JP2014094893A - Stable pharmaceutical composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a stable pharmaceutical composition containing loxoprofen or salt thereof and scopolamine butylbromide.SOLUTION: A pharmaceutical composition contains loxoprofen or salt thereof, scopolamine butylbromide, and metal oxide.

Description

  The present invention relates to a stable pharmaceutical composition. More particularly, it relates to a stable pharmaceutical composition containing loxoprofen or a salt thereof and butyl scopolamine bromide.

  Loxoprofen is a type of non-steroidal anti-inflammatory analgesic (NSAID), including rheumatoid arthritis, osteoarthritis, low back pain, shoulder periarthritis, cervical-shoulder arm syndrome, toothache, acute upper respiratory inflammation, post-surgical / post-traumatic It is known as effective for anti-inflammatory, analgesic and antipyretic after tooth extraction (Non-patent Document 1). Loxoprofen is a compound that has recently been converted to so-called switch OTC, and is expected as an active ingredient in OTC pharmaceuticals.

However, loxoprofen is also a kind of NSAIDs, and as a side effect, there is a possibility that disorders due to increased gastrointestinal motility may occur.
Therefore, from the viewpoint of taking measures to reduce side effects while obtaining sufficient antipyretic analgesic effect, it has been proposed to take butyl scopolamine bromide having analgesic / antispasmodic action together with loxoprofen, and a formulation containing loxoprofen and butyl scopolamine bromide As such, a capsule containing these two components is known (Patent Document 1).

  However, in Patent Document 1, no study is made regarding the stability of the capsule, and it is not known at all that loxoprofen or a salt thereof and butyl scopolamine bromide interact.

JP 2000-26313 A

Fifteenth revised Japanese Pharmacopoeia explanation book Yodogawa Shoten Co., Ltd. C-4790-4759

First, the present inventor studied to make a pharmaceutical composition containing loxoprofen or a salt thereof and butyl scopolamine bromide as a solid preparation.When loxoprofen or a salt thereof and butyl scopolamine bromide are mixed and stored, surprisingly, It has been found that an interaction occurs between these compounds, the mixture is solidified by this interaction, and it is difficult to maintain a stable state during storage.
Accordingly, an object of the present invention is to provide a stable pharmaceutical composition containing loxoprofen or a salt thereof and butyl scopolamine bromide.

  Therefore, in order to solve the above-mentioned problems, the present inventor has intensively studied the storage stability of a pharmaceutical composition containing loxoprofen or a salt thereof and butyl scopolamine bromide, and in addition to these two compounds, a xanthine derivative, tranexam Loxoprofen or a salt thereof by coexisting at least one selected from the group consisting of an acid or a salt thereof, a silicic acid compound, a carbonic acid compound, a phosphoric acid compound, a hydroxide, a metal oxide, and a cellulose derivative or a salt thereof It was found that the interaction with butyl scopolamine bromide was suppressed, and the present invention was completed.

  That is, the present invention includes loxoprofen or a salt thereof, butyl scopolamine bromide, xanthine derivative, tranexamic acid or a salt thereof, silicic acid compound, a carbonic acid compound, a phosphoric acid compound, a hydroxide, a metal oxide, and a cellulose derivative or a salt thereof. The present invention provides a pharmaceutical composition containing one or more selected from the group consisting of:

  Moreover, this invention provides the pharmaceutical formulation containing the said pharmaceutical composition and a desiccant.

  In the present invention, one or more selected from the group consisting of xanthine derivatives, tranexamic acid or salts thereof, silicic acid compounds, carbonic acid compounds, phosphoric acid compounds, hydroxides, metal oxides and cellulose derivatives or salts thereof. In the pharmaceutical composition, the interaction between loxoprofen or a salt thereof and butyl scopolamine bromide can be improved. Therefore, according to the present invention, a pharmaceutical composition comprising loxoprofen or a salt thereof and butyl scopolamine bromide having excellent storage stability can be provided.

The pharmaceutical composition of the present invention comprises loxoprofen or a salt thereof, butyl scopolamine bromide, a xanthine derivative, tranexamic acid or a salt thereof, a silicic acid compound, a carbonic acid compound, a phosphoric acid compound, a hydroxide, a metal oxide and a cellulose derivative or 1 type, or 2 or more types chosen from the group which consists of the salt.
Hereinafter, each component used in the present invention will be described.

  Loxoprofen or a salt thereof used in the pharmaceutical composition of the present invention includes loxoprofen itself, a pharmaceutically acceptable salt of loxoprofen, and further a solvation of loxoprofen or a pharmaceutically acceptable salt thereof with water, alcohol or the like. Things are also included. These are known compounds, and can be produced by known methods, or commercially available products can be used. In the present invention, loxoprofen or a salt thereof is preferably loxoprofen sodium hydrate (chemical name: Monosodium 2- [4-[(2-oxocyclopentyl) methyl] phenyl] propanoate dihydrate).

The content of loxoprofen or a salt thereof in the pharmaceutical composition of the present invention may be determined by appropriately examining the daily dose according to the sex, age, symptoms, etc. of the user. For example, in terms of loxoprofen sodium anhydride, the amount that can be taken 10 to 300 mg of loxoprofen or a salt thereof is preferable, the amount that can be taken 30 to 240 mg is more preferable, and the amount that can be taken 60 to 180 mg is more preferable. In Japan, the daily dose may be divided into 1 to 4 doses, preferably 3 divided doses. As a single dose, 60 mg of loxoprofen sodium anhydride is preferable.
Moreover, as content of loxoprofen or its salt, it is preferable to contain 0.4-90 mass% in conversion of a loxoprofen sodium anhydride with respect to the pharmaceutical composition total mass of this invention, and 1.2-50 mass% It is more preferable to contain, it is more preferable to contain 3-40 mass%, and it is especially preferable to contain 5-40 mass%.

  The butyl scopolamine bromide used in the pharmaceutical composition of the present invention is a known compound, and can be produced by a known method or can be commercially available.

  The content of butyl scopolamine bromide in the pharmaceutical composition of the present invention may be determined by appropriately examining the daily dose according to the sex, age, symptoms, etc. of the user. As scopolamine bromide, an amount that can be taken from 3 to 1000 mg is preferred, an amount that can be taken from 5 to 500 mg is more preferred, and an amount that can be taken from 30 to 100 mg per day is even more preferred. The daily dose may be divided into 1 to 5 doses, and is preferably divided into 3 doses. The dose per dose is preferably 10 to 20 mg at a time, more preferably 10 mg and 20 mg as butyl scopolamine bromide.

The content ratio of loxoprofen or a salt thereof and butyl scopolamine bromide contained in the pharmaceutical composition of the present invention may be appropriately determined and determined according to the daily dose of each component described above. Alternatively, those containing 0.01-100 parts by mass of butyl scopolamine bromide are preferred, and those containing 0.02-20 parts by mass are more preferred, relative to 1 part by mass of the salt (in terms of sodium loxoprofen).
Moreover, as content of butyl scopolamine bromide, what contains 1-10 mass% with respect to the pharmaceutical composition total mass of this invention is preferable, what contains 2-8 mass% is more preferable, 3-7 mass% What is contained is more preferable.

  Hereinafter, “xanthine derivative, tranexamic acid or salt thereof, silicic acid compound, carbonate compound, phosphate compound, hydroxide, metal oxide and cellulose derivative or salt thereof used in the pharmaceutical composition of the present invention” 1 type or 2 types or more ”will be described.

  The xanthine derivative used in the pharmaceutical composition of the present invention is preferably a compound represented by the following general formula (I).

[Wherein, R ₁ and R ₂ each independently represent a hydrogen atom or a methyl group. R ₃ represents a hydrogen atom, a methyl group, a monohydroxypropyl group or a dihydroxypropyl group. ]

In R ₃ described above, the monohydroxypropyl group is preferably a 2-hydroxypropyl group. The dihydroxypropyl group is preferably a 2,3-dihydroxypropyl group.

In the general formula (I),
(1) R ₁ is a methyl group, R ₂ is a methyl group, and R ₃ is a methyl group means caffeine.
(2) R ₁ is a methyl group, R ₂ is a methyl group, and R ₃ is a hydrogen atom means theophylline.
(3) R ₁ is a hydrogen atom, R ₂ is a methyl group, and R ₃ is a methyl group means theobromine.
(4) R ₁ is a methyl group, R ₂ is a hydrogen atom, and R ₃ is a methyl group means paraxanthine.
(5) A compound in which R ₁ is a methyl group, R ₂ is a methyl group, and R ₃ is a 2-hydroxypropyl group means proxyphylline.
(6) The case where R ₁ is a methyl group, R ₂ is a methyl group, and R ₃ is a 2,3-dihydroxypropyl group means diprofylline.

