WO2008007926A1

WO2008007926A1 - Transdermal preparations containing hydrophobic non-steroidal anti-inflammatory drugs

Info

Publication number: WO2008007926A1
Application number: PCT/KR2007/003413
Authority: WO
Inventors: Yang-Gyu Choi; Han-Moe Ki; Young-Chang Ah; Jung-Ju Kim
Original assignee: Amorepacific Corporation; Pacific Phamaceutical Co., Ltd.
Priority date: 2006-07-14
Filing date: 2007-07-13
Publication date: 2008-01-17
Also published as: KR20080006960A

Abstract

A transdermal preparation employing the interaction between the acrylic adhesive system containing a hydrophilic monomer and the hydrophobic adhesive layer, the hydrophilic monomer allowing that the concentration of the drug in the patch preparation is maintained to be the saturation concentration and the hydrophobic adhesive layer allowing the prevention of loss of the water absorbed from the skin is disclosed.

Description

TRANSDERMAL PREPARATIONS CONTAINING HYDROPHOBIC NON-STEROIDAL ANTI-INFLAMMATORY

DRUGS

Technical Field

[1] The present invention relates to a transdermal preparation allowing high- concentrated hydrophobic drugs to be continuously permeated into the skin. More specifically, the invention relates to a patch of a transdermal preparation containing non-steroidal anti-inflammatory drugs, in particular one of ketoprofen, diclofenac, flurbiprofen, felbinac, aceclofenac and loxoprofen. Particularly, the invention relates to a patch-type arthritis treatment agent. Background Art

[2] Currently, for the purpose of treating the arthritis, a variety of transdermal preparations containing non-steroidal anti-inflammatory drugs such as ketoprofen, diclofenac, flurbiprofen, felbinac, piroxicam and the like were developed and are marketed. Many researches on the transdermal preparations are carried out to meet the market needs. Main research fields include a research on the permeation enhancement of drug for more rapid and effective treatment, a research on the decrease of skin trouble caused by a patch type product, a research on adhesive substances not causing pains when the patch is detached after use, and the like.

[3] The typical transdermal preparations containing the non-steroidal anti-inflammatory drugs, which are used for the purpose of the arthritis treatment, can directly deliver the drug in an inflamed area. The transdermal preparations directly deliver the drug to a lesion to maintain a concentration in the synovial fluid, on which the drugs act, at 1/5 ~ 1/2 of a level in the oral administration. Accordingly, the transdermal preparations exhibit the effects similar to the oral administration and the drug concentration in the blood is lower by about 100 times than the oral preparations, so that they do not cause the side effects such as gastrointestinal tract disorder. Owing to such advantages, the transdermal preparations containing the non-steroidal anti-inflammatory drugs are widely used. However, they are still considered to have the efficacies lower than the oral preparations. Therefore, if a concentration of drug in the lesion such as synovial fluid can be increased as much as the oral preparation by improving a drug permeation, it is possible to obtain a treatment effect same as that of the oral preparation without causing the side effects of the non-steroidal anti-inflammatory drugs such as gastrointestinal tract disorder, which is expected to be more effective for the arthritis treatment. [4] In the transdermal preparation fields of a drug-in-adhesive type, as technology for increasing the drug permeation, it is widely used a technology for using permeation enhancer to increase diffusion and distribution of the drug, containing the drug at a saturation concentration in a system to increase a chemical activity of the drug, or hydrating the skin to lower barrier function of skin for the drug, thereby easily diffusing the drug.

[5] As a specific example, a Korean Patent No. 10-0213465 discloses a multi-layered patch for obtaining high drug permeability. The patch uses an elastic backing and comprises an adhesive layer for adhering the backing and a drug layer, the drug layer containing the drug of a high concentration adding polyvinyl pyrrolidone or ethylene- vinyl acetate and an adhesive layer for providing an adhesive power and controlling a drug release, thereby obtaining high drug permeability and the skin adhesive power. However, it is not easy to produce such patch because it has a multi-layered structure. In addition, since the adhesive layers are separately provided to give the adhesive power, the drug permeation is slow, thereby exhibiting the limited effect only.

[6] A Korean Patent No. 10-0188180 discloses technologies for increasing the drug permeability into the skin using multi-layered structure that is composed acrylic adhesives having difference water-absorption capacity and each acrylic adhesives layer can be changed drug solubility by water discharged from skin.

[7] According to one technology suggested, plural adhesive layers consisting of acrylic adhesives resins having different water-absorption capacity are adapted to contain the drug and an acrylic adhesive layer having a low water-absorption capacity is located at the lowest layer. Thereby, although the content of the drug is decreased as the initial drug is permeated into the skin, the water moves to the upper layer and decrease the drug solubility in the upper acrylic adhesive layer, so that the drug is supplied to the lowest layer by concentration gradation of drug. As a result, the drugs are continuously delivered to the skin.

[8] According to another technology suggested in the above patent, the acrylic adhesive layer having a high water-absorption capacity is located at the lowest layer, the drug of a high concentration is initially permeated and the drug permeation is decreased as time goes by, so that the drug is constantly permeated into skin. According to the first technology, since only the acrylic adhesive layers having similar solubility for the drug are used, a concentration difference of drug between acrylic adhesives layers is small, so that a desired effect is little. In addition, the concentration difference of drug in the adhesive layers is decreased during long time storage, so that a desired effect cannot be achieved. According to the second technology, when the acrylic adhesive layer having a high water-absorption capacity is located at the lowest layer, the hydrophobic drug contained in the upper layer is not smoothly moved to lower layer, so that the high drug permeability cannot be obtained.

[9] In addition, U.S. Patent No. 6,676,962 discloses a transdermal preparation containing a non-steroidal anti-inflammatory drug having a carboxyl group as an active material, having a backing which is inactive for the active agent also has unidirectional or dual directional flexibility and using an acrylic adhesives base. In particular, according to the technology suggested, in consideration of use convenience, the flexible woven-fabric, knitted fabric, non-woven fabric or flexible foam (PE, PVC, EVA) as a backing is adopted so that it is easily used in the joint region and it is possible to obtain the higher drug permeability when the foam is adopted.

[10] According to U.S. Patent No. 5,702,720, the polyvinyl pyrrolidone which is hy- drophilic polymer is used so that the water, which is exuded from the skin, is easily discharged to the outside and the physical properties of the patch are not deteriorated. In particular, the polyvinyl pyrrolidone, which is hydrophilic polymer, is used to decrease the pain the pain caused when the patch is detachedand increase the cohesion to reduce the residual of adhesives on the skin after detachment of patch

[11] According to Korean Patent Un-examined Publication No.2002-035451 disclosing a transdermal preparation containing the diclofenac diethyl ammonium, the polyvinyl pyrrolidone, which is hydrophilic polymer, is used to absorb the water discharged from the skin, such as sweat, thereby enabling the patch not to be easily detached during the attachment and preventing the adhesive from being remained when detaching the patch.

[12] In addition to the prior arts as mentioned above, many technologies are disclosed in the fields. However, it is still needed a patch achieving the high permeability of drug in a short time and maintaining the high permeability of drug to maximize the treatment effect, increasing an compliance of a patient due to an optimized adhesion property and enabling the patch to be easily produced. The invention is provided to meet the requirements.

