JP2016027058A - Loxoprofen-containing oral composition 6 - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a loxoprofen-containing analgesic-antipyretic composition with a reduced risk of gastric mucosa disorder.SOLUTION: The analgesic-antipyretic composition comprises loxoprofen, an antacid, and caffeine.SELECTED DRAWING: None

Description

  The present invention relates to an oral composition containing loxoprofen and an antacid, or an oral composition containing lactose or a xanthine derivative in loxoprofen and an antacid.

  Nonsteroidal antipyretic analgesics and anti-inflammatory agents (NSAIDs) such as loxoprofen, ibuprofen and aspirin are widely prescribed for symptoms such as the common cold. However, since NSAID has a pharmacological action mechanism that suppresses the biosynthesis of prostaglandins, it is well known that it inevitably causes the side effect of gastric mucosal damage. In order to reduce gastric mucosal damage caused by NSAID, a method of using an antacid, a gastric mucosa protective agent, a proton pump inhibitor, a histamine H2 receptor antagonist, or the like in general is known.

  On the other hand, since loxoprofen is a prodrug, gastric mucosal damage is considered to be less than that of other NSAIDs. However, in actual medical practice, in order to avoid gastric mucosal damage in advance, Similarly, the above combination prescription may be performed. However, a composition containing an antacid in loxoprofen has not been known so far, and a composition containing lactose or a xanthine derivative in loxoprofen and an antacid has not been known.

In addition, the following are mentioned as a composition relevant to this invention.
1) The composition which mix | blended lactose and / or corn starch as a filler with the loxoprofen is disclosed (refer patent document 1).
2) It has been reported that when caffeine is used in combination with loxoprofen, the analgesic action and the like are synergistically enhanced (see Patent Document 2).
3) As a preparation technique for internal use liquids containing loxoprofen and expectorants, surfactants, thickeners, pH adjusters, if necessary, solubilizers, buffers, preservatives, fragrances, pigments, sweeteners, etc. It is disclosed that it can be used, and among them, there are descriptions of synthetic aluminum silicate, magnesium silicate, magnesium carbonate, magnesium oxide, magnesium aluminate metasilicate and the like as specific examples of the thickener (Patent Document 3). But specific formulation examples are not disclosed.

  However, since any of the above prior arts is essentially different from the content of the present invention, there is no description suggesting the content of the present invention, nor is it implied.

Japanese Patent Laid-Open No. 9-255569 Japanese Patent Laid-Open No. 11-139971 JP 2001-172175 A

  It is useful if the gastric mucosal damage caused by loxoprofen can be reduced, and it is more beneficial if the gastric mucosal damage can be reduced easily and inexpensively.

  The present inventor has been diligently researching for this purpose. As a result, any NSAID does not necessarily hold the conventional argument that gastric mucosal damage can be suppressed by antacids, and the effect on gastric mucosal damage varies greatly depending on the amount of antacid added. This study revealed for the first time.

  Specifically, it was found that in an oral composition containing loxoprofen and an antacid, the gastric mucosal disorder inhibitory effect is different from that of ibuprofen, which is the same phenylpropionic acid-based NSAID. Therefore, even if the relationship between the ratio of antacids to ibuprofen and gastric mucosal damage can be known, it is impossible to infer the results of loxoprofen from the results. Furthermore, it was found that loxoprofen significantly reduces the gastric mucosal damage-reducing action of antacids compared to ibuprofen (see Table 5 below).

  In addition, it was found that addition of lactose to loxoprofen and antacids significantly amplifies the gastric mucosal damage-reducing effect of the antacids (see Table 6 described later), thereby completing the present invention. It was.

  On the other hand, as OTC drugs (particularly cold medicine), in addition to NSAIDs (for example, ibuprofen), xanthine derivative caffeine is already marketed. The inventors of the present invention have examined the combination of loxoprofen and a xanthine derivative as well as such a prescription, and have confirmed for the first time that the risk of gastric mucosal damage tends to increase. Therefore, research has also been conducted on means for eliminating such undesirable phenomena caused by the combined use.

