JP7026457B2 - Oral pharmaceutical composition containing loxoprofen or a salt thereof and vitamins B12 - Google Patents

Description

The present invention relates to an oral pharmaceutical composition containing loxoprofen or a salt thereof and vitamin B12s. More specifically, the present invention relates to an oral pharmaceutical composition that reduces gastric mucosal damage of loxoprofen by containing loxoprofen or a salt thereof and vitamin B12s.

Loxoprofen, a propionic acid-based non-steroidal antipyretic antipyretic anti-inflammatory drug (hereinafter sometimes referred to as NSAID), has antipyretic, analgesic, and anti-inflammatory effects based on the inhibitory effect on prostaglandin biosynthesis, like other NSAIDs. Have. Loxoprofen is a prodrug that is absorbed from the gastrointestinal tract in an unchanged form with a weak gastric mucosal stimulating effect after oral administration and becomes an active substance in the body. (See, for example, Non-Patent Document 1).

Vitamin B12 is one of the water-soluble vitamins and was isolated from the liver as an anemia anemia factor. It is a corrin ring compound containing cobalt in the center of the molecule. Vitamin B12 refers to cobalamin in a broad sense and cyanocobalamin in a narrow sense. In addition to cyanocobalamin, compounds having vitamin B12 activity include hydroxocobalamin in which a hydroxyl group is bound to cobalt, mecobalamin in which a methyl group is bound (also referred to as methylcobalamin), and adenosylcobalamin in which 5'-deoxyadenocin is bound. Vitamin B12 is involved in many metabolic systems in vivo and plays an important role in normal development, hematopoiesis, and myelin sheath formation in nervous tissue. Cyanocobalamin and hydroxocobalamin are applied to neuralgia when vitamin B12 deficiency or metabolic disorder is presumed to be involved (see Non-Patent Document 2). In addition, mecobalamin (also referred to as methylcobalamin) has an indication for peripheral neuropathy, and is expected to improve neuralgia by nerve repair action (see, for example, Non-Patent Document 3).

As a conventional technique for reducing gastromucosal damage of loxoprofen, a combination of loxoprofen with a crude drug such as kanzo, shokyo or keihi (Patent Document 1), and a combination of an antipyretic analgesic and anti-inflammatory agent and a proton pump inhibitor (Patent Document 2). , Concomitant use of loxoprofen and an acid suppressant (Patent Document 3), Concomitant use of loxoprofen with citrus sugar, martitol, fructose, xylitol, trehalose, lactitol or lactitol (Patent Document 4), Concomitant use of loxoprofen with tranexamic acid (Patent Document) 5), and a technique for adding hypromellose, carboxymethyl cellulose or methyl cellulose when loxoprofen and caffeine are used in combination (Patent Document 6) are known.

In addition, it is known that the combined use of vitamins B1, B2 or C with loxoprofen enhances the anti-inflammatory effect, thereby reducing the dose, and thus reducing side effects such as gastric mucosal damage (). See Patent Document 7).

On the other hand, Patent Document 8 presents an analgesic composition containing a propionic acid-based analgesic and two or more kinds of B vitamins, and vitamin B12 or folic acid is used alone in combination with ibuprofen, which is a propionic acid-based analgesic. Although it does not show an enhancing effect, it is described that the analgesic effect is enhanced by the combined use of vitamin B12 and folic acid. And the prescription example of the liquid preparation containing loxoprofen sodium, vitamin B12 and folic acid is described. Further, Patent Document 9 presents an analgesic composition containing vitamin B12 as an active ingredient, and vitamin B12 has an analgesic effect equivalent to that of a combination of ibuprofen and tranexamic acid, which have been known to have a strong analgesic effect. Although folic acid alone has no analgesic effect, it has been described that the analgesic effect is enhanced by combining it with vitamin B12, and as one of the prescription examples, a film containing vitamin B12, folic acid, dry aluminum hydroxide gel, and loxoprofen. The coating agent is described. However, it has not been known what kind of pharmacological action the combined use of vitamin B12 and loxoprofen has.

Japanese Unexamined Patent Publication No. 2004-161667 Special Table 2007-522217 Publication Japanese Patent Application Laid-Open No. 2006-052210 JP-A-2005-139165 JP-A-2010-083882 Japanese Unexamined Patent Publication No. 2014-031370 Japanese Unexamined Patent Publication No. 2011-168580 Japanese Unexamined Patent Publication No. 2008-247822 Japanese Unexamined Patent Publication No. 2008-247823

Pharmacology and Treatment Vol.16 No.2 1988 p.611-619 16th Amendment Japanese Pharmacy Manual 2011, Hirokawa Bookstore Prescription Drugs 2016 Edition, JAPAN

An object of the present invention is to provide an oral pharmaceutical composition in which gastric mucosal damage caused by loxoprofen is alleviated and can be used as an antipyretic agent, an analgesic agent, an anti-inflammatory agent or a sensation therapeutic agent in a wider range and for a long period of time.

