KR100557878B1 - Piroxicam patch preparation solubility- and stability-enhanced by alkali metal hydroxide solution - Google Patents

Abstract

The present invention relates to a patch composition that significantly increases the solubility and stability in the matrix of the non-steroidal anti-inflammatory analgesic pyroxycam, and more particularly, contains pyroxycamp, an effective drug of the anti-inflammatory analgesic component, in the matrix Pyrroxycampal transdermal composition containing a solubilizer, a dissolution aid, an absorption accelerator, and a polymer as a constituent thereof, and using an aqueous hydroxide solution of an alkali metal selected from sodium hydroxide and potassium hydroxide in order to improve the solubility and stability in the matrix of pyroxicam. And to provide a transdermal patch containing the composition, the patch of the present invention is more than several times in the skin permeability than conventional pyrocampa patch.

Pyroxycam, patch, transdermal composition, alkali metal, solubility

Description

Piroxicam patch preparation solubility- and stability-enhanced by alkali metal hydroxide solution}

1 is a graph comparing the percutaneous permeability in the hairless mice of the patch of the present invention and known pyoxycampa patch,

Figure 2 is an exploded perspective schematic view of the patch of the present invention.

※ Explanation of symbols for main parts of drawing

1-support

2-adhesive layer

3-breathable matrix layer

4-monolayer or multilayer matrix layer containing pyroxycam

5-release layer

The present invention relates to a transdermal administration composition and patch agent of pyroxicam, which is a type of NSAID anti-inflammatory drug, and provides a patch that greatly improves the solubility and stability of pyroxicam in an aqueous matrix of an alkali metal hydroxide. will be.

Pyroxycam used as an active ingredient in the present invention is superior to other nonsteroidal drugs (NSAID), and has a long half-life, which is suitable for use as a patch drug. However, due to low solubility, the stability of the product is not only reduced, it is difficult to expect effective drug concentration through the skin. In Korean Patent Laid-Open No. 2000-0047908, Tromethamine is used as a dissolving agent of pyroxicam to overcome these problems, but there is a limit in dissolving sufficient drugs, and in the case of high doses, not only skin side effects are concerned but also patch agents. Changes in physical properties and skin absorption of drugs are also affected.

Therefore, the present inventors have conducted a long research, and when manufacturing a patch using a very small amount of alkali metal hydroxide in the production of the pyroxicamp patch, it significantly increases the solubility of the pyrocampam, while ensuring the stability of the patch and the skin of the drug The present invention has been completed by discovering the surprising fact that absorption is maximized.

The present invention is a transdermal administration composition containing pyroxicam, which has an anti-inflammatory analgesic effect, as an effective drug, and which contains an absorption accelerator, a dissolving agent, a dissolving aid, and an adhesive polymer as a conventional composition, and has lauryl ether as an absorption accelerator. 0.1 to 30% by weight in the total composition: 0.1 to 10% by weight aqueous solution of sodium hydroxide as the solubilizer and stabilizer in the total composition: and 50 to 70% by weight of the adhesive polymer in the total composition. A stretchable film was used as the support of the drug, and a PET film was used as the release film. Between the drug and the film, a breathable paper or non-woven fabric with a thickness of 20 to 70 µm was used to reduce skin side effects due to prolonged adhesion.

Features of the present invention are as follows.

The transdermal composition contains 0.1 to 5% by weight of an alkali metal hydroxide of the total composition in order to improve the solubility and stability of the active drug pyroxycam in the matrix. Potassium hydroxide or sodium hydroxide is used as an alkali metal hydroxide. Pyroxycam is a representative poorly soluble drug and shows high solubility in strong alkali solution. So, the solution of sodium hydroxide dissolved by adding a very small amount of sodium hydroxide solution and evaporating water during the manufacturing process is very low density in the matrix. It exists. Therefore, there is no change in the physical properties of the patch due to the alkalizing agent administration, it is possible to prevent the side effects of the alkalizing agent that may occur during long-term adhesion.

Lauryl ether, an absorption promoter used in the present invention, is contained in an amount of 0.1 to 30% by weight in the total composition. This significantly increases the skin absorption rate for pyroxycam compared to other absorption accelerators, and can maximize the effect of the patch when administered to the matrix composition. In addition, the transdermal administration composition of the present invention contains 20 to 70% by weight of the adhesive polymer in the total composition, which uses acrylic resin and organic solvent materials as pharmaceutically usable components.

As the absorption promoter, alone or a mixture of two or more selected from fatty acids oleic acid, lauryl acid, palmitic acid, stearic acid, capric acid, caprylic acid and myristic acid together with lauryl ether and its derivatives may be used.

As the solubilizer, together with an aqueous sodium hydroxide solution, triethanolamine which is alkanolamine, diethanolamine, ethanolamine, isopropanolamine, diisopropanolamine and isopropylamine which is alkylamine, diisopropylamine, triethylamine, diethylamine, ethylene In diamine, single or 2 or more types of mixtures can be used.

