A pharmaceutical composition for oral administration comprising loxoprofen or a salt thereof and vitamin B12

Abstract

To provide an oral pharmaceutical composition that reduces the risk of gastric mucosal injury due to loxoprofen, and can be used as an antipyretic, an analgesic agent, an inflammation therapeutic agent or a common cold therapeutic agent over an extended period of time.SOLUTION: An oral pharmaceutical composition contains (a) loxoprofen or salt thereof and (b) vitamin B12 (excluding one containing folate).SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to an oral pharmaceutical composition containing loxoprofen or a salt thereof and a vitamin B12. More specifically, the present invention relates to an oral pharmaceutical composition containing loxoprofen or a salt thereof and a vitamin B12, thereby reducing gastric mucosal damage caused by loxoprofen. [Background technology]

[0002] Loxoprofen, a propionic acid-based nonsteroidal antipyretic, analgesic, and anti-inflammatory drug (hereinafter sometimes referred to as NSAID), has antipyretic, analgesic, and anti-inflammatory effects based on the inhibitory effect on prostaglandin biosynthesis, similar to other NSAIDs. Loxoprofen is a prodrug that is absorbed from the digestive tract as an unchanged form with weak irritation to the gastric mucosa after oral administration and becomes an active form in the body, and is therefore known to have the characteristic of causing little damage to the gastric mucosa (see, for example, Non-Patent Document 1).

[0003] Vitamin B12 is a water-soluble vitamin that was isolated from the liver as an antipernicious anemia factor. It is a corrin ring compound containing cobalt at the center of the molecule. Vitamin B12 refers to cobalamin in the broad sense, and cyanocobalamin in the narrow sense. Compounds with vitamin B12 activity include cyanocobalamin, hydroxocobalamin in which a hydroxyl group is bound to cobalt, mecobalamin (also called methylcobalamin) in which a methyl group is bound, and adenosylcobalamin in which 5'-deoxyadenosine is bound. In the body, vitamin B12 is involved in many metabolic systems and plays an important role in normal growth, hematopoiesis, and myelin sheath formation in nervous tissue. Cyanocobalamin and hydroxocobalamin are used for neuralgia when vitamin B12 deficiency or metabolic disorder is suspected to be involved (see Non-Patent Document 2). In addition, mecobalamin (also called methylcobalamin) is also indicated for peripheral neuropathy, and is expected to improve neuralgia through its nerve repair effect (see, for example, Non-Patent Document 3).

[0004] Known conventional techniques for reducing gastric mucosal damage caused by locofecoxib include the combination of locofecoxib with herbal medicines such as licorice, ginger or cinnamon (Patent Document 1), the combination of an antipyretic, analgesic or anti-inflammatory agent with a proton pump inhibitor (Patent Document 2), the combination of locofecoxib with an antacid (Patent Document 3), the combination of locofecoxib with sucrose, maltitol, fructose, xylitol, trehalose, lactose or lactitol (Patent Document 4), the combination of locofecoxib with tranexamic acid (Patent Document 5), and a technique of adding hypromellose, carboxymethylcellulose or methylcellulose when using locofecoxib in combination with caffeine (Patent Document 6).

[0005] It is also known that combining rofecoxib with vitamins B1, B2 or C enhances the anti-inflammatory effect, thereby allowing the dosage to be reduced, thereby making it possible to alleviate side effects including gastric mucosal damage (see Patent Document 7).

[0006] On the other hand, Patent Document 8 presents an analgesic composition containing a propionic acid analgesic and two or more kinds of vitamin B, and describes that the propionic acid analgesic ibuprofen does not show an enhancing effect when vitamin B12 or folic acid is used alone, but the analgesic effect is enhanced by combining vitamin B12 and folic acid. A prescription example of a liquid containing loxoprofen sodium, vitamin B12, and folic acid is described. Patent Document 9 presents an analgesic composition containing vitamin B12 as an active ingredient, and describes that vitamin B12 has an analgesic effect equivalent to that of the combination of ibuprofen and tranexamic acid, which have been known to have a strong analgesic effect, and that folic acid alone does not have an analgesic effect, but the analgesic effect is enhanced by combining it with vitamin B12. One prescription example is a film coating agent containing vitamin B12, folic acid, dried aluminum hydroxide gel, and loxoprofen. However, it was not known what pharmacological effects would be achieved by combining vitamin B12 with loxoprofen. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] JP2004-161667A [Patent Document 2] Special publication 2007-522217 [Patent Document 3] JP2006-052210A [Patent Document 4] JP 2005-139165 A [Patent Document 5] JP2010-083882A [Patent Document 6] JP2014-031370A [Patent Document 7] JP2011-168580A [Patent Document 8] JP 2008-247822 A [Patent Document 9] JP 2008-247823 A [Non-patent literature]

