JP2005097277A - Preventing or treating agent of bruxism - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a preventing or treating agent of bruxism and diseases associated with the bruxism. <P>SOLUTION: This preventing or treating agent of bruxism and diseases associated with the bruxism is provided by using at least 1 kind selected from a serotonin 5-HT<SB>4</SB>receptor agonist, an acetylcholine release-accelerating agent and a cholinesterase inhibitor as an active ingredient. As the serotonin 5-HT<SB>4</SB>receptor agonist, metoclopramide, cisapride, mosapride or tegaserod or their salts or their hydrates are cited. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a preventive or therapeutic agent for bruxism, and more particularly, a preventive or therapeutic agent for diseases related to bruxism and bruxism, which comprises as an active ingredient a drug having an action of suppressing reflux of gastric acid in the esophagus. About.

  It is thought that bruxism is an abnormal functional movement during sleep, oral malpractice, or sleep-related complications, such as tooth wear and fracture, masticatory muscle discomfort and pain, and temporomandibular disorders. It is known to have a major adverse effect.

  Regarding the development of bruxism, it was previously thought that occlusion was involved, but in recent years, it has become known that occlusion hardly participates in the development of bruxism (see, for example, Non-Patent Document 1).

On the other hand, with regard to the treatment of bruxism, so far, sprint (night guard) therapy that puts something like a boxing mouthpiece so that the upper and lower teeth do not touch, consciously restraining the exercise being performed unconsciously At present, there are only symptomatic treatments such as self-implicit therapy, biofeedback therapy, and drug therapy. Among these, there is a problem that the effect of Sprint therapy is questionable and it is expensive. In addition to antidepressants such as diazepam, tricyclic antidepressants, and muscle relaxants, there are reports that L-dopa is effective as a preventive or therapeutic agent for bruxism (for example, non-patented). Reference 2). However, none of these methods is a fundamental treatment method. Therefore, an effective and fundamental treatment method for bruxism is eagerly desired.
Lavigne GJ, Manzini C. Bruxism.In: Kryger MH, Roth T, and Dement W, eds.Principles and practice of sleep medicine.Philadelphia: WB Saunders, 2000: 773-85. Lobbezoo F, Lavigne GJ, Tanguay R, and Montplaisir JY. Mov Disord 12: 73-78, 1997.

  An object of the present invention is to provide an effective and fundamental preventive or therapeutic agent for bruxism and diseases associated with bruxism.

  The inventors have found that gastric acid esophageal reflux during sleep causes bruxism, and that gastric acid esophageal reflux occurs due to transient lower esophageal sphincter relaxation (TLESR). Focusing on the frequent occurrence, it was inferred that prevention or treatment of bruxism would be possible if gastric acid reflux in the esophagus could be prevented (see Reference Examples 1 and 2 below). Therefore, as a result of extensive research in view of the above circumstances, drugs that inhibit the reflux of gastric acid in the esophagus, such as drugs that prevent relaxation of the lower esophageal sphincter, such as gastrointestinal motility improvers, are related to bruxism and bruxism. The present invention has been found for the first time to be useful in the prevention or treatment of diseases, and the present invention has been completed.

