IL95574A - Colestyramine preparation - Google Patents

Abstract

Preparations containing colestyramine for reducing lipid levels.

Description

) >0ΝΊ>υσϊη -ι>¾)οη Colestyramine preparation KNOLL Aktiengesellschaft C: 81603 Colestyramine as products containing lipid-lowering acents The present invention relates to colestyramine as products which contain lipid-lowering agents and are in the form of particles whose longest particle diameter is from 1 to 4 ram.

Colestyramine is a lipid-lowering agent known in medicine and is an anion exchanger resin composed of a copolymer of styrene and divinylbenzene which contains quaternary ammonium groups .

To date it has been marketed only as powder (see Rote Liste 1990, list of finished drugs of the members of the Bundesverband der Fharmazeutischen Industrie e.V.). One disadvantage of this presentation is that, on intake, colestyramine leaves an unpleasant sandy taste in the mouth (see, for example, Knodel et al., Medical Toxicology 2 (1987) 10, page 13, first paragraph of Section 1.2 in which the disadvantageous effects of lipid-lowering agents are dealt with) . Since it is now customary for colestyramine to have to be taken in single doses of about 4 g twice to eight times a day, this frequently results in the patients taking less than the prescribed dose or even stopping the therapy with colestyramine (see EP-A 261 693, page 2, lines 7-8).

There has been no lack of attempts to offer colestyramine in a different presentation. Thus, US-A 4,814,354 describes colestyramine-containing sweets, EP-A 347 014 describes a baked product containing colestyramine, and DE-A 38 08 191 describes aqueous colestyramine-containing suspensions. However, it is not possible in this way to eliminate the unpleasant sandy taste.

It is furthermore known that colestyramine can be administered together with other lipid-lowering agents in order to achieve an effect which is better than that of the single components. Malmendier et al. (Clin. Chim. Acta 162 (1987) 221), as well as Carlson et al. (in "Treatment of Hyperlipoproteinaemia" , XIX + 284P. Raven Press: New York 1984) describe the combined use of colestyramine and fenofibrate in patients with familial hypercholesterolemia. The combined use of colestyramine and bezafibrate is described, for example, in Br. Med. J. 297 (1988) 6642, the combined use of colestyramine and clofibrate for example in J. Lipid Res. 21 (1980) 65 and the combined use of colestyramine and gemfibrozil in US- A 4,814,354.

It is an object of the present invention to prepare colestyramine as products which contain lipid- lowering agents and are in a presentation which does not display the abovementioned disadvantages .

We have found that this object is achieved by colestyramine as products which contain lipid-lowering agents and are in the form of particles whose longest particle diameter is from 1 to 4 mm.

Colestyramine can be compressed to a microtablet which, as a rule, is cylindrical and has a size of from 1 to 4 mm (both height and diameter), in particular of from 2.0 to 3.5 mm. Besides this, other forms such as beads or irregularly shaped granules are also possible in principle.

The forms can be produced in a conventional manner, for example that described in EP-A 166 315. It is possible to add the conventional pharmaceutical auxiliaries to the formulation, such as binders, inactive ingredients, preservatives, wetting agents, flow regulators, lubricants and/or antioxidants (see, for example, H. Sucker et al.: Pharmazeutische Technologie, Thieme Verlag Stuttgart, (1978)). The forms can additionally be provided with the conventional pharmaceutical coatings.

The preferred binder used for compression is microcrystalline cellulose, of which the drug contains from 2 to 20, preferably from 3 to 8, % by weight. It is advantageous to employ in the granulation cellulose - 3 - O.Z. 0480/01072 derivatives such as methylcellulose, hydroxypropylmethyl-cellulose, hydroxyethylcellulose and polyvinylpyrrolidone in an amount of from 2 to 10, preferably 3 to 6, % by weight .

The formulations obtainable in this way normally contain the active compound in an amount of from 80 to 99% by weight.

The dosage depends on the age, condition and weight of the patient. As a rule, the daily dose of active compound is from 0.03 to 0.4 g/kg of body weight.

The colestyramine-containing products can also contain other lipid-lowering agents . Fenofibrate and gemfibrozil are preferred, as are similar compounds of this type such as clofibrate, beclobrate, bezafibrate, ciprofibrate and etofibrate (called fibrates hereinafter) .

The drug on administration can be in the form of a combination of the two active compounds in the same formulation or in the form of a kit of parts. A kit of parts is defined as a type of pharmaceutical pack in which the individual active components are present wholly or partly in separate dose form in the same pack.

The form preferred for the combination of the active compounds in the same form is the microtablet. In the case of separate administration, the colestyramine is preferably in the microtablet form, and the fibrate is in a conventional commercial form such as tablet, film-coated tablet, sugar-coated tablet, capsule or else as microtablet.

The statements on the formulation of colestyramine also apply to the combination of colestyramine and fibrate .

When colestyramine and fibrate are combined in one form, for example as microtablet, the latter can contain the active compounds in the colestyramine : fibrate ratio of from 2 : 1 to 99 s 1 by weight, depending on the conventional dose of the fibrate active - 4 - O.Z. 0480/01072 compound.

Combination of the two active compounds makes it possible to lower the individual doses of these active compounds, the dosage depending specifically on the age, condition and weight of the patient. In general, the daily doses of active compounds are from 0.03 to 0.4 g of colestyramine per kg of body weight and from 1 to 15 mg of fibrate per kg of body weight.

EXAMPLES EXAMPLE 1 13.5 kg of colestyramine (from RShm & Haas Deutschland GmbH, colestyramine 40 μ) were mixed with 675 g of directly tablettable lactose and 600 g of microcrystalline cellulose in a conventional high-performance pharmaceutical mixer. Then 75 g of highly disperse silica and 150 g of magnesium stearate were added, and mixing was continued. This mixture was then compressed to microtablets with a diameter of 3.5 mm and the same height, the individual mass being 30 mg.

EXAMPLE 2 13.5 kg of colestyramine (see above) were mixed with a solution, of 0.7 kg of polyvinylpyrrolidone (mean molecular mass 25,000) in 2.1 kg of isopropanol in a conventional high-performance pharmaceutical mixer with cutter, and were granulated. Drying at 50 °C was followed by screening through an oscillating screen with a mesh width of 0.8 mm. The granules were then mixed with 70 g of highly disperse silica and 70 g of magnesium stearate. The composition ready for compression was compressed to microtablets with a diameter of 3 mm and the same height, the individual mass being 17 mg.

Claims (3)

- 5 - 95574/2 CLAIMS:

1. A lipid-lowering composition comprising from 80 to 99% colestyramine as lipid-lowering agent, that composition being in the form of microtablets whose longest diameter is from 1 to 4 mm, and that composition further comprising conventional pharmaceutical auxiliaries .

2. A composition as claimed in claim 1, containing another lipid-lowering agent in addition to the colestyramine .

3. A composition as claimed in claim 2, containing fenofibrate or gemfibrozil as the additional lipid-lowering agent. the Applicants, REINHOLD COHN AND PARTNERS