Medicaments having controlled release of the active compound

Controlled release medicament pellets comprising PA0 a) a core which contains as active ingredient a compound of the formula ##STR1## or a compound from the group of 3-(4-fluorophenylsulphonamido)-1,2,3,4-tetrahydro-9-carbazole propanoic acid or 2-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-1,2-benzisothiazol-3 (2H)-one 1,1-dioxide monohydrochloride, an intensive disintegrating agent, a wetting agent and a binder, PA0 b) a double layer which controls release comprising PA1 (b1) an acrylic-based outer undigestible water-permeable lacquer layer, and PA1 (b2) an inner jacket layer comprising a hydrophobic additive and hydroxypropylcellulose of type M or H.

The invention relates to a new active compound release system in pellet 
form with which the release of active compound can be controlled with 
respect to time, can be established in pulsed form and can also be 
adjusted in its particular gradient. The pellets according to the 
invention consist of a core which contains the active compound and is 
surrounded by a polymer-containing jacket and an undigestible lacquer 
layer which is permeable to water. 
The therapeutic benefit of a medicament is determined not only by the 
nature of the active compound used but to a high degree by the specific 
galenical presentation form. In the case of many medicaments, optimization 
of the formulation form increases the action efficacy, reduces the 
undesirable side effects, increases the treatment reliability and at the 
same time improves patient compliance. By means of special galenical 
formulations, the active compound reaches the absorption organ at the 
correct point in time and in the optimum dosage (compare K. Heimann, 
Therapeutic Systems, Rate-controlled Drug Delivery; Concept and 
Development; New York (1984) Thieme Stratton). 
There are numerous attempts at developing systems, even for sparingly 
soluble active compounds, which should guarantee controlled release, with 
respect to time and location, of the active compound in optimum 
concentrations. Thus, for example, attempts have been made to achieve 
continuous or discontinuous release, controlled with respect to time, of 
active compounds via osmotic mechanisms by forcing the active compound out 
of a given opening (compare DE-Al 3,715,227). 
The possibility of continuous release, controlled with respect to time, has 
also been attempted with erosion systems or with lacquered systems, the 
lacquer layer being a partly membrane having a retarding action (compare 
WO 88/00046). However, a disadvantage of such continuously releasing 
systems is the fact that the release of active compound often decreases in 
time, and in the case of non-eroding matrix systems and lacquered systems 
the disadvantage is that the active compound often is not released 
quantitatively. Further disadvantages which may be mentioned for these 
systems are the fact that, for example, the osmotic systems are very 
complicated and expensive to prepare, and often the known disadvantages of 
individual dose medicament forms occur, such as, for example, dose dumping 
and wide variability in the passage time in the body, according to the 
individual and diet. Moreover, multi-pulsed bursts of release cannot be 
realized in practice with these systems. 
To avoid the disadvantage of the release of active compound decreasing with 
time, attempts have also been made to prepare multi-layered tablets having 
a different concentration of active substance in the various layers 
(DE-OS) (German Published Specification) 1,767,765), or to increase the 
concentration of the active compound from the shell to the core with an 
increasing concentration gradient (compare German Patent Specification 
2,651,176). Such formulation forms can be prepared only with great 
technical effort, do not allow bursts of release of any desired frequency 
and in tablet form are subject to a high degree to the different passage 
times and dietary habits of the patient. 
To avoid some of these disadvantages, tablets or capsules with controlled 
release of the active compound which contain a relatively large number of 
small dosage units in the form of cores, beads, granules or pellets have 
also been proposed (see DE-OS (German Published Specification) 1,617,724 
and U.S. Pat. No. 3,247,066). The beads or pellets described therein are 
said to release the medicament over a period of up to 12 hours. As a 
result of the dimensions and large number of small beads, the release 
functions largely independently of the various physiological conditions of 
individual patients. The cores, containing the active compound, of these 
beads or pellets are surrounded by an undigestible film which is permeable 
to water and readily tears. In addition to the active compound, the core 
contains a colloid which is swellable in water. On contact with the 
water-containing body fluid, the core starts to absorb water and to swell, 
which in the end, after a certain period of time, leads to bursting of the 
film coating and to increased release or absorption of the active compound 
released. The start of the main absorption is some time after the time of 
intake and can largely be controlled via the nature and thickness of the 
film coating and the nature and amount of the swelling substances. 
