JP2005289906A - Medicinal composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a medicinal composition not only simultaneously formulating ibuprofen having bad formulation properties with other active ingredients and hard to prepare a stable formulation though the ibuprofen is ingredient effective for cold syndrome, or the like, with an antitussive ingredient and an expectorant ingredient, effectively suppressing a formulation change such as browning, improving the stability and having a high product value. <P>SOLUTION: It is found that the medicinal composition with a suppressed change in color tone with time is obtained by formulating the ibuprofen with dimemorfan or its salt as the antitussive ingredient and potassium cresolsulfonate as the expectorant ingredient. The medicinal composition characterized as suppressing the change in color tone with time is obtained by formulating these ingredients. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

The present invention relates to a pharmaceutical composition comprising, as a main ingredient, ibuprofen, an antipyretic analgesic component, as a pharmaceutical composition. In more detail, by blending ibuprofen with antitussive component dimemorphan or its salt and expectorant component cresol sulfonate potassium, the composition change such as browning is effectively suppressed, and the long-term stability is greatly improved. It is about things.

  Cold syndrome is mostly a viral respiratory infection, but the main symptoms are local symptoms such as cough, sore throat, nasal congestion, nasal discharge, phlegm, fever, chills, They range from systemic symptoms such as muscle pain, joint pain and general malaise.

In order to make these symptoms disappear early, various ingredients such as antipyretic analgesic components that relieve pain and fever, antitussive components that relieve cough symptoms, and expectorant components that relieve manic symptoms are blended ( Non-patent document 1). In recent years, ibuprofen having a powerful antipyretic analgesic action has been used as an antipyretic analgesic component (Non-patent Document 2).
Ibuprofen is a non-steroidal anti-inflammatory agent and has effects as a cold syndrome, anti-inflammation, and analgesic in addition to rheumatoid arthritis, arthralgia and arthritis, neuralgia, neuritis, cervical arm syndrome, etc. (Non-patent Document 3) . Conventionally, ibuprofen has been used for these diseases as an ethical drug (Non-patent Document 4). However, due to its effectiveness and safety, it has recently been sold as a general cold remedy.
However, the melting point of ibuprofen is as low as 75 to 77 ° C., and when blended with other agents, the melting point of other blended components may be lowered. For this reason, other active ingredients and ibuprofen are blended. It has been pointed out that the preparation is poor in stability and tends to be accompanied by a decrease in the content of active ingredients and a change in appearance (Non-patent Document 5).
For example, regarding a combination preparation containing ibuprofen, antitussives with improved antitussive effect by including a technique (Patent Document 1) related to an antitussive agent in which mequitazine and a narcotic antitussive component are added to ibuprofenme, and ibuprofen and dimemorphan or a salt thereof. Although the technique regarding the effectiveness, such as a medicine (patent document 2), is already known, it has not yet been applied to the technique regarding the stability improvement which suppresses the color tone change of those combination preparations.
Antitussive drugs mixed with cold medicine are roughly divided into narcotic and non-narcotic ones. Although narcotic antitussives have a long track record of effectiveness, they have the problem of causing side effects such as drug dependence and constipation. On the other hand, non-narcotic antitussives have the disadvantage of being less effective than narcotics, but in recent years, highly effective non-narcotic antitussives have come to be used. As an example, tipepidine hibenzate has an antitussive effect, and also has an expectorant effect (bronchial gland secretion enhancing action) that makes it easy to discharge by diluting sputum, and at the same time acts on the cough center and exhibits a good antitussive effect (non-cough) Patent Documents 6 and 7). In addition, it is widely used for the treatment of colds and cough symptoms in children because of its few side effects. Has occurred. One method for concealing such browning over time is to coat the surface with a water-soluble polymer compound or sugar in the case of tablets. Although coating is an effective means of concealing browning, it is not a fundamental solution to the problem. In addition, the coating delays the elution time of the drug and delays the onset of the drug effect, which is a big pain for the cold medicine that requires immediate effect.
Dimemorphan is an active ingredient typified as a non-narcotic antitussive agent, and acts directly on the cough center of the medulla at low doses to show antitussive activity. In pharmacological studies using dogs and cats, codeine phosphate and dextrose It is known to exhibit an antitussive effect superior to that of Lometrfan.
In addition, as a component of the common cold medicine, a component having an expectorant effect that promotes airway secretion and liquefies viscous sputum is required. Typical examples thereof include lysozyme chloride and ethylcysteine hydrochloride. However, lysozyme chloride is a basic protein, and its stability is likely to be lost due to a change in the combination with ibuprofen having an acidic group (Non-patent Document 4). As a result, it is necessary to take measures such as formulation, and the manufacturing process is complicated.
A pharmaceutical composition in which (A) ibuprofen is blended with (C) potassium cresolsulfonate at the same time as (B) dimemorphan or a salt thereof and as an expectorant has not been known.

