Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
- 1 - O.Z. 0050~35072
Pharmaceutical composition
The present invention relates to a novel pharma-
ceutical composition which contains a calcium-an-tagonistic
active compound, with or without additional active com~
pounds.
In therapy by medication, the use of oral pharmaceuti-
cal compositions with sustained release of` the active
constituents is conventionally practiced and is in parti-
cular necessary to lengthen the time for which a drug
acts, especially in the case of drugs with relatively
10 short biological hal~-lives. Compositions ~or oral
administration which show sustained release of the active
compounds substantially increase patient compliance.~
The fact that these pharmaceutical forms have to be taken
; less frequently than conventional non-sustained release composi-
tions ensures greater therapeutic sa~ety.
Moreover, the use of compositions for oral administration
with sustained release of the active compounds o~ten
avoids undesirable concentration peaks in
the plasma.
Sustained release compositions are required to have an
initial phase with rapid active compound release followed
by a phase in which the concentration is sustained, so as
to lengthen the period for which the plasma concentration
is at the therapeutically desired level. The initial
phase is absolutely essential in order to reach the
requisite plasma level very rapidly. This type of`
sustained-release drug is described as ideal, cf.
Pharmazeutische Technologie (Thieme Verlag, Stuttgart),
- 2 ~ 0.Z. 0050/35072
1978, page 487. Frequently also, sustained release
drugs which do not have an initial dose effectj but only
release the sustaining dose, are employed - especially in
therapeutic agents for long-term or continuous treatment.
The sustaining dose is released uniformly, in a ~ersistant
manner.
On repeatedly taking a drug, a steady state is
set up between the active compound eliminated from the
plasma and the active compound taken up by the plasma,
the steady state depending on the biological half-life.
To reach steady state concentrations of` the
therapeutically required order, frequent administration
is necessary with compounds of short half-lives, and this
is undesirable from the point of view of patient compli-
ance.
A similar situation applies to compounds of longer
half life, where a major proportion is metabolized before
reaching the body's principal circulatory system (as in
the case of the first-pass effect in the intestine and/or
the liver). Consequently, sustained relea~e composi-
tions of compounds exhibiting a pronounced first~pass
effect are generally viewed very critically (Der Internist
19 (1978), 333, Pharm. Ind. 40 (1978), 374, especially
page 381, left-hand column).
Substances exhibiting a pronounced first-pass
effect include a range of ~-receptor blocking agents, eg.
propranolol, or of calcium antagonists, eg. veraparnil and
gallopamil.
U.S. Patent 4,248,858 describes a novel sustained
_ 3 O.Z. 0050/35072
release composition of propranolol. In this, 160 mg
of propranolol are present in a compressed core, the release
of active compound being sustained because the material is
embedded in gelling agents and insoluble polymers. The
core is separated from an outer coating, which contains a
further 20 mg of propranolol, capable of rapid
release, by a film which is resistant to gastric juices and
which is intended to prevent the active compound in the
sustained release core from being released whilst the core
is stlll in the stomach
This composition is only suitable for substances
like propranolol which, on first pass through the liver,
~orms 4-hydroxypropranolol, whose activity is similar to
that of propranolol itself (Brit. J. Pharmacy (lg71) ~3,
222).
The present invention relates to a novel pharma-
ceutical composition which contains a calcium-antagonistic
active compound, with or without additional active com-
pounds, is intended for oral administration to ~o-
duce a sustained action for continuous therapy and con-
tains only the sustaining dose of active compound, bound
with pharmaceutical auxiliaries, in which composition the
calcium-antagonistic active compound is gallopamil or
verapamil and wherein, at the sustaining dose, the ratio
of the constituents with rapid release of active compound
to those with slow release of active compound is from 1 :
0.6 to 1 : 6.
Verapamil (X = H) and gallopamil (X = O~H3) have
the formula
_ 4 _ O.Z. 0050/35072
CH~O~-C-CH2-cH2-c~2-l`1-cH2-cH -~Oo'A,3
X C~3
In drugs, the compounds are preferably employed as hydro-
chlorides.
In addition to these compounds, the novel composi-
tion may contain further active compounds, such as di-
uretics, psychopharmaceuticals and hypotensive agents.
These additional active compounds are present in the phase
with rapid and/or slow release of active compound, depend-
ing on the order of magnitude of the biological half-life
of the particular compound.
10The ratio of rapidly released verapamil or
gallopamil to slowly released active compound in the
pharmaceutical is from 1 : 0.6 to 1 : 6, preferably from
1 : 1 to 1 : 4, especially from 1 : 1.2 to 1 : 3.
This ratio ensures, provided the right dosage is
given, that substantially constant and therapeutically -
correct plasma levels result, the active compounds being
released during the time of passage through the stomach
and small intestine (as a rule from 3 to 5 hours).