[0008] [Non-Patent Document 1] Pharmacology and Treatment Vol.16 No.2 1988 p.611-619 [Non-Patent Document 2] 16th Revised Japanese Pharmacopoeia Commentary 2011, Hirokawa Shoten [Non-Patent Document 3] Medical Drugs Collection 2016 Edition, JAPIC Summary of the Invention [Problem to be solved by the invention]

[0009] An object of the present invention is to provide an oral pharmaceutical composition which reduces gastric mucosal damage caused by loxoprofen and can be used more widely and for a long period of time as an antipyretic, analgesic, anti-inflammatory agent or cold remedy. [Means for solving the problem]

[0010] The inventors have conducted research into pharmaceutical compositions containing rofecoxib that can be used more widely as an antipyretic, analgesic, anti-inflammatory or cold treatment, and have unexpectedly discovered that the gastric mucosal damage caused by rofecoxib can be alleviated by combining it with vitamin B12, which is involved in the formation of myelin sheaths in nervous tissue and the repair of peripheral nerves, thereby completing the present invention.

[0011] That is, the present invention is as follows. (1) An oral pharmaceutical composition containing (a) loxoprofen or a salt thereof and (b) a vitamin B12 derivative (excluding those containing folic acid). (2)(b) The oral pharmaceutical composition according to (1), wherein the vitamin B12 compound is one or more selected from the group consisting of cyanocobalamin, hydroxocobalamin and mecobalamin. (3) The oral pharmaceutical composition according to (1) or (2), further comprising (c) one or more selected from vitamin B1 and vitamin B6. (4) The oral pharmaceutical composition according to (1) or (2), further comprising (c) both vitamin B1 and vitamin B6. (5) (c) The oral pharmaceutical composition according to (3) or (4), wherein the vitamin B1 is one or more selected from thiamine, thiamine disulfide, fursultiamine, benfotiamine, octotiamine, and salts thereof, and the vitamin B6 is pyridoxine hydrochloride or pyridoxal phosphate hydrate. (6) The pharmaceutical composition for oral administration according to any one of (1) to (5), which is used as an antipyretic, analgesic, anti-inflammatory agent or anti-cold agent. (7) The pharmaceutical composition for oral administration according to any one of (1) to (6), which is a solid formulation. (8) The pharmaceutical composition for oral administration according to any one of (1) to (7), further comprising vitamin E. (9) The pharmaceutical composition for oral administration according to any one of (1) to (8), further comprising one or more selected from the group consisting of allylisopropylacetylurea, glycine, magnesium aluminometasilicate, magnesium oxide, caffeine, and anhydrous caffeine. (10) A pharmaceutical composition for oral administration comprising the following components (a), (b) and (c): (a) Loxoprofen or a salt thereof (b) Vitamin B12 (wherein the vitamin B12 is one or more selected from cyanocobalamin, hydroxocobalamin, and mecobalamin) (c) Vitamin B1 and vitamin B6 (wherein the vitamin B1 is one or more selected from thiamine chloride hydrochloride, thiamine nitrate, fursultiamine hydrochloride, and benfotiamine, and the vitamin B6 is pyridoxine hydrochloride or pyridoxal phosphate hydrate). Effect of the Invention

[0012] The oral pharmaceutical composition of the present invention containing loxoprofen or its salt and vitamin B12 has reduced gastric mucosal damage caused by loxoprofen, and can be used widely and for a long period of time as an antipyretic, analgesic, anti-inflammatory or cold remedy. Furthermore, it can provide the neuralgia-improving effect of vitamin B12, and is therefore particularly useful as an analgesic for pain originating from the nervous system. [Brief description of the drawings]

