CA2009736A1

CA2009736A1 - Medicaments having controlled release of the active compound

Info

Publication number: CA2009736A1
Application number: CA002009736A
Authority: CA
Inventors: Manfred Bucheler; Andreas Ohm; Roland Rupp; Josef Schmoll; Axel Wollenschlager
Original assignee: Individual
Current assignee: Bayer AG
Priority date: 1989-02-11
Filing date: 1990-02-09
Publication date: 1990-08-11
Also published as: AU4927090A; IE900470L; DK0386440T3; EP0386440B1; GR3005664T3; ATE79029T1; HU206044B; ZA90971B; IL93315A0; DE59000232D1; US5204121A; JPH02300126A; HUT57585A; EP0386440A1; ES2044246T3; AU622273B2; NZ232430A; HU900749D0

Abstract

Medicaments having controlled release of the active compound A B S T R A C T

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

Le A 26 708

Description

Z~ 3736 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 accord-ing to the invention consist of a core which contains the active compound and i8 6urrounded by a polymer-containing ~acket and an undigestible lacquer layer which i~ perme-able 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 ~pecial galenical fox-mulations, the active compound reaches the absorption organ at the correct point in time and in the optimum dosage (compare R. Heilmann, Therapeutic Systems, Rate-controlled Drug Delivery; Concept and Development; New York (1984) Thieme Stratton).
There are numerou~ attempts at developing sy~-tems, even for sparingly soluble active compounds, which should guarantee controlled release, with re~pect to time and location, of the ~ctive compound in optimum con-centrations. Thu0, for example, attempt~ have been made to achieve continuous or discontinuous release, con-Le A 2~ 708 - 1 -trolled 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, ha~ alEo been attempted with erosion systems or with lacquered systems, the lscquer layer being a partly permeable membrane having a retard-ing action (compare WO 88/00046). However, a disadvan~age of æuch continuouæly releasing ~ystems i~ 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 i8 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 form-~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 6y8-tems.
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 variou~ layers (DE-OS (German Publi~hed Specification) 1,767,765), or to increa~e the concentr~tlon of the active compound from the ~hell to the core with an increa~ing concentrntion gradient (compare German Patent Le A 26 708 - 2 -z~

Specification 2,651,176). Such formulation forms can be prepared only with great technical effort, do not allow bur~ts of release of any desirQd frequency and in tablet form are ~ub~ect to a high degree to the different passage times and dietary habits of the patient.
To avoid some of th~se disadvantages, tablets or capsules with controlled relea~e 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. Patent Specification 3,247,066). The beads or pellets described therein are said to relea~e 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 i~ permeable to water and readily tears. In addit~on 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 ~well, which in the end, after a certain period of time, leads to bursting of the film coating and to increased reloase or ~bsorption of the active compound released. The start of the main absorption iB some time after the time of intake and can largely be controlled via the nature and thickne~ of the fllm coating and the nature and ~mount of the swelling ~ub~tance~. Gelatine is mentioned a~ the preferred ~welling colloid ~nd Le A ?~ ~Q8 - 3 -ethylcellulose i~ mentioned as the preferred material for the lacquer shell. The aim of this application is con-trolled release of the active compound regardless of the pH of the variou~ body fluids, for example acid gastrlc ~uice and alkaline intestinal fluid.
One disadvantage of this system is that sctive compound contents can already be released by diffusion before the lacquer layer tear6. Furthermore, although delay times can be achieved by this system, the gradient which can be achieved in the subsequent release of active compound after bur6ting of the shell i~ not optimum. A
steep release of active compound is desirable in par-ticular for sctive compounds having a "first pass effect~
which can be saturated, in order to achieve a good bioavailability with little ~tress 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 mean that undesirable reactions of the body fluid with the sctive compound alre&dy 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 "burstingl' medicsment form is al80 de~cribed in European Patent A-210,540. The prin-ciple, called in that specification a ~time-controlled explosion system", for controlled release o the active compound is distinguished by the fact that a hydrophilic layer containing powerful ~welling agents or Le A 26 708 - 4 -disintegrating agents lies directly underneath a water-permeable lacquer layer or membrane. These layers are either free of acti~e compound (compare Figures 1 and 2) or already contain active compound (compare F~9~ 3 ~
4). As a result of the direct contact of the disintegrat-~~~Ing agents or swelling layer with the outer me~brane, theexplosion pressure ~tarts to build up in this system Lmmediately after water has diffused through the outer membrane. As a result of this build-up, it i6 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 ethylcel-lulose layer which makes up about ~0% of the weight (6ample 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 Figure 3, show that the maximum lag tLme 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 advan-tages. Any desired release profiles, e~en over a periodof 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, aftex which very steep rQlease~ or even less stsep relea~es cnn then be Le A 26 708 - 5 -3~7~6 programmed a~ 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 de6ired interval of time. This allow3 a reduction in the dose because of the reduced metabolization and avoids unnecessary stres~ to the metabolizing organs. The active compound release can be adapted to suit the daytLme requirement or the biological rhythm by suitable combina-tion of pellet groups with different release properties.According to this ~ystem, the active compound~ can likewise be provided in certain ab60rption sections (absorption windows) in different regions of the ga6tro-intestinal 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 increa~es 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 Le A 26 7Q8 - 6 2(~ 736 ~ R

