WO2014181724A1

WO2014181724A1 - Dysphagia therapeutic agent

Info

Publication number: WO2014181724A1
Application number: PCT/JP2014/061821
Authority: WO
Inventors: 憲昭武田; 自治陣内
Original assignee: 国立大学法人徳島大学
Priority date: 2013-05-10
Filing date: 2014-04-28
Publication date: 2014-11-13
Also published as: JP6324951B2; JPWO2014181724A1

Abstract

The purpose of the present invention is to provide a means for alleviating dysphagia, without changing the inherent physical properties of a food or beverage or taking a stimulating substance with food or before or after eating. Provided is a therapeutic agent for treating dysphagia that contains a TRPV1 agonist, and that is used so as to be applied to the external auditory canal.

Description

Drugs for dysphagia

The present invention relates to a remedy for dysphagia, a method of treatment and the like.

Dysphagia is a disorder that makes it difficult to chew or swallow food and drink due to illness and aging. Normally, chewed food is sent to the pharynx by the tongue and swallowed. At that time, when the soft palate is raised, the oral cavity and the nasal cavity are blocked, and the trachea is blocked by the epiglottis. In this way, food is transferred to the esophagus by opening a route to the esophagus at the moment of swallowing. On the other hand, patients or elderly people suffering from dysphagia typically suffer from poor movement of the lips, tongue, palate, pharynx, etc., resulting in poor formation of the bolus, poor delivery from the oral cavity to the pharynx and esophagus, and swallowing There is a reduction or delay in reflection. This causes problems such as the entry of food and drink into the lungs.

Swallowing disorders can cause a variety of problems. For example, if suffocation occurs due to aspiration that causes food and drink to enter the trachea, death occurs. In addition, swallowing pneumonia develops when bacteria enter the trachea along with food and drink by aspiration. This swallowing pneumonia can cause death, especially in the elderly. Furthermore, if there is a dysphagia, it is difficult to take food and drink, so that the comfort of daily meals is impaired, and weight loss, lack of nutrition, or dehydration may occur.

As means for assisting swallowing of persons suffering from dysphagia, there are methods of imparting viscosity and gel properties to food and drink itself. These means are intended to prevent food and drink from being fed into the esophagus from the mouth at once, and to prevent pneumonia and suffocation due to aspiration, by providing the food and drink with viscosity and gel properties. For example, a method in which a coagulant such as gelatin or agar is added to foods and drinks to cool and solidify, a method in which starch such as corn or potato is added and heated to increase the viscosity, or a thickened material such as pregelatinized starch or guar gum. There is a method of adding saccharides to increase the viscosity. However, these means need to be heated or cooled, and the viscosity changes with time. Therefore, it is not necessarily excellent in handleability. Moreover, since these means change the original texture and taste of food and drink, they cannot enable the patient to enjoy the original texture and / or taste of food and drink.

In addition to the above-mentioned methods for imparting viscosity and gel properties to foods and drinks, cough reflex and swallowing reflex are induced by acting capsaicin, which is a pungent component of pepper, and capsinoid, which is a derivative thereof, on the oral cavity and pharynx. A pharmaceutical or food composition for improving dysphagia has been proposed (Patent Document 1 and Non-Patent Document 1). In addition, a means for stimulating the pharynx and larynx with food containing ginger rhizomes or extracts thereof has been proposed (Patent Document 2).

However, since these means also require the use of irritating substances at the same time or before the meal to induce the cough reflex, the food should have the original texture and / or taste of food and drink. It is difficult to make it enjoyable.

International Publication No. 2007/125717 JP2008-000005

Under the present situation as described above, the present invention improves dysphagia more effectively without changing the physical properties of the food and drink itself or taking a stimulating substance at the same time as or before and after the meal. One object is to provide a means to do this.

The present inventors have conducted research day and night in order to solve the above-mentioned problems, and take stimulants by applying an agonist of transient receptor potential vanilloid-1 (TRPV1) typified by capsaicin to the ear canal. Thus, it was found that the swallowing reflex can be stimulated and the dysphagia can be improved without directly stimulating the pharynx and larynx. Based on this knowledge, the inventors have made further studies and completed the present invention.

