CA1333996C

CA1333996C - Dhp delayed release preparation

Info

Publication number: CA1333996C
Application number: CA000597992A
Authority: CA
Inventors: Andreas Ohm; Helmut Luchtenberg; Manfred Bucheler; Roland Rupp; Heinrich Feltkamp
Original assignee: Bayer AG
Current assignee: Bayer AG
Priority date: 1988-04-29
Filing date: 1989-04-27
Publication date: 1995-01-17
Anticipated expiration: 2012-01-17
Also published as: ATE72972T1; ES2035979T3; US4966772A; EP0339420B1; EP0339420A2; EP0339420A3; JPH01313427A; DE3814532A1; DE58900891D1

Abstract

A solid medicament preparation having long-lasting action containing a sparingly soluble dihydropyridine active compound of the formula (I)

Description

1 33~99~

The invention relates to solid medicament prepa-rations consisting of a core and a coat appLied thereto and having a long-lasting action for dihydropyri-dines, and processes for their preparation.
Active compounds from the dihydropyridine class of substances and their use as circulatory agents have already been disclosed (compare Brit. Pat. 1,173,862, Brit. Pat.
1,358,951, US Pat. 4,256,749, German Offenlegungsschrift 3,311,003 and US Pat. 4,264,611). In the galenical prepa-ration of these potent active compounds, difficulties fre-quently occur since the substances only have a very lo~
solubility, are frequently light-sensitive and their ab-sorbability in biological systems frequently leads to pro-blems.
Numerous experiments have been undertaken to pro-duce optimum galenical preparations which improve the bio-availability of these potent active compounds. Thus, for example, some active compounds have been dissolved in spe-cific organic solvent systems and filled into gelatin cap-sules in order to ensure a rapid and effective onset of action (compare Brit. Pat. 1,362,627). The conversion of dihydropyridines such as nifedipine into co-precipitates or "solid solutions" using ~ater-soluble polymers in order to improve the bioavailability has also been investi-gated (compare Brit. Pat. 1,579,818). However, using thesegalenical preparations, no reduction in intake to once to a maximum of t~ice daily can be achieved ~ith the dihydro-pyridines mentioned, inter alia.
For the treatment of diseases ~hich have to be treated over relatively long periods of time, such as, for example, hypertonia and angina pectoris, it is desirable to keep the frequency of intake of medicaments as lo~ as pos-sible. This is not only more agreeable to the patient, but it also increases the safety of treatment, in that it Le A 25 848 reduces the disadvantages of irregular intake and stabi-lizes the active compound concentration present in the body. In this way, the risk of undesired over- or under-dosage is minimized at the same time (peak blood levels of the active compound occur rapidly after intake from re-leasing administration forms or, with a higher admini-stration frequency, on irregular or forgotten intake).
Of particular advantage are administration forms which release the active compound corresponding to the needs of the patient.
Thus, for example, a diurnal rhythm is described for the course of the blood pressure (Lemmer, ~. in:
Chronopharmakologie, Tagesrhythmen und Arzneimittelwirkung (Chronopharmacology, diurnal rhythms and medicament action), ~iss. Verl. GmbH, Stuttgart 1984): during the night both normo- and hypertonic values (systolic and diastolic) fall to a minimum (towards 04.00 hours), to climb steeply again after that in the early hours of the morning (also during the sleep) (blood pressure maximum towards 10.00 hours).
A blood pressure medicament suited to the diurnal rhythm accordingly should have the advantage compared to con-ventional delayed release systems of only supplying the patient with active compound when active compound is required. In particular, the steep rise in blood pressure in the early hours of the morning can be safely checked by the release of disproportionately high amounts of active compound in spite of the sleep of the patient, without supplying the body in the times with a falling off of blood pressure with active compound which is not then required (example: evening (nightly) intake, placebo phase during the falling off of blood pressure, beginning of release of active compound in the early hours of the morning).
The like also applies to angina pectoris: in patients with stable angina pectoris or with Prinzmetal angina pectoris time-dependent differences in the ECG and Le A 25 848 in the frequency of onset can be detected under corporeal loading. Epidemiological studies have shown that the fre-quency distribution of cardiac infarct attacks is subject to a diurnal rhythm. Cardiac morbidity thus exhibits a maximum in the early hours of the morning.
80th for the doctor and for the patient, a require-ment exists, for example for the long-term therapy of car-diac circulation disorders, to get the highly active di-hydropyridines into an available form in uhich a once daily administration suffices for disease treatment.
Medicament preparations having relatively retarded release of active compound ~delayed release forms) have already been described for dihydropyridines. Thus the production of a slow-release preparation has been investigated, for example, by means of a specific particle size distribution of the crystalline active compound or by means of a selec-ted specific surface area of the active compound crystals (compare German Offenlegungsschrift 3,033,919). Further-more, specific tablet preparations have been proposed ~hich, according to the principle of the osmotic pump, release the active compound from the interior of the tab-let, which is surrounded with a semipermeable lacquer layer, over a relatively long period of time through a previously defined opening and thus attain a delayed release effect (compare US-PS 3,916,899).
The previously known preparation forms having rela-tively delayed release of active compound, in particular those for dihydropyridines, exhibit a series of disadvan-tages. Their delayed release action is only limited to a fe~ hours, so that the patient as a rule, as previously, has to administer t~ice or more times daily; after several hours the rate of release of the active compound slackens considerably so that even the blood level can fall beneath the necessary limit of effectiveness.
In the abovementioned osmotic system, local irri-tations of the tissue can occur in the stomach or Le A 25 848 intestinal tract, depending on the capsule filling employed, o~ing to an excessive concentration of active compound.
Due to the nature of the osmotic system, a part of the active compound can remain in the medicament form S and thus not be available for the desired absorption.
Moreover, the production of this medicament form is very complex since in this case organic solvents have to be em-ployed in the production process and the lacquer layer of each tablet has to be bored through with the aid of a laser beam.
In all previously described delayed release medica-ment forms, an adjustment of the release of active com-pound to diurnally rhythmic biological events (for example blood pressure) and pathological events (pathological ECG
changes, angina pectoris attacks) is not possible (on single dosing). Lacquering with a gastric juice-resistant coating which causes a part or the whole dose to be re-leased from the medicament form after leaving the stomach (discontinuously releasing delayed release form) is already Z0 unreliable for reasons of the pH dependence of the liber-ation of active compound, since the dwell times in the stomach vary enormously from patient to patient and, more-over, depend on the absorption of nutrient (dwell times in the stomach about 0.2-12 hours) . With such a medicamen~
25 form, the release of a part ot tne medicament substance can be delayed temporarily; however, the reproducibility of this lag time is not given by the abovementioned reasons so that, for example, a safer adaptation to diurnal rhythm-dependent biological processes cannot thus be achieved.
It has now been found that solid medicament prepa-rationS consisting of a core and a coat applied thereto having a long-lasting action, and ~hich contain a sparingly soluble dihydropyridine active compound, in particular of the general formula I

