Patches containing asenapine

Abstract

The object of the present invention is to provide an asenapine-containing patch with excellent adhesiveness and operability, that is, by using a silicone adhesive base to improve skin permeability while suppressing cold flow during storage or application, by maintaining an appropriate dosage form for a long time and maintaining the stability of the drug in the patch during storage, thereby continuously obtaining sufficient drug efficacy. The present invention relates to a patch having a support and an adhesive layer, the adhesive layer containing asenapine and a silicone adhesive base, and the loss tangent (tan δ) of the adhesive layer is 0.75 to 1.5 at 1.0 Hz.

Description

Technical Field

[0001] The present invention relates to a patch containing asenapine in an adhesive layer and a method for producing the patch. Background Art

[0002] Asenapine is a drug known as a therapeutic drug for central nervous system diseases such as schizophrenia, and sublingual tablets (Sycrest (registered trademark) sublingual tablets and Saphris (registered trademark) sublingual tablets) are already on the market. Currently, no dosage forms other than sublingual tablets are sold.

[0003] Patches containing asenapine are described in, for example, Patent Documents 1 to 5, and studies have focused on patches using a rubber-based adhesive base or an acrylic-based adhesive base.

[0004] An asenapine-containing patch prepared by combining a silicone adhesive and a polyacrylate adhesive is described in Patent Document 6, especially Example 14.

[0005] Prior art literature

[0006] Patent Literature

[0007] Patent Document 1: International Publication No. 2014 / 017593

[0008] Patent Document 2: International Publication No. 2014 / 017594

[0009] Patent Document 3: International Publication No. 2014 / 017595

[0010] Patent Document 4: International Publication No. 2017 / 018321

[0011] Patent Document 5: International Publication No. 2017 / 018322

[0012] Patent Document 6: International Publication No. 2010 / 127674 Summary of the invention

[0013] The present inventors have found that, in the course of studying patches containing asenapine, patches using asenapine and a silicone adhesive base have higher skin permeability than patches using a rubber-based adhesive base. On the other hand, cold flow (so-called "tongue sticking out") is likely to occur in the adhesive base layer during storage or application, and this affects the temporal stability of asenapine, resulting in a decrease in skin permeability as the asenapine content decreases.

[0014] Cold flow refers to the phenomenon that the adhesive flows and deforms at room temperature during storage or application. In the case of cold flow, the adhesive layer protrudes from the side of the patch of the laminated support and adhesive layer along the edge beyond the range covered by the support, and therefore cannot maintain the shape of the patch. Problems such as the protruding adhesive layer adhering to the inner surface of the packaging material of the patch may occur, affecting the time stability of asenapine, reducing the skin permeability due to the reduction of asenapine content, or making it difficult to remove the patch from the packaging material.

[0015] Therefore, an object of the present invention is to provide an asenapine-containing patch with excellent operability, that is, by improving skin permeability by using a silicone adhesive base, while suppressing cold flow during storage or application, maintaining the stability of the drug in the patch and maintaining an appropriate dosage form for a long time, thereby continuously obtaining sufficient drug efficacy.

[0016] The inventors have found that by adjusting the loss tangent (tan δ) of the adhesive layer to a specified range, and by suppressing the cold flow of the patch containing asenapine and a silicone adhesive base, the patch has excellent adhesion and operability, and further, the drug stability of the patch can be maintained and the appropriate administration form can be maintained for a long time, and the sustainability can obtain sufficient drug effect, and the results of further research have completed the present invention. That is, the present invention relates to the following content.

[0017] [1] A patch comprising a support and an adhesive layer, characterized in that:

[0018] The adhesive layer comprises asenapine and / or a pharmaceutically acceptable salt thereof and a silicone adhesive base.

[0019] The loss tangent (tan δ) of the adhesive layer is 0.75 to 1.5 at 1.0 Hz.

[0020] [2] The patch according to [1], wherein the viscosity of the adhesive layer is 3,000 to 60,000 Pa·s at 90°C.

[0021] [3] The patch according to [1], wherein the viscosity of the adhesive layer is 3500 to 60000 Pa·s at 90°C.

[0022] [4] The patch according to any one of [1] to [3], characterized in that the silicone adhesive base contains one or more selected from the group consisting of a high-viscosity amine-compatible silicone adhesive base, a medium-viscosity amine-compatible silicone adhesive base and a low-viscosity amine-compatible silicone adhesive base.

