JP6260736B1 - Solid preparation - Google Patents

Abstract

Ambroxol hydrochloride or bromohexine hydrochloride causes stability problems when combined with other active ingredients, but is selected from the group consisting of ibuprofen, ambroxol or a salt thereof, and bromhexine or a salt thereof. To provide a pharmaceutical composition that is excellent in stability by a simple means. A solid preparation comprising (a) ibuprofen, (b) at least one selected from the group consisting of ambroxol or a salt thereof, and bromohexine or a salt thereof, and (c) carbocysteine. . [Selection figure] None

Description

  The present invention relates to a pharmaceutical composition comprising (a) ibuprofen, (b) at least one selected from the group consisting of ambroxol or a salt thereof, and bromohexine or a salt thereof, and (c) carbocysteine.

Ibuprofen is effective for anti-inflammatory and analgesia of rheumatoid arthritis, joint pain and arthritis, neuralgia and neuritis, spinal and lumbago, etc., as well as antipyretic and analgesia of acute upper respiratory tract inflammation (cold). Yes, it is formulated as an antipyretic analgesic component of a general cold medicine (Non-patent Document 1).
Ambroxol hydrochloride is widely known as a compound having an airway mucosa lubricating action and a mucolytic action and an excellent expectorant action. In addition, it is approved as a switch OTC drug and is blended in general cold medicine and cough medicine (Non-patent Document 2).
Bromhexine hydrochloride is widely known as a compound having an excellent expectorant action because it has an action of promoting secretion of a lung surface active substance and an action of enhancing ciliary movement. (Non Patent Literature 3)
Therefore, the combination of these active ingredients has been studied, and a solid preparation containing ibuprofen and ambroxol hydrochloride or bromhexine hydrochloride is known (Patent Documents 1 and 2).

  To date, it has been known that ambroxol hydrochloride or bromohexine hydrochloride causes stability problems when it is blended with other active ingredients. For example, when ambroxol hydrochloride and vitamins are blended, the stability of ambroxol hydrochloride is lowered, so that it is improved by separate granulation (Patent Document 3). In addition, it has been reported that the content of ambroxol hydrochloride decreases with time even if it is mixed with ibuprofen. As a solution, the stability of ambroxol hydrochloride is improved by separately granulating ibuprofen and ambroxol hydrochloride, and coating ibuprofen granules to form coated granules (Patent Literature). 4). However, the separate granulation and granule coating still have room for improvement due to increased costs and complicated manufacturing.

OTC Handbook 2002-03 Academic Information Distribution Center, Inc. Page 14 OTC Handbook 2008-09 Academic Information Distribution Center, Inc. Page 235 Japanese Pharmacopoeia 17th revision C-4881

Japanese Patent Laid-Open No. 10-45577 Special table 2006-506407 gazette No. 4899304 JP 2007-55924 A

An object of the present invention is to provide a pharmaceutical composition excellent in stability by a simple means in a pharmaceutical composition comprising ibuprofen and one kind selected from the group consisting of ambroxol or a salt thereof and bromohexine or a salt thereof. There is to do.

  As a result of various studies to solve the above problems, the present inventors have found that ibuprofen and ambroxol or a salt thereof, or bromhexine or a salt thereof contain carbocysteine as an expectorant, The present inventors have found that a decrease in the content of sole or a salt thereof or bromhexine or a salt thereof can be suppressed, and that an excellent preparation can be obtained by a simple method without increasing the number of production steps, and the present invention has been completed.

That is, the present invention comprises (1) (a) ibuprofen, (b) at least one selected from the group consisting of ambroxol or a salt thereof, and bromohexine or a salt thereof, and (c) carbocysteine. A solid formulation,
(2) (b) Ambroxol or a salt thereof is ambroxol hydrochloride, The solid preparation according to claim 1,
(3) The solid preparation according to claim 1, wherein (b) bromohexine or a salt thereof is bromohexine hydrochloride.
It is.

  According to the present invention, it has become possible to provide a solid preparation excellent in stability by a simple method by blending ibuprofen and ambroxol or a salt thereof or bromohexine or a salt thereof.

  The pharmaceutical composition of the present invention can be provided as a pharmaceutical composition that has a simple production process and is excellent in stability without requiring time and labor for production.

