WO2005123046A1

WO2005123046A1 - Novel transdermal preparation and its producing method

Info

Publication number: WO2005123046A1
Application number: PCT/KR2005/001838
Authority: WO
Inventors: Young Chang Ah; Yang Gyu Choi; Jin Hyuk Choi; Jung Ju Kim
Original assignee: Amorepacific Corporation
Priority date: 2004-06-15
Filing date: 2005-06-15
Publication date: 2005-12-29
Also published as: KR100682729B1; KR20060049598A

Abstract

Disclosed herein is a transdermal preparation comprising a hydrophobic polymeric pressure-sensitive adhesive matrix layer. Since the transdermal preparation comprises a polymeric matrix layer in which droplets containing an active ingredient are uniformly dispersed, it shows superior skin absorption. In addition, the transdermal preparation can be produced in a simple manner, and can contain an active ingredient at a high concentration, irrespective of the solubility of the active ingredient. Accordingly, the transdermal preparation can be applied to a variety of drugs. Further disclosed is a method for producing the transdermal preparation.

Description

NOVEL TRANSDERMAL PREPARATION AND ITS PRODUCING METHOD

Technical Field The present invention relates to a transdermal preparation comprising a hydrophobic polymeric pressure-sensitive adhesive matrix layer, and a method for producing the transdermal preparation.

Background Art Delivery of pharmacologically active ingredients through the skin improves the compliance of patients and makes it easy to avoid the occurrence of first-pass effects, by which active ingredients absorbed through the digestive tracts upon oral administration are metabolized in the liver, resulting in reduction of efficacy and causing side effects. In addition, transdermal delivery of active ingredients allows patients themselves to modulate the duration of active ingredients. For these advantages, a great deal of research has focused on the treatment of diseases using the delivery of active ingredients through the skin. Formulations that have been produced as a result of the research are collectively termed "transdermal preparations". Transdermal preparations developed hitherto other than external preparations in the form of a lotion or cream are largely classified into two groups, i.e. transdermal preparations operated by a passive transfer system, and those operated by an active transfer system. According to the passive transfer system, active ingredients are delivered depending only on the distribution and diffusion of the active ingredients as a function of concentration. In contrast, according to the active transfer, system, active ingredients are delivered by externally applied physical energies, such as electricity, ultrasonic waves, heat, magnetic field, etc. Transdermal preparations for delivering active ingredients by the passive transfer system are further divided into reservoir type and matrix type in terms of their structure. The reservoir type transdermal preparations are easy to control the permeation rate of active ingredients and to modulate the content of the active ingredients in a broad range according to the compositions present in reservoirs.

Drawbacks of the reservoir type are complex production processes, a large thickness, and a great inconvenience of use due to poor flexibility. On the other hand, the matrix type transdermal preparations have a form in which an active ingredient is dissolved or its particles are dispersed in a pressure-sensitive adhesive or a polymeric material. The matrix type transdermal preparations suffer from the disadvantage in that since characteristics of materials constituting an active ingredient-containing matrix have a great influence on the matrix, the active ingredients cannot be contained in high concentrations in the matrix. However, the matrix type transdermal preparations are advantageous in terms of simple production processes, a small thickness (100 ~ 1,000 μm), and a convenience of use due to their good flexibility. For these reasons, application of the matrix type transdermal preparations to joint sites is particularly advantageous. The matrix type transdermal preparations are subdivided in terms of the following criteria: location of an active ingredient-containing layer, state of the active ingredient contained in the layer, and use of a semi-permeable membrane to modulate the delivery rate of the active ingredient. The present invention provides a matrix type transdermal preparation which delivers an active ingredient through the skin. The production of conventional matrix type transdermal preparations, which deliver active ingredients by the passive transfer system without physical damage to the horny layer (stratum corneum), which is the outermost layer of the skin, includes the following techniques. U.S. Patent No. 3,632,740 describes the simplest technique for producing a matrix type transdermal preparation by dissolving an active ingredient in an amount lower than the saturation concentration in an acrylic or rubber-based pressure-sensitive adhesive. The disadvantages of this technique are that the content of the active ingredient is very limited, and the kind of the active ingredient that can be contained in the pressure-sensitive adhesive is varied according to the particular type of the pressure- sensitive adhesive used. On the other hand, there have been attempts to overcome the limitations of simple mixing methods of active ingredients and pressure-sensitive adhesives in the formation of matrixes for transdermal preparations for the purpose of delivering the active ingredients. For example, U.S. Patent Nos. 5,958,447 and 5,965,154 describe techniques for dispersing an active ingredient in a crystalline form by mixing an excess of the active ingredient with a pressure-sensitive adhesive or polymeric material. U.S. Patent Nos. 6,211,425 and 5,948,433 disclose techniques for excessively containing an active ingredient scarcely soluble in a pressure-sensitive adhesive by dissolving the active ingredient in a solvent and uniformly mixing the solution with the adhesive. Further, techniques for modulating the delivery rate and content of an active ingredient by mixing polymers having different solubility parameters to the active ingredient are disclosed in U.S. Patent No. 6,235,306, Korean Patent Application No. 2002-7016273, and Korean Patent Nos. 194968 and 0336975. A technique associated with the use of a semi-permeable membrane in order to control the delivery rate of active ingredients is known in U.S. Patent No. 4,201,211. U.S. Patent Nos. 4,668,232 and 5,505,956 describe techniques for adjusting the delivery rate of an active ingredient using moisture, e.g., sweat, secreted when a transdermal preparation is attached to the skin. U.S. Patent No. 5,164,189 discloses a technique for controlling the diffusion rate of an active ingredient present in a matrix by the use of a diffusion accelerator. Korean Patent Application No. 2001-0019869 suggests a technique for including an active ingredient in polymer nanoparticles and mixing the polymer nanoparticles with a pressure-sensitive adhesive. Korean Patent No. 393478 reports a technique for dispersing liquid regions inside a matrix into the form of droplets. U.S. Patent No. 4,997,656 teaches a technique for forming a matrix capable of stabilizing an active ingredient unstable in water or oil using a heat-sensitive and water-sensitive amphiphilic polymer. However, the techniques comprising dissolving an active ingredient in a solvent or skin absorption enhancer and mixing the solution with a polymeric material, including a pressure-sensitive adhesive, have disadvantages in that when the solvent or the skin absorption enhancer is used in an excessively large amount, adhesiveness of the transdermal preparations to the skin is greatly deteriorated. In addition, since the solvent or the skin absorption enhancer is required to be compatible with the polymeric material, an increase in the amount of the active ingredient is restricted and the kind of the pressure-sensitive adhesive used is limited depending on the particular solvent used. According to the technique disclosed in Korean Patent No. 393478 (i.e. in the case where liquid regions are present in a matrix), a self-emulsifiable surfactant is mixed with an aqueous pressure-sensitive adhesive containing water so that the active ingredient is present in the liquid regions. However, the technique cannot be applied to the formation of matrixes using organic solvents. The techniques associated with the use of nanoparticles and a semi-permeable membrane for controlling the delivery rate of active ingredients are disadvantageous in terms of complex production processes and an economic burden of high costs. In addition, methods for controlling the water content by forming several layers also have the disadvantage of complicated production procedure.

Technical Tasks to be accomplished by the Invention The present inventors have conducted extensive research to produce a matrix type transdermal preparation for delivering an active ingredient through the skin that can contain an active ingredient at a high concentration, irrespective of the solubility of the active ingredient, shows superior skin absorption, and can be produced in a simple manner.