Gelatine is mentioned as the preferred swelling colloid and ethylcellulose 
is mentioned as the preferred material for the lacquer shell. The aim of 
this application is controlled release of the active compound regardless 
of the pH of the various body fluids, for example acid gastric juice and 
alkaline intestinal fluid. 
One disadvantage of this system is that active compound contents can 
already be released by diffusion before the lacquer layer tears. 
Furthermore, although delay times can be achieved by this system, the 
gradient which can be achieved in the subsequent release of active 
compound after bursting of the shell is not optimum. A steep release of 
active compound is desirable in particular for active compounds having a 
"first pass effect" which can be saturated, in order to achieve a good 
bioavailability with little stress on the organism from the active 
compound. Another disadvantage is that in these core-lacquer pellets, the 
active compound is already wetted with the aqueous release medium very 
early on. This can means that undesirable reactions of the body fluid with 
the active compound already take place hours before the lag time is 
reached, such as, for example, recrystallization and therefore a change in 
the solution and absorption properties or chemical changes to the active 
compound. 
One variant of this "bursting" medicament form is also described in 
European Patent A-210,540. The principle, called in that specification a 
"time-controlled explosion system", for controlled release of the active 
compound is distinguished by the fact that a hydrophilic layer containing 
powerful swelling agents or disintegrating agents lies directly underneath 
a water-permeable lacquer layer or membrane. These layers are either free 
of active compound (compare FIGS. 1 and 2) or already contain active 
compound (compare FIGS. 3 and 4). As a result of the direct contact of the 
disintegrating agents or swelling layer with the outer membrane, the 
explosion pressure starts to build up in this system immediately after 
water has diffused through the outer membrane. As a result of this 
build-up, it is difficult to guarantee lag times of several hours. The 
release data of Table 1 show different lag times for the various layers of 
the ethylcellulose membrane, and these are only less than 4 hours even 
with a very thick ethylcellulose layer which makes up about 30% of the 
weight (sample C). The publication by Satoshi Ueda et al. in Proceed 
Intern. Symp. Control. Rel. Bioact. Mater., 15 (1988) Controlled Release 
Society, Inc., No. 254, pages 450-451 also demonstrates this. The results 
presented there, in particular FIG. 3, show that the maximum lag time 
which can be achieved in this system is less than 5 hours, it already 
being impossible to achieve the desired gradient in the release curve 
after this time. 
In contrast, the active compound release system according to the invention 
exhibits a number of advantages. Any desired release profiles, even over a 
period of more than 12 hours, can be realized by combination of the 
pellets according to the invention, for example by using different pellet 
groups. The long delay times, which have not been possible to date, after 
which very steep releases or even less steep releases can then be 
programmed as desired are of particular advantage. The increased breakdown 
of the active compound in a first pass effect which can be saturated is 
overcome by this pulsed, controllable active compound release at any 
desired interval of time. This allows a reduction in the dose because of 
the reduced metabolization and avoids unnecessary stress to the 
metabolizing organs. The active compound release can be adapted to suit 
the daytime requirement or the biological rhythm by suitable combination 
of pellet groups with different release properties. According to this 
system, the active compounds can likewise be provided in certain 
absorption sections (absorption windows) in different regions of the 
gastrointestinal tract. Premature enzymatic, bacterial or chemical 
breakdown of the active compound is in this way excluded. Unnecessary 
irritation in the absorption organs is avoided. At the same time, the risk 
of intake at the wrong time by the patient is reduced. The independence of 
the desired delay time from the various pH values and eating habits 
increases the medicament reliability and the efficacy of the treatment. 
