Note: Descriptions are shown in the official language in which they were submitted.
100-6572
~2~i3~137
PHARMACEUTIC~L 9,10-DIHYDRO ERGOT ALKALOID CONTAINING
COMPOSITIONS
This invention relates to pharmaceut;cal compositions con
taining 9,10-dihydro ergot alkaloids,
9,10-dihydro ergot alkaloids encompass the 9910-
dihydro-derivatives of natural ergot alkaloids as well as
ergo~ alkaloids obtainable by fermenta~ion or by chemical
synthesis. They may e.g. have substituents, e.g. usually
known in the chemistry of ergot alkaloids and may exist
in the form of isomers, e.g. as 8R- and 8S-isomers, e.g.
as descri.bed in "Ergot alkaloids and related compounds,
Editors B.Berde and H.D.Schild, Springer Verlag, Berlin,
Heidelberg, New York 1978, herein~fter referred to as Berde and
.~ .
The mos~ preferred compounds are dihydroergocornine, di-
hydroergocristine, dihydro-a-ergocryptine, dihydro-~-ergo-
cryptine, and co-dergocrine and dihydroergotamine.
Co^dergocrine is the generic name of a molar 3:3:2:1 ~ix-
ture of dihydroergocornine, dihydroergocristine, dihydro-
a-ergocryptine and dihydro ~-ergocryptine,(see Berde and
Schild, page 58).
For pharmaceutical use co~dergocrine may be used in the form
3n of an acid addition salt, e.g. the e~hane-sulphonate, the
maleate~ fu~arate, tar~rate, hydrochloride or preferably
~: . the mesulate. They exhibit the same order of activity
-2- ~63~7 100-6572
as ~he free base form and are prepared in manner known per se.
The methanesulphonate salt is listçd in the Merck Index,
1983, under the brand name HYDERGI~ see the reference
3596 on pages 526-527. This is also known as ergoloid
mesylates.
The pharmacological and clinical properties have been ex-
tensively reviewed in the book of Berde and Schild.
lo Co-dergocrine modifies cerebral neurotransmission and im-
proves impaired cerebral metabolic function. Furthermore,
it has a stabilizing effect on ~he tonus of cranial vessels
and has anti-hypertensive activity.
Co-dergocrine is therefore indicated for the treatment of
cerebral insufficienty in the elderly and of cerebrovascu-
lar disorders, especially when associated with hyperten-
sion, as well as for the prevention of migraine.
Usual oral daily dosages are 3 to 6 mg. A recommended oral
daily dosage is 4.5 mg~ preferably divided into smaller
dosages of 1.5 mg three times a day.
Dihydroergocornine, dihydroergocristine, dihydro-~-ergo-
cryp~ine and dihydro-~-ergocryptine may be used individually
for the same indications in thc same dosa9e order.
The pharmacological and clinical properties of dihydro-
er~otamine haYe been reviewed as well in Berde and Schild.
.
: :~
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~263~
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The compound may be administered ln the form of the
free base or of a pharmaceu~ically acceptable ac1d addi-
tion ~alt. Such acid addition salts are known.
A typical acid addition salt form is the methanesulphonate
salt (the mesylate), d scribed in The Merck Index 1983,
reference 3151, ant sold under the brand name DIHYDERGOT.
Dihydroergota~ine is indicated for use in the treatment
o of hypotens~on and orthostatic circulation disturbances,
in the trea~ment of acute migraine attacks and related
vascular headaches as well as in the interval treatment
of migraine and other v.ascular headaches.
Further dihydroergotamine is indicated.to be active in
the treatment of Herpes Zoster.
The drug is usually orally administered in daily closages
of about 1 - 10 mg.
The pre~ent inventlon provides a con~rolled release formu-
latlon for oral administration comprising
a 9,10-dihydro ergot alkaloid
a pharmaceutically acceptable hydrophilic swelling substance
and
a pharmaceutically acceptable inert fatty material.
: , .