[0023] [5] The patch according to [4], wherein the silicone adhesive base comprises a high-viscosity amine-compatible silicone adhesive base and a medium-viscosity amine-compatible silicone adhesive base.

[0024] [6] The patch according to [5], characterized in that the mass ratio of the high-viscosity amine-compatible silicone adhesive base to the medium-viscosity amine-compatible silicone adhesive base is 90:10 to 10:90.

[0025] [7] The patch according to [4], wherein the silicone adhesive base comprises a high-viscosity amine-compatible silicone adhesive base and a low-viscosity amine-compatible silicone adhesive base.

[0026] [8] The patch according to [7], characterized in that the mass ratio of the high-viscosity amine-compatible silicone adhesive base to the low-viscosity amine-compatible silicone adhesive base is 90:10 to 30:70.

[0027] [9] The patch according to any one of [1] to [8], wherein the adhesive layer consists of asenapine and a silicone adhesive base.

[0028]

[10] The patch according to any one of [1] to [8], wherein the adhesive layer further contains an antioxidant.

[0029]

[11] The patch according to

[10] , wherein the adhesive layer consists of asenapine, a silicone adhesive base and an antioxidant.

[0030]

[12] The patch according to

[10] or

[11] , wherein the antioxidant is one or more selected from the group consisting of butylated hydroxytoluene, mercaptobenzimidazole, ethylenediaminetetraacetic acid and citric acid.

[0031]

[13] The patch according to [1] to

[12] , wherein the weight of the adhesive layer is 30 to 200 g / m 2 .

[0032] According to the present invention, the patch comprising a silicone adhesive layer containing asenapine can suppress cold flow and maintain the shape of the patch, thus having excellent storage stability and handling properties. In addition, the patch of the present invention also has excellent adhesiveness. DETAILED DESCRIPTION

[0033] The patch of the present invention comprises, for example, a support and an adhesive layer laminated on the support.

[0034] The support can be made of any material that can keep the patch, especially the shape of the adhesive layer. The material of the support can be a synthetic resin such as a polyamide, polyester, cellulose derivative and polyurethane such as polyethylene, polypropylene, polybutadiene, ethylene-vinyl chloride copolymer, polyvinyl chloride, nylon (trade name), etc. The properties of the support are fabrics such as films, sheets, sheet-like porous bodies, sheet-like foams, woven fabrics, knitted fabrics, nonwoven fabrics, and laminates thereof. The thickness of the support is not particularly limited, and is usually preferably about 2 to 3000 μm.

[0035] The adhesive layer comprises asenapine and a silicone adhesive base. In addition to asenapine and a silicone adhesive base, the patch of the present invention may further comprise other additives such as an antioxidant, a tackifying resin, a plasticizer, an absorption promoter, a solubilizer, a cross-linking agent, a preservative, a filler, a storage agent, and a fragrance as required.

[0036] Asenapine of the present invention is a compound called trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxetane[4,5-c]pyrrole. Asenapine has multiple optical isomers, and any optical isomer can be used, and it can also be a mixture of optical isomers such as a racemate. The acid added to asenapine is not particularly limited as long as it is a pharmaceutically acceptable acid. The acid addition salt of asenapine can be an anhydrous substance or a hydrate.

[0037] The acid in the acid addition salt of asenapine includes hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, maleic acid, malonic acid, succinic acid, tartaric acid, citric acid, ascorbic acid, salicylic acid, benzoic acid, etc. For example, asenapine maleate is available on the market in the form of sublingual tablets (Sycrest (registered trademark) sublingual tablets and Saphris (registered trademark) sublingual tablets).

[0038] The desalting agent can be used as long as it can convert the acid addition salt of asenapine into asenapine free base by salt exchange reaction with the acid addition salt of asenapine. That is, the desalting agent refers to a component that converts the acid addition salt of asenapine into asenapine free base. As desalting agents, alkali metal hydroxides, alkali metal salts, alkaline earth metal hydroxides, alkaline earth metal salts, low molecular weight amines, etc. can be listed, and one of them can be used alone or in combination. As alkali metal hydroxides, lithium hydroxide, sodium hydroxide, and potassium hydroxide can be listed. As alkali metal salts, sodium carbonate, potassium carbonate, sodium bicarbonate, trisodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, tripotassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium lactate, sodium citrate, disodium tartrate, sodium hydrogen tartrate, and sodium oleate can be listed. Low molecular weight amines are amines with a molecular weight of 30 to 300, for example, monoethanolamine, diethanolamine), triethanolamine, isopropanolamine, and diisopropanolamine can be listed. The desalting agent can be selected by considering the pKa of the acid added to asenapine. When the desalting agent is sodium hydroxide or sodium acetate, the drug is less decomposed during the preparation of the patch.

