Transdermal patch

Abstract

The present invention provides a transdermal patch having a high skin permeation amount of mirogabalin. A transdermal patch according to the present invention is characterized by comprising: a support; and an adhesive layer that is integrally laminated on one surface of the support and contains an adhesive agent and a salt of mirogabalin which is precipitated as a crystal in the adhesive agent and is a salt formed with an acid having a pKa value of less than 3.5. The transdermal patch is also characterized in that the content of the salt of mirogabalin in the adhesive layer is preferably 2-60 mass%. As a result, the transdermal patch has a high skin permeation amount of mirogabalin.

Description

Adhesive patch

[0001] This invention relates to a transdermal patch for the transdermal administration of mirogabalin as a drug.

[0002] Mirogabalin, as an oral besylate, is thought to exert its analgesic effect by binding to the α2δ subunit, which plays an auxiliary role in the function of voltage-gated calcium channels that serve as pathways for Ca ions in presynaptic terminals. By inhibiting the influx of calcium ions, it suppresses the excessive release of excitatory neurotransmitters. Mirogabalin besylate is used clinically as an oral medication.

[0003] Patent Document 1 discloses an orally disintegrating tablet containing (A) granules containing mirogabalin besylate and (B) drug-free granules containing crystalline cellulose, or a drug-free mixed powder containing crystalline cellulose.

[0004] WO2022 / 024979 publication

[0005] However, oral medications such as the orally disintegrating tablets mentioned above generally require frequent administration and have restrictions on timing, such as being taken after meals, which can be a burden on patients. Furthermore, oral medications can cause side effects due to a rapid increase in blood concentration. Therefore, there is a need to resolve the problems associated with oral medications and reduce the burden on patients.

[0006] Therefore, one method is to administer drugs to the human body through the skin by applying a transdermal patch to the skin. With transdermal patches, patients can apply them to their own skin, making medication administration easy. In addition, it is possible to reduce the number of administrations, relax restrictions on the timing of administration, and reduce the occurrence of side effects due to a gradual increase in blood concentration.

[0007] Therefore, the present invention provides a patch that allows for high skin penetration of mirogabalin.

[0008] The adhesive patch of the present invention is characterized by comprising a support, and an adhesive layer laminated and integrated on one surface of the support, the adhesive layer containing a salt of mirogabarin which precipitates as crystals in the adhesive and forms a salt with an acid having a pKa of less than 3.5.

[0009] The adhesive patch of the present invention has an adhesive layer containing a salt of mirogabalin, which precipitates as crystals in the adhesive and forms a salt with an acid having a pKa of less than 3.5, thus providing a high skin permeability of mirogabalin.

[0010] In the numerical ranges described stepwise in this specification, the upper or lower limit of one step in the numerical range can be arbitrarily combined with the upper or lower limit of another step in the numerical range. In the numerical ranges described in this specification, the upper or lower limit of that numerical range may be replaced with values ​​shown in the examples or values ​​that can be uniquely derived from the examples. In this specification, numbers connected by "~" mean a numerical range that includes the numbers before and after "~" as the lower and upper limits.

[0011] [Adhesive Layer] The adhesive patch of the present invention comprises a support and an adhesive layer laminated and integrated on one surface of the support. The adhesive layer contains an adhesive and a salt of mirogabarin which precipitates as crystals in the adhesive and forms a salt with an acid having a pKa of less than 3.5.

[0012] (Salts of Mirogabalin) Mirogabalin has an amino group in its molecular structure and forms an acid addition salt when reacted with an acid. The salts of mirogabalin used in transdermal patches are acid addition salts of mirogabalin with an acid having a pKa of less than 3.5, and are pharmaceutically acceptable salts. The pKa of the acid refers to the pKa in water at 25°C. Note that "pharmaceutically acceptable salt" means a salt that can be used as a medicine.

[0013] Here, in the present invention, acid HA is A － and H ＋ When the acid dissociates and reaches ionization equilibrium equation (1), the acid dissociation constant Ka is defined by equation (2), and pKa is defined by the common logarithm of the reciprocal of the acid dissociation constant Ka (3). When the acid is a polyprotein acid, the ionization proceeds in multiple stages, but in this invention, pKa refers to pKa1 calculated based on the ionization constant of the first stage.

[0014]

[0015] Acids with a pKa of less than 3.5 that form a salt with mirogabalin are not particularly limited and include, for example, hydrohalogens such as hydrofluoric acid (3.2), hydrobromic acid (-9.0), and hydroiodic acid (-10); inorganic acids such as hydrochloric acid (-6.3), nitric acid (-1.4), perchloric acid (-10), sulfuric acid (-3.0), and phosphoric acid (2.15); lower alkanesulfonic acids such as methanesulfonic acid (-1.9), trifluoromethanesulfonic acid (-14), and ethanesulfonic acid (-1.5); arylsulfonic acids such as benzenesulfonic acid (-2.8) and p-toluenesulfonic acid (-2.8); and organic acids such as malic acid (3.4), fumaric acid (3.0), citric acid (3.13), oxalic acid (1.3), and maleic acid (1.92). Acids with a pKa of less than 3.5 include inorganic acids and aryl sulfonic acids, hydrochloric acid and benzenesulfonic acid (besylic acid) are more preferred, and benzenesulfonic acid (besylic acid) is even more preferred. The values ​​in parentheses are the pKa values ​​in water at 25°C.

[0016] Acids with a pKa of less than 3.5 preferably contain an aromatic ring in their molecule. When an acid has an aromatic ring in its molecule, as will be described later, it can move smoothly from the adhesive layer into the water and dissolve, thereby increasing the amount of the patch that penetrates the skin.

[0017] An aromatic ring structure refers to a structure in which carbon atoms are bonded in a ring and possess aromatic properties. In other words, an aromatic ring structure is a ring structure that follows Hückel's rule and has (4n+2) π electrons (where n is a natural number). Examples of aromatic ring structures include benzene ring structures and naphthalene ring structures, with benzene ring structures being preferred. Specific examples of aromatic rings include benzene rings, naphthalene rings, anthracene rings, biphenyls, and phenoxyphenyls.

[0018] Mirogabarin salts are salts with acids having a pKa of less than 3.5, and are highly polar. They precipitate as crystals without dissolving in the adhesive layer. The crystalline mirogabarin salts draw moisture present on the skin to which the patch is applied into the adhesive layer. The mirogabarin salts dissolve in the moisture drawn into the adhesive layer and are released from the adhesive layer.

[0019] Without an action to draw moisture into the adhesive layer, it is difficult for moisture to penetrate it. On the other hand, the salt of mirogabalin actively draws moisture into the adhesive layer, thus lowering the barrier to moisture entering the adhesive layer and making it easier for moisture to penetrate it.

[0020] By using a salt of mirogabarin with an acid having a pKa of less than 3.5, the polarity (water solubility) of the mirogabarin salt is increased. The highly polar mirogabarin salt does not move through the adhesive that makes up the adhesive layer, but dissolves directly in the moisture drawn into the adhesive layer. The mirogabarin salt is smoothly released from the adhesive layer through the channels formed by the moisture drawn into the adhesive layer. Therefore, the patch using the above mirogabarin salt has a high skin permeability.

[0021] In general, with crystal-precipitation type adhesive patches, the drug is first dissolved in the adhesive and then released from the adhesive layer. Therefore, even if a large amount of drug is contained in the adhesive, the saturation solubility of the drug in the adhesive becomes the limit, and there is an upper limit to the amount of drug released and the amount that can be absorbed into the skin.

[0022] On the other hand, in the patch of the present invention, when the mirogabarin salt is released from the adhesive layer, it not only dissolves in the adhesive but also directly dissolves in the water dissolved in the adhesive layer and is released from the adhesive layer. Therefore, it is not affected by the saturation solubility of the mirogabarin salt in the adhesive layer. Accordingly, the patch of the present invention can contain a large amount of mirogabarin salt in the adhesive layer, improve the amount of mirogabarin salt released from the adhesive layer, and provide high skin permeability.

[0023] Furthermore, while the mirogabarin salt dissolves in water and diffuses through the adhesive layer, the diffusion rate of the mirogabarin salt through water is higher than the diffusion rate of the drug through the adhesive, allowing the mirogabarin salt to be released smoothly from the adhesive layer.

