NL8400548A - PHARMACEUTICAL PREPARATION FOR THE PROPHYLAXIS AND TREATMENT OF ARTERIOSCLEROSIS. - Google Patents

Description

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Br / Bl / lh / 14

Pharmaceutical preparation for the prophylaxis and treatment of arteriosclerosis.

The present invention relates to an agent for the prophylaxis and cure of arteriosclerosis, which contains dilthiazem or a pharmaceutically acceptable acid addition salt thereof as the active ingredient.

It is known that dilthiazem (chemical name: d-3-acetoxy-cis-2,3-dihydro-5- / 2- (dimethylamino) ethyl 7-2- (p-methoxyphenyl) -1,5-benzothiazepine -4 (5H) -on) has excellent coronary vasodilator activity and thus is useful as a coronary vasodilator, but it was not known at all that this compound exhibited anti-arteriosclerosis activity.

Arteriosclerosis is divided pathogenically into three groups: atherosclerosis, Mönkeberg sclerosis (medial sclerosis) and arteriolosclerosis. Atherosclerosis is usually caused by lipid deposition and plaque formation in the intima of the coronary artery, basilar artery, renal artery, thoracic aorta and abdominal aorta, and the like. Mönkeberg sclerosis is often observed in the medium sized arteries of the extremities, such as the femoral artery, tibial artery, and is caused by calcification of arterial media. Arteriolosclerosis is a sclerotic alteration, which is seen in the arteriolae in the kidney, adrenal, mild, fallopian tube, pancreas, and the like.

As a result of extensive investigations conducted by inventors into an improved agent for the prophylactic and cure of arteriosclerosis, it has been found that dilthiazem exhibits excellent anti-sclerosis activity and is effective for the prophylactic and cure of arteriosclerosis.

The object of the invention is to provide an improved medicament for the prophylactic and treatment of arteriosclerosis. Another object of the invention is an 8400548

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To provide new use of the known dilthiazem or pharmaceutically acceptable acid addition salt thereof as a medicament for the prophylactic and treatment of arterio-sclerosis. These objects and advantages of the invention will become apparent to those skilled in the art from the following description.

According to the invention, it has been found that dilthiazem and a pharmaceutically acceptable salt thereof (for example the hydrochloride) have the following pharmacological and toxicological properties: (1) Anti-arteriosclerosis activity: (a) Activities against Mönkeberg sclerosis and arteriolosclerosis:

Mönkeberg sclerosis and arteriolosclerosis were brought about in rats as follows. Spontaneously hypersensitive male rats (age: 7-8 months, one group: 9-12 rats) were fed a high lipid feed (prepared by adding hydrogenated oil (7 wt%), cholesterol (3 wt .%), bile acid (0.5 wt.%) and 20 thiouracil (0.3 wt.% and normal food) were given and the animals were further given vitamin D ^ at a fixed time every day for the first four days (8 mg / kg) through a stomach tube in the form of a solution in olive oil (2 ml).

To investigate the activities of dilthiazem on the above-mentioned experimentally induced aortic Mönkeberg sclerosis and damage in the peripheral arteriolae, an aqueous solution of dilthiazem hydrochloride was administered once (or twice) a day, for one hour (or one hours and 7 hours) after administration of vitamin to the animals via a gastric tube. The administration of dilthiazem hydrochloride was continued even after the end of the administration of vitamin D2 and on the eighth day after the start of the experiment the abdomen was opened under ether anesthesia and blood was collected from the abdominal aorta and the rats were then sacrificed . After autopsy, a histo-pathological examination of the aorta was performed. The results are shown in Table A and Table B.

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TABLE A

Dilthiazem hydrochloride ... column dose (mg / kg / day)

Findings ____3 0 60 x 2 120 ... findings at autopsy:

Subdural bleeding 8/12 0/11 4/9

Periaortic bleeding 7/12 1/11 0/9

Subcutaneous bleeding. 6/12 0/11 1/9

Findings for histodiagnosis +++ 3/12 0/11 0/9

Degree of ++ 1/12 0/11 1/9 Aortic Damage + 5/12 5/11 1/9 3/12 6/11 7/9 (Qpm.) T 1) The number in the table indicates the number of rats with the damage / total number of rats.

