JP7241214B2 - Oral pharmaceutical composition containing loxoprofen or its salt and vitamin E - Google Patents

Description

The present invention relates to an oral pharmaceutical composition that enhances the efficacy of loxoprofen or a salt thereof and is used as an antipyretic agent, analgesic agent, therapeutic agent for inflammation, or therapeutic agent for the common cold, which reduces gastric mucosal damage. More particularly, it relates to an oral pharmaceutical composition containing loxoprofen or a salt thereof and vitamin E.

Loxoprofen, which is a propionate non-steroidal antipyretic, analgesic, anti-inflammatory drug (hereinafter sometimes referred to as NSAID), has antipyretic, analgesic, and anti-inflammatory effects based on the inhibition of prostaglandin biosynthesis, as with other NSAIDs. have. After oral administration, loxoprofen is absorbed from the gastrointestinal tract as an unchanged form with a weak gastric mucosal stimulating effect, and is a prodrug that becomes active in the body. (For example, see Non-Patent Document 1).

Techniques for further suppressing gastric mucosal disorders by orally administering loxoprofen or a salt thereof and other active ingredients in combination include techniques for incorporating an antacid (magnesium oxide) (see Patent Document 1), glucosamine or chondroitin. (see Patent Document 2), technology for containing the anticholinergic isopropamide iodide (see Patent Document 3), technology for containing the antihistamine clemastine fumarate (see Patent Document 4), antiplasmin A technique for incorporating the drug tranexamic acid (see Patent Document 5) is disclosed.

On the other hand, vitamin E is a kind of fat-soluble vitamin and is also called tocopherol. In terms of pharmacological action, in addition to correcting endocrine imbalance by activating the pituitary-adrenal system, its membrane-stabilizing action stimulates plasma membranes of capillary wall endothelial cells and medial muscle cells, mitochondria, endoplasmic reticulum, lysosomes, etc. It stabilizes biological membranes and improves the permeability and resistance of blood vessel walls. In addition, it promotes peripheral blood circulation, suppresses adhesion and aggregation of platelets, improves the dynamics of the microcirculatory system, and suppresses the production of lipid peroxide as an antioxidant, playing an important role in the peripheral metabolic system. (Non-Patent Document 2). From the above pharmacological actions, the efficacy effects include prevention and treatment of vitamin E deficiency, peripheral circulatory disorders, and prevention of increase in lipid peroxide (Non-Patent Documents 2 and 3). However, no pain-related effects are known.

As described above, the effect of loxoprofen or its salt in combination with other active ingredients has been studied, but oral administration of loxoprofen or its salt in combination with vitamin E has an analgesic effect and gastric mucosa. It was not known what effect it would have on injury suppression. So far, an external anti-inflammatory analgesic with enhanced skin permeability containing loxoprofen or a salt thereof and tocopherol acetate, natural vitamin E, tocopherol or d-σ-tocopherol as an antioxidant has been known (Patent Document 6). ). In addition, it is known that an anti-adenoviral agent containing loxoprofen or a salt thereof may further contain a vitamin agent, and vitamin E has been mentioned as an example of a vitamin agent (Patent Document 7). In addition, tocopherol is described as an example of fats and oils that can be added together with crospovidone for the purpose of stabilizing the formulation when producing soft capsules containing loxoprofen or a salt thereof as an active ingredient (Patent Document 8). However, an oral composition containing loxoprofen or a salt thereof and vitamin E is not known, and the effect of the combined use is unknown.

Japanese Patent Application Laid-Open No. 2006-052210 Japanese Unexamined Patent Application Publication No. 2008-195705 Japanese Patent Application Laid-Open No. 2010-150250 Japanese Patent Application Laid-Open No. 2011-173861 Japanese Patent Application Laid-Open No. 2010-083882 Japanese Unexamined Patent Application Publication No. 2011-037903 Japanese Patent Application Laid-Open No. 2008-285475 Japanese Patent Application Laid-Open No. 2014-058491

Pharmacology and Therapy Vol.16 No.2 1988 p.611-619 16th Edition Japanese Pharmacopoeia Commentary 2011, Hirokawa Shoten JAPIC Prescription Drugs 2013 Edition, Japan Medical Information Center

Since loxoprofen is a prodrug, it is thought that gastric mucosal damage is less likely than other NSAIDs, but there is still a risk of developing gastric mucosal damage. An object of the present invention is to provide a novel loxoprofen-containing oral pharmaceutical composition that is used as an antipyretic, analgesic, therapeutic agent for inflammation, or therapeutic agent for the common cold with reduced risk of gastric mucosal disorder.