[0024] The pKa of the acid forming the salt of mirogabalin is less than 3.5, preferably 3 or less, more preferably 2 or less, and more preferably 1 or less. The pKa of the acid forming the salt with mirogabalin is not limited, but preferably -9 or higher, more preferably -7 or higher, more preferably -6 or higher, and more preferably -4 or higher. The pKa of the acid forming the salt of mirogabalin is preferably -9 or higher and less than 3.5, more preferably -7 or higher and less than 3.5, more preferably -7 or higher and 3 or less, more preferably -6 or higher and 3 or less, more preferably -4 or higher and 2 or less, and more preferably -4 or higher and 1 or less. When the pKa of the acid is less than 3.5, as described above, the water draw-in into the adhesive layer and the dissolution effect in this water are increased, and the amount of the patch permeable to the skin is improved.

[0025] The particle size of the mirogabarin salt in the adhesive layer is preferably 0.5 μm or more, more preferably 1 μm or more, more preferably 2 μm or more, more preferably 3 μm or more, more preferably 4 μm or more, and more preferably 5 μm or more. The particle size of the mirogabarin salt in the adhesive layer is preferably 50 μm or less, more preferably 45 μm or less, more preferably 40 μm or less, more preferably 38 μm or less, more preferably 35 μm or less, more preferably 33 μm or less, more preferably 30 μm or less, more preferably 25 μm or less, more preferably 20 μm or less, and more preferably 15 μm or less. The particle size of the mirogabarin salt in the adhesive layer is preferably 0.5 to 50 μm, more preferably 1 to 45 μm, more preferably 2 to 40 μm, more preferably 3 to 38 μm, more preferably 4 to 35 μm, more preferably 5 to 33 μm, more preferably 5 to 25 μm, more preferably 5 to 20 μm, and more preferably 5 to 15 μm. If the particle size of the mirogabarin salt is 0.5 μm or larger, aggregation of the mirogabarin salt during the manufacture of the patch can be reduced, and fluctuations in the mirogabarin salt content in the patch can be reduced. If the particle size of the mirogabarin salt is 50 μm or smaller, the overall surface area of ​​the mirogabarin salt can be increased, allowing the mirogabarin salt to dissolve efficiently in water, and increasing the skin penetration rate of the patch.

[0026] Note that the particle size of the salt of milogabalin in the adhesive layer refers to the value measured in the following manner. The patch is cut across the entire length of the thickness of the adhesive layer in a plane perpendicular to the surface of the adhesive layer. Using a scanning electron microscope (SEM), under the conditions of an acceleration voltage of 5.0 kV, detection mode: secondary electron image, and magnification: 550 times, a SEM secondary electron image of the cross-section of the patch is obtained. By analyzing the obtained SEM secondary electron image using image analysis software, the equivalent circle diameter (the diameter of a perfect circle having the same area) of the crystals of the salt of milogabalin exposed on the cross-section is measured. For 500 crystals randomly selected from one patch, the equivalent circle diameter is measured, and when arranged in ascending order of the equivalent circle diameter as d １ , d ２ , ··· d ｉ ··· d ５００ when, the cumulative volume fraction Q ｉ is calculated based on formula (A). Note that for the scanning electron microscope (SEM), for example, a commercially available device of "Model: JSM-6010LV" from JEOL Ltd. can be used. For the image analysis software, for example, software commercially available under the product name "WinROOF2018" from Mitani Trading Co., Ltd. can be used.

[0027]

[0028] Q ｉ When Q ｊ is 0.5 or less and closest to 0.5, the cumulative volume fraction at that time is defined as Q ｊ , and when the equivalent circle diameter at that time is defined as d ｊ , the volume-based median diameter D 50 is calculated based on formulas (B) and (C). The volume-based median diameter D 50 is taken as the particle size of the salt of milogabalin.

[0029]

[0030] In the SEM backscattered electron image of the adhesive layer surface (the surface that adheres to the skin) under an accelerating voltage of 20 kV, the area percentage occupied by mirogabarin salt is preferably 0.1% or more, more preferably 0.2% or more, more preferably 0.25% or more, more preferably 0.45% or more, more preferably 1% or more, more preferably 2% or more, more preferably 10% or more, and more preferably 20% or more. In the SEM backscattered electron image of the adhesive layer surface under an accelerating voltage of 20 kV, the area percentage occupied by mirogabarin salt is preferably 60% or less, and more preferably 50% or less. In SEM backscattered electron images of the adhesive layer surface (the surface that adheres to the skin) under an accelerating voltage of 20 kV, the area percentage occupied by mirogabarin salt is preferably 0.1 to 60%, more preferably 0.2 to 60%, more preferably 0.25 to 60%, more preferably 0.45 to 60%, more preferably 1 to 60%, more preferably 2 to 60%, more preferably 2 to 50%, more preferably 10 to 50%, and more preferably 20 to 50%. When the area percentage occupied by mirogabarin salt is 0.1% or more, a large amount of mirogabarin salt is contained in the vicinity of the adhesive layer surface that adheres to the skin, allowing the mirogabarin salt to easily draw in moisture present on the skin to which the patch is applied. As the mirogabarin salt dissolves in this drawn-in moisture, it can be smoothly released from the adhesive layer. Therefore, the patch has a high skin permeability. When the area ratio occupied by mirogabarin salt is 60% or less, the mirogabarin salt can be released gradually, extending the duration of the patch, reducing the burden on the patient, and maintaining the adhesiveness of the adhesive layer for a long period of time. In this invention, "adhesive layer surface" refers to the surface that is attached to the skin, that is, the skin-facing side of the adhesive. The area ratio occupied by mirogabarin salt in the SEM backscattered electron image of the adhesive layer surface (the surface attached to the skin) is sometimes simply referred to as "area ratio occupied by mirogabarin salt".

[0031] Furthermore, the area percentage occupied by mirogabarin salt, based on the SEM backscattered electron image of the adhesive layer surface (the side that adheres to the skin) under an accelerating voltage of 20 kV, refers to the value measured in the following manner.

[0032] If a release liner is laminated on the adhesive layer of the patch, remove the release liner from the patch to expose the adhesive layer. Using a scanning electron microscope (SEM), obtain an SEM backscattered electron image of the adhesive layer surface of the patch with an acceleration voltage of 20 kV, detection mode: backscattered electron imaging, and magnification of 50x. Using image analysis software, specify a processing area of ​​1500 μm x 1500 μm near the center of the SEM backscattered electron image and perform binarization to obtain the area occupied by mirogabarin salt (crystal distribution area). Calculate the area ratio occupied by mirogabarin salt based on the following formula (D). For example, a scanning electron microscope (SEM) commercially available from JEOL Ltd. under the product name "Model: JSM-6010LV" can be used. For example, image analysis software commercially available from Mitani Corporation under the product name "WinROOF2018" can be used. Area percentage occupied by mirogabalin salt (%) = 100 × (area of ​​crystal distribution) / (total area of ​​the treated area) (D)

[0033] As described above, the mirogabarin salt dissolves in the moisture drawn into the adhesive layer and is released from the adhesive layer. In this process, when the mirogabarin salt dissolves in the moisture, a void is created where the dissolved mirogabarin salt was located. Moisture and the mirogabarin salt flow into this void, forming a water channel that reaches deep into the adhesive layer, and the mirogabarin salt dissolves in this water channel. The water channel continues to the surface of the adhesive layer and opens onto the surface of the adhesive layer.

[0034] To improve the release of mirogabarin salts, it is preferable to allow moisture to penetrate in the depth direction of the adhesive layer's thickness, and to sequentially dissolve the mirogabarin salts contained in the adhesive layer into the moisture. To allow moisture to penetrate into the adhesive layer, it is preferable to sequentially dissolve the mirogabarin salts in the moisture drawn into the adhesive layer.

[0035] Therefore, it is preferable that the adhesive layer satisfies the preferred range for the particle size of the mirogabarin salt and the preferred range for the area ratio occupied by the mirogabarin salt. By adjusting the form in which the mirogabarin salt is contained, the mirogabarin salt contained in the adhesive layer can be sequentially dissolved and released by the moisture in the adhesive layer, thereby increasing the amount of the patch that penetrates the skin.

[0036] Preferably, the particle size of the mirogabarin salt is 0.5 to 50 μm and the area ratio occupied by the mirogabarin salt is 0.1 to 60%, more preferably the particle size of the mirogabarin salt is 1 to 45 μm and the area ratio occupied by the mirogabarin salt is 2 to 60%, more preferably the particle size of the mirogabarin salt is 2 to 40 μm and the area ratio occupied by the mirogabarin salt is 2 to 60%, and more preferably the particle size of the mirogabarin salt is 4 to 35 μm and the area ratio occupied by the mirogabarin salt is 2 to 50%.