That is, the present invention provides <1> a preventive or therapeutic agent for bruxism comprising an agent that prevents relaxation of the lower esophageal sphincter as an active ingredient;
<2> preventive or therapeutic agent for bruxism comprising a gastrointestinal motility improving agent as an active ingredient;
<3> A preventive or therapeutic agent for bruxism comprising at least one selected from serotonin 5-HT ₄ receptor agonist, acetylcholine release promoter and cholinesterase inhibitor as an active ingredient;
<4> a preventive or therapeutic agent for bruxism comprising a serotonin 5-HT ₄ receptor agonist as an active ingredient;
<5> The prophylactic or therapeutic agent according to <3> or <4>, wherein the serotonin 5-HT ₄ receptor agonist is metoclopramide, cisapride, mosapride or tegaserod or a salt thereof;
<6> Preventive or therapeutic agent for diseases related to bruxism, which comprises a drug that contracts the lower esophageal sphincter as an active ingredient;
<7> a preventive or therapeutic agent for diseases related to bruxism comprising an agent for improving gastrointestinal motility as an active ingredient;
<8> A prophylactic or therapeutic agent for diseases associated with bruxism comprising at least one selected from serotonin 5-HT ₄ receptor agonists, acetylcholine release promoters and cholinesterase inhibitors;
<9> A preventive or therapeutic agent for diseases related to bruxism comprising a serotonin 5-HT ₄ receptor agonist as an active ingredient;
<10> The prophylactic or therapeutic agent according to <8> or <9>, wherein the serotonin 5-HT ₄ receptor agonist is metoclopramide, cisapride, mosapride or tegaserod or a salt thereof;
<11> Diseases related to bruxism are temporomandibular disorders, dental hypersensitivity, occlusal trauma, tooth wear, tooth wedge defect, gingival recession, tooth fracture, tooth shaking, root resorption, alveoli <6> to <10> the prophylactic or therapeutic agent according to any one of <6> to <10>, which is bone resorption, masseter hypertrophy, masticatory muscle pain, broken crown restoration, loss of crown restoration or headache; and <12> The prophylactic or therapeutic agent according to any one of <6> to <11>, wherein the disease associated with bruxism is temporomandibular disorder;
I will provide a.

The present invention also provides:
<13> A method for preventing or treating bruxism, comprising administering an effective amount of a drug that prevents relaxation of the lower esophageal sphincter;
<14> A method for preventing or treating bruxism-related diseases, comprising administering an effective amount of a drug that prevents relaxation of the lower esophageal sphincter;
<15> A method for preventing or treating bruxism, comprising administering an effective amount of an agent for improving gastrointestinal motility;
<16> A method for preventing or treating a disease associated with bruxism, which comprises administering an effective amount of an agent for improving gastrointestinal motility;
<17> Use of a drug for preventing relaxation of the lower esophageal sphincter for the manufacture of a preventive or therapeutic agent for bruxism;
<18> Use of a drug that prevents relaxation of the lower esophageal sphincter for the manufacture of a preventive or therapeutic agent for diseases related to bruxism;
<19> Use of a gastrointestinal motility improving agent for the manufacture of a preventive or therapeutic agent for bruxism;
<20> Use of a gastrointestinal motility improving agent for the manufacture of a preventive or therapeutic agent for diseases related to bruxism;
<21> A method for preventing or treating bruxism characterized by injecting an endoscopically biocompatible polymer into the lower esophageal sphincter; and <22> an endoscopically living organism in the lower esophageal sphincter. A method of preventing or treating a disease associated with bruxism characterized by injecting a biocompatible polymer;
I will provide a.

According to the present invention, a drug or the like that prevents relaxation of the lower esophageal sphincter, represented by an agent for improving gastrointestinal motility, has an action of suppressing the reflux of gastric acid that causes bruxism in the esophagus. It is extremely useful in the fundamental prevention or treatment of diseases related to
Furthermore, the present invention also leads to a significant reduction in the cost of treating bruxism and diseases associated with bruxism (especially the cost of splint therapy).

  Hereinafter, the present invention will be described in detail by showing the meanings of symbols, terms, and the like described in the present specification, embodiments of the present invention, and the like.

  As used herein, “prophylactic or therapeutic agent” refers to a single drug or an agent containing a plurality of drugs. Note that an agent containing a plurality of drugs is an agent obtained by simultaneously formulating a single drug or a plurality of drugs obtained by separately formulating a single drug at the same time or at regular intervals. An agent for effective administration for treatment.

The “agent for preventing relaxation of the lower esophageal sphincter” used in the present specification is not particularly limited as long as it is an agent for preventing relaxation of the lower esophageal sphincter. Specific examples include gastrointestinal motility improving agents such as serotonin 5-HT ₄ receptor agonists, acetylcholine release promoters or cholinesterase inhibitors.

