DE3406837A1 - ARTERIOSCLEROSIS MEDICINAL PRODUCT AND PROPHYLACTIC - Google Patents

Description

TANABE SEIYAKU CO., LTD., OSAKA-SHI, OSAKA-FU / JAPAN

Atherosclerosis drugs and prophylactic agents

The invention relates to an agent for prophylaxis and healing of arteriosclerosis and is characterized in that the medicament according to the invention contains as the active ingredient diltiazem or a pharmaceutically acceptable acid addition salt thereof.

It is known that diltiazem (chemical name: d-3-acetoxy-cis-2,3-dihydro-5- / 2- (dimethylamino) ethyl7 ~ 2- (p-methoxyphenyl) -1,5-benzothiazepin-4 (5H) -one) a has very good coronary vasodilator activity and is therefore suitable as a coronary vasodilator, however it has never been found before that this compound also has an anti-arteriosterotic activity

15 has vity.

Atherosclerosis is pathologically divided into three groups of atherosclerosis, namely Mönkeberg's Sclerosis (medial sclerosis) and arteriolosclerosis. Atherosclerosis is generally caused by lipid deposition and plaque formation in the intima of the coronary artery, basilar artery, renal artery, torax aorta, Abdominal aorta and the like. Mönkeberg's sclerosis is common in those of medium size Arteries of the extremities such as the femoral artery, tibial artery or the like are observed and is induced by calcification of the orterial media. Arteriolosclerosis is a sclerotic change, those of arterioles in the kidneys, adrenal glands, spleen, ovaries, pancreas, or the like is detected.

Due to the inventors' intensive studies to improve the prophylaxis and cure of Atherosclerosis, it has now been found that diltiazem has excellent anti-arteriosclerotic activity and is suitable as prophylaxis and for the treatment of arteriosclerosis.

It is therefore an object of the invention to provide an improved medicament for prophylaxis and treatment of atherosclerosis. Another object of the invention is to provide a new use for the known diltiazem or a pharmaceutically acceptable acid addition salt thereof 30th

as medicine for the prophylaxis and treatment of arteriosclerosis. These goals and benefits of the present invention will be apparent to one skilled in the art from the following description. 5

It was found according to the invention that diltiazem and pharmaceutically acceptable salts thereof (e.g. the hydrochloride), the following pharmacological ones and have toxic properties: 10

(1) Anti-arteriosclerosis activity

(a) Activity against Mönkeberg's sclerosis and arteriolosclerosis:

Mönkeberg's sclerosis and arteriolosclerosis were induced in rats in the following manner: Spontaneous hypertensive made male rats (ages 7 to 8 months, one group consisted of 9 to 12 rats) were made nourished with a high lipid food (this was made by adding hydrogenated oil (7 wt.%), Cholesterol (3 wt.%), Cholic acid (0.5 wt.%) And thiouracil (0.3 wt.%) To a normal Food) and during the first 4 days vitamin D (8 mg / kg) was given to the animals by means of a gastric tube given in the form of a solution in olive oil (2 ml) at a certain time a day.

To investigate the activities of diltiazem in the above-induced Mönkeberg's sclerosis in the aorta and damage, in the peripheral arterioles,

an aqueous solution of diltiazem hydrochloride was administered to the animals by means of a gastric tube once (or twice) daily, namely 1 hour (or 1 hour and 7 hours) after the administration of vitamin D ₂ . The administration of diltiazem hydrochloride was continued even after the administration of vitamin D ₂ had been discontinued and on the eighth day after the initiation of the experiment, the abdomen was opened under ether anesthesia and blood was collected from the abdominal aorta and then the rats were sacrificed . After the autopsy
a histopathological examination of the aorta was performed and the results are in Table 1
and 2 shown.

Table 1

Finding Dose
chloride Findings of the histodiagnosis: 3/12 Diltiazem hydro
(mg / kg / day) 120 0 + + + 1/12
5/12
3/12 60x2 Autopsy findings: Degree of ++
Aortic ₊
sions 4/9 subdural bleeding 8/12 0/11 0/9 periaortic blu
services 7/12 1/11 1/9 subcutaneous bleeding 6/12 0/11 0/9 0/11 1/9
1/9
7/9 0/11
5/11
6/11

Note: (1) The numbers in the table indicate the

Number of rats with lesions / total number of rats.

