WO2011108644A1

WO2011108644A1 - Solid pharmaceutical composition and pharmaceutical preparation

Info

Publication number: WO2011108644A1
Application number: PCT/JP2011/054917
Authority: WO
Inventors: 武利伊藤; 千晶高橋; 里依奥井
Original assignee: ライオン株式会社
Priority date: 2010-03-03
Filing date: 2011-03-03
Publication date: 2011-09-09
Also published as: JP5817715B2; JPWO2011108644A1

Abstract

Disclosed is a solid pharmaceutical composition which contains (A) a propionic acid or acetic acid nonsteroidal anti-inflammatory drug, (B) an aminoalkyl methacrylate copolymer E, and (C) silicon dioxide. The mass ratio of the component (B) relative to the component (A) expressed as (B)/(A) is 0.5-2, and the mass ratio of the component (C) relative to the component (A) expressed as (C)/(A) is 0.5-2.

Description

Solid pharmaceutical composition and pharmaceutical preparation

The present invention relates to a solid pharmaceutical composition containing non-steroidal anti-inflammatory of propionic acid or acetic acid type, and a pharmaceutical preparation comprising the same.

Propionic acid-based or acetic acid-based non-steroidal anti-inflammatory drugs are often poorly soluble drugs with low solubility in water. As a technique for improving the dissolution property of a poorly soluble drug and increasing the dissolution rate, a technique for preparing a composition containing a poorly soluble drug and a polymer compound is known (Patent Document 1: JP-A-3-83922, Patent Document 2: Japanese Patent Application Laid-Open No. 8-291063). For example, Japanese Patent Application Laid-Open No. 8-291063 proposes an easily absorbable preparation containing a poorly soluble drug containing a carboxyl group, a specific amino group-containing polymer compound, and an excipient. However, the easily absorbable preparation has a problem that the composition is very easy to be cured and agglomerated and solidified immediately after production, and the dissolution property is low.

In addition, many polymer compounds are required to improve the dissolution property of the hardly soluble drug using a polymer compound. However, if the ratio of the polymer compound is increased until sufficient dissolution is obtained, the adhesion to the production apparatus such as a granulator, a mixer, and a tableting machine may become extremely difficult to formulate, and it may not be possible. It was an economy. Therefore, it has been desired to develop a fast-dissolving preparation that further enhances the dissolution property of a non-steroidal anti-inflammatory drug, which is a poorly water-soluble drug, within a relatively low amount of the polymer compound.

Japanese Patent Laid-Open No. 3-83922 JP-A-8-291063

The present invention contains propionic acid or acetic acid-based non-steroidal anti-inflammatory, with good manufacturability, improved elution of propionic acid or acetic acid-based non-steroidal anti-inflammatory drugs, and suppressed aggregation and solidification The object is to provide a solid pharmaceutical composition and a pharmaceutical preparation comprising the same.

The present inventors have used (A) a propionic acid or acetic acid-based non-steroidal anti-inflammatory drug in combination with a solid pharmaceutical composition containing (B) aminoalkyl methacrylate copolymer E, thereby The problem that coagulation solidification occurs while improving the elution property of the component) includes (C) silicon dioxide, the content ratio of the component (B) to the component (A), and the component (A) to the component (A) The content ratio of the component (C) to a specific value, particularly (C) by using a large amount of silicon dioxide, the manufacturability, particularly the manufacturability in a range where the amount of the polymer compound is relatively low, I found out that it can be solved.

Accordingly, the present invention provides the following solid pharmaceutical composition and pharmaceutical preparation.
[1]. (A) A propionic acid-based or acetic acid-based non-steroidal anti-inflammatory drug, (B) an aminoalkyl methacrylate copolymer E, and (C) silicon dioxide, and represented by (B) / (A) The mass ratio of the component (B) to the component (A) is 0.5 to 2, and the mass ratio of the component (C) to the component (A) represented by (C) / (A) is 0. A solid pharmaceutical composition that is 5-2.
[2]. (A) The solid pharmaceutical composition according to [1], wherein the component is ibuprofen.
[3]. The solid pharmaceutical composition according to [1] or [2], wherein the components (A), (B) and (C) are wet-granulated using a liquid containing (D) hydroxypropylcellulose.
[4]. The solid pharmaceutical composition according to any one of [1] to [3], further comprising (E) aluminum hydroxide or magnesium aluminate metasilicate.
[5]. The solid pharmaceutical composition according to any one of [1] to [4], further comprising (F) acetaminophen.
[6]. The solid pharmaceutical composition according to any one of [1] to [5], wherein the total content of the components (A), (B) and (C) in the solid pharmaceutical composition is 50 to 100% by mass.
[7]. [1] A pharmaceutical preparation comprising the solid pharmaceutical composition according to any one of [6] and being a tablet, granule, fine granule or capsule.

According to the present invention, the non-steroidal anti-inflammatory of propionic acid or acetic acid, which has good manufacturability, improves the elution of propionic acid or acetic acid-based non-steroidal anti-inflammatory drugs, and suppresses aggregation and solidification, is achieved. It is possible to provide a solid pharmaceutical composition to be contained and a pharmaceutical preparation comprising the same.