The compounds of the general formula (I), especially the above-mentioned compounds are known, and in the present invention, commercially available products can be used in addition to those produced by known methods.
In addition, as the caffeine and theophylline, those in which a double salt is formed (sodium benzoate caffeine (double salt of sodium benzoate and caffeine), aminophylline (double salt of theophylline and ethylenediamine)) or the like may be used. it can.

  As the xanthine derivative used in the pharmaceutical composition of the present invention, caffeine is preferable from the viewpoint of using the pharmaceutical composition of the present invention as an antipyretic analgesic or a general cold medicine. Specific examples of the caffeine include caffeine hydrate, anhydrous caffeine, sodium benzoate caffeine and caffeine citrate. Among these, caffeine hydrate, anhydrous caffeine, and sodium benzoate caffeine are more preferable.

  The content of the xanthine derivative in the pharmaceutical composition of the present invention is appropriately determined based on the interaction inhibitory effect of loxoprofen or a salt thereof and butyl scopolamine bromide and the daily dose according to the sex, age, symptom, etc. of the user. The amount that can be taken 10 to 1000 mg per day is preferred, the amount that can be taken 20 to 800 mg is more preferred, and the amount that can be taken 40 to 600 mg is even more preferred.

The content of the xanthine derivative is preferably 2 to 90% by mass, more preferably 10 to 85% by mass, and more preferably 20 to 80% by mass with respect to the total mass of the pharmaceutical composition of the present invention. More preferred.
In addition, the content ratio of loxoprofen or a salt thereof and a xanthine derivative may be determined by appropriate examination according to the daily dose of each component described above, but 1 part by mass of loxoprofen or a salt thereof (loxoprofen sodium) Those containing 0.03 to 100 parts by mass of xanthine derivatives are preferable, those containing 0.08 to 27 parts by mass are more preferable, and those containing 0.2 to 10 parts by mass are preferable. Further preferred.

  Tranexamic acid or a salt thereof used in the pharmaceutical composition of the present invention includes tranexamic acid itself, a pharmaceutically acceptable salt of tranexamic acid, and further, tranexamic acid or a pharmaceutically acceptable salt thereof, water, alcohol, etc. And solvates thereof. These are known compounds, and can be produced by known methods, or commercially available products can be used. In the present invention, as tranexamic acid or a salt thereof, tranexamic acid is preferable from the viewpoint of using the pharmaceutical composition of the present invention as an antipyretic analgesic, a general cold medicine, or the like, and Japanese Pharmacopoeia tranexamic acid is preferable.

  The content of tranexamic acid or a salt thereof in the pharmaceutical composition of the present invention is the dose per day depending on the interaction inhibitory effect of loxoprofen or a salt thereof and butyl scopolamine bromide, the sex, age, symptoms, etc. of the user. The amount that can be taken in terms of free form of tranexamic acid is preferably 50 to 2000 mg, more preferably 70 to 750 mg, and even more preferably 400 to 750 mg.

Moreover, as content of tranexamic acid or its salt, what is contained 10-95 mass% is preferable with respect to the pharmaceutical composition total mass of this invention, What contains 30-85 mass% is more preferable, 40-80 What contains the mass% is still more preferable.
Moreover, the content ratio of loxoprofen or a salt thereof and tranexamic acid or a salt thereof may be appropriately determined and determined according to the daily dose of each component described above, but 1 part by mass of loxoprofen or a salt thereof. It is preferable to contain 0.1 to 200 parts by mass of tranexamic acid or a salt thereof in terms of free form of tranexamic acid, and more preferably 0.2 to 25 parts by mass with respect to (loxoprofen sodium anhydrate equivalent). Preferably, what contains 2 to 12.5 parts by mass is more preferable.

Examples of the silicate compound used in the pharmaceutical composition of the present invention include silicate compounds and salts of silicate compounds. As a salt of such a silicic acid compound, an inorganic salt is preferable.
Examples of the inorganic salt include metal salts. Examples of the metal constituting such metal ions include alkaline earth metals such as magnesium and calcium; alkali metals such as sodium; group 13 metals such as aluminum. Can be mentioned.

Specific examples of the above silicate compounds include synthetic aluminum silicate, hydrous magnesium silicate, hydrous magnesium silicate (natural), synthetic sodium magnesium silicate, hydrous silicon dioxide, magnesium aluminate silicate, calcium silicate. , Magnesium silicate, magnesium aluminum silicate, light anhydrous silicic acid, diatomaceous earth, silicon dioxide, bentonite, magnesium aluminate metasilicate and the like. These may be used alone or in combination of two or more. In addition, these are well-known things and can manufacture by a well-known method, and can use a commercially available thing.
Among the above-mentioned silicic acid compounds, hydrous silicic acid compounds such as hydrous silicon dioxide, hydrous magnesium silicate, hydrous magnesium silicate (natural) or salts thereof; light anhydrous silicic acid such as light anhydrous silicic acid or salts thereof; Silicic acid such as silicon dioxide, calcium silicate, magnesium aluminate silicate, magnesium aluminate metasilicate or a salt thereof is preferred. Among these, a salt of a hydrous silicate compound, light anhydrous silicic acid, and a silicate are more preferable.

  The content of the silicic acid compound in the pharmaceutical composition of the present invention is not particularly limited, and per day depending on the inhibitory effect on the interaction between loxoprofen or a salt thereof and butyl scopolamine bromide, the sex, age, symptoms, etc. of the user. It may be determined by appropriate examination according to the dose. For example, the amount of the silicic acid compound that can be taken from 1 to 1500 mg per day is preferred, the amount that can be taken from 5 to 1000 mg is more preferred, and the amount that can be taken from 10 to 500 mg is even more preferred.

Moreover, as content of a silicic acid compound, what contains 0.05-80 mass% with respect to the pharmaceutical composition total mass of this invention is preferable, and what contains 0.1-60 mass% is more preferable, 0 More preferably, the content is from 2 to 55% by mass.
Further, the content ratio of loxoprofen or a salt thereof and a silicate compound may be determined by appropriate examination according to the daily dose of each component described above, but 1 part by mass of loxoprofen or a salt thereof (loxoprofen) Those containing 0.003 to 150 parts by mass of a silicate compound are preferable, those containing 0.02 to 35 parts by mass are more preferable, and those containing 0.05 to 10 parts by mass are preferable. Is more preferable.

The carbonate compound used in the pharmaceutical composition of the present invention includes potassium carbonate, magnesium carbonate, aluminum hydroxide / magnesium carbonate mixed dried gel, aluminum hydroxide / magnesium carbonate / calcium carbonate coprecipitation product, calcium carbonate, precipitated carbonate Calcium, sodium hydrogen carbonate, sodium hydrogen carbonate hydrate, potassium hydrogen carbonate, aluminum hydroxide / sodium hydrogen carbonate coprecipitation products, etc., including carbonate compounds, using bandit bones, stone decision, oysters, etc. Also good. These are known compounds and the like, and can be produced by a known method or commercially available.
Among these, salts composed of metal ions such as alkali metals (sodium, potassium, etc.) and alkaline earth metals (magnesium, calcium, etc.) and carbonate ions or hydrogen carbonate ions, and hydrates of such salts A coprecipitation product is preferable, and a salt composed of alkaline earth metal ions and carbonate ions or a coprecipitation product thereof is more preferable.

  The content of the carbonic acid compound in the pharmaceutical composition of the present invention is not particularly limited, and is taken per day according to the inhibitory effect on the interaction between loxoprofen or a salt thereof and butyl scopolamine bromide, the sex, age, symptoms, etc. of the user. Depending on the amount, it may be determined by appropriate examination. The amount that can be taken 1 to 1500 mg of carbonic acid compound per day is preferred, the amount that can be taken 5 to 1000 mg is more preferred, and the amount that can be taken 10 to 500 mg is more preferred.

Further, the content of the carbonic acid compound is preferably 0.05 to 80% by mass, more preferably 0.1 to 60% by mass, more preferably 0.2% to the total mass of the pharmaceutical composition of the present invention. What contains -55 mass% is further more preferable.
In addition, the content ratio of loxoprofen or a salt thereof and a carbonic acid compound may be appropriately determined and determined according to the daily dose of each component described above, but 1 part by mass of loxoprofen or a salt thereof (loxoprofen sodium) Those containing 0.003 to 150 parts by mass of a carbonic acid compound are preferable, those containing 0.02 to 35 parts by mass are more preferable, and those containing 0.05 to 10 parts by mass are further included. preferable.

