The drug contains glycopyronilaxylate.

Abstract

The invention relates to a drug containing glycopyronium salicylate or its solvate salt, in which it is used for the treatment or prevention of hyperstimulation of salivation and similar conditions. The invention proposes: a therapeutic drug capable of treating hyperstimulation of salivation by paste; and a novel salt of glycopyronium suitable for transdermal absorption.

Description

Medicines containing glycopyrronium salicylate

[0001] The present invention relates to a medicament comprising glycopyrronium salicylate.

[0002] Glycopyrronium is the generic name for 3-(2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidium. Because glycopyrronium is a quaternary ammonium cation, it exists as a salt rather than in a free state. For example, glycopyrronium bromide and tosylate salts are known as active ingredients in ethical drugs. Other glycopyrronium salts known include iodide, acetate, and sulfate (all of which are described in Patent Document 1), chloride, benzoate, edisylate, and oxalate salts (all of which are described in Patent Document 2), and fatty acid salts (Patent Document 3).

[0003] Glycopyrronium has muscarinic acetylcholine receptor antagonist (anticholinergic) effects, and its inhalation formulation for chronic obstructive pulmonary disease (bromide salt: Seebri®), its topical formulation for primary hyperhidrosis (tosylate salt: QBREXZA®), and its oral solution for sialorrhea (bromide salt: CUVPOSA®) have been approved as prescription drugs in Japan and / or overseas.

[0004] Sialorrhea, also known as hypersalivation, is a condition characterized by the drooling of saliva outside the mouth. Sialorrhea is not simply a drooling problem; it can also lead to social problems, perioral dermatitis, and an increased risk of aspiration pneumonia. For severe cases of sialorrhea that require treatment, drug therapy is attempted.

[0005] Drooling often occurs in association with neuromuscular diseases (such as Parkinson's disease and amyotrophic lateral sclerosis). Because these patients often also suffer from swallowing disorders, topical medications (patches) are preferable to oral medications. The advantages of patches (especially transdermal formulations) include ease of administration to patients with swallowing difficulties, the potential for reduced side effects due to reduced drug exposure, ease of administration, ease of medication management, and ease of discontinuation of administration.

[0006] Pharmaceuticals are classified by route of administration into "oral medications," "injectable medications," and "topical medications." Topical medications are medications other than oral medications and injectable medications that allow drugs to be absorbed through the skin or mucous membranes. Specific topical medications that allow drugs to be absorbed through the skin include patches, ointments, and topical preparations. Furthermore, patches can be classified by the site of action into transdermal and local-acting preparations. Transdermal preparations are defined as preparations that exert their medicinal effects by circulating the drug absorbed through the skin in the systemic bloodstream. On the other hand, local-acting preparations are defined as preparations that exert their medicinal effects by increasing the drug concentration in target tissues near the application site without significantly increasing the blood concentration of the drug absorbed through the skin.

[0007] Known topical glycopyrronium medications include a transdermal drug delivery system containing glycopyrronium bromide for treating sialorrhea (Patent Document 4) and a topical composition containing glycopyrronium tosylate (Patent Document 2). Patent Document 4 does not provide any examples, nor does it describe the efficacy in animals or humans, leaving doubts about the feasibility of the transdermal drug delivery system, and it is unclear whether it can be considered a transdermal absorption formulation. Patent Document 2 describes a topical application as a specific example of a topical composition. While this is a topical medication, it is not a transdermal absorption formulation and is applied by application, so strict control of the dosage or maintaining a consistent drug absorption cannot be expected, making it difficult to achieve a sustained, stable blood drug exposure.

[0008] To make a drug into a transdermal formulation, it must have high skin permeability. Generally, the amount of drug absorbed during transdermal administration is determined by the administration area and the skin permeability of the drug. Because repeated administration to the same site must be avoided for skin safety reasons, there is a limit to how much drug can be absorbed by expanding the administration area. Transdermal formulations of glycopyrronium bromide or tosylate, which aim to achieve a sustained and stable blood exposure level, are not commercially available in Japan or overseas.