As a result of researching a pharmaceutical composition containing loxoprofen, which can be more widely used as an antipyretic agent, an analgesic agent, an anti-inflammatory agent or a sensation therapeutic agent, the present inventors have found that vitamin B12 involved in the formation of myelin sheath in nervous tissue and the repair of peripheral nerves. The present invention was completed by discovering the fact that the gastric mucosal disorder of loxoprofen can be unexpectedly reduced when the same type is used in combination.

That is, the present invention is as shown below.
(1) An oral pharmaceutical composition containing (a) loxoprofen or a salt thereof and (b) vitamins B12 (excluding those containing folic acid).
(2) The oral pharmaceutical composition according to (1), wherein the vitamin B12s are at least one selected from cyanocobalamin, hydroxocobalamin and mecobalamin.
(3) The oral pharmaceutical composition according to (1) or (2), which further contains (c) one or more selected from vitamin B1 and vitamin B6.
(4) The oral pharmaceutical composition according to (1) or (2), which further contains (c) vitamins B1 and vitamin B6.
(5) (c) Vitamin B1 is one or more selected from thiamine, thiamine disulfide, fursulfiamine, benfotiamine, octothiamine and salts thereof, and vitamin B6 is pyridoxine hydrochloride or pyridoxal phosphorus. The oral pharmaceutical composition according to (3) or (4), which is an acid ester hydrate.
(6) The oral pharmaceutical composition according to any one of (1) to (5), which is used as an antipyretic agent, an analgesic agent, an anti-inflammatory agent or a cold remedy agent.
(7) The oral pharmaceutical composition according to any one of (1) to (6), which is a solid preparation.
(8) The oral pharmaceutical composition according to any one of (1) to (7), which further contains vitamin E.
(9) The item according to any one of (1) to (8), further containing one or more selected from allylisopropylacetylurea, glycine, magnesium aluminometasilicate, magnesium oxide, caffeine, and anhydrous caffeine. Oral pharmaceutical composition.
(10) Oral pharmaceutical composition containing the following components (a), (b) and (c) (a) Loxoprofen or a salt thereof (b) Vitamin B12s (where, vitamin B12s are cyanocobalamin, hydroxocobalamin). One or more selected from cobalamin and mecobalamin)
(C) Vitamin B1 and Vitamin B6 (Here, vitamin B1 is one or more selected from thiamine chloride hydrochloride, thiamine nitrate, flusultiamine hydrochloride and benfothamine, and vitamin B6. Is pyridoxin hydrochloride or pyridoxal phosphate ester hydrate).

The oral pharmaceutical composition containing loxoprofen or a salt thereof and vitamin B12 of the present invention is broader and longer-term as an antipyretic agent, an analgesic agent, an anti-inflammatory agent or a cold remedy agent because the gastric mucosal damage of loxoprofen is reduced. Can be used for. Furthermore, since it can bring about the neuralgia-improving effect of vitamins B12, it is particularly useful as an analgesic for pain derived from the nervous system.

It shows the effect of gastric mucosal damage on loxoprofen sodium dihydrate alone and in combination with vitamin B12. The changes in ulcer area in combination with loxoprofen sodium dihydrate alone and vitamins B1, B6 and B12 are compared with those in combination with the anti-ulcer agent lafutidine. The changes in the number of gastric mucosal ulcers in combination with loxoprofen sodium dihydrate alone and vitamins B1, B6 and B12 are compared with those in combination with the anti-ulcer agent lafutidine. The ratio of black stool in combination with loxoprofen sodium dihydrate alone and vitamins B1, B6 and B12 is compared with that in combination with the anti-ulcer agent lafutidine. The effects of loxoprofen sodium dihydrate alone and the combined use of vitamins B1, B6 and B12 on gastrointestinal inflammation in terms of white blood cell count are compared with the combined use of the anti-ulcer agent lafutidine.

In the present invention, the "loxoprofen" is loxoprofen or a salt thereof (including a hydrate of a salt), preferably loxoprofen sodium, and more preferably loxoprofen sodium dihydrate.

The loxoprofen of the present invention is listed in the 16th revised Japanese Pharmacopoeia as loxoprofen sodium hydrate.

