JP2006070027A - Administration agent to mucous membrane in oral cavity - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a medicine used for prophylaxis and/or treatment of xerostomia, rapidly exhibiting excellent sialogogic effects and reducing or avoiding adverse effects on digestive organs. <P>SOLUTION: A medicine is used for, e.g. prophylaxis and/or treatment of the xerostomia. The medicine in the form of administration to the mucous membrane in the oral cavity comprises a spirooxathiolane-quinuclidine derivative represented by general formula (I) (wherein, R<SP>1</SP>and R<SP>2</SP>may each be the same or different and are each independently a hydrogen atom, an alkyl group, a cyclopentyl group, a cyclohexyl group, a monoaryl-substituted or a diaryl-substituted methylol group or an aryl-substituted alkyl group) or an acid addition salt thereof as an active ingredient. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to an oral mucosal agent containing a spirooxathiolane quinuclidine derivative or an acid addition salt thereof as an active ingredient.

  Traditionally, oral mucosal agents for dry mouth disease include moisturizers used as a substitute for saliva, such as artificial saliva, and sputum that stimulates saliva secretion using stimulation by acids such as citric acid and vitamin C. Substances and gums are used. However, these drugs are not drugs that can achieve sufficient effects, and development of drugs that are highly effective against dry mouth diseases is desired.

In recent years, 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine hydrochloride addition salt hydrate (“Cevimeline hydrochloride hydrate” is sometimes referred to as a therapeutic agent for dry mouth disease of Sjogren's syndrome ) Oral formulation has been used, and its salivary secretion promoting effect has been clarified (Japanese Patent Laid-Open Nos. 61-280497 and 6-24981). However, oral preparations of cevimeline hydrochloride hydrate may have symptoms such as nausea, abdominal pain and vomiting as side effects of the digestive system. These side effects are presumed to be caused by the high concentration of active ingredients in tissues such as the stomach and small intestine, which are the absorption sites when cevimeline hydrochloride hydrate is orally administered. Is not certain. If the above-mentioned side effects can be avoided in a preparation using cevimeline hydrochloride hydrate, it can be expected to be highly useful as a therapeutic agent for dry mouth disease, but such a preparation has not been provided.
Japanese Patent Laid-Open No. 61-280497 JP-A-6-24981

  An object of the present invention is to provide a medicament for the prevention and / or treatment of dry mouth disease. More specifically, it is a medicament for the prevention and / or treatment of dry mouth disease, which can quickly exert an excellent salivary secretion promoting effect and reduce or avoid the side effects of digestive organs. It is an object of the present invention to provide a medicament.

  As a result of diligent research to solve the above problems, the present inventors have conducted oral mucosal administration containing a spirooxathiolanquinuclidine derivative represented by the following general formula (I) or an acid addition salt thereof as an active ingredient: It has been found that the above-mentioned problems can be solved by providing a medicine in the form. More specifically, the oral mucosa dosage form containing the above active ingredient has excellent absorbability and transferability to the salivary glands, and exhibits excellent salivary secretion promoting action without causing side effects of digestive organs I found out that I can do it. In addition, the present inventors can provide a medicine having further excellent oral mucosa absorbability by using a specific pH condition or a hydrophilic solvent in the above medicine, and higher prevention in an oral mucosa-adhesive patch. And / or discovered that a therapeutic effect can be exhibited. The present invention has been completed based on the above findings.

That is, according to the present invention, the following general formula (I)
(In the formula, R ¹ and R ² may be the same or different and are each independently a hydrogen atom, an alkyl group, a cyclopentyl group, a cyclohexyl group, a monoaryl-substituted or diaryl-substituted methylol group, or an aryl-substituted alkyl group. And a spirooxathiolane quinuclidine derivative or an acid addition salt thereof as an active ingredient. This medicament is used as a medicament for prevention and / or treatment of dry mouth disease.

  According to a preferred embodiment of the above invention, the aforementioned medicament, wherein the spirooxathiolane quinuclidine derivative is 2-methylspiro (1,3-oxathiolane-5,3 ′ quinuclidine); The above drug which is 2-methylspiro (1,3-oxathiolane-5,3 ′ quinuclidine); the active ingredient is 2-methylspiro (1,3-oxathiolane-5,3 ′ quinuclidine) hydrochloride or a hydrate thereof The above-mentioned medicament; the above-mentioned medicament, wherein the active ingredient is cis-2-methylspiro (1,3-oxathiolane-5,3′quinuclidine) hydrochloride or a hydrate thereof; and the active ingredient is cis-2-methylspiro (1, 3-oxathiolane-5,3 ′ quinuclidine) monohydrochloride 1/2 hydrate as described above is provided.

  Furthermore, according to a preferred embodiment of the present invention, the above medicine in the form of a pharmaceutical composition containing a water-soluble or swellable polymer and / or a hydrophilic solvent; Methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxymethylethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, xanthan gum, karaya gum, gum arabic, tragacanth gum, guar gum, gelatin, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylic acid or a metal salt thereof, Carboxyvinyl polymers, salts of alginic acid, propylene glycol alginate, pullulan, and lower alkyl vinyl ether / maleic anhydride copolymers and And one or more polymers selected from the group consisting of derivatives thereof; water-soluble or swellable polymers are methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxymethylethylcellulose, hydroxypropylcellulose, hydroxy The above-mentioned pharmaceutical which is one or more polymers selected from the group consisting of propylmethylcellulose and sodium carboxymethylcellulose; the hydrophilic solvent is monoethanolamine, diethanolamine, triethanolamine, diisopropanolamine, triisopropanolamine , Ethanol, isopropanol, glycerin, ethylene glycol, propylene glycol, 1,3-butylene glycol, N-methyl-2-pyrrolidone, polyethylene glycol 300, polyethylene glycol 400, triethyl citrate, glycerin fatty acid ester, polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80, the above-mentioned pharmaceutical which is one or more solvents selected from the group consisting of: The above medicament is provided as one or more solvents selected from the group consisting of monoethanolamine, diethanolamine, triethanolamine, diisopropanolamine, and triisopropanolamine.

