JP2024035210A - pharmaceutical composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a pharmaceutical composition that comprises pirenzepine and herbal medicine, which is less prone to discoloration and/or solidification when stored at high temperatures.

SOLUTION: A pharmaceutical composition comprises following components (A), (B) and (C): (A) pirenzepine or a salt thereof, (B) herbal medicine or its extract, and (C) methyl methionine sulfonium chloride.

SELECTED DRAWING: None

COPYRIGHT: (C)2024,JPO&INPIT

Description

PHARMACEUTICAL COMPOSITIONS FIELD OF THE INVENTION The present invention relates to pharmaceutical compositions.

Pirenzepine selectively antagonizes muscarinic receptors in the gastric mucosa and has a specific acid secretion suppressing effect, as well as enhancing gastric mucosal blood flow, mucus, and mucosal defense factors such as prostaglandins, thereby reducing stress and other symptoms. acts suppressively against experimental gastric mucosal damage caused by Among over-the-counter drugs, pirenzepine is used as a treatment for gastritis and peptic ulcers. Further, Patent Document 1 reports that by containing pirenzepine hydrochloride together with aldioxa and the like in an internal preparation, decomposition of the aldioxa and the like is suppressed and changes in the properties of the preparation are suppressed.

On the other hand, herbal medicines such as chinpi and licorice are known to have various pharmacological effects and are widely used in medicines. Since herbal medicines contain components with various properties, storage stability of medicinal products containing herbal medicines tends to be a problem. Therefore, techniques for improving the storage stability of pharmaceuticals containing herbal medicines have been studied. For example, solid preparations that can suppress caking (solidification) and discoloration have been developed by combining herbal medicine extracts or Chinese herbal extracts with calcium silicate and light silicic anhydride. A solid preparation containing first and second adsorbents (Patent Document 2) has been reported.
However, although pharmaceuticals must be stored, stored, and transported under temperature-controlled conditions (at least 30°C or below, so-called room temperature), especially after delivering the medicine to a patient, Therefore, ensuring storage stability under high temperature conditions is extremely important from the perspective of providing higher quality pharmaceuticals.

Japanese Patent Application Publication No. 2006-104145 JP2013-32346A

The present inventor conducted an investigation to develop a pharmaceutical composition containing pirenzepine and herbal medicine, and found that discoloration and solidification occur when stored at high temperatures.
Therefore, an object of the present invention is to provide a pharmaceutical composition containing pirenzepine and a crude drug that is inhibited from discoloration and/or solidification during high-temperature storage.

As a result of intensive studies to solve the above problems, the present inventor surprisingly found that discoloration and/or solidification under high temperature storage can be suppressed by incorporating methylmethionine sulfonium chloride together with pirenzepine and herbal medicine. They discovered this and completed the present invention.

That is, the present invention comprises the following components (A), (B) and (C):
The present invention provides a pharmaceutical composition containing (A) pirenzepine or a salt thereof, (B) a crude drug, and (C) methylmethionine sulfonium chloride.

According to the present invention, it is possible to suppress discoloration and/or solidification of a composition containing pirenzepine and a crude drug during high-temperature storage. Therefore, it is possible to provide a pharmaceutical composition containing these with excellent storage stability.

The pharmaceutical composition of the present invention contains pirenzepine or a salt thereof as component (A).
Pirenzepine used in the present invention has the chemical name 11-[(4-methylpiperazin-1-yl)acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6 -one, a compound with the molecular formula C ₁₉ H ₂₁ N ₅ O ₂ .
The compound may be produced by a known method, or a commercially available product may be used.
The salt of pirenzepine may be any pharmaceutically acceptable salt, such as inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, etc. Examples include acid addition salts with organic acids such as oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, picric acid, methanesulfonic acid, p-toluenesulfonic acid, and glutamic acid. It will be done. Among them, hydrochloride is preferred.
Pirenzepine or a salt thereof may be a solvate or a non-solvate, and both are included. In the present invention, preferred examples of solvates include hydrates, alcoholates, acetonates, and the like.

The content of pirenzepine or its salt in the pharmaceutical composition of the present invention may be appropriately determined depending on the dosage form, dosage, etc., but from the viewpoint of improving the effect of suppressing gastric mucosal damage, The content is preferably 0.1 to 60% by mass, more preferably 0.5 to 35% by mass, and particularly preferably 0.8 to 10% by mass.

