WO2009123206A1

WO2009123206A1 - Oral pharmaceutical composition

Info

Publication number: WO2009123206A1
Application number: PCT/JP2009/056701
Authority: WO
Inventors: 真也青山; 篤士松尾; 茂樹澤村
Original assignee: 小林製薬株式会社
Priority date: 2008-03-31
Filing date: 2009-03-31
Publication date: 2009-10-08
Also published as: JP2009242365A; JP5542309B2

Abstract

Disclosed is an oral pharmaceutical composition containing a phenylpropionic acid-type analgesic anti-inflammatory agent, in which the activity of the analgesic agent is reduced. Also disclosed is an oral pharmaceutical composition containing a phenylpropionic acid-type analgesic anti-inflammatory agent, wherein the phenylpropionic acid-type analgesic anti-inflammatory agent can exhibit its efficacy for a prolonged period. Specifically disclosed is an oral pharmaceutical composition comprising (a) a phenylpropionic acid-type analgesic anti-inflammatory agent, (b) tranexamic acid, and (c) a dried aluminum hydroxide gel.

Description

Oral pharmaceutical composition

The present invention relates to an oral pharmaceutical composition. More specifically, the present invention relates to an oral pharmaceutical composition comprising a phenylpropionic acid-based anti-inflammatory analgesic as an active ingredient, wherein the gastric mucosal damage caused by the anti-inflammatory analgesic is reduced and the sustainability is improved. Furthermore, the present invention relates to a method for reducing gastric mucosal damage caused by phenylpropionic acid anti-inflammatory analgesics.

Phenylpropionic antipyretic analgesics and antiphlogistics such as ibuprofen have been widely used as drugs (antipyretic analgesics) for inflammatory diseases and associated pain and fever because they have excellent analgesic and anti-inflammatory properties. In particular, ibuprofen is suitably used as a therapeutic agent for arthralgia accompanied by inflammation since it has a high antiphlogistic effect in the periphery among known antipyretic analgesic and anti-inflammatory agents. However, phenylpropionic acid anti-inflammatory analgesics are prone to side effects such as peptic ulcer and gastrointestinal hemorrhage because they easily cause damage to the gastric mucosa. Various attempts have been made to improve the effect and to reduce the gastrointestinal disorder itself (see, for example, Patent Documents 1 to 10).

In addition, in order to suppress the above side effects, even in the case of severe pain or fever, the interval between doses must be increased (for example, the interval between doses must be 4 hours or longer) or the dose must be decreased. There were restrictions such as.

For this reason, there is still a need for an effective method for reducing gastrointestinal disorders of phenylpropionic acid anti-inflammatory analgesics such as ibuprofen.
Japanese Patent Publication No. 64-8602 Japanese Patent Publication No. 1-24131 Japanese Patent Laid-Open No. 5-148139 Japanese Patent Laid-Open No. 9-48728 Japanese Patent Laid-Open No. 7-188004 JP 10-259130 A Japanese Patent Laid-Open No. 11-12187 Japanese Patent Laid-Open No. 11-158066 JP 2006-1920 A Japanese Patent Laid-Open No. 2004-59579

An object of the present invention is to provide an oral pharmaceutical composition in which gastric mucosal damage caused by phenylpropionic acid anti-inflammatory analgesics is reduced. Another object of the present invention is to provide a sustained-effect oral pharmaceutical composition in which the action of a phenylpropionic acid-based anti-inflammatory analgesic is sustained over a long period of time. A further object of the present invention is to provide a method for reducing the gastric mucosal damage of a phenylpropionic acid anti-inflammatory analgesic.

The inventors of the present invention have been diligently studied to solve the above-mentioned problems. By using a combination of tranexamic acid and dry aluminum hydroxide gel in a phenylpropionic acid-based anti-inflammatory drug such as ibuprofen, the phenylpropionic acid-based anti-inflammatory drug is used. It was found that gastric mucosal damage caused by drugs was significantly reduced.

