Organic derivatives of montmorillonite for treating lipid disturbances

Pharmaceutical compositions having hypocholesterolemic and hypolipemic activity comprising a dimethyl-dialkylammonium montmorillonite and use thereof in treatment of lipid disturbances.

This invention relates to pharmaceutical compositions containing, as an 
active principle, organic derivatives of montmorillonite. 
It is known that certain organic derivatives of montmorillonite, and 
particularly the dimethyl-dialkylammonium montmorillonites, can be used as 
gelation agents for various organic media. 
Thus the dimethyl-dialkylammonium montmorillonite sold by the National Lead 
Company under the registered trademark "Bentone" can, for instance, be 
used in the paint and varnish industry to modify the viscosity, rigidity, 
or plasticity of these paints and varnishes (Chemical Engineering, March 
1952, pages 226-230). 
Numerous other uses of these "Bentones" are described in the literature. 
Among them, one may mention the use of the "Bentones" as granulating 
agents and as binders in the preparation of tablets containing hydrolabile 
drugs (Amer. Jour. Pharm. 136 (5) p. 206-215, 1964). In the preparation of 
these tablets, the "Bentones" are used in amounts varying between 2 and 8% 
of the total weight of the tablets. 
It has now been found that these dimethyl-dialkylammonium montmorillonites 
have remarkable pharmacological properties and, in particular, 
hypocholesterolemic and hypolipemic properties. These properties are 
illustrated further below wherein the usefulness of these products as 
drugs is shown. 
Among these drugs, there are preferred, in particular, those which are 
characterized by the fact that the dimethyl-dialkylammonium has 10 to 50 
carbon atoms. 
The dimethyl-dialkylammonium montmorillonites can consist, for instance, of 
dimethyl-dipentadecylammonium montmorillonites, 
dimethyl-dihexadecylammonium montmorillonites, 
dimethyl-diheptadecylammonium montmorillonites, 
dimethyl-dioctadecylammonium montmorillonites, or mixtures of the above. 
Among these drugs, most preferred are dimethyl-dioctadecylammonium 
montmorillonite (product sold under the registered trademark "Bentone 34" 
by the National Lead Company), and the mixture of 
dimethyl-dipentadecylammonium montmorillonite and 
dimethyl-dihexadecylammonium montmorillonite in proportions of 70% and 30% 
respectively (product sold under the registered trademark "Bentone 38" by 
the National Lead Company). 
These drugs are used, for instance, in the treatment or prevention of lipid 
disturbances associated with atherosclerotic manifestations, 
hypercholesterolemias, with or without xanthomatosis, 
hypertriglyceridemias, or hyperlipemias, whether acute or chronic. 
The customary dose, which varies in accordance with the product used, the 
patient treated, and the ailment in question, may for instance be from 2 g 
to 30 g per day, orally in humans. 
Another object of the present invention is to provide pharmaceutical 
compositions which contain at least 15% dimethyl-dialkylammonium 
montmorillonite as the active principle. 
Among the preferred pharmaceutical compositions of the invention mention 
may be made, in particular, of: 
(a) those characterized by the fact that they contain as an active 
principle 20 to 90% dimethyl-dioctadecylammonium montmorillonite, and 
(b) those characterized by the fact that they contain as an active 
principle 20 to 90% of a mixture formed of 70% 
dimethyl-dipentadecylammonium montmorillonite and 30% 
dimethyl-dihexadecylammonium montmorillonite. 
As drugs, the dimethyl-dialkylammonium montmorillonites can be incorporated 
in pharmaceutical compositions intended for the digestive tract. 
These pharmaceutical compositions may, for instance, be solid or liquid and 
be in the pharmaceutical forms currently used in human medicine such as 
for instance simple or effervescent tablets, lozenges, granules, 
suspensions, jellies and jams. They are prepared in accordance with 
customary methods. The active principle or principles can be incorporated 
therein with the excipients customarily used in these pharmaceutical 
compositions such as talc, gum arabic, lactose, starch, magnesium 
stearate, aqueous or non-aqueous vehicles, fats of animal or vegetable 
origin, paraffin derivatives, glycols, various wetting, dispersing, or 
emulsifying agents, and preservatives. 