A representative invention is shown below.
Item 1.
A therapeutic agent for dysphagia comprising a TRPV1 agonist and used to be applied to the ear canal.
Item 2.
A therapeutic agent for dysphagia, which is used to apply to the external auditory canal, including capsaicin or menthol.
Item 3.
Item 3. The therapeutic agent according to

Item

1 or 2, further comprising a pharmaceutically acceptable excipient.
Item 4.
Applying a pharmaceutical composition comprising a TRPV1 agonist to the ear canal of a patient in need of treatment for dysphagia.
Item 5.
A pharmaceutical composition comprising a TRPV1 agonist for application to the ear canal to treat dysphagia.
Item 6.
Use of a TRPV1 agonist in the manufacture of a pharmaceutical composition for application to the ear canal to treat dysphagia.
Item 7.
Item 4. The therapeutic agent according to any one of Items 1 to 3, which is applied to the ear canal repeatedly at a frequency of once a day to once a week.
Item 8.
A prophylactic agent for swallowing pneumonia, comprising a TRPV1 agonist and used to be applied to the ear canal.
Item 9.
A prophylactic agent for swallowing pneumonia, which contains a capsaicin compound or menthol and is used to be applied to the ear canal.
Item 10.
Item 10. The prophylactic agent according to

Item

8 or 9, further comprising a pharmaceutically acceptable excipient.
Item 11.
Item 11. The prophylactic agent according to any one of Items 8 to 10, which is repeatedly applied to the ear canal at a frequency of once a day to once a week.

According to the present invention, a TRPV1 agonist or other substance that stimulates the vagus auricular branch is applied to the ear canal to treat or ameliorate dysphagia, preferably ingestion of food and drink is impossible New patients can be taken orally. According to the present invention, since the TRPV1 agonist or the substance that stimulates the vagus auricular branch is applied to the external auditory canal, the active ingredient may be diluted (or washed away) by eating and drinking, and the effect may be impaired. In addition, the therapeutic effect of dysphagia can be exhibited stably for a long period (for example, 30 minutes to several hours). Thus, for example, a therapeutic effect that is sustained during a meal can be obtained by application before the meal. Further, according to the present invention, it is possible to swallow without adding a thickening to the food or drink, changing the physical properties of the food or drink itself, or applying an irritating substance to the oral cavity. Can be made smooth. Therefore, according to the present invention, not only the food and drink can be swallowed, but also the food texture and / or taste inherent in the food and drink can be enjoyed. Is planned. Furthermore, according to the present invention, it is possible to prevent swallowing pneumonia through improvement of swallowing function. In addition, improvement of the swallowing function is expected to improve the general condition (Performance status), QOL, and / or cognitive function.

The result which evaluated the improvement effect of the swallowing function by apply | coating capsaicin to an external auditory canal by the warhead method 5 minutes after application | coating is shown. The result of having evaluated the improvement effect of the swallowing function by apply | coating capsaicin to an external auditory canal by SMRC method 5 minutes after application | coating is shown. S is a sensory function, M is a motor function, R is a reflex function, and C is a clearance function. The numerical value of the vertical axis | shaft of a figure shows an evaluation score. The result which evaluated the improvement effect of the swallowing function by apply | coating capsaicin to an external auditory canal by the warhead method 5 minutes after application | coating, 30 minutes, and 1 hour after is shown. The numerical value of the vertical axis | shaft of a figure shows an evaluation score. The result of having evaluated the improvement effect of the swallowing function (reflex function) by apply | coating capsaicin to an external auditory canal by SMRC method 5 minutes after application | coating, 30 minutes, and 1 hour after is shown. The numerical value of the vertical axis | shaft of a figure shows an evaluation score. The result which evaluated the improvement effect of the swallowing function when capsaicin is alternately applied to the left and right external auditory canals for one week at a frequency of once a day is shown by the warhead method. The numerical value of the vertical axis | shaft of a figure shows an evaluation score. The result of having evaluated the improvement effect of the swallowing function when capsaicin is alternately applied to the left and right external auditory canals for one week at a frequency of once a day is shown by the SMRC method. S is a sensory function, M is a motor function, R is a reflex function, and C is a clearance function. The numerical value of the vertical axis | shaft of a figure shows an evaluation score. The improvement mechanism of the swallowing function by applying capsaicin to the ear canal is shown.