Examples of the phosphate compound used in the pharmaceutical composition of the present invention include metal ions such as alkali metals (sodium, potassium, etc.) and alkaline earth metals (magnesium, calcium, etc.), phosphate ions, and phosphoric acid (one). Examples thereof include salts composed of hydrogen ions, dihydrogen phosphate ions, glycerophosphate ions or pyrophosphate ions, and hydrates of such salts. Specific examples of such phosphoric acid compounds include calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, tetrasodium pyrophosphate, trisodium phosphate, sodium hydrogen phosphate hydrate, anhydrous sodium pyrophosphate, anhydrous phosphoric acid Examples thereof include sodium hydrogen and calcium glycerophosphate, and bandit bones and oysters containing a phosphate compound may be used. These are known compounds and the like, and can be produced by a known method or commercially available.
Among the phosphate compounds as described above, a salt composed of alkaline earth metal ions and hydrogen phosphate ions is preferable.

  The content of the phosphoric acid compound in the pharmaceutical composition of the present invention is not particularly limited, and per day depending on the inhibitory effect on the interaction between loxoprofen or a salt thereof and butyl scopolamine bromide, the sex, age, symptoms, etc. of the user. It may be determined by appropriate examination according to the dose. The amount that can be taken 1 to 1500 mg of carbonic acid compound per day is preferred, the amount that can be taken 5 to 1000 mg is more preferred, and the amount that can be taken 10 to 500 mg is more preferred.

In addition, the content of the phosphoric acid compound is preferably 0.05 to 80% by mass, more preferably 0.1 to 60% by mass with respect to the total mass of the pharmaceutical composition of the present invention. What contains 2-55 mass% is still more preferable.
Further, the content ratio of loxoprofen or a salt thereof and a phosphoric acid compound may be appropriately determined and determined according to the daily dose of each component described above, but 1 part by mass of loxoprofen or a salt thereof (loxoprofen) What contains 0.003-150 mass parts of phosphoric acid compounds with respect to a sodium anhydride is preferable, What contains 0.02-35 mass parts is more preferable, What contains 0.05-10 mass parts Is more preferable.

Examples of the hydroxide used in the pharmaceutical composition of the present invention include dihydroxyaluminum aminoacetate (aluminum glycinate), magnesium alumina hydroxide, aluminum hydroxide, aluminum hydroxide gel, sodium hydroxide, magnesium hydroxide, and dry. Aluminum hydroxide, dry aluminum hydroxide gel, aluminum hydroxide / sodium bicarbonate coprecipitation product, aluminum hydroxide / magnesium carbonate mixed dry gel, aluminum hydroxide / magnesium carbonate / calcium carbonate coprecipitation product, magnesium hydroxide / Examples include a coprecipitation product of potassium aluminum sulfate. These are known compounds, and can be produced by known methods, or commercially available products can be used.
Among these, a salt composed of a metal ion and a hydroxide ion, a coprecipitation product of such a salt, and a (dry) gel are preferable. Examples of the metal include alkali metals (sodium, potassium, etc.); alkaline earth metals (magnesium, calcium, etc.); Group 13 metals (aluminum, etc.), and alkaline earth metals are preferred.

  The content of the hydroxide in the pharmaceutical composition of the present invention is not particularly limited, and the effect of suppressing the interaction between loxoprofen or a salt thereof and butyl scopolamine bromide, the sex, age, symptoms, etc. of the user per day It may be determined by appropriate examination according to the dose. An amount capable of taking 1-1500 mg of hydroxide per day is preferred, an amount capable of taking 5-1000 mg is more preferred, and an amount capable of taking 10-500 mg is even more preferred.

In addition, the content of hydroxide is preferably 0.05 to 80% by mass, more preferably 0.1 to 60% by mass with respect to the total mass of the pharmaceutical composition of the present invention. What contains 2-55 mass% is still more preferable.
Further, the content ratio of loxoprofen or a salt thereof and a hydroxide may be appropriately determined and determined according to the daily dose of each component described above, but 1 part by mass of loxoprofen or a salt thereof (loxoprofen) What contains 0.003-150 mass parts of hydroxide is preferable with respect to sodium anhydride), What contains 0.02-35 mass parts is more preferable, What contains 0.05-10 mass parts Is more preferable.

As the metal in the metal oxide used in the pharmaceutical composition of the present invention, an alkaline earth metal (magnesium, calcium, etc.), a transition metal (titanium, iron, etc.), a group 13 metal (aluminum, etc.) and the like are preferable.
Examples of the metal oxide composed of the above metals include aluminum oxide, magnesium oxide, titanium oxide, yellow iron sesquioxide, brown iron oxide, black iron oxide, iron sesquioxide, and synthetic hydrotalcite. These are known compounds and can be produced by a known method or commercially available.

  The content of the metal oxide in the pharmaceutical composition of the present invention is not particularly limited, and per day depending on the inhibitory effect of the interaction between loxoprofen or a salt thereof and butyl scopolamine bromide, sex, age, symptoms, etc. of the user. It may be determined by appropriate examination according to the dose. The amount that can be taken 0.01 to 800 mg of metal oxide per day is preferred, the amount that can be taken 0.1 to 600 mg is more preferred, and the amount that can be taken 1 to 400 mg is more preferred.

The content of the metal oxide is preferably 0.0002 to 80% by mass, more preferably 0.002 to 60% by mass, more preferably 0.002 to 60% by mass, based on the total mass of the pharmaceutical composition of the present invention. What contains 02-55 mass% is further more preferable.
In addition, the content ratio of loxoprofen or a salt thereof and a metal oxide may be determined by appropriate examination according to the daily dose of each component described above, but 1 part by mass of loxoprofen or a salt thereof (loxoprofen) What contains 0.00003-80 mass parts of metal oxide with respect to sodium anhydrate equivalent) is preferable, What contains 0.0004-20 mass parts is more preferable, What contains 0.005-7 mass parts Is more preferable.

  Cellulose derivatives or salts thereof used in the pharmaceutical composition of the present invention include cellulose itself, etherified hydroxy groups in cellulose, etherified cellulose esters, cross-linked polymers thereof and salts thereof, etc. Is mentioned. Examples of such salts include metal salts such as alkali metal salts (sodium salts, potassium salts, etc.) and alkaline earth metal salts (calcium salts, etc.).

Specifically, celluloses such as crystalline cellulose and powdered cellulose; carboxyalkyl celluloses such as carmellose, carmellose potassium, carmellose calcium, carmellose sodium or salts thereof; carboxyalkyl cellulose derivatives such as croscarmellose sodium or salts thereof; Hydroxyalkyl celluloses such as hydroxyethyl cellulose, low-substituted hydroxypropyl cellulose, (not low-substituted) hydroxypropyl cellulose; hydroxyalkylalkyl celluloses such as hypromellose (hydroxypropylmethylcellulose 2208, hydroxypropylmethylcellulose 2906, hydroxypropylmethylcellulose 2910, etc.); Hydroxypropyl methylcellulose acetate succinate, etc. Shi alkyl cellulose derivatives and the like. Moreover, as carbon number of the alkyl group in the said carboxyalkyl cellulose, a carboxyalkyl cellulose derivative, a hydroxyalkyl cellulose, a hydroxyalkyl alkyl cellulose, and a hydroxyalkyl alkyl cellulose derivative, 1-4 are preferable.
These are known compounds and can be produced by a known method or commercially available.

  Among the above cellulose derivatives or salts thereof, cellulose, carboxyalkyl cellulose or salt thereof, carboxyalkyl cellulose derivative or salt thereof, hydroxyalkyl cellulose, hydroxyalkylalkyl cellulose are preferred, hydroxyalkyl cellulose, hydroxyalkylalkyl cellulose are more preferred, Low-substituted hydroxypropylcellulose and hypromellose are more preferable. Among these, those listed in official documents established in countries and regions are preferable. The official documents include Japanese Pharmacopoeia, US Pharmacopoeia, British Pharmacopoeia, European Pharmacopoeia, Chinese Pharmacopoeia and so on. In Japan, the Japanese Pharmacopoeia low-substituted hydroxypropyl cellulose and the Japanese Pharmacopoeia hypromellose are particularly preferred.

Further, the substitution degree of the hydroxypropoxy group of the low-substituted hydroxypropylcellulose is preferably 3 to 35%, more preferably 5 to 16%.
Further, the substitution degree of the methoxy group in the hypromellose is preferably 15 to 35%, and more preferably 16.5 to 30%. On the other hand, the substitution degree of the hydroxypropoxy group is preferably 3 to 35%, more preferably 4 to 32%.