(2) The symbols +++, ++, + and - in the

Table have the following meanings:

+++ both remarkable calcium deposits in the media as well as perivascular Bleeding;

++ either noticeable calcium deposits in the media or perivascular bleeding;
15th

+ minor lesions in both or minor lesion in one and no lesion in the other;
20th

.- no lesion in either.

The rating "noteworthy" and "low" for the calcium deposits and the media for the perivascular Bleeding was performed as follows.

Limescale deposits in the media

"Noteworthy": When examining one cross-sectional part and one longitudinal section (length

about 1.5 cm) of the torax aorta and the abdominal aorta became caliform deposits in a large area found on the elastic membranes in the media and in the tissue between the elastic membranes and tears of the elastic membranes were also observed or scattered focal ones calcareous deposits found.

"Minor": There were single focal calcareous Ab-10 deposits found on the elastic membranes and the tissues between the elastic membranes or small calcareous deposits were found on the elastic membranes.

Bleeding

"Noteworthy": There was bleeding in a wide area along with severe cell infiltration 20 found.

"Low": Only some bleeding with low cell infiltration was found.

25 From Table 1 it can be seen that in the group which no diltiazem had been administered, subdural periaortic and subcutaneous bleeding in more than half of the test animals were found. It is assumed that Mönkeberg's sclerosis in these animals

and arteriolosclerosis by the administration of a

Highly lipid-rich food and induced by vitamin D

and that the blood vessel walls in this part were weakened by the bleeding. Against it took the frequency in the group given diI-tiazem at subdural periaortic and subcutaneous bleeding and its severity. In particular, were among the group that diltiazem was administered at a dose of 60 mg χ 2 / kg / day, these lesions were almost not observed. the end These facts indicate that diltiazem is bleeding due to Mönkeberg's sclerosis and arteriolosclerosis can inhibit. In addition, due to the findings of the aortic lesions, there were noticeable calcium deposits in the media or perivascular bleeding in four of twelve animals from the group that did not receive diI-tiazem given, while the group given diltiazem no noticeable calcium deposits in the media or pervascular bleeding, except in one animal, showed. In addition, no lesion was found in the groups that had been given diltiazem more than half of the animals were found. From these facts it can be seen that diltiazem also builds up calcium deposits in the media or perivascular hemorrhage.

Table 2

ι Dose of diltiazem hydrochloride
(mg / kq / day) Nutrition. With high lipid +
Vitamin D ~ food 60 χ 2 120 Serum choleste ^
rin (mg / dl) nourishment
with normal
food 0 130 ^, 6111 ^ 2 ** **
114.0 ± 7 _? 6th Protiirambin
time (sec.) 0 94.3 ± 3.6 * 26 _; 5 ± 4 ^ 5 29 ₇ 9 ± 4 ^ 6 63.6 + 4 ^ 2 60 _? 0 ± 9 ₇ 8 ** 14.7 + Oj ,!

*) p <0.05
**) p <0.01

CD CO C »GO

From Table 2 it can be seen that the animals fed with a high lipid-rich diet plus vitamin D » had hyperlipemia, that is, the animals were in a condition in which atherosclerosis can be easily induced- compared to the group that nourished on a normal diet had been. Of the groups that were in a state in which atherosclerosis was easily induced the groups given diltia'zem showed an extremely lower level Prolongation of prothrombin time compared to the group that did not receive diltiazem. That means that the group that was not given diltiazem had atherosclerosis in the hyperlipemic Condition progressed and bleeding due to a rupture of the arteries, causing blood coagulation factors were consumed, and as a result, the blood coagulation ability markedly decreased, while in the groups given diltiazem, the progression of arteriosclerosis and the bleeding due to an arterial rupture was avoided even in the hyperlipemic state and as a result a lowering of the blood coagulation ability was effectively inhibited.

The results shown in Tables 1 and 2 thus show that diltiazem is both Mönkeberg's Effectively inhibits both sclerosis and arteriosclerosis.