~2 ~3 ~
-~- 100-6572
The invention specially provides such a controlled release
formulation in which the 9,10-dihydro ergot alkaloid is a
pepti`de alkaloid.
Hydrophilic s~elling substances that are preferred include
one or more natural, partially or totally synthetic,anionic
or, preferably, nonionic hydrophilic gums, modi~ied cellu-
lose substances or pro~ein aceous substances such as, for
example~ acacia, gum tragacanth, locust bean gum~ guar gum,
karaya gum9 agar, peptin, carrageen, soluble and insoluble
alginates9 methylcellulose, hydroxypropylmethylcellulose3
hydroxypropylcellulose, hydroxyethylcellulose, sodiumcar-
boxymethylcellulose, carboxypolymethylene, gelatin.
Preferred are cellulose hydrocolloids which include methyl
cellulose, hydroxypropylcellulose and especially hydroxy-
propylmethylcellulose and sodium carboxymethylcellulose.
Suitable pharmaceutically acceptablP inert fatty materials
include bees~ax; fatty acids; long chain fatty alcohols,
such as, for example, cetyl alcohol, myristyl alcohol,
stearyl alcohol, esters, e.5. glycerides such as glyceryl
esters of fatty acids or hydrogenated aliphatic acids such
as, for example, glyceryl mono-stearate, glyceryl distea-
r~ate, 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 preferahly fatty ma~erials have a melting point from
45C to 65C and include glyceride~ such as glyceryl pal-
mitates and stearates and fatty acids such as hydrogenated
castor oil and fatty acid esters such as cetyl palmitate.
.,
~3 ~7
5 100-6572
The formulation contains preferably both hydroxypropyl-
methylcellulose as a swell;ng 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 ex-
cipients such as calcium sulfate~ calciuro phosphate,lactose,
mannitol,sucrose,sorbitol~colloidal silica,and magnesium
stearateOPreferably a soluble excipient,especially lactose
is present. Tha ratio of hydrocolloid to other excipient,
10 - may be e.~.from l 0.5 to 1:2.
The formulat1on may be produced in conventional manner by
mixing the ingredients together, preferably ~elting the
fatty materialO The resultant mixture is in powder form.
The po~der can be pressed to Form a tablet, but is pre-
ferably filled into a capsule.
IF the fatty material is melted, the drug and addltional
excipients such as lactose~ silica, calcium sulphate or
calcium phosphate may be taken up in the mGlten fatty ma~erial.
2Q The mlxture is then allowed to solidify and is then divi-
ded into small particles (granules).
The resultant granulate may be mixed with a~preferably
porous, hydrophilic swelling substance and further exci-
pients, e.g. ~agnesium stearate/and the mixture may be
pressed to form a tablet or may be preferably filled into
a capsul 2 o
In a preferred aspect the present inYention accordingly
~3Q provides a formulation containing a 9,10-dihydro ergot
alkaloid in a fatty material matrix granulate~ the granu-
late particles being in contact with a hydrophilic
s~elling substance.
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-6- 100-6572
Preferably the s~elling substance is present in a porous
formO
We have surprisingly found that the formulation posse~s an
excellent stability, despite the fact that the alkaloids
are sensitive to many chemical reagents. Moreover, the
formulations have a satisfactory pharmac.odynamic and
pharmacokinetic profileO
The resultant retarded formulations in general have com-
parable bioavailability in standard clinical trials to
conventional non-retarded formul ati ons oontai ni ng the same
amounts of alkaloidsO 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 may thus be administered only once a day
in the known indica~ions of the alkaloids at approx;mately
the same daily doses as employed in the conventional
non-retarded forms.
The 9,10-dihydro ergot alkaloids especially encompass
~ 9,10-dihydro peptide ergot alkaloids of formula I
H ~ CO~U.
~ ~CH~ H R2
.
3~ ~7
7 100-6572
The groups Rl and R2 may be the same of different, e.g.