Disclosure of Invention Technical Problem

[13] As described above, an object of one embodiment of the invention is to deliver the hydrophobic drug through the skin in a quick and effective method. Typically, the drug permeation through the skin exhibits a peak at a predetermined level or more and then gradually decreased due to loss of the drug. In order to solve the problem, an object of one embodiment of the invention is to provide a transdermal preparation enabling high amount of drug to be continuously permeated through the skin until a patch containing the drugs is detached from the skin.

[14] Another object of one embodiment of the invention is to provide a transdermal preparation comprising a drug containing adhesives layer. [15] Still another object of one embodiment of the invention is to provide a transdermal preparation having skin irritation minimized. [16] Still yet another object of one embodiment of the invention is to maintain an optimized adhesion until a transdermal preparation is detached from the skin. [17] In addition, an object of one embodiment of the invention is to directly deliver a non-steroidal anti-inflammatory agent to a lesion in a high concentration, thereby quickly and effectively treating the arthritis. [18]

Technical Solution [19] In order to achieve the above objects, there is provided a transdermal preparation of a layered structure for a hydrophobic drug, the preparation comprising: [20] a backing layer (1) located at the highest part of the layered structure and having a flexibility; [21] a hydrophobic adhesive layer (2) placed below the backing layer and containing a hydrophobic adhesives to prevent water absorbed from skin from being lost and the drug from being reverse-transferred; and [22] a drug adhesive layer (3) for adhering the transdermal preparation to the skin, which is placed below the hydrophobic adhesive layer and contains a hydrophobic drug and an acrylic adhesive, the acrylic adhesive comprising a hydrophilic monomer for promoting the water absorption from the skin. [23] [24] The transdermal preparation according to a preferable embodiment of the invention further comprisese a release layer (4) placed below the drug adhesive layer, protecting the drug adhesive layer until the transdermal preparation is used and released when the preparation is used.

Advantageous Effects

[25] When the transdermal preparation of the invention is used, it is possible to provide a transdermal preparation capable of enabling the hydrophobic drug of a high concentration to be continuously absorbed through the skin until the patch is detached from the skin. The transdermal preparation of the invention can minimize the skin irritation and provides a sufficient adhesion while the preparation is attached to the skin and the drug takes effect. Brief Description of the Drawings

[26]

[27] FIG. 1 is a schematic view showing a layered structure of a transdermal preparation according to an embodiment of the invention. [28]

Best Mode for Carrying Out the Invention

[29] Hereinafter, a preferred embodiment of the present invention will be described with reference to the accompanying drawings. In the following description of the present invention, a detailed description of known functions and configurations incorporated herein will be omitted when it may make the subject matter of the present invention rather unclear.

[30] Fig. 1 shows a layered structure of a transdermal preparation according to an embodiment of the invention. A detailed description of each layer is as follows.

[31] [structure of the transdermal preparation of the invention]

[32] 1) backing layer (1): it should have a flexibility for applying to a stretchable joint region.

[33] 2) hydrophobic adhesive layer (2): it is an adhesive layer having an liphophilic property and prevents the water exuded from the skin from volatilizing to maintain the water in the drug layer, thereby maintaining a chemical activity of the drug to the maximum.

[34] 3) drug adhesive layer (3): it provide an adhesion, comprises a drug, an acrylic adhesives containing N-vinylpyrrolidone as a monomer having a high solubility for the drug, a permeation enhancer, a physical property adjuster (excipient, etc.) and the like.

[35] 4) release layer (4): it is provided to protect the drug adhesive layer 3 until the transdermal preparation is used.

[36]

[37]

[38] 1. backing layer (1)

[39] The transdermal preparation containing the non-steroidal anti-inflammatory agent is used to treat musculoskeletal related diseases such as rheumatism, arthritis and the like. In particular, since the preparation is mainly used for the moveable joint region, a backing having a sufficient flexibility is used. The backing having the flexibility includes, but not limited to, woven or non- woven fabric of polyester based, polyvinyl based, urethane and cotton raw materials.

[40] The transdermal preparation of the invention comprises the backing layer 1 made of the woven or non- woven fabric having a unidirectional or dual directional flexibility. The woven fabric consists of a polyester based resin, urethane based resin or cotton, and the non- woven fabric consists of the polyester based resin or urethane based resin. The woven or non- woven fabric made of the polyester based, polyurethane based or cotton raw material has a flexibility. However, since it has no occlusion effect, it is difficult to obtain an effect of preventing the drug from being reverse-absorbed and a thermal insulation effect. The transdermal preparation of the invention comprises the hydrophobic adhesive layer 2 below the backing layer 1. The hydrophobic adhesive layer 2 provides the occlusion effect, so that the above problems can be solved.

[41]

[42] 2. hydrophobic adhesive layer 2

[43] As described above, in the transdermal preparation of the invention, the hydrophobic adhesive layer 2 serves to complement the disadvantage of the backing layer 1 having the flexibility having no occlusion effect. In order to provide the occlusion effect, the hydrophobic adhesive layer 2 preferably comprises a polyisobutylene, styrene-isoprene-styrene based, or styrene-butadiene-styrene based adhesive. Hy- drophobicity of adhesive layer 2 can also prevent the drug form being resverse- transferred to the backing layer 1.

[44]

[45] As a more important function, the hydrophobic adhesive layer 2 prevents the water, which has been absorbed in the drug adhesive layer 3 from the skin, from exuding to the outside, thereby maintaining the chemical activity of the drug in the drug adhesive layer 3 to the maximum. The drug adhesive layer 3 contains the drug in a high concentration before it is applied to the skin. From the application to the skin, as the water exuded from the skin is introduced into the drug adhesive layer 3, the solubility of the hydrophobic drug is slowly decreased, so that the drug is continuously present at the saturation concentration in the drug adhesive layer 3, thereby maintaining the drug permeation into the skin to the highest. Meanwhile, if the water introduced from the skin is discharged to the outside through the drug adhesive layer 3, the above effect cannot be obtained. Accordingly, in order to prevent this, the hydrophobic adhesive layer 2 is placed on the drug adhesive layer 3, thereby preventing the water from being discharged to the outside. Preferably, the hydrophobic adhesive layer 2 contains an adhesive having a very low solubility (less than 3%) for the drug, so as to prevent a back-diffusion of the drug. In other words, the above function of the drug adhesive layer 3 can be achieved only when the hydrophobic adhesive layer 2 prevents the water exudation.

[46] Since the hydrophobic adhesive layer 2 also has a function of keeping the attachment part warm, it improves the blood circulation and the drug absorption. Since the polyisobutylene (PIB) based adhesive, styrene-isoprene-styrene (SIS) or styrene- butadiene-styrene (SBS) based adhesive and the like can be adapted to the movement of the joint region without disturbing the movement of the backing layer 1, it is preferable as an adhesive constituting the hydrophobic adhesive layer 2.

