Note: Descriptions are shown in the official language in which they were submitted.
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O.Z. 0480/01072
Colestyramine as products containing lipid-lowering
agents
Description
The present invention relates to colestyramine a~
products which contain lipid-lowering agents and are in
the form of particles whose longest particle diameter is
fxom 1 to 6 mm.
ColestyraminQ is a lipid-lowering agent known in
medicine and i8 an anion exchanger resin composed of a
copolymer of styrene and divinylbenzene which contain~
quaternary ammonium group~.
To date it has been market~d only as powder ~see
Rote Liste 19~0, li~t of finished drug~ of the member~ of
the Bundesverband der Pharmazeutischen Industrie e.V.).
One disadvantage of this presentation is that, on intake,
cole~tyramine leaves an unpleasant sandy taste in the
mouth (see, for example, Rnodel ~t al., Medical Toxi-
colo~y 2 (lg87) 10, page 13, first paragraph o~ Section
1.2 in which the di~advantageou~ effects of lipid-
lowering agents are dealt with). Since it is now cu~-
tomary for colestyrsmine to have to be taXan in single
do~es of about 4 g twica to eight.times a day, this
frequently results in the patients taking 1 S8 than the
prescribed dose or eve~ ~topping the therapy with coles-
tyramine ~3ee EP-A 261 6g3, pag 2, line 7 8).
There has been no lack of attempt~ to offer
colestyr~mine in a dif~erent presentation. Thu~, VS-A
4,814,354 de~cribe~ colestyramine-containing s~eet~,
EP-A 347 014 descxibes a baked product containing c012~-
tyramine, and DE-A 38 08 191 describe~ aqueous
colestyræmine-containing suspen~ion3. However, it i8 not
pos~ible in thi~ way to eliminate the unpleasant sandy
taste.
It is furthermore known that cole~tyramine can be
administer2d to~ether with other lipid-lowering agent~ in
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order to achieve an effect which is better than that of
the ~ingle component~. Malmendier et al~ (Clin. ChLm.
Acta 162 tl987~ 221), as well as Carlson et al. (in
~ITreatment of Hyperlipoproteinaemia", XIX + 284P. Raven
Press: New York 1984) describe the combined use of
colestyramine and fenofibrate in patients with hereditary
hypercholesterolemia. The combined use of colestyramine
and bezafibrate i~ described, for example, in Br. Med. J.
297 (1988) 6642, the combined u~e of colestyramine and
clofibrate for example in J. Lipid Re~. 21 (1980) 65 and
the combined u~e of colestyramine and gemfibrozil in US-
A 4,814,354.
The object on which the invention was based was
to prepare colestyramine as product~ which contain lipid-
lowering agents and are in a prs~entation, which do not
display the abovementioned disadvantage~.
Accordingly, colestyramine as products which
contain lipid-lowering agents have been found in the form
of particles whose longest particle diameter i~ from 1 to
6 mm.
Colestyr~mine can be compressed to particle~ with
a longe~t pArticle diameter of from 1 to 6 mm. A pre-
ferred form is the so-called microtablet which, a~ a
rula, i5 cylindrical and has a size of from 1 to 4 mm
(~oth height and diameter), in particular of fro~ 2.0 to
3.5 mm. Be~ides this, other forms su~h as bead or
irregularly ~haped granule~ are also possi~le in
principle.
The forms can be produced in a conven~ional
manner, for e~ampl2 that described in EP-A 166 315. It i8
po~sib~e to add the conventional pharmaceutical auxili-
arie~ to the formulation,` ~uch a~ binder~, inactive
ingredients, pre~ervatives, wetting agents, flow regula-
tor~, lubricant~ and/or antioxidants (see, for example,
H. ~ucker et al.: Pharma~euti~che ~echnologie", ~hieme
~erlag Stuttgart, (1378)). The form8 can additionally be
provided with the conventional pharmaceutical coating~.
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O.Z. 0480~01072 - 3 -
The preferred binder used for compression is
microcrystalline cellulosP, of which the drug con~ains
from 2 to 20, preferably fLom 3 to 8, ~ by weight. It is
advantageous to employ in the granulation cellulo~e
derivatives such as methylcellulose, hydroxypropylmethyl-
cellulose, hydro~yethylcellulosQ and polyvinylpyrrolidone
in an amount of from 2 to 10, preferably 3 to 6, % by
wei~ht.
The fonmulations obtainable in this way normally
contain the active compound in an amount of from 80 to
99% by weight.
~he dosage depends on the age, condition and
weight of the patient. As a rule, ths daily dose of
active compou~d is between 0.03 and 0.4 g/kg. of body
weight.
The cole~tyramine-containing product~ can al80
contain other lipid-lowering agents. Fenofibrate and
gemfibrozil are preferred, a~ are ~imilar compound~ of
this type ~uch a~ clofibrate, beclobrate, bezafibrate,
ciprofibrate and etofibrate (called fibrates herein-
after).
The drug on administration can be a combination
of the two active compounds in the same formulation or be
in the form of a so-called kit o~E parts. A kit of parts
is defined a~ a type of pharmaceutical pack in which the
indi~idual active componsnt~ are pre~ent wholly or partly
in ~eparate dose ~or~ in the ~ame pack.
The form pre~erred for the combination of the
active compound~ in the ~ame form is ~he microtablet. In
the case of separate admini~tration, the cole~tyramine i8
preferably in the microtablet form~ and the fibrate i~ in
a con~entional commerclal form ~uch a~ tablet, film-
coated tablet, ~ugar-coa~ed tablet, capsule or else a~
microtablet.
The ~tatements on the formulation of colestyr-
amine al30 apply to the combination of cole~tyramine and
fibrate.
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O.Z. 04aO/01072 - 4 -
When cole~tyramine and fibrate ~re combined in
one form, for example as micro~ablet, the latter can
contain the active compounds in the colestyramine
fibrate ratio of from 2 : 1 to 99 s 1 by weigh~, depend-
S ing on the conventional dose of the fibrate active
: co~pound.
Combina~ion of the two active compounds makes it
possible to lower the individual doses of these active
compounds, the dosage depending specifically on th~ age,
condition and weight of the patient. In general~ the
daily do~e~ of active compound~ are betw~en 0.03 and
0.4 g of colestyramine per kg of body weight and between
1 and lS mg of fibrate per kg of body weight.
Ex2mples
Example 1
13.5 kg of colestyramine (from R~hm & Haas
Deut~chland GmbH, cole~tyramine 40 ~) were mixed with
675 g of directly tablettable lactose and 600 g of
microcrystalline ~elluIo~e in a ~onventional high-
2G performance pharmaceutical mixer. Then 75 g of highlydi~per~e ilica and 150 g of magne~ium stearate were
added, and mixing was continued. ~his mixture for comp-
ression was then compre~sed to microtablets with a
diam~ter of 3.5 mm and the sa~a height, the indiYidual
ma~ being 30 mg.
Example 2
13.5 kg o colestyramine (see above) were mixed
with a solution o 0.7 kg of polyvinylpyrrolidone (mean
molecular mas~ ~S0OOO) in 2.1 kg of iBopropanol in a
; 3~ conventional high-performance pharmaceutical mixer with
cutter, and were gr~nlllated. Drying at 50C wa~ followed
by ~creening through an oscillating screen with a me~h
width of 0.8 mm. The granules were then mixed with 70 g
of highly di~per~e Rilica and 70 g of magne~ium ~tearate.
The co~po~ition rea~y for compression wa~ compres~ed to
microtablets with a diameter of 3 mm and the ~ame height,
the individual mas~ being 17 mg.
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