As indicated in the literature, the dimethyl-dialkylammonium 
montmorillonites can be obtained, for instance, by reacting a 
montmorillonite in the sodium form with the desired quaternary ammonium 
compound in chloride form. 
Various examples of the manner of carrying out the invention will now be 
given, by way of illustration and not of limitation.

EXAMPLE 1 
20 g sachets were prepared having the following formulation: 
______________________________________ 
Bentone 34 10 g 
Pluronic F 38 0.05 g 
polyvinyl pyrrolidone 0.40 g 
caramel flavoring 0.15 g 
granulated sugar 9.40 g 
______________________________________ 
The Bentone 34 (dimethyl-dioctadecylammonium montmorillonite), the 
granulated sugar and the caramel flavoring are introduced into a mixer. 
It is wetted with an alcoholic solution of polyvinyl pyrrolidone and 
Pluronic F 68 (condensation polymer of ethylene and propylene oxides). It 
is granulated, dried, and the grains sized. The granulate obtained can 
then be placed in 20 g sachets. 
EXAMPLE 2 
15 g sachets were prepared having the following formulation: 
______________________________________ 
Bentone 34 10 g 
Pluronic F 68 0.05 g 
polyvinyl pyrrolidone 0.40 g 
caramel flavoring 0.15 g 
granulated sugar 4.40 g 
______________________________________ 
The Bentone 34 (dimethyl-dioctadecylammonium montmorillonite), the 
granulated sugar and the caramel flavoring are introduced into a mixer. 
The mixture is wetted with an alcoholic solution of polyvinyl pyrrolidone 
and Pluronic F 68 (condensation polymer of ethylene and propylene oxides). 
It is granulated and dried and the grains sized. 
The granulate obtained can then be placed in 15 g sachets. 
EXAMPLE 3 
20 g sachets were prepared of the following formulation: 
______________________________________ 
Bentone 38 10 g 
Pluronic F 68 0.05 g 
polyvinyl pyrrolidone 0.40 g 
caramel flavoring 0.15 g 
granulated sugar 9.40 g 
______________________________________ 
The Bentone 38 (mixture of dimethyl-dipentadecylammonium montmorillonite 
and dimethyl-dihexadecylammonium montmorillonite in proportions of 70% and 
30% respectively), the granulated sugar and the caramel flavoring are 
introduced into a mixer. 
The mixture is wetted with an alcoholic solution of polyvinyl pyrrolidone 
and Pluronic F 68 (condensation polymer of ethylene and propylene oxides). 
It is granulated and dried and the grains sized. 
The granulate obtained can then be placed in 20 g sachets. 
Pharmacological Study 
(1) Effects of Bentone 38 on the Fecal Excretion of Fats 
Wistar rats of about 250 g are given for 8 days a feed composed of a 
semisynthetic standard ration (U.A.R. 210) containing 5.5% lipids. At the 
end of this period of 8 days the animals are weighed, distributed at 
random in two lots (control lot, treated lot) and placed in individual 
metabolic cages with standard rations for 3 days. The feces are collected 
quantitatively and weighed, and the lipids are extracted by means of 
methanol-chloroform. The determinations of cholesterol and total fatty 
acids in the feces are effected in accordance with the customary 
techniques (first stage). 
The animals of each lot are then placed back in collective cages. The 
animals of the control lot then receive the aforementioned standard ration 
for 16 days. During the same time, the animals of the treated lot receive 
the said standard ration plus 2.5 g of Bentone 38 per kg. At the end of 
this period of 16 days, the animals are placed in individual metabolic 
cages in order to collect their feces for 3 days, the animals receiving 
their respective rations during this time (2nd stage). 
The determinations of the cholesterol and the total fatty acids in the 
feces are carried out in the same manner as at the end of the first stage. 
The results obtained with the animals of the control lot are set forth in 
Table 1 below: 
Table 1 
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Weight 
Animals of the Weight Total 
of the animals of the 24 Cholesterol 
fatty acids 
control lot 
in g hr. feces in g 
mg/24 hr. 
mg/24 hr. 
