JP2010024239A - Enterokinesis inhibitor - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an inhibitor to enterokinesis aggravative action caused by nonsteroidal anti-inflammatory drugs, and to provide an antiinflammatory composition decreased in enterokinesis aggravating action. <P>SOLUTION: The inhibitor to enterokinesis aggravating action caused by a nonsteroidal antiinflammatory drug selected from diclofenac sodium and loxoprofen sodium includes tiquizium bromide or scopolamine butylbromide as an active ingredient. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a medicament having an inhibitory action on the increase in gastrointestinal motility caused by a nonsteroidal anti-inflammatory agent, and an anti-inflammatory pharmaceutical composition in which the action to enhance the gastrointestinal motility is reduced.

Non-steroidal anti-inflammatory drugs such as aspirin and indomethacin are therapeutic agents for pain such as headache, muscle pain, joint pain, postoperative pain, rheumatoid arthritis, infection, sore throat, otitis media, sinusitis, etc. However, it is known that administration of these non-steroidal anti-inflammatory agents causes gastric mucosal damage and ulcers. There is a detailed study by Davenport et al. Regarding aspirin-induced gastric mucosal damage (Davenport, HD, Gastroenterology, 46, 245, 1964), and in an acidic environment such as in the stomach, aspirin enters a lipid-soluble non-dissociated state and crosses the cell membrane Therefore, the gastric mucosa barrier (mucosal barrier) is broken, and as a result, the back diffusion of H ^{+ to} the mucous membrane is increased.

  However, indomethacin causes gastric mucosal damage, whereas phenylbutazone is known to have a higher incidence of duodenal mucosal damage than the stomach. The details are considered different. Recently, these non-steroidal anti-inflammatory drugs suppress the action of cyclooxygenase and inhibit the synthesis of prostaglandin E group, which suppresses the contraction of gastric ring-shaped muscle, resulting in increased gastric motility and mucosal damage. (Sanders, KM, Am. J. Physiol., 247, G117-G126, 1984).

  It has been suggested that indomethacin's gastric motility-increasing action is an important factor in mucosal dysfunction in the process of mucosal damage caused by indomethacin, and atropine inhibits gastric acid secretion and gastric motility to inhibit ulcer formation (Ueki, S., et al., Digestive Diseases and Sciences, 33, pp.209-216, 1988). Since atropine has been experimentally confirmed to inhibit indomethacin-induced gastric motility and gastric contraction, atropine seems to protect the gastric mucosa from ulceration by inhibiting the gastric motility-inducing action of indomethacin. Yes (supra Ueki et al.).

  A tertiary amine type anticholinergic agent such as atropine (sometimes referred to herein as “tertiary amine anticholinergic agent”) and a quaternary ammonium salt anticholinergic agent such as butylscopolamine bromide (herein) (In some cases, it is referred to as “quaternary ammonium anticholinergic agent”). However, it is known that tertiary amine anticholinergic agents and quaternary ammonium anticholinergic agents have a common pharmacological action called anticholinergic action, but their effects on gastric juice secretion or gastrointestinal motility are different. Clinically, it is necessary to properly use the two according to the characteristics of both of them (Clinical pharmacology system, Handbook of clinical pharmacology and therapeutics, 13, Gastrointestinal disease, IV. Gastric disease, pp.145-146, 1988).

  For example, tertiary amine anticholinergic agents are generally superior in gastrointestinal motility inhibitory action over gastric juice secretion action, and are clinically suitable as antispasmodic agents for symptomatic treatment for abdominal pain. Quaternary ammonium anticholinergic agents, on the other hand, have a strong neuromuscular blocking action and show excellent effects in inhibiting secretion and movement, and are relatively selective for the gastrointestinal tract compared to tertiary amine anticholinergic agents. have. As described above, the tertiary amine anticholinergic agent atropine is known to exert an inhibitory action against gastric hyperactivity caused by nonsteroidal anti-inflammatory agents such as indomethacin (Ueki et al. Such a function is not conventionally known for quaternary ammonium anticholinergic agents.