1 is a DSC chart of Example 1 granules (solid pharmaceutical composition) and ibuprofen.

Hereinafter, the present invention will be described in detail. The solid pharmaceutical composition of the present invention contains (A) a propionic acid-based or acetic acid-based non-steroidal anti-inflammatory drug, (B) an aminoalkyl methacrylate copolymer E, and (C) silicon dioxide. ) / (A), the content ratio of the component (B) to the component (A) is 0.5 to 2, and the component (A) represented by (C) / (A) ( The component mass ratio of component C) is 0.5-2.

(I) Solid pharmaceutical composition (A) Propionic acid-based or acetic acid-based non-steroidal anti-inflammatory drug Propionic acid-based and acetic acid-based compounds are those having a propionic acid group and an acetic acid group, respectively. Two or more kinds can be used in appropriate combination. Non-steroidal anti-inflammatory drugs include known ones. For example, propionic acid non-steroidal anti-inflammatory drugs include ibuprofen, ketoprofen, naproxen, flurbiprofen, loxoprofen sodium and the like. Examples of acetic acid non-steroidal anti-inflammatory drugs include diclofenac, diclofenac sodium, indomethacin, felbinac and the like. Of these, ibuprofen is preferred. By blending the component (A), an antipyretic analgesic effect can be obtained.

The content of the component (A) is not particularly limited as long as it is within the permissible range of blending into an internal drug (drug approval standard amount). In the case of an OTC pharmaceutical, for example, the daily dose of ibuprofen is preferably 200 to 600 mg, more preferably 390 to 450 mg. Further, it is preferably 1 to 50% by mass in the solid pharmaceutical composition, more preferably 5 to 50% by mass, and even more preferably 10 to 50% by mass.

(B) Aminoalkyl methacrylate copolymer E
The aminoalkyl methacrylate copolymer E is a chemical name: methyl methacrylate, butyl methacrylate, dimethylaminoethyl methacrylate copolymer, and is a component described in a pharmaceutical additive standard or a Japanese Pharmacopoeia pharmaceutical ingredient standard. . As the component (B), commercially available products can be used. For example, Eudragit E100, Eudragit EPO (monomer molar ratio; methyl methacrylate 1: butyl methacrylate 1: dimethylaminoethyl methacrylate 2) of Evonik Product name) etc., and can be used singly or in appropriate combination of two or more.

Component (A) is a poorly water-soluble drug, and improvement in dissolution is a problem, but by mixing (A) component and (B) component together, the dissolution property of (A) component is improved. . The mechanism is unknown, but (A) a propionic acid-based or acetic acid-based non-steroidal anti-inflammatory drug has a carboxy group and (B) component (dimethylaminoethyl methacrylate) amino group ( It is expected that the component (A) and the component (B) are combined. Complexation can be confirmed by the component (A) becoming amorphous (non-crystallized). Amorphization of the component (A) can be confirmed by, for example, the peak of the component (A) in DSC or XRD.

The content of the component (B) is not particularly limited as long as it is within the range acceptable for internal use (unprecedented amount of pharmaceutical use), but the daily dose is preferably 60 to 1800 mg, more preferably 100 to 1200 mg. Further, the mass ratio of the component (B) to the component (A) represented by (B) / (A) is 0.5 to 2. When (B) / (A) is less than 0.5, the elution improvement of the component (A) is insufficient, and when it exceeds 2, the elution improvement of the component (A) and the coagulation solidification suppressing effect are obtained. Insufficient and adheres to manufacturing equipment such as a blender or a tableting machine. Further, from the viewpoint of ease of production, the upper limit is preferably 1.5 or less, and more preferably 1 or less. The effect of the present invention is greatly influenced by the content ratio of the component (B) to the component (A), and the content of the component (B) is not particularly limited, but is 0.1 to 50 in the solid pharmaceutical composition. % By weight is preferred, 1 to 50% by weight is more preferred, and 1 to 30% by weight is even more preferred.

(C) Silicon dioxide By mix | blending silicon dioxide, the elution of (A) component can be improved and aggregation of a composition can be suppressed. (D) Silicon dioxide has general names such as light anhydrous silicic acid, hydrous silicon dioxide, silica, white carbon and the like. Moreover, a commercial item can also be used, "Silicia" of Fuji Silysia Chemical Ltd., "Syrossphere" (all are brand names), etc. are mentioned, It can use individually by 1 type or in combination of 2 or more types. .

