KR20080006960A - Transdermal preparations containing hydrophobic non-steroidal anti-inflammatory drugs - Google Patents

Abstract

A transdermal preparation is provided to continuously allow a highly concentrated hydrophobic drug to be absorbed into skin until a patch is detached from the skin with minimized skin side effects and provide the enough adhesive capability during the time of exhibiting the medical efficacy by being attached to the skin. A transdermal preparation for a hydrophobic drug comprises a supportive layer(1) which is the uppermost portion of a layered structure and has the elasticity; a hydrophobic adhesive layer(2) which is layered under the supportive layer and prevents the loss of moisture absorbed from skin and the reverse conversion of the drug; and a drug adhesive layer(3) which is layered under the hydrophobic adhesive layer, includes a drug and attaches the transdermal preparation to the skin and is characterized in that the drug adhesive layer includes a hydrophobic drug such as a non-steroidal antiphlogistics and an acryl adhesive agent and the acryl adhesive agent includes a hydrophilic monomer promoting the skin absorption from the skin and is selected from the group consisting of acrylic acid, methyl methacrylate, ethyl acrylate, hydroxyethyl acrylate, butyl acrylate, octyl acrylate, 2-ethylhexyl acrylate, and hexyl acrylate. The preparation further comprises a release layer(4) which is layered under the drug adhesive layer and protects the drug adhesive layer before use.

Description

Transdermal preparations containing hydrophobic non-steroidal anti-inflammatory drugs

1 is a schematic view showing a lamination structure of a transdermal dosage form according to the present invention.

The present invention relates to transdermal formulations in which high concentrations of hydrophobic drugs can be continuously absorbed into the skin. More specifically, the present invention relates to patches, which are transdermal administration preparations containing one component of nonsteroidal anti-inflammatory drugs, in particular ketoprofen, diclofenac, flubiprofen, felbinac, aceclofenac, loxoprofen. More specifically, the present invention relates to a therapeutic agent for attaching arthritis.

Currently, ketoprofen, diclofenac, flubiprofen for the purpose of treating arthritis. Various transdermal formulations containing nonsteroidal anti-inflammatory drugs, such as felbinac, pyroxycam, and the like, have been developed and marketed. There are many studies on transdermal preparations in line with this market environment.The main research areas are to increase the absorption of drugs for faster and more effective treatments, to reduce skin side effects that can occur in the products to be attached, and to relieve pain after use. It can be largely summarized as a study on adhesive properties that do not cause.

Conventional transdermal formulations containing nonsteroidal anti-inflammatory drugs that are used for the treatment of arthritis can deliver the drug directly to the topical area. These transdermal formulations deliver drugs directly to the affected area to maintain levels in the synovial synovial fluid on which the drug acts, up to one-fifth to one-half the level of oral administration. The drug concentration of the drug is about 100 times lower than oral drugs, and there are no side effects such as gastrointestinal disorders. Due to these advantages, transdermal formulations containing NSAIDs are widely used, but are still recognized to have lower efficacy than oral formulations. Therefore, if the concentration of drug in the affected area such as synovial fluid of the joint can be increased above the oral drug by increasing the absorbency of the drug, the therapeutic effect equivalent to the oral drug can be obtained without causing the gastrointestinal side effects of the NSAIDs. It is expected to be more effective in the treatment of arthritis.

In the field of drug-in-adhesive type transdermal preparation, the drug absorption enhancer is used to increase the diffusion and dispensing effect of the drug by using a drug absorption enhancer, or to contain the drug concentration in the system in a saturated concentration. Techniques for maintaining high chemical activity or hydrating the skin to lower the penetration barrier of the drug to facilitate the diffusion of the drug are widely used.

As a more specific example, Korean Patent No. 10-0213465 prepared a patch in a multilayer structure to obtain high drug absorption. It uses an elastic support and uses a pressure-sensitive adhesive layer for adhesion between the support and the drug layer, polyvinylpyrrolidone or ethylene-vinylacetate to give a drug layer containing a high concentration of the drug, and gives adhesion and simultaneously releases the drug. It consists of a pressure-sensitive adhesive layer to improve high drug absorption and skin adhesion. However, since the multilayer structure is not easy to manufacture, and the adhesive layer is set aside to give adhesion, there is a limit in obtaining a quick effect as the drug absorption rate is slowed.

One technique for attempting to increase drug absorption using a difference in the solubility of a drug by attaching a transdermal formulation to the skin and using moisture released from the skin is disclosed in Korean Patent No. 10-0188180. One of the disclosed techniques contains a drug in a plurality of adhesive layers composed of acrylic adhesive resins having different water-functions, and an acrylic pressure-sensitive adhesive layer having a low water-function in the lowermost layer, so that the moisture is transferred to the upper layer even when the initial drug is absorbed and the amount of drug is reduced. By moving, the drug solubility of the upper layer was reduced to supply the drug to the lower layer so that the drug could be continuously delivered to the skin. Another technique disclosed in this patent is to have a high functional acrylic pressure-sensitive adhesive layer is arranged in the lowermost layer so that a high concentration of drug is initially absorbed and drug absorption decreases over time so that it is constantly absorbed. In the case of the first technique, since only the acrylic pressure-sensitive adhesive layer having similar solubility to the drug is used, the difference in concentration of the drug is not so large that the desired effect is not large, and the difference in drug concentration between the pressure-sensitive adhesive layers during the long time storage is obtained to obtain the desired effect. Can't. In the second case, when the acrylic adhesive layer having a high water content is arranged at the lowermost layer, there is a problem in that high drug absorption cannot be obtained because the transition of the hydrophobic drug contained in the upper layer is not smooth.

In addition, U.S. Patent No. 6,676,962 contains a non-sterile anti-inflammatory analgesic agent having a carboxyl group as an active substance, has a stretch in one or two directions as a support inactive to the active substance, and particularly as a technique for transdermal administration formulations using an acrylic adhesive base. In consideration of ease of use, it is easy to use in the joint area by using woven-fabric, knitted fabric, nonwoven fabric, and elastic foam (PE, PVC, EVA). A technique for obtaining higher drug absorption is disclosed.

In US Pat. No. 5,702,720, polyvinylpyrrolidone, which is a hydrophilic polymer, is used in order to allow the moisture emitted from the skin to be easily discharged to the outside and to prevent the physical properties of the patch from deteriorating. Particularly, polyvinylpyrrolidone, a hydrophilic polymer, was used for the reduction of adhesive strength to reduce pain and the cohesiveness for leaving no adhesive on the skin.

Korean Patent Laid-Open Publication No. 2002-035451 discloses a technique for transdermal administration formulations containing diclofenac diethyl ammonium, which also uses hydrophilic polymer polyvinylpyrrolidone to absorb moisture such as sweat emitted from the skin, thereby preventing it from sticking. It discloses a technique that keeps the adhesive well and does not leave an adhesive when it is peeled off.

In addition to the invention exemplified as described above, many techniques are disclosed in the art, but by reaching and sustaining a high drug absorption rate in a short time, the therapeutic effect can be maximized, and the patient's compliance due to optimal adhesive properties is improved, There is still a need for the development of a patch that is easy to manufacture, and the present invention has been attempted to meet these needs.