Polyhydric alcohols including propylene glycol, polyethylene glycol, dipropylene glycol, diethylene glycol, diethylene glycol monoethyl ether, and glycerol together with ethanol and methylene chloride; Polar aprotic solvents including acetylacetone, dimethylsulfoxide, dimethylacetamide, dimethylformamide, N-alkyl pyrrolidine; And a single or a mixture of two or more thereof may be used in the Tween 80.

As the tacky polymer, an acrylate polymer, vinyl acetate-acrylate, or a mixture thereof is used together with an acrylic resin, and a rosin-based resin, a polyterpene resin, a petroleum resin, a terpene phenol resin, natural or synthetic rubbers, and silicones, if necessary. Polymers or mixtures thereof can be used.

The patch of the present invention is a support (1) to support, an adhesive layer (2) to help adhesion to the skin, a breathable matrix layer (3), a single layer or multilayer matrix layer (4) containing pyrocampum, It is to provide a transdermal dosing patch comprising a release layer (5).

Next, the present invention will be described in more detail with reference to Examples, which should not be construed as limiting the present invention thereto.

Examples 1 to 8

Bubbles were removed after mixing pyricamp, ethanol, tacky polymer, lauryl ether, isopropylamine, and alkali metal hydroxide aqueous solution. The mixture was transferred to a release paper with a thickness of about 500 μm, all the volatile solvent was removed from the drying furnace, and then covered with a breathable matrix layer, an adhesive layer was applied thereon, a support film was adhered, and the patch was cut to an appropriate size to prepare a patch.

Pyrochammer-containing patch percutaneous administration compositions were prepared in a manner as illustrated in Table 1 below.

Experimental Example 1 Stability Experiment

The patch prepared in Examples 1 to 8 was sealed and shielded under conditions of acceleration at 40 ° C. and a relative humidity of 75%. The results are shown in the stability column of Table 1.

Experimental Example 2 Solubility Experiment

The compositions prepared in Examples 1-10 were quantified using spectrometa. The result is shown in the solubility column of Table 2.

Experimental Example 3: The product of the patch prepared in Example 9 of the present invention and the commercially available pyroxicam patch (Korean Patent Publication No. 2000-0047908) was used to measure the blood concentration using a mouse without the transdermal permeation Were respectively measured. The collected blood was analyzed by collecting plasma after centrifugation, measured by high performance liquid chromatography (HPLC) and the results are shown in FIG. 1.

The analysis conditions are as follows.

<Analysis Condition>

Column: μ Bondapak CN (5μ.3.9 x 150mm)

Mobile phase: Acetonitrile / 0.05 M phosphate buffer (pH 3.3) = 25/75

Flow rate: 1.0 ml / min.

Detector: UV 365nm.

As shown in Figure 1, the patch of the present invention it can be seen that the percutaneous permeation rate of pyroxicam is significantly higher than the conventional patch.

As described above, the present invention improves the solubility and stability of the active drug pyroxycam having an anti-inflammatory analgesic component in the matrix layer to maximize the absorption promotion of the drug.

Claims (8)

It contains non-steroidal anti-inflammatory analgesic agent, pyroxycam, as an effective drug, and contains 0.1 to 5 parts by weight of alkali metal hydroxide as a dissolving agent and stabilizer, and lauryl ether as an absorption accelerator in 0.1 A transdermal administration composition comprising -30 parts by weight and containing 0.5 to 20 parts by weight of a component selected from a solubilizer, a dissolution aid, an absorption accelerator, and a humectant in the total composition. delete The triethanolamine, diethanolamine, ethanolamine, isopropanolamine, diisopropanolamine and the alkylamine isopropylamine, diisopropylamine, and triamine, as described in claim 1, together with the hydroxide of the alkyllimetal as a solubilizer. Transdermal administration composition comprising one or a mixture of two or more selected from ethylamine, diethylamine, ethylenediamine. The polyhydric alcohol of claim 1, further comprising propylene glycol, polyethylene glycol, dipropylene glycol, diethylene glycol, diethylene glycol monoethyl ether and glycerol together with ethanol and methylene chloride; Polar aprotic solvents including acetylacetone, dimethylsulfoxide, dimethylacetamide, dimethylformamide, N-alkyl pyrrolidine; And one or two or more mixtures selected from Tween 80. The resin according to claim 1, wherein an acrylate polymer, vinyl acetate-acrylate, or a mixture thereof is used together with the acrylic resin as the tacky polymer, and a rosin-based resin, a polyterpene resin, a petroleum resin, a terpene phenol resin, and natural Or synthetic rubbers, silicone polymers or mixtures thereof. The transdermal composition according to claim 1, wherein the alkali metal hydroxide is potassium hydroxide or sodium hydroxide. delete delete

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