JP2013035777A - Solid pharmaceutical composition and pharmaceutical formulation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To stabilize a soluble state of (A) a propionic acid-based or acetic acid-based non-steroidal anti-inflammatory drug once dissolved in the stomach (acidic), and further to provide a solid pharmaceutical composition suppressed in gastric damage caused by the component (A).SOLUTION: The solid pharmaceutical composition contains: (A) a propionic acid-based or acetic acid-based non-steroidal anti-inflammatory drug; (B) an aminoalkyl methacrylate copolymer E; (C) a polyvinylpyrrolidone or hydroxypropyl methylcellulose; and (D) an excipient.

Description

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

  Orally administered drugs are not absorbed until they are dissolved in body fluids. Drugs have many poorly water-soluble components, and antipyretic analgesic propionic acid or acetic acid non-steroidal anti-inflammatory drugs are one of them. If the dissolution is insufficient, the effect is not sufficiently exhibited in the living body, and there is a problem that it takes time to develop it, and means for improving the solubility and dissolution rate have been studied.

JP-A-3-83922 JP-A-8-291063

  The reason why a preparation containing (A) a propionic acid-based or acetic acid-based non-steroidal anti-inflammatory drug and (B) an aminoalkyl methacrylate copolymer E is advantageous in other amorphization means is the above (A) The point which shows the solubility (supersaturated dissolution) greatly exceeding the solubility of a component is mentioned. However, the once dissolved component (A) tends to precipitate over time in an acidic solution. The present invention has been made in view of the above circumstances, and stabilizes the dissolved state of the dissolved component (A) in the stomach (acidic), and further suppresses gastric damage due to the component (A). And it aims at providing the pharmaceutical formulation formed by mix | blending this.

  As a result of intensive studies to achieve the above object, the present inventors have found that (A) a propionic acid-based or acetic acid-based non-steroidal anti-inflammatory drug, (B) an aminoalkyl methacrylate copolymer E, (D) By blending (C) polyvinylpyrrolidone or hydroxypropylmethylcellulose with a solid pharmaceutical composition containing a mold, it is possible to maintain the dissolved state of component (A) in acidity, and to reduce stomach damage It has been found that this has been achieved, and the present invention has been made.

Accordingly, the present invention provides the following solid pharmaceutical composition.
[1]. (A) Propionic acid-based or acetic acid-based non-steroidal anti-inflammatory drug, (B) aminoalkyl methacrylate copolymer E, (C) polyvinylpyrrolidone or hydroxypropylmethylcellulose, and (D) excipient A solid pharmaceutical composition characterized by the above.
[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 mass ratio of the component (A) and the component (C) represented by (C) / (A) is 0.1 to 2.
[4]. The solid pharmaceutical composition according to [1], [2], or [3], wherein the particles comprising (A) component, (B) component, and (D) component and particles containing (C) component are blended.
[5]. [1] A pharmaceutical preparation comprising the solid pharmaceutical composition according to any one of [4], which is a tablet, granule, fine granule or capsule.

  According to the present invention, it contains ibuprofen that stabilizes the dissolved state in the stomach (acidic) of the dissolved (A) propionic acid-based or acetic acid-based non-steroidal anti-inflammatory drug and further reduces gastric damage. A solid pharmaceutical composition can be provided.

Hereinafter, the present invention will be described in detail.
(I) Solid pharmaceutical composition The solid pharmaceutical composition of the present invention comprises (A) a propionic acid-based or acetic acid-based non-steroidal anti-inflammatory drug, (B) an aminoalkyl methacrylate copolymer E, and (C) polyvinylpyrrolidone. Alternatively, it contains hydroxypropylmethylcellulose and (D) an excipient.

(A) Propionic acid-based or acetic acid-based non-steroidal anti-inflammatory drugs Propionic acid-based and acetic acid-based drugs refer to those having a propionic acid group and an acetic acid group, respectively.
1 type can be used individually or in combination of 2 or more types as appropriate. Non-steroidal anti-inflammatory drugs include known ones. Examples of propionic acid non-steroidal anti-inflammatory drugs include ibuprofen, ketoprofen, naproxen, flurbiprofen, and the like. Examples of acetic acid non-steroidal anti-inflammatory drugs include diclofenac, indomethacin, felbinac, etodolac and the like.

  The content of the component (A) is not particularly limited as long as it is within the blending tolerance range for pharmaceuticals (drug approval standard amount). When it is set as an OTC pharmaceutical, for example, 200 to 600 mg is preferable as the daily dose of ibuprofen, and 390 to 450 mg is more preferable. Moreover, 1-50 mass% is preferable in a solid pharmaceutical composition, 5-50 mass% is more preferable, and 10-50 mass% is further more preferable.