  According to a further preferred embodiment, the pharmaceutical composition having a pH of 6.5 to 9 in the pharmaceutical composition; a patch, a sublingual agent, a buccal agent, a solution, a mouthwash, a spray, an aerosol, an ointment, a jelly Oral mucosa patch comprising the above-mentioned medicine in the form of an agent or a film-like pharmaceutical composition; (1) a water-insoluble support layer, and (2) a mucoadhesive adhesive layer laminated on the support layer Said pharmaceutical in the form of an agent; the water-insoluble support layer is selected from the group consisting of ethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, cellulose acetate phthalate, shellac, polyisobutylene, and polyisoprene Contains one or more substances, and the mucoadhesive adhesive layer produces adhesiveness with moisture in the oral cavity That the aforementioned medicament containing a soluble or swellable polymer and a hydrophilic solvent are provided in the water.

  From another aspect, according to the present invention, the use of a spirooxathiolanquinuclidine derivative represented by the above general formula (I) or an acid addition salt thereof for the manufacture of a medicament of the above oral mucosa dosage form; A method for preventing and / or treating a dry disease, comprising the step of administering to the oral mucosa a pharmaceutical composition comprising a spirooxathiolanquinuclidine derivative represented by the above general formula (I) or an acid addition salt thereof A method is provided.

  The medicament of the present invention can transfer an active ingredient spirooxathiolanquinuclidine derivative or an acid addition salt thereof from the oral mucosa into the salivary gland very quickly, and exhibits an excellent salivary secretion promoting effect immediately after administration. be able to. In addition, by achieving absorption of the active ingredient from the oral mucosa in the medicament of the present invention, the distribution of the active ingredient in the digestive tract can be remarkably reduced, and digestive organs that have been problematic in conventional oral preparations The occurrence of side effects can be reduced or eliminated.

  The spirooxathiolane quinuclidine derivative represented by the above general formula (I) or an acid addition salt thereof is a known substance and can be easily obtained by those skilled in the art according to the method disclosed in JP-A-61-280497. is there. In general formula (I), examples of the alkyl group include carbon such as methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group, amyl group, or hexyl group. The lower alkyl of number 1-6 can be mentioned. As the aryl group, a substituted or unsubstituted monocyclic or polycyclic aryl group can be used. For example, a phenyl group, a tolyl group, a xylyl group, a diphenyl group, etc. can be mentioned. The monoaryl-substituted or diaryl-substituted methylol group is a group having 1 or 2 identical or different aryl groups on the hydroxymethyl group, and the above aryl groups can be used as the aryl group. As the aryl-substituted alkyl group, a group having one or two or more same or different aryl groups on the alkyl group can be used, and the above-described ones can be used as the alkyl group and the aryl group. Examples of the aryl-substituted alkyl group include a benzyl group and a diphenylmethyl group.

  Examples of the spirooxathiolane quinuclidine derivative include 2-methylspiro (1,3-oxathiolane-5,3 ′ quinuclidine), 2-diphenylmethylspiro (1,3-oxathiolane-5,3 ′ quinuclidine), or 2 -Methyl-2-phenylspiro (1,3-oxathiolane-5,3 ′ quinuclidine) and the like are preferable, and these cis-isomers are more preferable. Of these, 2-methylspiro (1,3-oxathiolane-5, 3 'quinuclidine) is particularly preferred.

  As the spirooxathiolanquinuclidine derivative, any geometric isomer, enantiomer, or diastereomer in a pure form, any mixture thereof, racemate, or the like may be used. Regarding the geometric isomer, it is preferable to use a cis isomer of a spirooxathiolane quinuclidine derivative. The cis isomer of 2-methylspiro (1,3-oxathiolane-5, 3 'quinuclidine) is a particularly preferred active ingredient. In addition to the case where the pure cis form is used as the active ingredient of the medicament of the present invention, it is also possible to use a mixture of cis form and trans form, which contains more cis form, as the active ingredient of the medicament of the present invention. it can.

  Examples of acid addition salts of spirooxathiolanquinuclidine derivatives include acid addition salts with inorganic or organic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, sulfamic acid, lactic acid, tartaric acid, succinic acid, or maleic acid can do. As the acid addition salt, for example, 2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine hydrochloride addition salt is preferable, but the active ingredient of the medicament of the present invention is limited to this specific acid addition salt. There is no. Any hydrate or solvate of a spirooxathiolane quinuclidine derivative or an acid addition salt thereof may be used as an active ingredient of the medicament of the present invention. The most preferred active ingredient is (±) -cis-2-methylspiro (1,3-oxathiolane-5,3 ′) quinuclidine / monohydrochloride / 1/2 hydrate (generic name “cevimeline hydrochloride hydrate”) This active ingredient is an active ingredient of “Evozac Capsule 30 mg” (manufactured and sold by Daiichi Pharmaceutical Co., Ltd. for oral administration).

  The form of the medicament of the present invention is not particularly limited as long as it is a form suitable for oral mucosal administration. For example, it is a patch, spray, mouthwash, buccal, sublingual, liquid, ointment, jelly, aerosol. Or it is preferable that it is a form, such as a film-form pharmaceutical composition. More preferably, it is in the form of a patch, gargle, spray or film-like pharmaceutical composition. The property of the medicament of the present invention is not particularly limited, and may be any property such as a solid, semi-solid, liquid, or gel.