The pharmaceutical composition of the present invention contains a crude drug or an extract thereof as component (B).
Herbal medicines include acacia, aniseed, aloe, fennel, turmeric, ubai, uyaku, corydalis, enmeisou, scutellariae, scutellariae, oren, processed garlic, zebra root, cuckoo, calamus root, licorice, licorice, pheasant, kujin, cinnamon bark, Ketsumeishi, gentian, gennoshoko, red ginseng, goshuyu, pepper, gobaiko, colombo, konzurango, hawthorn, Japanese pepper, yamana, perilla, peony, shukusha, ginger, cypress, green bark, red-bud oak, stone iris, centaurium grass, sojutsu, soybean, Preferred are rhubarb, rhubarb, ginseng, clove, chimpi, chili pepper, spruce, bittern, nikuzuku, carrot, mentha, mentha, hihatsu, sandalwood, hop, homica, sinaha, yakuchi, chili pepper, ryutan, and ryokyo. .
Among these, licorice, ginger, chimpi, and carrot are particularly preferred, since their coexistence with components (A) and (C) has a great effect of improving storage stability and improves stomach health.
In the present invention, "licorice" refers to the roots and stolons of Glycyrrhiza uralensis Fischer or Glycyrrhiza glabra Linne (Fabaceae, Leguminosae), and the concept also includes those from which the periderm has been removed (licorice without the skin). .
"Ginger" is the rhizome of the ginger Zingiber officinale Roscoe (Zingiberaceae), sometimes with the periderm removed.
"Chinpi" is the mature pericarp of Citrus unshiu Marcowicz or Citrus reticulata Blanco (Rutaceae, Rutaceae).
"Carrot" is a herbal medicine whose origin is Panax ginseng CA Meyer (Panax schinseng Nees) (Araliaceae Araliaceae), but it can also be obtained by removing the fine roots of Panax ginseng CAMeyer or lightly blanching it. Preferably.

The form of the herbal medicine can be adjusted as necessary, and the whole herbal medicine can be cut or crushed into small pieces, small lumps, or ground into powder. For example, powdered licorice powder such as "licorice powder", "gingyo powder", "chinpi powder", "carrot powder", etc. can be used in the present invention.
"Extracts of crude drugs" are crude drugs that have been subjected to some kind of extraction process. Note that "extracts of crude drugs" also include those that have been subjected to processing treatments such as heating, drying, and pulverization in addition to extraction treatment. Specifically, after cutting licorice etc. to an appropriate size as necessary, an appropriate extracting solvent is added to infuse it, a concentrated solution of the infusion (soft extract, tincture, etc.), and then these are dried. Herbal medicine extracts (dried extracts, etc.) are also included in the "extracts of crude drugs" of the present invention.

The method for producing crude drug extracts is not particularly limited, and for example, the methods described in the 17th revised Japanese Pharmacopoeia, General Rules for Preparations, "extracts," "infusions/decoctions," "tinctures," and "liquid extracts." It can be produced by referring to known methods for producing plant extracts. Specifically, it can be produced by cutting, heating, crushing, etc., as necessary, and then adding an appropriate extraction solvent to perform extraction. The obtained extract may be further concentrated, dried, etc., if necessary.

Examples of the extraction solvent include lower monohydric alcohols such as methanol, ethanol, isopropanol, and n-butanol (preferably linear or branched aliphatic alcohols having 1 to 6 carbon atoms); ethylene glycol, propylene; Lower polyhydric alcohols such as glycol, 1,3-butylene glycol, and glycerin; Ethers such as diethyl ether; Ketones such as acetone and ethyl methyl ketone; Esters such as ethyl acetate; Nitriles such as acetonitrile; Pentane, hexane Alkanes such as , cyclopentane and cyclohexane; Halogenoalkanes such as dichloromethane and chloroform; Aromatic hydrocarbons such as benzene and toluene; Amides such as dimethylformamide; Sulfoxides such as dimethyl sulfoxide; Water (including hot water) etc. These may be used alone or in combination of two or more. In the present invention, the extraction solvent is preferably a solvent containing at least water or a linear or branched aliphatic alcohol having 1 to 6 carbon atoms; More preferably, the solvent is selected from aliphatic alcohols and mixtures of water/linear or branched aliphatic alcohols having 1 to 6 carbon atoms, and is selected from the group consisting of water, ethanol, and water/ethanol mixtures. It is particularly preferable that the solvent be used as a solvent.

The extraction operation is not particularly limited, and any known method used for extraction operations from plants can be adopted, such as immersion in an extraction solvent (chilling, hot immersion, percolation, etc.), supercritical fluid or Examples include extraction using critical fluid. In addition, in order to increase extraction efficiency, stirring or homogenization in an extraction solvent may be performed.
The extraction temperature is not particularly limited and varies depending on the extraction solvent used, extraction procedure, etc., but is preferably about 5° C. to below the boiling point of the extraction solvent.
The extraction time is not particularly limited and varies depending on the extraction solvent used, extraction procedure, etc., but is preferably about 1 hour to 14 days.

In the present invention, commercially available products can be used as the herbal medicine or extract thereof, and specific commercially available products of licorice include (local) licorice extract, (local) licorice powder, (local) licorice crude extract, and licorice. Examples include dry extract (manufactured by Nippon Powder Yakuhin Co., Ltd.). Specific commercially available ginger products include ginger powder (manufactured by Nippon Powder Pharmaceutical Co., Ltd.). Specific commercial products of Chimpi include Chimpi dry extract (manufactured by Alps Yakuhin Kogyo), Chimpi extract (manufactured by Nippon Powder Yakuhin), and the like. Specific commercially available carrot products include Dried Carrot Extract-A (manufactured by Alps Yakuhin Kogyo), Carrot Powder, Carrot Extract (manufactured by Nihon Powder Yakuhin Co., Ltd.), Riken Dried Ginseng Extract (manufactured by Riken Chemical Industry), etc. can be mentioned.

