CA1147657A - Antihypertensive pharmaceutical compositions - Google Patents
Antihypertensive pharmaceutical compositionsInfo
- Publication number
- CA1147657A CA1147657A CA000346083A CA346083A CA1147657A CA 1147657 A CA1147657 A CA 1147657A CA 000346083 A CA000346083 A CA 000346083A CA 346083 A CA346083 A CA 346083A CA 1147657 A CA1147657 A CA 1147657A
- Authority
- CA
- Canada
- Prior art keywords
- composition according
- active agent
- active agents
- agents
- active
- 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.)
- Expired
Links
- 230000003276 anti-hypertensive effect Effects 0.000 title claims abstract description 5
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 5
- 239000013543 active substance Substances 0.000 claims abstract description 40
- 230000000054 salidiuretic effect Effects 0.000 claims abstract description 14
- 206010020772 Hypertension Diseases 0.000 claims abstract description 11
- 229960002508 pindolol Drugs 0.000 claims abstract description 11
- 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
- 239000000203 mixture Substances 0.000 claims description 20
- 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 12
- 229960004070 clopamide Drugs 0.000 claims description 12
- ALAXZYHFVBSJKZ-UHFFFAOYSA-N endralazine Chemical compound C1CC=2N=NC(NN)=CC=2CN1C(=O)C1=CC=CC=C1 ALAXZYHFVBSJKZ-UHFFFAOYSA-N 0.000 claims description 11
- 229960002029 endralazine Drugs 0.000 claims description 11
- 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 description 7
- 229960002817 metolazone Drugs 0.000 claims description 7
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 claims description 6
- 229960002003 hydrochlorothiazide Drugs 0.000 claims description 6
- 239000002552 dosage form Substances 0.000 claims description 2
- 239000012730 sustained-release form Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 description 10
- 239000012458 free base Substances 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
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 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
- 239000008120 corn starch Substances 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 239000002253 acid Substances 0.000 description 4
- 235000019359 magnesium stearate Nutrition 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
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000001631 hypertensive effect Effects 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 150000003839 salts Chemical group 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 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
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical group CS(O)(=O)=O AFVFQIVMOAPDHO-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
- 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
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 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 description 1
- IKCLCGXPQILATA-UHFFFAOYSA-N 2-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1Cl IKCLCGXPQILATA-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 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
- 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 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
- 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 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-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
- 229960003515 bendroflumethiazide Drugs 0.000 description 1
- 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 description 1
- 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 description 1
- 229960001541 benzthiazide Drugs 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
- 229960004064 bumetanide Drugs 0.000 description 1
- 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 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
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229960001523 chlortalidone Drugs 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 229940000425 combination drug Drugs 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
- 229960003199 etacrynic acid Drugs 0.000 description 1
- 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 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229960003883 furosemide Drugs 0.000 description 1
- 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 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000003979 granulating agent Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 229960003739 methyclothiazide Drugs 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000000810 peripheral vasodilating agent Substances 0.000 description 1
- 229960005483 polythiazide Drugs 0.000 description 1
- 229920000046 polythiazide Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000006794 tachycardia Effects 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229960000356 tienilic acid Drugs 0.000 description 1
- 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 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000000304 vasodilatating effect 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
Landscapes
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Cardiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Heart & Thoracic Surgery (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (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
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.
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.
.
. ., . . ~
., , ~ , . . , , ~ : , , .: ., : -, .
't;
~` , . . , .`.
'7~S~7
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.
.
. ., . . ~
., , ~ , . . , , ~ : , , .: ., : -, .
't;
~` , . . , .`.
'7~S~7
- 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 '~
;' ' ~ .'~ .- :
,..
~ .
'7~5~7
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 '~
;' ' ~ .'~ .- :
,..
~ .
'7~5~7
- 3 - 1()0-51~1 :
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.
.
' i . , ., .~ .
..
, , ., , . , ~
' ~ :
~ JI
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.
."'`~ .
.',~ ; , , .;........................................... , ... .
.. . .
. ~ . .
- . : , .: ~
~ . .
. ~ , . . .
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.
:
. .
.;
, : , .
-~ 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 ' .. ., ,..... ~.. __ ~
., .
~'~ ,. .
., ' - : :
;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 ,, .
.. ,, .
`' ' ':' "
: , . ~. , . .
:
; - 8 100-5141 `` .
, ~ _. _ .
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 - - '' '' ' ' .. ,. 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.:
.
Example ~:
....
:..
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).
~ - .
...
.
." . ' , ., .
, . .
: ' ,~ .
"
, .<
~;~ F
.' . .
.'~1'" ' ' ' ' ' ' ~
~ . .
-'~ ' , ~
' ' ~ , " ' ., .' .
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.
.
' i . , ., .~ .
..
, , ., , . , ~
' ~ :
~ JI
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.
."'`~ .
.',~ ; , , .;........................................... , ... .
.. . .
. ~ . .
- . : , .: ~
~ . .
. ~ , . . .
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.
:
. .
.;
, : , .
-~ 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 ' .. ., ,..... ~.. __ ~
., .
~'~ ,. .
., ' - : :
;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 ,, .
.. ,, .
`' ' ':' "
: , . ~. , . .
:
; - 8 100-5141 `` .
, ~ _. _ .
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 - - '' '' ' ' .. ,. 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.:
.
Example ~:
....
:..
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).
~ - .
...
.
." . ' , ., .
, . .
: ' ,~ .
"
, .<
~;~ F
.' . .
.'~1'" ' ' ' ' ' ' ~
~ . .