(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. 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 A) component and the (B) component interact with each other. This interaction 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 as an internal medicine (unprecedented amount of pharmaceutical use), but the daily dose (per adult, the same shall apply hereinafter) is preferably 60 to 1800 mg, 100 -1200 mg is more preferred. Moreover, 0.3-3 are preferable and, as for the containing mass ratio of (B) component with respect to (A) component represented by (B) / (A), 0.5-2 are more preferable. When (B) / (A) is 0.3 or more, the elution of the component (A) is further improved. When it exceeds 3, there is a possibility that the preparation becomes too large and the ingestibility is deteriorated. 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, 1-50% by weight is more preferred, and 1-30% by weight is even more preferred.

(C) Polyvinylpyrrolidone or hydroxypropylmethylcellulose By blending the specific water-soluble polymer compound of the present invention, the dissolved state of dissolved (A) ibuprofen in the stomach (acidic) can be stabilized.

  The content of the component (C) is not particularly limited as long as it is within the range acceptable as an internal medicine (unprecedented amount of pharmaceutical use), but the daily dose is preferably 10 to 1000 mg, more preferably 20 to 500 mg. Moreover, 0.01-3 are preferable, as for the mass ratio of (C) component with respect to (A) component represented by (C) / (A), 0.08-3 are more preferable, 0.1-2 Is more preferable, and 0.12 to 2 is particularly preferable. If the ratio of (C) / (A) is less than 0.01, the dissolved state in the stomach (acidic) of dissolved (A) ibuprofen may be insufficient, and if it exceeds 3, May become too large and the dosage may be poor. In the present invention, the content ratio of the component (C) to the component (A) is greatly affected, and the content of the component (C) is not particularly limited, but 0.1 to 50% by mass in the solid pharmaceutical composition Preferably, 0.5-30 mass% is more preferable.

(D) Molding agent Examples of the molding agent of the present invention include silicon dioxide, crystalline cellulose, sugar alcohol, saccharide, and the like, which can be used singly or in appropriate combination of two or more. By blending an excipient, aggregation of the preparation is prevented and manufacturability is also improved. Silicon dioxide has general names such as light anhydrous silicic acid, hydrous silicon dioxide, silica, white carbon and the like. Commercially available products can also be used, such as “Silicia” and “Syrosphere” (both trade names) of Fuji Silysia Chemical Co., Ltd. Examples of the sugar alcohol include sorbitol, erythritol, xylitol, mannitol, maltitol, lactitol, and palatinit. Examples of the saccharide include lactose, corn starch, powdered sugar, sucrose, and glucose. As the excipient, crystalline cellulose is preferred.

  The content of the component (D) is not particularly limited as long as it is within the range acceptable as an internal medicine, but the daily dose is preferably 50 to 1000 mg, more preferably 100 to 800 mg. Moreover, the content mass ratio of (D) component with respect to (A) component represented by (D) / (A) is preferably 0.3 to 3, and more preferably 0.4 to 2. By setting (D) / (A) to 0.3 or more, the anti-aggregation effect and manufacturability (grindability etc.) of the preparation are improved. Although content of (D) component is not specifically limited, 0.1-50 mass% is preferable in a solid pharmaceutical composition, and 0.5-35 mass% is more preferable.

  The solid pharmaceutical composition of the present invention can contain optional components other than the above components as long as the effects of the present invention are not impaired. Optional ingredients include physiologically active ingredients such as active ingredients of pharmaceuticals other than the above ingredients and functional ingredients of functional foods, binders, disintegrants, lubricants, flavorings, flavoring agents (sweeteners, acidulants, etc.), pigments , Stabilizers, coating agents, plasticizers, hiding agents, and the like, can be used alone or in appropriate combination of two or more. The content of optional components other than the components (A) to (D) in the solid pharmaceutical composition may be 0% by mass or 0 to 80% by mass.

  The solid pharmaceutical composition of the present invention can be obtained, for example, by mixing or uniformly mixing the components (A), (B), (C) and (D). Furthermore, from the viewpoint of fast solubility, it is preferable to prepare a mixture containing the component (A), the component (B) and the component (D) in advance, and add the component (C) thereto. For mixing, a Boule type mixer, a V type mixer, or the like can be used. In view of improving the solubility by making the component (A) amorphous with the component (B), it is preferable to heat to 40 ° C. or higher during or after mixing. The heating time is not particularly limited and is preferably 6 to 20 hours. Further, in the case of mixed pulverization (co-grinding), it can be made amorphous without heating. In view of the solubility of the component (A), the particles containing the component (A), the component (B) and the component (D), and the particles containing the component (C) may be prepared and blended in advance. The granulation method is not particularly limited, and for example, the mixture (A), the component (B), and the component (C) containing the component (C) may be pulverized with a mixer or the like. Further, wet granulation such as fluidized bed granulation, stirring granulation, extrusion granulation may be used. The wet granulation binder can be a known binder such as HPC or starch, or water alone. Moreover, dry granulation can also be performed with a roller compactor or the like. 20-1000 micrometers is preferable and, as for the average particle diameter of the particle | grains containing (A) component, (B) component, and (D) component, and the particle | grains containing (C) component, 50-850 micrometers is more preferable. The average particle diameter of the present invention is a value obtained by measuring a 50% diameter (median diameter, volume basis) using a laser diffraction particle size distribution measuring device (for example, LS13 320 manufactured by BECKMAN COULTER). is there.