As a result of this research, the inventors have found that the combined use of loxoprofen or a salt thereof and vitamin E alleviates gastric mucosal damage, and at the same time, supplementarily enhances the drug efficacy, leading to the completion of the present invention.

That is, the present invention is as shown below.
(1) An oral pharmaceutical composition containing (a) loxoprofen or a salt thereof and (b) vitamin E.
(2) The oral pharmaceutical composition according to (1), which is used as an antipyretic, analgesic, therapeutic agent for inflammation, or therapeutic agent for the common cold.
(3) The oral pharmaceutical composition according to (1) or (2), which is a solid formulation.
(4) The content of (a) loxoprofen or a salt thereof is 10 to 180 mg in terms of anhydrous and (b) the content of vitamin E is 1 to 500 mg per dosage unit (1) to (3) An oral pharmaceutical composition according to any one of

The oral pharmaceutical composition containing loxoprofen or a salt thereof and vitamin E of the present invention is useful because it supplementarily enhances the efficacy of loxoprofen. Furthermore, it is useful because it remarkably reduces damage to the gastric mucosa caused by loxoprofen.

FIG. 1 shows the results of investigating the effect of loxoprofen sodium dihydrate alone and the combined use of loxoprofen sodium dihydrate and vitamin E on gastric mucosa injury. FIG. 2 shows the results of investigating the effect of the number of flinchings in loxoprofen sodium dihydrate alone and in combination with loxoprofen sodium dihydrate and vitamin E.

In the present invention, "loxoprofen or a salt thereof" refers to loxoprofen or a salt thereof (including salt hydrates), preferably loxoprofen sodium, more preferably loxoprofen sodium dihydrate. be. Loxoprofen or a salt thereof of the present invention is listed in the Japanese Pharmacopoeia 16th Edition as loxoprofen sodium hydrate.

In the present invention, "vitamin E" includes congeners α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, and derivatives thereof such as succinate, acetate, nicotinate and phosphate. and dl-isomers, which are optical isomers, and salts thereof such as α-tocopherol calcium succinate. Preferably, tocopherol, tocopherol succinate calcium, tocopherol acetate and tocopherol nicotinate listed in the Japanese Pharmacopoeia 16th Edition, and d-α- listed in the Japanese Pharmaceutical Standards 2002 Tocopherol, d-α-tocopherol acetate, d-α-tocopherol succinate and the like can be used.

Since vitamin E other than the above is also commercially available, it is easily available.

The content of loxoprofen or a salt thereof in one dosage unit (single dosage) of the composition of the present invention is 10 to 180 mg in terms of anhydride, 1 to 3 times a day, preferably 20 to 3 times a day. 90 mg, 1-3 times a day.

In addition, the content of vitamin E in one administration unit (one dose) of the composition of the present invention is not particularly limited, but it is 1 to 500 mg once a day, 1 to 3 times a day, preferably once. 3 to 100 mg, 1 to 3 times a day.

In addition, if the composition of the present invention is a liquid formulation to be taken once a day at 50 mL, the content of loxoprofen or a salt thereof in the liquid formulation is preferably 10 to 180 mg/50 mL in terms of anhydride. 1 to 500 mg/50 mL.

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

The composition and the like of the present invention include, for example, tablets (including chewable tablets, effervescent tablets, orally disintegrating tablets, etc.), troches, drops, hard capsules, soft capsules, granules, fine granules, powders, Solid formulations such as pills and dry syrups; Semi-solid formulations such as lozenges, chewing gums, jellies and jelly drops; The dosage form described in the Japanese Pharmacopoeia 16th Edition, General Rules for Preparations, etc. can be used. In the present invention, solid formulations are preferred from the viewpoint of ease of administration and manufacturing, and an oral administration composition selected from the group consisting of tablets, capsules, pills, granules, powders and fine granules. More preferably, it is a product, and particularly preferably a tablet or hard capsule. These compositions may also optionally contain other active ingredients such as antitussives, expectorants, antihistamines, anti-inflammatory agents, gastrointestinal ingredients, antacids, anticholinergics, other vitamins, xanthine derivatives. A sedative may be appropriately blended within a range that does not impair the present invention, and if there is a problem in storage stability due to a change in blending, it may be formulated by appropriately dividing into granules or the like.

