JP2005289904A - 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 with an antihistaminic ingredient and an antitussive ingredient but also effectively suppressing a formulation change such as browning, improving the stability and having 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 mequitazine as the antihistaminic ingredient and dimemorfan or its salt as the antitussive 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

TECHNICAL FIELD The present invention relates to a pharmaceutical composition comprising an antipyretic analgesic component ibuprofen as a main ingredient. More specifically, the present invention relates to a pharmaceutical composition in which long-term stability is remarkably improved by blending ibuprofen with antihistamine component mequitazine and antitussive component dimemorphan or a salt thereof, and effectively suppressing changes in formulation such as browning. It is.

  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 eliminate these symptoms early, cold medicine aims to improve antipyretic analgesic components that relieve pain and fever, antihistamine components that relieve nasal symptoms such as nasal congestion and nasal discharge, and cough symptoms Various ingredients such as the antitussive component described above are blended. Furthermore, ibuprofen having a strong antipyretic analgesic action is blended as an antipyretic analgesic component. (Non-Patent Document 1). Ibuprofen is a non-steroidal anti-inflammatory agent, and has effects as a cold syndrome, anti-inflammatory and analgesic in addition to rheumatoid arthritis, arthralgia and arthritis, neuralgia, neuritis, cervical arm syndrome, etc. Reference 2). Conventionally, ibuprofen has been used for these diseases as an ethical drug (Non-Patent Documents 3 and 4), but due to its effectiveness and safety, it has recently been sold as a general cold medicine for general use. (Non-Patent Document 5).
In the technology related to a combination drug containing ibuprofen, a technology related to an antitussive agent in which mequitazine and a narcotic antitussive component are added to ibuprofen (Patent Document 1), an antitussive agent having improved antitussive effect by including dimemorphan or a salt thereof and ibuprofen, etc. Techniques relating to effectiveness, such as literature 2), are already known, but have not yet been applied to techniques relating to stability improvement that suppress changes in color tone of these blended preparations.
However, ibuprofen has a low melting point of 75-77 ° C., and when blended with other agents, it may cause a melting point drop of the other blended components. Therefore, a formulation in which other active ingredients and ibuprofen are blended Has been pointed out that it 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 6).
For example, when the above-mentioned ibuprofen and clemastine fumarate are blended, browning over time is likely to occur, and in the currently used cold medicines containing ibuprofen and clemastine fumarate, for example, in the dosage form such as a tablet, this In many cases, the surface of the preparation is coated with a water-soluble polymer compound or sucrose to conceal the browning. 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 requires time to develop the drug effect, which is a big pain for cold medicines that require immediate effects.
Antitussive drugs are broadly classified into narcotic and non-narcotic drugs.Narcotic antitussive drugs have a long track record of effectiveness, but they also have the disadvantage of causing side effects such as drug dependence and constipation. The use of drugs is desired. For example, tipepidine hibenzate is known as a non-narcotic antitussive with an expectorant effect and a good antitussive effect, with few side effects, but the formulation formulated with ibuprofen is prone to browning over time and is accompanied by a change in appearance Therefore, the current situation is that it cannot be a product with high product value.
Mequitazine is a phenothiazine antihistamine that suppresses symptoms such as bronchial asthma, allergic rhinitis, urticaria and dermatitis. Conventional phenothiazine-based drugs have a strong central nerve inhibitory action and have drawbacks such as drowsiness and malaise, but mequitazine is an agent in which these disadvantages are improved. In addition, mequitazine has an early onset of drug efficacy, and is therefore an optimal component for cold medicines that require immediate efficacy. Dimemorphan is a typical active ingredient as a non-narcotic antitussive, and it does not provide sufficient antitussive effects compared to narcotic antitussives. It acts directly and exhibits an antitussive action, and is known to exhibit an antitussive effect superior to codeine phosphate and dextromethorphan in pharmacological experiments using dogs and cats.
However, a pharmaceutical composition in which (A) ibuprofen and (B) mequitazine and (C) dimemorphan or a salt thereof are simultaneously blended has not been known so far.