  As a method of “preventing relaxation of the lower esophageal sphincter”, in addition to the method of using the “medical agent preventing relaxation of the lower esophageal sphincter”, the lower esophageal sphincter described in US Pat. No. 6,238,335 is endoscopically used. And a method of injecting a biocompatible polymer (for example, ethylene vinyl alcohol copolymer). Using this technique, the polymer injected into the lower esophageal sphincter coagulates to form a permanent sponge-like implant that prevents relaxation of the lower esophageal sphincter and prevents acid reflux in the esophagus. And / or prevention or treatment of diseases associated with bruxism.

The “gastrointestinal motility improving agent” used in the present specification is not limited as long as it is an agent that protects the relaxation of the lower esophageal sphincter by promoting the release of acetylcholine and promotes gastrointestinal motility such as esophageal peristalsis. Specific examples include serotonin 5-HT ₄ receptor agonists, acetylcholine release promoters or cholinesterase inhibitors.

Specific examples of the “serotonin 5-HT ₄ receptor agonist” used in the present specification include metoclopramide, cisapride, mosapride or tegaserod, or salts thereof. Usually, mosapride is used as mosapride citrate and tegaserod is used as tegaserod maleate.

  As the “acetylcholine release promoter” or “cholinesterase inhibitor” used in the present specification, specifically, 2- [N-4,5-dimethoxy-2 described in WO 96/36619 pamphlet is used. -Hydroxybenzoyl] amino] -4-[(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole hydrochloride trihydrate.

  Examples of the “salt” used herein include a salt with an inorganic acid, a salt with an organic acid, a salt with an inorganic base, a salt with an organic base, a salt with an acidic or basic amino acid, and the like. Of these, pharmacologically acceptable salts are preferred.

  Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and preferable examples of the salt with organic acid include, for example, acetic acid and succinic acid. And salts with acids, fumaric acid, maleic acid, tartaric acid, citric acid, lactic acid, stearic acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, and the like.

  Preferable examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, aluminum salt, ammonium salt and the like. Preferable examples of the salt with an organic base include salts with diethylamine, diethanolamine, meglumine, N, N′-dibenzylethylenediamine and the like.

  Preferable examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like, and preferable examples of the salt with basic amino acid include salts with arginine, lysine, ornithine and the like. It is done.

  As used herein, “disease related to bruxism” is not limited as long as it is caused by bruxism. Specifically, for example, temporomandibular disorders, dental hypersensitivity, occlusal trauma, dental Bite, tooth wedge defect, gingival retraction, tooth fracture, tooth movement, root resorption, alveolar bone resorption, masseter hypertrophy, masticatory muscle pain, crown restoration restoration, crown restoration omission, headache Etc. Among these, temporomandibular disorders can be mentioned as a preferable disease.

  As used herein, “temporomandibular disorders” means, for example, a group of chronic diseases whose main symptoms are temporomandibular joint and masticatory muscle pain, joint noise, opening disorders, or jaw movement abnormalities. Masticatory muscle disorders, joint capsule / ligament disorders, joint disc disorders, osteoarthritis and the like.

The route of administration, dosage and frequency of administration of serotonin 5-HT ₄ receptor agonists as a preventive or therapeutic agent for bruxism and diseases related to bruxism depends on the patient's symptoms, type of ulcer / gastritis・ Varies depending on degree, age, heart / liver / kidney function, etc. Normally, serotonin 5-HT ₄ receptor agonist is orally administered to adults at 0.6 to 150 mg per day. For example, the adult daily dose of metoclopramide is preferably 10-30 mg. The adult daily dose of cisapride is preferably 7.5-15 mg. The adult daily dose of mosapride is preferably 0.75-150 mg, more preferably 7.5-15 mg as mosapride citrate. The daily adult dose of tegaserod is preferably 0.6 to 120 mg, more preferably 6 to 12 mg as tegaserod maleate.

