DK164021B - USE OF DILTIAZEM FOR THE PREPARATION OF A PHARMACEUTICAL PREPARATION FOR TREATING HYPERLIPIDEMIA - Google Patents

Description

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DK 164021 B

The present invention relates to a novel use of d-3-acetoxy-cis-2,3-dihydro-5- [2- (dimethylamino) ethyl] -2- (p-methoxyphenyl) -1,5-benzothiazepine 4 (5H) -one or a pharmaceutically acceptable acid addition salt thereof for the preparation of a pharmaceutical composition for the treatment of hyperlipidemia.

It is known that d-3-acetoxy-cis-2,3-dihydro-5- [2- (dimethylamino) ethyl] -2- (p-methoxyphenyl) -1,5-benzothiazepin-4 (5H) -one is useful as a drug with excellent coronary vasodilatory activity (cf. Anzneim-Forsch. (Drug. Res.), 21, 1338-1343 (1971)), but it has not been known before that this compound exhibits hypolipidemic activity.

As a result of extensive studies in the present invention, it has been found that d-3-acetoxy-cis-2,3-dihydro-5- [2- (dimethylamino) ethyl] -2- (p methoxyphenyl) -1,5-benzothi azepine-4 (5H) -one (hereinafter referred to as "diltiazem") or as a pharmaceutically acceptable acid addition salt thereof has excellent activity in lowering the total amount of serum lipids and serum cholesterol and consequently is useful as a hypolipidemic agent.

Diltiazem's excellent hypolipidemic activity was confirmed by the following experiments.

A gelatin capsule with the test compound was administered orally to male Beagle dogs once daily for 6 months (six days a week) and the ratio of total serum lipids after 6 months to total serum lipids on the first day of the trial was calculated (total serum serum lipids on the first day of the experiment was set to 100).

The result was that the ratio in the group to which the test compound was not administered was 131.0 (mean for 5 dogs), while the ratio in the group to which diltiazem hydrochloride (20 mg / kg / day) was administered was 61.3 (mean for 5 dogs). ). Furthermore, by similar calculation of the ratio of serum cholesterol at 6 months to serum 30 cholesterol on the first day of the trial, the ratio in the group to which the test compound was not administered was found to be 101.1 (average for 5 dogs), whereas in the group to which diltiazem hydrochloride (20 mg / kg / day) administered was 82.3 (average for 5 dogs). In addition, the compound in question has very low toxicity. For example, diltiazem, hydrochloride has an LD 50 value (50% lethal dose) of 740 mg / kg 72 hours after oral administration to male ddY mice.

The active compound, diltiazem, can be administered in the form of either a free base or a pharmaceutically acceptable acid addition salt.

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Suitable examples of pharmaceutically acceptable acid addition salts are salts with inorganic acids such as hydrogen chloride, hydrogen bromide, sulfate, nitrate or perchlorate or salts with organic acids such as acetate, oxalate, malonate, tartrate, citrate, lactate or aspartate.

Diltiazem or a pharmaceutically acceptable acid addition salt may be administered orally or parenterally, but oral administration is preferred. The compound may be administered in any conventional dosage form, for example, in solid compositions such as tablets, pills, powders, capsules or granules and in liquid preparations such as solutions, suspensions, emulsions or dispersions. For parenteral administration, they can be used in a form intended for injection or instillation.

Diltiazem or a pharmaceutically acceptable acid addition salt thereof may be used in admixture with conventional pharmaceutically acceptable carriers or diluents. Acceptable carriers or diluents include, for example, gum arabic, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone, lactose, sucrose, corn starch, potassium phosphate, glycerin, magnesium stearate, talc, polyethylene glycol, potato starch, sodium lauryl sulfate.

The dose of diltiazem or a pharmaceutically acceptable acid addition salt thereof may vary according to the patient's age and body weight, the nature and severity of the disease, the route of administration, and the like, but is preferably in the range of 10 to 400 mg / day, more preferably 30 to 360. mg / day by oral administration to adults.

Diltiazem and pharmaceutically acceptable acid addition salts thereof are useful as a hypolipidemic agent and can be used to treat hyperlipidemia in animals and humans.

The use of diltiazem in trials for pharmacological activities and toxicity is shown below.

Experiment 1.

30 Male Beagle Dogs (age: 44 to 51 weeks, average weight: 13.2 kg, group: 5 dogs) were fed with commercially available dog feed (Dog chow) provided by Purina Co. and water in different bowls.