The content of the component (C) is not particularly limited as long as it is within a range acceptable as an internal medicine, but when it is used as an OTC pharmaceutical, it is preferably 1 to 3000 mg as a daily dose of silicon dioxide. The content ratio of the component (C) to the component (A) represented by (C) / (A) is 0.5 to 2. If the above (C) / (A) is less than 0.5, the effect of improving the elution of the component (A) and the effect of suppressing aggregation and solidification are insufficient, and if it is too large, granulation may be difficult. Furthermore, the upper limit is preferably 1 or less from the viewpoint of ease of production and administration. The effect of the present invention is greatly influenced by the content ratio of the component (C) to the component (A), and the content of the component (C) is not particularly limited, but is 50% by mass or less in the solid pharmaceutical composition. Thus, a solid pharmaceutical composition having no powderiness and excellent feeling of administration can be obtained, and 5 to 30% by mass is more preferable. Silicon dioxide is one of the excipients used as a lubricant, but usually a blending amount of about several mass% of the whole preparation is sufficient when a lubricant effect is expected.

(D) Hydroxypropylcellulose When wet granulation of the above components (A) to (C), by using hydroxypropylcellulose as a binder, solidification of the ibuprofen granulated product can be prevented and a high elution state can be maintained. , Elution can be improved.

The content of the component (D) is not particularly limited as long as it is within the range acceptable as an internal medicine, but when used as a wet granulation binder, the amount of hydroxypropyl cellulose relative to 100% by mass of the granulated product is particularly limited. However, it is preferably 0.1 to 20% by mass, more preferably 1 to 10% by mass. As the hydroxypropyl cellulose, a commercially available product can be used, and for example, HPC-SSL, HPC-SL, HPC-L, HPC-M, HPC-H, etc. of Nippon Soda Co., Ltd. can be suitably used.

The total content of the components (A), (B) and (C) in the solid pharmaceutical composition of the present invention is preferably 50% by mass or more, more preferably 50 to 100% by mass. In the solid pharmaceutical composition of the present invention, in addition to the above components, other components can be blended in an appropriate amount within a range not impairing the effects of the present invention. In that case, the components (A), (B) and (C) The total content of can be 95% by mass.

The total content of (A), (B), (C) component (D) as necessary in the solid pharmaceutical composition of the present invention is preferably 60 to 100% by mass, more preferably 80 to 100% by mass. 90 to 100% by mass is more preferable. In the solid pharmaceutical composition of the present invention, in addition to the above-mentioned components, other components can be blended in appropriate amounts within a range that does not impair the effects of the present invention.

As other components, (E) aluminum hydroxide (such as dry aluminum hydroxide), magnesium aluminate metasilicate, and (F) acetaminophen are preferable.
(E) Aluminum hydroxide or magnesium aluminate metasilicate can be used individually by 1 type or in combination of 2 or more types.
Aluminum hydroxide and magnesium aluminate metasilicate are antacids, but by blending these components, the amorphous component (A) is prevented from recrystallizing during low-temperature storage and is eluted. The property is maintained even after low temperature storage. As a result, the crystallinity, dissolution property, and suppression of aggregation and solidification with time after low-temperature storage are improved.

The content of the component (E) is not particularly limited as long as it is within the range acceptable for internal use, but the daily dose is preferably 200 to 1500 mg, more preferably 200 to 1300 mg. The mass ratio of the component (E) to the component (A) represented by (E) / (A) is preferably 0.3 to 5, more preferably 0.3 to 4, and 0.3 to 3 Is more preferable. If the above (E) / (A) is less than 0.3, the effect of suppressing recrystallization may be insufficient. If it exceeds 5, the composition blending amount increases, resulting in problems such as reduced dosing properties and uneconomical properties. The effect of the present invention is greatly influenced by the content ratio of the component (E) to the component (A), and the content of the component (E) is not particularly limited, but is 1 to 50% by mass in the solid pharmaceutical composition. It is preferably 10 to 30% by mass, more preferably 15 to 20% by mass.

(F) Acetaminophen Acetaminophen is an antipyretic analgesic or an analgesic auxiliary agent. Surprisingly, (F) component is blended with the composition containing (A) component and (B) component. By doing so, aggregation and solidification over time (during high-temperature storage) is further suppressed.

The content of the component (F) is not particularly limited as long as it is within the range acceptable for internal use, but the daily dose of acetaminophen is preferably 60 to 1800 mg, more preferably 100 to 1200 mg.

Further, the content ratio of the component (F) to the component (A) represented by (F) / (A) is preferably 0.3 to 3. When the ratio is 0.3 or more, the effect of the present invention is improved, that is, the dissolution property of the component (A) is improved and the aggregation and solidification is suppressed over time. May adhere to the manufacturing equipment, resulting in manufacturing problems such as difficulty in uniform mixing and tableting. Furthermore, the lower limit is more preferably 0.4 or more, and further preferably 0.5 or more from the viewpoint of elution. Moreover, from the ease of manufacture, the upper limit is more preferably 2.5 or less, and even more preferably 2 or less. The effect of the present invention is greatly influenced by the content ratio of the component (F) to the component (A), and the content of the component (F) is not particularly limited, but is 1 to 70% by mass in the solid pharmaceutical composition. It is preferably 5 to 60% by mass, more preferably 5 to 50% by mass.