2) The symbols +++, ++, + and - in the table have the following meanings: 5 +++ * Significant in both calcareous deposition in the media and perivascular haemorrhage.

++: Significantly either in terms of calcareous deposition in the media or perivascular haemorrhage.

+: Slight damage to both or minor damage to one and no damage to the other.

No damage on either.

The evaluation of "significant" and "minor" in the calcareous deposition in the media and perivascular haemorrhage, as noted above, was performed as follows:

Calcareous deposition in the media "Noteworthy": if examining every 20 section in cross section and each cousin, longitudinal section 8400548 -4- (length: approximately 1.5 cm) of the thoracic aorta and of the abdominal aorta, calcareous deposits are observed over a wide area on the elastic membranes in the media and on the tissues between the elastic membranes and also cracks in the elastic membranes or dispersed focal calcareous deposits are observed.

"Slight": on the elastic membranes and tissues between the elastic membranes, only a single focal calcareous deposit is observed or to some extent a slight calcareous deposit is observed on the elastic membranes.

Hemorrhage "Significant": Significant hemorrhage over a wide area is observed along with strong cellular infiltration.

"Minor": bleeding with low cellular infiltration is observed in part.

As is clear from Table A above, in the group to which no dilthiazem was administered, subdural, perioral and subcutaneous haemorrhages were observed in more than half of the test animals. It is believed that in these animals Mönkeberg sclerosis and arterio sclerosis were brought about by the administration of a feed with a high lipid content and vitamin and thereby weakened the blood vessel wall in this portion, leading to bleeding. In contrast, in the group to which dilthiazem was administered, frequency and degree of subdural, periaortal, and subcutaneous bleeding all decreased. In particular, in the group administered dilthiazem at a dose of 60 mg x 2 / kg / day, these lesions were hardly observed. From these facts, it is clear that dilthiazem might inhibit bleeding from Mönkeberg sclerosis and arteriosclerosis. In addition, according to the aortic lesion findings, significant calcareous media deposition and pervascular haemorrhage were observed in four of twelve animals in the non-dilthiazem-treated 8400548 -5-9 * groups, while in the dilthiazem groups treated groups no significant calcareous deposition in the media or pervascular bleeding was observed apart from one animal. Moreover, in the dilthiazem-treated groups, no damage was observed in more than half of the animals. From these facts, it is clear that dilthiazem could also inhibit calcareous deposition in the media or perivascular haemorrhage.

TABLE B

10 ----—----

Dilthiazem hydrochloride dose (mg / kg / day)

Feeding Feeding with (food with normal high lipid content + vitamin D,) 15 0 0 60 x 2 120

Serum choles- * ** ** terol (mg / dl) 63.6 + 4.2 94.3 + 3.6 130.6 ± 11.2 114.0 + 7.6

Prothrombin ** 20 time (sec.) 14.7 ± 0.1 60.0 ± 9.8 26.5 + 4.5 29.9 + 4.6 I ____ J- (note): *) p <0, 05 ++) P <0.01

As is clear from Table B above, the animals, when fed a high lipid + vitamin D2 feed, exhibited hyperlipaemia, ie, the animals are in a state where arteriosclerosis could easily be caused in compared to the group fed on a normal feed. Moreover, the groups in a state in which arteriosclerosis can be easily caused exhibit the dilthiazem-treated groups an extremely smaller extension of the prothrombin time compared to the non-dilthiazem-treated group. This means that in the non-dilthiazem-treated group, arteriosclerosis progressed to a hyperlipemic state, which may lead to bleeding due to artery rupture, causing blood clotting factors. w -6- are thus significantly reduced in blood clotting capacity, whereas in contrast to the dilthiazem-treated groups, progression of arteriosclerosis prevented bleeding due to fracture of the artery even in the hyperlipemic state and a reduction in blood clotting capacity was thus effectively inhibited.

Thus, it is clear from the test results indicated in Tables A and B that dilthiazem is effective for inhibiting Mönkeberg sclerosis and arteriosclerosis.