Antitussives and expectorants include, for example, codeine, codeine phosphate hydrate, dihydrocodeine, dihydrocodeine phosphate, dibunate sodium, dimemorphan phosphate, tipepidine citrate, tipepidine hibenzate, dextromethorphan, dextrose Lomethorphan hydrobromide hydrate, dextromethorphan phenolphthalin salt, noscapine hydrochloride, trimetoquinol hydrochloride, phenylephrine hydrochloride, pseudoephedrine hydrochloride, pseudoephedrine sulfate, l-methylephedrine hydrochloride, dl-methyl Examples include ephedrine hydrochloride, ambroxol hydrochloride, bromhexine hydrochloride and the like.

Antihistamines include, for example, azelastine hydrochloride, alimemazine tartrate, ebastine, epinastine hydrochloride, emedastine fumarate, oxatomide, olopatadine hydrochloride, carbinoxamine, diphenyldisulfonate, carbinoxamine maleate, d-chlor pheniramine maleate, dl-chlorpheniramine maleate, ketotifen fumarate, diphenylpyraline hydrochloride, diphenylpyraline teocrate, diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, triprolidine hydrochloride, tripelennamine hydrochloride, tonjilamine hydrochloride, fexofenadine, phenetazine hydrochloride, promethazine hydrochloride, promethazine, mequitazine, methdilazine hydrochloride, loratadine and the like.

Examples of anti-inflammatory agents include glycyrrhizic acid, derivatives thereof, and salts thereof (eg, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, etc.), tranexamic acid, and the like.

Gefarnate, cetraxate hydrochloride, sofalcon, teprenone, methylmethionine sulfonium chloride and the like can be mentioned as gastrointestinal ingredients.

Antacids include, for example, glycine (also called aminoacetic acid), magnesium silicate, magnesium aluminosilicate, magnesium aluminum silicate, magnesium oxide, magnesium hydroxide, coprecipitation products of magnesium hydroxide and potassium aluminum sulfate. , magnesium carbonate, synthetic hydrotalcite, magnesium aluminometasilicate, dry aluminum hydroxide gel, synthetic aluminum silicate, magnesium alumina hydroxide, aluminum hydroxide gel, aluminum hydroxide-sodium hydrogen carbonate coprecipitate, hydroxide Aluminum/magnesium carbonate mixed dry gel, aluminum hydroxide/magnesium carbonate/calcium carbonate coprecipitate product, bentonite, calcium silicate, calcium carbonate, precipitated calcium carbonate, calcium hydrogen phosphate, magnesium and aluminum such as calcium hydrogen phosphate anhydrous and calcium salts, dry sodium carbonate, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate hydrate, sodium hydrogen phosphate hydrate, anhydrous sodium monohydrogen phosphate, potassium hydroxide, potassium hydrogen carbonate, sodium such as potassium carbonate and a component that raises the pH of gastric acid such as a salt selected from potassium.

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, iodine diphenylpiperidinomethyldioxolane, funnel extract, funnel root, funnel root total alkaloid citrate and the like.

Other vitamins include vitamin A, vitamin C, vitamin B1, vitamin B2, vitamin B5, vitamin B6, vitamin P, nicotinic acid, nicotinamide, panthenol, calcium pantothenate, sodium pantothenate, biotin, aspartic acid. Potassium Magnesium Equivalent Mixture, Inositol Hexanicotinate, Ursodeoxycholic Acid, L-Cysteine, L-Cysteine Hydrochloride, Orotin, Gamma Oryzanol, Calcium Glycerophosphate, Calcium Gluconate, Glucunolactone, Glucuronic Acid, Sodium Chondroitin Sulfate, Carrots and coix seed are given.

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

Sedatives include allylisopropylacetylurea and bromvalerylurea.

In formulating, it can be manufactured by using a known method and additives as appropriate. Additives may be added as appropriate within a range that does not impair the effects of the present invention. Examples of additives include excipients, disintegrants, lubricants, coating agents and the like.

Excipients include, for example, 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, metasilicic acid. Magnesium aluminate, synthetic hydrotalcite, synthetic aluminum silicate, lactose, sucrose, D-mannitol, erythritol, glucose, fructose and the like can be mentioned.

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

Lubricants include, for example, magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, glycerin fatty acid ester, polyethylene glycol, hardened oil and the like.