Japanese Patent Laid-Open No. 10-45595 JP 2001-97856 A Sepie IP Gold package insert (Zeria Shinyaku Co., Ltd.) 14th revision Japanese Pharmacopoeia Manual C-268 (Yodogawa Shoten) 2003 26th edition Japanese ethical drugs (Jiho Co., Ltd.) Purfen Tablets, Tablets 200, Granules (Kaken Pharmaceutical Co., Ltd.) Perak Cold 3 package insert (Daiichi Pharmaceutical Co., Ltd.) Sato et al. Pharmacy Vol.27, No.12 (1976)

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 further improves stability over the long term. It is to provide a high pharmaceutical composition.

As a result of intensive studies to solve the above-mentioned problems, the present inventors suppressed color change over time by adding (B) mequitazine and (C) dimethylmorphane or a salt thereof to (A) ibuprofen. It was found that the obtained effective and stable pharmaceutical composition was obtained, and the present invention was completed. That is, the present invention is a pharmaceutical composition characterized by containing mequitazine and dimemorphan or a salt thereof in ibuprofen.

By blending (A) ibuprofen with (B) mequitazine and (C) dimemorphan or a salt thereof, not only can a highly effective pharmaceutical composition be obtained for cold syndrome, but also color change over time. The present invention provides a stable pharmaceutical composition in which is suppressed.

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.
The mequitazine in the invention is not limited as long as it is used for ordinary pharmaceuticals, and for example, products listed in the Japanese Pharmacopoeia can be used. Moreover, as the compounding quantity, it is good to set it as 0.3-5.0 weight part with respect to 100 weight part of ibuprofen, Most preferably, it is 0.4-3.0 weight part. If the amount of mequitazine is less than 0.3 parts by weight, the above-mentioned medicinal effects and effects cannot be expected, and if it exceeds 5.0 parts by weight, there is a question in terms of safety, which is preferable. Absent.
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 dimethylmorphane or a salt thereof is 1.2 parts by weight or less, the above-mentioned medicinal effects and effects cannot be expected, and if it exceeds 20.0 parts by weight, there is a question in terms of safety. Absent.