The present invention relates to new medicaments having controlled release 
of the active compound and containing at least one pellet group, 
characterized in that the pellets are built up from 
a) a core which contains as an active substance a compound of the general 
formula 
##STR2## 
in which R represents nitro or the group 
##STR3## 
in the ortho- or meta-position, R.sup.1 represents alkyl having 1-4 C 
atoms, which is optionally interrupted by an oxygen in the chain, and 
R.sup.2 represents alkoxy having 1-4 C atoms, or represents the radical 
##STR4## 
or a compound from the group of 
3-(4-fluorophenylsulphonamido)-1,2,3,4-tetrahydro-9-carbazole propanoic 
acid or 
2-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-1,2-benzisothiazol-3(2H)-one 
1,1-dioxide e.g. as monohydrochloride salt, 
an intensive disintegrating agent from the group comprising crosslinked 
sodium carboxymethylcellulose or sodium starch glycolate (NF XVI), sodium 
laurylsulphate as a wetting agent and Polyvinylpyrrolidon e.g. PVP-25 as a 
binder, and 
b) a double layer which controls the release, consisting of 
b1) an outer undigestible water-permeable lacquer layer which essentially 
consists of acrylic resins based on poly(meth)acrylic acid esters having a 
neutral character (NE type) or having a low content of quaternary ammonium 
groups (R type), the NE type consisting of copoly(meth)acrylic acid esters 
having the structural element 
##STR5## 
wherein R.sup.3 represents H or CH.sub.3 and 
R.sup.4 represents CH.sub.3 or C.sub.2 H.sub.5, 
and having an average molecular weight of about 800,000, and 
the R type differing from this in that R.sup.4, in a molar ratio of 1:20 to 
1:40, represents the group 
##STR6## 
and it has an average molecular weight of about 150,000, or consists 
essentially of ethylcellulose, and wherein such outer layer (b1) may 
contain additionally auxiliary agents such as anti adhesives as magnesium 
stearate or calcium stearate and conventional plasticizers such as 
polyethylene glycol 20,000, dialkyl (1-4 C atoms) diphthalate, glycerol 
triacetate or citric acid esters, such as triethyl citrate, and 
b2) an inner jacket which controls the migration of the water in the 
direction of the core and consists of 10 to 40% of hydroxypropylcellulose 
of type M or H (HPC-M or HPC-H) and consists to the extend of 60% to 90% 
of a hydrophobic additive, such as calcium stearate or hydrogenated castor 
oil. 
Pellets having a particle diameter of 0.8 to 3.5 mm, preferably of 1.0 to 3 
mm, in particular 1.5 to 2.5 mm, and weighing 0.5-20 mg, in particular 
2-10 mg per pellet, are of particular interest. The weight content of the 
core containing the active compound is 20-50%, in particular 25-40% of the 
total weight of the pellet, and the core preferably has a diameter of 
0.5-1.5 mm. The content of dihydropyridine active compounds in the core is 
preferably 40-90%, in particular 60-85% of the core weight. 
The outer lacquer layer is preferably up to 0.3 mm, in particular up to 0.2 
mm thick. The weight of the lacquer layer is up to 50%, in particular up 
to 35%, based on the total weight of the pellet. 
The migration-controlling jacket layer has a thickness of about 0.1 to 0.5 
mm, in particular 0.2 to 0.4 mm. The weight of this jacket layer is about 
25-65%, in particular 30-55% of the pellet weight. 
The content of hydroxypropylcellulose in the jacket is about 10 to 40%, in 
particular 15 to 30% of the total jacket weight, and the content of the 
lipophilic constituent of the jacket is, in particular, 70 to 85% of the 
weight of the jacket layer. 
