JP2811401B2 - Cataplasm - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

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

[0002]

BACKGROUND OF THE INVENTION Piroxicam is useful as an anti-inflammatory analgesic, has been widely used in clinical practice as an oral preparation, and has also been used as a suppository and an ointment. However, in the case of oral preparations and suppositories, in addition to severe side effects such as peptic ulcer with perforation, gastrointestinal dysfunction such as vomiting and melena, shock symptoms, stomatitis, stomach abdominal pain, stomach sagging, anorexia, nausea ,vomiting,
It has been reported to cause side effects such as diarrhea and loose stool.

In order to avoid such side effects and efficiently supply the drug to the local area, it is preferable that the drug is delivered transdermally without passing through the digestive tract. Ointments and cataplasms are typical of dosage forms intended for transdermal absorption. However, in the case of an ointment, there is a drawback that, due to its properties, the dosage is inevitably inevitable, and that the agent adheres to clothes or the like after application and is lost from the skin. On the other hand, cataplasms are a good dosage form without such disadvantages. As a cataplasm containing piroxicam, lornoxicam, tenoxicam, piroxicam or sulindac are 1.0 to 3
0.0% by weight of sodium polyacrylate, 0.01 to
5.0 wt% aluminum hydroxide, 30.0-90.
It has already been reported that it is blended with a base consisting of 0% by weight of purified water (JP-A-1-316314).

[0004] This cataplasm is said to be more effective than cataplasms containing non-steroidal anti-inflammatory analgesics such as indomethacin, diclofenac, flurbiprofen and ketoprofen. However, the effect is not sufficient, and the physical properties as a cataplasm are also unsatisfactory for use, and have not yet been provided in clinical settings. Further, simply adding piroxicam to the base of the conventional poultice did not provide sufficient effects, and did not satisfy the conditions required for a poultice. That is, for example, generally known is a technique of crosslinking a water-soluble polymer containing a carboxyl group in a molecule with an aluminum compound,
This technique is unsuitable for use in plasters containing piroxicam having good transdermal absorbability. For example, when aluminum hydroxide is used as a crosslinking agent, there is a disadvantage that the progress of the crosslinking reaction is slow and the release paper or release film applied to the surface of the plaster does not peel off at the time of use and cannot withstand actual use. When a non-woven fabric is used, the plaster penetrates into the non-woven fabric, and in extreme cases, it exudes from the back of the support, and has a drawback that it does not form a poultice. Further, aluminum potassium sulfate, dried potassium aluminum sulfate, aluminum ammonium sulfate, dried aluminum ammonium sulfate, aluminum chloride, and the like are also known as cross-linking agents. However, since the produced paste lacks flexibility and has too high a hardness, an adhesive portion is formed. Has the disadvantage that it cannot follow the movement of the skin and falls off the skin. Furthermore, potassium aluminum sulfate, dried potassium aluminum sulfate, aluminum ammonium sulfate, dried aluminum ammonium sulfate, and aluminum chloride are known as strong astringents. Is not preferred. It has also been proposed to use aluminum stearate as a crosslinking agent, but aluminum stearate has extremely low solubility in water, the crosslinking reaction does not proceed at all, and does not form a poultice. Was something.

[0005]

Accordingly, an object of the present invention is to provide a piroxicam-containing cataplasm which is excellent in percutaneous absorption of piroxicam and satisfies various conditions as a cataplasm.

[0006]

Means for Solving the Problems In view of such circumstances, the present inventors have conducted intensive studies on the percutaneous absorbability of piroxicam and various performances of poultices. By using a plaster having a pH of 5.5 to 8.0, percutaneous absorbability can be enhanced, and the hydrophilic base is further dissolved in a water-soluble compound having a carboxyl group in a molecule of 2 to 50% by weight. A polymer substance and / or a salt thereof;
01 to 1% by weight amino acid aluminum complex and 20 to
By containing 90% by weight of water, all the ideal properties that cataplasms should have, such as moderate internal cohesion and viscoelasticity of the plaster, strong adhesion to the skin, and good stability over time of the main drug, are obtained. The present inventors have found that a piroxicam poultice having good physical properties can be obtained and completed the present invention.

