DD249634A1 - CHOLESTEROL SENDING AGENT AND METHOD FOR THE PRODUCTION THEREOF - Google Patents

Abstract

The invention relates to a cholesterol-lowering agent and a process for its preparation from powdery strong base anion exchangers with quaternary ammonium groups, pectin and optionally Geschmackskorrigemzien in granular form. The combination preparation is prepared by building up a granulate in a discontinuously operating fluidized-bed granulating dryer of known type from an anion exchanger ground in a water-moist state by injecting an aqueous pectin solution with simultaneous drying.

Description

Field of application of the invention

The invention relates to the preparation of eings ~ OTa1-2U-ver-successive combination preparation based on pulverulent strongly basic anion exchangers in pharmaceutically suitable formulation. It can be used for long-term therapy of hypercholesterolemia.

Characteristic of the known technical solution

Agents for the treatment of hypercholesterolemia based on high-polymer, water-insoluble and non-toxic strongly basic anion exchangers with quaternary ammonium groups have been known for some time. These are preferably prepared from styrene-divinylbenzene copolymers and are known internationally as cholestyramine. Such agents and their preparation are described, for example, in US Pat. Nos. 3,383,281 and 4,393,145, in DE-PS 2,822,546 and in DD Pat. No. 147,819. They are currently used very successfully for the treatment of cholestatic conditional pruritus. In the treatment of patients with hypercholesterolemia, however, there are still reservations about these known agents or they are even rejected in the long-term therapy. On the other hand, however, the study "Li pid Research Clinic Coronary Primary Prevention Trial" (JAMA 251 [1984], 351-373) has clearly demonstrated that by taking cholestyramine the total cholesterol and LDL cholesterol levels in the blood are significantly lowered and thereby the risk of onset of ischemic heart disease could be reduced by up to 50%.

Cause of the reservations and the limited use of the known Cholestyraminpräparate are especially the side effects in a long-term therapy, with daily 15 to 30 g of cholestyramine must be administered. These manifest themselves primarily in the frequent occurrence of constipations, which lead to discontinuation of therapy or to a reduction in the intake of the preparation.

The powdery character and the sandy taste of the known preparations are also perceived as unpleasant and disturbing.

Object of the invention

The aim of the invention is therefore to provide a production method for a cholesterol-lowering agent based on a strongly basic anion exchanger with quaternary ammonium groups, which has a good compatibility with improved intake and taste properties, without the cholesterol lowering effect decreases in comparison to known agents ,

Explanation of the essence of the invention

The object of the invention is to comminute a spherical strongly basic anion exchanger with quaternary ammonium groups under mild conditions without degradation of the functional groups and to bring the resulting powder after addition of a natural product and optionally other Geschmackskorrigemzien in a no longer powdery formulation.

The object of the invention is achieved by a strongly basic anion exchanger based on gelatinous or porous styrene-divinylbenzene copolymers having a degree of crosslinking of 1 to 7% by weight in a pin mill in a water-moist condition with a water content of 40 to 80 Ma .-% in the presence of a preservative to a particle size below 200, to, preferably below 160μ.ιτι, crushed. The water-moist pulverulent anion exchanger is then fluidized in a discontinuously operating fluidized bed granulating dryer by sucking in warm air.

By injecting an aqueous pectin solution by means of compressed air, a granulate is built up, wherein the aqueous pectin solution optionally contains Geschmackskorringenzien.

Simultaneously with the granule build-up, the drying process expires. Following granulation drying, a powder flavor is mixed in the same apparatus.

The strongly basic anion exchanger used for grinding generally has trimethylammonium groups as a functional group and is preferably used in the chloride form. He must have pharmaceutical grade in terms of its purity. The preservative used is preferably sorbic acid in an amount of up to 0.5% by mass, calculated on the dry matter of the anion exchanger. The sorbic acid is added to the anion exchanger before the grinding, so that it comes to an intimate mixing of the two components during the milling process.

Based on the finished granules, 50 to 90% by weight of moist pulverulent anion exchanger, calculated on the dry substance, are used, and 5 to 30% by mass of pectin are added during the granulated drying. The proportion of Geschmackskorrigenzien can be up to 45% by weight, based on the finished granules.