The therapeutic agent for dysphagia or the preventive agent for swallowing pneumonia preferably contains a TRPV1 agonist. Here, TRPV1 is a non-selective cation channel with a high calcium ion permeability having a 6-transmembrane region belonging to the Transient ReceptorPotential superfamily, and is also called vanilloid receptor 1 (VR1) or capsaicin receptor. The TRPV1 agonist is a substance that activates TRPV1 and enhances calcium permeability. The TRPV1 agonist is not particularly limited as long as it has such properties, and a known and later-developed TRPV1 agonist may be appropriately selected and used. it can. In this document, the therapeutic agent for dysphagia and the preventive agent for swallowing pneumonia may be collectively expressed as a therapeutic agent for dysphagia.

Examples of known TRPV1 agonists include capsaicin, capsaicin derivatives, and capsinoid compounds. In this document, capsaicin, capsaicin derivatives and capsinoid compounds are collectively referred to as “capsaicin compounds”. Examples of capsaicin derivatives include N-vanillyl-alkanedienamide, N-vanillyl-alkanedienyl, N-vanillyl-cis-monounsaturated alkanamide, dihydrocapsaicin, norhydrocapsaicin, norhydrocapsaicin, homocapsaicin, homo The compound which has vanillyl machines, such as dihydrocapsaicin, can be mentioned.

Capsinoid compounds are fatty acid esters of vanillyl alcohol, and typical examples thereof include capsiates such as capsiate, dihydrocapsiate, nordihydrocapsiate, vanillyl decanoate, vanillyl nonanoate, and vanillyl octanoate. In addition, fatty acid esters of various linear or branched fatty acids and vanillyl alcohol having fatty acid chain length comparable to nordihydrocapsiate are included, but not limited thereto.

As other TRPV1 agonists, compounds lacking vanillyl function such as piperine, dialdehyde sesquiterpene (for example, wobble ganal, polygodial or isoberellal), scutigeral, triprenylphenol and the like can be mentioned. Still other TRPV1 agonists are US Pat. Nos. 4,599,342, 5,962,532, 5,762,963, 5,221,692, 4,313, No. 958, No. 4,532,139, No. 4,544,668, No. 4,564,633, No. 4,544,669, No. 4,493,848, No. Nos. 4,532,139, 4,564,633, 4,544,668, and International Publication WO00 / 50387. Therefore, the therapeutic drug for dysphagia or the preventive drug for swallowing pneumonia can include one or more of the above TRPV1 agonists in combination.

The therapeutic agent for dysphagia or the preventive agent for swallowing pneumonia may contain, as an active ingredient, a substance that stimulates the auricular branch (Arnold nerve) of the vagus nerve other than the TRPV1 agonist. Examples of such materials include TRPM8 agonists and TRPA1 agonists. Examples of the TRPM8 agonist include menthol, icilin, eucalyptol, linalool, geraniol, and hydroxycitronellal. A preferred TRPM8 agonist is menthol. Examples of the TRPA1 agonist include allyl isothiocyanate, which is a pungent component of wasabi. Examples of substances that stimulate Arnold nerves other than TRPM8 agonist and TRPA1 agonist include menthone, camphor, pregol, cineol, 3-menthoxypropane-1,2-diol, N-alkyl-p-menthane- 3-carboxamide, 3-menthoxy-2-methylpropane-1,2-diol, p-menthane-3,8-diol, 3-menthoxypropan-1-ol, 4-l-menthoxybutan-1-ol (Mentyl 3-hydroxybutanoate), menthyl 3-hydroxybutanoate, 1- (2-hydroxy-4-methyl-cyclohexyl) ethanone, menthyl lactate, menthol glycerol ketal, N-methyl-2,2-isopropylmethyl-3 -Methylbutanamide, menthyl glyoxylate, menthyl succinate, gluta Menthyl, peppermint oil, spearmint oil, eucalyptus oil and peppermint oil, or the like can be raised. Therefore, the therapeutic drug for dysphagia or the preventive drug for swallowing pneumonia can contain one or a combination of two or more of these. The substances that stimulate the auricular branch (Arnold nerve) of the vagus nerve can be collectively referred to as a TRP channel agonist (ie, a TRP agonist).