That is, the present invention provides the following component (a):
(B), (c) and (d): (a) 0.05 to 5% by weight of piroxicam, (b) 2 to 50% by weight of a water-soluble polymer having a carboxyl group in the molecule and / or a salt thereof, It is intended to provide a poultice having a hydrophilic plaster having a pH of 5.5 to 8.0 containing (c) 0.01 to 1% by weight of an amino acid aluminum complex and (d) 20 to 90% by weight of water.

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 "%"), especially 0.1 to 2%. Is preferred. If the amount is less than 0.05%, the effect is insufficient, and if it exceeds 5%, the effect is not so much improved.

The water-soluble polymer substance having a carboxyl group in the molecule of component (b) and / or a salt thereof used in the present invention may be a water-soluble polymer having a carboxyl group in the molecule irrespective of whether it is natural, synthetic or semi-synthetic. There is no particular limitation as long as it is a water-soluble polymer substance and / or a salt thereof. Specific examples thereof include sodium alginate, polyacrylic acid, sodium polyacrylate, carboxyvinyl polymer, sodium carboxymethylcellulose, and gelatin. The component (b) is contained in an amount of 2 to 50% in the plaster, particularly 4 to 25%.
It is preferable to include them. If the amount is less than 2%, the plaster becomes brittle, and if it is more than 50%, the hardness of the plaster becomes too high and the adhesion to the skin deteriorates, and both are not preferred.

[0010] Examples of the amino acid aluminum complex of the component (c) include N-acetyl-L-glutamine aluminum complex, dihydroxyaluminum aminoacetate and the like. Component (c) is 0.01 in the plaster
１1%, preferably 0.02 to 0.4%. If the content is less than 0.01%, the plaster becomes brittle, and if it exceeds 1%, the hardness of the plaster becomes too high, and the adhesion to the skin is lowered, which is not preferable.

The water (d) is contained in an amount of 20 to 90%, preferably 25 to 80%. If the amount is less than 20%, the plaster lacks flexibility, and if it exceeds 90%, the plaster becomes brittle, and both are not preferred.

In the plaster of the poultice of the present invention, in addition to the above-mentioned essential components, if necessary, components used in ordinary plasters may be blended. Such optional components include known surfactants, absorption promoters, preservatives, adhesives, antioxidants, humectants, inorganic powders, coloring agents, fragrances, and the like.

In the present invention, the pH of the plaster is 5.5 to 5.5.
It must be 8.0. If the pH is less than 5.5, the transdermal absorbability is not sufficient, and if it exceeds 8.0, it is not preferable in view of continuous application in terms of skin irritation. this
For adjusting the pH, pharmaceutically acceptable acids, alkalis, and the like can be used.

The plaster of the poultice of the present invention is produced by mixing and stirring the above-mentioned components in a conventional manner. The cataplasm of the present invention can be obtained by supporting the obtained plaster on a support. The support used herein is not particularly limited as long as it is a flexible woven fabric, nonwoven fabric, film, or sheet. For example, a fiber such as rayon, polyester, polyolefin, or urethane is used as a woven or nonwoven fabric, or a polymer film And a foam sheet, but a support having elasticity in all directions is preferable.
These may be provided with an anchor coat 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 is covered with a protective film, or the plaster is spread on the protective film, and A method of attaching a support is exemplified. The poultice thus obtained can be stored in an airtight container or the like as necessary.

[0015]

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

[0016]

EXAMPLES Hereinafter, the present invention will be described in more detail by way of 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. 4 g of sodium carboxymethylcellulose (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 are added thereto and uniformly stirred ( A). On the other hand, gelatin 1 was added to 50 g of purified water preheated to 60 ° C.
g, 1 g of polyoxyethylene (10) hydrogenated castor oil and 0.05 g of sodium edetate are dissolved (B). 4 g of kaolin dispersed in the remaining purified water, tartaric acid in the amount shown in Table 1, and the above (A) and (B) were added, and the mixture was stirred with a stirrer until it became uniform, and a cataplasm containing piroxicam was added. I got a body. Polyester, polypropylene, the basis weight of the nonwoven fabric of 1 m ² per 75g made of rayon fibers,
The plaster was spread so as to be 0.1 g / cm ^2, and the surface was covered with a polyester film.
Piroxicam poultices a to e of the present invention containing mg / cm ²
I got

