GB2141027A

GB2141027A - Diltiazem hypolipidemic compositions

Info

Publication number: GB2141027A
Application number: GB08414498A
Authority: GB
Inventors: Kohki Takashima; Shuji Nitta
Original assignee: Tanabe Seiyaku Co Ltd
Current assignee: Tanabe Seiyaku Co Ltd
Priority date: 1983-06-10
Filing date: 1984-06-07
Publication date: 1984-12-12
Also published as: IT8467596A0; JPS6317810B2; CH661867A5; DK284084A; FR2547730B1; SE465352B; IT1196710B; SE8403042D0; BE899867A; FR2547730A1; JPS59231018A; DE3419425A1; DK164021C; DE3419425C2; HK45489A; SG21089G; DK164021B; DK284084D0; NL8401793A; GB2141027B

Abstract

Hypolipidemic composition comprising as an active ingredient d -3-acetoxy-cis-2,3-dihydro-5-[2- (dimethylamino)-ethyl]-2-(p-methoxyphenyl)-1,5-benzothiazepin -4(5H)-one diltiazem) or a pharmaceutically acceptable acid addition salt thereof.

Description

SPECIFICATION Hypolipidemic composition The present invention relates to a novel hypoli pidemiccomposition. More particularly, it relates to a hypolipidemic composition comprising as an active ingredient d - 3 - acetoxy - cis - 2,3 - dihyro - 5 - [2 (dimethylamino)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 - dihyro - 5 [2 - (dimethylamino)ethyl] - 2 - (p - methoxyphenyl) 1,5- benzothiazepin - 4(5H) - one is useful as a medicine having excellent coronary vasodilating activity (cf. Anzneim.-Forsch. (Drug. Res.), 21, 1338 1343(1971)), it has never been known thatthis compound shows hypolipidemic activity.

As a result of extensive study by the present inventors, it has been found that d - 3 - acetoxy - cis 2,3 - dihyro - 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 of lowering total serum lipids and also lowering serumcholesterol and hence is useful as a hypolipidemic agent.

The excellent hypolipidemic activity of diltiazem was confirmed bythe following experiments.

A gelatine capsule of the test compound was orally administered to male Beagle dogs once a day for 6 months (six days in a week), and the relative value of the total serum lipids after 6 monthsto the total serum lipids atthe first day of experiment was calculated (wherein the total serum lipids at the first day of experiment was counted as 100).As a result, the value in the group of non-administration of the test compound was 131.0 (in average of 5 dogs), but on the other hand,that in the group of administration of diltiazem hydrochloride (20 mg/kglday) was 63.1 (in average of 5 dogs). Besides,whenthe relative value of theserum cholesterol after 6 months to the serum cholesterol atthe first day of experiment was calculated likewise, the relative value in the group of non-administration ofthetest compound was 101.1 (in average of 5 dogs), but on the other hand, that in the group of administration of diltiazem hydrochlor ide (20 mg/kg/day) was 82.3 (in average of 5 dogs).

Moreover, the compounds of the present invention have very low toxicity. For example, diltiazem hydrochloride has LD50 (50 % lethal dose) of 740 mg/kg 72 hours after oral administration to ddY male 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 ofthe pharmaceutically acceptable acid addition salt are inorganic acid salts such as hydrochloride, hydrobromide, sulfate, nitrate, or perchlorate, and organic acid salts such as acetate, oxalate, malonate, tartrate, citrate, lactate or aspartate.

The diltiazem or a pharmaceutically acceptable acid addition salts of the present invention can be administered by oral or parenteral route, but preferably by oral route. The compounds can be adminis tered in anyconventionai dosageforms,forexample, in solid preparations such as tablets, pills, powders, capsules, or granules, and in liquid preparationssuch as solutions, suspensions, emulsions, or dispersions.

For parenteral administrationrthey may be used in the form of an injection or installation.

The diltiazem or its pharmaceutically acceptable acid addition salts of the present invention may be used in admixture with conventional pharmaceutically acceptable carriers or diluents. Acceptable carriers or diluents include, for example, gum arabic, gelatin, sorbitol, tragacanth gum, polyvinylpyrrolidone, lactose, sucrose, corn starch, potassium phosphate, glycine, magnesium stearate, talc, polyethylene gly- col, potato starch, sodium lau ryl sulfate.

The dose of diltiazem or its pharmaceutically acceptable salt mayvary according to the age and body weight of the patient, the kind and severity of the disease, the administration route and the like, but is preferably in the range of 10 to 400 mg/day, more preferably 30 to 360 mg/day, for oral administration in adult.

The diltiazem and its pharmaceutically acceptable acid addition salts of the present invention are useful as a hypolipidemic agent and are usable forthe treatment of hyperlipidemia in animals including human being.

Experiments for the pharmacological activities and toxicity of the compounds of the present invention are shown below.

Experiment 1 Male Beagle dogs (44to 51 weeks old, average weight: 13.2 kg, one group: 5 dogs) were fed with a commercially available dog foods (Dog chow&commat;, manufactured by Purina Co.) and water in separate cage. A gelatin capsule packed with the test compound (diltiazem hydrochloride) was orally administered once a day (dose: 20 mg/kg/day) for 6 months (onSunday, itwas not administered). In control dogs, only gelatine capsulewithouttest compoundwas administered likewise. At an interval of one month after the initiation of experiment, blood was collected from a radiad skin vein, and thetotal serum lipids were measured by Sperryand Brand method (cf.

Journal of Biological Chemistry, Vol.213, page 69, 1955), and the serum cholesterol was measured by Zakmethod (cf. American Journal of Clinical Patholo gy,Vol. 24, page 1307,1954), and the change of the total serum lipids and serum cholesterol with lapse of time were observed. The results are shown in Tables 1 and 2.