Le A 25 848 ¢~R 1 R300C~2 I, R4 ~ R5 in ~hich R1 stands for one or t~o identical or different substituents from the group comprising nitro, halogen, trifluoromethyl or OCHFz or in which ~ stands for ~ ~ or for ~

R2 stands for a nitro group or for the radical COOR6, where R6 denotes alkyl having 1 to 10 C atoms ~hich is optionally substituted by alkoxy having 1 to 4 carbon atoms or by one or more halogens 15 or where R2 together with R5 stands for the lactone group -CO-O-CH2-, R3 stands for alkyl having 1 to 10 C atoms, ~hich is optionally substituted by alkoxy having 1 to 4 C atoms or by one or more fluorines and R4 and R5 are identical or different and in each case stand for alkyl having 1 to 4 C atoms, which is optionally substituted by hydroxyl, ~here the core-coat administration form Le A 25 848 `_ 1 333996 a) comprises a core ~hich contains at least one of the abovementioned dihydropyridines in slo~-release form and b~ comprises a coat situated around the core which contains no active compound and ~hich only dissolves slo~ly, and c) if desired, additionally containing on the coat, a rapid-release initial dose of the active compound with a diameter of the form being bet-ween 0.5 and 15 mm show surprisinq effectiveness.
Those preparations may be mentioned as preferred ~hich contain 10 X to 100 %, preferably 50 X to 100 Z, of the total dihydropyridine active compound of the adminis-tration form in the core.
Depending on the type of active compound, the pre-parations according to the invention preferably contain intotal 1 to 200 mg, in particular 10 to 150 mg, of at least one active compound from the dihydropyridine class.
The slo~-release core of the preparation prefer-ably contains the active compound in finely ground or micronized crystalline form.
Cores having slo~ release are preferably taken to mean those cores ~hich contain the active compound in delayed release form and release it to less than 75 % in a time of one hour / test conditions correspond to the specification for solid formulations of the active compound, for example for nifedipine, nitrendipine, nimodipine and nisoldipine:
according to one of the conditions mentioned belo~:
Condition A: USP paddle, 4 l of synthetic gastric juice without pepsin plus 0.1 % T~een 80, 100 rpm, 37C, Condition B- USP paddle, 0.9 l of 0.1 N hydrochloric acid plus 0.25 % of Texapon K12, 100 rpm, 37C, Condition C: USP paddle, 0.9 l of methanol/~ater (40:60), 50 rpm, 37C.
The retardation of the release of the core can be carried out by the customary methods (for example nifedi-Le A 25 848 o~ na~^~

