JP2010100550A - Medicinal composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a medicinal composition exhibiting excellent effects for inhibiting rhinitis (such as allergic rhinitis symptom) and rhinorrhea without causing side effects (sleepiness or the like) of an antiallergic drug having antihistaminic actions as main actions. <P>SOLUTION: The medicinal composition contains a mediator-isolation inhibitor (amlexanox or the like) and an anticholinergic drug (bella donna total alkaloid or the like) as active ingredients. The medicinal composition is useful as a preventive and therapeutic drug (rhinitis symptom-ameliorating drug of the allergic rhinitis, cold or the like) against the rhinitis and the rhinorrhea. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a pharmaceutical composition that strongly improves nasal inflammation symptoms such as allergic rhinitis. More specifically, the present invention relates to a pharmaceutical composition that does not have a sleep sedative effect due to an antihistamine action and exhibits an immediate and powerful improvement against nasal inflammation symptoms such as allergic rhinitis.

  It is known that type I allergic diseases such as allergic rhinitis show a biphasic reaction of immediate phase reaction and late phase reaction. The immediate phase reaction in this type I allergic disease induces sneezing, rhinorrhea, and nasal congestion immediately after inducing an antigen such as pollen. On the other hand, the late-phase reaction is characterized by nasal congestion that reappears several hours after antigen induction. The "Nose Allergy Diagnosis Guidelines 2005", Life Science Co., Ltd. (Non-Patent Document 1) usually describes antihistamine or antihistamine action for the treatment of sneezing, rhinorrhea and nasal congestion due to allergic rhinitis. Anti-allergic drugs with the main action are prescribed. However, as described in Non-Patent Document 1, it is reported that antihistamines and antiallergic drugs mainly having an antihistamine action have a central inhibitory action and frequently cause side effects such as sleepiness. Has been.

  On the other hand, mediator release inhibitors such as amlexanox that suppress histamine release from mast cells are used as antiallergic agents that do not have antihistaminic action that causes side effects of sleepiness. However, as described in Non-Patent Document 1, since this release inhibitor is poor in immediate effect and relatively weak in inhibitory effect, prophylactic use such as initial treatment in hay fever and perennial allergic rhinitis Is recommended for mild treatment.

  Regarding pharmaceuticals containing mediator release inhibitors such as amlexanox, JP 2003-55221 (Patent Document 1) contains amlexanox and xanthines (caffeine, theophylline, etc.) and has improved stability to light. Compositions (especially aqueous compositions) are disclosed.

  JP-A-2000-95675 (Patent Document 2) describes a mouth containing a rhinitis therapeutic drug selected from parasympatholytic drugs, antihistamines, sympathomimetic drugs, antiallergic drugs, anti-inflammatory drugs and anti-inflammatory enzymes. Dissolved or chewable solid oral pharmaceutical compositions for the treatment of rhinitis are disclosed. This document also describes that caffeine may be further contained. Further, a formulation example containing chlorpheniramine maleate as an antihistamine, phenylpropanolamine hydrochloride as a sympathomimetic drug, belladonna total alkaloid as a parasympatholytic agent, and anhydrous caffeine is described. It is also described that a drug dissolves rapidly in a dissolution test using chlorpheniramine acid as an indicator component.

  JP 2001-233765 A (Patent Document 3) contains ibuprofen, antihistamine component, antitussive component (such as codeine phosphate), bronchodilator component (such as methylephedrine hydrochloride) and isopropamide iodide as antipyretic analgesic components. A common cold medicine is disclosed. In this document, chlorpheniramine maleate is exemplified as an antihistamine component, and amlexanox is exemplified. Isopropamide iodide is a component known as an anticholinergic agent. It is also described that it is blended as Further, it is also described that the common cold medicine may contain anticholinergic drugs (such as belladonna (total) alkaloids), central nervous excitatory components (such as caffeine), vitamin components, expectorant components, and the like. However, as described above, since it contains an antihistamine component, drowsiness occurs as a side effect. In addition, although amlexanox is illustrated as an antihistamine component, amlexanox does not have an antihistamine action.

However, a preparation combining a mediator release inhibitor (such as amlexanox) and an anticholinergic agent and its pharmacological activity are not known.
JP 2003-55221 A (Claims) JP 2000-95675 A (Claims, Example 1 and Test Example 1) JP 2001-233765 A (claims, paragraphs [0008] [0009] [0013]) “Nose Allergy Diagnosis Guidelines 2005”, Life Sciences Co., Ltd.