Ibuprofen used in the present invention is a compound represented by the chemical formula C ₁₃ H ₁₈ O ₂ and is not particularly limited as long as it is pharmaceutically acceptable. Ibuprofen can be produced by a known method, or a commercially available product can be used. The content of ibuprofen in the solid preparation of the present invention is not particularly limited as long as it shows the medicinal effect, but is usually 5 to 90% by mass, preferably 10 to 80% by mass.

Ambroxol or a salt thereof used in the present invention is a compound represented by the chemical formula C ₁₃ H ₁₈ Br ₂ N ₂ O or a salt thereof, and any of these may be used alone or in combination of two or more. It may be used. As such ambroxol or a salt thereof, a commercially available product can be used in addition to a known method. Ambroxol or a salt thereof is not particularly limited as long as it is pharmaceutically acceptable. Examples of the salt include salts of inorganic acids such as hydrochloride, hydrobromide, and phosphate, And organic acid salts such as acetate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, carbonate, etc. Particularly preferred is hydrochloride. The content of ambroxol or a salt thereof in the solid preparation of the present invention (when two or more of ambroxol or a salt thereof are contained, the total content thereof, the same shall apply hereinafter) Although it will not specifically limit if it is the quantity shown, It is 0.01-50 mass% normally, Preferably it is 0.1-30 mass%, More preferably, it is 1-10 mass%.

Bromohexine or a salt thereof used in the present invention is a compound represented by the chemical formula C ₁₄ H ₂₀ Br ₂ N ₂ or a salt thereof, and these may be used alone or in combination of two or more. good. As such bromhexine or a salt thereof, a commercially available product can be used in addition to production by a known method. Bromohexine or a salt thereof is not particularly limited as long as it is pharmaceutically acceptable. Examples of the salt include salts of inorganic acids such as hydrochloride, hydrobromide, phosphate, and acetic acid. Organic salts such as salt, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, carbonate, etc. Is the hydrochloride salt. The content of bromhexine or a salt thereof in the solid preparation of the present invention (when two or more of bromhexine or a salt thereof are contained, the total content thereof, the same shall apply hereinafter) should be an amount showing its medicinal effect. Although it will not specifically limit, it is 0.01-30 mass% normally, Preferably it is 0.01-20 mass%, More preferably, it is 0.05-10 mass%.

  The mixing ratio of ibuprofen and ambroxol or a salt thereof is preferably 0.001 to 10 parts by mass, particularly preferably 0.01 to 1 part by mass of ambroxol or a salt thereof with respect to 1 part by mass of ibuprofen. is there. Moreover, the blending ratio of ibuprofen and bromhexine or a salt thereof is preferably 0.001 to 1 part by weight, particularly preferably 0.01 to 0.1 part by weight of bromhexine or a salt thereof relative to 1 part by weight of ibuprofen.

Carbocysteine used in the present invention is a compound represented by the chemical formula C ₅ H ₉ NO ₄ S and is not particularly limited as long as it is pharmaceutically acceptable, but usually L-carbocysteine is used. . Carbocysteine can be produced by a known method, or a commercially available product can be used. The content of carbocysteine in the solid preparation of the present invention is not particularly limited, but is usually 1 to 90% by mass, preferably 5 to 80% by mass.

  In addition, the total amount of ibuprofen and ambroxol or a salt thereof, or the total amount of ibuprofen and bromhexine or a salt thereof and the carbocysteine, the total ratio of ibuprofen and ambroxol or a salt thereof, or ibuprofen and bromhexine Or 0.03-100 mass parts is preferable with respect to 1 mass part of total amounts of the salt, 0.05-20 mass parts is more preferable, Especially preferably, it is 0.05-10 mass parts.

  The solid preparation of the present invention is not particularly limited as long as it is a dosage form stipulated in the Japanese Pharmacopoeia, but is preferably a tablet, powder, fine granule, granule, pill, or capsule. . The tablets prescribed in the Japanese Pharmacopoeia General Rules for Preparation include orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets and dissolving tablets, film-coated tablets, sugar-coated tablets, laminated tablets and the like. In addition, the tablet can be provided with a score line or a mark for improving discrimination. Furthermore, the tablet of this preparation may be a round tablet or an atypical tablet.

  In the solid preparation of the present invention, other active ingredients, excipients, disintegrants, binders, fluidizing agents, lubricants, refreshing agents, which are usually used within the qualitative and quantitative ranges that do not impair the effects of the present invention. Agents, colorants, flavoring agents, fragrances, coating agents and the like can be blended.