The core contains the dihydropyridine active compounds in a weight ratio of 
40 to 90%, in particular 50 to 85%, based on the core weight. The content 
of intensive disintegrating agent is about 3 to 30%, in particular 5 to 
20% of the core weight. The wetting agent content (sodium laurylsulphate) 
of the core weight is 0.5 to 5%, in particular 1 to 3%, and the binder 
content (PVP-25) is about 3 to 25%, in particular 5 to 20% of the core 
weight. 
The formulation according to the invention is particularly suitable for the 
active compounds nifedipine, nimodipine, nisoldipine and 
methyl-4-(2-benzyloxyphenyl)-5-cyclopropyl 
-carbamoyl-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate, both in 
racemic form and as the enantiomers and 
3-(4-fluorophenylsulphonamido)-1,2,3,4-tetrahydro-9-carbazole-propanoic 
acid and 
2-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-1,2-benzisothiazol-3-(2H)-1,1 
-dioxide monohydrochloride. 
The core preferably contains crosslinked sodium carboxymethylcellulose 
(croscarmellose sodium USP XXI N.F. 16 type A) as the intensive 
disintegrating agent, sodium laurylsulphate as the wetting agent and 
polyvinylpyrrolidone 25 (PVP 25) as the binder. 
The jacket preferably contains hydroxypropylcellulose in the form of HPC-M 
or HPC-H, and calcium stearate as the lipophilic additive. 
The lacquer preferably contains poly(meth)acrylic acid esters of the types 
RS, RL and NE30D, in particular the polymers known by the tradenames 
Eudragit RS.RTM., Eudragit RL.RTM. and Eudragit NE30D.RTM., which are 
marketed by the company Roehm Tech. Inc., USA. 
By the combination according to the invention of a water-permeable but 
insoluble lacquer layer with a jacket layer which contains no active 
compound and controls the migration of the water to the core as a result 
of a certain mixture of hydrophobic and hydrophilic constituents, without 
leading to bursting of the lacquer shell, with the active 
compound-containing core which contains the active compound and at the 
same time intensive disintegrating agents, the release of the active 
compound from the particular pellets can be delayed for a period of more 
than 12 hours. Pulsed release which, with a single daily intake, can be 
adapted to suit the different active compound requirement of the daily 
rhythm of the patient can be achieved by combination of different pellet 
groups. This is of importance above all for long-term therapy, for example 
of high blood pressure. Thus, for example, the phase of low blood pressure 
during the night can be coordinated with a corresponding lag phase, so 
that the delayed release coincides with the increase in blood pressure in 
the early hours of the morning. 
The gradient of the release can be controlled via the content of the 
disintegrating agent portion in the core. Very narrow release intervals 
can be achieved even after delay times of more than 6 hours. 
The standardized release interval (SRI) may be defined as follows: 
SRI=(t80-t20)/t50, t80 being the time at which 80% of the active compound 
is released, and analogously t20 and t50 being the time at which 20 and 
50% respectively of the active compound is released. An SRI of less than 
0.25, in particular 0.20, can be achieved by the pellets according to the 
invention even after a delay time of more than 6 hours. 
Another characteristics of the pellets according to the invention is that 
less than 5% of the active compound is released in up to 90% of the lag 
time. This allows very precise adjustment of the retarded or pulsing 
bursts of release. 
Slower releases, that is to say higher SRI values, can of course also be 
achieved by means of the pellets according to the invention, for example 
by reducing the disintegrating agent content in the core. Uniform 
(non-pulsed) releases can likewise be realized, for example by using a 
higher number of pellets, the lag times of which are distributed uniformly 
over the entire release period. 
