JPH0873354A - Prophylactic and remedial agent for respiratory tract anaphylaxis and/or respiratory tract disorder - Google Patents

Abstract

PURPOSE: To provide a novel prophylactic and therapeutic agent for respiratory tract anaphylaxis and/or respiratory tract disorder and a prophylactic and therapeutic agent for asthma induced by them (particularly in the form of an inhalant). CONSTITUTION: This prophylactic and therapeutic agent for respiratory tract anaphylaxis, disorder and asthma contains 6-[4-(1-cyclohexyl-2,3,4-tetrazol-5-yl) butoxy]-3,4- -dihydrocarbostyril or its salt, as an active ingredient.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a prophylactic / therapeutic agent for airway hypersensitivity, and further a prophylactic / therapeutic agent for airway disorder, a prophylactic / therapeutic agent for asthma caused by airway hypersensitivity and / or airway disorder, preferably inhalation. The present invention relates to a prophylactic / therapeutic agent for these diseases in the form of a drug.

[0002]

PRIOR ART AND PROBLEMS TO BE SOLVED BY THE INVENTION 6-
[4- (1-Cyclohexyl-1,2,3,4-tetrazol-5-yl) butoxy] -3,4-dihydrocarbostyril or a salt thereof and a method for producing the salt are described in JP-B-63-63.
No. 20235, which has an inhibitory action on platelet aggregation, an inhibitory action on phosphodiesterase (PDE), an antiulcer action, an antihypertensive action and an antiinflammatory action, and is an antithrombotic agent, cerebral circulation improving agent, antiinflammatory agent. It is known to be useful as an anti-ulcer agent, an antihypertensive agent, an anti-asthma agent, a phosphodiesterase inhibitor, etc. Furthermore, it is known that this compound is useful as a therapeutic agent for antiallergic diseases
(JP-A-5-320050). On the other hand, the etiology of asthma may include airway hypersensitivity, reversibility of airway narrowing (paroxysmal dyspnea), inflammation, etc., and β-stimulants and xanthine preparations are bronchodilators as therapeutic agents for asthma attacks. It has been used and it is known that theophylline, which is a PDE inhibitor, is also useful for bronchodilation and asthma attack. However, bronchodilators are mainly intended for symptomatic treatment to relieve an already occurring seizure, often require long-term administration and regular administration, and have a problem in efficacy and safety. In addition, inhaled steroids and oral steroids are potent anti-inflammatory agents that enhance the bronchodilating effect of β-stimulants, suppress airway mucosal edema, and suppress airway secretion, and are useful as anti-asthma agents. It is known, but due to its strong side effects there are major problems and it is not yet complete. Therefore, development of a new anti-asthma drug that is more useful and has excellent safety is desired.

[0003]

Means for Solving the Problems As a result of various researches, the inventors of the present invention have completed 6- [4- (1-cyclohexyl-1,
2,3,4-Tetrazol-5-yl) butoxy] -3,4
-The inventors have found that dihydrocarbostyril or a salt thereof is useful as a prophylactic or therapeutic agent for airway hypersensitivity and / or airway disorder, and have completed the present invention. As described above, 6- [4- (1-cyclohexyl-1,2,
3,4-tetrazol-5-yl) butoxy] -3,4-dihydrocarbostyril or a salt thereof is known as a PDE inhibitor and has a bronchodilator effect and was considered to be useful during an asthma attack. . However, 6- [4- (1
-Cyclohexyl-1,2,3,4-tetrazole-5-
Il) butoxy] -3,4-dihydrocarbostyril or a salt thereof is not only a symptomatic treatment that suppresses an asthma attack by bronchodilation, but is also considered to be one of the main etiologies of asthma. It has been found to have excellent preventive and therapeutic effects on disorders, etc.
This compound is fast acting and can be administered over a long period of time. Therefore, according to the present invention, an excellent anti-asthma drug that is more useful in terms of safety is provided. According to the research conducted by the present inventor, further, 6- [4- (1
-Cyclohexyl-1,2,3,4-tetrazole-5-
Ile) butoxy] -3,4-dihydrocarbostyril or a salt thereof is used as an inhalant to suppress side effects such as occasional pain, headache, and palpitations, and is superior to airway hypersensitivity and airway disorder. It exerts preventive and therapeutic effects, and when it has an asthma attack, it has an excellent fast-acting effect.
By rapidly showing bronchodilation, it was found that asthma attacks are suppressed, long-term efficacy is maintained, and even at low concentrations, it is effective and more useful.

6- [4- (1-cyclohexyl-1,2,3,4-tetrazol-5-yl) which is the active ingredient of the present invention
Butoxy] -3,4-dihydrocarbostyril can easily form a salt by reacting with a pharmaceutically acceptable acid. Examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid, and organic acids such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid and benzoic acid. it can.

