JPH05306218A - Bronchodilator - Google Patents

Abstract

PURPOSE:To obtain a bronchodilator, comprising sec-cedrenol as an active ingredient and useful for treating airway obstructing symptoms. CONSTITUTION:The objective bronchodilator is obtained by including sec- cedrenol, expressed by formula I and having excellent bronchodilator action and high safety as an active ingredient. This compound of formula I is obtained by oxidizing alpha-cedrene, present in cedar oil and expressed by formula II in the presence of cobalt resinate or reacting the alpha-cedrene with a microorganism belonging to the genus Rhodococcus. This bronchodilator is useful for treating airway obstructing symptoms represented by dyspnea caused by bronchial asthma, acute or chronic bronchitis, pulmonary tuberculosis, pulmonary emphysema, etc.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a bronchodilator, more specifically, bronchial asthma, acute / chronic bronchitis, pulmonary tuberculosis,
The present invention relates to a medicine for treating airway obstructive symptoms such as dyspnea associated with emphysema and the like.

[0002]

2. Description of the Related Art Bronchial asthma, acute / chronic bronchitis, pulmonary tuberculosis, dyspnea associated with emphysema, etc. cause bronchial stenosis due to an allergic reaction or other causes. Yes, and sometimes even fatal, its treatment is important. A drug for treating these symptoms is a bronchodilator, and conventionally, β-receptor stimulants, anticholinergic agents, etc. have been used.

However, the β-receptor stimulant has a problem that it cannot be administered to patients with hypertension or heart disease, while the anticholinergic drug has a drawback that the onset of action is slow and there are many side effects.

On the other hand, some sesquiterpenes have various pharmacological actions, but few have bronchodilator action.

[0005]

In view of the above facts, the present inventors have diligently studied the pharmacological action of sesquiterpenes. As a result, sec -cedrenol has an excellent bronchodilator action and is highly safe. They have found that they are useful as bronchodilators and completed the present invention.

That is, the present invention provides a bronchodilator containing sec -cedrenol as an active ingredient.

Used as an active ingredient in the present invention
sec -Cedrenol is a known compound and can be produced, for example, by oxidizing α-cedrene present in cedar oil in the presence of cobalt resinate according to the following reaction formula [Kato, Fragrance No. 123, 31 , 197
8].

[0008]

[Chemical 1]

The sec -cedrenol is α-
It can also be produced by reacting sedren with a microorganism belonging to the genus Rhodococcus.

Since sec -cedrenol has an excellent bronchodilator effect and is highly safe as will be shown in Examples below, it is useful for treating airway obstruction symptoms such as bronchial asthma and acute / chronic bronchitis.

The sec -cedrenol can be administered as it is or in various dosage forms. The administration form of the bronchodilator of the present invention is not particularly limited, and oral preparations such as tablets, capsules, granules, fine granules, powders and liquids, injections, external preparations, suppositories, inhalants, etc. It can be administered by any of the parenteral agents.

Examples of oral solid carriers include starch,
Lactose, sucrose, mannitol, carboxymethyl cellulose, corn starch, inorganic salts and the like can be mentioned, and if necessary, further, a binder, a disintegrating agent, a surfactant, a lubricant, a fluidity promoter, a flavoring agent, a coloring agent, a flavoring agent. Etc. can be mentioned. More specifically, starch, dextrin, gum arabic powder, gelatin, hydroxypropyl starch, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, ethyl cellulose, polyvinylpyrrolidone, macrogol, etc. as binders; Starch, hydroxypropyl starch, sodium carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, etc .; sodium lauryl sulfate as a surfactant, soybean lecithin, sucrose fatty acid ester, polysorbate 80, etc .; as a lubricant Talc, waxes, hydrogenated vegetable oil, sucrose fatty acid ester, aluminum stearate, polyethylene Recall the like; light anhydrous silicic acid as flow promoters, dry aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate and the like can be used.