From the viewpoint of improving physiological activity, the content of the crude drug or extract thereof in the pharmaceutical composition of the present invention is preferably 0.001 to 20% by mass, and 0.01 to 20% by mass based on the total mass of the pharmaceutical composition. The content is more preferably 15% by mass, even more preferably 0.1 to 10% by mass, and particularly preferably 1 to 6% by mass.
In addition, when converting the content of the crude drug or its extract into the amount of the crude drug, it is preferably contained in an amount of 0.005 to 30% by mass based on the total mass of the pharmaceutical composition, and 0.05% by mass in terms of the crude drug equivalent. It is more preferable to contain 25% by mass, even more preferably 0.5 to 15% by mass, and particularly preferably 2 to 10% by mass.

The content mass ratio of component (A) and component (B) in the pharmaceutical composition of the present invention may be determined by appropriately considering the daily dose of each component described below. Component (B) is preferably 0.01 to 30 parts by weight, more preferably 0.1 to 15 parts by weight, and particularly preferably 1 to 5 parts by weight, per 1 part by weight of A). In addition, when converting the content of component (B) into the amount of herbal medicine, from the same point of view, 0.01 to 30 mass of component (B) in terms of herbal medicine should be added to 1 part by mass of component (A). parts, more preferably 0.5 to 20 parts by weight, particularly preferably 2 to 10 parts by weight.

The pharmaceutical composition of the present invention contains methylmethionine sulfonium chloride as component (C).
Methylmethionine sulfonium chloride used in the present invention is a compound having the chemical name (3-amino-3-carboxypropyl)dimethylsulfonium chloride and the molecular formula C ₆ H ₁₄ ClNO ₂ S, and is also referred to as MMSC.
The compound may be produced by a known method, or a commercially available product may be used.

The content of methylmethionine sulfonium chloride in the pharmaceutical composition of the present invention is 0.01 to 60% by mass based on the total mass of the pharmaceutical composition, from the viewpoint of suppressing discoloration and/or solidification derived from pirenzepine and crude drugs. The content is preferably from 0.1 to 15% by mass, more preferably from 0.5 to 7% by mass.

In the pharmaceutical composition of the present invention, the content ratio of component (A) to component (C) is 0.1 part by mass of component (A) to 1 part by mass of component (A) from the viewpoint of stability of the preparation. ~10 parts by weight is preferable, 0.2 to 5 parts by weight is more preferable, and 0.5 to 1 part by weight is particularly preferable.
In addition, in the pharmaceutical composition of the present invention, the content ratio of component (B) and component (C) is such that, from the viewpoint of stability of the preparation, 0 part of component (C) is added to 1 part by mass of component (B). The amount is preferably from 0.01 to 10 parts by weight, more preferably from 0.07 to 5 parts by weight, and particularly preferably from 0.15 to 1 part by weight. In addition, when converting the content of component (B) into the amount of herbal medicine, from the same point of view, 0.05 to 25 mass parts of component (C) should be added to 1 part by mass of component (B) in terms of herbal medicine. parts by weight, more preferably 0.1 to 15 parts by weight, and particularly preferably 0.15 to 7 parts by weight.
Furthermore, in the pharmaceutical composition of the present invention, the content mass ratio of component (C) to the total amount of component (A) and component (B) [(C)/{(A)+(B)}] is the content ratio of pirenzepine and From the viewpoint of suppressing discoloration and/or solidification derived from crude drugs, the ratio is preferably 0.001 to 10, more preferably 0.01 to 5, and particularly preferably 0.1 to 1. When converting the content of component (B) into the amount of herbal medicine, from the same viewpoint, the content mass ratio of component (C) to the total amount of component (A) and component (B) converted into herbal medicine [( C)/{(A)+(B)}] is preferably 0.005 to 20, more preferably 0.05 to 15, particularly preferably 0.1 to 5.

In the present invention, the pharmaceutical composition may be in any form such as solid, semi-solid, or liquid, and depending on the purpose of use, it may be in the form commonly used for pharmaceuticals, quasi-drugs, etc. can. For example, tablets (including orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolving tablets, oral tablets (including lozenges, sublingual tablets, buccal tablets, adhesive tablets, and gums), capsules) Solid preparations such as tablets, granules (including effervescent granules), powders, and pills; oral liquid preparations (including elixirs, suspensions, emulsions, and lemonades), syrups, oral liquids, etc. Liquid preparations: Can be in the dosage forms described in the 17th revised Japanese Pharmacopoeia, General Rules for Preparations, etc., such as semi-solid preparations such as oral jelly preparations and oral semi-solid preparations.
In the present invention, a solid composition is preferable from the viewpoint of formulation stability, ease of administration, production efficiency, etc., and the dosage form is selected from the group consisting of tablets, capsules, granules, powders, and pills. are more preferred, and dosage forms selected from the group consisting of tablets and granules are particularly preferred.

The pharmaceutical composition of the present invention can be manufactured according to methods known in the pharmaceutical field, quasi-drug field, etc., depending on the shape and dosage form described above, such as the method described in the 17th edition Japanese Pharmacopoeia, General Rules for Preparations, etc. Can be done.
In addition to the above-mentioned components, the pharmaceutical composition of the present invention includes carriers used in the pharmaceutical field, quasi-drug field, etc. (e.g., excipients, binders, disintegrants, lubricants, colorants, One or more types of flavoring agents, fragrances, coating agents, etc.) may be blended.

