KR100406576B1 - Transdermal delivery system for piroxicam - Google Patents

Abstract

The present invention relates to a composition of the percutaneous absorbent of phyroxicam, and more particularly, to improve the percutaneous permeability of phyroxicam, a nonsteroidal anti-inflammatory analgesic agent, as a active ingredient, The present invention relates to a percutaneous absorbent composition using a combination of the pyroxycamonoethanolamine salt or the pyroxycamdieethanolamine salt prepared by adding thereto.

Description

Transdermal delivery patch {Transdermal delivery system for piroxicam}

The present invention relates to a composition of the percutaneous absorbent of phyroxicam, and more particularly, to improve the percutaneous permeability of phyroxicam, a nonsteroidal anti-inflammatory analgesic agent, as a active ingredient, The present invention relates to a percutaneous absorbent composition using a combination of the pyroxycamonoethanolamine salt or the pyroxycamdieethanolamine salt prepared by adding thereto.

Pyroxycam, a nonsteroidal anti-inflammatory drug, is widely used because it shows excellent effects on myalgia, osteoarthritis and rheumatoid arthritis. On the other hand, it is well known that pyroxicam is well absorbed during oral administration, but it is known to put a heavy burden on the gastrointestinal system during long-term or overdose. The method is used [Ref. S. Santoyo et al. European journal of pharmaceutics and biopharmaceutics, issue 50, 245-250, (2000). Pyroxycam has a high drug efficacy and long half-life compared to other nonsteroidal drugs, making it difficult to develop as a transdermal absorbent because it is almost insoluble in most organic solvents as well as drugs or aqueous solutions suitable for use as a transdermal absorbent.

On the other hand, the invention relating to the preparation of chlorides to improve the solubility and physicochemical safety of pyroxicam is disclosed in EP 0123520, US Patent 4434164. EP 0123520 describes a process for the preparation of pyoxycham chloride with a need for a carrier such as cellulose or lactose. US Pat. Disclosed is a method in which a crystalline crystalline form of the pyroxiumethanolamine salt can be prepared by dissolving each in a carbon solvent and slowly adding the ethanolamine solution to the pyroxycam solution. In US Patent 4994457, there is an example of the invention using pyoxycham ethanolamine salts, but it is based on oral products, and EP 0123520 is also limited to oral products.

Examples of the method for administering the nonsteroidal anti-inflammatory drugs through the skin include U.S. Patent No. 5196417 (Pyroxycam emulsion using an oil phase in which polyethylene lead is dispersed), 5413776 (Polyoxyethylene alkyl ether or fatty acid alkylolamide). Pyoxycampa plasterase containing water as an accelerator of absorption), 5676970 (Platase containing an ethylene oxide and polyethylene nonionic surfactant, water-soluble polymer), Japanese Patent No. 10087494 (polyoxyethylene glycol stearic) Pyoxycamp patches comprising esters), EP 0617956 (platases containing polyoxyethylene nonionic surfactants and ethylene oxide).

The prior art discloses a transdermal absorbent composition that overcomes the low solubility of phyroxicam to increase skin permeability, but by combining a form of phyroxicam and a phyroxam salt, it is attached to the skin using an adhesive to provide excellent skin permeability. There have been no reported examples of the development of a formulation that can be represented.

Therefore, the present inventors concentrated on the improvement of the percutaneous permeability to maximize the therapeutic effect, and as a result, the percutaneous absorbent composition prepared by dispersing the form of the pyroxycam salt in the acrylic adhesive has excellent skin permeability, and the amount of drug per area of the preceding patch. Higher permeability is shown in much smaller amounts, and it was also found that the addition of skin absorption accelerators shows excellent skin permeability.

Accordingly, it is an object of the present invention to provide a transdermal absorption composition of the pyroxycam salt which prevents crystallization due to the low solubility of pyroxycam and maximizes skin permeability from the matrix.

1 shows a cross-sectional view of a transdermal administration system according to the present invention.

<Description of Symbols for Main Parts of Drawings>

1: back layer 2: auxiliary adhesive layer

3: substrate layer 4: release paper

The present invention contains a non-steroidal anti-inflammatory analgesic component, pyroxycam and pyoxycammonoethanolamine salt or pyroxycam and pyrocamphamethanolamine salt as active ingredients, and is contained in a polymer base in a complex. The present invention relates to a transdermal absorption agent containing a dissolution aid, absorption accelerator, crystallization inhibitor, and moisturizer.