Japanese Patent Laid-Open No. 10-45595 JP 2001-97856 A Sepie Gold capsule package insert (Zeria Shinyaku Co., Ltd.) Sepie IP Gold package insert (Zeria Shinyaku Co., Ltd.) 14th revision Japanese Pharmacopoeia Manual C-268 (Yodogawa Shoten Purfen Tablets, Tablets 200, Granules (Kaken Pharmaceutical Co., Ltd.) Sato Pharmacy Vol. 27, no. 12 (1976) 2003 26th edition Japanese ethical drugs (Jiho Co., Ltd.) Package insert for Asverine Tablets (Tanabe Seiyaku Co., Ltd.)

The object of the present invention is a preparation in which an ingredient effective for cold syndrome is blended with ibuprofen, which effectively suppresses blending changes such as browning and has a long-term stability, and has a high product value. It is to provide a pharmaceutical composition.

As a result of intensive studies by the present inventors to solve the above-mentioned problems, the color change over time can be achieved by adding (B) dimemorphan or a salt thereof and (C) potassium cresolsulfonate to (A) ibuprofen. It was found that a pharmaceutical composition that is effective against cold syndrome and stable in terms of formulation can be obtained, and the present invention has been completed. That is, the present invention is a pharmaceutical composition comprising (A) ibuprofen and (B) dimemorphan or a salt thereof and (C) potassium cresolsulfonate.

According to the present invention, by providing (A) ibuprofen with (B) dimemorphan or a salt thereof and (C) potassium cresolsulfonate, a stable pharmaceutical composition in which color change over time is suppressed is provided.

The ibuprofen of this invention should just be used for a normal pharmaceutical, for example, a Japanese pharmacopoeia listed product can be used. The concentration of ibuprofen can be appropriately increased or decreased, and the compounding amount is preferably 400 to 600 mg, particularly preferably 400 to 500 mg as a daily dose for an adult. If the amount of ibuprofen is less than 400 mg, the above-mentioned medicinal effects and effects cannot be expected, and if it exceeds 600 mg, a question arises from the viewpoint of safety, which is not preferable.
Dimemorphan or a salt thereof in the present invention may be used as long as it is used in ordinary pharmaceuticals. For example, it is desirable to use a phosphate that is listed in the Japanese Pharmacopoeia Standards for Pharmaceutical Ingredients, but as other salts, Hydrochloride, sulfate, nitrate, maleate or fumarate can be used. Moreover, as the compounding quantity, it is good to set it as 1.2-20.0 weight part with respect to 100 weight part of ibuprofen, Most preferably, it is 1.6-15.0 weight part. If the amount of dimemorphan or a salt thereof is less than 1.2 parts by weight, the above-mentioned medicinal effects and effects cannot be expected, and if it exceeds 20.0 parts by weight, it is not preferable because a question arises from the viewpoint of safety. .
The potassium cresol sulfonate of the present invention may be used for ordinary pharmaceuticals, and for example, Japanese Pharmacopoeia listed standard for pharmaceutical ingredients can be used. Moreover, as the compounding quantity, it is good to set it as 5.0-100.0 weight part with respect to 100 weight part of ibuprofen, Most preferably, it is 7.5-80.0 weight part. When the amount of potassium cresol sulfonate is less than 5.0 parts by weight, the expected effect described above cannot be obtained, and this is not preferable in terms of medicinal effect. Moreover, when it mixes exceeding 100.0 weight part, since a question arises from a viewpoint of safety, it is not preferable.