[0039] The content of the above-mentioned asenapine can be appropriately set by those skilled in the art, but is preferably 0.5 to 30 mass percent, more preferably 1 to 20 mass percent, more preferably 1.5 to 12 mass percent, and particularly preferably 2 to 10 mass percent, calculated as free asenapine relative to the total amount of the adhesive layer.

[0040] In the patch of the present invention, the loss tangent (tan δ) of the adhesive layer is preferably 0.75 to 1.5 at 1.0 Hz, preferably 0.85 to 1.5, more preferably 0.85 to 1.45, more preferably 0.85 to 1.3, and further preferably 0.9 to 1.3. If the loss tangent is small, the adhesiveness becomes poor or it is difficult to manufacture, and if the loss tangent is large, cold flow is likely to occur.

[0041] The loss tangent (tanδ), which is a viscoelasticity index, is a value calculated by the following formula when a composition containing asenapine and a silicone adhesive base is sandwiched between two plates in dynamic viscoelasticity measurement and a stress change is measured when periodic vibration strain is applied to one plate. The dynamic viscoelasticity measurement is performed at a temperature of 32°C and a frequency of 1 Hz, for example, using a rotational rheometer.

[0042] Loss tangent (tanδ) = loss modulus (G”) / storage modulus (G’)

[0043] In the patch of the present invention, the viscosity is preferably 3000 to 60000 Pa·s, preferably 3500 to 60000 Pa·s, more preferably 4500 to 55000 Pa·s, particularly preferably 5500 to 28000 Pa·s, and further preferably 5500 to 20000 Pa·s at 90° C. If the viscosity at 90° C. is low, cold flow is likely to occur, and if the viscosity at 90° C. is high, adhesiveness deteriorates or manufacturing becomes difficult.

[0044] The viscosity in the present invention is a value obtained by measuring the viscosity of a sample (adhesive layer, etc.) at a specified temperature using a flow tester (manufactured by SHIMADZU, product name "FLOWTESTER CFT-500"), and the viscosity of the adhesive layer of the present invention is a value measured by the above method when the adhesive layer is arranged on the surface of a support.

[0045] In the patch of the present invention, the cold flow area ratio is less than 40%, preferably less than 15%, and further preferably less than 10%.

[0046] The cold flow area ratio in the present invention refers to the percentage of the area of ​​the cold flow portion (the portion extending from the original patch) when the area of ​​the cold flow (ie, the area of ​​the original patch) is 100%.

[0047] The silicone-based adhesive base is a compound having an organopolysiloxane skeleton.

[0048] Examples of the silicone adhesive base include a mixture of silicone rubber and silicone resin, or a mixture obtained by dehydration polycondensation of the mixture in the presence of an alkali catalyst or the like, and a condensate of silicone rubber and silicone resin is preferred.

[0049] The silicone rubber constituting the silicone adhesive base is a long-chain polymer having hydroxyl groups at both ends of a polyorganosiloxane. The organosiloxane unit of the silicone rubber is preferably a silicone rubber containing dimethylsiloxane as a main component.

[0050] The silicone resin constituting the silicone adhesive base is not particularly limited, but a silicate resin having a three-dimensional structure is preferred.

