GB2044101A - Antihypertensive pharmaceutical compositions - Google Patents
Antihypertensive pharmaceutical compositions Download PDFInfo
- Publication number
- GB2044101A GB2044101A GB8005245A GB8005245A GB2044101A GB 2044101 A GB2044101 A GB 2044101A GB 8005245 A GB8005245 A GB 8005245A GB 8005245 A GB8005245 A GB 8005245A GB 2044101 A GB2044101 A GB 2044101A
- Authority
- GB
- United Kingdom
- Prior art keywords
- composition according
- active agents
- active agent
- weight ratio
- endralazine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 9
- 230000003276 anti-hypertensive effect Effects 0.000 title claims description 4
- 206010020772 Hypertension Diseases 0.000 claims abstract description 17
- ALAXZYHFVBSJKZ-UHFFFAOYSA-N endralazine Chemical compound C1CC=2N=NC(NN)=CC=2CN1C(=O)C1=CC=CC=C1 ALAXZYHFVBSJKZ-UHFFFAOYSA-N 0.000 claims abstract description 16
- 230000000054 salidiuretic effect Effects 0.000 claims abstract description 16
- 229960002029 endralazine Drugs 0.000 claims abstract description 15
- 229960002508 pindolol Drugs 0.000 claims abstract description 11
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229960002003 hydrochlorothiazide Drugs 0.000 claims abstract description 8
- AQCHWTWZEMGIFD-UHFFFAOYSA-N metolazone Chemical compound CC1NC2=CC(Cl)=C(S(N)(=O)=O)C=C2C(=O)N1C1=CC=CC=C1C AQCHWTWZEMGIFD-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229960002817 metolazone Drugs 0.000 claims abstract description 8
- PHUTUTUABXHXLW-UHFFFAOYSA-N pindolol Chemical compound CC(C)NCC(O)COC1=CC=CC2=NC=C[C]12 PHUTUTUABXHXLW-UHFFFAOYSA-N 0.000 claims abstract 2
- 239000013543 active substance Substances 0.000 claims description 46
- 239000000203 mixture Substances 0.000 claims description 22
- LBXHRAWDUMTPSE-AOOOYVTPSA-N 4-chloro-N-[(2S,6R)-2,6-dimethyl-1-piperidinyl]-3-sulfamoylbenzamide Chemical compound C[C@H]1CCC[C@@H](C)N1NC(=O)C1=CC=C(Cl)C(S(N)(=O)=O)=C1 LBXHRAWDUMTPSE-AOOOYVTPSA-N 0.000 claims description 14
- 229960004070 clopamide Drugs 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 7
- 230000001631 hypertensive effect Effects 0.000 claims description 5
- 239000012730 sustained-release form Substances 0.000 claims description 3
- 239000002552 dosage form Substances 0.000 claims description 2
- 239000008247 solid mixture Substances 0.000 claims 1
- JIVPVXMEBJLZRO-CQSZACIVSA-N 2-chloro-5-[(1r)-1-hydroxy-3-oxo-2h-isoindol-1-yl]benzenesulfonamide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC([C@@]2(O)C3=CC=CC=C3C(=O)N2)=C1 JIVPVXMEBJLZRO-CQSZACIVSA-N 0.000 abstract description 2
- ZUNJWRJEKCRIMZ-UHFFFAOYSA-N 3-(benzylsulfanylmethyl)-6-chloro-1,1-dioxo-3,4-dihydro-2h-1$l^{6},2,4-benzothiadiazine-7-sulfonamide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(S(N2)(=O)=O)=C1NC2CSCC1=CC=CC=C1 ZUNJWRJEKCRIMZ-UHFFFAOYSA-N 0.000 abstract description 2
- CESYKOGBSMNBPD-UHFFFAOYSA-N Methyclothiazide Chemical compound ClC1=C(S(N)(=O)=O)C=C2S(=O)(=O)N(C)C(CCl)NC2=C1 CESYKOGBSMNBPD-UHFFFAOYSA-N 0.000 abstract description 2
- CYLWJCABXYDINA-UHFFFAOYSA-N Polythiazide Polymers ClC1=C(S(N)(=O)=O)C=C2S(=O)(=O)N(C)C(CSCC(F)(F)F)NC2=C1 CYLWJCABXYDINA-UHFFFAOYSA-N 0.000 abstract description 2
- 229960003515 bendroflumethiazide Drugs 0.000 abstract description 2
- HDWIHXWEUNVBIY-UHFFFAOYSA-N bendroflumethiazidum Chemical compound C1=C(C(F)(F)F)C(S(=O)(=O)N)=CC(S(N2)(=O)=O)=C1NC2CC1=CC=CC=C1 HDWIHXWEUNVBIY-UHFFFAOYSA-N 0.000 abstract description 2
- NDTSRXAMMQDVSW-UHFFFAOYSA-N benzthiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(S(N2)(=O)=O)=C1N=C2CSCC1=CC=CC=C1 NDTSRXAMMQDVSW-UHFFFAOYSA-N 0.000 abstract description 2
- 229960001541 benzthiazide Drugs 0.000 abstract description 2
- MAEIEVLCKWDQJH-UHFFFAOYSA-N bumetanide Chemical compound CCCCNC1=CC(C(O)=O)=CC(S(N)(=O)=O)=C1OC1=CC=CC=C1 MAEIEVLCKWDQJH-UHFFFAOYSA-N 0.000 abstract description 2