[0037] The loss coefficient (tanδ, loss modulus G'' / storage modulus G') of the adhesive layer at 30°C is preferably 0.03 or higher, more preferably 0.1 or higher, and even more preferably 0.3 or higher. The loss coefficient (tanδ) of the adhesive layer at 30°C is preferably 10 or less, more preferably 5 or less, even more preferably 3 or less, and even more preferably 2 or less. The loss coefficient (tanδ, loss modulus G'' / storage modulus G') of the adhesive layer at 30°C is preferably 0.03 to 10, more preferably 0.1 to 5, even more preferably 0.3 to 3, and even more preferably 0.3 to 2. When the loss coefficient (tanδ) of the adhesive layer at 30°C is within the above range, the mirogabarin salt dissolves in water, and voids are created in the areas where the dissolved mirogabarin salt was present. However, before these voids are blocked, the mirogabarin salt and water flow in smoothly, extending and forming water channels to the depths of the adhesive layer, thereby increasing the amount of adhesive permeable to the skin. Because a water channel can be formed throughout the adhesive layer, the mirogabalin salt contained in the entire adhesive layer can be released smoothly, allowing the patch to maintain its excellent medicinal effect over a long period of time.

[0038] To increase the loss factor, for example, (1) lower the crosslinking density of the adhesive that makes up the adhesive layer, (2) include a plasticizer in the adhesive layer, and (3) lower the weight-average molecular weight of the polymer that makes up the adhesive.

[0039] The loss coefficient (tanδ, loss modulus G'' / storage modulus G') of the adhesive layer at 30°C refers to the value measured according to the following procedure. A laminate with a thickness of approximately 2 mm is prepared by stacking multiple adhesive layers of the adhesive agent. A test specimen is prepared by punching out this laminate into a disc shape with a diameter of 7.9 mm. The test specimen is fixed by sandwiching it between parallel plates, and dynamic viscoelasticity measurement is performed using a viscoelasticity tester under the following conditions to measure the storage modulus G' and loss modulus G'' at 30°C. The loss coefficient is calculated by dividing the loss modulus G'' by the storage modulus G'. As a viscoelasticity tester, for example, a device commercially available from T.A. Instruments, Inc. under the product name "ARES" or an equivalent product can be used. • Measurement mode: Shear mode • Temperature range: -70°C to 150°C • Heating rate: 5°C / min • Measurement frequency: 1 Hz

[0040] The content of mirogabarin salt in the adhesive layer is preferably 2% by mass or more, more preferably 4% by mass or more, more preferably 7% by mass or more, more preferably 10% by mass or more, and more preferably 13% by mass or more. The content of mirogabarin salt in the adhesive layer is preferably 60% by mass or less, more preferably 55% by mass or less, more preferably 50% by mass or less, more preferably 40% by mass or less, and more preferably 30% by mass or less. When the content of mirogabarin salt is 2% by mass or more, the skin permeability of the patch can be improved. When the content of mirogabarin salt is 60% by mass or less, the adhesion of the adhesive layer to the skin can be improved, and the release of mirogabarin salt from the adhesive layer to the skin can be smoothly performed. Therefore, the patch has a high skin permeability. Note that the content of mirogabarin salt in the adhesive layer refers to the value calculated based on the mass of mirogabarin obtained by converting the mirogabarin salt to the free base form.

[0041] In the present invention, when expressing the mass of the mirogabarin salt contained in the adhesive layer, the mass of mirogabarin obtained by converting the mirogabarin salt to its free base form shall be used. When calculating the mass percentage (e.g., mass%) or molar percentage (e.g., molar ratio) of the constituent components (excluding the mirogabarin salt) contained in the adhesive layer, the calculation shall be performed using the total mass of the mirogabarin salt including the acidic portion.

[0042] (Adhesive) The adhesive layer contains an adhesive. The adhesive is not particularly limited and examples include rubber-based adhesives, acrylic-based adhesives, and silicone-based adhesives. Rubber-based adhesives and acrylic-based adhesives are preferred, and acrylic-based adhesives are more preferred. The adhesive may be used alone or in combination of two or more types.

[0043] The content of acrylic adhesive in the adhesive is preferably 50% by mass or more, more preferably 60% by mass or more, more preferably 70% by mass or more, more preferably 80% by mass or more, more preferably 90% by mass or more, more preferably 95% by mass or more, more preferably 99% by mass or more, and more preferably 100% by mass.

[0044] The content of rubber-based adhesive in the adhesive is preferably 50% by mass or more, more preferably 60% by mass or more, more preferably 70% by mass or more, more preferably 80% by mass or more, more preferably 90% by mass or more, more preferably 95% by mass or more, more preferably 99% by mass or more, and more preferably 100% by mass.

[0045] In the adhesive layer, the content of the adhesive is preferably 20% by mass or more, more preferably 30% by mass or more, more preferably 40% by mass or more, more preferably 50% by mass or more, more preferably 55% by mass or more, and more preferably 60% by mass or more. In the adhesive layer, the content of the adhesive is preferably 99% by mass or less, more preferably 98% by mass or less, more preferably 95% by mass or less, more preferably 92% by mass or less, more preferably 90% by mass or less, more preferably 88% by mass or less, and more preferably 80% by mass or less. In the adhesive layer, the content of the adhesive is preferably 20 to 99% by mass, more preferably 20 to 95% by mass, more preferably 20 to 88% by mass, more preferably 20 to 80% by mass, more preferably 30 to 80% by mass, more preferably 40 to 80% by mass, more preferably 50 to 80% by mass, more preferably 55 to 80% by mass, and more preferably 60 to 80% by mass.

[0046] The adhesives that make up the adhesive have a solubility parameter (SP value) of 8 to 30 (cal / cm³). 3 ) 1 / 2 Preferably, the polymer contains a monomer component, and the solubility parameter is 9 to 25 (cal / cm³). 3 ) 1 / 2 It is more preferable that the polymer contains a monomer component, and that the solubility parameter is 15 to 25 (cal / cm³). 3 ) 1 / 2 It is more preferable that the adhesive contains a polymer containing a monomer component. When the adhesive contains a polymer containing a monomer component having a solubility parameter within the above range, it has a suitable affinity for the mirogabarin salt, allowing the mirogabarin salt to move smoothly within the adhesive layer to reach moisture and dissolve quickly in the moisture. The mirogabarin salt can be easily released from the adhesive layer.

[0047] Solubility parameter is 8-30 (cal / cm³) 3 ) 1 / 2 Examples of monomers include 2-ethylhexyl acrylate (SP value: 16.8 (cal / cm³)). 3 ) 1 / 2 ), 2-ethylhexyl methacrylate (SP value: 16.5 (cal / cm³)3 ) 1 / 2 ), methyl acrylate (SP value: 18.2 (cal / cm³) 3 ) 1 / 2 ), 2-hydroxyethyl acrylate (SP value: 23.9 (cal / cm³) 3 ) 1 / 2 ), 2-hydroxyethyl methacrylate (SP value: 22.0 (cal / cm³) 3 ) 1 / 2 ), diacetone acrylamide (SP value: 21.5 (cal / cm³) 3 ) 1 / 2 ), dodecyl acrylate (SP value: 16.5 (cal / cm³) 3 ) 1 / 2 ), dodecyl methacrylate (SP value: 16.4 (cal / cm³) 3 ) 1 / 2 ), ethyl acrylate (SP value: 17.9 (cal / cm³) 3 ) 1 / 2 ), n-octyl acrylate (SP value: 16.8 (cal / cm³) 3 ) 1 / 2 ), N-vinyl-2-pyrrolidone (SP value: 21.1 (cal / cm³) 3 ) 1 / 2 ), acrylic acid (SP value: 23.4 (cal / cm³) 3 ) 1 / 2 ), vinyl acetate (SP value: 18.5 (cal / cm³) 3 ) 1 / 2 ), glycidyl methacrylate (SP value: 9.3 (cal / cm³) 3 ) 1 / 2 ), n-butyl acrylate (SP value: 8.3 (cal / cm³) 3 ) 1 / 2 ), ethyl acrylate (SP value: 8.8 (cal / cm³) 3 ) 1 / 2 Examples include the following. The numbers in parentheses represent the monomer solubility parameters.

[0048] The definition and calculation method of the solubility parameter are described on pages 28-30 of the document "Hansen Solubility Parameters: A User's Handbook" (by Charles M. Hansen, CRC Press, June 15, 2007).

[0049] The solubility parameter of a monomer can be calculated based on the following formula (i) proposed by Hansen: δ = (δd 2 +δp 2 +δh 2 ) 1 / 2 (i) (In equation (i), δ is the solubility parameter, δd is the term due to London's dispersion force (van der Waals force) (dispersion term), δp is the term due to molecular polarity (polarity term), and δh is the term due to hydrogen bonding (hydrogen bonding term).)