Rl = (Cl_4)alkyl, and
R2 = (Cl-~)alkyl~ or
benzyl, and
X - CH2 or S.
9,10-dihydro eryot alkaloids encompass 9,lO-dihydro peptide
ergot alkaloids of formula I in which the carbon atom in
position 9' is replaced by a sul~ur atom~ as disclosed
in the British patent 2,109,795 B. The compounds ~ay pre
ferably be used in pharmaceutical form as acid addition
s~ltsO
The preferred compound of formula I wherein X = S is 9'-
thia-9,10 dihydroergotamine. This is preferably used in the
form oF the hydrogen malonate. The preferred indication is
for the prevention and treatment of vascular headaches and
for the treatment of orthostatic syndrome. No publications
on the clln~ca~ use of this active agent have been made
and no specific sustained release forms o~ this agent
; have been described.
~ Epicryptine is the generic name of a compound o~ the
25~ formula I in which Rl ~ ~sopropyl, R2 = 2R-butyl and X =
CH2, and is disclosed in the British patent 2,114,980 B.
Its chemical name is: (SR,8R,lOR)-N-[(2R,55~11S,12$)-5
(2R-butyl)-octahydro-12-hydroxy-2-isopropyl-3,6-dioxo-8H-
oxazolo[3,2-a]pyrrolo~291-c~pyrazinyl~-6-methyl-ergoline-
8-carboxylic acid amide~ Epicryptire is also known as
30 ~ epicript~ne- -
~ ~6 3~
-8- 100-6572
The compound may be administered in the form of a pharma-
ceutically acceptable acid additîon salt. Preferably
the free base is used.
It is indicated for use in the treatment of lactation,
galactorrhoea, hyperprolactinaemic hypogonadism, acrome-
galy or prolactinoma.
Epicryptine is also indicated for use in the treatment of
cerebral insufficiency, e.g. for senile dementia, particu
larly the early forms thereof, and for increasing vigi-
lance.
Additionally epicryptine is useful in the treatment of
hypertonia, especially ~or geriatrics, and of stroke. The
preferred indication is hypertension.
The compound is administered at a daily dosage of from
about 0~1 to 15 mg, preFerably 2 to 5 mg.
The administra~ion of the ergot alkaloids used according
to the inven~ion can orcasionally be associated with adverse side effectsg
e.g. effects on the heart, vascular effects, central nervous
system effects, autonomic and peripheral nervous syste~
and endocrine effects. See Berde and Schild, pages 815-820.
We pre~erably keep the concentration of the ergot alkaloids
on a therapeutically active level but between narrow limits
and avoid the drug burst which may occur just after admini-
stration of non-controlled release preparations. This leads
to ~emporary high blood leYels and to proportionately strong
adverse effects.
The formulations of the present invention are well tolera-
ted.
MoreoYer, the present formulations provide similar profiles
of activity in food interaction studies, e.g. before and
af~er administration of breakfast, with fasted subjects.
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9 100-6572
The present invention especially provides controllPd release formu-
lations for oral administration con~aining co-dergocrine,dihydroergo-
tamine or epicryptine as active agents in unit dosage forms.
The pharmaceutical formula~ions according to the inven~ion,contain
preferably 1 to 15 mg of 9,lO~dihydro ergot alkaloi~.
Preferred ratios of 9,10-dihydro ergot alkaloid to swelling substance
are from about 1:4 to 1:50,e.9O 1:4 to 1:25.
Preferred ratios of 9,10-dihydro ergot alkaloid to fatty material
are from 1:0.5 to 1:10.
lo Preferred amounts of co-dergocrine in unit dosage form are from 2 to10 mg,especially 3-6,e.g.4.5 or 3 mg.Preferably co-dergocrine is in
mesylate form.
Preferably the ratio of co-dergocrine to swelling substance is from
1:50 to l:lO,especially from 1:10 to 1:30,e.g. from 1:15 to 1:25.
The ratio of co-dergocrine to the fatty material is preferably from
1:1 to l:lO,especially from 1:1 to 1:5.
