Transdermal preparation containing flurbiprofen with improved stability and permeability

Abstract

The present invention provides a transdermal preparation having a multi-layered structure comprising a hydrophobic adhesive layer and a drug adhesive layer, wherein the structure of each layer and the ratio of adhesives contained therein are optimized. The transdermal preparation of the present invention can increase the skin permeability of a drug without using a skin permeation enhancer, and exhibits excellent adhesion and product stability without causing skin irritation, and thus can be advantageously used as a transdermal delivery system of a drug in the pharmaceutical and medical fields.

Description

Transdermal formulation with improved stability and permeability containing flurbiprofen

[0001] This application claims priority to Korean Patent Application No. 10-2023-0158673, filed November 15, 2023, the entire disclosure of which is incorporated herein by reference.

[0002] The present invention relates to a transdermal administration preparation with improved stability and permeability, and more particularly, to a transdermal administration preparation with improved stability and permeability containing flurbiprofen.

[0003] Transdermal drug delivery systems are designed to target drugs that are absorbed into the skin or primarily into the subcutaneous layer, and a variety of drugs, including non-steroidal anti-inflammatory drugs, which are representative drugs developed as transdermal drug delivery systems, are being developed as transdermal drug delivery systems.

[0004] Nonsteroidal anti-inflammatory drugs are drugs that relieve inflammation or pain, and various drugs such as ketoprofen, flurbiprofen, diclofenac, piroxicam, indomethacin, felbinac, ibuprofen, and loxoprofen have been developed and are commercially available as transdermal agents.

[0005] Transdermal medications have the advantage of being simple to administer and having fewer side effects of gastrointestinal disorders compared to oral medications.

[0006] However, since the absorption and action of transdermal drugs can vary greatly between individuals and may differ depending on the characteristics of the skin, individual administration methods and dosage adjustments may be necessary, especially for children, the elderly, and patients with skin lesions. In addition, long-term use of transdermal drugs may cause side effects such as skin irritation, itching, allergic reactions, redness, and dermatitis due to skin penetration enhancers contained in the drug. Furthermore, skin irritation and allergic reactions to these skin penetration enhancers can vary greatly from individual to individual, so even if no side effects were observed in skin irritation tests during product development, unexpectedly severe irritation or rashes may occur in some users during actual use, which is inconvenient.

[0007] Thus, there is a need to develop a transdermal drug delivery formulation that has excellent drug permeation and improved product stability without using skin penetration enhancers that may cause skin irritation.

[0008] Korean Patent Registration No. 10-00663163 discloses a transdermal drug delivery system containing a non-steroidal anti-inflammatory drug, characterized by a layered structure comprising a flexible support layer, a hydrophobic adhesive layer, and a drug-adhesive layer. However, no research has been conducted on a flurbiprofen transdermal drug delivery system that improves both product stability and skin permeability, as in the present invention.

[0009] The problem to be solved by the present invention is to provide a transdermal administration preparation having excellent skin permeability, improved stability, and no skin irritation without using a skin penetration enhancer.

[0010] The problems to be solved by the present invention are not limited to the problems mentioned above, and other technical problems not mentioned can be clearly understood by a person having ordinary skill in the technical field to which the present invention belongs from the description below.

[0011] In order to achieve the above-mentioned problem, according to one aspect of the present invention, a multilayered transdermal drug delivery system comprises: an elastic support (1); a hydrophobic adhesive layer (2), wherein a first side of the hydrophobic adhesive layer is in contact with one side of the elastic support (1), and the hydrophobic adhesive layer (2) includes a rubber-based adhesive; a drug adhesive layer (3), wherein a first side of the drug adhesive layer (3) is in contact with a second side of the hydrophobic adhesive layer (2), and the drug adhesive layer (3) includes an acrylic-based adhesive and a drug; And a peeling layer (4), wherein one side of the peeling layer (4) is in contact with the second side of the drug adhesive layer (3), and the acrylic adhesive is a mixture of an acrylic adhesive having a functional group and an acrylic adhesive without a functional group in a ratio of 40:60 to 90:10 based on the solid weight %, the acrylic adhesive having a functional group includes a functional group of a carboxyl group (-COOH) and a hydroxyl group (-OH), and a drug included in the drug adhesive layer (3) is flurbiprofen, a transdermal administration preparation is provided.

[0012] According to the present invention, in a multilayered transdermal drug delivery formulation including a hydrophobic adhesive layer and a drug adhesive layer, it was discovered that by optimizing the structure of each layer and the ratio of the adhesive contained therein, the skin permeability of the drug can be increased without using a skin penetration enhancer, and since the skin penetration enhancer is not used, side effects that vary from person to person can be avoided. In addition, it was confirmed that the transdermal drug delivery formulation of the present invention not only exhibits excellent adhesiveness, but also has excellent product stability (content stability and flexibility stability) and is free of skin irritation. Therefore, the transdermal drug delivery formulation of the present invention can be usefully used as a transdermal drug delivery system in the pharmaceutical and medical fields.

[0013] The effects of the present invention are not limited to the effects described above, and should be understood to include all effects that can be inferred from the composition of the invention described in the description or claims of the present invention.

[0014] Figure 1 is a schematic diagram showing the matrix structure of the transdermal administration preparation of the present invention.

[0015] Figure 2 shows the skin penetration amount (μg / cm) of flurbiprofen of products to which Comparative Examples 1 to 3 and Examples 1 to 3 were applied. 2 ) is a graph showing the

[0016] Figure 3 is a graph of the skin penetration rate (%) of flurbiprofen of products to which Comparative Examples 1 to 3 and Examples 1 to 3 were applied.

[0017] Figure 4 shows the skin permeation amount of flurbiprofen (μg / cm) for 24 hours in Example 2 and other companies' products. 2 ) is a graph showing the

[0018] Figure 5 is a graph showing the skin penetration rate (%) of flurbiprofen for 24 hours in Example 2 and third-party products.

[0019] Figure 6 shows the skin permeation amount of flurbiprofen (μg / cm) of products to which Examples 2 to 5 were applied. 2 ) is a graph showing the

[0020] Figure 7 is a graph showing the skin penetration rate (%) of flurbiprofen of products to which Examples 2 to 5 were applied.

[0021] Figure 8 shows the skin permeation amount of flurbiprofen (μg / cm) of Examples 4 to 5 and other companies' products. 2 ) is a graph showing the

[0022] Figure 9 is a graph showing the skin penetration rate (%) of flurbiprofen of Examples 4 to 5 and other companies' products.