The agents of the present invention are prepared by formulating the active ingredient in the form of common pharmaceutical preparations. Such a preparation is prepared by using a diluent or an excipient such as a filler, a filler, a binder, a moisturizer, a disintegrant, a surface active agent and a lubricant which are usually used. Various forms of this pharmaceutical preparation can be selected according to the therapeutic purpose, and typical examples thereof include tablets, pills,
Examples include powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (solutions, suspensions, etc.) and inhalants.

In the case of molding into tablets, those conventionally known in this field can be widely used as carriers, for example, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid. Excipients such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, ceramic, methylcellulose, potassium phosphate, binders such as polyvinylpyrrolidone, dry starch, sodium alginate, agar powder , Laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters,
Sodium lauryl sulfate, stearic acid monoglyceride, starch, disintegrating agent such as lactose, sucrose, stearin,
Disintegration inhibitors such as kao butter and hydrogenated oil, quaternary ammonium bases, absorption promoters such as sodium lauryl sulfate, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid. , Purified talc, stearates, phonic acid powder, lubricants such as polyethylene glycol, and the like. Further, the tablet may be a tablet coated with a usual coating, if necessary, such as a sugar-coated tablet, a gelatin-coated tablet, an enteric-coated tablet, a film coating agent or a double-layered tablet, or a multi-layered tablet.

In the case of molding in the form of pills, those conventionally known in this field can be widely used as carriers, for example, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin and talc, Gum arabic powder,
Examples include tragacanth powder, gelatin, binders such as ethanol, disintegrators such as laminaran and agar. When molding in the form of suppositories, conventionally known carriers can be widely used, for example, polyethylene glycol,
Examples thereof include cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semisynthetic glycerides.

In the case of molding in the form of suppositories, conventionally known carriers can be widely used, and examples thereof include polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semisynthetic glycerides. it can.

Injectables are used in the form of solutions, emulsions and suspensions, which are preferably sterilized and isotonic with blood. In forming the solutions, emulsions and suspensions, all diluents commonly used in this field can be used, such as water,
Examples thereof include ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters. In this case, a sufficient amount of salt, glucose or glycerin for preparing an isotonic solution may be contained in the therapeutic agent, and a usual solubilizing agent, buffer, soothing agent, etc. may be added. Further, if necessary, a coloring agent, a preservative, a fragrance, a flavoring agent, a sweetening agent and the like and other pharmaceuticals may be contained in the therapeutic agent.

The inhalant of the present invention is manufactured by a conventional method. That is, it is produced by making the above-mentioned active ingredient compound into a powder or liquid form, blending it into an inhalation propellant and / or a carrier, and filling it into an appropriate inhalation container. When the active ingredient compound is a powder, an ordinary mechanical powder inhaler can be used, and when it is in a liquid state, an inhaler such as a nebulizer can be used. As the propellant, heretofore known ones can be widely used, and Freon-11, Freon-12, Freon-21, Freon-22, Freon-113, Freon-
114, Freon-123, Freon-142c, Freon-
134a, Freon-227, Freon-C318, 1,1,
Examples thereof include freon compounds such as 1,2-tetrafluoroethane, hydrocarbons such as propane, isobutane and n-butane, ethers such as diethyl ether, compressed gas such as nitrogen gas and carbon dioxide gas.

If desired, the inhalant of the present invention may further contain conventionally used surfactants, oils, seasonings, cyclodextrins or derivatives thereof, and the like. Here, as the surfactant, for example, oleic acid, lecithin, diethylene glycol dioleate, tetrahydrofurfuryl oleate, ethyl oleate,
Isopropyl myristate, glyceryl trioleate, glyceryl monolaurate, glyceryl monooleate, glyceryl monostearate, glyceryl monoricinoleate, cetyl alcohol, stearyl alcohol, polyethylene glycol 400, cetylpyridinium chloride, sorbitan trioleate (trade name span 85), sorbitan monooleate (trade name span 8
0), sorbitan monolaurate (trade name span 20),
Polyoxyethylene hydrogenated castor oil (trade name HCO-6
0), polyoxyethylene (20) sorbitan monolaurate (trade name Tween 20), polyoxyethylene (20)
Sorbitan monooleate (trade name Tween 80), lecithin derived from natural resources (trade name Epiclon), oleyl polyoxyethylene (2) ether (trade name BRIDGE 92), stearyl polyoxyethylene (2) ether (trade name BRiji 72) ), Lauryl polyoxyethylene (4) ether (trade name Brij 30), oleyl polyoxyethylene (2) ether (trade name Genapol 0-020), block copolymer of oxyethylene and oxypropylene (trade name Synperonic) Etc. Examples of the oil include corn oil, olive oil, cottonseed oil, sunflower oil and the like.