  As a result, surprisingly, the exacerbation of gastric mucosal damage caused by the combined use of loxoprofen and xanthine derivatives was caused by the addition of antacids to the gastric mucosal damage caused by the combination of loxoprofen and antacids. It has been found that it is remarkably suppressed to an extent that cannot be inferred from the suppressing action (see Table 7 described later), and the present invention has been completed.

  In general, it is known that NSAIDs can reduce gastric mucosal damage to some extent if taken after meals. However, antipyretic anti-inflammatory analgesics are essentially useless, and it is inherently difficult to limit them to post-meal use. Therefore, it is meaningful to embody a loxoprofen formulation with reduced gastrointestinal disturbances, especially more useful for patients who need to take for a long period of time or who have restricted their diet and water intake. It is.

The present invention
(1) An oral composition comprising loxoprofen and an antacid,
(2) The oral composition according to (1) above, further comprising lactose,
(3) The oral composition according to the above (1) or (2), further comprising a xanthine derivative,
(4) The oral composition according to any one of (1) to (3), wherein loxoprofen is loxoprofen sodium,
(5) The oral composition according to any one of (1) to (3), wherein loxoprofen is loxoprofen sodium dihydrate,
(6) The antacid is dry aluminum hydroxide gel, magnesium aluminate silicate, magnesium silicate, synthetic aluminum silicate, natural aluminum silicate, synthetic hydrotalcite, magnesium oxide, magnesium alumina hydroxide, aluminum hydroxide gel , One or more selected from the group consisting of magnesium hydroxide, sodium hydrogen carbonate, magnesium carbonate, precipitated calcium carbonate, magnesium metasilicate aluminate, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate, borei and aminoacetic acid The oral composition according to any one of (1) to (5),
(7) Any one selected from the above (1) to (5), wherein the antacid is one or more selected from the group consisting of magnesium oxide, precipitated calcium carbonate, sodium bicarbonate and aminoacetic acid. Oral composition according to
(8) The oral composition according to any one of (1) to (5), wherein the antacid is magnesium oxide,
(9) The xanthine derivative is selected from the above (3) to (8), which is one or more selected from the group consisting of caffeine, theophylline, aminophylline, theobromine, diprofylline, proxyphylline and pentoxyphylline. The oral composition according to any one of the above,
(10) The oral composition according to any one of (3) to (8), wherein the xanthine derivative is one or more selected from the group consisting of caffeine, theophylline and aminophylline. object,
(11) Any one selected from the above (3) to (8), wherein the xanthine derivative and the caffeine are caffeine, anhydrous caffeine, sodium benzoate caffeine, caffeine hydrochloride, and caffeine citrate. Oral composition according to
(12) The oral composition according to (11), wherein the xanthine derivative and caffeine are one or two selected from caffeine and anhydrous caffeine,
(13) The oral composition according to any one of (1) to (12), wherein gastric mucosal damage caused by loxoprofen is reduced;
(14) The oral composition according to the above (13) for use as an antipyretic,
(15) The oral composition according to the above (13) for use as an analgesic,
(16) The oral composition according to the above (13) for use as a therapeutic agent for inflammation,
(17) The oral composition according to the above (13) for use as a cold medicine,
(18) The oral composition according to any one of (1) to (12), which is used as an agent for reducing gastric mucosal damage caused by loxoprofen,
(19) The oral composition according to any one of (1) to (18), which is administered between meals,
(20) The oral composition according to any one of (1) to (18), which is administered to a patient who needs to take for a long time,
(21) The oral composition according to any one of (1) to (18), which is administered to a patient whose intake of food and water is restricted,
(22) An antipyretic characterized by using loxoprofen and an antacid in combination;
(23) The antipyretic according to (22), further comprising lactose or a xanthine derivative,
(24) An analgesic characterized by using loxoprofen and an antacid in combination,
(25) The analgesic according to (24), wherein lactose or a xanthine derivative is used in combination.
(26) A therapeutic agent for inflammation characterized by the combined use of loxoprofen and an antacid
(27) The therapeutic agent for inflammation according to (26), further comprising lactose or a xanthine derivative,
(28) A cold medicine characterized by using loxoprofen and an antacid, and (29) A cold medicine according to (28), further comprising lactose or a xanthine derivative.

