JP2018012693A - Oral pharmaceutical composition containing loxoprofen or a salt thereof and vitamin E - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an oral pharmaceutical composition used as an antipyretic agent, an analgesic agent, an inflammatory therapeutic agent or a cold remedy agent in which the risk of gastric mucosal damage caused by loxoprofen is reduced. ) An oral pharmaceutical composition containing Vitamin E. [Selection diagram] None

Description

  The present invention relates to an oral pharmaceutical composition used as an antipyretic agent, analgesic agent, inflammatory treatment agent, or cold treatment agent that enhances the medicinal effect of loxoprofen or a salt thereof and also reduces gastric mucosal damage. More specifically, the present invention relates to an oral pharmaceutical composition containing loxoprofen or a salt thereof and vitamin E.

  Loxoprofen, a non-steroidal antipyretic analgesic / anti-inflammatory agent (hereinafter sometimes referred to as NSAID), has antipyretic / analgesic / anti-inflammatory effects based on the inhibitory action of prostaglandin biosynthesis, similar to other NSAIDs. Have. Loxoprofen is a prodrug that is absorbed from the gastrointestinal tract and remains active in the body as an intact substance with a weak gastric mucosal irritation effect after oral administration, and is also known to have the characteristics of less gastric mucosal damage. (For example, refer nonpatent literature 1).

  As a technique for further suppressing gastric mucosal damage by oral administration of loxoprofen or a salt thereof and other active ingredients in combination, a technique containing an antacid (magnesium oxide) (see Patent Document 1), glucosamine or chondroitin (See Patent Document 2), an anticholine drug containing isopropamide (see Patent Document 3), an antihistamine drug clemastine fumarate (see Patent Document 4), antiplasmin The technique (refer patent document 5) etc. which contain the drug tranexamic acid are indicated.

  On the other hand, vitamin E is a kind of fat-soluble vitamin and is also called tocopherol. In addition to correcting endocrine dysfunction by activating the pituitary-adrenal system, pharmacological effects include plasma membranes of capillary wall endothelial cells and medial muscle cells, mitochondria, endoplasmic reticulum, lysosomes, etc. Stabilizes biological membranes and improves the permeability and resistance of blood vessel walls. In addition, it promotes peripheral blood circulation, suppresses platelet adhesion / aggregation ability, improves microcirculatory kinetics, and plays an important role in peripheral metabolic systems, such as suppressing the formation of lipid peroxide as an antioxidant action. (Non-Patent Document 2). Examples of the efficacy effect include prevention and treatment of vitamin E deficiency, peripheral circulatory disturbance, and prevention of increase in lipid peroxides from the above pharmacological actions (Non-patent Documents 2 and 3). However, the effect on pain is not known.

  As described above, the effect of the combination of loxoprofen or a salt thereof and other active ingredients has been studied, but the analgesic effect and gastric mucosa can be obtained by oral administration of loxoprofen or a salt thereof and vitamin E in combination. It has not been known what kind of influence occurs on the disorder suppressing action. 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-adenovirus agent containing loxoprofen or a salt thereof may further contain a vitamin agent, and vitamin E has been cited as an example of a vitamin agent (Patent Document 7). In addition, tocopherol has been described as an example of fats and oils that can be added together with crospovidone for the stabilization of a preparation when producing a soft capsule containing loxoprofen or a salt thereof as an active ingredient (Patent Document 8). However, an oral composition in which loxoprofen or a salt thereof and vitamin E are blended is not known, and the combined use effect is unknown.

JP 2006-052210 A JP 2008-195705 A JP 2010-150250 A JP 2011-173861 A JP 2010-038882 A JP 2011-037903 A JP 2008-285475 A JP 2014-058491 A

Pharmacology and Treatment Vol.16 No.2 1988 p.611-619 16th revision Japanese Pharmacopoeia Manual 2011, Yodogawa Shoten JAPIC Prescription Drug Collection 2013 Edition, Japan Medical Information Center

  Since loxoprofen is a prodrug, gastric mucosal damage is thought to be less than other NSAIDs, but there is still a risk of developing gastric mucosal damage. An object of the present invention is to provide an oral pharmaceutical composition used as an antipyretic agent, analgesic agent, inflammatory therapeutic agent, or cold remedy agent containing a new loxoprofen compound with reduced risk of gastric mucosal damage.

  As a result of this study, it was found that the combination of loxoprofen or a salt thereof and vitamin E reduced gastric mucosal damage, and at the same time, the medicinal effect was supplementarily increased, and the present invention was completed.