In addition, the present inventors have found that the combination of tranexamic acid and dry aluminum hydroxide gel with a phenylpropionic acid-based anti-inflammatory analgesic agent makes the anti-inflammatory analgesic action last for a long period of time, whereby the phenylpropionic acid-based anti-inflammatory analgesia It was confirmed that the chance of side effects can be reduced by reducing the number of doses.

That is, the present inventors have shown that a pharmaceutical composition comprising a phenylpropionic acid-based anti-inflammatory analgesic in combination with tranexamic acid and dry aluminum hydroxide gel exhibits an effective antipyretic analgesic / anti-inflammatory effect with a small number of doses, and is The present invention was completed by confirming that it is useful as a highly safe antipyretic analgesic / anti-inflammatory agent with reduced gastric mucosal damage.

The present invention has the following aspects:
(I) Oral pharmaceutical composition (I-1) (a) Phenylpropionic acid-based anti-inflammatory analgesic, (b) tranexamic acid, and (c) dry aluminum hydroxide gel, .
(I-2) (a) The oral pharmaceutical composition according to (I-1), wherein the phenylpropionic acid anti-inflammatory analgesic is ibuprofen.
(I-3) The oral pharmaceutical composition described in (I-1) or (I-2), which is an antipyretic analgesic / anti-inflammatory agent.

(II) Method for reducing gastric mucosal damage (II-1) (a) A combination of (b) tranexamic acid and (c) dry aluminum hydroxide gel in (a) a phenylpropionic acid anti-inflammatory analgesic The method of reducing the gastric mucosal disorder of the said phenylpropionic acid type anti-inflammatory analgesic.
(II-2) The method according to (II-1), wherein the phenylpropionic acid anti-inflammatory analgesic is ibuprofen.

According to the oral pharmaceutical composition of the present invention, (a) a phenylpropionic acid-type anti-inflammatory analgesic is used in combination with (b) tranexamic acid and (c) a dry aluminum hydroxide gel, thereby producing a phenylpropionic acid-type anti-inflammatory analgesic. The side effect of gastric mucosal disorder, which is a problem with drugs, can be reduced. Further, according to the oral pharmaceutical composition of the present invention, (a) a phenylpropionic acid antiphlogistic analgesic is used in combination with (b) tranexamic acid and (c) a dried aluminum hydroxide gel. Since the action effect of the anti-inflammatory analgesic is sustained, the number of doses can be reduced, and as a result, the occurrence of side effects such as gastric mucosal damage can be reduced. That is, the oral pharmaceutical composition of the present invention is useful as a highly safe oral pharmaceutical composition that suppresses the occurrence of side effects such as gastric mucosal damage caused by phenylpropionic acid anti-inflammatory analgesics.

I. Oral Pharmaceutical Composition The oral pharmaceutical composition of the present invention comprises (a) a phenylpropionic acid anti-inflammatory analgesic (hereinafter also referred to as “component (a)”), and (b) tranexamic acid (hereinafter referred to as “this”). And (c) dry aluminum hydroxide gel (hereinafter also referred to as “(c) component”).

(A) Phenylpropionic acid-type anti-inflammatory analgesic In the present invention, phenylpropionic acid-type anti-inflammatory analgesic (component (a)) means a drug having an anti-inflammatory, analgesic or / and antipyretic action having a phenylpropionic acid skeleton. Examples thereof include aluminoprofen, ibuprofen, oxaprozin, zaltoprofen, thiaprofenic acid, nabumetone, naproxen, fenoprofen (calcium salt), pranoprofen, flurbiprofen, and loxoprofen (sodium salt). These can be used individually by 1 type or in combination of 2 or more types. Flurbiprofen, ibuprofen, and pranoprofen are preferable, and ibuprofen [chemical name: 2- (4-isobutylphenyl) propionic acid] is more preferable.