  As a quaternary ammonium anticholinergic agent, tiquidium bromide ("Thiaton", manufactured and sold by Hokuriku Pharmaceutical Co., Ltd.) is used clinically, and it exhibits excellent effects as a therapeutic agent for gastritis, stomach / duodenal ulcer, etc. It has been known. This anticholinergic agent has been shown to be effective as a therapeutic agent for peptic ulcer (Nippon Pharmacology, Folia pharmacol. Japon., 90, pp.273-283, 1987), and suppresses indomethacin gastric damage. It is suggested that the mechanism of action is a gastric acid secretion inhibitory action and a cytoprotective action that seems to be caused directly on the stomach wall (page 282, right column 18). Line -21).

Davenport, H.D., Gastroenterology, 46, 245, 1964 Sanders, K.M., Am. J. Physiol., 247, G117-G126, 1984 Ueki, S., et al., Digestive Diseases and Sciences, 33, pp.209-216, 1988 Clinical pharmacology, Handbook of clinical pharmacology and therapeutics, 13, Gastrointestinal disorders, IV. Gastric disorders, pp.145-146, 1988 Japanese Pharmacology, Folia pharmacol. Japon., 90, pp.273-283, 1987

  The subject of this invention is providing the pharmaceutical which has the inhibitory action with respect to the gastrointestinal motility increase which nonsteroidal anti-inflammatory agents, such as indomethacin, diclofenac sodium, and ibuprofen, cause. Another object of the present invention is to provide an anti-inflammatory pharmaceutical composition with reduced gastrointestinal motility enhancing action.

  As a result of diligent research to solve the above-mentioned problems, the present inventors have found that quaternary ammonium anticholinergic agents are effective against non-steroidal anti-inflammatory agents such as indomethacin, diclofenac sodium, ibuprofen, etc. And found to have an extremely excellent inhibitory action. Further, it has been found that an anti-inflammatory pharmaceutical composition in which the action for enhancing gastrointestinal motility is remarkably reduced can be provided by combining a non-steroidal anti-inflammatory agent and a quaternary ammonium anti-cholinergic agent. The present invention has been completed based on these findings.

  That is, the present invention provides an inhibitor for the gastrointestinal motility-promoting action caused by a non-steroidal anti-inflammatory agent, which comprises a quaternary ammonium anticholinergic agent as an active ingredient. According to a preferred embodiment of the present invention, the above-mentioned inhibitor wherein the quaternary ammonium anticholinergic agent is thixidium bromide or butylscopolamine bromide, and the nonsteroidal anti-inflammatory agent is diclofenac sodium, loxoprofen sodium, indomethacin, piroxicam, ketoprofen The above inhibitor is provided which is ibuprofen, zaltoprofen, or ampiroxicam. The inhibitor of the present invention is useful for the prevention and / or treatment of gastrointestinal disorders such as damage formation of the gastrointestinal mucosa caused by administration of a nonsteroidal anti-inflammatory agent.

  From another aspect of the present invention, a pharmaceutical composition comprising a nonsteroidal anti-inflammatory agent and a quaternary ammonium anticholinergic agent is provided. According to a preferred embodiment of the present invention, the pharmaceutical composition wherein the quaternary ammonium anticholinergic agent is thixidium bromide or butylscopolamine bromide, and the nonsteroidal anti-inflammatory agent is diclofenac sodium, loxoprofen sodium, indomethacin, piroxicam, There is provided the above pharmaceutical composition which is ketoprofen, ibuprofen, zaltoprofen, or ampiroxicam.

  Another aspect of the present invention is a method for suppressing the gastrointestinal motility-promoting action caused by a nonsteroidal anti-inflammatory agent, wherein the effective amount of a quaternary ammonium anticholinergic agent is applied to a mammal, preferably a human. A method comprising a step of administering; a method for preventing and / or treating gastrointestinal disorders such as damage formation of gastrointestinal mucosa caused by administration of a non-steroidal anti-inflammatory agent, wherein the gastrointestinal tract is caused by the non-steroidal anti-inflammatory agent A method comprising the step of administering to a mammal, preferably a human, an effective amount of a quaternary ammonium anticholinergic agent for inhibiting the hyperkinetic activity; and a quaternary for the production of the inhibitor or the pharmaceutical composition. There is provided the use of an ammonium-based anticholinergic agent, preferably tiquidium bromide or butyl scopolamine bromide.

