WO2006006577A1 - Loxoprofen-containing composition for oral administration - Google Patents

Abstract

A loxoprofen-containing composition for oral administration which is reduced in the fear of arousing gastric mucosal disorders. The composition for oral administration comprises loxoprofen and an antacid agent.

Description

 Specification

 Composition for oral administration containing loxoprofen

 Technical field

 [0001] The present invention relates to a composition for oral administration containing loxoprofen and an antacid, or a composition for oral administration containing lactose or a xanthine derivative in mouth-and-mouth fen and antacid.

 Background art

 Non-steroidal antipyretic analgesic / anti-inflammatory drugs (NS AID) such as loxoprofen, ibuprofen, and aspirin are widely prescribed for symptoms such as the common cold. However, NSAID has a pharmacological action mechanism that suppresses the biosynthesis of prostaglandins, so 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 in which an antacid, a gastric mucosa protective agent, a proton pump inhibitor, a histamine H2 receptor antagonist or the like is used in combination is generally known.

 [0003] On the other hand, loxoprofen is a prodrug, so it is considered that there is less gastric mucosal damage compared to other NSAIDs, but it should be avoided in advance in actual medical settings. As with other NSAIDs, the above combination prescription may occur. However, so far, no composition containing an antacid in loxoprofen is known, and no composition containing lactose or a xanthine derivative in loxoprofen and an antacid is known.

 [0004] In addition, examples of the yarn composition related to the present invention include the following.

 1) A composition in which lactose and / or corn starch is blended with loxoprofen as a filler is disclosed (see Patent Document 1).

 2) It has been reported that when caffeine is used in combination with loxoprofen, the analgesic action is synergistically enhanced (see Patent Document 2).

3) As preparation technology for oral liquids containing loxoprofen and expectorants, surfactants, thickeners, pH adjusters, and solubilizers, buffers, preservatives, fragrances, pigments, sweeteners, etc. In which a synthetic key is used as a specific example of a thickener. There are descriptions of aluminum silicate, magnesium silicate, magnesium carbonate, magnesium oxide, magnesium aluminate metasilicate, etc. (see Patent Document 3), but no specific formulation examples are 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.

 Patent Document 1: Japanese Patent Laid-Open No. 9-255569

 Patent Document 2: JP-A-11 139971

 Patent Document 3: JP 2001-172175 A

 Disclosure of the invention

 Problems to be solved by the invention

 [0006] It would be useful if the gastric mucosal damage caused by loxoprofen could be reduced, and it would be more beneficial if the gastric mucosal damage could be reduced easily and inexpensively.

 [0007] The present inventor has been diligently researching for this purpose. As a result, if any NSAID can suppress gastric mucosal damage caused by antacids, the conventional argument does not necessarily hold, and the effect on gastric mucosal damage varies greatly depending on the amount of antacid added. This was also clarified for the first time by this study.

 [0008] Specifically, in the composition for oral administration containing loxoprofen and an antacid, the gastric mucosal disorder inhibiting effect is different from that of ibuprofen, which is the same ferropropionic acid-based NSAID. It was found to behave. Therefore, even if the relationship between the mixing ratio of antacids to ibuprofen and gastric mucosal damage can be known, it is impossible to analogize the results of forceful xoxoprofen. In addition, it was found that loxoprofen significantly reduced the gastric mucosal damage reduction effect of loxoprofen compared to ibuprofen (see Table 5 below).

 [0009] Further, the addition of lactose to loxoprofen and antacids found that the effect of reducing gastric mucosal damage by antacids was significantly amplified (see Table 6 below), and the present invention was completed. It came to do.

[0010] On the other hand, OTC drugs (especially cold medicines) are already marketed in which xanthine derivative caffeine is blended in addition to NSAID (eg, ibuprofen). Book The inventors examined the combined use of loxoprofen and a xanthine derivative as well as such a prescription, and confirmed for the first time that the risk of gastric mucosal damage tended 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 a xanthine derivative was caused by the further addition of an antacid, which was observed during the combined use of loxoprofen and an antacid. It was found that the agent was remarkably suppressed (see Table 7 to be described later), which cannot be inferred from the gastric mucosal disorder inhibiting action of the agent, and the present invention was completed.

[0012] Generally, it is known that gastric mucosal damage can be alleviated to some extent by taking NSAID after meals. However, antipyretic anti-inflammatory analgesics are essentially useless, and it is inherently difficult to limit them to after-meal use. Therefore, it is meaningful to implement a loxoprofen preparation with reduced gastrointestinal disturbances, especially for patients who need to take it for a long period of time or who are restricted from eating or drinking water. More useful.