  The medicament of the present invention can deliver the active ingredient directly from the oral mucosa to the salivary glands. Since salivary glands are located very close to the oral mucosa, the oral mucosal administration using the pharmaceutical of the present invention achieves a more efficient and direct salivary secretion promoting effect than conventional oral pharmaceuticals be able to. The human salivary glands are roughly classified into two types: the major salivary glands (the parotid gland, the submandibular gland and the sublingual gland) that are located far from the oral mucosa and connected by a long conduit from the opening of the oral mucosal surface; There are small salivary glands that exist widely in the vicinity of the oral mucosal surface such as the lips, tongue, palate and cheeks. Usually, most of the saliva is said to be secreted from the major salivary glands, and the amount of saliva secreted from the minor salivary glands is said to be small. The research on the small salivary gland has not been sufficiently advanced, and there is no established method for accurate measurement of the amount of saliva. There is a high possibility that it is related to the function of the minor salivary gland, and the saliva secreted from the minor salivary gland is considered to be important from the aspect of the moisturizing effect of the oral mucosa.

  Since the active ingredient can be directly delivered to the small salivary gland located particularly near the oral mucosa, the medicament of the present invention can achieve effective prevention and / or treatment for dryness of the oral mucosa. For small salivary glands located in the vicinity of the oral mucosa, the diffusion distance of the active ingredient in the oral mucosa is very short, so that a high drug concentration can be achieved immediately after administration, and a small amount of the active ingredient Can be expected to be highly effective. It can also be expected that some of the active ingredients reach the minor salivary gland directly through a short conduit. Since the small salivary glands are widely distributed in the oral cavity, a spray, a mouthwash, a buccal agent, a liquid agent, or an aerosol that can be applied to a wide range of oral mucosa is preferable for a medicine that targets the small salivary gland as a target site. The spray is a form in which a solution-like composition is ejected by air pressure or the like, and the aerosol is a form in which a solution-like or powder-like composition is ejected using a propellant such as a liquefied gas or a compressed gas. By these means, the powder may be ejected directly to the oral mucosa, or the aqueous composition in the form of a solution or suspension may be ejected to the oral mucosa.

  The medicament of the present invention is preferably prepared as a pharmaceutical composition containing a water-soluble or swellable polymer and / or a hydrophilic solvent. A polymer that is soluble or swellable in water is a polymer that is soluble in water or that can be uniformly dispersed and may swell due to water absorption during dissolution or dispersion. It is. This polymer has adhesiveness to the oral mucosa, and is a substance that plays a role of supplying the active ingredient on the oral mucosal surface when the active ingredient of the medicament of the present invention is absorbed into the oral mucosa.

  The type of polymer that is soluble or swellable in water is not particularly limited. For example, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxymethyl ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose sodium, xanthan gum, karaya gum, gum arabic, From tragacanth gum, guar gum, gelatin, polyvinyl pyrrolidone, polyvinyl alcohol, polyacrylic acid or its metal salt, carboxyvinyl polymer, salt of alginic acid, propylene glycol alginate, pullulan, and lower alkyl vinyl ether / maleic anhydride copolymer and its derivatives One or two or more polymers selected from the group consisting of: For example, one or more polymers selected from the group consisting of methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxymethylethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and sodium carboxymethylcellulose can be used.

  As the hydrophilic solvent, an organic solvent mixed with water can be used, and this hydrophilic solvent promotes the oral mucosa absorbability of the active ingredient and / or is used as a solubilizer of the active ingredient. The type of the hydrophilic solvent is not particularly limited. For example, monoethanolamine, diethanolamine, triethanolamine, diisopropanolamine, triisopropanolamine, ethanol, isopropanol, glycerin, ethylene glycol, propylene glycol, 1,3-butylene glycol, One or more solvents selected from the group consisting of N-methyl-2-pyrrolidone, polyethylene glycol 300, polyethylene glycol 400, triethyl citrate, glycerin fatty acid ester, polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80 Preferably, monoethanolamine, diethanolamine, triethanolamine, diisopropanolamine, and triisopropyl are used. One or two or more solvents selected from the group consisting of ropanolamines can be used. More preferably, triethanolamine can be used.

  The polymer that is soluble or swellable in water can be used in an amount of 5 to 80% by weight, preferably about 10 to 60% by weight, based on the total weight of the pharmaceutical composition. The hydrophilic solvent can be used in an amount of 1 to 30% by weight, preferably about 5 to 20% by weight, based on the total weight of the pharmaceutical composition. However, it goes without saying that the blending amount can be appropriately selected by those skilled in the art.

  The medicament of the present invention in the form of a pharmaceutical composition is preferably prepared to have a pH of 4 to 9, preferably a pH of 6.5 to 9, more preferably a pH of 7 to 8.5. The pharmaceutical composition having such a pH has particularly good oral mucosal absorption of the active ingredient. If the pH is higher than 9, the oral mucosa tissue may be denatured and irritation may occur. The pH of the preparation can be measured by measuring the pH of the solution when dissolved or suspended in water 3 times the weight of the preparation. In order to adjust the pH of the pharmaceutical composition, for example, mineral acids such as hydrochloric acid, alkali metal hydroxides, alkaline earth metal hydroxides, carbonates, bicarbonates and other inorganic substances, monoethanolamine, diethanolamine Organic bases such as triethanolamine, diisopropanolamine, and triisopropanolamine, or organic acids such as methanesulfonic acid, p-toluenesulfonic acid, and oxalic acid can be used as the pH regulator. The pH adjuster can be used, for example, in a proportion of about 0.01 to 20% by weight, preferably about 0.1 to 15% by weight, based on the total weight of the pharmaceutical composition. Two or more pH regulators may be used in appropriate combination.