[0017]

[Table 1]

Example 2 0.25 g of piroxicam and 15 g of concentrated glycerin, sodium carboxymethylcellulose (Selogen F-SH)
(Daiichi Kogyo Seiyaku Co., Ltd.) 5 g, sodium polyacrylate (Aronbis SS (Nippon Pure Chemical Co., Ltd.)) 5 g, N-
Add 0.15 g of acetyl-L-glutamine aluminum and stir 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 and 1 g of polyoxyethylene (10) monooleate were dissolved in 67 g of heated water.
g, sodium edetate 0.03 g and the above (A) were added, and the mixture was stirred with a stirrer until uniform, to obtain a plaster base containing piroxicam. This plaster was spread on a nonwoven fabric having a basis weight of 100 g per 1 m ² composed of polyester and rayon fibers so as to be 0.1 g / cm ^{2. The} surface was covered with a polypropylene film, and 0.25 mg of piroxicam was coated.
The piroxicam poultice of the present invention containing / cm ² was obtained.

Example 3 To 20 g of concentrated glycerin was added 0.5 g of piroxicam, and the mixture was stirred. Further, sodium carboxymethylcellulose (Daicel CMC1240 (Daicel Chemical Industries, Ltd.)) 3
g, sodium polyacrylate (Panakayak CP (Nippon Kayaku Co., Ltd.)) 5 g, aluminum glycinate 0.1
g and uniformly stirred (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, and 3.5 g of a 10% aqueous solution of polyacrylic acid (Gerimer AC10H (Nippon Pure Chemical Co., Ltd.)) and 1 g of polysorbate 80 were added.
g, 0.05 g of sodium edetate and the above (A) and (B) were added, and the mixture was stirred by a stirrer until the mixture became uniform to obtain a plaster base containing piroxicam. This plaster was spread on a nonwoven fabric having a basis weight of 120 g per 1 m ^{2 of} polyester fiber so as to have a weight of 0.1 g / cm ^2, and the surface thereof was covered with a polypropylene film.
A piroxicam poultice of the present invention containing cm ² was obtained.

Example 4 1 g of piroxicam was added to 1 g of polyethylene glycol monolaurate, 3 g of propylene glycol and 1 g of castor oil.
And stir. 25 g of concentrated glycerin and sodium carboxymethylcellulose (Daicel CMC12
60 (Daicel Chemical Industries, Ltd.) 5 g, sodium polyacrylate (Aronbis M (Nippon Pure Chemical Co., Ltd.)) 5
g, N-acetyl-L-glutamine aluminum 0.3
g and uniformly stirred (A). 1 g of lactic acid and 5 purified water
7.7 g and (A) were added, and the mixture was stirred with a stirrer until the mixture became uniform, to obtain a plaster base 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 The piroxicam poultice of the present invention containing 0.1 mg / cm ² of piroxicam was obtained.

Example 5 3 g of sodium carboxymethylcellulose (Daicel CMC2200 (Daicel Chemical Industries, Ltd.)), 4 g of sodium polyacrylate (4 g of Aronbis MS (Nippon Pure Chemical Co., Ltd.), 0.2 g of acetylglutamine aluminum in 20 g of concentrated glycerin (A) Dissolve 1 g of gelatin and 2 g of polyvinyl alcohol (EG-05 (Nippon Gosei Kogyo KK)) in 44.47 g of heated purified water (B). 0.5 g of polyethylene glycol, medium chain fatty acid triglyceride (O
DO (Nisshin Oil Co., Ltd.) 0.5 g and piroxicam 0.1 g.
Add 25 g and stir uniformly (C). 4 g of kaolin, 0.08 g of tartaric acid, 20 g of D-sorbitol, and the above (A), (B) and (C) were added, and the mixture was stirred until uniform using a stirrer to obtain a plaster paste containing piroxicam. This plaster nonwoven having a mass per unit area of 1 m ² per 80g 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 the present invention Was obtained.