[0013] [Figure 1] This shows the effects of loxoprofen sodium dihydrate alone and in combination with vitamin B12 on gastric mucosal damage. [Diagram 2] This study compared the change in ulcer area when loxoprofen sodium dihydrate was administered alone and in combination with vitamins B1, B6, and B12, and when it was administered in combination with the antiulcer drug lafutidine. [Diagram 3] This study compared the changes in the number of gastric mucosa ulcers when loxoprofen sodium dihydrate was administered alone and in combination with vitamins B1, B6 and B12, and when it was administered in combination with the anti-ulcer drug lafutidine. [Figure 4] The rate of black stools when using loxoprofen sodium dihydrate alone and in combination with vitamins B1, B6 and B12 was compared with that when used in combination with the antiulcer drug lafutidine. [Diagram 5] This study compared the effects of loxoprofen sodium dihydrate alone and in combination with vitamins B1, B6 and B12 on gastrointestinal inflammation as measured by white blood cell counts, and compared it with the effects of loxoprofen sodium dihydrate in combination with the antiulcer drug lafutidine. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] In the present invention, "loxacin" refers to loxacin or a salt thereof (including a hydrate of the salt), preferably loxacin sodium, and more preferably loxacin sodium dihydrate.

[0015] The loxoprofen of the present invention is listed in the 16th edition of the Japanese Pharmacopoeia as loxoprofen sodium hydrate.

[0016] In the present invention, "vitamin B12" refers to a compound having vitamin B12 activity in vivo, specifically including cyanocobalamin, hydroxocobalamin, mecobalamin, and adenosylcobalamin. The cyanocobalamin of the present invention is listed in the 16th edition of the Japanese Pharmacopoeia. In addition, in the present invention, "hydroxocobalamin" refers to hydroxocobalamin or a salt thereof, preferably hydroxocobalamin acetate (listed in the 16th edition of the Japanese Pharmacopoeia), hydroxocobalamin hydrochloride (listed in the Japanese Pharmacopoeia Non-Drug Standards 2002), hydroxocobalamin acetate, and hydroxocobalamin hydrochloride (listed in the OTC Drug Manufacturing and Sales Approval Standards). The mecobalamin of the present invention is listed in the 16th edition of the Japanese Pharmacopoeia.

[0017] Vitamin B12 supplements other than those listed above are also available commercially and are easily available.

[0018] In the present invention, "vitamin B1" refers to a compound having vitamin B1 activity, specifically thiamine, thiamine disulfide, fursultiamine, benfotiamine, octotiamine, and salts thereof. Preferred examples include thiamine chloride hydrochloride and thiamine nitrate (listed in the 16th revised Japanese Pharmacopoeia), fursultiamine hydrochloride, and benfotiamine. These are applicable to neuralgia, muscle pain, joint pain, peripheral neuritis, and peripheral nerve paralysis in cases where vitamin B1 deficiency or metabolic disorder is suspected to be involved, and therefore are preferably incorporated into the antipyretic, analgesic, inflammation treatment, or cold treatment of the present invention. In the present invention, "vitamin B6" refers to a compound having vitamin B6 activity, specifically pyridoxine, pyridoxal, pyridoxamine, and salts or esters thereof. Preferred examples include pyridoxine hydrochloride (listed in the 16th revised Japanese Pharmacopoeia), and pyridoxal phosphate hydrate (listed in the Japanese Pharmacopoeia Non-Drug Standards). Pyridoxine hydrochloride and pyridoxal phosphate hydrate are applicable to angular cheilitis, cheilitis, glossitis, acute and chronic eczema, seborrheic eczema, contact dermatitis, and peripheral neuritis in cases where vitamin B6 deficiency or metabolic disorder is suspected to be involved, and therefore are preferably incorporated into the antipyretic, analgesic, anti-inflammatory agent, or anti-cold agent of the present invention.

[0019] The content of loxoprofen in a single dose of the composition of the present invention is 10 to 180 mg, 1 to 3 times a day, and preferably 20 to 90 mg, 1 to 3 times a day.

[0020] The content of vitamin B12 in the present invention in a single dose is not particularly limited, but is 0.1 to 2000 μg per dose, 1 to 3 times per day, and preferably 0.3 to 500 μg per dose, 1 to 3 times per day.

[0021] The content of vitamin B1 in the present invention in a single dose is not particularly limited, but is 1 to 100 mg per dose, 1 to 3 times per day, and preferably 1 to 30 mg per dose, 1 to 3 times per day.

