AU629288B2 - Low dose benazepril and thiazide diuretic composition - Google Patents
Low dose benazepril and thiazide diuretic composition Download PDFInfo
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- AU629288B2 AU629288B2 AU48703/90A AU4870390A AU629288B2 AU 629288 B2 AU629288 B2 AU 629288B2 AU 48703/90 A AU48703/90 A AU 48703/90A AU 4870390 A AU4870390 A AU 4870390A AU 629288 B2 AU629288 B2 AU 629288B2
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- Australia
- Prior art keywords
- composition
- benazepril
- dose
- thiazide diuretic
- hydrochlorothiazide
- 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
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- 239000000203 mixture Substances 0.000 title claims description 23
- XPCFTKFZXHTYIP-PMACEKPBSA-N Benazepril Chemical compound C([C@@H](C(=O)OCC)N[C@@H]1C(N(CC(O)=O)C2=CC=CC=C2CC1)=O)CC1=CC=CC=C1 XPCFTKFZXHTYIP-PMACEKPBSA-N 0.000 title claims description 17
- 229960004530 benazepril Drugs 0.000 title claims description 17
- 239000003451 thiazide diuretic agent Substances 0.000 title claims description 17
- 229940121792 Thiazide diuretic Drugs 0.000 title claims description 14
- 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 23
- 229960002003 hydrochlorothiazide Drugs 0.000 claims description 19
- 206010020772 Hypertension Diseases 0.000 claims description 7
- 229960003619 benazepril hydrochloride Drugs 0.000 claims description 7
- VPSRQEHTHIMDQM-FKLPMGAJSA-N benazepril hydrochloride Chemical compound Cl.C([C@@H](C(=O)OCC)N[C@@H]1C(N(CC(O)=O)C2=CC=CC=C2CC1)=O)CC1=CC=CC=C1 VPSRQEHTHIMDQM-FKLPMGAJSA-N 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 230000003276 anti-hypertensive effect Effects 0.000 claims description 5
- 229960002155 chlorothiazide Drugs 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 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 claims description 3
- 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 claims description 3
- 239000002775 capsule Substances 0.000 claims description 3
- 229960001523 chlortalidone Drugs 0.000 claims description 3
- 229960003515 bendroflumethiazide Drugs 0.000 claims 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 claims description 2
- 229960001541 benzthiazide Drugs 0.000 claims 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 claims description 2
- 229960003176 cyclothiazide Drugs 0.000 claims 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 claims description 2
- 229960003313 hydroflumethiazide Drugs 0.000 claims 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 claims description 2
- 229920000046 polythiazide Polymers 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 229940100691 oral capsule Drugs 0.000 claims 1
- 229940096978 oral tablet Drugs 0.000 claims 1
- 239000007935 oral tablet Substances 0.000 claims 1
- 229960004813 trichlormethiazide Drugs 0.000 claims 1
- 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 claims 1
- 239000002934 diuretic Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000013543 active substance Substances 0.000 description 4
- 239000005541 ACE inhibitor Substances 0.000 description 3
- 229940097420 Diuretic Drugs 0.000 description 3
- 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
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 3
- 239000011162 core material Substances 0.000 description 3
- 230000001882 diuretic effect Effects 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 description 2
- 101710129690 Angiotensin-converting enzyme inhibitor Proteins 0.000 description 2
- 101710086378 Bradykinin-potentiating and C-type natriuretic peptides Proteins 0.000 description 2
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 description 2
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000035487 diastolic blood pressure Effects 0.000 description 2
- 229940030606 diuretics Drugs 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000000902 placebo Substances 0.000 description 2
- 229940068196 placebo Drugs 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- AYQMNFRCBKOMIA-UHFFFAOYSA-N 1-benzazepin-2-one Chemical compound O=C1C=CC=C2C=CC=CC2=N1 AYQMNFRCBKOMIA-UHFFFAOYSA-N 0.000 description 1
- QISOBCMNUJQOJU-UHFFFAOYSA-N 4-bromo-1h-pyrazole-5-carboxylic acid Chemical compound OC(=O)C=1NN=CC=1Br QISOBCMNUJQOJU-UHFFFAOYSA-N 0.000 description 1
- QRAOZQGIUIDZQZ-UHFFFAOYSA-N 4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1,4-benzoxazine Chemical compound C=1C=C2N(C)CCOC2=CC=1B1OC(C)(C)C(C)(C)O1 QRAOZQGIUIDZQZ-UHFFFAOYSA-N 0.000 description 1
- PXRKCOCTEMYUEG-UHFFFAOYSA-N 5-aminoisoindole-1,3-dione Chemical compound NC1=CC=C2C(=O)NC(=O)C2=C1 PXRKCOCTEMYUEG-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-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
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical compound [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 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
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 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
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229960005483 polythiazide Drugs 0.000 description 1
- 239000001253 polyvinylpolypyrrolidone Substances 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- -1 with inorganic acid Chemical class 0.000 description 1
Classifications
-
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
A Our Ref: 302970 2 9 2
AUSTRALIA
Patents Act COMPLETE SPERCIFICTrATION FORM
(ORIGINAL)
Application Number: Lodged: Re C C Re..
