Note: Descriptions are shown in the official language in which they were submitted.
2 9 ~
Case 100-6717
Pharmaceutical formulations with controlled release of the active
substance
This invention relates to pharmaceutical formulations with controlled
release of active substances having an influence on blood circulation,
including the heart and chosen from the group of Pindolol and a
4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine
dicarboxylate ester, especially Darodipine and Isradipine.
Darodipine is the generic name of diethyl-4-(2,1,3-benzoxadiazol-
4-yl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate.
10 ' It is disclosed in the British Patent GB 2.037766 B. For pharmaceutical
use Darodipine is used as the free base.
The pharmacological and clinical properties have been extensively
reviewed. Darodipine is a potent calcium antagonist on isolated
coronary arteries and other peripheral blood vessels. Haemodynamic
studies in healthy subjects show a reduction in total peripheral
resistance and arterial blood pressure.
Darodipine is indicated for the treatment of angina pectoris, of
hypertension, of stroke and of cerebral vasospasms.
Usual oral daily dosages are e.g. for the treatment of angina pectoris
75 to 300 mg, preferably given in 3 divided doses and for the treatment
of hypertension 37.5 to 150 mg, given in 2 to 3 divided doses.
"~
,
1298784
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Pindolol is the generic name of l-(lH-Indol-4-yloxy)-3-[(1-methyl
ethyl)amino]-2-propanol and is described in the British Fatent
No 1.138.969.
For pharmaceutical use Pindolol is preferably used in the form of
the free base. The pharmacological and clinical properties have
been extensively reviewed.
Pindolol is a ~-adrenoceptor antagonist (~-blocker). It acts on
both ~1- and ~2-adrenoceptors. It protects the heart against excessive
stimulation by catecholamines during physical and mental stress and
also at rest; its intrinsic sympathomimetic activity (ISA), however,
provides the heart with basal stimulation similar to that elicited
by normal resting sympathetic activity. Heart rate and contractility
at rest and intracardiac conduction are thus not unduly depressed.
As a consequence, the risk of bradycardia or of heart block is small
and a non-elevated cardiac output is not reduced. The high vascular
resistance of established hypertension is lowered by Pindolol and
thus tissue and organ perfusion is not impaired.
Pindolol is indicated for the treatment of, inter alia
- Arterial hypertension,
- Angina pectoris (prevention of attacks).
- Sinus and atrial tachycardia, paroxysmal tachycardia,
tachycardia in patients with atrial flutter or fibrillation.
supraventricular and ventricular extrasystoles, drug-induced
extrasystoles (digitalis) and
- Hyperkinetic heart syndrome
and is normally administered orally.
lZ98784
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The oral dosage is adapted to the requirements of the individual
patient and is usually within the range of 10-30 mg per day.
For arterial hypertension, S to 15 mg are given as a single daily
dose in the morning. Alternatively 20-30 mg are divided into 2 or 3
doses per day.
For angina pectoris and cardiac arrhythmias, the daily dosage of
10-30 mg is generally divided into 2 or 3 single doses.
For hyperkinetic heart syndrome, the dosage is 10-20 mg, usually
once a day, preferably in retard form.
Isradipine is the generic name of isopropyl methyl-4-(2,1,3-benzoxa-
diazol-4-yl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylate.
It is generally administered as the free base.
It is disclosed in the British Patent GB 2.037.766 B.
The pharmacological and clinical properties of Isradipine have been
extensively investigated. It is a potent calcium antagonist and
influences in particular the coronary and the peripheral arteries.
The drug is especially indicated for the treatment of e.g. hyper-
tension, angina pectoris and cerebral insufficiency.
Usual oral daily dosages are 10 to 20 mg, preferably divided into
smaller dosages of 5 to 10 mg two times a day.
The administration of the active substances mentioned above can
occasionally be associated with adverse side effects, e.g. head-
aches in case of Darodipine, tiredness, dizziness, gastrointestinal
disturbances (mainly nausea), headache, sleep disturbances (e.g.
vivid dreams), when Pindolol and headache, flush, palpitation and
lZ9878~
- 4 - Case 100-6717
tachycardia, when Isradipine is administered.
We have now found it is preferred to keep the concentration of the
active substance at a therapeutically active level between narrow
limits and to avoid the usual drug burst just after administration
of non-controlled release preparations, which leads to temporary high
b100d levels and to proportionately strong adverse effects.
Therapy can be improved by administering two or three times a day
smaller doses, the sum of which equals the total daily dosage.
However, this manner is cumbersome and still does not meet the
requirement of providing blood levels of active substance only
between narrow limits.