Surprisingly, very long delay times with only thin layers of the placebo 
content of the small pellets can be achieved by the synergistic 
interaction of the lacquer layer and jacket layer. In the formulations 
known to date, the lag time or the delay period was controlled only via 1 
or 2 parameters, for example only by erosion or, as in European Patent 
A-210,540, on the one hand by the water-permeable lacquer layer and on the 
other hand by the nature and amount of the disintegrating agent in the 
adjacent jacket region. In the system according to the invention, the 
jacket layer free from active compound provides a further control 
parameter for the delay time. The lacquer and jacket layer allow effective 
control of the rate of migration of the water to the core. They ensure 
uniform penetration of the water front and therefore very precise control 
of the lag times with steep releases. The expert is therefore for the 
first time in a position to employ the known advantageous of pellets 
having a particle diameter of less than 3 mm for sustained release 
formulations or for long-acting formulations, adjusted to suit the daily 
rhythm, with pulsed release. 
Customary galenical measures can also be used without problems for the 
pellets according to the invention. Thus, for example, the lacquer and/or 
jacket layer can be stained with customary medicament dyestuffs for the 
purpose of light stabilization or for better distinguishability, and salts 
which influence the osmosis or the pH or flavor improvers can be added. 
The pellets according to the invention are prepared by customary methods. 
The core can be prepared in a continuous or discontinuous procedure by, 
for example, rolling granulation, mixing granulation, fluidized bed 
granulation or fluidized bed spraying granulation or by tabletting. Mixing 
granulation and rolling granulation methods, for example plate, drum and 
rotor granulation, are particularly preferred. The constituents of the 
core (active compound, disintegrating agent and auxiliaries) preferably 
have particle sizes of less than 100 .mu.m in order to achieve a high 
spherically or surface quality. 
The core is prepared, for example, by mixing the active compound, the 
intensive disintegrating agent, the wetting agent and the binder in a 
mixer, adding water and/or organic solvents, such as lower aliphatic 
alcohols or acetone, as the granulating liquid, granulating for 0.5-3 
hours and then drying at 30.degree.-120.degree. C. , preferably 
40.degree.-100.degree. C. The resulting granules are then sieved. 
The jacket layer is likewise applied to the cores by customary methods, for 
example by spraying on from a solution, melt or suspension. The process 
can be carried out in a mechanical mixer, in a fluidized bed, on a 
granulating plate, in a granulating drum or in a rotor granulator. The 
jacket material can also be applied in powder form with addition of 
granulating liquid, for example in a discontinuous or continuous manner in 
the apparatuses customary for rolling granulation. 
The hydrogel-forming agent hydroxypropylcellulose (HPC-M or HPC-H) is 
preferably employed with a particle size of less than 100 .mu.m, in 
particular less than 65 .mu.m, in the preparation of the jacket layer. 
The lacquer is applied in the customary manner, for example by spraying on 
from an organic solution or from an aqueous suspension in lacquering 
kettles, rotating drums or plates or in customary coaters. The lacquer is 
preferably applied from an aqueous dispersion at elevated temperatures at 
which film formation occurs, preferably at 30.degree.-100.degree. C., in 
particular at 40.degree.-80.degree. C. 
In the case of application of the lacquer from a solution, organic solvents 
from the group comprising lower aliphatic alcohols, such as ethanol, 
methanol and isopropanol, volatile ketones, such as, for example, acetone, 
and halogenated hydrocarbons, such as, for example, methylene chloride or 
chloroform, are preferably employed. 
Capsules are filled with the mixed or non-mixed pellet groups using the 
customary filling and sealing machines. In addition to filling the 
capsules with pellets, it is also possible to introduce the pellets into a 
compressed tablet. A preferred process for the preparation of the pellets 
according to the invention comprises a procedure in which 
a) the core is prepared by mixing the active compound, the disintegrating 
agent, the wetting agent and the binder, subsequently granulating the 
mixture for 0.5 to 3 hours with the addition of water and/or organic 
solvents, such as lower aliphatic alcohols or acetone, as the granulating 
liquid and then drying the mixture at 30.degree. to 120.degree. C. and 
sieving the resulting granules, and 
b) the jacket layer is applied by spraying from a solution, melt or 
suspension of the hydroxypropylcellulose and the hydrophobic additive in a 
fluidized bed, on a granulating plate, in a mechanical mixer or in a rotor 
granulator, or the jacket material is applied in powder form, with 
addition of granulating liquid, in a discontinuous or continuous manner in 
apparatuses customary for rolling granulation, and 
c) the lacquer constituents are either sprayed on as a solution in organic 
solvents, such as lower aliphatic alcohols, volatile ketones or 
halogenated hydrocarbons, or applied from an aqueous suspension in 
lacquering kettles, rotating drums or plates or in customary coaters at 
temperatures between 30.degree. and 100.degree. C. and are crosslinked by 
means of heat. 