Disclosure of the Invention The present invention relates to transdermal preparation comprising a hydrophobic polymeric pressure-sensitive adhesive matrix layer, and a method for producing transdermal preparation.

In accordance with one aspect of the present invention, there is provided a transdermal preparation comprising a hydrophobic polymeric pressure-sensitive adhesive matrix layer wherein droplets containing an active ingredient and an alkanolamine are uniformly dispersed in the hydrophobic polymeric pressure-sensitive adhesive matrix layer, the alkanolamine being a liquid material represented by the following formula: R' R¹ — N \ R^< (wherein R , R and R are each independently a C_2~9 alkyl group substituted with one hydroxyl group, or a hydrogen, at least one of R , R and R being C₂~₉ alkyl substituted with one hydroxyl group). The matrix layer of the transdermal preparation according to the present invention preferably contains 40-90% by weight of the hydrophobic polymeric pressure-sensitive adhesive, 5-60% by weight of the alkanolamine, and 0.5-25% by weight of the active ingredient, based on the total weight of the matrix layer after formation. It is preferred that the thickness of the matrix layer is between 10 μm and 120 μm. Examples of hydrophobic polymeric pressure-sensitive adhesive that can be applied to the formation of the matrix layer of the transdermal preparation according to the present invention include acrylic pressure-sensitive adhesives, rubber-based pressure-sensitive adhesives and silicone pressure-sensitive adhesives. These pressure-sensitive adhesives may be used alone or in combination. The acrylic pressure-sensitive adhesive is preferably a polymer prepared from at least one monomer selected from the group consisting of: acrylic monomers having a Cι._ι₈ alkyl group, including methylmethacrylate, ethylmethacrylate, propylmethacrylate, butylmethacrylate, pentylmethacrylate, hexylmethacrylate, heptylmethacrylate, octylmethacrylate, nonylmethacrylate, decylmethacrylate, undecylmethacrylate, dodecylmethacrylate and tridecylmethacrylate; and acrylic monomers having an acrylic acid, methacrylic acid or hydroxyl group. The rubber-based pressure-sensitive adhesive is preferably at least one adhesive selected from the group consisting of natural rubbers, styrene copolymers, polyisoprenes and polyisobutylenes. The alkanolamines that can be contained in the matrix layer of the transdermal preparation according to the present invention preferably have a melting point of

0-35°C at normal pressure. Specific examples of the alkanolamine include ethanolamine, diethanolamine, triethanolamine, isopropanolamine, diisopropanolamine and triisopropanolamine. These alkanolamines can be used individually or in combination. Korean Patent No. 0332210, which is the prior art using a composition most similar to that used in the present invention, describes the use of tromethamine as an alkanolamine and dimethylsulfoxide as a dissolution assistant in order to improve the solubility and skin absorption of piroxicam. However, since tromethamine is not a liquid, it cannot be dispersed in the matrix layer of the transdermal preparation according to the present invention and thus droplets are not formed. Accordingly, when a drug poorly soluble in an organic solvent applied to a general acrylic pressure- sensitive adhesive is used at a high concentration in a solution type composition, the drug cannot be contained in the matrix layer without occurrence of crystal precipitation. In connection with the use of the alkanolamine as a skin absorption enhance Japanese Patent No. 2004-131495 suggests the use of an alkanolamine and an alkanolamide as skin absorption enhancers of meloxicam. However, poorly soluble drugs, such as meloxicam, cannot be dissolved by the alkanolamine alone in a solution of a pressure-sensitive adhesive using an organic solvent, such as ethylacetate and further the alkanolamine itself is not readily compatible with organic solvents, such as ethylacetate and hexane, and thus a uniform solution cannot be attained, making it impossible to formulate the meloxicam. The active ingredient contained in the matrix layer of the transdermal preparation according to the present invention may be ionic, weakly ionic, or non-ionic. Specific examples of active ingredients that can be applied in the present invention include clonidine, lisinopril, nisoldipine, perindopril, terazosin, terazosin derivatives, e.g., terazosin HCl, alprazolam, amlodipine, amlodipine derivatives, e.g., amlodipine besylate, atrovastatin, auranofin, azatadine, azatadine derivatives, e.g., azatadine maleate, bupivacaine, bupivacaine derivatives, e.g., bupivacaine HCl, buprenorphine, buspione, buspione derivatives, e.g., buspione HCl, cetirizine, cetirizine derivatives, e.g., cetirizine HCl, cerivastatin, cerivastatin derivatives, e.g., cerivastatin Na, clonazepam, colchicine, cyclobenzaprine, cyclobenzaprine HCl, doxazosin, doxazosin derivatives, e.g., doxazosin mesylate, felodipine, fentanyl, sufentanil, finasteride, goserilin, goserilin derivatives, e.g., goserilin acetate, granisetron, granisetron HCl, hexoprenalme, hexoprenalme HCl, indapamide, ketotifen fumarate, leucovorin, leucovorin Ca, levothyroxine, levothyroxine Na, loratadine, metolazone, medroxyprogesterone, medroxyprogesterone acetate, naltrexone, naltrexone HCl, nitroglycerin, norgestrel, nomegestrol, nomegestrol HCl, olanzapine, simvastatin, celecoxib, rofecoxib, meloxicam, tenoxicam, isoxicam, piroxicam, ketoprofen, ketorolac, ketorolac derivatives, flurbiprofen, fenoprofen, naproxen, indomethacin, aceclofenac, diclofenac, isosorbide, isosorbide mononitrate, isosorbide dinitrate, suprofen, lidocaine, hydrocortisone, cortisone, indoprofen, tulobuterol, tulobuterol HCl, tramadol, tramadol HCl, oxybutynin, tolterodine and derivatives thereof, and pharmaceutically acceptable salts thereof. The matrix layer of the transdermal preparation according to the present invention may further include at least one skin absorption enhancer. The skin absorption enhancer is preferably present in an amount of from 0.5 to 15% by weight, based on the total weight of the matrix layer after formation. Examples of skin absorption enhancers that can be used in the present invention include, for example: fatty acids, including linoleic acid, oleic acid, palmitic acid, stearic acid, capric acid and myristic acid; polyhydric alcohols, including propyleneglycol, polyethyleneglycol, dipropyleneglycol, diethyleneglycol and glycerol; surfactants, including Tween 80, labrasol and cremophor; fatty acid alcohols, including oleyl alcohol and stearyl alcohol; fatty acid esters, including isopropyl myristate, propyleneglycol caprylate, propyleneglycol laurate and polyethyleneglycol laurate; and fatty acid alkanolamides, including lauryl dimethanolamide. In order to improve the coat-facilities for the formation of the matrix layer and to improve formulation stability after drying, the matrix layer of the transdermal preparation according to the present invention may further include at least one thickener. It is preferred that the content of the thickener is between 0.5 and 15% by weight, based on the total weight of the matrix layer after formation. Examples of thickeners that can be used in the present invention include polyvinylpyrrolidone, polyethyleneoxide, silicon oxides, aluminum oxides and titanium oxides. The transdermal preparation of the present invention may further comprise a backing layer and a release paper, in addition to the matrix layer having self-adhesive force and containing droplets dispersed therein. In addition, in order to improve adhesion between the backing layer and the matrix layer, the transdermal preparation of the present invention may further comprise a tie-layer. Furthermore, the transdermal preparation of the present invention may further comprise a skin-adhesive layer for improving the adhesion to the skin and increasing the attachment maintenance time