Furthermore, the present invention provides
An antipyretic method, an analgesic method, an inflammatory treatment method, or a cold treatment method, wherein the oral composition according to any one of (1) to (12) is administered between meals,
An antipyretic method, an analgesic method, wherein the oral composition according to any one of (1) to (12) is administered to a patient who needs to take it over a long period of time; Inflammation treatment method or cold treatment method,
An antipyretic method and analgesia characterized by administering the oral composition according to any one of (1) to (12) above to a patient whose intake of food or water is restricted Method, inflammation treatment method or common cold treatment method,
A combination of loxoprofen and an antacid, or a combination of loxoprofen and an antacid with lactose or a xanthine derivative, an antipyretic method, an analgesic method, an inflammation treatment method or a cold treatment method, and selected from the above (1) to (12) A method for alleviating gastric mucosal damage with loxoprofen, comprising administering an oral composition according to any one of the above.

  In the present invention, “loxoprofen” is loxoprofen or a salt thereof (including a hydrous salt), preferably loxoprofen sodium, and more preferably loxoprofen sodium dihydrate.

In the present invention, the “antacid” has an acid neutralizing action, and is preferably dry aluminum hydroxide gel, magnesium aluminate silicate, magnesium silicate, synthetic aluminum silicate, natural aluminum silicate. , Synthetic hydrotalcite, magnesium oxide, magnesium hydroxide alumina, aluminum hydroxide gel, magnesium hydroxide, sodium hydrogen carbonate, magnesium carbonate, precipitated calcium carbonate, magnesium metasilicate aluminate, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate Borei and aminoacetic acid,
Preferred are magnesium oxide, precipitated calcium carbonate, sodium bicarbonate and aminoacetic acid,
More preferably, it is magnesium oxide.

In the present invention, “lactose” is a sugar contained in milk and is an oligosaccharide.
In the present invention, the “xanthine derivative” is a purine base contained in coffee, tea, and cocoa, such as caffeine, theophylline, aminophylline, theobromine, diprofylline, proxyphylline, or pentoxyphyllin. The “caffeine” includes caffeine, anhydrous caffeine, sodium benzoate caffeine, caffeine hydrochloride, caffeine citrate and the like. The “xanthine derivative” is preferably caffeine, theophylline or aminophylline, more preferably caffeine,
Even more preferred is caffeine or anhydrous caffeine.

  In the present invention, “gastric mucosal disorder” refers to gastric mucosal lesions (eg, hemorrhoids, bleeding, edema) and gastric ulcers resulting from acute and chronic gastritis, and disorders of the upper gastrointestinal tract including the duodenum, which is the adjacent site of the stomach. is there.

  In the present invention, “between meals” means between meals or on an empty stomach.

  In the present invention, the term “patient that needs to be taken for a long period of time” is not particularly limited as long as it is a patient that is taken for the purpose of prevention / treatment of chronic diseases. For example, rheumatoid arthritis, deformable knee List patients with arthropathy, chronic stiff shoulders and low back pain.

  In the present invention, the “patient with restricted dietary and water intake” is particularly if the intake of food and water is restricted compared to normal cases for the purpose of disease prevention and treatment. Although there is no limitation, for example, patients with acute and chronic nephritis, artificial dialysis, peritoneal dialysis, diabetic kidney disease and the like can be mentioned.