[0023] Figure 10 is a graph showing changes in the flurbiprofen content of Comparative Examples 1 to 3 and Examples 1 to 3 under harsh conditions.

[0024] Figure 11 is a graph showing the change in the total amount of flexible substances generated from flurbiprofen in Comparative Examples 1 and 2 and Examples 1 and 2 under harsh conditions.

[0025] Figure 12 is a design plan for applying test substances to the rabbit abdomen for skin irritation testing.

[0026] The present invention is a multilayered transdermal drug delivery system comprising: an elastic support (1); a hydrophobic adhesive layer (2), wherein a first side of the hydrophobic adhesive layer is in contact with one side of the elastic support (1) and the hydrophobic adhesive layer (2) includes a rubber-based adhesive; a drug adhesive layer (3), wherein a first side of the drug adhesive layer (3) is in contact with a second side of the hydrophobic adhesive layer (2) and the drug adhesive layer (3) includes an acrylic-based adhesive and a drug; And a peeling layer (4), wherein one side of the peeling layer (4) is in contact with the second side of the drug adhesive layer (3), and the acrylic adhesive is a mixture of an acrylic adhesive having a functional group and an acrylic adhesive without a functional group in a ratio of about 40:60 to 90:10 based on the solid weight %, the acrylic adhesive having a functional group includes a functional group of a carboxyl group (-COOH) and a hydroxyl group (-OH), and the drug included in the drug adhesive layer (3) is flurbiprofen.

[0027] The term "about" as used herein means a range of + / - 10% of the target value to which it refers, and includes all values ​​in a range equal to or similar to the value following the term "about."

[0028] In the present invention, the drug adhesive layer (acrylic adhesive layer, acrylic layer) (3) has a structure in which one side is in contact with the hydrophobic adhesive layer (2) and the other side is in contact with the peeling layer (4) (see Fig. 1), and includes an acrylic adhesive and a drug.

[0029] The drug included in the above drug adhesive layer (3) may be included in an amount of about 5 to 40 wt% based on the total weight of the drug adhesive layer (3). Preferably, the drug may be included in an amount of about 10 to 30 wt%, about 12 to 25 wt%, about 13 to 21 wt%, about 14 to 20 wt%, about 14 to 16 wt%, or about 18 to 20 wt% based on the total weight of the drug adhesive layer (3).

[0030] The drug adhesive layer (3) containing flurbiprofen shows a slight change in adhesive strength after containing the main ingredient flurbiprofen compared to before containing the main ingredient flurbiprofen. The flurbiprofen component can make the physical properties of the adhesive layer more flexible, thereby imparting soft physical properties. The drug adhesive layer (3) shows the best adhesive strength when the content of flurbiprofen, which is an API, is in the range of about 13 to 21 wt% based on the total weight of the drug adhesive layer.

[0031] In one embodiment, the thickness of the drug adhesive layer (3) can be manufactured to be about 10 to 40 μm, preferably about 19 to 30 μm.

[0032] The weight of the drug adhesive layer is divided by the cross-sectional area of ​​the corresponding plaster (70 cm 2 ) can be calculated by dividing by (assuming density is 1, g = cm 3 ), a more accurate thickness can be determined by applying the density of the matrix. For example, if the weight of the drug adhesive layer is 138.0 mg / plaster, the thickness can be expected to be approximately 19.7 μm (assuming the density is 1).

[0033] (138.0 x 10 -3 cm 3 ) / (70cm 2 )= 1.9714285 x10 -3 x10 -2 m ≒19.7 μm

[0034] If the drug-containing adhesive layer is too thin, the concentration of the active ingredient increases, potentially leading to drug crystal precipitation. This weakens the adhesive strength and reduces marketability. Conversely, if the drug-containing adhesive layer is too thick, the concentration of the active ingredient decreases, which can reduce skin permeability and, therefore, efficacy.

[0035] The above drug adhesive layer (3) includes a mixture of an acrylic adhesive having a functional group and an acrylic adhesive without a functional group, and the solid weight % ratio of the acrylic adhesive having a functional group: the acrylic adhesive without a functional group is 40:60 to 90:10, preferably 50:50 to 80:20. At this time, the acrylic adhesive having a functional group is an adhesive that includes both functional groups of a carboxyl group (-COOH) and a hydroxyl group (-OH). When the acrylic adhesive is included in the drug adhesive layer (3) at this ratio, the skin permeability is improved while the stability is also excellent, so that both stability and permeability can be improved. In this case, skin irritation can be minimized by not using a skin penetration promoter, and for example, the skin irritation index can be 0.0.

[0036] In terms of stability, when flurbiprofen is mixed with an acrylic adhesive having a functional group, stability issues such as a decrease in content and the generation of a large amount of reactive substances may occur. On the other hand, when flurbiprofen is used with an adhesive without a functional group, it shows good stability (maintained content, low generation of reactive substances), but in this case, skin permeation is reduced. That is, in terms of skin permeation, the drug flurbiprofen shows higher skin permeation when using an acrylic adhesive having a functional group than when using an acrylic adhesive without a functional group. Therefore, the present invention provides a mixing ratio of adhesive types that can achieve excellent skin permeation while maintaining excellent stability of flurbiprofen.

[0037] In one embodiment, the acrylic adhesive having a functional group included in the drug adhesive layer (3) may be included in an amount of about 30 to 76 wt% based on the total weight of the drug adhesive layer (3), and the acrylic adhesive without a functional group may be included in an amount of about 12 to 47 wt% based on the total weight of the drug adhesive layer (3).

[0038] More specifically, the drug adhesive layer (3) may include about 5 to 40 wt% of the drug, about 30 to 76 wt% of the acrylic adhesive having a functional group, and about 12 to 47 wt% of the acrylic adhesive without a functional group, based on the total weight of the drug adhesive layer (3).

[0039] More specifically, the drug adhesive layer (3) may include about 14 to 16 wt% of the drug, about 50 to 60 wt% of the acrylic adhesive having a functional group, and about 25 to 35 wt% of the acrylic adhesive without a functional group, based on the total weight of the drug adhesive layer (3).

[0040] More specifically, the drug adhesive layer (3) may include about 18 to 20 wt% of the drug, about 35 to 45 wt% of the acrylic adhesive having a functional group, and about 35 to 45 wt% of the acrylic adhesive without a functional group, based on the total weight of the drug adhesive layer (3).

