JPS62223123A - Expectorant - Google Patents

Abstract

PURPOSE:To provide an expectorant containing an N-acetylneuraminic acid salt as an active component, acting to rhelogical property of phlegm, promote the transfer of phlegm toward the oral cavity by the ciliary movement of trachea and facilitating the expectoration of phlegm. CONSTITUTION:An N-acetylneuraminic acid salt of formula (Z is Li or K when n=1) or Z is Ba or Mg when n=2) is used as an expectorant. The compound of formula changes the rheological properties of phlegm (i.e. fluidity, yield value, stickiness, etc.) to convert the phlegm to an easily expectorable state and promotes the transferability of phlegm by ciliary movement. It is administered as finely pulverized inhalable aerosol, e.g. powdery aerosol, liquid aerosol, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to an expectorant. More specifically, the present invention relates to an expectorant comprising N-acetylneuraminate, which acts on the rheological properties of sputum and promotes its movement toward the oral cavity through ciliary movement.

(Conventional technology) Mucous secretions are present in the human respiratory tract.

It plays the important role of providing constant temperature and humidity to the inhaled outside air, and also removing foreign substances.

And what is called phlegm is mainly composed of respiratory secretions.

By the way, a certain amount of secretions may be unconsciously swallowed or dispersed during breathing, but they are not coughed up.

Therefore, the phenomenon of coughing up sputum itself means that some abnormality is occurring in the respiratory system. Furthermore, the fact that the sputum that should be coughed up accumulates and stagnates in the respiratory tract is a condition that makes it easy for transrespiratory tract infections to be transmitted. Therefore, expectoration is of great significance in the treatment of respiratory diseases.

However, there is a problem in that sputum sometimes has a very high viscosity or a very strong adhesive force, causing great pain when dissolving it. Therefore,
Expectorants are known to ease the difficulty of expelling sputum, but most of these have conventionally been administered systemically orally or by injection. The expectorant administered in this way dilutes phlegm by increasing the secretion of the respiratory tract mucosa, promotes its release from the mucous membrane,
It had no effect on secretion, and had a so-called expectorant effect by lowering the viscosity of the sputum itself. However, systemic administration poses various clinical problems in terms of mechanism of action and effects.

Furthermore, no drug has been known to date that can treat low-viscosity sputum that is difficult to dissolve, such as in patients with diffuse panbronchiolitis and emphysema.

The present inventors have conducted intensive research to solve these various problems, and as a result, they have arrived at sialic acid, which is useful as a compound that can be used by topical administration. Furthermore, extensive research was conducted on the expectorant action of N-acetylneuraminate, a typical sialic acid, leading to the present invention.

(Object of the Invention) The present invention provides an expectorant consisting of N-acetylneuraminic acid salt, which activates the movement of cilia by local administration, acts on the rheological properties of sputum, and facilitates the dissolution of sputum. The purpose is to

(Means for Solving the Problems) The expectorant of the present invention contains N-acetylneuraminic acid salt represented by the following general formula as an active ingredient.

(However, when n is 1, Z represents lithium or potassium; when n is 2, Z represents barium or magnesium.) N-acetylneuraminic acid itself is a known compound. The salt can be obtained by neutralizing with an alkali metal or alkaline earth metal hydroxide or carbonate thereof, and then separating the corresponding alkali metal salt or alkaline earth metal salt from the system.

In the present invention, such compounds are used in known topical administration forms, such as micronized aerosol inhalable forms.

The action of N-acetylneuraminate as an expectorant is
Firstly, the rheological properties of sputum, i.e. the fluidity of sputum,
This is because it affects the yield value, stringiness, adhesive strength, stress relaxation time, etc. to make sputum easy to melt, and promotes the transportability of sputum by fimbriae. It particularly acts on sputum with low viscosity and promotes transport by cilia. N - confirmed by comparing before and after application of acetylneuraminate.

Hereinafter, the synthesis methods of the compounds of the present invention and their effects will be explained in detail with reference to Examples and Reference Examples.

Reference Example I Synthesis of N-acetylneuraminic acid lithium salt N-acetylneuraminic acid (2.0g, 0.00647mole)
To an aqueous solution (l OOml) of lithium carbonate (0,
239 g, 0.00323 mole) was added thereto, and the mixture was stirred at room temperature for 30 minutes. After filtering the reaction mixture, freeze Pf
i, h, and the obtained solid was smoked under reduced pressure to give a melting point of 70.0-
2.03 g iTh of colorless needles decomposed at 95.5°C were obtained. Yield 99.5%.