C
Re
C..
C*
C C *e Re..
Complete Specification Lodged: Accepted: Published: Priority: Related Art: Applicant(s): Address for Service:
.RC.
Re..
0R
C
IR C
C.
C.
C. S C C C
S*
Ciba-Geigy AG Klybeckstrasse 141 4002 BASLE
SWITZERLAND
ARTHUR S. CAVE CO.
Patent Trade Mark Attornerys Level 10, 10 Barrack Street SYDNEY NSW 2000 Complete specification for the invention entitled "Lnw dose benazep .il/thiazide diuretic
A
composition".
The following statement is a full description of this invention, including the best method of performing it know: to me:- I I I I lla- Ib -la- Low dose benazeprilthiazide diuretic composition The invention relates to a pharmaceutical composition for treating mild to moderate hypertension containing the angiotensin converting enzyme inhibitor benazepril in combination with thiazide diuretics, and to a method of treatment of hypertension utilizing this composition.
9* Bcnazepril hydrochloride is a new orally active, non-sulfhydril containing, angiotensin converting enzyme inhibitor having the structure 0
COOH
The compound is described in U.S. 4,410,520. Thiazide diuretics, the second component Sof the instant combination, have long been a mainstay of antihypertensive therapy. All of the active agents of the instant invention are well known compounds in the art; their synthesis, routes of administration, etc. are well known. Additionally, there has been some S literature published in recent years on combining angiotensin converting enzyme "inhibitors with thiazide diuretics. See for example US 4,472,380, especially columns 9 and 10 and example 127 thereof; US 4,217,347, especially columns 2-3 and the examples; American J. Hypert. 38-41 (1988); European patent application 0,215,357; J. Hypertension 1 (Suppl. 384 386 (1983); and Amer. J. Hypert. 1 part 13A-14A, Abstract 1226 (1988). However, each of these deal with angiotensin converting enzyme inhibiting drugs other than benazepril and/or diuretics in amounts substantially greater than that in the present invention. Probably the most significant reference is Merck's South African Patent Application 83 3903, claiming priority of US Application 383,435.
This reference discloses angiotensin converting enzyme inhibitors of benazepril type in amounts of 2.5-100 rag/day in combination with diuretics generically in the range of 0.5-100 mg/day. Hydrochlorothiazide is only mentioned in amounts of at least mg/day.
eu I II asaa rar~BRrrPP 9 sgl~XL~"' e *i It is an object of the present invention to provide a pharmaceutical composition to treat and a method of treating mild to moderate hypertension with a minimum amount of active agent while achieving pressure reductions not achievable with the individual active agents at the same dosage.
The invention is; a fixed ratio low dose combination of 4-6 mg benazepril or a pharmaceutically acceptable salt thereof with 80-120 of 1/8 of the initial daily antihypertensive clinically recommended dose of a thiazide diuretic given as a once daily dosage. The inventive composition is a daily unit dose for administration to a human adult having mild to moderate hypertension comprising about 4 to about 6 mg, preferably about 5 mg, benazepril hydrochloride or any other pharmaceutically acceptable salt of benazepril and about 80 to about 120 preferably about 100 of 1/8 the usual initial antihypertensiv adult clinical dose of a thiazide diuretic, when such diuretic is used alone.
Pharmaceutically acceptable salts of benazepril are acid addition salts with pharmacologically harmless acids, e.g. with inorganic acid, for example hydrochloric acid, sulfuric acid or phosphoric acid, or with organic carbonic, sulfonic or sulfo acids, for example acetic, propionic, glycolic, maleic, fumaric, tartaric, citric, benzoic, methanesulfonic, ethanesulfonic, or 2-hydroxyethanesulfonic acid. Preferred is the hydrr-hlorid,, i.e the acid addition salt with hydrochloic acid.