  Antipyretic agent, analgesic agent, inflammatory treatment agent, or cold treatment agent characterized by "using loxoprofen and antacid agent in combination" or loxoprofen and antacid agent, and "using lactose or xanthine derivative together" Is an antipyretic agent, analgesic agent, inflammatory treatment agent, or common cold treatment agent for separately administering loxoprofen and an antacid or lactose or xanthine derivative to loxoprofen and an antacid simultaneously or at approximately the same time.

  The oral composition containing loxoprofen and an antacid and the oral composition containing lactose or a xanthine derivative in the loxoprofen and antacid have an excellent alleviating effect on gastric mucosal damage caused by loxoprofen. . Therefore, the antipyretic agent, analgesic agent, inflammatory treatment agent, or cold treatment agent of the present invention is for patients who need to be administered between meals or take for a long period of time, and patients whose intake of food and water is restricted. Safer to administer.

  Loxoprofen, dry aluminum hydroxide gel, magnesium silicate, synthetic aluminum silicate, natural aluminum silicate, magnesium oxide, sodium hydrogen carbonate, magnesium carbonate, precipitated calcium carbonate, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate, volley, amino Acetic acid (glycine), lactose, caffeine, anhydrous caffeine, sodium benzoate caffeine, theophylline and aminophylline are listed in the Japanese Pharmacopoeia XIV.

  Further, other salts and hydrates of loxoprofen can be produced by known methods.

  Magnesium aluminate silicate, synthetic hydrotalcite, magnesium hydroxide, magnesium metasilicate aluminate, diprofylline and proxyphylline are listed in Japanese Pharmacopoeia Pharmaceutical Standard 2002.

  Furthermore, aluminum hydroxide gel is listed in Pharmaceutical Additives Standard 2003, theobromine is available as a standard for pharmaceutical testing, and others can be produced by known methods.

  Antipyretic agent, analgesic agent, inflammatory treatment agent, or cold treatment agent characterized by "using loxoprofen and antacid agent in combination" or loxoprofen and antacid agent, and "using lactose or xanthine derivative together" In the above, the antacid, lactose and xanthine derivative and loxoprofen can be administered in the form of a combination drug. Alternatively, the antacid, lactose, xanthine derivative and loxoprofen can be administered simultaneously or nearly simultaneously as a formulated formulation for each.

  The single dose of loxoprofen varies depending on the indication and age, but is usually 20 mg to 180 mg, which is administered 1 to 3 times a day.

When the composition of the present invention is a solid preparation, the content of loxoprofen is usually 10 mg to 400 mg, preferably 20 mg to 180 mg.
When the composition of the present invention is a liquid preparation, the content of loxoprofen is usually 0.1 mg / mL to 200 mg / mL, and preferably 1 mg / mL to 100 mg / mL.

  The content ratio of the antacid is preferably 0.01 parts by weight or more, and more preferably 0.02 parts by weight or more with respect to 1 part by weight of loxoprofen. The upper limit is not particularly limited, but is preferably 100 parts by weight or less, and more preferably 30 parts by weight or less.

  When lactose is further contained in the loxoprofen and the antacid, the lactose content is preferably 0.01 to 1 part by weight, more preferably 0.05 to 1 part by weight of loxoprofen. Parts by weight to 0.9 parts by weight.

  When the loxoprofen and the antacid contain a xanthine derivative, the content ratio of the xanthine derivative is preferably 0.01 to 10 parts by weight, more preferably 1 part by weight of loxoprofen. 0.1 to 2 parts by weight.

  In the present invention, in addition to the above active ingredients, as needed, hypnotic sedatives, antitussives, expectorants, antihistamines, antiallergic drugs, sympathomimetic drugs, parasympathomimetic drugs, anti-inflammatory enzymes, vitamins, Herbal medicines and the like can be contained as long as the effects of the present invention are not impaired.

