WO2005046654A1

WO2005046654A1 - Antiphlogistic and analgesic plaster comprising piroxicam compound

Info

Publication number: WO2005046654A1
Application number: PCT/KR2004/002966
Authority: WO
Inventors: Young Kweon Choi; Hyun Suk Yu; Young Moo Lee; Seon Mook Lim
Original assignee: Icure
Priority date: 2003-11-17
Filing date: 2004-11-16
Publication date: 2005-05-26
Also published as: KR20050047198A; KR100552650B1

Abstract

The present invention relates to a piroxiacm-containing plaster, specifically, a plaster comprising piroxicam as a NSAID anti-inflammatory agent, solubilizer, co-solvent, epidermal permeation enhancer, dispersing agent and pressure sensitive adhesive as a support, which can provide with long lasting anti-inflammatory effect, superior stability and adhering force to the conventional plasters therefore, it can be useful as an effective piroxicam-containing plaster to treat and alleviate various inflammation and pain inconsistently.

Description

[DESCRIPTION] [Invention Title] ANTIPHLOGISTIC AND ANALGESIC PLASTER COMPRISING PIROXICAM COMPOUND [Technical Field] ι> The present invention relates to an ant i-inflammatory plaster comprising piroxicam as an effective ingredient. [Background Art]

2> Drug plaster has been introduced to the treatment of various diseases as one of TTS (Transdermal Treatment System) from long years ago. For example, the drug plaster containing various drugs such as nitroglycerin for treating angina pectoris, nicotine for abstaining from smoking, estradiol for treating various diseases caused by menopause and clonidine for lowering blood pressure has been developed and sold on the market. In contrary to topical active-substance plaster acting on specific local, TTS shows systemic action due to distributed active substance into the circulatory blood vessel in human body already absorbed through skin.

