NL8401793A - HYPOLIPIDEMIC PREPARATION. - Google Patents

Description

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HYPOLIPIDEMIC PREPARATION

The present invention relates to a new hypolipidemic preparation. More particularly it relates to a hypolipidemic preparation, which as an active ingredient d-3-acetoxy-cis-2,3-dihydro-5- [1- (di- 5 contains methylamino) ethyl] -2- (p-methoxyphenyl) -1,5-benzothiazepin-4 (5H) -one or a pharmaceutically acceptable acid addition salt thereof.

It is known that d-3-acetoxy-cis-2,3-dihydro-5- [2- (dimethylamino) ethyl] -2- (p-methoxyphenyl) -1,5-benzothiaze-10 pin-4 (5H ) is inappropriate as a drug having excellent coronary vasodilatation activity (see Anzneim.-Forsch. (Drug. Res.) 21, 1338-1343 (1971)), this compound is not known to exhibit hypolipidemic activity.

As a result of an extensive study by the 15 current inventors, it has been found that d-3-acetoxy-cis-2,3-dihydro-5- [2- (dimethylamino) ethyl] -2- (p-methoxyphenyl) -1 5-Benzothiazepin-4 (5H) -one (hereinafter referred to as "diltiazem") or a pharmaceutically acceptable acid addition salt thereof has excellent activities for lowering the total serum lipids and also for lowering serum cholesterol and therefore useful as a hypolipidemic agent.

The excellent hypolipidemic activity of diltiazem is confirmed by the following experiments.

A gelatin capsule containing test compound 25 was administered orally once a day for 6 months (six days a week) to male Beagle dogs, and the relative value of total serum lipids at six months compared to total serum lipids on the first day of experiment was calculated (counting total serum lipids as one hundred on the first day of the experiment).

As a result, the value in the group to which the test compound had not been administered was equal to 131.0 (the average of 5 dogs), and on the other hand, that in the group where diltiazem hydrochloride had been administered (20 mg / kg / day) -35 was equal to 63.1 (average of 5 dogs). Furthermore, if the relative value of serum cholesterol after six months 8401793 - 2 - relative to serum cholesterol on the first day of the experiment was similarly calculated, the relative value in the group to which the test compound had not been administered was 101.1 (the average of 5 dogs) and, on the other hand, for the group administered diltiazem hydrochloride (20 mg / kg / day) equal to 82.3 (the average of 5 dogs). In addition, the compounds of the present invention have very low toxicity. For example, diltiazem hydrochloride has an LDj.q (50% lethal dose) of 740 mg / kg, 72 hours after oral administration to male ddY mice.

The active compound, diltiazem of the present invention, can be administered in the form of either a free base or a pharmaceutically acceptable acid addition salt. Suitable examples of pharmaceutically acceptable acid addition salts are inorganic acid salts, such as hydrogen chloride, hydrogen bromide, sulfate, nitrate, or perchlorate, and inorganic acid salts, such as acetate, oxalate, malonate, tartrate, citrate, lactate, or aspartate.

Diltiazem or a pharmaceutically acceptable acid addition salt of the present invention can be administered orally or parenterally, but preferably by the oral route. The compounds can be administered in any conventional administration form, for example, in solid preparations, such as tablets, pills, powders, capsules, or granules, and in liquid preparations, such as solutions, suspensions, emulsions, or dispersions. Injection or instillation may be used for parenteral administration.

Diltiazem or pharmaceutical acid addition salts according to the present invention can be used in a mixture with known pharmaceutically acceptable carriers or diluents. Acceptable carriers or diluents include (e.g. gum arabic, gelatin, sorbitol, gum tragacanth, polyvinylpyrrolidone, lactose, sucrose, corn starch, potassium phosphate, flycine, magnesium stearate, talc, polyethylene glycol, potato starch, sodium lauryl sulfate.

The dose of diltiazem or its pharmaceutically acceptable salt table may be varied according to the age * 4 0 1 7 9 3 - 3 - and the patient's body weight, the type and severity of the disease, the route of administration, etc., but preferably in the range of 10-400 mg / day, more preferably 30-360 mg / day, for oral administration to adults.

Diltiazem and its pharmaceutically acceptable acid addition salts of the present invention are useful as hypolipidemic agents and are useful for the treatment of hyperlipidemia in animals, including humans.

Experiments regarding the pharmacological activity and toxicity of the compounds of the present invention are shown below.

Experiment 1

Male Beagle dogs ('44 -51 weeks old, average weight 13.2 kg, group of 5 dogs) were fed a commercially available dog food (Dog chow®, manufactured by Purina Co.) and water in a separate bin. A gelatin capsule containing the test compound (diltiazam hydrochloride) was administered orally once a day (dose: 20 mg / kg / day) for 6 months (not administered on Sunday). Control dogs were similarly administered only a gelatin capsule without a test compound. After a month period following the start of the experiment, blood was collected from a superficial cutaneous vein and the total serum lipid content was determined by the method of Sperry and Brand (see Journal of Biological Chemistry, vol. 213, page 69, 1955), and the serum cholesterol level was measured by the method of Zak (see American Journal of Clinical Pathology, vol. 24, page 30 1307, 1954), and the change in total serum lipid and serum cholesterol levels over time. Viewed. The results are shown in Tables 1 and 2.