RIOOC ~ COR2 in which R represents nitro or the group 0-CH2 ~ in the ortho- or meta-position, S Rl represent~ alkyl having 1 - 4 C atoms, which is optionally interrupted by an oxygen in the chain, and R2 represents alkoxy having 1 - 4 C atoms, or repres-ent~ the radical NH ~
or a compound from the group of 3-(4-Fluorophenylsulfon-amido)-1.2.3.4-tetrahydro-9-carbazole propanoic acid or 2-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-1.2-benziso-thillzol-3(2H)-one 1,1-dioxidemonohydrochloride, an intensive disintegrating agent from the group comprising crosslinked sodium carboxymethylcellulose or sodium starch glycolate (NF XVI), sodium laurylsulphate as a wetting agent and PVP-25 as a binder, and b) a double layer which controls the release, consisting of bl) an outer undigestible water-permeable lacquer layer whlch es~entially ¢on~i~t~ of acrylic resins ba~ed on poly(meth)acryllc acid estQr~ having a neutral charac-ter (NE type) or hsving a low content of quaternary ammonium groups (R type), the NE type consisting of copoly(meth)acrylic acid esters hnving the structural element Le A 26 708 - 7 -~ S~7 ...------CH2-lCH2 ~
C=O C=O

wherein R3 repreeents H or CH3 and R4 represents CH3 or C~H5 and having an average molecular weight of about 800,000, and the R type differing ~rom this in that R4, in a molar ratio of 1:20 to 1:40, r~presents the group ~ / CH3 -CH2-CH2-N \ CH3 and it has an average molecular weight of about 150,000, or consists essentia1ly of ethylcellulose, and wherein such outer layer may contain additionally auxiliary agents such as anti adhesives as magnesium stearate or calcium ~tearate and conventional plasticizer~ 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 ~acket which controls the migration of Le A ~ 708 - 8 -X~ 373~.

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 extent of 60~ to 90~ of a hydrophobic additive, such as calcium 6tearate or hydro-genated 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 par-ticular interest. The weight content of the core contain-ing 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 prefer-ably 40 - 90%, in particular 60 - 85% of the core weight.
The outer lacquer layer i8 preferably up to O.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 ~acket layer has a thickness of about 0.1 to 0.5 mm, in particular 0.2 to O.4 mm. The weight of this ~acket layer is about 25 -65%, in particular 30 - 55% of the pellet weight.
The content of hydroxypropylcellulo~e in the jacket is about 10 to 40%, in particular 15 to 30% of the total ~acket weight, and the content of the lipophilic constituent of the ~acket i~, in particular, 70 to 85% of the weight of the ~acket layer.
The core contain~ the dihydropyridine nct$ve compounds in a wei~ht ratio of 40 to 90~, in particulsr 50 to 85%, ba~ed on the core weight. The content of ~e A 26 708 - 9 -~q~ 73~;