The present invention provides a controlled release formulation of
the active substances having a prolonged action of the active
substance to reduce the number of times the active substance has to
be administered each day and to reduce certain adverse reactions.
Additionally the present formulations provide under the test
conditions excellent bioavailability in food interaction studies,
e.g. as described in Examples 3 and 18 hereinafter.
The present invention accordingly provides a controlled release
formulation for oral administration comprising an active substance
chosen from the
- group of Pindolol and a 4-~2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-
2,6 -dimethyl-3,5-pyridine dicarboxylate ester
- a pharmaceutically acceptable hydrophilic swellable substance and
optionally
- a pharmaceutically acceptable inert fatty material.
1298784
- 5 - Case 100-6717
In other aspect the present invention provides a controlled release
formulation for oral administration and
containing Pindolol, and having a relative bioavailability of more
than 85% compared with a non controlled release oral Pindolol
formulation on administration to a subject in the fasted state.
In a further aspect the present invention provides a controlled re-
lease formulation for oral administration and
containing Isradipine, and having a relative bioavailability of more
than 65% compared with a non controlled release oral Isradipine
formulation on administration to a subject in the fasted state.
In an additional aspect the present invention provides a controlled
release formulation for oral administration comprising an active
substance chosen from the group of Pindolol and a 4-(2,1,3-benzoxa-
diazol-4-yl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylate
ester), having bioavailability differences on administration to a
subject in the fasted state and to a subject in the unfasted state
of at most 20%.
~25~84
- 6 - Case 100-6717
Preferred amounts of Darodipine in unit dosage form are from 10
to 200 mg, especially 20 to 150, e.g. 100 mg.
Preferred amounts of Pindolol in unit dosage form are from 10 to
20 mg, especially 15 and 20 mg. Preferably Pindolol is in the base
form, but an acid addition salt form is possible as well.
Preferred amDunts of Isradipine in unit dosage form are from 5 to
40 mg, especially 10 to 20 mg.
Preferred swellable substance is a cellulose compound, which in water
turns into a colloid.
~ Hydrophilic swellable substances that are preferred include one
or more natural, partially or totally synthetic, anionic or,
preferably, nonionic hydrophilic gums, modified cellulose
substances or protein aceous substances such as, for example,
acacia, gum tragacanth, locust bean gum, guar gum, karaya gum,
agar, peptin, carrageen, soluble and insoluble alginates, methyl-
cellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose,
hydroxyethylcellulose, sodiumcarboxymethylcellulose, carboxypoly-
methylene, gelatin.
Preferred are cellulose hydrocolloids which include methylcellulose,
hydroxypropylcellulose and especially hydroxypropylmethylcellulose
and sodium carboxymethylcellulose.
Preferably the weight ratio of Darodipine to swellable substance
is from 1:0.2 to 1:2, especially from 1:0.5 to 1, of Pindolol to
swellable substance from 1:5 to 1:20 especially from 1:8 to 1:15
and of Isradipine to swellable substance from 1:2 to 1:20,
especially from 1:4 to 1:10.
1298784
- 7 - Case 100-6717
Suitable pharmaceutically acceptable inert fatty materials include
beeswax; fatty acidsi long chain fatty alcohols, such as, for
example, cetyl alcohol, myristyl alcohol, stearyl alcohol, esters,
e.g. glycerides such as glyceryl esters of fatty acids or hydrogenated
aliphatic acids such as, for example, glyceryl mono-stearate,
glyceryl distearate, glyceryl esters of hydrogenated castor oil and
the like; oils such as mineral oil and the like. Fatty materials
are preferably such with melting points between 30 and 90C.
Most preferably fatty materials have a melting point from 45C to 65C
and include glycerides such as glyceryl palmitates and stearates and
fatty acids such as hydrogenated castor oil and fatty acid esters
such as cetyl palmitate.
Preferably the weight ratio of Darodipine to the fatty material is
from 10:10.2 to 10:5, especially 10:0.5 to 10:1; of Pindolol to the
fatty material from 1:0.1 to 1:3, particularly 1:0.1 to 1:2,
especially 1:0.25 to 1:1.4and of Isradipine to the fatty material
from 1:0.3 to 1:2, especially 1:0.5 to 1:1.5, in particular 1:0.5 to
1:1.
The formulations contain preferably both hydroxypropyl-methyl-
cellulose as a swellable agent and cetyl palmitate as a fatty
material.