  A particularly preferred pharmaceutical composition includes a patch comprising (1) a water-insoluble support layer and (2) a mucoadhesive adhesive layer laminated on the support layer. The patch can be administered to the oral mucosa by cutting it into an appropriate size and attaching it to the oral mucosa. The adhesive layer has a function of adhering and fixing the pharmaceutical composition to the oral mucosa, and the active ingredient added to the adhesive layer elutes from the adhesive layer and reaches the oral mucosal surface. The active ingredient penetrates and diffuses inside the mucous membrane and reaches the salivary glands. The water-insoluble support layer has a function of protecting the pharmaceutical composition from saliva, water drawn into the mouth, and food and drink.

  The water-insoluble support layer is, for example, one or two selected from the group consisting of ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate, shellac, polyisobutylene, and polyisoprene. More than one species can be included. As the above-mentioned pharmaceutical composition, in addition to the above-described two-layered form, a pharmaceutical composition including any one layer or a plurality of both layers and including three or more layers may be used.

  In the production of the medicament of the present invention in the form of a pharmaceutical composition, one or more commonly used additives for preparations may be used. As the additive for preparation, for example, one or more kinds of excipients, binders, lubricants, coloring agents, flavoring agents, fragrances, surfactants, sweeteners, preservatives and the like may be used. it can. An active ingredient having other pharmacological activity can also be blended.

  Examples of the excipient include anhydrous silicic acid, mannitol, sorbitol, anhydrous calcium phosphate and the like, examples of the binder include tragacanth and sodium alginate, and examples of the lubricant include magnesium stearate and talc. , Stearic acid or a salt thereof, or a sucrose fatty acid ester. Examples of the colorant include blue No. 1, yellow No. 4, titanium dioxide, and the like. Examples of the flavoring agent include menthol, peppermint oil, limonene, cineol, citric acid, fumaric acid, tartaric acid, and various fragrances. Examples of the surfactant include an anionic surfactant, a nonionic surfactant, an amphoteric surfactant, and a cationic surfactant. More specifically, for example, sodium lauryl sulfate, sucrose Fatty acid ester, lactose fatty acid ester, lactitol fatty acid ester, maltitol fatty acid ester, stearic acid monoglyceride, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monostearate, polyoxyethylene (10, 20, 40, 60, 80, 100 mol) hydrogenated castor oil, polyoxyethylene alkyl ether, polyoxyethylene polyoxypropylene alkyl ester, polyoxyethylene polyoxypropylene alkyl ether, alkylol amide, 2-alkyl-N-ca Bokishimechiru -N- hydroxyethyl imidazolinium betaine and the like. Examples of the sweetener include xylitol, erythritol, sodium saccharin, stevioside, stevia extract, paramethoxycinnamic aldehyde, neohesperidyl dihydrochalcone, and perilartin. Examples of the preservative include paraoxybenzoate, Examples thereof include sodium benzoate. These pharmaceutical additives can be used, for example, in a proportion of 0.5 to 10% by weight, preferably 1 to 5% by weight, based on the total weight of the pharmaceutical composition. Those skilled in the art can appropriately select depending on the kind of additive and the purpose of blending.

  Other active ingredients having pharmacological activity include, for example, prevention of bad breath, periodontal disease, oral disease, throat, considering that dry mouth disease of Sjogren's syndrome is likely to cause periodontal disease such as caries and stomatitis. An active ingredient effective for dental diseases such as pharyngeal diseases such as inflammation, dental caries prevention and hypersensitivity, local anesthetics, anti-inflammatory agents, anti-inflammatory analgesics, and the like can be used. Moreover, you may mix | blend the active ingredient with which the prevention and / or treatment effect is anticipated with respect to a dry mouth disease other than the active ingredient contained in the pharmaceutical of this invention.

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples. In the following Examples, (±) -cis 2-methylspiro (1,3-oxathiolane-5,3′quinuclidine) monohydrochloride monohydrate was used as an active ingredient (hereinafter, this active ingredient was referred to as “ (Cevimeline hydrochloride hydrate) and (±) -cis 2-methylspiro (1,3-oxathiolane-5,3 ′ quinuclidine) monohydrochloride is referred to as “Cevimeline hydrochloride”). The combinations of the components and the blending ratios for the examples are summarized in each table.
"Moisturizer (liquid type)"
Example 1
30 mg of cevimeline hydrochloride hydrate was accurately weighed and dissolved by adding MaIlvaine buffer at pH 8.0 (MaIlvaine buffer: a mixture of 0.1 mol / L citric acid and 0.2 mol / L disodium hydrogen phosphate) The total amount was 10 mL to prepare a test solution for gargle.
Example 2
30 mg of cevimeline hydrochloride hydrate was accurately weighed and dissolved by adding an aqueous solution of 0.3% triethanolamine-hydrochloric acid (pH 8.0) to make a total volume of 10 mL, which was used as a test solution for gargle.
Example 3
30 mg of cevimeline hydrochloride hydrate was accurately weighed and dissolved by adding an aqueous solution of 1.5% triethanolamine-hydrochloric acid (pH 8.0) to make a total volume of 10 mL, which was used as a test solution for gargle.
Example 4
30 mg of cevimeline hydrochloride hydrate was accurately weighed and dissolved by adding a 10% aqueous ethanol solution to make a total volume of 10 mL to obtain a test solution for gargle.

"Mucosal adhesive patch"
<Method for preparing mucoadhesive patch>
(1) Preparation method of support layer The support layer of Comparative Example 1 was prepared by mixing the components shown in Table 1 at various blending ratios, adding an appropriate amount of distilled water, and sufficiently stirring to dissolve the liquid. And uniformly dried at 90 ° C. for 20 minutes to prepare a uniform film having a thickness of about 30 μm. The support layers of Examples 1 to 6 were prepared by mixing the components shown in Table 1 in respective compounding ratios, adding an appropriate amount of methylene chloride / ethanol (1: 1) and thoroughly stirring to dissolve the liquid. And uniformly dried at 80 ° C. for 10 minutes to prepare a uniform film having a thickness of 30 to 40 μm.