Examples of other ingredients include physiologically active ingredients such as active ingredients of pharmaceuticals other than the above ingredients and functional ingredients of functional foods, excipients such as binders and disintegrants, lubricants, fragrances, flavoring agents (sweetness) And sour agents), surfactants and the like.

Specifically, as the physiologically active component, anti-inflammatory agents other than the component (A) such as aspirin, acetaminophen, etodolac, mefenamic, meclofenamic, piroxicam, isopropylantipyrine, tranexamic acid; nitrazepam, triazolam, phenobarbital , Hypnotics and sedatives such as amibarbital, allylisopropylacetylurea, bromvalenylurea; antiepileptics such as phenytoin, metalbital, primidone, clonazepam, carbamazepine, valproic acid; antidepressants such as meclizine hydrochloride, dimenhydrinate Antidepressants such as imiplanin, noxiptylline, phenelzine; psychopsychiatric agents such as haloperidol, meprobamate, chlordiazepoxide, diazebam, oxazebam, sulpiride; papaverine, atro Antidiabetics such as digoxin, digitoxin, methyldigoxin, ubidecalenone; arrhythmic agents such as pindolol, adimarin, disopyramide; diuretics such as hydrochlorothiazide, spironolactone, triamterene, furosemide, bumetanide; reserpine, dihydromesylate Antihypertensive agents such as ergotoxin, prazosin hydrochloride, metoprolol, propranolol, atenolol; coronary vasodilators such as nitroglycerin, isosorbide nitrate, diltiazem, nifedipine, dipyridamole; noscapine, salbutamol, procaterol, turopterol, tranilast, dextrose hydrobromide Antitussives such as lomethorphan and dihydrocodeine phosphate; bromhexine hydrochloride, ambroxol hydrochloride, guaifenesin Expectorants; cerebral circulation improving agents such as nicardipine and pinpocetine; sympathomimetic agents such as methylephedrine hydrochloride; antibiotics such as erythromycin, josamycin, chloramphenicol, tetracycline, rifampicin, griseofulvin; diphenhydramine, promethazine, mequitazine, clemastine Antihistamines such as fumarate; steroids such as triamcinolone, dexamethasone, betamethasone, prednisolone, danazol, methyltestosterone, chlormadinone acetate; vitamin A, vitamin B, vitamin C (ascorbic acid, etc.), vitamin D, vitamin E , Vitamin K, vitamins such as folic acid (vitamin M); dimethicone, famotidine, ranitidine, cimetidine, nizatidine, metoclopramide, famot Gin, omeprazole, sulpiride, trepibutone, sucralfate, antacids (synthetic hydrotalcite, magnesium oxide, etc.) and other gastrointestinal diseases; caffeine, dicoumarol, cinnarizine, clofibrate, gefarnate, brovenesid, mercaptopurine, methotrexate Ursodeoxycholic acid, dihydroergotamine mesylate, glucuronolactone, γ-aminobutyric acid, chondroitin, sodium chondroitin sulfate, lactoferrin, milk protein, cysteine, collagen and the like.

As the binder, for example, starch, pregelatinized starch, sucrose, gelatin, gum arabic powder, methylcellulose, carmellose, carmellose calcium, carmellose sodium, hydroxypropylmethylcellulose, polyvinylpyrrolidone, pullulan, dextrin and the like can be used. .

Examples of excipients include disintegrants such as carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, crospovidone; lactose, corn starch, talc, crystalline cellulose, Powdered sugar, mannitol, light anhydrous silicic acid, calcium carbonate, L-cysteine and the like can be used.

As the lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, talc, stearic acid, sucrose fatty acid ester and the like can be used. Examples of the fragrances include menthol, limonene, plant essential oils (mint oil, mint oil, lychee oil, orange oil, lemon oil, etc.) and the like.

Examples of the sweetener include saccharin sodium, aspartame, stevia, dipotassium glycyrrhizinate, acesulfame potassium, thaumatin, sucralose, fructose and the like.
Examples of the acidulant include citric acid, tartaric acid, malic acid, succinic acid, fumaric acid, lactic acid, and salts thereof.
Examples of the surfactant include nonionic surfactants, anionic surfactants, cationic surfactants, and amphoteric surfactants.

The solid pharmaceutical composition of the present invention can be produced, for example, by the following methods (1) to (4), among which the method (2) is preferable.
(1). Components (A), (B) and (C), and if necessary, (E), (F) and other optional components are mixed in a Bole type mixer, V type mixer, etc. Aged at night.
(2). (A), (B) and (C) components, (E), (F) and other optional components as required, wet granulation using fluidized bed granulation, stirring granulation, extrusion granulation, etc. To do. The binder is preferably added with the component (D) liquid as a binder liquid.
(3). Components (A), (B) and (C), and optionally (E), (F) and other optional components can be dry granulated with a roller compactor or the like. Depending on the granulation conditions, aging overnight may be necessary near room temperature.
(4). Components (A), (B) and (C), and if necessary, (E), (F) and other optional components are mixed and pulverized by a pin mill, a ball mill or the like. In this case, aging is unnecessary.
Furthermore, it can be pulverized, pulverized, and sized by a vibration sieve, a comb mill, a flash mill, a power mill or the like. The mixing of the component (A) and the component (B) is not particularly limited as long as it is at room temperature (20 ° C.) or more, and the component (A) becomes amorphous by the component (B).