The content of the cellulose derivative or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and is one day depending on the interaction inhibitory effect of loxoprofen or a salt thereof and butyl scopolamine bromide, the sex, age, symptoms, etc. of the user. It may be determined by appropriate examination according to the per dose. The amount capable of taking 1 to 1500 mg of the cellulose derivative or salt per day is preferred, the amount capable of taking 5 to 1000 mg is more preferred, and the amount capable of taking 10 to 500 mg is even more preferred.
Further, the content of the cellulose derivative or a salt thereof is preferably 0.05 to 80% by mass, more preferably 0.1 to 60% by mass with respect to the total mass of the pharmaceutical composition of the present invention. What contains 0.2-55 mass% is still more preferable.
In addition, the content ratio of loxoprofen or a salt thereof and a cellulose derivative or a salt thereof may be appropriately determined and determined according to the daily dose of each component described above. Loxoprofen or a salt thereof is 1 part by mass. The content of cellulose derivative or salt thereof is preferably 0.003 to 150 parts by mass, more preferably 0.02 to 35 parts by mass, more preferably 0.05 to 10 masses (relative to loxoprofen sodium anhydrate). Those containing parts are more preferred.

The pharmaceutical composition of the present invention can be formulated into various dosage forms by using known formulation additives according to known methods described in the 16th revised Japanese Pharmacopoeia General Rules for Preparations.
In addition, the dosage form according to the pharmaceutical composition of the present invention is not particularly limited, but from the viewpoint of ease of administration and management of drug dosage, etc., loxoprofen or a salt thereof, butyl scopolamine bromide, xanthine One or more selected from the group consisting of derivatives, tranexamic acid or salts thereof, silicic acid compounds, carbonic acid compounds, phosphoric acid compounds, hydroxides, metal oxides, and cellulose derivatives or salts thereof (hereinafter referred to as xanthine derivatives) Etc.) are preferred. Specific examples of solid preparations include, for example, tablets (orally disintegrating tablets, chewable tablets, dispersible tablets, dissolving tablets; including oral tablets such as troches, sublingual tablets, buccal tablets, adhesive tablets, and gums) Examples include oral preparations such as capsules, pills, granules, fine granules, powders, dry syrups, oral jelly, and parenteral preparations such as suppositories, vaginal tablets, and vaginal suppositories. A formulation is preferred. In addition, the pharmaceutical composition of the present invention may be coated with a sugar coating or a film coating by a known method.

  In the present invention, it has been found for the first time that an interaction is caused by contact of loxoprofen or a salt thereof and butylscopolamine bromide in a pharmaceutical composition. Based on this finding, the interaction between the two components can be improved by containing loxoprofen or a salt thereof and butyl scopolamine bromide so as not to substantially contact each other. That is, in the present invention, a pharmaceutical composition containing loxoprofen or a salt thereof and butyl scopolamine bromide so as not to substantially contact each other and further containing a xanthine derivative or the like can also be mentioned as an embodiment of the present invention.

  In the present invention, the phrase “containing so as not to substantially contact each other” means containing in a pharmaceutical composition such that loxoprofen or a salt thereof and butyl scopolamine bromide do not come into contact with each other to the extent that they do not exhibit an interaction. However, it is preferable to contain so that loxoprofen or a salt thereof and butyl scopolamine bromide do not come into contact with each other.

  The solid preparation according to the present invention includes (A) loxoprofen or a salt thereof, or a solid composition containing loxoprofen or a salt thereof, and (B) a solid composition containing butyl scopolamine bromide itself or butyl scopolamine bromide. And the components constituting these solid compositions include those in which loxoprofen or a salt thereof and butyl scopolamine bromide are arranged so as not to contact each other. These solid compositions are in the form of powder, granules, tablets, and the like.

  As specific forms of the solid preparation, the following (I)-(VIII) can be exemplified, and these are described in known methods as described above, for example, the 16th revised Japanese Pharmacopoeia General Rules for Preparations, etc. According to the known methods, it can be produced and formulated using appropriate formulation additives.

(I) One of loxoprofen or a salt thereof and butyl scopolamine bromide is granulated by an appropriate method to form a granular material, and the other loxoprofen or a salt thereof or butyl scopolamine bromide is blended without granulation. Preparations prepared by coating powders, granules, etc., as well as the granules, in a suitable manner. When using the xanthine derivative etc. which concern on this invention, a xanthine derivative etc. may be contained in the said granular material, and may be contained separately from a granular material.

(II) Loxoprofen or a salt thereof and butyl scopolamine bromide are granulated separately by a suitable method to form a granular material, and a powder or a granule prepared by blending them, and the granular material by a more appropriate method. Coated formulation. The xanthine derivative or the like may be contained in any one of the granular materials, may be contained in both granular materials, or may be formulated separately from these granular materials.
(III) A capsule filled with the powder or granule produced in (I) or (II) above.
(IV) A tablet obtained by tableting the granular material produced in the above (I) or (II) by an appropriate method. Tableting can be achieved not only by the compression method but also by molding into a certain shape by an appropriate method.

(V) A multilayer tablet prepared so that loxoprofen or a salt thereof and butyl scopolamine bromide do not substantially contact each other, and a preparation in which the multilayer tablet is further coated by an appropriate method. The multi-layer tablet is preferably one in which loxoprofen or a salt thereof and butyl scopolamine bromide are located in different layers, and the multi-layer tablet having three or more layers includes a layer containing loxoprofen or a salt thereof and a layer containing butyl scopolamine bromide. Those positioned so as not to contact each other are more preferable. In addition, the granular material manufactured by said (I) and (II) can be used as loxoprofen or its salt, and a butyl scopolamine bromide. In the multilayer tablet, the xanthine derivative or the like may be located in either the layer containing loxoprofen or a salt thereof or the layer containing butyl scopolamine bromide, or may be located separately in both layers. Furthermore, you may locate in the intermediate | middle layer of either layer.
(VI) Either loxoprofen or a salt thereof and butyl scopolamine bromide was placed in a core tablet (also referred to as a core tablet or a central tablet) so that loxoprofen or a salt thereof and butyl scopolamine bromide were not substantially in contact with each other. Nucleated tablets, and preparations obtained by coating the nucleated tablets with an appropriate method. In addition, the granular material manufactured by said (I) and (II) can be used as loxoprofen or its salt, and a butyl scopolamine bromide. In the dry-coated tablet, the xanthine derivative or the like may be positioned in the core tablet, may be positioned in the outer shell, or may be separately positioned in either the core tablet or the outer shell.

(VII) In place of the granular material of (I) or (II) above, either or both of loxoprofen or a salt thereof and butyl scopolamine bromide is added to a cyclodextrin such as α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin. A preparation using an inclusion compound included in dextrins. The xanthine derivative or the like may be located in the vicinity of either one of the clathrate compounds, or may be located in the vicinity of both clathrate compounds.
(VIII) A preparation containing either one of loxoprofen or a salt thereof and butyl scopolamine bromide in a preparation prepared by a usual method, and having a sugar coating layer or a film coating layer provided on the other sugar coating layer or coating layer. And a preparation prepared so that loxoprofen or a salt thereof and butylscopolamine bromide do not substantially contact each other (when the dosage form is a tablet, it is called a sugar-coated tablet or a film-coated tablet). The xanthine derivative or the like may be located in a preparation prepared by a usual method, may be located in a sugar coating layer or a film coating layer, and is separately located in either a sugar coating layer or a film coating layer. Further, it may be located in any of the sugar coating layer and the film coating layer in the preparation.

Granules in the above (I) and (II) are known granulations such as extrusion granulation, rolling granulation, stirring granulation, fluidized bed granulation, spray drying granulation, crushed granulation, melt granulation, etc. Depending on the method, it may be prepared using appropriate formulation additives. In the present invention, any of the granular material containing loxoprofen or a salt thereof and the granular material containing butyl scopolamine bromide may be produced by the same granulation method or by different granulation methods. It may be.
The granular material containing loxoprofen or a salt thereof can be produced by granulation by an appropriate method based on a known method, but a commercially available product can be used.

  In addition, the pharmaceutical composition of the present invention contains loxoprofen sodium hydrate 60 mg, butyl scopolamine bromide 10 mg, crystalline cellulose appropriate amount, carboxymethylcellulose calcium 10 mg and magnesium stearate 1 mg, and a total mass other than capsules of 150 mg. Those are preferred.