(2) Preparation method of bilayer preparation (see Fig. 1)
Each component of the adhesive layer 1) in Table 1 is uniformly mixed at each compounding ratio, 20 mg of this is weighed, KBr tablet molding machine (Shimadzu Corporation, P / N 202-32010, molding machine inner diameter 13 mm), hand press (Shimadzu) Using a mill, SSP-10A type, P / N200-64175), compression molding was performed at about 140 kg / cm ² for 1 minute. This was overlaid with a support layer (thickness 30 to 40 μm) having a diameter of 13 mm, and compressed and molded again at about 140 kg / cm ² for 30 seconds. Thereafter, it was punched out to a diameter of 7 mm and used as a test drug for animal testing (thickness 180 to 200 μm).

(3) Preparation method of three-layer preparation (see FIG. 1)
Each component of the adhesive layer 1) in Table 1 is uniformly mixed at each compounding ratio, 20 mg of this is weighed, and a KBr tablet molding machine (Shimadzu Corporation, P / N 202-32010, molding machine inner diameter 13 mm) and hand press (Shimadzu) After compression molding at about 140 kg / cm ² for 1 minute using a mill, SSP-10A type, P / N200-64175), the center part was punched out to a diameter of 5 mm. Each component of the adhesive layer 2) is similarly mixed and molded, and then the center part is punched out to a diameter of 5 mm, and the adhesive layer 1) having a diameter of 5 mm is fitted into the punched part, and a support layer (diameter of 13 mm from above) ( The thickness was 30 to 40 μm), and these were again compressed at about 140 kg / cm ² for 30 seconds and molded. Thereafter, the adhesive layer 1) was punched out to a diameter of 7 mm so that the adhesive layer 1) was in the center, and used as a test drug for animal testing (thickness 180 to 200 μm).

Example 5
13. As a support layer, 80.0 parts by weight of hydroxypropyl methylcellulose acetate succinate (hereinafter abbreviated as “HPMCAS”) in an appropriate amount of methylene chloride / ethanol (1: 1), 5.0 parts by weight of ethylcellulose, polyethylene glycol 400 0 parts by weight was added and dissolved by stirring, 1.0 part by weight of iron sesquioxide was added and dispersed uniformly, and this was spread and dried on a PET film to prepare a uniform film having a thickness of about 30 μm. Separately, as the adhesive layer 1), 25.1 parts by weight of hydroxypropyl methylcellulose (hereinafter abbreviated as “HPMC”), 25.1 parts by weight of polyvinylpyrrolidone, 5.8 parts by weight of polyethylene glycol 400, yellow iron sesquioxide 1.1. Part by weight, 0.6 part by weight of sodium bicarbonate and 42.3 parts by weight of cevimeline hydrochloride hydrate were added and mixed uniformly. As the adhesive layer 2), 43.5 parts by weight of HPMC, 43.5 parts by weight of polyvinylpyrrolidone, 10.0 parts by weight of polyethylene glycol 400, 2.0 parts by weight of titanium oxide, and 1.0 part by weight of sodium bicarbonate were added. Mix evenly. These were tableted in accordance with the above-mentioned preparation method of the three-layer preparation.

Example 6
As a support layer, 44.0 parts by weight of carboxymethyl ethyl cellulose (hereinafter abbreviated as “CMEC”) in an appropriate amount of methylene chloride / ethanol (1: 1), 44.0 parts by weight of ethyl cellulose, 10.0 parts by weight of triethyl citrate The mixture was stirred and dissolved, and 2.0 parts by weight of yellow iron sesquioxide was added and dispersed uniformly. This was spread on a PET film and dried to prepare a uniform film having a thickness of about 30 μm. Separately, as the adhesive layer 1), 25.1 parts by weight of hydroxypropyl cellulose, 25.1 parts by weight of polyvinylpyrrolidone, 5.8 parts by weight of polyethylene glycol 400, 1.1 parts by weight of iron sesquioxide, 0.6 parts by weight of sodium bicarbonate And 42.3 parts by weight of cevimeline hydrochloride hydrate were added and mixed uniformly. As the adhesive layer 2), 43.5 parts by weight of hydroxypropyl cellulose, 43.5 parts by weight of polyvinyl pyrrolidone, 10.0 parts by weight of polyethylene glycol 400, 2.0 parts by weight of titanium oxide, 1.0 part by weight of sodium bicarbonate Was added and mixed uniformly. These were tableted in accordance with the above-mentioned preparation method of the three-layer preparation.

Example 7
As a support layer, 80.0 parts by weight of HPMCAS, 5.0 parts by weight of white shellac, and 14.0 parts by weight of polyethylene glycol 400 were added to an appropriate amount of methylene chloride / ethanol (1: 1) and dissolved by stirring. 0.0 part by weight was added and dispersed uniformly, and this was spread on a PET film and dried to prepare a uniform film having a thickness of about 30 μm. Separately, as adhesive layer 1), HPMC 24.2 parts by weight, polyvinylpyrrolidone 24.2 parts by weight, polyethylene glycol 400 5.8 parts by weight, yellow iron sesquioxide 1.2 parts by weight, sodium bicarbonate 2.3 parts by weight, 42.3 parts by weight of cevimeline hydrochloride hydrate was added and mixed uniformly. As the adhesive layer 2), 42.0 parts by weight of HPMC, 42.0 parts by weight of polyvinylpyrrolidone, 10.0 parts by weight of polyethylene glycol 400, 2.0 parts by weight of titanium oxide, and 4.0 parts by weight of sodium bicarbonate were added. Mix evenly. These were tableted in accordance with the above-mentioned preparation method of the three-layer preparation.