[47] The adhesive, which can be used in the hydrophobic adhesive layer 2, has a basic structure made of one selected from polyisobutylene such as Vistanex MMLlOO (Mv 1,200,000) and MML 120 (Mv 1,600,000) available from an Exxon-Mobile company, and Oppanol BlOSFN (Mv 40,000), B12SNF (Mv 55,000), B13SFN (Mv 65,000) and B15SFN (Mv 85,000) available from a BASF company, styrene-isoprene-styrene copolymer such as Kraton D1107, D1112 and Dl 113 (Shell Chemicals) and styrene- butadiene-styrene copolymer such as Kraton DI lOl and Dl 102, and can additively contain a liquid phase component such as polymer resin, liquid paraffin and the like so as to complement the adhesion. A thickness of the hydrophobic adhesive layer 2 is preferably 40-100 D. When the thickness of the coating of the hydrophobic adhesive layer 2 is less than 40 D, the effect of suppressing the water discharge is low, and when the thickness is greater than 100 D, the use feeling to the skin is low.

[48]

[49] 3. drug adhesive layer 3

[50] In the transdermal preparation for delivering the drug through the skin, an amount of the drug to be permeated can be expressed by a following equation 1.

[51] <equation 1>

[52] d_Q _ KC_MDA dr L

[53] where, dQ/dT: an amount of the drug permeated through the skin,

[54] K: a distribution coefficient of the drug,

[55] D: a diffusion coefficient of the drug,

[56] C : a drug concentration in the patch,

M

[57] A: an area of the patch, and

[58] L: a thickness of the skin.

[59] The distribution coefficient K of the equation 1 can be expressed by a ratio of a saturation concentration (C ) in the skin and a saturation concentration (C ) of the

SS SM drug in the patch, i.e., equation 2. [60] <equation 2>

[61]

[62] When the equation 2 is substituted for the equation 1, a following equation 3 is obtained.

[63] <equation 3>

[64] dQ _ &AL _ss C _M

ell L C _SM

[65] The skin permeation enhancer deteriorates a barrier function of the skin to diffuse the drug more easily, or increase a solubility of the drug in the skin to distribute the more drug to the skin, thereby increasing the drug permeation. In addition, it is possible to match a concentration of the drug in the patch to the saturation concentration, i.e., to make C close to C , thereby maximizing the drug permeation. However, as can be analogized from the equation 3, although the drug is under saturated state in the initial state of the patch, when the patch is attached to the skin and the drug begins to be permeated, the drug concentration in the patch is gradually decreased, so that the drug permeation is lowered as time goes by.

[66] Accordingly, in order to maintain the drug permeation (released amount of the drug from the patch) to the skin from the patch containing the non-steroidal antiinflammatory drug to the highest level during the attachment, the inventors attempted to maintain the drug concentration in the patch at the saturation concentration for the duration of an entire use.

[67] According to the transdermal preparation of the invention, the drug adhesive layer comprises a drug, a permeation enhancer and an acrylic adhesive having a hydrophilic part. Here, the hydrophilic acrylic adhesive contains a hydrophilic monomer such as N- vinylpyrrollidone in addition to monomers to be contained in a typical acrylic adhesive. Therefore, even though the drug adhesive layer is hydrophilic, it is able to contain a large amount of drugs such as ketoprofen, diclofenac, flurbiprofen, felbinac, aceclofenac and loxoprofen. In addition to the above-mentioned N-vinylpyrrolidone, other hydrophilic monomers including pyrrolidonethyl acrylate, polyethylene glycol monomethacrylate(the molecular weight of polyethylene glycol is approximately 100-1000), polyethylene glycol monomethyl ether monomethacrylate(the molecular weight of polyethylene glycol is 100-2000) may be used in order to provide hy- drophilicity to the acrylic adhesive.

[68] The monomer of the acrylic adhesive in the drug adhesive layer may be acrylic acid, methyl methacrylate, ethyl acrylate, hydroxy ethyl acrylate, butyl acrylate, octyl acrylate, 2-ethylhexyl acrylate and hexyl acrylate.

[69] The above patch was prepared to apply it to an in vitro drug permeation and a human skin, and the drug permeation was checked. As a result, after the drug permeation reached a peak, it was maintained for 24 hours or more. This is caused by the following mechanism: a large quantity of the drug can be contained by the hydrophilic monomers of a component of the acrylic adhesive in the patch under state that there is no water, and the water can be quickly introduced from the skin when the patch is attached to the skin, thereby changing an environment into a hydrophilic environment due to the hydrophilic polymers. Therefore, the solubility of the hydrophobic drug is continuously slowly decreased, so that the drug can be continuously permeated to the skin in the high concentration during the attachment, thereby maintaining the drug permeation to the skin for a long time.

[70] As described above, in case of a typical transdermal preparation, the drug permeation is high at early stage, but as time goes by, the drug is permeated into the skin, so that a concentration of the drug is lowered and the drug permeation to the skin is thus gradually decreased. In order to improve the problem, according to the invention, during the application to the skin, the drug is maintained at the saturation concentration in the drug adhesive layer 3 so that the chemical activity of the drug is maximized. In other words, under state that there is no water in the drug adhesive layer 3, the non-steroidal anti-inflammatory drugs such as ketoprofen is dissolved in a large quantity so that the drug can be much contained. However, when a patch is attached and then water is absorbed in the drug layer, a solubility of the hydrophobic drug is gradually decreased. Even though the drug concentration in the drug adhesive layer 3 becomes low continuously by the permeation of the drug through the skin, it is possible to maintain the chemical activity of the drug at the highest level, equally to the situation before using the patch. Such mechanism can be achieved by introducing a hydrophilic monomer such as N- vinyl pyrrolidone as one of components of the acrylic adhesive. In other words, the hydrophilic monomer is contained in a specific content and changes the solubility of the drug depending on the water contents in the drug adhesive layer, thereby maximizing the permeation of the drug to the skin. The object of the present invention can be achieved only by adding a separate means to control evaporation of the water absorbed to the drug adhesive layer. The separate means is the hydrophobic adhesive layer 2 consisting of the hydrophobic adhesive.

[71] In the mean time, in order to contain the drug such as non-steroidal antiinflammatory drug in the drug adhesive layer 3 in a high concentration, oil or surfactant may also be added in a large quantity, thereby achieving the object of the invention. However, in this case, although the large quantity of the drug can be contained in the patch, an affinity between the drug adhesive layer and the drug is high due to the oil or surfactant added in the drug adhesive layer 3, so that it has a negative influence on the drug permeation to the skin. In addition, when the oil or surfactant is used, the adhesion is lowered, as compared to a case where a polymer material is used. Further, when the patch is detached after completing the application, the adhesive can be remained at the skin.

[72] In case that the water discharged from the skin is present between the patch and the skin, the patch may be detached while being applied to the skin, or skin irritation may be caused. However, according to the invention, the water discharged from the skin is absorbed to the drug adhesive layer, it is possible to solve the problems.

[73] A most preferable acrylic adhesive having a hydrophilic monomer is 2-ethylhexyl acrylate/vinylpyrrolidone copolymer solution(Jeoksu Chemicals, Japan), which is listed in "Dictionary of Additives for Medicine." In addition, desired water absorption ability and solubility of the drug may be controlled by changing the composition of the acrylic monomer in the adhesive, particularly changing the content of the N- vinylpyrrolidone. The amount of the N-vinylpyrrolidone to be contained in the acrylic adhesive may be 2-50% by weight. The unlimited examples will be explained by the following Reference Examples.