In the present invention, it is preferable to use a heated mixture of (A) a propionic acid-based or acetic acid-based non-steroidal anti-inflammatory drug and (B) an aminoalkyl methacrylate copolymer E. In the present invention, the heated mixture refers to a mixture obtained by heating and mixing the component (A) and the component (B) and then cooling to a solid. The heating and mixing temperature is preferably 40 ° C. or higher, more preferably 50 ° C. or higher, and further preferably 70 ° C. or higher. The upper limit is preferably 100 ° C. or less from the viewpoint of stability such as discoloration. The cooling temperature is preferably 35 ° C. or lower, more preferably 30 ° C. or lower, and it may be allowed to cool to room temperature. In the present invention, since the component (C) is used, there is little influence by the production method. However, by using a heated mixture, the component (A) made amorphous by the component (B) is prevented from recrystallizing during low-temperature storage. In addition, elution properties after low-temperature storage are easily maintained.

The method using the heated mixture includes a step of heating and mixing the component (A) and the component (B) in the range of the heating and mixing temperature, and examples thereof include the following methods.
(5). A method in which the components (A), (B) and (C), and optional components as necessary, are heated and mixed within the range of the heating and mixing temperature.
(6). The components (A) and (B) are heated and mixed within the range of the above heating and mixing temperature, and the resulting heated mixture, the component (C), and optional components as necessary are fluidized bed granulated, stirred granulated, Wet granulation using extrusion granulation or the like. The binder is preferably added with the component (D) liquid as a binder liquid.
(7). The components (A) and (B) are heated and mixed within the range of the above heating and mixing temperature, and the obtained heated mixture, the component (C), and optional components as needed are dry granulated with a roller compactor or the like. You can also
(8). The components (A) and (B) are heated and mixed within the range of the heating and mixing temperature, and the resulting heated mixture, the component (C), and optional components are mixed as necessary.
Further, after heating, it may include a step of cooling to an environmental temperature, for example, room temperature (20 ° C.), and a step of pulverizing, crushing, and sizing with a vibration sieve, a com mill, a flash mill, a power mill, or the like.
In addition, when adding (E) and / or (F), you may add at the time of heat mixing of (A) and (B) component, respectively, and may add after heat mixing, but add at the time of heat mixing. It is preferable to do.

As described above, the solid pharmaceutical composition of the present invention is a compound in which the component (A) is non-crystallized and the component (A) and the component (B) are combined. The structure of the solid pharmaceutical composition of the present invention is such that, for example, a composite composed of (A) component and (B) component in which (A) component is amorphized and co-melted is between the particles of (C) component. Predicted to be held.

The average particle size of the solid pharmaceutical composition is preferably 20 to 1000 μm, more preferably 50 to 850 μm, and even more preferably 80 to 600 μm. The average particle size is a median diameter by a laser diffraction scattering particle size distribution measuring instrument (dry) (D _50).

(II) Pharmaceutical preparation The solid pharmaceutical composition can be taken internally, in this case (in this case, the solid pharmaceutical composition and the pharmaceutical preparation are the same composition) or mixed with other optional ingredients to form a pharmaceutical preparation be able to. For example, it can be used as a granule (granule, fine granule, powder) or tableted as necessary to obtain a solid pharmaceutical preparation for internal use such as a tablet or capsule. The content of the solid pharmaceutical composition is preferably 30 to 100% by mass, more preferably 50 to 100% by mass in the pharmaceutical preparation.

An appropriate amount of optional ingredients other than the solid pharmaceutical composition can be blended in the pharmaceutical preparation. As an arbitrary component, the component mix | blended with a tablet, a granule, and a capsule can be mix | blended in the range which does not impair the effect of this invention. These components can be used individually by 1 type or in combination of 2 or more types, The appropriate quantity can be mix | blended. The following are mentioned as an arbitrary component. In addition, said pharmaceutical (C) can be mix | blended with a pharmaceutical formulation separately from a solid pharmaceutical composition. The content of the component (C) in the pharmaceutical preparation is not particularly limited as long as it is an amount acceptable as an OTC pharmaceutical, but it is usually preferably 10 to 60% by mass.

