KR102088662B1 - Medicine for improving dysphagia - Google Patents

Abstract

A substance P (substance P) decomposition enzyme angiotensin (angiotensin) inhibitory action of the enzyme, the composition for improving dysphagia, characterized in that the topical administration of a dose that does not affect blood pressure, and the composition comprising Medicines for improving dysphagia.

Description

Medicine for improving dysphagia {MEDICINE FOR IMPROVING DYSPHAGIA}

The present invention relates to a pharmaceutical composition for the improvement of dysphagia and prevention of aspiration pneumonia.

The dysphagia is often difficult to swallow when eating and drinking, and furthermore, it is often necessary to give up food intake and nutrition in the mouth, which is a big problem from the point of view of QOL. At the same time, mental and physical stress is too great for those who care for eating and drinking. In addition, although the rate of pneumonia increases rapidly as a cause of death in the elderly, most of them are regarded as aspiration pneumonia due to dysphagia.

Symptoms of dysphagia are often due to cerebral vascular disorders, Parkinson's disease, aging, and cerebral basal ganglia injury due to overdosing of antipsychotics. Substance P (synthesis of substance P) propelled by the dopamine neuron decreases as activity of the nigrostriatal dopaminergic neurons decreases in this region. Synthetic material P is released from the nerve endings of the vagal nerve and the glosssopharyngeal nerve sensory branch, causing swallowing reflex. Therefore, a decrease in the amount of substance P is a trigger to cause swallowing (suction) by lowering the swallowing reflection, and in particular, when bacteria in the oral cavity enter the lungs due to inapparent aspiration, it causes septic (suction) pneumonia. . Therefore, the improvement of swallowing reflex is very important in improving QOL and reducing the burden of nursing, or accidental (absorptive) pneumonia, in people with dysphagia who are forced to eat and drink.

Rehabilitation therapy has been performed as a treatment for existing dysphagia. However, in some cases, rehabilitation treatment requires excessive effort on the subject, and in some cases, it is impossible to adapt to the symptoms. According to the following non-patent documents and patent documents, as a countermeasure using drugs, it is a conventional example that capsaicin, which is a spicy component, improves swallowing reflection by promoting the release of substance P at the nerve terminal. It has been reported (Patent Document 1), but it is also pointed out that chronic use of capsaicin causes depletion of substance P. In addition, formulations used to treat Parkinson's disease, such as levodopa or amantadine, are also suggested to improve dysphagia by acting on the dopamine nerve, a black matter progenitor (non-patent document 1), but side effects Essays must be administered carefully. On the other hand, the angiotensin (angiotensin) converting enzyme, as the angiotensin I, the substance P as a substrate, is involved in the decomposition, and by taking the angiotensin converting enzyme inhibitor, it is estimated that the substance P decomposition is suppressed and the dysphagia is estimated to be improved , It has been reported that the development of pneumonia is suppressed (Non-Patent Document 1). However, in order to inhibit the action of an angiotensin converting enzyme by oral administration, an angiotensin converting enzyme inhibitor, when used as a dose as a coercive agent, lowers the blood pressure to a person with normal blood pressure or hypotension. . In particular, in the case of the elderly, excessive blood pressure reduction may cause dizziness, insomnia and fatigue, as well as a decrease in blood flow in the brain, and thus may have various adverse effects. In addition, even if it was a dose as a blood pressure lowering agent, oral administration of an angiotensin converting enzyme inhibitor, improvement of dysphagia was observed only by long-term administration for several weeks or more, and an immediate effect was not confirmed.