  Accordingly, an object of the present invention is to provide a pharmaceutical composition that exhibits no side effects due to antihistaminic activity and exhibits high antiallergic activity, or a rhinitis therapeutic agent such as allergic rhinitis and a rhinorrhea symptom therapeutic agent.

  Another object of the present invention is a pharmaceutical composition that has no central inhibitory action such as sleepiness due to antihistaminic action and has an immediate and powerful therapeutic effect on rhinitis (such as allergic rhinitis), or allergic rhinitis, etc. It is to provide a therapeutic agent for rhinitis and a therapeutic agent for rhinorrhea.

  As a result of intensive studies to solve the above problems, the present inventor has found that a pharmaceutical composition containing a mediator release inhibitor (such as amlexanox) and an anticholinergic drug (such as belladonna total alkaloid) as an active ingredient is attributed to an antihistaminic action. It can quickly and powerfully (especially synergistically) suppress allergic rhinitis and other nasal inflammation without causing the side effects of sleepiness, and is therefore useful for the treatment of rhinitis (allergic rhinitis, etc.) As a result, the present invention was completed.

  That is, the pharmaceutical composition of the present invention contains a mediator release inhibitor and an anticholinergic agent as active ingredients. The mediator release inhibitor may be, for example, amlexanox or a salt thereof. The anticholinergic agent is selected from the group consisting of, for example, belladonna total alkaloids, belladonna extract, atropine, homatropine, scopolamine, funnel extract, duck extract, isopropamide iodide, methylbenactidium bromide, and propanterin bromide or a salt thereof. It may be at least one kind.

  The pharmaceutical composition of the present invention is useful as a prophylactic / therapeutic agent for rhinitis (for example, allergic rhinitis, rhinitis symptoms in cold syndrome). For example, the pharmaceutical composition of the present invention can be used as a therapeutic agent for rhinitis such as allergic rhinitis in a preventive and preventive manner in order to effectively suppress symptoms of rhinitis (for example, allergic rhinitis). The pharmaceutical composition is also useful for the improvement of nasal inflammation symptoms in cold syndrome, particularly cold syndrome, and is also useful as a preventive and therapeutic agent for nasal discharge symptoms (eg, nasal discharge symptoms in nasal inflammation symptoms). .

  In the present specification, regarding a pharmaceutical composition, “including (or containing) a mediator release inhibitor and an anticholinergic agent” means a form containing both components of a mediator release inhibitor and an anticholinergic agent, a mediator It means both forms (kits, sets) in which a preparation containing a release inhibitor and a preparation containing an anticholinergic agent are combined. In the present specification, “pharmaceutical composition” may be used synonymously with “pharmaceutical formulation”.

  The pharmaceutical composition (such as a prophylactic / therapeutic agent for allergic rhinitis) of the present invention contains a mediator release inhibitor and an anticholinergic agent as active ingredients, and thus is excellent for rhinitis (allergic rhinitis symptoms, etc.) or rhinorrhea. Has a therapeutic effect. In addition, the pharmaceutical composition of the present invention is capable of suppressing central effects such as side effects caused by the prescription of antihistamines or antiallergic drugs mainly having antihistamine effects, for example, sleepiness caused by antihistamine actions that occur frequently. Has no effect. Therefore, safety and patient quality of life (QOL) can be significantly improved. In addition, the pharmaceutical composition of the present invention immediately and strongly suppresses nasal inflammation and rhinorrhea due to the synergistic effect of the combination of mediator release inhibitor and anticholinergic agent. Therefore, a sufficient therapeutic effect can be obtained for nasal inflammation symptoms and rhinorrhea symptoms more than moderate. Moreover, in addition to not exhibiting the side effects of sleepiness due to antihistamine action, it is possible to reduce the dose by a synergistic effect, and further improve QOL by improving medical economy, improving taste and / or taking ability. Improvement can be expected.