intensive disintegrating agent is about 3 to 30%, in particu-lar 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 particu-larly 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-fluoro-phenylsulfonamido)-1.2.3.4-tetrahydro-9-carbazole-propanoic acid and 2-[4=[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-1,2-benzisothiazol-3-(2H)-one l,l-dioxide monohydrochloride.
The core preferably contains crosslinked sodium carboxymethylcellulose (cro.scarmellose sodium USP XXI N.F. 16 type A) as the intensive disintegrating agent, sodium laury~-sulphate as the wetting agent and polyvinylpyrrolidone as the binder. A preferred polyvinylpyrrolidone is PVP-25, a poly-vinylpyrrolidone having a molecular weight of about 25,000.
The jacket preferably contains hydroxypropyl-cellulose in the form of HPC-M or HPC-H, and calcium stearate as the lipophilic additive~.
The lacquer preer~bly cont~.ins poly(meth)acrylic acid esters of the types RS, RL and NE30D, in particular the polymers known by the tradenames Eudragit RS(R), Eudragit RL( ) and Eudragit NE30D( ), which are marketed by the company Roehm Tech. Inc., USA.

sy 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 mi-gration of the water to the core as a result of a certain mixture of hydrophobic and hydro-- lOa -2~ f~

philic constituents, without leading to bursting of the lacquer shell, with the active compound-containing core whi~h 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 combina-tion of different pellet groups. This is of importanceabove 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 a~ent 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 i8 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 part$cular 0.20, can be achieved by the pe~lets according to the invention even after a delay time of more than 6 hours.
Another characterlstic of the pellets according to the invention i8 that le88 than 5~ of the active Le A 26 70B

X~3 compound i~ released in up to 90~ of the lag time. Thi~
allows very precise ad~ustment of the retarded or pul~ing bur~ts of release.
Slower releases, that i8 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-pul~ed) releases can likewi~e 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 tLmes with only thin layers of the placebo content of the 6mall pellets can be achieved by the synergistic interaction of the lacquer layer and ~acket 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 ad;acent ~acket region. In the system according to the invention, the ~acket layer free from active compound provides a further control parameter for the delay time.
The lacyuer and ~acket layer allow effective control of the rate of migration of the water to the core. They ensure uniform penetration of the water front and there-fore very precise control of the lag times with steep releases. The expert is therefore for the fir~t time in a position to employ the known advantages of pellets having a particle diameter of le88 than 3 mm for Le A 26 708 - 12 -~ustained release formulations or for long-actinq formu-lations, ad~usted to suit the daily rhythm, with pulsed release.
Cu~tomary galenical measures can also be used without problems for the pellets according to the inven-tion. Thus, for example, the lacquer and/or ~acket layer can be stained with customary medicamen~ dy~stuffs for the purpose of light ~tabilization or for better distin-guishability, and salt~ which influence the osmosiæ er the pH or flavour improvers can be added.
The pellets according to the invention are prepared by customary method3. The core can be prepared in a continuous or discontinuous procedure by, for example, rolling granulation, mixing granulation, fluid-ized bed granulation or fluidized bed spraylng granula-tion 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 le~s than 100 ~m in order to achieve a high sphericity or surface quality.
The core i~ prepared, for example, by mixing the active compound, the intensive disintegrating agent, the wetting agen1: and the binder in a mixer, adding water and/or organic solvents, ~uch as lower aliphatic alcohols or acetone, as the granulating liquid, granulating for O.5 - 3 hours and then drying at 30 - 120C, preferably 40 - 100C. The resulting granules are then sieved.
The ~acket lnyer i8 likewi~e spplied to the cores by cu~tomary method~, for ex~mple hy spraying on from a Le A ?6_708 - 13 -3~73~