[74] A content of the acrylic adhesives in the drug adhesive layer 3 is preferably 40-80 wt% for a total composition of the drug adhesive layer, more preferably 50-70 wt%. When a content of the acrylic adhesives is less than 40 wt%, the adhesion to the skin is not sufficient. When the content is more than 80 wt%, the amount of the drug is relatively decreased, so that the drug permeation is lowered.

[75] The permeation enhancer is a long chain fatty acid having a carbon number of

10-18 and derivatives thereof and includes, for example, lauryl alcohol, oleyl alcohol, sorbitan monolaurate, polyethyleneglycol monolaurate, propyleneglycol monolaurate, glycerin monolaurate, caprylic monolaurate, isopropylmyristate and transcutol. The permeation enhancers can be used in an individual or mixture form.

[76] The hydrophobic drug of the drug adhesive layer is preferably contained in an amount of 10-40 wt% for a total drug adhesive layer, more preferably 15-30 wt%. When an amount of the drug is less than 10 wt%, a drug efficacy is insufficient. When the amount is more than 40 wt%, crystals of the drug are produced and the cohesive force of the adhesive layer is sharply decreased, so that the adhesive is remained at the skin when detaching the patch after the use thereof.

[77]

[78] 4. release layer 4

[79] The release layer 4 is a layer placed below the drug adhesive layer 3 and protecting the drug adhesive layer 3 until the transdermal preparation is used. When applying to the skin, the layer is released. It is preferred that silicon or Teflon is coated on a polyester film or paper. Mode for the Invention

[80] Hereinafter, embodiments of the invention will be more specifically described.

However, it should be noted that the embodiments do not limit a scope of the invention defined in the claims. [81]

[82] [Reference Example]

[83] (A) Production of Acrylic Adhesive: AP05

[84] 95 parts by weight of 2-ethylhexylacrylate, 5 parts by weight of N-vinylpyrrolidone,

0.5 parts by weight of azobisisobutyronitrile(AIBN), 200 parts by weight of ethyl acetate were put in a reaction vessel equipped with a reflux cooler and a agitator, and slowly stirred at N -atmosphere and 6O⁰C for 15 hours for polymerization. A proper amount of ethylacetate was added to the polymer solution obtained as above in order for the content of solids to be controlled to about 30%. As a result, 2-ethylhexyl acrylate/vinylpyrrolidone copolymer as an acrylic adhesive was obtained. The mean molecular weight of the acrylic adhesive obtained as above was about 1,200,000.

[85]

[86] (B) Production of Acrylic Adhesive: APlO

[87] 90 parts by weight of 2-ethylhexylacrylate, 10 parts by weight of N- vinylpyrrolidone, 0.5 parts by weight of azobisisobutyronitrile were subject to copoly- merization by adding 200 parts by weight of ethylacetate thereto under the same conditions as those of (A). A proper amount of ethylacetate was added to the polymer solution obtained as above in order for the content of solids to be controlled to about 30%. As a result, 2-ethylhexyl acrylate/vinylpyrrolidone copolymer as an acrylic adhesive was obtained. The mean molecular weight of the acrylic adhesive obtained as above was about 1,200,000.

[88]

[89] (C) Production of Acrylic Adhesive: AP20

[90] 80 parts by weight of 2-ethylhexylacrylate, 20 parts by weight of N- vinylpyrrolidone, 0.5 parts by weight of azobisisobutyronitrile were subject to copoly- merization by adding 200 parts by weight of ethyl acetate thereto under the same conditions as those of (A). A proper amount of ethyl acetate was added to the polymer solution obtained as above in order for the content of solids to be controlled to about 30%. As a result, 2-ethylhexyl acrylate/vinylpyrrolidone copolymer as an acrylic adhesive was obtained. The mean molecular weight of the acrylic adhesive obtained as above was about 1,100,000.

[91]

[92] (D) Production of Acrylic Adhesive: AP30

[93] 70 parts by weight of 2-ethylhexylacrylate, 30 parts by weight of N- vinylpyrrolidone, 0.5 parts by weight of azobisisobutyronitrile were subject to copoly- merization by adding ethyl acetate thereto under the same conditions as those of (A). A proper amount of ethyl acetate was added to the polymer solution obtained as above in order for the content of solids to be controlled to about 30%. As a result, 2-ethylhexyl acrylate/vinylpyrrolidone copolymer as an acrylic adhesive was obtained. The mean molecular weight of the acrylic adhesive obtained as above was about 1,000,000.

[94]

[95] (E) Production of Acrylic Adhesive: AP40

[96] 60 parts by weight of 2-ethylhexylacrylate, 40 parts by weight of N- vinylpyrrolidone, 0.5 parts by weight of azobisisobutyronitrile were subject to copoly- merization by adding ethyl acetate thereto under the same conditions as those of (A). A proper amount of ethyl acetate was added to the polymer solution obtained as above in order for the content of solids to be controlled to about 30%. As a result, 2-ethylhexyl acrylate/vinylpyrrolidone copolymer as an acrylic adhesive was obtained. The mean molecular weight of the acrylic adhesive obtained as above was about 1,000,000.

[97]

[98] <Comparative example 1>

[99] DuroTak 87-2074 8.0g (based on solid content of the adhesive, same hereinafter)

(National Starch & Chemicals), which is a commercially available acrylic adhesive, ketoprofen 1.5g, and propylene glycol monolaurate 0.5g were put in a beaker and stirred for one hour to prepare a solution containing a drug having a uniform phase and then air bubbles were removed from the solution. The solution was coated on a silicon- treated polyester film 4 so as to have a thickness of 50 D after drying and then dried at 8O⁰C for 20 minutes. After the drying, the drug adhesive layer 3 coated on the film 4 was covered with the backing 1 (flexible polyester woven fabric), which was then pressed with a roller, thereby producing a patch (20 x 40 cm ).

[100]

[101] <Comparative example 2>

[102] With regard to the adhesive layer containing a drug, DuroTak 87-2074 7.3g, ketoprofen 2.2g, and glycerol monolaurate 0.5g were put in a beaker and stirred for one hour to prepare a solution having a uniform phase and then air bubbles were removed from the solution. The solution was coated on a silicon-treated polyester film 4 so as to have a thickness of 50 D after drying and then dried at 8O⁰C for 20 minutes. After that, the adhesive layer 3 coated on the film was covered with the backing 1 (flexible polyester non- woven fabric), which was then pressed with a roller, thereby producing a patch (20 x 40 cm ).

[103]

[104] <Comparative example 3>

[105] With regard to the adhesive layer containing a drug, 7.4 g (based on solid content of the adhesive, same hereinafter) of APlO produced according to the above Reference Example, ketoprofen 2.1g, and glycerol monolaurate 0.5g were put in a beaker and stirred for one hour to prepare a solution having a uniform phase and then air bubbles were removed from the solution. The solution was coated on a silicon-treated polyester film 4 so as to have a thickness of 50 D after drying and then dried at 8O⁰C for 20 minutes. After that, the adhesive layer 3 coated on the film was covered with the backing 1 (flexible polyester non- woven fabric), which was then pressed with a roller, thereby producing a patch (20 x 40 cm ).