[0041] The term "acrylic pressure-sensitive adhesive" above refers to any polyacrylate, polyacrylic polymer, acrylate polymer, or acrylic polymer that is adhesive. The acrylic polymer may be any one of a homopolymer, copolymer, or terpolymer of various acrylic acids or esters. The acrylic pressure-sensitive adhesive for practicing the present invention is a polymer of one or more monomers of acrylic acid and other copolymerizable monomers. Furthermore, the acrylic pressure-sensitive adhesive includes a copolymer of alkyl acrylate and / or methacrylate and / or copolymerizable secondary monomers. The acrylic pressure-sensitive adhesive having a functional group may be a copolymer with a functional monomer.

[0042] The term "functional group-free acrylic adhesive" above refers to an acrylic adhesive having no or substantially no functional (functional) or reactive moieties. These are generally acrylic esters that can be copolymerized with other monomers that do not have functional groups, such as vinyl acetate.

[0043] Acrylate monomers that can be utilized include acrylic acid, methacrylic acid, butyl acrylate, butyl methacrylate, hexyl acrylate, hexyl methacrylate, 2-ethylbutyl acrylate, 2-ethylbutyl methacrylate, isooctyl acrylate, isooctyl methacrylate, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, decyl acrylate, decyl methacrylate, dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate and tridecyl methacrylate.

[0044] Functional monomers that can be used and copolymerized with the above alkyl acrylate or methacrylate include acrylic acid, methacrylic acid, maleic acid, maleic anhydride, hydroxyethyl acrylate, hydroxypropyl acrylate, acrylamide, dimethylacrylamide, acrylonitrile, dimethylaminoethyl acrylate, dimethylaminoethyl methacrylate, t-butylaminoethyl acrylate, t-butylaminoethyl methacrylate, methoxyethyl acrylate, and methoxyethyl methacrylate.

[0045] As a suitable acrylic adhesive, a functional acrylic adhesive may be a commercially available Duro-Tak adhesive, for example, Duro-Tak 87-2074, Duro-Tak 87-2979, etc., but is not limited thereto.

[0046] As a suitable acrylic adhesive, a functional group-free acrylic adhesive may be used, such as, but not limited to, commercially available Unitac NF-04, Durotec 87-9301, Durotec 87-6911, Durotec 87-6908, Durotec 87-4098, and Durotec 87-900A.

[0047] In the present invention, the hydrophobic adhesive layer (2) has a structure in which one side is in contact with the elastic support (1) and the other side is in contact with the drug adhesive layer (3) (see Fig. 1), and includes a rubber-based adhesive.

[0048] In one embodiment, the rubber-based adhesive may be at least one adhesive selected from the group consisting of a polyisobutylene adhesive, a styrene-isoprene-styrene adhesive, and a styrene-butadiene-styrene adhesive.

[0049] In one embodiment, the thickness of the hydrophobic adhesive layer (rubber adhesive layer, rubber layer) (2) is suitably about 10 to 100 μm. Preferably, it may be about 20 to 60 μm, about 35 to 45 μm, more preferably about 38 to 42 μm, and most preferably about 39 μm.

[0050] In one embodiment, the hydrophobic adhesive layer (2) and the drug adhesive layer (3) may have a weight % ratio of the hydrophobic adhesive layer (2):drug adhesive layer (3) based on the solid weight. That is, the ratio of the acrylic layer may be about 50 to 20 wt % with respect to the total weight of the hydrophobic adhesive layer (2) and the drug adhesive layer (3). Preferably, the ratio of the rubber layer:acrylic layer may be about 55:45 to 70:30. That is, the ratio of the acrylic layer may be about 45 to 30 wt % with respect to the total weight of the rubber layer and the acrylic layer.

[0051] In the present invention, the elastic support (1) has one side in contact with the hydrophobic adhesive layer (2), and the other side is exposed to the outside of the transdermal drug delivery system (see Fig. 1). The elastic support (1) is made of a woven or non-woven fabric having elasticity in one or both directions, and may be at least one selected from the group consisting of polyester, polyethylene (PE), nylon, polypropylene (PP), polyethylene terephthalate (PET), ethylene vinyl acetate (EVA), non-woven / PET composites, PET / PE composites, and PET / EVA composites.

[0052] In the present invention, the peeling layer (4) has one side in contact with the drug adhesive layer (3), and the other side is exposed to the outside of the transdermal administration preparation (see Fig. 1). The peeling layer (4) is a layer that protects the drug adhesive layer (3) before the transdermal administration preparation is used, and is peeled off before skin application. The peeling layer (4) may be a peeling layer surface-treated with at least one selected from the group consisting of a polyethylene terephthalate (PET) film, a polyethylene (PE) film, a polyester film, a polyvinyl chloride (PVC) film, a polyvinylidene chloride film, a polyethylene / paper composite, a PET / PE composite, and a PET / EVA composite using a silicone or fluorine treatment agent.

[0053] The multilayered transdermal administration preparation of the present invention can be manufactured into the matrix structure described above by a conventionally used plaster manufacturing method, and examples of the manufacturing method are described in the examples below, but are not limited thereto.

[0054]

[0055] Hereinafter, the present invention will be described in more detail through examples and test examples. However, the following examples and test examples are intended to illustrate the present invention and are not intended to limit the scope of the present invention.

[0056]

[0057] Examples 1-3. Preparation of plaster with drug-adhesive layer applied

[0058] In the following Test Example 1, three types of adhesives with excellent stability and adhesive properties were selected, and by applying these, plasters having drug adhesive layers of Examples 1 to 3 of Table 1 below were manufactured (see Fig. 1). As comparative examples, plasters of Comparative Examples 1 to 3 were manufactured by varying the ratio of the adhesive.

[0059] As shown in Fig. 1, the plaster structure has a hydrophobic adhesive layer (2) under an elastic support (1), a drug-containing adhesive layer (3) under that, and a peeling layer (4) under the drug-containing adhesive layer, so that the peeling layer is removed when attached to the skin.

[0060]

[0061] To prepare a hydrophobic adhesive layer, a rubber adhesive solution was uniformly mixed, applied to a silicone-treated PET film, and dried. A flexible support was then placed over it and pressed.

[0062] To manufacture a drug-containing adhesive layer, the drug and adhesive were uniformly mixed and then applied to a silicone-treated PET film and dried.