The relative values of the total serum lipids and the serum cholesterol in tables were calculated bythe following equations: Total serum lipids after admin Relative value istration of test compound (mg/dl) of total serum = - - x100 lipids Total serum lipids before admin istration of test compound (mg/dll Serum cholesterol after admin Relative value istration of test compound (ntg/dl) of serum = - - x100 cholesterol Serum cholesterol before admin istration oftest compound (mgldi) Table 1

Dose of # Relative value of total serum lipids diltiazem (average # standard deviation) hydro- ------------------------------------ chloride # Period (month) after adminisL of test compd.

(mglkgfday) 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 # 8.4 #6.3 #6.1 # 7.7 # 7.1 # 7.2 The change of the relative value (in average) as shown in the aboveTable 1 can be illustrated as in the accompanying Fig. 1.

Table2

Dose of Relative value of serum cholesterol diltiazem @ (average + standard deviation} hydro cholride Period (month) after administ. of test compd.

(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 # 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 # 6.8 The change of the relative value (in average) as shown in the above Table 2 can be illustrated as in the accompanying Fig. 2.

(Note): In the above Tables 1 and 2,0 month means thefirst day of the initiation of experiment.

Experiment2 (Acute toxicity) Diltiazem hydrochloride was orally administered to ddY mice orWistar rats, and 72 hours afterthe administration, LD50thereofwas calculated by Litchfield Wilcoxon method.The results are shown in Table3.

Table3

Animals Sex LD50 (mg/kg) Mice Male 740 IFemate 640 Rats Male 560 Female 610 The preparations ofthe present invention are illustrated by the following Examples, but it should not be construed to be limited thereto.

Example 1 (Tablets) Diltiazem hydrochloride 45.0g Corn starch 20.1g Lactose 82.49 Polyvinylpyrrolidone 3.0 g Crystalline cellulose 38.0 g Magnesium stearate 1.5 9 Totally 190 g A mixture of diltiazem hydrochloride, lactose and corn starch is mixed with an alcohol solution of polyvinylpyrrolidone, and the mixture is kneaded and granulated by awet granulation method, and then dried.-Magnesium stearate and crystalline cellulose are added to the dried granules, and the mixture is compressed to tablets of 8 mm in diameter (medium weight of each tablet: 190 mg).

Example 2 (Injection) Diltiazem hydrochloride (lOg) is dissolved in distilled waterfor injection (2 liters). The solution is filtered with a membrane filter (pore size: 0.22 m), and is poured into ampoules under sterilization conditions, and the ampoules are sealed to give ampoules for injection (solution content in each ampoule: 2 ml).

Example 3 (Powders) Diltiazem hydrochloride 109 Lactose 90 g Totally 1009 The above-mentioned ingredients are homogeneously mixed in a double conical mixer to give 10-fold powders.

Claims

1. A hypolipidemic composition, which comprises as an active ingredient d - 3 - acetoxy - cis -2,3dihydro -5- [2- (dimethylamino)ethyl] - 2 - (p - methoxyphenyl) - 1,5 - benzothiazepin - 4(5H) - one or apharmaceutical ly orveterinarily acceptable acid addition saltthereof in admixture with a pharmaceutically orveterinarily acceptable carrier our diluent.

2. Acomposition according to Claim 1,wherein the active ingredient is d - 3 - acetoxy- cis - 2,3 dihydro - 5[2 - (dimethylamino)ethyl] - 2 - (p methoxyphenyl) - 1,5 - benzothiazepin - 4(5H) - one hydrochloride.

3. A composition according to Claim 1 or Claim 2, which is in a dosage form suitablefororal administration.

4. A composition according to Claim 3, wherein the dosage form contains 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 in a dose of 1 Oto 400 mgtday.

5. A hypolipidemic composition as claimed in Claim 1 and substantially as hereinbefore described.

6. Use of d - 3 - acetoxy - cis - 2,3 - dihydro - 5 - [2 - (di - methylamino)ethyl] - 2 - (p - methoxyphenyl) - 1,5 - benzothiazepin - 4(5H) - one or a pharmaceutically acceptable acid addition saltthereoffor the treatment of hyperlipidemia.

7. A package containing as an active pharmaceutical ingredient d - 3 - acetoxy - cis - 2,3 dihydro - 5 - [2- (dimethylamino)ethyl] - 2 - (p methoxyphenyl) - 1,5 - benzothiazepin - 4(5H) - one or a pharmaceutically or veterinarily acceptable salt thereoftogetherwith or bearing instructions for the use thereof as a hypolipidemic agent.

8. A method of preparing a hypolipidemic medicament comprising formulating, as the active compound, d - 3 - acetoxy - cis -2,3 - dihydro .5 - [2 - (dimethylamino)ethyl] - 2 - (p - methoxyphenyl) - 1,5 benzothiazepin - 4(5H) - one or a pharmaceutically or veterinarily acceptable salt thereof into a hypolipidemic medicament.

9. A method as claimed in Claim 8 which comprises mixing the active compound with a pharmaceuti callyorveterinarilyacceptable diluent,excipientor carrier.

10. A method of preparing a pharmaceutical or veterinary package bearing instructions forthe contents to be used as a hypolipidemic agent, characterised inthata pharmaceutical orveterinaryformulation, respectively, comprising d - 3 - acetoxy - cis - 2,3 dihydro-5- [2 - (dimethylamino)ethyl] - 2 - (p methoxyphenyl) -1,5 - benzothiazepin - 4(5H) - one or a pharmaceutically orveterinarily acceptable salt thereof is placed into the container of the package.