[0050] Furthermore, δd, δp, and δh in equation (i) above can be determined by the following equations (ii) to (iv) based on the Van Krevelen and Hoftyzer methods: δd = ΣFdi / V (ii) δp = (ΣFpi 2 ) 1 / 2 / V (iii) δh=(ΣEhi / V) 1 / 2　 (iv) (In equation (ii), Fdi is the molar attractive force constant due to London's dispersion force; in equation (iii), Fpi is the molar attractive force constant due to the inter-dipole force; in equation (iv), Ehi is the hydrogen bond energy; and in equations (ii) to (iv), V is the molar volume of the monomer.)

[0051] In this invention, the molar attractive force constants Fdi, Fpi, and Ehi are those determined by the Van Krevelen and Hoftyzer methods. The molar volume V is calculated by dividing the molar mass of the monomer by the density of the monomer.

[0052] In adhesives, the solubility parameter is 8 to 30 (cal / cm³). 3 ) 1 / 2The content of the polymer containing the monomer component is preferably 50% by mass or more, more preferably 60% by mass or more, more preferably 70% by mass or more, more preferably 80% by mass or more, more preferably 90% by mass or more, more preferably 95% by mass or more, and more preferably 99% by mass or more.

[0053] Solubility parameter is 8-30 (cal / cm³) 3 ) 1 / 2 In a polymer containing a monomer component, the solubility parameter is 8 to 30 (cal / cm³). 3 ) 1 / 2 The monomer component content is preferably 50% by mass or more, more preferably 60% by mass or more, and even more preferably 70% by mass or more.

[0054] The adhesive layer has a solubility parameter (SP value) of 8 to 30 (cal / cm³). 3 ) 1 / 2 The adhesive contains 50% by mass or more of a polymer containing the monomer component, and preferably the area ratio of the mirogabarin salt is 0.1 to 60%, and the solubility parameter (SP value) is 8 to 30 (cal / cm²). 3 ) 1 / 2 The adhesive contains 50% by mass or more of a polymer containing the monomer component, and it is more preferable that the area ratio occupied by the mirogabarin salt is 0.2 to 60%. When the adhesive layer has the above configuration, it can easily draw in moisture present on the skin to which the patch is applied, and the mirogabarin salt dissolves in this drawn-in moisture, allowing the mirogabarin salt to be smoothly released from the adhesive layer. Therefore, the patch has a high skin permeability.

[0055] (Rubber-based adhesives) Examples of rubber-based adhesives include styrene-block copolymers such as styrene-isoprene-styrene block copolymer (SIS block copolymer) and styrene-isoprene-butadiene-styrene block copolymer (SIBS block copolymer), polyisobutylene, polybutadiene, and natural rubber. Styrene-block copolymers and polyisobutylene are preferred, styrene-block copolymers are more preferred, and styrene-isoprene-styrene block copolymer (SIS block copolymer) is even more preferred. Rubber-based adhesives may be used alone or in combination of two or more types.

[0056] The content of styrene-based block copolymer in the rubber-based adhesive is preferably 50% by mass or more, more preferably 60% by mass or more, more preferably 70% by mass or more, more preferably 80% by mass or more, more preferably 90% by mass or more, more preferably 95% by mass or more, and more preferably 99% by mass or more.

[0057] (Acrylic Adhesive) The acrylic adhesive contains an acrylic polymer. Preferably, the acrylic adhesive is an acrylic polymer containing an alkyl (meth)acrylate component. The acrylic polymer has a moderate affinity for the mirogabarin salt, allowing the mirogabarin salt to move smoothly through the adhesive layer. On the other hand, the affinity between the acrylic adhesive and the mirogabarin salt is lower than the affinity between water and the mirogabarin salt. Therefore, when the mirogabarin salt comes into contact with moisture, it quickly migrates to the moisture side, dissolves, and is released from the adhesive layer. Thus, the adhesive can impart a high skin permeability of the mirogabarin salt. (Meth)acrylate means acrylate or methacrylate. The acrylic polymer may be used alone or in combination of two or more types.

[0058] The alkyl group of the alkyl (meth)acrylate is preferably a group represented by *-CnH2n+1 (wherein n is a positive integer). The number of carbon atoms in the alkyl group of the alkyl (meth)acrylate is preferably 1 to 16, more preferably 1 to 14, and more preferably 2 to 12. In this invention, * represents a bond and means a single bond.

[0059] Examples of alkyl (meth)acrylates include methyl (meth)acrylate, ethyl (meth)acrylate, n-propyl (meth)acrylate, isopropyl (meth)acrylate, n-butyl (meth)acrylate, isobutyl (meth)acrylate, hexyl (meth)acrylate, n-octyl (meth)acrylate, isooctyl (meth)acrylate, 2-ethylhexyl (meth)acrylate, decyl (meth)acrylate, dodecyl (meth)acrylate, tridecyl (meth)acrylate, hexadecyl (meth)acrylate, cyclododecyl (meth)acrylate, and cyclohexyl (meth)acrylate.

[0060] The alkyl (meth)acrylate is preferably 2-ethylhexyl (meth)acrylate and dodecyl (meth)acrylate, and more preferably 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, and dodecyl methacrylate. The alkyl (meth)acrylate may be used alone or in combination of two or more types.

[0061] The number of carbon atoms in the alkyl (meth)acrylate alkyl group is preferably 1 to 16, more preferably 1 to 14, and even more preferably 5 to 14.

[0062] The content of the acrylic polymer in the acrylic adhesive is preferably 50% by mass or more, more preferably 60% by mass or more, more preferably 70% by mass or more, more preferably 80% by mass or more, more preferably 90% by mass or more, more preferably 95% by mass or more, and more preferably 99% by mass or more.

[0063] The content of alkyl (meth)acrylate components in the acrylic polymer is preferably 40% by mass or more, more preferably 45% by mass or more, more preferably 50% by mass or more, more preferably 55% by mass or more, more preferably 58% by mass or more, and more preferably 70% by mass or more.

[0064] The content of 2-ethylhexyl (meth)acrylate in the acrylic polymer is preferably 60% by mass or more, more preferably 65% ​​by mass or more, preferably 70% by mass or more, preferably 80% by mass or more, and particularly preferably 85% by mass or more. By setting the content of 2-ethylhexyl (meth)acrylate within the above range, the affinity with the mirogabarin salt is made appropriate, the release of the mirogabarin salt can be facilitated, and the patch can be given a high skin penetration rate.

[0065] The adhesive layer contains an acrylic adhesive containing an acrylic polymer containing an alkyl (meth)acrylate component, and preferably the area proportion occupied by the mirogabarin salt is 0.1 to 60%. More preferably, the adhesive layer contains an acrylic adhesive containing an acrylic polymer containing an alkyl (meth)acrylate component having 1 to 16 carbon atoms in the alkyl group, and preferably the area proportion occupied by the mirogabarin salt is 0.2 to 60%. When the adhesive layer has the above configuration, it can easily draw in moisture present on the skin to which the patch is applied, and the mirogabarin salt dissolves in this drawn-in moisture, allowing the mirogabarin salt to be smoothly released from the adhesive layer. Therefore, the patch has a high skin permeability.

[0066] Acrylic polymers may contain other monomer components in addition to alkyl (meth)acrylate components. Examples of other monomers include hydroxyalkyl (meth)acrylate, N-vinyl-2-pyrrolidone, (meth)acrylic acid, acrylamide, dimethylacrylamide, acrylonitrile, dimethylaminoethyl (meth)acrylate, t-butylaminoethyl (meth)acrylate, vinyl acetate, and vinyl propionate. These other monomers may be used alone or in combination of two or more.

[0067] In the acrylic polymer, the content of monomer components containing polar groups is preferably 10% by mass or less, and more preferably 7% by mass or less. In the acrylic polymer, the content of monomer components containing polar groups is preferably 1% by mass or more, and more preferably 2% by mass or more. In the acrylic polymer, the content of monomer components containing polar groups is preferably 1 to 10% by mass, and more preferably 2 to 7% by mass. When the content of monomer components containing polar groups in the acrylic polymer is within the above ranges, the migration of the mirogabarin salt from the adhesive to the water can be facilitated, and the patch can be given a high skin permeability.

[0068] Examples of polar groups include hydroxyl groups (-OH groups), carboxyl groups (-COOH), amino groups (-NH2), sulfo groups (-SO3H), phosphonic acid groups [-P(=O)(OH)2], and phosphate groups [-O-P(=O)(OH)2].