The relative values of total serum lipid content and serum cholesterol levels in the tables were calculated using the following equations: 8401793 · »*

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Total serum lipid content after

Relative value of test compound administration (mg / dl) ........— ----------- --------- - 100 the total serum lipi Total serum lipid content for administration of the test compound (mg / dl) serum cholesterol level after the

Relative value of administration of test compound (mg / dl the serum cholesterol -. 7 I,., 7 x serum cholesterol content for administration of the test compound (mg / dl)

Table 1 p - ............ ... *

Diltiazem dose- Relative value of total serum lipid hydrochloric acid content (mean + standard deviation) the (mg / kg / day) period (month) after administration of the test-15 compound 0 1 2 3 4 5 6 0 100 111.2 115.3 159.9 130.6 123.6 131.0 ± 24.3 ± 29.5 ± 84.1 ± 30.8 ± 38.8 ± 22.5 20 100 79.2 77.6 78.5 79.0 69.2 63.1 20 ± 8.4 ± 6.3 ± 6.1 ± 7.7 ± 7.1 ± 7.2

The change in the relative value (as an average), as shown in Table 1 above, can be illustrated in the accompanying Figure 1.

Table 2 25 Diltiazem dose- Relative value of serum cholesterol hydrogen chloride (mean _ + standard deviation) de (mg / kg / day) Period (month) after test compound administration 0 1 2 3 4 5 6 * -r- --- -------- 30 0 100 117.4 108.6 96.2 105.0 110.3 101.1 ± 4.0 ± 5.5 ± 4.7 ± 6.6 ± 3.5 ± 7.5 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.S

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The change in the relative value (as an average) as shown in Table 2 above can be illustrated in the accompanying Figure 2.

(Note): In Tables 1 and 2 above bete-5, 0 months has the first day at the start of the experiment.

Experiment 2 (acute toxicity)

Diltiazem hydrochloride was administered orally to ddY mice or Wistar rats and 72 hours after administration, its LD 1 g was calculated by the Litchfield Wilcoxon method. The results are shown in Table 3.

Table 3

Animal sex LD ^ g (mg / kg) 15 mice male 740 female 640 rats male 560 female 610

The formulations of the present invention are illustrated by the following examples, but should not be limited thereto.

Example 1 (tablets)

Diltiazem hydrochloride 45.0 g 25 corn starch 20.1 g lactose 82.4 g polyvinylpyrrolidone 3.0 g crystalline cellulose 38.0 g magnesium stearate 1.5 g 30 Total 190 g

A mixture of diltiazem hydrochloride, lactose and corn starch is mixed with an alcoholic solution of polyvinylpyrrolidone, and the mixture is kneaded and granulated by a wet granulation method, then dried. Magnesian stearate and crystalline cellulose are added to the dried granules, and the mixture 8401793 V * - 6 - is compressed into tablets with a diameter of 8 mm (average weight of each tablet 190 mg).

Example 2 (injection) 5 Diltiazem hydrochloride (10 g) is dissolved in distilled water (2 liters) intended for injection. The solution is filtered through a membrane filter (pore size 0.22 µm), and poured into ampoules under sterile conditions, and the ampoules are sealed and provide ampoules for injection (each ampoule contains 2 ml of solution).

Example 3 (powders) diltiazem hydrochloride 10 g lactose 90 g

Total 100 g

The above ingredients are mixed homogeneously in a double-conical mixer to provide 10-fold powders.

8401793

Claims (8)

A hypolipidemic preparation, comprising as an active ingredient an effective amount of d-3-acetoxy-cis-2,3-dihydro-5- [2- (dimethylamino) ethyl] -2- (p-methoxy-phenyl) -1 5-benzothiazepin-4 (5H) -one or a pharmaceutically acceptable acid addition salt thereof, mixed with a pharmaceutically acceptable carrier or diluent. Preparation according to claim 1, characterized in that the active ingredient d-3-acetoxy-cis-2,3-dihidro-5- [2- (dimethylamino) ethyl] -2- (p-methoxyphenyl) -1, 5-10 is benzothiazepin-4 (5H) -one hydrochloride. Preparation according to claim 1 or 2, characterized in that the dosage form is suitable for oral administration. Preparation according to claim 3, characterized in that the dosage form comprises the active d-3-acetoxy-cis-2,3-dihydro-5- [2- (dimethylamino) ethyl] -2- (p-methoxyphenyl ) -1,5-benzothiazepin-4 (5H) -one or a pharmaceutically acceptable acid addition salt thereof at a dose of 10-400 mg / day. 5. The use of d-3-acetoxy-cis-2,3-dihydro-5-20 [2- (dimethylamino) ethyl] -2- (p-methoxyphenyl) -1,5-benzothiazepin-4 (5H) -one or a pharmaceutically acceptable acid addition salt thereof for the treatment of hyperlipidemia. A method for the treatment of hyperlipidemia, comprising administering an effective amount of 25 d-3-acetoxy-cis-2,3-dihydro-5- [2- (dimethylamino) ethyl] -2- (p-methoxyphenyl) -1,5-benzothiazepin-4 (5H) -one or a pharmaceutically acceptable acid addition salt thereof to a patient with hyperlipidemia. A method according to claim 6, characterized in that the active compound is administered by the oral route. A method according to claim 7, characterized in that the active compound is administered at a dose of 10-400 mg / day. 8401793