Note: Descriptions are shown in the official language in which they were submitted.
1~39Z22
Case lCO-5129
(
GALENICAL CO.~POSITIONS
The invention provides galenieal eompositions for oral
application of ergot alkaloidswhie}l are characterised by a
prolonged effeet and a good bioavailability of the active
agent~
It is undisputed amongst medieinal speeialists, that
under many eireumstanees it is preferred to apply a drug
onee a day instead of more times a day. This mav be
aehieved in so-ealled "retard systems" by sustaining and
delaying the release of the active agent, with the aim of
produeing a longer duration of therapeutie effect. In the
field of the ergot therapy, a retarclation ~Jith elassieal
systems, e.g.with a ~atrix system or with the aid of
miero-eneapsulation, induees eaeh time an important
deerease of the total bioavailability.
It is also known, that ergot alkaloids are stable
in the presenee of aeids, ~7hieh means that they do not
disintegrate in the gastrie juices, and that the resorp-
tion of ergot alkaloids takes place mainly in the
intestinal traet. Enteric coated drugs containins an ergot
alka]oid are therefore not expected to provide an improved
bioavailability.
It is therefore surprising tha-t with the ai.d of an
enteric coating one observes that the duration of action
of an ercJot alkaloid is not only significantly proloncJed but
that, moxeover, the total bioavailability is not signifi-
cantly reduced when the coated core contains, in addition to the
1~39ZZZ
ergot alkaloid, a polyalkoxyalkene sterol ether.
The invention therefore provides, more specifically, a
solid enteric-coated composition for oral application, the
core of the composition containing an ergot alkaloid and a
polyalkoxyalkylene sterol ether.
The invention also provides a process for the produc-
tion of compositions according to the invention, by enteric
coating a core comprising an ergot alkaloid and a poly-
alkoxyalkylene sterol ether (hereinafter designated sterol
ether).
The term "core" comprises any mixture of an ergot
alkaloid and a sterol ether, if desired in admixture with
further physiologically acceptable material, that can be
surrounded by a enteric-coating. The term "core" com-
prises, in a wide sense, not only tablets, pellets or
granules but also capsules, e.g. soft or hard gelatinecapsules filled with a liquid or waxy mixture of an ergot
alkaloid, a sterol ether and optionally pharmaceutically
acceptable material. Such capsules may then be enteric-
coated, e.g. in conventional manner. When tablet cores
are used they have preferably a hardness of from ca 10 toca 70N.
The pellets or granules may, after application of the
enteric-coating, be used as such or to fill capsules, e.g.
hard gelatine capsules. Suitable applications of the
~39222
- 2a -
compositions according to the invention are therefore
tablets, pellets, granules or capsules.
The term "solid compositions" means compositions which
are of a definite shape, i.e. not wholly liquid. Hence
the term solid composition covers capsules partially filled
with pellets, enteric coated granules and pellets and soft
gelatine capsules containing liquids.
The term "ergot alkaloids" comprises natural ergot
~ t
il39Z2Z
- 3 - 100-51~9
alkaloids such as ergotamine, ergocri,stine, a-ergocryptine,
~-ergocryptine and ergoco~ ine, synthetic or semi-synthetic
derivatives thereof such as ergovaline, dihydroergotoxine
(also kno~m as co-dergocrine) and dihydroergotamine in free
base form or in the form of an acid addition salt with
pharmaceutically acceptable organlc or inorganic acids
such as methanesulphonic, maleic, tartaric or hydrochloric
acid.
The active agents which are of special interest for use
in the invention, are compounds of formula I
; - NH ~
Ç[~ R2
HN~LRl
wherein Rl is hydrogen or halogen,
R2 is hydrogen or Cl 4alkyl,
R3 is isopropyl, sec.-butyl, isobutyl or benzyl,
R4 is methyl, ethyl or isopropyl, and
either R5 is hydrogen and
R6 is hydrogen or methoxy
or R5 and R6 together are an additional bond,
or mixtures thereof.
When Rl is halogen, it is preferably bromine.