(b) Activity against atherosclerosis

Atherosclerosis was determined in rabbits in the following manner

- 12 -

Induced: White Japanese rabbits (weight about 3 kg, a group of 6 animals) were treated with a highly lipid-rich Food (which was made by adding cholesterol (2 wt%) and peanut oil (7 wt%) to it normal food) fed for 8 weeks.

To examine the activities of diltiazem in arteriosclerosis induced experimentally in the above manner To examine the aorta, an aqueous solution of diltiazem hydrochloride (30 mg / kg) was given to the animals by means of a nasogastric tube once a day after starting the diet with the highly lipid-rich food administered. Eight weeks after the initiation of the experiment, the abdomen was placed under pentobarbital anesthesia opened and blood was collected from the abdominal aorta and then the rabbits were sacrificed and then atheromas were found in the aorta. The results are shown in Tables 3 and 4.

Table 3

Number of rabbits with
Atheromas in the aorta + ++ +++ Group, the one
high lipid
Get food
would have
Group the one
high lipdrich
Food and dil
tiazem received
would have 3 ■ 1 2
4 2 0

Note: The symbols +++ / ++ and + have the following meanings:

+++ bold streaks and plaques were about 1/3 or larger

Area of the intima of the aorta noted;

++ 30 or more greasy streaks were found and they were

coalesced fatty streaks or plaques noted;

+ less than 30 greasy streaks were found.

From Table 3 above, it can be seen that the group that did not receive diltiazem had a high Degree (+++) of atheromas was found in two out of six animals, but that in contrast Such a high level of atheroma was not found in the group given diltiazem became. This shows that diltiazem is effective in reducing fat deposition in blood vessels and

25th inhibited by atheromas.

Taböllei 4

Dose of ciltiazem hydrochloride
(mg / kg / day) Diet high in lipid
rich food 30th Serum-choleste-
rin (mg / dl) nourishment
with normal
food 0 3586 ± 320 ** Serum triglyce
ride (mg / dl) 0 3452 ± 418 ** 851 ± 150 * Serum phospho-
lipids (mg (dl) 50 ± 12 954 + 264 * 1481 + 183 188 ± 84 • *
1445 + 188 99 ± 25

p,
: ρ <0 ₇ 01

CD CD OO

From Table 4 it can be seen that in both groups, that is, in the animals to which diltiazem was administered as well as those who did not receive this administration, the animals developed hyperlipemia showed, i.e. that the animals were in a condition in which fat deposits and Could induce atheromas. In the diltiazem-treated group, the fatty deposits and atheromas were found but noticeably inhibited while the animals were in a "condition in which fatty deposits and Atheromas could easily be induced. As a result, diltiazem is used for prophylaxis and treatment effective from atherosclerosis.

(2)

acute toxicity

Diltiazem hydrochloride was orally administered to ddY mice or Wistar rats, and 72 hours after the administration, the 50% lethal dose (LD ₁ by the Litchfield-Wilcoxon method. The results are shown in Table 5).

Table 5

animals gender LD ₅₀ (mg / kg) mouse
rat masculine
Female
masculine
Female 740
640
560
610

Based on the above pharmacological and topxical properties of diltiazem, it can be seen that 'this compound effective for prophylaxis and for

the treatment of atherosclerosis, such as arteriosclerosis (i.e. coronary artery sclerosis, Renal arteriosclerosis), Mönkeberg's SkIerosis (i.e. arteriosclerosis of the extremities) and other arteriosclerotic symptoms in a Set of organs is.

In addition, a prophylactic or a remedy is used against arteriosclerosis generally administered for a relatively long time and as a result, undesirable side effects occur occasionally, while diltiazem for a long time Period of time without undesirable side effects can be administered and therefore particularly as Suitable as a prophylactic and as a remedy for atherosclerosis.

The diltiazem used according to the invention can either as the free base or as a pharmaceutically acceptable acid addition salt thereof. Examples are for suitable acceptable acid addition salts

Salts of organic acids, for example that

Acetate, oxalate, malonate, 'tartrate, citrate, lactate or Aspertate, or salts of inorganic acids, for example the hydrochloride, hydrobromide, sulfate, Nitrate or perchlorate.

