Note: Descriptions are shown in the official language in which they were submitted.
2 ~i3`~ 100-~243
BROMOCRIPTINE COMPOSITIONS
This invention relates to pharmaceutical compositions, containing
bromocriptine.
Bromocriptine is the generic name for the compound 2-bromo-12'-
hydroxy-2'-(l-methylethyl)-5'a-(2-methylpropyl)ergotamin-3l,6'-
tri-one and is listed in the Merck Index, 1976, Appendix A 2.
Bromocriptine is a well-known dopamine agonist used in the treatment
of e.g. hyperprolactinemia, acromegaly and Parkinson's disease.
It is usually administered in the for~ of the mesylate in daily
dosages of e.g. 5-7.5 mg, 10-60 mg and 20-80 mg respectively.
Its pharmacological and clinical properties have been recently
extensively reviewed in M.O. Thorner et al.: Bromocriptine A
clinical and pharmacological review, Raven Press, New York 1980.
However the pharmacokinetic profile was not been established
conclusively From extensive pharmacokinetic studies we have found
tha~ 6romocriptine is rapidly absorbed and rapidly eli~inated from
plasma after oral administration (t l/Z = 3 to 5 hours). Although
its duration of action appears to extend well beyond t 1/2 in some
applications (e.g. hypoprolactinaemia effect), we have found that it
is generally necessary to administer the daily doses in 2 to 4 small
doses to achieve a lasting therapy and to decrease potential unwanted
side effects, which are ~hought to be related to the rapid absorp-
tion of the drug. Some of these side effects are due to dopaminergic
activity of the compound acting on dopaminergic reCeptGrS in the
gastro-intestinal tract, e.g. nausea and emesis.
~A
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There exists thus a need for a controlled release formulation of
bromocriptine which provides a prolonged action of bromocriptine
to reduce the number of times bromocript~ne has to be administered
each day and to reduce certain adverse reactions.
The present invention provides a controlled release formulation for
oral administration comprising
bromocriptine
a pharmaceutically acceptable hydrophilic swelling substance and
a pharmaceutically acceptable inert fatty material.
The preferred amounts of bromocriptine in the unit dosage form
are from 2 to 20 mg, especially 5 and 10 mg. The bromocriptine may
be in free base form or in the form of a pharmaceutically acceDtable
acid addition salt. Preferably the bromocrintine is in mesylate salt
form. Reference herein to bromocriptine is intended both the free
base form and such salt forms.
Hydrophilic swelling substances that can be used include one or more
natural, partially or totally synthetic anionic or, preferably,
nonionic hydrophilic gums, modified cellulosic substances or protein-
aceo~s substances such as~ for example, acacia, gum tragacanth, locust
bean gum, guar gum, karaya gum, agar, pectin, carrageen, soluble and
insoluble alginates, methylcellulose, hydroxypropylmethylcellulose,
hydrcxypropylcellulose, hydroxyethylcellulose, sodiuncarboxvmethyl-
cellulose, carboxypolymethylene,gelatin.
Preferred are cellulose hydrocolloids which include methyl cellulose,
hydroxypropylcellulose and especially hydroxypropylmethylcellulose
and sodium carboxymethylcellulose. Preferably the weight ratio of
~romocriptine to the hydrophilic swelling substance is from 1:10 to
1:35, especially from 1:16 to 1:25.
The weight ratios refer to the amount of active substance bromo-
criptine, not the total weight of any salt.
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Usable pharmaceutically acceptable inert fatty materials include
beeswax fatty acids; long chain fatty alcohols such as, for
example, cetyl alcohol, myristyl alcohol, stearyl alcohol,
glycerides such as glyceryl esters of fatty acids or nydro-
genated 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 meltinq Doints betb~een
30 and 90C.
Most preferred 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 bromocrip~ine to the fatty material is from
1:1 to 1:10, esoeicallY from 1:6 to l:lQ.