As described above, the present invention aims to deliver a hydrophobic drug more quickly and effectively through the skin. In general, the absorption of the drug through the skin peaks above a certain level, the absorption tends to gradually decrease due to the loss of the drug. It is an object of the present invention to provide a transdermal formulation that can be absorbed through the skin of a high concentration of drugs continuously to overcome the above problems until the patch containing the drug from the skin.

It is yet another object of the present invention to provide a transdermal formulation for which the drug layer itself has adhesive properties.

Another object of the present invention is to provide a transdermal formulation for minimizing skin side effects.

It is yet another object of the present invention to maintain good adhesion until the transdermal formulation is detached from the skin.

Another object of the present invention is to treat arthritis more quickly and effectively by delivering a high concentration of nonsteroidal anti-inflammatory drugs directly to the affected area.

In order to achieve the above object, the transdermal dosage form according to the present invention is a transdermal dosage form of a laminated structure for a hydrophobic drug,

A support layer 1 having elasticity as the top of the laminated structure;

A hydrophobic adhesive layer (2) laminated under the support layer and including a hydrophobic adhesive to prevent loss of moisture absorbed from the skin and reverse migration of the drug; A drug adhesive layer (3) laminated under the hydrophobic adhesive layer and containing a drug and adhering the transdermal formulation to the skin, wherein the drug adhesive layer comprises a hydrophobic drug and an acrylic adhesive and the acrylic adhesive is removed from the skin It is characterized by including a hydrophilic monomer for promoting the water absorption of.

The transdermal dosage form is characterized in that it further comprises a release layer 4 which protects the drug adhesive layer until use of the transdermal dosage form and which is peeled off during use.

Hereinafter, the transdermal administration preparation according to the present invention will be described in more detail.

1 shows a laminated structure of a transdermal dosage form according to the present invention. Detailed description of each layer is as follows.

[Configuration of Transdermal Dosage Formulation According to the Present Invention]

1) Supporting layer (1): It must have elasticity for application to the moving joint site.

2) Hydrophobic adhesive layer (2): It is a lipophilic adhesive layer to prevent the moisture from the skin is volatilized to the outside to maintain the moisture in the drug layer to maximize the chemical activity of the drug.

3) Drug adhesive layer (3): It consists of acrylic adhesive containing N-vinylpyrrolidone as monomer to contain high concentration of drugs and drugs, absorption enhancer and other physical property controlling agent (excipients, etc.) and imparts adhesion. .

4) Peeling layer (4): It aims to protect the drug adhesion layer 3 until a transdermal administration formulation is used.

1. Support layer (1)

Transdermal administration formulations containing nonsteroidal anti-inflammatory drugs are used for musculoskeletal related diseases such as rheumatism, arthritis, and the like, and in particular, since they are mainly used for joints with high mobility, a flexible support is used. As the flexible support, woven and non-woven fabrics made of polyester, polyvinyl, urethane, cotton, or the like are used.

The transdermal dosage form according to the present invention comprises a support layer (1) made of a woven or nonwoven fabric having elasticity in one or both directions, wherein the woven fabric is composed of polyester resin, urethane resin or cotton, and the nonwoven fabric is made of poly It is characterized by consisting of an ester resin or a urethane resin. While the woven or nonwoven fabric made of the polyester-based or polyurethane-based or cotton raw material has elasticity, most of the woven or non-woven fabrics do not have an occlusion effect. In the transdermal dosage form according to the present invention, a hydrophobic adhesive layer 2 is present under the support layer 1, and the hydrophobic adhesive layer 2 is responsible for the sealing effect as described above.

2. Hydrophobic adhesive layer (2)

As described above, in the transdermal dosage form according to the present invention, the hydrophobic adhesive layer 2 serves to compensate for the shortcomings of the support layer 1 that are elastic but lack a sealing effect. In order to give the sealing effect, the hydrophobic adhesive layer (2) preferably comprises a polyisobutylene, a styrene-isoprene-styrene-based, or a styrene-butadiene-styrene-based adhesive. Through this sealing effect it is possible to prevent the drug back to the support layer (1).

A more important role of the hydrophobic adhesive layer 2 is to prevent external diffusion of moisture absorbed from the skin to the drug adhesive layer 3 so that the chemical activity of the drug in the drug adhesive layer 3 is maximized. To be maintained. The drug adhesive layer 3 contains a high concentration of the drug before applying to the skin, and since the moisture emitted from the skin flows into the drug adhesive layer 3 from the skin application, the solubility of the hydrophobic drug is gradually lowered. By maintaining the drug in the drug adhesive layer (3) in a saturated concentration continuously while applying the transdermal administration formulation by the so that the skin absorption rate of the drug can be maintained to the maximum. However, when the water flowing from the skin is discharged to the outside through the drug adhesive layer (3) does not have the same effect as above. In order to prevent this, the hydrophobic adhesive layer 2 may be laminated on the drug adhesive layer 3, in particular, to prevent external discharge of moisture. Preferably, a very low solubility (less than 3%) adhesive for the drug was used for the hydrophobic adhesive layer 2 to prevent the back diffusion of the drug. That is, the function of the drug adhesive layer 3 as described above can be achieved only when the divergence of moisture is prevented by the hydrophobic adhesive layer (2).

The hydrophobic adhesive layer 2 also has a function of warming the attachment site, thereby improving blood circulation and drug absorption. Polyisobutylene (PIB) adhesives, styrene-isoprene-styrene (SIS) or styrene-butadiene-styrene (SBS) -based adhesives do not interfere with the movement of the support layer 1 without affecting the movement of the joint area. Since it has the merit which can be matched, it is preferable as an adhesive which comprises the hydrophobic adhesive layer 2.

Adhesives that may be used as the hydrophobic adhesive layer 2 include Vistanex MML100 (Mv 1,200,000), MML 120 (Mv 1,600,000) from Exxon-Mobile, Oppanol B10SFN (Mv 40,000) from BSF, B12SNF (Mv 55,000), and B13SFN (Mv 65,000). ), Polyisobutylene such as B15SFN (Mv 85,000), styrene-isoprene-styrene copolymers such as Kraton D1107, D1112, D1113 (Shell Chemicals), Kraton D1101, D1102 (Shell Chemicals), etc. One of the same styrene-butadiene-styrene copolymers has a basic structure, and may additionally contain a liquid component such as a polymer resin, liquid paraffin, etc. to compensate for adhesive force. It is preferable that the coating thickness of the hydrophobic adhesive layer 2 is 40-100 micrometers. When the thickness of the hydrophobic adhesive layer 2 is less than 40 micrometers, the effect of suppressing moisture release is low, and when the thickness of 100 micrometers or more, there is a disadvantage that the feeling of use is low on the skin.

3. Drug adhesive layer (3)

The amount of drug absorbed in the transdermal formulation for delivering the drug through the skin can be expressed mathematically as shown in Equation 1 below.

는 피부를 통해 흡수된 약물의 양, K 는 약물의 분배　 계수, D 는 약물의 확산 계수, C _M 은 패취 내의 약물 농도, A 는　 패취의 면적,　 L 은 피부의 두께를 각각 의미한다. Where

Is the amount of drug absorbed through the skin, K is the distribution coefficient of the drug, D is the diffusion coefficient of the drug, C _M is the drug concentration in the patch, A is the patch area, and L is the skin thickness.

The distribution coefficient K in Equation 1 may be expressed as a ratio of the saturation concentration ( C _SS ) in the skin and the saturation concentration ( C _SM ) of the drug in the patch, respectively, and may be expressed as Equation 2 below. .