The present invention will be described in more detail as follows.

In the present invention, the chloride is cationic as a compound having an amine group, and pyroxam is an amphoteric ion having two pKa values (pKa ₁ = 1.86 and pKa ₂ = 5.46). [Reference Junichi Jinno et al. Journal of pharmaceutical sciences, 89, 2000, 268-273] In general, amphoteric ions have high molecular intermolecular relative charges, which results in low solubility, resulting in low solubility in biopolymeric membranes. [References Gerard. C. Mazzenga and Bret Berner Journal of controlled release, 16, 1991, 77-88] As zwitterions, pyricampam become anions under basic conditions, and these cations are electrically neutral by forming salts with pyrocampam; It has chemically stable properties and acquires the property to move the hydrophobic skin barrier without structural modification of the drug. Therefore, by forming a salt, it is possible to improve the low solubility of pyroxicam and to inhibit and delay crystallization together with an increase in skin permeability by increasing the solubility of the active ingredient in the matrix. Experiments with transdermal fluxes using amphoteric salts (barcrofen salt, phenylalanine salt) have already reported that the salt forms are more permeable than exist in ionic form. [Ref. Gerard. C. Mazzenga et.al. Journal of controlled release, 20, 1992, 163-170.

The chloride having an amine group is selected from the group consisting of primary amine, secondary amine and tertiary amine, preferably monoethanolamine, diethanolamine and triethanolamine. The chlorinating agent reacts equivalently with the pyroxycam base to form a salt. The solubility of each salt is shown in the order of pyroxicamponoethanolamine salt> pyroxicampiethanolamine salt> pyroxicampriethanolamine salt. In addition, salt formation can minimize skin irritation that may be caused by high pH of amines.

US Pat. No. 4,678,666 uses organic amines such as alkanolamines (dialkanolamines and trialkanolamines) as a solubilizer to simply improve the solubility of pyroxicam, and its use is limited to gels and ointments. While the content of kam is 0.3 to 2% by weight, the amount of organic amine used to dissolve the phyxicam is 1 to 3%. The solubility of pyoxycham is increased due to excessively used amines. In the thermodynamic activity of the active ingredient is lowered, rather, the permeability may be lowered. U. S. Patent No. 5436241 used tetrahydroxypropylethylenediamine as a dissolving agent for dissolving pyricampam, which is also limited to gels. EP 0276561 used 0.5-10 units of alkanolamines (monoalkanolamines, dialkanolamines, trialkanolamines) per unit of pyroxicam as an alkalizing agent to promote absorption. In Korean Patent No. 10-0212961, alkanolamine is 0.5-25% by weight of pyroxicam as an absorption aid and 9-40% by weight of alkanolamines is added. Korean Patent Publication No. 2000-47908 also uses tromethamine as a dissolving agent. However, in the case of tromethamine, since it exists in a solid state at room temperature, it is disclosed that crystals remain undesirably when it exceeds 12% by weight. As mentioned above, all are only transdermal formulations administered only with phyroxam and alkanolamines are used as simple additives and their solubility of the active drug in the base is present because the percentage by weight is higher than the percentage by weight of phyroxam. The increase in the concentration of the drug increases, but absorption from the skin may rather decrease because the increase in the concentration of the drug does not have a desirable effect on activity as mentioned above in terms of thermodynamics. Also excessive skin alkanolamine may cause skin irritation. Korean Patent Laid-Open Publication No. 2000-0013593 describes a skin preparation agent, alkanolamines are disclosed as solubilizers, and mention that they form salts by reacting with pyroxicam in aqueous solution. Considering the equivalence ratio by adding 8% by weight of ethanolamine, the ratio of diethanolamine is very high, making it difficult to think of it as a salt concept, and it is necessary to control pH and temperature, and the manufacturing method is complicated.