In addition to the above essential ingredients, this pharmaceutical composition may contain other antipyretic analgesics, other antitussives, other expectorants, anticholinergics, antihistamines, bronchodilators, anti-inflammatory / One or more selected from anti-inflammatory enzyme drugs, sleepiness prevention drugs (central nervous stimulants), vitamins, herbal medicines, herbal medicines, and antacids can be added.
Specifically, as other antipyretic analgesics, aspirin or a salt thereof, etenzamide, isopropylantipyrine, ketoprofen, naproxen, loxoprofen or a salt thereof, pranoprofen, diclofenac or a salt thereof, chlorpheniramine maleate as an antihistamine (Including d-form and dl-form), mequitazine, carbinoxamine maleate, diphenhydramine or its salt, promethazine or its salt, homochlorcyclidine or its salt, anti-inflammatory / anti-inflammatory enzyme drug, lysozyme chloride, semi-alkali proteinase, tranexam Contains acid, serrapeptase, bromelain and related substances, and contains anti-cholinergic ingredients such as belladonna total alkaloids, isopropamide iodide, funnel extract, and other antitussives. , Dihydrocodeine or a salt thereof, codeine or a salt thereof, dextromethorphan or a salt thereof, noscapine or a salt thereof, eprazinone or a salt thereof, methoxyphenamine or a salt thereof, and the like, and methylephedrine hydrochloride (d form) as a bronchodilator , Dl form), ephedrine hydrochloride, methoxyphenamine hydrochloride, trimethquinol hydrochloride, theophylline, aminophylline and the like as other expectorants, potassium guaiacol sulfonate, L-methylcysteine hydrochloride, L-ethylcysteine hydrochloride blended like, blended and caffeine as drowsiness preventing agent (central nervous stimulant), as vitamins, vitamin B ₁ or a derivative or a salt thereof, vitamin B ₂ or derivatives thereof, or salts thereof, vitamin Herbal medicine such as C Chinese herbal medicine, antacid, etc. can be blended, and these can be used alone or in combination of two or more. Here, the salt includes hydrochloride, nitrate, sulfate, phosphate, oxalate, maleate, fumarate, hydrobromide, potassium salt, sodium salt, calcium salt, magnesium salt, etc. It is done.

  Carriers used for preparation of preparations in solid preparations include excipients such as crystalline cellulose, lactose, starch, maltose, mannitol, xylitol, erythritol, magnesium aluminate metasilicate, hydroxypropylcellulose, hydroxypropylmethylcellulose, gelatin, polyvinyl Binders such as pyrrolidone, disintegrants such as croscarmellose sodium, carmellose, carmellose calcium, carmellose sodium, low-substituted hydroxypropylcellulose, lubricants such as magnesium stearate, hydrogenated castor oil, talc, macrogol, There are glidants such as light anhydrous silicic acid, and disintegration aids, buffering agents, preservatives, fragrances, pigments, flavoring agents and the like can be used as necessary.

    The pharmaceutical composition of the present invention is prepared by an ordinary method such as tablets, granules, fine granules, powders, capsules, pills, chewables, drops, foams, orally disintegrating agents. Can be prepared. Of these, tablets, granules, fine granules, powders, or capsules are often prepared. More preferred are tablets, granules and fine granules, and particularly preferred are tablets.

The pharmaceutical composition of the present invention can be orally administered to an adult usually once or several times per day, and the dosage can be appropriately increased or decreased depending on age, weight and medical condition.

  Hereinafter, the present invention will be specifically described with reference to examples.

Example 1
After weighing and mixing uniformly according to the following components and weight blending ratio, the obtained mixed powder was directly compressed to obtain a tablet having a tablet weight of 280 mg.

Ibuprofen 17.86
Belladonna Total Alkaloid 0.02
dl-methylephedrine hydrochloride 2.98
Mequitazine 0.24
Dimemorphan phosphate 1.19
Potassium cresol sulfonate 9.92
Anhydrous caffeine 2.98
Crystalline cellulose 59.31
Croscarmellose sodium 4.00
Light anhydrous silicic acid 0.50
Magnesium stearate 1.00 (parts by weight)

Example 2
After weighing and mixing uniformly according to the following components and weight blending ratio, the obtained mixed powder was directly compressed to obtain a tablet having a tablet weight of 280 mg.

Ibuprofen 17.86
Belladonna Total Alkaloid 0.02
dl-methylephedrine hydrochloride 2.98
Mequitazine 0.24
Dimemorphan phosphate 0.40
Potassium cresol sulfonate 14.29
Anhydrous caffeine 2.98
Crystalline cellulose 55.73
Croscarmellose sodium 4.00
Light anhydrous silicic acid 0.50
Magnesium stearate 1.00 (parts by weight)

Example 3
After weighing and mixing uniformly according to the following components and weight blending ratio, the obtained mixed powder was directly compressed to obtain a tablet having a tablet weight of 280 mg.

Ibuprofen 17.86
Belladonna Total Alkaloid 0.02
dl-methylephedrine hydrochloride 2.98
Mequitazine 0.24
Dimemorphan phosphate 3.17
Potassium cresol sulfonate 1.19
Anhydrous caffeine 2.98
Crystalline cellulose 66.06
Croscarmellose sodium 4.00
Light anhydrous silicic acid 0.50
Magnesium stearate 1.00 (parts by weight)

Example 4
After weighing and mixing uniformly according to the following components and weight blending ratio, the obtained mixed powder was directly compressed to obtain a tablet having a tablet weight of 280 mg.