[Patent Document 1] Patent Publication 2004-300103

[Non-Patent Document 1] Phenomena and Countermeasures of Aoi Pneumonia, Orui Kow, Senior Citizen The 52nd Annual Meeting of the Japanese Society of Medicine (2010) 47: 558-560

As described above, the compositions or treatments for the prevention of dysphagia or prevention of aspiration pneumonia to date have all been accompanied by side effects. Therefore, the present inventor makes the development of a medicament the first subject for the prevention of miscommunicative (aspiration) pneumonia with less side effects or for improving dysphagia. In addition, a drug containing an angiotensin converting enzyme inhibitory agent applied as a specific administration method as an active ingredient without side effects such as lowering blood pressure and preventing or improving hypotonic pneumonia Let's develop the second task. In addition, although oral administration does not expect a short-term improvement effect of dysphagia after administration, the development of a medicament using an angiotensin converting enzyme inhibitor as an active ingredient, which is adapted to a specific administration method aimed at improving the dysphagia after administration, is the third. Let's do the task.

The present inventors, as a result of various studies in consideration of the above-mentioned matter, by administering an angiotensin (angiotensin) converting enzyme inhibitor to the pharyngeal (pharyngeal) topically, do not show a coercive action, strong dysphagia (dysphagia) It has been shown that improvement can be obtained.

The medicine for improving dysphagia of the present invention, completed according to the above-described results, is characterized in that the angiotensin converting enzyme inhibitory component, which is administered topically to the pharynx, is an active ingredient.

The drug for improving dysphagia of the present invention includes a therapeutic agent for dysphagia and a prophylactic agent for dysphagia.

According to the present invention, an angiotensin (angiotensin) converting enzyme inhibitor, by using a dosing method and / or dosage that does not affect blood pressure, improve dysphagia and prevent accidental (aspiration) pneumonia A pharmaceutical composition that can be expected is provided. In addition, the present invention, it is possible to improve dysphagia (dysphagia) at a time when there is no effect by oral administration, that is, it exhibits immediate efficacy.

1 is a graph showing the results of examining the effect of lowering the swallowing reflection by repeated administration of haloperidol according to Experimental Example 1.
2 is a graph showing the results of investigating the effect of improving the swallowing reflex by topical administration of the pharyngeal portion of a captopril aqueous solution in a model of guinea pig dysphagia repeatedly administered haloperidol according to Example 1 .
3 is a graph showing the results of investigating the effect of improving the swallowing reflex by topical administration of the pharyngeal portion of the lysinopril aqueous solution in the guinea pig dysphagia model repeatedly administered with haloperidol according to Example 2.
[Fig. 4] Lowering of swallowing reflection by topical administration of the pharyngeal portion of the substance P receptor antagonist of the normal guinea pig according to Example 3 and improvement effect by pre-local administration of the capdopryl aqueous solution to the pharyngeal portion It is a graph showing the results of the investigation.
[Fig. 5] In the guinea pig dysphagia model repeatedly administered with haloperidol according to Example 4, for the effect of improving the swallowing reflex due to topical administration of the pharyngeal portion of the aqueous solution of lysinopril, by topical administration of the pharyngeal portion of the substance P receptor antagonist It is a graph showing the results of investigating the action.
6 is a graph showing the results of examining the effect of improving the swallowing reflex after 30 minutes of administration according to topical administration of the pharyngeal portion of the captopril aqueous solution and oral systemic administration in the guinea pig dysphagia model repeatedly administered with haloperidol according to Comparative Example 1.
7 is a graph showing the results of examining the effect of improving the swallowing reflex after 120 minutes after administration according to topical and oral systemic administration of the pharyngeal part of the lysinopril solution in the guinea pig dysphagia model repeatedly administered with haloperidol according to Comparative Example 2 to be.
8 is a graph showing the results of investigating the effects of pre-administration of captopril aqueous solution and lisinopril aqueous solution according to an increase in blood pressure by intravenous administration of angiotensin I in normal rats according to Comparative Example 3.

1. Drug for improving dysphagia: an angiotensin converting enzyme inhibitor

An angiotensin converting enzyme inhibitory substance is an inhibitor of an enzyme that converts angiotensin I to angiotensin II, and is generally used in the treatment of hypertension. The angiotensin converting enzyme also degrades the substance P having low substrate selectivity into the substrate. By taking an angiotensin-converting enzyme inhibitory action substance, it is possible to improve the dysphagia by suppressing the decomposition of substance P and increasing the concentration of substance P in the body.