[0051] Examples of silicone adhesive bases include dimethylpolysiloxane, polymethylvinylsiloxane, and polymethylphenylsiloxane. Specific examples of silicone adhesive bases include MD series (Dow Corning) such as MD7-4502 silicone adhesive and MD7-4602 silicone adhesive. Corning) company); such as BIO-PSA (registered trademark) 7-4301 silicone adhesive, BIO-PSA (registered trademark) 7-4302 silicone adhesive, BIO-PSA (registered trademark) 7-4201 silicone adhesive, BIO-PSA (registered trademark) 7-4202 silicone adhesive, BIO-PSA (registered trademark) 7-4101 silicone adhesive, BIO-PSA (registered trademark) 7-4102 silicone adhesive, BIO-PSA (registered trademark) 7-4601 silicone adhesive, BIO-PSA (registered trademark) 7-4602 silicone adhesive, BIO-PSA (registered trademark) 7-4501 silicone adhesive, BIO-PSA (registered trademark) 7-4502 silicone adhesive, BIO-PSA (registered trademark) 7-4601 silicone adhesive, BIO-PSA (registered trademark) 7-4602 silicone adhesive, BIO-PSA (registered trademark) 7-4501 silicone adhesive, BIO-PSA (registered trademark) 7-4502 silicone adhesive, BIO-PSA (registered trademark) BIO-PSA series (manufactured by Dow Corning Corporation), such as BIO-PSA (registered trademark) 7-4401 silicone adhesive, BIO-PSA (registered trademark) 7-4402 silicone adhesive, BIO-PSA (registered trademark) 7-4100 silicone adhesive, BIO-PSA (registered trademark) 7-4200 silicone adhesive, BIO-PSA (registered trademark) 7-4300 silicone adhesive, BIO-PSA (registered trademark) 7-4400 silicone adhesive, BIO-PSA (registered trademark) 7-4500 silicone adhesive, and BIO-PSA (registered trademark) 7-4600 silicone adhesive, Dow Corning (registered trademark) 7-9800A, Dow Corning (registered trademark) 7-9800B, Dow Corning (registered trademark) 7-9700A, and Dow Corning (registered trademark) 7-9700B.

[0052] The silicone adhesive base of the present invention is preferably an amine-compatible silicone adhesive base. As an amine-compatible silicone adhesive base, for example, after polydimethylsiloxane and silicone resin are condensed, the remaining silanol group during condensation such as trimethylsilylation is blocked by trimethylsilyl group, etc., and the remaining silanol concentration is suppressed.

[0053] Furthermore, silicone-based adhesive bases can be roughly classified into three types according to their viscosity: high viscosity, medium viscosity, and low viscosity. However, in the present invention, these can be used in combination as appropriate.

[0054] According to JIS K6800-1985 or ISO 6354, tack refers to the property of an adhesive that can form adhesion after being brought into contact with the surface of an adherend with a very light force.

[0055] The high viscosity amine-compatible silicone adhesive base in the present invention is an amine-compatible silicone adhesive base having a weight ratio of silicone resin to silicone rubber of about 52.5:47.5 (w / w) to 57.5:42.5 (w / w), preferably 55:45 (w / w). Examples of the high viscosity amine-compatible silicone adhesive base include BIO-PSA (registered trademark) 7-4302 silicone adhesive and BIO-PSA (registered trademark) 7-4301 silicone adhesive.

[0056] The medium viscosity amine-compatible silicone adhesive base in the present invention is an amine-compatible silicone adhesive base having a weight ratio of silicone resin to silicone rubber of about 57.5:42.5 (w / w) to 62.5:37.5 (w / w), preferably 60:40 (w / w). Examples of the medium viscosity amine-compatible silicone adhesive base include BIO-PSA (registered trademark) 7-4202 silicone adhesive and BIO-PSA (registered trademark) 7-4201 silicone adhesive.

[0057] The low-viscosity amine-compatible silicone adhesive base in the present invention is an amine-compatible silicone adhesive base having a weight ratio of silicone resin to silicone rubber of about 62.5:37.5 (w / w) to 67.5:32.5 (w / w), preferably 65:35 (w / w). Examples of the low-viscosity amine-compatible silicone adhesive base include BIO-PSA (registered trademark) 7-4102 silicone adhesive and BIO-PSA (registered trademark) 7-4101 silicone adhesive.

[0058] On the other hand, the present invention comprises a high-viscosity amine-compatible silicone adhesive base and a medium-viscosity amine-compatible silicone adhesive base. The mass ratio of the high-viscosity amine-compatible silicone adhesive base to the medium-viscosity amine-compatible silicone adhesive base can be appropriately determined, but is preferably 90:10 to 10:90, more preferably 87.5:12.5 to 12.5:87.5, and particularly preferably 75:25 to 25:75.

