JPH05148139A - Antipyretic analgesic agent containing ibuprofen - Google Patents

Abstract

PURPOSE:To obtain an ibuprofen-containing antipyretic analgesic agent highly safe on its employment by depressing the gastrointestine-injuring property of the ibuprofen and simultaneously synergistically improving its antipyretic analgesic activity. CONSTITUTION:(a) 1 pt.wt. of ibuprofen is compounded with (b) 0.01-30 pts.wt., preferably 0.1-20 pts.wt., of acetaminophen and (c) 0.05-100 pts.wt., preferably 0.1-50 pts.wt., [based on 1 pt.wt. of the total amount of (a)+(b)] of a magnesium antiacid, preferably magnesium oxide or magnesium carbonate, as essential ingredients to obtain the ibuprofen-containing antipyretic analgesic agent having the above-mentioned activities. The ingredient (a) can be added to the composition in an amount of usually 0.1-99wt.%, preferably 1.0-90wt.%. The antipyretic analgesic agent can orally be administered at a daily dose of usually 100-6000mg for an adult as the sum of (a), (b) and (c) once or devided into several times.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an ibuprofen-containing antipyretic analgesic, and more particularly to an ibuprofen-containing antipyretic analgesic comprising ibuprofen, acetaminophen and a magnesium antacid.

[0002]

2. Description of the Related Art Many antipyretic and analgesic drugs have been known. Among them, combinations of aniline derivative-based acetaminophen and the like with salicylic acid derivative-based aspirin, ethoxybenzamide and the like are widely used. However, salicylic acid derivative-based antipyretic analgesics have drawbacks such as being liable to cause gastric disorders, and by combining ibuprofen and an aniline derivative-based antipyretic analgesic in place of the salicylic acid derivative-based antipyretic analgesic, excellent efficacy and acute toxicity are obtained. An attempt was made to develop an antipyretic analgesic (Japanese Patent Laid-Open No. Sho 56-56).
-97224, 56-154416, and 59-104315). Ibuprofen has excellent antipyretic, analgesic and anti-inflammatory effects, and has become widely used as a non-steroidal drug. However, it has been pointed out that when ibuprofen is orally administered, gastrointestinal discomfort, gastric pain, nausea and the like may occur as in the case of the salicylic acid derivative-based antipyretic analgesic, which causes gastrointestinal disorders as a side effect. For this reason, in order to reduce gastrointestinal disorders caused by oral administration of ibuprofen, the drug may be used in combination with a salicylic acid drug (JP-A-61-1).
34315), and combined use with an antacid and / or a mucosa coating agent (JP-A-63-198620). However, an antipyretic analgesic containing such a drug cannot necessarily satisfy both the antipyretic and analgesic effect and the reduction of gastrointestinal disorders.

[0003]

SUMMARY OF THE INVENTION However, the present inventor provides an antipyretic analgesic which is free from the drawbacks of conventional antipyretic analgesics, such as being prone to gastrointestinal disorders, and which is excellent in analgesic action and antipyretic action and highly safe. The purpose is to do.

[0004]

Means for Solving the Problems As a result of intensive studies to achieve the above-mentioned object, the inventors of the present invention suppressed gastrointestinal disorders by simultaneously mixing ibuprofen with acetaminophen and a magnesium antacid. In addition, the inventors have found that the synergistic antipyretic and analgesic action is further improved and these drawbacks are improved, and the present invention has been completed.

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION The ibuprofen-containing antipyretic analgesic of the present invention is an antipyretic analgesic comprising ibuprofen, acetaminophen, and a magnesium antacid as described above. The ibuprofen used in the present invention includes ibuprofen (2- (4-isobutyl).
phenyl) propionic acid) and salts thereof, etc., and usually 0.1 to 99% by weight, preferably 1.0 to 90% by weight can be added to the composition. Examples of acetaminophen used in the present invention include acetaminophen (N- (4-hydrox
yphenyl) acetamide) and salts thereof. The acetaminophen content is as follows:
0.01 to 30 parts by weight of acetaminophen can be added to 1 part by weight of ibuprofen, and preferably 0.1 to 20 parts by weight can be added. When it deviates from this range, it becomes difficult to exhibit the above-mentioned synergistic effect.