  The inhibitor of the present invention has the action of reducing or eliminating the increase in gastrointestinal motility caused by non-steroidal anti-inflammatory agents, and treatment and / or prevention of gastrointestinal disorders caused by administration of non-steroidal anti-inflammatory agents. Useful for. In addition, the anti-inflammatory pharmaceutical composition of the present invention has an excellent feature that an action to enhance gastrointestinal motility is reduced or eliminated, and an inflammatory disease can be treated without causing gastrointestinal disorders.

It is the figure which showed the effect | action of the inhibitor of this invention with respect to the gastric motility enhancement effect which diclofenac sodium (5 mg / kg, subcutaneous administration) causes in an awake rat. It is the figure which showed the effect | action of the inhibitor of this invention with respect to the gastric motility enhancement effect which indomethacin (25 mg / kg, subcutaneous administration) causes in awake rat. It is the figure which showed the effect | action of the inhibitor of this invention with respect to the gastric vestibular part enhancement effect which diclofenac sodium causes in an awake dog. It is the figure which showed the effect | action of the inhibitor of this invention with respect to the gastric motility enhancement effect which indomethacin (25 mg / kg, subcutaneous administration) causes in awake rat. In the figure, “solvent” means 0.5% CMC. It is the figure which showed the effect | action of the inhibitor of this invention with respect to the gastric motility enhancement effect which diclofenac sodium (100 mg / kg, subcutaneous administration) causes in an awake rat. In the figure, “solvent” means 0.5% CMC. It is the figure which showed the effect | action of the inhibitor of this invention with respect to the gastric motility enhancement effect which ibuprofen causes in awake rat. In the figure, “solvent” means 0.5% CMC. It is the figure which showed the effect | action of the inhibitor (intraduodenal administration) of this invention with respect to the increase in the gastric motility index which indomethacin causes in an awake rat, and gastric mucosa damage formation. In the figure, “solvent” means 0.5% CMC. It is the figure which showed the effect | action of the inhibitor (intraduodenal administration) of this invention with respect to the increase in the gastric motility index which diclofenac sodium causes in awake rat, and gastric mucosa damage formation. It is the figure which showed the effect | action of the inhibitor (intraduodenal administration) of this invention with respect to the increase in the gastric motility index which ibuprofen causes in awake rat, and gastric mucosa damage formation. In the figure, “solvent” means 0.5% CMC. It is the figure which showed the effect | action with respect to gastric-mucosal damage formation by simultaneous oral administration of indomethacin, diclofenac sodium, or ibuprofen, and the inhibitor of this invention in awake rat. In the figure, “solvent” means 0.5% CMC.

  The inhibitor of the present invention is an inhibitor against the gastrointestinal motility-promoting action caused by a non-steroidal anti-inflammatory agent, and is characterized by containing a quaternary ammonium anticholinergic agent as an active ingredient. As used herein, the term “gastrointestinal tract” should be interpreted in the broadest sense including the stomach, duodenum, small intestine, and large intestine, but preferably means the stomach and duodenum, more preferably the stomach. . As used herein, the term “gastrointestinal disorders” should be interpreted in the broadest sense including mucosal disorders and ulceration in mucosa and muscle tissue. In addition, as used herein, the term “gastrointestinal motility-promoting action caused by a nonsteroidal anti-inflammatory agent” is used as a concept that includes gastrointestinal motility, as well as gastrointestinal tract contraction. It can be easily confirmed according to the method described in Ueki et al. (Ueki, S., et al., Digestive Diseases and Sciences, 33, pp.209-216, 1988).

  The type of the quaternary ammonium anticholinergic agent that is the active ingredient of the inhibitor of the present invention is not particularly limited, but any quaternary ammonium anticholinergic agent that has already been used clinically is suitable as the inhibitor of the present invention. Can be used. Such anticholinergic agents include, for example, thixium bromide, methylatropine bromide, butropium bromide, methyl anisotropin bromide, scopolamine hydrobromide, butyl scopolamine bromide, propantheline bromide, methylbenactic bromide. Examples thereof include palladium, barreta bromide, prifinium bromide, trospium bromide, N-methyl scopolamine methylsulfate, timepidium bromide, cyclonium iodide, and diponium bromide.