[0059] On the other hand, the present invention comprises a high-viscosity amine-compatible silicone adhesive base and a low-viscosity amine-compatible silicone adhesive base. The mass ratio of the high-viscosity amine-compatible silicone adhesive base to the low-viscosity amine-compatible silicone adhesive base can be appropriately determined, but is preferably 90:10 to 30:70, more preferably 90:10 to 50:50, particularly preferably 87.5:12.5 to 50:50, and further preferably 75:25 to 50:50.

[0060] Examples of the antioxidant include tocopherol and its ester derivatives, ascorbic acid, ascorbyl stearate, nordihydroguaiaretic acid, butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), citric acid, 2-mercaptobenzimidazole, and ethylenediaminetetraacetic acid. The antioxidant may be used alone or in combination of two or more.

[0061] As long as the plasticizer imparts flexibility to the adhesive layer, it is sufficient. As the plasticizer, for example, mineral oil (for example, paraffin oil, naphthenic oil and aromatic oil), animal oil (for example, squalane and squalene), vegetable oil (for example, olive oil, camellia oil, castor oil, tall oil and peanut oil), silicone oil, dibasic acid ester (for example, dibutyl phthalate and dioctyl phthalate), liquid rubber (for example, liquid polybutene and liquid polyisoprene), liquid fatty acid ester (for example, isopropyl myristate, hexyl laurate, diethyl sebacate and diisopropyl sebacate), polyol (for example, diethylene glycol, polyethylene glycol, propylene glycol and dipropylene glycol), triacetin, triethyl citrate and crotonamide etc. can be listed. Plasticizer can be used alone or in combination of two or more.

[0062] Absorption enhancers are components that regulate the skin permeability of asenapine or its pharmaceutically acceptable salt. As absorption enhancers, there is no particular limitation as long as they are compounds that are generally considered to have an absorption enhancing effect on the skin. For example, fatty alcohols such as isostearyl alcohol, fatty acids such as capric acid, fatty acid derivatives such as propylene glycol monolaurate, isopropyl myristate, isopropyl palmitate, lauric acid diethanolamide, etc., glycols such as propylene glycol, polyethylene glycol, etc., etc. can be cited. One type of absorption enhancer can be used alone, or two or more types can be used in combination.

[0063] There is no particular limitation on the crosslinking agent, and preferred examples include thermosetting resins such as amino resins, phenolic resins, epoxy resins, alkyd resins, and unsaturated polyesters, isocyanate compounds, blocked isocyanate compounds, organic crosslinking agents, and inorganic crosslinking agents such as metals or metal compounds.

[0064] The preservative is not particularly limited, and preferred examples thereof include ethyl paraben, propyl paraben, butyl paraben, etc. The filler is not particularly limited, and preferred examples thereof include calcium carbonate, magnesium carbonate, silicates (aluminum silicate, calcium silicate, magnesium silicate, etc.), and cellulose derivatives (hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, etc.).

[0065] Examples of the filler include aluminum hydroxide, calcium carbonate, magnesium carbonate, silicates (eg, aluminum silicate, magnesium silicate), silicic acid, barium sulfate, calcium sulfate, calcium zincate, zinc oxide, and titanium oxide.

[0066] Examples of the storage agent include disodium ethylenediaminetetraacetate, sodium ethylenediaminetetraacetate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, etc. The storage agent may be used alone or in combination of two or more.

[0067] In another aspect of the present invention, the adhesive layer further includes one or more selected from the group consisting of ascorbic acid, mercaptobenzimidazole, and citric acid.

[0068] In another aspect of the present invention, the weight of the adhesive layer is preferably 30 to 200 g / m 2 , more preferably 30 to 150 g / m 2 , and more preferably 30 to 130 g / m 2 If the mass is too small, problems such as poor adhesion and difficulty in manufacturing may occur, and if the mass is too large, physical properties may deteriorate such as cold flow may occur easily.

[0069] The patch may also include a release liner. Relative to the adhesive layer, the release liner is laminated on the surface opposite to the support. If a release liner is provided, it is possible to reduce the adhesion of dust, etc. to the adhesive layer during storage.

[0070] The material of the release liner is not particularly limited, and films commonly known to those skilled in the art can be used. As the material of the release liner, for example, polyesters such as polyethylene terephthalate and polyethylene naphthalate; polyolefins such as polyethylene and polypropylene; films such as polyvinyl chloride and polyvinylidene chloride; laminated films of high-quality paper and polyolefins; films such as nylon (registered trademark), aluminum, etc. are listed. As the material of the release liner, polypropylene or polyethylene terephthalate is preferred.