 Means for solving the problem

[0013] The present invention provides:

 (1) a composition for oral administration containing loxoprofen and an antacid;

 (2) The composition according to (1), further containing lactose,

 (3) The composition described in (1) to (2) above, further containing a xanthine derivative,

(4) The composition according to any one of (1) to (3), wherein the loxoprofen is loxoprofen sodium,

 (5) The composition according to any one of (1) to (3), wherein the 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, water Aluminum oxide gel, magnesium hydroxide, sodium bicarbonate, magnesium carbonate, precipitated calcium carbonate, metasilicate magnesium aluminate, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate, volley The composition according to item 1, wherein the composition is one or more selected from the group consisting of the amino acids also having at least one amino acid selected from the above (1) to (5),

 (7) The antacid is one or more selected from the group consisting of magnesium oxide, precipitated calcium carbonate, sodium hydrogen carbonate and aminoacetic acid, and is selected from the above (1) to (5) Any one of the compositions according to paragraph 1,

 (8) The composition described in any one of the above items (1) to (5), wherein the antacid is acid magnesium, and the forces (1) to (5) are also selected.

 (9) Xanthine derivative power The above (3) to (8), which are one or more selected from the group consisting of caffeine, theophylline, aminophylline, theopromine, diprofylline, proxyphylline and pentoxyphyllin. Force is also selected, the composition described in paragraph 1;

(10) Xanthine Derivative Power One or more selected from the group consisting of caffeine, theophylline, and aminophyllinker, and the above (3) to (8) power is also selected. Composition,

 (11) Any one selected from the above (3) to (8), wherein the xanthine derivative and caffeine are caffeine, anhydrous caffeine, sodium benzoate caffeine, caffeine hydrochloride, or caffeine caffeine 1 The composition described in the paragraph,

 (12) The composition described in (11) above, wherein the xanthine derivative and caffeine are one or two selected from caffeine and anhydrous caffeine,

 (13) The composition according to any one of (1) to (12), wherein the force is also selected for use as an antipyretic agent,

 (14) The composition according to any one of (1) to (12) above, which is used as an analgesic,

 (15) The composition according to any one of (1) to (12), which is used as an anti-inflammatory agent,

 (16) The composition described in any one of (1) to (12) above, which is selected as a cold medicine,

(17) The composition described in any one of (1) to (16) above for administration between meals, (18) The above-mentioned (1) to (17) force selected for administration to a patient who needs to take for a long period of time any of the compositions described in item 1, and

 (19) The composition described in any one of (1) to (18) above, which is selected for administration to a patient whose intake of food and water is restricted,

 I will provide a.

[0014] Furthermore, the present invention provides:

 (1) to (12) force selected from any one of the above, wherein the composition described in item 1 is applied between meals; The antipyretic method and the analgesic method characterized by administering the composition described in any one of the above (1) to (12), wherein the force is also selected, to a patient who needs to take for a long time , Inflammation treatment method or cold treatment method,

 The antipyretic method comprising administering the composition described in any one of the above (1) to (12) force to a patient whose intake of food or water is restricted An analgesic method, an inflammatory treatment method or a common cold treatment method, and

 Antipyretic method, analgesic method, inflammatory treatment method or common cold treatment method by using loxoprofen and antacid in combination or lactose or xanthine derivative in combination with loxoprofen and antacid

 I will provide a.

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

[0015] In the present invention, the "antacid" has an acid neutralizing action, and is preferably a dry aluminum hydroxide gel, magnesium aluminate, magnesium silicate, or 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 magnesium phosphate, anhydrous phosphorus Calcium hydrogen hydrogen, calcium hydrogen phosphate, volley and aminoacetic acid Preferred are magnesium oxide, precipitated calcium carbonate, sodium bicarbonate and aminoacetic acid,

 More preferred is magnesium oxide.

 In the present invention, “lactose” is a saccharide contained in milk and is an oligosaccharide.

In the present invention, the “xanthine derivative” is a purine base contained in coffee, tea, and cocoa, and is caffeine, theophylline, aminophylline, theobromine, diprofilin, proxyphylline, pentoxyphylline, and the like. Examples of “caffeine” include caffeine and anhydrous caffeine, sodium benzoate caffeine, caffeine hydrochloride, caffeine caffeine and the like. The “xanthine derivative” is preferably caffeine, theophylline or aminophylline, more preferably caffeine, and still more preferably caffeine or anhydrous caffeine.