(b) Efficacy against atherosclerosis: Atherosclerosis was induced in rabbits as follows. Japanese white rabbits (weight: about 3 kg, one group: 6 rabbits), were fed for 8 weeks with a high lipid feed (prepared by adding cholesterol (2 wt%) and arage oil (7 wt. %) to normal feed).

To investigate the activities of dilthiazem on the above-mentioned experimentally induced atherosclerosis in the aorta, an aqueous solution of dilthiazem hydrochloride (30 mg / kg) was administered once daily after the start of feeding with a high lipid feed via a gastric tube administered to the animals. Eight weeks after the start of the trial, the abdomen was opened under pento-25 barbital anesthesia, and the blood was collected from the abdominal aorta, and the rabbits were then sacrificed and the aortic atheroma was observed.

The results are as reported in Tables C and D.

TABLE C

30 Number of rabbits exhibiting atheroma in the aorta + ++ +++

Group to which food with a high lipid content is administered 3 1 2

Group to which food with a high lipid content and dilthiazem is administered 4 20 8400548. . * * -7- (Note) ï The +++, ++ and + symbols have the following meanings: +++: In about 1/3 of the area or more of the * * intima of the aorta, bold stripes and plaques observed.

5 ++: 30 or more fat stripes were observed and a coalesced fat stripe or plaque was also observed.

+: Less than 30 fat stripes were observed. As is clear from Table C above, in the non-dilthiazem-treated group, a high (+++) degree of atheroma was observed in two animals out of a total of six animals, whereas in the dilthiazem-treated group, however, no such strong degree of atheroma was observed * It is thus clear that dilthia-15zem is effective for inhibiting fat deposition on a blood vessel and inhibiting the progression of atheroma.

TABLE · D

———— "· ί '·" ·' '-. "11 11"

Dilthiazem hydrochloride dose (mg / kg / day} ^ Feeding Feeding with normal feed containing a high lipid feed 0 0 30 25 -: ---

Serum cholesterol ** (mg / dl) 50 + 12 3452 + 418 3586 + 320

Serum triglycerides (mg / dl) 188 + 84 9541 264 851 + 150

Serum phospho-** ** 30 lipi <3 and (mg / dl) 99 + 25 114451188 1481 + 183 (Note): *: p <. 0.05 **: p <0.01

As is clear from Table D, the animals of both dilthiazem-administered and non-dilthiazem-administered groups exhibited hyperlipaemia, i.e., the animals were in a state in which fat deposition and atheroma could be easily caused.

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However, in the dilthiazem-treated group, fat deposition and atheroma were remarkably inhibited, while the animals were in a state where fat deposition and atheroma could be easily caused. Dilthiazem 5 is therefore effective for the prophylactic and treatment of arterosclerosis.

(2) Acute toxicity:

Dilthiazem hydrochloride was administered orally to ddY mice or Wistar rats and the 50% lethal dose (LD ^ Q) was measured by the Litchfield-Wilcoxon method 72 hours after administration. The results are shown in Table E.

TABLE E

i _ ^ _

Animals Gender LD50 15 -: ----

Mouse male 740 female 640

Rat male 560 female 610 20 In view of the above-mentioned pharmacological and toxicological properties of dilthiazem, it is clear that this compound is useful for the prophylactic and treatment of arteriosclerosis, such as atherosclerosis (eg coronary arteriosclerosis, brain arterio-sclerosis, renal arteriosclerosis), Mönkeberg sclerosis (for example, arteriosclerosis in the extremities) and further arteriosclerosis in various organs.

In addition, a prophylactic agent and medicine for arteriosclerosis usually has to be administered for quite a long time, which sometimes causes unwanted side effects, but dilthiazem can be administered for a long time without any unwanted side effect and is thus extremely good as a prophylactic agent and medicine. for arteriosclerosis. The dilthiazem used in the invention can be used either in the form of a free base or in the form of a pharmaceutically acceptable acid addition salt thereof. Suitable examples of the pharmaceutically acceptable acid addition salts are the salts of organic acids, such as the acetate, 8400548-9 oxalate, malonate, tartrate, citrate, lactate or aspartate, and salts of inorganic acids, such as the hydrochloride, hydrobromide, sulfate, nitrate or perchlorate,

The dose of dilthiazem and a salt thereof can vary depending on the ages of the patients, the types and severity of the ailments and the like, although a dose in the range of about 30 to 400 mg / day / body is preferred.