The release of the pellets according to the invention is determined in 
accordance with the USP paddle method. In each case capsules filled with 
pellets and containing 30 mg of active compound are employed. The test is 
carried out at 37.degree. C. in 4,000 ml. of release medium at 100 
revolutions per minute. The release medium is brought to pH 6.8 with a 
buffer (DAB-9; diluted 1:10) and additionally contains 0.25% of sodium 
laurylsulphate and 0.68% of sodium chloride. 
The administration forms which can be prepared from the pellets according 
to the invention, such as capsules or compressed tablets, can be prepared 
by customary methods, combinations with other active compounds also being 
possible. If immediately acting initial doses are desired, the pellets 
according to the invention can also be combined with fast-releasing forms 
of the abovementioned dihydropyridines, for example with coprecipitates or 
with non-lacquered cores.

EMBODIMENT EXAMPLES 
Example 1 
Preparation of the core 
850 g of micronized nifedipine are mixed with 80 g of crosslinked sodium 
carboxymethylcellulose, 50 g of PVP-25 and 20 g of sodium laurylsulphate 
in an intensive mixer. 200 ml of distilled water are then added and 
granulation is carried out for 3 hours at room temperature with a 
decreasing speed of rotation (3,000.fwdarw.400 revolutions per minute). 
The resulting cores are dried at 80.degree. C. and sieved (diameter 
1.25-1.5 mm). 
Application of the jacket 
1,000 g of these cores are initially introduced into a rotor granulator and 
a mixture of 510 g of hydroxypropylcellulose M (corresponding to 30% of 
the jacket content) and 1,190 g of hydrogenated castor oil (corresponding 
to 70% of the jacket content) and water as the granulating liquid is added 
continuously and the cores ar coated with a jacket in a rotor granulator 
(250 revolutions per minute) at room temperature. (Dose rate of the powder 
1,000 g/hour). The bed moisture content is regulated here at 25% absolute 
moisture by metering the granulating liquid. Lacquer application 
The jacketed cores (2,700 g) are sprayed at 60.degree.-70.degree. C. in a 
rotor coater with a 10% strength aqueous dispersion consisting of 50.6% of 
Eudragit RS, 44.9% of magnesium stearate and 4.5% of PEG 20,000, in each 
case based on the weight of the solid content. After 1.5 hours, pellet 
groups with a lacquer content of 30% are obtained. Pellets with a lacquer 
content of 80% are obtained after 4.0 hours. 
The following delay times results, depending on the thickness of the 
lacquer layer: 
______________________________________ 
Amount of lacquer layer 
based on the core weight 
Delay time 
______________________________________ 
0 % (no lacquer) 1.5 hours 
30 % 4.0 hours 
80 % 8.5 hours 
______________________________________ 
Example 2 
Core-jacket-lacquer pellets of the following recipe are prepared 
analogously to Example 1: 
______________________________________ 
Parts by weight: 
______________________________________ 
Core (1 part) 
Nifedipine 73% 
Crosslinked sodium carboxymethyl- 
15% 
cellulose 
PVP 25 10% 
Sodium laurylsulphate 
2% 
Jacket (1.7 parts) 
Hydroxypropylcellulose M 
30% 
Calcium stearate 70% 
Lacquer (0.1-1.09 parts) 
Eudragit RS 50.6% 
Magnesium stearate 44.9% 
PEG 20,000 4.5% 
______________________________________ 
Amount of lacquer applied 
Curve based on the core weight = 100% 
Delay time 
______________________________________ 
1 0% (no lacquer) 1.0 hour 
2 10% 2.0 hours 
3 28% 4.0 hours 
4 44% 5.6 hours 
5 64% 7.0 hours 
6 109% 12 hours 
______________________________________ 
The release rates for the various lacquer amounts can be seen from FIG. 1. 