As an active ingredient mixed together in the acrylic polymer material according to the present invention as the most important feature of the present invention, a pyrocampomonoethanolamine salt or a pyroxicamdieethanolamine salt is essentially used, and the content is 1 to about the substrate layer composition. 25%, preferably 3-18%. When the amount of the compound active ingredient is less than 1%, it is difficult to expect a clinical effect, and when it is more than 25%, the adhesion decreases, crystals are precipitated, and further clinical effects are hard to expect. Although it is also possible to use a mixture of pyoxycham and pyoxycammonoethanolamine salts or pyoxychamdiethanolamine salts, the ratio of pyroxycam in the total active ingredient may not exceed 80%. When pyroxicam exceeds 80%, the drug crystallizes in the matrix layer and the skin permeability decreases and the adhesion decreases. Pyroxycam triethanolamine salt is disclosed in US Pat. No. 4,434,164 to decrease its physicochemical properties by forming a salt, and this comparative example also shows a decrease in skin permeability.

On the other hand, in the selection of a solvent for dissolving the effective drug, the solvent should have a good solubility to the drug and at the same time volatile so that the patch can be removed when drying. Pyroxycams are very soluble in halogenated hydrogen carbon solvents, and pyoxycamponoethanolamine salts or pyoxycamdieethanolamine salts have good solubility in methanol. Therefore, by using a mixture of halogenated hydrogen carbon solvent and methanol, it is possible to effectively dissolve the pyoxycham and monoethanolamine salt or diethanolamine salt, so that it exists as crystals in the solution to prevent the solubility in the patch from being lowered. .

As the active ingredient, the pyroxycam and the pyroxycamonoethanolamine salt or the pyroxycamdieethanolamine salt are dispersed in an acrylic polymer matrix having a carboxyl group due to their chemical structure, so that the amino group of the pyroxycam and its salts interact with the carboxyl group. Since the active ingredient is hard to escape from the matrix, the skin permeability is greatly reduced and the adhesive force is reduced, thereby containing acrylic polymer without carboxyl group. For example, the acrylic polymer without a carboxyl group may include vinyl derivatives such as acrylate, hydroxypropyl acrylate, acrylamide, acrylimide vinyl acetate, and vinyl ether, methacrylate, hydroxypropyl methacrylate, methacrylamide, and methacrylate. Mead and the like is prepared as a monomer, in addition to the monomers used in the production of a well-known acrylic pressure-sensitive adhesive may be used. These may be used alone, or two or more thereof may be mixed and used to contain 50 to 95% by weight, preferably 60 to 90% by weight of the total composition of the matrix layer. When the amount of the acrylic polymer is 50% by weight or less, the adhesive strength is lowered, and when the amount of the acrylic polymer is 95% by weight or more, the amount of the active ingredient is lowered, and further excellent adhesion may not be expected.

On the other hand, polyethylene glycol monoglycerides, polyglyceryl fatty acid derivatives, cetiaryl octanoate as dissolution aids and accelerators in the substrate layer to further promote skin absorption of the anti-inflammatory analgesic active ingredient in the transdermal absorbent system according to the present invention Isopropyl myristate (crodamol CAP), vegetable oil (peanut oil), dimethylformamide, fatty acids, fatty acid derivatives, propylene glycol, propylene glycol fatty acid esters and the like may be used. Ball A40, Crawball PK40, Crawball A70, Crawball EP40, Labrafil 2609 and plurol olake in polyglyceryl fatty acid derivatives. These absorption aids may be used alone or in combination of two or more, and contain 1 to 35%, preferably 5 to 20% by weight of the total composition constituting the matrix layer. If the dissolution aid and absorption accelerator are used in an amount less than 1% by weight, there is no additive effect. When the dissolution aid and absorption accelerator are used in an amount of more than 35% by weight, the adhesive force is lowered and it is difficult to maintain the matrix form.

On the other hand, in the present invention, in order to increase the permeation enhancement effect by reducing the side effects of sweat and accumulation of secretions and deterioration of the adhesive properties of the patch propylene glycol, polyethylene glycol 200, polyethylene glycol 300 polyethylene glycol 400, 1-methyl 2-pyrrolidone, glycerin, etc. are used, each of which can be used alone or in combination of two or more, and is contained in the total composition constituting the matrix layer 0.5 to 25% by weight, preferably 1 to 10% by weight. If the moisturizing agent is used less than 0.5% by weight has no additive effect, when the moisturizing agent is more than 25% by weight, the polymer matrix becomes soft and sticky, leaving a residue on the skin.