Example 8
As a support layer, 80.0 parts by weight of HPMCAS, 5.0 parts by weight of ethyl cellulose and 14.0 parts by weight of polyethylene glycol 400 were added to an appropriate amount of methylene chloride / ethanol (1: 1) and dissolved by stirring. 0 part by weight was added and dispersed uniformly, and this was spread on a PET film and dried to prepare a uniform film having a thickness of about 30 μm. Separately, 35.0 parts by weight of HPMC, 35.0 parts by weight of polyvinyl pyrrolidone, 10.8 parts by weight of polyethylene glycol 400, 1.0 part by weight of yellow iron sesquioxide, 1.0 part by weight of triethanolamine, cevimeline hydrochloride as an adhesive layer 17.2 parts by weight of hydrate was added and mixed uniformly. These were tableted and molded according to the above-described preparation method of the bilayer preparation.

Example 9
As a support layer, 80.0 parts by weight of HPMCAS, 5.0 parts by weight of white shellac, and 14.0 parts by weight of polyethylene glycol 400 were added to an appropriate amount of methylene chloride / ethanol (1: 1) and dissolved by stirring. 0.0 part by weight was added and dispersed uniformly, and this was spread on a PET film and dried to prepare a uniform film having a thickness of about 30 μm. Separately, as the adhesive layer, HPMC 26.0 parts by weight, polyvinylpyrrolidone 26.0 parts by weight, polyethylene glycol 400 10.5 parts by weight, titanium oxide 1.0 parts by weight, triethanolamine 2.0 parts by weight, cevimeline hydrochloride hydrated 34.5 parts by weight of the product was added and mixed uniformly. These were tableted and molded according to the above-described preparation method of the bilayer preparation.

Example 10
As a support layer, 80.0 parts by weight of HPMCAS, 5.0 parts by weight of ethyl cellulose, and 14.0 parts by weight of polyethylene glycol 400 were added to an appropriate amount of methylene chloride / ethanol (1: 1) and dissolved by stirring. 0 part by weight was added and dispersed uniformly, and this was spread on a PET film and dried to prepare a uniform film having a thickness of about 30 μm. Separately, as the adhesive layer, HPMC 8.0 parts by weight, polyvinylpyrrolidone 8.0 parts by weight, polyethylene glycol 400 10.0 parts by weight, yellow iron sesquioxide 1.0 part by weight, triethanolamine 4.0 parts by weight, cevimeline hydrochloride 69.0 parts by weight of hydrate was added and mixed uniformly. These were tableted and molded according to the above-described preparation method of the bilayer preparation.

Example 11
As a support layer, 46.0 parts by weight of CMEC, 38.0 parts by weight of ethyl cellulose, and 15.0 parts by weight of triethyl citrate were added to an appropriate amount of methylene chloride / ethanol (1: 1) and dissolved by stirring. 0.0 part by weight was added and dispersed uniformly, and this was spread and dried on a PET film to prepare a uniform film having a thickness of about 30 μm. Separately, as adhesive layer 1), HPMC 25.1 parts by weight, polyvinylpyrrolidone 25.1 parts by weight, polyethylene glycol 400 5.8 parts by weight, yellow iron sesquioxide 1.1 parts by weight, triethanolamine 0.6 parts by weight, 42.3 parts by weight of cevimeline hydrochloride hydrate was added and mixed uniformly. As the adhesive layer 2), 43.5 parts by weight of HPMC, 43.5 parts by weight of polyvinylpyrrolidone, 10.0 parts by weight of polyethylene glycol 400, 2.0 parts by weight of titanium oxide, and 1.0 part by weight of triethanolamine were added. Mix evenly. These were tableted in accordance with the above-mentioned preparation method of the three-layer preparation.

As a control support layer, 80.0 parts by weight of hydroxyethyl cellulose, 10.0 parts by weight of polyvinyl pyrrolidone, and 9.0 parts by weight of polyethylene glycol 400 were added to an appropriate amount of distilled water, dissolved by stirring, and 1.0 part by weight of iron sesquioxide. Was uniformly dispersed and spread on a PET film and dried to prepare a uniform film having a thickness of about 30 μm. Separately, 44.5 parts by weight of hydroxypropyl cellulose, 44.5 parts by weight of polyvinyl pyrrolidone, 10.0 parts by weight of polyethylene glycol 400, and 1.0 part by weight of sodium hydrogen carbonate were added and mixed uniformly as an adhesive layer. These were tableted and molded according to the above-described preparation method of the bilayer preparation.

Test Example 1: Effect of pH and Additives on Drug Absorption from Human Oral Mucosa After healthy teeth volunteers brushed their teeth, each test solution (Examples 1 to 4) was garnished for 2 minutes, and the gargle was collected. The oral cavity was washed twice with 10 mL of distilled water for 10 seconds. All washings were added to the test solution after rinsing. The amount of cevimeline hydrochloride in the test solution before and after gargle was measured by HPLC, and the difference was calculated as the amount absorbed into the oral mucosa.

  FIG. 2 shows the effects of pH and additives on oral mucosal absorption of cevimeline hydrochloride hydrate. At pH 8.0, triethanolamine-hydrochloric acid buffer absorbs more than MaIlvaine buffer (mixture of 0.1 mol / L citric acid and 0.2 mol / L disodium hydrogen phosphate). The oral mucosa absorbability was good when the concentration was 1.5% rather than 0.3%. From these results, it was suggested that triethanolamine has an effect of promoting mucosal absorption of cevimeline hydrochloride hydrate. The absorption amount of cevimeline hydrochloride hydrate was higher at pH 8.0 than at pH 6.0.