The magnesium-based antacid used in the present invention includes magnesium silicate, magnesium oxide, magnesium hydroxide, magnesium carbonate, aluminum hydroxide / magnesium carbonate mixed dry gel, and aluminum hydroxide / calcium carbonate / magnesium carbonate. Precipitated products, magnesium aluminometasilicate, dimagnesium aluminate silicate, magnesium bismuth aluminate silicate, coprecipitated products of magnesium hydroxide / potassium aluminum sulfate, particularly preferred magnesium-based antacid, Magnesium oxide and magnesium carbonate. In the present invention, one of these antacids may be used in combination with ibuprofen, or two or more of them may be used in combination with ibuprofen. The amount of these antacids blended is 1 for ibuprofen and acetaminophen.
0.05 to 100 parts by weight, preferably 0.1 to 50 parts by weight, can be blended with respect to parts by weight. 0.0
If it is less than 5 parts by weight, the gastrointestinal disorder is not reduced and the antipyretic and analgesic effect is not improved. If it exceeds 100 parts by weight, the dose will increase and the side effects of the magnesium antacid will appear.

The antipyretic analgesic of the present invention further comprises a sedative hypnotic such as allylisopropylacetylurea, bromvalerylurea, etc., isothibenzyl hydrochloride, diphenylpyraline hydrochloride, diphenhydramine hydrochloride, difeterol hydrochloride, triprolidine hydrochloride, triperenamine hydrochloride, if necessary. Tonzylamine hydrochloride, phenetazine hydrochloride, metzirazine hydrochloride, diphenhydramine salicylate, carbinoxamine diphenyldisulfonate, alimemazine tartrate, diphenhydramine tannate diphenylpyraline, mebuhydroline napadisylate, promethazine methylene disalicylate, carbinoxamine maleate, dl.
-Chlorpheniramine maleate, d-chlorpheniramine maleate, antihistamines such as difeterol phosphate, sodium caffeine benzoate, caffeine,
Central stimulants such as anhydrous caffeine, vitamin B1 and derivatives thereof and salts thereof, vitamin B2 and derivatives thereof and salts thereof, vitamin C and derivatives thereof and salts thereof, hesperidin and derivatives thereof and vitamins such as salts thereof Agents and the like can be appropriately mixed. The antipyretic analgesic of the present invention is effective against headache, toothache, post-extraction toothache, sore throat, earache, arthralgia, neuralgia, backache, muscle pain, analgesia such as menstrual pain, chills, antipyreticity during fever, etc. Is. The antipyretic analgesic of the present invention is usually 100 to 600 as a total of ibuprofen, acetaminophen and magnesium-based antacid per day for adults.
0 mg can be orally administered in one to several divided doses. This dose can be appropriately increased or decreased depending on the age, body weight and symptoms of the patient.

Further, the antipyretic analgesic of the present invention is used in various dosage forms such as tablets, granules, powders, capsules, syrups and dispersants. These preparations can be prepared by a conventional method. As a carrier that can be used for preparing a solid preparation, excipients such as lactose, starch, sucrose, mannitol, crystalline cellulose (for example, Avicel: registered trademark, manufactured by Asahi Kasei Co., Ltd.); hydroxypropyl cellulose, carboxymethyl cellulose, gelatin. , Binders such as sodium carboxymethylcellulose, gum arabic; disintegrators such as carboxymethylcellulose calcium, polyvinylpyrrolidone or cross-linked products thereof, low-substituted hydroxypropylcellulose; nonionic surface active agents such as sucrose fatty acid ester and polyoxysorbitan fatty acid ester Agents: Lubricants such as calcium stearate, magnesium stearate, dimethylpolysiloxane, talc, polyethylene glycol, hardened oil, etc., and other coating agents if necessary As a coating agent, there are hydroxypropylcellulose, hydroxypropylmethylcellulose, eudragit, polyvinylpyrrolidone, polyethylene glycol, cerac, methylcellulose, ethylcellulose, cellulose acetate phthalate, hydroxypropylcellulose phthalate, sucrose, gum arabic, calcium carbonate, It is also possible to apply sugar coating with talc, gelatin or the like as the main component. Excipients that can be used to prepare liquid formulations include purified water, ethanol, glycerin, sucrose, propylene glycol, polyethylene glycol, polyoxyethylene sorbitan fatty acid ester, aluminum metahydroxide, agar, tragacanth gum, etc. If necessary, a solubilizing agent, a buffering agent, a preservative, a flavoring agent, a coloring agent, a flavoring agent and the like can be used.

[0009]

INDUSTRIAL APPLICABILITY The ibuprofen-containing antipyretic and analgesic agent of the present invention has excellent antipyretic and analgesic activity, reduces the gastrointestinal disorder effect of ibuprofen, and is highly safe in use. Next, the effects of the present invention will be specifically described by showing experimental examples.

