JP3122748B2 - Antipyretic analgesic containing ibuprofen - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

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

[0002]

BACKGROUND OF THE INVENTION Many antipyretic analgesics are conventionally known. Among them, a combination of an aniline derivative-based acetaminophen or the like with a salicylic acid derivative-based aspirin or ethoxybenzamide is widely used. However, salicylic acid derivative-based antipyretic analgesics have disadvantages such as easily causing stomach disorders.Instead of salicylic acid derivative-based antipyretic analgesics, by combining ibuprofen and aniline derivative-based antipyretic analgesics, efficacy and acute toxicity are reduced. 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 been widely used as a nonsteroidal drug. However, oral administration of ibuprofen may cause gastric discomfort, stomach pain, nausea, and the like, similarly to salicylic acid derivative-based antipyretic analgesics, and it has been pointed out that gastrointestinal disorders are caused as side effects. For this purpose, for the purpose of reducing gastrointestinal disorders caused by oral administration of ibuprofen, a combination with a salicylic acid-based drug (Japanese Patent Laid-Open No. 61-134315) or a combination with an antacid and / or a mucosal coating agent is used. (JP-A-63-198620). However, antipyretic analgesics containing such drugs cannot always satisfy both antipyretic analgesic effects and reduction of gastrointestinal disorders.

[0003]

However, the present inventor has solved the drawbacks of the conventional antipyretic analgesic, such as gastrointestinal disorders, and provided an antipyretic analgesic which is excellent in analgesic action and antipyretic action and has high safety. The purpose is to do.

[0004]

Means for Solving the Problems The present inventors have conducted intensive studies in order to achieve the above object, and as a result, the gastrointestinal disorders were suppressed by simultaneously mixing acetaminophen and a magnesium antacid with ibuprofen. The present inventors have further found that the synergistic antipyretic analgesic effect can be improved and the above-mentioned disadvantages can be improved, and the present invention has been accomplished. That is, the ibuprofen-containing antipyretic analgesic of the present invention comprises 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 per 1 part by weight of ibuprofen. (C) 0.05 to 100 parts by weight of a magnesium antacid based on 1 part by weight of the total amount of ibuprofen and acetaminophen.

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION As the ibuprofen used in the present invention, ibuprofen (2- (4-isob)
utyl phenyl) propionic aci
d) and salts thereof, and the like.
To 99% by weight, preferably 1.0 to 90% by weight. Acetaminophen (N- (4-hy
Droxphenyl) 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 is out of this range, the above-mentioned synergistic action is hardly achieved.

The magnesium antacid used in the present invention includes magnesium silicate, magnesium oxide, magnesium hydroxide, magnesium carbonate, a mixed dry gel of aluminum hydroxide and magnesium carbonate, and a mixture of aluminum hydroxide, calcium carbonate and magnesium carbonate. Precipitates, magnesium aluminate metasilicate, dimagnesium aluminate silicate, and coprecipitates of magnesium hydroxide / potassium aluminum sulfate are mentioned. 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 may be used in combination with ibuprofen. The compounding amount of these antacids can be 0.05 to 100 parts by weight, preferably 0.1 to 50 parts by weight, per 1 part by weight of the total amount of ibuprofen and acetaminophen. When the amount is less than 0.05 parts by weight, gastrointestinal disorders are not reduced, and the antipyretic analgesic effect is not improved. On the other hand, if it exceeds 100 parts by weight, the dose will increase and the side effects of the magnesium-based antacid will appear.

The antipyretic analgesic of the present invention may further comprise, if necessary, a sedative-hypnotic such as allylisopropylacetyl urea or bromvalerylurea, isotipendyl hydrochloride, diphenylpyraline hydrochloride, diphenhydramine hydrochloride, dipheterol hydrochloride, triprolidine hydrochloride, tripelenamine hydrochloride, or hydrochloric acid. Tonsilamine, phenetazine hydrochloride, methdilazine hydrochloride, diphenhydramine salicylate, carbinoxamine diphenyldisulfonate, alimemazine tartrate, diphenhydramine tannate, diphenylpyraline theoculate, mebuhydrolin napadisylate, promethazine methylene disalicylate, carbinoxamine maleate, dl
-Antihistamines such as chlorpheniramine maleate, d-chlorpheniramine maleate, dipheterol phosphate, sodium benzoate caffeine, caffeine,
Central stimulants such as anhydrous caffeine, vitamin B1 and its derivatives and their salts, vitamin B2 and its derivatives and their salts, vitamin C and its derivatives and their salts, hesperidin and its derivatives and their vitamins such as their salts Agents and the like can be appropriately compounded.

The antipyretic analgesic of the present invention is useful for relieving headache, toothache, pain after tooth extraction, sore throat, ear pain, arthralgia, neuralgia, back pain, muscle pain, menstrual pain, chills, fever during fever, etc. It is effective for. In addition, the antipyretic analgesic of the present invention is usually administered to an adult in a daily amount of 100 to 6 as a total amount of ibuprofen, acetaminophen and a magnesium antacid.
000 mg can be orally administered once or several times. This dose can be appropriately adjusted according to the age, weight, and symptoms of the patient.

