KR20160018806A - Medicine for improving dysphagia - Google Patents

Abstract

A composition for improving dysphagia characterized by locally administering an inhibitor of angiotensin converting enzyme which is a substance P (substance P) degrading enzyme to a dose not affecting blood pressure, Drugs for improving dysphagia.

Description

{MEDICINE FOR IMPROVING DYSPHAGIA}

The present invention relates to a pharmaceutical composition for improving dysphagia and preventing aspiration pneumonia.

Swallowing disorders are often difficult to swallow when they eat and drink, and in many cases they have to give up their food intake and nutrition in their mouths, which is a big problem from a QOL point of view. At the same time, mental and physical stress is too great for those who care about eating and drinking. In addition, the proportion of pneumonia in the elderly is rapidly increasing as the cause of death, but most of them are regarded as aspiration pneumonia due to dysphagia.

Symptoms of dysphagia are often due to cerebral basal gang injury due to cerebrovascular disorders, Parkinson's disease, aging, and overdose of antipsychotic drugs. The degradation of nigrostriatal dopaminergic neurons in this area diminishes the synthesis of substance P controlled by the dopaminergic neurons. The synthesized substance P is released from the nerve endings of the vagal nerve and the glottopharyngeal nerve sensory branch, causing a swallowing reflex. Therefore, the reduction of the amount of substance P is an opportunity to induce the ashes (aspiration) by lowering the dorsal reflex. Especially, when the bacteria in the oral cavity enter the lungs due to inapparent aspiration, . Therefore, the improvement of swallowing reflex is important for the improvement of the QOL and the burden of nursing care, or prevention of the pneumonia (aspiration) pneumonia of the swallowing disorder holders who are forced to inconvenience by eating and drinking.

Rehabilitation therapy has been performed as a treatment for existing swallowing disorders. However, rehabilitation treatment may force the subject to excessive effort, and may not be able to adapt to the symptoms. According to the following non-patent documents and patent documents, as a countermeasure using a drug or the like, capsaicin, which is a spicy ingredient, promotes the release of substance P at the nerve endings, (Patent Document 1), but it has also been pointed out that the chronic use of capsaicin causes depletion of substance P. It has also been suggested that a preparation used for the treatment of Parkinson's disease such as levodopa or amantadine acts on dopaminergic neuron dopaminergic neurons to improve dysphagia (Non-Patent Document 1) , It should not be administered carefully. On the other hand, angiotensin converting enzyme is involved in degradation of substance P as a substrate in the same manner as angiotensin I, and it is presumed that the substance P degradation is suppressed by the administration of angiotensin converting enzyme inhibitor to improve swallowing disorder , And the incidence of pneumonia is suppressed (Non-Patent Document 1). However, in order to inhibit the action of angiotensin converting enzyme by oral administration, an angiotensin converting enzyme inhibitor is used as a pressure-reducing agent as it is, and when blood pressure is lowered to a person having normal blood pressure or hypotension, caution is required in use . In particular, in the case of the elderly, excessive blood pressure lowering may result in various adverse effects as the brain blood flow decreases as well as dizziness, insomnia and fatigue. In addition, oral administration of an angiotensin converting enzyme inhibitor showed improvement in dysphagia only by prolonged administration for several weeks or more, even if it was a blood pressure lowering agent, and no immediate effect was confirmed.

[Patent Document 1] JP-A-2004-300103

[Non-Patent Document 1] Phenomenon and countermeasures of aspiration pneumonia in elderly people of Oruuikou The 52nd Annual Meeting of the Japan Society of Geriatric Medicine (2010) 47: 558-560

As described above, the composition or the treatment for prevention of aspiration pneumonia or the improvement of dysphagia to date has accompanied all side effects inevitably. Therefore, the first problem of the present inventors is to develop a medicament for the prevention of pneumonia (aspiration) pneumonia with less side effects or for the improvement of dysphagia. In addition, there is also provided a pharmaceutical composition comprising, as an active ingredient, an angiotensin converting enzyme inhibitory agent, which is applied by a specific administration method, which does not involve side effects such as blood pressure lowering and prevents the prevention of pneumoconiosis (aspiration) As a second problem. In addition, the oral administration does not expect a short-term swallowing improvement effect after administration, but the development of a medicament containing an angiotensin converting enzyme inhibitory agent, which is adapted to a specific administration method for improving swallowing disorder after administration, .

