Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
.~ 765~ 100~5141
ANTIHYPERTENSIVE PHARMACEUTICAL COMPOSITIONS
Thls invention relates to anti~ypertension an~
'~ pharmaceutical co~positions therefor.
Various types of hvvertension exist and many diffe-
rent active agents are known for treating hypertension,
but these all have limitations. For example salidiuretics,
; beta-blocking agents such as pindolol and peripheral vaso-
- dilating agents have been successfully used. A recent
clinically tested anti-hypertensive agent with peripheral
10 vasodilating activity is 5-benzo~1-3-hyfl.xa2inc-5,5,7,8-te-
trahydropyrido~4,3-c]pyridazine also known as BQ 22-70~
and which has the generic name, and is hereinafter referred
to as, endralazine.
~;~ It has now heen surprisinyly found from clinical
15 trials that the co-administration of the following active
agents:-
a) endralazine
b) a salidiuretic and
` c) pindolol
20 and pharmaceutical compositions containing these active
~^~ agents lead to especiaIly advantageous anti-hypertensive
`. effects suitable, e.g. for the treatment of moderate to
severe hypertension, even when treatment with beta-blocking
agents and/or salidiuretics has been unsatisfactory. These
25 effects include a quick onset and high level of activity.
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Moreover, these effec~s are much more bene~icial
than could be expected in view of the activities of each of
the active agents a~, b) and c). The compositions are well
tolerated and provoke surprisingly little oedema and tachy-
cardia and other undesirable side effects of peripheralvasodilation.
Accordingly in one aspect the present invention pro-
vides a pharmaceutical composi~ion comprising as active
agents:-
` 10 a) endralazine
b) a salidiuretic and
c) pindolol.
These compositions may be made in conventionalmanner using conventional galenical techniques, if desired
using suitable pharmaceutical excipients. For example active
agents a), b) and c) may be mixed together. As endralazine
has in general a shorter duration of activity than pindolol,
it is preferred to provide the endralazine component in
su~tained release form, e.g. in a wax matrix. Endralazine
is susceptible to moisture so i.t is preferred to use dry
galenical technlques and pharmaceutical excipients chosen
; from the following: lactose, PVP, colloidal silica, talc
and preferably calcium sulphate, corn starch and magnesium
stearate. These and other conventional pharmaceutical ex-
cipients may be mixed with acLive agents b) and c), e.g.
diluents, fillers, granulating agents, disintegrating
agents, binding agents, lubricating agents, dyes, and sta-
bilizing agents.
-~ In another aspect the present invention accordirgly
provides a process for the production of a pharmaceutical
compos;tion as defined above which comprises formulating
active agents a), b) and c) together, if desired active
agent a) being so formulated to be released in gastro-in-
testinal juices more ~lowly than active agent c).
- 35 The ~inal compositions are preferably in solid form
arld may be granules, pellets, capsules, dragees or tablets.
` It is pxeferred to have a unit dosage form, preferably a
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mantle tablet, with a sustained re]ease ccre containing the
endralazinP component r and an outer layer containing the
active agents b) and c), which releases these two active
agents before active agent a) in the gastro-intestinal
juices,
In a further aspect the present invention provides
a method of treating a hypertensi~te subject which comprises
administering concomitantly effective ~no~mts of active
agents a), b) and c) as stated above.
In yet a further aspect the present i~vention pro-
vides a pack containing active agents a), b) and c) as sta-
ted above, at least one of which is presented separately,
for concomitant administration in the treatment of hyper-
tension. Conveniently the pack is provided with instructions
for the concomitant administration of pxedetermined amounts
of active agents a), b) and c).
In genera- any salicliuretic may be used as active
agent b). ~ suitable salidiuretic is e.g. one of the ollo-
wing:-
2-aminomethyl-4 tert-butyl-6-iodophenol (~IK 447); bendroflu-
methiazide; benzthiazide; bumetanide; chlorothiaæide: chlor-
thalidone; clopamide; cyclothLazlde; ethacrynic acid; furo-
semide; hydrobenzthiazide; hydrochlorothiazide; hydroflume-
thiaziae; methyclothiazide; metolazone; polythiazide; quine-
; 25 thazone; ticrynafen; trichlorme~hiazide.
Particularly suitable salidiuretics are hydrochloro-
thiazide and metolazone. With salidiuretics causing relati-
veIy lit~le potassium loss and particularly with c:Lopamide,
especially advantageous effects have been observed.
The active agents may be in free form or in pharma-
ceutically acceptable salt form, e.~. in pharmaceutically
~, acceptable acid addition salt form. Acids suitable for salt
formation include hydrochloric acid, fumaric acid, methane-
; sulfonlc acid, hydrobromic acid, sulfuric acid and maleic
~ 35 acid.
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Endralazine is conveniently provi.ded in methane
sulphonate salt form, pindolol is conveniently provided in
free base form, and the salidiuretic is also conveniently
: in free base form.
The activity of any pharmaceutically accep-table
salt form of active agent a) r b~ or c~ is general].y of the
same ordex as that of t~e respective free base form. How-
ever as used herein, except when othe:rwise sta-ted, all
amo~mts of active agents a~, b~ and c) refer to the amount
of free base form. Similar considerations apply to weight
ratios.