Coating agents include aminoalkyl methacrylate copolymer, gum arabic, ethyl cellulose, carnauba wax, carboxyvinyl polymer, magnesium stearate, shellac, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, pullulan, povidone, polyvinyl alcohol, macrogol, and the like. . These additives are not limited to those mentioned above, and one of them may be used, or two or more thereof may be used in combination.

The present invention will be described in more detail below with reference to test examples and formulation examples, but the present invention is not limited to these examples. In the following formulation examples, tocopherol acetate is used as vitamin E, but tocopherol, calcium tocopherol succinate, tocopherol acetate, or tocopherol nicotinate may also be used.

(Formulation Example 1) Hard Capsule (Table 1)
Per Capsule (mg) a b c
―――――――――――――――――――――――――――――――――――
Loxoprofen Sodium (as Anhydrous) 60 60 60
Vitamin E 3 20 100
Maize starch Appropriate amount Appropriate amount Crystalline cellulose 10 20 50
Polyvinyl alcohol 5 5 5
Croscarmellose sodium 8 8 8
Hypromellose 18 22 25
Light silicic anhydride 10 20 30
Povidone 5 6 3
Lactose Appropriate Appropriate Magnesium stearate 5 5 5
―――――――――――――――――――――――――――――――――――
Take the above ingredients and amounts, and manufacture capsules according to the Japanese Pharmacopoeia General Rules "Capsules".

(Formulation Example 2) Tablet (Table 2)
Per tablet (mg) d e f
―――――――――――――――――――――――――――――――――――
Loxoprofen Sodium (as Anhydrous) 60 60 60
Vitamin E 3 20 100
D-mannitol 253 264 273
Trehalose 30 43 48
Maize starch appropriate amount appropriate amount Hypromellose 20 30 40
Hydroxypropyl cellulose 10 20 30
Macrogol 400 60-30
Povidone - 6 3
Magnesium stearate 5 5 5
Titanium oxide 3 4 5
Talc 2 3 3
Carnauba wax Trace Trace Trace ――――――――――――――――――――――――――――――――――――
Take the above ingredients and amounts, and manufacture tablets according to the General Rules for Preparations of the Japanese Pharmacopoeia, "Tablets." If desired, a coating is applied.

(Formulation Example 3) Granules (Table 3)
Per packet (mg) ghi
―――――――――――――――――――――――――――――――――――
Loxoprofen Sodium (as Anhydrous) 60 60 60
Vitamin E 3 20 100
Erythritol 105 111 125
Corn starch qs qs qs Hydroxypropyl cellulose 10 20 30
Aspartame 9 12 15
Perfume Trace Trace Trace――――――――――――――――――――――――――――――――――――
Prepare granules by taking the above ingredients and amounts according to the section "Granules" in the General Rules for Pharmaceutical Preparations of the Japanese Pharmacopoeia.

(Test Example 1) Suppressive effect test on loxoprofen-induced gastric mucosal damage (1) Test substance Loxoprofen sodium dihydrate manufactured by Daiichi Sankyo Chemical Pharma Co., Ltd., and d-α-tocopherol as vitamin E Succinate (manufactured by Riken Vitamin Co., Ltd.) was used. These test substances were prepared by suspending tragacanth (manufactured by SIGMA) in a 0.5% tragacanth solution in water for injection (manufactured by Otsuka Pharmaceutical Factory).

(2) Animals used Crl: CD male rats aged 6 weeks (Japan SLC) were used after a 5-day quarantine period and 2-day acclimatization. Animals were individually housed in a controlled rat housing room with a temperature of 20-26°C, humidity of 40-70%, and lighting hours of 6-18 hours. Solid samples (CRF-1, Oriental Yeast Co., Ltd.) and tap water were given ad libitum, and after preliminary breeding for 1 week, animals exhibiting favorable changes in body weight and general symptoms were selected and tested.

(3) Test method A test substance was orally administered to rats that had been fasted for 18 hours or longer using a disposable polypropylene syringe (manufactured by Terumo) equipped with an oral probe for disposable rats (manufactured by Fuchigami Kikai). The test substance was used while being stirred using 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 quickly removed, and after filling the inside with 10 mL of physiological saline, it was immersed in 1% formalin and fixed until the next day. .

The fixed stomach was incised along the greater gulf and the length of the gastric mucosal injury was measured using a digital vernier caliper. The length of the gastric mucosal injury of the individual was calculated by measuring the major axis and summing them.