These components may be formulated as a hydrate or a solvate. For example, loxoprofen can be used as loxoprofen sodium dihydrate.

The proportion of the component (a) contained in the oral pharmaceutical composition of the present invention is not limited, but the amount of the component (a) contained in the oral pharmaceutical composition per daily adult administration is 100 to 1200 mg, Preferably 100 to 600 mg, more preferably 150 to 600 mg can be mentioned.

In order to be within this range, the content of component (a) in 100% by weight of the oral pharmaceutical composition can be appropriately adjusted from the range of 2 to 92% by weight, preferably 5 to 50% by weight.

(B) Tranexamic acid tranexamic acid [4- (aminomethyl) cyclohexane-1-carboxylic acid] (component (b)) is a kind of amino acid that has been conventionally known to have hemostatic, anti-inflammatory and anti-allergic effects. .

The ratio of the component (b) contained in the oral pharmaceutical composition of the present invention is not particularly limited, but the amount of the component (b) contained in the oral pharmaceutical composition per adult daily administration is 50 to 1000 mg, Preferably 50 to 800 mg, more preferably 100 to 800 mg can be mentioned. The content ratio of component (b) in 100% by weight of the oral pharmaceutical composition can be appropriately adjusted within the range of 0.5 to 80% by weight, preferably 5 to 50% by weight.

As a proportion of the component (b) that is preferably used for reducing gastric mucosal damage of the phenylpropionic acid-based anti-inflammatory analgesic [component (a)] and improving the persistence of the anti-inflammatory analgesic effect, 4 to 1000 parts by weight, preferably 8 to 800 parts by weight, and more preferably 17 to 533 parts by weight can be mentioned with respect to parts by weight.

(C) Dry aluminum hydroxide gel Dry aluminum hydroxide gel [component (c)] has been conventionally used as a antacid or a digestive organ drug. There are mainly two forms of powder (powder) and fine granules, but any form can be used without any particular limitation.

The proportion of the component (c) contained in the oral pharmaceutical composition of the present invention is not particularly limited, but the amount of the component (c) contained in the oral pharmaceutical composition per daily adult administration is 65 to 1200 mg, 60 to 1000 mg is preferable, and 100 to 1000 mg is more preferable. In order to be within this range, the content of component (c) in 100% by weight of the oral pharmaceutical composition can be appropriately adjusted from the range of 1 to 90% by weight, preferably 5 to 50% by weight.

As a ratio of the component (c) suitable for reducing gastric mucosal damage of the component (a) together with the component (b) and improving the sustainability of the action effect, the component (a) is 100 parts by weight of the component. 5 to 1200 parts by weight, preferably 10 to 1000 parts by weight, more preferably 16 to 667 parts by weight.

The oral pharmaceutical composition of the present invention may contain any of (b) tranexamic acid and (c) dry aluminum hydroxide gel in addition to the above (a) phenylpropionic acid anti-inflammatory analgesic. As long as it does not adversely affect the gastric mucosal disorder alleviation effect and sustainability effect of the invention, it does not limit the presence or absence of other medicinal ingredients such as medicinal ingredients used in anti-inflammatory, analgesic or antipyretic applications.