2318g-6922 plne accordlng to Canadlan Patent No. 1,180,277, or other methods correspondlng to the prlor art.
The coat contalns no actlve compound. Mlxed wlth pharmaceutlcally customary auxlllarles such as, for example, lactose, starch, cellulose and cltrlc acld, lnter alla and magnesium stearate as a lubrlcant, the coat materlal forms a hydrophlllc gel-formlng polymer. Thls hydrophlllc polymer con-trols the dlssolutlon rate and eroslon of the coat. Control factors for the dlssolutlon~eroslon rate of the coatlng materlal are, lnter alla, the layer thlckness of the coat and the ratio polymer(s)/resldual auxlllarles.
Sultable hydrophlllc gel-formlng polymers are, for example, modlfled starch and/or cellulose-llke substances such as methylcellulose, hydroxypropylmethylcellulose, hydroxypropyl-cellulose and sodlum carboxymethylcellulose.
The eroslon and dlssolutlon rate of the coat can also be controlled vla the dlfferent degrees of vlscoslty of the polymer, ln whlch case the rate ls lncreased lf low vlscoslty qualltles are employed and ls slower wlth the employment of hlgh vlscoslty types. Customarlly, the concentratlon of the polymer ln the coat-lng materlal ls 5 - 100 ~, preferably 25 - 90 %. The concentra-tlon employed ls dependent on the degree of vlscoslty of the polymer(s~ and on the solublllty~hydrophlllclty of the auxlllarles employed and the amount thereof.
Customary known galenlcal measures such as, for example, lacquerlng the core wlth a gastrlc ~ulce-reslstant layer or other lacquers, the use of flavorinq and aroma substances and lubrlcants and customary auxlllarles, whlch are famlllar to the galenlcal expert, can, of course, also be employed and used ln the prepara-tlon accordlng to the lnventlon.
Sultable solld admlnlstratlon forms for the core-coat prlnclple accordlng to the lnventlon are, for example, pellets and press-coated tablets. The slze of the 7a preparation may vary from O.S - 15 mm. 1 333996 A particular advantage in the use of pellets lies in the division of the total dose of active compound into a number of subunits ~so-called multiple dose) ~hich per-mits pellets ~ith different thicknesses or with differently-omposed coatings to be combined in such a ~ay that nearly any desired release profile of the administration form containing the total dose (for example capsule) can be set, for example a linear release of active compound or a continuous increase in the rates of release of active compound or a release of the active compound in pulses. The initial dose can be introduced here, for example, by non-coated active compound cores.
In the case of press-coated tablets, the initial dose can be applied to the pLacebo coat so that a discontinu-ous, pulsed release is achieved here.
The lag time set until the release of active com-pound in the core by eroding away of the coating material causes the desired delayed release effect. The lag time due to eroding a~ay/dissolving of the coating is in this case not decisively influenced by pH.
It may be explicitly indicated therefrom that the delayed release preparation according to the invention differs from the previously known core-coat preparations in that the coating contains no active compound.
The cores of the inventive formulations can be produced by known methods, e.g. by mixing Nifedipine crystals with a specific surface of 1-4 m2/g with suitable carriers as described in EP-B 47 899).
From the prior art, multilayer tablets based on casein matrices have already been described ~hich contain t~o or three layers ~hich can in each case, in turn, con-tain active compounds (compare US Pat. 3,184,386). The tablets described there contain active compound in the outer coating in contrast to the present invention.
Coated tablets are also described in US Pat.
3,558,768 ~hich contain active compounds in slo~-release form both in the core and in the coating.
Coated tablets ~hich contain no active compound in the coating material are also described in Il Farmaco, Le A 25 848 No 3, March 84, 67 f (Conte et al.). However, the release kinetics of these tablets differ considerably from the core-coat principle according to the invention des-cribed here: after a lag time, the active compound is con-tinuously released over a long time by zero order kinetics.
The coat material serves here as a diffusion barrier but not for setting a discontinuously occurring release of the active compound. In contrast to the core-coating principle according to the present invention, the "reser-voir coated tablet" can only be employed in active com-pounds having a certain minimum water solubility.
Salomon et al. (Pharm. Ind. 41, No. 8, p. 799 f.
1979) also describe coated tablets which contain no act-ive compound in the coat material. These are also "reservoir coated tablets". In principle, that stated above applies.
The diffusion principle described in the preYiously mentioned examples is not suitable for sparingly soluble dihydropyridines. A delayed release method based on a dif-fusion principle leads in the case of the sparingly solubledihydropyridines to extremely slow release of the active compound and to comparatively low levels of drug resulting therefrom.
A further administration form which specifically 25 favorably influences the saturatable first pass effect of psoralens is described in DE 3,115,033 A 1. However, the coat material in this case contains active compound.
Moreover, the delay until the release of active compound from the core of the coated tablets or pellets is not achieved by the application of high contents of hydrophilic, gel-forming polymers in the coat, but by a lacquering of the core/pellet (a thin lacquer f1~mJ.
In German Offenlegungsschrift 2,651,t76, pellets having a controlled release of active compound are des-cribed. The formulations described there already differfrom the coated preparations according to the invention in Le A 25 848 that they also contain active compound in the coat.
Moreover, the formulations described there can only be ob-tained by complex me~hods by continuously applying many layers, whereas the press-coated tablets according to the inven-tion are produced by simple pressing and in the case of thecoated pellets, only one layer is continuously applied to the slow-release cores.
By means of the principle of the preparation accor-ding to the invention, the customary disadvantages of nor-mal delayed release tablets or pellets and also of pre-viously known multilayer or press-coated tablets and pellets or of preparation forms which are based on the osmotic prin-ciple are avoided.
In particular, an adaptation of the release of act-ive compound to diurnal rhythm-dependent biological pro-cesses, such as, for example, the blood pressure, can be carried out by means of the coated administration form according to the invention, without having to administer the form at uncustomary times of day. As a further advan-tage of this form, it may be mentioned that in active com-pounds which show increased bioavailability on absorption in low sections of the gastrointestinal tract in comparison to absorption in the stomach, this administration form leads to improved bioavailability of the active compound administered. The discontinuous release of this delayed release form caused by the erosion of the coat, which, moreover, takes place independently of pH, must be empha-slzed. In this way, the release of the sparingly soluble dihydropyridines according to the invention can also be delayed in a suitable manner.
In the case of the coated pellets (medicament form, for example, capsule), the setting of any release kinetics of the active compound (by combination of different coated pellets) may be mentioned as a further additional advantage.
In this way, such a delayed release preparation can corres-pond to the requirements of a previously given active Le A 25 848 compound as if "made to measure".
In regard to the long-existing need with respect to medicament preparat;on forms having long-lasting action, it is more than surprising that previously nobody has described or produced the simple to prepare and very effective coated medicament form having a slo~-release core according to the invention. By means of the present invention, the patient can be placed in the position of only having to administer the medicament once daily which, in particular with long-term therapy, represents a safer and more acceptable type of treatment.
The curve of Fig. 1 shows the principle of the discontinuous release of active compound for Example 1.
Examples Example 1 Core: nifedipine S-50 ~m 20.0 9 Avicel~ 34.8 9 maize starch 12.0 9 lactose 10.0 9 are mixed and granulated ~ith maize starch 2 9 T~een 80 1 9 in 30 ml of ~ater after drying magnesium stearate 0.2 9 is admixed.
The mixture is pressed in a tablet press to give cores having a weight of 80 mg, size 6 mm diameter.
Coating:
hydroxypropyl-cellulose type L 31.0 9 hydroxypropyl-cellulose type M 106.0 9 lactose, fine 111.5 9 are granulated using 150 ml of water, and the mixture is subsequently dried. Admixing with Le A 25 848 ~r~e,n~,f~