Examples of oral liquid preparations include suspensions, emulsions, syrups, and elixirs. These various dosage forms include flavoring agents, flavoring agents,
A colorant can also be added.

Further, as the parenteral liquid carrier, distilled water for injection, physiological saline, glucose solution, vegetable oil for injection,
Sesame oil, peanut oil, soybean oil, corn oil, propylene glycol, polyethylene glycol, etc. are used,
Further, if necessary, a bactericidal agent, an antiseptic agent, a stabilizer, a tonicity agent, a soothing agent and the like can be added.

The bronchodilator of the present invention can be administered orally or parenterally, and, for example, sec -cedrenol 0.1 to 20 mg / kg per adult per day is 1 to 3.
It is preferable to administer in divided doses orally.

[0016]

EXAMPLES The present invention will now be described in detail with reference to examples, but the present invention is not limited thereto.

Reference Example 1 Rhodococcus KSM-7358 strain (FERM BP-3
747) was cultured in a slant medium of the following medium A at 30 ° C. for 3 days. 0.5% of this in a 500 ml Sakaguchi flask
50 ml of the below-mentioned medium B containing α-cedrene was inoculated. Culturing was carried out at 30 ° C. for 2 days, and this was used as preculture.
0.5 ml of this preculture liquid was inoculated into 50 ml of medium B containing 0.5% α-cedrene, and shake culture was carried out at 30 ° C. for 4 days. The resulting culture was extracted with hexane, to quantify the hexane Kayo fraction by gas chromatography, se
25 mg of c -cedrenol was obtained.

[0018]

(Medium A) Polypeptone (casein peptone) 17 g Polypeptone S (soybean peptone) 3 g K ₂ HPO ₄ 2.5 g Glucose 2.5 g NaCl 5 g Agar 15 g Purified water to a total volume of 1 liter (pH after sterilization) 7.1-7.5). (Medium B) Na ₂ SO ₄ 0.71 g NH ₄ NO ₃ 3.5 g FeCl ₃ .6H ₂ O 0.01 g MgCl ₂ .6H ₂ O 0.17 g CaCl ₂ .2H ₂ O 0.1 g 50 mM phosphate buffer (PH 7) make the total volume 1 l.

The Rhodococcus KSM-used here is used.
The mycological properties of strain 7358 are as follows.

(1) Morphological properties Bacteria having a size of 0.8 to 1.0 × 1.0 to 12 μm and having polymorphism. That is, at the initial stage of culture, branched hyphae are formed, and then the hyphae are ruptured to become short rod-shaped. Also,
This strain is non-motile and has no flagella. No spores were found, Gram positive, no acid resistance.

(2) Cultural properties (a) Flat culture of broth agar: It grows well and forms a milky white opaque, rough-surfaced, cone-shaped colony, and a flesh-colored or pale orange color at the latter stage of culture. Present. The shape of the settlement is circular curly and wavy at the periphery. (B) Meat broth agar slope culture; grows well and exhibits milky white color. (C) Broth liquid culture; growth is weak, but it grows in both upper and lower layers of the surface of the culture solution. (D) Meat broth gelatin stab culture; grows well. No liquefaction is observed. (E) Litmus milk; liquefy only the upper layer. The litmus dye was changed from purple to pink, and a partial decolorization reaction was observed.

(3) Physiological properties (a) Nitrate reduction; Negative (nitrate broth medium) (b) Denitrification reaction; Negative (c) MR test; Negative (d) VP test; Negative (e) Indole formation; Negative (f) Hydrogen sulfide production; Weak positive (g) Starch hydrolysis; Negative (h) Utilization of citric acid; Coser medium: Positive Christensen medium: Positive (i) Utilization of nitrates; Positive (j) Utilization of ammonium salts Generation of positive (k) dye; King A medium: negative King B medium: negative (l) urease; positive (m) oxidase; negative (n) catalase; positive (o) growth pH range; growth pH: 3-10 Optimum growth pH: 5 to 9.0 (p) Growth temperature range; Growth temperature: 10 to 37 ° C Optimal growth temperature: 25 to 30 ° C (q) Attitude toward oxygen; Aerobic but still standing conditions Even under You can grow separately. (R) OF test; weak oxidative type (can be distinguished by Andrade indicator, but when BTB indicator is used, no change is observed even after 7 days of culture) (s) Growth in NaCl-containing medium; 5,
It grows in both% and 7%.

