DE2106156A1 - ! Medicines to lower serum cholesterol - Google Patents

Description

¹¹ Medicines for lowering serum cholesterol "Priority: July 24, 1970, Great Britain, ITr. 35 916/70

The invention relates to a medicament for regulating or lowering the serum cholesterol level in warm-blooded animals.

Atherosclerosis is a common disease in humans} WiI-ehe by increased serum lipid levels, especially an increased one Serum cholesterol levels. Hach you « early perception is a decrease in serum cholestsrin levels desirable by adults, and have become numerous® Attempts have been made to achieve such a reduction through appropriate diet and to bring about therapeutic measures.

Lowering serum cholesterol can go in several ways Way to be achieved. For example, agents can be used to suppress cholesterol synthesis or to increase excretion administer the products of cholesterol catabolism Most of these treatments, however, are non-compliant

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of harmful side effects, Another method for gene * The increase in serum cholesterol in warm-blooded animals consists in

from the inhibition of the absorption of the cholesterol / Kagen intestinal tract.

The cholesterol can either come from an administered diet or from the metabolism, i.e. from the normal flow of bile.

The object of the invention was to provide a new medicament for lowering the serural cholesterol level, which acts on the aforementioned absorption from the gastrointestinal tract and is essentially non-toxic in effective doses. These The object is achieved by the invention.

The subject of the invention is thus a medicament for lowering the serum gholesterin level, which is characterized in that it

A) at least 20 percent by weight, based on the total Medicines, made up of at least one non-ionic surface-active Compound of the general formula

^ HCH ₂ CH ₂ -N _n
^ ^ ^N (C ₃ H ₆ C) _s (C ₂ H ₄ O) _d H

in which a, b, c, d, p, q, r and s mean integers measured in such a way that the partial molecular weight of the (C ₂ H ₄ O) groups is 0% by weight of the total molecular weight and the partial molecular weight of the (0 , H ^ O) groups is 2250 to 325Ο,
and, if necessary, off

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B) other active substances
as well as, if applicable

C) at least one pharniacologically acceptable carrier consists.

The nonionic surface-active compounds of the aforementioned general ones contained in the medicaments of the invention Formula v / ground by successive, random Addition of ethylene oxide and propylene oxide produced by ethylenediamine.

A specific example of the surface-active compounds of the aforementioned general formula is a corresponding commercially available compound (hereinafter referred to as "surface-active compound I") i ^ ei which the partial molecular weight of the (C ₂ H, O) groups is about 10 56 of the total molecular, weight and the partial molecular weight of the (CHgO) groups is about 2750 (ie 2500 to 3000). The aforementioned compound is also preferred in the invention »v / ie also a commercially available compound of the above general formula, in which the partial molecular weight of (CpH ^ G) groups of about 25 ° i

Total molecular weight and that partial molecular weight of the (C ₃ H ₆ O) groups is about 2-50 (ie 2500 to 3000) (hereinafter referred to as "surface-active compound II").

Specific examples of pharmacologically suitable according to the invention In the case of solid preparations, compatible carriers are starch, talc and lactose. Also suitable as a carrier are digestible capsules that contain the active ingredients, such as gelatin capsules, as well as v / ater together with taste-enhancing

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syrups and coloring agents for making syrups.

Preferred medicaments according to the invention contain the surface-active ones Compound (A) as the only pharmaceutical, ecological active ingredient, in particular in a proportion of more than 75 percent by weight, based on the total drug.

The medicaments of the invention can be marketed in unit doses, each dose preferably from 0.01 to 1 g, in particular 0.1 to 0.5 g, of the surface-active compound (A).

To regulate or lower the serum cholesterol level of The medicaments of the invention are administered orally to warm-blooded animals, including humans. The surface-active compounds (A) can, by definition, be used alone or in combination with other active ingredients and / or pharmacologically acceptable Supports used v / earth. The medicaments according to the invention can also be administered together with the overall diet. In the latter case, the amount of surfactant compound (A) administered may be less than 1 percent by weight of the Diet, with corresponding proportions of at most 0.5 percent by weight to be favoured. For humans, the aforementioned diet can consist of conventional foods, which the surface active compound (A) was added. The same goes for a diet for animals, where the surface-active Compound (A) added to the animal feed either as such or in the form of a preparation containing other components will. The medicaments of the invention can also be incorporated into drinking water.

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To achieve an effective lowering of the serum cholesterol level - the medicaments of the invention are intended to "treat animals" or administered to patients in doses which correspond to a daily amount of the surface-active compound (A) from 1 to 10 g. Ira general one subdivides thereby the daily dose in several smaller and more easily tolerated partial doses.

