JP5598108B2 - Solid composition for internal use - Google Patents

Description

  The present invention relates to a solid composition for internal use having high stability over time.

The common cold medicine generally contains an antitussive expectorant, an antihistamine and the like together with an antipyretic analgesic component. However, a formulation containing ibuprofen or acetaminophen, which is an active ingredient of antipyretic analgesics, and bromhexine hydrochloride, ambroxol hydrochloride, which is an expectorant, and clemastine fumarate, which is an antihistamine, are stable over time. There was a problem of being inferior.
For example, JP 2009-19052 A (Patent Document 1) proposes a method for stabilizing bromhexine hydrochloride and ambroxol hydrochloride by adding acetaminophen to a preparation containing ibuprofen. Yes. JP 2007-55924 A (Patent Document 2) discloses a preparation containing ibuprofen and ambroxol, and by coating ibuprofen with a coating base containing talc, A method has been proposed for suppressing the decomposition of the above. Furthermore, in order to improve the stability of bromhexine hydrochloride, methods of using sugar alcohols or coating a film have been attempted, but the effect was not sufficient in the coexisting system of ibuprofen and acetaminophen.

JP 2009-19052 A JP 2007-55924 A

  Improvements have been made in the stability over time when clemastine fumarate is added to a preparation containing ibuprofen or acetaminophen alone. However, the present inventors have newly found that when clemastine fumarate is simultaneously added to a system containing both ibuprofen and acetaminophen, stability with time decreases. The present invention has been made in order to solve the above-described problem. A solid composition for internal use having high temporal stability even when clemastine fumarate is added to a composition containing ibuprofen and acetaminophen. The purpose is to provide.

  As a result of intensive studies to achieve the above object, the present inventors blended (C) clemastine fumarate with a solid composition for internal use containing (A) ibuprofen and (B) acetaminophen. At that time, it was found that (D) silicon dioxide was blended at a specific ratio to prevent decomposition of (C) clemastine fumarate, and high stability over time was obtained, which led to the present invention. .

Accordingly, the present invention provides the following solid composition for internal use.
Claim 1:
(A) ibuprofen, (B) acetaminophen, (C) clemastine fumarate, and (D) silicon dioxide, represented by (D) / {(A) + (B) + (C)} The solid composition for internal use, wherein the blending ratio of the component (D) to the total amount of the components (A) to (C) is 0.04 to 0.45 by mass ratio.
Claim 2:
(D) / {(A) + (B) + (C)}, and the blending ratio of component (D) to the total amount of components (A) to (C) is 0.05 to The solid composition for internal use according to claim 1, which is 0.45.
Claim 3 :
The solid composition for internal use according to claim 1 or 2 , wherein the blending ratio of the component (D) with respect to the whole composition is 0.001 to 0.2 in terms of mass ratio.
Claim 4 :
The blending ratio of the component (D) to the total amount of the components (A) and (B) represented by (D) / {(A) + (B)} is 0.002 to 1 in mass ratio. Item 4. The solid composition for internal use according to any one of Items 1 to 3 .
Claim 5 :
The internal use according to any one of claims 1 to 4 , wherein the blending ratio of the component (B) to the component (A) represented by (B) / (A) is 0.5 to 3 by mass ratio. Solid composition.
Claim 6:
The compounding quantity of (A) component is 0.05-30 mass% in a composition, the compounding quantity of (B) component is 0.05-50 mass% in a composition, and the compounding quantity of (C) component is. The solid composition for internal use according to any one of claims 1 to 5, wherein the content is 0.0004 to 1% by mass in the composition.
Claim 7:
Furthermore, it contains bromhexine hydrochloride and / or ambroxol hydrochloride, and is represented by (D) / {(A) + (B) + (C) + bromhexine hydrochloride and / or ambroxol hydrochloride} The mixing ratio of the component (D) to the total amount of the components (A) to (C) and bromohexine hydrochloride and / or ambroxol hydrochloride is 0.002 to 0.5 by mass ratio. The solid composition for internal use of any one of thru | or 6.
Claim 8:
(D) The particle size of silicon dioxide is 0.1-100 micrometers, The solid composition for internal use of any one of Claims 1 thru | or 7.