Especially preferred compositions of the invention
~3922Z
contain dihydroergotoxine, bromocryptine or dihydroergot-
amine in free base form or, preferably, in acid addition
salt form as active agent.
Preferred sterol ethers Eor use in the compositions of
the invention have a hydrophilic-lipophilic balance value
(HLB group number) of from about 10 to about 20, especially
from 12 to 16. They preferably are ethers of lanosterol,
dihydrocholesterine and, particularly, of cholesterine or
mixtures of such ethers. Especially suitable sterol ethers
are sterols etherified with an average of 8 to 75, prefer-
ably 9 to 30 alkylene oxide units. The hydroxy group in
the end alkylene unit of such sterol ethers may be par-
tially or completely acylated, e.g. by acyl radicals of
aliphatic carboxylic acids, such as acetyl. Especially
preferred are sterol ethers etherified with ethylene oxide
and/or propylene oxide units. These sterol ethers are also
known in the literature as polyoxyalkylene sterol ethers,
e.g. polyoxyethylene sterol ethers, and polyalkylene glycol
sterol ethers, e.g. polyethylene glycol sterol ethers.
The sterol ethers may be obtained by conventional
manner by etherifying the sterol with the corresponding
amount of epoxide and optionally acylating the so obtained
alcohols. They are in general available on the market and
are e.g. offered for sale by the firm Amerchol under the
trade name Solulan~. Examples of Solulan~ types which
1~39ZZZ
- 4a -
are available on the market and are suitable for use in
the compositions according to the invention are such
obtainable by alkoxylation of e.g.
a) 1 mol cholesterin with about 24 mol ethylene oxide
(Solulan~ C-24)
~1392Z2
5 ~ 100-512~
b) 1 equi'valent of lanolinalcohols with about 16 equival.ents
ethylene o~lde (Solulan~ 16)
c) 1 equivaient of lanolir.a,~cohols wlth about 25 equivaler.ts
ethylene oxide ( Solulan~ 25)
d) 1 equivalent of lanolin alcohols ~7ith about 75 equivalents
ethylene oxide (Solulan~ 16)
e) 1 equivalent of lanolin alcohols with about 10 equivalents
propylene oxide (Solulan~ PB-10) and also the
f) partially acetylated derivative of 1 equivalent of
lanolin alcohols ethoxylated ~lith aboutlO equivalents
ethylene oxide (Solulan~ 98) and the
g) completely acetylated deri~ative of 1 equivalent or
lanolin alcohols ethoxylated with about 9 equiva].ents
ethylene o~ide (Solulan~ 97)
The term "about" ln the above paragraphs a) to g)
indicates that the given number of ethylene oxide or
propylene oxide equivalents involved is a mean value, i.e.
that some sterol ethers bear more and others less ethylene-
oxy- or propyleneoxy-groups.
Lanolin alcohols are also kno~n as wool fat alcohols
(Handbuch der Kosmetika,und Riechstoffe, 2. Ed. 19~0,
Vol. I, page 1101 (Janistyn)) and are a mixture of i.e.
cholesterin , dihydrocholesterin and lanosterol.
The term "enteric coating"comprises any pharmaceutically
acceptable coating preventing the release of the act_ve
agent in the stomach and sufficiently disintegratirlg in thé
intestinal tract (by contact with approximately nelltral
'~ !
1~392~Z
- 6 - 100-512g
or alkaline intestine juices) to al]o~J the resorpti~n of
the active agent through the ~7alls of the intestinal tract.
Various in vitro tests for determining ~7hether or not a
coating is classified as an enteric coating have been
published in the pharmacopoeia Gf various countries.
More speci~ically, the term "enteric coating" accord-
ing to the invention refers to a coating ~7hich remains
intact for at least 1 hour, e.g. 2 hours, in contac-t ~7ith
artificial gastric juices such as HCl of pH 1.2 at 36
to 38C and thereafter disintegrates with 30 minutes in
artificial intestinal juices such as a KH2P04 buffered
solution of pH 6.8.
