KR101395557B1 - Transdermal drug delivery system and preparation method thereof - Google Patents

Abstract

The present invention relates to percutaneous absorption preparations and methods for their preparation. The percutaneously absorbable preparation of the present invention includes a drug storage layer containing a drug, a peripheral adhesive layer disposed on the drug storage layer, and a release-controlled adhesive layer including a drug protective layer below the drug storage layer exist.
The transdermal absorption preparation according to the present invention contains rastiticin as a drug and is less likely to cause side effects than oral administration or administration to an injection, and a water-soluble polymer can be applied to the release-controlled adhesive layer to effectively control the dose of the drug. In addition, by applying the water-soluble polymer, detachment of the skin of the preparation can be effectively prevented as compared with the conventional percutaneous absorption preparation.

Description

[0001] The present invention relates to a transdermal drug delivery system and preparation method thereof,

The present invention relates to a percutaneous absorption preparation for delivering a drug through the skin and a method for producing the same.

BACKGROUND ART In general, senile dementia including Alzheimer's disease (AD) or Parkinson's disease is a disease characterized by gradual loss of cognitive function, and many biochemical, genetic and medical researches are under way. The symptoms of dementia that have been recognized so far are accompanied by various dysfunctions, language disorders, poor judgment and learning disabilities due to a decrease in cognitive function and intellectual ability, and also symptoms such as personality change, emotional instability, Lt; / RTI >

Dementia is a unique symptom resulting from the basic physiological dysfunction of the brain, which is accompanied by a gross generalized brain atrophy and enlargement of the ventricle, and a considerable loss of cortical cells, Purkinje cells of the cerebellum, and eukaryotic cells of the spinal cord On cerebral specific function

Causing serious impairment, which is perceived to be associated with decreased acetylcholine levels in cerebral neurons.

Such acetylcholine is reduced in its concentration by an enzyme called acetylcholinesterase, which decomposes acetylcholine into choline and acetic acid, and examples of such acetylcholinesterase inhibitors include donepezil and ribastigmine. Among them, ribastigmine (N-ethyl-N-methyl-3- [1- (dimethylamino) ethyl] -phenylcarbamate) has a high degree of transition from the body to the central nervous system (CNS) The frequency is low.

Therefore, studies have been actively conducted to prevent and treat dementia by increasing the concentration of acetylcholine using such a ribastigmine.

At this time, when such levastigmine is orally administered, there is a problem that the drug may be converted into an inactive metabolite by the liver. In addition, since the drug passes through the digestive tract, there is a concern that the digestive tract may be disturbed and the drug absorption degree may be affected by the conditions in the digestive tract.

When levastigmine is injected into the human body in the form of an injection as a method other than oral administration, there is a problem that the blood concentration of the ribastidin is rapidly increased.

In order to solve the problems of the prior art as described above, it is intended to provide a transdermal preparation for inducing continuous drug efficacy without side effects by administering ribastigmine to the human body without passing through liver or digestive organs. Also, it is intended to provide a percutaneous absorption preparation which is capable of controlling the permeation amount of a drug and is superior in adhesion to the skin as compared with conventional percutaneous absorption preparations.

To achieve the above object, according to one aspect of the present invention, there is provided a percutaneous absorption preparation for administration of a drug, which comprises a drug storage layer containing ribastigmine, a polymer solvent for forming a matrix, a skin permeation enhancer, And a release-controlling adhesive layer having a function of controlling the release of the drug when it is permeated.

The release-controlling pressure-sensitive adhesive layer may further comprise a drug-protecting layer.

The drug storage layer is characterized by comprising 20 to 40 parts by weight of ribastigmine, 50 to 60 parts by weight of a polymer solvent for forming a matrix, and 2 to 10 parts by weight of a skin penetration enhancer.

Also, the polymer solvent for forming the matrix contained in the drug storage layer may include one or more selected from the group consisting of polydimethyloxane, acrylate, methacrylate, polyisobutylene, and styrene-isoprene-styrene do.