Here, preferably up to 3% by weight of synthetic sweeteners and / or up to 40% by weight of sugar and up to 2% by weight of powder aroma are used. The pectin serving as a binder in the granule structure is preferably used as a 1 to 10% strength aqueous solution. For this purpose, commercially available and required on a large scale for the production of jams liquid pectin can be used, the z. B. from apples or citrus fruits. However, it is also possible to prepare an aqueous solution from dry pectin.

If dry pectin is used, it is also possible with a pectin content of more than 5% by mass, based on the finished granules, that only the pectin fraction required for the formation of granules is injected as aqueous solution during the granulation drying. The remaining amount of dry pectin can be mixed in this case with the wet powdered anion exchanger before drying. In order to avoid lump formation from both components, it may be expedient to predry the pulverulent anion exchanger before mixing.

For example, saccharin or sodium cyclamate can be used as synthetic sweeteners and disaccharides, such as sucrose or monosaccharides, such as fructose, as sugars. The sweeteners and sugars are preferably added to the last part of the amount of pectin to be injected in order to locate the sweetener substantially on the surface of the granules.

In order to avoid a thermal damage of the quaternary ammonium group during the granulation drying process, which is known to result in an odor impairment due to the release of amines, the exhaust air temperature is kept constantly below 50 ⁰ C throughout the process. The injected pectin amount is controlled by metering pump so that a uniformly structured granules with a particle size of 0.2 to 1.5 mm is formed. Following the granulation process, the granules are dried in a fluidized bed until the residual moisture has fallen below 10% by mass, preferably below 8% by mass.

The powder flavors, preferably those with apple, raspberry, lemon or orange flavor, are mixed with the dry granules for a short time in a fluidized bed.

In order to achieve a further equalization of the granules, screening is often expedient.

In the preparation according to the invention, a loosely structured, sour-tasting combination preparation is obtained in which the strongly basic anion exchanger undergoes intimate bonding with the natural substance pectin acting as binder during the granulation drying. The anion exchanger is embedded in the natural substance and enveloped by it.

This coating causes the preparation to be easily swallowed in both a dry state and in a slurry in a liquid compared to the known preparations without the appearance of a sandy taste. In addition, in the clinical testing of the combined preparation, it was surprisingly found that not only the ingestibility and the taste were improved over the known preparations; but that the side effects decreased significantly and at the same time increased the cholesterol-lowering effect.

Since both cholestyramine and pectin are relatively poorly tolerated when used separately, it was not to be expected that in the case of the fixed combination according to the invention the negative ingestion properties of both components would largely be compensated.

The increase in cholesterol-lowering effect of the combination preparation was also not expected.

It is well known that pectins also have a cholesterol lowering property. On the other hand, however, it is also known that pectins can be anionically bound relatively strongly to strongly basic anion exchangers. It was to be expected that due to this binding, the fixed amount of cholestyramine and pectin due to the mechanism of action of both

Single components can no longer contribute to the cholesterol-lowering effect of the drug. -

In the following examples, the preparation procedure for the combination preparation is explained and the result of the clinical testing is shown.

embodiments

Example 1:

1. Grinding

200 l of gel-type strongly basic styrene-divinylbenzene-based anion exchanger (type I) with a degree of crosslinking of 3.0% by weight of divinylbenzene, loading form chloride, quality - pharmaceutical, are freed from adhering water by means of a sieve spinner.

Characteristics of the exchanger:

H ₂ O content: 63.2Ma .-%

Grain size: 0.3 to 1.2 mm

Weight capacity: 3.90 mmol / g dry exchanger

In the presence of 0.25% by weight of sorbic acid, based on dry anion exchangers, the water-moist exchanger is ground in a pin mill to a particle size below 200 μm, at least 96% by weight having a particle size below δδμ, ηη.

2. granulation drying

recipe:

100g granules, based on the dry substance, contain:

76.8 g strong basic anion exchanger (cholestyramine),

20.0 g of pectin,

2.0g sodium cyclamate,

1.0g raspberry powder flavor and

0.2 g of sorbic acid.

In the fluidized section of a fluidized bed granulation dryer, type WSG 60 Fa. Glatt, FRG, 73 kg of the powdered anion exchanger, water content 58Ma .-%, submitted and stirred up with the aid of the sucked air. The temperature of the supply air is adjusted to 7O ⁰ C. Be of a heatable storage container by means of peristaltic 96kg apple pectin as a 7.5% strength aqueous solution, which was heated to 5O ⁰ C, promoted with a throughput of 30 kg / h to the fluidized-bed granulator and sprayed there by use of compressed air.