solution, melt or suspension. The proces~ 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 ~acket material can al50 be applied in S powder form with addition of granulating liquid, for example in a discontinuous or continuous manner in the apparatuses cu~tomary for rolling granulation.
The hydrogel-forming agent hydroxypropylcellulose (HPC-M or HPC-H) i6 preferably employed with a particle size of less than 100 ~m, in particular less than 65 ~m, in the preparation of the ~acket layer.
The lacquer i~ applied in the cu~tomary manner, for example by spraying on from an organic solution or from an aqueous ~uspension in lacquering kettles, rotat-ing drums or plates or in customary coaters. The lacqueris preferably applied from an aqueous dispersion at elevated temperatures at which film formation occurs, preferably at 30 - lOODC, in particular at 40 - 80C.
In the case of application of the lacquer from a solution, organic sol~ents from the group comprising lower aliphatic alcohols, such as ethanol,methanol and isopropanol, volatile ketones, ~uch as, for example, acetone, and halogenated hydrocarbons, ~uch as, for example, methylene chloride or chloroform, are preferably employed.
Cap~ules are filled with the mixed or non-mixed pellet groups using the customary fllling ~nd seallng machines. In addition to filling the eap~ule~ with pellets, it i8 al~o po~sible to lntroduce the pellets into a compre~sed tablet.

Le A 26 708 - 14 -2~ 736 A preferred process for the preparation of the pellets according to the invention comprises a procedure in which a) the core i8 prepared by mixing the active compound, S the disintegrating agent, the wetting agent and the binder, subsequently granulating the ~ixture for 0.5 to 3 hours with the addition of water snd/or organic 801vent8, such as lower aliphatic alcohol6 or acetone, as the granulating liquid and then drying the mixture at 30 to 120C and sieving the resulting granules, and b) the ~acket layer is applied by spraying from a ~olution, melt or su~pension of the hydroxypropyl-cellulose and the hydrophobic additive in a fluid-ized bed, on a granulating plate, in a mechanical mixer or in a rotor granulator, or the ~acket material is applied in powder form, with addition of granulating liquid, in a discontinuous or continuous manner in apparatu~es customary for rolling granulation, and c) the lacquer con~tituents are either sprayed on a6 a solution in organic solvents, ~uch as lower alipha-tic alcohols, volatile ketones or halogenated hydrocarbons, or applied from an aqueous ~uspension in lacguering kettles, rotating drums or plates or in customary coaters at temperatures between 30 and lOO-C and sre crosslinked by means of heat.
The relea~e of the pellets according to the invention iB determined ln accordance with the USP paddle Le A 26 7Q8 - 15 -3~ 73~:~

method. In each case capsules filled with pellets and containing 30 mg of active compound are employed. The test i6 carried out at 37~C in 4,000 ml of relea~e medium at 100 revolutions per minute. The relea e medium is brought to pH 6.8 with a buffer (D~B-9; diluted 1:10) and additionally contain~ 0.25~ of sodium lauryl6ulphate and O.68% of sodium chloride.
The administration form~ which can be prepared from the pellets according to the invention, ~uch a~
capsules or compre6sed tablets, can be prepared by customary methods, combin~tion6 with other active com-pounds 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 copre-cipitates or with non-lacquered cores.
The following embodiment examples illustrate the core-~acket-lacquer pellets (CJL pellets) according to the invention~
~mbodiment 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-2S and 20 g of sodium lauryl6ulphate in an inten-sive mixer. 200 ml of di~tilled water ~re then added and granulation i8 carried out for 3 hourE at room tempera-ture with a decreasing speed of rotation (3,000 -~ 400 revolution~ per minute). The resultin~ core~ ~re dried st 00C and sieved (diameter 1.25 - 1.5 mm).

Le A 26 708 - 16 -~g?~

Application of the ~acket 1,000 g of these cores are initially introduced into a rotor granulator and a ~ixture of 510 q of hydroxypropylcellulose ~ (corresponding to 30% of the ~acket content) and 1,190 g of hydrogenated castor oil (corre6ponding to 70% of the ~acket content) and water as the granulating liquid i8 added continuously and ~he cores are coated with a ~acket in a rotor granulator (250 revolutions per minute) at room temperature. (Dose rate of the powder 1,000 g/hour). The bed moi~ture content is regulated here at 25~ absolute moisture by metering the granulating liquid.
Lacquer application The ~acketed cores (2,700 g) are sprayed at 60 -70C in a rotor coater with a 10% strength aqueousdLspersion 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 time6 result, depending on the thickne~s 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 Le A 26 7p8 - 17 -Example 2 Core-~acXet-lacquer pellets of the following recipe are prepared analogously to Example 1:
Par~s bY weiaht:
Core (1 part) Nifedipine 73 %
Crosslinked ~odium carboxymethyl-cellulose 15 %
PVP 25 10 %
Sodium laurylsulphate 2 %