A gelatin capsule packed with the test compound (diltiazem, hydrogen chloride) was administered orally once daily (except Sunday) (dose 20 35 mg / kg / day) for 6 months. To the control group, a gelatin capsule without test compound was administered in the same manner. At an interval of one month after the start of the experiment, blood was collected from a radial skin vein and the total amount of serum ipids was measured using the Sperry and Brand method 3.

DK 164021 B

(cf. Journal of Biological Chemistry, vol. 213, p. 69, 1955), while serum cholesterol was measured by the Zak method (cf. America! Journal of Clinical Pathology, vol. 24, p. 1307, 1954) and the temporal change in the total amount of serum lipids and serum cholesterol observed-5 is taken. The results are shown in Tables I and II.

The ratio of total amount of serum lipids and serum cholesterol in the tables was calculated using the following terms:

Ratio of Total Amount of Serum Lipids After Administered Total Quantification of Test Compound (mg / dl) x 100 Serum Lipids Total Amount of Serum Lipids Prior to Administering Test Compound (mg / dl)

Ratio of Serum Cholesterol after administration 15 for serum = of test compound (mg / dl) _ x 100 cholesterol Serum cholesterol before administration of test compound (mg / dl)

Table I

Dose of Ratio of Total Amount of Serum Lipids Diltiazem, (Average in Standard Deviation) - Hydrogen Chloride Period (Month) after administration of the test compound.

(mg / kg / day) 0123 456 0 100 111.1 115.3 159.9 130.6 123.6 131.0 ± 24.3 ± 29.5 ± 84.1 ± 30.8 ± 38.8 ± 22.5 30 20 100 79.2 77.6 78.5 79.0 69.2 63.1 ± 8.4 ± 6.3 ± 6.1 ± 7.7 ± 7.1 ± 7.2 The change in the ratio (average) as shown in the above Table I 35 can be illustrated as in FIG. First

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Table II

Dose of Ratio of Serum Cholesterol Diltiazem, (mean in standard deviation) 5 Hydrogen Chloride Period (month) after administration of test compounds.

(mg / kg / day) 0 1 2 3 4 5 6 0 100 117.4 108.6 96.2 105.0 110.3 101.1 ± 4.0 ± 5.5 ± 4.7 ± 6.6 ± 3.5 in 7.5 10 20 100 109.3 89.2 83.1 90.9 78.2 82.3 ± 12.1 ± 11.8 ± 5.7 ± 6.9 ± 9.6 ± 6.8 15 The change in the ratio (average) as shown in the above Table II can be illustrated as in fig. First

note: In the above tables I and II, month 0 means the first day of the experiment.

Experiment 2

Acute toxicity:

Diltiazem, hydrochloride, was orally administered to ddY mice or Wistar rats, and 72 hours after administration, 50% lethal dose (LDjq) was calculated by the Litchfield-Wilcoxon method. The result is shown in Table 25 (III).

Table III

Animal sex LD5Q (mg / kg) 30

Mouse male 740 female 640 male rat 560 35 female 610

The present invention is illustrated by the following examples.

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Example 1 (Tablet)

Diltiazem hydrochloride 45.0 g 5 Corn starch 20.1 g

Lactose 82.4 g

Polyvinyl pyrrole idon 3.0 g

Crystalline cellulose 38.0 g

Magnesium stearate 1.5 g 10

Total 190 g

A mixture of diltiazem, hydrochloride, lactose and corn starch is mixed with an all alcoholic solution of polyvinyl pyrrolidone and the mixture is kneaded and granulated by a wet granulation method and then dried.

Magnesium stearate and crystalline cellulose are added to the dried granules and the mixture is pressed into 8 mm diameter tablets (average weight of the tablets: 190 mg).

Example 2 (Injection) 20 Diltiazem hydrochloride (10 g) is dissolved in distilled water for injection (2 liters). The solution is filtered with a membrane filter (pore size .22 µm), poured onto ampoules under sterile conditions and the vials are sealed to form vials for injection (solution content of each vial: 2 ml).

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Example 3 (Powders)

Diltiazem, hydrochloride 10 g

Lactose 90 g 30

Total 100 g

The above ingredients are mixed homogeneously to form 10-fold powders.

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Claims (1)

Use of d-3-acetoxy-cis-2,3-dihydro-5- [2- (dimethylamino) ethyl] -2- (p-methoxyphenyl) -1,5-benzopthi azepine n-4 (5H) - on (dithiazem) or a pharmaceutically acceptable acid addition salt thereof for the preparation of a pharmaceutical composition for the treatment of hyperlipidemia. 10 15 20