[0071] Next, an example of a method for producing the patch of the present invention will be described.

[0072] First, a mixture for forming an adhesive layer is prepared by dissolving or dispersing the above-mentioned asenapine, silicone adhesive base, and other components in a solvent using a mixer to obtain the mixture for forming an adhesive layer.

[0073] As the solvent, toluene, hexane, ethyl acetate, cyclohexane, heptane, butyl acetate, ethanol, methanol, xylene, isopropyl alcohol, etc. These are appropriately selected depending on the component to be dissolved or dispersed, and one kind may be used alone or two or more kinds may be mixed and used in combination.

[0074] Next, the obtained mixture for forming an adhesive layer can be directly spread on a support and dried to form an adhesive layer, and then a release liner for protecting the adhesive layer is adhered to the adhesive layer or spread on a release-treated paper or film and dried to form an adhesive layer, a support is placed thereon, and the adhesive layer is pressed and transferred to the support to obtain a patch.

[0075] Example

[0076] Example 1: Preparation of patch (high viscosity + medium viscosity)

[0077] Patches 1 to 7 were prepared according to the ingredients shown in Table 1. The mass of the adhesive was 100 g / m 2 (setting value).

[0078] Table 1

[0079]

[0080] PSA-4202: BIO-PSA (registered trademark) 7-4202 Silicone adhesive (manufactured by Dow Corning)

[0081] PSA-4302: BIO-PSA (registered trademark) 7-4302 Silicone adhesive (manufactured by Dow Corning)

[0082] Example 2: Dynamic viscoelasticity test

[0083] Using patches 1 and 3 to 7 as samples, the loss elastic modulus and storage elastic modulus were measured under the following conditions, and the loss tangent (tan δ value) was calculated (N=1 or 2).

[0084] Measurement conditions

[0085] Equipment: HAAKE MARS III (manufactured by Thermo Fisher Scientific Inc.)

[0086] Sample part: parallel plate with a diameter of 8 mm

[0087] Gap spacing: 1mm

[0088] Sample volume: 130mg±10mg

[0089] Temperature: 32℃

[0090] Frequency: 1Hz

[0091] - Tilt: 1%

[0092] Table 2 shows the results of loss tangent (tan δ value) calculated from the values ​​of storage elastic modulus and loss elastic modulus obtained by the dynamic viscoelasticity test.

[0093] Table 2

[0094]

[0095] Example 3: Viscosity measurement

[0096] The viscosity (N=2) of Patches 1 and 3 to 7 at 90° C. was measured using a flow tester (manufactured by SHIMADZU CORPORATION, product name “FLOWTESTER CFT-500”) under the following measurement conditions.

[0097] Measurement conditions

[0098] Heating temperature: 5.0℃ / min

[0099] Die hole diameter: 0.5mm

[0100] Die length: 1.0mm

[0101] Test weight: 50.0kg

[0102] Table 3

[0103]

[0104] Example 4: Cold flow evaluation test

[0105] In the patch 3 to 6 (round 2.49cm 2 ) was placed on the surface of the sample (cold flow induction) and stored in a constant temperature and humidity chamber at 32°C and 60% RH for 48 hours. The cold flow area ratio was calculated (the area without cold flow (circular 2.49 cm 2 The results are shown in Table 4.

[0106] Table 4

[0107]

[0108] The cold flow area ratios of patches 3 to 6 were all less than 15%, which yielded good results. Furthermore, the cold flow area ratios of patches 3 to 5 were all less than 10%, which yielded even better results.

[0109] Example 5: Stability testing over time

[0110] According to the ingredients shown in Table 5, patches 8 to 17 were prepared.

[0111] Table 5

[0112]

[0113]

[0114] Patches 8 to 17 were respectively packaged in aluminum packaging bags, and immediately after preparation and after storage at 60°C for two weeks (60°C for two weeks), the analogs of asenapine were measured using high performance liquid chromatography (HPLC) under the following measurement conditions. The results are shown in Table 6.

[0115] Measurement conditions

[0116] Column: ODS column

[0117] Mobile phase solution: methanol / 0.01 mol / L sodium lauryl sulfate / 0.1% phosphoric acid aqueous solution = 3 / 1

[0118] Detection wavelength: 230nm

[0119] Also, the numbers in parentheses in the table represent the relative retention time RRT of any analog, which was calculated by the following method.