[0009] Patent Publication No. 2008-534480, Patent Publication No. 2017-128593, Patent Publication No. 2018-519289, Patent Publication No. 2010-530902

[0010] For the treatment or prevention of sialorrhea, topical medications, particularly transdermal preparations, are preferred over oral medications, but while glycopyrronium bromide is commercially available as an oral medication, topical medication (inhalant), and injection, and glycopyrronium tosylate is commercially available as a topical medication (applied liniment), neither salt is commercially available as a transdermal preparation. Against this background, the present invention aims to provide a pharmaceutical (transdermal preparation) that enables the treatment or prevention of sialorrhea by application, and further to provide a novel glycopyrronium salt suitable for use as a transdermal preparation.

[0011] The present inventors believed that the lack of a medicinal product for the treatment or prevention of sialorrhea by patch application, i.e., a transdermal absorption preparation, was due to the active ingredients, glycopyrronium bromide and tosylate. As a result of extensive research, the present inventors discovered that in order to provide a medicinal product that can treat or prevent sialorrhea by patch application, it is necessary to select glycopyrronium salicylate as the active ingredient, and thus completed the present invention.

[0012] The main features of the present invention are as follows: [1] A pharmaceutical comprising glycopyrronium salicylate or a solvate thereof, used for treating or preventing sialorrhea. [2] The pharmaceutical according to [1], characterized in that the pharmaceutical is used as a patch. [3] The pharmaceutical according to [2], characterized in that the pharmaceutical is used as a patch once daily. [4] A pharmaceutical comprising glycopyrronium salicylate or a solvate thereof, characterized in that the pharmaceutical is used for treating or preventing sialorrhea by applying a patch once daily and changing it every 24 hours. [5] The pharmaceutical according to [1] to [4], wherein the pharmaceutical is a transdermal formulation. [6] Glycopyrronium salicylate or a solvate thereof. [7] A pharmaceutical comprising glycopyrronium salicylate or a solvate thereof. [8] A transdermal formulation having a plaster layer and a release liner on a support, the plaster layer containing an active ingredient, the active ingredient being glycopyrronium salicylate.

[0013] [9] Glycopyrronium salicylate or a solvate thereof for treating or preventing sialorrhea.

[10] Use of glycopyrronium salicylate or a solvate thereof for the manufacture of a medicament for treating or preventing sialorrhea.

[11] A method for treating or preventing sialorrhea by administering glycopyrronium salicylate or a solvate thereof to a patient in need thereof.

[0014] According to the present invention, it is possible to provide a pharmaceutical, i.e., a transdermal preparation, which contains glycopyrronium salicylate as an active ingredient and exhibits excellent therapeutic or preventive effects against sialorrhea when applied by patch application.

[0015] Transdermal formulations (0.5cm) containing various glycopyrronium salts were used in a rat pilocarpine-induced salivary secretion model. ２ 1 shows the effect of transdermal formulations (0.25 cm) containing various glycopyrronium salts on saliva secretion in a rat pilocarpine-induced saliva secretion model. ２ ) on saliva secretion.

[0016] The medicament for treating or preventing sialorrhea of ​​the present invention is described below. The medicament for treating or preventing sialorrhea of ​​the present invention is typically a pharmaceutical composition for treating or preventing sialorrhea. The active ingredient used in the medicament for treating or preventing sialorrhea of ​​the present invention is 3-(2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidium salicylate (hereinafter referred to as "glycopyrronium salicylate"), represented by the following formula (1). Unless otherwise specified herein, the present invention also includes solvates of glycopyrronium salicylate. Note that, in this specification, the term glycopyrronium salicylate may also include solvates. Based on its structure, glycopyrronium exists as four stereoisomers: (3R,2R), (3R,2S), (3S,2R), and (3S,2S). Glycopyrronium salicylate, the active ingredient of the present invention, may be a mixture containing several stereoisomers, but a mixture of the (3R,2S) and (3S,2R) stereoisomers is preferred, and the (3S,2R) stereoisomer alone is preferred.