magnesium stearate 1.5 9 The mixture is presse~ in a press-coater tablet press to give press-coated tablets of size 9 mm diameter (total tablet weight 330 mg).
Example 2 As Example 1, but a rapidly releasing initial dose of 10 mg of nifedipine in a mixture of auxiliaries custo-marily used for film lacquering (hydroxypropylmethylcellulose HPMC, PEG 4000) is applied to the press-coated tablet. A further film lacquer which has a light protection function (HPMC, PEG, iron oxide, red) is subsequently applied.
Example 3 As Example 2, but containing nisoldipine instead of nifedipine.
15 Example 4 As Example 1, but containing nitrendipine instead of nifedipine.
Example 5 As Example 4 but containing a 3-fold amount of 20 nimodipine instead of nifedipine. Additionally, the ini-tial dose of 30 mg of nimodipine is pressed into the form of a solid solution (co-precipitate) (2 layer coated tab-let, not lacquered). An additional light protection layer ls unnecessary.
25 Example 6 a) b) c) Core: nimodipine, microfine 78 9 90 9 88 9 hydroxypropylcellulose type L 15 9 lactose 5 9 polyvinylpyrrolidone 25 - 5 9 5 9 sodium lauryl sulphate 2 9 2 9 2 9 Na254 _ _ 5 powdered sugar - 3 9 35 are mixed and converted by pelletizing with water as a granulating liquid into spherical particles in the diameter Le A 25 848 range between 0.5-1.5 mm.
Coat Nimodipine cores and coating powder are simultane-ously mixed and metered into a continuously working rotor granulator, and water is sprayed in as a granuLating liquid. The coating powder mixture is composed as follows:
Example 6a rice starch 20 %
castor oil, hydrogenated 50 %
10 hydroxypropylcellulose type M 30 X
Example 6b corn starch pregelatinized 30 Z
15 hydroxypropylceLlulose type M 40 %
hydrogenated castor oil 33 %
Example 6c hydrogenated castor oil 70 %
hydroxypropylcellulose type M 30 %
The coating powder mixture from Examples 6a to 6c is applied to the cores in the following amounts:
Example 6a - 250 % of the core weight Example 6b - 300 % of the core ~eight Example 6c - 150 ~ of the core weight.
It will be appreciated that the instant specification and claims are set forth by way of illustration and not limitation, and that various modifications and changes may be made without departing from the spirit and scope of the present invention.