It is also convenient to incorporate in the formulation
ot'ner soluble or i~soluble pharmaceutical
excipients such as calcium sulfate, calcium phosphate, lactose
and colloidal silica. The weight ratio of bromocriptine to these
other excipients is convenientlv from 1:5 to 1:40, e.g. 1:15
to 1:40.
The formulation may be produced in conventional manner by mixing
the ingredients together~if desired melting the fatty material
The resultant mixture is in powder form . The powder can ~e
pressed to form a tablet, but is preferably filled into a
capsule.
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We have surprisingly found that the formulations Fossess an excellent
sta6ility, despite the fact that bromocriptine is sensitive to
many chem;cal reagents. Moreover, the formulations have a satisfactory
pharmacodynamic and pharmacokinetic profile.
The resultant retarded formulations in general have comparable bio-
availability in standard clinical trials to conventional non-retarded
formulations containing the same amount of bromocriptine. The formu-
lations of the invention, even if administered once a day, can still
produce a t~erapeutic effect for at least 24 hours and even as much
as 35 hours. The formulation may thus be administered only once a
day in the known indications of bromocriptine at approximately the
same daily doses as employed in the CnVent;nalnon-retarded forms.
Preferred formulations are such, which show in in vitro release
experiments a release rate of bromocriptine of less than 50% in
2,5 hours, preferably a release rate of less than 65% in 8 hours,
as measured in 0,1 n HCl solution. Most preferably,the formulation
will release at least 80% of the active ingredient within 24 hours.
-- 5 --
In the following examples all temperatures are in degrees
Centigrade and are uncorrected.
Further information on the properties etc. of the pharma-
ceutical excipients named hereinafter may be obtained from
the manufacturer, listed hereinafter, manufacturer's bro-
chures or other sources, especially H.P. Fiedler Lexikon
der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende
Gebiete, 2nd Edition 1981, Edito Cantor Aulendorf, W.
Germany.
Silica is e.g. brand Aerosil~ 200 available from Deutsche-
Gold und Silberscheidanstalt, Frankfurt, W. Germany.
Glycerol ditripalmitostearate is e.g. brand Preciro
Ato 5 available from ETS Gattefosse 929100 Boulogne-
Brillancourt 7 France.
HydroxypropylmethylCellUlOSe 15000 cps and 4000 cps are
e.g. brands Methoce ~ K15M and Methocel E4M available
from Dow Chemical Company, Michigan 48640 USA.
Cetyl palmitate is e.g. brand Cutina~ CP available from
Henkel 4000, Dusseldorf, W. Germany.
,
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EXAMPLE 1: Comeosition_ of each caesu!e
Ingredient mg
1) Bromocriptine mesylate 5,735
2) Lactose (200 mes'n) 124.265
3) Silica 10
4) Glycerol dttripalmitostearate 40
5) Hydroxypropylmethylcellulose
4000 cps 110
290
Capsule (Hard gelatine) 78
)equivalent to 5 mg bromocriptine base
Preparation (Charge of 6000 capsules)
Ingredients 1), 2) and 3) are sieved and mixed. Ingredient 4) 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
crushed mass is broken up and sieved (through 250 micron openings).
Ingredient 5) is sieved (through 360 micron openings) and mixed
in over 10 minukes. The mixture is then encapsulated.
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In vitro release
Gastric jutce 0.1 n HCl (pH 1.2)
TimeRelease of bromocriptine
(hours)
1 7 %
2 13 %
4 28 %
6 42 %
24 100 %
EXAMPLE 2: Comeosition of each ca~sule
Ingredient mg
1) Bromocriptine mesylate 5.735
2) Calcium sulfate . 2H20 124.265
3) Cetylpalmitate 20.0
4) Hydroxypropylmethylcellulose 120.0
(15000 cps)
270.0
Capsule (hard gelatine) 78.0
)equi~alent to 5 m~ bromocriptine base
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Preparation
Analogous to Example 1, with the difference, that now ingredients
1) and 2) are mixed, followed by addition of ingredient 3) in
molten form, after which the mixture is cooled and ingredient 4)
is added.