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. Ingredients that can be used for preparing a solid preparation include excipients such as lactose, starch, sucrose, mannitol, and crystalline cellulose (for example, Avicel: registered trademark, manufactured by Asahi Chemical Industry Co., Ltd.); hydroxypropyl cellulose, carboxymethyl cellulose, gelatin Binders such as sodium carboxymethylcellulose and gum arabic; disintegrants such as calcium carboxymethylcellulose, polyvinylpyrrolidone or its crosslinked product, and low-substituted hydroxypropylcellulose; nonionic surfactants such as sucrose fatty acid esters and polyoxysorbitan fatty acid esters Agents: Lubricants such as calcium stearate, magnesium stearate, dimethylpolysiloxane, talc, polyethylene glycol, hardened oil, etc. In addition, coloring agents, sweeteners, etc. as required It can be used. In addition, a coating can also be applied, and as a coating agent, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, Eudragit, polyvinyl pyrrolidone, polyethylene glycol, shellac, methyl cellulose, ethyl cellulose, cellulose acetate phthalate, hydroxypropyl cellulose phthalate, and sucrose, Sugar-coating can also be performed with gum arabic, calcium carbonate, talc, gelatin or the like as a main component.

[0010] Components that can be used in the preparation of liquid preparations include purified water, ethanol, glycerin, sucrose, propylene glycol, polyethylene glycol, polyoxyethylene sorbitan fatty acid ester, aluminum metahydroxide, agar, tragacanth gum and the like. Other dissolution aids, buffers, preservatives, flavors, coloring agents,
Flavoring agents and the like can be used.

[0011]

EFFECT OF THE INVENTION The antipyretic analgesic containing ibuprofen of the present invention is excellent in antipyretic analgesic action, reduces the gastrointestinal dysfunction of ibuprofen, and has high safety in use. Next, experimental examples will be shown to specifically explain the effects of the present invention.

EXPERIMENTAL EXAMPLE 1 (Gastrointestinal disorders) Six-week-old male SD rats (body weight: 130-150 g) were grouped into groups of 7-10 rats and used in the experiment. After the animals were fasted for 24 hours, each test drug was added to each group of animals at 1.0 ml / 100 g.
B. W. Oral administration, 4 hours after that, the stomach was removed and 2%
After fixation with formalin, it was cut longitudinally along the bay and the presence or absence of gastric mucosal damage was determined under a stereoscopic microscope, and the ulcer incidence was determined. The test drug was used by suspending it in a 5% gum arabic aqueous solution at the time of use. 50% ulcer-inducing drug amount (UD ₅₀ )
It was calculated by the chfield & Wilcoxon method. Table 1 shows the results. The numerical value was shown by 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

[0014] alone is reduced UD ₅₀ value when formulating acetaminophen ibuprofen that does not cause gastric disorder, generation of ulcer was observed at lower doses. The addition of magnesium-based antacids to ibuprofen and acetaminophen significantly suppressed the occurrence of gastric damage.

EXPERIMENTAL EXAMPLE 2 (Analgesic Activity) A 5-week-old male ddY mouse (body weight: 20-25 g) was used
Groups consisted of 19 to 25 animals, which were used for the experiment. Each test drug was administered to each group of animals at 0.1 ml / 10 gB. W. Oral administration and 60 minutes later, 0.7% acetic acid was added at 0.1 ml / 10 ml.
gB. W was administered intraperitoneally at a rate of W. Immediately after that, 20
The number of rises per minute was measured, and the inhibition rate was calculated from the number of rises in the control group (the group to which 1% carboxymethylcellulose was orally administered without addition of the test drug) according to the following formula 1. The ED ₅₀ value was determined.

[0016]

[Formula 1] Rising number of control group−Rising number of drug group Inhibition rate (%) = ━━━━━━━━━━━━━━━━━━━━━━━━ × 100 Rising of control group number

The test drug was used by suspending it in a 1% carboxymethylcellulose aqueous solution at the time of use. 50% effective dose (ED
₅₀ ) was calculated by the Litchfield & Wilcoxon method. Table 2 shows the results. The numerical value was shown by the amount of the analgesic / antipyretic component.

[0018]

[Table 2]Table 2: Pain relief  Drug (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 mixing ibuprofen with acetaminophen as an antipyretic analgesic, the ED ₅₀ value became 51% of that of ibuprofen alone, and the analgesic action was synergistically enhanced. By combining ibuprofen with acetaminophen and a magnesium-based antacid that has no analgesic effect by itself, the ED ₅₀ value can be increased by ibuprofen +
Acetaminophen amounted to 31%, and marked enhancement of analgesic effect was observed.