[106]

[107] <Comparative example 4>

[108] With regard to the adhesive layer containing a drug, 7.Og of AP20, ketoprofen 2.5g, and glycerol monolaurate 0.5g were put in a beaker and stirred for one hour to prepare a solution having a uniform phase and then air bubbles were removed from the solution. The solution was coated on a silicon-treated polyester film 4 so as to have a thickness of 50 D after drying and then dried at 8O⁰C for 20 minutes. After that, the adhesive layer 3 coated on the film was covered with the backing 1 (flexible polyester non- woven fabric), which was then pressed with a roller, thereby producing a patch (20 x 40 cm²).

[109]

[110] <Comparative example 5>

[111] With regard to the hydrophobic adhesive layer 2 comprising a hydrophobic adhesives, Oppanol B 12SNF(BASF company) (Mv 55,000) 50g, which was poly- isobutylene of a low-molecular weight, Vistanex MMLlOO (Exxon-Mobile company) (Mv 1,200,000) 2Og, which was polyisobutylene of a high-molecular weight, Sukroez Su- 120 (Kolon) 30g, which was hydrogenated petroleum resin, and hexane 30 D were put in a beaker and stirred to prepare a uniform solution. The solution was coated on a polyester film so as to have a thickness of 30 D after drying and then dried at 6O⁰C for 10 minutes. After that, it was covered with the flexible backing 1 (flexible polyester woven fabric), which was then pressed with a roller. With respect to the drug adhesive layer 3 containing a drug, 7.3g of AP30 produced according to the above Reference Example, which was an acrylic adhesives, ketoprofen 2.2g, and glycerol monolaurate 0.5g were put in a beaker and stirred for one hour to prepare a solution having a uniform phase and then air bubbles were removed from the solution. The solution was coated on a silicon-treated polyester film 4 so as to have a thickness of 50 D after drying and then dried at 8O⁰C for 20 minutes. The film was separated from the hydrophobic adhesive layer 2 pre-prepared, which was then put on the dried drug adhesive layer 3, thereby producing a patch (20 x 40 cm ).

[112]

[113] <Embodiment 1 >

[114] With respect to the hydrophobic adhesive layer 2, Oppanol B 12SNF 50g (Mv

55,000), which was polyisobutylene of a low-molecular weight, Vistanex MMLlOO 2Og, which was polyisobutylene of a high-molecular weight, Regalite R 1100 30g (Eastman company), which was hydrogenated petroleum resin, and hexane 300 D were put in a beaker and stirred to prepare a uniform solution. The solution was coated on a silicone-treated polyester film so as to have a thickness of 50 D after drying and then dried at 6O⁰C for 10 minutes. After that, the prepared hydrophobic adhesive layer 2 was covered with the flexible backing 1, which was then pressed with a roller. With respect to the drug adhesive layer 3 containing a drug, 7.4g of AP05 produced according to the above Reference Example, which were acrylic adhesives, ketoprofen 2.1g and propylene glycol monolaurate 0.5g were put in a beaker and stirred for one hour to prepare a solution having a uniform phase and then air bubbles were removed from the solution. The solution was coated on the silicon-treated polyester film 4 so as to have a thickness of 50 D after drying and then dried at 8O⁰C for 20 minutes. The film was separated from the hydrophobic adhesive layer 2 pre-prepared, which was then put on the dried drug adhesive layer 3, thereby producing a patch (20 x 40 cm ).

[115]

[116] <Embodiment 2>

[117] The hydrophobic adhesive layer 2 was prepared with the same method as the embodiment 1. With respect to the drug adhesive layer 3 containing a drug, 7.3g of APlO produced according to the above Reference Example, which was an acrylic adhesives, ketoprofen 2.2g and propylene glycol monolaurate 0.5g were put in a beaker and stirred for one hour to prepare a solution having a uniform phase and then air bubbles were removed from the solution. The solution was coated on the silicon- treated polyester film 4 so as to have a thickness of 50 D after drying and then dried at 8O⁰C for 20 minutes. The film was separated from the hydrophobic adhesive layer 2 pre-prepared, which was then put on the dried drug adhesive layer 3, thereby producing a patch (20 x 40 cm ).

[118]

[119] <Embodiment 3>

[120] The hydrophobic adhesive layer 2 was prepared with the same method as the embodiment 1. With respect to the drug adhesive layer 3 containing a drug, 7.3g of AP20 produced according to the above Reference Example, which were acrylic adhesives, ketoprofen 2.2g and propylene glycol monolaurate 0.5g were put in a beaker and stirred for one hour to prepare a solution having a uniform phase and then air bubbles were removed from the solution. The solution was coated on the silicon- treated polyester film 4 so as to have a thickness of 50 D after drying and then dried at 8O⁰C for 20 minutes. The film was separated from the hydrophobic adhesive layer 2 pre-prepared, which was then put on the dried drug adhesive layer 3, thereby producing a patch (20 x 40 cm ). [121]

[ 122] <Embodiment 4>

[123] The hydrophobic adhesive layer 2 was prepared with the same method as the embodiment 1. With respect to the drug adhesive layer 3 containing a drug, AP30 7.3g, which is an acrylic adhesives produced according to the above Reference Example, ketoprofen 2.2g and glycerol monolaurate 0.5g were put in a beaker and stirred for one hour to prepare a solution having a uniform phase and then air bubbles were removed from the solution. The solution was coated on the silicon-treated polyester film 4 so as to have a thickness of 50 D after drying and then dried at 8O⁰C for 20 minutes. The film was separated from the hydrophobic adhesive layer 2 pre-prepared, which was then put on the dried drug adhesive layer 3, thereby producing a patch (20 x 40 cm ).

[124]

[125] <Embodiment 5>

[126] The hydrophobic adhesive layer 2 was prepared to have a thickness of 4OD with the same method as the embodiment 1. With respect to the drug adhesive layer 3 containing a drug, AP30 7.3g, which is an acrylic adhesive produced according to the above Reference Example, ketoprofen 2.2g and propylene glycol monolaurate 0.5g were put in a beaker and stirred for one hour to prepare a solution having a uniform phase and then air bubbles were removed from the solution. The solution was coated on the silicon-treated polyester film 4 so as to have a thickness of 50 D after drying and then dried at 8O⁰C for 20 minutes. The film was separated from the hydrophobic adhesive layer 2 pre-prepared, which was then put on the dried drug adhesive layer 3, thereby producing a patch (20 x 40 cm ).