The above-exemplified TRPV1 agonists and other substances that stimulate the Arnold nerve are all known, and can be produced according to known techniques or obtained commercially.

The active ingredient of a preferred therapeutic agent for dysphagia or a preventive agent for swallowing pneumonia is a TRPV1 agonist or a TRPM8 agonist, more preferably capsaicin, a capsinoid compound, or menthol, and more preferably capsaicin.

The amount of the TRPV1 agonist or other Arnold nerve stimulating substance contained in the dysphagia therapeutic agent or the preventive drug for swallowing pneumonia is not particularly limited as long as the therapeutic effect of dysphagia can be obtained by applying to the ear canal. . Therefore, the amount of the TRPV1 agonist or other Arnold nerve stimulating substance contained in the dysphagia treatment drug or the preventive drug for swallowing pneumonia can be appropriately adjusted according to the strength of the actuation force, for example, It may be 0.0001 to 1% by weight, preferably 0.001 to 0.1% by weight.

The therapeutic agent for dysphagia or the preventive agent for dysphagic pneumonia may consist of only a TRPV1 agonist or other substance that stimulates the Arnold nerve, but any other other agents may be used as long as they do not interfere with the therapeutic effect of dysphagia. It may contain a pharmacologically active ingredient, a physiologically active ingredient, and / or an additive. Examples of such pharmacologically active components or physiologically active components include bactericidal components, antipruritic components, vitamins, analgesic components, and herbal medicine components.

Examples of the bactericidal component include acrinol, alkylpolyaminoethylglycine, isopropylmethylphenol, cetylpyridinium, decalinium, benzalkonium, chlorhexidine, cetrimide, resorcin, benzethonium, hinokitiol, benzoic acid, chlorobutanol, acetic acid, phenol, iodotinchi and these Can increase the amount of salt.

Examples of the antipruritic component include crotamiton. Examples of vitamins include vitamin A, vitamin B, vitamin C, vitamin E, derivatives thereof, and salts thereof. Examples of analgesic components include ketoprofen, flurbiprofen, piroxicam, ibuprofen, and mefenamic acid. Examples of the crude drug component include sicon, hamamelis, taisan, toki, horse chestnut seeds, and powders and extracts thereof.

As additives, for example, excipients (water, aqueous solvents, aqueous or oily bases, etc.) commonly used for preparing solids, semisolids, liquids, etc., pH adjusters, buffers, stable Various additives such as an agent, a thickener, a surfactant and a preservative can be mentioned. Although the component of a typical additive is illustrated below, it is not limited to these.

Examples of the excipient include water, animal and vegetable oils (eg, olive oil, corn oil, peanut oil, sesame oil, castor oil, etc.), lower alcohols (eg, ethanol, propanol, propylene glycol, 1,3-butylene glycol). Phenol, etc.), higher fatty acids and esters thereof, waxes, higher alcohol, polyhydric alcohol, hydrophilic petrolatum, purified lanolin, absorption ointment, hydrolanolin, hydrophilic ointment, starch, pullulan, gum arabic, gum tragacanth, gelatin, dextran, cellulose Derivatives (eg, methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, etc.), synthetic polymers (eg, carboxyvinyl polymer, sodium polyacrylate, polyvinyl alcohol) Polyvinylpyrrolidone), propylene glycol, macrogol (e.g. macrogol 200 to 600, etc.), as well as, but are combinations of two or more thereof, but are not limited to.

In particular, as an excipient when a therapeutic agent for dysphagia or a preventive agent for swallowing pneumonia is used as an ointment, higher fatty acids and esters thereof (adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipic acid Esters, myristic acid esters, palmitic acid esters, diethyl sebacate, hexyl laurate, cetyl isooctanoate, lanolin and lanolin derivatives, etc., waxes (whale wax, beeswax, ceresin etc.), higher alcohols (cetanol, stearyl alcohol, ceto) Stearyl alcohol, etc.), hydrocarbons (hydrophilic petrolatum, white petrolatum, purified lanolin, liquid paraffin, etc.), animal and vegetable oils, and combinations of two or more thereof. If desired, in addition to the ointment base, the ointment of the present invention may contain paraffin such as liquid paraffin, lanolin, animal and vegetable oils, natural wax, hydrogenated soybean phospholipid (lecithin), and higher alcohol. .