[0069] Examples of monomers containing polar groups include carboxyl group-containing vinyl monomers such as acrylic acid, methacrylic acid, itaconic acid, maleic acid, mesaconic acid, citraconic acid, glutaconic acid, and butylmaleic acid; hydroxyalkyl (meth)acrylates; sulfonic acid group-containing (meth)acrylates such as 3-sulfopropyl (meth)acrylate; and phosphate group-containing (meth)acrylates such as 2-acryloyloxyethyl acid phosphate and 2-methacryloyloxyethyl acid phosphate.

[0070] The polymerization of acrylic polymers can be carried out by conventionally known methods. For example, one method is to polymerize the above-mentioned monomers in the presence of a polymerization initiator. Specifically, a predetermined amount of monomer, polymerization initiator, and polymerization solvent are supplied to a reactor and heated at a temperature of 60 to 80°C for 4 to 48 hours to radically polymerize the monomers.

[0071] Examples of polymerization initiators include azobis polymerization initiators such as 2,2'-azobisisobutyronitrile (AIBN), 1,1'-azobis(cyclohexane-1-carbonnitrile), and 2,2'-azobis-(2,4'-dimethylvaleronitrile); and peroxide polymerization initiators such as benzoyl peroxide (BPO), lauroyl peroxide (LPO), and di-tert-butyl peroxide. Examples of polymerization solvents include ethyl acetate, cyclohexane, and toluene. Furthermore, the polymerization reaction is preferably carried out under a nitrogen gas atmosphere.

[0072] The adhesive layer preferably contains an acrylic adhesive and the area proportion occupied by mirogabarin salt is 0.1 to 60%, and preferably contains an adhesive containing 80% by mass or more of an acrylic adhesive and the area proportion occupied by mirogabarin salt is 0.2 to 60%. When the adhesive layer has the above configuration, it can easily draw in moisture present on the skin to which the patch is applied, and the mirogabarin salt dissolves in this drawn-in moisture, allowing the mirogabarin salt to be smoothly released from the adhesive layer. Therefore, the patch has a high skin permeability.

[0073] (Transdermal Absorption Enhancer) The adhesive layer preferably contains a transdermal absorption enhancer. Conventional transdermal absorption enhancers used in patches can be used. Fatty acids, fatty acid esters, nonionic surfactants, diethylene glycol alkyl ethers, higher alcohols, and polyhydric alcohols are preferred as transdermal absorption enhancers, with fatty acids and nonionic surfactants being more preferred. The transdermal absorption enhancer may be used alone or in combination of two or more types.

[0074] Examples of fatty acids include saturated fatty acids such as lauric acid (12 carbon atoms), myristic acid (14 carbon atoms), palmitic acid (16 carbon atoms), stearic acid (18 carbon atoms), and isostearic acid (18 carbon atoms), and unsaturated fatty acids such as palmitoleic acid (16 carbon atoms), oleic acid (18 carbon atoms), and erucic acid (22 carbon atoms), with oleic acid, isostearic acid, and myristic acid being preferred. The number of carbon atoms in the fatty acid is preferably 12 to 24, more preferably 13 to 22, and even more preferably 14 to 20.

[0075] Examples of fatty acid esters include alkyl fatty acid esters such as isopropyl myristate (isopropyl myristate, number of carbon atoms in the fatty acid residue: 14), isopropyl palmitate (number of carbon atoms in the fatty acid residue: 16), ethyl oleate (number of carbon atoms in the fatty acid residue: 18), and decyl oleate (number of carbon atoms in the fatty acid residue: 18). The number of carbon atoms in the fatty acid residue of the fatty acid ester is preferably 10 to 26, more preferably 12 to 22, and even more preferably 13 to 20.

[0076] Examples of nonionic surfactants include glycerin fatty acid esters (e.g., glycerin fatty acid monoesters such as glyceryl monooleate and glyceryl monostearate), polyglycerin fatty acid esters, polyethylene glycol fatty acid esters, polyoxyethylene glycerin fatty acid esters, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene alkyl ethers, and polyoxyethylene polyoxypropylene block copolymers. Glycerin fatty acid esters are preferred, and glycerin fatty acid monoesters are more preferred.

[0077] The number of carbon atoms in the fatty acid residue of the glycerol fatty acid ester is preferably 10 to 26, more preferably 12 to 22, and even more preferably 13 to 20.

[0078] Diethylene glycol alkyl ethers are preferably diethylene glycol monoalkyl ethers. In diethylene glycol alkyl ethers, the number of carbon atoms in the alkyl group is preferably 1 to 6, and more preferably 1 to 4. Examples of alkyl groups include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, and t-butyl group, with methyl group and ethyl group being preferred.

[0079] The diethylene glycol monoalkyl ether is not particularly limited, and examples include diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol mono-n-propyl ether, diethylene glycol monoisopropyl ether, diethylene glycol mono-n-butyl ether, diethylene glycol monoisobutyl ether, and diethylene glycol mono-t-butyl ether. Diethylene glycol monoethyl ether, diethylene glycol monomethyl ether, and diethylene glycol mono-n-butyl ether are preferred, and diethylene glycol monoethyl ether is more preferred.

[0080] Higher alcohols are monohydric alcohols having eight or more carbon atoms, such as oleyl alcohol (18 carbon atoms) and octyldodecanol (20 carbon atoms). The number of carbon atoms in higher alcohols is preferably 8 to 26, more preferably 10 to 24, more preferably 12 to 22, and more preferably 14 to 20.

[0081] Polyhydric alcohols are alcohols that have two or more hydroxyl groups (-OH) in their molecule. Examples include dihydric alcohols such as propylene glycol and polyethylene glycol, and trihydric alcohols such as glycerin.

[0082] Fatty acids, fatty acid esters, nonionic surfactants, and higher alcohols have polar and nonpolar groups in their molecules, which helps mirogabarin salts dissolved in water to move into the skin and can impart a high skin permeability to the patch.

[0083] Polyhydric alcohols have high hydrophilicity, and the polyhydric alcohols themselves can form channels through which the mirogabarin salt dissolves, as well as promote the attraction of water into the adhesive layer. Therefore, the release of the mirogabarin salt from the adhesive layer can be promoted, improving the amount of the patch that penetrates the skin.

[0084] The content of the transdermal absorption enhancer in the adhesive layer is preferably 0.5% by mass or more, more preferably 1.0% by mass or more, more preferably 1.5% by mass or more, more preferably 2.0% by mass or more, more preferably 2.5% by mass or more, more preferably 3.0% by mass or more, and more preferably 3.5% by mass or more. The content of the transdermal absorption enhancer in the adhesive layer is preferably 15.0% by mass or less, more preferably 13.0% by mass or less, more preferably 11.0% by mass or less, more preferably 9.0% by mass or less, more preferably 8.5% by mass or less, more preferably 8.0% by mass or less, more preferably 7.8% by mass or less, and more preferably 7.5% by mass or less. The content of the transdermal absorption enhancer in the adhesive layer is preferably 0.5 to 15.0% by mass, more preferably 1.0 to 13.0% by mass, more preferably 2.0 to 11.0% by mass, and more preferably 3.0 to 8.0% by mass. When the amount of transdermal absorption enhancer in the adhesive layer is within the above range, the transdermal absorption enhancer reduces the concentration of the enhancer near the surface of the adhesive layer, making it easier for moisture to penetrate into the adhesive layer. As a result, it can easily draw in moisture present on the skin to which the patch is applied, and the mirogabarin salt dissolves in this drawn-in moisture, allowing for the smooth release of the mirogabarin salt from the adhesive layer. Furthermore, the amount of skin permeability can also be improved by the action of the transdermal absorption enhancer. Therefore, the patch has a high amount of skin permeability.

[0085] The adhesive layer preferably contains an acrylic adhesive and a transdermal absorption enhancer, and more preferably contains an adhesive containing 80% by mass or more of an acrylic adhesive and a fatty acid as the transdermal absorption enhancer.

[0086] The adhesive layer has a solubility parameter (SP value) of 8 to 30 (cal / cm³).3 ) 1 / 2 Preferably, the adhesive contains a polymer containing a monomer component in an amount of 50% by mass or more, and also contains a transdermal absorption enhancer, with a solubility parameter (SP value) of 8 to 30 (cal / cm³). 3 ) 1 / 2 It is more preferable that the adhesive contains 50% by mass or more of a polymer containing the monomer component, and also contains a fatty acid as a transdermal absorption enhancer.

[0087] The adhesive layer preferably contains an acrylic adhesive comprising an acrylic polymer containing an alkyl (meth)acrylate component and a transdermal absorption enhancer, and more preferably contains an acrylic adhesive comprising an acrylic polymer containing an alkyl (meth)acrylate component and a fatty acid as the transdermal absorption enhancer.