- 229960004064 bumetanide Drugs 0.000 abstract description 2
- 229960002155 chlorothiazide Drugs 0.000 abstract description 2
- 229960001523 chlortalidone Drugs 0.000 abstract description 2
- 229960003176 cyclothiazide Drugs 0.000 abstract description 2
- BOCUKUHCLICSIY-QJWLJZLASA-N cyclothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(S(N2)(=O)=O)=C1NC2C1[C@H](C=C2)C[C@H]2C1 BOCUKUHCLICSIY-QJWLJZLASA-N 0.000 abstract description 2
- -1 dopamide Chemical compound 0.000 abstract description 2
- 229960003199 etacrynic acid Drugs 0.000 abstract description 2
- AVOLMBLBETYQHX-UHFFFAOYSA-N etacrynic acid Chemical compound CCC(=C)C(=O)C1=CC=C(OCC(O)=O)C(Cl)=C1Cl AVOLMBLBETYQHX-UHFFFAOYSA-N 0.000 abstract description 2
- 229960003883 furosemide Drugs 0.000 abstract description 2
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 abstract description 2
- 229960003313 hydroflumethiazide Drugs 0.000 abstract description 2
- DMDGGSIALPNSEE-UHFFFAOYSA-N hydroflumethiazide Chemical compound C1=C(C(F)(F)F)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O DMDGGSIALPNSEE-UHFFFAOYSA-N 0.000 abstract description 2
- 229960003739 methyclothiazide Drugs 0.000 abstract description 2
- 229960005483 polythiazide Drugs 0.000 abstract description 2
- 229920000046 polythiazide Polymers 0.000 abstract description 2
- AGMMTXLNIQSRCG-UHFFFAOYSA-N quinethazone Chemical compound NS(=O)(=O)C1=C(Cl)C=C2NC(CC)NC(=O)C2=C1 AGMMTXLNIQSRCG-UHFFFAOYSA-N 0.000 abstract description 2
- 229960000577 quinethazone Drugs 0.000 abstract description 2
- 229960000356 tienilic acid Drugs 0.000 abstract description 2
- AGHANLSBXUWXTB-UHFFFAOYSA-N tienilic acid Chemical compound ClC1=C(Cl)C(OCC(=O)O)=CC=C1C(=O)C1=CC=CS1 AGHANLSBXUWXTB-UHFFFAOYSA-N 0.000 abstract description 2
- 229960004813 trichlormethiazide Drugs 0.000 abstract description 2
- LMJSLTNSBFUCMU-UHFFFAOYSA-N trichlormethiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NC(C(Cl)Cl)NS2(=O)=O LMJSLTNSBFUCMU-UHFFFAOYSA-N 0.000 abstract description 2
- SSEAPVMQZPKNQZ-UHFFFAOYSA-N 2-(aminomethyl)-4-tert-butyl-6-iodophenol Chemical compound CC(C)(C)C1=CC(I)=C(O)C(CN)=C1 SSEAPVMQZPKNQZ-UHFFFAOYSA-N 0.000 abstract 1
- 230000000694 effects Effects 0.000 description 10
- 239000012458 free base Substances 0.000 description 10
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
- JZQKKSLKJUAGIC-UHFFFAOYSA-N pindolol Chemical compound CC(C)NCC(O)COC1=CC=CC2=C1C=CN2 JZQKKSLKJUAGIC-UHFFFAOYSA-N 0.000 description 10
- 239000003826 tablet Substances 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 229920002261 Corn starch Polymers 0.000 description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 5
- 239000008120 corn starch Substances 0.000 description 5
- 235000019359 magnesium stearate Nutrition 0.000 description 5
- 150000003839 salts Chemical group 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 229940124531 pharmaceutical excipient Drugs 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010030113 Oedema Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000002876 beta blocker Substances 0.000 description 2
- 229940097320 beta blocking agent Drugs 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 239000008119 colloidal silica Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 230000002093 peripheral effect Effects 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 208000001871 Tachycardia Diseases 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- BFAKENXZKHGIGE-UHFFFAOYSA-N bis(2,3,5,6-tetrafluoro-4-iodophenyl)diazene Chemical compound FC1=C(C(=C(C(=C1F)I)F)F)N=NC1=C(C(=C(C(=C1F)F)I)F)F BFAKENXZKHGIGE-UHFFFAOYSA-N 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 239000001175 