Jacket (1.7 parts) Hydroxypropylcellulose M 30 %
Calcium ~tearate 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 wei ht = 100% Delay time 1 0 % (no lacquer) 1.0 hour 2 10 % 2.0 hour6 3 28 % 4.0 hours 4 44 % 5.6 hours 64 % 7.0 hour~
6 109 % 12 hours The relen~e rates for the variou~ lacquer Le_A 26 70.8 - 18 -~t~ 7~t;

amounts can be seen from Figure 1.
Example 3 CJL pellets of the following recipe were prepared analogously to Example 1:
Parts by wei~ht Core (1 part) Nisoldipine 73 %
Crosslinked sodium carboxymethyl-cellulose 15 ~
0 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 Amount of lacquer applied Curve based on the core_wei~ht = 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 2S 5 63 % 5.5 hour~
6 107 ~ 10 hourQ

The release rates for the various lacquer Dmounts can be seen from Figure 2.

Le A ?6 ~Q~ 19 -3f-'3~;;~;~ti;

Example 4 CJL pellets of the following recipe were prepared analogously to Example 1:

Core (1 part) Nimodipine 73 %
Cro~slinked sodium carboxymethyl-cellulose 15 Sodium laurylsulphate 2 Jacket (1.3 parts) Hydroxypropylcellulose M 30 %
Calcium ~tearate 70 %

Lacquer (0.1 - 1.07 parts) Eudragit RS 50.6 ~
Magnesium steaxate 44,9 %
PEG 20,000 4.5 %

Amount of lacquer applied ased on the core weiqht = 100 % Delay time 0 % 0.7 hour 10 ~ 1.5 hours 29 ~ 3.4 houxs 48 % 5.1 hours 67 % 6.5 hours 107 % 10.3 hours Exam~l~_S
CJL pellets of the following rec~pe were prepared Le A 26 708 - 20 -;2~

analogously to Example 1:
Parts by weiaht Core (1 part) Nisoldipine 60 %
Sodium starch glycolate 23 %
PVP 25 15 %
Sodium laurylsulphate 2 4 Jacket (1.2 parts) Hydroxypropylcellulose H 20 %
Hydrogenated castor oil 80 %

Lacquer (0.1 - 1.2 parts) Eudragit NE30D 55 %
Magne~ium stearate 44 %
Glycerol triacetate 1 %

Example 6 CJL pellets of the following recipe were prepared analogously to Example 1:
Parts bY weiaht Core (1 part) 4-(2-benzyloxyphenyl)-1,4-dihydro-2.6-dimethylpyridine-(3-carboxylic acid 70 %
methyl ester)-(5-Carboxylic acid cyclo-propylamide) Sodium starch glycolate lB %
PVP 25 10 %
Sodium laurylsulphate 2 %

Jacket ~1 part) Hydroxypropylcellulose H 30 %
Calcium stearate 70 %

Lacauer (0.1 - 1.2 parts) Eudragit NE30D 50.6 %
Magnesium stearate 44.9 %
PEG 20.000 4.5 %
Le A 26 708 - 21 -

Claims

1. Pellets for use in medicaments having controlled release of an active compound, which pellets are characteri-zed in that they are built up from a) a core which contains an active compound of the general formula in which R represents nitro or the group in the ortho- or meta-position, R1 represents alkyl having 1 - 4 C atoms, which is optionally interrupted by an oxygen in the chain, and R2 represents alkoxy having 1 - 4 C atoms, or re-presents the radical or a compound from the group of 3-(4-fluorophenylsulfonamido)-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 which is a cross-linked sodium carboxymethylcellulose or a sodium starch glycolate (NF XVI), sodiumlaurylsulfate as a wetting agent and a polyvinylpyrrolidone as a binder, and b) a double layer which controls the release, con-sisting of b1) an outer undigestible water-permeable lacquer layer which comprises ethylcellulose or which consists essentially of acrylic resin based on a poly(meth)acrylic acid ester having a neutral character (NE type) or having a low content of quaternary ammonium group (R type), the NE
type consisting of copoly(meth)acrylic acid esters having the structural element wherein R3 represents H or CH3 and R4 represents CH3 or C2H5 and having an average molecular weight of about 800,000, and the R type having the structural element wherein R3 and R4 are as defined above and the molar ratio of quaternary ammonium groups to R4 is 1:20 to 1:40 and having an average molecular weight of about 150,000, and b2) an inner jacket which controls the migration of - 23a -the water in the direction of the core and comprises 10 to 40% of hydroxypropylcellulose of type M or H (HPC-M or HPC-H) and 60%
to 90% of a hydrophobic additive.