In the present invention, angiotensin converting enzyme inhibitory substances are mainly captopril, lisinopril, enalapril, benazepril, imidaapril, aracepril ), Perindopril, Kinapril, Temoapril, TRANSADLAPRIL, Cirazapril, Deapril, etc. and their active metabolites.

2. Mode of administration: Route of administration

The drug for improving dysphagia using the angiotensin-converting enzyme inhibitory substance of the present invention as an active ingredient can be administered to the active ingredient topically. More specifically, the drug for improving dysphagia of the present invention contains an active ingredient of an angiotensin converting enzyme inhibitory substance in the oral cavity (intraoral site), pharyngeal site, laryngeal site, and respiratory tract. And an agent for improving dysphagia administered topically to at least one selected site. By topically administering to at least one site selected from the pharynx, larynx and airways as above, it is possible to improve dysphagia with immediate effect without causing a decrease in blood pressure caused by an angiotensin-converting enzyme-inhibiting substance. ) It can prevent aspiration pneumonia.

More preferably, the drug for improving dysphagia of the present invention includes a drug for improving dysphagia by topically administering an angiotensin converting enzyme inhibitory agent of an active ingredient to the pharynx. For topical administration, it can be used, for example, in a form applied directly to the pharyngeal mucosa.

3. Dosage Form

The drug for improving dysphagia of the present invention is adapted to be absorbed by intraoral mucosa, pharyngolaryngeal mucosa and respiratory tract mucosa. More specifically, it can be used as a liquid agent, such as a spray containing an active ingredient angiotensin converting enzyme inhibitory substance, a film preparation, an adhesive in the oral cavity and pharynx, a sprayer, and direct application.

(1) Examples of the film preparation or the edible and water-soluble film base used for adhesion in the oral cavity and pharynx include, for example, gelatin, pectin, arabinoxylan, sodium alginate, carrageenan, xanthan gum, Guar gum, pullulan, hypromerose, hydroxy propyl cellulose, water-soluble hydroxy ethyl cellulose, methyl cellulose, carboxy methyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone (Polyvinylpyrrolidone), polyethylene glycol, etc. can be used. have.

(2) As a carrier used for inhalants (sprayers) or sprays (sprays), sugars, sugar alcohols, amino acids and / or inorganic salts can be used. Examples of sugars include lactose, glucose, sucrose, maltose, trehalose, maltodextrin, dextran, and the like. Sugar alcohols include mannitol, xylitol, erythritol, maltitol, sorbitol, arabitol, xylose, and the like. Examples of amino acids include leucine, isoleucine, lysine, valine, threonine, methionine, cysteine, cystine, phenylalanine, tryptophan, and glycine. Examples of the inorganic salts include calcium carbonate, sodium chloride, and calcium phosphate. Preferably lactose can be used.

(3) The liquid agent for direct application can add an emulsifying agent, a suspending agent or a preservative as needed. Examples of emulsifiers include polysorbate 80, laurocrocrogol, glyceryl monostearate, sodium lauryl sulfate, and lecithin. Polyvinyl suspending agents Alcohol, popidone, sodium carmellose, methyl cellulose, hydroxy propyl cellulose, hydroxy methyl cellulose, sodium alginate, gum arabic, and the like.

4. Target

The drug for improving dysphagia of the present invention can be administered to a patient with dysphagia or a patient with dysphagia, an elderly person, a patient with cerebrovascular disorder, a patient with Parkinson's disease, or a person receiving treatment for a psychotic drug.

In addition, since spraying, spraying, or direct application is a method that does not require a swallowing action, it can be used regardless of the degree of dysphagia. Therefore, for severe dysphagia, it is preferable to administer by spraying, spraying, or directly applying.