That is, the present invention is as follows.
(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 agent, analgesic agent, inflammatory treatment agent, or cold treatment agent.
(3) The oral pharmaceutical composition according to (1) or (2), which is a solid preparation.
(4) The content of (a) loxoprofen or a salt thereof per dosage unit is 10 to 180 mg in terms of anhydride, and (b) the content of vitamin E is 1 to 500 mg (1) to (3) The oral pharmaceutical composition of any one of these.

  The pharmaceutical composition for oral use containing loxoprofen or a salt thereof and vitamin E according to the present invention is useful because it enhances the efficacy of loxoprofen. Furthermore, loxoprofen is useful because it significantly reduces gastric mucosal damage.

FIG. 1 shows the results of examining the effects of gastric mucosal injury in loxoprofen sodium dihydrate alone or in combination of loxoprofen sodium dihydrate and vitamin E. FIG. 2 shows the results of examining the influence of the number of flinching in loxoprofen sodium dihydrate alone or in the combined use of loxoprofen sodium dihydrate and vitamin E.

  In the present invention, “loxoprofen or a salt thereof” is loxoprofen or a salt thereof (including a hydrate of a salt), preferably loxoprofen sodium, more preferably loxoprofen sodium dihydrate. is there. Loxoprofen or a salt thereof of the present invention is listed in the 16th revised Japanese Pharmacopoeia as loxoprofen sodium hydrate.

  In the present invention, “vitamin E” includes α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, and derivatives of these succinates, acetates, nicotinates, phosphates, etc. In addition to the dl-isomer which is an optical isomer, these salts such as calcium α-tocopherol succinate ester can be mentioned. Preferably, tocopherol, tocopherol succinate calcium, tocopherol acetate and tocopherol nicotinate listed in the 16th revision Japanese Pharmacopoeia, and d-α- listed in Japanese Pharmacopoeia Standards for Pharmaceuticals 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 can be easily obtained.

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

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

  In addition, if the composition of the present invention is a solution that is taken 50 mL once a day, the content of loxoprofen or a salt thereof in the solution 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.

  Examples of the composition of the present invention include tablets (including chewable tablets, effervescent tablets, orally disintegrating tablets), troches, drop agents, hard capsules, soft capsules, granules, fine granules, powders, Solid preparations such as pills and dry syrups; semi-solid preparations such as electuary, chewing gum, jelly, and jelly-like drops; liquid preparations such as syrups, drinks, suspensions, spirits, and liquids, The dosage form described in the 16th revision Japanese Pharmacopoeia General Rules for Preparations can be used. In the present invention, it is preferably a solid preparation in terms of ease of administration, production and the like, and is an oral administration composition selected from the group consisting of tablets, capsules, pills, granules, powders and fine granules. More preferably, it is a tablet, or a hard capsule. These compositions may further contain other active ingredients as necessary, such as antitussives / anti expectorants, antihistamines, anti-inflammatory agents, gastrointestinal agents, antacids, anticholinergic agents, other vitamins, and xanthine derivatives. The sedative may be appropriately blended within the range not impairing the present invention, and if there is a problem in storage stability due to the blending change, the sedative may be appropriately granulated and formulated.

  Antitussives and expectorants include, for example, codeine, codeine phosphate hydrate, dihydrocodeine, dihydrocodeine phosphate, dibutanate sodium, dimemorphan phosphate, tipepidine citrate, tipepidine hibenzate, dextromethorphan, dextst Lomethorphan hydrobromide hydrate, dextromethorphan phenolphthaline salt, noscapine hydrochloride, trimethquinol hydrochloride, phenylephrine hydrochloride, pseudoephedrine hydrochloride, pseudoephedrine sulfate, l-methylephedrine hydrochloride, dl-methyl Examples include ephedrine hydrochloride, ambroxol hydrochloride, bromohexine 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-chlore. Pheniramine maleate, dl-chlorpheniramine maleate, ketotifen fumarate, diphenylpyraline hydrochloride, diphenylpyraline theocrate, diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, triprolidine hydrochloride, Tripelenamine hydrochloride, tondylamine hydrochloride, fexofenadine, phenetadine hydrochloride, promethazine hydrochloride, promethazine, mequitazine, methodirazine hydrochloride, loratadine And the like.