EXPERIMENTAL EXAMPLE 3 (Antipyretic Effect) Male 8-week-old Wistar rats (body weight: 200-24)
0g) was used for the experiment with 5 to 7 animals per group. 30 animals
After measuring the body temperature twice at minute intervals, a 7.5% aqueous yeast solution was added thereto at 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 six times every hour thereafter. The inhibition rate for the heat generation area of the control group was determined from the heat generation area up to 6 hours after drug administration, and the ED ₅₀ value was calculated from the inhibition rate. The test drug was used by suspending it in a 5% aqueous gum arabic solution before use. The 50% effective dose (ED ₅₀ ) is Litchfield & Wilcox
It was calculated by the on method. Table 3 shows the results. Numerical values were indicated by the amount of analgesic and antipyretic components.

[0021]

[Table 3]Table 3: Antipyretic action  Drug (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 mixing acetaminophen with ibuprofen, the ED ₅₀ value can be increased by ₅ % for ibuprofen alone.
1%, synergistically enhancing the antipyretic effect. Furthermore, by simultaneously adding a magnesium-based antacid, the ED ₅₀ value was significantly reduced as compared with ibuprofen + acetaminophen, and gastrointestinal disorders were also suppressed.

The present invention will be specifically described below with reference to examples, but the present invention is not limited to the following examples. still,
The analgesic action, antipyretic action, and gastrointestinal dysfunction in Examples and Comparative Examples were evaluated by the same operation as in Experimental Examples 1 to 3 described above. The tablets were pulverized, and the contents of the hard capsules and the soft capsules were respectively taken out and suspended in a solvent. The numerical values are shown by the amount of each preparation. Hard capsule,
For soft capsules, the amount is indicated by the content.

[0024]

Example 1 Tablet (1 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 Rotary tableting machine To give tablets. The evaluation results are shown below. Analgesia ED _50: 85.4mg / kg antipyretic ED _50: 12.8mg / kg gastrointestinal disorders act UD _50: administrable 1000 mg / kg
, The ulcer incidence was 30%.

Example 2 Tablet (1 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 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 package) Ibuprofen 120 mg Acetaminophen 90 mg Magnesium oxide 100 mg Synthetic hydrotalcite 270 mg Allylisopropylacetylurea 60 mg Caffeine 80 mg Partially pregelatinized starch 35 mg Corn starch 15 mg Hydroxypropyl cellulose 5 mg The mixture was granulated by a granulation method, dried and sized 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 extruded and granulated, dried and sized to obtain granules. . The evaluation results are shown below. Analgesia ED _50: 231.0mg / kg antipyretic ED _50: 34.5mg / kg gastrointestinal disorders act UD _50: administrable 1000 mg / kg
, The ulcer incidence was 10%.

Example 5 Powder (in one packet) Ibuprofen 130 mg Acetaminophen 50 mg Magnesium carbonate 100 mg Magnesium aluminosilicate 200 mg Bovaline 200 mg Caffeine 80 mg Hydroxypropyl cellulose 25 mg Corn starch 75 mg The above ingredients were granulated by a fluid granulation method. A powder was obtained. The evaluation results are shown below. Analgesic action ED ₅₀ : 180.5 mg / kg Antipyretic action ED ₅₀ : 25.8 mg / kg Gastrointestinal disorder action UD ₅₀ : Administerable 1000 mg / kg
, The ulcer incidence was 20%.

Example 6 Hard Capsule (in One Capsule) Ibuprofen 50 mg Acetaminophen 50 mg Magnesium Silicate 200 mg Actizol (Asahi Kasei) 50 mg Hardened Oil 30 mg The above components were mixed to obtain a hard capsule in a conventional manner. The evaluation results are shown below. Analgesia ED _50: 123.2mg / kg antipyretic ED _50: 15.4g / kg gastrointestinal disorders act UD _50: administrable 1000 mg / kg
, The ulcer incidence was 20%.

Example 7 Hard capsule (in one 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 components were mixed to obtain a hard capsule in a usual manner. The evaluation results are shown below. Analgesic action ED ₅₀ : 215.4 mg / kg Antipyretic action ED ₅₀ : 26.9 mg / kg Gastrointestinal disorder action UD ₅₀ : Administerable 1000 mg / kg
, The ulcer incidence was 30%.

Example 8 Soft Capsules (In One Capsule) Ibuprofen 60 mg Acetaminophen 65 mg Magnesium oxide 50 mg Safflower fatty acid 200 mg dl-tocopherol 5 mg The above components were obtained by a conventional method. The evaluation results are shown below. Analgesic effect ED _50: 86.6mg / kg antipyretic ED _50: 12.4mg / kg gastrointestinal disorders action UD _50: 236mg / kg

──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-59-104315 (JP, A) JP-A-56-97224 (JP, A) JP-A-56-154416 (JP, A) JP-A-2- 286614 (JP, A) JP-A-63-198620 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) A61K 31/192, 31/167 A61K 33/06

Claims (1)

(57) [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 antacid based on 1 part by weight of the total amount of ibuprofen and acetaminophen. Antipyretic analgesic containing ibuprofen.