In addition to the above essential ingredients, this pharmaceutical composition may contain other antipyretic analgesics, other antitussives, other anti-inflammatory agents, anticholinergic agents, antihistamines, bronchodilators, expectorants. In addition, one or more selected from drowsiness prevention drugs (central nervous stimulants), vitamins, herbal medicines, traditional Chinese medicines, and antacids can be blended.
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, and other antihistamines such as chlormaleate Phenylamine (including d-form and dl-form), carbinoxamine maleate, diphenhydramine or its salt, promethazine or its salt, homochlorcyclidine or its salt, anti-inflammatory / anti-inflammatory enzyme, lysozyme chloride, semi-alkali proteinase, tranexam It contains acid, serrapeptase, glycyrrhizic acid or its salt, bromelain and related substances, etc., and belladonna total alkaloids, isopropamide iodide, funnel extract, etc. In combination with other antitussives, dihydrocodeine or its salt, codeine or its salt, dextromethorphan or its salt, noscapine or its salt, eprazinone or its salt, methoxyphenamine or its salt, etc., bronchodilator Methylephedrine hydrochloride (including d-form and dl-form), ephedrine hydrochloride, methoxyphenamine hydrochloride, trimethquinol hydrochloride, theophylline, aminophylline and the like, and as expectorant, potassium cresol sulfonate, potassium guaiacol sulfonate, L-methylcysteine hydrochloride, L-ethylcysteine hydrochloride, etc. are blended, caffeine is blended as a sleepiness prevention drug (central nervous stimulant), vitamin B ₁ or a derivative thereof or a salt thereof, vitamins B ₂ or Such derivatives or salts thereof, vitamin C, and the like, herbal medicines, herbal medicines, antacids, and the like 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 1.19
Glycyrrhizic acid 5.56
Anhydrous caffeine 2.98
Crystalline cellulose 63.67
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 0.08
Dimemorphan phosphate 3.17
Potassium cresol sulfonate 9.92
Anhydrous caffeine 2.98
Crystalline cellulose 57.49
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 15.87
Belladonna Total Alkaloid 0.02
dl-methylephedrine hydrochloride 2.98
Mequitazine 0.08
Dimemorphan phosphate 0.40
Potassium cresol sulfonate 9.92
Anhydrous caffeine 2.98
Crystalline cellulose 62.25
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 23.81
Belladonna Total Alkaloid 0.02
dl-methylephedrine hydrochloride 2.98
Mequitazine 0.48
Dimemorphan phosphate 3.17
Potassium cresol sulfonate 9.92
Anhydrous caffeine 2.98
Crystalline cellulose 51.14
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 17.86
Belladonna Total Alkaloid 0.02
dl-methylephedrine hydrochloride 2.98
Mequitazine 0.48
Dimemorphan phosphate 0.40
Potassium cresol sulfonate 9.92
Anhydrous caffeine 2.98
Crystalline cellulose 59.86
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
Belladonna Total Alkaloid 0.02
dl-methylephedrine hydrochloride 2.98
Cremastine fumarate 0.05
Lysozyme chloride 3.57
Tipepidine hibenzate 2.98
Anhydrous caffeine 2.98
Crystalline cellulose 64.06
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
dl-methylephedrine hydrochloride 2.98
Cremastine fumarate 0.05
Tipepidine hibenzate 3.97
Lysozyme chloride 3.57
Anhydrous caffeine 2.98
Crystalline cellulose 63.09
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
Belladonna Total Alkaloid 0.02
dl-methylephedrine hydrochloride 2.98
Cremastine fumarate 0.05
Tipepidine hibenzate 2.98
Glycyrrhizic acid 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 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 6 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 shown in Table 1, the formulation according to the present invention (Examples 1 to 6, ibuprofen, mequitazine, dimemorphan combination group) was dramatically shaded compared to Comparative Examples 1 to 4 (mequitadine, dimethylmorphan non-contained group). Proven that the changes have improved.

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 using the pharmaceutical composition of Example 1 described above, four typical local symptoms due to a prominent cold syndrome (nasal congestion, nasal discharge, sputum, cough) Twelve adult men and women suffering from cold syndrome with each symptom) 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.

The test results are shown in Table 2 for the improvement rate (over 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. In addition, the present invention is a pharmaceutical composition characterized by not only suppressing changes in color tone over time but also showing high effectiveness against local symptoms in cold syndrome.

Claims (6)

(A) Ibuprofen contains (B) mequitazine and (C) dimemorphan or a salt thereof.
The pharmaceutical composition according to claim 1, wherein the blending ratio of (B) mequitazine is 0.3 to 5.0 parts by weight with respect to 100 parts by weight of (A) ibuprofen.
The pharmaceutical composition according to claim 1, wherein the blending ratio of (C) dimemorphan or a salt thereof is 1.2 to 20.0 parts by weight with respect to 100 parts by weight of (A) ibuprofen.
In addition, other antipyretic analgesics, other antihistamines, other antitussives, expectorants, anticholinergics, bronchodilators, anti-inflammatory / anti-inflammatory enzymes, anti-somnia drugs (central nervous stimulants), vitamins, The pharmaceutical composition according to claim 1, comprising one or more selected from crude drugs, traditional Chinese medicines, and antacids.
  The pharmaceutical composition according to claim 1 or 4, which is a tablet, fine granule, powder, granule or capsule. (A) A pharmaceutical composition containing ibuprofen, wherein (B) mequitazine and (C) dimemorphan or a salt thereof are blended to suppress a change in color tone of the preparation and prevent a blending change.