3> Piroxicam, one of NSAID (Non-steroidal Ant i-inflammatory Drug) has been used in treating or alleviating various inflammation diseases such as rheumatic arthritis (RA), back pain, myalgia etc till now. Generally, it has been known NSAID has lots of limits to use in long term or over-dosing oral administration caused by severe adverse action for example, hepatic disorder or gastric disorder together with other problems such as lower bio- availability in oral administration requiring over dosing because of its hepatic first-pass effect, inconvenience of injectable administration have forced to develop topical preparation such as gel, liquid, cataplasm, plaster and the like till now. Among those preparations, since gel and liquid preparations have several disadvantage for example, difficulty in in-time and quantitative administration, inconvenience of administration such as possibility of dirting clothes etc and lower bio-availability because of lower skin-permeating ability. Piroxicam is good to develop as a topical preparation due to its potent pharmacological activity and long half-life however, it has also some requirements such as the need to increase the drug content in the preparation because of its low water solubility, the difficulty in selecting suitable solubilizer and _. epidermal permeation enhancer for maintaining the adhesive property of the preparation. > Accordingly, there have been lots of efforts to develop new piroxicam- containing TTS to overcome the disadvantages of piroxicam showing low water solubility till now. > For example, Korean Patent No. 92-27130 discloses a method for enhancing the skin permeability using by alcohol, amine, glyceride etc; United States Patent No. 4,678,666 disclose piroxicam containing gel and ointment using organic amine as a solubilizer however, since the amount of used organic amine, i.e., 2 to 3 w%, is too higher comparing with that of piroxicam, i.e., 0.3 to 3 w%, the skin permeation force of piroxicam in the preparation is significantly decreased; United States Patent Nos. 5,496,819 and 5,676,970 disclose a plaster comprising various surfactants such as triacetin or triethylcitrate, ethyleneoxide, and polyethylene non-ionic surfactant, however, there has no disclosure on the method of increasing the concentration of piroxicam to enhance skin permeation rate, and the patent suggests and disclose 0.25 w% piroxicam therein; Korean Patent No. 97-73591 discloses a method for enhancing the skin permeation rate and the solubility of piroxicam using high molecular electrolyte and accelerator, however, it has limits to improve the inconvenience in administration such as transfer of drug to clothes and to solve the difficulty in qualitative administration because its limited disclosure on just a semi-solid preparation; United States Patent No. 5,436,241 discloses tetrahydroxypropylethylenediamine as a drug solubilizer, however, it is also limited to gel preparation; Korean .Patent No. 10-212961 discloses alkanolamine as an absorption adjuvant, however, the plaster is not suitable to use since the amount of used alkanolamine, i.e., 9 to 40 w%, is too higher comparing with that of piroxicam, i.e., 0.5 to 25 w% too; Korean Patent No. 2000-47908 disclose trometamine as a solubilizer however it suggest that the plaster is not preferable the crystal can be formed when the amount of troemtamine exceeds in 12 w%; the disclosures of which above cited literatures or patents is incorporated herein by reference. > As can be seen in the above described literature or patent, as the amount of used alkanolamine as a solubilizer increases, the solubility of active ingredient increases, however, the increased alkanolamine gives rise to decreasing skin permeation rate caused by the difficulty in drug release since the affinity between piroxicam and other components in the preparation has increased with the increased alkanolamine. The prior arts mainly related to a method of using strong organic solvent, high molecular electrolyte and alkaline substance such as organic amine and a method of enhancing the solubility of piroxicam using by harsh condition for example, mixing at high temperature in the process for preparing adhesive substance. However, since most of organic acid or additive which can dissolve piroxicam remains too much in the preparation, they also give rise to several problems, for example, it cause to decreased skin permeability of drug and the decrease of skin adhering force due to its decreased adhesive force of the preparation resulting from remaining excessive organic acid or additives. > The inventors of the present invention have intensively investigated to improve and overcome the problems of conventional patch comprising piroxicam till now. > As a result of the investigation, the inventors have discovered that the inventive patch can accomplish various advantages such as improved drug solubility, drug stability, increased skin permeability and so on by adopting specific components; alkanolamide as a solubilizer, N-alkyl-pyrrolidone as a co-solvent, sole or combination of non-ionic surfactant, fatty acid, fatty acid derivative as epidermal permeation enhancer, polyvinylpyrrolidone as a dispersion agent and specific structured patch; multi-layered structure comprising primer layer consisting of rubber adhesive for preventing the reverse diffusion of drug from support and improving skin adhesive ability, which can maintain long-lasting ant i-inflammatory effect of piroxicam and endow with superior stability and adhesive ability to conventional patches, and have finally completed the present invention. [Disclosure] [Technical Problem]

?> The present invention improve the reduction of adhesive ability due to the existing solubilizer and organic solvent, the difficulty in handling, low skin-permeability and the reduction of adhesive ability. o> Accordingly, the present invention manufacture piroxicam-contaning plaster comprising the specific solubilizer, co-solvent, dispersion agent and epidermal permeation enhancer at a fixed ratio and provide an effective piroxicam-containing plaster maintaining long-lasting ant i-inflammatory effect and endowing with superior stability, skin-permeability, and adhesive- ability to conventional patches. [Technical Solution] ι> Accordingly, it is an object of the present invention to provide novel plaster composition comprising piroxicam (CιsHi₃N₃θS) as a NSAID anti- inflammatory agent, solubilizer, co-solvent, epidermal permeation enhancer, dispersion agent and pressure sensitive adhesive as a support. Specifically, present invention provide with piroxicam-containing plaster composition comprising 1 to 25 w% piroxicam as an active ingredient, 1 to 35 w% alkanola ide as a solubilizer, N-alkyl-pyrrolidone as a co-solvent, 1 to 30 w% at least one epidermal permeation enhancer selected from non-ionic surfactant, fatty acid and fatty acid derivative, 1 to 30 w at least one dispersing agent selected from polyvinylpyrrolidone and cellulose derivative derivative, and 30 to 90 w% pressure sensitive adhesive as a support. > Preferably, alkanolamide may be used as a solubilizer; N-alkyl- pyrrolidone as a co-solvent; non-ionic surfactant, fatty acid, fatty acid derivative and the mixture thereof as epidermal permeation enhancer; and acrylic adhesive, water soluble adhesive, rubber adhesive and the like as a pressure sensitive adhesive. More preferably, piroxicam in an amount rangingm about 1 to 25 w% may be used as an active ingredient; non-ionic surfactant, fatty acid, fatty acid derivative or the mixture thereof in an amount ranging from 1 to 30 w% may be used as an epidermal permeation enhancer, sole or the combination thereof consisting of polyvinypyrrolidone, cellulose etc in an amount ranging from 1 to 30 w% may be used as a dispersing agent; and pressure sensitive adhesive in an amount rainging from 30 to 90w may be used as a support .

