Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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PHARMACEUTICAL COMPOSITION CONTAINING ERGOT ALKALOIDS
This invention relates to new pharmaceutical com-
positions of ergot allcaloids.
The invention provides pharmaceutical compositions
comprising a solid solution or dispersion of one or more
ergot alkaloids in pharmaceutically acceptable solid
polymer which is soluble or swellable in gastric juices.
In the term "ergot alkaloids" is included naturally
occurring ergot alkaloids for example ergotamine, ergo-
cristine, ergocrypine and ergocornine; their synthetic
derivatives, for example ergovaline; their hydrogenated
forms, for example dihydroergotamine, and the salts of
any of these. Suitable salts are those derived from
pharmaceutically acceptable acids, for example organic
acids such as methanesulphonic, tartaric and maleic
acids or inorganic acids such as hydrochloric acid.
Preferably the polymer is a polyalkylene glycol,
polyvinylpyrrolidone, a copolymer of vinylpyrrolidone
and vinyl acetate or a mixture of these. If mixtures
of polymers are used, the proportion of different polymers
in the mixture is not critical; preferably, however, equal
quantities of two or three different polymers may be present.
In the case of mixtures, one or more of the polymers may
be a liquid, for example a low molecular weight polyalkylene
glycol, provided that the resulting mixture of polymers is
a solid.
Suitable polyalkylene glycols include polyethylene
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glycol and polypropylene glycol and their copolymers having
a ~olecular weight of 200 to 20,000, preferably 4000 to
15,000, more preferably 6000 to 13,000. By "polyvinyl-
pyrrolidone" is meant uncrosslinked poly (N-vinyl)pyrrolidone,
suitably of molecular weight between 10,000 and 100,000,
preferably 11,500 to 40,000, more preferably 20,000 to
30,000. The copolymer of vinylpyrrolidone and vinyl acetate
pr~ferably contains 60% by weight vinylpyrrolidone and 40%
by weight vinyl acetate and preferably has a molecular weight
of 30,000 to 100,000, more preferab~y 40,000 to 90,000.
The solid solution or dispersion of ergot alkaloid
and polymer may also contain certain additional pharma-
ceutically acceptable ingredients, particularly surfactants
such as sodium lauryl sulphate or polyethylene glycol fatty
acid esters, preferably polyethylene glycol stearate; and
stabilisers such as acids, preferably methanesulphonic
acid, maleic acid and tartaxic acid, to adjust the pH of
thé composition. The preferred pH range for the composition
is pH 4-6, preferably pH 4-5.
In the solid solution or dispersion, the proportion
by weight of ergot alkaloid to solid polymer together
with additional ingredients, if present, may lie between
0.1:99.9 and 50:50, preferably between 5:95 and 15:85.
Wh~re additional ingredients are present, the proportion
by weight of the additional ingredients to the ergot
al~aloid is suitable from 1:45 to 10:1.
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The solid solution or dispersion is preferably a
tru~ solid solution of the ergot alkaloid in the polymer;
that is, it consists of only one solid phase. It may,
how~ver, consist of a finely dispersed discontinuous phase
of the ergot alkaloid in a continuous phase or matrix of
the polymer.
The invention also provides a process for the-pre-
par~tion of pharmaceutical compositions comprising the step
o~ working up one or more ergot alkaloids into a solid
solution or dispersion in a pharmaceu~ically acceptable solid
polymer which is soluble or swellable in gastric juices,
preferably consisting of a polyalkylene glycol, polyvinyl-
pyrrolidone, a copolymer of vinylpyrrolidone and vinyl acetate,
or ~ mixture of these. The solid solution or dispersion may
be ~sed without further admixture, or may be compounded in
kno~n manner with one or more conventional pharmaceutically
acceptable excipients, and optionally with additional active
ingredients.
Preferably, the solid solution or dispersion is
obtained by dissolving the ergot alkaloid, the polymer and
optionally any additional ingredients in a common solvent
and evaporating to dryness the clear solution so obtained.