  In the present invention, as a mediator release inhibitor, an active ingredient having a production release inhibitory action of a chemical mediator (histamine, leukotriene) based on a type I allergic reaction and having a low antihistamine action (particularly no antihistamine action), for example, , Sodium cromoglycate, tranilast, amlexanox, repirinast, ibudilast, tazanolast, pemirolast potassium, etc., and salts thereof. Salts include inorganic acids (hydrochloric acid, nitric acid, sulfuric acid, etc.), organic acids (acetic acid, fumaric acid, maleic acid, etc.), inorganic bases (alkali metals such as ammonia, sodium, and potassium, alkaline earth metals such as calcium and magnesium) And a salt with an organic base (alkylamine etc.). These release inhibitors can be used alone or in combination of two or more.

  Of these release inhibitors, tranilast, amlexanox, and pemirolast potassium are practically preferred. In particular, the mediator release inhibitor is preferably a component having anti-asthma action and anti-allergic action based on the release inhibitory action and anti-leukotriene action, such as amlexanox. Amlexanox may be a free form or a salt (hydrochloride, nitrate, fumarate). Preferred amlexanox is free.

  An effective amount of a mediator release inhibitor (such as amlexanox or a salt thereof) is 0.1 to 1000 mg, preferably 0.5 to 500 mg (for example, 1 to 300 mg) per day in oral administration as a free form, Preferably it is about 10-300 mg (for example, 25-250 mg), especially about 50-200 mg (for example, 75-150 mg).

  While mediator release inhibitors have the advantage of having no side effects of sleepiness, they are disadvantageous in that they are slow-acting and relatively ineffective, and prevent prophylactic initial treatment of hay fever and perennial allergic rhinitis. Are recommended only for mild treatment. However, when mediator release inhibitors are combined with anticholinergic drugs, in addition to not exhibiting drowsiness side effects due to antihistamine action, synergistic nasal inflammation (eg, nasal inflammation with rhinorrhea) and nasal Improve leakage symptoms. Therefore, a high therapeutic effect can be obtained even for nasal inflammation symptoms of moderate symptoms or higher, and the application range of mediator release inhibitors can be expanded.

  As an anticholinergic agent, parasympathetic blockade, for example, natural alkaloids (plant alkaloids contained in belladonna, funnel, datsura, hyos, etc., eg, belladonna total alkaloids, belladonna extract, atropine, scopolamine, funnel extract, datsura extract, etc.) Natural alkaloid derivatives such as scopolamine derivatives (such as N-methyl scopolamine methylsulfate and butyl scopolamine bromide) and atropine derivatives (such as methyl atropine); amprotropin, adiphenine, dicyclomine; Xiphenidyl, Lepodova; Homatropin, Oikatropin, Tropicamide, Methylatropine, Cyclopentrate; Isopropamide iodide, Methylbenactidium bromide, Propa bromide Terin, methyl anisotropin bromide, papaverine hydrochloride, oxapium iodide, valetamate bromide, piperidate hydrochloride, butropium bromide, trepibutone, trospium chloride, etomidrine, timipedium bromide, tiquidium bromide, prifinium bromide, ethyl pipeteta bromide In addition to narate, thiemonium iodide, dicycloberine hydrochloride, furopropion, ipratropium bromide, flutropium bromide, oxitropium bromide and the like, these salts (pharmaceutically acceptable salts) and the like can be exemplified. Salts include inorganic acids (hydrochloric acid, nitric acid, sulfuric acid, etc.), organic acids (acetic acid, fumaric acid, maleic acid, etc.), inorganic bases (alkali metals such as ammonia, sodium, and potassium, alkaline earth metals such as calcium and magnesium) And a salt with an organic base (alkylamine etc.). The anticholinergic drug (natural alkaloids and the like) may be an optically active form (d-form, 1-form etc.), dl-form (racemic form) and the like. These anticholinergic agents can be used alone or in combination of two or more.

  Among these anticholinergics, natural alkaloids (such as belladonna total alkaloids, belladonna extract, atropine, scopolamine, funnel extract, duck extract, etc.), isopropamide iodide, methylbenactidium bromide, propantheline bromide, or salts thereof Is practically preferred. In particular, natural alkaloids (such as belladonna total alkaloids) and isopropamide iodide are preferred.