5. Time and frequency of administration

The swallowing disorder improving agent of the present invention may be administered topically to the pharynx, larynx, and / or airways. Single topical administration means the first administration when used several times a day or repeated administration, and a swallowing improvement effect can be obtained at each administration time. In addition, the present invention can improve dysphagia at a time when there is no effect expression when administered orally. That is, since it is immediate-acting, an angiotensin converting enzyme inhibitor component can be applied directly to the pharyngeal mucosa, preferably, for example, before every meal and / or before bedtime, more preferably 30 minutes before that.

6. Dosage

A single dose may be an amount that does not show a drop in blood pressure, and an amount that improves dysphagia, and can improve the dysphagia in an amount that is much less than the amount required to lower the blood pressure. More specifically, the single dose is less than the minimum dose at which a hypotensive action is expected, preferably an amount of 1/10, more preferably an amount of 1/100. For example, in the case of lisinopril, the single dose is 250 μg, which is less than the minimum dose (2.5 mg) expected to lower blood pressure when administered to humans, and preferably 1/10 of that. It is 25 μg, and can be reduced to 1 μg according to the following examples. That is, in the case of lysinopril, which maintains high inhibitory activity in the angiotensin-inhibiting substance used in the example, the weight-reducing effect dose obtained in the following example is 5 ng / kg when the body weight is calculated, and the weight of a general person is 60 kg. When the dose is 300 ng or more / time, a swallowing improvement effect can be obtained.

Hereinafter, the present invention will be described in detail in Examples and the like, but the present invention is not intended to be any limited interpretation by the following description.

As described above, it is known that dysphagia caused by a cerebral basal ganglia disorder is caused by administration of an antipsychotic drug that suppresses the action of dopamine neurons such as haloperidol. Accordingly, the present inventors constructed an animal model for dysphagia-induced dysfunction caused by repeated overdosage of haloperidol, and evaluated drug efficacy.

[Experimental Example 1]

6 weeks old Hartley-based female guinea pigs (330-390 g) raised 1 week after arrival, physiological saline or haloperidol (haloperidol) solution at a dose of 1 mg / kg, twice a day at approximately 12 hour intervals, 7 Daily injections were made subcutaneously. Thereafter, the guinea pig limbs were fixed and 500 μl of distilled water was injected into the site immediately before the pharynx with a spray device over about 5 seconds, and the number of swallowing up to 10 and 30 seconds was injected, based on the pharyngeal muscle movement. It was measured by. Then, physiological saline or haloperidol solution (1 mg / kg) was injected again.

[result]

The measurement was conducted four times at 1 minute intervals. The results are shown in FIG. 1. As can be seen in Figure 1, the number of negative (의 水) of the repeated administration group of haloperidol was significantly decreased compared to the guinea pig group repeatedly administered with saline. Based on these results, a model of guinea pig dysphagia caused by repeated administration of haloperidol was used in the evaluation of drug effect in the following experiment.

[Example 1] Effect of topical administration of captopril

As in Experimental Example 1, 6 weeks of Hartley-based female guinea pigs (330 to 390 g) were repeatedly administered 1 mg / kg of haloperidol solution, and on the 8th day, the above as well as negative reflex were measured and the values were determined in advance. initial value). The following day, 100 μl of distilled water or captopril 50 mM, 50 μM and 50 nM aqueous solution (pH 7.0) was sprayed directly into the guinea pig pharyngeal mucosa in single doses using a spray device. . After 30 minutes of spraying, negative reflections were measured as well as prior value measurements (measured values).

The results are shown in FIG. 2. As can be seen in Figure 2, the distilled water spray group did not show a significant change in the number of negative numbers, but a significant increase in negative number was observed in the captopril 50 mM and 50 μM aqueous solution spray group.

[Example 2] Effect of topical administration of lysinopril

As in Example 1, a model of guinea pig dysphagia causing repeated administration of haloperidol was prepared, and 100 μl of 0.5 nM to 500 μM aqueous solution (pH 7.0) of ricinopril was applied to the guinea pig pharyngeal mucosa using a spray device. By spraying directly, the effect on negative reflection was measured.