[127]

[128] <Embodiment 6>

[129] With respect to the hydrophobic adhesive layer 2, Kraton D 1107 50g (Shell

Chemicals), which was a copolymer of styrene-isoprene-styren, Regalite R 1100 30g (Eastman), which was hydrogenated petroleum resin, liquid paraffin 30g and hexane 300 D were put in a beaker and stirred to prepare a uniform solution. The solution was coated on a silicon-treated polyester film so as to have a thickness of 50 D after drying and then dried at 6O⁰C for 10 minutes. After that, the prepared hydrophobic adhesive layer was covered with the flexible backing 1 (flexible polyester woven-fabric), which was then pressed with a roll. With respect to the drug adhesive layer 3 containing a drug, 7.3g of AP30, which is an acrylic adhesive produced according to the above Reference Example, ketoprofen 2.2g and propylene monolaurate 0.5g were put in a beaker and stirred for one hour to prepare a solution having a uniform phase and then air bubbles were removed from the solution. The solution was coated on the silicon- treated polyester film 4 so as to have a thickness of 50 D after drying and then dried at 80⁰C for 20 minutes. The film was separated from the hydrophobic adhesive layer 2 pre-prepared, which was then put on the dried drug adhesive layer 3, thereby producing a patch (20 x 40 cm ).

[130]

[131] <Embodiment 7>

[132] With respect to the hydrophobic adhesive layer 2, Kraton DI lOl 50g (Shell

Chemicals), which was a copolymer of styrene-isoprene-styrene, Regalite R 1100 30g (Eastman), which was hydrogenated petroleum resin, liquid paraffin 30g and hexane 300 D were put in a beaker and stirred to prepare a uniform solution. The solution was coated on a silicon-treated polyester film so as to have a thickness of 50 D after drying and then dried at 60⁰C for 10 minutes. After that, the prepared hydrophobic adhesive layer was covered with the flexible backing 1 (urethane), which was then pressed with a roll. With respect to the drug adhesive layer 3 containing a drug, 7.3g of AP30, which was an acrylic adhesive produced according to the above Reference Example, ketoprofen 2.2g and propylene monolaurate 0.5g were put in a beaker and stirred for one hour to prepare a solution having a uniform phase and then air bubbles were removed from the solution. The solution was coated on the silicon-treated polyester film 4 so as to have a thickness of 50 D after drying and then dried at 80⁰C for 20 minutes. The film was separated from the hydrophobic adhesive layer 2 pre-prepared, which was then put on the dried drug adhesive layer 3, thereby producing a patch (20 x 40 cm²).

[133]

[134] <Embodiment 8>

[135] The hydrophobic adhesive layer 2 having the thickness of 6OD was prepared in the same manner of the Embodiment 1.

[136] With respect to the drug adhesive layer 3 containing a drug, 7.Og of AP20, which is an acrylic adhesive produced according to the above Reference Example, ketoprofen 2.Og and glycerol monolaurate 1.Og were put in a beaker and stirred for one hour to prepare a solution having a uniform phase and then air bubbles were removed from the solution. The solution was coated on the silicon-treated polyester film 4 so as to have a thickness of 50 D after drying and then dried at 80⁰C for 20 minutes. The film was separated from the hydrophobic adhesive layer 2 pre-prepared, which was then put on the dried drug adhesive layer 3, thereby producing a patch (20 x 40 cm ).

[137]

[138] <Embodiment 9>

[139] The hydrophobic adhesive layer 2 was prepared in the same manner of the

Embodiment 1.

[140] With respect to the drug adhesive layer 3 containing a drug, 7.Og of AP30, which is an acrylic adhesive produced according to the above Reference Example, ketoprofen 2.5g and glycerol monolaurate 0.5g were put in a beaker and stirred for one hour to prepare a solution having a uniform phase and then air bubbles were removed from the solution. The solution was coated on the silicon-treated polyester film 4 so as to have a thickness of 50 D after drying and then dried at 8O⁰C for 20 minutes. The film was separated from the hydrophobic adhesive layer 2 pre-prepared, which was then put on the dried drug adhesive layer 3, thereby producing a patch (20 x 40 cm ).

[141]

[142] <Embodiment 10>

[143] The hydrophobic adhesive layer 2 was prepared in the same manner of the

Embodiment 1.

[144] With respect to the drug adhesive layer 3 containing a drug, 6.7g of AP40, which is an acrylic adhesive produced according to the above Reference Example, ketoprofen 2.8g and glycerol monolaurate 0.5g were put in a beaker and stirred for one hour to prepare a solution having a uniform phase and then air bubbles were removed from the solution. The solution was coated on the silicon-treated polyester film 4 so as to have a thickness of 50 D after drying and then dried at 8O⁰C for 20 minutes. The film was separated from the hydrophobic adhesive layer 2 pre-prepared, which was then put on the dried drug adhesive layer 3, thereby producing a patch (20 x 40 cm ).

[145]

[ 146] <Embodiment 11 >

[147] The hydrophobic adhesive layer 2 was prepared in the same manner of the

Embodiment 1.

[148] With respect to the drug adhesive layer 3 containing a drug, 7.Og of AP30, which is an acrylic adhesive produced according to the above Reference Example, ketoprofen 2.5g and isopropyl alcohol 0.5g were put in a beaker and stirred for one hour to prepare a solution having a uniform phase and then air bubbles were removed from the solution. The solution was coated on the silicon-treated polyester film 4 so as to have a thickness of 50 D after drying and then dried at 8O⁰C for 20 minutes. The film was separated from the hydrophobic adhesive layer 2 pre-prepared, which was then put on the dried drug adhesive layer 3, thereby producing a patch (20 x 40 cm ).

[149]

[150] <Embodiment 12>

[151] The hydrophobic adhesive layer 2 was prepared in the same manner of the

Embodiment 1.

[152] With respect to the drug adhesive layer 3 containing a drug, 7.Og of AP30, which is an acrylic adhesive produced according to the above Reference Example, ketoprofen 2.5g and transcutol 0.5g were put in a beaker and stirred for one hour to prepare a solution having a uniform phase and then air bubbles were removed from the solution. The solution was coated on the silicon-treated polyester film 4 so as to have a thickness of 50 D after drying and then dried at 8O⁰C for 20 minutes. The film was separated from the hydrophobic adhesive layer 2 pre-prepared, which was then put on the dried drug adhesive layer 3, thereby producing a patch (20 x 40 cm ).

[153]

[154] <Embodiment 13>

[155] The hydrophobic adhesive layer 2 was prepared in the same manner of the

Embodiment 1.

[156] With respect to the drug adhesive layer 3 containing a drug, 7.Og of AP20, which is an acrylic adhesive produced according to the above Reference Example, diclofenac 2.5g and propylene glycol monolaurate 0.5g were put in a beaker and stirred for one hour to prepare a solution having a uniform phase and then air bubbles were removed from the solution. The solution was coated on the silicon-treated polyester film 4 so as to have a thickness of 50 D after drying and then dried at 8O⁰C for 20 minutes. The film was separated from the hydrophobic adhesive layer 2 pre-prepared, which was then put on the dried drug adhesive layer 3, thereby producing a patch (20 x 40 cm ).

[157]

[158] <Embodiment 14>

[159] The hydrophobic adhesive layer 2 was prepared in the same manner of the

Embodiment 1.

[160] With respect to the drug adhesive layer 3 containing a drug, 7.Og of AP20, which is an acrylic adhesive produced according to the above Reference Example, flurbiprofen 2.5g and propylene glycol monolaurate 0.5g were put in a beaker and stirred for one hour to prepare a solution having a uniform phase and then air bubbles were removed from the solution. The solution was coated on the silicon-treated polyester film 4 so as to have a thickness of 50 D after drying and then dried at 8O⁰C for 20 minutes. The film was separated from the hydrophobic adhesive layer 2 pre-prepared, which was then put on the dried drug adhesive layer 3, thereby producing a patch (20 x 40 cm ).