Examples of excipients include lactose, crystalline cellulose, sucrose, mannitol, light silicic anhydride, and the like.
Examples of the binder include hydroxypropyl methylcellulose, hydroxypropylcellulose, gelatin, polyvinylpyrrolidone, polyvinyl alcohol, pullulan, and the like.
Examples of the disintegrant include carmellose, carmellose calcium, croscarmellose sodium, crospovidone, and low-substituted hydroxypropylcellulose.
Examples of the lubricant include magnesium stearate and talc.
Examples of the coloring agent include tar pigments, iron sesquioxide, and the like.
Examples of flavoring agents include stevia and aspartame.
Examples of the flavor include orange flavor, lemon flavor, grapefruit flavor, vanilla flavor, mint flavor, apple flavor, ginger flavor, honey flavor, grape flavor, menthol, peppermint oil, caramel, and the like.
As a coating agent, for example, a film forming agent such as carboxymethyl ethyl cellulose, cellulose acetate phthalate, methacrylic acid copolymer S, methacrylic acid copolymer L, methacrylic acid copolymer LD, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, etc. Examples include molecules. In addition, when forming a film, plasticizers such as triethyl citrate, triacetin, and polyethylene glycol; powders such as talc, titanium oxide, yellow iron sesquioxide, iron sesquioxide, legal pigments, light anhydrous silicic acid, and hydrated silicon dioxide, etc. can also be blended.
In the present invention, one type or two or more types of these carriers can be blended in an appropriate combination.

Furthermore, the pharmaceutical composition of the present invention may contain medicinal ingredients other than the above-mentioned ingredients, if desired, within a range that does not impair the effects of the present invention. Such medicinal ingredients are not particularly limited, and may be selected based on appropriate consideration depending on the disease/symptom to which the pharmaceutical composition is applied. , gastric mucosal repair agents (mucosal protective ingredients), antacids, and the like.

Examples of local anesthetics include ethyl aminobenzoate, oxesazein, and the like.
Examples of the digestive agent (choleretic agent) include ursodeoxycholic acid, animal bile (bear bile, ox bile), and the like.
Examples of digestive enzymes include starch-digesting enzymes (biodiastase, takadiastase), fat-digesting enzymes (lipase), and the like.
Examples of the gastric mucosal repair agent (mucosal protective component) include sodium copper chlorophin, potassium copper chlorophin, cetraxate hydrochloride, sofalcon, gefarnate, trimebutine maleate, sodium azulene sulfonate, and the like.
Examples of antacids include proton pump inhibitors such as omeprazole, lansoprazole, and rabeprazole sodium; H2 receptor antagonists such as cimetidine, ranitidine hydrochloride, and famotidine; sodium bicarbonate, precipitated calcium carbonate, anhydrous calcium hydrogen phosphate, and phosphate. Inorganic salts such as calcium oxyhydrogen, magnesium aluminate silicate, magnesium aluminate metasilicate, magnesium silicate, magnesium hydroxide, magnesium carbonate, aldioxa, synthetic aluminum silicate, synthetic hydrotalcite; coracoid, stone determination, Examples include borei, aminoacetic acid, and the like.
In the present invention, one type or a combination of two or more of these medicinal ingredients can be blended as appropriate. The content of such medicinal ingredients can be appropriately set within a range that does not impair the purpose of the present invention.

The method of administering the pharmaceutical composition of the present invention is not particularly limited, and includes oral administration and parenteral administration, and can be appropriately selected depending on the purpose of use of the composition, etc., but oral administration is preferable.
The usage and dosage of the pharmaceutical composition are not particularly limited, and may be appropriately selected and determined depending on the purpose of use of the composition, the administration method, the dosage form of the composition, etc. The above-mentioned dose is, for example, an amount that allows 10 to 150 mg of component (A) to be taken per day, preferably an amount that allows 20 to 130 mg, and more preferably 40 to 60 mg. Further, the amount is such that 10 to 2000 mg of component (B) can be taken, preferably 50 to 1000 mg, and more preferably 100 to 500 mg.

Furthermore, in the present invention, the pharmaceutical composition may be housed in an airtight package (hereinafter, a pharmaceutical composition housed in an airtight package will be referred to as a "packaged pharmaceutical composition"). ). By housing the pharmaceutical composition of the present invention in an airtight package, discoloration and solidification caused by pirenzepine and herbal medicine can be further suppressed. In this case, the packaged pharmaceutical composition may include, in addition to the airtight packaging, packaging that does not fall under the following "airtight packaging" (hereinafter also referred to as "other packaging"), and The pharmaceutical composition may be housed directly or indirectly in an airtight package. An example of a mode in which the pharmaceutical composition is indirectly housed in an airtight package includes a mode in which the pharmaceutical composition is housed in the above-mentioned "other package" and this is housed in the airtight package.