To the last third of the pectin solution, 760 g of sodium cyclamate dissolved in water are added. After completion of the pectin feed, the granules are post-dried for 30 minutes in a fluidized bed. The exhaust air temperature rises up to 45 ⁰ C. After cooling the granules, 380 g of raspberry powder flavor are added and mixed in a fluidized bed for 5 minutes. There are obtained 41 kg of granules with a residual moisture of 7.3Ma .-% and a weight capacity of 4.15 mmol / g of dry granules.

Example 2:

1. Grinding -

200I macroporous strongly basic anion exchanger styrene-Divinylbenzenbasis (type I) with a degree of crosslinking of 4,3Ma .-% divinylbenzene, preparation of the polymer by suspension polymer in the presence of 45mA .-% gasoline mixture (bp. 140 to 200 ⁰ C), loading form chloride , Quality - pharmaceutical, are treated analogously as described in Example 1, further.

Characteristics of the exchanger:

pre-grinding after grinding Grain size: 0.3-1.2 mm 96Ma .-% below 160 ^ m Water content (wt .-%): 65.2 60.3 Weight capacity: 4.1 - (mmol / g dry exchanger)

2. Granulated drying recipe:

100g granules, based on the dry substance, contain:

73.0 g strongly basic anion exchanger (cholestyramine),. '

5.8 g pectin, 20.0 g sucrose,

1.0g apple powder flavor and

0.2 g of sorbic acid.

The granules are prepared as described in Example 1. In this case, 64 kg of powdered exchanger and 2.0 kg dry pectin, dissolved in 100 liters of water and 7,0kg of sucrose and 350g apple powder flavoring used.

The sugar is, as described in Example 1, described in the case of Natriumzyklamates, added to the last third of the amount of pectin einzudüsenden. There are obtained 37 kg of granules with a residual moisture content of 5.9% by mass and a weight capacity of 3.7 mmol / g of dry granules. ,

3. Clinical testing on humans

Number of patients: 55.

Disease: primary hypercholesterolemia

Ingested dose: 24g / d Cholestyramine-Wolfen

29 g / d cholestyramine granules according to Example 1

Consumption amount divided into 2 portions / d Duration of intake: 6 weeks

After taking 6 weeks ausBlutproben -4- 249 634 of the patients determined the following lipid parameters (average values): 0.05 ns ²¹ 0.05 Choiestyramin-Wolfen Granules P ¹¹ acc. example Total cholesterol (mmol / L) LDL-cholesterol (mmol / L) AproteninB (g / L) 7,39 4,85 1,72 7.08 4.60 1.51 1) MCNemarTest 2) not significant

Particularly impressive were the reduction of side effects and the improvement of the functional properties. In cholestyramine wolves, constipation occurred in 23 cases, but only in 5 cases in cholestyramine granules (p <0.01). Forty-one patients reported that the granules were better to use than four, which found cholestyramine wolves more ingestible (p <0.01).

Claims (3)

1. Cholesterol lowering agent based on pulverulent strongly basic anion exchangers with quaternary ammonium groups, characterized in that it is present as granules, which 50 to 90 wt .-% strongly basic anion exchanger, 5 to 30 wt .-% pectin and optionally up to 45Ma. -% Geschmackskorrigemzien and up to 0.5Ma .-% preservative contains. 2. A process for the preparation of a cholesterol-lowering agent based on pulverulent strongly basic anion exchangers with quaternary ammonium groups, characterized in that a stored or porous strongly basic anion exchanger based on styrene-divinylbenzene copolymers and a degree of crosslinking of 1 to 7Ma .-% in a water-wet condition having a water content of 40 to 80% by weight in the presence of a preservative in a pin mill of known type, ground to a particle size below 200 / zm and from the water-moist powder resins in a discontinuous fluidized bed granulating dryer of known type by injection of aqueous pectin solution, which optionally contains Geschmackskorrigemzien, while drying with a maximum exhaust air temperature of 50 ° C, a granulate is built up, which is then mixed with a powder flavor. 3. The method according to item 2, characterized in that in the fluidized bed granulation drying 50 to 90Ma .-% anion exchange resin, 5 to 30Ma .-% pectin and optionally up to 45Ma .-% Geschmackskorringenzien, based on the total mass of the agent used.