The thickness of the coating ma~ vary and depends
inter alia on its permeability in water and acids and
the desired retard effect. In general satisfactory
results are obtained with a coating of 5 - 100 ~m,
preferably 20 - 80 ~m,thickness. The coatinc3 is suitably
selected from macromGlecular polymers. Suitable polymers
are listed in e.g. HageYs Handbuch der pharmazeutischer
Praxis, 4th Ed. Vol. 7a, pages 739 to 742 and 776 to 778,
(Springer Verlag, 1971) and Remington's Pharmaceutical
Sciences, 13th Ed., pages 1689 to 1691 (Mack Publ. Co.,
1970) and comprise e.g. cellulose ester derivatives,
cellulose ethers, acrylic resins, such as methylacrylate
copolymers and copolymers. of m~leic acid and phthalic acid
derivatives.
The preferred films are made from cellulose acetate
li39Z2~
~ 7 - 100--5129
phthalate; copolymers derived from me~hylacrylic acid and
es-ters thereof, containing at least 40% methylacr~lic acid;
and especially hydroxypropyl methylcellulose phthalate.
~n example of an appropriate cellul.ose acetate phthalate is
the marketed product C~P (E~stman Kodak, P~ochester N.Y.,
USA). Example.s of suitable hydroxypropyl methyl cellulose
phthalates are the rnarketed products IIP 50 and HP 55
(Shinetsu, Tokyo, Japan).
- Since a coating consisting essentially of CAP
disintegrates at a higher pH as e.g. a coating consisting
essentially of HP 50 the release of the active agent from
compositions provided with the former coating will be morc
delayed than from compositions provided with the latter
coating. In such a way, one can,by suitable selection of the
coating, obtain a retard effect that takes into account the
properties of the active agent involved in an optimal way.
The process according to the invention may be carried
ou-t in a manner analogous to methods known for the
application of an enteric-coating.
20 For the preparation of coated tablets, pellets or
granules one proceeds e.g. by spraying the corcs
~ith a solution of the enteric-coating.
Suitable solvents for the enteric-coating are .~or
example organic solvents, e.g. an alcohol such as e~hanc)l,
a ketone such as acetone, halogenated hydrocarbons such as
CH2C12 or mixtures of ~uch so].vents, e.g. ethanal/acet:one
1:1. Conveni.er~tly a softener such as di-n-butylphthalate
:1139222
- 8 - 100-5129
(
is added to such a solution.
Con~eniently the cores are warmed up at 25 up to 40C
e.g. by means of warm air of 40 up to 70C, before
spraying. To avoid sticking of the cG.res the spray
procedure is prefera~ly interrupted at certain time
intervals and the cores 'chen waxmed up again. The spray
pressu~e ma;~ vary ,7ithin ~ide rangest in general
sati.sfactory results are obtained with a spr~y pressure
of from about 1 to about 1.5 bar. It is, ho~ever, also
possible to proceed ~ithout interru~tion o the spray
procedure, e.g. by automatic regulation of the spray amount
in function of the tem~erature cf exhaust air and/or co~es.
The enteric-coated compositions of the invention have
the ad~antageous property that, after p.o. a-dmir.istration
to man the maxim~n concentration of the active agent in the
blood plasma n~y be obtained after about 4 - 6 hours, whereas
the initial pea~ after administration of a ncrmal com osition
e.g. a tablet, is already reached after 0.5 - 1 hour.
The sust.ained reiease effect of the compositions of
the invention is also illustrated by clete~mination of the
concentra ior of active agent (and metabolites) in the
secreted urine: the maxln;um ccncentl-ation in the ~ine may be
found apprcximately G hours after aclministration ~herecls
this ma~imum is obtained af-ter about 2 hours when a normal
25 composition is ad~inistered.
ln acldition, the plasma level after ad~ istration
of the co~lpositions according to the in~ention n~y be bet~een
1~39~
- 9 - 100-5123
6 and 24 hours after application, higher than after
administration of a normal composition e.g. a tablet. This
is illustrated by the area under the plasma concentration
level (AUC) and is a measure of the excellent bioavailability
of the compositions of the invention.