?> It is another object of the present invention to provide novel plaster consisting of support layer (1) for preventing from drug diffusion as a base layer, primer layer (2) located thereon for preventing from the reverse diffusion of drug and improving skin adhesive ability, drug containing layer (3) located thereon containing piroxicam thereon, and release liner (4) located at the uppermost which could be released by patient's hand. i> Hereinafter the present invention shall be explained in detail as follows:

5> The inventive plaster according to the present invention may comprise active ingredient, solubilizer, co-solvent, epidermal permeation enhancer, pressure sensitive adhesive, dispersion agent and other conventionally used additives in the art. The composition in the plaster may comprise piroxicam as an active ingredient in an amount of from 1 to 25 w% preferably, 3 to 20 w% more preferably, in total weight of inventive composition of which weight ratio of active ingredient can provide with optimum conditions such as good skin permeating ability, inconstant efficacy and stability of drug, and economic interest. If the amount of piroxicam in the composition is less than 1 w , the sufficient efficacy of drug could not exert and if more than 25 w%, various problems, for example, formation of drug crystal, decrease of adhesive force etc may occur.

6> The alkanolamide adopted by a solubilizer in the present invention is prepared by the condensation reaction between fatty acid, fatty acid derivative and alkanolamine and has been used as a potent solubilizer and binder in the field of cosmetic, sanitary good, cleansing product etc. There have several reports on the use of alkanolamide, for example, Korean Patent No. 199-67226 discloses alkanolamide used as a solubilizer for hydrophobic antibacterial agent; Korean Patent No. 2001-8665 discloses lauric diethanolamide used as an epidermal permeation enhancer of oxybutidine! Korean Patent No. 2002-66047 disclose the use as an epidermal permeation enhancer of ketoprofen; United States Patent No. 5,413,776 discloses the use of lauricdiethanolamide as an epidermal permeation enhancer in piroxicam- containing plaster. However, the disclosure of the above-cited reference did not suggest nor teach on the use of alkanolamide for the purpose of increasing the Methanolamide, ethanolamide, propanolamide, isopropanolamide and the like, preferably, ethanolamide, more preferably, monoethanolamide laurate, monoethanolamide capric acid, caprylmonoethanolamide, capric acid/capric acid monoethanolamide, caprylmonoethaolamide, capric acid/capric acid monoethanolamine amide, monoethanolamide decanoate, monoethanolamide myristate, monoethaolamide palmitate, monoethanolamine stearate, monoethanolamine isostearate, monoisopropanolamide isostearate, oleic acid monoethanol amide, linolenic acid monoethanolamie amide, octyldecanoic acid monoethanolamide, 2-heptylundecanoic acid monoethanolamide, or alkanolamide derived from coconut oil fatty monoethanolamide, beef tallow fat monoethanolamide, bean oil fat monoethanolamide and coconut palm fatty acid monoethanolamide, most preferably, at least one selected from coconut fatty acid diethanol amide, ethanol amide laurate, diethanolamide myristate, diethanolamide stearate, diethanolamine oleic acid in the amount ranging 2 to 35 w%, preferably, 3 to 30 w% in total composition can be used as an alkanolamide in the present invention. If the amount of alkanolamide is less than 1 w%, there shows no solubilizing effect whereas if the amount is more than 35 w%, the physical property of the plaster can be worse. Alkanolamine such as methanolamine, ethanolamine, propanolamine, isopropyl mine or other isopropylamine, preferably, ethanolamine, more preferably, sole or the combination of monoethanolamine, diethanolamine, triethanolamine and the like may be added to the inventive plaster of the present invention to enhancing the solubility for piroxicam in the amount ranging from 0.3 to 3 w%, preferably, 2 to 3 w% in total composition. If the amount of alkanolamine is less than 1 w%, the uniformity between adhesive and piroxicam is not so enough to obtain uniformed drug releasing rate whereas if the amount is more than 7 w%, the drug releasing rate may be decreased due to the interaction between alkanolamine and piroxicam and the adhesive ability due to the increased amount of alkanolamine in the preparation. The alkanolamine in the inventive plaster can play a role as a plasicizer as well as show improving effect on the adhesive property of the plaster. s> N-alkyl-pyrrrolidone, preferably, N-methyl-2-pyrrolidione may be used in the present invention as a co-solvent. N-methyl-2-pyrrolidone is easily disappeared in the drying process in spite of its good solubility for piroxicam therefore it can improve skin permeability and minimize skin irritation. The amount of N-alkyl-pyrrolidone ranging from 0.5 to 3 folds of the amount of piroxicam can be preferably used. If the amount is less than 0.5 fold of the amount of piroxicam, additional other solvent to solve piroxicam is necessary and the remaining co-solvent may cause to deteriorate the physical property of plaster, i.e., adhesive force and attachment force to skin etc.