Examples of pH adjusters include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, and boric acid; lactic acid, acetic acid, citric acid, tartaric acid, malic acid, succinic acid, oxalic acid, gluconic acid, fumaric acid, propion Organic acids such as acid, acetic acid, aspartic acid, glutamic acid, aminoethylsulfonic acid; inorganic bases such as sodium hydrogen carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide; monoethanolamine, tri Examples thereof include organic bases such as ethanolamine, diisopropanolamine, triisopropanolamine, and lysine.

Examples of the buffer include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer, aspartate, and aspartate.

Examples of the stabilizer include dibutylhydroxytoluene (BHT), sodium edetate, sodium sulfite, dry sodium sulfite, and butylhydroxyanisole (BHA).

Examples of the thickener include xanthan gum, hydroxypropylmethylcellulose, hydroxypropylcellulose, macrogol 400, macrogol 1500, macrogol 4000, carboxyvinyl polymer, and the like.

Examples of the surfactant include polysorbate 60, sorbitan stearate, sorbitan monostearate, diethyl sebacate, polyoxyl stearate, polyoxyethylene hydrogenated castor oil 60, and polysorbate 80.

Examples of preservatives include butyl paraben, methyl paraben, propyl paraben, ethyl paraben, sodium benzoate, and benzyl alcohol.

As long as the therapeutic drug for dysphagia or the preventive drug for swallowing pneumonia is in a form suitable for application to the external auditory canal, the formulation form is not particularly limited, and can be any dosage form. From the viewpoint of being suitable for application to the external auditory canal, the therapeutic agent for dysphagia or the preventive agent for swallowing pneumonia is preferably an external preparation for skin, for example, cream, liquid, ointment, gel, lotion , Patches, sprays, aerosols and the like. Of these, creams, liquids, ointments, and patches are preferable.

Swallowing disorder is improved by applying a therapeutic drug for dysphagia to the ear canal. Therefore, the therapeutic agent for dysphagia is applied to the ear canal of a subject (eg, a human) suffering from dysphagia. Here, the application means that a therapeutic agent for dysphagia or a preventive agent for swallowing pneumonia is directly applied (for example, applied) directly to the ear canal. The therapeutic or prophylactic agent may be applied only to the ear canal of either the left or right ear of the subject, or may be applied to the ear canal of both ears. It is preferable to apply alternately to the left and right ear canals. For example, the left and right ear canals have a certain time (for example, 10 seconds, 30 seconds, 1 minute, 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 5 hours, 10 hours, 1 day, 2 days, 3 days, Alternate application at intervals of 4 days, 5 days, 6 days, or 1 week) or more (and / or below) is also a preferred embodiment. It is also preferable to alternately apply to the left and right external auditory canals before a certain period (for example, 1 to 30 minutes) every time when eating or drinking. In other embodiments, it can be applied once a day to a week, or once every 1-3 days. By alternately applying to the left and right external auditory canals, desensitization can be avoided, and dysphagia can be treated more effectively or swallowing pneumonia can be prevented.

The applied amount of the therapeutic agent for dysphagia or the preventive agent for swallowing pneumonia is not particularly limited, and can be appropriately selected as long as a therapeutic effect is obtained. For example, about 0.01 mg to 1 g, preferably 0.05 mg to 0.5 g of the active ingredient can be applied to the ear canal at a time. In addition, the therapeutic agent for dysphagia or the preventive agent for swallowing pneumonia has an application amount of the active ingredient on the skin surface of the ear canal of 0.01 mg to 1 g / cm ² , preferably 0.05 mg to 0.5 g / can be applied so that the cm ^2. Here, the active ingredient means a TRPV1 agonist or other substance that stimulates the Arnold nerve.

The frequency of applying a therapeutic agent for dysphagia or a preventive agent for swallowing pneumonia to the ear canal is also not particularly limited as long as a therapeutic effect is obtained. For example, 10 times / day to 1 time / week, 5 times / day to 1 time / It can be appropriately selected from 3 days, 3 times / 1 day to 1 time / 2 days, 1 to 3 times / day, and the like. The timing of applying the therapeutic agent is not limited as long as it can improve dysphagia and facilitate intake of food and drink. Preferably, the therapeutic agent is applied before eating or drinking. Specifically, in one preferred embodiment, it is applied immediately before and after eating and drinking (for example, 1 minute before) to 2 hours before (more preferably 1 hour before), more preferably 5 to 30 minutes before eating and drinking. is there.