calcium sulphate Substances 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 239000003979 granulating agent Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000000810 peripheral vasodilating agent Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 230000006794 tachycardia Effects 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Pharmaceutical compositions containing a) 6-benzoyl-3-hydrazino-5,6,7,8-tetrahydropyrido-[4,3-c]pyridazine (endralazine) b) a salidiuretic and c) pindolol are useful for the treatment of hypertension. The salidiuretic may be 2-aminomethyl-4-tertbutyl-6-iodophenol, bendroflumethiazide, benzthiazide, bumetanide, chlorothiazide, chlorthalidone, dopamide, cyclothiazide, ethacrynic acid, furosemide, hydrobenzthiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, metolazone, polythiazide, quinethazone, ticrynafen or trichloromethiazide.
Description
SPECIFICATION
Antihypertensive pharmaceutical compositions
This invention relates to anti-hypertension and pharmaceutical compositions therefor.
Various types of hypertension exist and many different active agents are known for treating hypertension, but these all have limitations. For example salidiuretics, beta-blocking agents such as pindolol and peripheral vasodilating agents have been successfully used. A recent clinically tested anti-hypertensive agent with peripheral vasodilating activity is 6-benzoyl-3-hydrazino-5,6,7,8-tetrahydropyrido[4,3- cipyridazine also known as BQ 22-708 and which has the generic name, and is hereinafter referred to as, endralazine.
It has now been surprisingly found from clinical trials that the co-administration of the following active agents:
a) endralazine
b) a salidiuretic and
c) pindolol and pharmaceutical compositions containing these active agents lead to especially 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-effects include a quick onset and high level of activity.
Moreover, these effects are much more beneficial 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 tachycardia and other undesirable side effects of peripheral vasodilation.
Accordingly in one aspect the present invention provides a pharmaceutical composition comprising as active agents:
a) endralazine
b) a salidiuretic and
c) pindolol.
'These compositions may be made in conventional manner 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 sustained release form, e.g. in a wax matrix. Endralazine is susceptible to moisture so it is preferred to use dry galenical techniques 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 excipients may be mixed with active agents b) and c), eg. diluents, fillers, granulating agents, disintegrating agents, binding agents, lubricating agents, dyes, and stabilizing agents.
In another aspect the present invention accordingly provides a process for the production of a pharmaceutical composition 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 slowly than active agent c).
The final compositions are preferably in solid form and may be granules, pellets, capsules, dragees or tablets. It is preferred to have a unit dosage form, preferably a mantle tablet, with a sustained release core containing the endralazine component, 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 hypertensive subject which comprises administering concomitantly effective amounts of active agents a), b) and c) as stated above.
In yet a further aspect the present invention provides a pack containing active agents a), b) and c) as stated above, at least one of which is presented separately, for concomitant administration in the treatment of hypertension. Conveniently the pack is provided with instructions for the concomitant administration of predetermined amounts of active agents a), b) and c).