As used herein, the term "airtight packaging" refers to packaging that can prevent solid or liquid foreign substances from entering during normal handling, transportation, storage, etc., and is based on the 17th revised Japanese Pharmacopoeia General Rules. This is a concept that includes defined "airtight containers" and "sealed containers." As the airtight package, either fixed or irregular shapes can be used, and specific examples include bottle packaging, SP (Strip Package) packaging, PTP (Press Through Package) packaging, pillow packaging, stick packaging, etc. can be mentioned. The airtight package may be a combination of a plurality of these, for example, a mode in which the pharmaceutical composition is first packaged in PTP packaging and then further packaged in pillow packaging.

The packaging material (material) of the airtight package is not particularly limited, and includes, for example, glass, plastic (polyester such as polyethylene terephthalate and polyethylene naphthalate); polyethylene (low density (LDPE), medium density (MDPE), high density (HDPE)). Materials used in fields such as pharmaceuticals, such as polyolefins such as polypropylene; polycarbonates; polystyrene, etc.), metals (aluminum, etc.), can be used individually or in combination of two or more as appropriate.

For example, the packaging material used for bottle packaging is not particularly limited, and examples include the above-mentioned glass, plastic, metal, etc., and one or more of these can be appropriately combined. The material for bottle packaging is preferably glass, polyethylene, or polypropylene, more preferably glass, low-density polyethylene (LDPE), high-density polyethylene (HDPE), or polypropylene, and even more preferably glass, high-density polyethylene (HDPE), or polypropylene. Glass is particularly preferred.
When packaging a bottle, for example, an appropriate amount of the pharmaceutical composition may be stored in the bottle, and then the bottle may be sealed with a suitable stopper or lid. The size of the bottle may be appropriately selected according to the quantity of the composition to be stored, and the capacity of the bottle is, for example, about 10 to 500 mL, preferably 14 to 400 mL, and 24 to 350 mL. More preferred.

Furthermore, the packaging materials used for SP packaging, PTP packaging, pillow packaging, stick packaging, etc. are not particularly limited, and include, for example, biaxially oriented polypropylene (OPP), biaxially oriented polyester (PET), glycol-modified PET ( PET-G), biaxially oriented nylon (ONy, PA), cellophane, paper, low-density polyethylene (LDPE), linear low-density polyethylene (L-LDPE), ethylene-vinyl acetate copolymer (EVA), free Oriented polypropylene (CPP, IPP), ionomer resin (IO), ethylene-methacrylic acid copolymer (EMAA), polyacrylonitrile (PAN), biaxially oriented polyvinylidene chloride (PVDC), ethylene-vinyl alcohol copolymer resin (EVOH) ), polyvinyl chloride (PVC), cyclic polyolefin (COC), unstretched nylon (CNy), polycarbonate (PC), polystyrene (PS), rigid vinyl chloride (VSC), and aluminum foil (AL). metal foils, etc., and one type or two or more types of these can be suitably combined.

When performing SP packaging, PTP packaging, pillow packaging, stick packaging, etc., it is sufficient to manufacture sheets using one or more of the above-mentioned packaging materials using a known method. It is also possible to have a multilayer structure by appropriately combining materials. An example of a method for forming a sheet into a multilayer structure using two or more types of packaging materials includes a method of manufacturing a laminated sheet by laminating the packaging materials. The laminated sheet can be manufactured by known methods such as extrusion lamination, dry lamination, coextrusion lamination, thermal lamination, wet lamination, non-solvent lamination, and heat lamination. Furthermore, known commercial products can be used as sheets for SP packaging, PTP packaging, pillow packaging, and stick packaging.

Among the above-mentioned sheets, examples of a single-layer sheet using one type of packaging material include a PVC sheet and a CPP sheet, and examples of a laminated sheet using two or more types of packaging materials include the following sheet configuration: Laminated PVC and PVDC (PVC/PVDC, hereinafter similarly abbreviated), PVC/PVDC/PE/PVC, PVC/PVDC/PE/PVDC/PVC, CPP/COC/CPP, PVC/PCTFE, CPP /PCTFE, PVC/AL/PA, PVC/AL, CPP/AL, CPP/CPP/CPP (the sheet on the left uses two or more types of CPP), etc., but is limited to only these. It is not something that will be done.

In the form of PTP packaging, a desired number of pockets are formed on a resin sheet or the like using a known method, and the composition is stored one piece or one dosage unit at a time, and then a sheet made of metal foil such as aluminum foil is placed on the lid. One example is to use it as a material and cover it. Note that it is also possible to use a so-called double-sided aluminum PTP packaging using a sheet made of aluminum foil as the sheet forming the pocket. In the case of PTP packaging, it is preferable to further package the PTP packaging with pillow packaging (for example, aluminum pillow packaging).
Examples of SP packaging, pillow packaging, and stick packaging include packaging one composition or one dosage unit at a time using a resin sheet, a sheet made of aluminum foil, or the like using a known method. In the case of SP packaging, pillow packaging, or stick packaging, it is preferable to use a sheet made of aluminum foil.

In addition, in this specification, the occupancy rate (volume ratio) of the pharmaceutical composition inside the package in the packaged pharmaceutical composition is usually 25 to 90% when the package is bottle packaging, and 28 to 90%. 75% is preferred, and 30-50% is more preferred. In addition, when the package is SP packaging, PTP packaging, pillow packaging, or stick packaging, it is usually 30 to 98%, preferably 40 to 95%, more preferably 45 to 93%, and particularly preferably 50 to 90%. . In this case, the occupancy rate refers to the occupancy rate of the composition to the total volume inside the package, and fillers, inner plugs, etc. to prevent damage to the composition stored inside the package are not included. , are not taken into consideration when calculating the space occupancy rate.