When the active ingredient compound of the present invention is liquefied, for example, the compound may be dissolved in a liquid carrier. Examples of the liquid carrier include water, salt water, organic solvents and the like, and among these, water is preferable. In addition, upon dissolution, a surfactant such as polyethylene glycol having a molecular weight of 200 to 5000, polyoxyethylene (20) sorbitan monooleate, sodium carboxymethyl cellulose, methyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol and the like can be appropriately added. When the active ingredient compound of the present invention is powdered, it is powdered according to a conventional method. For example, a fine powder is formed together with lactose, starch and the like, and the powder is prepared by stirring so as to form a uniform mixture.

The amount of the active ingredient to be contained in the drug of the present invention is not particularly limited and can be selected within a wide range, but it is usually 1 to 70% by weight, preferably 5 to 50% by weight in the whole composition.

There are no particular restrictions on the method of administration of the drug of the present invention, including various formulation forms, patient age, sex and other conditions,
It is administered by a method depending on the degree of disease. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are orally administered. In the case of an injection, it may be administered intravenously alone or in a mixture with a normal replacement fluid such as glucose or amino acid, and if necessary, may be administered intramuscularly, intradermally, subcutaneously or intraperitoneally alone. In the case of suppositories, it is administered rectally, and in the case of inhalants, it is administered by inhalation in the oral cavity.

The dose of the drug of the present invention is appropriately selected depending on the usage, the age of the patient, the sex and other conditions, the degree of disease, etc., but usually the amount of the carbostyril derivative (I) or its salt is the daily weight. It is recommended to use 0.6 to 50 mg per kg. In addition, the active ingredient in the dosage unit form is 10-100.
It is recommended to contain 0 mg. When used as an inhalant, the daily dose is preferably 0.001 to 10 mg / kg, preferably 0.01 to 1 mg / kg.

[0016]

EXAMPLES Next, the agents of the present invention will be described more specifically with reference to formulation examples and pharmacological experiment examples.

Formulation Example 1 6- [4- (1-Cyclohexyl-1,2,3,4-tetrazol-5-yl) butoxy] -3,4-dihydrocarbostyril 150 g Avicel (trade name, Asahi Kasei Corporation) 40g Corn starch 30g Magnesium stearate 2g Hydroxypropyl methylcellulose 10g Polyethylene glycol-6000 3g Castor oil 40g Methanol 40g After mixing and polishing the active compound of the present invention, Avicel, cornstarch and magnesium stearate, sugar coating R10mm
Tablet with the key. The obtained tablets are hydroxypropylmethyl cellulose, polyethylene glycol-600.
A film coating agent consisting of 0, castor oil and methanol is coated to produce a film coated tablet.

Formulation Example 2 6- [4- (1-Cyclohexyl-1,2,3,4-tetrazol-5-yl) butoxy] -3,4-dihydrocarbostyril 150 g Citric acid 1.0 g Lactose 33.5 g Dicalcium phosphate 70.0 g Pluronic F-68 30.0 g Sodium lauryl sulfate 15.0 g Polyvinylpyrrolidone 15.0 g Polyethylene glycol (Carbowax 1500) 4.5 g Polyethylene glycol (Carbowax 6000) 45.0 g Corn starch 30.0 g Dry Sodium lauryl sulphate 3.0 g Dry magnesium stearate 3.0 g Ethanol Appropriate The active compound of the invention, citric acid, lactose, dicalcium phosphate, Pluronic F-68 and sodium lauryl sulphate are mixed. The above mixture was added to No. Sieve through a 60 screen, wet granulate with an alcoholic solution containing polyvinylpyrrolidone, Carbowax 1500 and 6000. Alcohol is added as needed to make the powder a pasty mass. Add corn starch and continue mixing until uniform particles are formed. No. Pass 10 screens, put in a tray and open at 100 ° C for 1
Dry for 2-14 hours. The dried particles were Sift through a 16 screen, dry sodium lauryl sulfate and dry magnesium stearate are added and mixed and compressed into the desired shape on a tablet machine. The core is treated with a varnish and sprinkled with talc to prevent moisture absorption. The undercoat layer is coated around the core. Apply varnish enough times for internal use. Further subbing layers and smooth coatings are applied to make the tablets completely round and smooth. Color coating is applied until the desired shade is obtained. After drying, the coated tablets are polished into tablets of uniform gloss.

Formulation Example 3 6- [4- (1-cyclohexyl-1,2,3,4-tetrazol-5-yl) butoxy] -3,4-dihydrocarbostyril 5 g polyethylene glycol (molecular weight: 4000) 3 g sodium chloride 0.9 g polyoxyethylene sorbitan monooleate 0.4 g sodium metabisulfite 0.1 g methyl-paraben 0.18 g propyl-paraben 0.02 g distilled water for injection 10.0 ml parabens, sodium metabisulfite and chloride Dissolve sodium with stirring at 80 ° C. in about half of the above distilled water. The resulting solution was cooled to 40 ° C. and the active compound of the invention, then polyethylene glycol and polyoxyethylene sorbitan monooleate were dissolved in the solution. Next, distilled water for injection is added to the solution to adjust the final volume, and the solution is sterilized by sterilizing filtration using an appropriate filter paper to prepare an injection.