Specifically, as the physiologically active component, anti-inflammatory agents other than the component (A) such as aspirin, acetaminophen, etodolac, mefenamic, meclofenamic, piroxicam, isopropylantipyrine, tranexamic acid; nitrazepam, triazolam, phenobarbital , Hypnotics and sedatives such as amibarbital, allylisopropylacetylurea, bromvalenylurea; antiepileptics such as phenytoin, metalbital, primidone, clonazepam, carbamazepine, valproic acid; antidepressants such as meclizine hydrochloride, dimenhydrinate Antidepressants such as imiplanin, noxiptylline, phenelzine; psychopsychiatric agents such as haloperidol, meprobamate, chlordiazepoxide, diazebam, oxazebam, sulpiride; papaverine, atro Antidiabetics such as digoxin, digitoxin, methyldigoxin, ubidecalenone; arrhythmic agents such as pindolol, adimarin, disopyramide; diuretics such as hydrochlorothiazide, spironolactone, triamterene, furosemide, bumetanide; reserpine, dihydromesylate Antihypertensive agents such as ergotoxin, prazosin hydrochloride, metoprolol, propranolol, atenolol; coronary vasodilators such as nitroglycerin, isosorbide nitrate, diltiazem, nifedipine, dipyridamole; noscapine, salbutamol, procaterol, turopterol, tranilast, dextrose hydrobromide Antitussives such as lomethorphan and dihydrocodeine phosphate; bromhexine hydrochloride, ambroxol hydrochloride, guaifenesin Expectorants; cerebral circulation improving agents such as nicardipine and pinpocetine; sympathomimetic agents such as methylephedrine hydrochloride; antibiotics such as erythromycin, josamycin, chloramphenicol, tetracycline, rifampicin, griseofulvin; diphenhydramine, promethazine, mequitazine, clemastine Antihistamines such as fumarate; steroids such as triamcinolone, dexamethasone, betamethasone, prednisolone, danazol, methyltestosterone, chlormadinone acetate; vitamin A, vitamin B, vitamin C (ascorbic acid, etc.), vitamin D, vitamin E , Vitamin K, vitamins such as folic acid (vitamin M); dimethicone, famotidine, ranitidine, cimetidine, nizatidine, metoclopramide, famot Gastrointestinal disease treatments such as gin, omeprazole, sulpiride, trepibutone, sucralfate, antacids (aluminum hydroxide, synthetic hydrotalcite, magnesium oxide, magnesium metasilicate aluminate, etc.); caffeine, dicoumarol, cinnarizine, black Examples include fibrates, gefarnates, brobenesids, mercaptopurines, methotrexates, ursodeoxycholic acid, dihydroergotamine mesylate, glucuronolactone, γ-aminobutyric acid, chondroitin, sodium chondroitin sulfate, lactoferrin, milk protein, cysteine, collagen and the like.

Examples of the binder include starch, pregelatinized starch, sucrose, gelatin, gum arabic powder, methylcellulose, carmellose, carmellose calcium, carmellose sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, pullulan, dextrin and the like. Can be used.

Hereinafter, although an Example and a comparative example are shown and this invention is demonstrated concretely, this invention is not restrict | limited to the following Example. In the following examples, unless otherwise specified, the ratio indicates a mass ratio.

[Examples 1 to 16, Comparative Examples 1 to 10]
Each component in Tables 1 to 4 was wet granulated according to a conventional method using an LFS-GS-2J high speed mixer (wet agitation granulator) manufactured by Fukae Pautech Co., Ltd. As the binder liquid, an 8% by mass aqueous solution of hydroxypropylcellulose (Nippon Soda Co., Ltd. HPC-SSL) was used, and the amount of the aqueous solution that was 5% by mass of the total amount of (A) to (C) was dropped. did. The obtained granule (solid pharmaceutical composition) was dried at 50 ° C. for 18 hours, and the following evaluation was performed. In the examples, the composition did not adhere to the production apparatus, and the manufacturability was also good. The average particle diameter (median diameter (D ₅₀ ) by laser diffraction scattering type particle size distribution analyzer (dry type)) in the examples was in the range of 80 to 600 μm.

[Elution rate (%)]
The dissolution test of ibuprofen was confirmed by the dissolution test with the Japanese Pharmacopoeia. A pH 4.5 acetate buffer was used as a test solution, and measurement was performed under the conditions of 130 mg / 900 mL (dissolution after 5 minutes).

[Inhibition of aggregation and solidification after drying]
Judgment was made visually according to the following criteria.
<Standard>
◎: Not at all ○: Slight agglomeration is observed, but it can be easily loosened ×: Considerable agglomeration is observed, lump is solidified and cannot be loosened XX: Remarkably agglomerated and the whole is solidified

DSC measurement of granulated particles (solid pharmaceutical composition) and ibuprofen of Example 1 was performed. In the granulated particles of Example 1, no ibuprofen peak was observed by DSC, and it was confirmed that ibuprofen was amorphous and was a composite.