  ADVANTAGE OF THE INVENTION According to this invention, the solid composition for internal use which mix | blended clemastine fumarate stably with the coexistence system of ibuprofen and acetaminophen, and improved the temporal stability over a long term can be provided.

  The solid composition for internal use of the present invention contains (A) ibuprofen, (B) acetaminophen, (C) clemastine fumarate, and (D) silicon dioxide, and is a total of components (A) to (C). The mixing ratio of the component (D) with respect to the amount is 0.002 to 0.5 in mass ratio.

(A) Ibuprofen Ibuprofen (A) is one of antipyretic analgesic components, and is a drug used as one of the main components of antipyretic analgesics that suppress symptoms such as fever and headache. Examples of ibuprofen include ibuprofen and its salts, and the daily dose is preferably 450 mg in accordance with the approved standard amount of the drug. However, in the case of cold medicine in combination with acetaminophen, The minimum amount is 90 mg or more, and the total proportional distribution with respect to the daily upper limit (ibuprofen 450 mg, acetaminophen 900 mg) is 0.5 to 1 (0.5 ≦ ibuprofen / 450 + acetaminophen / 900 ≦ 1). It is preferable to do so. In the case of a tablet, make 3 to 9 tablets.
This component (A) is usually preferably blended in an amount of 0.05 to 30% by mass, more preferably 10 to 20% by mass in the composition.

(B) Acetaminophen (B) The acetaminophen component is also an antipyretic analgesic component, and is a drug used as one of the main components of an antipyretic analgesic that suppresses symptoms such as fever and headache. The daily dose is preferably 900 mg as a cold medicine in accordance with the drug approval standard amount. When combined with ibuprofen, the daily dose is at least 180 mg as a daily medicine. It is preferable that the total proportional distribution with respect to (ibuprofen 450 mg, acetaminophen 900 mg) is 0.5 to 1.
In the case of an over-the-counter medicine, the daily dose of ibuprofen is 90 to 600 mg, the daily dose of acetaminophen is preferably 100 to 2000 mg, the daily dose of ibuprofen is 200 to 450 mg, and the daily dose of acetaminophen is 180 to 1500 mg. preferable.

  (B) It is preferable to mix | blend 0.05-50 mass% normally in a composition, More preferably, 10-30 mass% is mix | blended. Acetaminophen is preferably coated acetaminophen coated with hydroxypropyl cellulose (recorded in the 15th revised Japanese Pharmacopoeia) from the viewpoint of capping prevention.

In the present invention, these components (A) and (B) are used in combination from the viewpoint of effectiveness. It is preferable to mix | blend so that the total amount of (A) and (B) component may be 0.1-60 mass% of the whole composition from the point of a formulation physical property and manufacturability, More preferably, it is 10-50 mass. %.
Moreover, as for the mixture ratio of (B) component with respect to (A) component, 0.5-3 are preferable by mass ratio, (B) / (A), More preferably, it is 0.7-1.5.

(C) Clemastine fumarate The clemastine fumarate (C) is a component used as an antihistamine such as sneezing, runny nose and cough. The daily dose is preferably 1.34 mg as a drug approval reference amount. In the case of an over-the-counter drug, 0.5 to 2 mg is preferable and 1 to 1.5 mg is particularly preferable as the daily dose of clemastine fumarate.
(C) It is preferable to mix | blend 0.0004-1 mass% in a composition, More preferably, 0.01-0.5 mass% is mix | blended.

(D) Silicon dioxide When (C) component is mix | blended with said (A) and (B) component, (D) silicon dioxide is mix | blended. In the present invention, by blending silicon dioxide, even if the (C) component is blended with the composition in which the (A) and (B) components coexist, the temporal stability of the (C) component is not impaired. The solid composition for internal use excellent in stability over a long period of time can be obtained. As silicon dioxide, hydrous silicon dioxide, light anhydrous silicic acid, etc. can be used suitably. The particle diameter of silicon dioxide is preferably from 0.1 to 100 μm, more preferably from 1 to 20 μm. The particle size can be measured by a laser diffraction / scattering particle size distribution analyzer.
The daily dose of component (D) is preferably 3.8 g at maximum.