(II) Pharmaceutical preparation The solid pharmaceutical composition can be used internally, and as it is, the pharmaceutical preparation (in this case, the solid pharmaceutical composition and the pharmaceutical preparation are the same composition), or a pharmaceutical preparation mixed with other optional ingredients It can be. For example, it can be granulated (granule, fine granule, powder) or, if necessary, tableted into a solid pharmaceutical composition for internal use such as tablets and capsules. 100 mass% may be sufficient as content of a solid pharmaceutical composition, 20-100 mass% is preferable in a pharmaceutical formulation, and 30-100 mass% is more preferable. The upper limit may be 98% by mass. In addition, the said (D) component can be mix | blended with a pharmaceutical formulation separately from a solid pharmaceutical composition. If the compounding quantity of (D) component in a pharmaceutical formulation is a compounding quantity accept | permitted as an OTC pharmaceutical, it will not specifically limit, 0.5-50 mass% is preferable.

In the case of a granule, it can be appropriately crushed or sieved. 20-1000 micrometers is preferable and, as for the average particle diameter of a solid pharmaceutical composition, 50-850 micrometers is more preferable.
In the case of a tablet, from the viewpoint of ease of handling of the tablet and swallowability, the tablet diameter is preferably 8.0 to 13 mmφ, and more preferably 8.0 to 11 mmφ. In addition, the tablet mass per tablet is appropriately about 180 to 600 mg.

  In the case of making a tablet, the components (A) to (D) and an appropriate amount of optional components may be mixed as needed, and the mixture may be filled in a tableting machine and tableted to obtain a tablet. Moreover, it can also granulate with a granulator and can also be used as a granule and a fine granule. The following are mentioned as an arbitrary component.

  Specifically, as the physiologically active ingredient, anti-inflammatory agents other than (A) such as aspirin, acetaminophen, mefenamic, meclofenamic, piroxicam, isopropylantipyrine, tranexamic acid; nitrazepam, triazolam, phenobarbital, amibarbita Hypnosis and sedatives such as le, allyl isopropyl acetyl urea, bromvalenyl urea; analgesics such as caffeine; antiepileptics such as phenytoin, metalbital, primidone, clonazepam, carbamazepine, valproic acid; meclizine hydrochloride, dimenhydrinate, etc. Antidepressants such as imiplanin, noxiptylline, phenelzine; psychopsychiatric agents such as haloperidol, meprobamate, chlordiazepoxide, diazebam, oxazebam, sulpiride; Antispasmodic agents such as lopin and etmidrin; cardiotonic agents such as digoxin, digitoxin, methyldigoxin and ubidecalenone; arrhythmic agents such as pindolol, adimarin and disopyramide; diuretics such as hydrochlorothiazide, spironolactone, triamterene, furosemide and bumetanide; reserpine and dihydrosilicic acid 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, guaifene Expectorants such as nicotine; cerebral circulation improving agents such as nicardipine and pinpocetine; sympathomimetics such as methylephedrine hydrochloride; antibiotics such as erythromycin, josamycin, chloramphenicol, tetracycline, rifampicin, griseofulvin; diphenhydramine, promethazine, mequitazine Antihistamines such as clemastine fumarate; steroids such as triamcinolone, dexamethasone, betamethasone, prednisolone, danazol, methyltestosterone, chlormadinone acetate; vitamins A, vitamins B, vitamins C (ascorbic acid, etc.), vitamins D, Vitamins such as vitamin E, vitamin K, folic acid (vitamin M); dimethicone, famotidine, ranitidine, cimetidine, nizatidine, metoclopramide, Gastrointestinal disease treatments such as motidine, omeprazole, sulpiride, trepibutone, sucralfate, antacids (synthetic hydrotalcite, magnesium oxide, etc.); Examples include oxycholic acid, dihydroergotamine mesylate, glucuronolactone, γ-aminobutyric acid, chondroitin, sodium chondroitin sulfate, lactoferrin, milk protein, cysteine, collagen, and dry aluminum hydroxide gel.