As a result of various studies in view of the above-mentioned facts, the inventors of the present invention found that administration of an angiotensin converting enzyme inhibitory substance to the pharyngeal locale does not produce a coercive action, Improvement effect can be obtained.

The drug for improving dysphagia according to the present invention, which is completed according to the above-described results, is characterized by using an angiotensin converting enzyme inhibitory component, which is locally administered to the pharynx, as an active ingredient.

The drug for improving swallowing disorder of the present invention includes a therapeutic agent for dysphagia and an agent for preventing dysphagia.

According to the present invention, an angiotensin converting enzyme inhibitory substance can be administered orally or parenterally to the patient by administering a dose and / or administration dose that does not affect blood pressure to improve swallowing disorder and to prevent aspiration pneumonia (aspiration pneumonia) Can be expected. In addition, the present invention can improve dysphagia at a time when oral administration is not effective, that is, exhibits immediate effect.

1 is a graph showing the results of examining swallowing reflex reduction effect by repeated administration of haloperidol according to Experimental Example 1. FIG.
2 is a graph showing the results of examining the effect of improving the swallowing reflex by topical administration of a pharyngeal part of an aqueous solution of captopril in a guinea pig swallowing disorder model administered repeatedly with haloperidol according to Example 1 .
[Fig. 3] A graph showing the results of examining the effect of topical administration of pharyngeal part of ricinofluric aqueous solution for improving swallowing reflex in a guinea pig swallowing disorder model administered repeatedly with haloperidol according to Example 2. Fig.
[Figure 4] Reduction of swallow reflection due to local administration of the pharyngeal part of the substance P receptor antagonistic substance of the normal guinea pig according to Example 3 and an improvement effect according to local administration to the pharyngeal part of the aqueous solution of the captopril And the results are shown in FIG.
5 is a graph showing the effect of topical application of the pharyngeal part of the substance P receptor antagonist on the hypo-reflex action of the pharyngeal part of the aqueous solution of lisinopril in the model of guinea pig swallowing disorder administered repeatedly with haloperidol according to Example 4 The results are shown in FIG.
FIG. 6 is a graph showing the results of examining the effect of oral administration of the pharyngeal part of the aqueous solution of the cortoflur in oral guinea pig swallowing disorder model repeatedly administered with haloperidol according to Comparative Example 1, and the effect of improving the swallowing reflex after 30 minutes of administration.
7 is a graph showing the results of examining the effect of oral administration of oral phytopathogenic ricinoflur in aqueous humor of ritinopril in the model of guinea pig swallowing disorder repeatedly administered with haloperidol according to Comparative Example 2, to be.
8 is a graph showing the results of examining the effect of an aqueous solution of a captoppyrl solution and an aqueous solution of ricinopril according to an increase in blood pressure by administration of an angiotensin I vein in a normal rat according to Comparative Example 3. Fig.

1. Improvement of dysphagia: Angiotensin converting enzyme inhibitor

Angiotensin converting enzyme inhibitors are inhibitors of enzymes that convert angiotensin I to angiotensin II and are commonly used in the treatment of hypertension. Angiotensin converting enzyme decomposes substance P with low substrate selectivity into substrate. By taking an angiotensin converting enzyme inhibitory substance, it is possible to suppress the decomposition of substance P, thereby increasing the concentration of substance P in the body, thereby improving swallowing disorder.

In the present invention, the angiotensin converting enzyme inhibitory substance is mainly selected from the group consisting of captopril, lisinopril, enalapril, benazepril, imidapril, alacepril ), Perindopril, quinapril, temocapril, TRANDOLAPRIL, Cilazapril, delapril, etc., and their active metabolites.

2. Mode of administration: Route of administration

The effective ingredient of the angiotensin converting enzyme inhibitory substance of the present invention can be administered topically, as an effective ingredient for improving swallowing disorders. More specifically, the drug for ameliorating the swallowing disorder of the present invention comprises an effective amount of an angiotensin converting enzyme inhibitory substance in an intraoral site, a pharyngeal site, a laryngeal site, and a respiratory tract And at least one site selected from the group. As described above, the topical administration to at least one site selected from the pharynx, larynx and airways can improve the swallowing disorder with an immediate effect without causing the blood pressure lowering effect by the angiotensin converting enzyme inhibitory substance, Aspiration pneumonia can be prevented.