  Other active ingredients that can be incorporated into the solid preparation of the present invention include, for example, antipyretic analgesics, antihistamines, antitussives, noscapines, bronchodilators, expectorants, hypnotic sedatives, vitamins, anti-inflammatory agents, gastric mucosa protective agents , Herbal medicines, Chinese herbal prescriptions, caffeine and the like, and may contain one or more selected from the group consisting of these.

  Examples of excipients that can be blended in the solid preparation of the present invention include lactose, starches, crystalline cellulose, sucrose, sugar alcohol and the like, and examples of disintegrants include low-substituted hydroxypropylcellulose, sodium starch glycolate. Crospovidone, carmellose, carmellose sodium, carmellose calcium, pregelatinized starch, etc., and binders include hydroxypropylcellulose, hypromellose, gelatin, pregelatinized starch, polyvinylpyrrolidone, pullulan, etc. Examples of the agent include light anhydrous silicic acid, hydrous silicon dioxide, and the like. Examples of the lubricant include sucrose fatty acid ester, hydrogenated oil, stearic acid, magnesium stearate, calcium stearate, and the like. , Ment Le, peppermint oil, eucalyptus oil, and the like.

The solid preparation of the present invention can be produced by a conventional method, and the method is not particularly limited. Moreover, ibuprofen, ambroxol or a salt thereof, or bromohexine or a salt thereof, and carbocysteine may be mixed in any form, and the effects of the present invention are exhibited.
For example, (a) ibuprofen (hereinafter also referred to as (a) component), (b) ambroxol or a salt thereof, or bromohexine or a salt thereof (hereinafter also referred to as (b) component), and (c) carbocysteine ( Hereinafter, when producing a preparation containing (c) component), the component (a), the component (b) and the component (c) may be simply mixed, or may be granulated after mixing. Moreover, you may mix, after manufacturing the granulated material containing 1 or more types of (a) component, (b) component, or (c) component. Furthermore, these granulated products may be coated.
Specific examples include the following. After producing the granulated product containing the component (a) and the component (c), the component (b) is mixed, or after producing the granulated product containing the component (a) and the component (b), (c ) Components are mixed, or the granulated product containing (a) component and (c) component, and the granulated product containing (b) component and (c) component are manufactured, and then two granulated products are prepared. Mixing, etc.
That is, in the solid preparation of the present invention, (a) component, (b) component, (c) component may be present in the same granulated product, (a) component, (b) component, (c) component May exist in different granulated products, or may not be granulated.

  The granulation method is not particularly limited, and can be produced by a wet granulation method, a dry granulation method, a melt granulation method, or the like, but a wet granulation method is preferred. Examples of the wet granulation method include agitation granulation method, fluidized bed granulation method, kneading granulation method, extrusion granulation method, and rolling fluidization granulation method. In addition, conventional granule additives such as the above active ingredients and excipients may be appropriately blended with the obtained granulated product, and the mixture thus obtained can be tableted into tablets. . When a tablet is produced, it may be produced by a direct tableting method.