The drug permeation enhancer contained in the drug storage layer may be selected from the group consisting of N-cyclohexyl-2-pyrrolidone, 1-butyl (3-dodecyl-2-pyrrolidone) 3-dodecyl-2-pyrrolidone, 1,5-dimethyl-2-pyrrolidone and 1-ethyl-2-pyrrolidone 1-hexyl-2-pyrrolidone, 1-hexyl-2-pyrrolidone, 1-hexyl- (2-hydroxyethyl) pyrrolidone, 3-hydroxy-N-methyl-2-pyrrolidone, 1-lauryl-4-methyloxycarbonyl-2-pyrrolidone, N-methyl-2-pyrrolidone, N-carprylyl-2-pyrrolidone, N-dodecyl-2-pyrrolidone, glycerol lauryl alcohol, , Oleyl alcohol, isopropyl myristate propylene mono-oleate, oleyl macrogolglyceride, oleic acid, oleic acid, oleic acid, oleic acid, maleic acid, acid, lauroyl macrogoglyceride, linoleoyl macrogoglyceride, propylene glycol caprylate / caprate, sorbitan monostearate monools, But are not limited to, sorbitan monostearate mono-oleate, glycerol monolaurate, propylene glycol monolaurate, propylene glycol monocaprylate, sorbitan monolaurate ), Lauryl lactate, caprylic / capric triglyceride ceride, corn oil PEG-8 ester, corn oil PEG-6 ester, or triacetin.

Further, the drug protecting layer includes one selected from the group consisting of a polyester film, a polyester film deposited with aluminum, a multi-deposited film, a polyester film laminated with a nonwoven fabric, a polyurethane film, or a polyethylene film.

Further, the release-controlling and pressure-sensitive adhesive layer includes those containing a water-soluble polymer and a pressure-sensitive adhesive.

The water-soluble polymer may be at least one selected from the group consisting of hydroxyethylcellulose, ethylcellulose polymers, polyvinylpyrrolidone (PVP), polyethylene oxide (PEO), polyethylene glycol (PEG), polyacrylic acid (PAA) Cellulose (HPC), and the like.

The water-soluble polymer is used in an amount of 0.1 to 5 parts by weight based on the total weight of the release-controlling pressure-sensitive adhesive layer.

Also, the pressure-sensitive adhesive may be an acrylic pressure-sensitive adhesive containing no functional group or one or two or more selected from the group consisting of -COOH, -0H, and -NH2 functional groups, and the pressure-sensitive adhesive has a weight of 31 By weight to 63 parts by weight.

The method for preparing a percutaneous absorption preparation according to another aspect of the present invention includes the steps of preparing a drug storage layer solution by mixing the drug with a solution of ribastigmine, a polymer solvent for forming a matrix, and a skin permeation enhancer, And a release-controlling adhesive layer containing a drug-protecting layer on one side of the drug storage layer.

The percutaneous absorption preparation according to the present invention has an effect of treating or preventing dementia without side effects existing in oral agents or injections by containing the ribastigmine in the drug storage layer. In addition, the dosage of the drug can be controlled through the skin penetration enhancer and the water-soluble polymer, so that the human body dose of ribastigmine can be controlled. In addition, by including the water-soluble polymer in the release-controlling adhesive layer, it is possible to reduce the easy release of the percutaneous absorption preparation from the skin.

1 is a cross-sectional view of a percutaneous absorption preparation according to the present invention.

The present inventors have made intensive researches to overcome the problems of the prior art, and as a result, they have completed the invention of a percutaneous absorption preparation capable of delivering a desired amount of a drug into the body at a constant rate. In addition, water-soluble polymers such as hydroxyethylcellulose, ethylcellulose polymers, polyvinylpyrrolidone (PVP), polyethylene oxide (PEO), polyethylene glycol (PEG), polyacrylic acid (PAA) , And hydroxypropylcellulose (HPC), thereby controlling the rate of drug release and tightening the contact between the drug layer and the skin, thereby maintaining the binding force between the skin and the preparation even when excessive moisture or sweat is released The present invention has been completed.

Accordingly, the transdermal absorption preparation of the present invention is characterized by comprising a release-controlling adhesive layer, a drug storage layer. The release-controlling adhesive layer is a layer for regulating the release rate of the drug, and the drug storage layer is a layer for storing the drug. And a release-regulating adhesive layer and a drug storage layer in this order from the order of contact with the skin.

The drug storage layer comprises ribastigmine, a polymer solvent for forming a matrix, and a skin permeation promoter. The ribastigmine and the skin permeation enhancer are present in a completely dissolved state in the polymer solvent for forming the matrix. The thickness of the drug storage layer is preferably 50 to 60 mu m.