[0063] The release layer (silicon-treated PET film) was removed from the pre-manufactured hydrophobic adhesive layer and laminated onto the drug adhesive layer to manufacture the plaster products of Examples 1 to 3 and Comparative Examples 1 to 3, respectively.

[0064]

[0065] Test Example 1. Comparison of flexibility stability under harsh conditions (60°C, 80% RH) by mixing the main ingredient flurbiprofen and each acrylic adhesive.

[0066] When the main drug ingredient in the drug-based adhesive layer, flurbiprofen, and the acrylic adhesive come into contact, a flexible substance is created. The amount of the flexible substance created can vary depending on the type of functional group in the acrylic adhesive and the type of residual monomer.

[0067] A screening experiment was conducted to find an acrylic adhesive with excellent stability that produces less flexible substances when reacted with the drug flurbiprofen.

[0068] Fluorbiprofen and acrylic adhesive were mixed in a weight ratio of 1:1 and left under harsh conditions (temperature 60℃, humidity 80% RH), and the generated flexible substances were analyzed after 2, 4, and 6 weeks.

[0069] The equipment and conditions for analyzing flexible substances are as follows.

[0070] - Analytical equipment: Ultra-high-performance liquid chromatography (UPLC)

[0071] - Mobile phase: pH 2.5 buffer: acetonitrile = 7:3 (v / v)

[0072] - Detector: UV wavelength 254 nm

[0073] The total amount (%) of flexible substances is shown in Table 2 below, and the maximum value (Individual Max) among individual flexible substances is shown in < >.

[0074] Applying the global standard (international standard) based on the ICH guidelines, individual flexible substances (%), rather than total flexible substances, are managed to not exceed 0.5% or 1.0%. Therefore, it is important to confirm the maximum values ​​for individual flexible substances.

[0075] Since this test example mixed the main ingredient, flurbiprofen, with each adhesive in equal proportions, the results may be more severe than those for the actual manufactured product's flexibility stability. However, a comparison of the application of each adhesive suggests that the adhesive will be more stable when applied to flurbiprofen.

[0076] Functional group presence / absenceFunctional group typeAdhesive typeTotal amount of flexible material (%)Initial periodHarsh 2 weeksHarsh 4 weeksHarsh 6 weeksFunctional group-COOHDurotec 87- 21960.00%0.64%2.10%<1.96%>4.59%<4.38%>Durotec 87- 20510.00%0.29%1.17%<0.96%>2.84%<2.32%>-OHDurotec 87- 25160.00%0.43%<0.26%>1.08%<0.79%>2.09%<1.66%>Zelva GMS 788 NA0.00%0.17%0.67%<0.57%>1.38%<1.27%>-OH,-COOHDurotec 87- 20740.11%0.28%<0.15%>0.91%<0.38%>1.71%<0.67%>Non-functionalized Unitec NF-040.00%0.50%<0.24%>1.02%<0.35%>1.44%<0.60%>Durotech 87- 93010.00%0.00%0.06%0.26%<0.13%>Durotech 87- 69110.00%0.10%0.10%0.21%<0.13%>Durotech 87- 69080.00%0.00%0.00%0.00%

[0077] Looking at the results in Table 2 above, we can see that there is a clear difference in stability depending on the presence or absence of a functional group. The adhesive without a functional group was the most stable when applied, and among the adhesives with functional groups, the adhesive containing both a hydroxyl group (-OH) and a carboxyl group (-COOH) was the most stable when applied. In addition, the adhesive with only a hydroxyl group (-OH) was more stable when applied than the adhesive with only a carboxyl group (-COOH). Therefore, when applying the adhesive, the stability ranking according to the functional group can be expressed in the order of non-functional group (Non-functional) > (-OH, -COOH) > (-OH) > (-COOH).

[0078] Through adhesive screening experiments, adhesives with excellent stability were selected, and among them, three types of adhesives with excellent adhesive properties (Durotech 87-2074, Durotec 87-9301, and Unitech NF-04) were selected to manufacture the example plaster.

[0079]

[0080] Test Example 2. Evaluation of crystal precipitation of raw pharmaceutical ingredients in plaster

[0081] In order to measure the difference in physical properties (whether crystals are precipitated and adhesive strength) according to changes in the concentration of the raw pharmaceutical ingredient (API) in the acrylic adhesive layer containing the drug, the thickness of the hydrophobic adhesive layer was fixed at 35 to 45 μm, and the plaster was manufactured by changing the thickness of the adhesive layer containing the drug.

[0082] The physical properties of the manufactured plaster, including whether crystals were precipitated, were checked and are shown in Table 3 below. Those with precipitated crystals are marked with an O, those with only a small amount of crystals are marked with a △, and those with no crystals are marked with an X.

[0083] Thickness of hydrophobic adhesive layerDetermination of API concentration (weight %) in acrylic adhesive layerDetermination of precipitationDetermination of adhesionRefrigerated long-term acceleration35~45 μm7%XXXAverage9%XXX11%XXX13%XXXExcellent adhesion15%XXX17%XXX19%XXX21%XXX22%XX△Presence of sample with weak adhesionDetermination of precipitation weakens adhesion23%X△O25%△OO30%OOO40%OOO

[0084] As shown in Table 3 above, it was confirmed that crystals were precipitated when the concentration of the main component in the drug adhesive layer (acrylic adhesive layer) was about 23 wt% or more.

[0085] It was confirmed that no crystal precipitation occurred in all of the plasters of Comparative Examples 1 to 3 and Examples 1 to 3 manufactured as shown in Table 1, and that the adhesive strength was excellent.

[0086]

[0087] Test Example 3. Skin penetration test of products applying the drug adhesive layers of Comparative Examples 1 to 3 and Examples 1 to 3.

[0088] A skin penetration test was conducted as follows for products to which an adhesive layer containing a drug was applied as in Comparative Examples 1 to 3 and Examples 1 to 3.

[0089] A Franz cell (Franz type diffusion cell) device was used, and human cadaver epidermis was used as the skin. PBS (phosphate buffer, pH 7.4) was added to the receptor portion below the Franz cell, and the temperature was maintained at 32°C while the PBS was stirred at 600 rpm. The skin was placed on the receptor of the Franz cell, and each prepared plaster was placed on top of it, and then firmly fixed with a clamp to prevent movement. To quantify the drug permeated over time, 0.25 ml of the receptor liquid was taken at regular intervals and quantified using HPLC. 0.25 ml of PBS was added again to match the amount of liquid taken from the receptor.