9> As an epidermal permeation enhancer for improving skin permeation ability of piroxicam, non-ionic surfactant such as monoglyceride, sorbitane ester, sorbitane ester oxyethylene etc, fatty acid such as oleic acid, linoleic acid, capric acid, myristic acid etc, or fatty acid derivative such as oleyl alcohol, isopropyl myristate, propylene glycol laurate, polyethylene glycol laurate or polyglycery-6-olate etc can be used herein. Those epidermal permeation enhancers can be use as a sole or the combination thereof in the amount ranging from 1 to 30 w , preferably, 5 to 20 w% more preferably. o> As a dispersing agent for preventing from the formation of piroxicam crystal, polyvinylpyrrolidone such as povidone K90, K25 etc can be used herein. Those dispersing agents can be used as a sole or the combination thereof with other solubilizer according to the distribution of M. W. The dispersion agent can provide piroxicam with the uniformity with other components in the plaster, inhibit the formation of piroxicam crystal and improve physical property of the plaster such as adhesive force, cohesive force, adhering force etc. The dispersion agent can be used in the amount ranging from 1 to 30 w%, preferably, 3 to 20 w%, more preferably. If the amount of dispersing agent is less than 1 w%, there shows no dispersion effect whereas if more than 30 w%, the adhesive force of the preparation is decreased and the handling of the preparation gets worse because of its increased viscosity. ι> As a pressure sensitive adhesive in the present invention, acrylic adhesive consisting of acrylate polymer, rubber adhesive and water soluble adhesive prepared by adding several additive i.e., adhesive resin such as oil resin, rosin resin, terpene resin etc, oil, anti-oxidants to natural or synthetic rubber can be used in the present invention. Those pressure sensitive adhesive can be use as a sole or the combination thereof in the amount ranging from 30 to 90 w%, preferably, from 45 to 80 w% more preferably. If the amount of the adhesive is less than 30 w%, the cohesive force of the preparation is collapsed resulting in unfavorable problems such as skin transfer etc and the amount of active ingredient and other components can be limited to use and the adherence power is lessened if more than 90 w%. > Besides the above described components, other additives, for example, essential oil such as 1-menthol, peppermint oil etc, anti-oxidant , preservative and inorganic filler etc in the amount ranging from 0.2 to 5 w%, among total composition in of drug layer can be further added to improve the physical property of the present preparation.