The ribastigmine is used to selectively inhibit acetylcholinesterase in the brain and is injected into the body for a long time by the percutaneous absorption preparation of the present invention. The ribastigmine also includes a pharmaceutically acceptable salt in the form of a free base. In addition, the above-mentioned ribastigmine preferably comprises 20 to 40 parts by weight, based on the total weight of the composition, including ribastigmine, a polymer solvent for forming a matrix, and a skin penetration promoting agent.

Also, the polymer solvent for forming the matrix is used for forming the matrix of the drug storage layer, and preferably a group consisting of polydimethyloxane, acrylate, methacrylate, polyisobutylene, and styrene-isoprene-styrene One or more of which are used. The polymer solvent for forming the matrix is included in the drug storage layer in an amount of 10 to 90 parts by weight, preferably 50 to 60 parts by weight, based on the total weight of the drug storage layer, including the ribastigmine, a polymer solvent for forming a matrix and a skin penetration enhancer .

In the percutaneous absorption preparation according to the present invention, the skin penetration enhancer is used for controlling the permeation rate at which the drug is transferred, preferably N-cyclohexyl-2-pyrrolidone, 1 Butyl-3-dodecyl-2-pyrrolidone, 1,5-dimethyl-2-pyrrolidone, 1-ethyl-2-pyrrolidone, 1-hexyl-4-methyloxycarbonyl-2-pyrrolidone, 1- (2-hydroxyethyl) pyrrolidone, 1-hexyl-2-pyrrolidone, 1- 2-pyrrolidone, 1-lauryl-4-methyloxycarbonyl-2-pyrrolidone, N-methyl- N-methyl-2-pyrrolidone, N-carprylyl-2-pyrrolidone, N-dodecyl-2-pyrrolidone (N -dodecyl-2-pyrrolidone), glycerol lauryl alcohol (glyc erol lauryl alcohol, oleyl alcohol, isopropyl myristate, sorbitan mono-oleate, propylene monolaurate, propylene monooleate, oleate, oleic macrogolglyceride, oleic acid, lauroyl macrogoglyceride, linoleoyl macrogoglyceride, propylene glycol caprylate Propylene glycol caprylate / caprate, sorbitan monostearate mono-oleate, glycerol monolaurate, propylene glycol monolaurate, propylene glycol monolaurate, Propylene glycol monocaprylate, sorbitan monolaurate, lauryl monolaurate, One or more of the group consisting of lauryl lactate, caprylic / capric triglyceride, corn oil PEG-8 ester, corn oil PEG-6 ester, triacetin, More preferably, one or more of the group consisting of glycerol monooleate, glycerol monolaurate, propylene glycol monolaurate, propylene glycol monocaprylate, and sorbitan monolaurate is used. The skin penetration enhancer preferably includes 0.1 to 40 parts by weight, more preferably 0.1 to 40 parts by weight, based on the total weight of the mixture of the ribastigmine, the polymer solvent for forming the matrix, and the skin penetration enhancer, And preferably 2 to 10 parts by weight.

In the percutaneously absorbable preparation according to the present invention, the release-controlling adhesive layer includes a drug-protecting layer for allowing the drug to be administered toward the skin without being despread. The drug protection layer may be selected from the group consisting of a polyester film, a polyester film on which aluminum is deposited, a polyester film on which multiple vapor deposition films or nonwoven fabrics are laminated, a polyurethane film, and a polyethylene film. The thickness of the drug-protecting layer is preferably 10 to 200 mu m, more preferably 10 to 100 mu m, in order to prevent the drug-protecting layer from bending and feeling inconvenience when attached to the skin.

The release-controlled pressure-sensitive adhesive layer according to the present invention is added with a water-soluble polymer in order to closely contact the drug storage layer with the skin, but also to prevent the release of the drug from the skin due to excessive sweat release and to control the skin absorption of the drug. That is, the water-soluble polymer is used to improve the absorption control ability of the drug and improve the adhesion. The water soluble polymer is preferably selected from the group consisting of hydroxyethylcellulose, ethylcellulose polymers, polyvinylpyrrolidone (PVP), polyethylene oxide (PEO), polyethylene glycol (PEG), polyacrylic acid (PAA) Hydroxypropylcellulose (HPC), and the like. The water-soluble polymer is preferably contained in an amount of 0.1 to 10 parts by weight based on the total weight of the release-controlling adhesive layer, more preferably 0.1 to 5 parts by weight in order to minimize release of the drug and desorption by moisture Do.