Le A 25 848

Claims

1. A solid medicament composition having long-lasting action containing a sparingly soluble dihydropyridine active compound of the general formula (I) in which (I) R1 stands for one or two identical or different substituents selected from nitro, halogen, trifluoromethyl and OCHF2 or in which stands for or for R2 stands for a nitro group or for the radical COOR6, where R6 denotes alkyl having 1 to 10 C atoms which is optionally substituted by alkoxy having 1 to 4 C atoms or by one or more halogens or where R2 together with R5 stands for the lactone group -CO-O-CH2-, R3 stands for alkyl having 1 to 10 C atoms, which is optionally substituted by alkoxy having 1 to 4 C atoms or by one or more fluorine atoms and R4 and R5 are identical or different and in each case stand for alkyl having 1 to 4 C atoms, which is optionally substituted by hydroxyl, wherein the composition is in the form of a coated core construction in which the core contains at least one of the above-mentioned dihydropyridines in slow-release form and in which the coating situated around the core contains no active compound and only dissolves slowly.

2. A composition according to claim 1, wherein the core contains 10-100 % of the total dihydropyridine active compound.

3. A composition according to claim 1, wherein the core contains 50-100 % of the total dihydropyridine active compound.

4. A composition according to claim 1, comprising 1-200 mg of dihydropyridine active compound in total.

5. A composition according to claim 1, wherein the slow-release core contains the active compound in delayed release form.

6. A composition according to claim 1, wherein the active compound-free coat contains a hydrophilic, gel-forming polymer.

7. A composition according to claim 1, wherein the active compound-free coat comprises modified starch, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose or sodium carboxymethylcellulose as a hydrophilic gel-forming polymer.

8. A composition according to claim 1, further comprising a rapid-release initial dose of said active compound as an additional coating around said coated core.

9. A composition according to claim 1, wherein said dihydropyridine active compound is nifedipine, nitrendipine, nimodipine or nisoldipine.

10. A composition according to claim 7, wherein said dihydropyridine active compound is nifedipine, nitrendipine, nimodipine or nisoldipine.

11. A composition according to claim 1, wherein at least 50 % of the total dihydropyrine active compound is in slow-release form.

12. A composition according to claim 10, wherein at least 50 % of the total dihydropyrine active compound is in slow-release form.

13. A composition according to claim 10, wherein the composition is a tablet containing a total of 1 to 200 mg of said dihydropyridine active compound.

14. A composition according to claim 12, wherein the composition is a tablet containing a total of 1 to 200 mg of said dihydropyridine active compound.

15. A use of a composition according to any one of claims 1 to 14 in the treatment of a cardiac circulation or heart disorder.

16. A commercial package comprising a composition according to any one of claims 1 to 14 as active ingredient, together with instructions for the use thereof in the treatment of a cardiac circulation or heart disorder.