IN
Preferably the diuretic is selected from bendroflumethiazide (5 mg) chlorthalidone (25 mg) chlorothiazide (500 mg) hydrochlorothiazide (50 mg) hydroflumethiazide (50 mg) methylchlorothiazide (2.5 mg) polythiazide (2 mg) trichlonnethiazide (2 mg) benzthiazide (50 mg) cyclothiazide (2 mg) 0.5 0.75 mg; 2.5 3.75 mg; 50 75 mg; 3 7.5 mg; 5 7.5 mg; 0.25 0.38 mg; 0.2 0.3 mg; 0.2 0.3 mg; 0.5 0.75 mg; 0.2 0.3 mg.
The usual minimum initial clinical antihypertensive adult dose is shown in parenthesis, followed by the dosage range useful in this invention. The initial clinical dose applied I I e I I, Ilr;l lla~ssolssRP P as- -3nowadays may differ from the dose given in parenthesis in the list above for some cases.
For example hydrochlorothiazide is often given in an initial dose of 25 mg.
More preferably, the thiazide diuretic is selected from chlorothiazide, hydrochlorothiazide, methylchlorothiazide, and chlorthalidone. Most preferably, the thiazide diuretic is selected from chlorothiazide and hydrochlorothiazide; it is in particular hydrochlorothiazide.
The most advantageous composition comprises benazepril hydrochloride and hydrochlorothiazide in a weight ratio of about 0.8 to 1, for example about 5 mg benazepril hydrochloride and about 6.25 mg hydrochlorothiazide.
In a clinical double-blind randomized trial with 334 men and women having a sitting diastolic blood pressure of 95-114 mmHg, the efficacy of the preferred combination of the invention comprising 5 mg benazepril hydrochloride and 6.25 mg hydrochlorothiazide given once daily was compared with the efficacy of other compositions and of the single drugs during six weeks. The results are summarized in the following table: *p 0 0 0 0.
fle 0
C
C
5 mg benazeprila) 6.25 mg hydrochlorothiazide S 10 mg benazepril 12.5 mg hydrochlorothiazide mg benazepril 25 mg hydrochlorothiazide 20 mg benazepril mg hydrochlorothiazide mg benazepril 6.25 mg hydrochlorothiazide 5 mg benazepril 25 mg hydrochlorothiazide placebo placebo 9.9 mnmHg b 9.6 mmHg -13.9 mmHg 9.8 mmHg 6.9 mmHg -10.3 mmHg -10.7 mmHg 3.9 mmHg a) as the hydrochloride b) reduction of sitting diastolic blood pressure The clinical results demonstrate that the low dose composition of the invention has a surprising efficacy.
The composition can be put together by methods which are standard in the art in any convenient dosage form, including tablet, capsule, powder, etc. Any suitable pharmaceutical adjuvant or carrier may also be included. Administration may be by any route by which both benazepril and the thiazide diuretic may be simultaneously administered, but is most I I -4preferably oral. The most suitable dosage form is a solid oral dosage form suck~ as a tablet or capsule. While other antihypertensive active agents may be added, most preferably only benazepril and only one thiazide diuretic are present in any one cc-nposition.
The instant invention will be more fully understood by reference to the following ezfample, which illustrates, but does not limit the invention.