[Example 17]
The following composition was mixed and tableted with a tableting tester to obtain a tablet having a diameter of 10 mm.
Composition g
Example 1 Granules (solid pharmaceutical composition) 390 g
Acetaminophen 130g
Bromhexine hydrochloride 4g
Cremastine fumarate 0.45g
Anhydrous caffeine 25g
Ascorbic acid 100g
Dextromethorphan hydrobromide hydrate 16g
dl-Methylephedrine hydrochloride 20g
Silicon dioxide (Silicia 740) 10g
150 g of crystalline cellulose (Theolas KG801)
Lactose 150g
Low substituted hydroxypropylcellulose 30g
Croscarmellose sodium 20g
Magnesium stearate 3g

[Example 18]
The following composition was mixed to obtain a fine granule.
Composition g
399 g of the granule of Example 4 (solid pharmaceutical composition)
Anhydrous caffeine 25g
Bromhexine hydrochloride 4g
Cremastine fumarate 0.45g
Ascorbic acid 100g
Dihydrocodeine phosphate 8g
dl-Methylephedrine hydrochloride 20g
30 g of silicon dioxide (Silicia 740)
D-mannitol 150g
Fragrance 0.5g

[Example 19]
The following composition was mixed and tableted with a tableting tester to obtain a tablet having a diameter of 10 mm.
Composition g
Granules of Example 5 (solid pharmaceutical composition) 409.9 g
Acetaminophen 130g
Anhydrous caffeine 25g
150 g of crystalline cellulose (Theolas PH302)
D-mannitol 150g
Low substituted hydroxypropylcellulose 30g
Crospovidone (XL-10) 20g
Magnesium stearate 3g

[Example 20]
The following composition was mixed to obtain a fine granule.
Composition g
630 g of the granule of Example 6 (solid pharmaceutical composition)
Anhydrous caffeine 25g
60 g of allyl isopropyl acetyl urea
Erythritol 50g
Lactose 50g

[Example 21]
The following composition was mixed and tableted with a tableting tester to obtain a tablet having a diameter of 10 mm.
Composition g
315 g of the granule of Example 5 (solid pharmaceutical composition)
Acetaminophen 100g
Anhydrous caffeine 25g
Ambroxol hydrochloride 15g
Cremastine fumarate 0.45g
Ascorbic acid 100g
Dextromethorphan hydrobromide hydrate 16g
dl-Methylephedrine hydrochloride 20g
Magnesium carbonate 200g
Crystalline cellulose (Theolas KG801) 100g
Croscarmellose sodium 20g
Magnesium stearate 3g
Fragrance 0.5g

[Example 22]
The following composition was mixed to obtain a fine granule.
Composition g
472.5 g of granules (solid pharmaceutical composition) obtained in the same manner except that ibuprofen in Example 5 was changed to naproxen
Anhydrous caffeine 25g
Magnesium carbonate 200g
D-mannitol 100g
Sucralose 0.5g
Fragrance 0.5g

[Example 23]
The following composition was mixed and filled into gelatin capsules to form capsules.
Composition g
472.5 g of granules (solid pharmaceutical composition) obtained in the same manner except that ibuprofen in Example 5 was changed to ketoprofen
Anhydrous caffeine 25g
60 g of allyl isopropyl acetyl urea
150 g of crystalline cellulose (Theolas PH302)
D-mannitol 150g
The elution properties of the component (A) in Examples 17 to 23 were as high as those in Examples 1 to 16, and there was no aggregation and solidification.

[Examples 24 to 28]
Each component in Table 5 was wet granulated in accordance with a conventional method using an LFS-GS-2J high speed mixer (wet stirring granulator) manufactured by Fukae Pautech Co., Ltd. Water was used as the binder liquid, and an amount of the aqueous solution that was 5% by mass of the total amount of (A) to (C) was added dropwise. The obtained granule (solid pharmaceutical composition) was dried at 50 ° C. for 18 hours. In the examples, the composition did not adhere to the production apparatus, and the manufacturability was also good.
About the obtained granule (solid pharmaceutical composition), the elution test of ibuprofen and the aggregation solidification suppression evaluation after drying were performed similarly to the said Example.

[Examples 29 to 38]
Each component in Tables 6 and 7 was wet granulated according to a conventional method using an LFS-GS-2J high speed mixer (wet stirring granulator) manufactured by Fukae Pautech Co., Ltd. Water was used as the binder liquid, and the hydroxypropylcellulose aqueous solution was added dropwise so that the solid content was 5% by mass of the total amount of (A) to (C). The granules were dried at 50 ° C. for 18 hours.
The obtained granule (solid pharmaceutical composition) was stored at 50 ° C. for 1 month (encapsulated in an aluminum pouch), and the eluate of ibuprofen was used in the same manner as in the above examples for the initial and those stored at 50 ° C. for 1 month. The test was conducted to evaluate the aggregation and solidification inhibition after drying.