In the present invention, "vitamin B12s" are compounds having vitamin B12 activity in vivo, and specific examples thereof include cyanocobalamin, hydroxocobalamin, mecobalamin, and adenosylcobalamin. The cyanocobalamin of the present invention is listed in the 16th revised Japanese Pharmacopoeia. Further, in the present invention, "hydroxocobalamin" is hydroxocobalamin or a salt thereof, preferably hydroxocobalamin acetate (listed in the 16th revised Japanese Pharmacy), hydroxocobalamin hydrochloride (pharmaceuticals outside the Japanese Pharmacy). (Listed in Standard 2002), Hydroxocobalamin acetate and Hydroxocobalamin hydrochloride (listed in the general-purpose pharmaceutical manufacturing and marketing approval standards). The mecobalamin of the present invention is listed in the 16th revised Japanese Pharmacopoeia.

Vitamin B12s other than the above are also commercially available and can be easily obtained.

In the present invention, the "vitamin B1s" are compounds having vitamin B1 activity, and specific examples thereof include thiamine, thiamine disulfide, fursultiamine, benfothamine, octothiamine and salts thereof. Preferred examples include thiamine chloride hydrochloride and thiamine nitrate (listed in the 16th revised Japanese Pharmacopoeia), fursultiamine hydrochloride, and benfotiamine. Since these have the application of neuralgia, myalgia / arthralgia, peripheral neuritis / peripheral nerve palsy when vitamin B1 deficiency or metabolic disorder is presumed to be involved, the antipyretic agent, analgesic agent, and inflammatory therapeutic agent of the present invention. Alternatively, it is preferable to add it to an anti-inflammatory agent. In the present invention, "vitamin B6s" are compounds having vitamin B6 activity, and specific examples thereof include pyridoxine, pyridoxal, pyridoxamine, and salts or esters thereof. Pyridoxine hydrochloride (listed in the 16th revised Japanese Pharmacopoeia) and pyridoxal phosphate ester hydrate (listed in the Japanese Pharmacopoeia non-Japanese Pharmacopoeia) are preferable. Pyridoxine hydrochloride and pyridoxal phosphate hydrate are presumed to be associated with vitamin B6 deficiency or metabolic disorders: angular cheilitis, cheilitis, glossitis, sudden / chronic eczema, seborrheic eczema, contact dermatitis , It is preferable to add it to the antipyretic agent, analgesic agent, inflammatory therapeutic agent or cheilitis therapeutic agent of the present invention because it has an application of peripheral neuritis.

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

The content of the vitamin B12s of the present invention in a single dose is not particularly limited, but is 0.1 to 2000 μg once, 1 to 3 times a day, preferably 0.3 to 500 μg, 1 to 3 times a day. Times.

The content of the vitamin B1s of the present invention in a single dose is not particularly limited, but is 1 to 100 mg once, 1 to 3 times a day, preferably 1 to 30 mg, 1 to 3 times a day. Times.

The content of the vitamin B6s of the present invention in a single dose is not particularly limited, but is 1 to 300 mg once, 1 to 3 times a day, preferably 1 to 100 mg, 1 to 3 times a day. Times.

Further, if the composition of the present invention is a liquid preparation to be taken 50 mL once a day, the content of loxoprofen in the liquid preparation is preferably 10 to 180 mg / 50 mL. The amount of vitamin B12 is 0.1 to 2000 μg / 50 mL. The amount of vitamin B1 is 1 to 100 mg / 50 mL, and that of vitamin B6 is 1 to 300 mg / 50 mL.

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

The compositions of the present invention include, for example, tablets (including chewable tablets, effervescent tablets, orally disintegrating tablets, etc.), drops, hard capsules, soft capsules, granules, fine granules, powders, pills, etc. Solid preparations such as dry syrups; Semi-solid preparations such as licking agents, chewing gum agents, jelly agents, jelly-like drops, whipped agents; The dosage form can be the one described in the 16th revised Japanese Pharmacy Regulations, etc.

In the present invention, a solid preparation is preferable from the viewpoint of ease of administration, manufacturing aspect, etc., and an oral administration composition selected from the group consisting of tablets, capsules, pills, granules, powders and fine granules. It is more preferably a product, and particularly preferably a tablet or capsule. These compositions may further include other active ingredients, such as antitussives / expectorants, antihistamines, anti-inflammatory agents, gastrointestinal agents, antacids, anticholinergic agents, other vitamins, xanthin derivatives, as needed. , An antacid may be appropriately blended within a range that does not impair the present invention, and by combining each of them, it may be used as an oral pharmaceutical composition as a cold medicine, an anti-fever analgesic, an antitussive expectorant, or an oral medicine for rhinitis. good. As the active ingredient used in combination, an antacid, other vitamins, a xanthine derivative or a sedative are particularly preferable. Further, in terms of stability and quality, if there is a problem in storage stability due to a change in the formulation, the product may be formulated by appropriately granulating it in the manufacturing process.