3> The inventive piroxicam-containing plaster of the present invention could provide all the components in the preparation with equal distribution. Accordingly, it could provide with superior advantages to conventional preparations: it can maintain the uniform distribution and high skin permeability of piroxiacm sufficiently and stably; accordingly, it can maintain ant i-inflammatory effect due to piroxicam sufficiently for a long time; it also provide with superior stability and adherence force of the preparation. > Present invention also provide with formulated plaster depicted in Fig. 1 using by the above- described composition as an exemplary embodiment. > The piroxicam-containing plaster depicted in Fig. 1 consists of four components in order to the drug be permeated through skin effectively: support layer (1) for preventing from drug diffusion as a base layer, primer layer (2) located thereon for preventing from the reverse diffusion of drug and improving skin adhesive ability, drug containing layer (3) located thereon containing piroxicam thereon, and release liner (4) located at the uppermost which could be released by patient's hand. > Preferably, the support (1) is made from the materials showing good humid permeability and elasticity, which do not interact between drug and other composition in drug layer (3). However, it is not preferable that the material of the support may effect on drug release. Synthetic resin film such as polyethylene, polypropylene, polyester and polyurethane etc, sheet, sheet foams, woven or non-woven and their laminates thereof can be preferably used as a support (3) in the present invention. Preferable thickness of the support layer ranges from 30 to 200 urn, however if the width is out of the range, the skin adhering force of patch can be worse due to the decrease of adhesive force and elasticity when the patch is applied to skin. > The primer layer (2) existed in inner side of the support (1) plays a role of preventing from the reverse diffusion of drug and improving skin adhesive ability and it consists of rubber adhesive prepared by adding several additive i.e., adhesive resin such as oil resin, rosin resin, terpene resin etc, oil, anti-oxidants to natural or synthetic rubber. Preferable thickness of the primer layer ranges from 5 to 40 urn, however if the thickness is out of the range, it could not prevent from the reverse diffusion of drug sufficiently or improve skin adhesive ability resulting in preventing cohesive force of adhesive agent and lowering skin adhering ability in the end, > The drug containing layer (3) consists of mainly piroxicam, pressure sensitive adhesive, solubilizer, co-solvent, dispersing agent, epidermal permeation accelerator and skin irritation preventing agent or plasticizer may be added thereto if required. The drug layer containing piroxicam and other components consists of mono-layer or multi-layer having more than two layers having thickness of each layer ranging from 10 to 150 um, preferably, from 20 to 120 um and thickness of total layers ranging from 30 to 500 um, preferably, from 50 to 200 um. The drug containing layer can be formed by mono layer or bi-layer of which component of each layer may be same or different from each other in order to form multi-layer laminated with each layers wherein the closest layer to skin could release felbinac most rapidly and the layer showing the slowest releasing velocity is positioned to be closest to primer layer (2) preferably.

)> The release liner (4) can be formed with polyester film coated with silicone or fluoride, polyethylene film or paper to be attached to drug containing layer (3).

)> The suitable embodiment of the piroxicam-containing plaster shall be explained as follows, however, it is not intended to limit the scope of the present invention to following embodiment:

[> Appropriate combination ratio of all the compositions without solubilizer and pressure sensitive adhesive are added to organic solvent such as toluene, ethylacetate, isopropylalcohol etc, mixed, stirred to solve each other and remaining pressure sensitive adhesive is added thereto to form uniform sticky material. Solubilizer is added thereto, mixed sufficiently removing air bubble. The produced material is spread onto the release liner, dried in dryer, and remaining support layer is compressed and transferred to obtain inventive plaster of the present invention. ι> The plaster of the present invention can be modified and improved into well-known figure or structure in the art, for example, circle, square, rectangle, oval structure or type if required.