In general any salidiuretic may be used as active agent b). A suitable salidiuretic is e.g. one of the following:
2-aminomethyl-4-tert-butyl-6-iodophenyl (MK447); bendroflumethiazide; benzthiazide; bumetanide; chlorothiazide: chlorthalidone; clopamide; cyclothiazide; ethacrynic acid; furosemide; hydrobenzthiazide; hydrochlorothiazide; hydroflumethiazide; methyclothiazide; metolazone; polythiazide; quinethazone; ticrynafen; trichlormethiazide.
Particularly suitable salidiuretics are hydrochlorothiazide and metolazone. With salidiuretics causing relatively little potassium loss and particularly with clopamide, especially advantageous effects have been observed.
The active agents may be in free form or in pharmaceutically acceptable salt form, e.g. in pharmaceutically acceptable acid addition salt form. Acids suitable for salt formation include hydrochloric acid, fumaric acid, methanesulfonic acid, hydrobromic acid, sulfuric acid and maleic acid.
Endralazine is conveniently provided 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 acceptable salt form of active agent a), b) or c) is generally of the same order as that of the respective free base form. However as used herein, except when otherwise stated, all amounts 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 concomitantly or in combination are useful in the treatment of hypertension in standard clinical trials with hypertensive subjects. For example, in one clinical trial 56 hypertensive subjects suffering from moderate to severe hypertension were treated with a daily dose of 2.5-20 mg of endralazine, 5 mg clopamide and 10 mg of pindolol. The active agents were administered once or twice a day over several weeks and generally all the active agents were administered 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.
An indicated in these clinical trials fixed combinations are well received by a large number of hypertensive subjects.
For the treatment of hypertension the exact daily dosage 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.
However, in general, the total daily dosage is in the range of from about 5 mg to about 40 mg of active agent a) and preferably from about 5 to 20 mg. The daily dosage of active agent b) is generally in the range from about 20 to 100% of the daily dose indicated for its use as a diuretic for the treatment of oedema. In the cae of clopamide, the preferred daily dose is generally in the range from about 5 to about 10 mg. The daily dosage of active agent c) is generally from about 10 to about 20 mg.
Conveniently these active agents a), b) and c) are administered in divided doses 2,3 or 4times a day, containing, e.g. 5 or 10 mg of active agent a), or preferably in a single dose once a day containing, e.g. 10 or 20 mg of active agent a).
As indicated weight ratio of active agents a), b) and c) is from about 1:30:2 to about 1:0.01:0.5 respectively.
Naturally the weight ratio will depend on the salidiuretic used. For hydrochlorothiazide a suitable weight ratio of active agents a), b) and c) is from about 1:20:2 to about 1 :2.5:0.5. For clopamide and metolazone a suitable weight ratio of active agents a), b) and c) is from about 1:2:2 to about 1:0.25:0.5. For clopamide preferredweight 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 hydrochlorothiazide
may be formulated by taking into account the activity of the particular salidiuretic compared to the known salidiuretic activities of the clopamide, metolazone and hydrochlorothiazide.
As will be appreciated pindolol is the generic term for 4-(2-hydroxy-3-isopropylaminopropoxy)indole, and clopamide is the generic term for N [cis-2',6'-dimethylpiperidyl-(1 ')j-3-sulfamoyl-4-chlorobenzoic acid amide.
The following examples illustrate the compositions of the invention.
Example 1: Tablet
The following composition may be formulated using standard tabletting techniques and is useful for oral administration once or twice a day for the treatment of moderate or severe hypertension.
Ingredient Tablet
(mg)
Endralazine (in methane sulfonate form) 13.5 (=10 mg base)
Clopamide (in free base form) 10
Pindolol (in free base form) 10
Lactose 68.5
Corn starch 40
Silica (colloidal) 0.5 Polyvinylpyrrolidone 5 Tale 5 Magnesium stearate 1
total 153.5
The three active agents are mixed with the lactose, the colloidal silica and a portion of the corn starch. The mixture is sieved and kneaded with an alcoholic solution of polyvinylpyrrolidone. The is again sieved, dried and the dry granulate broken down. The remaining corn starch, talc and magnesium stearate are then added and the mixture pressed into a tablet.