[0017]

[0018] The compounds of the present invention can be produced by the methods shown in the following reaction schemes 1 and 2, or by a combination of known methods.

[0019] [Reaction Scheme 1]

[0020] (In the formula, R represents a hydrogen atom or an alkali metal atom.)

[0021] [Step 1-1] Silver salicylate (3) can be obtained by reacting salicylic acid (2) with a silver salt (e.g., silver oxide or silver nitrate) in an appropriate solvent (e.g., distilled water, acetone, acetonitrile, or a mixture thereof) usually at a temperature between 0°C and the boiling point of the solvent, for 10 minutes to 3 days in the dark.

[0022] [Step 1-2] Glycopyrronium bromide (4) is reacted with the silver salicylate produced in Step 1-1 in an appropriate solvent (e.g., distilled water, acetone, acetonitrile, or a mixture thereof) usually at a temperature between 0°C and the boiling point of the solvent for 1 hour to 3 days in the dark, and the precipitated silver bromide is filtered to obtain glycopyrronium salicylate (1).

[0023] [Reaction scheme 2]

[0024]

[0025] [Step 2-1] Glycopyrronium bromide (4) is reacted with silver acetate in a suitable solvent (e.g., distilled water, acetone, acetonitrile, or a mixture thereof) usually at a temperature between 0°C and the boiling point of the solvent for 1 hour to 3 days in the dark, and the precipitated silver bromide is filtered to give glycopyrronium acetate (5).

[0026] [Step 2-2] Glycopyrronium acetate (5) produced in step 2-1 can be reacted with salicylic acid in an appropriate solvent (e.g., distilled water, acetone, acetonitrile, or a mixture thereof) typically at a temperature between 0°C and the boiling point of the solvent for 1 hour to 3 days to obtain glycopyrronium salicylate (1).

[0027] The pharmaceutical for treating or preventing sialorrhea of ​​the present invention is typically, but not limited to, a patch comprising a backing, a plaster layer, and a release sheet, and is preferably a transdermal preparation. The plaster layer contains an adhesive and glycopyrronium salicylate and is typically layered on the backing or the release sheet.

[0028] There are no particular limitations on the adhesive, as long as it is an adhesive that can be used as a patch. Although the adhesive strength varies depending on the type of adhesive, the type and amount can be appropriately selected according to the desired application time. Examples of the adhesive include acrylic adhesives, rubber adhesives, and silicone adhesives.

[0029] Specific examples of the acrylic adhesive include acrylic acid-octyl acrylate copolymer, acrylic acid ester-vinyl acetate copolymer, ethyl acrylate-octyl acrylate-vinylpyrrolidone copolymer, 2-ethylhexyl acrylate-vinyl acetate copolymer, 2-ethylhexyl acrylate-hydroxyethyl-vinyl acetate-glycidyl methacrylate copolymer, 2-ethylhexyl acrylate-vinylpyrrolidone copolymer, 2-ethylhexyl acrylate-methyl acrylate-acrylic acid-glycidyl methacrylate copolymer, 2-ethylhexyl acrylate-vinylpyrrolidone copolymer, 2-ethylhexyl acrylate-methyl acrylate-acrylic acid-glycidyl methacrylate copolymer, 2-ethylhexyl acrylate-vinylpyrrolidone copolymer, 2-ethylhexyl acrylate-octyl acrylate copolymer, 2-ethylhexyl acrylate-octyl acrylate-vinylpyrrolidone ... Examples of the copolymer include 2-ethylhexyl acrylate, vinyl acetate, hydroxyethyl acrylate, and glycidyl methacrylate copolymer, 2-ethylhexyl acrylate, vinyl acetate, butyl acrylate, and acrylic acid copolymer, 2-ethylhexyl acrylate, vinyl acetate, and acrylic acid copolymer, 2-ethylhexyl acrylate, diacetone acrylamide, acetoacetoxyethyl methacrylate, and methyl methacrylate copolymer, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, and dodecyl methacrylate copolymer, and aminoalkyl methacrylate copolymer E.