Experimental Example 1 (Gastrointestinal disorder action) Six-week-old male SD rats (body weight: 130 to 150 g) were used in an experiment with one group consisting of 7 to 10 rats. After fasting the animals for 24 hours, 1.
0 ml / 100 g B.I. W. Oral administration, 4 hours after that, the stomach was removed, fixed with 2% formalin, and cut longitudinally along the bay to determine the presence or absence of gastric mucosal damage under a stereoscopic microscope.
The ulcer incidence was calculated. The test drug was suspended in a 5% aqueous solution of gum arabic before use. 50% ulcerative drug dose (UD
₅₀ ) was calculated by the Litchfield & Wilcoxon method. The results are shown in Table 1. The values are expressed as the amount of ibuprofen in each drug.

[0011]

[Table 1] When acetaminophen, which does not cause gastric disorders alone, was added to ibuprofen, the UD ₅₀ value decreased, and ulcers were observed at lower doses. Addition of magnesium antacids to ibuprofen and acetaminophen significantly suppressed the occurrence of gastric disorders.

Experimental Example 2 (Analgesic action) Male ddY male mice (body weight 20 to 25 g) aged 5 weeks were
A group of 19 to 25 animals was used for the experiment. Each test drug was administered to animals in separate groups at 0.1 ml / 10 g B.I. W. 60 minutes after oral administration, 0.7% acetic acid 0.1 ml / 1
It was intraperitoneally administered at a rate of 0 g. Immediately after that, the rising number for 20 minutes was measured, and the suppression rate was calculated according to the following formula 1 from this and the rising number of the control group (the group to which 1% carboxymethylcellulose was orally administered without adding the test drug). Based on the above, the ED ₅₀ value was determined. The test drug was suspended in a 1% carboxymethylcellulose aqueous solution before use. 50% effective dose (ED ₅₀ ) is Litchfi
It was calculated by the eld & Wilcoxon method. The results are shown in Table 2. The numerical value was represented by the amount of analgesic and antipyretic component.

[0013]

[Formula 1]

[0014]

[Table 2] By blending ibuprofen with acetaminophen, which is an antipyretic analgesic, the ED ₅₀ value was lowered to 51% of that of ibuprofen alone, and the analgesic effect was enhanced. By combining not only acetaminophen with ibuprofen, but also a magnesium-based antacid that does not have an analgesic effect by itself, the ED ₅₀ value decreased to 31% of ibuprofen + acetaminophen, and the analgesic effect was synergistic. The enhancement was recognized.

Experimental Example 3 (antipyretic effect) Male Wistar rats (body weight: 200 to 24) of 8 weeks old
0 g) was used in the experiment by making 5 to 7 animals per group. 30 animals
After measuring the body temperature twice at intervals, a 7.5% aqueous yeast solution was added thereto at 1.0 ml / 100 g B.I. W. It was administered subcutaneously. Three hours later, each test drug was administered to animals in separate groups at 0.5 ml / 100 gB. W. Orally administered, then 1
Body temperature was measured 6 times every hour. The inhibition rate for the fever area of the control group was determined from the fever area up to 6 hours after drug administration, and the ED ₅₀ value was calculated from the inhibition rate. The test drug was suspended in a 5% aqueous solution of gum arabic before use. 5
0% effective dose (ED ₅₀ ) is Litchfield & Wi
It was calculated by the lcoxon method. The results are shown in Table 3.
The numerical value is shown as the amount of analgesic and antipyretic component.

[0016]

[Table 3] Addition of acetaminophen to ibuprofen reduced the ED ₅₀ value compared to ibuprofen alone.
By combining not only acetaminophen but also a magnesium-based antacid with ibuprofen, the gastrointestinal disorders were suppressed more than ibuprofen + acetaminophen, and the antipyretic and analgesic action was synergistically improved. Hereinafter, the present invention will be specifically shown by showing examples, but the present invention is not limited to the following examples. The analgesic action, antipyretic action, and gastrointestinal disorder action in Examples and Comparative Examples are as follows.
Evaluation was performed by the same operation as in the above-mentioned Experimental Examples 1 to 3. The tablets were crushed, and the hard capsules and soft capsules were used by taking out the contents and suspending them in a solvent. Numerical values are shown for each formulation. For hard capsules and soft capsules,
The amount of contents is shown.

[0017]

【Example】

Example 1 Tablet (in one tablet) Ibuprofen 65 mg Acetaminophen 65 mg Magnesium oxide 50 mg Magnesium carbonate 100 mg Hydroxypropyl cellulose 6 mg Crystalline cellulose 50 mg Corn starch 10 mg Carboxymethyl cellulose 20 mg Magnesium stearate 4 mg The above ingredients were tabletted on a rotary tableting machine. A tablet was obtained. The evaluation results are shown below. Analgesic effect ED ₅₀ : 85.4 mg / Kg Antipyretic effect ED ₅₀ : 12.8 mg / Kg Gastrointestinal disorder effect UD ₅₀ : At an administrable 1000 mg, the ulcer incidence was 30%.