  The pharmaceutical composition of the present invention includes drugs other than loxoprofen or a salt thereof and butylscopolamine bromide, such as antipyretic analgesics, antihistamines, antitussives, noscapine, bronchodilators, expectorants, hypnotic sedatives, vitamins, antiseptics It may contain one or more selected from the group consisting of inflammatory agents, gastric mucosal protective agents, anticholinergic agents, herbal medicines, Kampo prescriptions and the like.

  Examples of antipyretic analgesics include aspirin, aspirin aluminum, ibuprofen, isopropylantipyrine, ethenzamide, sazapyrine, salicylamide, sodium salicylate, thiaramide hydrochloride, lactylphenetidine, and the like.

Antihistamines include, for example, azelastine hydrochloride, alimemazine tartrate, istipendil hydrochloride, iproheptin hydrochloride, epinastine hydrochloride, emedastine fumarate, carbinoxamine diphenyl disulfonate, carbinoxamine maleate, clemastine fumarate. Acid salt, dl-chlorpheniramine maleate, d-chlorpheniramine maleate, ketotifen fumarate, dipheterol hydrochloride, dipheterol phosphate, diphenylpyraline hydrochloride, diphenylpyraline theocrate, diphenhydramine Hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, triprolidine hydrochloride, tripelenamine hydrochloride, tondilamine hydrochloride, phenetazine hydrochloride, promethazine hydrochloride, promethad Methylene two salicylates, mequitazine, methdilazine hydrochloride, main blanking hydro Linna Paji sills salts include emetine Das Chin fumarate salt.

  Antitussives include, for example, aloclamide hydrochloride, eprazinone hydrochloride, carbetapentane enoate, cloperastine hydrochloride, cloperastine phendizoate, codeine phosphate, dihydrocodeine phosphate, dibunato sodium, dimemorphan Examples thereof include phosphate, dextromethorphan hydrobromide, dextromethorphan / phenol phthaline salt, tipepidine citrate, and tipepidine hibenzate.

  Examples of noscapine include noscapine hydrochloride and noscapine.

  Examples of bronchodilators include trimethquinol hydrochloride, phenylpropanolamine hydrochloride, phenylephrine hydrochloride, pseudoephedrine hydrochloride, pseudoephedrine sulfate, methylephedrine, dl-methylephedrine hydrochloride, l-methylephedrine hydrochloride, dl. -Methylephedrine saccharin salt, methoxyphenamine hydrochloride, etc. are mentioned.

As an expectorant, for example, ambroxol hydrochloride, ammonia fennel, ethylcysteine hydrochloride, ammonium chloride, carbocysteine, guaifenesin, potassium guaiacolsulfonate, potassium cresolsulfonate, bromhexine hydrochloride, methylcysteine hydrochloride, Examples thereof include l-menthol and lysozyme hydrochloride.
Examples of the hypnotic sedative include allyl isopropyl acetyl urea and bromovalerylurea.

Examples of vitamins include vitamin B ₁ , vitamin B ₂ , vitamin B ₅ , vitamin B ₆ , vitamin B ₁₂ , vitamin C, hesperidin and derivatives thereof and salts thereof (for example, thiamine, thiamine chloride hydrochloride, thiamine). Nitrates, dicetiamine hydrochloride, sethiamine hydrochloride, fursultiamine, fursultiamine hydrochloride, octothiamine, chicotiamine, thiamine disulfide, bisibhiamine, bisbenchamine, prosultiamine, benfotiamine, riboflavin, riboflavin phosphate Esters, riboflavin butyrate, sodium riboflavin phosphate, panthenol, panthetin, calcium pantothenate, sodium pantothenate, pyridoxine hydrochloride, pyridoxal phosphate, cyanocobalamin, mecobara Min, ascorbic acid, sodium ascorbate, calcium ascorbate, hesperidin, etc.).

  Examples of the anti-inflammatory agent include glycyrrhizic acid and derivatives thereof and salts thereof (for example, dipotassium glycyrrhizinate and monoammonium glycyrrhizinate), seaprose, semi-alkaline proteinase, serrapeptase, proctase, pronase, bromelain and the like.

  Examples of the gastric mucosa protective agent include aminoacetic acid, aldioxa, gefarnate, sucralfate, cetraxate hydrochloride, sofalcone, teprenone, copper chlorophyllin potassium, copper chlorophyllin sodium, methylmethionine sulfonium chloride and the like.

  Anticholinergic agents include, for example, oxyphencyclimine hydrochloride, dicyclomine hydrochloride, methixene hydrochloride, scopolamine hydrobromide, datsura extract, tipidium bromide, methyl atropine bromide, methyl anisotropin bromide, methyl scopolamine bromide, methyl- 1-hyostiamine bromide, methylbenactidium bromide, pirenzepine hydrochloride, belladonna alkaloid, belladonna extract, belladonna total alkaloid, iodopropamide, diphenylpiperidinomethyldioxolane iodide, funnel extract, funnel root, funnel root total alkaloid quench Examples include acid salts.

  Herbal medicines include, for example, akamegashiwa (red buds), asenyaku (asenyaku), inyoukaku (horny lamb), fennel (yuka), turmeric (depressed gold), engosaku (yenkogyo), enmaiso (extended herb), ogon (yellow jade) ), Ousei (yellow spirit), Owaku (yellow twilight), Spruce (cherry bark), Auren (yellow ream), Onji (distant), Gajutsu (weather), valerian (deer grass), chamomile, caronin (karojin), Licorice, licorice, bellflowers, kokushi (coconut), cucumber (cucumber leaves), keigai (cocoon), keihi (cinnamon), ketsumeishi (actual child), gentian, gennoshouko (current evidence), Koubushi (Kosuke), Gooh (Gyuhuang), Goshi (Gomiko), Saishin (Spicy), Salamander (Sambu), Zion (Purple), Zykopi (Peel), Peonies (Glue), Ji Jakkou, Shajin, Shazenshi (car forerunner), Shazenso (car forerunner), Beast gall (including yutan (gum gal)), Shakyo (ginger), Giryu (land dragon), Xinyi ), Sexan (Ishizuchi), Senega, Senkyu (Ryukyu), Zenko (Mae-Hu), Senburi (Senshu), Sojutsu (蒼朮), Sohakuhi (Mulberry white skin), Soyo (Soba), Taisan (Oiso), Chixetsu carrot (bamboo ginseng), clove (clove), chimpi (chonse), touki (to home), tokong (napping root), Nantenjitsu (southern), carrot (carrot), baimo (shellfish), bacmond (wheat) Gate winter), mint (thin load), Hange (half-summer), bankouka (Banka), Hampi (anti-nose), peony (white bean), peanut (white moth), bukuryo (茯苓), button pi (peony skin), maou (Mao), herbal medicines such as Lokujo These extracts (extract, tincture, dried extract, etc.) and the like can be mentioned.

  The Kampo prescription includes, for example, Kakkon-to, Katsue-yu, Koso-san, Saiko-Kei-to, Sho-saiko-to, Shosei-ryu, Mumon-tou-yu, Hanka-kopaku-to, Mao-to, and the like.

In the present invention, since the pharmaceutical composition of the present invention contains loxoprofen or a salt thereof and butyl scopolamine bromide, from the viewpoint of being used as an antipyretic analgesic or the like, as a drug other than loxoprofen or a salt thereof and butyl scopolamine bromide, Drugs such as antipyretic analgesics such as antipyrine and etenzamid, and gastric mucosa protective agents such as methylmethionine sulfonium chloride are preferred.
The pharmaceutical composition of the present invention is preferably used as an antipyretic analgesic or the like. Therefore, the efficacy and effects include headache, toothache, post-extraction pain, sore throat, ear pain, joint pain, neuralgia, low back pain, muscle pain, shoulder pain, bruise pain, fracture pain, sprain pain, menstrual pain (physiology) Pain) / traumatic pain analgesia, fever during chills / fever, relief of cold symptoms (sore throat, chills, fever, headache, joint pain, muscle pain).

Next, the pharmaceutical preparation of the present invention will be described.
The pharmaceutical preparation of the present invention contains the above-described pharmaceutical composition of the present invention and a desiccant. By storing the pharmaceutical composition of the present invention in the presence of a desiccant, the interaction between loxoprofen or a salt thereof and butyl scopolamine bromide can be further suppressed.

  The desiccant contained in the pharmaceutical preparation of the present invention is not particularly limited as long as it can suppress or improve the interaction when stored together with loxoprofen or a salt thereof and butyl scopolamine bromide. Also, the shape is not limited, and examples thereof include a plate shape or a bag-like sheet shape, a column shape (tablet shape), and the like, and paper wrapping or film coating is applied to the column shape. It may be given.