  Examples of the dosage form include powders, fine granules, granules, tablets, capsules and the like. At the time of formulation, it can also be produced by a conventional method using an ordinary formulation carrier.

  When an oral solid preparation is prepared by a conventional method, an excipient and, if necessary, a binder, a disintegrant, a lubricant, a coloring agent, etc. are added to the main drug, and then a powder, fine powder is prepared by a conventional method. Granules, granules, tablets, capsules, etc.

  Examples of the excipient include lactose, sucrose, glucose, corn starch, mannitol, sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, light anhydrous silicic acid, aluminum silicate, calcium silicate, magnesium aluminate metasilicate, Examples thereof include calcium hydrogen phosphate.

  Examples of the binder include polyvinyl alcohol, methylcellulose, ethylcellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, macrogol and the like.

  Examples of the disintegrant include crystalline cellulose, agar, gelatin, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin, low-substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethyl Examples include starch and sodium carboxymethyl starch.

  Examples of the lubricant include magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, polyethylene glycol, colloidal silica and the like.

  Examples of the colorant include those permitted to be added to pharmaceuticals such as iron sesquioxide, yellow ferric oxide, carmine, caramel, β-carotene, titanium oxide, talc, sodium riboflavin phosphate, yellow aluminum lake, etc. Can be mentioned. Of course, granules and tablets may be coated with sugar coating and other coatings as necessary.

  In order to show the advantageous effects of the present invention, reference examples and test examples are shown below. However, these examples are illustrative and the present invention is not limited to the following specific examples in any case. Absent. Those skilled in the art can implement the present invention by appropriately changing the conditions described in the following examples, and such changes are included in the scope of the claims of the present application.

[Reference Example 1]
Changes in esophageal pH during sleep, changes in lower esophageal sphincter pressure and temporal muscle activity in patients with bruxism

Method A catheter with a pH electrode and a pressure sensor was placed in the subject in the esophagus and the center of the lower esophageal sphincter 5 cm above the upper part of the lower esophageal sphincter, and the pH in the esophagus and the lower esophageal sphincter pressure during sleep were recorded. Disposable type electrodes (bipolar induction) were applied to the skin in front of one temporal muscle, and the amount of muscle activity during sleep was recorded. At the same time, video images and audio were recorded, and it was confirmed that it was bruxism during sleep. FIG. 1 shows the results of recording esophageal pH, lower esophageal sphincter pressure, and temporal muscle activity during sleep for about 2 minutes from 2 hours after going to bed. In the figure, 1) When the pH in the esophagus is suddenly decreased, the pH in the esophagus is defined as a “decreased pH in the esophagus” 2) Temporary lower esophageal sphincter pressure The decrease was defined as “TLESR episode”, and 3) jaw movement with frequent and rhythmic temporal muscle activity was defined as “bruxism episode”.

Results A “TLESR episode” was observed immediately before the period corresponding to the “decreased esophageal pH episode”, and a “bruxism episode” was observed during that period.

[Reference Example 2]
Measurement of lower esophageal pH, lower esophageal sphincter pressure and temporal muscle activity in patients with bruxism (n = 6)

Method According to the method of Test Example 1, for subjects, the esophageal pH during sleep, the lower esophageal sphincter pressure, and the amount of muscle activity in one frontal temporal muscle were measured for 4 hours from 1 hour to 5 hours after bedtime. Recorded. At the same time, video images and audio were recorded, and it was confirmed that it was bruxism during sleep. The temporal relationship between “bruxism episode”, “TLESR episode” and “reduced esophageal pH episode” was investigated. The results are shown in Table 1. In addition, the Wilcoxon rank sum test was used for the significant difference test.

Results From Table 1, the “bruxism episode” occurred significantly after the “TLESR episode” and the “reduced intraesophageal pH episode”.

