JPH01190631A - Remedy for bronchial asthma - Google Patents

Abstract

PURPOSE:To obtain a remedy for bronchial asthma having highly selective excellent bronchodilating action and high safety, by using a specific xanthine derivative as an active component. CONSTITUTION:The objective drug contains, as an active component, pentoxifylline of formula which is known to be effective in ameliorating the subjective symptom, mental symptom and memorization activity caused by cerebrovascular disorder. The compound exhibits nearly the same bronchodilation action to respiratory tract as that of theophylline of formula II known as a xanthine-type remedy for bronchial asthma. It exhibits the activity even by duodenal administration and necessitates higher dose than theophylline for the development of the central excitation, diuretic and cardiac excitation actions. Accordingly, it is a drug having separated main effect and side effect and having high safety compared with theophylline and is extremely useful for ameliorating the symptom of bronchial asthma and the reversible bronchospasm caused by chronic bronchitis and pulmonary emphysema.

Description

DETAILED DESCRIPTION OF THE INVENTION - Part 1 The present invention relates to a therapeutic agent for bronchial asthma containing a xanthine derivative represented by the following formula (I) as an active ingredient, and is useful in the medical field.

1.1 ulCH3 Various drugs, including bronchodilators, are widely used clinically as therapeutic agents for bronchial asthma.

Among them, xanthine compounds are also used as therapeutic agents for bronchial asthma, and theophylline (Theophylline)
yl l lne Ship name; The Merck
Index l 0 edition, 9114; Formula (■)) is a commercially available representative H3. On the other hand, the xanthine derivative represented by the formula (1) according to the present invention is
line ship name; The Merck 1nd
exl 0 edition, 7002), has been recognized to be effective against subjective symptoms, mental symptoms, and memory ability due to cerebrovascular disorders, and is widely used clinically as a microcirculation improving agent. However, it was thought that there was no possibility of pentoxifylline being used as a treatment for bronchial asthma (Applied Pharmacology, 15, 153 (1978).
).

-1 (゛ YO'.■ However, theophylline represented by the above formula (■) has a small separation between the main action and side effects (and tends to cause side effects such as central nervous excitement, diuresis, cardiac excitement, and increased gastric juice secretion). Furthermore, since the effective blood concentration range is very narrow, it is necessary to monitor the drug once, and there are also many points to keep in mind when using it, such as the need to be careful about interactions when used in combination with other drugs. However, there were many problems in clinical use.

The present invention aims to improve these drawbacks of theophylline and develop a drug that has fewer side effects, a wide safety margin, and fewer interactions with other drugs.

In view of the above-mentioned circumstances, the present inventors of the present invention conducted extensive research into xanthine compounds as drugs that overcome the drawbacks of theophylline. The present inventors have discovered that pentoxifylline has a completely unexpected bronchodilatory effect, and has very low side effects such as central nervous stimulation, diuresis, and cardiac stimulation, and has completed the present invention. .

The therapeutic agent for bronchial asthma containing the xanthine derivative represented by the formula (I) (hereinafter referred to as the compound of the present invention) of the present invention as an active ingredient can be administered either orally or parenterally. Examples of dosage forms for oral administration include tablets, capsules, powders, and fine granules.

Examples include granules and syrups, and examples of dosage forms for parenteral administration include injections, skewers, inhalants, ointments, and patches. Pharmacologically and pharmaceutically acceptable additives can be added to one part of these preparations, including excipients, disintegrants or disintegration aids, binders, lubricants, coating agents, pigments, etc. , a diluent, a base, a solubilizing agent or a solubilizing agent, 9 an isotonizing agent, a PL adjuster, a stabilizer, etc. are used.

In oral formulations and mucosal administration formulations, excipients include glucose, lactose, D-mannitol, and starch.

Microcrystalline cellulose, etc. are used as disintegrants and disintegration aids, carboxymethylcellulose, starch, carboxymethylcellulose calcium, etc. are used as binders, hydroquinepropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, gelatin, etc. are used as lubricants, and stearin is used as a lubricant. Magnesium acid, talc, etc., as a coating agent, hydroxypropyl methylcellulose, Eudragift, cellulose acetate phthalate.

Hydroxypropyl methylcellulose phthalate.

Glycerin fatty acid ester, sucrose, titanium oxide, etc. are used as the base, polyethylene glycol, hard fat, etc. are used, and sorbitan trioleate, etc. are used as the dispersant.In addition, for transdermal preparations, petrolatum, liquid paraffin, etc. are used as the base. , polyethylene glycol, etc., as adhesives, sodium polyacrylate, polyvinyl alcohol.

Methylcellulose, polybutene, etc. as a base fabric, formulation components such as cotton fabric, and in the case of injections, distilled water for injections, as a solubilizing agent or solubilizing agent that can constitute an aqueous or ready-to-dissolve injection. Physiological saline, propylene glycol, etc. as tonicity agents, glucose, sodium chloride, D-mannitol, glycerin, etc. as N pu regulators, inorganic acids.

Formulative ingredients such as organic acids or inorganic bases are used.

The dose of the compound of the present invention to be administered orally to a patient is usually 100-1200+g per -day for adults, but it can be adjusted as appropriate depending on age, symptoms, etc.

Example 1 - The excellent effects of the compounds of the present invention will be explained below using test examples. At that time, theophylline was used as a comparison drug. Statistical tests were performed using a 5student's t-test.

Test Example 1 [Extracted Guinea Pig Tracheal Relaxation Effect] The trachea was removed from a Covertley male guinea pig (weighing around 400 g), and a tracheal section chain specimen was prepared. There are 9 specimens
The specimen was suspended in a Ronkulinger liquid bath (37°C) aerated with a mixed gas of 5% CO2 and 5% CO2, and the resting tension was measured isotropically. Drugs were applied cumulatively in the bath and relaxation by isoproterenol 10M was expressed as 100%. The results are shown in Table 1.