Accordingly, the compositions of the invention show a
therapeutically desirable retard e~fect together with an
excellent bioavailability and allow consequently treat-
ment with one unit dGsage a day.
The compositions of the invention, especially the
tablets may in addition be covered by an outer medicament
layer. This outer layer may contain in addition to an
active agent, such as an ergot alkaloid, carriers and/or
fillers which are soluble or dispersible in the gastric
juices such as talc, microcrvstalline cellulose, magnesiurn
stearate, mannitol, polyvinylpyrrolidone etc..Such composi-
tions may for example be used when a rapid onset of the
activity is required. The high initial concentration of
the ergot alkaloid in the blood is then maintained by its
sustained release out of the core in the intestinal tract.
The optimal weight ratio in the core of ergot alkaloid:
sterol ether depends to a great extent on the physical
properties of the sterol ether involved, the adjuvants
used and the type and the size of the composition, e.g.
the amount oE the abovementioned sterol ethers of the
type Solulan~ 16, Solulan ~ 25 and Solulan~ C-24is limited
in view oE their waxy nature.
~39222
- 10 -- 10~-51~9
However, in general satisfactory results are obtained
when a weight ratio ergot alkaloid : sterol ether rrom
1:1 to 1:25, preferably from 1:2 to 1:8,especially 1:4,is
used. The range 1:2 to 1:8 is especially preferred ~hen the
cores are present in solid soluti.on form of the ergot
a].kaloid and especailly when polyvinylpyrrolidone is
used as solid solvent.
The cores may be compounded with conventional
excipients for example binding agents, lubricants, fillers
and disintegrants. Suitable fillers for the prepara'ion
of tablet cores are e.g. silicagel,calcium carbonate,
sodium carbonate, lactose, starch, talc; suitable granula-
ting and disintegrating agents are e.g. starch and alginic
acid; suitable binding agents are e.g. starch and gelatine
and suitable lubricants,stearic acid and talc.
The use of cores in solid solution form is a special
embodiment of the invention. Such cores may be prepared
as follows.
An ergot alkaloid, a sterol ether and a pharmaceuti-
cally acceptable polymer which .is at least partly solublein an aqueous medium, especially a polyalkylene ~31ycol,
polyvinylpyrrolidone, a copolymer of vinylpyrrolidone and
vinyl acetate or a mixture of these are mixed tocJether.
Suitable polyalkylene glycols include polyethylene
25 glycol and polypropylene glycol and their copolymers having
a molecular weight of 200 to 20,000, preferably 4000 to
15,000, more preferably 6000 to 13,000. Ry "polyvinyl-
~1392~
- 11 100-5129
pyrrolidone" is meant uncrosslillked poly (~-vinyl)pyrrGli~
done-2, suitably of molecular weight between 10,000 and
100,000, preferably 11,500 to 40,000, more pre~erably 20,000
to 30,000. The copolymer of vinylpyrrolidone and vinyJ
acetate preferably contains 60% by weight vinylpyrrolidone
and 40% by weight vinyl acetate and preferably has a
molecular weiyht of 30,000 to 100,000, more pre~erably
40,000 to 90,000.
When desired stabilizers such as acids, preferclbly
methanesulphonic acid, maleic acid or tartaric acid
are'added to adjust the pH of the composition. The preferred
pH range fo~ the composition is pH 4-6, preferably pH 4 5.
The weight ratio ergot alkaloid : sterol ether :
- pharmaceutically acceptable polymer may vary between wide
ranges; however, iIl general, satisfactory results are
obtained with ratios varying in the range 1 : 1 - 10: 0.1-10,
especially 1 : 2 - 8: 0.1 - 10 and more preferably
1 : 2 - 5: 0.1 - 5.
For the preparation of the solid solutions according
to the invention the polymers are employed in solid form.