Examples of antitussive / sputum-removing agents include codeine, codeine phosphate hydrate, dihydrocodein, dihydrocodein phosphate, dibunato sodium, dimemorphan phosphate, chipepidin citrate, tipepidine hibenzate, dextromethorphan, and dextromethorphan. Lomethorphan hydrobromide hydrate, dextromethorphan phenolphthalin salt, noscapin hydrochloride, trimetokinol hydrochloride, phenilefurin hydrochloride, pseudoephedrine hydrochloride, pseudoephedrine sulfate, l-methyleffedrin hydrochloride, dl-methyl Examples thereof include efedrin hydrochloride, ambroxol hydrochloride, bromhexin hydrochloride and the like.

Examples of the antihistamine include azelastin hydrochloride, alimemazine tartrate, evastin, epinastine hydrochloride, emedastin fumarate, oxatomide, olopatazine hydrochloride, carbinoxamine, diphenyldisulfonate, carbinoxamine maleate, and d-chlor. Phenilamine maleate, dl-chlorpheniramine maleate, ketotiphenfumarate, diphenylpyraline hydrochloride, diphenylpyraline theocrate, diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydraminetannate, triprolidine hydrochloride, Examples thereof include tryperenamine hydrochloride, tonsilamine hydrochloride, fexophenazine, phenetazine hydrochloride, promethazine hydrochloride, promethazine, mequitazine, metodirazine hydrochloride, loratazine and the like.

Examples of the anti-inflammatory agent include glycyrrhizic acid and its derivatives, salts thereof (for example, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, etc.), tranexamic acid and the like.

Examples of the gastrointestinal drug component include gefarnate, cetraxate hydrochloride, sofalcone, teprenone, methylmethionine sulfonium chloride and the like.

Examples of the acid control agent include glycine (also called aminoacetic acid), magnesium silicate, magnesium silicate aluminumate, magnesium aluminum silicate, magnesium oxide, magnesium hydroxide, and co-precipitated products of magnesium hydroxide and potassium aluminum sulfate. , Magnesium carbonate, synthetic hydrotalcite, magnesium aluminometasilicate, dry aluminum hydroxide gel, synthetic aluminum silicate, magnesium hydroxide, aluminum hydroxide gel, aluminum hydroxide / sodium hydrogen carbonate co-precipitate product, hydroxylation Aluminum / magnesium carbonate mixed dry gel, aluminum hydroxide / magnesium carbonate / calcium carbonate co-precipitated product, bentonite, calcium silicate, calcium carbonate, precipitated calcium carbonate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate and other magnesium, aluminum And sodium such as calcium salt, dry sodium carbonate, sodium hydroxide, sodium hydrogencarbonate, sodium carbonate hydrate, sodium hydrogenphosphate hydrate, anhydrous sodium monohydrogen phosphate, potassium hydroxide, potassium hydrogencarbonate, potassium carbonate, etc. And components that raise the pH of gastric acid, such as salts selected from potassium.

Anticholinergic agents include scopolamine hydrobromide, dazzling extract, methylscopolamine bromide, methyl-l-hyoscyamine bromide, pyrenzepine hydrochloride, butylscopolamine bromide, belladonna alkaloid, belladonna extract, belladonna total alkaloid, isopropamide iodide, iodine. Examples thereof include diphenylpiperidinomethyldioxorane, scopolia extract, scopolia root, scopolia japonica total alkaloid citrate and the like.

Vitamins other than the above vitamins include vitamin A, vitamin C, vitamin B5, vitamin E, vitamin P, vitamin D, riboflavin, ascorbic acid, nicotinic acid, nicotinic acid amide, pantenol, calcium pantothenate, sodium pantothenate, and biotin. , Potassium aspartate / magnesium equal amount mixture, inositol hexanicotinate, ursodeoxycholic acid, L-cysteine, L-cysteine cysteine, orothin, gamma orizanol, calcium glycerophosphate, calcium gluconate, glucnolactone, glucuronic acid amide, chondroitin Examples include sodium sulfate, vitamins, carrots, and vitamins. Of these, vitamin C or vitamin E is preferable, and vitamin E includes α-tocopherol, β-tocopherol, γ-tocopherol, and δ-tocopherol as homologous substances, as well as these succinic acid esters, acetic acid esters, nicotinic acid esters, and phosphorus. Examples thereof include derivatives such as acid esters, dl-forms which are optical isomers, and salts of these such as α-tocopherol succinate calcium. Preferably, tocopherol, tocopherol succinate calcium, tocopherol acetate and tocopherol nicotinic acid ester listed in the 16th revised Japanese Pharmacy, and d-α- listed in the Japanese Pharmacy Non-Pharmaceutical Standard 2002. Tocopherol, d-α-tocopherol acetate, d-α-tocopherol succinate and the like can be used.

