Note: Descriptions are shown in the official language in which they were submitted.
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The present invention relates to particular
rap;dly absorbable solid medicament formulations conta;n-
ing ~ihydropyridines, polyvinylpyrrolidone snd cross-
linked polyvinylpyrrolidone, and a process for their
preparation~
Dihydropyridines and their calcium-antagonistic
action are kno~n ~compare Brit;sh Patent 1,173,862 and
Br;tish Patent 1,358,951)~ Mar-y representatives of th;s
class of substance are very sensitive to li~ht and have
an extremeLy lo~ solubility in aqueous media~ For
example, the uater-solubil;ty of nifedipine is onLy 10 mg
per litre, and the ~ater-solubil;ty of nimod;pine is only
2 mg per litre. ~ecause of these particular properties,
a number of d;ff;cult;es occur in formulating galenical
preparations, as can be seen from numerous patent
appl;cat;ons for part;cular formulat;ons of ~hese active
compounds~
U~S. Patent 3,784,6840 for example~ relates to
particular bitable gelatine capsuies ~hich contain nife~
d;pine in d;ssolved form ;n order to ut;l;se the coronary
action of nifed;pine advantageously. ~ritish Patent
1,456,618 descr;bes and claims solid ~edicament formula-
tions ~hich are said to ensure a good b;oava~lability of
the dihydropyrid;nes~
DT-O~ ~German Publ;shed Specification) 2~8Z2,882
l;ke~;se describes col;d ~edicament formulations, in
wh;ch the sparing solub;lity of dihydropyr;dines is said
to be compensated by using certain solubiLisins agents
and surface-active substances.
The absorbab;l;ty of n;fed;p;ne is also sa;d, in
EP-OS (European Publ;shed Specification 1,247, to be
;mproved by using polyethylene glycol (PEG~ and certain
porous carrier substances. This Application also states
that the poor solub;lity of n;fedipine can be compensated
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by forming co-precip-tates from nifedipin~ and polyvinyl-
pyrrolidone ~PVP), in which the nifedipine 1s present ;n
amorphous form as a solid solut~on.
These co-precipitates are prepared by dissolving
nifedipine and PVP in organic solvents, ~ith subsequent
evaporation of the solvent ;n order to obtain a vitreous
composition ~compare DT-OS (Ger0an Published Specifica-
t;on) 2,82Z,882). Such evaporaition of the or~anic sol-
vent can be carried out industrialLy only ~ith ~reat expen-
d;ture, since the PVP composition strongly b;nds the or~anic solvent and becomes very viscous shortly before dry-
in~. A volum;nous foamy composiition forms and, shortly
before the 0nd of drying, is very viscous, can no lon~er
be stirred and can be further processed only ~ith diffi-
culty. Complete removal of the solvent from the co-
precipitate is virtually impossible. Another disadvan
tage in using a nifed;pine-PVP co-precipitate in the pro-
duction of tablets is the fact that aLthough this co-
precipitate can be mixed ~ith other auxiliaries, it
cannot be granulated ~ith aqueous solut;ons. Ho~ever,
such a simple mixture bet~een the PYP co-precipitate and
other auxiliaries tends to demix dur;ng further mechanical
process;ng, for example to form tablets or during fill;ng
of capsules. In the end effect, this çan lead to medic~-
ment formulations with a very different content of activecompound in indiv;dual tablets or capsules tdeficient
"content un;formity"), which is extremeLy undesirable
~ith a highly active substance such as n;fedipine. More-
over, the add;tional auxiliaries ~hich are available for
selection are very l;mited, especially for the production
of tablets, because PVP acts at the same time as a binder,
and the disintegration of the tablets or capsules is
prevented by the presence of relatively large amounts of
PVP (30 to 100 mg per tablet or capsule)u
Accord;ng to DE-OS (German Published Specifica-
tion) 3,1420853, the disadvantages mentioned above are
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eliminatecl by using a larger amount of auxiliaries for absorption
of the solution containing dihydropyridine and polyvinylpyrroli-
done/acetone. Such formulations are acceptable if the active
compounds are to be used only in low dosages.
However, if higher dosages, for e~ample 30 or 100 mg of
active compound, are to be used, this method has the disadvantage
that the ratio of active compound to auxiliary must remain constant
and very large formulation forms are thus obtained, which the
patients find difficult to take (for example tablets weighing 2 g).
The present invention relates to new solid dihydropyri-
dine formulations with a rapid absorbability and a uniform content
of active compound, the relative standard deviation of which is at
most 1.5%, containing 1 part by weight of dihydropyridine as active
substance, 0.01 to 1.5 parts by weight of polyvinylpyrrolidone (PVP)
with an average molecular weight of 15,000 to 50,000 and as
stabilizer 1 to 12 parts by weight of crosslinked insoluble poly-
vinylpyrrolidone (PVPP) as adsorbant and as desintigrant, and, if
appropriate, other customary auxiliaries.