[0022] The content of the vitamin B6 in the present invention in a single dose is not particularly limited, but is 1 to 300 mg per dose, 1 to 3 times per day, and preferably 1 to 100 mg per dose, 1 to 3 times per day.

[0023] Furthermore, when the composition of the present invention is a liquid preparation to be taken once a day at 50 mL, the content of loxoprofen in the liquid preparation is preferably 10 to 180 mg / 50 mL, 0.1 to 2000 μg / 50 mL for vitamin B12, 1 to 100 mg / 50 mL for vitamin B1, and 1 to 300 mg / 50 mL for vitamin B6.

[0024] The composition of the present invention is produced according to a conventional method, but each drug may be produced separately depending on the administration method.

[0025] The compositions of the present invention may be in the dosage forms described in the General Provisions for Preparations of the 16th Edition of the Japanese Pharmacopoeia, etc., such as solid preparations such as tablets (including chewable tablets, effervescent tablets, orally disintegrating tablets, etc.), drops, hard capsules, soft capsules, granules, fine granules, powders, pills, and dry syrup; semi-solid preparations such as lozenges, chewing gums, jellies, jelly-like drops, and whipped preparations; and liquid preparations such as syrups, drinks, suspensions, spirits, and liquid preparations.

[0026] In the present invention, in terms of ease of administration and manufacturing, a solid preparation is preferred, an oral administration composition selected from the group consisting of tablets, capsules, pills, granules, powders and fine granules is more preferred, and a tablet or capsule is particularly preferred. These compositions may further contain other active ingredients, such as antitussives / expectorants, antihistamines, anti-inflammatory agents, gastrointestinal drug ingredients, antacids, anticholinergics, other vitamins, xanthine derivatives and sedatives, as necessary, within the scope of the present invention, and may be used as oral pharmaceutical compositions as cold medicines, antipyretics, expectorants and rhinitis medicines by combining each of them. As active ingredients to be used in combination, antacids, other vitamins, xanthine derivatives or sedatives are particularly preferred. In addition, in terms of stability and quality, if there is a problem with storage stability due to compounding changes, it is sufficient to prepare the formulation by appropriately dividing into granules during the manufacturing process.

[0027] Examples of antitussives / expectorants include codeine, codeine phosphate hydrate, dihydrocodeine, dihydrocodeine phosphate, dibunate sodium, dimemorfan phosphate, tipepidine citrate, tipepidine hibenzate, dextromethorphan, dextromethorphan hydrobromide hydrate, dextromethorphan phenolphthaline salt, noscapine hydrochloride, trimetoquinol hydrochloride, phenylephrine hydrochloride, pseudoephedrine hydrochloride, pseudoephedrine sulfate, l-methylephedrine hydrochloride, dl-methylephedrine hydrochloride, ambroxol hydrochloride, bromhexine hydrochloride, etc.

[0028] Examples of antihistamines include azelastine hydrochloride, alimemazine tartrate, ebastine, epinastine hydrochloride, emedastine fumarate, oxatomide, olopatadine hydrochloride, carbinoxamine, diphenyl disulfonate, carbinoxamine maleate, d-chlorpheniramine maleate, dl-chlorpheniramine maleate, ketotifen fumarate, diphenylpyraline hydrochloride, diphenylpyraline theoclate, diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, triprolidine hydrochloride, tripelennamine hydrochloride, thonzylamine hydrochloride, fexofenadine, fenethazine hydrochloride, promethazine hydrochloride, promethazine, mequitazine, methdilazine hydrochloride, loratadine, etc.

[0029] Anti-inflammatory agents include glycyrrhizinic acid and its derivatives and salts thereof (eg, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, etc.), tranexamic acid, and the like.

[0030] Examples of gastrointestinal drug ingredients include gefarnate, cetraxate hydrochloride, sofalcone, teprenone, methylmethionine sulfonium chloride, and the like.