Substituting Equation 2 into Equation 1 may be expressed as Equation 3.

Skin absorption enhancers enhance the absorption of the drug by lowering the barrier function of the skin to make the drug more easily spread or increase the solubility of the drug in the skin to allow the distribution of large amounts of the drug into the skin. In addition, the concentration of drug in the patch can be designed to achieve maximum drug absorption by saturating concentration, that is, by bringing C _M closer to C _SM . However, as can be inferred from Equation 3, the initial state of the patch is the saturation of the drug, but when the drug is attached to the skin and the drug begins to be absorbed, the concentration of the drug in the patch gradually decreases. Absorption is lowered.

Therefore, the inventors have found that the concentration of drug in the patch to maintain the highest level while adhering drug absorption from the patch containing the nonsteroidal anti-inflammatory drug to the skin (drug release rate of the patch) during saturation concentration for the entire period of use. Was to be maintained.

Transdermal administration formulations according to the invention consist of an acrylic adhesive having a drug, an absorption enhancer, and a hydrophilic portion for the purpose of maintaining the drug at a saturated concentration in the patch during application to the skin. Herein, the hydrophilic acrylic pressure-sensitive adhesive contains a certain amount of hydrophilic monomers such as N-vinylpyrrolidone in addition to the monomers contained in the basic acrylic pressure-sensitive adhesive, which is hydrophilic but also ketoprofen, diclofenac, flubiprofen, felbinac, aceclofenac, and loxoprofen. It is designed to contain a large amount of drugs such as. In order to impart hydrophilicity to the acrylic adhesive, in addition to the N-vinylpyrrolidone, the molecular weight of polyethylene glycol, pyrrolidonethyl acrylate (pyrrolidonethyl acrylate), polyethylene glycol monomethacrylate (polyethylene glycol monomethacrylate, polyethylene glycol) is 100 ~ 1000), hydrophilic monomers such as polyethylene glycol monomethyl ether monomethacrylate (polyethylene monomethyl ether monomethacrylate, the molecular weight of polyethylene glycol is 100 ~ 2000) and the like can be used.

The monomer of the acrylic pressure-sensitive adhesive of the drug adhesive layer is acrylic acid, methyl methacrylate, methyl acrylate, ethyl acrylate, butyl acrylate, and butyl acrylate. ), Octyl acrylate (octyl acrylate), 2-ethylhexyl acrylate (2-ethylhexyl acrylate), hexyl acrylate (hexyl acrylate) and the like can be used.

The patch was prepared and applied to in vitro drug absorption experiments and human skin to confirm drug absorption. As a result, it was confirmed that the absorbency of the drug remained high for more than 24 hours after reaching the peak. This phenomenon allows the drug to be contained in the patch in the absence of water due to the hydrophilic monomers, which are components of the acrylic adhesive, and when the patch is attached to the skin, moisture is quickly introduced from the skin to the hydrophilic environment. By slowly changing the solubility of the hydrophobic drug, the drug can be released into the skin at a consistently high concentration while sticking, thereby maintaining the skin absorption rate of the drug for a long time.

As described above, in general, transdermal formulations have a high initial drug absorption and then the drug is absorbed into the skin over time, thereby lowering the concentration of the drug, thereby gradually decreasing the skin absorbency of the drug. In order to improve this problem, the present invention is designed to maintain the chemical concentration of the drug by maintaining the saturation concentration of the drug in the drug adhesive layer (3) during application to the skin. That is, in the absence of water in the drug adhesive layer (3), a large amount of non-steroidal anti-inflammatory drugs such as ketoprofen can be dissolved to contain a large amount of the drug, but the patch adheres to the skin so that the water is the drug layer. Solubility of the hydrophobic drug is gradually lowered when absorbed into the drug, and even though the drug is absorbed through the skin and the concentration of the drug in the drug adhesive layer 3 is lowered, the chemical activity of the drug is maximized as before the patch is used. I can keep it. Such a mechanism can be achieved by introducing hydrophilic N-vinylpyrolidone into the monomer as an acrylic adhesive component. That is, by using an acrylic adhesive containing a specific amount of hydrophilic monomer as a drug layer, it is characterized in that the absorption of the drug is maximized by changing the solubility of the drug depending on the water content in the acrylic adhesive. Only by means of a separate means for controlling the evaporation of water once absorbed into the drug layer made of a hydrophilic acrylic pressure-sensitive adhesive is able to function in the present invention, the separate means is a hydrophobic pressure-sensitive adhesive layer (2) )to be.

On the other hand, the purpose can be achieved by adding a large amount of oil or surfactant to contain a drug such as the non-steroidal anti-inflammatory drugs described above in a high concentration in the drug adhesive layer (3). However, in this case, although a large amount of drug may be contained in the patch, the affinity between the drug adhesive layer and the drug is high due to the oil or surfactant added in the drug adhesive layer 3, and thus the negative effect on the skin absorption of the drug is increased. Crazy In addition, the use of oils or surfactants tends to lower the adhesion than the use of polymer materials, and may cause the adhesive to remain on the skin when peeled off after application.

If the moisture from the skin is present between the patch and the skin, the patch may detach or cause skin irritation during application. However, in the present invention, the moisture discharged from the skin is absorbed into the drug layer, so that problems such as detachment of the patch or skin irritation occur during application.

Representative examples of the acrylic adhesive containing the hydrophilic monomer used in the present invention include a 2-ethylhexyl acrylate / vinylpyrrolidone copolymer solution which is developed in Japan's chemistry and used in transdermal absorbents and is listed in the Japanese "Drug Additive Dictionary". Can be. In addition, it is possible to manufacture by changing the composition of the acrylic monomer according to the purpose, in particular, by changing the content of N-vinyrrolilidone to synthesize the pressure-sensitive adhesive to be easily used to control the water absorption capacity and solubility of the drug to be obtained in the present invention. Can be. The content of N-vinylpyrrolidone contained in the acrylic pressure-sensitive adhesive may be used up to 2 to 50% by weight, and examples thereof may be described by reference examples, but are not limited thereto.

The content of the hydrophilic acrylic pressure-sensitive adhesive in the drug adhesive layer 3 is preferably 40 to 80% by weight of the total drug adhesive layer composition, more preferably 50 to 70% by weight. If the content of the acrylic adhesive is less than 40% by weight, the adhesion to the skin is not sufficient, and if it exceeds 80% by weight, the amount of the drug is relatively decreased, so that the absorption of the drug is lowered.

Absorption enhancers include higher fatty acids and derivatives having 10 to 18 carbon atoms. Representative examples include lauryl alcohol, oleyl alcohol, sorbitan monolaurate, polyethylene glycol monolaurate, propylene glycol monolaurate, glycerin monolaurate, Caprylic monolaurate, isopropyl myristate, and the like, other transcutol and the like may be used, and the above absorption enhancers may be used alone or in combination.

The hydrophobic drug of the drug adhesive layer is preferably contained in an amount of 10 to 40% by weight of the total drug adhesive layer, more preferably 15 to 30% by weight. When the amount of the drug is less than 10% by weight, the efficacy of the drug is insignificant, and when the amount is greater than 30% by weight, the crystals of the drug are formed or the cohesive force of the adhesive layer is drastically reduced. Occurs.