  Examples of the desiccant include silica gel, silica alumina gel (allophane), natural zeolite, synthetic zeolite (molecular sieve), calcium chloride, quicklime (calcium oxide), bentonite clay (montmorillonite), magnesium chloride and magnesium oxide. 1 type or 2 types or more can be mentioned, and these and activated carbon may be mixed. Among these, one type or two or more types selected from silica gel, silica alumina gel (allophane), synthetic zeolite (molecular sieve) and calcium chloride are more preferable, and synthetic zeolite is more preferable in terms of interaction suppression.

  Various desiccants are commercially available. For example, Shiblet, MS-Tablet, MS-Serum W, Tokai Gel, Decite Kite 25, Alp sheet, Toray Chemical Co., Ltd. ) Packaged items, Dryan (registered trademark) tablets, Dryan (registered trademark) sheets, Sekawa, Allosheet, Zeosheet, Shinzo Kasei Co., Ltd., OZO Co., Ltd. OZO, IDi Co., Ltd. IDi-packing desiccant and the like.

The content of the desiccant may be determined by appropriate examination, but is preferably 0.05 to 35 parts by mass with respect to 1 part by mass of loxoprofen or a salt thereof contained in the pharmaceutical composition of the present invention, 0.15 -17 mass parts is more preferable.
Moreover, 0.001-10 mass parts is preferable with respect to 1 mass part of pharmaceutical composition of this invention, and, as for a desiccant, 0.005-5 mass parts is more preferable, and 0.01-3 mass parts is further more preferable.

As the pharmaceutical preparation of the present invention, one containing the pharmaceutical composition of the present invention and a desiccant in a container is preferable.
The container used for the pharmaceutical preparation of the present invention is not particularly limited as long as it can be used as a container for foods, supplements, pharmaceuticals, health foods, and the like, but any of a fixed container and an amorphous container can be used and sealed. What is possible is preferred. Examples of the fixed container include bottles, cans, and boxes. Examples of the amorphous container include bags (pillow packaging, stick packaging, PTP packaging, SP packaging, etc.) and the like. Of these containers, specifically, bottles and bags are preferable.
The forming member of the container is not particularly limited, and examples thereof include paper, glass, a resin or a resin film, or a member such as a metal or metal film. It may be a thing. Moreover, it is preferable that moisture permeation prevention processing is performed about the member which has moisture permeability, such as paper. The container may be transparent, translucent, or opaque.
The method for storing the pharmaceutical composition of the present invention and the desiccant in a container is not particularly limited, and any of them can be achieved by arranging them by appropriate means such as charging into the container.
For example, when the container is a bottle, the desiccant (preferably, a columnar shape (tablet shape)) is placed in the bottle, or stored in the back side (inner cap) of the bottle lid, and stored in the container. This can be achieved by storing the pharmaceutical composition in a bottle or the like. When stored in a bottle, the pharmaceutical composition of the present invention preferably has a solid dosage form.
Further, when the container is a bag, it can be achieved by storing the desiccant (preferably, a plate-like or bag-like sheet type) and the pharmaceutical composition of the present invention in the bag. When stored in a bag, the pharmaceutical composition of the present invention preferably has a solid dosage form.
Furthermore, when the pharmaceutical composition of the present invention is a solid preparation, it can be once packaged by SP packaging, PTP packaging, a bag, etc., and then the packaged solid preparation and desiccant can be enclosed in a bag. . For example, the form containing the said solid formulation which carried out stick packaging, SP packaging, or PTP packaging, and the desiccant which carried out pillow packaging or stick packaging is mentioned. More specifically, a form in which the solid preparation packed in SP or PTP and a plate-like or bag-like sheet-type desiccant are combined in a pillow package is included. Further, the pillow packaging form may be stored in a box or the like.

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in detail, this invention is not limited to these Examples.

Test Example 1 Examination of interaction (1)
Loxoprofen sodium hydrate 204.3 parts by mass and butyl scopolamine bromide 30 parts by mass were mixed, placed in a glass bottle and stored at 60 ° C. (Reference Example 1). As comparative controls, loxoprofen sodium hydrate alone (Control Example 1) and butyl scopolamine bromide alone (Control Example 2) were similarly placed in glass bottles and stored at 60 ° C.
About these reference examples 1 and control examples 1 and 2, the state in the glass bottle immediately after the start of storage, 1 day, 2 days, and 1 week after was evaluated, respectively. The results are shown in Table 1.

As shown in Table 1, there was no change in the storage of either loxoprofen sodium hydrate or butyl scopolamine bromide alone, and it remained as a white powder (Control Examples 1 and 2).
On the other hand, when a mixture of loxoprofen sodium hydrate and butyl scopolamine bromide was stored, the mixture solidified after one day (Reference Example 1).
From this, it was found that the state change of the mixture was a result of the interaction between loxoprofen or a salt thereof and butyl scopolamine bromide.

Test Example 2 Examination of interaction (2)
The compositions of the following Reference Example 2 and Examples 1 to 14 were obtained, put in glass bottles, and stored at 60 ° C.
Reference Example 2: 204.3 parts by mass of loxoprofen sodium hydrate and 30 parts by mass of butyl scopolamine bromide were mixed to obtain a composition.
Example 1: 204.3 parts by mass of loxoprofen sodium hydrate, 30 parts by mass of butyl scopolamine bromide and 250 parts by mass of anhydrous caffeine were mixed to obtain a composition.
Example 2: A composition was obtained in the same manner as in Example 1 except that caffeine anhydride was changed to 750 parts by mass of tranexamic acid.
Example 3 A composition was obtained in the same manner as in Example 1 except that anhydrous caffeine was replaced with 234.3 parts by mass of magnesium aluminate silicate.
Example 4: A composition was obtained in the same manner as in Example 1 except that anhydrous caffeine was replaced with 234.3 parts by mass of magnesium aluminate metasilicate.
Example 5: A composition was obtained in the same manner as in Example 1 except that anhydrous caffeine was replaced with 234.3 parts by mass of calcium silicate.
Example 6 A composition was obtained in the same manner as in Example 1 except that the anhydrous caffeine was replaced with 234.3 parts by weight of light anhydrous silicic acid.
Example 7: A composition was obtained in the same manner as in Example 1 except that anhydrous caffeine was replaced with 234.3 parts by mass of hydrous magnesium silicate (natural).
Example 8 A composition was obtained in the same manner as in Example 1 except that anhydrous caffeine was replaced with 234.3 parts by mass of precipitated calcium carbonate.
Example 9: A composition was obtained in the same manner as in Example 1 except that anhydrous caffeine was replaced with 234.3 parts by mass of anhydrous calcium hydrogen phosphate.
Example 10 A composition was obtained in the same manner as in Example 1 except that anhydrous caffeine was replaced with 234.3 parts by mass of magnesium hydroxide.
Example 11 A composition was obtained in the same manner as in Example 1 except that anhydrous caffeine was changed to 234.3 parts by mass of magnesium oxide.
Example 12 A composition was obtained in the same manner as in Example 1 except that anhydrous caffeine was replaced with 234.3 parts by mass of titanium oxide.
Example 13: A composition was obtained in the same manner as in Example 1 except that anhydrous caffeine was replaced with 234.3 parts by mass of low-substituted hydroxypropylcellulose.
Example 14 A composition was obtained in the same manner as in Example 1 except that anhydrous caffeine was replaced with 234.3 parts by mass of hypromellose (hydroxypropylmethylcellulose 2910).
And about the composition of the said reference example 2 and Examples 1-14, the state in the glass bottle immediately after a storage start, 1 day, 2 days later, and 1 week after was evaluated, respectively. The results are shown in Table 2.

As is apparent from Table 2, when the mixture of loxoprofen sodium hydrate and butyl scopolamine bromide was confirmed after storage at 60 ° C. for 1 week, as in Test Example 1, the interaction resulted in 1 After a day, it became solidified (Reference Example 2).
In contrast, in addition to a mixture of loxoprofen sodium hydrate and butyl scopolamine bromide, anhydrous caffeine (Example 1), tranexamic acid (Example 2), magnesium aluminate silicate (Example 3), and aluminate metasilicate. Magnesium silicate (Example 4), calcium silicate (Example 5), light anhydrous silicic acid (Example 6), hydrous magnesium silicate (natural) (Example 7), precipitated calcium carbonate (Example 8), anhydrous Calcium hydrogen phosphate (Example 9), magnesium hydroxide (Example 10), magnesium oxide (Example 11), titanium oxide (Example 12), low-substituted hydroxypropyl cellulose (Example 13), or hypromellose ( The composition containing Example 14) maintained the state immediately after the start of storage even after one week, and no change occurred.
Therefore, the interaction that occurs between loxoprofen or a salt thereof and butyl scopolamine bromide can be converted into a xanthine derivative, tranexamic acid or a salt thereof, a silicic acid compound, a carbonic acid compound, a phosphoric acid compound, a hydroxide, a metal oxide, and a cellulose derivative or a salt thereof. Turned out to be suppressed.