It is also convenient to incorporate in the formulation at least one
of other soluble or insoluble pharmaceutical excipients such as
calcium sulfate, calcium phosphate, lactose, mannitol, sucrose,
sorbitol, colloidal silica, and magnesium stearate. Preferably a
soluble excipient, especially lactose is present.
If these other excipients are present, then the weight ratio of
Darodipine to the other excipients is conveniently fram 10:1 to
'
.
, , ,
1298784
- 8 - Case 100-6717
1:2, especially 5:1 to 1:1; of Pindolol to the other excipients
from 1:0.2 to 1:10 especially 1:0.3 to 1:5 and of Isradipine to the
other excipients from 1:4 to 1:15, especially 1:5 to 1:10.
The formulation may be produced in conventional manner by mixing
the ingredients together, preferably melting the fatty material.
The resultant mixture is in powder form. The powder can be pressed
to form a tablet, but is preferably filled into a capsule.
If the fatty material is melted, the drug and additional excipients
such as lactose, silica, calcium sulphate or calcium phosphate may
be taken up in the molten fatty material. The mixture is the~
allowed to solidify and is then divided into small particles
(granules).
The resultant granulate may be mixed with a, preferably porous,
hydrophilic swellable substance and further excipients, e.g.
magnesium stearate, and the mixture may be pressed to form a tablet
or may be preferably filled into a capsule.
In a preferred aspect the present invention accordingly provides a
formulation containing the active substance in a fatty material
matrix granulate, the granulate particles being in contact with a
2 0 hydrophilic swelling substance.
Preferably the swellable substance is present in a porous form.
We have surprisingly found that the formulations possess an
excellent stability, despite the fact that the active substances
are sensitive to many chemical reagents. Moreover, the formulations
have a satisfactory pharmacodynamic and pharmacokinetic profile.
lZ98784
- 9 - Case lO0-67l7
The resultant formulations in general have comparable bio-
availability in standard clinical trials to conventional non-
retarded formulations containing the same amounts of active
substances. The formulations of the invention, even if administered
once a day, may produce a therapeutic effect for at least 24 hours
and even as much as 35 hours. The formulation for Darodipine and
Isradipine may be administeredonly once a day in the known indications
of the active substances at approximately the same daily doses as
employed in the conventional non-retarded forms. Steady state studies
show a narrow range between maximum and minimum active substance
levels in the blood.
The formulation for Pindolol may be administered twice a day.
The formulations of the present invention are well tolerated.
Moreover, the present formulations provide similar profiles of
activity in food interaction studies, e.g. before and after
administration of breakfast, with fasted subjects.
The once-a-day formulations may be formulated in conventional
manner, e.g. to be a capsule or tablet and may contain from lO to
200 mg of active substance. Preferably they have the release profile
as determined by in vivo or in vitro dissolution test, e.g. a release
of about 34 percent of Darodipin, 50 to 75 percent of Pindolol and 50
to 65 percent of Isradipin over 6 hours in O.l NHCl, e.g. as in the
experimental conditions in Examples l, 2 to 5, 16 and 17.
In the following examples all temperatures are in degrees Centigrade
and are uncorrected.
Further information on the properties etc. of the pharmaceutical
excipients named hereinafter may be obtained from the manufacturer,
listed hereinafter, manufacturer's brochures or other sources,
~25~ 4
- 10 - Case 100-6717
especially H.P. Fiedler Lexikon der Hilfsstoffe fur Pharmazie,
Kosmetik und angrenzende Gebiete, 2nd Edition 1981, Edito Cantor,
Aulendorf, W-Germany.
Silicon dioxide (silica) is e.g. brand Aerosil 200 available from
Deutsche-Gold und Silberscheideanstalt, Frankfurt, W-Germany.
Glycerol ditripalmitostearat is e.g. brand Precirol Ato 5@'available
from ETS Gattefosse 929100 Boulogne-Brillancourt, France.
Hydroxypropylmethylcellulose 15000 cps and 4000 cps are e.g. brands
Methocel KlSM and Methocel 4EM available from Dow Chemical Company,
0 Michigan 48640 USA.
Cetyl palmitate is e.g. brand Cutina~'CPA available from Henkel 4000,
Dusseldorf, W-Germany, or is available from Gattefosse or from A/S
Johan C. Martens and Company, Bergen, Norway.
3700/KD/AB
12g~7~4
- 11 - Case 100-6717
Example 1:
Ingredient mg
a) Darodipine 100
b) Lactose (200 mesh) 30
c) Cetyl palmitate 8
d) Hydroxypropylmethylcellulose
( 100 . 000 GpS ) 60
e) Mg stearate 2
200
10 P~reparation
Ingredients a) and b) are sieved and mixed.