More preferably, the drug for improving swallowing disorder of the present invention includes a drug for improving swallowing disorder, which locally administers an angiotensin converting enzyme inhibitory substance of the active ingredient to the pharynx. The topical administration can be carried out, for example, in the form of being applied directly to the pharyngeal mucosa.

3. Dosage Formulation

The swallowing disorder remedy of the present invention is adapted to be absorbed into an intraoral mucosa, a pharyngolaryngeal mucosa, and a respiratory tract mucosa. More specifically, it may be a liquid preparation such as a spray, film preparation, adhesive in the oral cavity or in the mouth, sprayer, or direct application containing the active ingredient angiotensin converting enzyme inhibitory substance.

(1) Examples of film-based and water-soluble film base materials used in film formulations or oral / intraoral adhesions include, for example, gelatin, pectin, arabinozylan, sodium alginate, carrageenan, Polyvinylpyrrolidone, polyethyleneglycol, etc. may be used as the filler, such as polyvinylpyrrolidone, polyvinylpyrrolidone, polyvinylpyrrolidone, polyvinylpyrrolidone, polyvinylpyrrolidone, polyvinylpyrrolidone, polyvinylpyrrolidone, have.

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

(3) An emulsifier, a suspending agent or a preservative may be added to the liquid for direct coating if necessary. Examples of the emulsifier include polysorbate 80, Lauromacrogol, glyceryl monostearate, sodium lauryl sulfate, and lecithin. Examples of the suspending agent include polyvinyl Alcohol, propidone, carmellose sodium, methylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, sodium alginate, and gum arabic.

4. Subjects to be administered

The swallowing disorder remedy of the present invention may be administered to a patient suffering from swallowing disorder, a patient suffering from swallowing disorder, an elderly person, a cerebrovascular disorder patient, a Parkinson's disease patient, or a person receiving psychotropic drug.

In addition, since spraying, spraying or direct application is a method that does not require submergence operation, it can be used regardless of the degree of swallowing dysfunction. Thus, for severe swallowing disorders, it is preferable to administer by spray, spray or direct application.

5. Time and time of administration

The dysphagia remedy of the present invention can be administered topically to the pharynx, larynx and / or airways. The single local administration means the first administration when used several times a day or repeatedly, and the swallowing improving action can be obtained at each administration time. Furthermore, the present invention can ameliorate dysphagia at a time when the oral administration does not show an effect. That is, since it is immediate, it is preferable to apply the angiotensin converting enzyme inhibitor component directly to the pharyngeal mucosa, for example, before every meal and / or before bedtime, more preferably 30 minutes before that.

6. Dosage

A single dose can improve the swallowing disorder in an amount that does not exhibit hypotension, and an amount that improves swallowing disorder, and in a much smaller amount than is required for hypotension. More specifically, the single dose is an amount less than the expected minimum dose, preferably 1/10, more preferably 1/100 the hypotensive effect. For example, in the case of lisinopril, a single dose is 250 μg, which is a dose of less than the expected minimum dose (2.5 mg), preferably 1/10, of hypotensive effect when administered to humans, more preferably 25 μg, and can be reduced to 1 μg according to the following examples. That is, in the case of ricinopril, which maintains a high inhibitory activity on the angiotensin inhibitory agent used in the examples, the swallowing improving action capacity obtained in the following examples is 5 ng / kg in terms of body weight, and the body weight of a human being is 60 kg If the dose is more than 300 ng / dose, the effect of improving the dysphagia can be obtained.

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

As described above, it is known that swallowing disorders caused by cerebral basal ganglia are caused by the administration of antipsychotic drugs that inhibit the action of dopaminergic neurons such as haloperidol. Thus, the present inventors constructed an animal model of impaired swallowing induced by overdose of haloperidol, and conducted a drug efficacy evaluation.

[Experimental Example 1]

A physiological saline solution or a haloperidol solution was administered at a dose of 1 mg / kg to a 6-week-old Hartley female (female) guinea pig (330 ~ 390 g) I was injected subcutaneously daily. Thereafter, the guinea pig limbs were fixed and 500 μl of distilled water was injected into the area immediately before the pharynx with a spray device over a period of about 5 seconds, and the number of times of swallowing up to 10 seconds and 30 seconds, . Then, saline or haloperidol solution (1 mg / kg) was injected again.