  Specific examples of these dosage forms include tablets, fine granules (including powders), capsules, liquids (including syrups) and the like, and additives and base materials suitable for each dosage form. Can be used according to the usual methods described in the Japanese Pharmacopoeia and the like.

  In the above dosage forms, various commonly used additives can be used depending on the dosage form. For example, an excipient, a stabilizer, a coating agent, a lubricant, an adsorbent, a binder, a disintegrant, a surfactant, a colorant, a pH adjuster, and a fragrance can be added.

  Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples, but the scope of the present invention is not limited thereto.

Example 1 Tablet (1) Ingredient (Table 1)
1 to 2 tablets (mg) (1a) (1b) (1c) (1d) (1e)
---------------------------------------
Loxoprofen sodium dihydrate
60 60 60 60 60
Magnesium oxide 60 240 − − −
Precipitated calcium carbonate − − 60 − −
Aminoacetic acid--480-
Sodium bicarbonate----240
Lactose 15----
Caffeine or theophylline-30---
Hydroxypropyl cellulose 40 50 30 80 70
Magnesium stearate appropriate amount appropriate amount appropriate amount appropriate amount appropriate amount -------------------------------------

(2) Manufacturing method Take the above ingredients and quantities, and manufacture tablets according to the section “General Tablets” “Tablet”.

(Example 2) Fine granule (1) component (Table 2)
In 1 package (mg) (2a) (2b) (2c) (2d) (2e)
---------------------------------------
Loxoprofen sodium dihydrate
60 60 60 60 60
Magnesium oxide 60 240 − − −
Precipitated calcium carbonate − − 60 − −
Aminoacetic acid--480-
Sodium bicarbonate----240
Lactose 15----
Caffeine or theophylline-30---
Hydroxypropyl cellulose 200 100 200 150 100
Magnesium stearate 5 10 7 9 10
Low substituted hydroxypropylcellulose
Appropriate amount Applicable amount Appropriate amount Appropriate amount Appropriate amount ------------------------------

(2) Production method Take the above ingredients and quantities, and produce a fine granule according to the section “Granule” of the General Rules for Preparations.

Example 3 Capsule (1) Ingredient (Table 3)
1 to 2 capsules (mg) (3a) (3b) (3c) (3d) (3e)
---------------------------------------
Loxoprofen sodium dihydrate
60 60 60 60 60
Magnesium oxide 60 240 − − −
Precipitated calcium carbonate − − 60 − −
Aminoacetic acid--480-
Sodium bicarbonate----240
Lactose 15----
Caffeine or theophylline-30---
Hydroxypropyl cellulose 40 50 30 80 70
Magnesium stearate 5 10 7 9 10
Polysorbate 80 10 15 10 10 20
Corn starch Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount --------------------------------------

(2) Manufacturing method Take the above components and the amount, and make a fine granule according to the section of the Japanese Pharmacopoeia General Rules “Granule”, then fill the capsule to make a hard capsule.

(Example 4) Syrup (1) component (Table 4)
In 60 mL (mg) (4a) (4b) (4c) (4d) (4e)
---------------------------------------
Loxoprofen sodium dihydrate
60 60 60 60 60
Magnesium oxide 60 240 − − −
Precipitated calcium carbonate − − 60 − −
Aminoacetic acid--480-
Sodium bicarbonate----240
Lactose 15----
Caffeine or theophylline-30---
Hydroxypropyl cellulose 40 50 30 80 70
Sodium benzoate 130 140 130 110 110 140
Citric acid 50 80 60 70 80
Concentrated glycerin 460 530 510 490 540
Polyvinyl alcohol 100 100 100 100 100
Ethanol (95%) 200 220 200 230 260
Purified water Remainder Remainder Remainder Remainder Remaining --------------------------------

(2) Manufacturing method Take the above components and quantities, and make a syrup according to the Japanese general formulation “Syrup” section, then fill it into a brown glass bottle to make a syrup.