(Figs. 2a~2c). The backing layer is used to maintain the shape of the transdermal preparation according to the present invention, prevent the active ingredient from being lost, and increase the convenience of use. The backing layer is composed of a water-permeable or water-impermeable film made of at least one material selected from the group consisting of polyolefmes (including polyethylene and polypropylene), polyesters, polyurethanes and aluminum; or a fabric or non- woven fabric made of one or more materials selected from the group consisting of polyolefmes, polyesters, nylons and cottons. As the release paper, there can be used a paper or polymer film coated with silicone or fluorinated hydrocarbon resin. The skin adhesive layer and the tie-layer that can be included individually and simultaneously in the transdermal preparation of the present invention preferably contain 70-99% by weight of a polymeric pressure-sensitive adhesive and 1—30% by weight of a pressure-sensitive adhesion improver, which is an additive for improving their pressure-sensitive adhesive properties, on a dry weight basis. It is preferred that both the skin adhesive layer and the tie-layer have a thickness of 10 μm to 100 μm. Examples of polymeric pressure-sensitive adhesives that can be contained in the skin adhesive layer and the tie-layer include acrylic pressure-sensitive adhesives; rubber-based pressure-sensitive adhesives, including natural rubbers, styrene copolymers, polyisoprenes and polyisobutylenes; and silicone pressure-sensitive adhesives, which may be used alone or in combination. Examples of pressure-sensitive adhesion improvers that can be contained in the skin adhesive layer and the tie-layer include fatty acid esters, including isopropyl myristate, propyleneglycol caprylate, propyleneglycol laurate, polyethyleneglycol laurate, propyleneglycol oleate and the like; polyethyleneglycol; polyethyleneglycol- polypropyleneglycol copolymers; polyvinylpyrrolidone; and inorganic fillers, including silicon oxides, aluminum oxides and titanium oxides. These adhesion improvers may be used alone or in combination. In accordance with another aspect of the present invention, there is provided a method for producing the transdermal preparation comprising a polymeric pressure- sensitive adhesive matrix layer wherein the matrix layer is formed by preparing a solution-phase mixture containing an active ingredient, a volatile organic solvent, a polymeric pressure-sensitive adhesive soluble in the volatile organic solvent, a polar aprotic organic solvent and an alkanolamine, and removing the volatile organic solvent from the solution-phase mixture to form droplets containing the active ingredient and uniformly dispersed in the matrix layer. Preferably, the solution-phase mixture contains 0.01—10% by weight of the active ingredient, 5-25% by weight of the polymeric pressure-sensitive adhesive, 20-60%) by weight of the volatile organic solvent, 6-55%) by weight of the polar aprotic organic solvent, and 1~15%> by weight of the alkanolamine. Examples of volatile organic solvents that can be used in the present invention include hydrocarbons, including hexane, heptane, etc.; alcohols, including methanol, ethanol, propanol, etc.; halogenated hydrocarbons, including methylene chloride, chloromethane, etc.; aromatic hydrocarbons, including benzene, toluene, xylene, etc.; and polar organic solvents, including ethylacetate, acetone, tetrahydrofuran, etc., which have a boiling point of 40-110°C under normal pressure. These organic solvents can be used alone or in combination as a mixture of two or more solvents. Polymeric pressure-sensitive adhesives that can be used to form the matrix layer may be in a state wherein the volatile organic solvent is dissolved. Examples of polar aprotic organic solvents that can be used in the present invention include dimethylsulfoxide, dimethylacetamide, dimethylformamide and dimethylisosorbide, which may be used alone or in combination. Of these, solvents having a boiling point higher than 150°C are preferred. Although the polar aprotic organic solvent preferably has a boiling point exceeding 150°C, it is dried to a considerable extent during drying of the volatile organic solvent because it forms an azeotropic mixture with the polar aprotic organic solvent in the course of the formation of the matrix layer of the transdermal preparation according to the present invention. Accordingly, a portion or none of the polar aprotic organic solvent may be contained in the transdermal preparation of the present invention. The polar aprotic organic solvent contained in the solution-phase mixture for the formation of the matrix layer of the transdermal preparation according to the present invention serves to improve low compatibility between the alkanolamine and the volatile organic solvent as main components for the formation of droplets, thus preventing phase separation of the droplet-forming materials in the solution-phase mixture. The use of the polar aprotic organic solvent allows the solution-phase mixture containing the droplet-forming materials to be uniform, thus facilitating spreading, i.e. coating, of the mixture on a release paper for the formation of the matrix layer. Specifically, the matrix layer in which droplets are dispersed is formed by mixing the polymeric pressure-sensitive adhesive dissolved in the volatile solvent, the polar aprotic organic solvent, the alkanolamine and the active ingredient (if necessary, a skin absorption enhancer and/or a thickener), coating the mixture on a film, e.g., a release paper, to a given thickness, and removing the volatile organic solvent by solvent evaporation. The droplets dispersed in the matrix layer are formed because the polymeric pressure-sensitive adhesive constituting the matrix layer shows low compatibility with the active ingredient and the alkanolamine, which form droplets. Removal of the organic solvent from the solution-phase mixture for the formation of the matrix layer leaves the pressure-sensitive adhesive and the non-volatile materials. The remaining polymeric pressure-sensitive adhesive causes phase separation because of low compatibility with the active ingredient and the alkanolamine constituting the droplets. At this time, the polymeric material forms the shape of the matrix layer. The liquid materials composed of active ingredient and the alkanolamine etc. are dispersed in the polymeric matrix layer while forming fine liquid spheres, i.e. droplets (Fig. 1). The matrix layer in which droplets are dispersed can be easily formed by evaporating the volatile organic solvent, can contain large amounts of a variety of active ingredients, independent of the polarity and dissolution characteristics of the active ingredients, and shows superior skin absorption. In addition, despite the presence of large amounts of the liquid materials in the matrix layer, the matrix layer can inhibit the liquid materials from soaking, which is a common problem of matrix layers containing liquid materials in large amounts. The matrix layer in which droplets are dispersed is formed, for example, in accordance with the following procedure. First, the active ingredient, the polymeric pressure-sensitive adhesive, the polar aprotic organic solvent, the alkanolamine, and if necessary, other additives are mixed in accordance with the given composition. Thereafter, the mixture is stirred until it becomes a transparent solution. At this time, the polymeric pressure-sensitive adhesive may be purchased as a solution in the volatile organic solvent. Alternatively, if the polymeric pressure-sensitive adhesive is purchased in a solid state, it is dissolved in the volatile organic solvent and then the resulting solution is used to form the matrix layer of the transdermal preparation according to the present invention. Air bubbles present in the solution composition are removed by stirring. The degassed composition is coated on a polyethylene terephthalate release paper coated with a silicone polymer in such a manner that the thickness of the resulting structure is maintained constant after drying. After coating, the structure is heated in an oven at 60~90°C for 10-30 minutes to remove the organic solvents, thereby achieving the formation of the matrix layer in which droplets are dispersed. The backing layer is laminated to the matrix layer thereby to complete the production of the transdermal preparation comprising the matrix layer in which droplets are dispersed. The amount of the volatile organic solvent used is preferably in the range of from 20% to 60% by weight, based on the weight of the solution-phase mixture prior to removal of the volatile organic solvent. The optimum content of the volatile organic solvent may vary depending on the composition of the solution-phase mixture. The skin adhesive layer and the tie-layer are formed, for example, by the following procedure. First, the polymeric pressure-sensitive adhesive and additives to improve the adhesive properties are mixed in accordance with the particular composition. Thereafter, the resulting mixture is stirred until it becomes a transparent solution. Air bubbles present in the solution are removed by stirring. The degassed solution is coated on a polyethylene terephthalate release paper coated with a silicone polymer in such a manner that the thickness of the resulting structure is maintained constant after drying. After coating, the structure is heated in an oven at 60~90°C for