In addition, a crystal inhibitor may be added if necessary. Examples thereof include well-known components such as polyvinylpyrrolidone, cellulose derivatives and polyethylene glycol derivatives, and preferably polyvinylpyrrolidone is used. 1 to 40% by weight, preferably 3 to 15% by weight. If the crystallization inhibitor is used less than 1% by weight, there is no additive effect. If the crystallization agent is more than 40% by weight, the thickening effect is greater than that of the crystallization inhibitory effect, which lowers the adhesive force of the polymer matrix, thereby lowering the product value.

Silica, zeolite, ceramics and the like can be used to reduce or increase the adhesion and to maintain the shape of the matrix and to ensure durability. At this time, the inorganic material as described above may be contained in an amount of 0.1 to 15% by weight in the pressure-sensitive adhesive agent, if it exceeds 15% by weight, the polymer matrix is cured and the drug in the pressure-sensitive adhesive crystallization and drug permeability is reduced.

The present invention relates to a system for percutaneous administration through skin adhesion by containing an active ingredient comprising pyroxycam and pyroxycam salts in a matrix. As shown in FIG. 1, a back layer, an auxiliary adhesive layer, a matrix layer, And release paper.

In the present invention, the backing layer may be a polymer film which is well known in the field of transdermal absorbents, including polyester, polypropylene, polyethylene, ethylene vinyl acetate, polyurethane, and the film used as the backing layer should be impermeable to the active ingredient. It may be permeable or impermeable to air or moisture.

The substrate layer is mainly composed of an active ingredient, an acrylic pressure-sensitive adhesive and a dissolution aid, an absorption accelerator, a crystallization inhibitor, a humectant, and the like, and a skin stimulant or a plasticizer may be added as necessary.

In the present invention, as the release paper, a widely known and commercialized product such as a silicone coated polyethylene film or a fluorocarbon diacrylate coated paper can be used. When removing the release paper from the patch, the debris of the matrix should be able to be easily removed without leaving the release paper.

In addition, when the adhesive layer is weak due to the large amount of the active ingredient or solvent in the substrate layer containing the active ingredient has been shown that the auxiliary pressure-sensitive adhesive layer may be added between the substrate layer and the back layer. A small amount of an active ingredient, a dissolution aid, an absorption accelerator, or the like may be added to the auxiliary adhesive layer.

Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited by the Examples.

Example 1

30 mg of pyroxycam is dissolved in 1 ml of methylene chloride, 240 mg of monoethanolamine salt and 100 mg of polyvinylpyrrolidone (Kollidon 30) are dissolved in 2 ml of methanol, and the two solutions are mixed. Polyglyceryl-3 oleate (plurol oleique ^® ) is added to the mixed solution, followed by sufficient stirring. 3.33 g of an acrylic pressure-sensitive adhesive solution (National Starch Chemical Co. Durotak ^® 2677) containing 1.33 g of polymer is added and stirred for 10 minutes. The solution was dried on a release paper (3M; 1362) coated with silicon, and then coated to have a thickness of 170 μm, followed by 20 minutes at 90 ^° C. and 20 minutes at 120 ^° C. After drying, the acrylic pressure-sensitive adhesive layer was transferred to a polyurethane film as a back layer by transferring pressure to obtain a final product.

[Examples 2 and 3]

Example 2 and 3 were prepared in the same manner as in Example 1, using polyethylene glycol-60 almond glyceride or peanut oil instead of polyglyceryl-3 oleate as the absorption accelerator. 3 was prepared.

division unit Example Comparative example 2 3 One 2 3 Piroxycam mg 30 40 250 40 40 Pyoxycamonoethanolamine salt mg 240 240 Pyoxycampriethanolamine salt mg 300 280 Absorption accelerator Polyethylene Glycol-60 Almond Glyceride Μl 400 Peanut oil Μl 400 400 400 Deterrent Polyvinylpyrrolidone mg 100 100 100 100 100 adhesive Durotak 2677 g 3.33 3.33 3.33 3.33 3.33