4. Release layer (4)

Laminated under the drug adhesive layer (3) to protect the drug adhesive layer (3) until the transdermal formulation is used, which is peeled off when applied to the skin, coated with silicone or teflon on the polyester film or paper It is preferable.

In the following, the present invention is described in more detail by way of examples, but the examples do not limit the scope of the invention according to the claims of the patent.

[Reference Example]

(A) Preparation of Acrylic Adhesive: AP05

95 parts by weight of 2-ethylhexyl acrylate, 5 parts by weight of N-vinylpyrrolidone, azobisisobutyronitrile (AIBN) 0.5 part by weight, 200 parts by weight of ethyl acetate were added to a reaction vessel equipped with a reflux condenser and a stirrer, and polymerization was performed for 15 hours while slowly stirring at 65 degrees Celsius under a nitrogen atmosphere. An appropriate amount of ethyl acetate was added to the obtained polymer solution, and the content of solid content was adjusted to about 30%. In this way, the copolymer of 2-ethylhexyl acrylate / vinylpyrrolidone was obtained as an acrylic adhesive. The weight average molecular weight of the obtained acrylic adhesive was about 1.2 million.

(B) Preparation of Acrylic Pressure Sensitive Adhesive: AP10

90 parts by weight of 2-ethylhexyl acrylate, 10 parts by weight of N-vinylpyrrolidone, azobisisobutyronitrile 0.5 parts by weight of copolymer was added by adding 200 parts by weight of ethyl acetate under the same conditions as in Reference Example (A). An appropriate amount of ethyl acetate was added to the obtained polymer solution, and the content of solid content was adjusted to about 30%. In this way, the copolymer of 2-ethylhexyl acrylate / vinylpyrrolidone was obtained as an acrylic adhesive. The weight average molecular weight of the obtained acrylic adhesive was about 1.2 million.

(C) Preparation of acrylic pressure sensitive adhesive: AP20

80 parts by weight of 2-ethylhexyl acrylate, 20 parts by weight of N-vinylpyrrolidone and 0.5 parts by weight of azobisisobutyronitrile were added and copolymerized with 200 parts by weight of ethyl acetate under the same conditions as in Reference Example (A). An appropriate amount of ethyl acetate was added to the obtained polymer solution, and the content of solid content was adjusted to about 30%. In this way, the copolymer of 2-ethylhexyl acrylate / vinylpyrrolidone was obtained as an acrylic adhesive. The weight average molecular weight of the obtained acrylic adhesive was about 1.1 million.

(D) Preparation of acrylic pressure sensitive adhesive: AP30

70 parts by weight of 2-ethylhexyl acrylate, 30 parts by weight of N-vinylpyrrolidone, and 0.5 parts by weight of azobisisobutyronitrile were added and copolymerized with ethyl acetate under the same conditions as in Reference Example (A). An appropriate amount of ethyl acetate was added to the obtained polymer solution, and the content of solid content was adjusted to about 30%. In this way, the copolymer of 2-ethylhexyl acrylate / vinylpyrrolidone was obtained as an acrylic adhesive. The weight average molecular weight of the acrylic adhesive obtained at this time was about 1 million.

(E) Preparation of acrylic adhesive: AP40

60 parts by weight of 2-ethylhexyl acrylate, 40 parts by weight of N-vinylpyrrolidone, and 0.5 parts by weight of azobisisobutyronitrile were added and copolymerized with ethyl acetate under the same conditions as in Reference Example (A). An appropriate amount of ethyl acetate was added to the obtained polymer solution, and the content of solid content was adjusted to about 30%. In this way, the copolymer of 2-ethylhexyl acrylate / vinylpyrrolidone was obtained as an acrylic adhesive. The weight average molecular weight of the acrylic adhesive obtained at this time was about 1 million.

Comparative Example 1

A commercially available acrylic adhesive Durotech 87-2074 (National Starch & Chemicals) 8.0 g (based on the solids of the adhesive, hereinafter), 1.5 g ketoprofen, 0.5 g propylene glycol monolaurate was added to the beaker and stirred for 1 hour A solution containing a drug having a uniform phase was prepared, the bubble was removed, and then coated on a siliconized polyester film 4 so as to have a thickness of 50 μm after drying, followed by drying at 80 ° C. for 20 minutes. After drying, a patch (20 × 40 cm 2) was prepared by covering the support 1 (polyester stretchable woven fabric) on the drug adhesive layer 3 coated on the film 4 and compressing it using a roll.

Comparative Example 2

The pressure-sensitive adhesive layer contains 7.3 g of Durotech 87-2074, 2.2 g of ketoprofen and 0.5 g of glycerol monolaurate in a beaker and stirred for 1 hour to prepare a solution with a uniform phase, and then remove bubbles. After drying, the film was coated on a siliconized polyester film 4 so as to have a thickness of 50 μm, dried at 80 ° C. for 20 minutes, and then the support 1 (polyester elastic nonwoven fabric) was covered on the adhesive layer 3 coated on the film. Compressed using a roll to produce a patch (20 x 40 cm 2).

Comparative Example 3

The pressure-sensitive adhesive layer containing the drug was uniformly prepared by adding 7.4 g of AP10 (based on the solid content of the adhesive, which is omitted later), 2.1 g of ketoprofen, and 0.5 g of glycerol monolaurate in a beaker and stirring for 1 hour. A solution having a phase was removed, bubbles were removed, and then coated on a siliconized polyester film 4 so as to have a thickness of 50 μm after drying, followed by drying at 80 ° C. for 20 minutes, followed by an adhesive layer 3 coated on the film. The support 1 (polyester stretchable nonwoven fabric) was covered on the top and pressed using a roll to prepare a patch (20 × 40 cm 2).

<Comparative Example 4>

The pressure-sensitive adhesive layer containing the drug was prepared by adding 7.0 g of AP20, 2.5 g of ketopropene, and 0.5 g of glycerol monolaurate in a beaker and stirring for 1 hour to prepare a solution having a uniform phase. After removal of the coating, it was coated on a siliconized polyester film 4 so that the thickness after drying was 50 μm, and dried at 80 ° C. for 20 minutes, and then on the adhesive layer 3 coated on the film, the support 1 (polyester stretchable nonwoven fabric) ) And pressed using a roll to produce a patch (20 x 40 cm 2).

Comparative Example 5

The hydrophobic adhesive layer 2 including the hydrophobic adhesive is 50 g of Oppanol® B12SNF (BASF), a low molecular weight polyisobutylene (Mv 55,000), and Vistanex MML100 (Exxon-Mobile), a high molecular weight polyisobutylene. (Mv 1,200,000) 20 g, hydrogenated petroleum resin, 30 g of Sukroez Su-120 (Koron Emulsification), 300 ml of hexane were added to a beaker, stirred to prepare a uniform solution, and dried on a silicone-treated polyester film and then the thickness was 30 It was coated so as to have a thickness of 占 퐉 and dried at 60 占 폚 for 10 minutes to cover the stretchable support 1 (polyester stretchy woven fabric) and crimped using a roll. The drug adhesive layer 3 containing the drug is an acrylic pressure-sensitive adhesive AP 7.3 g, ketoprofen 2.2 g, glycerol monolaurate 0.5 g prepared according to the above reference example in a beaker and stirred for 1 hour to form a uniform phase. The solution which had it was prepared, the bubble was removed, and it coat | coated to the siliconized polyester film 4 so that the thickness after drying might be 50 micrometers, and it dried at 80 degreeC for 20 minutes. The film was removed from the hydrophobic adhesive layer 2 prepared in advance, and laminated on the dry drug adhesive layer 3 to prepare a patch (20 × 40 cm 2).