Reference Example 2 Synthesis of N-acetylneuraminic acid potassium salt N-acetylneuraminic acid (2.0g, 0.00647mol
e) Potassium carbonate (0,
447 mg, 0.00323 mole) was added and pressed for 30 minutes at room temperature. After filtering the reaction mixture, it was freeze-dried, and the obtained solid was dried under reduced pressure, and the melting point was 12.5.0-1.
2.18 g of a white solid decomposed at 40.0°C was obtained.

Yield 97.096゜R'llaM Cm-': 1620.1560 Reference Example 3 Synthesis of N-acetylneuraminic acid barium salt N-acetylneuraminic acid (2.0g, 0.00647mol
Barium carbonate (0
, 638g, 0.00323mole) was added,
Stirred at room temperature for 1 hour. After filtering the reaction mixture, it was freeze-dried, and the crushed solid was vacuumed to a melting point of 185.
．． 2.39 g of colorless needle crystals decomposed at 0-194.0°C
)is.

Yield: 98.2%.

1RI7. ,, cm-': 1610.1565 Reference Example 4 Synthesis of N-acetylneuraminic acid magnesium salt N-acetylneuraminic acid (2.0g, 0.00647mole
) was added with IJI+ (0.189 g, 0.00323 mole) and stirred at room temperature for 1 hour. After filtration of the reaction mixture, the solid was frozen and dried under reduced pressure.
melting point 96.5-121.5℃ decomposition jll (color needle-like product 2
．． 06 g.

Yield 99.5%.

Example 1 Effect of test agent on ciliary pressure movement of the operculum mucosa (1) Experimental animals Bullfrogs (Saitama Experimental Animals) weighing 300 to 450 g were used, regardless of male size.

(2) Experimental materials The test agents used were lithium salt, potassium salt, barium salt, Mac I, and sia salt (manufactured by Kanto Dr. Aoi σ@) of N-acetylneuraminic acid.

(3) Experimental method Ciliary pressure was measured according to the particle transport method. After decapitating the frog, it was peeled off to avoid damaging the palatal mucosal surface as much as possible, fixed on a cork board in a Pel-IJ dish, and injected with the test agent in Tris-HCl Ringer's solution (p
H7, 8) The mixture was filled with 20Irll (the test agent was not added to the control) and left for about 30 minutes until the start of measurement. At the beginning of the measurement, remove Ringer's solution, place a small piece of cork (does not pass through a No. 6 medicated sieve, but passes through a No. 5 medicinal sieve) on the mucosal surface, and accurately measure the time (seconds) it takes to move l cm. did. The movement speed was measured after removing Ringer's solution or the drug solution from the mucosa of Caerlo's operculum.

(4) Results For barium salt, 10-2 and 10-'mg/me applied 1
0 minute application 1 branch. For potassium salt, to-'mg/ffLi! Application 10
After 15 minutes and 15 minutes, an increasing trend in mucociliary transport rate was observed. For lithium salts and magnesium salts, a tendency for the mucociliary transport rate to increase at the temperatures shown in Table 1 was observed.

(5) Judgment Potassium salt and barium salt of N-acetylneuraminic acid promoted mucociliary transport and could facilitate sputum dissolution. Since lithium salts and magnesium salts have a tendency to accelerate, it is thought that they facilitate the dissolution of sputum through a combined effect with other effects.

Example 2 Effect of test agent on rotational movement of ciliated cells (1) Test agent N-'7'' Lithium salt, potassium salt, barium salt, and magnesium salt of cetylneuraminic acid (all manufactured by Kanto Dr. Seiyaku Aji) were used. .

(2) Using human airway ciliary cells and frog ciliary cells, we observed the rotational movement of the cell population associated with ciliary movement, measured the relative change in rotational speed before and after applying the coating agent, and A comparative study was conducted on the effects of drugs on l t, 7.

(3) Method Human ciliated cells were obtained by using human bronchi, which are considered to be normal when viewed bronchoscopically, by performing bronchial scraping of the central airway under bronchoscopy. The palatal mucosa was removed from the frog fimbriae!! A population of ciliated cells, consisting of several cells that exhibit rotational movement accompanying movement, was sucked up using a microsyringe to avoid damage, transferred to a coverslip, and injected with chicken plasma (manufactured by Difco) and 50% chicken l-IJ embryos. Add extract (manufactured by Difco) drop by drop to bloodff)f
was formed, and the rotational movement within the clot was recorded on video.
The number of revolutions per minute was measured. The drug was dissolved in culture medium 199 and injected through a tube attached to the rose chamber, and the rotational movements were recorded on video immediately after injection, 5 minutes, 10 minutes, and 15 minutes later, and the rotations per minute were recorded. The number was measured.