(Test Example 1)
Test of inhibitory effect of loxoprofen on gastric mucosal damage (1) Test substance Loxoprofen sodium dihydrate is from Sankyo Co., Ltd., ibuprofen is from Sigma Chemical, and lactose is JP lactose ( Kobayashi Pharmaceutical Co., Ltd.), anhydrous caffeine manufactured by Wako Pure Chemical Industries, Ltd., and JP Nihon Magnesium Oxide manufactured by Yoshida Pharmaceutical Co., Ltd. were used.
Each test substance was prepared by suspending or dissolving in 0.5% tragacanth solution on the test day. The administration volume was orally administered at 5 mL per 1 kg body weight, and the same amount of 0.5% tragacanth was administered to the control group.

(2) Animals Environmental control breeding equipment purchased from Wistar-Imamichi male rats (Animal Breeding Research Institute) at 5 weeks of age and controlled at a temperature of 20 to 26 ° C., a humidity of 30 to 70%, and a lighting time of 7:00 to 19:00 (Japan) 5-6 animals were placed in a stainless steel rat breeding gauge, and the animals were fed with feed (mouse / rat breeding F-2, Funabashi Farm) and tap water freely passed through a water filter. After preliminary breeding for 8 days, the health condition was observed macroscopically on the day before the test, and after selecting good animals, the animals were randomly divided into 5 groups per group.

(3) Method In advance, 100% gastric mucosal disorder expression dose in loxoprofen sodium dihydrate single agent and ibuprofen single agent was determined, and the following tests were performed based on the dose.
The test substance is orally administered to animals fasted from 16:00 on the day before the test and 3.5 hours later, the carotid artery is exsanguinated under ether anesthesia and the stomach is removed. The stomach was cut along the large vagina, washed lightly with physiological saline, and then observed for bleeding spots under a stereomicroscope (Olympus 10 × 10 times).
As the ulcer index, the major axis of bleeding spots was measured in units of 0.5 mm, and the total of each animal was determined. Based on the ulcer index of the group administered with loxoprofen sodium dihydrate or ibuprofen alone and the ulcer index of the combination group such as magnesium oxide, the ulcer suppression rate was determined from the following equation.

A: Loxoprofen sodium dihydrate or ibuprofen monotherapy group ulcer index based on 100% gastric mucosa disorder expression level B: Ulcer index of additive combination group 100% gastric mucosal disorder of loxoprofen sodium dihydrate The expression level was 50 mg / Kg and that of ibuprofen was 100 mg / Kg. The following test results are based on these doses.

(4) Test results Tables 5 to 7 and FIGS. 1 to 3 show the results of the ulcer suppression rates of the obtained combination groups. Each value is an average value of 5 animals per group.
In the tables and figures, LxNa is loxoprofen sodium dihydrate, Ibu is ibuprofen, Mg oxide is magnesium oxide, Caf is caffeine, and the content ratio is the dose of each drug to loxoprofen sodium dihydrate. is there.

(Table 5-1)
Test substance (dose: mg / Kg) [Content ratio] Ulcer inhibition rate (%)
----------------------------------
LxNa (50) + Mg oxide (1) [1/50] 22
LxNa (50) + Mg oxide (3) [1/17] 36
LxNa (50) + Mg oxide (10) [1/5] 31
LxNa (50) + Mg oxide (25) [1/2] 27
LxNa (50) + Mg oxide (50) [1/1] 55
LxNa (50) + Mg oxide (100) [2/1] 46
LxNa (50) + Mg oxide (200) [4/1] 81
LxNa (50) + Mg oxide (400) [8/1] 100
----------------------------------
In Table 5-1, [Content Ratio] indicates the content ratio of Mg oxide to 1 part by weight of LxNa.