[0031] Examples of antacids include ingredients that increase the pH of gastric acid, such as magnesium, aluminum and calcium salts, such as glycine (also called aminoacetic acid), magnesium silicate, magnesium aluminium silicate, magnesium aluminum silicate, magnesium oxide, magnesium hydroxide, co-precipitation product of magnesium hydroxide and aluminum potassium sulfate, magnesium carbonate, synthetic hydrotalcite, magnesium aluminium metasilicate, dried aluminum hydroxide gel, synthetic aluminum silicate, magnesium alumina hydroxide, aluminum hydroxide gel, co-precipitation product of aluminum hydroxide and sodium hydrogen carbonate, mixed dried gel of aluminum hydroxide and magnesium carbonate, co-precipitation product of aluminum hydroxide, magnesium carbonate and calcium carbonate, bentonite, calcium silicate, calcium carbonate, precipitated calcium carbonate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, and salts selected from sodium and potassium, such as dry sodium carbonate, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate hydrate, sodium hydrogen phosphate hydrate, anhydrous sodium monohydrogen phosphate, potassium hydroxide, potassium hydrogen carbonate, potassium carbonate, and the like.

[0032] Examples of anticholinergic agents include scopolamine hydrobromide, Datura extract, methylscopolamine bromide, methyl-l-hyoscyamine bromide, pirenzepine hydrochloride, butylscopolamine bromide, belladonna alkaloids, belladonna extract, belladonna total alkaloids, isopropamide iodide, diphenylpiperidinomethyldioxolane iodide, Scolytsum extract, Scolytsum root, and Scolytsum root total alkaloid citrate.

[0033] Other vitamins included in the supplement include vitamin A, vitamin C, vitamin B5, vitamin E, vitamin P, vitamin D, riboflavin, ascorbic acid, nicotinic acid, nicotinamide, panthenol, calcium pantothenate, sodium pantothenate, biotin, an equal mixture of potassium and magnesium aspartate, inositol hexanicotinate, ursodeoxycholic acid, L-cysteine, L-cysteine ​​hydrochloride, orotin, gamma oryzanol, calcium glycerophosphate, calcium gluconate, gluconolactone, glucuronic acid amide, sodium chondroitin sulfate, garlic, carrot, and coix seed. Among them, vitamin C or vitamin E is preferred, and examples of vitamin E include α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol as homologues, as well as their derivatives such as succinate, acetate, nicotinate, and phosphate, and optical isomers such as dl-isomers, as well as salts thereof such as α-tocopherol succinate calcium. Preferably, tocopherol, tocopherol succinate calcium, tocopherol acetate, and tocopherol nicotinate listed in the 16th revised Japanese Pharmacopoeia, and d-α-tocopherol, d-α-tocopherol acetate, and d-α-tocopherol succinate listed in the Japanese Pharmacopoeia Non-Drug Standards 2002 can be used.

[0034] Xanthine derivatives include caffeine hydrate, anhydrous caffeine, sodium caffeine benzoate, and caffeine citrate.

[0035] Sedatives include allylisopropylacetylurea and bromvalerylurea.

[0036] The formulation can be produced by using known methods and additives as appropriate. The additives may be added as appropriate within the range that does not impair the effects of the present invention. Examples of additives include excipients, disintegrants, lubricants, coating agents, etc.

[0037] Examples of excipients include crystalline cellulose, powdered cellulose, potato starch, light anhydrous silicic acid, hydrated silicon dioxide, silicon dioxide, precipitated calcium carbonate, anhydrous calcium hydrogen phosphate, magnesium oxide, calcium lactate, calcium silicate, magnesium aluminometasilicate, synthetic hydrotalcite, synthetic aluminum silicate, lactose, sucrose, D-mannitol, erythritol, glucose, fructose, and the like.

[0038] Examples of disintegrants include carmellose, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropylcellulose, crospovidone, alginic acid, partially pregelatinized starch, bentonite, and the like.

[0039] Examples of the lubricant include magnesium stearate, calcium stearate, talc, sucrose fatty acid esters, glycerin fatty acid esters, polyethylene glycol, and hardened oils.

[0040] Examples of coating agents include aminoalkyl methacrylate copolymers, gum arabic, ethyl cellulose, carnauba wax, carboxyvinyl polymers, magnesium stearate, shellac, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, pullulan, povidone, polyvinyl alcohol, and macrogol.

[0041] These additives are not limited to those listed above, and one of these may be used alone or two or more of them may be used in combination.