Suitable solvents include lower alcohols, having from 1 to 4
carbon atoms, for example ethanol and methanol. The solids
are suitably dissolved by stirring with the solvent
at a temperature of fro~ 30 to 70C,
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preferably 40-60C, and the solvent may be removed by
evaporation under vacuum at the same temperatures. In
the preparation of the solution it is also possible to
add only a part of the polymer and the additional in-
gredients, if any, and to add the remainder during the
evaporation of the solvent. The resulting clear solution
is left to solidify at room temperature (15-25C) and
the solid solution or dispersion may then be ground to a fine powder
and dried, suitably under vacuum at 30C, to remove
all traces of the solvent.
The solid solution or dispersion may be used in the
preparation of galenic forms such as tablets and capsules.
For this purpose it may be compounded with conventional
excipients for example binding agents, lubricants, fillers
and disintegrants as well as colouring agents, sweeteners
and flavouring agents.
In the preparation of tablets, calcium carbonate,
sodium carbonate, lactose, starch and talc may be used
as fillers; starch and alginic acid as granulating and
disintegrating agents; starch and gelatine as binding
agents and magnesium stearate, stearic acid and talc as
lubricants. Common pharmaceutical retarding agents such
as waxes, fats, cellulose derivatives and other polymers
may also be used. The tablets may be uncoated or coated
in known manner.
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In the preparation of soft gelatine capsules, the
solid solution or dispersion is compounded in known manner
for example with a mixture of glycerol, sorbitol and
water together with preservative and optionally colouring
matter. For filling hard gelatin capsules~ the solid
solution or dispersion may be used alone or compounded in
known manner with pharmaceutically acceptable diluents
or carriers.
The pharmaceutical compositions according to the
present invention have the advantageous property of giving
increased absorption of the ergot alkaloids into the ;~
bloodstream of the recipient, thereby enhancing the
known pharmacological properties of the ergot alkaolids.
The following Examples illustrate the invention:
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EXAMPI,E 1:
34.6 g Dihydroergotamine methane6ulphonate, 195.4 g
polyvinylpyrrolidone (av. mol.wt. ~5,000) and 500 ml
methanol are charged into a 4 1 round-bottomed flask,
which is then attached to a rotary evaporator. The flask
is rotated at a bath temperature of 60C, until the
flask contents reach 60~C, by which time a clear solution
is obtained.
The bath temperature is maintained at 60C and the
pressure is reduced to approx. 250 Torr. Methanol is
removed by evaporation until the residue has a syrupy
consistency. The residue is decanted into an evaporat~ng
basin and left to solidify for two hours at room tem~
perature. The solid residue is dried in a vacuum oven at
30C, 1 Torr for 12 hours, ground to a fine powder and
dried again.
EXAMPLE 2:
34.6 g Dihydroergotamine methanesulphonate, 193.2 g
polyvinylpyrrolidone (av. mol.wt. 25,000) 2.26 g polyethylene .
glycol (1800~ stearate and 500 g methanol are charged into
a 4 1 round-bottomed flask. The procedure of Example 1
is repeated, to obtain a dry powdered mixture.
EXAMPLE 3: Tablet Composition
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The following ingredients are compounded together
in conventional manner and formed into tablets in a
tablettin~ press:
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Solid mixture of Example 1: 16.3 parts by weight `
lactose 104.0 " " "
corn starch 15 " " "
talc 12 " " "
cellulose powder32 l' ~' l'
silicon dioxide0.7 l~
EXAMPLE 4: Composition for soft ~elatin capsules
The following ingredients are compounded together
in conventional manner and the mixture used to fill soft
gelating capsules: :
Solid mixture of Example 1: 16.3 parts by weight ~`
Glycerol 9 " " " -
Polyethylene glycol 400 74.7 " " "
EXAMPLE 5: Composition for hard g_latin capsules
The follow$ng ingredients are compounded together .;
in conventional manner and the mixture used to fill hard
gelating capsules: -
Solid mixture of Example 1: 16.3 parts by weight
Silicon dioxide 0.7
~ corn starch 13
., lactose 65 " " " `.
, EXANPLES ~-8
Examples 3-5 are repeated using the solid mixture
of Example 2.
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