The results are shown in FIG. 3. As can be seen in FIG. 3, the distilled water spray group did not show a significant change in the number of negative water, but an increase in negative number was observed in a dose-dependent manner in the lisinopril aqueous solution spray group, and in the case of 50 nM or more, the captopril 50 μM aqueous solution spray group was the same. Significant negative number increased.

[Example 3] Participation of substance P and prevention of dysphagia

FK888 (10 μM, 50 μl / guinea pig), a substance P receptor antagonist, was administered topically to the guinea pig pharyngeal region once with a spray device and the number of negative reflections was measured as in Experiment 1.

The results are shown in FIG. 4. As can be seen in Figure 4, a decrease in swallowing reflex was observed by topical administration of the FK888 pharynx. In addition, 30 minutes before administration of FK888, as a result of single topical administration of captopril aqueous solution to the pharynx in a spray-type newsletter as in Example 1, the decrease in swallowing reflex due to FK888 administration was suppressed.

[Example 4] Mechanism for improving the participation and dysphagia of substance P

A guinea pig swallowing model inducing repeat administration of haloperidol was prepared, and 100 μl of a 50 nM aqueous solution of lisinopril was directly sprayed directly onto the mucous membrane of the neck using a spray-type newsletter, and then the lower limit dose not affect swallowing reflex. Phosphorus 10 nM, 100 μl of the substance P receptor antagonist, FK888, was topically administered to the mucous membrane of the pharynx using a sprayer to measure the number of negative numbers as in Experimental Example 1.

The results are shown in FIG. 5. As can be seen in FIG. 5, the increase in the number of negative numbers observed after 30 minutes of administration of 100 μl of a 50 nM aqueous solution of lisinopril was almost completely suppressed by FK888 (10 nM, 100 μl) administration 15 minutes after administration of lisinopril.

[Comparative Example 1] Advantages of captopril topical administration

In the action of improving dysphagia caused by an angiotensin converting enzyme inhibitory substance, changes in negative number were compared by oral administration (intragastric administration, p.o.) and topical administration (s.i.) to the pharyngeal mucosa using nebulizers. As in Example 1, a model of guinea pig dysphagia inducing repeated administration of haloperidol was prepared, and 100 μl single topical administration of captopril 50 μM aqueous solution or 50 mM aqueous solution to the pharyngeal mucosa using a sprayed newsletter, or the same dose of captopril Was orally administered (administered in the stomach). Negative times were measured 30 minutes after administration.

The results are shown in FIG. 6. As can be seen from FIG. 6, oral administration of any 50 μM aqueous solution of captopril and 50 mM aqueous solution, compared to that of improving the dysphagia 30 minutes earlier after administration, by single topical administration of 100 μl Did not go crazy.

[Comparative Example 2] Advantages of topical administration of lysinopril

As in Comparative Example 1, in the action for improving dysphagia caused by lysinopril, changes in negative number were compared by oral administration (administered intragastrically, p.o.) and topical administration to the pharyngeal mucosa (s.i.). A guinea pig swallowing model inducing repeated doses of haloperidol was prepared, and 100 μl of a 50 mM solution of lisinopril was topically administered to the pharyngeal mucosa using a spray-type newsletter, or the same dose of lisinopril was administered orally (into the stomach). Negative times were measured 2 hours after administration (the time at which the blood concentration was maximized in oral administration).

The results are shown in FIG. 7. As can be seen in FIG. 7, by topical administration of lysinopril 50 mM aqueous solution, 100 µl, dysphagia was improved 2 hours after administration, while oral administration was not affected.