10-30 minutes to remove the volatile organic solvent, thereby achieving the formation of the skin adhesive layer and the tie-layer. The skin adhesive layer and the tie-layer can be laminated to the matrix layer in which droplets are dispersed. After various transdermal preparations were produced, the adhesiveness and skin absorption of active ingredients were evaluated, and the formation of droplets in matrix layers was observed on the transdermal preparations. Transdermal preparations comprising a polyurethane non-woven fabric as a backing layer were evaluated for adhesiveness. After each sample of the transdermal preparations was attached to the forearm and knee of a healthy man, the attachment maintenance force was identified, and at the same time, the attachment force was measured on the sample using an apparatus. The skin absorption of active ingredients in the transdermal preparation was evaluated by measuring the permeation of the active ingredients by an in- vitro skin absorption test using a Franz diffusion cell. An optical microscope was used to observe the state of droplet dispersion.

Evaluation of physical properties of solvents lg each of ethanolamine, diethanolamine, triethanolamine, isopropanolamine and diisopropanolamine was added to 9g each of ethylacetate, dimethylsulfoxide, ethanol and n-hexane in transparent bottles, covered with caps, and mixed with vigorous stirring for one minute. The mixtures were allowed to stand at room temperature. After one hour, the mixtures were visually observed to determine whether or not phase separation took place.

Table 1: Observation results for compatibility between alkanolamines and organic solvents

In the above table, . "O": Compatible, i.e. no phase separation occurred. . "X": Incompatible, i.e. phase separation occurred.

Brief Explanation of Drawings The above and other objects, features and other advantages of the present invention will be more clearly understood from the following detailed description taken in conjunction with the accompanying drawings, in which: Fig. 1 is an exemplary diagram schematically showing the formation procedure of a matrix layer in which droplets are dispersed: Specifically, 1 represents a state before a volatile solvent is evaporated, i.e. a stable single solution phase, 2 represents a state during drying of the volatile solvent, i.e. a state wherein a liquid phase is separated from a pressure-sensitive adhesive, and 3 represents a state after the volatile solvent is evaporated, i.e. droplets containing an active ingredient are dispersed in a matrix layer; Figs. 2a to 2c are cross-sectional views of transdermal preparations comprising a matrix layer in which droplets are dispersed (1: backing layer, 2: matrix layer, 3: release paper, 4: tie-layer, and 5: skin adhesive layer): Specifically, Fig. 2a show a transdermal preparation comprising a matrix layer in which droplets are dispersed, Fig.

2b show a transdermal preparation comprising a matrix layer in which droplets are dispersed and a tie-layer, and Fig. 2c show a transdermal preparation comprising a matrix layer in which droplets are dispersed, a tie-layer, and a skin adhesive layer; and Figs. 3a and 3b show an optical micrograph (x 200) of a transdermal preparation produced in Comparative Example 1 and that (x 1,000) of a transdermal preparation produced in Example 3, respectively.

Best Mode for Carrying Out the Invention The present invention will now be described in more detail with reference to the following examples, comparative examples and experimental examples. However, these examples are not to be construed as limiting the scope of the invention.

Comparative Examples 1~6 An acrylic pressure-sensitive adhesive (87-2074, manufactured by National starch, U.S.A., solid content: 28%, crosslinked type, main solvent: ethylacetate), meloxicam and dimethylsulfoxide were mixed in accordance with the compositions indicated in Table 2, and stirred until the mixtures became uniform solutions. After the solutions were allowed to stand at room temperature, visual examination was conducted to observe crystallization of the active ingredient. Each of the samples in which no crystal was formed were coated on a release paper so as to have a thickness of 30 μm after drying, and dried at 80°C for 20 minutes. An optical microscope was used to observe whether droplets were formed or not. A polyurethane non-woven fabric as a backing layer was laminated to the dried coating layer to produce transdermal preparations. The transdermal preparation was stored at room temperature for two months, and it was observed whether the liquid droplets of its matrix layer were oozed out the backing layer or not.

Comparative Example 7 28.6g (corresponding to 8g on a dry weight basis) of acrylic pressure-sensitive adhesive (87-2074), 0.5g of meloxicam and 1.5g of diethanolamine were mixed and stirred. Thereafter, it was observed whether or not a crystal of the drug was precipitated and whether or not the phase of the mixture was uniform.

Examples 1-4 and Comparative Examples 8 and 9 An acrylic pressure-sensitive adhesive (87-2074), meloxicam, and a solution of dimethylsulfoxide and dimethanolamine (4/1, (w/w)) were mixed in accordance with the compositions indicated in Table 2, and stirred until the mixtures became uniform solutions. After the solutions were allowed to stand at room temperature for 24 hours, visual examination was conducted to observe crystallization of the active ingredient. Each of the samples in which no crystal was formed was coated on a release paper so as to have a thickness of 30 μm after drying, and dried at 80°C for 20 minutes. An optical microscope was used to observe whether droplets were formed or not. A polyurethane non- woven fabric as a backing layer was laminated to the dried coating layer to produce transdermal preparations. The transdermal preparation was stored at room temperature for two months, and it was observed whether the liquid droplets of its matrix layer were oozed out the backing layer or not.

Examples 5~8 and Comparative Examples 10 and 11 An acrylic pressure-sensitive adhesive (87-2074), meloxicam, and a solution of dimethylsulfoxide, dimethylisosorbide and diethanolamine (3/1/1 (w/w)) were mixed in accordance with the compositions indicated in Table 2, and stirred until the mixtures became uniform solutions. After the solutions were allowed to stand at room temperature for 24 hours, visual examination was conducted to observe crystallization of the active ingredient. Each of the samples in which no crystal was formed was coated on a release paper so as to have a thickness of 30 μm after drying, and dried at

80°C for 20 minutes. An optical microscope was used to observe whether droplets were formed or not. A polyurethane non-woven fabric as a backing layer was laminated to the dried coating layer to produce transdermal preparations. The transdermal preparation was stored at room temperature for two months, and it was observed whether the liquid droplets of its matrix layer were oozed out the backing layer or not. Table 2: Observation results for crystallization of poorly soluble drug in solutions before drying, formation of droplets in matrix layer, and soaking of liquid materials

O": Corresponding phenomenon occurred. '-": No observation made. ^;'X": Corresponding phenomenon did not occur. Examples 9~11 and Comparative Examples 12-14 An acrylic pressure-sensitive adhesive (87-2074), meloxicam, and a solution of dimethylsulfoxide, dimethylisosorbide and diethanolamine (2/2/1 (w/w)) were mixed in accordance with the compositions indicated in Table 3, and stirred until the mixtures became uniform solutions. After the solutions were allowed to stand at room temperature for 24 hours, visual examination was conducted to observe crystallization of the active ingredient. Each of the samples in which no crystal was formed was coated on a release paper so as to have a thickness of 30 μm after drying, and dried at 80°C for 20 minutes. An optical microscope was used to observe whether droplets were formed or not. A polyurethane non-woven fabric as a backing layer was laminated to the dried coating layer to produce transdermal preparations. The transdermal preparation was stored at room temperature for two months, and it was observed whether the liquid droplets of its matrix layer were oozed out the backing layer or not.