-'~ ' , ~
' ' ~ , " ' ., .' .
Claims (13)
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.
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.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH1785/79 | 1979-02-22 | ||
CH178579A CH643457A5 (en) | 1979-02-22 | 1979-02-22 | PHARMACEUTICAL PREPARATIONS FOR TREATING HYPERTENSION. |
Publications (1)
Publication Number | Publication Date |
---|---|
CA1147657A true CA1147657A (en) | 1983-06-07 |
Family
ID=4218544
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA000346083A Expired CA1147657A (en) | 1979-02-22 | 1980-02-20 | 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) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2537434A1 (en) * | 1982-12-09 | 1984-06-15 | Sandoz Sa | Endralazine pharmaceutical composition in depot form |
GB2367242B (en) * | 2000-09-21 | 2004-07-28 | Henderson Morley Res & Dev Ltd | Antiviral treatment |
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 IE IE336/80A patent/IE49073B1/en unknown
- 1980-02-20 PT PT70855A patent/PT70855A/en unknown
- 1980-02-20 NZ NZ192924A patent/NZ192924A/en unknown
- 1980-02-20 CA CA000346083A patent/CA1147657A/en not_active Expired
- 1980-02-20 AU AU55742/80A patent/AU538599B2/en not_active Ceased
- 1980-02-20 FR FR8003669A patent/FR2449450A1/en active Granted
- 1980-02-20 IT IT47950/80A patent/IT1145433B/en active
- 1980-02-21 JP JP1980480A patent/JPS55115823A/en active Pending
- 1980-02-21 PH PH23672A patent/PH17118A/en unknown
- 1980-02-21 AT AT0095580A patent/AT378915B/en not_active IP Right Cessation
- 1980-02-21 HU HU80402A patent/HU187271B/en unknown
- 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
Also Published As
Publication number | Publication date |
---|---|
ATA95580A (en) | 1985-03-15 |
AU5574280A (en) | 1980-08-28 |
PH17118A (en) | 1984-06-01 |
IT1145433B (en) | 1986-11-05 |
AT378915B (en) | 1985-10-25 |
IL59432A (en) | 1984-08-31 |
NL8001000A (en) | 1980-08-26 |
FR2449450A1 (en) | 1980-09-19 |
DE3005029A1 (en) | 1980-09-04 |
IL59432A0 (en) | 1980-05-30 |
AU538599B2 (en) | 1984-08-23 |
IE49073B1 (en) | 1985-07-24 |
IE800336L (en) | 1980-08-22 |
DE3005029C2 (en) | 1987-02-12 |
FR2449450B1 (en) | 1983-07-22 |
GB2044101A (en) | 1980-10-15 |
BE881763A (en) | 1980-08-18 |
CH643457A5 (en) | 1984-06-15 |
ZA801018B (en) | 1981-09-30 |
SE8001121L (en) | 1980-08-23 |
NZ192924A (en) | 1984-05-31 |
GB2044101B (en) | 1983-09-07 |
IT8047950A0 (en) | 1980-02-20 |
MY8500619A (en) | 1985-12-31 |
JPS55115823A (en) | 1980-09-06 |
SE8202357L (en) | 1982-04-15 |
HU187271B (en) | 1985-12-28 |
PT70855A (en) | 1980-03-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU695865B2 (en) | Novel pharmaceutical composition containing the ace inhibitor ramipril and a dihydropyridine compound | |
CA2182004C (en) | Film coated tablet of paracetamol and domperidone | |
KR100465895B1 (en) | Swallow tablet comprising paracetamol | |
GB2105590A (en) | Flotable controlled release preparations | |
RU97108687A (en) | COMPOSITIONS OF CISAPRID WITH LONG-TERM RELEASE OF THE ACTIVE SUBSTANCE FOR ORAL ADMINISTRATION | |
CA1147657A (en) | Antihypertensive pharmaceutical compositions | |
EP0205865B1 (en) | Pharmaceutical preparations with an antihypertensive and cardioprotective effect | |
US4794112A (en) | Acetaminophen/hydroxyzine analgesic combinations | |
CA1228817A (en) | Analgesic preparations | |
AU2003224419A1 (en) | Orally administrable pharmaceutical formulation | |
CA2234899C (en) | Fixed-dose association of an angiotensin-converting enzyme inhibitor and of a calcium channel antagonist, method for preparation and use thereof in the treatment of cardiovascularillnesses | |
CA1124647A (en) | Analgesic potentiation | |
EP1531831A1 (en) | Fosinopril formulation | |
MXPA00010368A (en) | Stabile compositions comprising levosimendan and alginic acid. | |
NO329495B1 (en) | Galenic forms of oral administration with prolonged release of molsidomine | |
CA2482114C (en) | Solid dosage form comprising caffeine | |
KR970006083B1 (en) | A pharmaceutical composition for treating gastrointestinal disorders | |
IE43611B1 (en) | Antihypertonic agent | |
JPH01283224A (en) | Hypotensive combination preparation | |
NZ199783A (en) | Sustained release compositions containing endralazine embedded in a wax matrix | |
JPH0262823A (en) | Antitussive oral composition | |
IE43955B1 (en) | Pharmaceutical composition and dosage units thereof | |
CA2049980A1 (en) | Therapeutic agents | |
MXPA98003747A (en) | Association at a fixed dose of an inhibitor of the angiotensin converter enzyme and an antagonist of calcium channels, a procedure for its preparation and its use for the treatment of cardiovascular diseases |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
MKEX | Expiry |