[0088] (Other additives) The adhesive layer may contain other additives such as tackifiers and antioxidants, provided that they do not affect the dissolution of the mirogabarin salt in water.

[0089] (Tackifiers) Examples of tackifiers include terpene resins, modified terpene resins, hydrogenated terpene resins, terpene phenol resins, rosin, hydrogenated rosin, rosin esters, petroleum resins, coumarone-indene resins, phenol resins, xylene resins, and alicyclic saturated hydrocarbon resins. Tackifiers may be used alone or in combination of two or more. The content of tackifiers in the adhesive layer is preferably 15 to 80 parts by mass, and more preferably 20 to 70 parts by mass, per 100 parts by mass of adhesive.

[0090] The thickness of the adhesive layer is preferably 20 to 200 μm, more preferably 30 to 150 μm, and particularly preferably 50 to 120 μm. When the thickness of the adhesive layer is 20 μm or more, the amount of mirogabarin salt necessary to obtain the desired pharmacological effect can be contained in the adhesive layer. When the thickness of the adhesive layer is 200 μm or less, strong drying conditions are not required during manufacturing to reduce residual solvent in the adhesive layer, thus suppressing the volatilization or decomposition of the mirogabarin salt in the adhesive layer.

[0091] The water absorption rate of the adhesive layer is preferably 0.5 to 20%, more preferably 1 to 20%, more preferably 1 to 15%, and more preferably 1 to 12%. When the water absorption rate of the adhesive layer is 0.5% or more, it can easily draw in moisture present on the skin to which the patch is applied, and the mirogabarin salt dissolves in this drawn-in moisture, allowing the mirogabarin salt to be smoothly released from the adhesive layer. Therefore, the patch has a high skin permeability. When the water absorption rate of the adhesive layer is 20% or less, the patch can be given excellent adhesion to the skin.

[0092] The water absorption rate of the adhesive layer can be adjusted by controlling the thickness of a highly hydrophobic barrier layer (hereinafter sometimes simply referred to as the "barrier layer") in the surface layer of the adhesive layer on the skin-contacting side, where there are almost no mirogabarin salts. For example, by including a large amount of highly hydrophilic mirogabarin salts in the surface layer of the adhesive layer on the skin-contacting side, the thickness of the barrier layer can be reduced, and the water absorption rate of the adhesive layer can be increased.

[0093] As described later, there are two methods for manufacturing the adhesive layer: the direct coating method and the transfer coating method. The direct coating method involves coating one surface of the support with an adhesive layer forming solution and drying it to laminate and integrate the adhesive layer onto the support. During the drying process of the adhesive layer forming solution, the mirogabarin salts in the solution gradually settle toward the support. By slowing down (fastening) the settling rate of the mirogabarin salts, the content of mirogabarin salts in the surface layer on the skin-adhering side of the adhesive layer can be increased (decreased), thereby making the barrier layer thinner (thicker).

[0094] The transfer coating method involves applying an adhesive layer-forming solution to the release surface of a release liner, drying it to form an adhesive layer, and then laminating and integrating a support onto this adhesive layer. During the drying process of the adhesive layer-forming solution, the mirogabarin salts in the solution gradually settle toward the release liner side. By increasing (decreasing) the settling rate of the mirogabarin salts, the content of mirogabarin salts in the surface layer of the adhesive layer on the skin-adhering side can be increased (decreased), thereby making the barrier layer thinner (thicker).

[0095] The settling rate of mirogabarin salt in the adhesive layer-forming solution is faster (slower) as the particle size of the mirogabarin salt increases (decreases).

[0096] In direct coating methods, the water absorption rate of the adhesive layer can be reduced (increased) by increasing (decreasing) the particle size of the mirogabarin salt. Conversely, in transfer coating methods, the water absorption rate of the adhesive layer can be reduced (increased) by increasing (decreasing) the particle size of the mirogabarin salt.

[0097] The above describes a method for controlling the water absorption rate of the adhesive layer by controlling the thickness of the barrier layer of the adhesive layer. However, the method is not limited to this, and the water absorption rate of the adhesive layer can also be adjusted by adjusting the particle size of the mirogabarin salt.

[0098] As described above, when mirogabarin salts dissolve in water, voids are created in the areas where the mirogabarin salts were present, and water flows into these voids. As the particle size of the mirogabarin salts increases, the voids also increase, making it easier for water to flow into the adhesive layer and thus increasing the water absorption rate of the adhesive layer.

[0099] The above describes a method for forming an adhesive layer and a method for controlling the water absorption rate of the adhesive layer by combining the particle size of the mirogabarin salt as needed. In the method for forming the adhesive layer, the degree of sedimentation of the mirogabarin salt can also be adjusted by controlling the time it takes for the mirogabarin salt to move through the adhesive layer forming solution by adjusting the drying time.

[0100] The water absorption rate of the adhesive layer refers to the value measured according to the following procedure. First, an adhesive patch is prepared, which has a support, an adhesive layer laminated and integrated on one surface of the support, and a release liner that is peelably laminated on the adhesive layer.

[0101] Area from the patch: 3.14 cm 2 The first test specimen is prepared by punching out the material in the thickness direction. The second test specimen is prepared by removing the release liner from the first test specimen. The mass (W0) of the second test specimen is measured.

[0102] Prepare a 100 mL glass bottle and fix the second test specimen to the inside of the glass bottle using adhesive tape, with the adhesive layer facing the glass bottle. Supply 50 mL of deionized water into the glass bottle so that the second test specimen is completely immersed in the deionized water. Leave the glass bottle in a constant temperature bath maintained at 32°C for 2 hours.

[0103] Next, remove the second test specimen from the glass bottle. Prepare a polyethylene terephthalate film with a release agent applied to one side. Attach the second test specimen to the release agent side of the polyethylene terephthalate film, with its adhesive layer facing the polyethylene terephthalate film.

[0104] The moisture adhering to the support of the second test specimen is wiped off with filter paper (Whatman No. 50). With the filter paper placed on the support of the second test specimen, a roller with a mass of 2 kg and a width of 4.5 cm is pressed against it at a linear pressure of 4.36 N / cm and a speed of 1 cm / s and passed back and forth once.

[0105] The polyethylene terephthalate film is peeled and removed from the adhesive layer of the second test specimen, and the mass (Wmm) of the second test specimen is immediately measured. The second test specimen is placed in a desiccator with its adhesive layer facing upwards. The internal pressure of the desiccator is set to 10 hPa using a vacuum pump, and it is dried for 18 hours. The second test specimen is recovered after drying, and its mass (Wdry) is measured. The water absorption amount (Q) and water absorption rate (%) are calculated based on the following formulas: Water absorption amount (Q) = Wimm - Wdry Water absorption rate (%) = 100 × Q / Wp

[0106] Here, Wp is the mass of the adhesive layer (the mass of the adhesive patch excluding the support and release liner). The area from the support constituting the adhesive patch is 3.14 cm². 2 A support piece is prepared by punching it out in this manner. The mass (Wb) of the support piece is measured. Wp is calculated based on the following formula: Wp = W ０ -Wb

[0107] The adhesive layer preferably has a water absorption rate of 0.5 to 20% and a surface area ratio of 0.1 to 60% occupied by mirogabarin salt, more preferably a water absorption rate of 1 to 20% and a surface area ratio of 0.2 to 60% occupied by mirogabarin salt, and even more preferably a water absorption rate of 1 to 15% and a surface area ratio of 0.25 to 60% occupied by mirogabarin salt. When the adhesive layer has the above configuration, it can easily draw in moisture present on the skin to which the patch is applied, and the mirogabarin salt dissolves in this drawn-in moisture, allowing the mirogabarin salt to be smoothly released from the adhesive layer. Therefore, the patch has a high skin permeability.

[0108] The adhesive layer preferably contains an acrylic adhesive and has a water absorption rate of 0.5 to 20%, and more preferably contains an adhesive containing 80% by mass or more of an acrylic adhesive and has a water absorption rate of 1 to 20%. When the adhesive layer has the above configuration, it can easily draw in moisture present on the skin to which the patch is applied, and the salt of mirogabarin dissolves in this drawn-in moisture, allowing the salt of mirogabarin to be smoothly released from the adhesive layer. Therefore, the patch has a high skin permeability.