Ingredient c) is melted by heating to 60 and is added to the
mixture which is heated to 55C. The mass is stirred for 2 minutes
or until it is a homogenous mixture and cooled overnight. The rushed
mass is broken up and sieved tthrough 250 micron openings). Ingredients
d) and e) are sieved (through 360 micron openings) and mixed in over
10 minutes. The mixture is then encapsulated.
In vitro release
Time (hours)Release of Darodipine
1 7
2 14
4 25
6 34
24 97
129878~
_ 12 Case l00-67l7
EXAMPLE 2: Capsule
Ingredient mg
a) Isradipine lO
b) Lactose 97
c) Glycerol ditripalmitostearatelO
d) Hydroxypropylmethylcellulose
4~00 cps 60
e) Silica
f) ,~agnesium Stearate 2
180
Preparation (Charge of 6000 capsules)
Ingredients a) and b) are sieved and mixed, Ingredient c) is
melted by heating to 56C (m.p. 54C) and is added to the mixture
, which is heated to 55C. The mass is stirred for 2 minutes or
until it is a homogenous mixture and cooled overnight. The
rushed mass is broken up and sieved (through 250 micron openings).
Ingredients d), e) and f) are sieved (through 360 micron openings)
and mixed in over lO minutes. The mixture is then encapsulated.
In vitro release
Time (hours) Release %
11
2 l9
4 43
6 64
24 l02
~-fi= ":
-- , . ~
,
129~784
- 13 - Case 100-6717
EXAMPLE 3: Capsule
Ingredients mg
a) Isradipine 10
b) Microcristalline cellulose 97
c) Cetyl palmitate 5
d) Hydroxypropylmethylcellulose 4000 45
cps
e) Silica
f) Magnesium stearate 2
160
Preparation
In analogous manner to that disclosed in Example.2
In vitro release
Time (hours) Release %
1 11
2 20
4 36
6 52
24 96
20EXAMPLE 4: Capsule
Ingredients mg In a clinical test a very
good retard profile and
a) Isradipine 10 relative bioavailability
of the composition of
b) Microcrystalline cellulose 47 Example 4 ln fasted and
c) Cetyl palmitate 10 in non-fasted subjects
could be established,
d) Hydroxypropylmethyl cellulose 15000 compared with non-retarded
cps 90 capsules containing the
e) Silica 1 same amount of Isradipine.
f) Magnesium stearate 2
160
~P
.:
~2~3~7~34
-14 - Case l00-67l7
Preparation
In analogous manner to that disclosed in Example 2 .
In vivo release
In a study to evaluate the bioavailability of the capsule of
Example 4, this capsule and a reference capsule containing Isradipine
in a non-prolonged release form were administered to fasting subjects.
The prolonged release capsule was additionally administered to non-
fasted subjects.
The composition of the conventional reference capsule containing
Isradipine in a non-prolonged release form was as follows:
Ingredients mg
a) Isradipine lO
b) Lactose l67
c) Corn starch l28
d) Sodium laurylsulphate 5.5
e) Silica 1.5
f) Polyethylenglycol 6000 8.0
The study employed an open-label three~way randomized crossover
desi~gn in 9 healthy male volunteers, $ubjects were given a single
oral dose of either a non-prolonged release reference capsule (lO mg)
in the fasted state or a prolonged release capsule according to
Example 4 ~lO mg) in the fasted and in the non-fasted state. The
intervals between the three different administration periods were
at least 7 days.
.
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~2~137l34
- 15 - Case 100-6717
Blood samples of each volunteer were collected from 0 to 48 hours
after each dose and plasma was analysed for Isradipine by using a
R~A technique (detection limit 0.1 nanogramlml).
The mean temporal plasma concentration data are plotted graphically
in figure 2, in which
O = 10 mg prolonged release capsule in the fasted state
O = 10 mg prolonged release capsule in the non-fasted state and
L~ = 10 mg conventional non~prolonged release capsule.
Plasmaconcentration in nanogram/ml vs. time
in hours
From the curves the following data are calculated:
Prolonged release Prolonged release Reference
capsule (10 mg) capsule (10 mg) tablet (10 mg)
non-fasted state fasted state fasted state
AUCo8 34.73 34.67 49.65
in ng hlml
Cmax 3,70 1.77 14,22
in ng/ml
-
Tmax 8,55 9 1,89
(in h~urs)
Geometri.~c mean for n = 9 sub.jects,
~UC08 = .~erea under the curve from 0 to 48 hours.
Compared with the reference form the relative bioavailability is more
than 65%.
. ~