  From the results of the above reference examples, it became clear that gastric acid caused reflux in the esophagus due to transient relaxation of the lower esophageal sphincter (TLESR), and bruxism frequently occurred immediately after TLESR.

[Test Example 1]
Measurement of temporal muscle activity during sleep when taking placebo and a serotonin 5-HT ₄ receptor agonist in patients with bruxism

Method A placebo and a serotonin 5-HT ₄ receptor agonist (mosapride citrate (5 mg; trade name: gasmotin (registered trademark): manufactured by Dainippon Pharmaceutical Co., Ltd.)) are asleep on subjects 1 in a double-blind manner. In accordance with the method of Reference Example 1, the amount of muscle activity in one frontal temporal muscle during sleep was recorded for 4 hours from 1 hour to 5 hours after going to bed. At the same time, video images and audio were recorded, and it was confirmed that it was bruxism during sleep. Table 2 below shows the frequency (times) of bruxism episodes per hour in each case after taking (1) placebo and (2) serotonin 5-HT ₄ receptor agonist.

Results From the results shown in Table 2, it was found that the frequency of bruxism episodes decreased when taking a serotonin 5-HT ₄ receptor agonist compared to taking a placebo.

  The agent for preventing relaxation of the lower esophageal sphincter represented by a gastrointestinal motility improving agent or the like according to the present invention has an action of suppressing the reflux of gastric acid in the esophagus that induces bruxism. It is extremely useful in the fundamental prevention or treatment of related diseases.

FIG. 1 shows (A) pH in the esophagus (vertical axis) and time (horizontal axis) and (B) lower esophageal sphincter pressure (vertical axis) during sleep (about 2 minutes from 2 hours after going to bed) in a patient with bruxism. It is the figure which showed time (horizontal axis) and (C) temporal muscle activity (vertical axis) and time (horizontal axis).

Claims (12)

  A preventive or therapeutic agent for bruxism comprising a drug that prevents relaxation of the lower esophageal sphincter as an active ingredient.   A preventive or therapeutic agent for bruxism comprising a gastrointestinal motility improving agent as an active ingredient. A preventive or therapeutic agent for bruxism comprising at least one selected from a serotonin 5-HT ₄ receptor agonist, an acetylcholine release promoter and a cholinesterase inhibitor as an active ingredient. A preventive or therapeutic agent for bruxism comprising a serotonin 5-HT ₄ receptor agonist as an active ingredient. The prophylactic or therapeutic agent according to claim 3 or 4, wherein the serotonin 5-HT ₄ receptor agonist is metoclopramide, cisapride, mosapride or tegaserod or a salt thereof.   A preventive or therapeutic agent for diseases related to bruxism, which comprises a drug that prevents relaxation of the lower esophageal sphincter as an active ingredient.   A preventive or therapeutic agent for diseases related to bruxism, comprising a gastrointestinal motility improving agent as an active ingredient. A prophylactic or therapeutic agent for diseases related to bruxism comprising at least one selected from serotonin 5-HT ₄ receptor agonists, acetylcholine release promoters and cholinesterase inhibitors as active ingredients. A preventive or therapeutic agent for diseases related to bruxism comprising a serotonin 5-HT ₄ receptor agonist as an active ingredient. The prophylactic or therapeutic agent according to claim 8 or 9, wherein the serotonin 5-HT ₄ receptor agonist is metoclopramide, cisapride, mosapride or tegaserod or a salt thereof.   Diseases related to bruxism are temporomandibular disorders, dental hypersensitivity, occlusal trauma, tooth wear, tooth wedge defect, gingival recession, tooth fracture, tooth shaking, root resorption, alveolar bone resorption, The preventive agent or therapeutic agent according to any one of claims 6 to 10, which is masseter muscle hypertrophy, masticatory myalgia, broken crown restoration, loss of crown restoration or headache. The prophylactic or therapeutic agent according to any one of claims 6 to 11, wherein the disease associated with bruxism is temporomandibular disorder.

Images