Examples of the xanthine derivative include caffeine hydrate, anhydrous caffeine, sodium benzoate caffeine, and caffeine citrate.

Examples of the sedative include allylisopropylacetylurea and bromvalerylurea.

In the formulation, it can be produced by appropriately using a known method and additives. Additives may be appropriately added as long as the effects of the present invention are not impaired. Examples of the additive include excipients, disintegrants, lubricants, coating agents and the like.

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

Examples of the disintegrant include carmellose, carmellose calcium, croscarmellose sodium, low-degree-of-substitution hydroxypropyl cellulose, crospovidone, alginic acid, partially pregelatinized starch, bentonite and the like.

Examples of the lubricant include magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, glycerin fatty acid ester, polyethylene glycol, hydrogenated oil and the like.

Examples of the coating agent include aminoalkyl methacrylate copolymer, arabic rubber, ethyl cellulose, carnauba wax, carboxyvinyl polymer, magnesium stearate, cellac, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, pullulan, povidone, polyvinyl alcohol, macrogol and the like. ..

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

Hereinafter, the present invention will be described in more detail with reference to test examples and pharmaceutical examples, but the present invention is not limited to these examples. Further, in the following preparation examples, mecothiamine is used as vitamin B12, benfothiamine is used as vitamin B1, and pyridoxine hydrochloride is used as vitamin B6. Vitamin B1s (thiamine chloride hydrochloride, thiamine nitrate, flusultiamine hydrochloride) and vitamin B6s (pyridoxal phosphate ester hydrate) can also be used.

(Formation Example 1) Hard capsule (Table 1)
In 1 capsule (mg) a b c d
――――――――――――――――――――――――――――――――――――――――
Loxoprofen sodium (as anhydrate) 60 60 60 60
Vitamin B12 0.003 0.01 2 0.06
Vitamin B1 8 20 50 25
Vitamin B6 6 15 50 50
Vitamin E 10 30 90-
Magnesium oxide 33.3 33.3-33.3
Corn starch Appropriate amount Appropriate amount Appropriate amount Crystalline cellulose 10 15 20 30
Polyvinyl alcohol 5 5 5 5
Croscarmellose Sodium 8 8 8 8
Hypromellose 18 22 25 20
Light anhydrous silicic acid 30 30 28 25
Povidon 5 6 3 5
Lactose Appropriate amount Appropriate amount Appropriate amount Magnesium stearate 5 5 5 5
――――――――――――――――――――――――――――――――――――――――

Take the above ingredients and amounts, and manufacture capsules according to the section of "Capsules" in the general rules of Japanese Pharmacopoeia.

(Formulation Example 2) Tablets (Table 2-1)
1 tablet (mg) efgh
――――――――――――――――――――――――――――――――――――――――
Loxoprofen sodium (as anhydrate) 60 60 60 60
Vitamin B12 0.003 0.01 2 0.002
Vitamin B1 8 20 50 8
Vitamin B6 6 15 50 16
Vitamin E 10 30 90 33.3
Anhydrous caffeine 50 50 50-
Magnesium oxide 33.3 33.3-33.3
D-mannitol 253 264 273 300
Trehalose 30 43 48 25
Corn starch Appropriate amount Appropriate amount Appropriate amount Hypromellose 20 30 40 30
Hydroxypropyl cellulose 13 16 18 15
Macrogol 400 60-30 30
Povidon-6 3 3
Magnesium stearate 5 5 5 5
Titanium oxide 3 4 5 5
Talc 2 3 3 3
Carnauba wax trace amount trace trace trace amount ――――――――――――――――――――――――――――――――――――――――

(Table 2-2)
1 tablet (mg) ijk
―――――――――――――――――――――――――――――――――――――――
Loxoprofen sodium (as anhydrate) 60 60 60
Vitamin B12 0.002 0.002 0.002
Vitamin B1 8 8 50
Vitamin B6 16 15 50
Vitamin C-150 150
Nicotinamide －-20
Anhydrous caffeine － -50
Magnesium oxide 33.3 33.3 33.3
D-mannitol 300 264 250
Trehalose 30 43 40
Lactose Appropriate amount Appropriate amount Corn starch Appropriate amount Appropriate amount Hypromellose 20 30 30
Hydroxypropyl cellulose 10 16 15
Macrogol 400 － － 20
Povidon-6 3
Magnesium stearate 5 5 5
Titanium oxide 4 4 5
Talc 3 3 3
Carnauba wax trace amount trace amount ――――――――――――――――――――――――――――――――――――――――

Take the above ingredients and quantity, and manufacture tablets according to the section of "Tablets" in the general rules of Japanese Pharmacopoeia. If desired, a skin is applied.

