CA1147657A

CA1147657A - Antihypertensive pharmaceutical compositions

Info

Publication number: CA1147657A
Application number: CA000346083A
Authority: CA
Inventors: David G. Holmes; Walter H. Aellig; Pavel Jerie; Walter Schutz
Original assignee: Sandoz AG
Current assignee: Sandoz AG
Priority date: 1979-02-22
Filing date: 1980-02-20
Publication date: 1983-06-07
Also published as: AT378915B; FR2449450B1; IE49073B1; AU538599B2; ZA801018B; HU187271B; IE800336L; IL59432A; IL59432A0; DE3005029A1; AU5574280A; MY8500619A; CH643457A5; PT70855A; BE881763A; SE8001121L; GB2044101A; IT8047950A0; ATA95580A; FR2449450A1

Abstract

Abstract ANTIHYPERTENSIVE PHARMACEUTICAL COMPOSITIONS

The present invention relates to the combination of a) 6-benzoyl-3-hydrazino-5,6,7,8-tetrahydxopyrido-[4,3-clpyridazine, b) a salidiuretic and c) pindolol and pharmaceutical composikions containing these active agents, useful e.g. for the treatment of hypertension.

Description

.~ 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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- 2 - 100-5141 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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0-51~11 ', 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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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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-~ 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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;7 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..
. .. ,.__. .. _ . . -- _.. , _ 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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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 .
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total 310.0 - - '' '' ' ' .. ,. I ---------- - -. . _ _ . _ _ . _ _ _ _ . _ 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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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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Claims

Claims:

1. An anti-hypertensive pharmaceutical composition comprising as active agents a) endralazine b) a salidiuretic and c) pindolol.
the weight ratio of active agent a), b) and c) being from about 1:30:2 to about 1:0.01:0.5 respectively.

2. A composition according to claim 1 wherein active agent b) is hydrochlorothiazide or metolazone.

3. A composition according to claim 1 wherein the active agent b) is clopamide.

4. A composition according to claim 3 wherein the weight ratio of active agent a), b) and e) is from about 1:2:2 to about 1:0.25:0.5.

S. A composition according to claim 4 wherein said weight ratio is 1-1:2.

6. A composition according to claim 4 wherein said weight ratio is 1:0.5:1.

7. A composition according to claim 4 wherein said weight ratio is 1:1:1.

8. A composition according to claim 1, 3 or 4 wherein the endralazine component is in sustained release form.

9. A composition according to claim 1, in unit dosage form.

10. A composition according to claim 9 having 5 mg of active agent a).

11. A composition according to claim 9 having 10 mg of active agent a).

12. A composition according to claim 9 having 20 mg of active agent a).

13. A pack containing active agents a), b) and e) as stated in claim 1, at least one of which is presented separately, for the concomitant administration in the treatment of hypertension.