As the airtight package, a commercially available package may be used as is, or a commercially available packaging material may be processed and used. Examples of bottle packaging for commercially available products include glass bottles (manufactured by Isoya Glass Industries Co., Ltd.), tablet bottles (manufactured by Tokyo Glass Co., Ltd.), and Z-series (manufactured by Hanshin Chemical Industries, Ltd.). It will be done. In addition, examples of commercially available pillow packaging include Lamizip (registered trademark) (manufactured by Seisaku Nippon Sha Co., Ltd.). Furthermore, packaging materials for SP packaging, PTP packaging, pillow packaging, and stick packaging include Sumilite VSS, Sumilite VSL, Sumilite NS, Sumilite FCL (manufactured by Sumitomo Bakelite Co., Ltd.), and TAS series (made by Taisei Kako Co., Ltd.). ), vinyl foil for PTP, super foil for PTP (manufactured by Mitsubishi Plastics Co., Ltd.), Nipaku aluminum foil (manufactured by Nippon Seiho Co., Ltd.), plain silver aluminum foil (manufactured by Daiwa Chemical Industry Co., Ltd.), etc. It will be done.

The method of housing the pharmaceutical composition in an airtight package is not particularly limited, and can be achieved by placing the composition inside the package by appropriate means such as introducing the composition into the package. In this case, a method may be used in which a desiccant (for example, a cylindrical (tablet-shaped) or sheet-shaped one) is introduced into the package together with the composition.

The pharmaceutical compositions and packaged pharmaceutical compositions of the present invention can be used as pharmaceuticals, quasi-drugs, etc., and the purpose of use is not particularly limited. Since it further contains (C) methylmethionine sulfonium chloride, it is preferably used for acute gastritis, acute exacerbation of chronic gastritis, gastric ulcer, duodenal ulcer, gastric mucosal lesions (erosion, bleeding, redness, adherent mucus), and digestion. It can be used as a medicine for improving organ symptoms (stomach pain, heartburn, hyperacidity, heaviness in the stomach, stomach discomfort, indigestion, etc.).

The present invention also provides the following components (A), (B) and (C):
(A) pirenzepine or a salt thereof; (B) a herbal medicine or extract thereof; and (C) methylmethionine sulfonium chloride. The present invention also relates to a method for stabilizing B) (preferably a method for suppressing discoloration and/or solidification of components (A) and (B) in a pharmaceutical composition during high-temperature storage).
In this aspect of the invention, the order of the step of containing component (A), the step of containing component (B), and the step of containing component (C) is not particularly limited, and component (A) and component (B) A composition containing component (C) may be produced directly or indirectly.
In addition, in this embodiment of the invention, the meanings of various words, the amounts of each component, etc. are all the same as explained for the above-mentioned pharmaceutical composition.

EXAMPLES Hereinafter, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited to these in any way.

[Sample 1]
0.5 g of pirenzepine (manufactured by Daiwa Pharmaceutical Co., Ltd.: pirenzepine hydrochloride hydrate) was placed in a glass bottle (3K standard bottle), and sample 1 was prepared.

[Sample 2]
Sample 2 was prepared by storing 0.5 g (2500 mg in terms of the amount of crude drug) of Chimpi (manufactured by Alps Yakuhin Kogyo Co., Ltd.: Chimpi dry extract) in a glass bottle (3K standard bottle).

[Sample 3]
Sample 3 was prepared by placing 0.5 g of licorice (Nippon Powder Pharmaceutical Co., Ltd.: licorice dry extract) (2500 mg in terms of herbal medicine equivalent) in a glass bottle (3K standard bottle).

[Sample 4]
0.5 g (5000 mg in terms of raw drug equivalent) of carrots (manufactured by Alps Yakuhin Kogyo Co., Ltd.: Carrot Dried Extract-A) was placed in a glass bottle (3K standard bottle), and sample 4 was prepared.

[Sample 5]
Sample 5 was prepared by mixing Sample 1 with 0.5 g of Chimpi (Chimpi dry extract, manufactured by Alps Yakuhin Kogyo Co., Ltd.) (2500 mg equivalent to the original herbal medicine).

[Sample 6]
Sample 6 was prepared by mixing Sample 1 with 0.5 g of licorice (Nippon Powder Pharmaceutical Co., Ltd.: licorice dry extract) (2500 mg in terms of the original herbal medicine).

[Sample 7]
Sample 7 was prepared by mixing Sample 1 with 0.5 g (5000 mg equivalent to the original herbal medicine) of carrot (Dried Carrot Extract-A, manufactured by Alps Yakuhin Kogyo Co., Ltd.).

[Sample 8]
Sample 8 was prepared by mixing Sample 5 with 0.5 g of methylmethionine sulfonium chloride (manufactured by Yonezawahama Riyaku Kogyo: MMSC).

[Sample 9]
Sample 9 was prepared by mixing Sample 6 with 0.5 g of methylmethionine sulfonium chloride (manufactured by Yonezawahama Riyaku Kogyo Kogyo: MMSC).