[0120] [Relative retention time (RRT) of any analogue] = [Retention time (RT) of the peak of any analogue] ÷ [Retention time (RT) of the peak of asenapine]

[0121] And, the amount (%) of the analogue was calculated by the following method.

[0122] [Analogue amount (%)] = [Peak area of ​​any analogue] ÷ [Peak area of ​​asenapine] × 100 Table 6

[0123]

[0124] Compared with patch 8, patch 9 (containing butylated hydroxytoluene), patch 14 (containing mercaptobenzimidazole), patch 15 (containing ethylenediaminetetraacetic acid), and patch 17 (containing citric acid) had relatively low asenapine analogs, indicating that asenapine was more stable.

[0125] Example 6: Preparation of patch (high viscosity + low viscosity)

[0126] Patches 18 to 25 were prepared according to the ingredients shown in Table 7. The mass of the adhesive was 100 g / m 2 (setting value).

[0127] Table 7

[0128]

[0129]

[0130] PSA-4102: BIO-PSA (registered trademark) 7-4102 Silicone Adhesive (manufactured by Dow Corning)

[0131] PSA-4302: BIO-PSA (registered trademark) 7-4302 Silicone Adhesive (manufactured by Dow Corning)

[0132] Silicone oil (dimethylsilicone oil 20 cSt): Q7-9120 Silicone Fluid (registered trademark) 20 cSt (manufactured by Dow Corning)

[0133] In the table, the loss tangent (tan δ), viscosity (Pa·s) and cold flow area ratio (%) were measured or calculated by using the method described in Examples 2 to 4.

[0134] In the table, the content of asenapine relative to the initial content (relative initial content (%)) was calculated by the following method.

[0135] Calculation of relative initial content (%)

[0136] The prepared patches were respectively packed into aluminum packaging bags, and the asenapine content was measured by the following measurement conditions using high performance liquid chromatography (HPLC) immediately after preparation and after storage at 60°C for two weeks (60°C for two weeks).

[0137] Measurement conditions

[0138] Column: ODS column

[0139] Mobile phase solution: methanol / 0.01 mol / L sodium lauryl sulfate / 0.1% phosphoric acid aqueous solution = 3 / 1

[0140] Detection wavelength: 230nm

[0141] The relative initial content was calculated by the following method.

[0142] [Relative initial content (%)] = [Asenapine content when stored at 60°C for two weeks] ÷ [Asenapine content immediately after preparation] × 100

[0143] In the table, the probe viscosity value (gf) was measured by the following method.

[0144] Measurement of probe viscosity value (gf)

[0145] The measurement was performed by using a probe tack tester (manufactured by Rigaku Kogyo Co., Ltd., product name "Probe tack tester with digital technology"). The probe tack test conditions are as follows.

[0146] Probe viscosity test conditions

[0147] Probe material: stainless steel

[0148] Probe diameter: 5mmφ

[0149] Contact time: 1 second

[0150] Contact weight: 4.9N / cm 2

[0151] Peeling speed: 10mm / sec

[0152] As shown in Table 7, it was confirmed that the cold flow area ratio of patches 18 to 20 was low and the tongue was suppressed from protruding from the adhesive layer, but the adhesiveness became low. On the other hand, it was confirmed that the cold flow area ratio of patch 25 became large and the tongue could not be suppressed from protruding from the adhesive layer. In contrast, it was confirmed that patches 21 to 24 suppressed the tongue from protruding from the adhesive layer and also had excellent adhesiveness.

[0153] Example 7: Testing of drug concentration

[0154] Patches 26 to 28 were prepared according to the ingredients shown in Table 8. The mass of the adhesive was 100 g / m 2 (setting value).

[0155] Table 8

[0156]

[0157]

[0158] In the table, the loss tangent (tan δ), viscosity (Pa·s), and cold flow area ratio (%) were measured or calculated by using the method described in Examples 2 to 4.

[0159] As shown in Table 8, it was confirmed that even when the drug concentration was changed, the cold flow area ratio could be lowered by setting the loss tangent (tan δ) within a predetermined range.

[0160] Example 8: Inspection of adhesive quality

[0161] Patches 29 to 32 were prepared according to the ingredients described in Table 9.