Example 4

20 mg of pyroxicam is dissolved in 1 ml of chloroform, 130 mg of diethanolamine salt and 100 mg of polyvinylpyrrolidone (Kollidon 30) are dissolved in 2 ml of methanol, and the two solutions are mixed. 50 µl of polyethylene glycol 400 and 355 µl of polyethylene glycol-60 almond glyceride (Crovol A 40 ^® ) were added to the mixed solution, followed by sufficient stirring. An acrylic pressure-sensitive adhesive solution containing 1.46 g of polymer (National Starch Chemical Co. Durotak ^® 2097) Add 3.65 g and stir for 10 minutes. The solution was dried on a release paper (3M; 1362) coated with silicon, and then coated to have a thickness of 170 μm, followed by 20 minutes at 90 ^° C. and 20 minutes at 120 ^° C. After drying, the acrylic pressure-sensitive adhesive layer was transferred to a polyurethane film as a back layer by transferring pressure to obtain a final product.

[Examples 5 to 11]

Examples 5 to 11 and Comparative Example 4 were prepared according to the same method as Example 4 based on the following prescription.

division unit Example Comparative example 5 6 7 8 9 10 11 4 Piroxycam mg 25 20 30 25 30 100 100 120 Pyoxycampiethanolamine salt mg 125 130 140 125 140 65 65 Absorption accelerator Polyethylene Glycol-60 Almond Glyceride Μl 380 355 355 380 380 380 190 380 Polyglyceryl Trioleate Μl 190 Moisturizer Polyethylene Glycol 400 Μl 25 Propylene glycol Μl 50 1-methyl-2-pyrrolidone Μl 50 Deterrent Polyvinylpyrrolidone mg 100 100 100 100 100 100 100 100 Silica mg 59 adhesive Durotak 4098 g 3.65 3.65 3.65 3.65 3.65 3.65 3.65 3.65

Experimental Example 1

In order to select the appropriate solubilizers and absorption promoters and to compare the solubility of pyroxicam and pyroxicam salts, pyricam and pyroxicam-monoethanolamine salts and pyroxicam-dietanolamine salts for various solvents and surfactants Solubility was measured. In the measurement method, after adding a certain excess amount of pyoxycham, pyoxycham-monoethanolamine salt, and pyoxycham-diethanolamine salt to each solvent, it was shaken at room temperature for 48hr, and the pH of the solution was used for HPLC. Quantification by The results of the measurement of pyroxycam solubility for each solvent or surfactant are shown in the following table.

Solvent Solubility (mg / ml) Piroxycam Pyoxycamonoethanolamine salt Pyoxycampiethanolamine salt Chroda mollabrafil 2609 Labra Sol black ball A40 black ball PK40 Plurol O Lake Twin 80 phosphate buffer (pH 7.4) 0.54 ± 0.014.89 ± 0.414.91 ± 17.96 ± 1.468.62 ± 1.142.53 ± 0.6413.54 ± 2.290.66 ± 0.03 0.16 ± 0.00838.78 ± 0.97226.75 ± 19.8143.26 ± 3.6651.34 ± 5.2715.97 ± 0.45157.53 ± 3.6541.63 ± 0.62 0.12 ± 0.056.72 ± 1.1530.99 ± 1.6459.12 ± 5.9314.58 ± 2.716.74 ± 1.1341.97 ± 1.9423.66 ± 2.16 Crodamol: Cetearyl octanoate and isopropyl myristate Labrafil2609: PEG-8 glyceryl linoleate Labrasol: PEG-8 glyceryl caprylate / caprate Crawball A40: PEG-20 almond glycerides Crobol PK40: PEG-12 palm kernel glycerides Plurol Olake: polyglyceryl-3 oleate

According to the results of the above table, it can be seen that the solubility of pyoxycammonoethanolamine salt or pyoxycamdieethanolamine salt is much better in aqueous solution and most organic solvents than pyroxicam.

Experimental Example 2

Hairless mouse skin was used to determine the skin permeability of the prepared phyroxicam patch and prior art patch. The skin of the hairless mouse (6 ~ 8 weeks old) is extracted immediately before the experiment, and the product to be tested is cut in a circle so that its area is 2cm ² and attached to the skin, and then clamped to a flow-through diffusion cell. The samples were fixed for 4 hours at intervals of 4 hours and quantified using high performance liquid chromatography. From this value, the permeation rate of the drug was calculated. In the receptor, isotonic phosphate buffer (pH 7.4) was added and maintained at 37 ^° C., followed by constant stirring with a magnetic stirrer. The analysis conditions are as follows.