  Of these, tiquidium bromide or butyl scopolamine bromide is preferred, and tiquidium bromide is particularly preferred. For example, in the case of using tiquidium bromide, it is possible to use a formulation sold by Hokuriku Pharmaceutical Co., Ltd. as “thiatone” as it is, and other quaternary ammonium anticholine specifically exemplified above. Even when an agent is used, a commercially available preparation can be used as it is. But the active ingredient of the inhibitor of this invention is not limited to the quaternary ammonium type | system | group anticholinergic agent already used clinically. As the active ingredient of the inhibitor of the present invention, any substance may be used as long as it has a quaternary ammonium structure in the molecule and has an anticholinergic action. The kind of the salt is not particularly limited, and a substance such as a hydrate or a solvate may be used. Needless to say, when there is an isomer based on an asymmetric carbon or a double bond or an isomer based on tautomerism, any isomer or a mixture thereof can be used.

  The administration route of the inhibitor of the present invention is not particularly limited, and may be administered by a suitable administration route according to the type of quaternary ammonium anticholinergic agent to be used. Examples of preparations for oral administration include tablets, capsules, powders, granules, fine granules, syrups, solutions, etc. Examples of preparations for parenteral administration include injections and drops. Suppositories, inhalants, transdermal absorption agents, and the like, but the preparation form of the inhibitor of the present invention is not limited thereto. In the production of these preparations, one or more kinds of any additive for preparations available in the art can be used. For example, when tiquidium bromide is used, it is preferable to use a preparation for oral administration.

  The type of non-steroidal anti-inflammatory agent to which the inhibitor of the present invention is applied is not particularly limited, but for example, mefenamic acid, aluminum flufenamic acid, acetaminophen, acemetacin, indomethacin, indomethacin farnesyl, progouritacin maleate, Alclofenac, diclofenac sodium, ampenac sodium, fenbufen, aspirin, ketophenylbutazone, phenylbutazone, sulpyrine, epilysole, emorphazone, thiaramide hydrochloride, tinolidine hydrochloride, actarit, aluminoprofen, ampiroxicam, ibuprofen, etodolac, lefetamine hydrochloride, Oxaprozin, ketoprofen, zaltoprofen, diflunisal, sulindac, thiaprofenic acid, tenoxicam, tolmetine nato Um, it can be cited nabumetone, naproxen, piroxicam, fenoprofen calcium, bucolome, pranoprofen, flurbiprofen, floctafenine, dimetotiazine mesylate, Mechiajin acid, mofezolac, Loxoprofensodium, and lobenzarit disodium. Of these, preferred are diclofenac sodium, loxoprofen sodium, indomethacin, piroxicam, ketoprofen, ibuprofen, zaltoprofen, ampiroxicam and the like.

  The inhibitor of the present invention can be administered at any time or period before, during and / or after the administration period of the nonsteroidal anti-inflammatory agent. It can be administered according to the administration period of the inflammatory agent. The dose of the inhibitor of the present invention can be appropriately selected according to the type of non-steroidal anti-inflammatory agent, the dose thereof, the age and weight of the patient, and for example, diclofenac sodium is 25 to 25 per day for an adult. In the case of oral administration of about 300 mg, tiquidium bromide can usually be administered orally in an amount of about 5 to 100 mg per adult day. The above dose may be divided and administered several times a day. Two or more quaternary ammonium anticholinergic agents may be used in combination as the inhibitor of the present invention. In the examples of the present specification, examples of methods for evaluating the inhibitory action of indomethacin, diclofenac sodium, and ibuprofen on the gastrointestinal motility increase and gastric mucosal damage formation are specifically shown. Those skilled in the art can refer to this example in making the determination.