  (D) The compounding ratio with respect to the total amount of the components (A) to (C) of silicon dioxide, that is, (D) / {(A) + (B) + (C)} exhibits excellent temporal stability. From a point, it is 0.002-0.5 by mass ratio. 0.005-0.5 is more preferable, 0.01-0.5 is still more preferable, 0.04-0.45 is especially preferable, 0.05-0.45 is especially preferable, 0.06-0.00. 3 is most preferred. When (D) / {(A) + (B) + (C)} is less than 0.002, the stabilizing effect of component (C) is not sufficient, and when it exceeds 0.5, the active ingredient is easily classified. It may be difficult to mix and homogenize, and a uniform drug product may not be produced.

  Moreover, 0.001-0.2 is preferable by mass ratio, and, as for the mixture ratio of (D) component with respect to the whole composition, More preferably, it is 0.01-0.2, More preferably, it is 0.03-0.1. is there. If this value is too small, the stabilizing effect of the component (C) may not be sufficient, and if it is too large, the active ingredient will be easily classified and mixing and homogenization will be difficult, and a uniform preparation may not be produced as a pharmaceutical product. .

  In the solid composition for internal use of the present invention, the mass ratio of the (D) component to the sum of the (A) component and the (B) component, that is, (D) / {(A) + (B)} is preferably 0.002-1, more preferably 0.01-0.5. If the amount is too small, the stabilizing effect of the component (C) may not be sufficient. If the amount is too large, a problem may occur in the mixing uniformity of the components (A) and (B).

  In the solid composition for internal use of the present invention, in addition to the above components, optional components may be blended within a range not impairing the effects of the present invention. As optional components, for example, components usually used as expectorants, binders, excipients other than component (D), lubricants other than component (D), flavorings, corrigents (sweeteners, acidulants, etc.) ), Pigments, stabilizers and the like, and a suitable amount can be used singly or in appropriate combination of two or more.

Specifically, bromhexine hydrochloride, ambroxol hydrochloride, or the like can be used as an expectorant. The daily dose of bromhexine hydrochloride is preferably 12 mg as a drug approval reference amount, and the daily dose of ambroxol hydrochloride is preferably 45 mg as a drug approval reference amount. In the case of an over-the-counter drug, 10-20 mg as a daily dose of bromohexine hydrochloride and 30-60 mg as a daily dose of ambroxol hydrochloride are preferable, and 10-15 mg as a daily dose of bromohexine hydrochloride, 1 ambroxol hydrochloride 1 A daily dose of 40-50 mg is particularly preferred. It is preferable to mix | blend this component with 0.005-5 mass% in a composition, More preferably, 0.1-2 mass% is mix | blended.
In addition, the total amount of the component (C) and bromohexine hydrochloride and / or ambroxol hydrochloride is blended so as to be 0.0054 to 6% by mass of the entire composition from the viewpoint of the properties of the preparation and manufacturability. Preferably, it is 0.1 to 3% by mass.

  The blending ratio of component (D) to the total amount of components (A) to (C) and bromohexine hydrochloride and / or ambroxol hydrochloride, that is, (D) / {(A) + (B) + (C ) + Bromohexine hydrochloride and / or ambroxol hydrochloride} is 0.002 to 0.5 in terms of mass ratio from the viewpoint of exhibiting excellent temporal stability. 0.005-0.5 is more preferable, 0.01-0.3 is still more preferable, 0.04-0.3 is especially preferable, and 0.05-0.3 is especially preferable. When (D) / {(A) + (B) + (C) + bromohexine hydrochloride and / or ambroxol hydrochloride} is less than 0.002, the stabilizing effect of component (C) is not sufficient. If it exceeds 5, the active ingredient is easy to classify and it becomes difficult to make the mixture uniform, and a uniform preparation as a pharmaceutical product may not be produced.