[0090] The equipment and conditions for analyzing the drug content are as follows.

[0091] - Analytical equipment: High-performance liquid chromatography (HPLC)

[0092] - Mobile phase: pH 2.5 buffer: Acetonitrile =1:1 (v / v)

[0093] - Detector: UV wavelength 254 nm

[0094] The skin permeation test results are shown in Tables 4 and 5 below. These represent the in-vitro absorption rate of the drug.

[0095] Table 4 below shows the skin permeation amount of flurbiprofen (μg / cm) of products to which Comparative Examples 1 to 3 and Examples 1 to 3 were applied. 2) and skin absorption (μg / cm 2 / hr) appears.

[0096] Permeation time Comparative example 1 Example 1 Example 2 Example 3 Comparative example 2 Comparative example 3 Example 1-1 Example 1-2 Comparative example 3-1 Comparative example 3-20 hr0.00.00.00.00.00.00.00.04 hr12.022.921.120.116.06.94.54.08 hr24.346.343.140.929.117.110.19.712 hr36.364.665.160.242.824.317.113.324 hr69.4109.1105.797.676.953.737.831.4 Skin absorption rate (μg / cm 2 / hr)2.94.54.44.13.22.21.61.3

[0097] The drug content of flurbiprofen in each manufactured plaster is 20mg / 70cm 2 285.714 μg / cm 2 , and the skin permeation rate (%) of flurbiprofen in each plaster was calculated by taking this as 100%. Table 5 below shows the skin permeation rate (%) of flurbiprofen in the products to which Comparative Examples 1 to 3 and Examples 1 to 3 were applied. In addition, Fig. 2 shows the skin permeation amount (μg / cm) of flurbiprofen in each plaster. 2 ) was presented as a graph, and the skin penetration rate (%) of flurbiprofen in each plaster was presented as a graph in Fig. 3.

[0098] Transmittance Time Comparison Example 1 Example 1 Example 2 Example 3 Comparative Example 2 Comparative Example 3 Example 1-1 Example 1-2 Comparative Example 3-1 Comparative Example 3-20 hr 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 4 hr 4.2% 8.0% 7.4% 7.0% 5.6% 2.4% 1.6% 1.4% 8 hr 8.5% 16.2% 15.1% 14.3% 10.2% 6.0% 3.6% 3.4% 12 hr 12.7% 22.6% 22.8% 21.0% 15.0% 8.9% 6.0% 4.7% 24 hr24.3%38.2%37.0%34.2%26.9%18.8%13.2%11.0%

[0099] As shown in Tables 4 and 5 above (see also FIGS. 2 and 3), it was confirmed that the plasters of Example 1 (F:NF=80:20), Example 2 (F:NF=65:35), and Example 3 (F:NF=50:50) showed significantly superior flurbiprofen skin permeation amount and skin permeation rate compared to the plasters of Comparative Example 1 (F:NF=100:0), Comparative Example 2 (F:NF=20:80), and Comparative Example 3 (F:NF=0:100).

[0100] In addition, the skin permeability was superior to that of the plaster using a single adhesive, such as Comparative Example 1 (single application of an adhesive with a functional group) and Comparative Example 3 (single application of an adhesive without a functional group), in the plaster using a mixture of two types of adhesives (Examples 1, 2, and 3). However, Comparative Example 2 (F:NF=20:80) showed a lower skin permeability than Comparative Example 1 (F:NF=100:0).

[0101] When applying one type of adhesive alone, the skin permeability was superior to that of an adhesive with a functional group (Comparative Example 1) than that of an adhesive without a functional group (Comparative Example 3). When applying two types of adhesives in combination, it was confirmed that the skin permeability tended to increase as the ratio of the adhesive with a functional group increased.

[0102] The skin permeation amount (μg / cm) of flurbiprofen for 24 hours in the plaster of Example 2 manufactured in Table 6 below and the commercially available product 2 ) and skin absorption (μg / cm 2 / hr) were compared. In addition, the 24-hour skin permeation amount (μg / cm) of flurbiprofen of the manufactured plaster of Example 2 and the commercially available product was compared. 2 ) is shown graphically in Figure 4.

[0103]

[0104] The skin permeation rate (%) of flurbiprofen in the plaster manufactured in Example 2 and the commercially available product is shown in Table 7 below. In addition, the skin permeation rate (%) of flurbiprofen in the plaster manufactured in Example 2 and the commercially available product for 24 hours is shown graphically in Figure 5.

[0105] Product Time Example 2Y Company AP ProductY Company AH ProductJ Company N ProductS Company PC ProductS Company P ProductG Company F Product0 hr0.0 %0.0 %0.0 %0.0 %0.0 %0.0 %0.0 %4 hr7.0 %4.6 %3.0 %5.7 %1.1 %0.5 %0.8 %8 hr14.3 %8.9 %5.9 %8.1 %1.9 %1.0 %1.1 %12 hr21.0 %13.0 %8.2 %9.4 %2.6 %1.4 %2.2 %24 hr34.1 %22.8 %13.9 %9.8 %3.9 %2.4 %2.2 %

[0106] As shown in Tables 6 and 7 above (see also Figs. 4 and 5), it was confirmed that the plaster of Example 2 exhibited significantly superior skin permeation amount, skin absorption rate, and skin permeation rate of flurbiprofen compared to commercially available products. Even though the plaster of Example 2 did not use a penetration enhancer, it was confirmed that it exhibited superior skin permeation results compared to commercially available products.

[0107]

[0108] Test Example 4. Preparation of plaster with changed main ingredient dosage and skin penetration test

[0109] Through the same process as Test Example 2, the dosage of the main ingredient flurbiprofen was 40 mg / 70 cm according to the composition in Table 8 below. 2 (1 sheet of plaster) was prepared as plaster (Examples 4 and 5).

[0110] Adhesive layer containing drug Example 2 Example 3 Example 4 Example 5 (F : NF = 65:35) (F : NF = 50:50) (F : NF = 65:35) (F : NF = 50:50)Raw material (mg / p)Weight ratio (%)(mg / p)Weight ratio (%)(mg / p)Weight ratio (%)(mg / p)Weight ratio (%)Drug Flurbiprofen 20.0 14.5% 20.0 14.5% 40.18.8% 40.18.8%Functional adhesive Durotec 207 476.6 55.5% 58.9 42.7% 112.5 52.8% 86.5 40.6%Non-functional adhesive Unitech NF 0 4 4 1.4 3 0.0% 59.0 42.8% 60.5 2 8.4% 86.5 40.6%Total 138.0 100.0% 137.9 100.0% 213.0 100.0% 213.0 100.0%

[0111] For the above manufactured examples, a skin permeation test was conducted as described in Test Example 3. The skin permeation amount of flurbiprofen (μg / cm) of the products to which Examples 2 to 4 were applied is shown in Table 9 below. 2 ) was shown. In addition, the 24-hour skin penetration rate (%) of flurbiprofen of the products to which Examples 2 to 5 were applied was shown graphically in Fig. 6.