The dose of diltiazem or a salt thereof can, depending

vary according to the age of the patient, the nature and severity of the diseases, etc., but is preferably in the range of about 30 to 400 mg / day / body weight.
5

The route of administration and the type of preparation of the drug (pharmaceutical composition) according to the present invention is not particularly specific; the agent can be administered orally or parenterally with oral administration being preferred.

The medicament according to the invention is in the form of conventional pharmaceutical medicament preparations for oral or parenteral administration in admixture used with conventional pharmaceutically acceptable carriers or diluents. Pharmaceutically acceptable Carriers are, for example, binders (e.g. syrup, gum arabic, gelatine, sorbitol, tragacanth resin, Polyvinylpyrrolidone etc.), diluents (e.g. lactose, sugar, corn starch, potassium phosphate, Sorbitol, glycine etc.), lubricants, e.g. magnesium stearate, talc, polyethylene glycol, silicon dioxide etc.), disintegrants (e.g. potato starch etc.) and Humectants (e.g. sodium lauryl sulfate, etc.). The preparations can be as tablets, pills, powder, Capsules, granules, present. For parenteral administration, the agent is in injectable or infusable form used as a suspension, dispersion or emulsion mixed with Glycerin, Propylene Glycol, Simple Syrup, Ethanol,

Fatty oils, ethylene glycol, sorbitol, etc ..

The invention is further illustrated in the following examples:
5

Example 1 10 tablet:

Diltiazem hydrochloride corn starch Lactose 15 polyvinylpyrrolidone crystalline cellulose magnesium stearate

a total of 190 g

A mixture of diltiazem hydrochloride, lactose and corn starch is made in an alcoholic solution of Polyvinylpyrrolidone mixed and the mixture is kneaded and granulated by wet granulation and then dried. Magnesium stearate and crystalline cellulose are added to the dried granulate and the mixture is compressed into tablets of 8 mm diameter (mean weight of a tablet 190 mg);

45.0 G 20.1 G 82.4 G 3.0 G 38.0 G 1, 5 q

Example 2

Injectable preparation:

Diltiazem hydrochloride (10 g) is dissolved in distilled water for injections (2 1). The solution is filtered with a membrane filter (pore size: 0.22 μια) and then filled into ampoules under sterile conditions and then the ampoules are closed, whereby ampoules for injections (content of solution in each ampoule: 2 ml) are obtained.

15 Example 3
Powder:

Diltiazem hydrochloride 10g

20 lactose 90 g

total 100 g

The above-mentioned ingredients are mixed homogeneously and packaged in 10 powder packs. 25th

Claims (11)

PATENT CLAIMS Medicinal product for prophylaxis and for the treatment of arteriosclerosis, characterized in that it is an active ingredient an effective amount of diltiazem or a pharmaceutically acceptable acid addition salt thereof together with a pharmaceutically acceptable carrier or diluent. 2. Medicament according to claim 1 for prophylaxis and treatment of atherosclerosis. 3. Medicament according to claim 1 for prophylaxis and treatment of Mönkeberg's sclerosis. 4. Medicament according to claim 1 for prophylaxis and treatment of arteriolosclerosis. 5. Medicament according to claim 1 in a form suitable for oral administration. 6. Process for the manufacture of a medicament for the prophylaxis or treatment of arteriosclerosis, characterized , 10 that the active ingredient is an effective amount of diltiazem or a pharmaceutically acceptable Acid addition salt thereof is used. 7. The method according to claim 6, characterized in that g e k e η η, that the medicine for the Treatment of atherosclerosis is intended. 8. The method according to claim 6, characterized in that the medicament for the Treatment of Mönkeberg's sclerosis. 9 '. The method according to claim 6, characterized in that the medicament for Treatment of arteriolosclerosis is appropriate. · ' 10. The method according to claim 6, characterized in that the drug for a Dosage in the range of 30 to 400 mg / day / body weight is suitable. 11. The method according to claim 6, characterized in / that the medicament is prepared in the form of a form to be administered orally.