Example 2: Retard tablet
The following composition may be formulated using standard tabletting techniques and is useful for oral administration once a day for the treatment of moderate or severe hypertension.
Ingredient Tablet
(mg)
Core
Endralazine (in methane sulfonate form) 13.6
Hydrogenated castor oil 65.9
Paraffin 8.0
Corn starch 11.5
Magnesium stearate 1.0
total 100.0
Pressed coat
Clopamide (in free base form) 5.0
Pindolol (in free base form) 10.0
Cellulose (microcrystalline) 172.5
Modified corn starch (Sta-Rx 1500@, Staley Co., Decatur, i11., USA) 21.0
Silica (colloidal) 0.4
Magnesium stearate 1.1
total 210.0
total 310.0
Example 3:
Clopamide may be replaced by the same weight of metolazone (in free base form) in the formulations of
Examples 1 and 2.
Example 4
Clopamide may be replaced by hydrochlorothiazide (in free base form) in the formulations of Examples 1 (100 mg in lieu of 10 mg) and 2 (50 mg in lieu of 5 mg).
Claims (18)
1. An anti-hypertensive pharmaceutical composition comprising as active agents
a) endralazine
b) a salidiuretic and
c) pindolol.
2. A solid composition according to claim 1.
3. A composition according to claim 1 or 2 wherein active agent b) is hydrochlorothiazide or metolazone.
4. A composition according to claim 1 or 2 wherein the active agent b) is clopamide.
5. A composition according to claim 1, 2, 3 or 4 wherein the weight ratio of active agents a), b) and c) is from about 1:30:2 to about 1:0.01:0.5 respectively.
6. A composition according to claim 4 wherein the weight ratio of active agent a), b) and c) is from about 1:2:2 to about 1:0.25:0.5
7. A composition according to claim 6 wherein said weight ratio is 1:1:2.
8. A composition according to claim 6 wherein said weight ratio is 1:0.5:1.
9. A composition according to claim 6 wherein said weight ratio is 1:1:1.
10. A composition according to any one of the preceding claims wherein the endralazine component is in sustained release form.
11. A composition according to any one of the preceding claims in unit dosage form.
12. A composition according to claim 11 having 5 mg of active agent a).
13. A composition according to claim 11 having 10 mg of active agent a).
14. A composition according to claim 11 having 20 mg of active agent a).
15. A pharmaceutical composition according to claim 1 substantially is hereinbefore described with reference to any one of the examples.
16. A pack containing active agents a), b) and c) as stated in claim 1, at least one of which is presented separately, for the concomitant administration in the treatment of hypertension.
17. A pack according to claim 16 provided with instructions for the concomitant administration of predetermined amounts of active agents a), b) and c).
18. A method of treating a hypertensive subject which comprises administering concomitantly effective amounts of active agents a), b) and c) as stated in claim 1.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH178579A CH643457A5 (en) | 1979-02-22 | 1979-02-22 | PHARMACEUTICAL PREPARATIONS FOR TREATING HYPERTENSION. |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2044101A true GB2044101A (en) | 1980-10-15 |
| GB2044101B GB2044101B (en) | 1983-09-07 |
Family
ID=4218544
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8005245A Expired GB2044101B (en) | 1979-02-22 | 1980-02-15 | Antihypertensive pharmaceutical compositions |
Country Status (20)
| Country | Link |
|---|---|
| JP (1) | JPS55115823A (en) |
| AT (1) | AT378915B (en) |
| AU (1) | AU538599B2 (en) |
| BE (1) | BE881763A (en) |
| CA (1) | CA1147657A (en) |