Example 6 3 g of sodium polyacrylate (Aronbis MS (Nippon Pure Chemical Co., Ltd.)) and 20 g of sodium carboxymethyl cellulose (Daicel CMC1340) were added to 20 g of concentrated glycerin.
g and 0.15 g of aluminum glycinate are added and uniformly stirred (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 heated purified water (B). 0.5 g of 1-menthol is added and dissolved in 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 is further added and stirred uniformly. (C). Kaolin 4
g, tartaric acid 0.06 g, D-sorbitol solution 20 g, and the above (A), (B) and (C) were stirred with a stirrer until uniform, to obtain a plaster patch containing piroxicam. 1m made of polyester and polypropylene fiber
0.1 g of this plaster on a nonwoven fabric with a basis weight of 100 g per ²
/ Cm ^2, and the surface was covered with a polypropylene film to obtain a piroxicam poultice of the present invention containing 0.25 mg / cm ² of piroxicam.

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

This plaster was spread on a nonwoven fabric having a basis weight of 80 g per 1 m ² consisting of polyester and polypropylene fibers so as to be 0.1 g / cm ^2, and the surface was covered with a polypropylene film, and piroxicam was coated at 0.25 mg / cm 2. ^Two
A piroxicam poultice of the present invention was obtained.

Example 8 In the formulation of Example 7, aluminum glycinate 0.15
0.15 g of aluminum glycinate and 0.30 g of acetylglutamine aluminum having the same aluminum equivalent are added instead of g, and a total of 100 g with purified water is added.
The piroxicam poultice of Example 8 containing 0.25 mg / cm ² of piroxicam was obtained in the same manner as in Example 7 except for the following.

Example 9 3 g of a carboxyvinyl polymer (Hibiswako 104 (Wako Pure Chemical Industries, Ltd.)) is added to 40 g of heated purified water while stirring vigorously to make it uniform (A). Concentrated glycerin 15
g to 5 g of sodium polyacrylate, N-acetyl-L
-Add 0.3 g of glitamin aluminum complex and stir uniformly (A). Polyethylene glycol laurate
0.5 g of 1-menthol, 0.3 g of castor oil, 0.25 g of piroxicam, and 0.5 g of methyl paraoxybenzoate per 5 g.
Add 0.05 g and 0.02 g of propyl parahydroxybenzoate and stir uniformly (B). 2 g of gelatin and 1 g of polyvinyl alcohol EG-05 (Nippon Gosei Kogyo Co., Ltd.) are dissolved in 17.08 g of heated purified water (C). 15 g of the D-sorbitol solution, (A), (B) and (C) were stirred until uniform using a stirrer to obtain a plaster base containing piroxicam.

This plaster was spread on a nonwoven fabric having a basis weight of 65 g per 1 m ^{2 of} polypropylene fiber so as to have a weight of 0.1 g / cm ² , the surface thereof was covered with a polypropylene film, and 0.25 mg / cm ^{2 of} piroxicam was contained. The piroxicam poultice of the present invention was obtained.

Comparative Example 1 With the composition shown in Table 1, 1.85 g of tartaric acid and 6 parts of purified water
The piroxicam poultice of Comparative Example 1 containing 0.25 mg / cm ² of piroxicam was prepared in the same manner as in Example 1 except that the amount was 7.75 g. The pH of the plaster was 5.2.

Comparative Example 2 In the formulation of Example 7, aluminum glycinate 0.15
0.1 g of aluminum glycinate and 0.05 g of aluminum hydroxide having the same aluminum equivalent
9 g was added to make a total of 100 g with purified water.
A piroxicam poultice of Comparative Example ² containing 25 mg / cm ² was obtained.

Comparative Example 3 In the formulation of Example 7, aluminum glycinate 0.15
Instead of g, 0.15 g of aluminum glycinate and 0.29 g of dry aluminum potassium sulfate having the same aluminum equivalent were added to make a total of 100 g with purified water, and otherwise the same production method as in Example 7 was used. Thus, a piroxicam poultice of Comparative Example 3 containing 0.25 mg / cm ² of piroxicam was obtained.