Production Example 1
Loxoprofen sodium hydrate 204.3 parts Hypromellose 16.2 parts by weight, croscarmellose sodium 24.3 parts by weight, light anhydrous silicic acid 8.1 parts by weight and crystalline cellulose 17.1 parts by weight, purified water The mixture was kneaded and granulated, and then granulated to obtain a granulated product. On the other hand, 30 parts by mass of butyl scopolamine bromide, 420 parts by mass of tranexamic acid, 16.2 parts by mass of hydroxypropyl cellulose, 24.3 parts by mass of croscarmellose sodium and 17.1 parts by mass of lactose hydrate were mixed and ethanol was used. After kneading and granulating, granulation was performed to obtain a granulated product. 32.4 parts by mass of talc was added to and mixed with the obtained two types of granulated products to obtain granules for tableting.
The obtained granules for tableting were tableted to obtain a tablet capable of taking 204.3 mg of loxoprofen sodium hydrate, 30 mg of butylscopolamine bromide and 420 mg of tranexamic acid per day.

Production Example 2
Loxoprofen sodium hydrate 204.3 parts, hypromellose 16.2 parts, croscarmellose sodium 24.3 parts, light anhydrous silicic acid 8.1 parts and crystalline cellulose 115.2 parts After kneading and granulating with water, the granules were sized to obtain a granulated product. On the other hand, 30 parts by mass of butyl scopolamine bromide, 240 parts by mass of anhydrous caffeine, 16.2 parts by mass of hydroxypropyl cellulose, 24.3 parts by mass of croscarmellose sodium and 115.2 parts by mass of lactose hydrate were mixed, and ethanol was added. The mixture was kneaded and granulated, and then granulated to obtain a granulated product. 16.2 parts by mass of magnesium stearate was added to and mixed with the obtained two types of granulated products to obtain granules for tableting.
The obtained granules for tableting were tableted to obtain tablets containing 204.3 mg of loxoprofen sodium hydrate, 30 mg of butyl scopolamine bromide and 240 mg of anhydrous caffeine per day.

Production Example 3
Loxoprofen sodium hydrate 204.3 parts, hypromellose 16.2 parts, carmellose 24.3 parts, calcium silicate 8.1 parts and crystalline cellulose 34.7 parts are mixed and purified water is used. After kneading and granulating, granulation was performed to obtain a granulated product. On the other hand, 30 parts by weight of butyl scopolamine bromide, 240 parts by weight of anhydrous caffeine, 180 parts by weight of allylisopropylacetylurea, 16.2 parts by weight of hardened oil and 40 parts by weight of D-mannitol were mixed and kneaded using ethanol. After granulation, the granules were sized to obtain a granulated product. 16.2 parts by mass of magnesium stearate was added to and mixed with the obtained two types of granulated products to obtain granules for tableting.
The obtained granules for tableting were tableted to obtain tablets containing 204.3 mg of loxoprofen sodium hydrate, 30 mg of butyl scopolamine bromide, 240 mg of anhydrous caffeine, and 180 mg of allylisopropylacetylurea per day.

Production Example 4
Loxoprofen sodium hydrate 204.3 parts, hydroxypropylcellulose 16.2 parts, carmellose calcium 24.3 parts, calcium silicate 8.1 parts and crystalline cellulose 25.2 parts After kneading and granulating with water, the granules were sized to obtain a granulated product. On the other hand, 30 parts by mass of butyl scopolamine bromide, 420 parts by mass of tranexamic acid, 180 parts by mass of allyl isopropyl acetylurea, 16.2 parts by mass of hydroxypropyl cellulose, 24.3 parts by mass of crospovidone and 25.2 parts by mass of lactose hydrate After mixing, kneading with ethanol and granulating, the granules were sized to obtain a granulated product. 16.2 parts by mass of magnesium stearate was added to and mixed with the obtained two types of granulated products to obtain granules for tableting.
The obtained granules for tableting were tableted to obtain tablets containing 204.3 mg of loxoprofen sodium hydrate, 30 mg of butyl scopolamine bromide, 420 mg of tranexamic acid and 180 mg of allylisopropylacetylurea per day.

Production Example 5
Loxoprofen sodium hydrate 204.3 parts, hydroxypropylcellulose 16.2 parts, croscarmellose sodium 24.3 parts, hydrous silicon dioxide 8.1 parts and crystalline cellulose 194.7 parts, After kneading and granulating with purified water, granulation was performed to obtain a granulated product. On the other hand, after mixing 30 parts by weight of butyl scopolamine bromide, 100 parts by weight of magnesium aluminate metasilicate, 16.2 parts by weight of hydroxypropylcellulose and 200 parts by weight of lactose hydrate, kneading with ethanol and granulating And granulated to obtain a granulated product. 16.2 parts by mass of magnesium stearate was added to and mixed with the obtained two types of granulated products to obtain granules for tableting.
The obtained granules for tableting were tableted to obtain tablets containing 204.3 mg of loxoprofen sodium hydrate, 30 mg of butyl scopolamine bromide and 100 mg of magnesium aluminate metasilicate per day.

Production Example 6
Loxoprofen sodium hydrate 204.3 parts, hydroxypropylcellulose 16.2 parts, low substituted hydroxypropylcellulose 24.3 parts, calcium silicate 8.1 parts and crystalline cellulose 170.4 parts The mixture was kneaded with purified water, granulated, and then granulated to obtain a granulated product. On the other hand, 30 parts by mass of butyl scopolamine bromide, 100 parts by mass of anhydrous calcium hydrogen phosphate, 16.2 parts by mass of hydroxypropyl cellulose, 24.3 parts by mass of crospovidone and 200 parts by mass of lactose hydrate were mixed and ethanol was used. After kneading and granulating, granulation was performed to obtain a granulated product. 16.2 parts by mass of magnesium stearate was added to and mixed with the obtained two types of granulated products to obtain granules for tableting.
The obtained granules for tableting were tableted to obtain tablets containing 204.3 mg of loxoprofen sodium hydrate, 30 mg of butyl scopolamine bromide and 100 mg of anhydrous calcium hydrogen phosphate per day.

Production Example 7
Loxoprofen sodium hydrate 204.3 parts by mass, hydroxypropylcellulose 16.2 parts by mass, carboxymethyl starch sodium 24.3 parts by mass, calcium silicate 8.1 parts by mass and crystalline cellulose 50.4 parts by mass, After kneading and granulating with purified water, granulation was performed to obtain a granulated product. On the other hand, 30 parts by mass of butyl scopolamine bromide, 750 parts by mass of tranexamic acid, 16.2 parts by mass of hydroxypropyl cellulose, 24.3 parts by mass of carmellose calcium and 60 parts by mass of lactose hydrate were mixed and kneaded using ethanol. And granulated, and then sized to obtain a granulated product. 16.2 parts by mass of magnesium stearate was added to and mixed with the obtained two types of granulated products to obtain granules for tableting.
The obtained granules for tableting were tableted to obtain tablets capable of taking 204.3 mg of loxoprofen sodium hydrate, 30 mg of butyl scopolamine bromide and 750 mg of tranexamic acid per day.

Production Example 8
Loxoprofen sodium hydrate 204.3 parts, hydroxypropylcellulose 16.2 parts, carmellose 24.3 parts, carnauba wax 8.1 parts and crystalline cellulose 4.4 parts are mixed and purified water is used. After kneading and granulating, granulation was performed to obtain a granulated product. Meanwhile, 30 parts by mass of butyl scopolamine bromide, 750 parts by mass of tranexamic acid, 100 parts by mass of magnesium aluminate metasilicate, 16.2 parts by mass of hydroxypropylcellulose, 24.3 parts by mass of croscarmellose sodium and 6 parts by mass of lactose hydrate Were mixed, kneaded using ethanol, granulated, and then granulated to obtain a granulated product. 16.2 parts by mass of magnesium stearate was added to and mixed with the obtained two types of granulated products to obtain granules for tableting.
The obtained granules for tableting were tableted to obtain a tablet that can be taken 204.3 mg of loxoprofen sodium hydrate, 30 mg of butyl scopolamine bromide, 750 mg of tranexamic acid, and 100 mg of magnesium aluminate metasilicate per day. .

