COMPOSE CARDIOTONIQUE

CARDIOTONIC COMPOSITION

Abrégé anglais

ABSTRACT OF THE DISCLOSURE
A cardiotonic dosage unit form comprises a soft
gelatine capsule containing a liquid cardiotonic composition
comprising (a) a cardiac glycoside, preferably digitoxin or
digoxin; (b) dimethyl formamide or dimethyl acetamide; and (c)
a liquid polyethylene glycol and also, optionally, (d) propylene
glycol or glycerin. The weight ratio of dimethyl acetamide or
dimethyl formamide to cardiac glyceride is from 5:1 to 15:1
and the polyethylene glycol forms at least 75% by weight of the
total composition contained in the gelatine capsule.

Revendications

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A cardiotonic dosage unit form comprising a soft
gelatine capsule containing a liquid cardiotonic composition
comprising (a) a cardiac glycoside; (b) dimethyl formamide or
dimethyl acetamide; and (c) a liquid polyethylene glycol the
weight ratio of dimethyl acetamide or dimethyl formamide to cardiac
glyceride being from 5:1 to 15:1 and the polyethylene glycol
forming at least 75% by weight of the total composition contained
in the gelatine capsule.
2. A composition as claimed in claim 1 also containing
propylene glycol or-glycerin.
3. A composition as claimed in claim 1 in which the
cardiac glycoside is digitoxin or digoxin.
4. A composition as claimed in claim 1, 2 or 3 in
which the polyethylene glycol forms from 80 to 95% by weight of
the composition contained in the soft gelatine capsule.
5. A composition as claimed in claim 1, 2 or 3 in
which the gelatine capsule contains from 100 to 300 milligrams
of composition.
6. A composition as claimed in claim 1, 2 or 3
containing from 50 to 300 micrograms of cardiac glycoside.

Description

641~
This invention is concerned with improvements
in and relating to pharmàceutical composition~ and,
more particularly, relates to cardiotonic compositions
containing, as active ingredient, a cardiac glycoside
derived from Digitalis purpurea or Digitalis lanarta
or a derivative thereof. For the sake of convenience
such material will hereinafter be ~impl~ referred to
as "cardiac glycosides".
Cardiac glycosides are widely used cardiotonic
agents and are commonly formulated as tablets for oral
administration. Of necessity, each tablet must contain
a very small amount of the active ingredient, (e.g. 250
micrograms or less) since these parti ular acti~e agents
are administered in such verg small doses, almost always
less than 0.5 mg. The fact that each tablet has to
contain so little of the active ingredient gives rise
to problems in formulation and, in particular, makes
it very difficult to ensure perfect compounding of the
- tableting mix so that each tablet contains the same
amount, with tolerable limits, of the acti~e ingredient,
(see, for example, ~homas et al, The ~ancet, December
1, 1973, pp 1267-8; Fraser et al9 5, Pharm. PharmacO,
197~, 25, pp 268-97~; and Shaw et al, Bribish Medical
~ournal, 1973, 4, pp 763-766).
It is an object of the present invention to provide
an improved dosage unit suitable for the oral admini-
stration of a cardiac glycoside.
Accordingl~, the present invention provides a
cardiotonic dosage unit form comprising a soft gelatine
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capsule containing a liquid cardiotonic composition comprising
(a) a cardiac glycoside; (b) dimethyl formamide or, preferably,
dimethyl acetamide; and (c) a liquid polyethylene glycol; and
optionally also (d) propylene glycol or glycerine.
The cardiac glycoside used in the compositions of the
invention may be, for example, digoxin, digitoxin, digitalin, b
lanatoside C, acetyl digitoxin, acetyl digoxin or methyl digoxin.
The most generally preferred cardiac glycosides are digitoxin
and digoxin, especially the latter.
The compositions in accordance with the invention will
generally be prepared by dissolving the cardiac glycoside in the
dimethyl acetamide or dimethyl formamide. The weight ratio of
dimethyl acetamide to dimethyl formamide to cardiac glycoside
is from 5:1 to 15:1 by weight preferably forming less than 25%
by weight of the total water/ethanol mixture. Suitably the
weight ratio of water/ethanol mixture of cardiac glycoside is
of the order of about 80:1 or even higher.
The solution of cardiac glycoside is mixed with the
polyethylene glycol (optionally containing propylene glycol or
glycerine) and the polyethylene glycol forms the major component
of the compositions of the invention being present in the amounts
of at least 75% by weight, preferably from 80-95% by weight, of
the
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total composition contained in the soft gelatine capsule~
~ he gelatine capsulè will be one formed of gelatine
containing a plasticiser such as gl~cerine, propylene
glycol, diethylene glycol or hexanetriol. ~urther, the
plasticiser may comprise one of those mentioned above
together with sorbitol in order to improve the proper-
ties of the capsules with respect to exposure to moisture
containing atmospheres. ~he amount of sorbitol will
preferably be about equal to the amount of glycerin
or other plasticiser. Accordingly, a preferred capsule
comprises gelatineplasticised with from about 8 to 15%
by weight of glycerin preferably about 12.5% by weight9
and f~om 12.5 to 15% by weight of sorbitol preferably
about 13.5% of sorbitol, the percentages being based
on the total weight ofgelatine glycerine and sorbitol.
~ he total weight of ingredients contained in the
gelatine capsule of the compositions of the invention
is suitabl~ from about 100 to 300 milligrams, and,
clearl~, the weight of cardiac glycoside contained in
each capsule will be that generally required ~or a unit
dose, for example from 50 to 300 microgram~.
The compositions of the invention are prepared in
the liquid phase so that it is possi~le to obtain accurate
and consistent dispersion of the acti~e ingredient (cardiac
glycoside) throughout the liquid phase of the composition.
Accordingly, it is possible to ensure that each dosage
unit (i e. capsule) contains the same amount (within
tolerable limits) of the active ingredient.
It has also been found, that the unit dosage forms
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of the invention give better or more rapid availability
of the active ingredient`(as indicated by release tests
carried out in artificial gastric ~uices) than do
comparable tablets, Thus, it has been found not only
do the capsules of the invention give a more rapid release
o~ their contents but also that they gi~e a more complete
release of their content than do the tablets which fre-
quently release onl~ about 50% or less of their contents.
It will be appreciated, therefore, that the capsules of
the invention cons.titute a much more reliable dosage
unit than do many tablets since they can be relied upon
to release substa~tially all of their active ingredient
content within a rel~tively short period of time whereas
this is not the case with tablets.
In order that the invention ma~ be.well understood
the following examples of formulations for 140 and 280
milligram capsules are given by way o~ illustration onl~.
Ex_mPle~1
140 M~_capsule containing 131 micro~rams of di~ox~n
Digoxin 00131 mg
Dimethyl acetamide o.75 ~mg
PEG 400 140~119 mg
amPle 2
1~2_~E_~Qpsule. containin~ 66 micro~rams of di oxin
Digoxin 0.066 mg
Dimethyl acetamide0.75 mg
PEG 400 140.559 mg
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140 Mg capsule containin~: 263 micrograms~ of di~;oxin
I)igoxin 0. 263 mg
Dimethyl acetamide 4. 500 mg
PEG 400 139~237 mg