In case one of the polymers uscd is liquid at roorr,
temperature, e.g. a polyalkylene glycol havinc~ a molccular
weight of about 200, then it is obvious that such a polymer
is not used alone, but in conjunction with a polyMer which
is solid at room ternperature.
The abovementioned constituents are dissolved by
stirring in a suitab,e solvent, for example in a lower
1~392;i~2
- 12 - 100-512~
alcohol such as etllanol or methanol, or in chloroform, at a
tempexature of from 30 to 70~C, preferably 40 to 60C, and
the solvent may be rernoved by evaporation under vacuum at
the same temperature. In the preparation of the solution it
is also possible to add on]y a part of the polymer and the
additional ingredients, if any, and to add the remainder
during the evaporation of the solvent. The resulting clear
solution is left to solidify at room ternperature (15 to 25C)
and the solid solution or dispersiGn may then he ground to a
fine powder and dried, suitably under vacuum at 30C, to
remove all traces of the solvent.
The solid solution (core of the composition) obtained
accordin~ to the above process is then compounded in known
manner with pharmaceutically acceptable diluents or carriers,
15 optionally with an additional amount of a sterol ether and
the total content of sterol ether in the core should
preferahly lie in the above given ranges.
The following examples illustrate the in-vention.
A11 temperatures are in degrees Celsius.
~39Z2:i~
- 13 - 10~-51~9
(
EX~`1PLE
rJablet cores cGnsisting of 3 g ciihydroergotamine 75 g
cholesterin which is ethoxylated with about 24 ml ethylene
oxide (Solulan~(C-24))and 22 g highly dispersed silicagel are
heated to 30 during 10 minutes ~Jith the aid of warm air of
50 in a coating pan which is repeatedly rotated. The
tablet cores are then sprayed, with the aid of a spray
pistol, with a solution of 5.4 g hydroxypropyl methylcel-
lulose r~hthalate (HP50) and 1.35 g di-n-butylp~thalate in
a 1:1 ethanol/acetone mixture at a spray pressure of
1 - 1.5 bar using conventional inte~val spray coating
procedures, and the so obtained coated tablets are
then dried.
EXA~PLE 2
One proceeds analogous to Example 1 using however
- 75 g lanolin alcohols ethoxylated ~ith about 25 equivalents
ethylene oxide (Solulan~ 25) instead o~ 75 g cholesterin
ethoxylated with about 2 4 mol ethylene oxide.
_~MPLE 3 - Coated tahlets wich core~ in solid solu~ion
form
15 g Dihydroeryotoxine methanesulphonate l.OS g
20 (Solulan~ C-24) 33.95 y po7yvinylpyrrolidone (average
molecular ~eight 25,000) and 250 ml methanol are charged
into a 1 litre rowld-bottomed flask. rhe flas}; is attaclled
to a rotary evaporator and rotated at a bath temperature
of 60 until the flas}; contents reach 60, by which time
a clear sollltion is obtained.
, . ,
- 1~3~2:~2
- i4 - 100-5129
The bath temperature is maintained at 60 and the
sol~7ent evaporateîd under reduced pressure until the residue
has a syrupy consistency. The residue is decanted into an
evaporating basin and left to solidify for 2 hours at room
temperature.
The solid residue is dried in a vacuum oven at 30,
ca. 1 Torr for ca. 12 hours, yround to a fine powder and
dried again.
26.8 g of the so obtained solid solutior. are then
mixed with the following adjuvants:
silicon dioxide1.0 g
(Aerosil~ 200, Deyùssa)
polyvinylpyrrolidone 8.0 g
(crosslinked)
corn starch 20.0 g
Talc 30.0 g
Solular~ C-24 30.0 g
cellulose granules42.0 g
(Elcema~G 250)
lactose 122.0 g
until an homogenous mixture is obtained and then pressed,
in conventional manner, to tablet cores of 140.0 mg
(hardness 10-32N).