Ibuprofen 17.86
Belladonna Total Alkaloid 0.02
dl-Methylephedro hydrochloride 2.98
Mequitazine 0.24
Dimemorphan phosphate 0.40
Potassium cresol sulfonate 1.19
Anhydrous caffeine 2.98
Crystalline cellulose 68.83
Croscarmellose sodium 4.00
Light anhydrous silicic acid 0.50
Magnesium stearate 1.00 (parts by weight)

Example 5
After weighing and mixing uniformly according to the following components and weight blending ratio, the obtained mixed powder was directly compressed to obtain a tablet having a tablet weight of 280 mg.

Ibuprofen 17.86
Belladonna Total Alkaloid 0.02
dl-methylephedrine hydrochloride 2.98
Mequitazine 0.24
Dimemorphan phosphate 3.17
Potassium cresol sulfonate 14.29
Anhydrous caffeine 2.98
Crystalline cellulose 52.96
Croscarmellose sodium 4.00
Light anhydrous silicic acid 0.50
Magnesium stearate 1.00 (parts by weight)

Example 6
After weighing and mixing uniformly according to the following components and weight blending ratio, the obtained mixed powder was directly compressed to obtain a tablet having a tablet weight of 280 mg.

Ibuprofen 15.87
dl-methylephedrine hydrochloride 2.98
d-Chlorpheniramine maleate 0.14
Dimemorphan phosphate 1.19
Potassium cresol sulfonate 5.56
Anhydrous caffeine 2.98
Crystalline cellulose 65.78
Croscarmellose sodium 4.00
Light anhydrous silicic acid 0.50
Magnesium stearate 1.00 (parts by weight)

Example 7
After weighing and mixing uniformly according to the following components and weight blending ratio, the obtained mixed powder was directly compressed to obtain a tablet having a tablet weight of 280 mg.

Ibuprofen 23.81
dl-methylephedrine hydrochloride 2.98
d-Chlorpheniramine maleate 0.14
Dimemorphan phosphate 1.19
Potassium cresol sulfonate 9.92
Anhydrous caffeine 2.98
Crystalline cellulose 53.48
Croscarmellose sodium 4.00
Light anhydrous silicic acid 0.50
Magnesium stearate 1.00 (parts by weight)

Example 8
After weighing and mixing uniformly according to the following components and weight blending ratio, the obtained mixed powder was directly compressed to obtain a tablet having a tablet weight of 280 mg.

Ibuprofen 17.86
dl-methylephedrine hydrochloride 2.98
Mequitazine 0.16
Dimemorphan phosphate 1.19
Glycyrrhizic acid 2.78
Potassium cresol sulfonate 5.56
Anhydrous caffeine 2.98
Crystalline cellulose 60.99
Croscarmellose sodium 4.00
Light anhydrous silicic acid 0.50
Magnesium stearate 1.00 (parts by weight)

Comparative Example 1
After weighing and mixing uniformly according to the following components and weight blending ratio, the obtained mixed powder was directly compressed to obtain a tablet having a tablet weight of 280 mg.

Ibuprofen 17.86
dl-methylephedrine hydrochloride 2.98
Cremastine fumarate 0.05
Tipepidine hibenzate 3.97
Lysozyme chloride 7.14
Anhydrous caffeine 2.98
Crystalline cellulose 59.52
Croscarmellose sodium 4.00
Light anhydrous silicic acid 0.50
Magnesium stearate 1.00 (parts by weight)

Comparative Example 2
After weighing and mixing uniformly according to the following components and weight blending ratio, the obtained mixed powder was directly compressed to obtain a tablet having a tablet weight of 280 mg.

Ibuprofen 17.86
Belladonna Total Alkaloid 0.02
dl-methylephedrine hydrochloride 2.98
Cremastine fumarate 0.05
Tipepidine hibenzate 2.98
Lysozyme chloride 5.56
Anhydrous caffeine 2.98
Crystalline cellulose 62.07
Croscarmellose sodium 4.00
Light anhydrous silicic acid 0.50
Magnesium stearate 1.00 (parts by weight)

Comparative Example 3
After weighing and mixing uniformly according to the following components and weight blending ratio, the obtained mixed powder was directly compressed to obtain a tablet having a tablet weight of 280 mg.