If other excipients like lactose or magnesium stearate are present,then
preferably the weight ratio of co-dergocrine to the other excipients is
conveniently from 1:5 ~o 1:40,especially 1:15 to 1:40.
Preferred amounts of dihydroergo~amine in unit dosage form are from 4
15 mg, ~.9.5 mg,especially 8-12,e.s.10 or 7.5 mg. Preferably dihydro-
ergotamine is in mesylate form as well.
Preferably the ratio of dihydroergotamine to swelling substance is from
1:4 to 1:20je~g.1:5 to 1:20,especially from 1:4 to 1:12 e.g. from 1:5
to 1:12.
The ratio of dihydroergotamine to the fatty material is preferably from
1:0.5 to 1:2,especially from 1:0.5 to 1:1.5 e.g. from 1:0.8 to 1:1.5.
If other excipients like lactose~silicon dioXide,magnesium s~earate or
tartaric acid3are present,then preferably the weight ratio of dihydro-
ergotamine to the other excipients is convenien~ly from 1:3 to 1:20,
especially from 1:4 to 1:15.
% ~3~ 7
-lo- 100-6572
Epicryptine may also be present as an acid addition salt,but the pre-
ferred form in the controlled release formulation is the free base.
The unit dosage form contains preferably an amount of 2 to 7 mg,
especially 5 mg of drug.
The present invention provides for the first time an oral pharmaceutical
formulation containing 9'-thia-9,10-dihydroergocryptine or epicryptine
for once-a-day administration.
Once-a-day formulations may be formulated in conventional mannerJe.g.
lo to be a capsule or tablet and may contain from 1 to 15 mg of active
agent. Preferably they have the same release profile as detenmined by
in vi~o or in vitro dissolution tests as for the formulations of the
present invention,e g. a release of about 50 to 90,e.g. 50 to 60, 70
to 80 or 80 to 90 per cent over 7 hours at 0.1 N~Cl,e.g. as in the ex-
perimental conditions in Example 2.
In the following examples all temperatures are in dPgrees Centigrade
and are uncorrected.
Further information on the proporties etc.of the pharmaceutical exci-
pients named hereinafter may be obtained from the manufacturer, listed
hereinafter, manufacturer's brochures or other sources,especially H.P.
Fiedler Lexikon der Hilfss~offe fUr Pharmazie,Kosmetik und angrenzende
Gebiete,2nd Edition 1981, Edito Cantor,Aulendorf, W.Germany.
Silicon diox;de (silica) is e.g. brand Aerosil 200 aYailable from
Deutsche-Gold und Silberscheideanstalt, Frankfurt, W.Germany.
Glycerol ditripalmi~ostearat is e.g. brand Preciro~ Ato 5 aYailable
from ETS Gattefossé 929100 Boulogne-Brillancourt, France.
Hydroxypropylmethylcellulose 15000 cps and 4000 cps are e.g.brands
Methocel KlSM and Methocel 4EM available from Dow Chemical Company,
Michigan 48640 USA.
Cetyl palmitate is e.g. brand Cutina CPA available from Henkel 4000,
DUsseldorf,W~Germany,or is available from Gattefossé or from A/S
Johan C.Martens and Company,Bergen, Norway.
,. ~
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~ 100-6572
EXAMPLE 1: Comeosltlon Of-each-caesule
Ingredient mg
a) Co-dergocrine (in mesylate form) 4.5
b) Lactose (200 mesh~ 1241265
c) Si1icon dioxide 10
d) Glycerol ditripalmitosbearate40
e) Hydroxypropylmethylcellulose 4000 cps 110
Capsule (Hard gelatine) 78
Preparation (Charge of 6000 capsules)
-
Ingredients a), b) and c) are sieved and mixed. Ingre-
dient d) is melted by heating to 56C tm.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 cooled macs is broken up and
sieved ~through 250 micron openings). In~redient e) is
sieved (through 360 micron openings) and mixed in over
10 minutes. The mixture is then encapsulated.