(Formulation Example 3) Granules (Table 3)
1 packet (mg) l mn
――――――――――――――――――――――――――――――――――――
Loxoprofen sodium (as anhydrate) 60 60 60
Vitamin B12 0.003 0.01 2
Vitamin B1 8 20 50
Vitamin B6 6 15 50
Vitamin E 10 30 90
Anhydrous caffeine 50 50-
Magnesium Oxide 33.3 33.3-
Allyl isopropyl acetyl urea 60 60 60
Glycine －-100
Erythritol 105 111 125
Corn starch Appropriate amount Appropriate amount Hydroxypropyl cellulose 15 17 17
Aspartame 9 12 15
Fragrance Trace amount Trace amount ――――――――――――――――――――――――――――――――――――

Take the above ingredients and amounts, and manufacture granules according to the section of "Granule" in the general rules of Japanese Pharmacopoeia. If desired, a skin is applied.

(Test Example 1) Suppressive effect test against loxoprofen-induced gastric mucosal damage (1) Test substance Loxoprofen sodium dihydrate was manufactured by Daiichi Sankyo Chemical Pharma Co., Ltd., and cyanocobalamin (nakalaitesk) was used as vitamin B12. Made by Co., Ltd.) was used. These test substances were prepared by suspending Tragant (manufactured by SIGMA) in a 0.5% Tragant solution dissolved in water for injection (manufactured by Otsuka Pharmaceutical Factory).

(2) Animals used Crl: CD male rats 6 weeks old (Japan SLC) were used after a quarantine period of 5 days and acclimation for 2 days. The animals were individually bred in a rat breeding room controlled at a temperature of 20 to 26 ° C, a humidity of 40 to 70%, and a lighting time of 6 to 18 o'clock. A solid sample (CRF-1, Oriental Yeast Co., Ltd.) and tap water were freely ingested, and after pre-breeding for one week, animals with good body weight transition and general symptoms were selected and tested.

(3) Test method The test substance was orally administered to rats fasted for 18 hours or more using a polypropylene disposable syringe (manufactured by Terumo) equipped with an oral sonde for disposable rats (manufactured by Fuchigami Instrument). The test substance was used while stirring with a magnetic stirrer.

Four hours after administration of the test substance, the animal was euthanized by cervical dislocation under light anesthesia with isoflurane, the stomach was immediately removed, 10 mL of physiological saline was filled inside, and the animal was immersed in 1% formalin and fixed until the next day. ..

A fixed stomach was incised along the bay and the length of gastric mucosal injury was measured using a digital caliper. For the length of gastric mucosal injury in an individual, the major axis was measured and the sum of them was calculated.

(4) Test Results Table 4 and FIG. 1 show the total length of gastric mucosal injury in combination with loxoprofen sodium dihydrate alone (L) and vitamin B12. Here, the numerical values in parentheses are the dose mg / Kg of each test drug, and are the results of N = 6 in each group.

(Table 4)
Test drug (mg / Kg) Ratio of total length of gastric mucosal injury (mm) to L ―――――――――――――――――――――――――――――― ―――――――――――
L (80) 30.05 1
L (80) + B12 (0.02) 11.85 0.39
――――――――――――――――――――――――――――――――――――――――

From Table 4 and FIG. 1, it was found that the combined use of loxoprofen sodium dihydrate (L) and vitamin B12 significantly reduced the gastric mucosal injury caused by loxoprofen.

(Test Example 2) Anti-ulcer effect test in the small intestine (1) Test substance Loxoprofen sodium / dihydrate is manufactured by Daiichi Sankyo Chemical Pharma Co., Ltd., and benfotiamine (Daiichi Sankyo) as vitamin B1. Chemical Pharma Co., Ltd.) was used, pyridoxine hydrochloride (manufactured by Nakaraitesk Co., Ltd.) was used as vitamin B6, and cyanocobalamin (manufactured by Nakaraitesk Co., Ltd.) was used as vitamin B12. In addition, a 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 sodium carboxymethyl cellulose (manufactured by Kanto Chemical Co., Ltd.) in a 0.5% sodium carboxymethyl cellulose solution dissolved in water for injection (manufactured by Otsuka Pharmaceutical Factory, Ltd.).

(2) Animals used Crl: CD male rats 5 weeks old (Japan Charles River Co., Ltd.) were used after a quarantine period of 7 days and acclimatization for 7 days. Animals were bred in a rat breeding room controlled at a temperature of 22 ± 3 ° C, a humidity of 50 ± 20%, and a lighting time of 8 to 20 o'clock. After free intake of solid samples (CRF-1, Oriental Yeast Co., Ltd.) and tap water and preliminary breeding for 2 weeks, animals with good body weight transition and general symptoms were selected and tested.