Formulation Example 4 6- [4- (1-Cyclohexyl-1,2,3,4-tetrazol-5-yl) butoxy] -3,4-dihydrocarbostyril 1.5 g Freon-11 25 g Freon-12 100 g Freon-114 25 g Sorbitan trioleate 0.5 g Using the above components, an aerosol is prepared in a conventional manner.

Formulation Example 5 6- [4- (1-Cyclohexyl-1,2,3,4-tetrazol-5-yl) butoxy] -3,4-dihydrocarbostyril 0.15 g Freon-11 30 g Freon-12 70 g Soybean lecithin 0.02 g An aerosol is prepared by the usual method using the above components.

Formulation Example 6 6- [4- (1-Cyclohexyl-1,2,3,4-tetrazol-5-yl) butoxy] -3,4-dihydrocarbostyril 0.15 g Freon-134a 60 g Freon-114 40 g Soybean lecithin 0.02 g An aerosol is prepared according to a conventional method using the above components.

Formulation Example 7 6- [4- (1-Cyclohexyl-1,2,3,4-tetrazol-5-yl) butoxy] -3,4-dihydrocarbostyril 10 g Lactose (Japanese Pharmacopoeia) 80 g Starch ( Japanese Pharmacopoeia) 30 g Talc (Japanese Pharmacopoeia) 5 g Magnesium stearate (Japanese Pharmacopoeia) 1 g The above ingredients are made into a fine powder and stirred to form a uniform mixture to prepare a powder.

Formulation Example 8 6- [4- (1-Cyclohexyl-1,2,3,4-tetrazol-5-yl) butoxy] -3,4-dihydrocarbostyril 10 g Lactose (Japanese Pharmacopoeia) 100 g The above ingredients Is made into a fine powder and stirred to form a uniform mixture to prepare a powder agent.

Pharmacological test 1 Cilostazol for nitric acid-induced airway hyperreactivity (airway obstruction)
Improvement of [6- [4- (1-cyclohexyl-1,2,3,4-tetrazol-5-yl) butoxy] -3,4-dihydrocarbostyril generic name] Test method: Male A / J system In mice (8 weeks old, n = 27),
Airway hyperreactivity (airway obstruction) was induced by daily nasal instillation of nitric acid, a liquefied product related to the atmospheric gas pollutant nitrogen dioxide, under ether anesthesia for 2 weeks. On the day after the final administration, the animals were anesthetized with pentobarbital, volume-respiratory ventilation was performed, and airway resistance was measured using a plethysmograph box. In addition, spontaneous respiration was extinguished by administering pancuronium bromide. The acetylcholine concentration when the airway resistance exceeded 1.5 times that before inhalation of acetylcholine was defined as a threshold value (PT ₅₀ ) and used as an index of airway hyperreactivity. Cilostazol was suspended in 5% gum arabic / saline,
Simultaneously with the administration of nitric acid, it was administered daily via the respiratory nasal route through the respiratory tract. Test results: The results are shown in Table 1. As is clear from the results shown in Table 1, nitric acid significantly reduced the PT ₅₀ value,
Clear airway hyperresponsiveness was noted. And to the airway hypersensitivity, 0.004-4 mg / individual administration of cilostazol into the airway showed a statistically significant improving effect.

[0026]

[Table 1] Table 1 Effect of cilostazol on airway hypersensitivity (airway obstruction) induced by nitric acid Normal nitric acid control 0.004 0.04 0.4 4 (nitric acid + AG) mg / individual mg / individual mg / individual mg / individual 5458 3296 ** 5000 7943 ## 7643 ## 10000 ## * 10000 ## ** Number of animals 8 5 3 3 3 2 3 Numerical values show the geometric mean of PT ₅₀ values (μg / ml). AG; 5% gum arabic / saline *** p <0.01; comparison with normal (ANOVA test) ## p <0.01; comparison with nitric acid (ANOVA test) * p <0.05, ** p <0.01; control Comparison with (ANOVA test)