Examples 12-14 and Comparative Examples 15-17 An acrylic pressure-sensitive adhesive (Gelva 2883, Solutia, U.S.A., non- crosslinked type, main solvent: ethylacetate), meloxicam, and a solution of dimethylsulfoxide, dimethylisosorbide and diethanolamine (2/2/1 (w/w)) were mixed in accordance with the compositions indicated in Table 3, and then ethylacetate was further added to the mixtures such that the total amount of ethylacetate was the same as that in the previous examples using 87-2074 as an pressure-sensitive adhesive. The resulting mixtures were stirred until they became uniform solutions. After the solutions were allowed to stand at room temperature for 24 hours, visual examination was conducted to observe crystallization of the active ingredient. Each of the samples in which no crystal was formed was coated on a release paper so as to have a thickness of 30 μm after drying, and dried at 80°C for 20 minutes. An optical microscope was used to observe whether droplets were formed or not. A polyurethane non-woven fabric as a backing layer was laminated to the dried coating layer to produce transdermal preparations. The transdermal preparation was stored at room temperature for two months, and it was observed whether the liquid droplets of its matrix layer were oozed out the backing layer or not.

Example 15 6g of polyisobutylene (Oppanol-BlOO, BASF, U.S.A.) was dissolved in hexane to obtain a solution having a solid content of 10%, and then 0.7g of diethanolamine, 1.4g of dimethylsulfoxide, 1.4g of dimethylisosorbide and 0.5g of meloxicam were added to the solution. The mixture was stirred until it became a uniform solution. After the solution was allowed to stand at room temperature for 24 hours, visual examination was conducted to observe crystallization of the active ingredient. Each samples in which no crystal was formed was coated on a release paper so as to have a thickness of 30 μm after drying, and dried at 80°C for 20 minutes. An optical microscope was used to observe whether droplets were formed or not. A polyurethane non-woven fabric as a backing layer was laminated to the dried coating layer to produce a transdermal preparation. The transdermal preparation was stored at room temperature for two months, and it was observed whether the liquid droplets of its matrix layer were oozed out the backing layer or not. Table 3: Observation results for crystallization of poorly soluble drug in solutions before drying, formation of droplets in matrix layer, and soaking of liquid materials

In Table 3, . "O": Corresponding phenomenon occurred. . "-": No observation made. . "X": Corresponding phenomenon did not occur.

Example 16 1 .1g (6g on a dry weight basis) of an acrylic pressure-sensitive adhesive (87- 2196, National starch, U.S.A., solid content: 35%), non-crosslinked type, main solvent: ethylacetate), 1.4g of dimethylsulfoxide, 1.4g of dimethylisosorbide, 0.7g of diethanolamine and 0.5g of tulobuterol were mixed and stirred until the mixture became transparent. After the solution was allowed to stand at room temperature for 24 hours, visual examination was conducted to observe crystallization of the active ingredient. The solution was coated on a release paper so as to have a thickness of 30 μm after drying, and dried at 80°C for 20 minutes. An optical microscope was used to observe whether droplets were formed or not. A polyurethane non-woven fabric as a backing layer was laminated to the dried coating layer to produce a transdermal preparation. The transdermal preparation was stored at room temperature for two months, and it was observed whether the liquid droplets of its matrix layer were oozed out the backing layer or not.

Example 17 15.8g (6g on a dry weight basis) of an acrylic pressure-sensitive adhesive (87- 2976, National starch, U.S.A., solid content: 38%, non-crosslinked type, main solvent: ethylacetate), 1.4g of dimethylsulfoxide, 1.4g of dimethylisosorbide, 0.7g of diethanolamine and 0.5g of water-soluble tulobuterol HCl were mixed and stirred until the mixture became transparent. After the solution was allowed to stand at room temperature for 24 hours, visual examination was conducted to observe crystallization of the active ingredient. The solution was coated on a release paper so as to have a thickness of 30 μm after drying, and dried at 80°C for 20 minutes. An optical microscope was used to observe whether droplets were formed or not. A polyurethane non- woven fabric as a backing layer was laminated to the dried coating layer to produce a transdermal preparation. The transdermal preparation was stored at room temperature for two months, and it was observed whether the liquid droplets of its matrix layer were oozed out the backing layer or not.

Example 18 21.4g (6g on a dry weight basis) of an acrylic pressure-sensitive adhesive (87-

2074), 1.4g of dimethylsulfoxide, 1.4g of dimethylisosorbide, 0.7g of diethanolamine and 0.5g of tramadol were mixed and stirred until the mixture became transparent. After the solution was allowed to stand at room temperature for 24 hours, visual examination was conducted to observe crystallization of the active ingredient. The solution was coated on a release paper so as to have a thickness of 30 μm after drying, and dried at 80°C for 20 minutes. An optical microscope was used to observe whether droplets were formed or not. A polyurethane non-woven fabric as a backing layer was laminated to the dried coating layer to produce a transdermal preparation. The transdermal preparation was stored at room temperature for two months, and it was observed whether the liquid droplets of its matrix layer were oozed out the backing layer or not.

Example 19 21.4g (6g on a dry weight basis) of an acrylic pressure-sensitive adhesive (87- 2074), 1.4g of dimethylsulfoxide, 1.4g of dimethylisosorbide, 0.7g of diethanolamine and 0.5g of tramadol HCl were mixed and stirred until the mixture became transparent. After the solution was allowed to stand at room temperature for 24 hours, visual examination was conducted to observe crystallization of the active ingredient. The solution was coated on a release paper so as to have a thickness of 30 μm after drying, and dried at 80°C for 20 minutes. An optical microscope was used to observe whether droplets were formed or not. A polyurethane non-woven fabric as a backing layer was laminated to the dried coating layer to produce a transdermal preparation. The transdermal preparation was stored at room temperature for two months, and it was observed whether the liquid droplets of its matrix layer were oozed out the backing layer or not.

Example 20 21.4g (6g on a dry weight basis) of an acrylic pressure-sensitive adhesive (87- 2074), 1.4g of dimethylsulfoxide, 1.4g of dimethylisosorbide, 0.7g of diethanolamine and 0.5g of cetirizine were mixed and stirred until the mixture became transparent.

After the solution was allowed to stand at room temperature for 24 hours, visual examination was conducted to observe crystallization of the active ingredient. The solution was coated on a release paper so as to have a thickness of 30 μm after drying, and dried at 80°C for 20 minutes. An optical microscope was used to observe whether droplets were formed or not. A polyurethane non-woven fabric as a backing layer was laminated to the dried coating layer to produce a transdermal preparation. The transdermal preparation was stored at room temperature for two months, and it was observed whether the liquid droplets of its matrix layer were oozed out the backing layer or not.

Example 21 21.4g (6g on a dry weight basis) of an acrylic pressure-sensitive adhesive (87- 2074), 1.4g of dimethylsulfoxide, 1.4g of dimethylisosorbide, 0.7g of diethanolamine and 0.5g of cetirizine HCl were mixed and stirred until the mixture became transparent.