Further, the release-controlling pressure-sensitive adhesive layer contains a pressure-sensitive adhesive, and as the acrylic pressure-sensitive adhesive, one or two or more functional groups selected from the group consisting of functional groups of -COOH, -0H or -NH2 are preferably used, Butyl acrylate, 2-hydroxyethyl acrylate, methyl methacrylate, methyl acrylate, glycidyl methacrylate, vinyl acetate, N-vinyl-2 One or two or more of the pressure-sensitive adhesives selected from the group consisting of pyrrolidone, diacetone acrylamide, t-octylacrylamide and 2- (dimethylaminoethyl) methacrylate may be mixed and used. The pressure-sensitive adhesive is included in an amount of 31 to 63 parts by weight based on the total weight of the release-controlling pressure-sensitive adhesive layer.

Hereinafter, the present invention will be described in detail with reference to the preferred embodiments, which will be readily apparent to those skilled in the art to which the present invention pertains. The present invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein.

Example

Example  One

3 g of ribastigmine corresponding to 30 parts by weight and 7 g of Eudragit E-100 as a polymer solvent for forming a matrix were dissolved in 6.67 g of methylene chloride to prepare 70 parts by weight of the polymer solution, A drug solution was prepared.

10 g of DT-9301 as an acrylic pressure-sensitive adhesive having a solid content of 35 to 42% was prepared as a solution to be used as a release-controlled adhesive layer to prepare a release-controlled pressure-sensitive adhesive layer.

The drug solution was coated on a PET release film coated with a silicone resin using a wrap coater and then completely dried for 5 minutes at 50 캜 and 100 RPM to form a drug storage layer having a thickness of 55 탆. The release-controlled adhesive layer was prepared by applying a solution prepared for use in the release-controlled adhesive layer onto a PET release film coated with a silicone resin, and then dried in a wrap coater at 100 ° C and 1300 RPM for 5 minutes to completely dry the solvent. Such a release-controlling adhesive layer was made to have a thickness of 20 mu m. Thereafter, the release film of the drug storage layer was removed and lapped with the release-controlled adhesive layer. Thus, the percutaneous absorption preparation according to the present invention was completed.

Example  2

6.6 g of Eudragit E-100, which is a polymer solvent for forming a matrix used in the preparation of the drug solution in the drug storage layer in Example 1, was added in an amount corresponding to 66 parts by weight, and further added as a skin penetration promoter And 0.4 g of IPM corresponding to 4 parts by weight of IPM corresponding to isopropyl myristate was added thereto.

Example  3

6.4 g of Eudragit E-100, a polymer solvent for forming a matrix used for preparing a drug solution in the drug storage layer in Example 1, was added in an amount corresponding to 64 parts by weight, and further added as a skin penetration promoter And 0.6 g of IPM corresponding to 6 parts by weight of IPM corresponding to isopropyl myristate was added.

Example  4

6.2 g of Eudragit E-100, a polymer solvent for forming a matrix used for preparing a drug solution in the drug storage layer in Example 1, was added in an amount corresponding to 62 parts by weight, and further added as a skin penetration promoter A transdermal absorption preparation was completed in the same manner as in Example 1, except that 8 g of IPM corresponding to 8 parts by weight of isopropyl myristate was added.

Example  5

6 g of Eudragit E-100, a polymer solvent for forming a matrix used for preparing a drug solution in the drug storage layer in Example 1, was added in an amount of 60 parts by weight, A percutaneous absorption preparation was completed in the same manner as in Example 1, except that 1 g of IPM corresponding to 10% by weight of IPM corresponding to the propyl methylate was added.

Example  6

26.7 g corresponding to 99 parts by weight of DT-9301 as an acrylic pressure-sensitive adhesive used in the emission-controlling adhesive layer in Example 1 was used, and 1 part by weight of PVP (K90), polyvinylpyrrolidone as a water- Was added in an amount of 0.1 g to prepare a percutaneous absorption preparation in the same manner as in Example 1.