  The effective amount of the anticholinergic agent is in a wide range depending on the type, for example, 0.01 to 200 mg, preferably 0.1 to 150 mg, more preferably about 0.2 to 100 mg as a daily dose in oral administration. You can choose from a range of More specifically, as a daily dose in oral administration, for belladonna total alkaloid, for example, 0.01 to 10 mg (for example, 0.03 to 5 mg), preferably 0.05 to 2 mg, particularly 0.1 About 1 mg (for example, 0.2 to 0.6 mg). For belladonna extract and funnel extract, for example, 5 to 200 mg, preferably about 10 to 100 mg, for atropine, homatropine and scopolamine, for example, 0.1 to 2.0 mg, preferably about 0.3 to 1.0 mg, for datsura extract For example, about 0.1 to 2.0 mg, preferably about 0.3 to 1.0 mg. For isopropamide iodide, for example, about 1 to 50 mg, preferably about 2 to 10 mg, methylbenactidium bromide and propane bromide In the case of terin, it is, for example, about 5 to 200 mg, preferably about 10 to 100 mg.

  In the pharmaceutical composition of the present invention, the compounding ratio of the mediator release inhibitor (such as amlexanox) and the anticholinergic is, for example, 0.00025 to 1000 mediator release inhibitor (such as amlexanox) per 1 part by weight of the anticholinergic drug. Parts by weight (for example, 0.0025 to 500 parts by weight), preferably 0.01 to 400 parts by weight (for example, 0.1 to 350 parts by weight), more preferably 1 to 300 parts by weight (for example, 5 to 300 parts by weight). Part), usually about 10 to 350 parts by weight (for example, 50 to 300 parts by weight).

  The pharmaceutical composition may contain other active ingredients. Examples of active ingredients include antipyretic analgesics or antipyretic analgesics, anti-inflammatory drugs, antitussives, expectorants, antitussive expectorants, antiasthma drugs, bronchodilators, antacids or mucosal protective drugs, antiallergic drugs, Examples include sympathomimetic drugs or α receptor stimulants, anti-inflammatory enzyme drugs, central nervous stimulants, crude drugs, gastric drugs, digestive drugs, vitamins, minerals, and the like.

  These active ingredients can be used alone or in combination of two or more. The pharmaceutical composition of the present invention is at least one selected from antipyretic analgesics, antitussives, bronchodilators, xanthines (for example, antipyretic analgesics, antitussives, bronchodilator components, or xanthines, Alternatively, all of the above components may not be included. In addition, the pharmaceutical composition of the present invention exhibits a high therapeutic effect on nasal inflammation and rhinorrhea even without an agent having an antihistamine action (such as an antihistamine).

  The pharmaceutical composition (pharmaceutical preparation) of the present invention may be various administration preparations such as solid preparations, semi-solid preparations, liquid preparations and the like. The solid preparation may be a tablet, pill, fine granule or granule, powder, capsule, chewable tablet and the like, and the solid preparation may be a film coating agent such as a film-coated tablet (sugar-coated tablet). Semi-solid preparations may be creams, jellies, ointments, gels, poultices and the like. The liquid preparation may be a liquid, an elixir, a suspension, an emulsion, a syrup, a drink and the like. Furthermore, the pharmaceutical composition may be a preparation for oral or parenteral administration. Oral preparations (internal use etc.) may be the above-mentioned solid preparations or liquid preparations, and parenteral administration preparations are external preparations such as nasal drops and eye drops in the form of sprays, liquids and the like. Alternatively, it may be a transdermal administration agent (ointment, cream, patch, etc.).

  The pharmaceutical composition (pharmaceutical preparation) of the present invention can be prepared using a carrier component or an additive. In solid preparations, excipients, binders, disintegrants and the like are usually used as carrier components or additives. Examples of excipients include sugar alcohols such as D-mannitol, D-sorbitol, erythritol, and xylitol, sugars such as lactose, glucose, fructose, sucrose, and powdered reduced maltose water candy, crystalline cellulose, powdered cellulose, potato starch, Corn starch, dextrin, β-cyclodextrin, carmellose sodium, light anhydrous silicic acid, hydrous silicon dioxide, silicon dioxide, precipitated calcium carbonate, anhydrous calcium hydrogen phosphate, magnesium oxide, titanium oxide, calcium lactate, aluminate metasilicate Examples thereof include magnesium, synthetic hydrotalcite, talc, and kaolin. Examples of the binder include cellulose derivatives such as methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, crystalline cellulose, polyvinyl alcohol, polyvinyl pyrrolidone (povidone), vinyl pyrrolidone copolymer (copolyvidone), Examples include acrylic polymer, gelatin, gum arabic, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol alginate, sucrose, and the like. Examples of the disintegrant include carmellose, carboxymethylcellulose calcium (carmellose calcium), croscarmellose sodium, low-substituted hydroxypropylcellulose (L-HPC), crospovidone, corn starch, hydroxypropyl starch, partially pregelatinized starch, Examples include alginic acid and bentonite.

