Note: Descriptions are shown in the official language in which they were submitted.
~95411
This inverltion is concerned with improvements
in and relating to pharmaceutical compositions 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 same
of convenience such materials will hereinafter be simply referred to
as "cardiac gl~-cosides".
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 arnount of the
active ingredlent, (e. g. 250 micrograms or less) since these
particular active agents are administered in such very small
doses, almost always less than 0. 5 mg. l`he fact that each tal)let
has to contain so little of the active ingredient gives rise to
problems in formulation and, in particular, rnakes it very difficult
to ens~lre perfect compounding of the tableting mix SO ~hat each
tablet contains the same amount, wi~h tolerable lirnits, of the active
ingredient, (see, for example, Thomas et al, The Lancet, l~ecember
1, 1973, pp 12ti7-8; Fraser et al, 5, Pharm. Pharmac., 1973,
2~ 25, p~ 2G8-973; and Shaw et al, British Medical .rournal, i973, 4,
pp 76~-76fi).
Tl is an object of the present inventiol~ to provide an
1~95411
improved dosage unit suitable for the oral administration of
a cardiac glycoside.
Accordingly, the present invention provides a
cardiotonic dosage unit form comprising a soft gelatine capsule
containing a liquid cardiotonic composition comprising
.
(a) a cardiac glycoside; (b) ethanol;
(c) water; (d) propylene glycol and/or glycerin,
and te) a liquid polyethylene glycol.
The cardiac glycoside used in the compositions of the
invention may be, for example, digoxin, digitoxin, digitalin,
ianatoside C, acetyl digitoxin, acetyl digoxin or methyl digoxin,
The most generally preferred cardiac glycosides are digitoxin
and Aigoxin, especially the latter.
'l'he compositions in accordance with the invention will
generally be prepared by dissolving the cardiac glycoside in a
mixture of the ethanol and water and for this purpose .it is generally
preferred that the amount of water bc as sm..ll as possible but s-ufficient
to ensure solution of the active ingredient in the water/a].cohol
mixture and will rnost generally be present in an amount by
weight less than the amount by weight of ethanol, the water
1095~
;~ prefor~blJ- for~ing less than 25% by weight of the total water/
~ he
ethanol mixture. SuitablJ th^ 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
propylene glycol (glycerin) polyethylene glycol mixture and the
polyethy].ene glycol forms the major component of the compositions
b41ng
of the invention generally~g present in the amounts of at least
75% by weight, preferably from 80-95% by weight, of the total
composition contained in the soft gelatine capsule.
The gelatine capsule will be one formed of gelatine
containing a plasticiser such as glycerine, propylene glycol,
diethylene glycol or hexanetriol, Further, the plasticiser
may comprise one of those me.ltioned ahove together with
sorbitol in order to improve the properties of the capsules with
respect ot exposure to moisture containing atmospheres. The amo-ul-lt
of sorbitol will preferably be about equal to the amount of glycerin
or other plasticiser. Accordingly-, a preferred capsule comprises
gelatin plasticised with from a.bout 8 to 15% of weight of glycerin
preferably about 12. 5% by weight, and from 12, 5 to 15% by weight of sorbifo].preierc~bly àbout 13. 5% cf sorbitol, the percentages being based on
the tctal weight of gelatin, glycerine and sorbitol.
109541 .l
The total weight of ingredients contained in the gelatine
capsule of the compositions of the invention is suitably from
about 100 to 300 milligrams, and, clearly, the weight of cardiac
glycoside contained in each capsule will be that generally required
for a unit dose, for example from 50 to 300 micro grams.
The compositions of the invention are prepared in the
liquid phase so that it is possible to obtain accurate and consistent
dispersion of the active ingredient(cardiac glycoside) throughout
the liquid phase o:f 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.
lt has also been found, that the unit dosage forms
of the invention give better or more rapid availability of the active
ingredient (as indicated by release tests carried out in artificial
gastric juices) than do comparable L~blets. Thus, it has been found
not only do the capsules of the invention give a more rapid release
of their contents but also that they give a more complete release
of their content than do the tablets which frequently release only
about 50% or less of their contents. It will be appreciated, therefore,
that the capsules of the invention constit-ute a much more reliable dosage
unit than do many tablets since they can be relied UpOll to release
substantially all of their active ingredient content within a relaiively
1t~9541~
short period of time whereas this is not the case with tablets,
In order that the invention may be well understood the
following examples of formulations for 140 and 280 milligram
capsules are given by way of illustration only,
EXAMPLE 1
140 Mg capsule containing 62,50 micrograms of digoxin.
Digoxin 0.0625 mg,
Ethanol abs, 8,5 mg
Water 1,5 mg,
Propylene glycol 4.75 mg
PEG 400 125,1875 mg
EYAMPLE 2,
140 Mg capsule containing 150 micrograms of digoxiD,
Digo~in 0.125 mg
Ethanol abs. 8.5 mg.
Water 1.5 mg
Prowlene glycol 4,75 mg
PEG 400 125,125 mg
lO9S~
EXAMPL:t3 3
280 Mg capsule containing 250 micrograms of digoxin.
Digoxin 0. 250 rng
Ethanol 17, 0 mg
Water 3. 0 mg
Propylene glycol9. 5 mg
PEG 400 250. 25 mg.
The rate of dissolution of, in 0. 6% H Cl of.
two capsules (capsules A and B) in accordance with Example 3
and a capsule (capsule C) in accordance with Example 1 was
investigated by the rnethod of E~eckett et al (The Pharmaceutical
Journal, August, 11, 1973, pp 111 and 112) and the results are
shown in the following table which also shows, by way of comparison,
the results obtained in similar tests for commercially available tablets
containingr a stated 0. 25 mg. of digoxin, Tablets, A, B, C and D, were
four capsules of the same commercially tablet and tablets E, E and
G were single samples of other commercially available tablets.
1095All .
TABLE
Percentage of di~oxin content dissolved,
Time _ Capsules Tablets
(minutes) A B C A B C D E F G
8 625 - - - - - - -
12 1468
31 ~0100 19 29 29 76 - - 69
- 72 - - - _ _ _ _ _
91 95 - 28 35 29 ~0 25:l 3079
- 93 - _ _ _ _ _ _ _
_ _ 37 45 53 95 - - 100
120 _ _ _ _ _ _ _ _ _103
240 93 _ _
, ~ , ,, . . . ~ .. .. . ... .. ~