[0112] Permeation Time Example 2 Example 3 Example 4 Example 50 hr0.00.00.00.04 hr20.016.017.614.68 hr40.929.149.335.812 hr60.042.881.065.424 hr97.676.9158.8130.5 Skin Absorption (μg / cm) 2 / hr)4.13.26.65.4Major components per unit area (μg / cm) 2 )20mg / 70cm 2 =286μg / cm 2 20mg / 70cm 2 =286μg / cm 2 40mg / 70cm 2 =571μg / cm 2 40mg / 70cm 2 =571μg / cm 2

[0113] 20mg / 70cm2 of the main ingredient flurbiprofen drug content per unit area2 = 285.714 μg / cm 2 , 40mg / 70cm 2 = 571.429 μg / cm 2 The results of calculating the skin penetration rate (%) by setting each as 100% are shown in Table 10 below. In addition, the 24-hour skin penetration rate (%) of flurbiprofen of the products to which Examples 2 to 5 were applied is shown in a graph in Fig. 7.

[0114] Transmittance Time Example 2 Example 3 Example 4 Example 50 hr0.0%0.0%0.0%0.0%4 hr7.0%5.6%3.4%2.8%8 hr14.0%10.2%9.5%6.9%12 hr21.0%15.0%15.6%12.6%24 hr34.2%26.9%30.7%25.2%

[0115] The skin permeation amount (μg / cm) of flurbiprofen in the plasters of Examples 4 and 5 and commercially available products for 24 hours is shown in Table 11 below. 2 ) and skin absorption (μg / cm 2 / hr) were compared. In addition, the 24-hour skin permeation amount (μg / cm) of flurbiprofen of the plasters of Examples 4 and 5 and the commercially available products was compared. 2 ) is shown graphically in Figure 8.

[0116] Product Example 4 Example 5 Company I CD Product Company G Z Product Company C C Product Main ingredient per unit area (μg / cm) 2 )40mg / 70cm 2 =571μg / cm 2 40mg / 70cm 2 =571μg / cm 2 40mg / 70cm 2 =571μg / cm 2 40mg / 98cm 2 =408μg / cm 20 hr0.00.00.00.00.04 hr17.614.617.316.66.08 hr49.335.832.726.710.412 hr81.065.445.633.514.324 hr158.8130.573.246.924.1 Skin absorption rate (μg / cm 2 / hr)6.65.43.02.01.0

[0117] The skin permeation rates (%) of flurbiprofen in the plasters of Examples 4 and 5 and commercially available products are shown in Table 12 below. In addition, the 24-hour skin permeation rates (%) of flurbiprofen in the plasters of Examples 4 and 5 and commercially available products are shown graphically in Figure 9.

[0118] Product Example 4 Example 5 Company I CD Product Company G Z Product Company C C Product Main ingredient per unit area (μg / cm) 2 )40mg / 70cm 2 =571μg / cm 2 40mg / 70cm 2 =571μg / cm 2 40mg / 70cm 2 =571μg / cm 2 40mg / 98cm 2 =408μg / cm 2 0 hr0.0%0.0%0.0%0.0%0.0%4 hr3.4%2.8%3.3%3.2%1.5%8 hr9.5%6.9%6.3%5.2%2.5%12 hr15.6%12.6%8.8%6.5%3.5%24 hr30.7%25.2%14.1%9.1%5.9%

[0119]

[0120] Test Example 5. Content and flexibility stability test of products applying drug adhesive layers of Comparative Examples 1 to 3 and Examples 1 to 4

[0121] In order to evaluate the stability of products to which the drug adhesive layers of Comparative Examples 1 to 3 and Examples 1 to 4 were applied, the changes in content and flexible substances were confirmed at the beginning, 2 weeks, 4 weeks, and 6 weeks under harsh conditions (temperature 60°C, humidity 80% RH).

[0122] The change in the flurbiprofen content (%) of Comparative Examples 1 to 3 and Examples 1 to 3 is shown in Table 13 below. In addition, the change in the flurbiprofen content (%) of Comparative Examples 1 to 3 and Examples 1 to 3 is shown graphically in Figure 10.

[0123] Content (%) Initial Harsh 2 weeks Harsh 4 weeks Harsh 6 weeks Comparison Example 1 100.0% 96.5% 94.1% 91.0% Practice Example 1-2 100.0% 96.6% 94.2% 91.3% Practice Example 2 100.0% 95.6% 93.2% 91.4% Practice Example 3 100.0% 97.5% 96.1% 93.8% Comparison Example 2 100.0% 99.4% 96.7% 96.1% Comparison Example 3-2 100.0% 99.7% 97.3% 96.1%

[0124] At the 6-week point in the harsh test, the smallest change in content was observed in Comparative Examples 2 and 3-2, which contained 80 to 100 wt% of the non-functional group adhesive. That is, as in Comparative Examples 2 and 3-2, the stability improved as the non-functional group ratio increased, but as confirmed in Tables 4 and 5, Comparative Examples 2 to 3 were found to have significantly lower skin permeability than Examples 1 to 3.

[0125] Content stability under harsh conditions (temperature 60℃, humidity 80% RH) was found to correlate with content stability under accelerated and long-term conditions. The predicted content results for the harsh 3-week period showed similar correlations with the results for the accelerated 6-month and long-term 24-month periods, enabling long-term data prediction.

[0126] Table 14 below shows the results of content stability under accelerated and long-term conditions of Example 2.

[0127] Change in content of Example 2 under harsh conditions Change in content of Example 2 under accelerated conditions Change in content of Example 2 under long-term conditions Initial 100.0% Initial 100.0% Initial 100.0% Severe 2 weeks 95.6% Accelerated 2 months 95.4% Long-term 3 months 99.0% Severe 4 weeks 93.2% Accelerated 4 months 94.6% Long-term 6 months 98.8% Severe 6 weeks 91.4% Accelerated 6 months 93.8% Long-term 9 months 98.3% Long-term 12 months 97.1%

[0128] As a result of checking the content stability of the product manufactured according to the present invention together with commercially available products from other companies, it was confirmed that the product manufactured according to the present invention exhibits excellent content stability as follows.