<Analysis Condition>

Column: Alltima C8 (4.8 X 150 mm)

Mobile phase: Methanol / water / phosphoric acid (700: 299: 1)

Detector: UV 320nm

Flow rate: 1ml / min

The following table shows the test results for drug content and skin absorption when the active drug contained in the transdermal composition is pyroxicam and the type and content of chloride, solubilizer and dissolution aid are changed.

division Average skin penetration rate (㎍ / cm ² / hr) Drug Content in Patches (mg / cm ² ) Example 1 13.87 2.23 Example 2 10.71 2.23 Example 3 7.00 2.32 Example 4 9.87 1.14 Example 5 5.67 1.15 Example 6 5.17 1.14 Example 7 5.21 1.3 Example 8 4.78 1.15 Example 9 5.53 1.3 Example 10 4.34 1.43 Example 11 6.19 1.43 Comparative Example 1 0.87 2.4 Comparative Example 2 0.32 2.37 Comparative Example 3 0.44 2.23 Comparative Example 4 3.73 1.15 Commercial item 4.13 2.4

In Table 2, the patch containing the monoethanolamine salt (Examples 1 to 3) and the patch containing the diethanolamine salt (Examples 4 to 11) are the patches of pyroxhamm (Comparative Examples 1 and 4). , It shows higher permeability than the patch containing triethanolamine salt (Comparative Examples 2 to 3) and it can be seen that the skin permeation effect of the drug is very improved compared to the commercially available products.

As described above, in the transdermal absorbent preparation composition containing pyoxycamp as a nonsteroidal anti-inflammatory analgesic active ingredient, solubility could be increased by blending pyoxycamponoethanolamine salt or pyoxycampdieethanolamine salt as an active ingredient. Only about 50% of the drug amount per unit area of the product can achieve the desired skin penetration effect as shown in Table 2.

Claims (6)

1 to 25% by weight, 50 to 95% by weight of the tacky polymer, with pyroxycam and pyoxycammonoethanolamine salts or as the active ingredient, in combination with 1 to 5: 5 to 100 ratios %, Polyethylene glycol monoglycerides, polyglyceryl fatty acid derivatives, cetiaryl octanoate-isopropyl myristate, vegetable oils (peanut oils), fatty acid esters and glycerol fatty acid esters, glycerol esters, propylene glycol, propylene as absorption accelerators 1 to 35% by weight of glycol fatty acid esters or mixtures thereof, 0.5 to 25% by weight as a moisturizer, 1 to 40% by weight of crystal inhibitors, and 0.1 to 15% by weight of inorganic substances to maintain the shape and adhesion of the matrix. Percutaneous administration patch The method of claim 1, wherein the adhesive polymer is a vinyl derivative such as acrylate, hydroxypropyl acrylate, acrylamide, acrylimide vinyl acetate, vinyl ether, methacrylate, hydroxypropyl methacrylate, methacrylamide, Transdermal dosing patch, characterized in that at least one compound selected from the acrylate polymer prepared by using methacrylimide as a monomer. The method of claim 1, wherein the moisturizing agent is one or more compounds selected from polyethylene glycol 200, polyethylene glycol 300 polyethylene glycol 400, propylene glycol, 1-methyl-2-pyrrolidone Patch The patch for transdermal administration according to claim 1, wherein the crystal inhibitor is at least one compound selected from polyvinylpyrrolidone, cellulose derivatives and polyethylene glycol derivatives. The patch for transdermal administration according to claim 1, wherein the inorganic material is at least one compound selected from silica, zeolite and ceramics. In the method of preparing a transdermal patch for containing peroxycham and pyoxycammonoethanolamine salts or pyroxycam and pyoxychamethanolamine salts as an active ingredient, halogenated as a solvent for effectively dissolving the active ingredient. A method for preparing a transdermal patch containing a hydroxycamphor and hydroxycamponoethanolamine salt or a hydroxycampham and a hydroxycampdieethanolamine salt characterized by mixing and using a hydrogen carbon solvent and methanol.