[Comparative Example 3] Effect on angiotensin I-induced blood pressure elevation

Examples 1 and 2 showed improvement of dysphagia, SD-type male rats (350) for the effect on blood pressure of 100 μl of captopril 50 μM aqueous solution or 100 μl of ricinopril 5 μM aqueous solution ~ 400 g). Each dose of captopril or ricinopril aqueous solution was administered orally, and blood pressure was measured after 1 hour. After that, angiotensin I was administered intravenously (300 ng / kg) to induce an increase in blood pressure and measure the change in average blood pressure.

The results are shown in FIG. 8. As can be seen in Figure 8, while suppressing the step-up reaction by administration of angiotensin I, 100 μl of captopril 50 mM solution or 100 μl of ricinopril 5 mM aqueous solution is suppressed, 100 μl of captopril 50 μM aqueous solution or 5 μM lisinopril aqueous solution 100 μl administration did not affect.

Overdosage of haloperidol is known to cause a decrease in swallowing reflex along with a decrease in the amount of substance P in the blood in human clinical trials, and it is considered that the haloperidol repeated administration induced guinea pig dysphagia model used in the present invention reflects the human clinical condition.

In Example 1, Example 2, and Comparative Example 3, it was found that an angiotensin converting enzyme inhibitory substance having a dose that does not affect blood pressure was administered topically to the pharynx to improve the swallowing reflex reduction.

In Example 3, a single topical administration of an angiotensin converting enzyme inhibitory substance to the pharyngeal region suppresses substance P decomposition in the pharyngeal tissue, and presumably suppresses dysphagia caused by the substance P receptor antagonist substance. do. In addition, in Example 4, a single topical administration of an angiotensin converting enzyme inhibitory agent to the pharyngeal region inhibits the degradation of substance P in the pharyngeal tissue, thereby enhancing the cause of swallowing reflexes by substance P. , It is thought that it improved the disorder of the guinea pig dysphagia model caused by repeated administration of haloperidol.

In Example 1, Example 2, Comparative Example 1, Comparative Example 2, and Comparative Example 3, the angiotensin-converting enzyme inhibitor was administered topically once to improve dysphagia at a low dose that does not affect blood pressure. It was judged that an improvement effect of early dysphagia that could not be obtained by oral administration could be obtained. In Comparative Example 1, a dose of 50 mM aqueous solution of captopril, 100 µl is a dose showing a predominant blood pressure lowering effect in various animal models. In addition, the dose of 50 mM, 100 µl of the lysinopril aqueous solution of Comparative Example 2 is almost the same as the clinical dose as a therapeutic agent for hypertension in humans according to the body weight exchange rate, but is a dose that exhibits a sufficient blood pressure lowering effect in humans and animals, but the blood concentration. Oral administration was not observed to improve dysphagia even at the highest time point. In other words, it was judged that even if the dose used for the treatment of hypertension was orally taken in human clinical practice, an early improvement effect of dysphagia on topical administration was not obtained. From the above results, a single topical administration to the pharynx of an angiotensin converting enzyme inhibitory substance does not induce depletion of substance P in the nerve endings, and also decreases blood pressure, such as taking dopamine preparations and angiotensin converting enzyme inhibitory substances orally. It is considered to be an excellent method of use as a drug for improving dysphagia, which does not involve various side effects of and can have early effects after administration.

All publications, patents and patent applications cited in this specification are incorporated into this specification by reference.

Claims (5)

Angiotensin converting enzyme inhibitory agent, and contains only lisinopril as an active ingredient; And
The dose of lysinopril is a dose that does not show a drop in blood pressure, and the dose that improves dysphagia is a dose of less than 2.5 mg / time to 300 ng / time or more,
The dysphagia improver for topical administration to the throat (pharyngolaryngeal site), and the dysphagia improver for topical administration, characterized in that it is administered by spray, spray, or direct application.
The agent for improving dysphagia for topical administration according to claim 1, wherein the dose is a dose that does not exhibit a drop in blood pressure, and is a dose that improves dysphagia.
The agent for improving dysphagia for topical administration according to claim 1 or 2, characterized in that it improves dysphagia at a time when oral administration does not express an effect.
delete delete

Images