?> The mixing procedure described above is just intended to explain in detail and the scope of the invention is not limited to the procedure. [Advantageous Effects]

4> the inventive piroxicam-containing plaster can provide with long lasting ant i-inflammatory effect, superior stability and adhering force to the conventional plasters therefore, it can be useful as an effective piroxicam-containing plaster to treat and alleviate various inflammation and pain inconsistently. [Description of Drawings]

5> The above and other objects and features of the present invention will become apparent from the following description, when taken in conjunction with the accompanying drawings, in which:

6> Fig. 1 presents a sectional diagram showing one embodiment example of inventive preparation;

7> Fig. 2 represents the comparison of skin permeation amount experimented in hairless mouse between the Examples, Comparative examples and conventional plaster. [Mode for Invention]

8> The following Examples and Experimental Examples are intended to further illustrate matrix type patch formulation of the present invention without limiting its scope.

9> Comparative Example 1: Preparation of Comparative plaster (1) o> The mixture of 8 w% povidone K25 and 7 w% povidone K90 used as a dispersing agent were dissolved in ethanol. 5% piroxicam and identical amount of N-methyl-2-pyrrolidone used as a co-solvent were added thereto and stirred to solve completely. 6 w% oleylalcohol and 6 w% polyglyceryl-6-olate used as an epidermal permeation enhancer were added thereto and mixed thoroughly. 68 w% aery adhesive used as a pressure sensitive adhesive was added thereto and stirred for 30 mins sufficiently to obtain sticky material. The sticky material was spread on a release liner in order to the mixture contains 0.38 2 mg/cm of drug and dried at 90^°C for 20 mins to remove volatile co-solvent and volatile ingredient in pressure sensitive adhesive. After the drying process, the exposed dug-containing layer was closed with already prepared support layer spread with primer layer. The plaster prepared by above procedure was cut into appropriate size to prepare piroxicam containing comparative plaster (1) to use as a sample in following Experimental Examples.

> Comparative Example 2: Preparation of Comparative plaster (2)

> Comparative plaster (2) was prepared through similar procedure to the procedure disclosed in above Comparative Example 1 except adopting 16 w% piroxicam, 57 w% acrylic adhesive as a pressure sensitive adhesive, and 1.2 2 mg/cm of drug content to use as a sample in following Experimental Examples. s> Comparative Example 3: Preparation of Comparative plaster (3) b> Comparative plaster (3) was prepared through similar procedure to the procedure disclosed in above Comparative Example 1 without dispersing agent except adopting 16 w% piroxicam, 62 w% acrylic adhesive as a pressure sensitive adhesive, 10 w coconut fat diethanolamide used as a solubilizer 2 and 1.2 mg/cm of dry drug content to use as a sample in following Experimental Examples. > Example 1: Preparation of inventive plaster (1) > Inventive plaster (1) was prepared through similar procedure to the procedure disclosed in above Comparative Example 1 except adopting 5 w% piroxicam, 58 w% acrylic adhesive as a pressure sensitive adhesive, 10 w% 2 coconut fat diethanolamide used as a solubilizer, and 0.17 mg/cm of dry drug content to use as a sample in following Experimental Examples. > Example 2: Preparation of inventive plaster (2) > Inventive plaster (2) was prepared through similar procedure to the procedure disclosed in above Comparative Example 1 except adopting 10 w% piroxicam, 53 w% acrylic adhesive as a pressure sensitive adhesive, 10 w% 2 coconut fat diethanolamide used as a solubilizer, and 0.75 mg/cm of drug content to use as a sample in following Experimental Examples. > Example 3: Preparation of inventive plaster (3) > Inventive plaster (3) was prepared through similar procedure to the procedure disclosed in above Comparative Example 1 except adopting 20 w% piroxicam, 43 w% acrylic adhesive as a pressure sensitive adhesive, 10 w% 2 coconut fat diethanolamide as a solubilizer and 1.5 mg/cm of dry drug content to use as a sample in following Experimental Examples. > Example 4: Preparation of inventive plaster (4)