Pharmacological test 2 Ameliorating effect of cilostazol on airway hyperresponsiveness in a bronchial asthma model Test method: Male Hartley guinea pig (body weight 330 to 570)
g, n = 51) and anti-ovalbumin guinea pig serum (3 hours and 48 hours homologous PCA antibody titers were 10,
(000 times) was passively sensitized by intraperitoneal administration of 0.5 ml. 48 hours after the passive sensitization, an ovalbumin physiological saline solution was atomized and inhaled by a nebulizer to induce asthma-like symptoms. Twenty-four hours later, anesthesia was performed by intraperitoneal administration of pentobarbital, and the animals were fixed in the dorsal position. A tracheal cannula was inserted into the cervical trachea, and artificial respiration was performed with a ventilation volume of 4.5 ml and a ventilation frequency of 50 times / min. A pressure transducer was connected to the side branch of the tracheal cannula to continuously measure the airway pressure. In addition, spontaneous inhalation was extinguished by intravenously administering galamine. 0.1 mg / ml of methacholine
Airway contraction (gradual contraction depending on inhalation time) by atomizing and continuously inhaling physiological saline solution with a nebulizer
Was triggered. Methacholine airway pressure before the start of inhalation, was studied airway hyperresponsiveness as an index of time (TP _100. seconds) until the rise of 100% after the start inhalation. Cilostazol was suspended in gum arabic, and 1 hour before ovalbumin inhalation,
It was administered into the respiratory tract by spontaneous inhalation by nasal drop under ether anesthesia. In addition, animals to which physiological saline was administered instead of anti-ovalbumin guinea pig serum were provided as a normal group. Test results: The results are shown in Table 2. As is clear from the results shown in Table 2, TP ₁₀₀ was shortened in the bronchial asthma model group, and airway hyperresponsiveness was observed, as compared with the normal group. Cilostazol 5 and 50 mg for this airway hyperresponsiveness
/ In the individual respiratory tract administration, TP ₁₀₀ was prolonged and airway hyperresponsiveness was improved. The airway pressure before inhalation of methacholine and the maximum increase in airway pressure due to methacholine were not different from those in the control group, and at this time point, cilostazol had no direct bronchodilator effect.

[0028]

[Table 2] Table 2 Improved use of cilostazol on airway hyperresponsiveness in a bronchial asthma model Normal control 5 mg / individual 105.7 ± 16.7 61.4 ± 9.7 87.6 ± 13.8 Number of animals 10 10 10 Numerical value indicates TP ₁₀₀ (sec). Mean ± standard error.

Pharmacological test 3 Ameliorating effect of cilostazol on ether-induced airway hyperreactivity Test method: Male Hartley guinea pigs (body weight 330 to 450)
g, n = 35) was anesthetized with ether. Twenty-four hours later, anesthesia was performed by intraperitoneal administration of pentobarbital, and the animals were fixed in the dorsal position. A tracheal cannula was inserted into the cervical trachea, and artificial respiration was performed with a ventilation volume of 4.5 ml and a ventilation frequency of 50 times / min.
A pressure transducer was connected to the side branch of the tracheal cannula to continuously measure the airway pressure. In addition, spontaneous inhalation was extinguished by intravenously administering galamine. A 0.1 mg / ml physiological saline solution of methacholine was atomized by a nebulizer and continuously inhaled to induce airway contraction (stepwise contraction depending on inhalation time). Methacholine airway pressure before the start of inhalation, was studied airway hyperresponsiveness as an index of time (TP _100. seconds) until the rise of 100% after the start inhalation.
Cilostazol was suspended in gum arabic and was intratracheally administered by spontaneous inhalation via nasal drop during anesthesia with ether.
In addition, a non-treatment group was prepared without ether anesthesia. Test results: The results are shown in Table 3. As is clear from the results shown in Table 3, TP ₁₀₀ was shortened in the ether anesthesia group and airway hyperresponsiveness was recognized as compared with the untreated group. This airway hyperresponsiveness to, and extension of the TP ₁₀₀ in the airway administration of 5mg / individual cilostazol, improved airways hyperreactivity is observed. There was no difference between the control group and the cilostazol group in the airway pressure before inhalation of methacholine and the maximum increase in the airway pressure due to methacholine, and at this time point, no direct bronchodilator effect of cilostazol was observed.

[0030]

Table 3 Effect of cilostazol on ether-induced airway hyperresponsiveness Untreated control 5 mg / individual 125.9 ± 20.4 105.7 ± 16.7 146.1 ± 46.0 Number of animals 5 10 10 Numerical value indicates TP ₁₀₀ (sec). Mean ± standard error.