[result]

The measurement was carried out four times at intervals of one minute. The results are shown in Fig. As can be seen from Fig. 1, the number of water-drinking cycles of the haloperidol-treated group was significantly lower than that of the group administered repeatedly with physiological saline. Based on these results, it was used as a haloperidol-induced guinea pig swallowing disorder model in the following experiments to evaluate drug efficacy

[Example 1] Effect of topical administration of captopril

In the same manner as in Experimental Example 1, a 1 mg / kg haloperidol solution was repeatedly administered to a 6 week Hartley female (female) guinea pig (330 to 390 g), and the water reflection on the 8th day was measured, initial value). The following day, 100 μL of 50 mM, 50 μM and 50 nM aqueous solution (pH 7.0) of distilled water or captopril were directly sprayed in a single dose on the guinea pig pharyngeal mucosa using a spray device . After 30 minutes of spraying, negative water reflection as well as pre-measurement was measured (measured value).

The results are shown in Fig. As can be seen in FIG. 2, no significant change in the number of negative numbers was observed in the distilled water spray group, but a significant increase in the negative number was observed in the 50 mM and 50 μM aqueous solution spray of the captopril.

[Example 2] Effect of local administration of ricinopril

As in Example 1, a haloperidol-induced guinea pig swallowing disorder model was prepared and 100 μl of 0.5 nM to 500 μM aqueous solution (pH 7.0) of lisinopril was applied to the guinea pig pharyngeal mucosa using a spray device And the effect on negative reflection was measured.

The results are shown in Fig. As can be seen from FIG. 3, although the number of the negative number of the distilled water spray group did not change greatly, the number of the negative number increase was observed in the dose of the lisinopril aqueous solution group. In the case of the 50 nM or more dose, Significant negative numbers were increased.

[Example 3] Prevention of participation and swallowing disorder of substance P

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

The results are shown in Fig. As can be seen from Fig. 4, a decrease in swallowing reflex was observed by topical administration of FK888 pharyngeal portion. In addition, as in Example 1, the aqueous solution of the captoppyrr was locally administered to the pharynx in the pharynx at 30 minutes prior to the administration of FK888. As a result, the decrease of the asphyxia caused by administration of FK888 was suppressed.

[Example 4] Mechanism of action of substance P to improve participation and swallowing disorder

A model of swallowing guinea pig swallowing haloperidol was prepared, and 100 μl of 50 nM ricinopril aqueous solution was sprayed directly onto the mucous membrane of the neck using a spray type remover, and then the lower limit dose 10 nM, 100 μl of substance P receptor antagonist FK888 was administered topically to the mucosa of the pharynx using a pulse-type remover, and the number of negative cycles was measured as in Experimental Example 1. [

The results are shown in Fig. As can be seen from Fig. 5, the increase in the number of negative counts observed after 30 minutes of administration of 100 占 퐇 of 50 nM aqueous solution of lisinopril was almost completely inhibited by the administration of FK888 (10 nM, 100 占 퐇) 15 minutes after administration of lisinopril.

[Comparative Example 1] Advantages of Topical Administration of Captopril

The effect of angiotensin converting enzyme inhibitory action on the dysphagic disorder was compared between the oral doses (p.o.) and the pharyngeal mucosa (s.i. Similarly to Example 1, a haloperidol-induced guinea pig swallowing disorder model was prepared, and either 50 μM aqueous solution of capto pril or 50 mM aqueous solution was administered to the pharyngeal mucosa using a single dose of 100 μl, (Administered in the stomach). The number of negative counts was measured 30 minutes after administration.

The results are shown in Fig. As can be seen from Fig. 6, compared with the oral administration of 50 μM aqueous solution of 50 μM of captoflur and the aqueous solution of 50 mM, .

[Comparative Example 2] Benefits of local administration of lisinopril

Similar to Comparative Example 1, changes in the number of negative counts were compared with oral administration (administered in the stomach) and local administration (s.i.) in the pharyngeal mucosa in the dysphonic dysfunction improvement effect of lisinopril. A haloperidol induced guinea pig swallowing model was prepared, and 100 μl of a 50 mM solution of ricinopril was administered topically to the pharyngeal mucosa or sprayed with the same dose of ricinopril by intramuscular route (using stomach). The number of negative counts was measured 2 hours after the administration (the time when the blood concentration was maximized in oral administration).