EXAtlPLE 3: Comeosition_of each caesule
Ingredient
1) Bromocriptine mesylate 11.47
2) Maleic acid 4.00
3) Lactose 78.53
4) Silica 10.00
5) Cetyl palmitate 40.00
6) Hydroxypropylmethylcellulose
1~.000 cps 130.00
274.00
Capsule (hard gelatine) 81.00
355.00
3 )corresponding to 10 mg bromocriptine base
Preparation
Analogous to Example 1, with the difference that now ingredients
1), 2), 3) and 4) are mixed, followed by addition of ingredient 5)
in molten form, after which the mixture is cooled and ingredient
6) is added.
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Comoarati~e clinical tests
.
Objectives: To study in healthy YOl unteers the tolerability,
bioavaila6i1ity and the prolactine suppression effects of two
oral control1ed release capsules A and B according to the
invention in comparison to a conventional capsule C and a placebo
capsule D.
A. Composition according to the invention
Ingredient mg
1. Bromocriptine in mesylate form 5.735
2. Lactose 184.265
3. Glycerol-ditripalmito stearate 20.000
4. Hydroxypropylmethylcellulose
(4000 cps) 60.000
)corresponding to 5 mg bromocriptine
The fat~y component A3. was added in molten form to a mixture
of components Al. and A2. and mixed therewith after which the
mixture was cooled to room temperature and component A4. was
mixed with the mixture of Al., A2. and A3.
B, Composition according to tne invention
Ingredient mg
1. Bromocriptine in mesylate form 5.735
2. Lactose 124.265
3. Silica 10.000
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4. Glycerol~ditripalmito stearate40.000
5, Hydroxypropylmethylcellulose110.000
(4000 cps)
The mixture was prepared analogous to the mixture under A,
with the exception that instead of mtxing A1. and A2.,
Bl., B2. and B3. were mixed.
C. Conventional compos i tion
Ingredient mg
1. Bromocriptine in mesylate form2.87
2. Maleic acid, milled 2.00
3. Lactose 170.63
4. Cornstarch 120.00
~. Silica 1.50
6. ~agnesiumstearate 3.00
)corresponding to 2,5 mg bromocriptine
The ingredients 1 to 6 were mixed together
D) Conventional placebo composition
Ingredient mg
1. Lactose 190,00
2. Glycerol ditripalmito stearate20.00
3. Hydroxypropy1methylcellulose
(4000 cps) 60.00
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The fatty component D2 was added in molten form to component Dl
and mixed therewith, after which the mixture was cooled to room
temperature and mixed with component D3.
Instead of 5 mg bromocriptine~ as present in capsule A and B, the
non-retarded capsule C contained only 2.5 mg bromocriptine to avoid
a too strong influence on the healthy volunteers by expected side
effects.
In a randomized double-blind design 8 healthy male volunteers re-
ceived at 8.00 h in the morning either one capsule A,B,C or D in such
a manner that each volunteer rece;ved the 4 different capsule
types, divided over 4 administration days, separated by an interval
of a week.
Prolactin inhibition
Blood samples were obtained from the 8 volunteers by an indwelling
cannulag in certain time intervals from 8.00 h, the time the
capsule was received, till 10.00 h on the third day (totally 50
hours), with a longer interruption from 18.00 till 8.00 h in the
second night. The prolactin levels were determined by a sDecific
radioimmunoassay.
The prolactin concentrations, measured after the administration of
capsules A, B and C were plotted graphically as corresponding mean
curves A (fig.l), B (fig.2~ and C (fig.3).
The prolactin concentrations, determined after the administration
of capsule D, were depicted as curve D in fig. 1,2 and 3, which was
compared with curves A, B and C (in nanograms/ml,time t in hours).