[0030] Specific examples of the rubber-based adhesive include styrene-isoprene-styrene copolymer, isoprene rubber, polyisobutylene, styrene-butadiene-styrene block copolymer, and styrene-butadiene rubber.

[0031] Specific examples of the silicone adhesive include dimethylpolysiloxane and dimethylpolysiloxane-silicate resin condensation products.

[0032] The pharmaceutical for treating or preventing sialorrhea of ​​the present invention may further contain additives to the plaster layer according to various purposes. Such additives are not particularly limited, but include, for example, absorption enhancers, stabilizers, solubilizers, buffers, antioxidants, flavorings, refreshing agents, flavoring agents, colorants, adhesion enhancers, pH adjusters, excipients, bulking agents, preservatives, solubilizers, solubilizers, and other medically acceptable additives.

[0033] The pharmaceutical for treating or preventing sialorrhea of ​​the present invention aims to provide sustained and stable absorption of the drug through the skin, and differs from locally acting pharmaceuticals in that it provides a stable amount of drug exposure in the blood and is applied continuously.

[0034] Examples of methods for producing the pharmaceutical for treating or preventing sialorrhea of ​​the present invention include: (I) a method in which glycopyrronium salicylate, an adhesive, and other additives are dissolved in an organic solvent such as ethyl acetate, ethanol, methanol, hexane, toluene, etc., or a mixture thereof, and the solution is applied to one side of a release sheet or a support, the solvent is evaporated, a drug-containing layer is formed, and the other side of the release sheet or support (the side on which the drug-containing layer has not been formed) is laminated thereto; and (II) a method in which glycopyrronium salicylate, an adhesive, and other additives are heated and melted, the molten material is applied to one side of a release sheet or a support, a drug-containing layer is formed, and the other side of the release sheet or support (the side on which the drug-containing layer has not been formed) is laminated thereto. The order in which the drug mixture in production method (I) and the molten material in production method (II) are applied to the support or release sheet is not limited. The adhesive may be applied to the support first and then the release sheet is laminated thereto, or the adhesive may be applied to the release sheet first and then the support is laminated thereto.

[0035] The support is not particularly limited as long as it can support the paste layer, and elastic or non-elastic supports can be used. Specific examples include woven fabric, nonwoven fabric, vinyl chloride film, polyethylene film, polypropylene film, polyester film, polyurethane film, and composite materials thereof. The thickness of the support is not particularly limited and can be determined appropriately. The release sheet that can be used is not particularly limited as long as it covers the paste layer, and vinyl chloride film, polyethylene film, polypropylene film, polyester film, polyurethane film, etc. can be used. Furthermore, in order to facilitate the release of the release sheet, a siliconized sheet or an embossed sheet can also be used.

[0036] The present invention will be described in more detail below with reference to examples, but the technical scope of the present invention is not limited to the described examples.

[0037] The nuclear magnetic resonance spectrum and melting point were measured under the following conditions. [Nuclear Magnetic Resonance Spectrum] The nuclear magnetic resonance spectra ( １ H-NMR spectrum measurement was carried out using a VARIAN (MR1008W041) spectrometer. The spectrum was expressed as a δ value (ppm) using tetramethylsilane as the standard substance. Splitting patterns were indicated by "s" for singlets, "d" for doublets, "t" for triplets, and "m" for multiplets. [Melting Point] Melting point measurements in the following Salt Production Examples and Comparative Salt Production Examples were carried out using a Rigaku (Thermo plus TG 8120) spectrometer. The measurement conditions were as follows: measurement temperature: room temperature to 200°C, heating rate: 5°C / min, and measurement interval: every 0.2 seconds.

[0038] Preparation of glycopyrronium salt: Six counter anions (carboxylic acids) suitable for pharmaceuticals were selected to attempt the synthesis of glycopyrronium salt. The selected carboxylic acids are shown in Table 1. The starting material used was commercially available (3RS,2SR)-glycopyrronium bromide salt.