'■> Inventive plaster (4) was prepared through similar procedure to the procedure disclosed in above Comparative Example 1 except adopting 25 w% piroxicam, 38 w% acrylic adhesive as a pressure sensitive adhesive, 10 w% 2 coconut fat diethanolamide as a solubilizer and 1.88 mg/cm of drug content to use as a sample in following Experimental Examples. i> Example 5: Preparation of inventive plaster (5) ι> Inventive plaster (5) was prepared through similar procedure to the procedure disclosed in above Comparative Example 1 except adopting 16 w% piroxicam, 47 w% acrylic adhesive as a pressure sensitive adhesive, 10 w% 2 coconut fat diethanolamide as a solubilizer and 1.2 mg/cm of drug content to use as a sample in following Experimental Examples. 5> Example 6: Preparation of inventive plaster (6)

5> Inventive plaster (6) was prepared through similar procedure to the procedure disclosed in above Comparative Example 1 except adopting 16 w% piroxicam, 45 w acrylic adhesive as a pressure sensitive adhesive, the mixture of 10 w% coconut fat diethanolamide and 2% diethanolamine as a 2 solubilizer and 1.2 mg/cm of drug content to use as a sample in following Experimental Examples. > Example 7' Preparation of inventive plaster (7) > Inventive plaster (7) was prepared through similar procedure to the procedure disclosed in above Comparative Example 1 except adopting 16 w piroxicam, 47 w% acrylic adhesive as a pressure sensitive adhesive, 10 w% coconut fat diethanolamide as a solubilizer, the mixture of 6% sorbitane monooleic acid and 5 w% ρolyglyceryl-6-olate used as an epidermal permeation 2 enhancer, and 1.2 mg/cm of drug content to use as a sample in following Experimental Examples. > Example 8: Preparation of inventive plaster (8)

> Inventive plaster (8) was prepared through similar procedure to the procedure disclosed in above Comparative Example 1 except adopting 16 w% piroxicam, 47 w% acrylic adhesive as a pressure sensitive adhesive, 10 w% coconut fat diethanolamide as a solubilizer, the mixture of 6% sorbitane monooleic acid and 6 w% oleyl alcohol used as an epidermal permeation 2 enhancer, and 1.2 mg/cm of drug content to use as a sample in following Experimental Examples.

> Example 9: Preparation of inventive plaster (9)

Ϊ Inventive plaster (9) was prepared through similar procedure to the procedure disclosed in above Comparative Example 1 except adopting 16 w% piroxicam, 47 w% acrylic adhesive as a pressure sensitive adhesive, 10 w% 2 lauric mono ethanol amide as a solubilizer, and 1.2 mg/cm of drug content to use as a sample in following Experimental Examples. 3> Example 10: Preparation of inventive plaster (10) i> Inventive plaster (10) was prepared through similar procedure to the procedure disclosed in above Comparative Example 1 except adopting 16 w% piroxicam, 47 w% acrylic adhesive as a pressure sensitive adhesive, 10 w% 2 lauric diethanolamide as a solubilizer, and 0.38 mg/cm of drug content to use as a sample in following Experimental Examples. > Experimental Example 1 > In order to examine the drug transdermal permeability of the formulations prepared by the procedures disclosed in Example 1 to 10, Comparative Example 1 to 3 and conventionally available plaster, the samples were attached to skin epidermis of four weeks old hairless mouse and then, in vitro drug permeability was measured by using Franz-diffusion cell at 32°C. 2 The effective drug permeation area of diffusion cell was 0.64cm and the volume of solution (phosphate buffer (pH 7.4), 40% Tween 20, 1% sodium ascorbate, 0.1% sodium citrate, 0.1% sodium azide) was 5.2m£. The samples were attached to the diffusion apparatus and the PBS (pH 7.4) was used as a mobile phase. The mobile phase was stirred with a speed of 600rpm. After several times lapse from spreading 0.25 ml of mobile phase was collected to determine the amount of permeated drug and collected phase was injected to HPLC (Capsel Pack C 18, UG120, 4.6mmxl50mm, Shisheido Co. Japan) using specific condition i.e., flow rate of 1.0 ml/min, the wavelength of UV detector of 260 nm, the column temperature of 40 ^°C , the eluting solution of mixed solvent (acetonitrile: phosphate buffer solution=60: 40). The PBS was prepared by mixing 0.01M potassium phosphate with > phosphoric acid adjusting the pH of 1.5. and 20 ul of each sample was injected. The drug permeation rate with time was determined in qualitative analysis and the results were shown in Table 1. > [Table 1]