Example:, Film.-cated tablets, containing 6.25 nig 6-chloro-3,4-dihydro-2H- 1 ,2,4-benzothiadiazine-7-sulfonamide-l1, 1-dioxide and 5.00 mg 1-carboxymthlyl-3S-(1J1-ethoxycarbonyl-3-phenylproo~ylamino)-2,3 ,4,5-tetrahydro- 11--f] benzazepine-2-one hydro- 'chloride are prepared as follows: gueits (for 2'00tablets) 6:.core materials 6-chloro-3,4-dihydro-2H- 1,2,4-benzothiadiazinie-7-sulfonamide- 1, 1 -dioxide (micronized) 12.50 g l-carboxymethyl-3S-(l S-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5tetrahydro-1H-[lbenzaze-pine-2-one iydrochiloride 10.00 g hydroxypropylmethylcellulose 6,00 g hydrogenated castor oil 12.00 g lactose (ground) 423.50 g 00~polyvinyl-polypyrrolidone 20.00 g Film materials hydroxrypropylmethylcellulose 7.34 g polyethiyleneglycol 8000 (flakes) 1.34 g talcum 5.32 g titanium dioxide 2.00 g The 6-chloro-3,4-dihydro-2F1- 1 ,2,4-benzothiiadiazine-7-sulfonamide- 1, 1-dioxide, the 1-carboxymethyl-3S-( 1S-ethioxycarbonyl-3-phenylpropylamidno)-2,3,4,5-tetrahydro- lI-I- [1]benzazepine-2-one hydrochloride and the core hydroxypro;, i-rnethylcellulose are mixed with part of d~e 'Lactose, Thte remaining lactose is added and the mixture is granulated with water, dried, and milled. The remaining core ingredients are admixed therewith and the homogenous mixture is compressed into tablets, which are coated with an aqueous suspension of the above coating materials,
Claims (13)
1. A low dose pharmaceutical composition for treating mild to moderate hypertension comprising 4 to 6 mg of benazepril or a pharmaceutically acceptable salt of benazepril and a thiazide diuretic in an amount of 80 to ,20 of 1/8 of the minimum recommended initial antihyperensive dose of said thiazide diuretic when used alone, each amount being per unit dose of said composition.
2. The composition of claim 1 wherein said thiazide diuretic is selected from bendro- flumethiazide, chlorthalidone, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methylchlorothiazide, polythiazid;-, trichlormethiazide, benzthiazide, and cyclothiazide.
3. The composition of claim 2 wherein said thiazide diuretic is hydrochlorothiazide.
4. The composition of claim 1 wherein said thiazide diuretic is present in an amount which is 1/8 of the minimum recommended initial antihypertensive dose when the thiazide diuretic is used alone.
5. The composition of claim 3 wherein said hydrochlnorontazide is present in an amount of 5mg to 7.5 mg per dose. 6, The composition of claim 5 wherein said hydrochlorothiazide is present in an amount S" of 6.25 mg per dose.
7. The composition of claim 1 wherein said benazepril or pharmaceutically acceptable salt thereof is benazepril hydrochloride.
8. The composition of claim 7 wherein said benazepril hydrochloride is present in an amount of 5 mg per dose.
9. The composition of claim 1 comprising 5 mg benazepril hydrochloride and 6.25 mg hydrochlorothiazide per dose. 1 -6- The composition of claim 1 which is a tablet, a powder, or a capsule.
11. The composition of claim 1 which is an oral tablet or oral capsule.
12. The composition of claim 1 substantially as herein described with reference to the example.
13. A method of treating mild to moderate hypertension comprising administering a com- position of claim 1.
14. The method of claim 12 wherein said administration is once daily. The method of claim 12 wherein said administration is orally.
16. A low dose pharmaceutical composition substantially as herein described with reference to any one of the foregoing Example. I r Dated this 14th day of July, 1992 CIBA-GEIGY AG By its Patent Attorneys DAVIES COLLISON CAVE a
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US30038389A | 1989-01-23 | 1989-01-23 | |
| US300383 | 1989-01-23 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU4870390A AU4870390A (en) | 1990-07-26 |
| AU629288B2 true AU629288B2 (en) | 1992-10-01 |
Family
ID=23158879
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU48703/90A Expired AU629288B2 (en) | 1989-01-23 | 1990-01-22 | Low dose benazepril and thiazide diuretic composition |
Country Status (24)