[Sample 10]
Sample 10 was prepared by mixing Sample 7 with 0.5 g of methylmethionine sulfonium chloride (manufactured by Yonezawahama Riyaku Kogyo: MMSC).

[Sample 11]
Pirenzepine hydrochloride (manufactured by Daiwa Pharmaceutical Co., Ltd.: pirenzepine hydrochloride hydrate) 0.5 g, ginger (made by Nippon Powder Pharmaceutical Co., Ltd.: ginger powder) 0.5 g, and methylmethionine sulfonium chloride (manufactured by Yonezawa Hamari Pharmaceutical Co., Ltd.: MMSC) 0 Sample 11 was a mixture of .5 g.

[Test Example 1] Storage Stability Test After each sample 1 to 11 was prepared, it was stored at 80°C for 1 day. Changes in appearance (color) before the start of storage and after storage for 1 day were visually evaluated by a panel. Those for which there was no change in appearance (color) were marked "○" (no change compared to before the start of storage), and those for which there was a change were marked "x" (changed compared to before the start of storage).
The results are shown in Table 1.

As shown in Table 1, samples 1 to 4 showed no change in appearance (color) after being stored at 80°C for 1 day, but samples 5 to 7, in which chimpi, licorice, or carrot was added to sample 1, After storage at ℃ for 1 day, changes in appearance (color) were observed.
On the other hand, in samples 8 to 11, in which sample 1 was added with chimpi, licorice, carrot, or ginger, and MMSC, no change in appearance (color) was observed after storage at 80°C for 1 day, and no discoloration was observed. .

[Test Example 2] Storage Stability Test After each of Samples 5 and 8 to 11 was prepared, the glass bottles were sealed and stored at 80° C. for 2 weeks. The presence or absence of solidification was visually evaluated by a panelist before the start of storage and after 2 weeks of storage. "No" was written for those that did not solidify, and "Yes" for those that did.
The results are shown in Table 2.

As shown in Table 2, in sample 5, solidification was observed after storage at 80°C for 2 weeks.
On the other hand, in Samples 8 to 11, no solidification was observed after storage at 80°C for 2 weeks.

From the above test results, it was found that by allowing MMSC to coexist in a mixture of pirenzepine or its salts and herbal medicines such as chimpi, licorice, ginseng, and ginger, or their extracts, it is possible to reduce the amount derived from pirenzepine and herbal medicines due to high-temperature storage. It has become clear that the occurrence of discoloration and/or solidification can be suppressed.

[Manufacture example 1]
Granules containing 3900 mg of the following ingredients per day (in 3 packages) were prepared according to a conventional method, and SP-wrapped using aluminum foil for strip packaging (manufactured by Nissan Kako Co., Ltd.).
Sodium hydrogen carbonate 240mg
Precipitated calcium carbonate 710mg
Magnesium metasilicate aluminate 900mg
Magnesium hydroxide 550mg
Pirenzepine hydrochloride hydrate 46.9mg
Methylmethionine sulfonium chloride 30mg
Licorice extract powder 75mg (original drug equivalent amount 525mg)
Dry soybean extract 30mg (original drug equivalent amount 270mg)
Ginger powder 100mg
Dried carrot extract 20mg (raw drug equivalent amount 290mg)
Hydrogenated Oil Hydroxypropyl Cellulose D-Mannitol Carmellose Calcium Lactate Sucralose L-Menthol Silicon Dioxide Flavor Corn Starch Dextrin

[Manufacture example 2]
Granules containing 3900 mg of the following ingredients per day (in 3 packages) were prepared according to a conventional method, and SP-wrapped using aluminum foil for strip packaging (manufactured by Nissan Kako Co., Ltd.).
Precipitated calcium carbonate 1000mg
Synthetic hydrotalcite 780mg
Magnesium hydroxide 300mg
Pirenzepine hydrochloride hydrate 46.9mg
Methylmethionine sulfonium chloride 30mg
Ardioxa 150mg
Dried carrot extract 20mg (raw drug equivalent amount 290mg)
Ginger powder 100mg
Hydrogenated Oil Hydroxypropyl Cellulose D-Mannitol Carmellose Calcium Lactate Sucralose L-Menthol Silicon Dioxide Flavor Corn Starch Dextrin

[Manufacture example 3]
Granules containing 3900 mg of the following ingredients per day (in 3 packages) were prepared according to a conventional method, and SP-wrapped using aluminum foil for strip packaging (manufactured by Nissan Kako Co., Ltd.).
Sodium hydrogen carbonate 240mg
Precipitated calcium carbonate 710mg
Magnesium metasilicate aluminate 900mg
Magnesium hydroxide 550mg
Pirenzepine hydrochloride hydrate 46.9mg
Methylmethionine sulfonium chloride 30mg
Chinpi powder 300mg
Clove powder 50mg
Ginger powder 100mg
Hydrogenated Oil Hydroxypropyl Cellulose D-Mannitol Carmellose Calcium Lactate Sucralose L-Menthol Silicon Dioxide Flavor Corn Starch Dextrin