  The pharmaceutical composition of the present invention provided from another viewpoint is characterized by comprising a non-steroidal anti-inflammatory agent and a quaternary ammonium anticholinergic agent. The pharmaceutical composition of the present invention is a composition in which the gastrointestinal motility enhancing action is substantially reduced or eliminated, and is used as a safe anti-inflammatory composition that does not cause damage to gastrointestinal mucosa such as stomach and duodenum. Can do. The types of the non-steroidal anti-inflammatory agent and the quaternary ammonium anticholinergic agent are not particularly limited, but those described above can be suitably used. Examples of the combination of active ingredients contained in the pharmaceutical composition of the present invention include, for example, diclofenac sodium, loxoprofen sodium, indomethacin, piroxicam, ketoprofen, ibuprofen, zaltoprofen, or ampiroxicam, and a non-steroidal anti-inflammatory agent, such as thixidium bromide Alternatively, a combination with butyl scopolamine bromide can be mentioned, and a combination of diclofenac sodium or loxoprofen sodium with tiquidium bromide or butyl scopolamine bromide can be mentioned more preferably.

  The compounding amount of the non-steroidal anti-inflammatory agent and the quaternary ammonium anticholinergic agent contained in the pharmaceutical composition of the present invention can be appropriately selected according to the type of each active ingredient. For example, the examples of the present specification specifically show an example of a method for evaluating the inhibitory effect of indium metacin, diclofenac sodium, and ibuprofen on the gastrointestinal motility, and the effect of tiquidium bromide on gastric mucosal damage formation. In view of this, those skilled in the art can refer to this example in determining the amount of the above-mentioned active ingredient in the composition of the present invention.

  The administration route of the pharmaceutical composition of the present invention is not particularly limited, and an appropriate administration route can be selected according to the types of the non-steroidal anti-inflammatory agent and the quaternary ammonium anticholinergic agent which are active ingredients. Examples of preparations for oral administration include tablets, capsules, powders, granules, fine granules, syrups, solutions, etc. Examples of preparations for parenteral administration include injections and drops. Suppositories, inhalants, transdermal absorption agents, and the like, but the formulation of the pharmaceutical composition of the present invention is not limited thereto.

  In the production of the pharmaceutical composition of the present invention, one or more arbitrary pharmaceutical additives available in the art can be used, but the pharmaceutical additive for producing a desired pharmaceutical preparation is used. Needless to say, the contractor can select as appropriate. Examples of pharmaceutical additives that are pharmacologically and pharmaceutically acceptable include, for example, excipients, disintegrants or disintegrants, binders, lubricants, coating agents, dyes, diluents, bases , Solubilizers or solubilizers, tonicity agents, pH regulators, stabilizers, propellants, and adhesives, but are not limited thereto.

  EXAMPLES Hereinafter, although an Example demonstrates this invention further more concretely, the scope of the present invention is not limited to the following Example. In the following examples, as an example of the excellent action of the inhibitor of the present invention, the inhibitory action of tiquidium bromide on the increase in gastric motility caused by nonsteroidal anti-inflammatory agents indomethacin, diclofenac sodium or ibuprofen, and gastric mucosa The inhibitory action of tiquidium bromide on the damage formation was shown specifically.

Example 1 Action of the inhibitor of the present invention (rat)
Male rats (Wistar strain, body weight approximately 250-320 g) are laparotomized under ether anesthesia, a balloon for measuring gastric pressure with an internal volume of about 10 ml is inserted from the front stomach and ligated to the tissue, and then the catheter for intraduodenal administration Was inserted and fixed in the duodenum and the abdomen was closed. An intragastric pressure measurement balloon and catheter were pulled out of the body through the skin, and experiments were performed under arousal using rats that had passed 4 hours or more after the operation. Connect a balloon for measuring gastric pressure to a transducer for measuring blood pressure (TP-400T, Nihon Kohden) and an amplifier for strain pressure (AP-621G, Nihon Kohden), and record the signal from the amplifier with a recorder to measure gastric movement. did. As a result, when diclofenac sodium (5 mg / kg) or indomethacin (25 mg / kg) was administered subcutaneously (sc), an increase in gastric motility in awake rats was observed (FIGS. 1 and 2: upper panel). In addition, intraduodenal administration of thidium bromide (30 mg / kg) (30 minutes pretreatment with id, diclofenac sodium or indomethacin) suppressed the increase in gastric motility caused by anti-inflammatory agents (Fig. 1 and Fig. 2: lower panel) ). The experiment was performed in three cases in both the tiquidium bromide administration group and the solvent (0.5% carboxymethylcellulose aqueous solution) administration group.