As shown in Table 1, as the concentration of piroxicam in the preparation increases, the skin permeation rate increase. It is confirmed that the skin permeation rate was affected according to the sort and the content of solubilizer and epidermal permeation enhancer where same amount of piroxicam was treated. If there has no solubilizer or dispersing agent, it easily extract crystal and decrease the storage-stability of preparation, which has limit to put high concentrated drug. Furthermore, it is confirmed that alkanilamide used as a solubilizer could increase the drug content in stable to the extent that the preparation contains high mount of drug (about 16 w% ) providing with high skin permeability without formation of any crystal .

'0> Experimental Example 2

'1> In order to compare the stability of inventive plasters and comparative plasters, stability test was performed in closed and light-shielded condition with a temperature of 40 ^°C , and relative humidity of 75% and the result was shown in following Table 2.

'2> [Table 2]

[Industrial Applicability]

3> As mentioned above, the inventive piroxicam-containing plaster can provide with long lasting ant i-inflammatory effect, superior stability and adhering force to the conventional plasters therefore, it can be useful as an effective piroxicam-containing plaster to treat and alleviate various inflammation and pain inconsistently.

4> While the invention has been described with respect to the above specific embodiments, it should be recognized that various modification and changes might be made to the invention by those skilled in the art which also fall within the scope of the invention as defined in the appended claims.

Claims

[CLAIMS] [Claim 1] A piroxicam-containing plaster composition comprising 1 to 25 w% piroxicam as an active ingredient, 1 to 35 w% alkanolamide as a solubilizer, N-alkyl-pyrrolidone as a co-solvent, 1 to 30 w% at least one epidermal permeation enhancer selected from non-ionic surfactant, fatty acid and fatty acid derivative, 1 to 30 w% at least one dispersing agent selected from poylvinylpyrrolidone, cellulose derivatives and 30 to 90 w% pressure sensitive adhesive as a support. [Claim 2] The plaster composition according to claim 1, wherein said alkanolamide is selected from the group consisting of methanolamide, ethanolamide, propanolamide, isopropanolamide and coconut fat amide. [Claim 3] The plaster composition according to claim 1, wherein said N-alkyl- pyrrolidone is N-methyl-pyrrolidone. [Claim 4] The plaster composition according to claim 1, wherein said N-alkyl- pyrrolidone is used in the amount ranging from 0.5 to 3 folds of that of piroxicam. [Claim 5] The plaster composition according to claim 1, wherein said non-ionic surfactant is selected from the group consisting of monoglyceride, sorbitan ester and sorbitan ester oxyethylene. [Claim 6] The plaster composition according to claim 1, wherein said fatty acid is selected from the group consisting of oleic acid, linoleic acid, capric acid and myristic acid. [Claim 7] The plaster composition according to claim 1, wherein said fatty acid derivative is selected from the group consisting of oleyl alcohol, isopropyl myristate, propylene glycol laurate, polyethylene glycol laurate and polyglyceryl-6-olate. [Claim 8] The plaster composition according to claim 1, wherein said polyvinylpyrrolidone is sole or the combination of povidone K90 or K25. [Claim 9] The plaster composition according to claim 1, wherein said pressure sensitive adhesive is at least one selected from the group consisting of acrylate polymer, rubber adhesive and water soluble adhesive. [Claim 10] A piroxicam-containing plaster consisting of support layer (1) for preventing from drug diffusion as a base layer, primer layer (2) located thereon for preventing from the reverse diffusion of drug and improving skin adhesive ability, drug containing layer (3) located thereon containing felbinac thereon, and release liner (4) located at the uppermost which could be released by patient's hand.