Test Example 2: Promotion of salivary secretion in rats (oral mucosa administration)
Rats (Wistar strain, rabbit, 12 weeks old, body weight 195-240 g) were fixed in the dorsal position under urethane (1.25 g / kg ip) anesthesia. Prior to the start of the test, the oral saliva was sufficiently wiped with a paper wiper (trade name: Kimwipe) in advance, and after 15 minutes, it was cut again into 35 × 30 mm, and three rolled paper wipers (weighed in advance). ) Was used to adsorb saliva in the oral cavity (time 0). Immediately after that, the test preparation (Examples 5, 6, 8 to 10, control) was administered, and then saliva was adsorbed by the same operation every 15 minutes, and the saliva secretion amount was calculated. After the test was completed, the state of the preparation application site was observed. The saliva secretion amount was calculated as follows.
"Saliva volume (mg) = (paper wiper weight after saliva adsorption)-(paper wiper weight before saliva adsorption)"

  3 and 4 show the effect of the oral mucosal administration agent of cevimeline hydrochloride hydrate on salivary secretion in rats. Example 5 or 6 of the oral mucosa-adhesive preparation containing 1.25 mg of cevimeline hydrochloride hydrate showed a tendency to increase salivary secretion from 45 minutes or 60 minutes of application, respectively. In addition, Example 9 (containing 3.0 mg) or Example 10 (containing 6.0 mg), which are oral mucosal adhesion preparations, increased rat saliva secretion from 15 or 30 minutes after the treatment, respectively. Moreover, Example 9 (contained 3.0 mg) and Example 10 (contained 6.0 mg) recognized the clear difference in the salivary secretion promotion effect between preparations. After the test, the condition of the oral mucosa tissue at the applied site was observed with the naked eye, but no irritation was observed.

Test Example 3: Drug transfer to each tissue of rats (comparison between oral mucosal administration and oral administration)
Rats (Wistar strain, rabbit, 9 weeks old, body weight 172-205 g) were fixed in the dorsal position under urethane (1.25 g / kg ip) anesthesia. After administration of test drug, 0.5 and 1, 2, 4 and 8 hours later, plasma and each tissue (small salivary gland, stomach, small intestine, liver, kidney) for observing the state of the preparation application site and measuring the concentration in each tissue ) Was collected. The collected small salivary glands were rinsed with saline in the surface, and the stomach and small intestine were rinsed in saline except for the contents. Each collected tissue was stored at −40 ° C. until measurement. The drug concentration in each tissue was measured by LC / MS / MS. The oral mucosa patch of Example 9 was used for the test and compared with oral administration.

  FIGS. 5 to 11 show changes in the concentration of cevimeline hydrochloride hydrate in rat tissues during oral administration and oral mucosa administration. Oral mucosal administration had lower drug concentrations in the stomach, small intestine, kidneys and liver and less change in concentration compared to oral administration. In particular, the drug concentration in the stomach, small intestine, kidney and liver at the beginning of administration (˜2 hours) was clearly low. Moreover, the plasma concentration was small at the initial administration compared with oral administration, and thereafter remained at a constant low concentration. These results suggest that oral mucosal administration may suppress the occurrence of gastrointestinal side effects (nausea, abdominal pain, diarrhea, pollakiuria, etc.) that are presumed to occur depending on the high gastrointestinal tissue concentration. . Furthermore, oral mucosal administration was considered to be acting by the drug reaching directly from the oral mucosa, since the concentration in the small salivary gland as the target site was remarkably high. From the above results, it was found that cevimeline hydrochloride hydrate has high absorbability from the oral mucosa, and that oral mucosa administration acts on the target site more directly than oral administration. Furthermore, since the concentration in the digestive system tissue was low and mucosal irritation was not observed, it was revealed that the administration method was excellent in safety. In addition, the oral mucosal administration group was considered to have the possibility that the drug is swallowed and absorbed from the gastrointestinal tract in addition to the absorption from the oral mucosa, Since it was very low compared to oral administration, it was assumed that the effect of swallowing the oral mucosa-adhesive preparation was small in this study.

Formulation Example 1: Film-form preparation A film-form, paper-form, or oblate-form oral mucosa-administered preparation containing cevimeline hydrochloride hydrate is released in a wide range in the oral cavity and adhered onto the oral mucosa. It is a thin film capable of absorbing a drug from the oral mucosa. This preparation for oral mucosal administration is described in, for example, JP-A-2001-506612 and JP-A-2001-506640, and those skilled in the art can easily produce the above-mentioned preparation by referring to these publications. Can do. The entire disclosure of each publication is incorporated herein by reference.

Formulation Example 2: Ointment, Jelly The jelly and ointment containing cevimeline hydrochloride hydrate are semi-solid preparations that can absorb the drug from the applied oral mucosa, and are prepared with the following formulation, for example be able to.

Formulation Example 3: Aerosol The aerosol in a form filled with a spray can together with a propellant so that a solution or suspension containing cevimeline hydrochloride hydrate is sprayed can be applied to a wide range of oral mucosa. It is a preparation capable of absorbing a drug from the mucosa. This aerosol agent can be manufactured by the following prescription, for example.

Formulation Example 4: Gargle (water-soluble polymer-containing type)
A gargle in the form of a solution containing cevimeline hydrochloride hydrate or dissolved in an appropriate amount of solution as needed can be applied to a wide range of oral mucosa and can absorb the drug from the oral mucosa. It is a formulation. For example, it can be produced according to the following formulation. The gargle in powder form is dissolved by adding 20 to 150 mL of water to 150 mg of cevimeline hydrochloride hydrate, and this solution or suspension is divided into 1 to 5 times / day and contained in the mouth. Include min / times.