<Example 1>

50 g of Oppanol® B12SNF (Mv 55,000), a low molecular weight polyisobutylene, as a hydrophobic adhesive layer (2), 20 g of Vistanex MML100, a high molecular weight polyisobutylene, and 30 g of hydrogenated petroleum resin Regalite R 1100 (Eastman) In addition, 300 ml of hexane was added to a beaker and stirred to prepare a uniform solution, and then dried on a silicone-treated polyester film to have a thickness of 50 μm and dried at 60 ° C. for 10 minutes. The stretchable support 1 was covered on the prepared hydrophobic adhesive layer 2 and pressed using a roll. The drug adhesive layer 3 containing the drug is prepared by acryl 7.57 g of acrylic adhesive AP05, 2.1 g of ketopropene, and 0.5 g of propylene glycol monolaurate prepared in the above reference example, and stirred for 1 hour to form a uniform phase. A solution having the same was prepared by removing the bubbles and coating the polyester film 4 treated with silicon so as to have a thickness of 50 占 퐉 after drying, followed by drying at 80 ° C for 20 minutes. The film was removed from the previously prepared hydrophobic adhesive layer 2 and laminated on the dry drug adhesive layer 3 to prepare a patch (20 × 40 cm 2).

<Example 2>

The hydrophobic adhesive layer 2 was manufactured similarly to the method manufactured in Example 1. Drug-containing adhesive layer (3) containing the drug is a homogeneous phase by adding 7.3 g of acrylic adhesive AP10, 2.2 g of ketopropene, 0.5 g of propylene glycol monolaurate prepared in the above reference example into a beaker and stirring for 1 hour. A solution having the same was prepared by removing the bubbles and coating the polyester film 4 treated with silicon so as to have a thickness of 50 占 퐉 after drying, followed by drying at 80 ° C for 20 minutes. The film was removed from the previously prepared hydrophobic adhesive layer 2 and laminated on the dry drug adhesive layer 3 to prepare a patch (20 × 40 cm 2).

<Example 3>

The hydrophobic adhesive layer 2 was manufactured similarly to the method manufactured in Example 1. Drug-containing adhesive layer (3) containing the drug is prepared in accordance with the above reference example acrylic adhesive AP20 7.3 g, ketoprofen 2.2 g, propylene glycol monolaurate 0.5 g into a beaker and stirred for 1 hour to form a uniform phase A solution having the same was prepared by removing the bubbles and coating the polyester film 4 treated with silicon so as to have a thickness of 50 占 퐉 after drying, followed by drying at 80 ° C for 20 minutes. The film was removed from the previously prepared hydrophobic adhesive layer 2 and laminated on the dry drug adhesive layer 3 to prepare a patch (20 × 40 cm 2).

<Example 4>

The hydrophobic adhesive layer 2 was manufactured similarly to the method manufactured in Example 1. Drug-containing adhesive layer (3) containing the drug is put in a beaker 7.3 g of acrylic pressure-sensitive adhesive AP30, 2.2 g ketopropene, 0.5 g of glycerol monolaurate prepared according to the above reference example and stirred for 1 hour to have a uniform phase The solution was prepared by removing the air bubbles and then coating the siliconized polyester film 4 so as to have a thickness of 50 μm after drying, followed by drying at 80 ° C. for 20 minutes. The film was removed from the previously prepared hydrophobic adhesive layer 2 and laminated on the dry drug adhesive layer 3 to prepare a patch (20 × 40 cm 2).

Example 5

The hydrophobic adhesive layer 2 was manufactured to have a thickness of 40 μm by the same method as prepared in Example 1. Drug-containing adhesive layer (3) containing the drug is put in a beaker to 7.3 g of acrylic adhesive AP30, 2.2 g ketopropene, 0.5 g propylene glycol monolaurate prepared according to the reference example in a beaker and stirred for 1 hour to form a uniform phase A solution having the same was prepared by removing the bubbles and coating the polyester film 4 treated with silicon so as to have a thickness of 50 占 퐉 after drying, followed by drying at 80 ° C for 20 minutes. The film was removed from the previously prepared hydrophobic adhesive layer 2 and laminated on the dry drug adhesive layer 3 to prepare a patch (20 × 40 cm 2).

<Example 6>

The hydrophobic adhesive layer 2 is 50 g of Kraton D1107 (Shell Chemicals), a styrene-isoprene-styrene copolymer, 30 g of hydrogenated petroleum resin Regalite R 1100 (Eastman), 30 g of liquid paraffin, and 300 ml of hexane in a beaker. After stirring and preparing into a uniform solution, and dried to a silicon treated polyester film to a thickness of 50 ㎛ and dried at 60 ℃ for 10 minutes to prepare a stretchable support (1) (polyester stretch fabric) thereon Covered and pressed using a roll. Drug-containing adhesive layer (3) containing the drug is put in a beaker to 7.3 g of acrylic adhesive AP30, 2.2 g ketopropene, 0.5 g propylene glycol monolaurate prepared according to the reference example in a beaker and stirred for 1 hour to form a uniform phase A solution having the same was prepared by removing the bubbles and coating the polyester film 4 treated with silicon so as to have a thickness of 50 占 퐉 after drying, followed by drying at 80 ° C for 20 minutes. The film was removed from the previously prepared hydrophobic adhesive layer 2 and laminated on the dry drug adhesive layer 3 to prepare a patch (20 × 40 cm 2).

<Example 7>

Hydrophobic adhesive layer (2) is 50 g Kraton D1101 (Shell Chemicals), a styrene-butadiene-styrene copolymer, 30 g hydrogenated petroleum resin Regalite R 1100 (Eastman), 30 g liquid paraffin, 300 ml hexane in a beaker After stirring and preparing into a uniform solution, dried on a siliconized polyester film and then coated to a thickness of 50 μm and dried at 60 ° C. for 10 minutes to cover the elastic support (1) (urethane) and compress using a roll. Prepared. Drug-containing adhesive layer (3) containing the drug is put in a beaker to 7.3 g of acrylic adhesive AP30, 2.2 g ketopropene, 0.5 g propylene glycol monolaurate prepared according to the reference example in a beaker and stirred for 1 hour to form a uniform phase A solution having the same was prepared by removing the bubbles and coating the polyester film 4 treated with silicon so as to have a thickness of 50 占 퐉 after drying, followed by drying at 80 ° C for 20 minutes. The film was removed from the previously prepared hydrophobic adhesive layer 2 and laminated on the dry drug adhesive layer 3 to prepare a patch (20 × 40 cm 2).

Example 8

The hydrophobic adhesive layer 2 was manufactured to have a thickness of 60 μm by the same method as prepared in Example 1. Drug-containing adhesive layer (3) containing the drug is a 7.0 g of acrylic pressure-sensitive adhesive AP20 prepared according to the reference example, 2.0 g of ketoprofen, 1.0 g of glycerol monolaurate in a beaker and stirred for 1 hour to have a uniform phase The solution was prepared by removing the air bubbles and then coating the siliconized polyester film 4 so as to have a thickness of 50 μm after drying, followed by drying at 80 ° C. for 20 minutes. The film was removed from the previously prepared hydrophobic adhesive layer 2 and laminated on the dry drug adhesive layer 3 to prepare a patch (20 × 40 cm 2).