(Table 5-2)
Test substance (dose: mg / Kg) [Content ratio] Ulcer inhibition rate (%)
----------------------------------
Ibu (100) + Mg oxide (2) [1/50] −51
Ibu (100) + Mg oxide (6) [1/17] -37
Ibu (100) + Mg oxide (20) [1/5] −151
Ibu (100) + Mg oxide (50) [1/2] −114
Ibu (100) + Mg oxide (100) [1/1] 32
Ibu (100) + Mg oxide (200) [2/1] 29
Ibu (100) + Mg oxide (400) [4/1] 71
Ibu (100) + Mg oxide (800) [8/1] 91
----------------------------------
In Table 5-2, [Content Ratio] indicates the content ratio of Mg oxide to 1 part by weight of Ibu.

From Table 5-1, Table 5-2, and FIG. 1, it can be seen that loxoprofen sodium dihydrate and ibuprofen have greatly different tendencies of ulcer inhibiting action by antacids. When loxoprofen sodium dihydrate was used in combination with magnesium oxide, an ulcer suppressing action was exhibited from an extremely small amount of 0.02 and a ulcer was not confirmed at a content ratio of 8. On the other hand, in the case of ibuprofen of the same phenylpropionic acid type NSAID, it has been found that even if magnesium oxide is contained, the ulcer is not suppressed, and on the contrary, it may be significantly worsened (content ratio 0.02 to 0.75). did.

  As described above, it has been found for the first time that when antacid is contained in loxoprofen, an ulcer suppressing action can be obtained at any content ratio.

(Table 6)
Test substance (dose: mg / Kg) Lactose [Content ratio] Ulcer inhibition rate (%)
------------------------------------
LxNa (50) + Mg oxide (50) + lactose [0] 55
LxNa (50) + Mg oxide (50) + lactose [1/4] 88
----------------------------------
Ibu (100) + oxidized Mg (100) + lactose [0] 32
Ibu (100) + Mg oxide (100) + lactose [1/4] -107
------------------------------------
In Table 6, “content ratio” indicates the content ratio of lactose relative to 1 part by weight of LxNa or Ibu.

  As shown in Table 6, it was found that when loxoprofen sodium dihydrate and magnesium oxide were further used in combination with lactose, the ulcer suppressing action was further enhanced. On the other hand, the same phenylpropionic acid type NSAID ibuprofen was tested with the same formulation, and the ulcer was worsened.

(Table 7)
Test substance (dose: mg / Kg) Caf [content ratio] Ulcer inhibition rate (%)
------------------------------------
LxNa (50) + Mg oxide (0) + Caf [1/1] -94
LxNa (50) + Mg oxide (50) + Caf [1/1] 34
LxNa (50) + Mg oxide (100) + Caf [1/1] 95
------------------------------------
LxNa (50) + Mg oxide (50) + Caf [0] 55
LxNa (50) + Mg oxide (100) + Caf [0] 46
------------------------------------
Ibu (100) + Mg oxide (0) + Caf [1/1] -2
------------------------------------
In Table 7, “Content ratio” indicates the content ratio of Caf to 1 part by weight of LxNa or Ibu.

  As shown in Table 7, the combined use of loxoprofen sodium dihydrate and caffeine resulted in a worsening of gastric mucosal damage compared to loxoprofen sodium dihydrate alone. By further using magnesium oxide as an agent, gastric mucosal damage was reduced, and by further doubling the amount of antacid, gastric mucosal damage was almost completely suppressed. As for ibuprofen, gastric mucosal damage was not particularly exacerbated even when used in combination with caffeine.

  The present invention relates to an antipyretic agent administered to a medicament with a reduced risk of gastric mucosal damage (particularly for patients who require administration between meals or for a long period of time, and patients whose intake of food or water is restricted). , An analgesic agent, an inflammatory treatment agent, or a cold treatment agent).

Claims (1)

  An antipyretic analgesic composition containing loxoprofen, magnesium oxide, and caffeine or anhydrous caffeine.