Pharmacological test 4 Effect of cilostazol on propranolol-induced airway contraction reaction after antigen-induced immediate asthmatic reaction Test method: Male Hartley guinea pigs (body weight 330-500)
g, n = 32) and anti-ovalbumin guinea pig serum (3 hours and 48 hours homologous PCA antibody titers were 10,
(000 times) was passively sensitized by intraperitoneal administration of 0.5 ml. 48 hours after the passive sensitization, the animals were anesthetized by intraperitoneal administration of pentobarbital and fixed in the dorsal position. Insert a tracheal cannula into the cervical trachea, ventilation volume of 4.5 ml,
Artificial respiration was performed at a ventilation rate of 50 times / minute. A pressure transducer was connected to the side branch of the tracheal cannula to continuously measure the airway pressure. In addition, the tachometer was driven by the ECG lead II, and the heart rate was also measured at the same time. In addition,
Spontaneous breathing was abolished by the intravenous administration of galamine. After administration of the antihistamine diphenhydramine, a physiological saline solution of ovalbumin was atomized with a nebulizer and inhaled for 1 minute. Thirty minutes later, the beta blocker propranolol was atomized with a nebulizer,
Specific airway constriction was induced by inhalation for 5 minutes. The effects of powder inhalation and intravenous administration of cilostazol into the respiratory tract on the airway constriction induced by propranolol were examined. In the case of powder inhalation, cilostazol was inhaled and administered into the respiratory tract 10 minutes before propranolol inhalation in the form of powder in the form of powder, which was pulverized by a jet mill (reference of administration method; Journal of Pharmacological). Methods, 8,
9-17, 1982). In addition, corn starch was administered by inhalation to the control group. In the case of intravenous administration of cilostazol, it was dissolved in 90% dimethyl sulfoxide (DMSO) and administered. Test results: Regarding the above results, the effect on propranolol-induced airway contraction is shown in Table 4, and the effect on heart rate is shown in Table 5. As is clear from the results in Table 4, cilostazol was intravenously administered at a dose of 5 mg / kg and 5 mg / kg into the respiratory tract.
In all of the inhaled doses in individuals, propranolol-induced airway contraction was suppressed. On the other hand, as is clear from the results in Table 5, the heart rate was increased by the intravenous administration, but was hardly changed by the powder inhalation administration.

[0032]

Table 4 Inhibitory effect of cilostazol on propranolol-induced airway contraction Intravenous administration Airway administration time Control cilostazol Control cilostazol (90% DMSO) (5 mg / kg) (corn starch) (5 mg / individual) 1 min 40.9 ± 8.3 18.8 ± 4.5 79.1 ± 7.6 63.3 ± 8.3 3 min 139.6 ± 29.7 52.2 ± 10.1 146.9 ± 12.2 95.4 ± 12.3 5 minutes 170.9 ± 48.6 50.9 ± 9.1 182.1 ± 18.7 106.0 ± 13.7 7 minutes 163.8 ± 47.6 43.0 ± 11.0 212.3 ± 27.9 108.2 ± 15.8 10 minutes 145.8 ± 44.2 37.3 ± 10.5 215.2 ± 29.0 95.0 ± 15.3 15 minutes 117.3 ± 40.8 27.9 ± 6.0 203.7 ± 31.6 91.4 ± 17.0 20 minutes 98.9 ± 37.5 17.9 ± 3.8 186.9 ± 31.2 81.7 ± 19.3 25 minutes 74.8 ± 30.1 11.6 ± 3.0 159.3 ± 29.8 72.6 ± 21.7 30 minutes 57.2 ± 25.1 6.9 ± 2.9 154.7 ± 30.0 65.9 ± 21.7 Number of animals 6 6 10 10 P value ¹⁾ p <0.01 p <0.01 The numerical value indicates the increase value (△%) of the airway pressure. Mean ± standard error. 1); As a result of analysis of variance by repeated measurement, an interaction with the control was observed at p <0.01.

[0033]

[Table 5] Table 5 Effect of cilostazol on heart rate Intravenous administration Airway administration time control Cilostazol control Cilostazol (90% DMSO) (5 mg / kg) (corn starch) (5 mg / individual) Previous value 204.0 ± 15.7 198.0 ± 11.3 199.2 ± 6.2 212.7 ± 7.2 1 min 209.0 ± 14.3 243.2 ± 11.6 196.1 ± 6.5 205.8 ± 6.3 2 minutes 203.6 ± 13.7 243.3 ± 11.8 195.0 ± 6.5 203.6 ± 5.6 3 minutes 201.0 ± 13.2 241.7 ± 12.2 194.3 ± 7.3 201.1 ± 5.6 4 minutes 200.2 ± 14.3 240.2 ± 12.4 194.2 ± 7.5 198.8 ± 6.0 5 minutes 200.2 ± 14.7 240.2 ± 13.2 194.1 ± 7.8 197.3 ± 6.6 10 minutes − − 197.1 ± 8.1 203.1 ± 7.5 Number of animals 5 6 9 10 P value ¹⁾ p <0.01 p <0.15 Numerical value indicates heart rate / minute. Mean ± standard error. 1); As a result of analysis of variance by repeated measurement, an interaction with the control was observed with intravenous administration at p <0.01, but not with inhalation administration.