.~ The active agents a~, b~ and c~ when administered
~r concomitantly or in combination are useful in the treatment
~: - of hypertension in standard clinical trials with hyperten-
sive subjects. For example, in one clinical trial 56 hyper-
tensive subjects sufferiny from moderate to severe hyperten~
sion were treated with a daily dose of 2.5-20 mg o~ endrala-
zine, 5 mg clopamide and 10 mg of pindolol. The active age.nts
. were admin~stered once or twice a day over several weeks and
- 20 generally all the active agents were admini.stered at the
same time of day. The blood pressure was recorded twice
daily and was found to fall to normal levels. A low number
and frequency of side effects was recorded also~ .
As indicated in these clinical trials fixed combi-
nations are well received by a large number of hypertensive
subjects.
For the treatment of hypertension the exact daily
: dosages of active agents a), b) and c) will, of course,
vary depending on the salidiuretic employed, the mode of
administration, and the condition to be treated.
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- 5 - 100-5141
However, in general, the total daily dosage is in
the range of from about 5 mg to about 40 my of active
agent a) and preferably from a~out 5 to 20 mg. The daily
dosage of active agent b) is generally in the range from
about 20 to 1006 of the daily dose indicated for its use
as a diuretic for the treatment of oedema. In the case of
clopamide, the preferred daily dose is generally in the
range from about S to about 10 mg. The daily dosage of
active agent c) is generally from a~out 10 to abo~t 20 mg.
:~ 10
Conveniently these active agents a), b) and c)
are administered in divided doses 2, 3 or 4 times a day,
containing, e.g. 5 or 10 mg of active agent a), or prefera
bly in a single dose once a dQy containing, e.g. 10 or 20 mg
of active agent a).
An indicated weight ratio of active aae~ts a), b)
and c) is from about 1:30:2 to about 1:0.01:0.5 respectively.
Naturally the weight r~tio will depend on the salidiuretic
used. For hydrochlorothiazide a suitable weight ratio of
active agents a), b) and c) is from about 1:20:% to about
1:2.5:0.5. For clopamide and metolazone a suitable weight
ratio of active agen~s a), b) and c) is from about 1:2:2 to
about 1:0.25:0.5. For clopa~de pre~erred~,eight ratios are 1:1:2 to
1:0.5:1, and especially 1:0.5:1; 1:1:1 and 1:1:2.
Indicated weight ratios when active agent b) is
, other than clopamide, metolazone and hydrochlorothlazide
may be formulated by taking into account the activity of
the particular salidiuretic compared to the known salidiu-
retic activities of the clopamide, metolazone an~ hydro-
chlorothiazide.
As will be appreciated pindolol is the generic term
for 4-(2-hydroxy-3-isopropylaminopropoxy)indole, and clopa-
mide is the generic term for N-[cis-2',6'-dimethylpiperidyl-
(1')]-3-sulfamoyl 4~chlorobenzoic acid amide.
The following examples illustrate the compositions
of the invention.
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- 6 - 100-5141
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-~ Exam-~le 1: Tablet
. The following composition may be formulated
; using standard tabletting techniques and is useful
for oral administration once or twi.ce a day for the
- treat~ent of ~oderate or severe hypertension.
.2
. In~redient Tablet
.~ ... ,.,~ ,,, ._ _ (mg ) _ __ .
~ndralazine (in methane
: sulfo~ate form) - 13~5 (=10 mg
base)
. Clopamide (in free base form) 10
Pindolol (in free base form) 10 i.
Lactose 58.5
Corn starch ~0
~ Silica (colloidal) 0.5
.~ . Polyvinylpyrrolidone 5
Talc 5
Magnesium stearate ,~
total 153.5
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The three active agents are mixed with the lactose,
the colloidal silica and a portion of the corn
starch. The mixture is sieve~ anc kneaded
with an alcoholic solution of polyvinylpyrrolidone.
T~e is again sieved, dried and the dry __ _
granulate broken down. The
; remaining corn starch, talc and magnesium stearate are
then added and the mix-ture pressed into a table-t.
,
Example 2: Retard tablet
10The following composition may be formulated
~- using standard tabletting techniques and is useful
for oral administration once a day fo~ t~ treatment
of moderatQ or seve~e hy~ertsnsion..
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Ingredient Tablet
15 Core
Endralazine (in methane
sulfonate for~) 13.6
Hy~ro~enated cas~or oil 65.9
Paraffin 8.0
20 Corn starch 11.5
Magnesium stearate 1.0
; -total 100.0
~ressed coat
~,., .
Clopamide ~in free base form) 5.0
Pindolol (in free base form) 10.0
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; - 8 100-5141
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Ingredient Tablet
. (m(3) .
Cellulose (microcrystalline) 172.5
Modified corn starch (Sta-R 1500
Staley Co., Decatur, Ill.X USA) 21.0
Silica (colloia~O 0.4
Ma~nesium stearate 1.1
. ._ .. . . . .......
: total 210.0 .
_ _n~_._ __ _ _ _ __ __~ A. __._ _ -- . _ _ _ .
total 310.0
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Example 3:
Clopamide may be replaced by the same weight of
metolazone (in free base form) in the formulations of
~:,
: Examples 1 and 2.:
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Example ~:
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Clopamide may be replaced by hydrochlorothiazide
:, 15 (in free base form) in the iormulat10ns of Exam. les 1
.:. (~00 m~ in lieu-of 10 mg) and 2 (50 mg in lieu of 5 mg).
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