[0162] Table 9

[0163]

[0164] In the table, the loss tangent (tan δ) and the cold flow area ratio (%) were measured or calculated by using the methods described in Examples 2 and 4.

[0165] As shown in Table 9, it can be confirmed that even if the mass of the adhesive is changed to 30 to 200 g / m2 In the case where the cold flow area ratio is within the range of, the cold flow area ratio can also be lowered by setting the loss tangent (tanδ) within the specified range.

Claims

1. A patch comprising a support and an adhesive layer, It is characterized in that The adhesive layer comprises asenapine and / or a pharmaceutically acceptable salt thereof and a silicone adhesive base. Wherein, the silicone adhesive base is a condensate of silicone rubber and silicone resin; The silicone adhesive base comprises only a moderately viscous amine-compatible silicone adhesive base, or The silicone adhesive base comprises a high-viscosity amine-compatible silicone adhesive base and a medium-viscosity amine-compatible silicone adhesive base, wherein the mass ratio of the high-viscosity amine-compatible silicone adhesive base to the medium-viscosity amine-compatible silicone adhesive base is 90:10 to 10:90, or The silicone adhesive base comprises a high-viscosity amine-compatible silicone adhesive base and a low-viscosity amine-compatible silicone adhesive base, wherein the mass ratio of the high-viscosity amine-compatible silicone adhesive base to the low-viscosity amine-compatible silicone adhesive base is 90:10 to 50:50; Furthermore, the weight ratio of the high-viscosity amine-compatible silicone adhesive base to the silicone rubber is 52.5:47.5 (w / w) to 57.5:42.5 (w / w), the weight ratio of the medium-viscosity amine-compatible silicone adhesive base to the silicone rubber is 57.5:42.5 (w / w) to 62.5:37.5 (w / w), and the weight ratio of the low-viscosity amine-compatible silicone adhesive base to the silicone rubber is 62.5:37.5 (w / w) to 67.5:32.5 (w / w); The loss tangent tanδ of the adhesive layer is 0.75 to 1.5 at 1.0 Hz.

2. The patch according to claim 1, It is characterized in that The high viscosity amine-compatible silicone adhesive base has a weight ratio of silicone resin to silicone rubber of about 55:45 (w / w), the medium viscosity amine-compatible silicone adhesive base has a weight ratio of silicone resin to silicone rubber of about 60:40 (w / w), and the low viscosity amine-compatible silicone adhesive base has a weight ratio of silicone resin to silicone rubber of about 65:35 (w / w).

3. The patch according to claim 1, It is characterized in that The viscosity of the adhesive layer is 3000 to 60000 Pa·s at 90°C.

4. The patch according to claim 1, It is characterized in that The viscosity of the adhesive layer is 3500 to 60000 Pa·s at 90°C.

5. The patch according to claim 1, It is characterized in that The cold flow area is less than 15%.

6. The patch according to claim 1, It is characterized in that The silicone adhesive base includes a high-viscosity amine-compatible silicone adhesive base and a medium-viscosity amine-compatible silicone adhesive base.

7. The patch according to claim 6, It is characterized in that The mass ratio of the high-viscosity amine-compatible silicone adhesive base to the medium-viscosity amine-compatible silicone adhesive base is 87.5:12.5 to 12.5:87.

5.

8. The patch according to claim 1, It is characterized in that The silicone adhesive base includes a high-viscosity amine-compatible silicone adhesive base and a low-viscosity amine-compatible silicone adhesive base.

9. The patch according to claim 8, It is characterized in that The mass ratio of the high-viscosity amine-compatible silicone adhesive base to the low-viscosity amine-compatible silicone adhesive base is 87.5:12.5 to 50:

50.

10. The patch according to any one of claims 1 to 9, It is characterized in that The adhesive layer is composed of asenapine and a silicone adhesive base.

11. The patch according to any one of claims 1 to 9, It is characterized in that The adhesive layer also contains an antioxidant.

12. The patch according to any one of claims 1 to 9, It is characterized in that The adhesive layer consists of asenapine, a silicone adhesive base and an antioxidant.

13. The patch according to claim 12, It is characterized in that The antioxidant is at least one selected from the group consisting of butylated hydroxytoluene, mercaptobenzimidazole, ethylenediaminetetraacetic acid, and citric acid.

14. The patch according to any one of claims 1 to 9, It is characterized in that The mass of the adhesive layer is 30 to 200 g / m 2 .

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