  Other carrier components or additives include lubricants (stearic acid, magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, glycerin fatty acid ester, hydrogenated oil, polyethylene glycol, dimethylpolysiloxane, beeswax, white beeswax, etc. ); Antioxidants (dibutylhydroxytoluene (BHT), propyl gallate, butylhydroxyanisole (BHA), tocopherol, citric acid, etc.); preservatives (paraoxybenzoates, etc.); coloring agents (turmeric extract, riboflavin) , Carotene solution, tar pigments, caramel, titanium oxide, bengara, etc.); flavoring agents (sweeteners such as aspartame, ascorbic acid, stevia, menthol, licorice crude extract, simple syrup, etc.); surfactants (polyoxyethylene) Castor oil, glyceryl monostearate, sorbitan fatty acid esters (such as sorbitan monostearate, sorbitan monolaurate), polyoxyethylene polyoxypropylene, polysorbates, sodium lauryl sulfate, macrogol, sucrose fatty acid esters, etc.) Agents (light anhydrous silicic acid, talc, hydrous silicon dioxide, etc.); Plasticizers (triethyl citrate, polyethylene glycol, triacetin, cetanol, etc.); Sweeteners or flavoring agents (sucrose, mannitol, D-sorbitol, xylitol, aspartame) Natural or synthetic sweeteners such as); flavoring agents or fragrances (such as menthol); pigments, cooling agents, preservatives or preservatives, adsorbents, wetting agents, antistatic agents and the like.

  In the coating preparation (eg, coated tablet), the coating base is a water-soluble base such as hydroxypropylmethylcellulose (hypromellose), hydroxypropylcellulose, methylcellulose, povidone, copolyvidone, polyvinyl alcohol, polyvinyl alcohol copolymer, macrogol, etc. Water-insoluble bases such as ethyl cellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate, methacrylic acid copolymer, acrylic acid copolymer, carboxyvinyl polymer, etc. Enteric base, polyvinyl acetal diethylaminoa Tate, aminoalkyl methacrylate copolymer, gastric base such as polyvinyl acetate diethylamino acetate, gum arabic, pullulan, carnauba wax, shellac, macrogols, glycerol fatty acid ester, such as magnesium stearate can be exemplified. These coating bases can be used alone or in combination of two or more. The coating layer may be formed in one layer or a plurality of layers. Preferred coating bases are hydroxypropyl methylcellulose and polyvinyl pyrrolidone polymers (povidone, copolyvidone, etc.). The coating agent may further contain additives such as a filler, a lubricant, a masking agent, a plasticizer, and a colorant as necessary.

  Solid preparations can be produced by conventional methods. The active ingredient (mediator release inhibitor, anticholinergic agent, etc.) and carrier component may be mixed to prepare a powder. Usually, the active ingredient and carrier component are granulated, and if necessary, the granulated product is prepared. A granule (fine granule or granule) is prepared by granulation, or a bare tablet can be prepared by tableting a mixture containing a granulated product (particularly, a mixture of the granulated product and a carrier component). Capsules can be prepared by filling capsules with the granules.

  Granulation can be performed by a conventional method such as a stirring granulation method, a fluidized bed granulation method, an extrusion granulation method, or a dry granulation method. A preferred granulation method is a fluidized bed granulation method. In granulation, the active ingredient and the carrier component are often granulated using a solution containing a binder. For example, by spraying a solution containing the binder on the fluidized bed of the active ingredient and the carrier component. Can be granulated. The coating preparation can be obtained by spraying a coating agent containing a coating base onto an uncoated preparation (elementary granule, plain tablet, etc.) using a film coating machine.