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

  As the disintegrant, for example, carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, crospovidone and the like can be used.

  As the lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, talc, stearic acid, sucrose fatty acid ester, sodium stearyl fumarate 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.

  EXAMPLES 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.

[Examples 1-11, Comparative Examples 1-6]
Components (A), (B) and (D) were mixed with powder, heated at 40 ° C. for 16 hours, cooled, and pulverized with a desktop mixer. The (C) component was added to the obtained pulverized product to obtain a granule. The average particle size of the granule was 200 to 400 μm.

[Examples 12 and 13]
Components (A) to (D) were mixed with powder, heated at 40 ° C. for 16 hours, cooled, and pulverized with a desktop mixer to obtain a granule.
The following evaluation was performed about the obtained granule. The results are also shown in the table. The average particle size of the granule was 200 to 400 μm. Amorphization was confirmed by the peak of the DSC (A) component.

<Elution (Elution of component (A))>
The following tests were performed based on the JP dissolution test method. The dissolution rate at 5 minutes and 15 minutes after the start of the test was tested. (5 minutes: dissolution rate, 15 minutes: effect of maintaining high solubility)
The test was conducted by introducing the prepared sample so that ibuprofen was 390 mg / 900 mL. The dissolution test solution used was a pH 1.2 test solution (Japanese Pharmacopoeia 1 solution) and tested with a dissolution tester (DISSOLUTION TESTER Toyama Sangyo Co., Ltd.)
The dissolution rate (%) is calculated from the amount of ibuprofen contained in the preparation and the dissolution amount of ibuprofen dissolved in the solution using the following formula, and the dissolution rate (%) obtained is dissolved according to the following evaluation criteria. Sex was evaluated.
Dissolution rate (%) = Amount of ibuprofen eluted (mg) / Amount of ibuprofen in formulation (mg) × 100
[Evaluation criteria]
◎: Elution rate 70% or more ○: 60% or more and less than 70% ×: Less than 60%

<Inhibition of gastric disorder>
(1) Four hours after oral administration, the stomach was removed under isoflurane anesthesia. Immediately after gastrectomy, 10 mL of physiological saline was injected into the stomach with a sonde, and placed in a 1% by mass formalin solution for 1 hour or longer and fixed.
(2) After fixation with formalin, open the stomach bay, wash the contents with saline, spread the stomach on filter paper and paste it, measure the length (mm) of the ulcer, and calculate the average value (n = 8) was calculated. From the average value obtained, gastric disorder suppression is shown according to the following evaluation criteria.
[Evaluation criteria]
○: Less than 10 mm ×: 10 mm or more

[Example 14]
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 1 (solid pharmaceutical composition) 1530 g
Acetaminophen 390g
240g anhydrous caffeine
180 g of allyl isopropyl acetyl urea
210g of dry aluminum hydroxide gel
150 g of silicon dioxide (Silicia 350)
200 g of crystalline cellulose (Theolas UF-711)
Low substituted hydroxypropylcellulose 30g
Croscarmellose sodium 80g
Magnesium stearate 8g

[Example 15]
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 2 (solid pharmaceutical composition) 1230 g
Acetaminophen 390g
240g anhydrous caffeine
180 g of allyl isopropyl acetyl urea
210g of dry aluminum hydroxide gel
150 g of silicon dioxide (Silicia 350)
290 g of crystalline cellulose (Theolas UF-711)
Low substituted hydroxypropylcellulose (LH-31) 30g
Croscarmellose sodium 80g
Magnesium stearate 8g

[Example 16]
The following composition was mixed and filled into gelatin capsules to form capsules.
Granules of Example 2 (solid pharmaceutical composition) 1230 g
Acetaminophen 390g
240g anhydrous caffeine
180 g of allyl isopropyl acetyl urea
210g of dry aluminum hydroxide gel
150 g of silicon dioxide (Silicia 740)
Crospovidone 80g
Magnesium stearate 8g

  The raw materials used in the above examples are shown below. Unless otherwise specified, the amount of each component in the table is a pure conversion amount.

Claims (5)

  (A) Propionic acid-based or acetic acid-based non-steroidal anti-inflammatory drug, (B) aminoalkyl methacrylate copolymer E, (C) polyvinylpyrrolidone or hydroxypropylmethylcellulose, and (D) excipient A solid pharmaceutical composition characterized by the above.   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 a mass ratio of the component (A) and the component (C) represented by (C) / (A) is 0.1 to 2.   The solid pharmaceutical composition according to claim 1, 2 or 3, wherein the particles comprising (A) component, (B) component and (D) component and particles containing (C) component are blended.   The pharmaceutical formulation which mix | blends the solid pharmaceutical composition of any one of Claims 1-4, and is a tablet, a granule, a fine granule, or a capsule.