Pharmacological test 5 Effect of cilostazol on depression caused by dyspnea due to histamine inhalation-comparison between oral administration and intratracheal administration-Test method: Male and female Hartley guinea pigs (body weight 300 to 60)
0 g, n = 60) was left in a transparent acrylic resin box having an inner volume of 4.5 l, and a histamine aqueous solution was sprayed with a nebulizer. After the start of spraying, the time until the guinea pig fell down due to dyspnea (falling time) was measured. Cilostazol was suspended in gum arabic and was forcibly administered using a sonde for oral administration in the case of oral administration, and was voluntarily inhaled by nasal administration under ether anesthesia in the case of intratracheal administration. Test results: Of the above results, Table 6 shows the results obtained by oral administration of cilostazol, and Table 7 shows the results obtained by the administration into the respiratory tract. As is clear from the results shown in Table 6, in oral administration, cilostazol was 100 mg / kg.
Had little effect on the stir time, but 300 mg / kg showed an inhibitory effect. On the other hand, as is clear from the results shown in Table 7, in the respiratory tract administration,
The inhibitory effect was shown at a dose of 5 ml / individual or more, and the inhibitory effect was observed at an extremely low dose by intratracheal administration rather than oral administration.

[0035]

[Table 6] Table 6 Inhibitory effect of oral administration of siloctazole on the depression caused by inhalation of histamine Time control Cilostazol Cilostazol 100 mg / kg 300 mg / kg Previous value 92.6 ± 4.6 108.4 ± 5.4 104.1 ± 8.0 1 hour 96.3 ± 5.1 117.9 ± 10.2 126.3 ± 15.0 2 hours 88.3 ± 5.0 106.6 ± 7.9 127.9 ± 17.8 4 hours 93.4 ± 5.8 125.6 ± 11.5 147.4 ± 25.2 6 hours 93.6 ± 5.7 125.6 ± 9.8 130.7 ± 17.7 Number of animals 7 7 7 P value ¹⁾ p <0.39 p <0.05 Numerical value indicates the collapse time (seconds). Mean ± standard error. 1); As a result of analysis of variance by repeated measurement, an interaction was observed at p <0.05 between the control and cilostazol 300 mg / kg.

[0036]

[Table 7] Table 7 Cilostazol for respiratory depression caused by histamine inhalation Time control Cilostazol Cilostazol 0.5 mg / individual 5 mg / individual value 79.1 ± 3.7 80.5 ± 3.3 81.3 ± 2.5 0.5 h 71.2 ± 3.6 84.4 ± 4.6 102.7 ± 2.6 1 h 69.2 ± 2.9 71.7 ± 3.5 88.1 ± 3.1 1.5 h 63.6 ± 3.4 69.3 ± 1.9 73.4 ± 2.4 Number of animals 10 10 10 p-value ¹⁾ p <0.05 p <0.01 Numerical value indicates the tumble time (seconds). Mean ± standard error. 1); As a result of repeated analysis of variance analysis, control and cilostazol 0.5 mg / individual and 5 mg
/ An interaction with an individual is p <0.05 and p <0.05, respectively.
Seen at 0.01.

Pharmacological Test 6 Effect of Cilostazol Powder Inhalation on Immediate Asthma Reaction by Inhalation of Antigen Test method: Male Hartley guinea pig (body weight 320 to 582)
g, n = 30) and anti-ovalbumin guinea pig serum (3 hours and 48 hours homologous PCA antibody titers were 10,
(000 times) was passively sensitized by intraperitoneal administration of 0.5 ml. 48 hours after the passive sensitization, the animals were anesthetized by intraperitoneal administration of pentobarbital and fixed in the dorsal position. Insert a tracheal cannula into the cervical trachea, ventilation volume of 4.5 ml,
Artificial respiration was performed at a ventilation rate of 50 times / minute. A pressure transducer was connected to the side branch of the tracheal cannula to continuously measure the airway pressure. In addition, spontaneous inhalation was extinguished by intravenously administering galamine. A physiological saline solution of ovalbumin was atomized with a nebulizer and continuously inhaled for 30 minutes. The effect of inhalation administration of cilostazol powder into the respiratory tract on the airway contraction induced immediately after inhalation of ovalbumin was examined. Cilostazol was inhaled into the respiratory tract 10 to 15 minutes before the start of inhalation of ovalbumin in the form of powder, which was pulverized with a jet mill (average particle size: 1.7 microns) (Reference for administration method; Journal o
f Pharmacological Methods, 8, 9-17, 1982). In addition, corn starch was administered by inhalation to the control group. Test results: The results are shown in Table 8. As shown in Table 8, 2.5 and 5 mg of cilostazol suppressed its airway contraction in response to the antigen-induced immediate asthmatic reaction.