More specifically, vitamins (fat-soluble vitamins such as vitamins A, D, E, K, and U; water-soluble vitamins such as vitamins B, C, and P); antipyretic / analgesic / anti-inflammatory drugs (such as sulpyrine) Pyrine antipyretic analgesics; salicylic acid such as sodium salicylate, aspirin, etenzamide, salicylamide, and sazapyrine; aniline drugs such as acetaminophen; phenamic acid drugs such as flufenamic acid and mefenamic acid; aryls such as diclofenac sodium and indomethacin Acetic acid drugs, pyrazolidine drugs such as phenylbutazone and oxyphenylbutazone, pyrimidine drugs such as bucolome, oxicam drugs such as piroxicam, isopropylantipyrine, etc .; antihistamines (clemastine fumarate, diphenhydramine hydrochloride, ma Antitussives (eg, codin phosphate, dihydrocodine phosphate, cloperastine, dextromethorphan, benzonate, etc.); expectorants (eg, bromhexine hydrochloride); L-cysteine hydrochloride, L-hydrochloride Mucosal lysates such as methylcysteine and acetylcysteine; mucus repairing agents such as carbocysteine; anti-inflammatory agents such as lysozyme chloride; anti-inflammatory agents such as glycyrrhizic acid; hypnotic sedatives such as allylisopropylacetylurea; ambroxol hydrochloride, etc. mucus lubricating agents; antifungal agents such as terbinafine hydrochloride; bronchodilators or asthma drug (e.g. pseudoephedrine, ephedrine hydrochloride, methylephedrine hydrochloride terbutaline, isoproterenol, salbutamol, beta _2, such as terbutaline - a Renarin receptor stimulants, theophylline, aminophylline, etc. xanthine drugs, cromoglycate such proxy Villingen); antacids; amino acids; crude drugs, and others. These medicinal ingredients can be used alone or in combination of two or more.

The dosage form of the oral pharmaceutical composition of the present invention is not particularly limited as long as it is a solid preparation for oral administration. Examples include powders, tablets, granules, pills, capsules (soft capsules, hard capsules), troches, chewable tablets, and dry syrups. Moreover, you may have a formulation form which controlled the release | release property of the medicinal component (for example, immediate release formulation, sustained release formulation, etc.). Also preferred are tablets, granules, pills, and capsules (soft capsules and hard capsules). Formulations having such dosage forms can be prepared according to conventional methods in the art.

The oral pharmaceutical composition of the present invention may be formulated with various carriers and additives that are pharmaceutically acceptable for oral administration in order to formulate and stabilize the oral dosage form as described above (for example, , Pharmacopeia or “Pharmaceutical Additives Encyclopedia” (published by Yakuji Nippo).

Carriers or additives for oral administration include bases such as succinated gelatin, gelatin, medium chain fatty acid triglyceride, calcium carbonate, carmellose sodium; emulsifiers such as glycerin fatty acid ester, soybean lecithin, methylcellulose, glyceryl monostearate Excipients such as lactose, sucrose, glucose, mannitol, sorbitol, corn starch, partially pregelatinized starch, crystalline cellulose, low-substituted hydroxypropylcellulose, carmellose sodium, talc, macrogol 400; starch, α-starch, Agar, gelatin, gum arabic, dextrin, methylcellulose, ethylcellulose, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose or Binders such as salts and crystalline cellulose; disintegrating agents such as calcium carbonate, crospovidone, starch, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, and carboxymethyl starch; magnesium stearate, talc, polyethylene glycol, silicic anhydride, etc. Lubricants; polyoxyethylene hydrogenated castor oil, suspending agents such as pluronics; surfactants such as polysorbate 80, lauromacrogol, cholesterol; precipitated calcium carbonate, gum arabic, pullulan, carnauba wax, hydroxypropylmethylphthalate, etc. Coating agents; whitening, glucose, saccharin sodium, sorbitol, citric acid, aspartame and other taste-masking agents; concentrated glycerin, triacetin, D-sorbitol, etc. Agent; ethyl parahydroxybenzoate, propyl parahydroxybenzoate, preservatives such as citric acid hydrate; can be mentioned titanium oxide, medicinal carbon, coloring agents and the like such as copper chlorophyllin sodium phosphate. In addition to the above components, as long as the effects of the present invention are not impaired, stabilizers, dispersants, fluidizers, buffering agents, wetting agents, thickeners, and preservatives that are generally acceptable as pharmaceutical additives Further, optional components such as a pH adjuster, a solvent and a solubilizing agent can be added as desired.