[0109] The adhesive layer has a solubility parameter (SP value) of 8 to 30 (cal / cm³). 3 ) 1 / 2 The adhesive contains 50% by mass or more of a polymer containing a monomer component, and preferably has a water absorption rate of 0.5 to 20%, and a solubility parameter (SP value) of 8 to 30 (cal / cm³). 3 ) 1 / 2 The adhesive contains 50% by mass or more of a polymer containing the monomer component, and more preferably has a water absorption rate of 1 to 20%. When the adhesive layer has the above configuration, it can easily draw in moisture present on the skin to which the patch is applied, and the salt of mirogabarin dissolves in this drawn-in moisture, allowing the salt of mirogabarin to be smoothly released from the adhesive layer. Therefore, the patch has a high skin permeability.

[0110] The adhesive layer preferably contains an acrylic adhesive comprising an acrylic polymer containing an alkyl (meth)acrylate component, and has a water absorption rate of 0.5 to 20%, and more preferably contains an acrylic adhesive comprising an acrylic polymer containing an alkyl (meth)acrylate component having 1 to 16 carbon atoms in the alkyl group, and has a water absorption rate of 1 to 20%. When the adhesive layer has the above configuration, it can easily draw in moisture present on the skin to which the patch is applied, and the salt of mirogabarin dissolves in this drawn-in moisture, allowing the salt of mirogabarin to be smoothly released from the adhesive layer. Therefore, the patch has a high skin permeability.

[0111] [Support] In the patch of the present invention, an adhesive layer is laminated and integrated onto one surface of the support. The support is required to have strength to prevent the loss of the drug in the adhesive layer and to impart self-retention properties to the patch. Examples of such supports include resin films, nonwoven fabrics, woven fabrics, knitted fabrics, and aluminum sheets.

[0112] Examples of resins that make up the resin film include cellulose acetate, rayon, polyethylene terephthalate, plasticized vinyl acetate-vinyl chloride copolymer, nylon, ethylene-vinyl acetate copolymer, plasticized polyvinyl chloride, polyurethane, polyethylene, polypropylene, and polyvinylidene chloride, with polyethylene terephthalate being preferred.

[0113] Examples of materials that make up the nonwoven fabric include polyethylene, polypropylene, ethylene-vinyl acetate copolymer, ethylene-(meth)acrylate methyl copolymer, nylon, polyester, vinylon, SIS copolymer, SEBS copolymer, rayon, and cotton, with polyester being preferred. These materials may be used individually or in combination of two or more.

[0114] The support may be a single layer or a laminated sheet formed by laminating multiple layers together. Examples of laminated sheets include those formed by laminating polyethylene terephthalate sheets with nonwoven fabrics or flexible resin films.

[0115] The thickness of the support is not particularly limited, but is preferably 2 to 200 μm, and more preferably 2 to 100 μm.

[0116] [Release Liner] In the adhesive patch of the present invention, a release liner may be laminated on one surface of the adhesive layer in a removable manner. The release liner is used to prevent the loss of drugs in the adhesive layer and to protect the adhesive layer.

[0117] Examples of release liners include paper and resin films. Examples of resins constituting the resin film include polyethylene terephthalate, polyethylene, polypropylene, polyvinyl chloride, and polyvinylidene chloride. It is preferable that the surface of the release liner that faces the adhesive layer is treated with a release agent.

[0118] [Method for Manufacturing Adhesives] The method for manufacturing adhesive patches is not particularly limited, and examples include: (1) a method in which an adhesive layer forming solution containing a salt of mirogabarin, an adhesive, and a solvent is coated onto one surface of a support and then dried to laminate and integrate an adhesive layer onto one surface of the support, and if necessary, a release liner is laminated onto the adhesive layer such that the side of the release liner that has been treated for mold release faces the adhesive layer (direct coating method); and (2) a method in which the adhesive layer forming solution is coated onto the side of the release liner that has been treated for mold release (release surface) and dried to form an adhesive layer on the release liner, and a support is laminated and integrated onto this adhesive layer (transfer coating method).

[0119] The adhesive layer-forming solution is obtained by uniformly stirring a salt of mirogabarin, an adhesive, and a solvent, as well as other additives as needed. Examples of solvents include toluene, n-hexane, cyclohexane, n-heptane, and ethyl acetate. The solvent may be used alone or in combination of two or more.

[0120] The method for manufacturing the adhesive can be either the direct coating method or the transfer coating method described above. If it is desired to adjust the area ratio occupied by the mirogabarin salt to a desired range in the SEM backscattered electron image of the adhesive layer surface under an accelerating voltage of 20 kV, the adjustment can be made in accordance with the following procedure.

[0121] When the direct coating method described in (1) above is adopted, the surface of the resulting adhesive layer can contain a large amount of mirogabarin salt by controlling the sedimentation of mirogabarin salt in the coating layer formed by coating the support with an adhesive layer forming solution.

[0122] Factors that influence the degree of sedimentation of mirogabarin salts in the coating layer include the particle size of the mirogabarin salts, the viscosity of the adhesive layer forming solution, the dispersion state of the mirogabarin salts in the adhesive layer forming solution immediately before coating the support, the coating speed of the adhesive layer forming solution onto the support, and the subsequent drying speed.

[0123] In the direct coating method described in (1) above, the degree of sedimentation of mirogabarin salt can be reduced by reducing the particle size of the mirogabarin salt. The degree of sedimentation of mirogabarin salt can be reduced by increasing the viscosity of the adhesive layer forming solution, for example, by increasing the solid content (solid content ratio) of the adhesive layer forming solution. The degree of sedimentation of mirogabarin salt can be reduced by making the dispersion state of mirogabarin salt in the adhesive layer forming solution more uniform immediately before coating the support. The time from coating to drying can be shortened by increasing the coating speed of the adhesive layer forming solution on the support and the subsequent drying speed, thereby reducing the degree of sedimentation of mirogabarin salt in the coated layer. In this way, by adjusting to reduce the degree of sedimentation of mirogabarin salt in the coated layer, a large amount of mirogabarin salt can be contained on the surface of the resulting adhesive layer.

[0124] In the transfer coating method described in (2) above, an adhesive layer-forming solution is applied to the release surface of the release liner to form a coating layer, and this coating layer is dried to form an adhesive layer. The adhesive is then manufactured by transferring the support onto this adhesive layer and laminating it together. Therefore, by increasing the degree of sedimentation of the mirogabarin salt, a large amount of mirogabarin salt can be contained on the surface of the resulting adhesive layer (on the release liner side). The degree of sedimentation of the mirogabarin salt can be increased by adjusting the procedure in the reverse of the procedure described in (1) above.

[0125] As described above, in either method (1) or (2) above, by controlling the factors that affect the degree of sedimentation of mirogabarin salt in the coating layer, either individually or in combination, the degree of sedimentation of mirogabarin salt in the coating layer can be easily adjusted, and the surface of the resulting adhesive layer can be made to contain a large amount of mirogabarin salt, and the area ratio occupied by mirogabarin salt can be adjusted to a desired range.

[0126] The present invention will be described more specifically below with reference to examples, but the present invention is not limited thereto. Specific numerical values ​​such as blending ratios (content), physical properties, and parameters used in the following description may be replaced with the corresponding upper limits (numerical values ​​defined as "less than or equal to" or "less than") or lower limits (numerical values ​​defined as "greater than or equal to") of the blending ratios (content), physical properties, and parameters described in the "Means for Solving the Problem" and "Modes for Carrying Out the Invention" sections.

[0127] The preparation methods or details of the adhesives used in the examples and comparative examples are described below.

[0128] [Salts of Milogabalin] ・Milogabalin besylate (pKa of benzenesulfonic acid: -2.8) ・Milogabalin hydrochloride (pKa of hydrochloric acid: -6.3) ・Milogabalin (free base form) ・Milogabalin propionate (pKa of propionic acid: 4.9)

[0129] [Adhesive] (Preparation of acrylic polymer (1)) 2-ethylhexyl methacrylate (SP value: 16.5 (cal / cm³) 3 ) 1 / 2 ) 80 parts by mass, 2-ethylhexyl acrylate (SP value: 16.8 (cal / cm³) 3 ) 1 / 2 ) 10 parts by mass, and dodecyl acrylate (SP value: 16.5 (cal / cm³) 3 ) 1 / 2A monomer composition containing 10 parts by mass and a reaction solution consisting of 75 parts by mass of ethyl acetate were fed into a polymerization machine, and the inside of the polymerization machine was made into a nitrogen atmosphere at 80°C. A polymerization initiator solution was prepared by dissolving 0.6 parts by mass of lauroyl peroxide in 17 parts by mass of ethyl acetate. While adding the polymerization initiator solution to the above reaction solution over 14 hours, the above monomer composition was copolymerized to obtain an acrylic polymer (1) solution.