Example 2 Effect of the inhibitor of the present invention (dog)
Male and female beagle dogs (approx. 10 kg) were opened under anesthesia (anesthesia was introduced with sodium thiopental 30 mg / kg iv, and anesthesia was maintained by inhalation of laughter and ethanol), and a strain gauge force transducer (F-121S, Star (Medical) was sewn chronically in the direction of the cricoid muscle of the gastric vestibule (upper 5 cm above the stomach pylorus). Subsequently, a catheter for intraduodenal administration was inserted and fixed in the duodenum and the abdomen was closed. Transducer wires and catheters were pulled out of the body between the shoulder blades through the skin and protected with a jacket attached to the dog. The experiment was performed under arousal at the time when more than 2 weeks had passed since the operation. The lead wire from the transducer was connected to a tension measuring amplifier (FS-04M, Star Medical), and the signal from the amplifier was recorded with a recorder to measure stomach movement. As a result, increased gastric vestibular motility in awake dogs was observed with diclofenac sodium (1 mg / kg) administered into the duodenum (FIG. 3: upper panel). Moreover, intraduodenal administration of tiquidium bromide (3 mg / kg) (diclofenac sodium 20-minute pretreatment) suppressed gastric hyperactivity caused by diclofenac sodium (FIG. 3: lower panel). The experiment was performed in three cases in both the tiquidium bromide administration group and the solvent (0.5% carboxymethylcellulose aqueous solution) administration group.

Example 3 Effect of the inhibitor of the present invention on gastric motility Inhibitory action on gastric motility (intra-duplex administration of tiquidium bromide)
After fasting male rats (Wistar strain, body weight approximately 250-400g) for 16-20 hours, laparotomy under ether anesthesia, after inserting a balloon for measuring gastric pressure with an internal volume of about 3 ml from the front stomach and ligating with tissue The catheter for intraduodenal administration was inserted into the duodenum and fixed, and the abdomen was closed. The balloon for intragastric pressure measurement and the catheter were pulled out of the body through the skin, and the experiment was conducted under awakening after 4 hours or more after the operation. The gastric pressure measurement balloon was connected to a pressure transducer (TP-400T, Nihon Kohden) and a strain pressure amplifier (AP-621G, Nihon Kohden), and the signal from the amplifier was recorded on a pen writing recorder to measure stomach movement. . After confirming stable contraction for 30 minutes or more, tiquidium bromide or a solvent (0.5% carboxymethylcellulose aqueous solution) was administered into the duodenum, and 30 minutes later, a nonsteroidal anti-inflammatory agent was administered subcutaneously.

  The total amount of contraction height recorded in the recorder was calculated, and the ratio of the total contraction height for 7 hours after administration of the nonsteroidal anti-inflammatory agent relative to the administration of tiquidium bromide or the solvent was expressed as a gastric motility index (%). The experiment was carried out in 8 cases in both tiquizyl bromide and solvent (0.5% carboxymethylcellulose aqueous solution) administration groups, and statistical analysis was p <0.05 compared with the solvent administration group using the student's t test. In the case of a significant difference. As a result, when indomethacin (25 mg / kg), diclofenac sodium (100 mg / kg) or ibuprofen (100 mg / kg) was administered subcutaneously, gastric motility of awake rats was enhanced. In addition, intraduodenal administration of tiquidium bromide (30 mg / kg) (30 minutes pretreatment with non-steroidal anti-inflammatory drugs) suppressed gastric hyperactivity caused by indomethacin, diclofenac sodium, or ibuprofen (FIGS. 4 to 5). 6, and FIGS. 7 to 9).