 [0018] 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 the upper digestive tract including the duodenum, which is the adjacent site of the stomach. It is a failure.

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

 [0020] In the present invention, the "patient that needs to be taken for a long period of time" is not particularly limited as long as it is a patient who is taken for the purpose of preventing or treating a chronic disease. For example, rheumatoid arthritis, Examples include knee osteoarthritis, chronic stiff shoulders and low back pain.

 [0021] In the present invention, "a patient whose intake of food and water is restricted" is a case where intake of food and water is restricted as compared with a normal case for the purpose of disease prevention / treatment. For example, patients with acute and chronic nephritis, artificial dialysis, peritoneal dialysis, diabetic kidney disease and the like can be mentioned.

[0022] The antipyretic agent, analgesic agent, inflammation characterized by "concomitant use of oral xoxoprofen and antacid" or "further use of lactose or xanthine derivative" in combination with loxoprofen and antacid of the present invention A therapeutic agent or a cold treatment agent is an antipyretic agent, an analgesic agent, an inflammatory treatment agent, or a cold treatment for separately administering loxoprofen and an antacid or lactose or a xanthine derivative to loxoprofen and an antacid simultaneously or at approximately the same time. It is an agent. The invention's effect

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

 BEST MODE FOR CARRYING OUT THE INVENTION

 [0024] Loxoprofen, dry aluminum hydroxide gel, magnesium silicate, synthetic aluminum carbonate, natural aluminum silicate, magnesium oxide, sodium bicarbonate, magnesium carbonate, precipitated calcium carbonate, anhydrous calcium hydrogen phosphate, Calcium hydrogen phosphate, borei, aminoacetic acid (glycine), lactose, caffeine, anhydrous caffeine, sodium caffeine benzoate, theophylline and aminophylline are listed in the Japanese Pharmacopoeia XIV.

 [0025] Other salts and hydrates of loxoprofen can be produced by known methods.

 [0026] Magnesium aluminate, synthetic hydrotalcite, magnesium hydroxide, magnesium aluminate metasilicate, diprofylline and proxyphylline are listed in Japanese Pharmacopoeia Standards for Pharmaceuticals 2002.

 [0027] Furthermore, hydroxyaluminum gel is listed in Pharmaceutical Additives Standard 2003, theopromin is available as a standard for pharmaceutical testing, and others can be produced by known methods.

 [0028] The antipyretic agent, analgesic agent, inflammation characterized by "concomitant use of oral xoxoprofen and an antacid" or "further use of lactose or a xanthine derivative" with loxoprofen and an antacid of the present invention In the therapeutic agent or the cold treatment agent, the antacid, lactose, 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 almost simultaneously as a preparation prepared for each.

[0029] The single dose of loxoprofen varies depending on the indication and age, but usually 20 mg to 180 mg, administered 1 to 3 times daily.

[0030] When the composition of the present invention is a solid preparation, the content of loxoprofen is usually from 10 mg to 400 mg, and preferably from 20 mg to 180 mg.

[0031] When the composition of the present invention is a liquid preparation, the content of loxoprofen is usually 0.1 mgZmL to 200 mgZmL, and preferably 1 mgZmL to lOOmg.

/ mL.

 [0032] 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.

 [0033] When the above-mentioned loxoprofen and the antacid further contain lactose, the lactose content ratio is preferably 0.01 to 1 part by weight, more preferably 1 part by weight of loxoprofen. From 0.05 parts by weight to 0.9 parts by weight.

 [0034] 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 with respect to 1 part by weight of loxoprofen, and The amount is preferably 0.1 to 2 parts by weight.

 [0035] In the present invention, in addition to the above active ingredients, if necessary, a hypnotic sedative, an antitussive, an expectorant, an antihistamine, an antiallergic agent, a sympathomimetic drug, a parasympathomimetic drug, an anti-inflammatory enzyme Further, vitamins, herbal medicines and the like can be contained within a range not impairing the effects of the present invention.

 [0036] Examples of these specific dosage forms include tablets, fine granules (including powders), capsules, liquids (including syrups) and the like, and additives suitable for each dosage form. Can be produced according to the usual method described in the Japanese Pharmacopoeia, etc.

 [0037] In each of the above dosage forms, various commonly used additives may be used depending on the dosage form. For example, excipients, stabilizers, coating agents, lubricants,

 An adsorbent, a binder, a disintegrant, a surfactant, a colorant, a pH adjuster and a fragrance can be added.