[0129] Table 15 below shows the change in the corrected content (%) based on the initial content value of flurbiprofen of Example 2 and commercially available products under harsh conditions, set to 100%.

[0130] Content Time Single-use Example 2 Y Company AH Product J Company N Product S Company P Product G Company F Product Y Company AP Product S Company PC Product Initial 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% Harsh 2 weeks 95.6% 90.5% 93.7% 96.1% 95.3% 84.0% 91.2% Harsh 4 weeks 93.2% 86.3% 91.9% 92.0% 92.1% 83.2% 88.6% Harsh 6 weeks 91.4% 79.1% 87.4% 91.4% 84.4% 77.9% 78.4%

[0131] The change in the total amount of flexible substances (%) of flurbiprofen in Comparative Examples 1 and 2 and Examples 1 and 2 is shown in Table 16 below. In addition, the change in the total flexible substances (%) of flurbiprofen in Comparative Examples 1 and 2 and Examples 1 and 2 is shown graphically in Figure 11.

[0132] Total flexible material (%) Initial Harsh 2 weeks Harsh 4 weeks Harsh 6 weeks Comparison Example 10.12% 0.66% 1.57% 3.24% Practice Example 1-10.19% 0.66% 1.50% 3.21% Practice Example 1-20.15% 0.64% 1.40% 3.00% Practice Example 20.22% 0.53% 0.86% 1.69% Comparison Example 20.02% 0.27% 0.48% 1.50%

[0133] It was confirmed that less flexible substances were generated (more stable) in Example 2 and Comparative Example 2, which contained 35 wt% or more of a non-functional adhesive.

[0134] Additionally, the results of the flexibility stability under accelerated and long-term conditions of Example 2 are shown in Table 17 below.

[0135] Changes in the flexible material of Example 2 under harsh conditions Changes in the flexible material of Example 2 under accelerated conditions Changes in the flexible material of Example 2 under long-term conditions Initial 0.22% Initial 0.22% Initial 0.22% Severe 2 weeks 0.53% Accelerated 2 months 0.46% Long-term 3 months 0.23% Severe 4 weeks 0.86% Accelerated 4 months 0.66% Long-term 6 months 0.24% Severe 6 weeks 1.69% Accelerated 6 months 1.13% Long-term 9 months 0.37% Long-term 12 months 0.43%

[0136] As a result of comparing the amount of flexible substances generated by the product manufactured by the present invention with products sold by other companies, it was confirmed that while the products of other companies showed a pattern of rapid increase in flexible substances, the products of the present invention showed a significantly lower amount of flexible substances generated (data not shown).

[0137]

[0138] Test Example 6. Content stability test of plaster with changed main ingredient dosage

[0139] The dosage of the main ingredient flurbiprofen is 40 mg / cm 2 A content stability test was conducted on Example 5 of the plastain manufactured with (1 sheet). Table 18 below shows the content stability results under accelerated and long-term conditions of Example 5.

[0140] Change in content of Example 5 under harsh conditions Change in content of Example 5 under accelerated conditions Change in content of Example 5 under long-term conditions Initial 100.0% Initial 100.0% Initial 100.0% Harsh 2 weeks 98.1% Accelerated 2 months 98.3% Long-term 3 months 99.1% Harsh 4 weeks 95.4% Accelerated 4 months 98.0% Long-term 6 months 98.1% Harsh 6 weeks 92.4% Accelerated 6 months 95.4% Long-term 9 months 97.6%

[0141] As a result of checking the content stability of the product of Example 5 manufactured according to the present invention together with commercially available products of other companies, it was confirmed that the product of Example 5 manufactured according to the present invention exhibited superior content stability compared to commercially available products, as follows.

[0142] Table 19 below shows the change in content (%) corrected based on the initial content value of flurbiprofen in Example 5 and commercially available products under harsh conditions, with 100% as the initial content.

[0143] Product Example 5G Company Z Product I Company CD Product C Company C Product Main ingredient per unit area (μg / cm) 2 )40mg / 70cm 2 =571μg / cm 2 40mg / 70cm 2 =571μg / cm 2 40mg / 70cm 2 =571μg / cm 2 40mg / 98cm 2 =408μg / cm 2 Initial 100.0% 100.0% 100.0% 100.0% Harsh 2 weeks 98.1% 94.2% 93.1% 94.0% Harsh 4 weeks 95.4% 90.3% 80.6% 89.4% Harsh 6 weeks 92.4% 88.6% 72.5% 86.0%

[0144]

[0145] Test Example 7. Skin Irritation Test

[0146] As a result of conducting a skin irritation test on a product manufactured through the present invention, it was confirmed to be a non-irritating product.

[0147] Skin irritation tests were conducted using New Zealand White rabbits, which are Specific Pathogen Free (SPF) rabbits. Figure 11 shows the design of applying test substances to the rabbit back for the skin irritation test.

[0148] First, the rabbit's abdominal skin was shaved 24 hours prior to application of the test substance. As shown in Figure 11, left / right and upper / lower sections were divided, with the abraded or non-abrasive skin distributed diagonally. The abraded skin was created by inflicting abrasions that did not bleed, so that the epidermis was damaged but the dermis was not.

[0149] The test substance was applied directly to the skin over a 2.5 cm × 2.5 cm area according to the Draize method. The test substance was wrapped with non-penetrating, low-irritation medical tape. The test substance was applied for 24 hours after each application.

[0150] The test group included animals that were healthy during the acclimation period and had no skin abnormalities upon hair removal. Their body weights were measured, and the required number of animals close to the average body weight were selected. All animals were observed for general symptoms at least once daily during the test period, and the day of test substance application was designated Day 0. Body weights were measured on Days 0 and 3.

[0151] Approximately 24 hours after application of the test substance, the patch was removed, and the contact area where the test substance was applied was gently washed with sterile water to ensure that no test substance remained.

[0152] Approximately 24 hours after application of the test substance (30 minutes after removal of the test substance) and 72 hours after application, changes such as erythema, edema, and crusting were visually observed at the application site. The appearance of erythema, crusting, and edema were determined based on the inflammatory response, with erythema assessed visually and edema assessed by gentle palpation. The severity of skin reactions was scored and recorded according to skin reaction criteria at approximately 24 and 72 hours after application.