[0039]

[0040] Preparation of Glycopyrronium Salicylate [Salt Production Example 1] 13 mL of distilled water and 500.0 mg (1.26 mmol) of (3RS,2SR)-glycopyrronium bromide were placed in a brown recovery flask and dissolved. 209.5 mg (1.26 mmol) of silver acetate was added at 40°C under light-shielded conditions, and the mixture was stirred for 24 hours. The reaction solution was filtered through Celite, washed with distilled water, and the filtrate was concentrated under reduced pressure. 10 mL of acetonitrile and 173.5 mg (1.26 mmol) of salicylic acid were added to the crude glycopyrronium acetate obtained, and the mixture was stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure and azeotroped with toluene to obtain crude glycopyrronium salicylate. 10 mL of toluene was added, and the mixture was stirred at room temperature for 5 hours. The suspension from which crystals precipitated was allowed to stand at -20°C for 9 days, after which the crystals were collected by filtration. After drying under reduced pressure at 40°C, 517.8 mg (yield 91%) of (3RS,2SR)-glycopyrronium salicylate was obtained. 1 H-NMR] (400 MHz, DMSO-d6) δ 7.63 (ddd, 1H), 7.58 (d, 2H), 7.35 (t, 2H), 7.27 (t, 1H), 7.10 (ddd, 1H), 6.59-6.53 (m, 2H), 5.85 (s, 1H), 5.39-5.35 (m, 1H), 3.83 (dd, 1H), 3.72-3.65 (m, 1H), 3.60 (d, 1H), 3.54-3.47 (m, 1H), 3.15 (s, 3H), 3.08 (s, 3H), 2.95-2.87 (m, 1H), 2.68-2.59 (m, 1H), 2.11-2.03 (m, 1H), 1.65-1.13 (m, 8H).mp 141℃.

[0041] [Salt Production Example 2] 5.30 g (31.2 mmol) of silver nitrate and 6.3 mL of distilled water were placed in a brown eggplant flask and suspended. 6.3 mL of an aqueous solution of 5.00 g (31.2 mmol) of sodium salicylate was added and stirred for 15 minutes at room temperature in the dark. The precipitated solid was collected by filtration using a Kiriyama funnel, washed with distilled water and then ethanol, and then dried under reduced pressure to obtain 6.50 g of silver salicylate (yield 85%). 1.50 g (3.77 mmol) of (3RS,2SR)-glycopyrronium bromide, 923 mg (3.77 mmol) of silver salicylate, and 35 mL of distilled water were placed in a brown eggplant flask and stirred for 20 hours at 40°C in the dark. The reaction solution was filtered through Celite and washed with distilled water. The filtrate was concentrated under reduced pressure and azeotroped with toluene to obtain crude glycopyrronium salicylate. 10 mL of toluene was added, and the mixture was sonicated to precipitate a small amount of solid, after which 20 mL of toluene was added and the mixture was stirred at room temperature overnight. The precipitated crystals were collected by filtration, washed with toluene, and dried under reduced pressure at 50°C to obtain 1.70 g (yield 99%) of (3RS,2SR)-glycopyrronium salicylate.