Example 2 Tablets (in one tablet) Ibuprofen 70 mg Acetaminophen 35 mg Magnesium carbonate 100 mg Aluminum glycinate 50 mg Gelatin 5 mg Polyvinylpyrrolidone 13 mg Corn starch 17 mg Croscarmellose 10 mg Magnesium stearate 5 mg The above ingredients were put on a rotary tableting machine. Tablets were obtained by tableting. The evaluation results are shown below. Analgesic effect ED ₅₀ : 263.8 mg / Kg Antipyretic effect ED ₅₀ : 23.5 mg / Kg Gastrointestinal disorder effect UD ₅₀ : 1000 mg / K that can be administered
In g, the ulcer incidence was 40%.

Example 3 Granules (in one package) Ibuprofen 120 mg Acetaminophen 90 mg Magnesium oxide 100 mg Synthetic hydrotalcite 270 mg Allyl isopropyl acetyl urea 60 mg Caffeine 80 mg Partially pregelatinized starch 35 mg Corn starch 15 mg Hydroxypropyl cellulose 5 mg The above ingredients are extruded. Granulation was carried out by a granulation method, dried and then granulated to obtain granules. The evaluation results are shown below. Analgesic effect ED ₅₀ : 106 mg / Kg Antipyretic effect ED ₅₀ : 15.9 mg / Kg Gastrointestinal disorder effect UD ₅₀ : 1000 mg / K that can be administered
In g, the ulcer incidence was 20%.

Example 4 Granules (in one package) Ibuprofen 60 mg Acetaminophen 120 mg Magnesium silicate 500 mg Gum arabic 5 mg Corn starch 20 mg The above ingredients were granulated by a granulation method, dried and granulated to obtain granules. .. The evaluation results are shown below. Analgesic effect ED ₅₀ : 231 mg / Kg Antipyretic effect ED ₅₀ : 34.5 mg / Kg Gastrointestinal disorder effect UD ₅₀ : Administerable 1000 mg / K
In g, the ulcer incidence was 10%.

Example 5 Powder (9 in one package ibuprofen 130 mg acetaminophen 50 mg magnesium carbonate 100 mg magnesium aluminometasilicate magnesium 200 mg blobhaline 200 mg caffeine 80 mg hydroxypropylcellulose 25 mg corn starch 75 mg The above ingredients were granulated by a fluid granulation method, The evaluation results are shown below: Analgesic effect ED ₅₀ : 201 mg / Kg Antipyretic effect ED ₅₀ : 30.1 mg / Kg Gastrointestinal disorder effect UD ₅₀ : Administerable 1000 mg / K
In g, the ulcer incidence was 20%.

Example 6 Hard capsule (in 1 capsule) Ibuprofen 50 mg Acetaminophen 50 mg Magnesium silicate 200 mg Actisol (Asahi Kasei) 50 mg Hardened oil 30 mg The above components were mixed to obtain a hard capsule. The evaluation results are shown below. Analgesic effect ED ₅₀ : 83.2 mg / Kg Antipyretic effect ED ₅₀ : 12.5 mg / Kg Gastrointestinal disorder effect UD ₅₀ : Administerable 1000 mg / Kg
In g, the ulcer incidence was 20%.

Example 7 Hard capsule (in 1 capsule) Ibuprofen 60 mg Acetaminophen 30 mg Magnesium carbonate 100 mg Vitamin B1 8 mg Corn starch 22 mg Magnesium stearate 2 mg The above ingredients were mixed to obtain a hard capsule. The evaluation results are shown below. Analgesic effect ED ₅₀ : 133 mg / Kg Antipyretic effect ED ₅₀ : 20 mg / Kg Gastrointestinal disorder effect UD ₅₀ : 807 mg / Kg

Example 8 Soft capsule (in 1 capsule) Ibuprofen 60 mg Acetaminophen 65 mg Magnesium oxide 50 mg Safflower fatty acid 200 mg d1-Tocopherol 5 mg A soft capsule was obtained from the above components by a conventional method. The evaluation results are shown below. Analgesic effect ED ₅₀ : 66.6 mg / Kg Antipyretic effect ED ₅₀ : 10.0 mg / Kg Gastrointestinal disorder effect UD ₅₀ : 1000 mg / K that can be administered
In g, the ulcer incidence was 20%.

[Procedure amendment]

[Submission date] December 1, 1992

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be corrected] Full text

[Correction method] Change

[Correction content]

[Document name] Statement

Title: Antipyretic analgesic containing ibuprofen

[Claims]

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an ibuprofen-containing antipyretic analgesic, and more particularly to an ibuprofen-containing antipyretic analgesic comprising ibuprofen, acetaminophen and a magnesium antacid.