The pharmaceuticals can be prepared in a conven-
tional manner. Thus, coated tablets or layer tablets,in which a layer or the core consis-ts of granules of the
sustained release composition and a further layer or the coating
consists of granules which rapidly release the active com-
pound, or sustained release coated pills, in~hich the sustained
release core is coated with a sugar layer which also contains the
97
_ 5 _ O.Z. 0050/35072
active compound but releases it rapidly, can be prepared
by conventional and widely used methods.
Granules which release the active compound rapidly
are obtained by granulating the latter with sugar,
cellulose, starch and binders, and adding mold lubricants
and~~low r~gulators to the granules.
- The content of active compound in the
granules can vary within wide proportions but is prefer-
ably from 40 to 80%. If these granules are used as the
coating material for coated tablets, or are used in two-
layer tablets, it is found that the rate of release of
active compound is substantially independent of the pres-
sure used when pressing the tablets.
If gelling agents are used, granules with sus-
tained release of active compound can be obtained, which
do not dissolve in the digestive tract but form swollen
particles from which the active compound slowly diffuses
into the digestive juices.
Particularly suitable gelling agents are algin-
ates, eg. sodium alginate, especially those which, as a10% strength aqueous solution, have a viscosity of from
100 to 3,000 cp at 20C. If low-viscosity alginates
are used, it is advisable to add water-insoluble natural
materials, such as celluloses or starches, whilst when
high-viscosity alginates are employed~the addition of
soluble substances, such as lactose or low molecular
weight polyethylene glycols, is useful. Sui~able rates o
4~3~
- 6 - 0 Z. 0050/35072
release can also be achieved by employing polyacrylic acid
deriv~tives and polymethacrylic acid deriva-tives. The
pressure employed for tableting can, in the case of the
granules with sustained release of the active compound,
also influence the rate of release.
It is also possible to introduce the active com-
pound in the form of sustained release granules or com-
pressed cores conjointly with the free or non--sustained
release active compound into one therapeutic unit, for
example a hard gelatin capsule.
The invention makes it possible to provide pharma-
ceuticals which contain verapamil or gallopamil and give
a constant and effective level of action over a long
period.
The novel sustained release drugs are exceptionally
useful as therapeutic agents for prolonged administration
a therapeutically active plasma level with relatively
little variation being achieved over the entire period of
therapy. A drop in the plasma level into the sub-
therapeutic range will not occur if the drug is taken
regularly. ~loreover, the novel sustained release form allows
the frequency of administration to be reduced to once or
twice daily, thereby substantially improving patient com-
pliance. The safety of -the drug is also improved~
Finally, the novel composition has the advantage
that it can be prepared very simply, by means of conven-
tional processes.
_ 7 _ O.Z. 0050/35072
EXAMPLE 1
A. Preparation of the starting granules
a) Granules with rapid release of active compound
10.6 kg of verapamil, 4 kg of cellulose powder,
0.6 kg of ~ Kollidon VA 64 and 4 kg of lactose were very
thoroughly mixed and then moistened by adding 6 liters
of water, with stirring. The mixture was then mechanic-
ally stirred vigorously and kneaded to give a crumbly
moist mass which was converted to granules by forcing it
through a sieve. The granules were dried and then
again sieved. 0.7 kg of cellulose powder and 0.1 kg
o~ magnesium stearate were added, giving granules suitable
for pressing.
b) Granules with sustained release of active compound
14 kg of verapamil, 25 kg of sodium alginate,
4 kg of ~ Kollidon 30 (linear polyvinylpyrrolidone, mole-
cular weight 30,000) and 5 kg of cellulose powder were
very thoroughly mixed and moistened with 17 kg of water,
while stirring. The mixture was then mechanically
stirred vigorously and kneaded to give a crumbly moist
mass which was converted to granules by forcing it through
a sieve. The granules were dried and then again
sieved. 1.75 kg of cellulose powder and 0.25 kg of
magnesium stearate were added, giving granules suitable
for pressing.
B. Preparation of the finished tablets
Tablets of the following composition were formed
on a press for the production of two-layer tablets:
lower layer: 190 mg of granules Aa (100 mg of verapamil)
~ 8 - O.Z. 0050/35072
upper layer: 500 mg of granules Ab (140 mg of verapamil).
To mask the flavor, the tablets obtained were
coated with a film-forming lacquer of cellulose deriva-
tives, conventional plasticizers and dyes.