 [Example]

The following examples and test examples illustrate the present invention in more detail. The scope is not limited to these.

 (Example 1) Tablet

(1) Ingredient

(table 1)

 1 to 2 tablets (mg) (l a) (l b) (l c) (I d) (1 e) Loxoprofen sodium 'dihydrate

 60 60 0 60 60 Magnesium oxide 60 240

 Precipitated calcium carbonate 60

 Aminoacetic acid I 480

 Sodium bicarbonate 1 240 Milk 1 5

 Caffeine or theophylline

30 80 70 ステアリン酸マグネシウム 適量 適量 適量 適量 量 o o Hydroxypropinorescenore Mouth 40

30 80 70 Magnesium stearate Appropriate amount Appropriate amount Appropriate amount Appropriate amount oo

 (2) Manufacturing method

 Take the above ingredients and quantity, and make tablets according to the section “General Tablet Preparations” “Tablets”.

(Example 2) Fine granules

(1) Ingredient

 (Table 2)

 In 1 package (mg) (2 a) (2 b) (2 c) (2 d) (2 e)

Loxoprofen sodium dihydrate

 60 60 60 60 60

Magnesium oxide 60 240--Precipitated calcium carbonate ― ― 60 ― ―

Aminoacetic acid-1 480 ―

Sodium bicarbonate ― ― ― ― 240

Lactose 15 1 ― ― ―

Caffeine or theophylline-30---

Hydroxypropynolose 200 100 200 1 50 100

Magnesium stearate 5 10 7 9 10

Low substituted hydroxypropylcellulose

 Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount

(2) Manufacturing method

 Take the above ingredients and quantity, and make a fine granule according to the section “Granule”. (Example 3) Capsule

(1) Ingredient

(Table 3) 1 to 2 capsules (mg) (3 a) (3 b) (3 c) (3 d) (3 e)

 Loxoprofen sodium dihydrate

 60 60 60 60 60

 Magnesium oxide 60 240

 Precipitated calcium carbonate 60 — one

 Aminoacetic acid-480

 Sodium hydrogen carbonate

 Lactose i

 Caffeine or theophylline

 Hydroxypropylcellulose 4

 Magnesium stearate

 Polysorbate 80 1 10 20

 Corn starch Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount

(2) Manufacturing method

 Take the above ingredients and amount, and make a fine granule according to the section of the General Rules for Pharmaceutical Preparations “Granule”, then fill it into a capsule to make a hard capsule.

(Example 4) Syrup

(1) Ingredient

(Table 4)

 In 60 mL (mg) (4 a) (4 b) (4 c) (4 d) (4 e)

 Loxoprofen sodium 'dihydrate

 60 60 60 60 60

 Magnesium oxide 60 240

 Precipitated calcium carbonate 1 1 60 1 1

 Aminoacetic acid

 sodium hydrogen carbonate

 Lactose

 Caffeine or theophylline

 Hydroxypropylcellulose

 Sodium benzoate 1

 Quenic acid

 Minato Glycerin 4

 Polybi Rare Co I

 Ethanol (95%) 2

 Purified water Remainder Remainder i Remainder Remainder Remainder

(2) Manufacturing method

 Take the above ingredients and amount, and make a syrup according to the general rules of syrup preparation “Syrup”, then fill it into a brown glass bottle to make a syrup.

(Test Example 1)

Inhibitory effect of loxoprofen on gastric mucosal damage by antacids

 (1) Test substance

Loxoprofen sodium dihydrate is from Sankyo Co., Ltd., ibuprofen is Sigm a Chemical product, lactose is manufactured by Nippon Pharmacy Lactose (manufactured by Kokai Pharmaceutical Co., Ltd.), anhydrous caffeine is manufactured by Wako Pure Chemical Industries, Ltd. ) Was used.

 [0038] Each test substance was prepared by suspending or dissolving in 0.5% tragacanth solution on the test day.

 The administration volume was 5 mL / kg body weight orally, and the same amount of 0.5% tragacanth was administered to the control group.

 (2) Animals

 Wistar— Imamichi male rat (Animal Breeding Research Institute) Purchased 5 weeks old, temperature controlled 20-26 ° C, humidity 30-70%, lighting time controlled from 7am to 7pm (manufactured by Nippon Tarera) ), 5-6 animals were placed in a stainless steel rat breeding gauge, and the animals were allowed to freely feed the feed (F-2 for breeding mice and rats, manufactured by Funabashi Farm) and tap water through a water filter. After preparatory 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

 A loxoprofen sodium dihydrate monohydrate and ibuprofen monotherapy were determined in advance to obtain a dose of 100% gastric mucosal damage, and the following tests were performed based on the dose.