[0002]

2. Description of the Related Art Many antipyretic and analgesic drugs have been known. Among them, combinations of aniline derivative-based acetaminophen and the like with salicylic acid derivative-based aspirin, ethoxybenzamide and the like are widely used. However, salicylic acid derivative-based antipyretic analgesics have drawbacks such as being liable to cause gastric disorders. By combining ibuprofen and an aniline derivative-based antipyretic analgesic in place of the salicylic acid derivative-based antipyretic analgesic, efficacy and acute toxicity can be improved. Attempts have been made to develop excellent antipyretic analgesics (JP-A-56-97224, JP-A-56-154416, and JP-A-59-104315). Ibuprofen has excellent antipyretic, analgesic and anti-inflammatory effects, and has become widely used as a non-steroidal drug. However, it has been pointed out that when ibuprofen is orally administered, gastrointestinal discomfort, gastric pain, nausea and the like may occur as in the case of the salicylic acid derivative-based antipyretic analgesic, and a gastrointestinal disorder is caused as a side effect. For this reason, in order to reduce gastrointestinal disorders caused by oral administration of ibuprofen, it may be used in combination with a salicylic acid drug (JP-A-61-134315) or in combination with an antacid and / or a mucosal coating agent. (JP-A-63-198620) has been proposed. However, an antipyretic analgesic containing such a drug cannot necessarily satisfy both the antipyretic and analgesic effect and the reduction of gastrointestinal disorders.

[0003]

SUMMARY OF THE INVENTION However, the present inventor provides a antipyretic analgesic which solves the drawbacks of the conventional antipyretic analgesics such as easy to cause gastrointestinal disorders and has excellent analgesic action and antipyretic action and high safety. The purpose is to do.

[0004]

Means for Solving the Problems As a result of intensive studies to achieve the above-mentioned object, the inventors of the present invention suppressed gastrointestinal disorders by simultaneously mixing ibuprofen with acetaminophen and a magnesium antacid. In addition, the inventors have found that the synergistic antipyretic and analgesic action can be further improved and the above-mentioned drawbacks can be improved, and the present invention has been completed. That is, the antipyretic analgesic containing ibuprofen of the present invention has the following (a),
It is characterized by containing the components (b) and (c). (A) Ibuprofen. (B) 0.01 to 30 parts by weight of acetaminophen relative to 1 part by weight of ibuprofen. (C) 0.05 to 100 parts by weight of a magnesium-based antacid based on 1 part by weight of the total amount of ibuprofen and acetaminophen.

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION The ibuprofen used in the present invention includes ibuprofen (2- (4-isob
utyl phenyl) propionic aci
d) and salts thereof, etc., and usually 0.1% in the composition.
˜99 wt%, preferably 1.0 to 90 wt%. Acetaminophen (N- (4-hy
Droxyphenyl) acetamide) can be added in an amount of 0.01 to 30 parts by weight, preferably 0.1 to 20 parts by weight, based on 1 part by weight of ibuprofen. When it deviates from this range, it becomes difficult to exhibit the above-mentioned synergistic effect.

The magnesium-based antacid used in the present invention includes magnesium silicate, magnesium oxide, magnesium hydroxide, magnesium carbonate, aluminum hydroxide / magnesium carbonate mixed dry gel, and aluminum hydroxide / calcium carbonate / magnesium carbonate. Precipitation products, magnesium aluminometasilicate, dimagnesium aluminate silicate, coprecipitation products of magnesium hydroxide / potassium aluminum sulfate, and particularly preferred magnesium antacids are magnesium oxide and magnesium carbonate. .. In the present invention, one of these antacids may be used in combination with ibuprofen, or two or more of them may be used in combination with ibuprofen. The amount of these antacids to be added may be 0.05 to 100 parts by weight, preferably 0.1 to 50 parts by weight, based on 1 part by weight of the total amount of ibuprofen and acetaminophen. When this amount is less than 0.05 parts by weight, gastrointestinal disorders are not reduced, and the antipyretic and analgesic effect is not improved. On the other hand, when the amount exceeds 100 parts by weight, the dose increases and the side effect of the magnesium-based antacid appears.

The antipyretic analgesic of the present invention further comprises a sedative hypnotic such as allylisopropylacetylurea, bromvalerylurea, etc., isothipendyl hydrochloride, diphenylpyraline hydrochloride, diphenhydramine hydrochloride, difeterol hydrochloride, triprolidine hydrochloride, tripelenamine hydrochloride, hydrochloric acid, if necessary. Tondylamine, phenetadine hydrochloride, metzirazine hydrochloride, diphenhydramine salicylate, carbinoxamine diphenyldisulfonate, alimemazine tartrate, diphenhydramine tannate diphenylpyraline, mebuhydroline napadisylate, promethazine methylene disalicylate, carbinoxamine maleate, dl.
-Chlorpheniramine maleate, d-chlorpheniramine maleate, antihistamines such as difeterol phosphate, sodium caffeine benzoate, caffeine,
Central stimulants such as anhydrous caffeine, vitamin B1 and its derivatives and salts thereof, vitamin B2 and its derivatives and salts thereof, vitamin C and its derivatives and salts thereof, hesperidin and its derivatives and vitamins such as salts thereof Agents and the like can be appropriately mixed.