Besides the lowering effect on serum cholesterol levels

inhibit some of the surface-active compounds

in

fertilize (A) / the medicaments according to the invention, e.g. the surface-active Compound I, the fat absorption to a certain degree and thereby lower the fat incorporation into the body. Corresponding medicaments according to the invention can thus a double healing effect can be awarded.

The examples illustrate the invention.

example 1

It gets the hypocholesterolemic (lowering the cholesterol) Effect of the surface-active compound I and II shown.

(Carworth Farm Group ^v ) Male rats of the strain CPY /. (10 rats per group) weighing 80 to 100 g, a hypercholesterolemic diet is administered, which in each case 63 # cane sugar, 10 ° ß> hydrogenated coconut ^{oil, 1 c} / o cholesterol and 0.5 $ ox bile extract and optionally 0.5 ^c ß> of the respective surface-active compound. This diet is given for 3 weeks. The rats are then killed and their serum is examined for the cholesterol level.

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From the test results shown in Table I is the den Gholesterin level lowering effect of the surface-active compound I and II can be seen.

Table I.

attempt group V-
manure I. Serur. " -Chole 3K-I sterol (mgtf 17th *)) 1 Comparative diet r-
manure II 245 + Comparative diet + above
area-active conn 5c3 + 26th **) 2 Comparative diet 216 + 6th Comparative diet + above
area-active conn 73 + **) J

*) Standard error of the mean value

**) Significantly lower than the comparative diet (p < 0.001) (p = statistical probability)

Comparative example 1

The experiments described in Example 1 are repeated, but other commercially available surface-active compounds are used which, although they also fall under the aforementioned general formula, in which the relative proportions of the (C2 ^ / 0) groups or However, (C ₇ HgO) groups do not correspond to the definition according to the invention. These surface-active compounds, which are described in more detail in Table II, are also randoin copolymers obtained by adding ethylene oxide and propylene oxide to ethylene diamine.

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Table II

Surface active
links
(Trade products) approximate partial molecule
large weight of the
(C ₅ HgO) groups Partial molecular weight
the (CpH-O) -GrUpPCn,
'/ 3 of the total molecular
lar ~ eweight L. 6750 20th M. 6750 40 H 6750 10 O 6750 80 P. 2750 40 Q 8750 70 R. 750 40 S. -1750 40 T 8750 40

When using the surface-active compounds listed in Table II (L to T) instead of the surface-active compound I and II, the results shown in Table Ha are obtained.

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Table! La

attempt group Serun Cholesterol
(mg '^ + SPM) 1 Comparative diet
Comparative diet + surfaces
active connection L 245 + 17
304 + 17 2 Comparative diet
Comparative diet + surfaces
active connection M 199 + 19
228 + 32 3 Forget diet
Comparative diet + surfaces
active connection Π 199 + 19
325 + 31 **) 4th Forget diet
Comparative diet + surfaces
active connection O 199 + 19
380 + 24 *) 5 Comparative diet
Compare isdiilt * + surfaces
active connection P 199 + 19
185 + 12 6th Comparative diet
Comparative diet + surfaces
active connection Q 216 + 26
281 + 24 7th Comparative diet
Comparative diet + surfaces
active connection R 216 + 26
287 + 29 8th Comparative diet
Comparative diet + surfaces
active connection p 216 + 26
363 + 30 *) 9 Comparative diet
Comparative diet + surfaces
active connection T 216 + 26
233 + 22

*) ■ significantly higher than with the comparative diet (p "< 0.001) **) significantly higher than with the comparative diet (0, C02 <p < 0.01)

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It can be seen that the aforementioned surface-active compounds used for comparison reduce the serum cholesterol level of Rats increase either significantly or to a statistically insignificant extent, or in the case of the surface-active compound P in statistically insignificant mass decrease.

Comparative example 2

To see if the cholesterol lowering effect the surface-active compound I or II on the foam-inhibiting Properties of these compounds attributed to iat, the experiment described in Example 1 is repeated, with however, instead of the aforementioned two surface-active compounds, two other commercially available foam-inhibiting compounds surface-active compounds are used, i.e. a polyoxyethylene ether derivative of a glyceridic oil (compound

X) and a silicone (compound Y). The test results are shown in Table III.

Table III

attempt group Serum cholesterol
(mg # + 3.FM) 1 Comparative diet
Comparative diet + compound.
dung X 194 + 27
220 + 27 2 Comparative diet
Comparative diet + conn
dung Y 194 + 27
196 + 28

The results listed in Table III show that with the neither foam-inhibiting surface-active compounds Lowering dec serum cholesterol levels can be achieved in rats

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Example

The 'cholesterol-lowering' ./irkunrr will be different Concentrations of the surface-active compound I in the Diet studied. The rats are given the hypercholesterolemic diet described in Example 1 and the serur.v cholesterol level is measured after 3 weeks.