Example 3 
CJL pellets of the following recipe were prepared analogously to Example 1: 
______________________________________ 
Parts by weight: 
______________________________________ 
Core (1 part) 
Nisoldipine 73% 
Crosslinked sodium carboxymethyl- 
15% 
cellulose 
PVP 25 10% 
Sodium laurylsulphate 
2% 
Jacket (1.7 parts) 
Hydroxypropylcellulose M 
30% 
Calcium stearate 70% 
Lacquer (0.11-1.07 parts) 
Eudragit RS 50.6% 
Magnesium stearate 44.9% 
PEG 20,000 4.5% 
______________________________________ 
Amount of lacquer applied 
Curve based on the core weight = 100% 
Delay time 
______________________________________ 
1 0% (no lacquer) 1.0 hour 
2 11% 2.0 hours 
3 29% 3.0 hours 
4 43% 4.0 hours 
5 63% 5.5 hours 
6 107% 10 hours 
______________________________________ 
The release rates for the various lacquer amounts can be seen from FIG. 2. 
Example 4 
CJL pellets of the following recipe were prepared analogously to Example 1: 
______________________________________ 
Parts by weight: 
______________________________________ 
Core (1 part) 
Nimodipine 73% 
Crosslinked sodium carboxymethyl- 
15% 
cellulose 
PVP 25 10% 
Sodium laurylsulphate 
2% 
Jacket (1.3 parts) 
Hydroxypropylcellulose M 
30% 
Calcium stearate 70% 
Lacquer (0.1-1.07 parts) 
Eudragit RS 50.6% 
Magnesium stearate 44.9% 
PEG 20,000 4.5% 
______________________________________ 
Amount of lacquer applied 
based on the core weight = 100% 
Delay time 
______________________________________ 
0% 0.7 hour 
10% 1.5 hours 
29% 3.4 hours 
48% 5.1 hours 
67% 6.5 hours 
107% 10.3 hours 
______________________________________ 
Example 5 
CJL pellets of the following recipe were prepared analogously to Example 1: 
______________________________________ 
Parts by weight 
______________________________________ 
Core (1 part) 
Nisoldipine 60% 
Sodium starch glycolate 
23% 
PVP 25 15% 
Sodium laurylsulphate 
2% 
Jacket (1.2 parts) 
Hydroxypropylcellulose H 
20% 
Hydrogenated castor oil 
80% 
Lacquer (0.1-1.2 parts) 
Eudragit NE30D 55% 
Magnesium stearate 
44% 
Glycerol triacetate 
1% 
______________________________________ 
Example 6 
CJL pellets of the following recipe were prepared analogously to Example 1: 
______________________________________ 
Parts by weight 
______________________________________ 
Core (1 part) 
4-(2-benzyloxyphenyl)-1,4-dihydro- 
70% 
2.6-dimethylpyridine-(3-carboxylic acid 
methyl ester)-(5-carboxylic acid cyclo- 
propylamide) 
Sodium starch glycolate 
18% 
PVP 25 10% 
Sodium laurylsulphate 2% 
Jacket (1 part) 
Hydroxypropylcellulose H 
30% 
Calcium stearate 70% 
Lacquer (0.1-1.2 parts) 
Eudragit NE30D 50.6% 
Magnesium stearate 44.9% 
PEG 20.000 4.5% 
______________________________________ 
It is understood that the specification and examples are illustrative but 
not limitative of the present invention and that other embodiments with 
the spirit and scope of the invention will suggest themselves to those 
skilled in the art.