The antipyretic analgesic of the present invention is effective for headache, toothache, post-extraction pain, sore throat, ear pain, arthralgia, neuralgia, back pain, muscle pain, menstrual pain, etc., chills, fever and fever. Effective against Further, the antipyretic analgesic of the present invention is usually 100 to 6 as a total amount of ibuprofen, acetaminophen and magnesium antacid per day for an adult.
000 mg can be administered orally in one to several divided doses. This dose can be appropriately increased or decreased depending on the age, body weight and symptoms of the patient.

Further, the antipyretic analgesic of the present invention is used in various dosage forms such as tablets, granules, powders, capsules, syrups and dispersants. These preparations can be prepared by a conventional method. As components that can be used for preparing a solid preparation, excipients such as lactose, starch, sucrose, mannitol, and crystalline cellulose (for example, Avicel: registered trademark, manufactured by Asahi Kasei Co., Ltd.); hydroxypropyl cellulose, carboxymethyl cellulose, gelatin. , Binders such as sodium carboxymethylcellulose, gum arabic; disintegrators such as carboxymethylcellulose calcium, polyvinylpyrrolidone or cross-linked products thereof, low-substituted hydroxypropylcellulose; nonionic surface active agents such as sucrose fatty acid ester and polyoxysorbitan fatty acid ester Agents: Lubricants such as calcium stearate, magnesium stearate, dimethylpolysiloxane, talc, polyethylene glycol, hardened oil, etc., and other coloring agents, sweeteners, etc. as required It can be used. Further, it can also be coated, as a coating agent, there are hydroxypropyl cellulose, hydroxypropyl methyl cellulose, Eudragit, polyvinylpyrrolidone, polyethylene glycol, shellac, methyl cellulose, ethyl cellulose, cellulose acetate phthalate, hydroxypropyl cellulose phthalate, sucrose, It is also possible to apply sugar coating with gum arabic, calcium carbonate, talc, gelatin or the like as the main component.

As components that can be used in the preparation of liquid preparations, there are purified water, ethanol, glycerin, sucrose, propylene glycol, polyethylene glycol, polyoxyethylene sorbitan fatty acid ester, aluminum metahydroxide, agar, tragacanth gum and the like. Other solubilizers, buffers, preservatives, fragrances, coloring agents, etc.
A flavoring agent or the like can be used.

[0011]

INDUSTRIAL APPLICABILITY The ibuprofen-containing antipyretic and analgesic agent of the present invention has excellent antipyretic and analgesic activity, reduces the gastrointestinal disorder effect of ibuprofen, and is highly safe in use. Next, the effects of the present invention will be specifically described by showing experimental examples.

Experimental Example 1 (Gastrointestinal disorder action) Six-week-old male SD rats (body weight: 130 to 150 g) were used in an experiment with one group consisting of 7 to 10 rats. After fasting the animals for 24 hours, 1.0 m of each test drug was applied to each group of animals.
1/100 g B.I. W. Oral administration was performed, and 4 hours later, the stomach was excised, fixed with 2% formalin, and cut longitudinally along the bay to determine the presence or absence of gastric mucosal damage under a stereoscopic microscope to determine the ulcer incidence. The test drug was suspended in a 5% aqueous solution of gum arabic before use. 50% ulcerative drug amount (U
D ₅₀ ) was calculated by the Litchfield & Wilcoxon method. The results are shown in Table 1. The values are shown as the amount of ibuprofen in each drug.

[0013]

[Table 1]Table 1: Gastrointestinal disorders Drug (weight ratio) UD ₅₀ (mg / kg)  Ibuprofen 34.4 Ibuprofen + acetaminophen (1: 1) 19.8 Ibuprofen + acetaminophen+ Magnesium oxide (1: 1: 2.2) 218 Ibuprofen + acetaminophen + magnesium carbonate+ Magnesium oxide (1: 1: 1.6: 0.6) 210

When acetaminophen was added to ibuprofen, which does not cause gastric disorders alone, the UD ₅₀ value decreased, and the occurrence of ulcer was observed at a lower dose. Addition of magnesium antacids to ibuprofen and acetaminophen significantly suppressed the occurrence of gastric disorders.