(3) Test method The test substance was orally administered to non-fasted rats using a disposable syringe (manufactured by Terumo) equipped with a disposable oral sonde (manufactured by Fuchigami Kikai). The administration was performed twice, 30 minutes before and 6 hours after the 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) equipped with a disposable oral sonde (manufactured by Fuchigami Instrument).
Twenty-four hours after administration of the ulcer-inducing substance, blood was collected from the abdominal vena cava under isoflurane anesthesia, and the white blood cell count (10 ² / μL) was measured. The contents of the removed small intestine were washed with physiological saline, passed through a 1% neutral buffered formalin solution, immersed in the same fixative, and lightly fixed for 30 minutes or longer. The lightly fixed small intestine was cut at intervals of about 20 cm, incised along the contralateral side of the intestinal membrane, attached to filter paper, and photographed with a scale. The ulcer area and the number of ulcers were calculated from the captured images using the image analysis software Image J (NIH).
In addition, the feces were observed the day after the administration of the ulcer-inducing substance, the total number of feces and the number of black stools were counted for the feces excreted overnight, and the ratio of black stools to the total number of feces was calculated for each individual. Calculated in.

(4) Test result 1 (ulcer area)
Table 5 and FIG. 2 show the total ulcer area in the combination of loxoprofen sodium alone (L or Lox, the same applies hereinafter) and vitamins B1, B6 and B12, and as a positive control, Lox and lafutidine (Laf). Each is shown. Here, the numerical values in parentheses are the dose mg / Kg of each test drug, and are the results of N = 7 in each group.

(Table 5)
Test drug (mg / Kg) Ulcer area (mm ² ) Ratio to L ―――――――――――――――――――――――――――――――――― ――――
L (60) 248 1
L (60) ＋ Laf (30) 206 0.83
L (60) ＋ B1 (400) ＋ B6 (800) ＋ B12 (0.96) 148 0.60
―――――――――――――――――――――――――――――――――――――

From Table 5 and FIG. 2, it was found that the combined use of loxoprofen sodium (L) and vitamins B1, B6 and B12 significantly reduced loxoprofen-induced ulcers. This result is surprising and superior to the anti-ulcer agent lafutidine.

(5) Test result 2 (number of ulcers)
Table 6 and FIG. 3 show the number of ulcers in the combination of loxoprofen sodium alone (L) and vitamins B1, B6 and B12, and as a positive control, Lox and lafutidine (Laf), respectively. Here, the numerical values in parentheses are the dose mg / Kg of each test drug, and are the results of N = 7 in each group.

(Table 6)
Test drug (mg / Kg) Ratio to the number of ulcers L ――――――――――――――――――――――――――――――――――――
L (60) 59 1
L (60) ＋ Laf (30) 44 0.75
L (60) ＋ B1 (400) ＋ B6 (800) ＋ B12 (0.96) 31 * 0.53
―――――――――――――――――――――――――――――――――――
*: There is a significant difference between the control group and the t-test (p <0.05).

From Table 6 and FIG. 3, it was found that the combined use of loxoprofen sodium (L) and vitamins B1, B6 and B12 significantly reduced the number of ulcers caused by loxoprofen. This result is surprising and superior to the anti-ulcer agent lafutidine.

(6) Test result 3 (black stool: gastrointestinal bleeding)
Tables 7 and 4 show the ratio of black stools to the total number of feces in the combination of loxoprofen sodium alone (L) with vitamins B1, B6 and B12, and as a positive control with Lox and lafutidine (Laf). = Number of black stools / total number of feces). Here, the numerical values in parentheses are the dose mg / Kg of each test drug, and are the results of N = 7 in each group.

(Table 7)
Test drug (mg / Kg) Ratio of black stool Ratio to L ――――――――――――――――――――――――――――――――――― ―――――
L (60) 21.7 1
L (60) ＋ Laf (30) 1.1 0.05
L (60) ＋ B1 (400) ＋ B6 (800) ＋ B12 (0.96) 0.0 0
――――――――――――――――――――――――――――――――――――――――

From Table 7 and FIG. 4, the combined use of loxoprofen sodium (Lox) and vitamins B1, B6 and B12 eliminated black stools caused by loxoprofen, and the results were astonishing, equal to or better than the anti-ulcer agent lafutidine. Is.

(7) Test result 4 (white blood cell count: inflammation)
Tables 8 and 5 show the white blood cell counts of loxoprofen sodium alone (L) in combination with vitamins B1, B6 and B12, and as a positive control in combination of Lox and lafutidine (Laf), respectively. Here, the numerical values in parentheses are the dose mg / Kg of each test drug, and are the results of N = 7 in each group.