The so obtainecl cores are thell, analo~ous to
Example 1, sprayed with a solu-tion of
1139222
- 15 - 100-51~9
cellulose acetate phthalate (C~P) 90.0 g
di-n-butylphthalate 22.5 g
acetone 240.0 g
ethanol 21.0 g
dichloromethane 526.5 ~
900.0 g
until the cores are coated with ca. 10 mg of the cellulose
acetate phthalate/di-n-butylphthalate mixture per core.
The so obtained coated tablets are resistant against
10 the gastric juices since the cores remain intact after a
treatrnent of 1 hour with artificial gastric juices of
pH = 1.2. The disintegration time in artificial intestine
juices is at pH 5.5 longer than 1 hour, and lies at pH 6.0
between 23-28 minutes and at pH 6.8 bet~een 12 and 16 minutes.
EXA~LE 4
One proceeds analogous to Example 3, sprayiny, however,
the tablet cores of 140 mg with a solution of 140.0 g
hydroxypropyl methylcellulose phthalate (HP 50) and 28 g
di-n-butylphthalate in a mixture of 616 g ethanol and 616 g
acetone, until the cores are coated with ca. 9 mg of the
20 hydroxyplopyl methylcellulose phthalate/di-n-butylphthalate
mixture (ratio 10:2) per core.
E~IPL~ 5
Analogous to Example 3 is obtained a solid solution
of 4 g dihydroergotoxine methanesulpholIate, 0.3 g Solulan 16
and 9.1 g polyvinylpyrrolidone (averaye mol ~eight 2000).
This solid solution is then mixed ~llth
1139ZZZ
-- 16 - 100-5129
( - .
silicon dioxide G.5 g
polyvinylpyrrolidone 4.0 g
(average mol weight 2000)
corn starch 10.0 g
t~lc 15.0 g
Solulan~ 16 15.0 g
cellulose granules 21.0 g
(~lcema G 250)
lactose 61.1 y
and this mixture pressed to tablets of 140.0 mg.
The so obtained tab].et cores are then sprayed,
analogous to Example 4, until each core is coated either
with ca 10 mg or with ca 15 mg of the mixture:hyaroxy-
propyl methylcellulose phthalate/di-n-butylphthalate.
Analogous to the procedure described in the above
Examples are obtained the tablets as listed below in
Table I.
In case Ib and Ic (see table) are used, the tablet
cores are in solid solution form.
1139222
~ 17 ~ 100-5;29
('
TABLE
¦E`~.~IPL~ 6 ¦ 7 ¦ 8 ~ ~ ~ J 13
Ia Dihydroergot- 4-0 4.0 4,0 4.0 4~04.0l _
oxinemesylate
Dihydroergot-
oxinemes~late 6.0 6,0
Ib Solulan~ C24 0,3 0.3 0,3 0.3 0,3 0.4
Ic Po]yvinyl-
pyrrolidone9.1 9.1 9.1 9.1 9,1 13.5
II Solulan~ C24 15.0 15.0 31.7 7.323.7 15.3 22,9 22.5
Sil;cion 2.4 2.4 0! 5 0~5 0,50,5 3.6 3,6
dioxide
corn starch24.0 24.0 10.0 10 0 10.010.0 35.0 36.0
Cellulose 72.0 72.0 21.0 21.0 21.021.0 108,C 108.0
.
.
lactose 110.8 110.8~4.4 68.8 52.461,1 '~'-o.4 lG6.4
~a~nesium 2.4 2.4 3.6 3.6
Kollidon~ 4 0 4.0 4~0 4.0
Polyvinyloyr- 9.1 13,5
rolidone(25)
talc 15.0 15.015. l
~3P~CP* 26.0 7,07.2 9.0 9.0 9.0 7,2 7.2
Di-n-butyl-
phthalate 1.8 _ _ _ 1,~ 1.8
. _._ . .. . , , ~ 1 )
total ~7ei~ht ?66.0 247.0 149.0 .l49 0 149.0 149.0 36~.0l369.
(rng)
*IIPMCP = Hydrox.ypropyl nlethylcellulose phthalate
(1) the cores of these tablets ~7ere pressed to possess
a hardness of 50-60N
, ,
q; . .