[0039] The test substance was orally administered to animals fasted from 16:00 the day before the test. 3.5 hours later, the carotid artery was exsanguinated under ether anesthesia, and the stomach was removed. The stomach was cut along the vaginal fistula, washed lightly with physiological saline, and observed for bleeding spots under a stereomicroscope (Olinnos 10 x 10x).

[0040] As the ulcer index, the major axis of the bleeding spot was measured in units of 0.5 mm, and the total of each animal was determined. Based on the ulcer index in the group administered with loxoprofen sodium dihydrate or ibuprofen alone and the ulcer index in the combination group such as magnesium oxide, the ulcer suppression rate was calculated from the following equation.

 (Formula 1)

 Ulcer inhibition rate (%) = [1 -B / A] X 100

A: Ulcer index of loxoprofen sodium dihydrate or ibuprofen monotherapy group based on 100% gastric mucosa damage B: Ulcer index in the additive combination group

 The amount of 100% gastric mucosal damage of loxoprofen sodium dihydrate was 50 mgZ Kg and that of ibuprofen was lOOmgZKg. The following test results are based on these doses.

 (4) Test results

 Tables 5 to 7 and Figures 1 to 3 show the results of ulcer suppression rates of the obtained combination groups. Each value is the average of 5 animals per group.

[0041] In the table and figure, LxNa is loxoprofen sodium dihydrate, Ibu is ibuprofen, Mg oxide is magnesium oxide, Caf is caffeine, and the content ratio is each drug for loxoprofen sodium dihydrate Dose.

 (Table 5-1)

 Test substance (dose: mg / Kg) [content ratio] Ulcer inhibition rate (%)

LxNa (50)-—Oxidized Mg (l) [1/50] 22

 LxNa (50)-—oxidized Mg (3) [1/17] 36

 LxNa (50)-—Oxidized Mg (10) [1/5] 31

 LxNa (50)-—oxidized Mg (25) [1/2] 27

 LxNa (50)-—oxidized Mg (50) [1/1] 55

 LxNa (50)-—Oxidized Mg (lOO) [2/1] 46

 LxNa (50)-—oxidized Mg (200) [4/1] 81

 LxNa (50)-—oxidized Mg (400) [8/1] 100

[0042] In Table 5-1, [Content ratio] indicates the content ratio of Mg oxide to LxNal parts by weight.

 (Table 5-2)

 Test substance (dose: mg / Kg) [content ratio] Ulcer inhibition rate (%)

Ibu (100) + oxidized Mg (2) [1 / 50J

Ibu (100) + Mg oxide (6) [1/17] Ibu (lOO)-oxidized Mg (20) [1/5] -151

 Ibu (lOO)-—oxidized Mg (50) [1/2] -114

 Ibu (lOO)-—oxidized Mg (lOO) [1/1] 32

 Ibu (lOO)-—Oxidized Mg (200) [2/1] 29

 Ibu (lOO)-—oxidized Mg (400) [4/1] 71

 Ibu (lOO)-—Oxidized Mg (800) [8/1] 91

[0043] In Table 5-2, "Content ratio" indicates the content ratio of Mg oxide to Ibul parts by weight.

 Table 5-1 and Table 5-2 and Figure 1 show that loxoprofen sodium dihydrate and ibuprofen differ greatly in the tendency of antacids to suppress ulcers. When loxoprofen sodium dihydrate was used in combination with magnesium oxalate, an extremely small amount of ulcer-inhibiting action with a content ratio of 0.02 was expressed, and at a content ratio of 8 ulcers were confirmed. On the other hand, in the case of ibuprofen, which is the same ferpropionic acid type NSAID, it has been found that even when magnesium oxide is contained, ulcers are not suppressed and conversely worsened (content ratio 0.02 to 0.75). did.

 [0044] As described above, it has been found for the first time that when an antacid is contained in loxoprofen, an ulcer suppressing action can be obtained even if the content ratio of V and deviation is small.