Example 22 21.4g (6g on a dry weight basis) of an acrylic pressure-sensitive adhesive (87- 2074), 1.4g of dimethylsulfoxide, 1.4g of dimethylisosorbide, 0.7g of diethanolamine and 0.5g of oxybutynin were mixed and stirred until the mixture became transparent. After the solution was allowed to stand at room temperature for 24 hours, visual examination was conducted to observe crystallization of the active ingredient. The solution was coated on a release paper so as to have a thickness of 30 μm after drying, and dried at 80°C for 20 minutes. An optical microscope was used to observe whether droplets were formed or not. A polyurethane non- woven fabric as a backing layer was laminated to the dried coating layer to produce a transdermal preparation. The transdermal preparation was stored at room temperature for two months, and it was observed whether the liquid droplets of its matrix layer were oozed out the backing layer or not. Example 23 21.4g (6g on a dry weight basis) of an acrylic pressure-sensitive adhesive (87- 2074), 1.4g of dimethylsulfoxide, 1.4g of dimethylisosorbide, 0.7g of diethanolamine and 0.5g of lidocaine were mixed and stirred until the mixture became transparent. After the solution was allowed to stand at room temperature for 24 hours, visual examination was conducted to observe crystallization of the active ingredient. The solution was coated on a release paper so as to have a thickness of 30 μm after drying, and dried at 80°C for 20 minutes. An optical microscope was used to observe whether droplets were formed or not. A polyurethane non- woven fabric as a backing layer was laminated to the dried coating layer to produce a transdermal preparation. The transdermal preparation was stored at room temperature for two months, and it was observed whether the liquid droplets of its matrix layer were oozed out the backing layer or not.

Example 24 21.4g (6g on a dry weight basis) of an acrylic pressure-sensitive adhesive (87- 2074), 1.4g of dimethylsulfoxide, 1.4g of dimethylisosorbide, 0.7g of diethanolamine and 0.5g of piroxicam were mixed and stirred until the mixture became transparent. After the solution was allowed to stand at room temperature for 24 hours, visual examination was conducted to observe crystallization of the active ingredient. The solution was coated on a release paper so as to have a thickness of 30 μm after drying, and dried at 80°C for 20 minutes. An optical microscope was used to observe whether droplets were formed or not. A polyurethane non- woven fabric as a backing layer was laminated to the dried coating layer to produce a transdermal preparation. The transdermal preparation was stored at room temperature for two months, and it was observed whether the liquid droplets of its matrix layer were oozed out the backing layer or not.

Example 25 21.4g (6g on a dry weight basis) of an acrylic pressure-sensitive adhesive (87- 2074), 1.4g of dimethylsulfoxide, 1.4g of dimethylisosorbide, 0.7g of diethanolamine and 0.5g of ketoprofen were mixed and stirred until the mixture became transparent. After the solution was allowed to stand at room temperature for 24 hours, visual examination was conducted to observe crystallization of the active ingredient. The solution was coated on a release paper so as to have a thickness of 30 μm after drying, and dried at 80°C for 20 minutes. An optical microscope was used to observe whether droplets were formed or not. A polyurethane non-woven fabric as a backing layer was laminated to the dried coating layer to produce a transdermal preparation. The transdermal preparation was stored at room temperature for two months, and it was observed whether the liquid droplets of its matrix layer were oozed out the backing layer or not.

Table 4: Observation results for crystallization of various drugs in solutions before drying, formation of droplets in matrix layer, and soaking of liquid materials

In Table 4, . "O": Corresponding phenomenon occurred. . "-": No observation made. . "X": Corresponding phenomenon did not occur.

Example 26 21.4g (6g on a dry weight basis) of an acrylic pressure-sensitive adhesive (87-

2074), 1.2g of dimethylsulfoxide, 1.2g of dimethylisosorbide, 0.6g of diethanolamine and 0.5g of meloxicam were mixed and stirred until the mixture became transparent.

After the solution was allowed to stand at room temperature for 24 hours, visual examination was conducted to observe crystallization of the active ingredient. The solution was coated on a release paper so as to have a thickness of 60 μm after drying, and dried at 80°C for 20 minutes. An optical microscope was used to observe whether droplets were formed or not. A polyurethane non- woven fabric as a backing layer was laminated to the dried coating layer to produce a transdermal preparation. The transdermal preparation was tested for the content of the drug, in- vitro skin absorption, in-vivo retention, and adhesiveness.

Example 27 32. lg (9g on a dry weight basis) of an acrylic pressure-sensitive adhesive (87- 2074) and lg of isopropyl myristate were mixed, stirred until the mixture became transparent, coated on a release paper so as to have a thickness of 30 μm after drying, and dried at 80°C for 20 minutes to form a skin adhesive layer. The release paper of the transdermal preparation produced in Example 26 was peeled off, and then the skin adhesive layer was laminated thereto to produce a transdermal preparation comprising the skin adhesive layer. The transdermal preparation was tested for in-vitro skin absorption, in-vivo retention, and adhesiveness.

Example 28 32. lg (9g on a dry weight basis) of an acrylic pressure-sensitive adhesive (87- 2074) and lg of isopropyl myristate were mixed, stirred until the mixture became transparent, coated on a release paper so as to have a thickness of 30 μm after drying, and dried at 80°C for 20 minutes to form a tie-layer. A polyurethane non-woven fabric as a backing layer was laminated to the tie-layer. After completion of the lamination, the release paper was peeled off. The resulting structure was laminated to a pressure- sensitive adhesive layer formed in the same manner as in Example 26 to produce a transdermal preparation comprising the tie layer. The transdermal preparation was tested for in-vitro skin absorption, in-vivo retention, and adhesiveness.

Example 29 21.4g (6g on a dry weight basis) of an acrylic pressure-sensitive adhesive (87- 2074), 1.2g of dimethylsulfoxide, 1.2g of dimethylisosorbide, 0.6g of diethanolamine and 1.5g of piroxicam were mixed and stirred until the mixture became transparent.

After the solution was allowed to stand at room temperature for 24 hours, visual examination was conducted to observe crystallization of the active ingredient. The solution was coated on a release paper so as to have a thickness of 60 μm after drying, and dried at 80°C for 20 minutes. An optical microscope was used to observe whether droplets were formed or not. A polyurethane non-woven fabric as a backing layer was laminated to the dried coating layer to produce a transdermal preparation. The transdermal preparation was tested for the content of the drug, in-vitro skin absorption, in-vivo retention, and adhesiveness.

Example 30 21.4g (6g on a dry weight basis) of an acrylic pressure-sensitive adhesive (87- 2074), 1.2g of dimethylsulfoxide, 1.2g of dimethylisosorbide, 0.6g of diethanolamine and 0.5g of ketoprofen were mixed and stirred until the mixture became transparent. After the solution was allowed to stand at room temperature for 24 hours, visual examination was conducted to observe crystallization of the active ingredient. The solution was coated on a release paper so as to have a thickness of 60 μm after drying, and dried at 80°C for 20 minutes. An optical microscope was used to observe whether droplets were formed or not. A polyurethane non-woven fabric as a backing layer was laminated to the dried coating layer to produce a transdermal preparation. The transdermal preparation was tested for the content of the drug, in-vitro skin absorption, in-vivo retention, and adhesiveness.

Example 31 23.6g (6.6g on a dry weight basis) of an acrylic pressure-sensitive adhesive (87- 2074), 5.6g of dimethylsulfoxide, 1.4g of diethanolamine, 0.5g of meloxicam and lg of propyleneglycolmonocaprylate were mixed and stirred until the mixture became transparent. After the solution was allowed to stand at room temperature for 24 hours, visual examination was conducted to observe crystallization of the active ingredient. The solution was coated on a release paper so as to have a thickness of 60 μm after drying, and dried at 80°C for 20 minutes. An optical microscope was used to observe whether droplets were formed or not. A polyurethane non-woven fabric as a backing layer was laminated to the dried coating layer to produce a transdermal preparation. The transdermal preparation was tested for the content of the drug, in-vitro skin absorption, in-vivo retention, and adhesiveness.