Example  7

6.6 g of Eudragit E-100, which is a polymer solvent for forming a matrix used in the preparation of the drug solution in the drug storage layer in Example 1, was added in an amount corresponding to 66 parts by weight, and further added as a skin penetration promoter 0.4 g of IPM corresponding to 4 parts by weight of isopropyl myristate was added. Further, 26.5 g of the acrylic pressure-sensitive adhesive DT-9301 (99.5 parts by weight) used in the release-controlled pressure-sensitive adhesive layer in Example 1 was used, and 0.5 part by weight of polyvinylpyrrolidone PVP (K90) Was added in an amount of 0.05 g to prepare a transdermal absorption preparation.

Example  8

6.4 g of Eudragit E-100, a polymer solvent for forming a matrix used for preparing a drug solution in the drug storage layer in Example 1, was added in an amount corresponding to 64 parts by weight, and further added as a skin penetration promoter 0.6 g of IPM corresponding to 6 parts by weight of isopropyl myristate was added. Further, 26.5 g of the acrylic pressure-sensitive adhesive DT-9301 (99.5 parts by weight) used in the release-controlled pressure-sensitive adhesive layer in Example 1 was used, and 0.5 part by weight of polyvinylpyrrolidone PVP (K90) Was added in an amount of 0.05 g to prepare a transdermal absorption preparation.

Example  9

6.6 g of E-100, which is a polymer solvent for forming a matrix used in the preparation of the drug solution in the drug storage layer in Example 1, was added to 66 parts by weight of E-100, 0.4 g of IPM corresponding to 4 parts by weight of IPM corresponding to the propyl starch was added. In addition, 99.7 parts by weight of DT-9301, which is an acrylic pressure-sensitive adhesive used in the release-controlled pressure-sensitive adhesive layer in Example 1, was used and 26.7 g of the acrylic pressure-sensitive adhesive corresponding to 1 part by weight of polyvinylpyrrolidone PVP (K90) Was added in the same manner as in Example 1, except that the addition amount of 0.1 g was further added.

Example  10

6.4 g of Eudragit E-100, a polymer solvent for forming a matrix used for preparing a drug solution in the drug storage layer in Example 1, was added in an amount corresponding to 64 parts by weight, and further added as a skin penetration promoter 0.6 g of IPM corresponding to 6 parts by weight of isopropyl myristate was added. In addition, 99.7 parts by weight of DT-9301, which is an acrylic pressure-sensitive adhesive used in the release-controlled pressure-sensitive adhesive layer in Example 1, was used and 26.7 g of the acrylic pressure-sensitive adhesive corresponding to 1 part by weight of polyvinylpyrrolidone PVP (K90) Was added in the same manner as in Example 1, except that the addition amount of 0.1 g was further added.

Example  11

6.6 g of Eudragit E-100, which is a polymer solvent for forming a matrix used in the preparation of the drug solution in the drug storage layer in Example 1, was added in an amount corresponding to 66 parts by weight, and further added as a skin penetration promoter 0.4 g of IPM corresponding to 4 parts by weight of isopropyl myristate was added. In Example 1, 2 g of ethanol was used in the solution used for the release-controlling adhesive layer, 26.64 g of 98 parts by weight of DT-9301 as an acrylic pressure-sensitive adhesive was used, and polyvinylpyrrolidone A percutaneous absorption preparation was completed in the same manner as in Example 1, except that 0.2 g corresponding to 2 parts by weight of PVP (K90) was further added.

Example  12

6.4 g of Eudragit E-100, a polymer solvent for forming a matrix used for preparing a drug solution in the drug storage layer in Example 1, was added in an amount corresponding to 64 parts by weight, and further added as a skin penetration promoter 0.6 g of IPM corresponding to 6 parts by weight of isopropyl myristate was added. In Example 1, 2 g of ethanol was used in the solution used for the release-controlling adhesive layer, 26.64 g of 98 parts by weight of DT-9301 as an acrylic pressure-sensitive adhesive was used, and polyvinylpyrrolidone A percutaneous absorption preparation was completed in the same manner as in Example 1, except that 0.2 g corresponding to 2 parts by weight of PVP (K90) was further added.

Table 1 summarizes the content of each substance according to Examples 1 to 12 in parts by weight.