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The prolactin curve D represents the normal prolactin concen-
tration of healthy volunteers durîng night and day.
In the evening, the concentration rises, during sleeD the
maximum is reached and in the first wakening hours the concentration
falls to a day-time "basal leYel" which is mantained to about
20~00 h. From curves A and B a prolactin secretion inhibition is
observed 1 hour after taking the corresponding capsules A and
B and lasting 35 hours.
Capsul e C produces a prolactin inhibition ;n healthy volunteers,
1 hour after taking a capsule C and lasting only 24 hours.
P~armacokinetics
Parallel to the prolactin concentrations, bromocriptine concen-
trations were measured in the blood samples obtained up till 24
hours after administration of the capsules.
The ~romocriptine conrentrations in the blood were plotted as mean
curves A, B and C in fig. 4 (in picograms/m1, time t in hours).
The concentrations of curve C in fig. 4, caused by the 2.5 mg
bromocriptine containing capsule C were doubled and plotted in
fig.5 as a curve C adapted to a double p~rtion of c~psule C,
together with curves A and B, so that bromocr;ptine levels
of equal dosages of bromocriptine (5 mg) can be compared.
From fig. 5 it is seen that the rate at which drug concentratio~
initially rise (i.e. absorption phase) is slightly reduced for
form A and markedly reduced for form B as compared with twice form C.
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It also appears from these mean curves1 that the bioavailabilities
(A~C*) of capsules A and B are somewhat lower than of two capsules C.
Based on the individual sub.jects data~ the reduction in bioavaila-
bility was an average of 12X for form A and 25% for form B.
Tole _bility
The side eifects experienced by each volunteer were recorded as
to type, duration and intensity (strong, moderate and weak). Overall,
the following side effects were noted:-
1) orthostatic hypotonia 8) head pressure
2) dizziness9) drowsiness
3) vomiting10) tiredness
4) nausea 11) weakness
5) nasalcongestion12) sweating
6) headache13~ heat senation
7) dry mouth14) abdominal cramps
15) palor
Side effects 1) to 6) are well krown for dopamine agonist drugslike Bromocriptine and were used to assess the relative
tolerability of the formulations in the table below:
*Area under the curve
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- nu~er olF~r--g re~ated side effects
_ _ ,
Intensity .~ B C D
5 mg drug 5 mg dPug 2.5 mg drug placebo
,
strong 10 S
moderate 16 9 1 0
weak 12 5 11 3
total 38 19 13 4
Capsule A produced significantly more drug related side effects
t~an all other forms.
Capsule B produced fewer drug related side effects than AJ
and the total number was not statistically d;fferent from the
2.5 mg conventional fonm C.
Capsule C produced significantly more drug related side effects
than place~o D.
On the 6asis of tolerabil;ty, Capsule B is to be preferred over
capsule A.
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In in vitro experiments (USP XXl, page 1243-1244, Apparatus 1, 1000
ml 0.1 n HCl,100 rotations per min.) the following release results
were obtained with capsules A, B and C -
Release time in hours Release of bromocriptine (in percents
of ~ight3
_
. . CaDsule A Capsule B Capsule C
..
0,5 13 4 99
1 23 8 100
2 42 15
4 66 28
6 81 39
8 89 48
94 57
14 98 68
24 100 86
From the viewpoint of pharmacokinetics capsules A and B are pre-
ferred and capsule B is especially preferred.
Summary:
- A daily dosage of two capsules of C, if adminis~ered simul~a-
neously~wsuld not be tolerated in clinical practice as reported
before.
- Both capsules A and B, if administered once a day surprisingly cause
a satisfactory therapeutically effective bromocriptine concentra-
tion for 24 hours and a prolactin suppression for 35 hours in the
blood, notwithstanding a slightly decreased bioavailability in
comparison with two capsules C. Capsule B is preferably used, since
it causes less side effects and its controlled absorption is better.