(Table 8)
Test drug (mg / Kg) White blood cell count (10 ² / μL) Ratio to L ―――――――――――――――――――――――――――――――― ―――――――
L (60) 189.0 1
L (60) ＋ Laf (30) 171.4 0.91
L (60) ＋ B1 (400) ＋ B6 (800) ＋ B12 (0.96) 132.7 0.70
――――――――――――――――――――――――――――――――――――――

From Table 8 and FIG. 5, it was found that the combined use of loxoprofen sodium (L) and vitamins B1, B6 and B12 significantly reduced gastrointestinal inflammation in terms of white blood cell count due to loxoprofen. This result is surprising and superior to the anti-ulcer agent lafutidine.

(Test Example 3) Pain-relieving effect test (1) Test substance Loxoprofen sodium dihydrate is manufactured by Daiichi Sankyo Chemical Pharma Co., Ltd., and benfotiamine (Daisankyo Chemical Pharma (Daisankyo Chemical Pharma) as vitamin B1. Pyridoxine hydrochloride (manufactured by Nakaraitesk Co., Ltd.) was used as vitamin B6, and cyanocobalamin (manufactured by Nakaraitesk Co., Ltd.) was used as vitamin B12.
These test substances were prepared by suspending or dissolving sodium carboxymethyl cellulose (manufactured by Kanto Chemical Co., Ltd.) in a 0.5% sodium carboxymethyl cellulose solution dissolved in water for injection (manufactured by Otsuka Pharmaceutical Factory, Ltd.).

(2) Animals used Crl: SD male rats 5 weeks old (Japan Charles River Co., Ltd.) were used after a quarantine period of 7 days and acclimatization for 7 days. The animals were bred in a rat breeding room controlled to have a temperature of 20.0 to 26.0 ° C., a humidity of 35 to 75%, and a lighting time of 7 o'clock on and 19:00 off. Solid samples (CRF-1, Oriental Yeast Co., Ltd.) and tap water were freely ingested, and animals with good body weight transition and general symptoms were selected and tested.

(3) Test method A rat is subjected to cold stress for 5 days (120 hours) by repeating the warm period (23 ° C: 2 hours) and the cold period (-3 ° C: 2 hours) 5 times a day (20 hours in total). , A fibromyalgia model was created. The patient was forcibly administered intragastrically using a flexible oral sonde and a syringe, and the 50% pain threshold was calculated based on the pain response by mechanical stimulation using von Frey filament according to the method of Chaplan et al. The evaluation points were the sum of the pain thresholds of the left and right hind limbs 0.5 and 2 hours after administration.

(4) Results From Table 9, when the 50% pain threshold was compared with the control group, a significant increase was observed in the combination group of L and vitamins B1, B6 and B12 0.5 and 2 hours after administration, and the pain was alleviated. It was suggested that it had an effect.

(Table 9)
Elapsed time (hours) after administration
Group (mg / kg) Pre 0.5 2
――――――――――――――――――――――――――――――――――――――
Sham 22.3 20.3 21
Control 3.1 2.1 2.6
L (45) + B1 (6.3) + B6 (12.5) + B12 (0.015) 3.1 6.7 ** 7.6 **
――――――――――――――――――――――――――――――――――――――
The numbers in the table indicate the 50% pain threshold (g). Each group shows the mean value of N = 7.
**: Indicates the significance level of P <0.01 for the Control group.

The oral pharmaceutical composition containing loxoprofen or a salt thereof and vitamin B12 of the present invention is useful as an antipyretic agent, an analgesic agent, an inflammatory therapeutic agent or a cold therapeutic agent because it significantly reduces gastric mucosal injury. , An oral analgesic composition that contributes to the QOL of patients with chronic pain. The oral pharmaceutical composition of the present invention comprises headache, dysmenorrhea (physiological pain), toothache, post-extraction pain, sore throat, low back pain, joint pain, muscle pain, stiff shoulder pain, ear pain, bruising pain, fracture pain, and numbness pain. , Suitable for pain relief such as traumatic pain, and for relieving fever during bad cold and fever.

Claims (4)

An oral pharmaceutical composition containing (a) loxoprofen or a salt thereof and (b) only one type of vitamin B12 as vitamin B (excluding those containing folic acid). (B) The oral pharmaceutical composition according to claim 1 , wherein the vitamin B12 is one selected from cyanocobalamin, hydroxocobalamin and mecobalamin. The oral pharmaceutical composition according to claim 1 or 2 , which is used as an antipyretic agent, an analgesic agent, an anti-inflammatory agent or a cold remedy agent. The oral pharmaceutical composition according to any one of claims 1 to 3 , which is a solid preparation.

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