[0038]

[Table 8] Table 8 Inhibitory effect of cilostazol on antigen-induced immediate asthmatic reaction Time control 2.5 mg 5 mg 3 minutes 211.9 ± 12.5 185.1 ± 16.3 219.7 ± 37.7 5 minutes 273.5 ± 8.9 210.0 ± 18.6 242.1 ± 39.5 10 minutes 346.1 ± 36.2 219.4 ± 18.9 241.8 ± 36.1 15 minutes 338.6 ± 41.1 198.9 ± 21.6 234.3 ± 33.2 20 minutes 319.2 ± 42.4 164.8 ± 15.1 220.6 ± 29.9 25 minutes 307.5 ± 33.9 150.0 ± 11.3 216.5 ± 21.7 30 minutes 299.3 ± 30.0 148.3 ± 14.9 225.2 ± 27.8 p-value ¹⁾ p <0.01 p <0.01 The value is the increase in airway pressure (△%) is shown. Mean ± standard error. There are 10 animals in each group. 1); As a result of analysis of variance by repeated measurement, an interaction with the control was observed at p <0.01.

Pharmacological test 7 Effect of cilostazol powder inhalation on histamine inhalation-induced bronchoconstriction reaction Test method: Male Hartley guinea pig (body weight 409 ± 3.7
(g, n = 21) was anesthetized by intraperitoneal administration of pentobarbital and fixed in the dorsal position. The cervical trachea was incised, a tracheal cannula was inserted, and artificial respiration was performed at a tidal volume of 10 ml / kg and a ventilation frequency of 60 times / min. A pressure transducer was connected to the side branch of the tracheal cannula to continuously measure the airway pressure. 25, 50, 100 and 200μ of histamine
Using a nebulizer, the g / ml solution was sequentially inhaled from the low concentration at 5 minute intervals for 20 seconds to obtain an inhaled histamine concentration-bronchoconstriction reaction. The effect of a 15 minute pretreatment with cilostazol on this contractile response was examined. Cilostazol is a jet-milled product (average particle size 1.7 microns)
Was inhaled and administered to the respiratory tract in an amount of 10 mg and 100 times as much as lactose in a powder state (reference of administration method; Journal of Pharmacological Methods, 8, 8.
9-17, 1982). The control group was inhaled with lactose. Test results: The results are shown in Table 9. As shown in Table 9, cilostazol inhibited the inhaled histamine concentration-bronchoconstrictor response in a dose-dependent manner at the doses of 10 and 100 μg inhaled.

[0040]

Table 9 Table 9 Inhibitory effect of cilostazol on histamine inhalation-induced bronchoconstrictor response Inhaled histamine concentration control Cilostazol Cilostazol (μg / ml) 10 μg / individual 100 μg / individual 25 27.4 ± 9.0 6.8 ± 2.4 * 10.7 ± 10.7 * 50 194.3 ± 20.8 48.4 ± 18.9 ** 35.2 ± 25.6 ** 100 665.5 ± 53.0 243.1 ± 43.2 ** 127.2 ± 39.3 ** 200 865.5 ± 34.6 664.5 ± 82.0 ** 444.3 ± 97.3 ** Number of animals 7 7 7 Numerical values indicate the increase in airway pressure (%). Mean ± standard error. * p <0.05, ** p <0.01; Mann-Whitney U test.

Claims (8)

[Claims] 1. A 6- [4- (1-cyclohexyl-1,2,
A preventive or therapeutic drug for airway hypersensitivity and / or airway disorder, which comprises 3,4-tetrazol-5-yl) butoxy] -3,4-dihydrocarbostyril or a salt thereof as an active ingredient. 2. A 6- [4- (1-cyclohexyl-1,2,
A preventive or therapeutic drug for airway hypersensitivity, which comprises 3,4-tetrazol-5-yl) butoxy] -3,4-dihydrocarbostyril or a salt thereof as an active ingredient. 3. 6- [4- (1-cyclohexyl-1,2,
A preventive and / or therapeutic agent for airway disorders, which comprises 3,4-tetrazol-5-yl) butoxy] -3,4-dihydrocarbostyril or a salt thereof as an active ingredient. 4. A 6- [4- (1-cyclohexyl-1,2,
A preventive or therapeutic drug for asthma caused by airway hypersensitivity and / or airway disorder, which comprises 3,4-tetrazol-5-yl) butoxy] -3,4-dihydrocarbostyril or a salt thereof as an active ingredient. 5. A 6- [4- (1-cyclohexyl-1,2,
A preventive or therapeutic drug for asthma caused by airway hypersensitivity, which comprises 3,4-tetrazol-5-yl) butoxy] -3,4-dihydrocarbostyril or a salt thereof as an active ingredient. 6. A 6- [4- (1-cyclohexyl-1,2,
A preventive or therapeutic agent for asthma caused by airway disorders, which comprises 3,4-tetrazol-5-yl) butoxy] -3,4-dihydrocarbostyril or a salt thereof as an active ingredient. 7. The drug according to claim 1, wherein the dosage form is an inhalant. 8. A 6- [4- (1-cyclohexyl-1,2,
An inhalant composition useful as a prophylactic or therapeutic agent for asthma, which comprises 3,4-tetrazol-5-yl) butoxy] -3,4-dihydrocarbostyril or a salt thereof as an active ingredient.