[0042] The present invention will be described in more detail below with reference to test examples and formulation examples, but is not limited to these examples. In the following formulation examples, mecobalamin is used as vitamin B12, benfotiamine is used as vitamin B1, and pyridoxine hydrochloride is used as vitamin B6, but as mentioned above, other vitamin B12s (cyanocobalamin, hydroxocobalamin), vitamin B1s (thiamine chloride hydrochloride, thiamine nitrate, fursultiamine hydrochloride), and vitamin B6s (pyridoxal phosphate hydrate) can also be used. EXAMPLES

[0043] (Formulation Example 1) Hard capsule [Table 1]

[0044] The above ingredients and amounts are taken and capsules are produced in accordance with the "Capsules" section of the Japanese Pharmacopoeia General Provisions for Preparations.

[0045] (Formulation Example 2) Tablets [Table 2-1]

[0046] [Table 2-2]

[0047] The above ingredients and amounts are taken and tablets are prepared in accordance with the "Tablets" section of the Japanese Pharmacopoeia General Provisions for Preparations. If desired, a coating may be applied.

[0048] (Formulation Example 3) Granules [Table 3]

[0049] The above ingredients and amounts are taken and granules are prepared in accordance with the "Granules" section of the Japanese Pharmacopoeia General Provisions for Preparations. If desired, a coating may be applied.

[0050] (Test Example 1) Test of inhibitory effect against loxoprofen-induced gastric mucosal damage (1) Test substance The loxoprofen sodium dihydrate used was manufactured by Daiichi Sankyo Chemical Pharma Co., Ltd., and cyanocobalamin (manufactured by Nacalai Tesque, Inc.) was used as vitamin B12. These test substances were prepared by suspending tragacanth (manufactured by SIGMA) in 0.5% tragacanth solution in water for injection (manufactured by Otsuka Pharmaceutical Factory, Inc.).

[0051] (2) Animals used Six-week-old Crl:CD male rats (Japan SLC) were used after a 5-day quarantine period and 2-day acclimation. The animals were individually housed in a rat breeding room with a controlled temperature of 20-26°C, humidity of 40-70%, and lighting time of 6-6 p.m. The animals were allowed free access to solid food (CRF-1, Oriental Yeast Co., Ltd.) and tap water. After preliminary breeding for one week, animals with good weight transition and general symptoms were selected for use in the study.

[0052] (3) Test method The test substance was orally administered to rats that had been fasted for 18 hours or more using a disposable polypropylene syringe (Terumo) equipped with a disposable oral probe for rats (Fuchigami Kikai).The test substance was used while stirring using a magnetic stirrer.

[0053] Four hours after administration of the test substance, the animals were euthanized by cervical dislocation under light anesthesia with isoflurane, and the stomach was promptly removed and filled with 10 mL of physiological saline, and then immersed in 1% formalin and fixed until the next day.

[0054] The fixed stomach was incised along the greater vein, and the length of the gastric mucosal lesion was measured using a digital caliper. The length of the gastric mucosal lesion in each individual was calculated by measuring the major axis and adding them together.

[0055] (4) Test results Table 4 and Figure 1 show the total length of gastric mucosal lesions caused by loxoprofen sodium dihydrate alone (L) and in combination with vitamin B12. The figures in parentheses indicate the dosage of each test drug in mg / kg, and N=6 for each group.

[0056] [Table 4]

[0057] Table 4 and Figure 1 show that the combined use of loxoprofen sodium dihydrate (L) and vitamin B12 significantly reduced gastric mucosal damage caused by loxoprofen.

[0058] (Test Example 2) Antiulcer effect test in the small intestine (1) Test substance The loxoprofen sodium dihydrate was manufactured by Daiichi Sankyo Chemical Pharma Co., Ltd., benfotiamine (manufactured by Daiichi Sankyo Chemical Pharma Co., Ltd.) was used as vitamin B1, pyridoxine hydrochloride (manufactured by Nacalai Tesque Co., Ltd.) was used as vitamin B6, and cyanocobalamin (manufactured by Nacalai Tesque Co., Ltd.) was used as vitamin B12. The histamine H2 receptor antagonist lafutidine (manufactured by Central Glass Co., Ltd.) was used as a positive control. These test substances were prepared by suspending or dissolving in a 0.5% sodium carboxymethylcellulose solution prepared by dissolving sodium carboxymethylcellulose (manufactured by Kanto Chemical Co., Ltd.) in water for injection (manufactured by Otsuka Pharmaceutical Factory, Ltd.).