  In the liquid preparation, an aqueous medium (purified water, ethanol-containing purified water, etc.), alcohols (ethanol, glycerin, etc.), a water-soluble polymer, etc. can be used as the carrier component. As the carrier component, purified water, ethanol-containing purified water and the like are often used. As the carrier component of the semi-solid preparation, an oily base (lipid such as vegetable oil, petrolatum, liquid paraffin, etc.), a hydrophilic base (emulsion base) and the like can be used. In liquid preparations and semi-solid preparations, additives include disintegration aids, antioxidants or antioxidants, surfactants, emulsifiers, dispersants, suspension agents, solubilizers, thickeners, pH adjusters. Agent or buffer, preservative or preservative (such as parabens), bactericidal agent or antibacterial agent, antistatic agent, corrigent or masking agent (eg sweetener), refreshing agent, colorant or pigment, flavoring agent Or a fragrance | flavor etc. are mentioned.

  The liquid preparation can be prepared by dissolving or dispersing each component in a carrier component, filtering or sterilizing if necessary, and filling a predetermined container. A semi-solid preparation can also be prepared by a conventional method, for example, by mixing each component and a carrier component, sterilizing if necessary, filling a predetermined container, or applying to a substrate.

  The pharmaceutical composition (pharmaceutical preparation) of the present invention comprises (1) a preparation containing two components (or a packaging form in which the preparation is accommodated or packaged) among mediator release inhibitors and anticholinergic agents, or (2) each component. May be two preparations (or a packaging form in which the two preparations are individually accommodated or packaged).

  The pharmaceutical composition and pharmaceutical preparation of the present invention can be applied to mammals (humans, dogs, cats, pigs, horses, cows, rabbits, rats, etc.), birds and the like, and are suitable for administration to humans. The dosage of the composition and preparation of the present invention can be selected according to the degree of symptoms, age, sex, body weight, route of administration and the like.

  The composition and the preparation of the present invention can be administered once or divided into a plurality of times (for example, 2 to 6 times) per day.

  The pharmaceutical composition of the present invention is useful for the treatment of nasal inflammation and rhinorrhea without showing side effects such as sleepiness due to antihistaminic action. Especially, it is suitable for the treatment or prevention of rhinitis accompanied by rhinorrhea (allergic rhinitis, nasal inflammation symptoms of cold syndrome) in order to suppress rhinorrhea symptoms such as rhinitis (allergic rhinitis etc.) very strongly. Yes. Therefore, the pharmaceutical composition of the present invention can be used as a nasal inflammation improving agent and a rhinorrhea symptom improving agent.

  Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited to these examples.

Example 1 (tablets)
Hydroxypropyl cellulose solution (HPC-L) in which Belladonna total alkaloid (2.4 g) was dissolved in 600 g of amlexanox, 1377.6 g of lactose, and 240 g of corn starch using a fluidized bed granulator ("MP-10" manufactured by Paulec Co., Ltd.). The solid content was sprayed and granulated by a conventional method. The granulated powder (2292 g) is sized (Power Mill: “P-3 type” manufactured by Showa Chemical Machinery Co., Ltd.), and 80 g of ECG505 and 10 g of magnesium stearate are added to and mixed with 1910 g of the sized powder. (Tumbler mixer: "TM-15 type" manufactured by Showa Chemical Machinery Co., Ltd.) and used as a tableting powder. This tableting powder was tableted using a rotary tableting machine (“Collect 19K” manufactured by Kikusui Seisakusho Co., Ltd.) to produce an uncoated tablet of 200 mg / tablet.

Example 2 (powder)
250 g of amlexanox, 219 g of mannitol, 100 g of crystalline cellulose, 100 g of corn starch, and 100 g of ECG505 were charged into a vertical granulator (manufactured by POWREC Co., Ltd.), and a hydroxypropyl cellulose solution (HPC-L solid content 30 g) in which belladonna total alkaloid (1 g) was dissolved. ) And stirring granulation was carried out by a conventional method. And it wet-sized (power mill: Showa Chemical Machinery Co., Ltd. "P-3 type"), and dried using the fluidized bed dryer (Paurec Co., Ltd. "MP-10"). Thereafter, the size was adjusted (power mill: “P-3 type” manufactured by Showa Chemical Machinery Co., Ltd.) to produce a sieved powder.