(4) Results Lithium salt, potassium salt of N-acetylneuraminic acid,
For barium salt and magnesium salt, no tendency to increase or decrease in rotational speed was observed at the concentrations shown in Table 2.

(5) Judgment Lithium salt, potassium salt of N-acetylneuraminic acid,
Since barium salts and magnesium salts do not inhibit the rotational movement of ciliated cells, they can be expected to become useful expectorants due to their combined effects with other effects.

Example 3 Simple Acute Toxicity 1 Test Simple acute ii by intravenous injection of the test drug into mice 3
The test was conducted as follows.

1. Test materials and methods (1.) Test agent lithium salt, potassium salt of N-acetylneuraminic acid,
Barium salt and magnesium salt (hereinafter referred to as "2", manufactured by Kanto Ishikawa Pharmaceutical a@) were used.

(2) 1 test animal dt, Iy Mt mouse Weight at start of test: 1.7.7-21.1 g Number of animals: 3 (3) Room temperature: 23±i℃ Humidity: 55±7 % (4) Administration route: Intravenous (5) Function/Method and Dosage” The test drug described in “2” was dissolved in physiological saline, and the administration solution j11 was 0.2 mJ per 20 g of mouse body! The concentration was adjusted to give the following and was injected into the tail vein. The dosage is 50
Three doses were given: 0.1000 and 2000 mg/kg.

(6) Observation of general symptoms and death status Immediately after administration until 7 days after administration, if there are any general symptoms or death.
I observed j.

2. Results (1) Mortality rate The mortality rate is shown in Table 3.

At 1000 and 2000 mg/kg, 3 out of 3 patients died with the magnesium salt, barium salt, and potassium salt of N-acetylneuraminic acid. At 500 mg/kg, 3 out of 3 patients died with N-acetylneuraminic acid barium salt.

There were no other deaths.

(2) General Symptoms Death cases were accompanied by clonic convulsions and urinary incontinence, and death occurred within 1 minute immediately after administration of Inujabun. Among the surviving cases, suppression of spontaneous coordination was observed in a small number of cases, but recovery occurred within 1 hour.

Reference Example 5 Dosage form When the expectorant of the present invention is used clinically, it is administered as the following formulation.

Formulation> N-acetylneuraminic acid salt is placed in an agate mortar and ground well to form a fine powder with a particle size of 1 to 20 μm. Lactose was added to this powder and pulverized and mixed, and then lactose was added little by little to this fine powder and mixed thoroughly to make it 10 to 40 times more concentrated.

20 to 40 mg of this is capsuled or divided by a conventional method,
It was made into a formulation.

The capsules were for powder aerosols, and the sachets were for liquid aerosols.

Administration method: Depending on the patient's symptoms, use a powdered aerosol or decide whether to use a liquid aerosol.

Typically, the expected dose from Example 1 is 0.5
The dosage is ~5 mg/dose, and the dose may be increased or decreased as appropriate from twice a day depending on the symptoms.

Note that the number of administrations per day is not limited based on the results of the Mulberry Sensile Mechanics Test and the results of the simple acute toxicity test.

Whether to use a powder aerosol or a liquid aerosol depends on the symptoms and condition of the patient. An inhaler or the like is used as a powder aerosol, and a nebulizer or the like is used as a liquid aerosol.

(Effects of the Invention) An expectorant containing N-acetylneuraminate as an active ingredient exhibits excellent expectorant action when administered locally.

It acts on the rheological properties of sputum, such as sputum, yield value, and viscosity, to make the sputum itself easier to expectorate. It works.

Procedural amendments Director General of the Patent Office Michibe Uga 1, Indication of the case Patent Application No. 51898 of 1988 2, Title of the invention Expectorant 3, Person making the amendment Relationship with the case Applicant name Mekto Co., Ltd. 4, Agent 5: Date of amendment order Voluntary 6: Subject of amendment The following sections of the detailed description of the invention in the specification should be corrected.

Claims (2)

[Claims] (1) An expectorant containing as an active ingredient a compound represented by the following general formula that acts directly on ciliary cells of the respiratory tract and on the rheological properties of sputum. ▲There are mathematical formulas, chemical formulas, tables, etc.▼・[Z] (However, when n is 1, Z represents lithium or potassium, and when n is 2, Z represents barium or magnesium.) (2) The expectorant according to claim (1), wherein the expectorant is administered to the respiratory tract by an aerosol inhalation method.