  Further, the blending ratio of the component (D) to the whole composition blended with bromohexine hydrochloride and / or ambroxol hydrochloride is preferably 0.001 to 0.2, more preferably 0.01 to 0 in terms of mass ratio. .1. If this value is too small, the stabilizing effect of the component (C) may not be sufficient, and if it is too large, the active ingredient will be easily classified and mixing and homogenization will be difficult, and a uniform preparation may not be produced as a pharmaceutical product. .

  As the binder, starch, pregelatinized starch, sucrose, gelatin, gum arabic powder, methylcellulose, polyvinylpyrrolidone, pullulan, dextrin and the like can be used. As the excipient, lactose, corn starch, talc, crystalline cellulose (such as Theolas), powdered sugar, mannitol, light anhydrous silicic acid, calcium carbonate, L-cysteine, magnesium carbonate, magnesium oxide, magnesium aluminate metasilicate, etc. are used. be able to. Examples of the lubricant include magnesium stearate, calcium stearate, polyethylene glycol, talc, stearic acid, and sucrose fatty acid ester. Examples of the fragrances include menthol, limonene, plant essential oil (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 and the like. As the acidulant, citric acid, tartaric acid, malic acid, succinic acid, fumaric acid, lactic acid, or a salt thereof can be used.

  The solid composition for internal use of the present invention can be obtained as a tablet by mixing the components (A) to (D) and optional components as necessary, filling the mixture in a tableting machine, and tableting. Moreover, it can also granulate with a granulator and can also be used as a granule and a fine granule.

  The composition of the present invention can be used as an antipyretic analgesic or a cold medicine, and is preferably an orally disintegrating tablet that disintegrates in the stomach from the viewpoint of ease of swallowing and exhibiting effectiveness. When it is set as a tablet, about 100-500 mg is suitable as a tablet mass per tablet from a viewpoint of handleability and swallowability.

  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. In the following examples, unless otherwise specified, the ratio indicates a mass ratio.

[Examples 1 to 5 , Reference Examples 1 and 2, Comparative Examples 1 to 6]
<Storage stability of ingredients>
The composition described in Table 1 was manually mixed in a plastic bag, and the mixture having an ibuprofen content of 130 mg was tableted with a tableting tester at a tableting pressure of 1 t to obtain a tablet having a diameter of 10 mm.
With respect to the clemastine fumarate of the tablet, the initial content and the content after storage in a glass bottle at 50 ° C. for 5 weeks were measured by a conventional method using a high performance liquid chromatogram. The remaining amount relative to the initial content is shown in Table 1.

The raw materials used in Examples 1 to 5, Reference Examples 1 and 2, and Comparative Examples 1 to 6 are as follows.

[ Reference Example 3 ]
The following components were mixed, and 267 mg of this was tableted with a tableting tester at a tableting pressure of 1 t to obtain a tablet with a diameter of 10 mm.
Ingredient Blending amount ibuprofen 130g
Acetaminophen 130g
Cremastine fumarate 0.45g
Bromhexine hydrochloride 4g
Anhydrous caffeine 25g
Ascorbic acid 100g
Dihydrocodeine phosphate 8g
dl-Methylephedrine hydrochloride 20 g
Silicon dioxide (Silicia 740) 1g
150 g of crystalline cellulose (Theolas KG801)
Lactose 150g
Hydroxypropylcellulose 30g
Crospovidone (XL-10) 20g
Magnesium stearate 3g
Total amount 771.45g

[Example 6 ]
The following components were mixed, and 240 mg of this was tableted with a tableting tester at a tableting pressure of 1 t to obtain a tablet with a diameter of 10 mm.
Ingredient Blending amount ibuprofen 120g
Acetaminophen 60g
Cremastine fumarate 0.45g
Bromhexine hydrochloride 4g
Anhydrous caffeine 25g
Ascorbic acid 100g
Dihydrocodeine phosphate 8g
dl-Methylephedrine hydrochloride 20 g
30 g of silicon dioxide (Silicia 740)
150 g of crystalline cellulose (Theolas KG801)
Fructose 150g
Hydroxypropylcellulose 30g
Croscarmellose sodium 20g
Magnesium stearate 3g
Fragrance 0.5g
Total amount 720.95g