  Examples of the anti-inflammatory agent include glycyrrhizic acid and derivatives thereof and salts thereof (for example, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate), 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 antacids include co-precipitation products of glycine (also called aminoacetic acid), magnesium silicate, magnesium aluminate silicate, magnesium aluminum silicate, magnesium oxide, magnesium hydroxide, magnesium hydroxide and potassium aluminum sulfate. , Magnesium carbonate, Synthetic hydrotalcite, Magnesium aluminate metasilicate, Dry aluminum hydroxide gel, Synthetic aluminum silicate, Magnesium alumina hydroxide, Aluminum hydroxide gel, Aluminum hydroxide / sodium bicarbonate coprecipitation product, Hydroxide Aluminum / magnesium carbonate mixed dry gel, aluminum hydroxide / magnesium carbonate / calcium carbonate coprecipitation product, bentonite, calcium silicate, calcium carbonate, precipitated calcium carbonate, calcium hydrogen phosphate , Magnesium such as anhydrous calcium hydrogen phosphate, aluminum and calcium salts, dry sodium carbonate, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate hydrate, sodium hydrogen phosphate hydrate, anhydrous sodium monohydrogen phosphate, hydroxylated Ingredients that increase the pH of gastric acid such as salts selected from sodium and potassium such as potassium, potassium hydrogen carbonate, potassium carbonate and the like can be mentioned.

  Anticholinergic agents include scopolamine hydrobromide, duck extract, methyl scopolamine bromide, methyl-1-hyostiamine bromide, pirenzepine hydrochloride, butyl scopolamine bromide, belladonna alkaloid, belladonna extract, belladonna total alkaloid, iodopropamide, 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 Equivalent mixture of potassium and magnesium, inositol hexanicotinate, ursodeoxycholic acid, L-cysteine, L-cysteine hydrochloride, orotine, gamma oryzanol, calcium glycerophosphate, calcium gluconate, gluconolactone, glucuronic acid amide, sodium chondroitin sulfate, Carrot and Yokuinin.

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

  Examples of sedatives include allyl isopropyl acetyl urea and bromovalerylurea.

  In formulating, it can be produced by appropriately using known methods and additives. Additives may be appropriately added within a range not impairing the effects of the present invention. Examples of additives include excipients, disintegrants, lubricants, and coating agents.

  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 metasilica. Examples thereof include magnesium 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-substituted hydroxypropylcellulose, 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, and hardened oil.

Examples of the coating agent include aminoalkyl methacrylate copolymer, gum arabic, ethyl cellulose, carnauba wax, carboxyvinyl polymer, magnesium stearate, shellac, hydroxypropylcellulose, hydroxypropylmethylcellulose, 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 may be used in combination.

  Hereinafter, the present invention will be described more specifically with reference to test examples and formulation examples, but the present invention is not limited to these examples. In the following formulation examples, tocopherol acetic acid is used as vitamin E, but tocopherol, tocopherol succinate calcium, tocopherol acetate or tocopherol nicotinate may be used.

(Formulation Example 1) Hard capsule (Table 1)
In 1 capsule (mg) a b c
―――――――――――――――――――――――――――――――――――
Loxoprofen sodium (as anhydride) 60 60 60
Vitamin E 3 20 100
Corn starch Appropriate amount Appropriate amount Appropriate amount Crystalline cellulose 10 20 50
Polyvinyl alcohol 5 5 5
Croscarmellose sodium 8 8 8
Hypromellose 18 22 25
Light anhydrous silicic acid 10 20 30
Povidone 5 6 3
Lactose appropriate amount appropriate amount appropriate amount magnesium stearate 5 5 5
―――――――――――――――――――――――――――――――――――
Taking the above ingredients and quantity, capsules are produced according to the section “General Capsule” of the Japanese Pharmacopoeia.

(Formulation Example 2) Tablet (Table 2)
In 1 tablet (mg) df
−――――――――――――――――――――――――――――――――――
Loxoprofen sodium (as anhydride) 60 60 60
Vitamin E 3 20 100
D-mannitol 253 264 273
Trehalose 30 43 48
Corn starch Appropriate amount 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 Trace ――――――――――――――――――――――――――――――――――――
Taking the above ingredients and amounts, tablets are produced according to the section “General Tablet Preparation Guidelines”. If desired, a coating is applied.

(Formulation example 3) Granules (Table 3)
1 package (mg) ghi
−――――――――――――――――――――――――――――――――――
Loxoprofen sodium (as anhydride) 60 60 60
Vitamin E 3 20 100
Erythritol 105 111 125
Corn starch Appropriate amount Appropriate amount Appropriate amount Hydroxypropylcellulose 10 20 30
Aspartame 9 12 15
Fragrance Trace Trace Trace Trace ――――――――――――――――――――――――――――――――――――
Taking the above ingredients and amount, granules are produced according to the section of the Japanese Pharmacopoeia General Rules “Granules”.