The oral pharmaceutical composition of the present invention can be prepared and administered as the aforementioned solid or liquid oral preparation (internal preparation). The dose of the oral pharmaceutical composition of the present invention depends on the patient's age, sex, degree of symptom to be treated, and administration method, and is contained in (a) a phenylpropionic acid anti-inflammatory analgesic The daily dose for adults is 100-1200 mg, preferably 100-600 mg, more preferably 150-600 mg; (b) the daily dose of tranexamic acid for adults is 50-1000 mg, preferably 50- 800 mg, more preferably 100 to 800 mg: (c) The daily dose of dry aluminum hydroxide gel for adults is 65 to 1200 mg, preferably 65 to 1000 mg, more preferably 100 to 1000 mg. Within this dosage range, it can be administered once to several times a day.

The oral pharmaceutical composition of the present invention can be preferably used for the purpose of suppressing inflammation. However, the active ingredient phenylpropionic anti-inflammatory analgesic, preferably ibuprofen, has an analgesic action and an antipyretic action in addition to the anti-inflammatory action. It can also be used for the purpose of soothing (analgesic) and suppressing fever (antipyretic).

The oral pharmaceutical composition of the present invention, particularly an oral pharmaceutical composition containing ibuprofen as a phenylpropionic antiphlogistic analgesic, is arthritis, tendonitis, joint pain accompanied by inflammation, low back pain, headache, menstrual pain (physiological pain), toothache Suitable for the improvement (anti-inflammatory) and analgesia of peripheral inflammation such as pain after extraction, bruise pain, sprain pain, fracture pain, trauma pain, sore throat, ear pain, neuralgia, muscle pain or stiff shoulder be able to.

II. Method for Reducing Gastrointestinal Mucosal Disorders of Phenylpropionic Acid-Based Antiphlogistic Analgesic The method of the present invention comprises (a) phenylpropionic acid-based analgesic analgesic, wherein (b) tranexamic acid and (c) dry aluminum hydroxide gel described above It can be implemented by using in combination.

Examples of the target component (a) include the drugs described in (I) above. Preferred are ibuprofen, ketoprofen and pranoprofen, and more preferred is ibuprofen.

The proportion of the component (b) used in combination with the component (a) is a range in which the gastric mucosal damage of the component (a) can be reduced without adversely affecting the detoxification and analgesic / anti-inflammatory action of the component (a). If it is, it will not be restrict | limited in particular. For example, the use ratio of the component (b) to 100 parts by weight of the component (a) can be appropriately selected from the range of usually 4 to 1000 parts by weight. The range is preferably 8 to 800 parts by weight, more preferably 17 to 533 parts by weight.

Moreover, as a ratio of (c) dry aluminum hydroxide gel used in combination with the component (a) and the component (b), the detoxification, analgesic and anti-inflammatory action of the component (a) is adversely affected by using three components together. There is no particular limitation as long as the gastric mucosal damage of component (a) can be reduced. For example, the proportion of the component (c) to 100 parts by weight of the component (a) can be appropriately selected from the range of usually 5 to 1200 parts by weight. The range is preferably 10 to 1000 parts by weight, more preferably 16 to 667 parts by weight.

According to the method of the present invention, the combination of the component (b) and the component (c) described above with the component (a) can be used while improving the sustainability of the action and effect of the component (a). It can reduce gastric mucosal damage, which is a side effect. Therefore, the present invention can be effectively used to prepare and provide an antipyretic analgesic / anti-inflammatory agent in an oral dosage form with reduced gastrointestinal disorders and high safety.

Hereinafter, the present invention will be described with reference to experimental examples and examples, but the present invention is not limited to these examples.

Experimental example 1
The effect of reducing the gastric mucosal damage of phenylpropionic acid-type anti-inflammatory analgesics by the combined use of tranexamic acid and dry aluminum hydroxide gel was evaluated using ibuprofen as the phenylpropionic acid-type anti-inflammatory analgesics.