The results are shown in Fig. As can be seen from Fig. 7, oral administration of ricinopril did not affect the swallowing disorder improving effect even after 2 hours of administration by the local administration of 50 mM aqueous solution, 100 μl.

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

Example 1 and Example 2 showed improvement in dysphagia. The effect on blood pressure of 100 μl of 50 μM aqueous solution of captopril and 100 μl of 5 μM aqueous solution of ricinopril was investigated in SD male rats (350 ~ 400 g). Captopril or ricinopril aqueous solution of each dose was orally administered and blood pressure was measured after 1 hour. Then, angiotensin I was intravenously administered (300 ng / kg) to induce an increase in blood pressure and the change in mean blood pressure was measured.

The results are shown in Fig. As can be seen from FIG. 8, administration of 100 μl of a 50 mM solution of a captopril / 50 mM solution or 100 μl of an aqueous solution of lisinopril 5 μM was inhibited by an angiotensin I administration, but 100 μl of a 50 μM aqueous solution of capto prilyl or a 5 μM aqueous solution of lisinopril 100 μl administration did not affect.

It is known that the overdose of haloperidol induces a decrease in swallowing reflexes together with a decrease in the amount of blood substance P in human clinical trials. It is believed that the haloperidol repeated-dose-induced guinea pig swallowing disorder model used in the present invention reflects human clinical status.

In Example 1, Example 2, and Comparative Example 3, it was found that swallowing reflex deterioration was improved by a single local injection of an angiotensin converting enzyme inhibitory substance having no effect on blood pressure to the pharynx.

In Example 3, monocyclic local administration to the pharyngeal portion of the angiotensin converting enzyme inhibitory substance inhibited substance P degradation in pharyngeal tissues, which inhibited dysphagia caused by the substance P receptor antagonist substance in advance, do. In addition, in Example 4, the monocyclic local administration of the angiotensin converting enzyme inhibitory substance to the pharynx suppresses the decomposition of the substance P in the pharyngeal tissues, so that the substance P causes swallowing reflex induction , And haloperidol-induced guinea pig swallowing disorder model.

In Example 1, Example 2, Comparative Example 1, Comparative Example 2, and Comparative Example 3, the angiotensin converting enzyme inhibitor was administered locally at a single dose to improve the swallowing disorder at a low dose that did not affect blood pressure, It was judged that the improvement effect of the early swallowing disorder which could not be obtained by the oral administration could be obtained. In Comparative Example 1, the dose of 50 mM, 100 μl of the aqueous solution of the captoprafil was the capacity to exhibit predominant hypotensive effect in various animal models. The dose of 50 mM, 100 μl of ricinopril aqueous solution of Comparative Example 2 is about the same as the clinical dose of human hypertensive agent according to the body weight exchange rate and is a dose showing sufficient blood pressure lowering action in humans and animals, The oral administration did not improve the swallowing disorder. In other words, it was judged that oral administration of the dose used for treatment of hypertension in human clinical trials could not achieve early improvement of swallowing disorder on topical administration. From the above results, it can be concluded that the monocyclic local administration to the pharyngeal portion of the angiotensin converting enzyme inhibitory substance does not cause the depletion of substance P in the nerve endings, and that the oral administration of the dopaminergic agent and the angiotensin converting enzyme inhibitor, And it was judged to be an excellent method of using as a drug for improving dysphagia which can exhibit early effects after administration.

All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety.

Claims (4)

The present invention relates to a method for the topical administration of dysphagia for at least one site selected from an intraoral site, a pharyngolaryngeal site and a respiratory tract, containing an angiotensin converting enzyme inhibitory substance as an active ingredient. ) Is an improving agent and is administered in a single dose.
2. The swallowing disorder improver according to claim 1, wherein the dose is a dose that does not exhibit blood pressure lowering, and is a dose that improves swallowing disorder.
3. The use according to claim 1 or 2, wherein the oral administration improves the dysphagia at a time when no effect is exerted.
4. The dysmenorrheic agent according to any one of claims 1 to 3, wherein the angiotensin converting enzyme inhibitory substance is capryl or ricinopril.

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