Example 32 23.6g (6.6g on a dry weight basis) of an acrylic pressure-sensitive adhesive (87- 2074), 5.6g of dimethylsulfoxide, 1.4g of diethanolamine, 0.5g of meloxicam, lg of propyleneglycolmonocaprylate and 0.5g of polyvinylpyrrolidone were mixed and stirred until the mixture became transparent. After the solution was allowed to stand at room temperature for 24 hours, visual examination was conducted to observe crystallization of the active ingredient. The solution was coated on a release paper so as to have a thickness of 60 μm after drying, and dried at 80°C for 20 minutes. An optical microscope was used to observe whether droplets were formed or not. A polyurethane non- woven fabric as a backing layer was laminated to the dried coating layer to produce a transdermal preparation. The transdermal preparation was tested for the content of the drug, in-vitro skin absorption, in-vivo retention, and adhesiveness.

Experimental Example 1: Measurement of in-vitro skin absorption In-vitro skin absoφtion test was conducted using a Franz diffusion cell. First, a part of the skin of a hairless mouse (female, 6-7 weeks) was excised, cut to a square size of 2 x 2 cm , and lifted on the Franz diffusion cell such that the dermis was located in a direction facing a receptor of the Franz diffusion cell and the horny layer was located in a direction opposite to the receptor. A matrix sample was cut to a square size of 1.5 x 1.5 cm , and attached and fixed to the skin. A phosphate buffer solution (pH 7.4) was filled into the receptor of the Franz diffusion cell. The experiment was performed in such a way that the phosphate buffer solution was completely changed with another fresh buffer solution with stirring at 600 rpm at 1, 3, 5, 7, 12 and 24 hours. The content of the active ingredient in the phosphate buffer solution sampled from the receptor was quantitatively analyzed by high performance liquid chromatography (HPLC). Experimental Example 2: Measurement of content of active ingredient The content of active ingredients in the matrix type transdermal preparations was determined by cutting each of the transdermal preparations to a size of 2 x 2 cm², extracting the preparation with 100 ml of methanol, and quantitatively analyzing the extract by high performance liquid chromatography (HPLC).

Experimental Example 3: Quantitative analysis High performance liquid chromatography (HPLC) for quantitative analysis was employed under the different analysis conditions according to the kind of the active ingredients. Meloxicam Mobile phase: Acetonitrile/0.05M aqueous sodium acetate solution (pH 3.3) = 500/500 (v/v) Stationary phase: Luna 5μ CI 8(2) (Phenomenex, 150 x 4.60 mm, 5μ) Flow rate of mobile phase: 1 ml/min. Measurement wavelength: 355 nm UV

Ketoprofen Mobile phase: Acetonitrile/methanol/distilled water = 400/300/300 (v/v) Stationary phase: Luna 5μ C18(2) (Phenomenex, 150 x 4.60 mm, 5μ) Flow rate of mobile phase: 1 ml/min. Measurement wavelength: 254 nm UV Piroxicam Mobile phase: 0.05M Diammonium phosphate/acetonitrile/ methanol = 500/100/400 (v/v/v) Stationary phase: Luna 5μ C18(2) (Phenomenex, 150 x 4.60 mm, 5μ) Flow rate of mobile phase: 1 ml/min. Measurement wavelength: 366 nm UV Calibration curve used for quantitative analysis was determined in accordance with the following procedure. The active ingredient with given weight was dissolved in methanol to prepare a reference solution. A chromatograph of the solution was obtained by HPLC analysis. The calibration curve was given by the area under the chromatograph.

Experimental Example 4: Adhesiveness test Each of the transdermal preparations was cut to a size of 4 x 4 cm , attached to the forearm and knee of a healthy man, and removed 24 hours later. The satisfaction degree was estimated by answering a questiomiaire about the adhesive force. The results are summarized in Table 5.

Table 5: Measurement results for content of active ingredients in samples, in-vitro skin absorption, and adhesiveness

Experimental Example 5: Observation by optical microscopy To confirm the shape and size of droplets dispersed in the matrix layers, the matrix layers were observed using an optical microscope. The shape and size were observed at a magnification of l,000x by an immersion method using cedar oil. The optical micrographs of the transdermal preparations produced in Comparative Example 1 and Example 3 are shown in Figs. 3a and 3b. Experimental Example 6: Adhesiveness test 2 (measurement of 180° peel adhesion) To observe the adhesive force of the matrix type transdermal preparations, 180° peel adhesion was measured using a TA-XT2iHR (manufactured by Stable micro system Co.). A substrate used for the measurement was made of stainless steel (Cheminstrument Co.). The test was conducted under the following measurement conditions. Sample size: 10 cm x 2.5 cm Interval: 10-40 mm Velocity: 2.0 mm/s Temperature: 25°C

Experimental Example 7: Stability test Each of the transdermal preparations was cut to a size of 7 x 7 cm², placed in a paper envelope internally coated with aluminum, and sealed. Tests shown in Experimental Examples 3 and 6 were conducted, crystal precipitation of the drugs was observed, and changes in appearance according to the changes in area were evaluated once every two months while the samples were stored at 40°C for 6 months. Table 6 shows the stability test results on the transdermal preparation produced in Example 32.

Table 6: stability test results on transdermal preparation at 40°C for six months

Industrial Applicability As apparent from the above description, the matrix type transdermal preparation of the present invention can be applied to patches and plasters. Since the transdermal preparation of the present invention comprises a polymeric matrix layer in which droplets containing an active ingredient are uniformly dispersed, it shows superior skin absoφtion. In addition, the transdermal preparation of the present invention can be produced in a simple manner, and can contain an active ingredient at a high concentration, irrespective of the solubility of the active ingredient. Accordingly, the transdermal preparation of the present invention can be applied to a variety of drugs. Furthermore, the present invention provides a method for producing the transdermal preparation.

Claims

1. A transdermal preparation comprising a hydrophobic polymeric pressure- sensitive adhesive matrix layer wherein droplets, containing an active ingredient and an alkanolamine, are uniformly dispersed in the hydrophobic polymeric pressure-sensitive adhesive matrix layer and the alkanolamine is a liquid material represented by the following formula: ' / R¹ N \ R³ (wherein R¹, R² and R³ are each independently a C₂~₉ alkyl group substituted with one hydroxyl group, or a hydrogen, at least one of R , R and R being C_2~9 alkyl substituted with one hydroxyl group).

2. The transdermal preparation according to claim 1, wherein the hydrophobic polymeric pressure-sensitive adhesive is present in an amount of 40-90%) by weight, the alkanolamine is present in an amount of 5-60% by weight, and the active ingredient is present in an amount of 0.5-25%) by weight, based on the total weight of the matrix layer after its formation.

3. The transdermal preparation according to claim 1, wherein the matrix layer has a thickness of from 10 μm to 120 μm.

4. The transdermal preparation according to claim 1, wherein the hydrophobic polymeric pressure-sensitive adhesive is at least one adhesive selected from the group consisting of acrylic pressure-sensitive adhesives, rubber-based pressure-sensitive adhesives and silicone pressure-sensitive adhesives.