Example 3 (granule)
250 g of amlexanox, 219 g of mannitol, 100 g of crystalline cellulose, 100 g of corn starch, and 100 g of ECG505 were charged into a vertical granulator (manufactured by POWREC Co., Ltd.), and a hydroxypropyl cellulose solution (HPC-L solid content 30 g) in which belladonna total alkaloid (1 g) was dissolved. ) And stirring granulation was carried out by a conventional method. Then, extrusion granulation (Dome Gran: manufactured by Fuji Powder Co., Ltd.) and ball making (Malmerizer: manufactured by Fuji Powder Co., Ltd.) were performed, and a fluidized bed dryer ("MP-10" manufactured by POWREC Co., Ltd.). Granules were made by drying using sieving and sieving.

Test Example 1: Toluene 2,4-diisocyanate (hereinafter referred to as TDI) -induced guinea pig rhinorrhea induction test Test materials and methods 1.1. Test substances, media and reagents Amlexanox (manufactured by Takeda Pharmaceutical Co., Ltd.) and Belladonna Total Alkaloid (manufactured by Alps Pharmaceutical Industries, Ltd.) are both refrigerated and protected from light in the test substance storage room of the test facility. The one stored in step 1 was used.

The medium was prepared with Metroles ^R 60 SH-50 (hereinafter, HPMC: manufactured by Shin-Etsu Chemical Co., Ltd.) and water for injection (manufactured by Otsuka Pharmaceutical Factory). That is, the medium (0.5% HPMC) and the required amount of HPMC were weighed with an electronic balance ("PM2500" manufactured by METTLER TOLEDO Co., Ltd.) and then stirred with water for injection to a concentration of 0.5 w / v%. Prepared by dissolving. HPMC was stored in the test substance storage room in the test facility, and water for injection was stored in the test substance storage room in the test facility at room temperature.

  TDI (Tokyo Chemical Industry Co., Ltd.) and ethyl acetate (Wako Pure Chemical Industries, Ltd.) were used. After purchase, the TDI was stored refrigerated and the ethyl acetate was stored at room temperature and light-shielded in the test substance storage room of the test facility.

1.2. Preparation of administration sample Preparation of medium (0.5% HPMC) is carried out so that the necessary amount of HPMC is weighed (electronic balance: PM2500, METTLER TOLEDO Co., Ltd.), and then the concentration is 0.5 w / v% with water for injection. The solution was stirred and dissolved. The prepared 0.5% HPMC was stored in the storage of the test substance storage room under refrigerated conditions and used within 8 days after preparation.

  Preparation of amlexanox (manufactured by Takeda Pharmaceutical Co., Ltd.) and belladonna total alkaloid (manufactured by Alps Pharmaceutical Co., Ltd.) are both weighed with an electronic balance ("AT250" manufactured by METTLER TOLEDO Co., Ltd.) Gradually 0.5% HPMC was added and suspended to adjust the target concentration. In addition, for the samples for combined administration of amlexanox and belladonna total alkaloids, suspensions each having a double concentration were prepared and mixed at a weight ratio of 1: 1.

  The reagent (TDI solution) was prepared by weighing a required amount of TDI (manufactured by Tokyo Chemical Industry Co., Ltd.) with an electronic balance (“AT250” manufactured by METTLER TOLEDO Co., Ltd.), and then ethyl acetate (Wako Pure Chemical Industries, Ltd.). ))) To a predetermined concentration.

  All samples were prepared before use, and the remaining administered samples were discarded.

1.3. Test animals and rearing conditions The animals were 3 week-old Kwl: Hartley male guinea pigs (SPF: Kiwa Laboratory Animal Research Institute), which are widely used as animals for allergic rhinitis models.

  Obtained animals had a quarantine period of 5 days followed by a 28 or 29 acclimation period. During this time, we measured the body weight (electronic balance: PG2002-S, METTLER TOLEDO Co., Ltd.) six times and observed the general condition every day for quarantine and acclimatization, and group animals with no change in weight and general condition. Used separately.

1.4. Grouping method After grouping the weights into groups on the day of grouping, the average body weight and the average amount of nasal discharge in each group were approximately equal by the random sampling method. The remaining animals after grouping were discarded on the day of grouping, and the animals for measurement were discarded after being lethal from the abdominal aorta under diethyl ether anesthesia after completion of the measurement.

1.5. Individual identification Identification was made by writing a quarantine / acclimated animal number on the ear with oil-based ink on the date of acquisition. After grouping, they were identified using a dye coating method with oil-based ink. Label each cage with the test number, date of acquisition, quarantine / acclimated animal number during the quarantine / acclimation period, and enter the test number, test substance name, and animal number after grouping. A color-coded label was attached.