[Example 39]
The following composition was mixed and tableted with a tableting tester to obtain a tablet having a diameter of 10 mm.
Composition g
390 g of granulated particles of Example 25
Bromhexine hydrochloride 4g
Cremastine fumarate 0.45g
Anhydrous caffeine 25g
Ascorbic acid 100g
Dextromethorphan hydrobromide hydrate 16g
dl-Methylephedrine hydrochloride 20g
Silicon dioxide (Silicia 740) 10g
150 g of crystalline cellulose (Theolas KG801)
Lactose 150g
Low substituted hydroxypropylcellulose 30g
Croscarmellose sodium 20g
Magnesium stearate 3g

[Example 40]
The following composition was mixed to obtain a fine granule.
Composition g
415 g of granulated particles of Example 26
Bromhexine hydrochloride 4g
Cremastine fumarate 0.45g
Ascorbic acid 100g
Dihydrocodeine phosphate 8g
dl-Methylephedrine hydrochloride 20g
30 g of silicon dioxide (Silicia 740)
D-mannitol 150g
Fragrance 0.5g

[Example 41]
The following composition was mixed and tableted with a tableting tester to obtain a tablet having a diameter of 10 mm.
Composition g
460 g of granulated particles of Example 27
Anhydrous caffeine 25g
150 g of crystalline cellulose (Theolas PH302)
D-mannitol 150g
Low substituted hydroxypropylcellulose 30g
Crospovidone (XL-10) 20g
Magnesium stearate 3g
Sucralose 1.5g
Fragrance 0.5g

[Example 42]
The following composition was mixed to obtain a fine granule.
Composition g
460 g of granulated particles of Example 36
Anhydrous caffeine 25g
60 g of allyl isopropyl acetyl urea
150 g of crystalline cellulose (Theolas KG801)
Lactose 150g

[Example 43]
The following composition was mixed and tableted with a tableting tester to obtain a tablet having a diameter of 10 mm.
Composition g
575 g of granulated particles of Example 28
Ambroxol hydrochloride 15g
Cremastine fumarate 0.45g
Ascorbic acid 100g
Dextromethorphan hydrobromide hydrate 16g
dl-Methylephedrine hydrochloride 20g
70g of dry aluminum hydroxide gel
150 g of crystalline cellulose (Theolas KG801)
Croscarmellose sodium 20g
Magnesium stearate 3g
Fragrance 0.5g

[Example 44]
The following composition was mixed to obtain a fine granule.
Composition g
460 g of granulated particles obtained by replacing ibuprofen in Example 25 with naproxen
70g of dry aluminum hydroxide gel
150 g of crystalline cellulose (Theolas PH302)
D-mannitol 150g
Hydroxypropylcellulose 30g
Crospopidone (Kollidon CL) 20g
Magnesium stearate 3g
Sucralose 0.5g
Fragrance 0.5g

[Example 45]
The following composition was mixed and filled into gelatin capsules to obtain capsules.
Composition g
460 g of granulated particles obtained by replacing ibuprofen in Example 26 with ketoprofen
60 g of allyl isopropyl acetyl urea
150 g of crystalline cellulose (Theolas PH302)
D-mannitol 150g
Hydroxypropylcellulose 30g
Crospopidone (Kollidon CL) 20g
Magnesium stearate 3g
Sucralose 1.5g
Fragrance 0.5g
The elution properties of the component (A) of Examples 40 to 45 were as high as those of Examples 25 to 38 even after storage at 50 ° C. for 1 month, and there was no aggregation and solidification.

[Examples 46 to 50]
Each component of Table 8 was mixed at 80 ° C. for 10 minutes, and stored at 5 ° C. and 50 ° C. (encapsulated in an aluminum pouch). About the mixture after a preservation | save, the elution test of ibuprofen and the aggregation solidification suppression evaluation after drying were performed similarly to the said Example about the thing after 1 month preservation | save at 50 degreeC. Moreover, crystallinity was measured by the following method about the thing after an initial and 3 months storage at 5 degreeC.

[Amorphous]
The amorphousness (suppression of recrystallization) of the component (A) was evaluated by DSC (manufactured by Rigaku Corporation, DSC-8230D). The criteria are as follows.
<Standard>
○: Amorphous Δ: Very low crystal (within 0.5 mW / mg as absolute value of peak)
×: Crystal

The raw materials used in the examples are shown below. In addition, the quantity in a table | surface is the quantity of each component.

Claims

(A) A propionic acid-based or acetic acid-based non-steroidal anti-inflammatory drug, (B) an aminoalkyl methacrylate copolymer E, and (C) silicon dioxide, and represented by (B) / (A) The mass ratio of the component (B) to the component (A) is 0.5 to 2, and the mass ratio of the component (C) to the component (A) represented by (C) / (A) is 0. A solid pharmaceutical composition that is 5-2.
The solid pharmaceutical composition according to claim 1, wherein the component (A) is ibuprofen.
The solid pharmaceutical composition according to claim 1 or 2, wherein the components (A), (B) and (C) are wet granulated using a liquid containing (D) hydroxypropylcellulose.
The solid pharmaceutical composition according to any one of claims 1 to 3, further comprising (E) aluminum hydroxide or magnesium aluminate metasilicate.
The solid pharmaceutical composition according to any one of claims 1 to 4, further comprising (F) acetaminophen.
The solid pharmaceutical composition according to any one of claims 1 to 5, wherein the total content of the components (A), (B) and (C) in the solid pharmaceutical composition is 50 to 100% by mass.
A pharmaceutical preparation comprising the solid pharmaceutical composition according to any one of claims 1 to 6 and being a tablet, granule, fine granule or capsule.