EXAMPLE 2 T0 5:
Composition of each capsuleEx.2 Ex~3 Ex.4 Ex.5
Ingredient mg mg mg mg
a) Co-dergocrine in mesylate form 4.5 4.5 3.0 3.0
b) Lactose (200 mesh) 165.5
c) Cetyl palmitate 10.0 8.0 8.0 8.0
dl) Hydroxypropylmethyl-
cellullose (15000 cps) 90.0 70.0 70.0
d2~ Hydroxypropylmethyl
:30 cellulose (4000 cps) 90.0
e) Magnesium stearate 1.0 1.0
:: Capsule (Hard gelatine; 78 mg)
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Preparation
The ingredients are mixed in analogous manner to that dis-
closed in Example l,except that constituent d) is re-
placed by an equivalent amount of cetyl palmitate, the
silicon dioxide c) is omitted and the hydroxypropylmethyl-
cellulose d) is mixed with magnesium stearate.
In vîtro release
In in vitro experimen~s (USP XXI, pages 1243~1244, Appa-
lo ratus 1, 1000 ml 0.1 n HCl, 100 rotations per min.) the
following release results were obtained:
Time (hours) Release of Time (hours) Release of
co-dergocrine co-dergocrine
Ex.2 Ex.3 Ex.4 Ex.5
1 15~ 16% 1 l9~o 20%
3 32 37 2 32 37
S 50 52 4 48 ~9
7 66 64 7 67 73
24 99 86 24 100 10~
_ . _ _ _
:~.
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-l3 l00-6573
EXAMPLE 6: Com~osition of each caesul e
I ngredi ent mg
a) Dihydroergotamine (in mesylate ~orm) lO.0
b) Lactose (200 mesh) 88.0
c) Silicon dioxide l.0
d) Glycerol ditripalmitostearate lO.0
e) Hydroxypropylmethylcellulose 4000 cps 90.0
f) Magnesium stearate l.0
Capsule (Hard gelatine) 62.0
Preparation (Charge of 6000 capsules)
Ingredients a), b) and c) are sieved and mixed. Ingreclient
d) 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 cooled mass is broken up and sieved
(through 800 micron openings). Ingredients e) and f) are
sieved (through 500 micron openings) and mixed in over lO
minutes. The mixture is then encapsulated.
In vitro release (Experimental condit;ons: see Example 2)
_, .
Time (hours) Release of dihydroergotamine (%~
z 17
4 29
6 41
24 96
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EXAMPL 7: Com~osition of each caesule
Ingredient mg
a) Dihydroergo~amine in mesylate form10~0
b) Lactose ~200 mesh) 107~0
c) Cetyl pal~itate lO~0
d) ~ydroxypropylmethylcellulose (1500.0 cps~ 70.0
e) Sili.con dioxide 1.0
f) Magnesi.um stearate 2,0
Capsule (Hard gelatine) 62.0
Pre_aration_
The ;ngredients are mixed in analogous manner to that dis-
closed in Example 6, except ~hat constituent d) is replaced
by an equivalent amount of cetyl palmitate.
In vi.tro_release (Exper;mentalcond;tions: see Example 2)
Time (hours) Release of dihydroergotamine (%)
1 24
2 41
4 65
6 80
zo 8 lOo
EXAMPLE 8 T0 10:
___~_
5Omposition of each capsuleEx.8 Ex.9 Ex.10
___ _ _ ~
Ingredi.ent mg mg mg
a) Dihydroergotamine in mesylate form 7.5 7,5 7.5
b) Tartaric acid 0.18 0.2 0.18
c) Lactose 81.32 144.3 81~32
d~ Cetyl palmitate 8~0 5.~ 8.0
e) Hydroxypropylmethylcellulose8040 4040 8000
(4000 cps)
. - -
~2 ~3~7
-15- 100-6572
The ingredient~ are mixed in analogous manner to that
disclosed in Example 6:
Consti:tuents a), b) and c) are occluded in constituent
d), the solidi~ied mixture is gran~lated and is mixed
with constituent e).