In a second experiment, the effect of the surface-active compound I is compared with that of a conventional hypocholecterinemic agent (ty-methylbenzyllinol acid). This conventional · Ι: 'ΐ ⁺ ^ ^Ί v / is used because it - like the surface-active compound I (or II) - also inhibits the absorption of the Iagen-Ds, rmtrakts.

Tabe lle IV

attempt group I. *) Seruni -Cholesterol
+ SFl-I. ') ■ x *) 1 Comparative diet I. ·) ■ 293 + 24 **) Comparative diet + 0.25 ^ 71 ± 5 Comparative diet + Ο, ΙΟ ^ ί I. *) 85 ± 7 · *) 2 Comparative diet I. *) 239 ± 26 Comparative diet + 0.10> j Comparative d ± at + $ 0.05
0 (-Methylbenzyllinoleic acid amide 102 + 12 Comparative Diet + $ 0.05 156 ± ίο, 222 ± 15

*) I = surface-active compound I **) significantly lower than with the comparative diet

(p <0.001)

***) significantly lower than with the comparative diet

(0.0KpC 0.02),

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The results listed in Table IV show that the

The hypocholesterolemic effect of the surface-active compound I is still effective even at a concentration of 0.05 ','■>, based on the diet, and that γ-methylbenzyllinoleic acid canide is not as effective as the surface-active compound I at the same concentration.

EXAMPLE 3

It becomes the effect there with a diet (normal, commercially available Rat chow) administered surface-active compound I to the Incorporation of fat in the body of rats based on the faecal fat content of rats examined. The test results are from Table V.

reasonable.

Tabe lle V

proportion of - daily Torch-jet increase the ver 0.1 \. ^r achit- salary (/' opposite am 0.2 rate, the administer the ver diet dung I, 0.5 g / rat followed i! en equal 5 ' 1.0 ge) diet (^ the administer followed I! Close) Ver .'- leiclis & jäi: 3.3 7.7 0 Yci \; üej chediitt- + 3.3 8.6 0.9 ο 1). ^% rf 1 Ll el i s act i ve 3.5 11.3 3.6 Connection I ■ 2.9 21.0 13.3 0.6 31, c 23.3

An acceptance of the Petiembau the order of greetings shown in Table V has a significant v / egeai of high caloric value of fat Abnormality in rats;: ufsequence.

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Example 4

For human medicine Orally administrable medicinal products are / manufactures, by filling soft gelatin-coated capsules with 0.5 g each of the surface-active compound I and II.

Example 5

Tablets each weighing 0.6 g are produced in the conventional manner, which contain 0.25 g of the surface-active compound I or II as well as starch, talc, lactose and magnesium stearate. These tablets are also suitable for human medicine. "

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Claims (6)

Patent claims 1. Medicines to lower serum cholesterol levels, characterized in that it A) at least 20 percent by weight, based on the total Medicaments, made from at least one non-ionic surface-active compound of the general formula H (C ₂ H ₄ O) JC ₃ H ₆ O) ^ / ITGH ₂ CH ₂ H
. H (C ₂ H ₄ O) ₁₃ (C ₃ H ₆ O) ₁₁ . (C ₃ H ₆ O) ₃ (C ₂ H ₄ O) _d H. in which a, b, c, d, p, q, r and s denote whole numbers such that the partial molecular weight of the (C ₂ H ₄ O) groups makes up 0 to 30 io of the total molecular weight and the partial molecular weight of the (C ₃ H ₆ O) groups is 2250 to 3250,
and, if necessary, off B) other active ingredients
as well as, if applicable C) there is at least one pharmacologically acceptable carrier, 2. Medicament according to claim 1, characterized in that in the non-ionic surface-active compound (A) the partial molecular weight of the (C ₉ H _A O) groups makes up about 10 $ of the total molecular weight and the partial molecular weight of the (C ₃ H ₆ O) groups is about 2750. 3. Medicament according to claim 1, characterized in that in the non-ionic surface-active compound (A) the partial molecular weight of the (C ₂ H ₄ O) groups is about 25 ^c p of Gesar.it- 10 9 885/1826 molecular weight and the sub-molecular weight of the (CUHgO) groups etv / a 2750. 4. Medicament according to claim 1 to 3, characterized in that that it is more than 75 percent by weight, based on the total (A) drug, the non-ionic surface-active compound / contains. 5. Medicament according to claim 1 to 4, characterized in that that as a pharmacologically acceptable carrier (ö) it is a digestible one Contains capsule. 6. Medicament according to claim 1 to 5 in Pora a unit dose, in particular for oral Yer & buchs, characterized in, that it contains 0.01 to 1 g, preferably 0.1 to 0.5 g, of the surface-active compound (A).