[Manufacture example 4]
Granules containing 3900 mg of the following ingredients per day (in 3 packages) were prepared according to a conventional method, and SP-wrapped using aluminum foil for strip packaging (manufactured by Nissan Kako Co., Ltd.).
Precipitated calcium carbonate 1000mg
Synthetic hydrotalcite 780mg
Magnesium hydroxide 300mg
Pirenzepine hydrochloride hydrate 46.9mg
Methylmethionine sulfonium chloride 30mg
Ardioxa 150mg
Keihi powder 100mg
Ginger powder 100mg
Hydrogenated Oil Hydroxypropyl Cellulose D-Mannitol Carmellose Calcium Lactate Sucralose L-Menthol Silicon Dioxide Flavor Corn Starch Dextrin

[Manufacture example 5]
Tablets of 3600 mg each containing the following ingredients per day (in 6 tablets) were manufactured according to a conventional method and housed in a bottle made of low-density polyethylene.
Precipitated calcium carbonate 1000mg
Synthetic hydrotalcite 780mg
Magnesium hydroxide 300mg
Pirenzepine hydrochloride hydrate 46.9mg
Methylmethionine sulfonium chloride 30mg
Ardioxa 150mg
Keihi powder 100mg
Ginger powder 100mg
Cellulose D-Mannitol Hydroxypropyl Cellulose Metasilicate Magnesium Aluminate Calcium Hydrogen Phosphate Silicon Dioxide L-Menthol Magnesium Stearate

[Manufacture example 6]
Tablets of 3600 mg each containing the following ingredients per day (in 6 tablets) were manufactured according to a conventional method and housed in a bottle made of low-density polyethylene.
Precipitated calcium carbonate 1000mg
Synthetic hydrotalcite 780mg
Magnesium hydroxide 300mg
Pirenzepine hydrochloride hydrate 46.9mg
Methylmethionine sulfonium chloride 30mg
Ardioxa 150mg
Dried carrot extract 20mg (raw drug equivalent amount 290mg)
Ginger powder 100mg
Cellulose D-Mannitol Hydroxypropyl Cellulose Metasilicate Magnesium Aluminate Calcium Hydrogen Phosphate Silicon Dioxide L-Menthol Magnesium Stearate

[Manufacture example 7]
Tablets of 3600 mg each containing the following ingredients per day (in 6 tablets) were manufactured according to a conventional method and housed in a bottle made of low-density polyethylene.
Sodium hydrogen carbonate 240mg
Precipitated calcium carbonate 710mg
Magnesium metasilicate aluminate 900mg
Magnesium hydroxide 550mg
Pirenzepine hydrochloride hydrate 46.9mg
Methylmethionine sulfonium chloride 30mg
Chinpi powder 300mg
Clove powder 50mg
Ginger powder 100mg
Cellulose D-Mannitol Hydroxypropyl Cellulose Calcium Hydrogen Phosphate Silicon Dioxide L-Menthol Magnesium Stearate

[Manufacture example 8]
Tablets of 3600 mg each containing the following ingredients per day (in 6 tablets) were manufactured according to a conventional method and housed in a bottle made of low-density polyethylene.
Sodium hydrogen carbonate 240mg
Precipitated calcium carbonate 710mg
Magnesium metasilicate aluminate 900mg
Magnesium hydroxide 550mg
Pirenzepine hydrochloride hydrate 46.9mg
Methylmethionine sulfonium chloride 30mg
Licorice extract powder 75mg (original drug equivalent amount 525mg)
Dry soybean extract 30mg (original drug equivalent amount 270mg)
Ginger powder 100mg
Dried carrot extract 20mg (raw drug equivalent amount 290mg)
Cellulose D-Mannitol Hydroxypropyl Cellulose Calcium Hydrogen Phosphate Silicon Dioxide L-Menthol Magnesium Stearate

Claims (4)

The following ingredients (A), (B) and (C):
A pharmaceutical composition containing (A) pirenzepine or a salt thereof (B) a crude drug or extract thereof (C) methylmethionine sulfonium chloride. Ingredients (B) include acalyx, aniseed, aloe, fennel, turmeric, ubai, uyaku, corydalis, enmeisou, scutellariae, scutellariae, orensis, processed garlic, zebra root, cuckoo, calamus root, kankyo, licorice, pheasant, kujin, Keihi, Ketsumeishi, Gentian, Gennoshoko, Red ginseng, Goshuyu, Pepper, Gobaiko, Colombo, Konzurango, Hawthorn, Japanese sage, Yamana, Shisoshi, Peony, Shukusha, Gingerbread, Schizophrenia, Green bark, Red bud oak, Stone iris root, Centaurium grass, Sojutsu, Japanese soybean, Japanese rhubarb, rhubarb, ginseng, clove, chimpi, chili pepper, spruce, bittern, nikuzuku, carrot, mentha, mentha, Japanese pepper, sandalwood, hop, homica, rapeseed leaf, yakuchi, Japanese apricot, ryutan, and ryokyo , and extracts thereof. The pharmaceutical composition according to claim 1, wherein the component (B) is one or more selected from the group consisting of licorice, ginger, chimpi, and ginseng, and extracts thereof. 4. The pharmaceutical composition according to claim 1, wherein the dosage form is selected from the group consisting of tablets, capsules, granules, powders, and pills.