[0042] Preparation of Other Glycopyrronium Salts [Comparative Salt Preparation Example 1] 20.0 g (111 mmol) of hippuric acid, 12.9 g (111 mmol) of silver oxide, 440 mL of acetone, and 220 mL of distilled water were placed in a brown eggplant flask, suspended, and stirred at room temperature for 15 hours in the dark. The precipitated solid was collected by filtration using a Kiriyama funnel, washed with distilled water, and dried under reduced pressure to obtain 29.2 g of silver hippurate (yield: 91%). 5.00 g (12.6 mmol) of (3RS,2SR)-glycopyrronium bromide, 3.61 g (12.6 mmol) of silver hippurate, and 100 mL of distilled water were placed in a brown eggplant flask, and stirred at 40°C for 12 hours in the dark. The reaction solution was filtered through Celite and washed with distilled water. The filtrate was concentrated under reduced pressure and azeotroped with toluene to obtain crude glycopyrronium hippurate. 100 mL of ethyl acetate was added, and after ultrasonic irradiation to precipitate a small amount of solid, the suspension was allowed to stand at −20° C. for 3 days. The crystals were then filtered, washed with ethyl acetate, and dried under reduced pressure at room temperature to obtain 5.10 g (yield 81%) of (3RS,2SR)-glycopyrronium hippurate. 1H-NMR] (400 MHz, DMSO-d6) δ 7.81-7.76 (m, 2H), 7.73-7.67 (m, 1H), 7.58 (d, 2H), 7.53-7.42 (m, 3H), 7.35 (t, 2H), 7.27 (t, 1H), 5.92 (s, 1H), 5.41-5.34 (m, 1H), 3.83 (dd, 1H), 3.72-3.65 (m, 1H), 3.60 (d, 1H), 3.54-3.46 (m, 1H), 3.41 (d, 2H), 3.15 (s, 3H), 3.08 (s, 3H), 2.95-2.85 (m, 1H), 2.69-2.59 (m, 1H), 2.12-2.03 (m, 1H), 1.65-1.13 (m, 8H).mp 135℃.

[0043] Comparative Salt Preparation Examples 2 and 3: Using the same method as in Salt Preparation Example 1, the glycopyrronium salts shown in Table 2 were synthesized from (3RS,2SR)-glycopyrronium bromide. The results also indicate whether or not crystals were formed. × indicates that crystals were not obtained. The instrumental analysis data for the resulting salts are shown in Table 3.

[0044]

[0045]

[0046] Comparative Salt Preparation Examples 4 and 5: Glycopyrronium acetate and glycopyrronium benzoate were synthesized. The acetate was prepared from (3RS,2SR)-glycopyrronium bromide with reference to Example 2 of JP-T-2008-534480, and the benzoate was prepared from (3RS,2SR)-glycopyrronium bromide with reference to Example 2 of JP-T-2016-510037. Crystals with a (3RS,2SR) configuration were obtained for both compounds. Analytical data are omitted.

[0047] [Comparative Salt Example 1] Glycopyrronium bromide salt was purchased and used as a commercially available product with a specified configuration of (3RS, 2SR). This was in the form of a crystal.

[0048] As described above, various glycopyrronium salts were synthesized. While glycopyrronium succinate and fumarate could not be crystallized, glycopyrronium salicylate, hippurate, acetate, and benzoate could be crystallized. When used as an active ingredient in pharmaceuticals, glycopyrronium salts are preferred in solid form (especially crystals) because they are easier to handle. For glycopyrronium salicylate, hippurate, acetate, and benzoate salts from which crystals could be obtained, small transdermal formulations were prepared using the products from the Salt Production Examples or Comparative Salt Production Examples (Glycopyrronium salicylate: Salt Production Example 1), and an in vitro skin permeation test was performed in Test Example 1.

[0049] The four glycopyrronium salts were dissolved in ethanol, which is used in the production of transdermal formulations, and their stability after 24 hours was evaluated. The acetate and benzoate salts were found to have decomposed by 20% and 10%, respectively, while the hippurate and salicylate salts were found to have decomposed by less than 1%. Small transdermal formulations were prepared for the hippurate and salicylate salts of glycopyrronium, which were stable in ethanol, as well as the prior art glycopyrronium bromide salt, and the efficacy of the three glycopyrronium salts was evaluated in a salivary-secreting animal model (Test Examples 2 and 3).