Medicament formulations which contain the dihydropyridine
active compound in a dosage of 1 to 100 mg, in particular 5 to
70 mg, may be mentioned as ~referred,
Preferred dihydropyridines which may be are compounds of
the general formula I
S5~
R400C ~ OORl
1 (I)
R3 - N / R2
~1
in which R represents phenyl, which is substituted by one or two
identical or different substituents selected from the group
consisting of nitro, chlorine, CF3, OCHF2 and =N-0-N=,
Rl and ~4 are identical or different and each
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represent alkyl (1 - 10 C atoms), ~hich is option-
ally substituted by Dlkoxy ~ 4 C atoms)~
fluortne, chlorine or an N-methyl-N-benzyl ~roup,
and
S R2 and R3 are identical or d;fferent 3nd each
represent alkyl (1 - 4 C atoms)O which is option-
alLy substituted by hydroxyl, or repre~ent cyano.
Those formulation forms which contaln a dihydro-
pyrid;ne from the group comprising ni~edipine, ni~odipine~
n;trendipine, nisoldipine, nicardipine and felodipine are
of particular importance.
Those formuLation forms ~hich conta;n 0.05 to
1.5 parts by ~eight, in particular 0.1 to 1 part by
ueight, o~ PVP and 2 to 8 parts by ~eight, in particular
2 to 6 parts by weight~ of PVPP per part by ueight of
dihydropyridine are to be singled out.
Preferred aux;liar;es uhich may be mentioned are:
~ett;ny agents, such as, for example, ssdium lauryl-
sulphate and T~een~R), these wetting agents being
employed in a maximum amount of 1 part by ~eight. There
may also be ment;oned: lubricants, such as, for example,
magnesium stearate. The presence of fillers, such as
sugars, for example lactose and mannitol, ~lycocol~
calcium carbonate, maize starch and Avicel, may also be
, ~
advantageous~ If appropriate, the tablets can also addi-
t;onally contain disinte~rating agents or can be subse-
quently provided ~ith a customary lacquering in order to
achieve, in the formul3tion accordin~ to the invention,
immediate soLubility~ retardation or resistance to ~as-
tric juice. The formuLations according to the invention,in particular the granuLes, can furthermore be eombined
with other galenical forms contain;ng the same or differ-
ent active coMpounds.
The soLid formuLation according to the invention
is prepared by a procedure in which 1 part by ~ei~ht o~
dihydropyridine and 0.01 to 1.5 parts by ~eight of PVP
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are dissolved in a corresponding amount of or~anic sol-
vents in ~hich the t~o solid constituents can be dis-
solved, a wetting ayent is suspended or dissolved therein,
if appropriate, and this solution is ~ranulated with 1 to
12 parts by weight of PYPP and the resultin~ ~ranules are
further processed to solid med;cament formulations, if
appropriate after add;tion of further auxiliari~sO
Preferred solid medicament formulations ~hich may
be mentioned are: tablets, pills, dragees, ~ranules,
powders, capsuLes, sachets and pellets.
Preferred organic solvents which may be ~entioned
are: ethanol, methanol, acetone, ~ethyLene chloride and
chloroform and mixtures of these ~olvents. They are
preferably employed in amounts of 6 ~o 50, ;n particular
8 to 20, parts by ~ei~ht, based on the dihydropyridine.
It could not be predicted that the medicament
formulations thus obtained retain a very sood bioavail-
ability and at the same time a good çontent unifor~ity.
The granules consisting of the PVPP ~etted ~ith dihydro-
pyridine-PVP solution ~hich are obtained by the process
according to the invention can be dried, sieved, further
processed, mixed uith other auxiliaries and compressed
to form tablets without problems. The bioavailability
of the formulatisns accordin~ to the invention is at
least equivalent to that of the for~ulations known
hitherto in respect of speed and level~ It moreover
has the advantage tha~ the process can be carried out
~ith very little energy and in a short time. The easy
drying and the shorter dryiny time associated thereuith
(a~ most 20X of the conventional drying time) should be
particularLy emphasised. The solid ~ormulations
obtained are very small and, in spite of their high con-
tent of active compound, ran also be taken by the pat;ent
~ithout trouble.
Due to the lo~ PVP content, drying of the moist
~ranules is effected in a considerably shorter time
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(max;mun of 20X of the convent;onal drying t;me). For
the same reasonO no lumps occur durin~ dryin~.