[0059] (2) Animals used Five-week-old Crl:CD male rats (Charles River Japan, Inc.) were used after a seven-day quarantine period and seven-day acclimation. The animals were kept in a rat breeding room with a controlled temperature of 22±3°C, humidity of 50±20%, and lighting time of 8-8 p.m. The animals were allowed free access to solid food (CRF-1, Oriental Yeast Co., Ltd.) and tap water. After two weeks of preliminary breeding, animals with good weight transition and general symptoms were selected for use in the study.

[0060] (3) Test method The test substance was orally administered to non-fasting rats using a disposable syringe (Terumo) attached with a disposable oral probe (Fuchigami Kikai). The administration was carried out twice, 30 minutes before and 6 hours after administration of the ulcer-inducing substance. The test substance was used while stirring with a magnetic stirrer. The ulcer-inducing substance was orally administered using a disposable syringe (manufactured by Terumo) attached with a disposable oral probe (manufactured by Fuchigami Kikai). Twenty-four hours after administration of the ulcerogen, blood was collected from the abdominal vena cava under isoflurane anesthesia, and white blood cell counts (10 2 The concentration of ulcers in the small intestine was measured (1 μL / μL). The contents of the excised small intestine were washed with physiological saline, passed through 1% neutral buffered formalin, and then immersed in the same fixative for 30 minutes or more. The lightly fixed small intestine was cut at intervals of approximately 20 cm, incised along the opposite side to the intestinal membrane, attached to filter paper, and photographed with a scale. The photographed images were used to calculate the ulcer area and number of ulcers using the image analysis software Image J (NIH). In addition, feces were observed on the day after administration of the ulcerogen, and the total number of feces and the number of black feces excreted overnight were counted, and the ratio of black feces to the total number of feces was calculated for each individual.

[0061] (4) Test result 1 (ulcer area) Table 5 and Figure 2 show the sum of ulcer areas in the cases of loxoprofen sodium alone (L or Lox, hereinafter the same), in combination with vitamins B1, B6 and B12, and in combination with Lox and lafutidine (Laf) as a positive control. The figures in parentheses indicate the dosage of each test drug in mg / kg, and the results are for N=7 in each group.

[0062] [Table 5]

[0063] From Table 5 and Figure 2, it was found that the combined use of loxoprofen sodium (L) with vitamins B1, B6 and B12 significantly reduced ulcers caused by loxoprofen. This result is surprising as it is superior to the antiulcer drug lafutidine.

[0064] (5) Test result 2 (number of ulcers) Table 6 and Figure 3 show the number of ulcers in the cases of loxoprofen sodium alone (L), in combination with vitamins B1, B6 and B12, and in the case of the positive control, in combination with Lox and lafutidine (Laf). The numbers in parentheses indicate the dosage of each test drug in mg / kg, and N=7 for each group.

[0065] [Table 6]

[0066] From Table 6 and Figure 3, it was found that the combined use of loxoprofen sodium (L) with vitamins B1, B6 and B12 significantly reduced the number of ulcers caused by loxoprofen. This result is surprising as it is superior to the antiulcer drug lafutidine.

[0067] (6) Test result 3 (black stool: gastrointestinal bleeding) Table 7 and Figure 4 show the ratio of black feces to the total feces count (=black feces count / total feces count) in the cases of loxoprofen sodium alone (L), combined with vitamins B1, B6 and B12, and combined with Lox and lafutidine (Laf) as a positive control. The figures in parentheses are the dose of each test drug in mg / kg, and N=7 results for each group.

[0068] [Table 7]

[0069] As shown in Table 7 and Figure 4, the combined use of loxoprofen sodium (Lox) with vitamins B1, B6 and B12 eliminated the black stools caused by loxoprofen. This result is surprising as it is equal to or better than the antiulcer drug lafutidine.

[0070] (7) Test result 4 (white blood cell count: inflammation) Table 8 and Figure 5 show the white blood cell counts in the cases of loxoprofen sodium alone (L), in combination with vitamins B1, B6 and B12, and in the case of the positive control, in combination with Lox and lafutidine (Laf). The numbers in parentheses indicate the dosage of each test drug in mg / kg, and N=7 results for each group.