[161]

[162] <Embodiment 15>

[163] The hydrophobic adhesive layer 2 was prepared in the same manner of the

Embodiment 1.

[164] With respect to the drug adhesive layer 3 containing a drug, 7.Og of AP20, which is an acrylic adhesive produced according to the above Reference Example, felbinac 2.5g and propylene glycol monolaurate 0.5g were put in a beaker and stirred for one hour to prepare a solution having a uniform phase and then air bubbles were removed from the solution. The solution was coated on the silicon-treated polyester film 4 so as to have a thickness of 50 D after drying and then dried at 8O⁰C for 20 minutes. The film was separated from the hydrophobic adhesive layer 2 pre-prepared, which was then put on the dried drug adhesive layer 3, thereby producing a patch (20 x 40 cm ).

[165]

[166] <Embodiment 16>

[167] The hydrophobic adhesive layer 2 was prepared in the same manner of the

Embodiment 1.

[168] With respect to the drug adhesive layer 3 containing a drug, 7.Og of AP20, which is an acrylic adhesive produced according to the above Reference Example, aceclofenac 2.5g and propylene glycol monolaurate 0.5g were put in a beaker and stirred for one hour to prepare a solution having a uniform phase and then air bubbles were removed from the solution. The solution was coated on the silicon-treated polyester film 4 so as to have a thickness of 50 D after drying and then dried at 8O⁰C for 20 minutes. The film was separated from the hydrophobic adhesive layer 2 pre-prepared, which was then put on the dried drug adhesive layer 3, thereby producing a patch (20 x 40 cm ).

[169]

[170] <Embodiment 17>

[171] The hydrophobic adhesive layer 2 was prepared in the same manner of the

Embodiment 1.

[172] With respect to the drug adhesive layer 3 containing a drug, 7.Og of AP20, which is an acrylic adhesive produced according to the above Reference Example, loxoprofen 2.5g and propylene glycol monolaurate 0.5g were put in a beaker and stirred for one hour to prepare a solution having a uniform phase and then air bubbles were removed from the solution. The solution was coated on the silicon-treated polyester film 4 so as to have a thickness of 50 D after drying and then dried at 8O⁰C for 20 minutes. The film was separated from the hydrophobic adhesive layer 2 pre-prepared, which was then put on the dried drug adhesive layer 3, thereby producing a patch (20 x 40 cm ).

[173]

[174] The inventors conducted following tests so as to evaluate the effects of the transdermal preparations of the invention.

[175]

[176] <test 1> assessment of the transdermal preparations : skin permeation test

[177] In order to assess the drug permeation of the patches prepared in the comparative examples and embodiments, the inventors cut the skin by 1.5 xl.5 cm , which was cut in the abdominal region of a hairless mouse (female, 6 weeks), put it on a Franz-type diffusion cell, put the patches, which were prepared in the comparative examples and embodiments, on the skin and then fixed them with a clamp so that the patches were not moved. A phosphate buffer solution (pH 7.4) was put in a receptor part and a temperature of the diffusion cell was maintained at 37⁰C. The buffer solution of a receptor was stirred at a constant speed of 300 rpm, the whole receptor solution was taken after a predetermined time period has lapsed and the receptor was again filled with the buffer solution. The taken solution was analyzed with a high performance liquid chromatography. Each analysis condition of ketoprofen, diclofenac, flurbiprofen, felbinac, aceclofenac and loxoprofen was as follows.

[178]

[179] [ketoprofen]

[180] column: YMC-Pack ODS-AM (1506.0mm, LD. 5D) (YMC Co., Ltd.)

[181] mobile phase: 70:30(V/V) = methanol: 0.1% acetic acid aqueous solution

[182] flow rate: 1 D/min.

[183] detection : UV wavelength 254 nm

[184]

[185] [diclofenac]

[186] column: YMC-Pack ODS-AM (1506.0mm, LD. 5D)

[187] mobile phase: 53:47(V/V) = acetonitrile:0.02M acetic acid sodium buffer solution

(pH 5.8)

[188] flow rate : 1 D/min.

[ 189] detection : UV wavelength 280 nm

[190]

[191] [flurbiprofen]

[192] column: YMC-Pack ODS-AM (1506.0mm, LD. 5D)

[193] mobile phase: 40:40:20(V/V/V) = acetonitrile:methanol:0.5% acetic acid aqueous solution

[194] flow rate: 1 D/min.

[195] detection : UV wavelength 254 nm

[196]

[197] [felbinac]

[198] column: YMC-Pack ODS-AM (1506.0mm, LD. 5D)

[199] mobile phase: 38:62 (V/V) = acetonitrile:20mM phosphate buffer solution (pH 7.4)

[200] flow rate: 1 D/min.

[201] detection : UV wavelength 254 nm

[202]

[203] [aceclofenac]

[204] column: YMC-Pack ODS-AM (1506.0mm, LD. 5D)

[205] mobile phase: 10:25:65(V/V/V) = methanol:acetonitrile:0.05M acetate buffer (pH

6.5)

[206] flow rate: 1 D/min. [207] detection : UV wavelength 275 nm [208] [209] [loxoprofen] [210] column: YMC-Pack ODS-AM (1506.0mm, LD. 5D) [211] mobile phase: 38:62 (VfV) = acetonitrile:20mM phosphate buffer solution (pH 7.4) [212] flow rate: 1 D/min. [213] [214] *detection : UV wavelength 254 nm [215] [216] The table 1 shows in vitro permeability (hairless mouse skin, n=6) of the drug. [217] Table 1

[218] [219] As shown in the table 1, as the content of N-vinylpyrrolidone in the acrylic adhesive was increased, the solubility of the drug in the preparation was increased and thus the permeated amount of the drug into skin as well as the content of the drug in the preparations could be increased(Embodiment 1, 2, 9, 10). Also, where the content of the drug is same, as the content of N-vinylpyrrolidone among the components of the acrylic adhesive was increased, the permeated amount of the drug into the skin was relatively decreased(Embodiment 3, 4, 5). This seems to be because N- vinylpyrrolidone, one of the components of the adhesive, has a high affinity with the drug. Since N-vinylpyrrolidone has a high affinity with the drug, the extent of the decline of solubility of the drug caused by the water absorbed from the skin to adhesive is not large. This suggests that when the amount of N-vinylpyrrolidone in the acrylic adhesive is increased and thus the saturation concentration of the drug becomes high, the content of the drug should also be increased in order to maintain a high permeated amount. In the mean time, when the thickness of the hydrophobic adhesive layer 2 was less than 40 D (comparative example 5), the drug permeation was low even though the ratio of the content of the drug to the content of the polymer resin belonged to an appropriate range.

[220] [221] <test 2> method of assessing the in vivo permeability of the drug and water content [222] In order to assess the in vivo drug permeation of the patches prepared according to the comparative examples 1-5 and the embodiments 1-4, 7-10, each circular patch, which was cut to have a diameter of 3.5 cm, was attached to the upper arm of an adult human for 12 and 24 hours and then detached. After that, the content of drug remained in the patch was compared with the initial content thereof, thereby quantifying the content of drug permeated through the skin. The result is shown in a table 2. The analysis conditions of each drug were same as the test 1.