By continuously using a remedy for dysphagia, it may be possible to stably improve dysphagia for a longer period of time. Thus, in a preferred embodiment, the therapeutic agent is administered over a period of time (eg, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 1 month, months, half a year). It is preferable to use continuously for 1 year) or more. By applying the therapeutic agent for dysphagia repeatedly for a certain period, a higher dysphagia improving effect is exhibited.

TRPV1 agonists such as capsaicin are also used as analgesics. Therefore, the subject to which the dysphagia therapeutic agent is applied may suffer from pain in addition to dysphagia, or may be a subject not suffering from pain. In one embodiment, the subject is preferably a patient with mild to moderate dysphagia with a headscore score of 3-7, and in another embodiment, the subject has a severe inability to ingest food or drink. Preferably, the patient suffers from dysphagia.

Test Example 1: One-time administration of capsaicin Ten patients (8 males and 2 females: average age 79.3 years) with mild to moderate dysphagia with a head score (total) of 3-7 points The subject applied 0.5 g of ointment containing 0.025% by weight of capsaicin to the right ear canal, swallowed endoscopically (VE) 5 minutes later, and compared with the score before administration. The ointment was prepared by dissolving 0.025 g of capsaicin in 500 μl of ethanol and kneading with 100 g of hydrophilic ointment. The evaluation of dysphagia was performed by the warhead method and the SMRC method. The evaluation criteria of the warhead method are as shown in Table 1 below, and the combined values of the four items were used for comprehensive evaluation of the swallowing function.

Figure 1 shows the results of evaluation by the Hyodo method. As shown in FIG. 1, by applying capsaicin to the ear canal, the score measured by the warhead method was significantly reduced. This indicates that the application of capsaicin to the ear canal caused a swallowing reflex and improved swallowing function.

The evaluation criteria of the SMRC method are as shown in Table 2 below, and were used for evaluation by swallowing function.

Results of evaluating each swallowing function by the SMRC method are shown in FIG. As a result, it was confirmed that swallowing function was improved by administering capsaicin to the ear canal as a whole. Among these, it was confirmed that the reflection function (R) was significantly improved.

Test Example 2: Persistence of improvement in swallowing function 6 patients with moderate or high dysphagia with a military head score (total value) of 6-8 (5 men, 1 woman: average age 80.6 years) In the same manner as in Test Example 1, 0.5 g of an ointment containing capsaicin was applied to the ear canal once. Then, before application, 5 minutes, 30 minutes, and 60 minutes after application, swallowing endoscopy was performed, and swallowing function was evaluated by the warhead method and SMRC method. FIG. 3 shows the result of the warhead method, and FIG. 4 shows the result of evaluating the reflection function by the SMRC method.

From the results shown in FIG. 3, it was confirmed that the effect of improving swallowing function by administering capsaicin to the external auditory canal lasted at least 60 minutes after administration. This means that, for example, once administered before a meal means that an effect of improving the swallowing function that lasts during the meal can be obtained. The results shown in FIG. 4 show that the improvement in reflex function lasted more than 60 minutes after administration of capsaicin, which confirms the results shown in FIG.

Test Example 3: Improvement of swallowing function by repeated administration 10 patients with moderate or high dysphagia with a head score (total value) of 4-9 (9 males, 1 female: average age 81.3 years) In this manner, 0.5 g of an ointment containing 0.025% by weight of capsaicin prepared in the same manner as in Test Example 1 was alternately applied to the left and right ear canal at a frequency of once a day for one week. Swallowing endoscopy was performed before application, 5 minutes after the first application, and 1 week after application, and the swallowing function was evaluated by the warhead method and SMRC method. FIG. 5 shows the results of the warhead method, and FIG. 6 shows the results of evaluating the reflection function by the SMRC method.