[0071] [Table 8]

[0072] From Table 8 and Figure 5, it was found that the combined use of loxoprofen sodium (L) with vitamins B1, B6 and B12 significantly reduced the digestive tract inflammation caused by loxoprofen as measured by white blood cell count. This result is surprising as it is superior to the antiulcer drug lafutidine.

[0073] (Test Example 3) Pain relief effect test (1) Test substance The sodium rofecoxib dihydrate used was manufactured by Daiichi Sankyo Chemical Pharma Co., Ltd., benfotiamine (manufactured by Daiichi Sankyo Chemical Pharma Co., Ltd.) was used as vitamin B1, pyridoxine hydrochloride (manufactured by Nacalai Tesque Co., Ltd.) was used as vitamin B6, and cyanocobalamin (manufactured by Nacalai Tesque Co., Ltd.) was used as vitamin B12. These test substances were prepared by suspending or dissolving in a 0.5% sodium carboxymethylcellulose solution prepared by dissolving sodium carboxymethylcellulose (manufactured by Kanto Chemical Co., Ltd.) in water for injection (manufactured by Otsuka Pharmaceutical Factory, Ltd.).

[0074] (2) Animals used Crl: 5-week-old male SD rats (Charles River Japan, Inc.) were used after a 7-day quarantine period and 7-day acclimation. The animals were kept in a rat breeding room with a controlled temperature of 20.0-26.0°C, humidity of 35-75%, and lighting time of 7:00 a.m. on, 7:00 p.m. off. They were allowed free access to solid food (CRF-1, Oriental Yeast Co., Ltd.) and tap water, and animals with good weight transitions and general symptoms were selected for use in the study.

[0075] (3) Test method A fibromyalgia model was created by subjecting rats to cold stress, which consisted of a warm period (23°C: 2 hours) and a cold period (-3°C: 2 hours) repeated five times a day (total 20 hours) for five days (120 hours). The rats were forced into the stomach using a flexible oral tube and a syringe, and the 50% pain threshold was calculated based on the pain response to mechanical stimulation using von Frey filaments according to the method of Chaplan et al. The evaluation point was the sum of the pain thresholds of the left and right hind paws 0.5 and 2 hours after administration.

[0076] (4) Results As shown in Table 9, when comparing the 50% pain threshold with the control group, the group administered L in combination with vitamins B1, B6, and B12 showed a significant increase at 0.5 and 2 hours after administration, suggesting that it has a pain-reducing effect.

[0077] [Table 9] [Industrial Applicability]

[0078] The oral pharmaceutical composition of the present invention containing loxoprofen or a salt thereof and vitamin B12 is useful as an antipyretic, analgesic, anti-inflammatory or cold remedy since it significantly reduces gastric mucosal damage, and is particularly useful as an oral analgesic composition that contributes to the QOL of patients with chronic pain. The oral pharmaceutical composition of the present invention is preferably used for pain relief from headaches, menstrual pain (period pain), toothache, pain after tooth extraction, sore throat, lower back pain, joint pain, muscle pain, stiff shoulders, earache, bruises, fracture pain, sprains, trauma pain, etc., and for reducing fever during chills and fever.

Claims

1. The tablet contains (a) loxoprofen or a salt thereof, (b) vitamin B12, (c) one or more selected from benfotiamine and its salt, and (d) vitamin B6. An oral pharmaceutical composition for reducing gastric mucosal damage (excluding those containing folic acid).

2. 2. The pharmaceutical composition for oral administration according to claim 1, wherein (b) the vitamin B12 compound is one or more selected from the group consisting of cyanocobalamin, hydroxocobalamin and mecobalamin.

3. 3. The pharmaceutical composition for oral administration according to claim 1, further comprising at least one selected from the group consisting of thiamine, thiamine disulfide, fursultiamine, octotiamine and salts thereof as a vitamin B1 group.

4. 4. The oral pharmaceutical composition according to claim 1, wherein (d) the vitamin B6 is pyridoxine hydrochloride or pyridoxal phosphate hydrate.

5. 5. The pharmaceutical composition for oral administration according to claim 1, which is used as an antipyretic, analgesic, anti-inflammatory agent or a cold remedy.

6. The oral pharmaceutical composition according to any one of claims 1 to 5, which is a solid formulation.

7. 7. The pharmaceutical composition for oral administration according to claim 1, which has an ulcer area of ​​60% or less compared to the ulcer area when only rofecoxib or a salt thereof is administered.

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