In ~ontrast to kno~n formulatlons, ~hich are pre-
pared by granulation ~ith oraanic solvents~ the residual
solvent contents are so greatly reduced by the present
invention that they are belo~ 0.05X and thus virtually
can no longer be detected by conventional analytical
methods. This reduction ;n residual solvent contents is
advantageous from the toxicological point of view,
especially for long~term treatments.
Tablets produced in th;s manner have dis;ntegra-
tion times of less than 5 minutes. Auxiliaries are saved
by the process according to the ;nvention, and not only
is oral administration thereby facilitated but at the
same time the production costs are also reduçed.
Example 1
30 ~ of nimodipines and 17 9 of PVP 25 are dis~
solved in 500 9 of acetone, and 0Y5 ~ of sodium lauryl-
sulphate is suspended in the solution. 107 9 of cross-
linked PVPP is granulated with this solution in agranulating apparatus. The ~ranules are dried and sieved.
After admixing 1.5 9 of magnesium stearate, the granules
are compressed to form tablets ~e;gh;ng 156 mg and each
containing 30 m~ of nimodipine. The tablets are distin-
guished by a lo~ ueight, ~ood disintegra~ion times andadvantageous release.
Example 2
The ~ranules obtained in Example 1 are compressed
to form tablets ~eigh;ng 520 mg and each containing 100 mg
of nimodipine.
Example 3
30 9 of nimodipine and 4 g of PVP 25 are dissolved
in ~00 9 of acetone, and 0.5 9 of sodium lauryl sulphate
is suspended in the so~ution. 180 9 of crosslinked PVPP
are granulated ~ith this solution in a granulatin3
apparatus. The granules are dried~ sieved and, after
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admixing 2.0 9 of magnesium suLphate, compressed to ~orm tab-
lets weighiny 216 mg and each contain;n~ 30 ~9 of nimodipine.
Example 4
30 9 of nimodipine, 45 9 of PVP 25 are dis-
solved in 500 9 of acetone, and 0.5 9 of sodium lauryl-
sulphate is suspended in the solution. 120 9 of cross-
linked PVPP are granulated ~ith this solution in a
granulating apparatus. The granules are dried, s;eved
and, after admixing 1.5 9 of magnesium stearate, pressed
to tablets ~eighing 197 mg and each containing 30 mg of
nimod;p;ne.
Example 5
rhe granules ~rom Example 1 are ~illed or bri-
quetted and capsules or sachet~ are filled ~ith the
granules obta;ned after sieving.
Example 6
The solvent acetone described ;n Example 1 is
replaced by the same amount of ~ethylene chloride or
chloroform or a mixture thereof.
Example 7
20 9 of nitrendipine, 15 9 of PVP Z5 and 1.5 9 of
T~een 80 are dissolved in acetone. 110 9 of crosslinked
PVPP are granulated with this solution in a granulating
apparatus. The ~ranules are dried and sieved. A mixture
25 of 20 9 of Avicel, 10 9 of maize starch and 1.5 9 of
magnesium stearate is added as an af~er~mixture. The
mixture is pressed to tablets weighing 178 mg and each
containing 20 mg of n;trendipine.
Example 8
This example is as Example 7, but instead of the
after-m;xture, granu~es obtained from 30 9 of ~actose,
20 9 of ~vicel and 5 9 of maize starch by aqueous granu-
lation are added. The t~o granules are mixed, lubricated
~ith 1.5 9 of magnesium stearate and pressed to tablets
~e;ghing 203 mg.
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Example 9
10 ~ of nifedipine and 5 y of PVP are dissolved
in 100 9 of acetone. 80 9 of crossl;nked PYPP are
0ranulated ~;th th;s solution in a ~ranulating ~pparatus.
S The granuLes are dried and sieved. After admixing 1.0 9
of nagnesium stearate, the 0ranules are co~pressed to form
tablets ~e;ghing 96 Mg. The 10 mg nifedipine tablets are
distinsuished by ~ood disintegrat;on, lo~ wei~ht and
advantageous release.
ExampLe 10
10 9 of nifedipine and 5 9 of PVP are dissolved
in a mixture of 100 g of acetone and 4 9 of ethanol. A
~ixture of 80 0 of crosslinked PVPP, 19 9 of Avicel and
15 9 of maize starch is granulated ~ith the soLution in a
granulatin~ apparatus. The granules are dried, sieved and
m;xed ~ith an after-mixture consist;n0 of 10 9 of AviceL,
10 9 of crossLinked PVPP and 1 9 of magnesium stearate
and compressed to form tablets ~eighin~ 150 mg and each
containing 10 mg of nifedipine.
Example 11
This example is as Example 9, ~ith the addition
of 1~0 9 of T~een 80tR), givin~ 10 m9 nifedipine tablets
~eigh;ng 151 mg.
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