Hereinafter, the present invention will be described in more detail with reference to Examples and Comparative Examples, but the present invention is not limited to these Examples and the like.
(Comparative Example 1)
6 g of ibuprofen, 0.45 g of ambroxol hydrochloride, 15 g of lactose, 0.36 g of hydroxypropylcellulose and 2 g of crystalline cellulose were mixed using a polyethylene bag. The mixture and an appropriate amount of water were added and kneaded in a mortar, and then sufficiently dried. Thereafter, the entire amount was passed through a sieve (aperture 710 μm) to obtain a granulated product.
(Comparative Example 2)
4.5 g of ibuprofen, 0.45 g of ambroxol hydrochloride, 15 g of lactose, 0.36 g of hydroxypropylcellulose, and 2 g of crystalline cellulose were mixed using a polyethylene bag. The mixture and an appropriate amount of water were added and kneaded in a mortar, and then sufficiently dried. Thereafter, the entire amount was passed through a sieve (aperture 710 μm) to obtain a granulated product.
(Comparative Example 3)
6 g of ibuprofen, 0.45 g of ambroxol hydrochloride, 7.5 g of lactose, 0.36 g of hydroxypropylcellulose, and 2 g of crystalline cellulose were mixed using a polyethylene bag. The mixture and an appropriate amount of water were added and kneaded in a mortar, and then sufficiently dried. Thereafter, the entire amount was passed through a sieve (aperture 710 μm) to obtain a granulated product.
(Comparative Example 4)
4.5 g of ibuprofen, 0.45 g of ambroxol hydrochloride, 5 g of ascorbic acid, 2.5 g of lactose, 0.36 g of hydroxypropylcellulose, and 2 g of crystalline cellulose were mixed using a polyethylene bag. The mixture and an appropriate amount of water were added and kneaded in a mortar, and then sufficiently dried. Thereafter, the entire amount was passed through a sieve (aperture 710 μm) to obtain a granulated product.
(Comparative Example 5)
4.5 g of ibuprofen, 0.45 g of ambroxol hydrochloride, 9 g of glycine, 0.36 g of hydroxypropylcellulose, and 1.5 g of crystalline cellulose were mixed using a polyethylene bag. The mixture and an appropriate amount of water were added and kneaded in a mortar, and then sufficiently dried. Thereafter, the entire amount was passed through a sieve (aperture 710 μm) to obtain a granulated product.
Example 1
6 g of ibuprofen, 0.45 g of ambroxol hydrochloride, 15 g of carbocysteine, 0.36 g of hydroxypropylcellulose, and 2 g of crystalline cellulose were mixed using a polyethylene bag. The mixture and an appropriate amount of water were added and kneaded in a mortar, and then sufficiently dried. Thereafter, the entire amount was passed through a sieve (aperture 710 μm) to obtain a granulated product.
(Example 2)
4.5 g of ibuprofen, 0.45 g of ambroxol hydrochloride, 15 g of carbocysteine, 0.36 g of hydroxypropylcellulose, and 2 g of crystalline cellulose were mixed using a polyethylene bag. The mixture and an appropriate amount of water were added and kneaded in a mortar, and then sufficiently dried. Thereafter, the entire amount was passed through a sieve (aperture 710 μm) to obtain a granulated product.
(Example 3)
6 g of ibuprofen, 0.45 g of ambroxol hydrochloride, 7.5 g of carbocysteine, 0.36 g of hydroxypropylcellulose, and 2 g of crystalline cellulose were mixed using a polyethylene bag. The mixture and an appropriate amount of water were added and kneaded in a mortar, and then sufficiently dried. Thereafter, the entire amount was passed through a sieve (aperture 710 μm) to obtain a granulated product.
Example 4
4.5 g of ibuprofen, 0.45 g of ambroxol hydrochloride, 0.45 g of carbocysteine, 0.36 g of hydroxypropylcellulose, and 1.5 g of crystalline cellulose were mixed using a polyethylene bag. The mixture and an appropriate amount of water were added and kneaded in a mortar, and then sufficiently dried. Thereafter, the entire amount was passed through a sieve (aperture 710 μm) to obtain a granulated product.
(Comparative Example 6)
4.5 g of ibuprofen, 0.12 g of bromohexine hydrochloride, 15 g of lactose, 0.36 g of hydroxypropylcellulose, and 2 g of crystalline cellulose were mixed using a polyethylene bag. The mixture and an appropriate amount of water were added and kneaded in a mortar, and then sufficiently dried. Thereafter, the entire amount was passed through a sieve (aperture 710 μm) to obtain a granulated product.
(Example 5)
4.5 g of ibuprofen, 0.12 g of bromohexine hydrochloride, 15 g of L-carbocysteine, 0.36 g of hydroxypropylcellulose, and 2 g of crystalline cellulose were mixed using a polyethylene bag. The mixture and an appropriate amount of water were added and kneaded in a mortar, and then sufficiently dried. Thereafter, the entire amount was passed through a sieve (aperture 710 μm) to obtain a granulated product.

(Test Example 1)
The solid preparations of Comparative Examples and Examples were stored at 25 ° C. and 60% RH for 2 days, then each bottle was filled and sealed, stored at 65 ° C. for 7 days, and ambroxol hydrochloride in the solid preparation after 7 days. The residual rate of salt or bromohexine hydrochloride was evaluated by HPLC method.
Table 1 or Table 3 showed the prescription amount per day regarding the granulated material obtained by the method described in the said Example and the comparative example. Table 2 shows the residual rate of ambroxol hydrochloride, and Table 4 shows the residual rate of bromohexine hydrochloride.