Comparative Example

As a membrane containing an acrylic adhesive on the drug storage layer and having a drug control function corresponding to the release-controlled adhesive layer of the present invention, Novartis's EXELON PATCH (9 mg / 5 Cm < 2 >) was used.

Experimental Example

Tests were conducted according to the skin permeation test method with Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 and Comparative Example 1, and the content of ribastigmine Was measured by HPLC (High Performance Liquid Chromatography), and the cumulative skin permeation amount for 24 hours was measured. The expected permeation amount per day per percutaneous absorption preparation is shown in Table 2.

High performance liquid chromatography (HPLC) operating conditions

Mobile phase: 0.01M Sodium-1-heptane sulfonate: ACN = 70: 30 (pH 3.0-phospho

ic acid)

Flow rate: 1.0 ml / min

Wavelength: 217 nm

Injection amount: 10 μl

Column: C18 4.6mm x 150mm UG Type

Temperature: 30 ℃

Skin penetration test method

Transmission device: Frantz Diffusion cell

Sample area: 0.636 cm2

Receptor solution: Phosphate buffer (PBS, pH = 7.4)

Stirring speed: 600 rpm

Skin: Human Cadaver skin

 As the IPM content of the drug storage layer increases, the skin permeability tends to increase. However, the physical properties of the patches were adversely affected and the cohesive force within the adhesive layer tended to decrease.

In addition, it can be seen that the permeation amount of the skin can be controlled by using PVP, which is a water-soluble polymer, in addition to IPM.

Thus, the present invention provides a percutaneous absorption preparation having a desired skin permeation amount and skin adhesion, and a method for producing the same.

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the invention is not limited to the disclosed exemplary embodiments, but, on the contrary, is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the appended claims. It is natural.

1. Peripheral adhesive layer
2. Drug storage layer
3. Drug protection layer
4. Release modifier adhesive layer

Claims (13)

In a percutaneous absorption preparation for administration of a drug,
a) a drug storage layer containing ribastigmine, a polymer solvent for forming a matrix, and a skin penetration enhancer; And
b) a release-controlling adhesive layer located below the drug storage layer and having a release-controlling function upon permeation of the drug; Lt; / RTI >
Wherein the release modifying adhesive layer is attached to the skin, the polymeric solvent is a methacrylate polymer, the skin permeation enhancer comprises isopropyl myristate, and the release modifying adhesive layer comprises polyvinylpyrrolidone (PVP ), And an acrylic pressure-sensitive adhesive,
And 0.1 to 5 parts by weight of a water-soluble polymer in 100 parts by weight of the total amount of the release-controlling and pressure-sensitive adhesive layer. delete The method according to claim 1,
Wherein the drug storage layer is prepared by mixing 20 to 40 parts by weight of ribastigmine, 50 to 60 parts by weight of a polymer solvent for forming a matrix, and 2 to 10 parts by weight of a skin permeation enhancer.
The percutaneous absorption preparation according to claim 1, wherein the methacrylate polymer is Eudragit E100. delete delete delete delete delete The percutaneous absorption preparation according to claim 1, wherein the acrylic pressure-sensitive adhesive contains no functional group or one or two or more functional groups selected from the group consisting of -COOH, -0H, and -NH ₂ functional groups. The percutaneous absorption preparation according to claim 1, wherein the acrylic pressure-sensitive adhesive comprises 31 to 63 parts by weight of 100 parts by weight of the total amount of the pressure-sensitive adhesive layer. Preparing a drug storage layer solution by mixing a drug, a lipid stigmine, a polymer solvent for forming a matrix, and a skin penetration enhancer;
Applying the solution to form a drug storage layer; And
Forming a release-controlling adhesive layer comprising polyvinylpyrrolidone (PVP) as a water-soluble polymer and an acrylic adhesive on one side of the drug storage layer; Lt; / RTI >
Wherein the release modifying adhesive layer is attached to the skin, the polymeric solvent is a methacrylate polymer, the skin permeation enhancer comprises isopropyl myristate,
And 0.1 to 5 parts by weight of a water-soluble polymer in 100 parts by weight of the total amount of the release-controlling and pressure-sensitive adhesive layer. 13. The method of claim 12, wherein the methacrylate polymer is Eudragit E100.

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