[Example 7 ]
The following components were mixed, and 244 mg of this was tableted with a tableting tester at a tableting pressure of 1 t to obtain a tablet with a diameter of 10 mm.
Ingredient Blending amount ibuprofen 110g
Acetaminophen 80g
Cremastine fumarate 0.45g
Bromhexine hydrochloride 4g
Anhydrous caffeine 25g
Ascorbic acid 100g
Dihydrocodeine phosphate 8g
dl-Methylephedrine hydrochloride 20 g
30 g of silicon dioxide (Silicia 350)
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
Total amount 731.45g

[Example 8 ]
The following ingredients were mixed, and 247 mg of this was tableted with a tableting tester at a tableting pressure of 1 t to obtain a tablet with a diameter of 10 mm.
Ingredient Blending amount Ibuprofen 100g
Acetaminophen 100g
Cremastine fumarate 0.45g
Bromhexine hydrochloride 4g
Anhydrous caffeine 25g
Ascorbic acid 100g
Dihydrocodeine phosphate 8g
dl-Methylephedrine hydrochloride 20 g
30 g of silicon dioxide (Silicia 740)
150 g of crystalline cellulose (Theolas KG801)
Lactose 150g
Hydroxypropylcellulose 30g
Crospovidone (XL-10) 20g
Magnesium stearate 3g
Total amount 740.45g

[Example 9 ]
The following components were mixed, and 261 mg of this was tableted with a tableting tester at a tableting pressure of 1 t to obtain a tablet with a diameter of 10 mm.
Ingredient Blending amount ibuprofen 90g
Acetaminophen 120g
Cremastine fumarate 0.45g
Ambroxol hydrochloride 15g
Anhydrous caffeine 25g
Ascorbic acid 100g
Dihydrocodeine phosphate 8g
dl-Methylephedrine hydrochloride 20 g
30 g of silicon dioxide (Silicia 740)
150 g of crystalline cellulose (Theolas KG801)
Fructose 150g
Hydroxypropylcellulose 30g
Croscarmellose sodium 20g
Magnesium stearate 3g
Fragrance 0.5g
Total amount 761.95g

[Example 10 ]
The following ingredients were mixed to obtain a powder.
Ingredient Blending amount ibuprofen 80g
Acetaminophen 140g
Cremastine fumarate 0.45g
Ambroxol hydrochloride 15g
Anhydrous caffeine 25g
Ascorbic acid 100g
Dihydrocodeine phosphate 8g
dl-Methylephedrine hydrochloride 20 g
30 g of silicon dioxide (Silicia 350)
150 g of crystalline cellulose (Theolas PH302)
350g of D-mannitol
Hydroxypropylcellulose 30g
Sucralose 0.5g
Fragrance 0.5g
Total amount 949.45g

[ Reference Example 4 ]
The following ingredients were mixed to obtain a powder.
Ingredient Blending amount ibuprofen 225g
Acetaminophen 450g
Cremastine fumarate 1.34 g
Bromhexine hydrochloride 12g
dl-methylephedrine hydrochloride 60g
24g dihydrocodeine phosphate
Anhydrous caffeine 75g
5 g of silicon dioxide (Silicia 350)
D-mannitol 500g
Lactose 700g
Total amount 2052.34g

[Example 11 ]
The following ingredients were mixed, and 257 mg of this was tableted with a tableting tester at a tableting pressure of 1 t to obtain a tablet with a diameter of 10 mm.
Ingredient Compounding amount ibuprofen 70g
Acetaminophen 160g
Cremastine fumarate 0.45g
Bromhexine hydrochloride 4g
Anhydrous caffeine 25g
Ascorbic acid 100g
Dihydrocodeine phosphate 8g
dl-Methylephedrine hydrochloride 20 g
30 g of silicon dioxide (Silicia 740)
150 g of crystalline cellulose (Theolas KG801)
Lactose 150g
Hydroxypropylcellulose 30g
Crospovidone (XL-10) 20g
Magnesium stearate 3g
Total amount 770.45g