______________________________________ 
After 
8 days 
of standard 
rations 
(1st stage) 
258 .+-. 3.2 
1.87 .+-. 0.09 
2.98 .+-. 0.14 
97.84 .+-. 5.6 
After 
16 days 
of standard 
rations 
(2nd stage) 
328 .+-. 4.0 
2.12 .+-. 0.09 
3.27 .+-. 0.18 
105 .+-. 3.25 
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Average of 11 rats .+-. standard error. 
The results obtained with the animals of the treated lot are set forth in 
Table 2 below: 
Table 2 
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Weight 
Animals of the Weight Total 
of the animals of the 24 Cholesterol 
fatty acids 
treated lot 
in g hr. feces in g 
mg/24 hr. 
mg/24 hr. 
______________________________________ 
After 
8 days 
of standard 
rations 
(1st stage) 
261 .+-. 3.0 
2 .+-. 0.12 
2.91 .+-. 0.23 
94.46 .+-. 4.62 
After 
16 days 
of standard 
rations con- 
taining 2.5 g 
of Bentone 38 
(2nd stage) 
334 .+-. 13.7 
1.96 .+-. 0.08 
4.37 .+-. 0.17 
113.84 .+-. 6.5 
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Average of 10 rats .+-. standard error. 
The results obtained show that the administration of the Bentone 38 
produces in the treated animals a significant increase in the excretion of 
fatty acids and cholesterol. 
(2) Effect of Bentone 34 and Bentone 38 on the Intestinal Absorption of 
Lipids in Rats 
Three lots of 15 rats of an average weight of 200 g are fed for 3 weeks 
with a standard ration enriched by 10% lard, 0.5% cholesterol and 0.5% 
bileacids. 
A first lot of animals, maintained with this hyperlipemic and steatogenous 
ration for 3 weeks is considered as a control. 
The other two lots receive, for the three weeks, the same ration to which 
the products studied have been added, namely 2% Bentone 34 and 2% Bentone 
38, respectively. These quantities are calculated so that the animals 
receive a daily dose of about 400 mg of product per rat per day. 
The weights of the animals are checked at the beginning and end of the 
experiment. The hepatic and plasmatic lipids are analyzed at the time of 
sacrifice after three weeks of experiments. 
The determination of the hepatic lipids gave the results set forth in Table 
3 below: 
Table 3 
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Total lipids 
Triglycerides 
Cholesterol 
Animals mg/g mg/g mg/g 
______________________________________ 
Controls 211.70 .+-. 0.48 
56.79 .+-. 2.98 
16.00 .+-. 0.33 
Treated with 
Bentone 34 
124.19 .+-. 5.27 
24.37 .+-. 1.44 
18.53 .+-. 0.65 
Treated with 
Bentone 38 
153.34 .+-. 3.92 
36.83 .+-. 2.51 
17.43 .+-. 0.23 
Normal rat 
37 5.6 4.5 
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Average of 15 rats .+-. standard error. 
The histological examination of hepatic tissue sections stained with Masson 
Trichrome and Red Oil furthermore show an extensive steatosis in the 
control animals and in the treated animals. However, it is less pronounced 
in the animals treated with the Bentone 34. 
The determination of the plasmatic lipids gave the results set forth in 
Table 4 below: 
Table 4 
______________________________________ 
Total lipids 
Triglycerides 
Cholesterol 
Animals mg/100 ml mg/100 ml mg/100 ml 
______________________________________ 
Controls 741.10 .+-. 47.2 
114.00 .+-. 7.8 
251.70 .+-. 11.02 
Treated with 
Bentone 34 
519.55 .+-. 29.06 
88.00 .+-. 7.7 
186.67 .+-. 11.37 
Treated with 
Bentone 38 
663.9 .+-. 23.6 
107.00 .+-. 7.74 
185.67 .+-. 7.07 
Normal rat 
350 100 70 
______________________________________ 
Average of 15 rats .+-. standard error. 
The results obtained with the compounds studied show that they exert a 
marked protective effect against the development of hyperlipemia and of 
hepatic steatosis caused by a ration enriched by triglycerides and 
cholesterol. 
If one takes into account the considerable charge of lipids and cholesterol 
in the ration, the absorption of which was facilitated by the addition of 
bile salts, it becomes obvious that the compounds studied have the 
property of preventing the intestinal absorption of cholesterol and 
lipids.