(T) Utilization of carbon source; L-arabinose-D-xylose-D-glucose + D-mannose + (weak) D-fructose + D-galactose-maltose + (weak) sucrose + lactose-trehalose. + (Weak) D-sorbitol + D-mannitol + inositol + glycerol + (weak) starch-D-ribose + However, +; used,-; not used.

(4) Chemical taxonomic properties (a) Glycolate test (glycolyl type) (b) Cell wall cross-linking amino acid meso -2,6-diaminopimelic acid (c) Cell wall constituent sugars arabinose and galactose are detected, but xylose is detected. Is not detected. (D) menaquinone system MK-8 (H ₂₎

Example 1 The bronchodilating activity of sec -cedrenol was measured by examining the inhibitory effect of the sample on spontaneous contraction using the isolated trachea. That is, the guinea pig (H
Artley system, male, 250-400g) was immediately beaten, and then the neck was immediately incised to remove the trachea between the thyroid cartilage and the tracheal bifurcation, cut into a spiral shape, and set on the Magnus device with a load of 0.5g. The tension was monitored and stabilized in a physiological saline solution at 37 ° C. under aeration of oxygen gas using an isotonic transducer. Epinephrine (0.3 μg / m
The relaxation effect of sec -cedrenol compared with the relaxation reaction by the addition of l) was measured as bronchodilator activity. As a result, sec -Cedrenol (30 μg / ml) caused a relaxation reaction by the addition of epinephrine (0.3 μg / ml).
When it was set to 00%, it showed a relaxing effect of 74%.

Example 2 Acute toxicity test: Male ICR mice (5 mice per group; 5 weeks old) were administered with sec -cedrenol once, and the acute toxicity was examined. As a result, no death was observed in the oral administration of 1 g / kg (observation period: 7 days).

Example 3 A tablet was prepared according to the following formulation.

[0028]

[Table 2] (Composition) sec -Cedrenol 119 g Lactose 3000 g Starch paste (5%) ^* Appropriate amount Magnesium stearate 5 g

(Manufacturing method) After the above ingredients were thoroughly mixed, a tablet having a diameter of 9 mm and a weight of about 320 mg was 10,000
0 tablets were produced. *: Take 50 g of starch in a 2 liter container, add 900 ml of purified water, gradually heat while thoroughly stirring, boil and bring to 1000 ml.

Example 4 An injection was prepared according to the following formulation.

[0031]

(Table 3) (Composition) sec -Cedrenol 50 mg Hydrogenated castor oil 200 mg Propylene glycol 150 mg Glucose 100 mg

(Manufacturing method) The above components were diluted with distilled water for injection to a total amount of 1
It was made into ml and made into an injection according to a conventional method.

[0033]

EFFECTS OF THE INVENTION Since sec -cedrenol has an excellent bronchodilator effect and is highly safe, it is useful as a therapeutic agent for airway obstruction associated with bronchial asthma, acute / chronic bronchitis, pulmonary tuberculosis, emphysema, etc. is there.

Front page continuation (72) Inventor Shigeka Tanaka 9-1030 Sonobe, Wakayama, Wakayama (72) Inventor Susumu Ito 3441-64, Higashiminecho, Utsunomiya City, Tochigi Prefecture

Claims (1)

[Claims] 1. A bronchodilator containing sec -cedrenol as an active ingredient.