<Preparation of test sample>
The composition of each test sample (Examples 1 to 13 and Comparative Examples 1 to 8) is shown in Table 1. Each test sample was prepared so that each component was suspended in a 1% aqueous gum arabic solution and the amount of each component contained in 5 mL thereof was the number of mg shown in Table 1. That is, Table 1 shows the number of mg of each component when the test sample is administered at 5 mL per 1 kg of the rat body weight.

<Experiment method>
(1) Donryu rats (6 weeks old) weighing 140-170 g (Japan SLC Co., Ltd.) 147 animals (21 groups × 7 animals), 20-25 ° C., 12 hours light condition—12 hours dark condition, free After habituation for 1 week under the conditions of drinking water and free intake, fast for 18 hours.
(2) Thereafter, each test sample shown in Table 1 (Examples 1 to 13 and Comparative Examples 1 to 8) is orally administered at a rate of 5 mL per kg of body weight three times every 4 hours.
(3) Four hours after the final administration, the number of dead rats is counted, and the surviving rats are euthanized with ether and the stomach is removed.
(4) The excised stomach is cut open, photographed, and the major axis (ulcer major axis) of the internal ulcer forming part is measured using a caliper.

<Experimental result>
Table 1 shows the mortality and ulcer major axis measured for each group of rats (Examples 1 to 13, Comparative Examples 1 to 8).

From this result, it can be seen that gastric mucosal damage is caused by administration of ibuprofen alone (Comparative Example 1), and that gastric mucosal damage of ibuprofen is increased by using tranexamic acid in combination with this ibuprofen (Comparative Example 2). It can also be seen that the dried aluminum hydroxide gel lacks the protective effect against gastric mucosal damage caused by ibuprofen (Comparative Examples 3, 5 to 8). Comparative Example 4 is a combination with components that are conventionally often used in combination with ibuprofen (anti-inflammatory analgesics, tranexamic acid and anhydrous caffeine), and it was also found that gastric mucosal damage increases in this case as well. In contrast, it was found that combining ibuprofen with both tranexamic acid and dry aluminum hydroxide gel significantly reduced and improved ibuprofen's gastric mucosal damage, which was not improved by individual combinations. In addition, there were no remarkable death results, and the results were very remarkable.

From these facts, it has been found that combining ibuprofen, which is a phenylpropionic acid anti-inflammatory analgesic, with tranexamic acid and dry aluminum hydroxide gel can prevent side effects such as gastric mucosal damage possessed by ibuprofen.

Therefore, according to the oral pharmaceutical composition of the present invention, since side effects such as gastric mucosal damage caused by conventional phenylpropionic acid anti-inflammatory analgesics do not occur, the interval between doses is taken during severe pain or fever. It has been found that it is possible to make it shorter (for example, less than 4 hours between doses) or increase the dose.

Experimental example 2
In order to evaluate the persistence of the effect of the phenylpropionic acid anti-inflammatory analgesic in the oral pharmaceutical composition of the present invention, the following experiment was conducted using anti-inflammatory action as an index. In addition, ibuprofen was used as a phenylpropionic acid type anti-inflammatory analgesic.

<Preparation of test sample>
Table 2 shows the composition of each test sample (Example 1, Comparative Examples 1, 3, 9, and 10). Each test sample was prepared such that each component was suspended in a 1% aqueous gum arabic solution, and the amount of each component contained in 5 mL thereof was the mg number shown in Table 2. That is, Table 2 shows the number of mg of each component when 5 mL of the test sample is administered per kg of rat body weight.