EXAMPLE 2
Aa) Following a procedure similar to Example 1 Aa,
granules with rapid release of active compound were pre-
pared by granulating sugars, celluloses or starches with
the active compound and a binder. Mold lubricants
and` ~low regulators were then added, giving granules
of the following compositions:
~L8~ 7
_ g _ 0 . Z . 0050/35072
U~ ~
o I I n ~ I o o
~ LO
o I o ~ ~ I o ~
Ln ~n
o ~ ,1 1 1 1 o
o ~o C~l
o
~ In Lr)
CL O I ~ u~ I I O O
U ~U
~ ~ In
C ~ I o o
o r) Lr)
~ I ~ I o ~ ~ o o
_l 10 ~J N
o
~1 i:L
~ o ~n ~
¢ " ~ ~ ' 2 ~ ~ 2
. LO ,n
I In o ~ I I o
In U~
L~ , o ~ , , o
CU
D
¢
~ C) ~
r~ ) O O E
t.) ~ E~
C ~ ~ ~ o
O ~ O
U~ ~ r1 0 0
3 S~
~ ~1) 0 0 a~
- 1~ - O.Z. 0050/35072
Ab) Using a method similar to Example 1 Ab, granules
with sustained release of active compound were prepared
with the following compositions:
0 . Z . 0050/35072
0 N
~ ~ I I ~ o I I i ~ Ln
C') ~
~ CO
~r C~ I G I O I I I
Ln ~D Ln ~
O I I O I ~ ~ I I
Ln Ln C~ C~i
t` O~` I I O I G
~ Ln
o
~J Ln Ln
S~ ~` O ~` I ~ O
0 r~ Ln
n. Ln ~ C~
r~ o t~ ~ I o
Ln
C
Ln n c~
o ~ o ~ I I o
~i ~ Ln
0
o
l_i ~
m E 0 0 ~Ln I
C o ~ Ln
Ln Ln
I~O O
Ln Ln
a: oa~ o
Ln ~
~ O
S~
a~
ri ~ ~o 0
o ~ 1 0 0
~ ~ o ~ ~ C~ ~ ~
0 ~o ~ s a~ V ~1 C
q~ ~ ~ o O E C~ o
c.) ~ t~ ~ 0 ~5 ~ ~ ~0 a
C E ~ O O ~1 ~ S
~ E ~1 0 ~ 0 ~ ~ ~,
v ~ 3 ~ o ~ ~
U~ ~ 0 ~ ~ ~ 3 C O
~ ~ O ~ ~ ~ ~ o O Q)
u~ a u~ ~ v ~
- 12 - O.Z. 0050/35072
TABLE 3
Substances Composition in parts per 100
Gallopamil 20 22.5
~odium alginate 50 44.4
Kollidon 30 7.5 6.6
Cellulose powder 4.5 5.5
Magnesium stearate 0.5 0.4
Lactose 17.5 10.6
B. Tablets were prepared, by a method similar to that
o~ Example 1 B, ~rom the granules listed in Tables 1 to 3.
The amounts of free active compound were from 60 to
150 mg, and the amounts of bound active compound from 80
to 150 mg in the case of verapamil; for gallopamil, the
corresponding values were from 30 to 80 and from 40 to
100 mg, respectively.
EXAMPLE 3
Compressed cores containing 140 mg of verapamil
were prepared from the granules obtained as described in
Example 1 Ab. The compressed cores were then coated
in a press coater with a layer of the granules of Example
1 Aa (active compound content 120 mg of verapamil), and
were subsequently coated with a film lacquer, by a method
similar to Example 1 B.
EXAMPLE 4
The granules obtained as described in Example 1 Ab
were pressed to form compressed cores containing 150 mg
of verapamil or 75 mg of gallopamil. The compressed
cores were then provided with coatings of the composition
- 13 - O.Z. 0050/35072
shown in Table 4, in such a way -that the coatings contained
90 mg of verapamil or 45 mg of gallopamil.
TABLE 4
Substances Composition in parts per 100
Verapamil 26.3 - 69.S - 35.4 45.7
Gallopamil - 26.3 - 69.5 - -
Water 26.3 26.3 5.2 5.2 25.8 20
Sugar 26.4 26.4 - - 24.6 15.1
Talc 10.5 10.5 17.4 17.4 8.9 12
Methylcellulose 10.5 lOr 5 - - 2.2 3
Gum arabic - - 3.5 3.5 0.9 1.2
Aerosil - - - - 2.2 3
Polyethylene 4 4 4 4
However, this process is involved, since the water
must be removed. Moreover it is very difficult to
achieve good content uniformity in the coating. The
best results were obtained with coatings having a low
content of active compound. The cores were given a
smooth coating with a 70% strength aqueous sugar solution
(from about 20 to 40 g of the solution being required per
10 kg batch of the cores), and a film coa-ting was then
applied on top as described above.
In the Examples -the registered trademarks stand
for the ~ollowing materials:
Kollidon V 64: Copolymer O~ vinylpyrrolidone and vinyl
acetate in the ration o~ 6 : 4
;
- 14 - O.Z. 0050/35072
Kollidon 30: Linear polyvinylpyrrolidone, molecular
weight 49,000
Kollidon 90: Linear polyvinylpyrrolidone, molecular
weight 13 100, 000
Eudragit RL: Polyacrylic acid and polymethacrylic
acid derivatives
Aerosil: Highly disperse silica