Production Example 9
Loxoprofen sodium hydrate 204.3 parts, hydroxypropylcellulose 16.2 parts, croscarmellose sodium 24.3 parts, light anhydrous silicic acid 8.1 parts and crystalline cellulose 65.2 parts The mixture was kneaded with purified water, granulated, and then granulated to obtain a granulated product. On the other hand, 30 parts by mass of butyl scopolamine bromide, 240 parts by mass of anhydrous caffeine, 100 parts by mass of magnesium aluminate metasilicate, 16.2 parts by mass of hydroxypropyl cellulose, 24.3 parts by mass of carmellose calcium and 65.2 of lactose hydrate. Mass parts were mixed, kneaded with ethanol, granulated, and then granulated to obtain a granulated product. 16.2 parts by mass of magnesium stearate was added to and mixed with the obtained two types of granulated products to obtain granules for tableting.
The obtained granules for tableting were tableted to obtain tablets containing 204.3 mg of loxoprofen sodium hydrate, 30 mg of butyl scopolamine bromide, 240 mg of anhydrous caffeine, and 100 mg of magnesium aluminate metasilicate per day.

Production Example 10
Loxoprofen sodium hydrate 204.3 parts by mass, hydroxypropylcellulose 16.2 parts by mass, croscarmellose sodium 24.3 parts by mass, light anhydrous silicic acid 8.1 parts by mass and lactose hydrate 95.2 parts by mass After mixing, kneading with purified water, granulating, and granulating, a granulated product was obtained. On the other hand, 30 parts by mass of butyl scopolamine bromide, 180 parts by mass of allyl isopropyl acetyl urea, 100 parts by mass of magnesium aluminate metasilicate, 16.2 parts by mass of hydroxypropyl cellulose, 24.3 parts by mass of low-substituted hydroxypropyl cellulose and 95 of crystalline cellulose .2 parts by mass was mixed, kneaded with ethanol, granulated, and then granulated to obtain a granulated product. 16.2 parts by mass of magnesium stearate was added to and mixed with the obtained two types of granulated products to obtain granules for tableting.
The obtained granules for tableting were tableted to obtain tablets containing 204.3 mg of loxoprofen sodium hydrate, 30 mg of butyl scopolamine bromide, 180 mg of allylisopropylacetylurea, and 100 mg of magnesium aluminate metasilicate per day.

Production Example 11
Loxoprofen sodium hydrate 204.3 parts, hydroxypropylcellulose 16.2 parts, carmellose calcium 24.3 parts, calcium silicate 8.1 parts and crystalline cellulose 185.2 parts After kneading and granulating with water, the granules were sized to obtain a granulated product. On the other hand, 30 parts by mass of butyl scopolamine bromide, 100 parts by mass of anhydrous calcium hydrogen phosphate, 16.2 parts by mass of hydroxypropyl cellulose, 24.3 parts by mass of carmellose calcium and 185.2 parts by mass of lactose hydrate were mixed, and ethanol was mixed. The mixture was kneaded and granulated, and then granulated to obtain a granulated product. 16.2 parts by mass of magnesium stearate was added to and mixed with the obtained two types of granulated products to obtain granules for tableting.
The obtained granules for tableting were tableted to obtain tablets containing 204.3 mg of loxoprofen sodium hydrate, 30 mg of butyl scopolamine bromide and 100 mg of anhydrous calcium hydrogen phosphate per day.

Production Example 12
23.1 parts by mass of hypromellose and 0.9 parts by mass of Macrogol 6000 are dissolved in 240 parts by mass of purified water, and 0.3 parts by mass of titanium oxide and 5.7 parts by mass of talc are dispersed therein, and a film coating solution is prepared. Prepared. Using the coating apparatus, the above-mentioned film coating solution was sprayed so as to have a film layer of 10 mg per tablet (plain tablet) obtained in Production Examples 1 to 11, and a coating was applied. Subsequently, glazing was applied with carnauba wax (trace amount), and film-coated tablets were obtained for each of the tablets obtained in Production Examples 1 to 11.

Test Example 3 Examination of interaction (3)
204.3 parts by mass of loxoprofen sodium hydrate and 30 parts by mass of butyl scopolamine bromide were mixed, placed in a glass bottle and stored at 60 ° C. (Control Example 3).
In addition to a mixture of 204.3 parts by mass of loxoprofen sodium hydrate and 30 parts by mass of butylscopolamine bromide, 234.3 parts by mass of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) as a desiccant in a glass bottle And stored at 60 ° C. (Reference Example 2).
And about the control example 3 and the reference example 2, immediately after the storage start, the state in the glass bottle after 1 day, 2 days later, and 1 week after was evaluated, respectively. The results are shown in Table 3.

As is clear from Table 3, when the mixture of loxoprofen sodium hydrate and butyl scopolamine bromide was confirmed after storage at 60 ° C. for 1 week, as in Test Example 1, the interaction resulted in 1 After a day, it became solidified (Control Example 3).
On the other hand, when a desiccant was added in addition to the mixture (Reference Example 2), the interaction between loxoprofen sodium hydrate and butyl scopolamine bromide was suppressed, and the mixture did not solidify even after 1 week. The powder state was maintained.

Production Example 13
Thirty tablets obtained in Production Example 1 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.

Production Example 14
Using the tablet obtained in Production Example 2, a pharmaceutical preparation was produced in the same manner as in Production Example 13.

Production Example 15
Using the tablets obtained in Production Example 3, a pharmaceutical preparation was produced in the same manner as in Production Example 13.

Production Example 16
Using the tablets obtained in Production Example 4, a pharmaceutical preparation was produced in the same manner as in Production Example 13.

Production Example 17
Using the tablet obtained in Production Example 5, a pharmaceutical preparation was produced in the same manner as in Production Example 13.

Production Example 18
A pharmaceutical preparation was prepared in the same manner as in Production Example 13 using the tablet obtained in Production Example 6.

Production Example 19
Using the tablet obtained in Production Example 7, a pharmaceutical preparation was produced in the same manner as in Production Example 13.

Production Example 20
A pharmaceutical preparation was produced in the same manner as in Production Example 13 using the tablet obtained in Production Example 8.

Production Example 21
Using the tablet obtained in Production Example 9, a pharmaceutical preparation was produced in the same manner as in Production Example 13.

Production Example 22
Using the tablets obtained in Production Example 10, a pharmaceutical preparation was produced in the same manner as in Production Example 13.

Production Example 23
Using the tablet obtained in Production Example 11, a pharmaceutical preparation was produced in the same manner as in Production Example 13.

Production Example 24
Thirty film-coated tablets of Production Example 1 obtained in Production Example 12 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to produce a pharmaceutical preparation. .

Production Example 25
In the same manner as in Production Example 24, 30 film-coated tablets of each of Production Examples 2 to 11 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) are placed in a glass bottle (3K standard bottle). Seed pharmaceutical formulations were made.

  According to the present invention, a pharmaceutical composition comprising loxoprofen or a salt thereof and butyl scopolamine bromide having excellent storage stability can be provided. Further, since it contains a loxoprofen or a salt thereof and butyl scopolamine bromide, a xanthine derivative having a central excitatory action, a cardiotonic / diuretic action, a gastric acid secretion enhancing action, a smooth muscle relaxing action, etc., the pharmaceutical composition of the present invention Is an excellent antipyretic analgesic.

Claims (7)

  A pharmaceutical composition comprising loxoprofen or a salt thereof, butyl scopolamine bromide, and a metal oxide.   The metal oxide is one or more selected from the group consisting of aluminum oxide, magnesium oxide, titanium oxide, yellow iron sesquioxide, brown iron oxide, black iron oxide, iron sesquioxide and synthetic hydrotalcite. Item 1. A pharmaceutical composition according to Item 1.   The pharmaceutical composition according to claim 1 or 2, wherein the content of loxoprofen or a salt thereof is 10 to 300 mg as a daily dose in terms of loxoprofen sodium anhydride.   The content of butyl scopolamine bromide is 3 to 1000 mg as a daily dose, The pharmaceutical composition according to any one of claims 1 to 3.   The pharmaceutical composition according to any one of claims 1 to 4, wherein the dosage form is a solid preparation.   The pharmaceutical formulation containing the pharmaceutical composition of any one of Claims 1-5, and a desiccant.   The pharmaceutical formulation which contains the pharmaceutical composition of any one of Claims 1-6, and a desiccant in a container.