Experimental Example 2 (Analgesic action) Male ddY male mice (body weight: 20 to 25 g) aged 5 weeks were
A group of 19 to 25 animals was used for the experiment. Each test drug was administered to each group of animals at 0.1 ml / 10 g B.I. W. 60 minutes after oral administration, 0.7% acetic acid was added to 0.1 ml / 10
gB. W was administered intraperitoneally. 20 minutes after that
The number of minutes of rising was measured, and the suppression rate was calculated according to the following formula 1 from this and the number of rising of the control group (the group to which 1% carboxymethylcellulose was orally administered without adding the test drug), and the inhibition rate was calculated based on this. Then, the ED ₅₀ value was obtained.

[0016]

[Equation 1]

The test drug was suspended in a 1% carboxymethyl cellulose aqueous solution before use. 50% effective dose (ED
₅₀ ) was calculated by the Litchfield & Wilcoxon method. The results are shown in Table 2. The numerical value is shown as the amount of analgesic and antipyretic component.

[0018]

[Table 2] Table 2: Analgesic drugs (weight ratio) ED ₅₀ (mg / kg) ibuprofen 137.0 ibuprofen + acetaminophen (1: 1) 70.3 ibuprofen + acetaminophen + magnesium oxide (1: 1) : 2.2) 21.9 ibuprofen + acetaminophen + magnesium carbonate + magnesium oxide (1: 1: 1.6: 0.6) 30.0

By blending ibuprofen with acetaminophen, which is an antipyretic analgesic, the ED ₅₀ value was 51% of that of ibuprofen alone, and the analgesic effect was synergistically enhanced. By combining ibuprofen with acetaminophen and a magnesium-based antacid that does not have an analgesic effect by itself, the ED ₅₀ value is ibuprofen +
It became 31% of acetaminophen, and a remarkable enhancement of the analgesic effect was observed.

Experimental Example 3 (antipyretic action) Male Wistar rats (body weight: 200 to 24) of 8 weeks old
0 g) was used in the experiment by making 5 to 7 animals per group. 30 animals
After measuring the body temperature twice at intervals, a 7.5% yeast aqueous solution was added to 1.0 ml / 100 gB. W. It was administered subcutaneously. Three hours later, each test drug was administered to each group of animals at 0.5 ml / 100 gB. W. After oral administration, the body temperature was measured 6 times every hour thereafter. The inhibition rate for the fever area of the control group was determined from the fever area up to 6 hours after drug administration, and the ED ₅₀ value was calculated from the inhibition rate. The test drug was suspended in a 5% aqueous solution of gum arabic before use. 50% effective dose (ED ₅₀ ) is Litchfield & Wilcox
It was calculated by the on method. The results are shown in Table 3. The numerical value is shown as the amount of analgesic and antipyretic component.

[0021]

[Table 3] Table 3: Antipyretic drugs (weight ratio) ED ₅₀ (mg / kg) ibuprofen 20.4 ibuprofen + acetaminophen (1: 1) 10.5 ibuprofen + acetaminophen + magnesium oxide (1: 1) : 2.2) 3.3 ibuprofen + acetaminophen + magnesium carbonate + magnesium oxide (1: 1: 1.6: 0.6) 4.5

By blending ibuprofen with acetaminophen, the ED ₅₀ value was 5 times that of ibuprofen alone.
It became 1%, and the antipyretic effect was synergistically enhanced. Further, by simultaneously adding a magnesium-based antacid, the ED ₅₀ value was significantly lower than that of ibuprofen + acetaminophen, and gastrointestinal disorders were also suppressed.

The present invention will be described concretely with reference to the following examples, but the present invention is not limited to the following examples. still,
The analgesic action, antipyretic action, and gastrointestinal disorder action in Examples and Comparative Examples were evaluated by the same operations as those in Experimental Examples 1 to 3 described above. The tablets were crushed, and the hard capsules and soft capsules were used by taking out the contents and suspending them in a solvent. Numerical values are shown for each formulation. Hard capsule,
Soft capsules are indicated by the amount of contents.

[0024]

Example 1 Tablet (in one tablet) Ibuprofen 65 mg Acetaminophen 65 mg Magnesium oxide 50 mg Magnesium carbonate 100 mg Hydroxypropyl cellulose 6 mg Crystalline cellulose 50 mg Corn starch 10 mg Carboxymethyl cellulose 20 mg Magnesium stearate 4 mg The above-mentioned components are rotary tablet presses. Tablets were obtained by tableting with. The evaluation results are shown below. Analgesic effect ED ₅₀ : 85.4 mg / kg Antipyretic effect ED ₅₀ : 12.8 mg / kg Gastrointestinal disorder effect UD ₅₀ : Administerable 1000 mg / kg
, The ulcer incidence was 30%.