In vitro release (Experi~ental conditions: see Example 2)
Time (hours) Release of dihydroergotamine
Ex.8 Ex.9 Ex.10
1 10% 14% 10%
2 19 26 22
4 33 49 41
6 46 67 56
15 24 96 99 101
C ompa rative clinical_ test
Objective : To study in healthy volunteers the bioavaila-
bility of co-dergocrine in an oral controlled release
capsule A according to Example 2 in comparison to co-der-
gocrine in a conventional tablet B-
Conventional composition in tablet form
Ingredient mg
1. Co-dergocrine in mesylate form 1~0
2. Stearic acid 2.0
3. Talc 4.0
4. Polyvinylpyrrolidone 4~0
5. Starch. 8~0
6. Lactose 141.0
The ingredients 1 to 6 were mixed together, granulated with
a mix~ure of alcohol and water, dried and.compressed to
a tablet.
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One dosage of t~o 4.5 mg co-dergocrine mesylate containing
capsules A (= 9 mg) was compared ~ith on~ dosage of 4 con-
ventional ta~lets B containing 1 mg co-dergocrine mesylate
(= 4 mg), The lower dose for the tablet was chosen to avoid
expeoted - ~ _ side effects due to the high peak
levels of the conventional non-controlled release tablets.
The study design was an open label~ 2 period design with each
subject randomly assigned to one of two treatment sequences,
follo~ed by a third treatment period in which all subjects
received the identical third treatment.
10 healthy male volunteers received on a fasted stomach both
treatments in the first hour periods, followed by one closage
of retard capsules A with food in period three.
Blood samples were obtained from the 10 volunteers by an
ind~elling cannula, at specific time points up to 24 hours
after administration of the capsules.
The co-dergocrine concent8r~ ions, measured after the admini-
stration of capsules A and~B, were plotted graphically as
shown in aocompanying in figure 1 as corresponding mean
curves A.l (without food), A.2 (with food) and B (without
food) in picograms ml, time T in hours).
From the measured co-dergocrine concentrations, the following
parameters were obtained (as arithmetic means).
~ Retard Caps.A Retard Caps.A Oral tablet g
with food without food without food
~UC
(Area under the2066 2066 2242*
curve90-24 hours)
Peak (in pico-
9r3m/ml) 172 162 511*
Time (in hours)5.9 3.9 0.9
*Ex~rapolated from 4 mg to 9 mg
This is justified since co-dergocrine mesylate shows linear dose propor-
tionality for the AUC in the O - 9 mg dose range.
~i3Ni8~
~17- 100-6572
The retard capsule A showed an AUC, similar to that of the
conventi`onal tablet B (corrected for the dose) when given
on an empty stomach or with a meal. Compared to the tablet
B the retard capsule A showed a statistically significant
lower peak level and a delayed time to peak (from less than
1 hour to 3.9 h on a Fasted stomach or 5.9 h when given
with a meal). In generals however, the profile of compound
A when given on a fasted stomach was similar to that when
given after a meal, except for the delay in the absorption
of drug with a full stomach (presumably due to a delay in
stomach emptying).
- The retard capsule A, given on a fasted stomach or with a
meal, provides sustained release of drug without dose dum-
1S ping and7 which is especially ~oteworthy, without signifi-
cant loss of bioavailability, compared to the oral tablet
reference Standard B.
Side effects such as headache and gastrointestinal upset
were transitory and ~ere mild to mod~rate in severity.
Single dose of retard capsules Ag administered as 2 x 4.5
mg retard capsules A are safe and well tolerated.
EXAMPLE 11:
2s The co-dergocrine and dihydroergotamine in the above
examples ~ay be replaced by an equ~valent amount of epi-
cryptine or 9'-thia-9,10-dihydrcergotamine.
.