As shown in Table 2, in Comparative Examples 1 to 3 in which ibuprofen and ambroxol hydrochloride were blended, a decrease in the content of ambroxol was confirmed. On the other hand, in Examples 1 to 4 in which carbostein was blended with ibuprofen and ambroxol hydrochloride, the decrease in the content of ambroxol hydrochloride could be suppressed regardless of the blending amount of carbocysteine. Moreover, in Comparative Example 4 or 5 which mix | blended ascorbic acid or glycine which is an acidic drug like carbocysteine, it was confirmed that the content of ambroxol falls further compared with Comparative Examples 1-3.
As shown in Table 4, in the solid preparation containing ibuprofen and bromhexine hydrochloride, similarly to ambroxol hydrochloride, Comparative Example 6 containing no L-carbocysteine was used in Example 5 containing In comparison, a decrease in the content of bromhexine was confirmed.

(Formulation examples 1 to 3)
Solid preparations were prepared according to the formulations described in Tables 5 to 7. The unit in the table is mg.

  For Formulation Example 1, each component was weighed and mixed according to Table 5, and granulated by stirring granulation method using water and ethanol. The obtained granulated product was dried and then passed through a sieve to obtain granulated granules. Tablets were obtained after mixing with the granulated granule and the ingredients added at the end of the tablet.

  For Formulation Example 2, each component was weighed and mixed according to Table 6 to obtain a powder.

  For Production Example 3, each component was weighed and mixed according to Table 7, and granulated by fluidized bed granulation using water and ethanol. The obtained granulated product was dried and then passed through a sieve to obtain granulated granules. After mixing with the granulated granule and the late powder additive component, it was compressed into tablets.

(Formulation example 4)
Formulation Example 4 was weighed and mixed so that the daily dose was 600 mg of ibuprofen, 10 mg of dihydrocodeine phosphate, 138 mg of crystalline cellulose, 52 mg of light anhydrous silicic acid, 16 mg of hypromellose, and 50 mg of hypromellose, light anhydrous silicic acid in water and ethanol. Using the solution in which 32 mg was dispersed, granulated product A was produced with a fluidized bed granulator. Lactose 12.6 mg, methylephedrine hydrochloride 60 mg, ambroxol hydrochloride 45 mg, L-carbocysteine 750 mg, chlorpheniramine maleate 7.5 mg, riboflavin 6 mg, crystalline cellulose 155.8 mg, hydroxypropylcellulose 90 mg, starch 36 mg of sodium glycolate, 12 mg of light anhydrous silicic acid, and 135 mg of calcium hydrogen phosphate were weighed and mixed, and granulated product B was produced with a stirring granulator using water. The resulting granulated product A, granulated product B, and 12 mg of light anhydrous silicic acid, 24 mg of hardened oil, and 18 mg of magnesium stearate were weighed and mixed as tableting ingredients to obtain tablets.

  The obtained pharmaceutical composition was a tablet having excellent pharmaceutical properties in which a decrease in the content of ambroxol was suppressed, like the granulated product obtained in Examples 1 to 5.

  According to the present invention, it is possible to provide a pharmaceutical composition containing ibuprofen and ambroxol or a salt thereof or bromohexine or a salt thereof and having improved stability by a simple method.

Claims (3)

It comprises (a) ibuprofen, (b) (b1) ambroxol or a salt thereof, and (b2) at least one selected from the group consisting of bromohexine or a salt thereof, and (c) carbocysteine. Solid preparation (however, solid preparation containing ambroxol or a salt thereof and tranexamic acid, and ibuprofen, ambroxol hydrochloride, L-carbocysteine, dextromethorphan hydrobromic acid hydrate, noscapine, d-chlor Phenylamine maleate, dl-methylephedrine hydrochloride, belladonna total alkaloid, anhydrous caffeine, riboflavin, hesperidin, hydroxypropylcellulose, povidone, crystalline cellulose, magnesium aluminate metasilicate, low substituted hydroxypropylcellulose, carme Uncoated tablets containing calcium calcium and stearate are coated with a coating containing hypromellose, talc, fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, purified white sugar, polyvinyl alcohol, gum arabic powder, titanium oxide and carnauba wax. Except sugar-coated products) . (B1) The solid preparation according to claim 1, wherein the ambroxol or a salt thereof is ambroxol hydrochloride. (B2) The solid preparation according to claim 1, wherein the bromhexine or a salt thereof is bromhexine hydrochloride.