It is a schematic diagram of an oral mucosa-adhesive patch containing cevimeline hydrochloride hydrate as an active ingredient. It is a graph which shows the influence of the additive which acts on the oral mucosa absorption of cevimeline hydrochloride hydrate. In the figure, TEA represents triethanolamine, and HCl represents hydrochloric acid. It is the graph which showed the influence with respect to the salivary secretion of the rat of the oral mucosa administration agent containing cevimeline hydrochloride hydrate as an active ingredient. In the figure, the control is an oral mucosa-adhesive preparation (no cevimeline hydrochloride hydrate, base alone), and the example is an oral mucosa-adhesive preparation (cebimerin hydrochloride 1.25 mg administered / rat). It is the graph which showed the influence with respect to the salivary secretion of the rat of the oral mucosa administration agent containing cevimeline hydrochloride hydrate as an active ingredient. In the figure, the control is an oral mucosa-adhesive preparation (no cevimeline hydrochloride hydrate, base alone), and the examples are oral mucosa-adhesive preparations (cebimerin hydrochloride hydrate 1.5-6.0 mg administered / rat). It is a graph which shows the oral cavity mucosa administration agent and the concentration transition in rat stomach tissue of cevimeline hydrochloride at the time of oral administration. It is a graph which shows the oral cavity mucosa administration agent and the concentration transition in rat small intestine tissue of cevimeline hydrochloride at the time of oral administration. It is a graph which shows the oral cavity mucosa administration agent and the time course of cevimeline hydrochloride concentration in rat bladder tissue at the time of oral administration. It is a graph which shows an oral-mucosal administration agent and a rat kidney tissue density transition of cevimeline hydrochloride at the time of oral administration. It is a graph which shows an oral-mucosal administration agent and a rat liver tissue transition of cevimeline hydrochloride at the time of oral administration. 2 is a graph showing changes in rat plasma concentration of cevimeline hydrochloride during oral mucosal administration and oral administration. It is a graph which shows an oral-mucosal administration agent and the concentration transition in the rat small salivary gland tissue of cevimeline hydrochloride at the time of oral administration.

Claims (15)

The following general formula (I)
(In the formula, R ¹ and R ² may be the same or different and are each independently a hydrogen atom, an alkyl group, a cyclopentyl group, a cyclohexyl group, a monoaryl-substituted or diaryl-substituted methylol group, or an aryl-substituted alkyl group. The pharmaceutical of the oral mucosa administration form containing the spirooxathiolanquinuclidine derivative or its acid addition salt represented by this as an active ingredient. The medicament according to claim 1 for the prevention and / or treatment of dry mouth disease. The medicament according to claim 1 or 2, wherein the spirooxathiolane quinuclidine derivative is 2-methylspiro (1,3-oxathiolane-5, 3 'quinuclidine). The medicament according to claim 1 or 2, wherein the spirooxathiolane quinuclidine derivative is cis-2-methylspiro (1,3-oxathiolane-5,3 'quinuclidine). The medicament according to claim 1 or 2, wherein the active ingredient is 2-methylspiro (1,3-oxathiolane-5,3'quinuclidine) hydrochloride or a hydrate thereof. The medicament according to claim 1 or 2, wherein the active ingredient is cis-2-methylspiro (1,3-oxathiolane-5,3'quinuclidine) monohydrochloride 1/2 hydrate. The medicine according to any one of claims 1 to 6, which is in the form of a pharmaceutical composition containing a water-soluble or swellable polymer and / or a hydrophilic solvent. Water-soluble or swellable polymers are methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxymethylethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, xanthan gum, karaya gum, gum arabic, tragacanth gum, guar gum, gelatin, polyvinylpyrrolidone, One or two selected from the group consisting of polyvinyl alcohol, polyacrylic acid or metal salt thereof, carboxyvinyl polymer, alginic acid salt, propylene glycol alginate, pullulan, and lower alkyl vinyl ether / maleic anhydride copolymer and derivatives thereof The medicament according to claim 7, which is a polymer of more than one species. The water-soluble or swellable polymer is one or more polymers selected from the group consisting of methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxymethylethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and sodium carboxymethylcellulose. The pharmaceutical according to claim 7. The hydrophilic solvent is monoethanolamine, diethanolamine, triethanolamine, diisopropanolamine, triisopropanolamine, ethanol, isopropanol, glycerin, ethylene glycol, propylene glycol, 1,3-butylene glycol, N-methyl-2-pyrrolidone, 10. The solvent according to claim 7, wherein the solvent is one or more solvents selected from the group consisting of polyethylene glycol 300, polyethylene glycol 400, triethyl citrate, glycerin fatty acid ester, polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80. The medicine according to any one of the above. The hydrophilic solvent is one or two or more kinds of solvents selected from the group consisting of monoethanolamine, diethanolamine, triethanolamine, diisopropanolamine, and triisopropanolamine. Medicines. The pharmaceutical according to any one of claims 1 to 11, wherein the pH of the pharmaceutical composition is in the range of 6.5-9. The patch, sublingual agent, buccal agent, liquid agent, gargle, spray, aerosol, ointment, jelly, or film-form pharmaceutical composition according to any one of claims 1 to 12. Medicine. The oral mucosal patch according to any one of claims 1 to 12, which comprises (1) a water-insoluble support layer, and (2) a mucoadhesive adhesive layer laminated on the support layer. Medicine. The water-insoluble support layer is one or more selected from the group consisting of ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate, shellac, polyisobutylene, and polyisoprene. The medicine according to claim 14, comprising a substance and a mucoadhesive pressure-sensitive adhesive layer containing a water-soluble or swellable polymer and a hydrophilic solvent that are made sticky by moisture in the oral cavity.