2. Pellets according to claim 1 wherein the wetting agent is sodium lauryl sulphate and the binder is PVP-25.

3. Pellets according to claim 1 wherein the outer lacquer layer b1 of the double layer contains one or more auxiliary components selected from magnesium stearate, calcium stearate, polyethylene glycol 20.000, dialkyl (1-4 C atoms) diphthalate, glycerol triacetate and citric acid esters.

4. Pellets according to claim 1 wherein the inner jacket b2 contains calcium stearate or hydrogenated castor oil as hydro-phobic additive.

5. Pellets according to any one of claims 1 to 4, wherein the core contains as the intensive disintegrating agent crosslinked sodium carboxymethylcellulose, the lacquer layer contains poly-methacrylic acid derivatives of types RS and NE30D and the jacket contains calcium stearate as the hydrophobic additive.

6. Pellets according to any of claims 1 to 4, wherein the pellets have a particle diameter of 0.8 to 3.5 mm.

7. Pellets according to claim 5, wherein the pellets have a particle diameter of 0.8 to 3.5 mm.

8. Pellets according to any one of claims 1 to 4 and 7, wherein the content of active compound in the core is 40 to 90%, based on the core weight.

9. Pellets according to any one of claims 1 to 4 and 7, wherein the lacquer layer has a thickness of up to 0.3 mm and its weight is up to 50% of the total weight of the pellets.

10. Pellets according to any one of claims 1 to 4 and 7, wherein the jacket layer has a thickness of about 0.1 to 0.5 mm.

11. Pellets according to any one of claims 1 to 4 and 7 wherein the jacket layer consists of about 15 to 30% of hydroxy-propylcellulose and about 70 to 85% of hydrophobic additive.

12. Pellets according to any one of claims 1 to 4 and 7 which contain an active compound selected from the group consisting of nifedipine, nimodipine, nisoldipine, methyl-4-(2-benzyloxy-phenyl)-5-cyclopropyl-carbamoyl-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate (in racemic form and/or the enantiomers), 3-(4-fluorophenylsulfonamido)-1.2.3.4-tetrahydro-9-carbazole-propanoic acid and 2-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-1.2-benz-isothiazol-3(2H)-one 1,1-dioxide monohydrochloride.

13. Pellets according to any one of claims 1 to 4 and 7 contained in capsules.

14. Pellets according to claim 12 contained in capsules.

15. Pellets according to any one of clalms 1 to 4 and 7 compressed into tablets.

16. Pellets according to claim 12 compressed into tablets.

17. A process for the preparation of pellets according to claim 1, characterized in that a) the core is prepared by mixing the active compound, the disintegrating agent, the wetting agent and the binder, subsequently granulating the mixture in a rotor granulator for 0.5 to 3 hours with the addition of water or an organic solvent as granulating liquid and then drying the mixture at 30 to 120°C and sieving the resulting granules, and b) the jacket is applied in powder form, with addition of granulating liquid, in a discontinuous or continuous manner in a rolling granulator, and c) the lacquer constituents are either sprayed on as a solution in an organic solvent, or applied from an aqueous suspension in lacquering kettles, rotating drums or plates or in coaters at a temperature between 30 and 100°C and are crosslinked by means of heat.

18. A process according to claim 17 wherein the granulat-ing liquid in step (a) is water, a lower aliphatic alcohol or acetone or a mixture thereof.

19. A process according to claim 18 wherein in step (c) the lacquer constituents are sprayed on as a solution in an organic solvent which is a lower aliphatic alcohol, volatile ketone or halogenated hydrocarbon.