Example 9

The hydrophobic adhesive layer 2 was manufactured similarly to the method manufactured in Example 1. Drug-containing adhesive layer (3) containing the drug is a 7.0 g of acrylic pressure-sensitive adhesive AP30, 2.5 g ketopropene, 0.5 g of glycerol monolaurate prepared according to the reference example in a beaker and stirred for 1 hour to have a uniform phase The solution was prepared by removing the air bubbles and then coating the siliconized polyester film 4 so as to have a thickness of 50 μm after drying, followed by drying at 80 ° C. for 20 minutes. The film was removed from the previously prepared hydrophobic adhesive layer 2 and laminated on the dry drug adhesive layer 3 to prepare a patch (20 × 40 cm 2).

<Example 10>

The hydrophobic adhesive layer 2 was manufactured similarly to the method manufactured in Example 1. Drug-containing adhesive layer (3) containing the drug is put into a beaker 6.7 g of acrylic pressure-sensitive adhesive AP40, 2.8 g ketopropene, 0.5 g of glycerol monolaurate prepared according to the above reference example and stirred for 1 hour to have a uniform phase The solution was prepared by removing the air bubbles and then coating the siliconized polyester film 4 so as to have a thickness of 50 μm after drying, followed by drying at 80 ° C. for 20 minutes. The film was removed from the previously prepared hydrophobic adhesive layer 2 and laminated on the dry drug adhesive layer 3 to prepare a patch (20 × 40 cm 2).

<Example 11>

The hydrophobic adhesive layer 2 was manufactured similarly to the method manufactured in Example 1. The drug adhesive layer 3 containing the drug is a solution having a uniform phase by adding 7.0 g of acrylic pressure sensitive adhesive AP30, 2.5 g of ketopropene, and 0.5 g of isopropyl alcohol prepared in the reference example in a beaker and stirring for 1 hour. It was prepared by removing the air bubbles and then coating the siliconized polyester film 4 so as to have a thickness of 50 μm after drying, followed by drying at 80 ° C. for 20 minutes. The film was removed from the previously prepared hydrophobic adhesive layer 2 and laminated on the dry drug adhesive layer 3 to prepare a patch (20 × 40 cm 2).

<Example 12>

The hydrophobic adhesive layer 2 was manufactured similarly to the method manufactured in Example 1. The drug adhesive layer 3 containing the drug is a solution having a uniform phase by adding 7.0 g of acrylic pressure sensitive adhesive AP30, 2.5 g ketoprofen, and 0.5 g of transcutol, prepared in accordance with the above reference example, into a beaker and stirring for 1 hour. It was prepared by removing the bubbles and coating the polyester film 4 treated with silicon so as to have a thickness of 50 탆 after drying, followed by drying at 80 ° C. for 20 minutes. The film was removed from the previously prepared hydrophobic adhesive layer 2 and laminated on the dry drug adhesive layer 3 to prepare a patch (20 × 40 cm 2).

Example 13

The hydrophobic adhesive layer 2 was manufactured similarly to the method manufactured in Example 1. Drug-containing adhesive layer 3 containing the drug is a solution having a uniform phase by putting 7.0 g of acrylic adhesive AP20, 2.5 g of diclofenac, and 0.5 g of propylene glycol monolaurate prepared according to the above reference example into a beaker and stirring for 1 hour. It was prepared by removing the bubbles, and then coated on a silicone-treated polyester film 4 so that the thickness after drying was 50 µm and dried at 80 ° C. for 20 minutes. The film was removed from the previously prepared hydrophobic adhesive layer 2 and laminated on the dry drug adhesive layer 3 to prepare a patch (20 × 40 cm 2).

<Example 14>

The hydrophobic adhesive layer 2 was manufactured similarly to the method manufactured in Example 1. Drug-containing adhesive layer (3) containing the drug is a homogeneous phase by adding the acrylic adhesive AP20 7.0 g, flubipropene 2.5 g, propylene glycol monolaurate 0.5 g prepared in accordance with the above reference example in a beaker and stirred for 1 hour The solution was prepared by removing the air bubbles, and then coating the siliconized polyester film 4 so as to have a thickness of 50 μm after drying, followed by drying at 80 ° C. for 20 minutes. The film was removed from the previously prepared hydrophobic adhesive layer 2 and laminated on the dry drug adhesive layer 3 to prepare a patch (20 × 40 cm 2).

<Example 15>

The hydrophobic adhesive layer 2 was manufactured similarly to the method manufactured in Example 1. Drug-containing adhesive layer (3) containing the drug has a uniform phase by stirring the acrylic adhesive AP20 7.0g, Pelbinak 2.5g, 0.5g propylene glycol monolaurate 0.5g prepared according to the reference example in a beaker for 1 hour The solution was prepared by removing the air bubbles and then coating the siliconized polyester film 4 so as to have a thickness of 50 μm after drying, followed by drying at 80 ° C. for 20 minutes. The film was removed from the previously prepared hydrophobic adhesive layer 2 and laminated on the dry drug adhesive layer 3 to prepare a patch (20 × 40 cm 2).

<Example 16>

The hydrophobic adhesive layer 2 was manufactured similarly to the method manufactured in Example 1. The drug adhesive layer 3 containing the drug is a solution having a uniform phase by adding 7.0 g of acrylic adhesive AP20, 2.5 g of aceclofenac and 0.5 g of propylene glycol monolaurate prepared according to the above reference example into a beaker and stirring for 1 hour. It was prepared by removing the bubbles, and then coated on a silicone-treated polyester film 4 so that the thickness after drying was 50 µm and dried at 80 ° C. for 20 minutes. The film was removed from the previously prepared hydrophobic adhesive layer 2 and laminated on the dry drug adhesive layer 3 to prepare a patch (20 × 40 cm 2).

<Example 17>

The hydrophobic adhesive layer 2 was manufactured similarly to the method manufactured in Example 1. Drug-containing adhesive layer (3) containing the drug is a homogeneous phase of the acrylic pressure-sensitive adhesive AP20 prepared according to the above reference example, 2.5 g roxofene pen 2.5 g, propylene glycol monolaurate 0.5 g into a beaker and stirred for 1 hour The solution was prepared by removing the air bubbles, and then coating the siliconized polyester film 4 so as to have a thickness of 50 μm after drying, followed by drying at 80 ° C. for 20 minutes. The film was removed from the previously prepared hydrophobic adhesive layer 2 and laminated on the dry drug adhesive layer 3 to prepare a patch (20 × 40 cm 2).

Experimental Example 1 Evaluation of Percutaneous Dosage Formulation: Skin Absorption Experiment

In order to evaluate the drug absorption of the patch prepared in Comparative Examples and Examples, the abdominal skin of the hairless mouse (hairless female, 6 weeks old) was cut to a size of 1.5 x 1.5 cm 2 and then the Franz type It is placed on a glass-type diffusion cell, and each patch prepared in Comparative Examples and Examples is placed on the skin and fixed using a clamp to prevent movement. Phosphate buffer solution (pH 7.4) was added to the bottom space and the diffusion apparatus temperature was maintained at 37 ° C. The buffer solution of the receptor was agitated at a constant speed of 300 rpm, and after a certain period of time, the entire amount of the solution of the receptor was taken and sampled by filling the buffer with the receptor again. The collected solution was analyzed by high performance liquid chromatography. The analysis conditions of ketoprofen, diclofenac, flubiprofen, felbinac, aceclofenac and roxofene are as follows.

