that

Test Example 2 A carrageenin edema test was carried out on the piroxicam pups produced in Example 6 in a group of 10 Wistar male rats from which the hindlimbs were depilated. The results are shown in Table 2.
Shown in. As is clear from Table 2, the edema inhibitory effect of the piroxicam poultice produced in Example 6 having a plaster pH of 7.3 was excellent.

[0033]

[Table 2]

Test Example 3 The piroxicam poultices prepared in Examples 7 and 8 and Comparative Examples 2 and 3 were placed in an airtight container and manufactured at 25 ° C. 1
Leave for 6 days, 7 days, 40 ℃, 50 ℃, 60
Leave it in a constant temperature bath at ℃ for 1 day and 7 days after production, then 20
After returning to ℃, the following tests were performed.

Film peeling test : It was observed whether the protective film on the surface of the plaster paste could be peeled or whether the plaster remained on the film surface at the time of peeling. Plaster penetration test : It was observed whether or not the plaster oozes out on the back surface of the support nonwoven fabric. Sticking test 1 : Each sample cut into 5 cm × 6 cm was stuck to the back of a human, and it was observed whether or not it was stuck for 12 hours from the start of sticking without dropping. Sticking test 2 : A sample was stuck on the inner side of the human upper arm, and it was observed whether or not the plaster remained on the skin when peeled off immediately after sticking. Adhesion test : The test was carried out in accordance with the adhesive force test method described on pages 79 to 80 of the Pharmaceutical Manufacturing Guidelines 1992 edition (edited by Japan Official Book Association, Pharmaceutical Industry Bulletin). It can be said that the adhesive strength to the extent that the No. 6 to No. 9 balls stop when the test is conducted according to this adhesive strength test method is strong and in a good range. The results are shown in Tables 3 and 4.

[0036]

[Table 3]

[0037]

[Table 4]

As is clear from Tables 3 and 4, Comparative Example 2
The piroxicam poultice using aluminum hydroxide produced as a cross-linking agent did not undergo a cross-linking reaction, the protective film did not peel from the plaster surface, and the plaster leached from the back surface of the non-woven fabric, which was the support. It was found that it did not take the form of a drug. Further, the piroxicam poultice prepared in Comparative Example 3 progressed curing in a short period of time but lost the tackiness which is one of important properties as a poultice, and the plaster became a hard rubber-like substance. I got it. In comparison with these, the piroxicam poultices of the present invention produced in Examples 7 and 8 had a sufficient internal cohesive force of the plaster immediately after the production, maintained the flexibility of the plaster for a long time, and had almost no adhesive force. It has been found to have the ideal properties required for poultices, such as unchanged.

[Brief description of drawings]

FIG. 1 is a diagram showing a time course of plasma piroxicam concentration when a piroxicam patch was applied to the back of a guinea pig in Test Example 1.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Office reference number FI technical display location A61K 9/70 364 9165-4C 47/18 N 7433-4C J 7433-4C 47/38 N 7433- 4C (72) Inventor You Iwasa 886-16 Shikato, Yotsukaido City, Chiba Prefecture

Claims (1)

[Claims] 1. The following components (a), (b), (c) and (d): (a) Piroxicam 0.05 to 5% by weight, (b) Water-soluble polymer having a carboxyl group in the molecule 2 to 50% by weight of a substance and / or its salt, (c) 0.01 to 1% by weight of an amino acid aluminum complex, (d) 20 to 90% by weight of water, and a hydrophilic salve having a pH of 5.5 to 8.0. A poultice with a body.