Table 1 N, S: There is no difference between drugs at the 5% significance level.

Test Example 2 [Suppressive effect of acetylcholine in guinea pigs on the increase in airway 1] A male Covertley guinea pig (body fE around 400 g) was anesthetized with urethane (1.5 g/kg, +, p,), and then a cannula was inserted into the trachea and carotid artery. were inserted, and airway resistance and blood pressure were measured. Airway resistance is Konzett-
R6ssler method [Archive fur Expert
lmentelle Pathologle und
Pharmakologie, 195 Near 1 (1
940)] was measured as a change in flow rate.

Acetylcholine (40 μg/kg) was administered into the jugular vein at 10 minute intervals, and the drug was administered into the jugular vein 1 minute before administration of acetylcholine.

In addition, the effects of the compounds of the present invention on administration into the gastrointestinal tract were also investigated. In this case, acetylcholine (40 μg/k
g) was administered into the jugular vein at 15 minute intervals, and the compound of the present invention was administered into the duodenum 5 minutes before administration of acetylcholine.

The effect of the drug was expressed as the rate of change in airway resistance increase due to acetylcholine before and after drug administration as an inhibition rate (%). The results are shown in Tables 2 and 3.

#: The drug was administered into the jugular vein.

N, S: There is no difference between drugs at the 5% significance level.

Table 3 #: The drug was administered into the duodenum.

X: There is a difference from the control at a mean level of 5%.

Tokyo: There is a difference from the control at a significance level of 1%.

Test Example 3 [Effect on mouse locomotor activity] - The drug was orally administered to DDY male mice (body weight around 22 g) that had been fasted overnight, and the locomotor activity for 60 minutes was measured using Animonox (Ty9eS, Farad Electronics).
) was used to determine A11l. The results are shown in Table 4.

Table 4 0: There is a difference from the control at a significance level of 1%.

Test Example 4 [Effect on rat urine excretion] Male Wistar rats (weighing around 200 g) that had been fasted overnight were watered 3 hours before the start of the experiment. Oral administration of drugs (
2.5■l/kg), the amount of urine urinated until the 5th hour -
was determined as d-1. /III constant value was expressed in terms of weight per 100 g of rat. The results are shown in Table 5.

Table 5 Book x: There is a difference from the control at a significance level of 1%.

Test Example 5 [Effect on isolated guinea pig atrium] The heart was extracted from a Covertley male guinea pig (body weight: approximately 400 g), and a left atrium specimen was prepared.

The specimens were suspended in Krebs-Nzerite [J] (30°C) aerated with a gas mixture of 95% CO2 and 5% CO2, and were heated with a rectangular wave IHz, 1 m5ec, through a bipolar platinum electrode.
Electrical stimulation of 3-5 V was applied and the resulting contractions were measured isometrically. The drug was applied cumulatively into the liquid bath, and the change in contractile force due to electrical stimulation before and after drug administration was expressed as an increase rate (%). The results are shown in Table 6.

As a result of the above test examples, it was revealed that the compound of the present invention exhibits a bronchodilatory effect on the respiratory system almost equivalent to that of theophylline, and also exhibits an effect when administered into the duodenum. On the other hand, since the compound of the present invention requires a higher dose than theophylline to exhibit its central arousal, diuretic, and cardiac 1a-a effects, the compound of the present invention has separate main effects and side effects compared to theophylline. It was revealed that this drug is highly safe.

From this, the compound of the present invention is expected to have a use as a therapeutic agent for bronchial asthma.

In addition, the acute ectropion of the compound of the present invention is 1225.1500 mg/kg (female, male) when orally administered to mice, and 2100.2380 mg/kg when orally administered to rats.
/kg (female, male).

1. Formulation examples of the compounds of the present invention will be explained below with reference to Examples, but the present invention is not limited to the specific details of these Examples.

Example 1 Tablets are prepared by the following method.

Compound of the present invention 100g lactose
Appropriate amount Corn starch 10 mg Magnesium stearate 1 g Hydroxypropyl methyl cellulose phthalate 71 g Polyethylene glycol 8000 0.5 mg Example 2 Capsules are prepared by the following method.

Compound of the present invention 50-g lactose
Appropriate amount Carboxymethylcellulose calcium 15g Hydroxypropyl cellulose 2ugly Stair I
20mg or more of Magnesium Peng is mixed in a conventional manner and filled into hard capsules.

Example 3 Granules are prepared by the following method.

Compound of the present invention 200mg lactose
Appropriate amount of crystalline cellulose
100 mg Hydroxypropyl methylcellulose phthalate 90 g Glycerin fatty acid ester 8a+g Example 4 An injection is prepared by the following method.

Compound of the present invention 100g Sodium chloride 35gml Example S A skewer is prepared by the following method.

Compound of the present invention 100mg Example 6 A poultice is prepared by the following method.

Compound of the present invention 100+g gelatin 1100mg polyvinyl alcohol methyl cellulose 100□2 glycerin 1500mg kaolin
850mg sodium polyacrylate 50-g polybutene
150 grams

15000mg Hikari J [1 text] The present invention provides a therapeutic agent for bronchial asthma containing a xanthine conductor as an active ingredient.

In other words, the compound of the present invention has an excellent bronchodilation effect with high selectivity and is highly safe, so it is extremely useful for alleviating bronchial asthma symptoms and reversible bronchospasm associated with chronic bronchitis and emphysema. be.

Claims (1)

[Scope of Claims] A therapeutic agent for bronchial asthma containing a xanthine derivative represented by the formula ▲ Numerical formula, chemical formula, table, etc. ▼ as an active ingredient.