[0153] The criteria for evaluating skin reactions were calculated by scoring 1) the formation of erythema and scabs (Table 20) and 2) the degree of reaction of edema formation (Table 21).

[0154] Erythema and crusting reaction degree: No erythema at all 0 Very mild erythema (barely visible to the naked eye) 1 Distinct erythema 2 Slightly severe erythema 3 Severe erythema (beet-colored redness) and mild crusting (deep damage) 4

[0155] Edema Formation Reaction Degree No edema 0 Very mild edema (barely visible to the naked eye) 1 Mild edema (distinctly swollen with clearly distinguishable margins) 2 Moderate edema (swelling of about 1 mm) 3 Severe edema (swelling of more than 1 mm and extending beyond the exposed area) 4

[0156] The values ​​for evaluating individual skin reactions were added up to calculate the average, and the value obtained by dividing the sum of the averages by 4 is the Primary Irritation Index (PII). If the Primary Irritation Index (PII) was 0.0 to 0.5, it was judged as non-irritating, 0.6 to 2.0 as mild irritating, 2.1 to 5.0 as moderately irritating, and 5.1 to 8.0 as strongly irritating. Irritation was evaluated by considering general symptoms observed during the test period in addition to the Primary Skin Irritation Index. A skin irritation test was conducted on two products, Example 2 and Comparative Example 2.

[0157]

[0158] (1) Results of skin irritation test in Example 2

[0159] No general symptoms or abnormal changes in body weight related to the application of the test substance were observed during the entire test period.

[0160] As a result of the skin reaction evaluation, the primary skin irritation index (PII) was 0.

[0161] Based on the above results, the test substance, flurbiprofen plaster 20 mg, was evaluated as a non-irritating product in a skin irritation test using New Zealand white rabbits under the test conditions.

[0162]

[0163] (2) Skin irritation test results of Comparative Example 2

[0164] Erythema and edema were observed at the site of application of the test substance in all animals.

[0165] No change in body weight was observed due to the test substance.

[0166] As a result of the skin reaction evaluation, the primary skin irritation index (PII) was 2.8.

[0167] Based on the above results, the test substance, flurbiprofen plaster 20 mg, was evaluated as a moderate irritant in a skin irritation test using New Zealand white rabbits under the test conditions.

[0168]

[0169] The product manufactured through the present invention (Example 2) exhibited the lowest skin irritation index (SI) of 0.0 in a skin irritation test. Accordingly, the present invention enabled the development of a flurbiprofen plaster product that does not cause skin irritation.

[0170]

[0171] The foregoing description of the present invention is for illustrative purposes only, and those skilled in the art will readily appreciate that the present invention can be readily modified into other specific forms without altering the technical spirit or essential characteristics of the present invention. Therefore, the embodiments described above should be understood as illustrative in all respects and not restrictive. For example, each component described as a single entity may be implemented in a distributed manner, and similarly, components described as distributed may be implemented in a combined manner.

[0172] The scope of the present invention is indicated by the claims set forth below, and all changes or modifications derived from the meaning and scope of the claims and their equivalent concepts should be interpreted as being included in the scope of the present invention.

Claims

1. As a multilayered transdermal drug delivery formulation, Flexible support (1); As a hydrophobic adhesive layer (2), a first side of the hydrophobic adhesive layer is in contact with one side of the elastic support (1), and a hydrophobic adhesive layer (2) containing a rubber-based adhesive; As a drug adhesive layer (3), the first side of the drug adhesive layer (3) is in contact with the second side of the hydrophobic adhesive layer (2), and the drug adhesive layer (3) includes an acrylic adhesive and a drug; and As a peeling layer (4), it includes a peeling layer (4) in which one side of the peeling layer (4) is in contact with the second side of the drug adhesive layer (3), The above acrylic adhesive is a mixture of an acrylic adhesive having a functional group and an acrylic adhesive without a functional group in a ratio of 40:60 to 90:10 based on the solid weight %. The above functional group-containing acrylic adhesive contains functional groups of carboxyl group (-COOH) and hydroxyl group (-OH), A transdermal administration preparation, wherein the drug included in the above drug adhesive layer (3) is flurbiprofen.

2. A transdermal administration preparation, wherein the drug contained in the drug adhesive layer (3) in the first paragraph is contained in an amount of 5 to 40 wt% based on the total weight of the drug adhesive layer (3).

3. A transdermal administration preparation, wherein in the first paragraph, the acrylic adhesive having a functional group included in the drug adhesive layer (3) is included in an amount of 30 to 76 wt% based on the total weight of the drug adhesive layer (3), and the acrylic adhesive without the functional group is included in an amount of 12 to 47 wt% based on the total weight of the drug adhesive layer (3).

4. A transdermal administration preparation according to claim 1, wherein the rubber-based adhesive is at least one adhesive selected from the group consisting of a polyisobutylene adhesive, a styrene-isoprene-styrene adhesive, and a styrene-butadiene-styrene adhesive.

5. A transdermal administration preparation according to claim 1, wherein the hydrophobic adhesive layer (2) has a thickness of 10 to 100 μm.

6. A transdermal administration preparation in the first paragraph, wherein the hydrophobic adhesive layer (2) and the drug adhesive layer (3) have a weight % ratio of the hydrophobic adhesive layer (2): drug adhesive layer (3) of 50:50 to 80:20 based on the solid weight.

7. A transdermal administration preparation according to claim 1, wherein the drug adhesive layer (3) comprises 5 to 40 wt% of the drug, 30 to 76 wt% of an acrylic adhesive having a functional group, and 12 to 47 wt% of an acrylic adhesive without a functional group, based on the total weight of the drug adhesive layer (3).

8. A transdermal administration preparation according to claim 1, wherein the drug adhesive layer (3) comprises 14 to 16 wt% of the drug, 50 to 60 wt% of an acrylic adhesive having a functional group, and 25 to 35 wt% of an acrylic adhesive without a functional group, based on the total weight of the drug adhesive layer (3).

9. A transdermal administration preparation according to claim 1, wherein the drug adhesive layer (3) comprises 18 to 20 wt% of the drug, 35 to 45 wt% of an acrylic adhesive having a functional group, and 35 to 45 wt% of an acrylic adhesive without a functional group, based on the total weight of the drug adhesive layer (3).

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