Example 4 Effect of inhibitor of the present invention on gastric mucosal damage formation
(1) Inhibitory effect on gastric mucosal damage formation (administration in tiquidium bromide duodenum)
Male rats (Wistar strain, body weight of about 220 to 320 g) were fasted for 16 to 20 hours, and then the rats were opened under ether anesthesia, and a catheter for intraduodenal administration was inserted into the duodenum and fixed, and the abdomen was closed. Rats were housed in individual cages for 3 days, fasted for 16 to 20 hours, tiquidium bromide or solvent was administered intraduodenum, and 30 minutes later, a nonsteroidal anti-inflammatory agent was subcutaneously administered. Seven hours later, the rats were euthanized by cervical dislocation, the stomach was removed, the length of damage (mm) occurring in the glandular stomach was measured with a stereomicroscope, and the total damage per animal was taken as the ulcer coefficient. The experiment was carried out in 10 patients in both the tiquidium bromide and solvent (0.5% carboxymethylcellulose aqueous solution) administration groups, and the statistical analysis was p <0.05 compared with the solvent administration group using the student's t test. In the case of a significant difference. As a result, when indomethacin (25 mg / kg), diclofenac sodium (100 mg / kg) or ibuprofen (100 mg / kg) was administered into the duodenum, formation of damage was observed in the gastric mucosa of rats. Moreover, thixium bromide (30 mg / kg) suppressed gastric mucosal damage formation caused by indomethacin, diclofenac sodium, or ibuprofen (FIGS. 7, 8, and 9).

(2) Inhibitory effect on gastric mucosal damage formation (Thiquidium bromide simultaneous oral administration)
Male rats (Wistar strain, body weight approximately 220 to 320 g) fasted for 16 to 20 hours were orally administered simultaneously with tiquidium bromide or a solvent and a nonsteroidal anti-inflammatory agent. Seven hours later, the rats were euthanized by cervical dislocation, the stomach was removed, the length of damage (mm) occurring in the glandular stomach was measured with a stereomicroscope, and the total damage per animal was taken as the ulcer coefficient. The experiment was carried out in 10 patients in both the tiquidium bromide and solvent (0.5% carboxymethylcellulose aqueous solution) administration groups, and the statistical analysis was p <0.05 compared with the solvent administration group using the student's t test. In the case of a significant difference. As a result, when indomethacin (25 mg / kg), diclofenac sodium (50 mg / kg) or ibuprofen (200 mg / kg) was orally administered, formation of damage was observed in the gastric mucosa. In addition, tiquidium bromide (20 mg / kg) suppressed gastric mucosal damage formation by simultaneous oral administration with indomethacin, diclofenac sodium, or ibuprofen (FIG. 10).

Example 5 Formulation example of the anti-inflammatory composition of the present invention
(1) Tablet loxoprofen sodium 60 mg
Tiquidium bromide 10 mg
D-mannitol appropriate amount carboxymethylcellulose 10 mg
Polyvinylpyrrolidone 2.5 mg
Magnesium stearate 1.5 mg
Hydroxypropyl methylcellulose 4 mg
Macrogol 6000 0.5 mg
Titanium oxide 1.5 mg
Carnauba low amount
156 mg

(2) Tablet diclofenac sodium 25 mg
Tiquidium bromide 10 mg
Lactose appropriate amount Corn starch 25 mg
Hydroxypropylcellulose 2 mg
Magnesium stearate 1 mg
Hydroxypropyl methylcellulose 4 mg
Macrogol 6000 0.5 mg
Titanium oxide 0.5 mg
Carnauba low amount
130 mg

(3) Capsules loxoprofen sodium 60 mg
Butyl scopolamine bromide 10 mg
Crystalline cellulose Appropriate amount Carboxymethylcellulose calcium 10 mg
Magnesium stearate 1 mg
150 mg

Claims (4)

An inhibitor comprising a non-steroidal anti-inflammatory agent selected from diclofenac sodium and loxoprofen sodium, which is an inhibitor of gastrointestinal motility-promoting action, comprising tiquidium bromide or butyl scopolamine bromide as an active ingredient. The inhibitor according to claim 1 for preventing and / or treating gastrointestinal disorders resulting from administration of a nonsteroidal anti-inflammatory agent selected from diclofenac sodium and loxoprofen sodium. The inhibitor according to claim 2, wherein the gastrointestinal disorder is gastrointestinal mucosal damage formation. A pharmaceutical composition comprising a non-steroidal anti-inflammatory agent selected from diclofenac sodium and loxoprofen sodium and tiquidium bromide or butyl scopolamine bromide.

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