[223] In order to measure the water content, which was an amount of water absorbed to the patch after the attachment, one patch was attached to the back region for 24 hours and then the initial weight of the patch before the attachment and the weight after the attachment for 24 hours were measured to calculate the water content after the attachment for 24 hours, with a following equation 4.

[224] <equation 4> [225]

W_Mr- W Ohr water content(%) * 100

W Ohr

[226] [227] W : weight of the patch before the attachment

Ohr [228] W : weight of the patch after the attachment for 24 hours

24hr ^{& r} [229] The result is shown in a table 2. The table 2 shows the in vivo drug permeation and the water content after the attachment for 24 hours.

[230] Table 2

[231]

[232] As can be seen from the table 2, the patch having an optimized combination ratio of the drug and the N- vinyl pyrrolidone, which was one of the components of the adhesive, exhibited the high drug permeability in the in vivo drug permeation test (embodiments 2, 3, 9, 10).

[233]

[234] [test 3] skin irritation test

[235] In order to check the skin irritation of the patches prepared in the embodiments 1-4,

10 and the like, the prepared patch was cut into a size of 2 x 2 cm , which was then attached to the forearm region of 10 human adult males. After 24 hours, the patch was removed. Then, after one hour, a primary irritation index of the attached region was determined according to a following determination criterion and a reaction degree of the skin was calculated from an equation 5.

[236] determination criterion>

[237] Table 3

[238]

[239] <equation 5>

[240] reaction degree (%) = {(sum of determination level x number of de- terminators )/(number of tested persons x 4)} x 100

[241]

[242] As a conversion result of the equation 5, the skin reaction degrees of the patches prepared in the embodiments 1-4 and 10 were respectively 0.6, 0.7, 0.5, 0.6 and 0.6%. In other words, they little caused the skin irritation. Accordingly, when applying the patch to the skin, it is expected that the skin side effect is very little.

[243]

[244] [test 4] adhesion test

[245] In order to assess the adhesive force of the patches containing the non-steroidal anti-inflammatory drug prepared in the comparative examples 1-5 and the embodiments 1-4, 6, 9, 10, the patch was cut to have a length of 20 cm and an area of 2.5 cm , thereby preparing a sample. Then, the patch was attached to a stainless steel plate in a longitudinal direction thereof and the attached patch was adhered by reciprocating a roll (500g) two times. After leaving the patch at it was for 30 minutes, an adhesion tester (Texture analyzer Model XT2i, Stable Micro System) was used to measure an adhesion when releasing the patch with a degree of 180 at a speed of 300 mm/minute under conditions of 2O⁰C and a relative humidity of 65%. The result is shown in a table 4 (n=3).

[246] Table 4

[247] [248] As shown in the table 4, the patches of the embodiments 1, 2, 3, 4, 6 exhibited the adhesion sufficient to be well attached to the skin while the drug effects its medical action. However, when the content of N-vinylpyrrolidone was high, the adhesion was decreased.

[249]

Industrial Applicability [250] As described above, when the transdermal preparation of the invention is used, it is possible to provide a transdermal preparation capable of enabling the hydrophobic drug of a high concentration to be continuously permeated through the skin until the patch is detached from the skin.

Claims

[1] A transdermal preparation of a layered structure for a hydrophobic drug, the preparation comprising: a backing layer (1) located at the highest part of the layered structure and having a flexibility; a hydrophobic adhesive layer (2) placed below the backing layer and containing a hydrophobic adhesives to prevent water absorbed from skin from being lost and the drug from being reverse-transferred; and a drug adhesive layer (3) for adhering the transdermal preparation to the skin, which is placed below the hydrophobic adhesive layer and contains a drug, a hydrophobic drug, and an acrylic adhesive, the acrylic adhesive comprising a hy- drophilic monomer, for promoting the water absorption from the skin.

[2] The transdermal preparation according to claim 1, further comprising a release layer (4) placed below the drug adhesive layer, protecting the drug adhesive layer until the transdermal preparation is used and released when the preparation is used.

[3] The transdermal preparation according to claim 1, wherein the hydrophobic adhesives of the hydrophobic adhesive layer are selected from a group consisting of a polyisobutylene adhesive, a styrene-isoprene-styrene adhesive and a styrene- butadiene-styrene adhesive.

[4] The transdermal preparation according to claim 3, wherein the hydrophobic adhesives layer has a thickness of 40-100 D.

[5] The transdermal preparation according to claim 1, wherein the hydrophobic drug is a non-steroidal anti-inflammatory drug.

[6] The transdermal preparation according to claim 5, wherein the hydrophobic drug is one or more selected from a group consisting of ketoprofen, diclofenac, flurbiprofen, felbinac, aceclofenac and loxoprofen.

[7] The transdermal preparation according to claim 1, wherein the hydrophobic drug of the drug adhesive layer is contained in an amount of 10-40 wt% for a total drug adhesive layer.

[8] The transdermal preparation according to claim 1, wherein the hydrophilic monomer is one or more selected from the group consisting of N- vinylpyrrolidone, pyrrolidone ethyl acrylate, polyethylene glycol monomethacrylate and polyethylene glycol monomethyl ether monomethacrylate.

[9] The transdermal preparation according to claim 1, wherein the monomer of the acrylic adhesive of the drug adhesive layer is one or more selected from the group consisting of acrylic acid, methyl methacrylate, ethyl acrylate, hy- droxylethyl acrylate, butyl acrylate, octyl acrylate, 2-ethylhexyl acrylate and hexyl acrylate. [10] The transdermal preparation according to claim 8, wherein the acrylic adhesive contains 2 to 50 parts by weight based on total monomers. [11] The transdermal preparation according to claim 8, wherein the acrylic adhesive of the drug adhesive layer is 2-ethylhexyl acrylate/vinylpyrrolidone copolymer. [12] The transdermal preparation according to claim 1, wherein the acrylic adhesives of the drug adhesive layer are contained in an amount of 40-80 wt% for a total drug adhesive layer. [13] The transdermal preparation according to claim 1, wherein the drug adhesive layer further comprises a permeation enhancer for enhancing the drug permeation, and wherein the permeation enhancer is a long chain fatty acid having a carbon number of 10-18 and derivatives thereof which are used in an individual or mixture form, the derivative is a fatty acid derivative or transcutol, the fatty acid derivative is selected from a group consisting of lauryl alcohol, oleyl alcohol, sorbitan monolaurate, polyethyleneglycol monolaurate, propy- leneglycol monolaurate, glycerin monolaurate, caprylic monolaurate and iso- propylmyristate and, the permeation enhancer is contained in an amount of 3~20wt% for a total drug adhesive layer. [14] The transdermal preparation according to claim 1, wherein the backing layer is made of a woven or non- woven fabric having a unidirectional or dual directional flexibility, and wherein the woven fabric consists of a polyester based resin, urethane based resin or cotton, and the non- woven fabric consists of the polyester based resin or urethane based resin.