Test Example 1 Male guinea pigs (Hartley, 5 weeks old, body weight 3) shaved with the piroxicam cataplasm of the present invention produced in a to e of Example 1 and the piroxicam cataplasm produced in Comparative Example 1
Affixed to the back (30 cm ²⁾ of 00～350G), blood was collected from a cannula inserted into the jugular vein 2, 4, 6, and 8 hours after before and administration administration, the plasma piroxicam concentration by high-performance liquid chromatogram It was quantified and the time course of piroxicam plasma concentration was observed. The result is shown in FIG. As is clear from FIG. 1, the percutaneous absorbability of piroxicam from the piroxicam cataplasm showed that the comparative example 1 in which the pH of the plaster was 5.2 showed only a plasma concentration having a measurement limit of 0.01 μg / ml or less. In comparison with the above, the sample of Example 1 in which the pH of the plaster was 5.5 or more showed a clearly high concentration of piroxicam in plasma, indicating that the transdermal absorbability was better when the pH of the plaster was 5.5 or more. It can be seen that

Test Example 2 A carrageenan edema test was carried out on the piroxicam pups prepared in Example 6 in accordance with a conventional method, using 10 male Wistar rats whose hairs on the hind legs were removed as a group. Table 2 shows the results.
Shown in As is clear from Table 2, the piroxicam cataplasm prepared in Example 6 in which the pH of the plaster was 7.3 had an excellent edema suppressing effect.

[0033]

[Table 2]

Test Example 3 The piroxicam poultices prepared in Examples 7, 8 and Comparative Examples 2 and 3 were put in an airtight container, and after production at 25 ° C., 1
Day, 7 days, 6 months, and 40 ℃, 50 ℃, 60 ℃
After standing for 1 day and 7 days after production,
After returning to ° C., the following test was conducted.

Film peeling test : It was observed whether the protective film on the surface of the plaster could be peeled off, and whether the plaster remained on the film surface at the time of peeling. Plaster permeability test : It was observed whether or not there was seepage of the plaster on the back surface of the nonwoven fabric of the support. Adhesion test 1 : Each specimen cut into a size of 5 cm × 6 cm was adhered to the back of a human, and it was observed whether the specimen was adhered without dropping for 12 hours from the start of the application. Adhesion test 2 : A specimen was adhered to the inner side of a human upper arm, and it was observed whether or not plaster remained on the skin when peeled immediately after application. Adhesion Test : A test was carried out in accordance with the adhesion test method described on pages 79 to 80 of the Pharmaceutical Manufacturing Guideline, 1992 edition (edited by the Japanese Official Standards Association, Pharmaceutical Times). When the test is performed in accordance with this adhesion test method, the adhesion at which the balls of Nos. 6 to 9 stop can be said to be in a strong and favorable range. The results are shown in Tables 3 and 4.

[0036]

[Table 3]

[0037]

[Table 4]

As apparent from Tables 3 and 4, Comparative Example 2
The piroxicam cataplasm using aluminum hydroxide as a cross-linking agent does not proceed with the crosslinking reaction, the protective film does not peel off from the plaster surface, and the plaster oozes from the back surface of the nonwoven fabric as a support, It was found that it did not take the form as an agent. Further, although the piroxicam poultice prepared in Comparative Example 3 progresses in cross-linking, it cures in a short period of time, but loses one of the important properties as a poultice, and the plaster becomes a hard rubber-like substance. I have. In comparison, the piroxicam cataplasms of the present invention produced in Examples 7 and 8 have sufficient internal cohesion of the plaster immediately after production, maintain the flexibility of the plaster for a long period of time, and have almost no adhesive force. It has been found that it has the ideal properties required for cataplasms, such as no change.

[Brief description of the drawings]

FIG. 1 is a diagram showing a time-dependent change in plasma piroxicam concentration when a piroxicam cataplasm was stuck to the back of a guinea pig in Test Example 1.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ identification code FI A61K 9/70 364 A61K 9/70 364 47/18 47/18 J N (58) Investigated fields (Int. Cl. ⁶ , DB A61K 31/54 ABE A61K 31/54 AAH A61K 9/70 341 A61K 9/70 352 A61K 9/70 357 A61K 9/70 364 A61K 47/18 CA (STN)

Claims (1)

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