Ibuprofen 17.86
dl-methylephedrine hydrochloride 2.98
Cremastine fumarate 0.05
Dimemorphan phosphate 1.19
Lysozyme chloride 7.14
Anhydrous caffeine 2.98
Crystalline cellulose 62.30
Croscarmellose sodium 4.00
Light anhydrous silicic acid 0.50
Magnesium stearate 1.00 (parts by weight)

Comparative Example 4
After weighing and mixing uniformly according to the following components and weight blending ratio, the obtained mixed powder was directly compressed to obtain a tablet having a tablet weight of 280 mg.

Ibuprofen 17.86
Belladonna Total Alkaloid 0.02
dl-methylephedrine hydrochloride 2.98
Cremastine fumarate 0.05
Tipepidine hibenzate 2.98
Potassium cresol sulfonate 9.92
Anhydrous caffeine 2.98
Crystalline cellulose 57.71
Croscarmellose sodium 4.00
Light anhydrous silicic acid 0.50
Magnesium stearate 1.00 (parts by weight)

Test Example 1 [color difference evaluation test]
Each of the tablets obtained in Examples 1 to 8 and Comparative Examples 1 to 4 was placed in a sealed glass bottle and stored for 7 days under a temperature condition of 60 ° C., and the color tone of the tablets before and after storage was measured. For the color tone measurement, a color tester (MODELSC-3; Suga Test Instruments Co., Ltd.) is used, and the color difference is calculated from the color tone parameters, L (lightness), a (hue) and b (saturation) of each sample by the following formula 1. The change in color tone before and after storage was evaluated.

The test results are shown in Table 1.

  As a result, as shown in Table 1, the formulations according to the present invention (Examples 1 to 8, ibuprofen, dimemorphan, potassium cresolsulfonate group) are Comparative Examples 1 and 2 (dimimephane, potassium cresolsulfonate non-group), It was proved that the color change was dramatically improved as compared with Comparative Example 3 (potassium cresol sulfonate non-blending group) and Comparative Example 4 (dimethomorph phosphate non-blending group).

Test Example 2 [Test example of effect of improving local symptoms of cold syndrome by combination preparation]
In order to evaluate the effect on the cold syndrome by using the pharmaceutical composition of Example 1 described above, four typical local symptoms caused by a prominent cold syndrome (nasal congestion, nasal secretion increase, epilepsy, Twelve adult men and women with cold syndrome who have cough symptoms) were orally administered 3 tablets once a day, 3 times a day after meals for 4 days, and the effect of improving each symptom was evaluated.

To determine the improvement effect,

Significant improvement: 3 or all 4 symptoms disappeared.
Improvement: 2 symptoms disappeared or all symptoms were relieved compared to before taking.
Mild improvement: More than 2 symptoms were relieved compared to before taking.
Unchanged: Same as before taking.
Aggravated: It became worse than the state before taking.

Evaluation based on the above five levels was performed.

  As a result of the test, Table 2 shows the improvement rate (more than mild improvement) for local symptoms due to cold syndrome. As a result, as shown in the table, it was confirmed that the inventive preparation showed an excellent improvement effect on local symptoms of cold syndrome.

According to the present invention, it has become possible to provide an ibuprofen-containing pharmaceutical composition in which the color tone change over time is suppressed and the long-term stability of the preparation is remarkably improved. Moreover, not only was the color change over time suppressed, but it was also highly effective against local symptoms in cold syndrome.

Claims (6)

A pharmaceutical composition comprising (A) ibuprofen, (B) dimemorphan or a salt thereof, and (C) potassium cresolsulfonate.
The blending ratio of (B) dimemorphan or a salt thereof and (C) potassium cresolsulfonate is 1.2 to 20.0 parts by weight and 5.0 to 100.0 parts by weight with respect to 100 parts by weight of (A) ibuprofen, respectively. The pharmaceutical composition according to claim 1, which is a part.
In addition to the pharmaceutical composition according to claim 1, other antipyretic analgesics, other antitussives, other expectorants, anticholinergics, antihistamines, bronchodilators, anti-inflammatory / anti-inflammatory enzymes, sleepiness prevention drugs ( The pharmaceutical composition according to claim 1 or 2, comprising one or more selected from central nervous stimulants), vitamins, herbal medicines, herbal medicines, and antacids.
A pharmaceutical composition comprising (A) ibuprofen, (B) dimemorphan or a salt thereof, and (C) potassium cresol sulfonate, wherein color change is suppressed and stability is good.
It is a tablet, a fine granule, a powder, a granule, or a capsule, The pharmaceutical composition of any one of Claims 1-4.
(A) A pharmaceutical composition containing ibuprofen, wherein (B) dimemorphan or a salt thereof and (C) potassium cresolsulfonate are used to suppress a change in color of the preparation and prevent a change in formulation.