[Ketoprofen]

Column: YMC-Pack ODS-AM (1506.0㎜, I.D. 5㎛) (Manufacturer: YMC Co., Ltd)

Mobile phase: 70:30 (V / V) = methanol: 0.1% acetic acid aqueous solution

Flow rate: 1ml / min

Detector: 254nm UV

[Diclofenac]

Column: YMC-Pack ODS-AM (1506.0㎜, I.D. 5㎛)

Mobile phase: 53: 47 (V / V) = acetonitrile: 0.02 M sodium acetate buffer (pH 5.8)

Flow rate: 1ml / min

Detector: 280nm UV

[Flubiprofen]

Column: YMC-Pack ODS-AM (1506.0 mm, I.D. 5 μm)

Mobile phase: 40: 40: 20 (V / V / V) = acetonitrile: methanol: 0.5% acetic acid aqueous solution

Flow rate: 1ml / min

Detector: 254nm UV

[Pelbinac]

Column: YMC-Pack ODS-AM (1506.0 mm, I.D. 5 μm)

Mobile phase: 38: 62 (V / V) = acetonitrile: 20 mM phosphate buffer (pH 7.4)

Flow rate: 1ml / min

Detector: 254nm UV

[Aceclofenac]

Column: YMC-Pack ODS-AM (1506.0 mm, I.D. 5 μm)

Mobile phase: 10: 25: 65 (V / V / V) = methanol: acetonitrile: 0.05 M acetate buffer (pH 6.5)

Flow rate: 1ml / min

Detector: 275nm UV

[LOXOXOPEN]

Column: YMC-Pack ODS-AM (1506.0 mm, I.D. 5 μm)

Mobile phase: 38: 62 (V / V) = acetonitrile: 20 mM phosphate buffer (pH 7.4)

Flow rate: 1ml / min

Detector: 254nm UV

The experimental results are shown in Table 1 below. Table 1 below shows the drug absorption in vitro (hairless mouse skin, n = 6).

Permeated amount for 6 hr (㎍ / ㎠) Permeated amount for 24 hr (㎍ / ㎠) Uniqueness Comparative Example 1 74 ± 18 212 ± 21 - Comparative Example 2 7 ± 16 235 ± 9 Crystal creation Comparative Example 3 127 ± 31 314 ± 39 No hydrophobic layer Comparative Example 4 131 ± 28 320 ± 34 No hydrophobic layer Comparative Example 5 182 ± 27 625 ± 41 Low hydrophobic layer thickness Example 1 217 ± 33 992 ± 53 - Example 2 226 ± 35 997 ± 48 - Example 3 221 ± 26 1004 ± 42 - Example 4 213 ± 34 956 ± 35 - Example 5 195 ± 32 924 ± 61 - Example 6 203 ± 39 912 ± 45 - Example 7 210 ± 26 927 ± 37 - Example 8 193 ± 24 891 ± 42 - Example 9 275 ± 25 1089 ± 52 - Example 10 262 ± 33 1071 ± 68 - Example 11 214 ± 46 984 ± 51 - Example 12 199 ± 39 893 ± 44 - Example 13 205 ± 17 941 ± 35 Diclofenac Example 14 189 ± 21 896 ± 38 Flubiprofen Example 15 215 ± 25 997 ± 37 Felbinac Example 16 174 ± 16 725 ± 28 Aceclofenac Example 17 185 ± 24 826 ± 39 Roxofene

As shown in Table 1, the higher the content of N-vinylpyrrolidone in the acrylic adhesive, the higher the solubility of the drug in the formulation was able to increase the drug content in the formulation (Examples 1, 2, 9, 10 ), The skin absorption of the drug also tended to increase. In addition, when the same amount of drug was contained, the skin absorbance of the drug was relatively decreased as the content of N-vinylpyrrolidone in the components of the acrylic adhesive increased (Examples 3, 4, 5). N-vinylpyrrolidone as a component has high affinity with the drug, and it is thought that the solubility decrease of the drug is relatively small even if water absorbed from the skin flows into the adhesive. This can be inferred that in the formulation, as the amount of N-vinylpyrrolidone, an acrylic adhesive component, increases, the saturation concentration increases, so that the drug content must be increased to maintain high drug absorption. On the other hand, when the thickness of the hydrophobic adhesive layer 2 is less than 40 μm (Comparative Example 5), even if the drug content and the hydrophilic hydrophilic acrylic pressure-sensitive adhesive was used, it was confirmed that the drug absorption is low.

Experimental Example 2 In vivo Absorption and Water Content Evaluation Method of Drugs

In order to evaluate the in vivo drug absorption of the patches prepared according to Comparative Examples 1 to 5 and Examples 1 to 4 and 7 to 10, each patch cut in a circular shape having a diameter of 3.5 cm was applied to the upper arm of an adult for 12 or 24 hours. After attaching and detaching, the amount of drug absorbed through human skin was quantified by comparing the amount of drug remaining in the patch with the initial content, and the results are shown in FIG. 2. Analytical conditions of each drug are the same as in Experiment 1 above.

In order to measure the moisture content, which is the amount of water absorbed by the patch after attachment, three patches were attached to the back area for 24 hours, and then the initial patch weight before attachment and the weight after attachment for 24 hours were measured and then attached for 24 hours using Equation 4 below. After the water content was calculated.

W _0hr : Weight of patch before attachment

W _24hr : Patch weight after 24 hours

The results are shown in Table 2 below. Table 2 shows the in vivo drug absorption and the water content after 24 hours attachment.

Permeated amount for 12 hr (㎍ / 8.042㎠) Permeated amount for 24 hr (㎍ / 8.042㎠) Water content after 24 hours attachment (%) Comparative Example 1 427 ± 23 709 ± 38 0.4 ± 0.2 Comparative Example 2 529 ± 26 818 ± 45 0.5 ± 0.3 Comparative Example 3 692 ± 37 1002 ± 53 2.8 ± 0.5 Comparative Example 4 714 ± 42 1016 ± 39 3.0 ± 0.6 Comparative Example 5 656 ± 36 1318 ± 57 3.5 ± 0.4 Example 1 906 ± 56 1776 ± 61 3.9 ± 0.7 Example 2 939 ± 39 1831 ± 56 3.9 ± 0.6 Example 3 921 ± 45 1812 ± 48 4.1 ± 0.7 Example 4 898 ± 32 1763 ± 50 4.1 ± 0.5 Example 7 923 ± 38 1715 ± 73 4.0 ± 0.6 Example 8 826 ± 59 1736 ± 81 4.1 ± 0.7 Example 9 1124 ± 63 2111 ± 77 4.3 ± 0.8 Example 10 1116 ± 51 2103 ± 65 4.5 ± 0.8

As shown in Table 2, as in Examples 2, 3, 9, and 10, the drug is also high in the in vivo drug absorption experiment in the formulation in which the content of N-vinylpyrrolidone, which is a component of the drug and the acrylic pressure-sensitive adhesive, is properly formulated Absorption could be obtained.