| Country | Link |
|---|---|
| JP (1) | JP3009694B2 (en) |
| KR (1) | KR0141479B1 (en) |
| AT (1) | AT401728B (en) |
| AU (1) | AU629288B2 (en) |
| BE (1) | BE1002736A4 (en) |
| CA (1) | CA2008126C (en) |
| CH (1) | CH680568A5 (en) |
| CY (1) | CY1835A (en) |
| DE (2) | DE4001496C2 (en) |
| DK (1) | DK175204B1 (en) |
| FR (1) | FR2641971B1 (en) |
| GB (1) | GB2227172B (en) |
| HK (1) | HK98995A (en) |
| IE (1) | IE61784B1 (en) |
| IL (1) | IL93117A0 (en) |
| IT (1) | IT1239744B (en) |
| LU (1) | LU87660A1 (en) |
| MX (1) | MX9203362A (en) |
| NL (1) | NL194958C (en) |
| NZ (1) | NZ232182A (en) |
| SA (1) | SA90100151B1 (en) |
| SE (1) | SE506179C2 (en) |
| SG (1) | SG176194G (en) |
| ZA (1) | ZA90429B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100221695B1 (en) * | 1991-08-12 | 1999-09-15 | 그린 마틴, 브라이언 쥐 테슬리 | Pharmaceutical Formulation Formulations |
| DK9200258U4 (en) * | 1992-03-11 | 1993-07-23 | Merck & Co Inc | Pharmaceutical preparation containing enalapril for use in hypertension |
| GB9613470D0 (en) | 1996-06-27 | 1996-08-28 | Ciba Geigy Ag | Small solid oral dosage form |
| CN102579346B (en) * | 2012-03-02 | 2013-09-25 | 海南美兰史克制药有限公司 | Liposome solid preparation of benazepril/hydrochlorothiazide medicine combination |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4217347A (en) * | 1977-12-27 | 1980-08-12 | E. R. Squibb & Sons, Inc. | Method of treating hypertension and medicaments therefor |
| US4472380A (en) * | 1978-12-11 | 1984-09-18 | Merck & Co., Inc. | Amino acid derivatives as antihypertensives |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4410520A (en) * | 1981-11-09 | 1983-10-18 | Ciba-Geigy Corporation | 3-Amino-[1]-benzazepin-2-one-1-alkanoic acids |
| ZA833903B (en) * | 1982-06-01 | 1984-11-28 | Merck & Co Inc | Benzofused lactams as antihypertensives |
| US4520021A (en) * | 1982-07-02 | 1985-05-28 | Merck & Co., Inc. | Substituted caprolactam derivatives as antihypertensives |
-
1990
- 1990-01-08 SE SE9000050A patent/SE506179C2/en not_active IP Right Cessation
- 1990-01-15 CH CH112/90A patent/CH680568A5/de not_active IP Right Cessation
- 1990-01-17 GB GB9001054A patent/GB2227172B/en not_active Expired - Lifetime
- 1990-01-18 LU LU87660A patent/LU87660A1/en unknown
- 1990-01-19 DE DE4001496A patent/DE4001496C2/en not_active Expired - Lifetime
- 1990-01-19 DE DE2001199041 patent/DE10199041I1/en active Pending
- 1990-01-19 IT IT47548A patent/IT1239744B/en active IP Right Grant
- 1990-01-19 NZ NZ232182A patent/NZ232182A/en unknown
- 1990-01-19 FR FR909000612A patent/FR2641971B1/en not_active Expired - Lifetime
- 1990-01-19 CA CA002008126A patent/CA2008126C/en not_active Expired - Lifetime
- 1990-01-22 IL IL93117A patent/IL93117A0/en not_active IP Right Cessation
- 1990-01-22 BE BE9000074A patent/BE1002736A4/en not_active IP Right Cessation
- 1990-01-22 IE IE23390A patent/IE61784B1/en not_active IP Right Cessation
- 1990-01-22 AT AT0013590A patent/AT401728B/en not_active IP Right Cessation
- 1990-01-22 KR KR1019900000697A patent/KR0141479B1/en not_active Expired - Lifetime
- 1990-01-22 NL NL9000158A patent/NL194958C/en not_active IP Right Cessation
- 1990-01-22 ZA ZA90429A patent/ZA90429B/en unknown
- 1990-01-22 JP JP2010782A patent/JP3009694B2/en not_active Expired - Lifetime
- 1990-01-22 DK DK199000174A patent/DK175204B1/en not_active IP Right Cessation
- 1990-01-22 AU AU48703/90A patent/AU629288B2/en not_active Expired
- 1990-04-04 SA SA90100151A patent/SA90100151B1/en unknown
-
1992
- 1992-06-25 MX MX9203362A patent/MX9203362A/en unknown
-
1994
- 1994-12-16 SG SG176194A patent/SG176194G/en unknown
-
1995
- 1995-06-22 HK HK98995A patent/HK98995A/en not_active IP Right Cessation
- 1995-12-01 CY CY183595A patent/CY1835A/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4217347A (en) * | 1977-12-27 | 1980-08-12 | E. R. Squibb & Sons, Inc. | Method of treating hypertension and medicaments therefor |
| US4472380A (en) * | 1978-12-11 | 1984-09-18 | Merck & Co., Inc. | Amino acid derivatives as antihypertensives |
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