[0050] <<Preparation of a transdermal formulation containing glycopyrronium salt>> [Preparation Example 1] A transdermal formulation containing glycopyrronium salicylate (6.5% as glycopyrronium) A mixed solution of glycopyrronium salicylate and a 2-ethylhexyl acrylate-vinyl acetate-hydroxyethyl acrylate-glycidyl methacrylate copolymer in ethyl acetate-ethanol-heptane-methanol was dissolved in ethanol at the blending ratio shown in Table 4. The resulting solution was dried to form a plaster with a concentration of 15 mg / cm ２ (0.98 mg / cm as glycopyrronium ２ The adhesive was then dried to remove the ethanol and the organic solvent contained in the adhesive, yielding a paste. A PET release sheet was then attached to the paste, and the resulting paste was cut to the desired size to obtain a transdermal absorption preparation.

[0051] Comparative Preparation Example 1: Transdermal preparation containing glycopyrronium benzoate (6.5% as glycopyrronium) In the same manner as in Preparation Example 1, a transdermal preparation containing glycopyrronium benzoate was prepared in the proportions shown in Table 4.

[0052] Comparative Preparation Example 2: Transdermal preparation containing glycopyrronium hippurate (6.5% as glycopyrronium) In the same manner as in Preparation Example 1, a transdermal preparation containing glycopyrronium hippurate was prepared in the proportions shown in Table 4.

[0053] Comparative Preparation Example 3: Transdermal preparation containing glycopyrronium acetate (6.5% as glycopyrronium) In the same manner as in Preparation Example 1, a transdermal preparation containing glycopyrronium acetate was prepared in the proportions shown in Table 4.

[0054] Comparative Preparation Example 4: Transdermal preparation containing glycopyrronium bromide (6.5% as glycopyrronium) In the same manner as in Preparation Example 1, a transdermal preparation containing glycopyrronium bromide was prepared in the proportions shown in Table 4.

[0055] [Preparation Reference Example 1] Placebo Patch A mixed solution of 2-ethylhexyl acrylate, vinyl acetate, hydroxyethyl acrylate, and glycidyl methacrylate copolymer in ethyl acetate, ethanol, heptane, and methanol was dissolved in ethanol. After drying the resulting solution, the plaster had a thickness of 15 mg / cm. ２ The adhesive was then dried to remove the ethanol and the organic solvent contained in the adhesive, yielding a plaster base. A PET release sheet was then attached to the plaster base, which was then cut to the desired size to obtain a patch.

[0056]

[0057] <Skin Permeability Test> [Test Example 1] In vitro skin permeability test of transdermal formulations containing various glycopyrronium salts (6.5% glycopyrronium) Test method Using the skin of nude mice (BALB / cSlc-nu / nu, male, 8-12 weeks old, Japan SLC Co., Ltd.), the skin permeability of glycopyrronium was evaluated in vitro for the following transdermal formulations produced according to Formulation Production Example 1 and Comparative Formulation Production Examples 1-3. - Glycopyrronium salicylate group (n=3) - Glycopyrronium benzoate group (n=3) - Glycopyrronium hippurate group (n=3) - Glycopyrronium acetate group (n=3) The transdermal formulations were applied to the collected nude mouse skin, and the transdermal formulations were placed in a vertical diffusion cell (opening inner diameter 15 mm, area: 1.767 cm ２ The amount of glycopyrronium permeated into the receptor solution was evaluated using a transdermal formulation large enough to fill the opening. PBS was used as the receptor solution, and the solution was stirred with a magnetic stirrer during the permeation test. After a certain period of time, the receptor solution was sampled, and the glycopyrronium concentration was measured using LC-MS / MS. The amount of glycopyrronium permeated per unit area was calculated from the glycopyrronium concentration in the receptor solution, the receptor volume, and the opening area.

[0058] Results The amount of glycopyrronium permeated per unit area 10 hours after the start of permeation for each transdermal formulation is shown in Table 5. The skin permeation amount of glycopyrronium salicylate was approximately three times that of glycopyrronium benzoate and hippurate, and approximately eight times that of glycopyrronium acetate, with the glycopyrronium salicylate group showing the highest in vitro skin permeation of the four groups. It was revealed that there were significant differences in the amount of skin permeation depending on the type of glycopyrronium salt.