[Example 12 ]
The following ingredients were mixed, and 247 mg of this was tableted with a tableting tester at a tableting pressure of 1 t to obtain a tablet with a diameter of 10 mm.
Ingredient Blending amount Ibuprofen 100g
Acetaminophen 100g
Cremastine fumarate 0.45g
Bromhexine hydrochloride 4g
Anhydrous caffeine 25g
Ascorbic acid 100g
Dihydrocodeine phosphate 8g
dl-Methylephedrine hydrochloride 20 g
30 g of silicon dioxide (Silicia 740)
150 g of crystalline cellulose (Theolas KG801)
Fructose 150g
Hydroxypropylcellulose 30g
Croscarmellose sodium 20g
Magnesium stearate 3g
Fragrance 0.5g
Total amount 740.95g

[Example 13 ]
The following ingredients were mixed to obtain a powder.
Ingredient Blending amount ibuprofen 130g
Acetaminophen 130g
Cremastine fumarate 0.45g
Ambroxol hydrochloride 15g
Anhydrous caffeine 25g
Ascorbic acid 100g
Dihydrocodeine phosphate 8g
dl-Methylephedrine hydrochloride 20 g
60 g of silicon dioxide (Silicia 350)
150 g of crystalline cellulose (Theolas PH302)
350g of D-mannitol
Hydroxypropylcellulose 30g
Sucralose 0.5g
Fragrance 0.5g
Total amount 1019.45g

[ Reference Example 5 ]
The following ingredients were mixed to obtain a powder.
Ingredient Compounding amount ibuprofen 300g
Acetaminophen 300g
Cremastine fumarate 1.34 g
Bromhexine hydrochloride 12g
dl-methylephedrine hydrochloride 60g
24g dihydrocodeine phosphate
Anhydrous caffeine 75g
300 g of silicon dioxide (Silicia 740)
D-mannitol 500g
Lactose 700g
Total amount 2272.34g

The stability of clemastine fumarate of Examples 6 to 13 and Reference Examples 3 to 5 was excellent as in Examples 1 to 5 and Reference Examples 1 and 2 .

Claims (8)

(A) ibuprofen, (B) acetaminophen, (C) clemastine fumarate, and (D) silicon dioxide, represented by (D) / {(A) + (B) + (C)} The solid composition for internal use, wherein the blending ratio of the component (D) to the total amount of the components (A) to (C) is 0.04 to 0.45 by mass ratio. (D) / {(A) + (B) + (C)}, and the blending ratio of component (D) to the total amount of components (A) to (C) is 0.05 to The solid composition for internal use according to claim 1, which is 0.45. The solid composition for internal use according to claim 1 or 2 , wherein the blending ratio of the component (D) with respect to the whole composition is 0.001 to 0.2 in terms of mass ratio. The blending ratio of the component (D) to the total amount of the components (A) and (B) represented by (D) / {(A) + (B)} is 0.002 to 1 in mass ratio. Item 4. The solid composition for internal use according to any one of Items 1 to 3 . The internal use according to any one of claims 1 to 4 , wherein the blending ratio of the component (B) to the component (A) represented by (B) / (A) is 0.5 to 3 by mass ratio. Solid composition. The compounding quantity of (A) component is 0.05-30 mass% in a composition, the compounding quantity of (B) component is 0.05-50 mass% in a composition, and the compounding quantity of (C) component is. The solid composition for internal use according to any one of claims 1 to 5, wherein the content is 0.0004 to 1% by mass in the composition. Furthermore, it contains bromhexine hydrochloride and / or ambroxol hydrochloride, and is represented by (D) / {(A) + (B) + (C) + bromhexine hydrochloride and / or ambroxol hydrochloride} The mixing ratio of the component (D) to the total amount of the components (A) to (C) and bromohexine hydrochloride and / or ambroxol hydrochloride is 0.002 to 0.5 by mass ratio. The solid composition for internal use of any one of thru | or 6. (D) The particle size of silicon dioxide is 0.1-100 micrometers, The solid composition for internal use of any one of Claims 1 thru | or 7.