<Experiment method>
(1) 35 Wistar rats (6 weeks old) (Japan SLC Co., Ltd.) with a body weight of around 120 g (5 groups × 7 animals), 20-25 ° C., 12 hours light condition-12 hours dark condition, free drinking water The animals were acclimated for 1 week under the conditions of free consumption and then fasted for 15 hours.
(2) Thereafter, each test sample (Example 1, Comparative Examples 1, 3, 9 and 10) described in Table 2 was orally administered at a rate of 5 mL per kg body weight.
(3) Sixty minutes after oral administration, the foot volume (foot volume immediately before injection) was measured, and an inflammation-inducing substance (carrageenin) was injected into the bulge portion of the sole of the foot.
(4) The paw volume was measured 1.5, 3 and 5 hours after injection (paw volume after injection).

The edema rate was calculated from the foot volume measured at each time point before and after injection according to the following formula.

As a control, the experiments of (3) to (4) were also performed on a group of rats (7 animals) (no treatment group) to which no test sample was administered, and the edema rate was calculated.

<Experimental result>
FIG. 1 shows the results of calculating the edema rate (%) over time for each test animal [test sample (Example 1, Comparative Examples 1, 3, 9, and 10) administration group, untreated group]. FIG. 1 shows that edema (increase in edema rate) can be suppressed over a long period of time by using tranexamic acid and dry aluminum hydroxide gel in combination with ibuprofen (Example 1).

Usually, the maximum concentration of ibuprofen in the blood reaches 1 hour after administration and the biological half-life is 2 hours. The maximum concentration of tranexamic acid in blood reaches 2 hours after administration and the biological half-life is 3 hours. It is. In other words, the medicinal effect reaches its maximum in 1 to 2 hours after taking, halves in 2 to 3 hours, and then decreases for a while. On the contrary, when tranexamic acid and dry aluminum hydroxide gel were used in combination with ibuprofen, the medicinal effect was maintained even after 3 hours as shown in FIG. This shows that the effect of ibuprofen is continuously maintained by using tranexamic acid and dry aluminum hydroxide gel in combination with ibuprofen (giving sustainability).

Formulation Examples 1 to 28: Soft capsules Soft capsules were prepared according to the formulation examples described in Tables 3 and 4 (Prescription Examples 1 to 28). Specifically, after dissolving and mixing glycerin fatty acid ester in medium chain fatty acid triglyceride, add the appropriate plasticizer, preservative, and coloring agent to gelatin and suspend the active ingredients uniformly. The capsule skin was filled to obtain a soft capsule.

Formulation Example 29: Granules Granules were prepared according to Formulation Example 29 in Table 5. Specifically, all the ingredients shown in Formulation Example 29 of Table 5 were granulated by an extrusion granulation method, dried and sized to obtain granules.

Formulation Example 30: Tablets Tablets were prepared according to Formulation Example 30 in Table 5. Specifically, all components shown in Formulation Example 30 of Table 5 were tableted with a rotary tableting machine to obtain tablets.

Formulation Example 31: Hard capsule A hard capsule was prepared according to Formulation Example 31 in Table 5. Specifically, hard capsules were obtained by a conventional method for all components shown in Formulation Example 31 of Table 5.

In Experimental Example 2, a graph comparing the edema rate (%) over time after carrageenin inoculation for the test substance administration group (Example 1, Comparative Examples 1, 3, 9 to 10) and the non-treatment group is shown.

Claims

An oral pharmaceutical composition comprising (a) a phenylpropionic acid-based anti-inflammatory analgesic, (b) tranexamic acid, and (c) a dry aluminum hydroxide gel.
(A) The oral pharmaceutical composition according to claim 1 or 2, wherein the phenylpropionic acid anti-inflammatory analgesic is ibuprofen.
The oral pharmaceutical composition according to any one of claims 1 to 2, which is an antipyretic analgesic / anti-inflammatory agent.
(A) phenylpropionic acid anti-inflammatory analgesic is used in combination with (b) tranexamic acid and (c) dry aluminum hydroxide gel to reduce gastric mucosal damage of the phenylpropionic anti-inflammatory analgesic how to.
5. The method according to claim 4, wherein the phenylpropionic acid anti-inflammatory analgesic is ibuprofen.