[0059] Mean±SD

[0060] <Drug Efficacy Test> [Test Example 2] Effect of pilocarpine-induced saliva secretion on transdermal absorption preparations containing various glycopyrronium salts (6.5% as glycopyrronium) at 0.5 cm ２Effects of application Test method Hairless rats (HWY / Slc, male, 8 weeks old, Japan SLC Co., Ltd.) were divided into the following four groups for the experiment: Placebo group (n=5) Glycopyrronium bromide group (n=5) Glycopyrronium hippurate group (n=5) Glycopyrronium salicylate group (n=5) Under isoflurane anesthesia, 0.5 cm of transdermal formulations containing various glycopyrronium salts (including placebo formulations) produced according to Formulation Example 1, Comparative Formulation Examples 2 and 4, and Reference Formulation Example 1 were applied to the neck of the rats. ２ The patch was applied once a day, every 24 hours, for two days. On the first and second days of application (23 and 47 hours after the initial application), rats were administered 0.5 mg / kg of pilocarpine hydrochloride into the tail vein under triple-anesthesia. A cotton ball was inserted into the oral cavity, and saliva was collected for 60 minutes. The amount of saliva secreted was calculated from the difference in weight of the cotton ball before and after saliva collection, and the average saliva secretion amount in the placebo group was set to 100%, and the saliva secretion rate for each individual was calculated using the following formula: Saliva secretion rate (%) = (saliva secretion amount of each individual / average saliva secretion amount of the placebo group) x 100 (formula).

[0061] Results The results of the saliva secretion rate for transdermal formulations containing each glycopyrronium salt on the first and second days of application are shown in Figure 1. On the first day of application, the glycopyrronium hippurate group and glycopyrronium salicylate group showed a significant saliva secretion inhibitory effect compared to the placebo group, but no significant effect was observed in the glycopyrronium bromide group. On the second day of application, all glycopyrronium salt groups showed a significant saliva secretion inhibitory effect compared to the placebo group, with the glycopyrronium salicylate group showing the strongest saliva secretion inhibitory effect.

[0062] [Test Example 3] Effects of 0.25 cm of transdermal preparations containing various glycopyrronium salts (6.5% as glycopyrronium) on pilocarpine-induced salivary secretion ２ Effects of application Test method: Apply the patch to an area of ​​0.25 cm ２ The test was carried out in the same manner as in Test Example 2, except that the following was changed:

[0063] Results Figure 2 shows the results for the saliva secretion rate for transdermal formulations containing each glycopyrronium salt on the first and second days of application. On the first and second days of application, all glycopyrronium salt groups showed a tendency to suppress saliva secretion compared to the placebo group, but none of the glycopyrronium bromide groups showed a significant effect. The glycopyrronium hippurate group showed a significant effect only on the first day of application. The glycopyrronium salicylate group showed the strongest and most significant suppression of saliva secretion on both evaluation days.

[0064] [Discussion] The saliva secretion suppression effect of transdermal formulations containing various glycopyrronium salts was confirmed to be the strongest. These results demonstrate that the use of glycopyrronium salicylate as an active ingredient makes it possible to provide a transdermal formulation containing a glycopyrronium salt that is highly effective against sialorrhea.

Claims

1. A medicine containing glycopyrronium salicylate or a solvate thereof, which is used to treat or prevent sialorrhea.

2. The medicine according to claim 1, characterized in that the medicine is applied as a patch.

3. The medicine according to claim 2, characterized in that the medicine is applied once a day.

4. A medicine containing glycopyrronium salicylate or a solvate thereof, which is applied once a day and replaced every 24 hours to treat or prevent sialorrhea.

5. The pharmaceutical composition according to any one of claims 1 to 4, which is a transdermal preparation.

6. Glycopyrronium salicylate or its solvate.

7. A medicine containing glycopyrronium salicylate or a solvate thereof.

8. A transdermal preparation having a plaster layer and a release liner on a support, the plaster layer containing an active ingredient, the active ingredient being glycopyrronium salicylate.