2. Test method 2.1. Sensitization and induction Sensitization starts on day 5 of habituation (sensitization day 1), and is applied to both nasal vestibules by applying a thin-shaft swab soaked in 10% TDI solution for 10 seconds. Was repeated once a day for 5 days.

  Induction was induced on day 26 of sensitization and day 32 of sensitization by contacting a thin-axis bar immersed in the TDI solution for provocation for 10 seconds to both nasal vestibules. The nasal discharge leaked in 15 minutes from the start of induction was absorbed into tissue paper, and placed in a sealed microtube, and the weight was measured. The amount of nasal discharge was calculated by subtracting the gauze and tube weights weighed in advance. All animals were fasted for 18 hours or more from the day before induction on the 32nd day of sensitization.

2.2. General condition observation and body weight measurement During the sensitization period, the general condition is observed once a day (from 7 am to 1 pm), and the sensitization is performed on the 1st, 8th, 15th, 22nd, Body weight measurements were performed on the 26th, 31st and 32nd days.

2.3. Administration The test substance was administered orally according to the clinical application route using a polypropylene disposable syringe fitted with a feeding tube. The amount of liquid to be administered was calculated at 5 mL / kg based on the body weight close to the administration day, and was administered once 60 minutes before induction between 9:00 am and 15:00 on the last induction day.

  The reagent (TDI solution) was administered from the nasal cavity with a thin shaft swab in contact with the nasal vestibule for 10 seconds.

3. Statistical methods and results After calculating the average value and standard error of the vehicle group for the amount of nasal discharge, the inhibition rate (%) of each individual nasal discharge amount of the test drug administration groups 1 to 3 with respect to the vehicle group average value was calculated. . Furthermore, the average value and standard error (mean ± se) of the inhibition rate (%) of the test drug administration groups 1 to 3 were calculated. In the significant difference test, two groups of the test drug administration group 1 and the test drug administration group 3 and two groups of the test drug administration group 2 and the test drug administration group 3 were compared. That is, the F-test for equivariance is performed at a significance level of 5%. If significant, the Aspin-Welch t-test is performed. If not significant, the Student t-test is performed at a significance level of 10% (*), 5% (**). ), 1% (***) (both sides).

  The results are shown in the tables and figures together with the group composition and the number of animals in the test examples. In addition, in FIG. 1, the suppression rate (%) of the test drug administration groups 1-3 with respect to the TDI induction | guidance | derivation guinea pig rhinorrhea reaction is shown by the average value +/- standard deviation.

  As is apparent from the tables and figures, compared to test drug administration group 1 (amlexanox alone group) or test drug administration group 2 (belladonna total alkaloid group), test drug administration group 3 (combination group of amlexanox and belladonna total alkaloid) Was found to significantly enhance the inhibitory effect on the rhinorrhea reaction. In addition, the degree of suppression of rhinorrhea in test drug administration group 3 (amlexanox and belladonna total alkaloid combination group) was compared with test drug administration group 1 (amlexanox alone group) or test drug administration group 2 (belladonna total alkaloid group). As a result, it was shown to be extremely powerful and almost completely suppress the nasal discharge.

FIG. 1 is a graph showing the results of Test Example 1.

Claims (7)

  A pharmaceutical composition comprising a mediator release inhibitor and an anticholinergic agent.   The pharmaceutical composition according to claim 1, wherein the mediator release inhibitor is amlexanox or a salt thereof.   The anticholinergic agent is at least one selected from the group consisting of belladonna total alkaloids, belladonna extract, atropine, homatropine, scopolamine, funnel extract, duck extract, isopropamide iodide, methylbenactidium bromide and propantherine bromide or a salt thereof. The pharmaceutical composition according to claim 1 or 2.   The pharmaceutical composition according to any one of claims 1 to 3, which is a preventive and therapeutic drug for rhinitis.   The pharmaceutical composition according to any one of claims 1 to 3, which is a prophylactic and therapeutic drug for allergic rhinitis.   The pharmaceutical composition according to any one of claims 1 to 3, which is a preventive and therapeutic drug for nasal inflammation in cold syndrome.   The pharmaceutical composition according to any one of claims 1 to 3, which is a prophylactic and therapeutic drug for rhinorrhea.

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