 (Table 6)

 Test substance (dose: mg / Kg) Lactose [Content ratio] Ulcer inhibition rate (%)

LxNa (50) + oxidized Mg (50) + lactose [0]

 LxNa (50) + Acid 匕 Mg (50) + Lactose [1Z4]

Ibu (100) + acid Mg (100) + lactose [0]

 Ibu (100) + acid Mg (100) + lactose [1Z4]

[0045] In Table 6, [Content Ratio] indicates the content ratio of lactose to LxNa or Ibul parts by weight.

As shown in Table 6, loxoprofen sodium dihydrate and acid It was found that the ulcer suppressing effect was further enhanced when sugar was further used in combination. On the other hand, when the same formulation of the same ferpropionic NSAID ibuprofen was tested with the same formulation, the ulcers worsened.

(Table 7)

Test substance (dose: mg / Kg) Caf [content ratio] Ulcer inhibition rate (%)

LxNa (50) + Mg oxide (0) + Caf (l / lJ 94

 LxNa (50) + Mg oxide (50) + Caf [l / l] 34

LxNa (50) + Mg oxide (100) + Caf [l / l] 95

LxNa (50) + Mg oxide (50) + Caf [0]

LxNa (50) + Mg oxide (100) + Caf [0]

Ibu (lOO) + oxidized Mg (0) + Caf [l / 1] 2 In Table 7, [Content ratio] indicates the content ratio of Caf to LxNa or Ibul parts by weight. As shown in Table 7, the combination of loxoprofen sodium dihydrate and caffeine increased gastric mucosal damage compared to single administration of loxoprofen sodium dihydrate. Furthermore, gastric mucosal damage was reduced by further use of the drug acid magnesium, and gastric mucosal damage was almost completely suppressed by doubling the amount of antacid. Note that ibuprofen did not exacerbate gastric mucosal damage even when used in combination with caffeine.

Industrial applicability

 The present invention relates to an antipyretic agent administered to a medicament with a further reduced risk of gastric mucosal damage (especially for patients who require administration between meals or for long periods 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

 The scope of the claims  [I] A composition for oral administration containing loxoprofen and an antacid. [2] The composition according to claim 1, further comprising lactose.  [3] The composition according to claim 1, further comprising a xanthine derivative.  [4] The composition according to any one of Claims 1 to 3, wherein the loxoprofen is loxoprofen sodium.  [5] Loxoprofen is loxoprofen sodium dihydrate 4. The composition according to any one of 3 selected from 3.  [6] The antacid is dry aluminum hydroxide gel, magnesium aluminate, magnesium silicate, synthetic aluminum silicate, natural aluminum silicate, synthetic hydrotalcite, magnesium magnesium hydroxide, magnesium alumina hydroxide , Aluminum hydroxide gel, magnesium hydroxide, sodium bicarbonate, magnesium carbonate, precipitated calcium carbonate, magnesium metasilicate magnesium phosphate anhydrous, calcium hydrogen phosphate, calcium hydrogen phosphate, volley and aminoacetic acid The composition according to any one of claims 1 to 5, wherein the composition is one kind or two or more kinds.  [7] The antacid is one or more selected from the group consisting of magnesium oxide, precipitated calcium carbonate, sodium bicarbonate, and aminoacetate, and is selected from claims 1 to 5. A composition according to item 1.  [8] The composition according to any one of [1] to [5], wherein the antacid is acid magnesium.  [9] From claim 3 to claim 8, wherein the xanthine derivative is one or more selected from the group consisting of caffeine, theophylline, aminophylline, theopromine, dibrofilin, proxyphylline and pentoxyphyllin. The composition described in item 1 is selected.  [10] The 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 aminophyllinker. object. [II] xanthine derivatives include caffeine, anhydrous caffeine, sodium benzoate caffeine, Caffeine hydrochloride, caffeine caffeine, selected from claims 3 to 8 The composition described in item 1 above. [12] The composition according to any one of claims 3 to 8, wherein the xanthine derivative is one or two selected from caffeine and anhydrous caffeine. [13] The composition according to any one of claims 1 to 12, for use as an antipyretic.  [14] The composition according to any one of claims 1 to 12, for use as an analgesic.  [15] The composition according to any one of claims 1 to 12, which is used as a therapeutic agent for inflammation. [16] The composition according to any one of claims 1 to 12, for use as a cold remedy.  [17] The composition of any one of claims 1 to 16, selected from claims 1 to 16, for administration between meals.  [18] The composition according to any one of claims 1 to 16, for administration to a patient who needs to take for a long time. [19] The composition according to any one of claims 1 to 16, selected from claims 1 to 16, for administration to a patient with restricted dietary and water intake.