(4) Test Results Table 4 and FIG. 1 show the total gastric mucosal injury length in the combined use of loxoprofen sodium dihydrate (L) and vitamin E. Here, the figures in parentheses are the dose mg/Kg of each test drug, and the results are N=6 for each group.

(Table 4)
Test drug (mg/Kg) Total gastric mucosal injury length (mm) Ratio―――――――――――――――――――――――――――――――― ――――――――
L(80) 30.05 1
L(80) + E(38.77) 19.70 0.66
――――――――――――――――――――――――――――――――――――――――
From Table 4 and FIG. 1, it was found that the combined use of loxoprofen sodium dihydrate (L) and vitamin E markedly reduced gastric mucosa damage caused by loxoprofen.

(Test Example 2) Formalin test (1) Test substance Loxoprofen sodium dihydrate manufactured by Daiichi Sankyo Chemical Pharma Co., Ltd. was used. As vitamin E, d-α-tocopherol succinate (manufactured by Riken Vitamin Co., Ltd.) was used. These test substances were prepared by suspending sodium carboxymethylcellulose (manufactured by Wako Pure Chemical Industries, hereinafter sometimes referred to as CMC) in a 0.5% CMC solution in water for injection (manufactured by Otsuka Pharmaceutical Factory).

(2) Animals used
Crl:CD(SD) 6-week-old male rats (Charles River Laboratories Japan, Inc.) were used. Animals were housed in a controlled rat housing room with a temperature of 20-26°C, humidity of 35-75%, and lighting hours of 7-19 hours. Solid feed (CRF-1, Oriental Yeast Co., Ltd.) and well water were given ad libitum, and after preliminary breeding for 1 week, animals with good weight transition and general symptoms were selected and tested.

(3) Test method A test substance was orally administered to rats using a disposable syringe attached with a flexible gastric tube.

After administration of the test substance, 0.1 mL of 2.5% formalin was subcutaneously administered to the left hind leg as a pain-inducing substance.

Immediately after formalin administration, pain is caused by formalin directly stimulating the peripheral nervous system. ) was measured by counting the number of times (times/minute).

(4) Test Results Table 5 and FIG. 2 show the effects of subcutaneous administration of formalin on the flinching frequency of test animals in loxoprofen sodium (L) and combination use of L and vitamin E. Here, the figures in parentheses are the dose mg/Kg of each test drug, and the results are N=8 for each group.

(Table 5)
Test drug (mg/Kg) Ratio to number of flinchings L―――――――――――――――――――――――――――――――――――――― ―――
Control (vehicle: 0.5% CMC solution) 107 1.43
L(45) 75 1
L(45) + E(25) 55 0.73
――――――――――――――――――――――――――――――――――――――――

From Table 5 and FIG. 2, it can be confirmed that loxoprofen sodium (L) alone reduces the number of flinchings, that is, has an analgesic effect. On the other hand, it was found that the combined use of loxoprofen sodium (L) and vitamin E markedly reduced the number of flinchings.

INDUSTRIAL APPLICABILITY The oral pharmaceutical composition containing loxoprofen or a salt thereof and vitamin E according to the present invention is extremely useful because it remarkably suppresses gastric mucosal damage caused by loxoprofen and additionally enhances analgesic action. The oral pharmaceutical composition of the present invention is used as an antipyretic agent, analgesic agent, therapeutic agent for inflammation, or therapeutic agent for the common cold. , muscle pain, stiff shoulder pain, ear pain, bruise pain, bone fracture pain, sprain pain, injury pain, etc.;

Claims (3)

(a) loxoprofen or a salt thereof and (b) α-tocopherol, and vitamin E selected from succinate esters, acetate esters, phosphate esters, and salts thereof in the same tablet, antipyretic, analgesic an oral pharmaceutical composition used as a drug, anti-inflammatory agent, or therapeutic agent for the common cold. Claim 1, containing only (a) loxoprofen or a salt thereof and (b) α-tocopherol, and vitamin E selected from succinate esters, acetate esters, phosphate esters thereof, and salts thereof as active ingredients. 3. Oral pharmaceutical composition according to . 3. The oral pharmaceutical according to claim 1 or 2, wherein the content of (a) loxoprofen or a salt thereof is 10 to 180 mg and (b) the content of vitamin E is 1 to 500 mg per dosage unit. Composition.

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