113922;~
. - i8 - 100-51~9
( ~ .
r X~ ~LE 14 : Tabl~-~t wlth an outer m.edic~.rent ~aver
~lântle table~)
a) The cores are p.repared analogous to Example 3 by mi:-
ing 26.8 g of a soli.d solution (consisting of 8.0 g
dihydroergotamiJIe Jn~sylate, 0.6 g So3ulan~)C-2~ and 18.2 g
polyvinylpyrroli.done) together with 1.0 g highly disperse
silicagel, 8.0 g crosslinked polyvinylpyrrolidorle, 20 g
corn starch, 47.4 g Solulan~ C-24, 42.0 g ce]lulose
granules, 104.8 g lactose and 30.0 g talc until the
mi~ture is homogenous. The mixture is then pressed to
cores of 140.0 mg.
b) The so obtained cores are sprayed ~J.ith a solution or
140.0 g hydroYypropyl methylcellulose phthalate and 28.0 g
di-n-butylphthalate in a mixture of 616 g ethanol and
15 616 g acetone, until the cores are coated with ca. 1.0 mg
per tablet.
c) The outer medicament layer is prepared ky mixing
4.0 g dihydroergotamine mesylate with 4.0 g highlv dis~ersed silica-
gel, 6.0 g magnesiwn stearate, 166.8 g cellulose powder,
20 40.0 g tâlc~ 191. 2 g corn starch and 348.0 g calcium
hydro(3en phosphate until the mixture is homogenous. Thi.s
mix~ture is then pressed ~ith the coa-tecl tablets (according
to Example 14 b) to prepare tablets with an outer medic~nent
layer, having a total weight of 530.0 mg per tablet.
E"~:~LE 15
One proceeds ana].ogous to any one ol Lxarl~lcs 1 to 14,
using 4 mg bromocryptine, 4 mg dihydroergovaline or4mcc~ ydro
~13922~
( - 19 - lC0-5129
,
er~onine instead of dihydxoeraoto~ine or dihydroerso-tar.line,
and oht~ins tablets containin~ the corresponding er~ot
alkaloid as active agen~.
EXAilPLE 16 : Clinical trial
_ _ _ _ _ _ _ _ _ . _ _ _
The composition according to EY.ample 4 ~7as com~ar~d
~ith a solid solution of dihydroergotoxine mesylate
(composition A) and a conventional composition of
dihydroergotoxine mesylate (composition B).
Each person treatecl obtained 4 mg dihydroergotoxine
mesylate.
The result is lis-ted in the follo~7ing table.
. _ ..... ..
Composition Example 4 B I A
. _ .. ...
Concentration in
Plasma alter
20' 0.0~7~0.012 o,,76fo,07& 0~2-~+0.064
40' 0.092+0.039 0,~72+0,070 0.50~ .0~9
Max. conc. in 0.615-0.077 0.507-0.071 0~538-0.037
plasma (ng.ml~l)
Time (in hours) 3.33-0,4~ 0.64-0.06 0.78-0,12
after ~hich max.
20 is reached
Bioavailability
AUC (0-24 hours) 4.77~-0.415 3.~75-0.279 3.754-0.171
(n~. ml
% eliminated by 1.010-0.154 U.737-0.121 0.740-0 . O o l
25 ~rine (0-96 hours) _ _
~ __
~139Z22
- 20 - 100-~129
The good retarding effect and the excellent bioavail-
ability of the composilion according to the i.nven~ion is
clearly illustrated by tne figures in the above table. On
the other hand, we found a clearly inferior b.ioavail-
abi.lity (60-7~% of composition B) when testing a marketed
composition of dihydroergotoxin retarded according to
conventional manner.
Analogous tests with other compositions accordiny
to the invention give similar good results. Additionally,
a marketed composition of dihydroergotamine retarded
according to conventional manner, showed a bioavailability
that was about 30 to 40~ inferior to that found with the
corresponding unretarded reference composition and
inferior to compositions according to the invention.