5. The transdermal preparation according to claim 4, wherein the acrylic pressure-sensitive adhesive is a polymer prepared from at least one monomer selected from the group consisting of acrylic monomers having a Cι~₁₈ alkyl group and acrylic monomers having an acrylic acid, methacrylic acid or hydroxyl group; and the rubber-based pressure-sensitive adhesive is at least one adhesive selected from the group consisting of natural rubbers, styrene copolymers, polyisoprenes and polyisobutylenes.

6. The transdermal preparation according to claim 1, wherein the alkanolamine is at least one compound selected from the group consisting of monoethanolamine, diethanolamine, triethanolamine, monoisopropanolamine, diisopropanolamine and triisopropanolamine .

7. The transdermal preparation according to claim 1, wherein the active ingredient is selected from the group consisting of clonidine, lisinopril, nisoldipine, perindopril, terazosin, terazosin HCl, alprazolam, amlodipine, amlodipine besylate, atrovastatin, auranofin, azatadine, azatadine maleate, bupivacaine, bupivacaine HCl, buprenoφhine, buspione, buspione HCl, cetirizine, cetirizine HCl, cerivastatin, cerivastatin Na, clonazepam, colchicine, cyclobenzaprine, cyclobenzaprine HCl, doxazosin, doxazosin mesylate, felodipine, fentanyl, sufentanil, finasteride, goserilin, goserilin acetate, granisetron, granisetron HCl, hexoprenalme, hexoprenaline HCl, indapamide, ketotifen fumarate, leucovorin, leucovorin Ca, levothyroxine, levothyroxine Na, loratadine, metolazone, medroxyprogesterone, medroxyprogesterone acetate, naltrexone, naltrexone HCl, nitroglycerin, norgestrel, nomegestrol, nomegestrol HCl, olanzapine, simvastatin, celecoxib, rofecoxib, meloxicam, tenoxicam, isoxicam, piroxicam, ketoprofen, ketorolac, flurbiprofen, fenoprofen, naproxen, indomethacin, aceclofenac, diclofenac, isosorbide, isosorbide mononitrate, isosorbide dinitrate, suprofen, lidocaine, hydrocortisone, cortisone, indoprofen, tulobuterol, tulobuterol HCl, tramadol, tramadol HCl, oxybutynin, tolterodine and derivatives thereof, and pharmaceutically acceptable salts thereof.

8. The transdermal preparation according to claim 1, wherein the matrix layer further includes at least one skin absoφtion enhancer.

9. The transdermal preparation according to claim 8, wherein the skin absorption enhancer is at least one material selected from the group consisting of fatty acids, polyhydric alcohols, surfactants, fatty acid alcohols, fatty acid esters and fatty acid alkanolamides, and is present in an amount of from 0.5 to 15% by weight, based on the total weight of the matrix layer after its formation.

10. The transdermal preparation according to claim 9, wherein the fatty acid is at least one acid selected from the group consisting of linoleic acid, oleic acid, palmitic acid, stearic acid, capric acid and myristic acid; the polyhydric alcohol is at least one alcohol selected from the group consisting of propyleneglycol, polyethyleneglycol, dipropyleneglycol, diethyleneglycol and glycerol; the surfactant is at least one material selected from the group consisting of

Tween 80, Labrasol and Cremophor; the fatty acid alcohol is at least one material selected from the group consisting of oleyl alcohol and stearyl alcohol; the fatty acid ester is at least one ester selected from the group consisting of isopropyl myristate, propyleneglycol caprylate, propyleneglycol laurate and polyethyleneglycol laurate; and the fatty acid alkanolamide is lauryl dimethanolamide.

11. The transdermal preparation according to claim 1 or 8, wherein the matrix layer further includes at least one thickener.

12. The transdermal preparation according to claim 11, wherein the thickener is at least one compound selected from the group consisting of polyvinylpyrrolidone, polyethyleneoxide, silicon oxides, aluminum oxides and titanium oxides, and is present in an amount of from 0.5% to 15%> by weight based on the total weight of the matrix layer after its formation.

13. The transdermal preparation according to claim 1, further comprising a backing layer and a release paper.

14. The transdermal preparation according to claim 13, wherein the backing layer is composed of a water-permeable or water-impermeable film made of at least one material selected from the group consisting of polyolefines, polyesters, polyurethanes and aluminum; or a fabric or a non- woven fabric made of at least one materials selected from the group consisting of polyolefines, polyesters, nylons and cottons.

15. The transdermal preparation according to claim 13, wherein the release paper is a paper or a polymer film coated with silicone or fluorinated hydrocarbon resin.

16. The transdermal preparation according to claim 13, further comprising at least one layer selected from the group consisting of a tie-layer and a skin-adhesive layer.

17. The transdermal preparation according to claim 16, wherein the tie-layer contains 70-99% by weight of a polymeric pressure-sensitive adhesive and 1-30% by weight of a pressure-sensitive adhesion improver on a dry weight basis, and has a thickness of 10 μm to 100 μm; and the skin adhesive layer contains 70-99% by weight of a polymeric pressure- sensitive adhesive and 1-30% by weight of a pressure-sensitive adhesion improver on a dry weight basis, and has a thickness of 10 μm to 100 μm.

18. The transdermal preparation according to claim 17, wherein the polymeric pressure-sensitive adhesive is at least one adhesive selected from the group consisting of acrylic pressure-sensitive adhesives, rubber-based pressure-sensitive adhesives and silicone pressure-sensitive adhesives; and the pressure-sensitive adhesion improver is at least one material selected from the group consisting of fatty acid esters, polyethyleneglycol, polyethyleneglycol- polypropyleneglycol copolymers, polyvinylpyrrolidone and inorganic fillers.

19. The transdermal preparation according to claim 18, wherein the rubber- based pressure-sensitive adhesive is at least one adhesive selected from the group consisting of natural rubbers, styrene copolymers, polyisoprenes and polyisobutylenes; the fatty acid ester is at least one ester selected from the group consisting of isopropyl myristate, propyleneglycol caprylate, propyleneglycol laurate, polyethyleneglycol laurate and propyleneglycol oleate; and the inorganic filler is at least one material selected from the group consisting of silicon oxides, aluminum oxides and titanium oxides.

20. A method for producing the transdermal preparation according to claim 1, wherein the matrix layer is produced by preparing a solution-phase mixture containing an active ingredient, a volatile organic solvent, a polymeric pressure-sensitive adhesive soluble in the volatile organic solvent, a polar aprotic organic solvent and an alkanolamine, and then by removing the volatile organic solvent from the solution-phase mixture thereby to form droplets, containing the active ingredient, dispersed uniformly in the matrix layer

21. The method according to claim 20, wherein the solution-phase mixture contains 0.01-10% by weight of the active ingredient, 5-25% by weight of the polymeric pressure-sensitive adhesive, 20~60%> by weight of the volatile organic solvent, 6-55%) by weight of the polar aprotic organic solvent, and 1-15% by weight of the alkanolamine.

22. The method according to claim 20, wherein the volatile organic solvent is at least one solvent selected from the group consisting of hydrocarbons, alcohols, halogenated hydrocarbons, aromatic hydrocarbons and polar organic solvents, and has a boiling point of 40-110°C under atmospheric pressure.

23. The method according to claim 22, wherein the volatile organic solvent is at least one solvent selected from the group consisting of ethylacetate, hexane, heptane, methanol, ethanol, propanol, methylene chloride, chloromethane, benzene, toluene, xylene, acetone and tetrahydrofuran.

24. The method according to claim 20, wherein the polar aprotic organic solvent is at least one solvent selected from the group consisting of dimethylsulfoxide, dimethylacetamide, dimethylformamide and dimethylisosorbide.