Example 2 Tablets (in one tablet) Ibuprofen 70 mg Acetaminophen 35 mg Magnesium carbonate 100 mg Aluminum glycinate 50 mg Gelatin 5 mg Polyvinylpyrrolidone 13 mg Corn starch 17 mg Croscarmellose 10 mg Magnesium stearate 5 mg The above ingredients were put on a rotary tableting machine. Tablets were obtained by tableting. The evaluation results are shown below. Analgesic effect ED ₅₀ : 171.9 mg / kg Antipyretic effect ED ₅₀ : 23.5 mg / kg Gastrointestinal disorder effect UD ₅₀ : Administerable 1000 mg / kg
, The ulcer incidence was 20%.

Example 3 Granules (in one packet) Ibuprofen 120 mg Acetaminophen 90 mg Magnesium oxide 100 mg Synthetic hydrotalcite 270 mg Allyl isopropyl acetyl urea 60 mg Caffeine 80 mg Partially pregelatinized starch 35 mg Corn starch 15 mg Hydroxypropyl cellulose 5 mg The above ingredients are extruded. Granulation was carried out by a granulation method, dried and then granulated to obtain granules. The evaluation results are shown below. Analgesic effect ED ₅₀ : 106.0 mg / kg Antipyretic effect ED ₅₀ : 15.9 mg / kg Gastrointestinal disorder effect UD ₅₀ : Administerable 1000 mg / kg
, The ulcer incidence was 30%.

Example 4 Granules (in one packet) Ibuprofen 60 mg Acetaminophen 120 mg Magnesium silicate 500 mg Gum arabic 5 mg Corn starch 20 mg The above ingredients were granulated by a granulation method, dried and then granulated to obtain granules. .. The evaluation results are shown below. Analgesic effect ED ₅₀ : 231.0 mg / kg Antipyretic effect ED ₅₀ : 34.5 mg / kg Gastrointestinal disorder effect UD ₅₀ : Administerable 1000 mg / kg
, The ulcer incidence was 10%.

Example 5 Powder (in one package) Ibuprofen 130 mg Acetaminophen 50 mg Magnesium carbonate 100 mg Magnesium aluminometasilicate 200 mg Brovaline 200 mg Caffeine 80 mg Hydroxypropylcellulose 25 mg Corn starch 75 mg The above ingredients were granulated by a fluid granulation method, I got a powder. The evaluation results are shown below. Analgesic effect ED ₅₀ : 180.5 mg / kg Antipyretic effect ED ₅₀ : 25.8 mg / kg Gastrointestinal disorder effect UD ₅₀ : Administerable 1000 mg / kg
, The ulcer incidence was 20%.

Example 6 Hard capsule (in 1 capsule) Ibuprofen 50 mg Acetaminophen 50 mg Magnesium silicate 200 mg Actisol (Asahi Kasei) 50 mg Hardened oil 30 mg The above components were mixed to obtain a hard capsule. The evaluation results are shown below. Analgesic effect ED ₅₀ : 123.2 mg / kg Antipyretic effect ED ₅₀ : 15.4 g / kg Gastrointestinal disorder effect UD ₅₀ : Administerable 1000 mg / kg
, The ulcer incidence was 20%.

Example 7 Hard capsule (in 1 capsule) Ibuprofen 60 mg Acetaminophen 30 mg Magnesium carbonate 100 mg Vitamin B1 8 mg Corn starch 22 mg Magnesium stearate 2 mg The above ingredients were mixed to obtain a hard capsule. The evaluation results are shown below. Analgesic effect ED ₅₀ : 215.4 mg / kg Antipyretic effect ED ₅₀ : 26.9 mg / kg Gastrointestinal disorder effect UD ₅₀ : Administerable 1000 mg / kg
, The ulcer incidence was 30%.

Example 8 Soft capsule (in 1 capsule) Ibuprofen 60 mg Acetaminophen 65 mg Magnesium oxide 50 mg Safflower fatty acid 200 mg dl-tocopherol 5 mg A soft capsule was obtained from the above components by a conventional method. The evaluation results are shown below. Analgesic effect ED ₅₀ : 86.6 mg / kg Antipyretic effect ED ₅₀ : 12.4 mg / kg Gastrointestinal disorder effect UD ₅₀ : 236 mg / kg

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Claims (1)

[Claims] 1. An antipyretic analgesic containing ibuprofen,
0.01 to 30 parts by weight of acetaminophen per 1 part by weight of ibuprofen, and 0.05 to 100 parts by weight of a magnesium-based antacid agent per 1 part by weight of ibuprofen and acetaminophen. Antipyretic analgesic containing ibuprofen