Experimental Example 3: Skin Irritation Test Method

In order to confirm the skin irritation of the patches prepared in Examples 1 to 4, 10, etc., the prepared patches were cut into 2 × 2 cm 2 size and attached to the forearm region of 10 healthy adult males. After 24 hours, the patch was removed, and after 1 hour, the degree of primary irritation at the attachment site was determined according to the following criteria, and the skin reactivity was calculated from Equation 5 below.

<Judge criteria>

Judgment score Stimulation degree 0 1 2 3 4 No irritation Minimal irritation Mild irritation (erythema) Severe irritation (erythema, edema) Severe irritation (erythema, edema)

As a result of converting to Equation 5, the skin reactivity of the patch prepared as in Examples 1 to 4 and 10 was 0.6, 0.7, 0.5, 0.6 and 0.6%, respectively, showing little irritation to the skin. Therefore, skin side effects are expected to be very low when applying patches to the skin.

Experimental Example 4 Adhesive Test Method

In order to evaluate the adhesive strength of the patch containing the nonsteroidal anti-inflammatory analgesic agents prepared in Comparative Examples 1 to 5 and Examples 1 to 4, 6, 9, and 10, the sample was cut to have a length of 20 cm and a width of 2.5 cm. After the preparation, the plate was attached to the stainless steel plate in the longitudinal direction, and the attached patch was bonded by reciprocating the roll (500 grams) twice. After leaving for 30 minutes, the adhesive force was measured using an adhesive tester (Texture analyzer Model XT2i, Stable Micro Systems) when peeled at an angle of 180 degrees at a rate of 300 mm / min at 20 degrees Celsius and 65% relative humidity. The results are shown in Table 4 below (n = 3).

Adhesion (g / 25mm) Comparative Example 1 428 ± 31 Comparative Example 2 419 ± 34 Comparative Example 3 712 ± 42 Comparative Example 4 693 ± 25 Comparative Example 5 518 ± 37 Example 1 529 ± 26 Example 2 611 ± 33 Example 3 629 ± 18 Example 4 573 ± 21 Example 6 501 ± 32 Example 9 493 ± 40 Example 10 367 ± 35

As shown in Table 4, the adhesive force of the patch prepared according to Examples 1, 2, 3, 4, 6 was confirmed to show the adhesive strength of the adhesion well while exhibiting the efficacy. However, at high levels of N-vinylpyrrolidone, the adhesion tended to decrease somewhat.

Using the transdermal formulation according to the present invention, it is possible to provide a transdermal formulation in which a high concentration of hydrophobic drug can be absorbed through the skin continuously until the patch is removed from the skin. Transdermal administration preparations according to the present invention can minimize the side effects of the skin and at the same time can achieve the effect of having sufficient adhesion for the time to adhere to the skin to take effect.

Claims (14)

As a transdermal transdermal formulation for hydrophobic drugs, A support layer 1 having elasticity as the top of the laminated structure; A hydrophobic adhesive layer (2) laminated under the support layer and including a hydrophobic adhesive to prevent loss of moisture absorbed from the skin and reverse migration of the drug; And A drug adhesive layer (3) laminated under the hydrophobic adhesive layer and containing a drug and adhering the transdermal formulation to the skin, wherein the drug adhesive layer comprises a hydrophobic drug and an acrylic adhesive and the acrylic adhesive is removed from the skin Drug-adhesive layer (3) comprising a hydrophilic monomer that promotes water absorption of constituents as a component Percutaneous dosage formulations for hydrophobic drugs, characterized in that comprising a. The method of claim 1, wherein the transdermal formulation further comprises a release layer (4) laminated under the drug adhesive layer and protecting the drug adhesive layer before use of the transdermal formulation and peeling upon use. Transdermal administration preparations. The method of claim 1, The hydrophobic pressure-sensitive adhesive of the hydrophobic pressure-sensitive adhesive layer is a transdermal dosage formulation for a hydrophobic drug, characterized in that at least one selected from the group consisting of a polyisobutylene pressure-sensitive adhesive, a styrene- isoprene-styrene pressure-sensitive adhesive and a styrene-butadiene-styrene pressure-sensitive adhesive . The method of claim 3, The hydrophobic adhesive layer is a transdermal dosage formulation for a hydrophobic drug, characterized in that the thickness of 40 to 100㎛. The method of claim 1, The hydrophobic drug, A transdermal formulation for hydrophobic drugs, characterized in that it is a nonsteroidal anti-inflammatory drug. The method of claim 5, The hydrophobic drug, A transdermal dosage formulation for hydrophobic drugs, characterized in that it is at least one selected from the group consisting of ketoprofen, diclofenac, flubiprofen, felbinac, aceclofenac, and loxoprofen. The transdermal dosage form for hydrophobic drugs according to claim 1, wherein the hydrophobic drug in the drug adhesive layer is contained in an amount of 10 to 40% by weight of the total drug adhesive layer. The method of claim 1, The hydrophilic monomer is at least one selected from the group consisting of N-vinylpyrrolidone, polyethylene glycol, pyrrolidone ethyl acrylate, polyethylene glycol monomethacrylate, and polyethylene glycol monomethyl ether monomethacrylate. Transdermal Dosage Formulation for Hydrophobic Drugs. The method of claim 1, The monomer of the acrylic pressure-sensitive adhesive of the drug adhesive layer is acrylic acid, methyl methacrylate, methyl acrylate, ethyl acrylate, butyl acrylate, and butyl acrylate. ), Octyl acrylate (octyl acrylate), 2-ethylhexyl acrylate (2-ethylhexyl acrylate), and hexyl acrylate (hexyl acrylate) is a percutaneous dosage formulation for a hydrophobic drug, characterized in that at least one. The method of claim 8, The acrylic pressure-sensitive adhesive is a transdermal dosage formulation for a hydrophobic drug, characterized in that containing 2 to 50 parts by weight of the hydrophilic monomer in the monomer composition. The method of claim 8, The acrylic pressure-sensitive adhesive of the drug pressure-sensitive adhesive layer is transdermal administration formulation for a hydrophobic drug, characterized in that 2-ethylhexyl acrylate / vinylpyrrolidone copolymer. The method of claim 1, The acrylic pressure-sensitive adhesive of the drug adhesive layer is a transdermal dosage formulation for a hydrophobic drug, characterized in that contained in an amount of 40 to 80% by weight of the total drug adhesive layer. The method of claim 1, The drug adhesive layer further contains an absorption enhancer for enhancing drug absorption, The absorption enhancer may include lauryl alcohol, oleyl alcohol, sorbitan monolaurate, ethylene glycol monolaurate, propylene glycol monolaurate, glycerin monolaurate, and capryl as higher fatty acids having 10 to 18 carbon atoms or derivatives thereof. A transdermal dosage formulation for hydrophobic drugs, characterized in that it is used alone or in combination with fatty acid derivatives such as ric monolaurate, isopropyl myristate or transcutol, in an amount of 3 to 20% by weight of the entire drug adhesion layer. The method of claim 1, The support layer is composed of a woven or nonwoven fabric having elasticity in one direction or in both directions, the woven fabric is composed of a polyester resin, urethane resin or cotton, the nonwoven fabric is composed of a polyester resin or urethane resin Percutaneous dosage formulations for hydrophobic drugs.

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