The mode of administration and type of preparation of the agent (pharmaceutical composition) of the invention is not prescribed, but the agent is administered orally or parenterally, preferably orally.

The agent according to the invention is used in the form of conventional pharmaceutical preparations suitable for oral or parenteral administration, mixed with conventional pharmaceutically acceptable carriers or diluents. The pharmaceutically acceptable carriers include, for example, binders (e.g., syrup, gum arabic, gelatin, sorbitol, gum tragacanth, polyvinyl-pyrrolidone, etc.), diluents (e.g., lactose, sugar, corn starch, potassium phosphate, sorbitol, glycine, etc.), lubricants ( for example, magnesium stearate, talc, polyethylene glycol, silica, etc.), disintegrants (eg, potato starch, etc.), and wetting agents (eg, sodium lauryl sulfate, etc.). The preparations can be tablets, pills, powders, capsules, granules. For parenteral administration, the agent can be used in the form of an injection or instillation and further in the form of a suspension, dispersion or emulsion, which is prepared by lubrication with glycerol, propylene glycol, simple syrup, ethanol, fatty oils, ethylene glycol , sorbitol, etc.

The invention is illustrated by the following examples, but it is not limited thereto.

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Example I (Tablet)

Dilthiazem hydrochloride 45.0 g

Corn starch 20.1 g Lactose 82.4 g

Polyvinylpyrrolidone 3.0 g

Crystalline cellulose 38.0 g

Magnesium stearate 1.5 g

Total 190 g 10

A mixture of dilthiazem hydrochloride, lactose and corn starch is mixed with an alcohol solution of polyvinylpyrrolidone and the mixture is kneaded and granulated by a wet granulation method and then dried. 15

Magnesium stearate and crystalline cellulose are added to the dried granulate, after which the mixture is pressed into tablets with a diameter of 8 mm (average weight of each tablet: 190 mg).

Example II

20 (Injection)

Dilthiazem hydrochloride (10 g) is dissolved in distilled water for injection (2 L). The solution is filtered through a membrane filter (pore size: 0.22 µm), after which ampoules are filled under sterile conditions and the ampoules are sealed to obtain ampoules for injection (amount of solution per ampoule: 2 ml).

Example III (Powders) Dilthiazem hydrochloride 10 g

Lactose 90 g

Total 100 g

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

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Claims (11)

1. Pharmaceutical composition for the prophylactic and treatment of arteriosclerosis, characterized by an effective amount of dilthiazem or a pharmaceutically acceptable acid addition salt thereof as active ingredient mixed with pharmaceutically acceptable carriers or diluents. Pharmaceutical preparation according to claim 1, characterized in that it is a pharmaceutical preparation for the prophylactic and treatment of atherosclerosis. Pharmaceutical preparation according to claim 1, characterized in that it is a pharmaceutical preparation for the prophylactic and treatment of Mönkeberg sclerosis. Pharmaceutical preparation according to claim 1, characterized in that a pharmaceutical preparation is for the prophylactic and treatment of arteriosclerosis. Pharmaceutical preparation according to claim 1, characterized in that it has a dosage form suitable for oral administration. Pharmaceutical preparation according to one or more of the preceding claims, characterized in that the preparation is in a dosage form such that a dose of 30 to 400 mg / day / body can be provided. 7. Use of dilthiazem or a pharmaceutically acceptable acid addition salt thereof for the prophylactic and treatment of arteriosclerosis. Use of dilthiazem or pharmaceutically acceptable acid addition salt thereof for the prophylactic and treatment of atherosclerosis. 9. Use of dilthiazem or pharmaceutically acceptable acid addition salt thereof for the prophylactic or treatment of Mönkeberg sclerosis. 10. Use of dilthiazem or a pharmaceutically acceptable acid addition salt thereof for the prophylactic and treatment of arteriosclerosis. Use of dilthiazem or pharmaceutically acceptable acid addition salt thereof for the prophylactic and treatment of atherosclerosis according to any one of claims 7-10 in an orally administered form. 8400548