[0130] (Acrylic polymer (2)) 2-ethylhexyl acrylate component (SP value: 16.8 (cal / cm 3 )) 68.15% by mass, vinyl acetate component (SP value: 18.5 (cal / cm 1 / 2 )) 26.5% by mass, 2-hydroxyethyl acrylate component (SP value: 23.9 (cal / cm 3 )) 5.2% by mass, and glycidyl methacrylate component (SP value: 9.3 (cal / cm 1 / 2 )) 0.15% by mass, an acrylic polymer (trade name "Duro-Tak 387-2287" manufactured by Henkel) 3 )) 1 / 2 )) 5.2% by mass, and glycidyl methacrylate component (SP value: 9.3 (cal / cm 3 )) 0.15% by mass, an acrylic polymer (trade name "Duro-Tak 387-2287" manufactured by Henkel) 1 / 2 )) 0.15% by mass, an acrylic polymer (trade name "Duro-Tak 387-2287" manufactured by Henkel)

[0131] (Acrylic polymer (3)) 2-ethylhexyl acrylate component (SP value: 16.8 (cal / cm 3 )) 1 / 2 ), acrylic acid component (SP value: 23.4 (cal / cm 3 )) 1 / 2 ), n-butyl acrylate component (SP value: 8.3 (cal / cm 3 )) 1 / 2 ), and vinyl acetate component (SP value: 18.5 (cal / cm 3 )) 1 / 2 ), an acrylic polymer, trade name "Duro-Tak 387-2051" manufactured by Henkel)

[0132] (Acrylic polymer (4)) N-vinyl-2-pyrrolidone (SP value: 21.1 (cal / cm 3 )) 10 parts by mass, ethyl acrylate (SP value: 8.8 (cal / cm 1 / 2 )) 3 )) 1 / 2) 50 parts by mass, and n-octyl acrylate (SP value: 16.8 (cal / cm³) 3 ) 1 / 2 A reaction solution consisting of a monomer composition containing 40 parts by mass of ethyl acetate and 50 parts by mass of ethyl acetate was supplied to a polymerizer, and the polymerizer was subjected to a nitrogen atmosphere at 80°C. A polymerization initiator solution was prepared by dissolving 1 part by mass of lauroyl peroxide in a mixed solvent containing 30 parts by mass of ethyl acetate and 20 parts by mass of cyclohexane. The monomer composition was copolymerized while adding the polymerization initiator solution to the reaction solution over 24 hours, and after polymerization was completed, ethyl acetate was further added to the reaction solution to obtain an acrylic polymer (4) solution with an acrylic polymer (4) content of 30% by mass.

[0133] (SIS) Rubber-based adhesive (styrene-isoprene-styrene block copolymer (SIS), Kraton Corporation product name "Kraton D DX401")

[0134] (Tackifiers) - Alicyclic saturated hydrocarbon resin (Arakawa Chemical Industries, Ltd. product name "Alcon P-90") - Liquid paraffin (Kaneda Corporation product name "Hycol M")

[0135] (Transdermal absorption enhancers) • Isopropyl myristate (IPM) • Oleic acid, isostearic acid, myristic acid, glyceryl monooleate (MGO) • Diethylene glycol monoethyl ether

[0136] (Solvents) Ethyl acetate, Toluene

[0137] (Examples 1-13, Comparative Examples 1-2) To obtain an adhesive layer containing each component in the amounts shown in the table, a solution for forming an adhesive layer was prepared by supplying a salt of mirogabarin (a drug), an adhesive, a transdermal absorption enhancer, and a tackifier to a solvent. The solid content (mass%) of the adhesive layer forming solution is shown in the table. In the table, the content (mass%) of the salt of mirogabarin (the entire salt of mirogabarin including the acidic portion) is listed in the upper row. The mass of mirogabarin obtained by converting the salt of mirogabarin to its free base form is listed in parentheses in the lower row. The content ratio (mass%) of each component in the obtained adhesive layer was the same as the content ratio of each component in the adhesive layer forming solution.

[0138] Using the obtained adhesive layer-forming solution, an adhesive layer was formed by the coating method shown in the table (direct coating method or transfer coating method shown below) to prepare a patch.

[0139] The water absorption rate of the adhesive layer of the obtained patch was measured according to the procedure described above, and the results are recorded in the table.

[0140] (Direct coating method) A polyethylene terephthalate film with a thickness of 38 μm was prepared as a support. An adhesive layer forming solution was applied to one surface of this support and dried at 60°C for 30 minutes, thereby laminating and integrating an adhesive layer with a thickness of 100 μm onto one surface of the support to produce an adhesive.

[0141] (Transfer Coating Method) A 75 μm thick polyethylene terephthalate film treated with silicone release agent was prepared as a release liner. An adhesive layer forming solution was applied to the silicone release agent surface of this polyethylene terephthalate film and dried at 60°C for 30 minutes to create a laminate in which a 100 μm thick adhesive layer was formed on the silicone release agent surface of the polyethylene terephthalate film. Then, a 38 μm thick polyethylene terephthalate film was prepared as a support, and the adhesive layer of the laminate was placed on top of this support so that one side of the support faced the adhesive layer of the laminate, and the adhesive layer of the laminate was transferred to the support to create a laminated and integrated product. After removing the release liner from the product, various performance characteristics were evaluated.

[0142] For the obtained adhesive patch, the particle size of the mirogabarin salt in the adhesive layer and the area ratio occupied by the mirogabarin salt in the SEM backscattered electron image of the adhesive layer surface under an accelerating voltage of 20 kV were measured in the manner described above, and the results are shown in the table.

[0143] In the table, "particle size of mirogabarin salt in the adhesive layer" is denoted as "particle size," and "area percentage occupied by mirogabarin salt in the SEM backscattered electron image of the adhesive layer surface under an accelerating voltage of 20 kV" is denoted as "area percentage (20 kV)."

[0144] The cumulative 24-hour skin penetration of the obtained transdermal patch was measured according to the following procedure, and the results are shown in the table.

[0145] [Skin Permeability Test (24-hour Cumulative Skin Permeation)] To evaluate the skin permeability of the patch immediately after manufacturing, a hairless mouse skin permeability test was performed using the following method.

[0146] The adhesive patch was cut to a diameter of 1.30 cm and an area of ​​1.33 cm. 2 A planar, circular test specimen was obtained. After filling the receptor side of a Franz-type diffusion cell, maintained at 32°C, with receptor solution, hairless mouse skin was fixed to the Franz-type diffusion cell, and the dermal side of the skin was brought into contact with the receptor solution. The test specimen was then attached to the stratum corneum side of the skin using an adhesive layer. The receptor solution used was phosphate-buffered saline adjusted to pH 7.4.

[0147] Twenty-four hours after applying the test specimen to the skin, the receptor fluid beneath the skin was collected, and the concentration of free nucleotide milogabalin was measured using HPLC. Next, the amount of free nucleotide milogabalin permeated was calculated from the free nucleotide milogabalin concentration and the amount of receptor fluid. The calculated amount of free nucleotide milogabalin permeated was measured across the area of ​​the test specimen (1.33 cm²). 2 The value obtained by dividing by ) is the 24-hour cumulative skin permeation of free base-type mirogabalin (mg / cm³). 2 The results obtained were recorded in the table as "24-hour cumulative skin permeation (mg / cm³)". 2 This was shown in the ) section.

[0148]

[0149]

[0150] (Cross-reference of related applications) This application claims priority under Japanese Patent Application No. 2025-17057, filed on 4 February 2025, and the disclosures of this application are incorporated herein by reference to those applications in their entirety.

[0151] According to the present invention, as described above, it is possible to provide a patch that exhibits excellent transdermal absorption of mirogabalin.

Claims

1. A patch comprising a support, and an adhesive layer laminated and integrated on one surface of the support, the adhesive layer containing an adhesive and a salt of mirogabarin which precipitates as crystals in the adhesive and forms a salt with an acid having a pKa of less than 3.

5.

2. The adhesive patch according to claim 1, characterized in that the content of the salt of mirogabalin in the adhesive layer is 2 to 60% by mass.

3. The patch according to claim 1 or 2, characterized in that the particle size of the mirogabalin salt is 0.5 to 50 μm.

4. The adhesive patch according to claim 1, characterized in that, in the SEM backscattered electron image of the adhesive layer surface under an accelerating voltage of 20 kV, the area ratio occupied by the salt of mirogabarin is 0.1 to 60%.

5. The adhesive patch according to claim 1 or 4, characterized in that the water absorption rate of the adhesive layer is 0.5 to 20%.

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