(Test Example 1) Inhibitory effect test against loxoprofen-induced gastric mucosal damage (1) Test substance Loxoprofen sodium dihydrate is manufactured by Daiichi Sankyo Chemical Pharma Co., Ltd., and vitamin E is d-α-tocopherol 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 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 after 2 days of habituation. The animals were individually housed in a rat housing controlled at a temperature of 20 to 26 ° C., a humidity of 40 to 70%, and a lighting time of 6 to 18 hours. A solid sample (CRF-1, Oriental Yeast Co., Ltd.) and tap water were freely ingested, preliminarily raised for 1 week, and then animals with good body weight changes and general symptoms were selected and tested.

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

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

  The fixed stomach was incised along a large bay, and the length of gastric mucosal injury was measured using a digital caliper. As for the length of gastric mucosal injury of 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 gastric mucosal injury length in the combined use of loxoprofen sodium dihydrate (L) and vitamin E. Here, the numerical value in parenthesis is the dose mg / Kg of each test drug, and each group is a result of N = 6.

(Table 4)
Study drug (mg / Kg) Total gastric mucosa 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 loxoprofen sodium dihydrate (L) and vitamin E combined significantly reduce gastric mucosal damage caused by loxoprofen.

(Test Example 2) Formalin test (1) Test substance Loxoprofen sodium dihydrate was manufactured by Daiichi Sankyo Chemical Pharma Co., Ltd. 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, Ltd., hereinafter referred to as CMC) in a 0.5% CMC solution dissolved in water for injection (manufactured by Otsuka Pharmaceutical Factory).

(2) Animals used
Crl: CD (SD) male rats 6 weeks old (Nippon Charles River Co., Ltd.) were used. The animals were housed in a rat breeding room controlled at a temperature of 20 to 26 ° C., a humidity of 35 to 75%, and a lighting time of 7 to 19 hours. Solid feed (CRF-1, Oriental Yeast Co., Ltd.) and well water were freely ingested and pre-bred for 1 week, and then animals with good weight transition and general symptoms were selected and tested.

(3) Test method The test substance was orally administered to rats using a disposable syringe equipped with a flexible gastric sonde.

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

  Immediately after formalin administration, pain is caused by direct stimulation of formalin to the peripheral nervous system, so pain assessment is performed every 5 minutes for the next 16 to 61 minutes, and the behavior of pain that appears in 1 minute (flinching) ) The number of times (times / minute) was measured and counted.

(4) Test Results Table 5 and FIG. 2 show the effect of the number of times the test animal flinched by subcutaneous administration of formalin in the combined use of loxoprofen sodium (L) and L with vitamin E. Here, the numerical value in parentheses is the dose mg / Kg of each test drug, and N = 8 for each group.

(Table 5)
Study drug (mg / Kg) Number of flinching ratio with L ――――――――――――――――――――――――――――――――――――― ―――
Control (medium: 0.5% CMC solution) 107 1.43
L (45) 75 1
L (45) + E (25) 55 0.73
――――――――――――――――――――――――――――――――――――――――

  From Table 5 and FIG. 2, the loxoprofen sodium (L) alone can confirm the decrease in the number of flinching, that is, the analgesic action. On the other hand, the combination of loxoprofen sodium (L) and vitamin E was found to significantly reduce the number of flinching.

  The oral pharmaceutical composition containing loxoprofen or a salt thereof and vitamin E according to the present invention is extremely useful because it significantly suppresses gastric mucosal damage caused by loxoprofen and also enhances analgesic action. The oral pharmaceutical composition of the present invention is used as an antipyretic agent, an analgesic agent, an inflammatory treatment agent or a cold treatment agent, and in particular, headache, menstrual pain (menstrual pain), toothache, post-extraction pain, throat pain, low back pain, joint pain. It is preferably used for analgesia such as muscle pain, stiff shoulder pain, ear pain, bruise pain, fracture pain, sprain pain, trauma pain, and antipyretic during chills and fever.

Claims (4)

  An oral pharmaceutical composition comprising (a) loxoprofen or a salt thereof and (b) vitamin E.   The oral pharmaceutical composition according to claim 1, which is used as an antipyretic agent, an analgesic agent, an inflammatory treatment agent or a cold treatment agent.   The oral pharmaceutical composition according to claim 1 or 2, which is a solid preparation.   The content of (a) loxoprofen or a salt thereof per dosage unit is 10 to 180 mg in terms of anhydride, and (b) the content of vitamin E is 1 to 500 mg. An oral pharmaceutical composition according to 1.