From the results shown in FIG. 5, the repeated swallowing of capsaicin once a day improves the overall swallowing function even more significantly after 1 week than before application or 5 minutes after the first application. Was confirmed. As shown in FIG. 6, all the swallowing functions of perception (S), movement (M), reflex (R), and clearance (C) evaluated by the SMRC method can be performed by repeated administration of capsaicin. It was confirmed that the function was further improved. In particular, the improvement of the reflection function was remarkable. In addition, 8 of the 10 patients who were subjects were unable to take orally before the start of the study, but after 1 week from the start of capsaicin administration, the swallowing function improved and swallowing using jelly was not possible. Direct training became possible, and three of them were able to be taken orally. This is a clinically very significant result. Surprisingly, patients who received repeated doses of capsaicin improved their swallowing function, improved their general condition (PS) and quality of life (PS), and improved their cognitive function. There was also an improvement.

From the results of Test Examples 1 to 3, it is possible to improve the swallowing function by stimulating the ear canal with a substance typified by capsaicin, the improvement effect of the swallowing function is persistent, and repeatedly It was confirmed that further significant improvement in swallowing function can be achieved by repeating the stimulation. With regard to repeated administration of capsaicin, since the possibility of a reduction in the improvement effect due to desensitization was initially considered, the increase in the effect of repeated administration is particularly significant. Moreover, it was confirmed that the improvement of swallowing function by repeated administration of a substance typified by capsaicin is particularly effective for the treatment of patients suffering from moderate to advanced swallowing dysfunction. Thus, since the swallowing function of a patient suffering from dysphagia can be improved by a substance typified by capsaicin, it is considered possible to prevent swallowing pneumonia through the improving action.

The mechanism of the improvement effect of swallowing function by administering capsaicin confirmed as described above to the ear canal will be discussed as follows. That is, stimulation of the vagus nerve sensory branches distributed in the bronchi and pharyngeal mucosa causes cough reflexes and swallowing reflexes. On the other hand, Arnold nerve, which is a branch of the vagus nerve, is distributed in the skin of the ear canal, and stimulation of the ear canal induces cough by vagus reflex through the Arnold nerve. Capsaicin is an agonist of TRPV1, one of the temperature-sensitive channels, and excites sensory nerves. Therefore, stimulation of the ear canal with capsaicin ointment is thought to stimulate the Arnold nerve and induce cough.

On the other hand, the stimulation of the external auditory canal by capsaicin ointment is transmitted from the Arnold nerve to the vagus nerve sensory branch distributed in the pharyngeal mucosa through the axon reflex and releases substance P in a retrograde manner. Substance P releases histamine from submucosal mast cells and stimulates the vagal nerve sensory branch that expresses the histamine H1 receptor. As a result, the mucous membrane of the pharyngeal larynx becomes hypersensitive and the swallowing function is thought to improve.

As these actions function synergistically, it is considered that stimulation of the external auditory canal with capsaicin improves the swallowing function, particularly the glottal closure reflex and cough reflex, in patients with dysphagia (FIG. 7). On the other hand, ACE inhibitors have been reported to reduce the prevalence of swallowing pneumonia. ACE inhibitors also inhibit kininase, a bradykinin-degrading enzyme, thereby enhancing the action of bradykinin and stimulating the vagus nerve sensory branches of the airways to cause a cough reflex. At the same time, swallowing function is improved by axonal reflex. Stimulation of the external auditory canal with capsaicin ointment also causes the same effect, which may be effective in preventing swallowing pneumonia. Also, TRPM8 agonists such as menthol cause similar effects as TRPV1 agonists such as capsaicin stimulate TRPV1, and thus external ear canal stimulation with TRPM8 agonists can improve swallowing function and prevent swallowing pneumonia There is a possibility.

Claims

A therapeutic agent for dysphagia comprising a TRPV1 agonist and used to be applied to the ear canal.
A therapeutic agent for dysphagia comprising a capsaicin compound or menthol and used to be applied to the ear canal.
Item 3. The therapeutic agent according to Item 1 or 2, further comprising a pharmaceutically acceptable excipient.
The therapeutic agent according to claims 1 to 3, which is repeatedly applied to the ear canal at a frequency of once a day to once a week.
A prophylactic agent for swallowing pneumonia, comprising a TRPV1 agonist and used to be applied to the ear canal.
A prophylactic agent for swallowing pneumonia, which contains a capsaicin compound or menthol and is used to be applied to the ear canal.