| CH (1) | CH643457A5 (en) |
| DE (1) | DE3005029C2 (en) |
| FR (1) | FR2449450A1 (en) |
| GB (1) | GB2044101B (en) |
| HU (1) | HU187271B (en) |
| IE (1) | IE49073B1 (en) |
| IL (1) | IL59432A (en) |
| IT (1) | IT1145433B (en) |
| MY (1) | MY8500619A (en) |
| NL (1) | NL8001000A (en) |
| NZ (1) | NZ192924A (en) |
| PH (1) | PH17118A (en) |
| PT (1) | PT70855A (en) |
| SE (2) | SE8001121L (en) |
| ZA (1) | ZA801018B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2367242A (en) * | 2000-09-21 | 2002-04-03 | Henderson Morley Res & Dev Ltd | Antiviral treatment |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2537434A1 (en) * | 1982-12-09 | 1984-06-15 | Sandoz Sa | Endralazine pharmaceutical composition in depot form |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2458155A1 (en) * | 1973-12-19 | 1975-07-03 | Sandoz Ag | NEW PHARMACEUTICAL PREPARATIONS |
-
1979
- 1979-02-22 CH CH178579A patent/CH643457A5/en not_active IP Right Cessation
-
1980
- 1980-02-11 DE DE3005029A patent/DE3005029C2/en not_active Expired
- 1980-02-13 SE SE8001121A patent/SE8001121L/en not_active Application Discontinuation
- 1980-02-15 GB GB8005245A patent/GB2044101B/en not_active Expired
- 1980-02-18 BE BE1/9727A patent/BE881763A/en not_active IP Right Cessation
- 1980-02-19 NL NL8001000A patent/NL8001000A/en not_active Application Discontinuation
- 1980-02-20 IL IL59432A patent/IL59432A/en unknown
- 1980-02-20 AU AU55742/80A patent/AU538599B2/en not_active Ceased
- 1980-02-20 IE IE336/80A patent/IE49073B1/en unknown
- 1980-02-20 IT IT47950/80A patent/IT1145433B/en active
- 1980-02-20 FR FR8003669A patent/FR2449450A1/en active Granted
- 1980-02-20 CA CA000346083A patent/CA1147657A/en not_active Expired
- 1980-02-20 PT PT70855A patent/PT70855A/en unknown
- 1980-02-20 NZ NZ192924A patent/NZ192924A/en unknown
- 1980-02-21 PH PH23672A patent/PH17118A/en unknown
- 1980-02-21 JP JP1980480A patent/JPS55115823A/en active Pending
- 1980-02-21 HU HU80402A patent/HU187271B/en unknown
- 1980-02-21 AT AT0095580A patent/AT378915B/en not_active IP Right Cessation
- 1980-02-22 ZA ZA00801018A patent/ZA801018B/en unknown
-
1982
- 1982-04-15 SE SE8202357A patent/SE8202357L/en not_active Application Discontinuation
-
1985
- 1985-12-30 MY MY619/85A patent/MY8500619A/en unknown
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2367242A (en) * | 2000-09-21 | 2002-04-03 | Henderson Morley Res & Dev Ltd | Antiviral treatment |
| GB2367242B (en) * | 2000-09-21 | 2004-07-28 | Henderson Morley Res & Dev Ltd | Antiviral treatment |
Also Published As
| Publication number | Publication date |
|---|---|
| AT378915B (en) | 1985-10-25 |
| FR2449450B1 (en) | 1983-07-22 |
| IE49073B1 (en) | 1985-07-24 |
| AU538599B2 (en) | 1984-08-23 |
| ZA801018B (en) | 1981-09-30 |
| HU187271B (en) | 1985-12-28 |
| IE800336L (en) | 1980-08-22 |
| IL59432A (en) | 1984-08-31 |
| IL59432A0 (en) | 1980-05-30 |
| DE3005029A1 (en) | 1980-09-04 |
| AU5574280A (en) | 1980-08-28 |
| MY8500619A (en) | 1985-12-31 |
| CH643457A5 (en) | 1984-06-15 |
| PT70855A (en) | 1980-03-01 |
| BE881763A (en) | 1980-08-18 |
| SE8001121L (en) | 1980-08-23 |
| IT8047950A0 (en) | 1980-02-20 |
| ATA95580A (en) | 1985-03-15 |
| FR2449450A1 (en) | 1980-09-19 |
| NL8001000A (en) | 1980-08-26 |
| GB2044101B (en) | 1983-09-07 |
| JPS55115823A (en) | 1980-09-06 |
| CA1147657A (en) | 1983-06-07 |
| PH17118A (en) | 1984-06-01 |
| IT1145433B (en) | 1986-11-05 |
| NZ192924A (en) | 1984-05-31 |
| SE8202357L (en) | 1982-04-15 |
| DE3005029C2 (en) | 1987-02-12 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |