ZA200208204B - Novel medical use of aldosterone synthase inhibitors alone or in combination with AT1-receptor antagonists. - Google Patents
Novel medical use of aldosterone synthase inhibitors alone or in combination with AT1-receptor antagonists. Download PDFInfo
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- ZA200208204B ZA200208204B ZA200208204A ZA200208204A ZA200208204B ZA 200208204 B ZA200208204 B ZA 200208204B ZA 200208204 A ZA200208204 A ZA 200208204A ZA 200208204 A ZA200208204 A ZA 200208204A ZA 200208204 B ZA200208204 B ZA 200208204B
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- South Africa
- Prior art keywords
- hypertension
- renal failure
- pharmaceutically acceptable
- acceptable salt
- receptor antagonist
- Prior art date
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Description
Combination of Organic Compounds
The invention relates to a pharmaceutical composition comprising : (i) an aldosterone synthase inhibitor or a pharmaceutically acceptable salt thereof alone or in combination with, (ii) an AT,-receptor antagonist or an AT, receptor antagonist combined with a diuretic or, in each case, a pharmaceutically acceptable salt thereof and (ii) a phamaceutically acceptable carrier.
The invention furthermore relates to a method for the prevention of, delay of progression of, treatment of a disease or condition selected from the group consisting of (a) hypertension, congestive heart failure, renal failure, especially chronic renal failure, restenosis after percutaneous transluminal angioplasty, and restenosis after coronary artery bypass surgery; (b) atherosclerosis, insulin resistance and syndrome X, diabetes mellitus type 2, obesity, nephropathy, renal failure, e.g. chronic renal failure, hypothyroidism, survival post myocardial infarction (Ml), coronary heart diseases, hypertension in the elderly, familial dyslipidemic hypertension, increase of formation of collagen, fibrosis, and remodeling following hypertension (antiproliferative effect of the combination), all these diseases or conditions associated with or without hypertension; and (c) endothelial dysfunction with or without hypertension, comprising administering the pharmaceutical composition of the present invention. in a preferred embodiment the present invention relates to a method of prevention of, delay of progression of or treatment of endothelial dysfunction with or without hypertension comprising administering to a warm-blooded animal, including man, in need thereof an effective amount of an aldosterone synthase inhibitor or a pharmaceutically acceptable salt thereof. :
AT-receptor antagonists (also called angiotensin Il receptor antagonists) are understood to be those active ingredients which bind to the AT;-receptor subtype of angiotensin ll receptor but do not result in activation of the receptor. As a consequence of the inhibition of the AT,
[CEN (1 "Ww n -2. receptor, these antagonists can, for example, be employed as antihypertensives or for g treating congestive heart failure. ¢ The class of AT, receptor antagonists comprises compounds having differing structural features, essentially preferred are the non-peptidic ones. For example, mention may be made of the compounds which are selected from the group consisting of valsartan, losartan, : candesartan, eprosartan, irbesartan, saprisartan, tasosartan, teimisartan, the compound with the designation E-1477 of the following formula
N 2 > \
NS
N N ,
COOH the compound with the designation SC-52458 of the following formula ead oN NT 7 \ —N
NZ “NH : \ /
N=N and the compound with the designation the compound ZD-8731 of the following formula
It] DEA (8 oo oo oo Bn So w [3 -3- & N “ — 0 ) - \ /
N=N or, in each case, a pharmaceutically acceptable salt thereof.
Preferred AT;-receptor antagonist are those agents which have been marketed, most preferred is valsartan or a pharmaceutically acceptable salt thereof.
A diuretic is, for example, a thiazide derivative selected from the group consisting of chlorothiazide, hydrochlorothiazide, methyiclothiazide, and chlorothalidon. The most preferred is hydrochlorothiazide.
Aldosterone synthase inhibitor is an enzyme which converts corticosterone to aldosterone to by hydroxylating cortocosterone to form 18-OH-corticosterone and 18-OH-corticosterone to aldosterone. The class of aldosterone synthase inhibitors know to be applied for the treatment of hypertension and primary aldosteronism comprises both steroidal and non- steroidal aldosterone synthase inhibitors, the later being most preferred. : Preference is given to commercially available aldosterone synthase inhibitors or those aldosterone synthase inhibitors that have been approved by the health authorities.
The class of aldosterone synthase inhibitors comprises compounds having differing structural features. For example, mention may be made of the compounds which are 1] . selected from the group consisting of the non-steroidal aromatase inhibitors anastrozole, . fadrozole (including the (+)-enantiomer thereof), as well as the steroidal aromatase inhibitor exemestane, or, in each case where applicable, a pharmaceutically acceptable salt thereof.
‘ow oo -
The most preferred non-steroidal aldosterone synthase inhibitor is the (+)-enantiomer of the : hydrochloride of fadrozole (US patents 4617307 and 4889861) of formula . =4y \ N
LO)
HCI N
Surprisingly, the pharmaceutical compositions according the present invention exhibit a beneficial, especially a synergistic (= more than additive), therapeutic effect, furthermore benefits resulting from combined treatment such as a surprising prolongation of efficacy, a : broader variety of therapeutic treatment and surprising beneficial effects on diseases and conditions associated with AT -receptors or aldosterone synthase inhibitors, respectively.
The compositions according to the present invention can be used for the prevention of, the delay of progression of and treatment of a disease or condition selected from the group consisting of (a) hypertension, congestive heart failure, renal failure, especially chronic renal failure, restenosis after percutaneous transluminal angioplasty, and restenosis after coronary artery bypass surgery; (b) atherosclerosis, insulin resistance and syndrome X, diabetes mellitus type 2, obesity, nephropathy, renal failure, e.g. chronic renal failure, hypothyroidism, survival post myocardial infarction (Ml), coronary heart diseases, hypertension in the elderly, familial dyslipidemic hypertension, increase of formation of collagen, fibrosis, and remodeling following hypertension (antiproliferative effect of the combination), all these diseases or conditions associated with or without hypertension; and : (c) endothelial dysfunction with or without hypertension. 6
The person skilled in the pertinent art is fully enabled to select a relevant animal test model o to prove the hereinbefore and hereinafter indicated therapeutic indications and beneficial effects.
These beneficial effects can, for example, be demonstrated in the test model as disclosed x by G. Jeremic et al. in J. Cardovasc. Pharmacol. 27:347-354, 1996. > Study design
In the study to be performed, permanent coronary artery occlusion (CAO) in rats is used as a model of acute myocardial infarction. The experiments are carried out with 5 treatment ~~ groups characterized by following features: : * sham-operated animals * CAO + vehicle * CAO + valsartan * CAO + aldosterone synthase inhibitor * CAO + AT,-receptor antagonist + aldosterone synthase inhibitor.
Following doses and routes of administration can be applied:
For example for the AT,-receptor antagonist valsartan ~ a) -3d to +2d: s.c. injections 2.5 mg/kg BW/12 h b) +3d to +28d: s.c. Alza osmotic minipumps 5 mg/kg/d
For the (+)-enantioner of the hydrochloride of fadrozole
Alza osmotic minipumps 0.4 mg/kg/d.
During the study following variables are measured: « infarct size : * LV chamber volume : * interstitial and perivascular collagen density in spared LV myocardium » COLI and COL-ll protein content in spared LV myocardium by Westem blot : * cardiomyocytes cross-sectional area and length in sections of LV myocardium * plasma concentrations of Ang Il and aldosterone * urine concentration of sodium, potassium and aldosterone * blood pressure in conscious animals oe « LV and carotid blood pressure in anesthetized animals. ’ Methodology
Infarct size: Six pm-thick transverse histological sections of the left ventricle are stained with nitroblue tetrazolium and acquired by a B/W XC-77CE CCD video camera (Sony). The resulting image is processed on a KS 300 image analysis system (Carl Zeiss Vision) using a
Ln, software specifically developed (Porzio et al., 1995). A single operator blinded to treatment : interactively defines the boundaries of the interventricular septum, and the infarcted area on each section is semiautomatically identified as the area of unstained ventricular tissue. The software automatically calculates for each component of the ventricular section defined as the chamber, septum, infarcted area, infarcted LV wall and viable LV wall, a set of geometric parameters (Porzio et al., 1995).
Histology: Hearts are fixed in situ, by retrograde perfusion with buffered 4% formaldehyde after arrest in diastole by i.v. injection of 0.5 M KCI. After fixation, the left ventricle (LV) and the free wall of the right ventricle are separately weighed; LV longer diameter is measured with a caliper. LV histological sections are stained with hematoxylin & eosin for qualitative examination and to quantify cardiomyocytes cross-sectional area with a semi-automated image analysis routine. Interstitial collagen deposition in LV is evaluated on Sirius red .stained sections with a semi-automated image analysis routine (Masson et al., 1998).
Collagen content in LV spared myocardium: LV tissue in the spared myocardium is homogenized, subjected to PAGE-SDS electrophoresis and electroblotted onto nitrocellulose membrane. The blots are exposed to primary antibodies, i.e. rabbit anti-rat collagen type | or type Ill antiserum (Chemicon). The primary antibodies are recognized by secondary antibodies conjugated to alkaline phosphatase (for collagen type I) or peroxidase } (collagen type lll).
Left ventricular chamber volume: LV chamber volume is determined in hearts arrested in diastole (KCl) and fixed in formalin under a hydrostatic pressure equivalent to the measured
LV end-diastolic pressure. A metric rod is inserted into the LV to measure LV inner length.
The transverse diameters of the LV chamber are measured in two 1-mm thick transverse sections near to the base and the apex of the ventricle (Jeremic ef al., 1996). The chamber volume is computed from an equation integrating transverse diameters and ineer length.
Systemic and Left ventricular hemodynamics: A microtip pressure transducer (Millar o SPC-320) connected to a recorder (Windograf, Gould Electronics) is inserted into the right carotid artery to record systolic and diastolic blood pressures. The pressure transducer is ; advanced into the LV to measure LV systolic (LVSP) and end-diastolic (LVEDP) pressures, the first derivative of LV pressure over time (+dP/dt) and heart rate.
Non-invasive blood pressure: Systolic blood pressure and heart rate are measured by the ¢ tail-cuff method (Letica LE 5002) in conscious rats. z Urine electrolytes, hormones: Rats are individually housed in metabolic cages and 24-h urine collected on 1 ml HCI 6N. Water intake is measured. Urine catecholamines are extracted on Bondelut C18 columns (Varian), separated by HPLC (Apex-l C18, 3 ym, 50x4.5 mm analytical column, Jones Chromatography) and quantified with an electrochemical detector (Coulochem ll, ESA) (Goldstein et al., 1981). Plasma and urine aldosterone, and plasma angiotensin Il is determined with specific radioimmunoassays (Aldoctk-2, DiaSorin and Angiotensin ll, Nichols Diagnostics). Urine sodium and potassium are measured by flamme photometry.
Sample size 10 animals analyzable in each treatment groups are sufficient to detect biologically significant differences. Only rats with an infarct size of at least 10% of the LV section area are included in the final analysis.
Accordingly, the composition of the present invention can be used for the prevention of, delay of progression of, and treatment of survival post myocardial infarction (Ml).
Endothelial dysfunction is being acknowledged as a critical factor in vascular diseases. The endothelium plays a bimodal role as the source of various hormones or by-products with opposing effects: vasodilation and vasoconstriction, inhibition or promotion of growth, fibrinolysis or thrombogenesis, production of anti-oxidants or oxidising agents. Genetically predisposed hypertensive animals with endothelial dysfunction constitute a valid model for assessing the efficacy of a cardiovascular therapy.
Endothelial dysfunction is characterized by, for example, increased oxidative stress, causing decreased nitric oxide, increased factors involved in coagulation or fibrinolysis such as plasminogen activating inhibitor-1 (PAIl-1), tissue factor (TF), tissue plasminogen activator (tPA), increased adhesion molecules such as ICAM and VCAM, increased growth : factors such as bFGF, TGFf, PDGF, VEGF, all factors causing cell growth, inflammation and fibrosis.
The treatment e.g. of endothelial dysfunction can be demonstrated in the following a pharmacological test:
Material and methods ‘
Male 20-24 week-old SHR, purchased from RCC Ldt (Fullingsdorf, Switzerland), are maintained in a temperature- and light-controlled room with free access to rat chow (Nafag 9331, Gossau, Switzerland) and tap water. The experiment is performed in accordance with the NIH guidelines and approved by the Canton Veterinary office (Bew 161,
Kantonales Veterindramt, Liestal, Switzerland). All rats are treated with the NO synthase inhibitor L-NAME (Sigma Chemicals) administered in drinking water (50 mg/l) for 12 weeks.
The average daily dose of L-NAME calculated from the water consumed was 2.5 mg/kg/d (range 2.1-2.7). :
The rats are divided into 5 groups: group 1, control (n = 40); Group 2, valsartan (5 mg/kg/d; n = 40); Group 3, the (+)-enantiomer of the hydrochloride of fadrozole (n = 30); Group 4, a combination of the (+)-enantiomer of the hydrochloride of fadrozole and valsartan (5 mg/kg/d); n = 30) and Group 5, valsartan (50 mg/kg/d; n = 30). The drugs are administered in drinking fluid. The pressor effect of Ang Il at 1 mg/kg obtained in controls normotensive rats is reducted by 49 % and 73 % after treatment with valsartan 5 and 50 mg/kg/d , respectively (Gervais et al. 1999). The response to Ang | injected in Wistar Kyoto rats pretreated with the (+)-enantiomer of the hydrochloride of fadrozole or valsartan 5 mg/kg/d is similar.
Body weight is measured every week. Systolic blood pressure and heart rate are recorded by tail cuff plethysmography 3 and 2 weeks before starting the study and at 2 weeks after drug administration. Urine is collected over a 24 hour period from rats kept in individual (metabolic) cages the week before starting treatment and at weeks 4 and 12 for volume 4 measurement and protein, creatinine, sodium and potassium determination using standard laboratory methods. At the same time points, blood samples are withdrawn from the retro- ] ‘ orbital plexus (maximum 1 mi) for creatinine, Na* and K* assays.
Ten rats from each group are sacrificed at 4 weeks for collection of kidney and heart for morphological analysis. The remaining rats are sacrificed at 12 weeks. Cardiac and kidney weight is recorded. Terminal blood sampling is performed in 5 % EDTA at 4 (morphometry ‘ study) and 12 (end of the study) weeks for aldosterone, determination by radioimmunoassay using a DPC coat-a-count aldosterone-RIA kit (Biihimann, Switzerland).
Statistical analysis: : F
All data are expressed as mean + SEM. Statistical analysis is performed using a one-way
ANOVA, followed by a Duncan’s multiple range test and a Newman-Keuls test, for comparison between the different groups. Results with a probability value of less than 0.05 are deemed statistically significant.
An improvement of regression of atherosclerosis without effecting the serum lipid levels can, for exmple, be demonstrated by using the animal model as disclosed by H. Kano et al. in Biochemical and Biophysical Research Communications 259, 414-419 (1999).
That the compounds or combinations according to the present invention can be used for the regression of a cholesterol diet-induced atherosclerosis, can be demonstrated using the test model described, e.g., by C. Jiang et al. in Br. J. Pharmacol. (1991), 104, 1033-1037.
That the compounds or compositions according to the present invention can be used for the treatment of renal failure, especially chronic renal failure, can be demonstrated using the test model described, e.g., by D. Cohen et al. in Jounal of Cardiovascular Pharmacology, 32: 87-95 (1998).
Further benefits when applying the composition of the present invention are that lower doses of the individual drugs to be combined according to the present invention can be used to reduce the dosage, for example, that the dosages need not only often be smaller but are also applied less frequently, or can be used in order to diminish the incidence of side effects. This is in accordance with the desires and requirements of the patients to be ° treated. : ’ All the more surprising is the experimental finding that the combined administration of combination according to the present invention results in a beneficial, especially a synergistic, therapeutic effect, but also in benefits resulting from the combined treatment and further surprising beneficial effects compared to a monotherapy applying only one of 2 the pharmaceutically active compounds used in the combinations disclosed herein. : w In particular, all the more surprising is the experimental finding that the combination of the present invention results in a beneficial, especially a synergistic, therapeutic effect but also in benefits resulting from combined treatment such as a surprising prolongation of efficacy, a broader variety of therapeutic treatment and surprising beneficial effects on diseases and conditions as specified hereinbefore or hereinafter.
Further benefits when applying the composition of the present invention are that lower doses of the individual drugs to be combined according to the present invention can be used to reduce the dosage, for example, that the dosages need not only often be smaller but are also applied less frequently, or can be used in order to diminish the incidence of side effects. This is in accordance with the desires and requirements of the patients to be treated.
The results of the studies clearly show that the composition according to the present invention can be used for the prevention of, delay of progression of, treatment of a disease or condition selected from the group consisting of (a) hypertension, congestive heart failure, renal failure, especially chronic renal failure, restenosis after percutaneous transluminal angioplasty, and restenosis after coronary artery bypass surgery; (b) atherosclerosis, insulin resistance and syndrome X, diabetes mellitus type 2, obesity, nephropathy, renal failure, e.g. chronic renal failure, hypothyroidism, survival post myocardial infarction (MI), coronary heart diseases, hypertension in the elderly, familial dyslipidemic hypertension, increase of formation of collagen, fibrosis, and remodeling following hypertension (antiproliferative effect of the combination), all these diseases or conditions associated with or without hypertension; and : (c) endothelial dysfunction with or without hypertension. ’ The compositions of the present invention can also be used for the prevention and delay of progression and preferably the treatment of other diseases.
A preferred composition comprises the combination of the (+)-enantiomer of the . hydrochloride of fadrozole and valsartan or valsartan combined with hydrochlorothiazide. 2 Preferably, the jointly therapeutically effective amounts of an AT;-receptor antagonist or of an AT;-receptor antagonist combined with a diuretic, in each case, in free or pharmaceutically acceptable salt form and an aldosterone synthase inhibitor in free or pharmaceutically acceptable salt form can be administered simultaneously or sequentially in any order, separately orin a fixed combination.
Furthermore, the invention relates to a method of the prevention of, delay of progression of, treatment of a disease or condition selected from the group consisting of (a) hypertension, congestive heart failure, renal failure, especially chronic renal failure, restenosis after percutaneous transluminal angioplasty, and restenosis after coronary artery bypass surgery; : (b) atherosclerosis, insulin resistance and syndrome X, diabetes mellitus type 2, obesity, nephropathy, renal failure, e.g. chronic renal failure, hypothyroidism, survival post myocardial infarction (MI), coronary heart diseases, hypertension in the elderly, familial dyslipidemic hypertension, increase of formation of collagen, fibrosis, and remodeling following hypertension (antiproliferative effect of the combination), all these diseases or conditions associated with or without hypertension; and (c) endothelial dysfunction with or without hypertension; comprising administering to a warm-blooded animal, including man, a therapeutically effective amount of an aldosterone synthase inhibitor in free or pharmaceutically acceptable salt form either alone or in combination with an AT-receptor antagonist or in combination with an AT;-receptor antagonist combined with a diuretic, in each case, in free or pharmaceutically acceptable salt form.
Furthermore, the invention relates to the use of a “ (a) pharmaceutical composition comprising () an AT,-receptor antagonist or an AT-receptor antagonist combined with a diuretic, or, " in each case, a pharmaceutically acceptable salt thereof, (i) an aldosterone synthase inhibitor or a pharmaceutically acceptable salt thereof and (i) a pharmaceutically acceptable carrier; or (b) an aldosterone synthase inhibitor or a pharmaceutically acceptable salt thereof,
for the manufacture of a medicament for the prevention of, delay of progression of, 4 treatment of a disease or condition selected from the group consisting of : () hypertension, congestive heart failure, renal failure, especially chronic renal failure, a restenosis after percutaneous transluminal angioplasty, and restenosis after coronary artery bypass surgery; : (B) atherosclerosis, insulin resistance and syndrome X, diabetes mellitus type 2, obesity, nephropathy, renal failure, e.g. chronic renal failure, hypothyroidism, survival post myocardial infarction (Ml), coronary heart diseases, hypertension in the elderly, familial dyslipidemic hypertension, increase of formation of collagen, fibrosis, and remodeling following hypertension (antiproliferative effect of the combination), all these diseases or conditions associated with or without hypertension; and (x) - endothelial dysfunction with or without hypertension.
The present invention likewise relates to a “kit-of-parts”, for example, in the sense that the components to be combined according to the present invention can be dosed independently or by use of different fixed combinations with distinguished amounts of the components, i.e. simultaneously or at different time points. The parts of the kit of parts can then e.g. be administered simultaneously or chronologically staggered, that is at different time points and with equal or different time intervals for any part of the kit of parts.
Preferably, the time intervals are chosen such that the effect on the treated disease or condition in the combined use of the parts is larger than the effect that would be obtained by use of only any one of the components.
The invention furthermore relates to a commercial package comprising the combination according to the present invention together with instructions for simultaneous, separate or sequential use. : These pharmaceutical preparations are for enteral, such as oral, and also rectal or : parenteral, administration to homeotherms, with the preparations comprising the pharmacological active compound either alone or together with customary pharmaceutical auxiliary substances. For example, the pharmaceutical preparations consist of from about 0.1 % to 90 %, preferably of from about 1 % to about 80 %, of the active compound.
Pharmaceutical preparations for enteral or parenteral, and also for ocular, administration are, for example, in unit dose forms, such as coated tablets, tablets, capsules or . suppositories and also ampoules. These are prepared in a manner which is known per se, for example using conventional mixing, granulation, coating, solubulizing or lyophilizing “ processes. Thus, pharmaceutical preparations for oral use can be obtained by combining the active compound with solid excipients, if desired granulating a mixture which has been obtained, and, if required or necessary, processing the mixture or granulate into tablets or : coated tablet cores after having added suitable auxiliary substances. :
The dosage of the active compound can depend on a variety of factors, such as mode of administration, homeothermic species, age and/or individual condition.
Preferred dosages for the active ingredients of the pharmaceutical combination according to the present invention are therapeutically effective dosages, especially those which are commerically available. : - + Normally, in the case of oral administration, an approximate daily dose of from about 1 mg to about 360 mg is to be estimated e.g. for a patient of approximately 75 kg in weight.
The dosage of the active compound can depend on a variety of factors, such as mode of . administration, homeothermic species, age and/or individual condition.
Valsartan, as a representative of the class of AT;-receptor antagonists, will be supplied in the form of suitable dosage unit form, for example, a capsule or tablet, and comprising a therapeutically effective amount, e.g. from about 20 to about 320 mg, of valsartan which may be applied to patients. The application of the active ingredient may occur up to three . times a day, starting e.g. with a daily dose of 20 mg or 40 mg of valsartan, increasing via 80 mg daily and further to 160 mg daily up to 320 mg daily. Preferably, valsartan is applied twice a day with a dose of 80 mg or 160 mg, respectively, each. Corresponding doses may ? be taken, for example, in the morning, at mid-day or in the evening.
B The following examples illustrate the above-described invention; however, it is not intended to restrict the scope of this invention in any manner.
-14- Co . Formulation Example 1:
Film-Coated Tablets: oe ComGnRNEglCOne RENT Unit (nO) || Standards etd STA REY Ba RE GE i Da ha TR ee AEE ra Ra ee
Valsartan [= active ingredient] 80.00
Microcrystalline cellulose/ 54.00 NF, Ph. Eur
Avicel PH 102
Colloidal anhydrous silica / 0.75 Ph. Eur/ colloidal silicon dioxide / Aerosil 200 NF
Magnesium stearate NF, Ph. Eur
Crm Blending saad freamnae alee 0 Bede Me oF
Colloidal anhydrous silica / 0.75 Ph. Eur/ colloidal silicon dioxide / Aerosil 200 NF
Magnesium stearate 200 | NF, Ph. Eur
EE Total tablet mass i rena ez 00 aut no amen aT one 0 TonhabBtWass lke ye a
Removed during processing.
The film-coated tablet is manufactured e.g. as follows:
A mixture of valsartan, microcrystalline cellulose, crospovidone, part of the colloidal anhydrous silica/colloidal silicon dioxide/Aerosile 200, silicon dioxide and magnesium ) stearate is premixed in a diffusion mixer and then sieve through a screnning mill. The resulting mixture is again pre-mixed in a diffusion mixer, compacted in a roller compacter and then sieve through a screening mill. To the resulting mixture, the rest of the colloidal anhydrous silica/colloidal silicon dioxide/Aerosile 200 are added and the final blend is made in a diffusion mixer. The whole mixture is compressed in a rotary tabletting machine and : the tabletts are coated with a film by using Diolack pale red in a perforated pan.
t 3 B So 5 “ »
No. . -15 - 8 Formulation Example 2:
Film-coated tablets: & Re EC SMP ORBNLS. ie as COMPOS ion Par Unit Th al Standards. fn Componeits sn | Composition Rel Unit (ha) | » Standards
Valsartan [= active ingredient] 160.00
Microcrystalline cellulose/ 108.00 NF, Ph. Eur
Avicel PH 102
Crospovidone 40.00 NF, Ph. Eur
Colloidal anhydrous silica / Ph. Eur/ colloidal silicon dioxide / Aerosil 200 NF
Soong Blending Rita oa anaes Lone
Ee ES eae EE Re Be)
Colloidal anhydrous silica / Ph. Eur/ colloidal silicon dioxide / Aerosil 200 NF pL A AY ER Sn Th me ep SH Seb oe Sen ue non tll SE i CO SEE Dr Ge sistas Si rt, et Cs Te
Coating: oh laine abe Ride nl ee
RNS En i a a fi A Total lable maces ; = alee aan RR RE
Bina GE se Re rd ‘tablettmass yin 3 30:00:54 57 alee de a cieneimacel IB ee
The film-coated tablet is manufactured e.g. as described in Formulation Example 1.
- Formulation Example 3: .
Film-Coated Tablets:
Valsartan 40.00 i A
Silica, colloidal anhydrous Ph. Eur, USP/NF (Colloidal silicon dioxide) [= Glidant]
Magnesium stearate USP/NF pessii l a
Crospovidone Ph. Eur [
Microcrystalline cellulose USP/NF ral A
RE
Silica, colloidal anhydrous, Ph. Eur, USP/NF (Colloidal silicon dioxide) [= Glidant]
Magnesium stearate 2.00 USP/NF [ri A
Opa bom OOF ert? [540
AL CE I
7 The composition of the Opadry® brown OOF16711 coloring agent is tabulated below. ’ “) Removed during processing
Opadry® Composition:
Siren ng Soil Dave 4 a REINER Sgmpositions
Iron oxide, black (C.I. No. 77499, E 172) EE ¢ Iron oxide, brown (C.I. No. 77499, E 172 EE
Iron oxide, red (C.I. No. 77491, E 172) EI
Iron oxide, yellow (C.I. No. 77492, E 172) EI
Titanium dioxide (C.l. No. 77891, E 171) (1400
Hypromellose (Ph. Eur) 80.00
The film-coated tablet is manufactured e.g. as described in Formulation Example 1.
Formulation Example 4:
Capsules:
PR Sa RT I oa Se EE AE A Ee I ER I TR Fa Ran 0 Componeith Bo [Soi Re a0) : Valsartan [= active ingredient] 80.00
Microcrystalline cellulose [25.10
I NE ho YE Shell al TE er Bo a ; net
Ce Ta Sli
Iron oxide, red 0.123 (C.1. No. 77491, EC No. E 172) )
Iron oxide, yellow (C.1. No. 77492, EC No. E 172)
Iron oxide, black : . (C.l. No. 77499, EC No. E 172) lade lee
The tablet is manufactured e.g. as follows:
. .
Granulation/Drying . Valsartan and microcrystallin cellulose are spray-granulated in a fluidised bed granulator with a granulating solution consisting of povidone and sodium lauryl sulphate dissolved in - purified water. The granulate obtained is dried in a fluidised bed dryer.
Milling/Blending
The dried granulate is milled together with crospovidone and magnesium stearate. The mass is then blended in a conical srew type mixer for approximately 10 minutes.
Encapsulation
The empty hard gelatin capsules are filled with the blended bulk granules under controlled temperature and humidity conditions. The filed capsules are dedusted, visually inspected, weightchecked and quarantied until by Quality assurance department.
Formulation Example 5:
Capsules: hick haw re Te CRE eR TE SE LA RS BEST SYA BET SE Ears GE On Ig, SE AT ST RAE
Womans cass [8020
Compotore moe
Poidore Jem
El CL
Sa RE el
Iron oxide, red : jr
Iron oxide, yellow 0.123 [EE iron oxide, black
Germeowem
I LL
Sava em aaa
The formulation is manufactured e.g. as described in Formulation Example 4. “
Formulation Example 6:
Hard Gelatine Capsule:
EL CL
Wegrosim soars [130
Pore Jam
Comoidone [too
Formulation Example 7:
A hard gelatin capsule, comprising as active ingredient e.g. (S)-N-(1-carboxy-2-methylprop- 1-yl)-N-pentanoyl-N-[2'(1H-tetrazol-5-yl)biphenyl-4-yl-methyllamine, can be formulated, for example, as follows:
Composition: (1) valsartan 80.0 mg : (2) microcrystalline cellulose 110.0 mg (3) polyvidone K30 45.2 mg (4) sodium lauryl sulfate 1.2mg (5) crospovidone 26.0 mg (6) magnesium stearate 2.6 mg
Components (1) and (2) are granulated with a solution of components (3) and (4) in water.
The components (5) and (6) are added to the dry granulate and the mixture is filled into size " 1 hard gelatin capsules. | :
Claims (11)
- ; What is claimed is» 1. Use of a pharmaceutical composition comprising (i) an aldosterone synthase inhibitor or a pharmaceutically acceptable salt thereof alone or in combination with, (i) an AT,-receptor antagonist or an AT, receptor antagonist combined with a diuretic or, : in each case, a pharmaceutically acceptable salt thereof and (ii) a pharmaceutically acceptable carrier; for the prevention of, delay of progression of, treatment of a disease or condition selected from the group consisting of (a) hypertension, congestive heart failure, renal failure, especially chronic renal failure, restenosis after percutaneous transluminal angioplasty, and restenosis after coronary artery bypass surgery; (b) atherosclerosis, insulin resistance and syndrome X, diabetes mellitus type 2, obesity, nephropathy, renal failure, e.g. chronic renal failure, hypothyroidism, survival post myocardial infarction (MI), coronary heart diseases, hypertension in the elderly, familial dyslipidemic hypertension, increase of formation of collagen, fibrosis, and remodeling following hypertension (antiproliferative effect of the combination), all these diseases or conditions associated with or without hypertension; and (c) endothelial dysfunction with or without hypertension.
- 2. Use according to claim 1 wherein said ATi-receptor antagonist is selected from the group consisting of valsartan, losartan, candesartan, eprosartan, irbesartan, saprisartan, tasosartan, telmisartan, the compound with the designation E-1477 of the following formula # >, Ny COOH[ty] M -22- _ the compound with the designation SC-52458 of the following formula N— . NPL ~N N , : 7 N\ —N NZ TNH \ / N=N and the compound with the designation the compound ZD-8731 of the following formula N $ == o) ) - \ / : N=N or, in each case, a pharmaceutically acceptable salt thereof. :
- 3. Use according to claim 2 wherein said AT-receptor antagonist is valsartan or a pharmaceutically acceptable salt thereof.
- 4. Use according to any one of claims claims 1 to 3 wherein said aldosterone synthase inhibitor is selected from the group consisting of anastrozole, fadrozole (including the (+)- enantiomer thereof, and exemestane, or, in each case where applicable, a pharmaceutically acceptable salt thereof.
- 5. Use according to any one of claims 1 to 4 wherein said aldosterone synthase inhibitor is (+)-enantiomer of the hydrochloride of fadrozole of formulaA N—/ N { oe no
- 6. Use according to any one of claims 1 to 5 wherein the diuretic is hydrochlorothiazide.
- 7. Use of a pharmaceutical composition comprising an aldosterone synthase inhibitor or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention of, delay of progression of, treatment of a disease or condition selected from the group consisting of () hypertension, congestive heart failure, renal failure, especially chronic renal failure, restenosis after percutaneous transluminal angioplasty, and restenosis after coronary artery bypass surgery; (B) atherosclerosis, insulin resistance and syndrome X, diabetes mellitus type 2, obesity, nephropathy, renal failure, e.g. chronic renal failure, hypothyroidism, survival post myocardial infarction (MI), coronary heart diseases, hypertension in the elderly, familial dyslipidemic hypertension, increase of formation of collagen, fibrosis, and remodeling following hypertension (antiproliferative effect of the combination), all these diseases or conditions associated with or without hypertension; and (x) endothelial dysfunction with or without hypertension.
- 8. A pharmaceutical composition comprising: (i) an aldosterone synthase inhibitor or a pharmaceutically acceptable salt thereof either: alone or in combination with, (i) an AT,-receptor antagonist or an AT, receptor antagonist combined with a diuretic or, 0 in each case, a pharmaceutically acceptable salt thereof; and ' (iii) a pharmaceutically acceptable carrier; . for the prevention of, delay of progression of, treatment of a disease or condition selected from the group consisting ofCase 4-31394A + » . (a) hypertension, congestive heart failure, renal failure, especially chronic renal failure, restenosis after percutaneous transluminal angioplasty, and restenosis after coronary artery bypass surgery; (b) atherosclerosis, insulin resistance and syndrome X, diabetes mellitus type 2, obesity, nephropathy, renal failure, e.g. chronic renal failure, hypothyroidism, survival post myocardial infarction (Ml), coronary heart diseases, hypertension in the elderly, familial dyslipidemic hypertension, increase of formation of collagen, fibrosis and remodeling following hypertension (antiproliferative effect of the combination), all these diseases or conditions associated with or without hypertension; and
- 9. Use according to claim 7 further comprising an AT, receptor antagonist or an AT -receptor antagonist combined with a diuretic, in each case, in free or pharmaceutically acceptable salt form.
- 10. Use according to claim 1 or 7, substantially as herein described and exemplified.
- 11. A pharmaceutical composition according to claim 8, substantially as herein described and exemplified. AMENDED SHEET :
Applications Claiming Priority (1)
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US19674200P | 2000-04-12 | 2000-04-12 |
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ZA200208204A ZA200208204B (en) | 2000-04-12 | 2002-10-11 | Novel medical use of aldosterone synthase inhibitors alone or in combination with AT1-receptor antagonists. |
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EP (1) | EP1282410A2 (en) |
JP (1) | JP2003530343A (en) |
KR (1) | KR20020089437A (en) |
CN (1) | CN1422152A (en) |
AR (1) | AR032316A1 (en) |
AU (2) | AU2001273938B2 (en) |
BR (1) | BR0110079A (en) |
CA (1) | CA2405895A1 (en) |
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SK (1) | SK14612002A3 (en) |
WO (1) | WO2001076574A2 (en) |
ZA (1) | ZA200208204B (en) |
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WO2004060399A1 (en) * | 2002-12-27 | 2004-07-22 | Takeda Pharmaceutical Company Limited | Body weight gain inhibitor |
SE0300988D0 (en) * | 2003-04-03 | 2003-04-03 | Astrazeneca Ab | New use |
WO2005099695A1 (en) * | 2004-04-19 | 2005-10-27 | Novartis Ag | Drug delivery systems for the prevention and treatment of vascular diseases |
ITTO20040760A1 (en) * | 2004-11-03 | 2005-02-03 | Uni Degli Studi Del Piemonte | USE OF A CORTICOSTEROID IN ASSOCIATION WITH OTHER ACTIVE PRINCIPLES FOR THE TREATMENT OF VASCULAR STENOSIS AND THE PREVENTION OF VASCULAR RESTENOSIS |
ES2397552T3 (en) * | 2004-12-24 | 2013-03-07 | Krka | Solid pharmaceutical composition comprising valsartan |
EP1674080A1 (en) * | 2004-12-24 | 2006-06-28 | KRKA, D.D., Novo Mesto | Solid pharmaceutical composition comprising valsartan |
EP1853261B1 (en) | 2005-03-03 | 2017-01-11 | Universität des Saarlandes | Selective inhibitors of human corticosteroid synthases |
TW200716636A (en) | 2005-05-31 | 2007-05-01 | Speedel Experimenta Ag | Heterocyclic spiro-compounds |
GT200600381A (en) | 2005-08-25 | 2007-03-28 | ORGANIC COMPOUNDS | |
EP1842543A1 (en) | 2006-04-05 | 2007-10-10 | Speedel Pharma AG | Pharmaceutical composition coprising an aldosterone synthase inhibitor and a mineralcorticoid receptor antagonist |
TW200808813A (en) | 2006-04-12 | 2008-02-16 | Speedel Experimenta Ag | Imidazo compounds |
TW200808812A (en) * | 2006-04-12 | 2008-02-16 | Speedel Experimenta Ag | Imidazo compounds |
EP2095819A1 (en) * | 2008-02-28 | 2009-09-02 | Maastricht University | N-benzyl imidazole derivatives and their use as aldosterone synthase inhibitors |
ES2582395T3 (en) | 2009-05-28 | 2016-09-12 | Novartis Ag | Substituted aminobutyric derivatives as neprilysin inhibitors |
ME01923B (en) | 2009-05-28 | 2015-05-20 | Novartis Ag | Substituted aminopropionic derivatives as neprilysin inhibitors |
JO2967B1 (en) | 2009-11-20 | 2016-03-15 | نوفارتس ايه جي | Substituted carbamoylmethylamino acetic acid derivatives as novel NEP inhibitors |
US8673974B2 (en) | 2010-11-16 | 2014-03-18 | Novartis Ag | Substituted amino bisphenyl pentanoic acid derivatives as NEP inhibitors |
US8877815B2 (en) | 2010-11-16 | 2014-11-04 | Novartis Ag | Substituted carbamoylcycloalkyl acetic acid derivatives as NEP |
KR20190025737A (en) | 2011-07-08 | 2019-03-11 | 노파르티스 아게 | Method of treating atherosclerosis in high triglyceride subjects |
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EP2956464B1 (en) | 2013-02-14 | 2018-03-28 | Novartis AG | Substituted bisphenyl butanoic phosphonic acid derivatives as nep (neutral endopeptidase) inhibitors |
EA201690278A1 (en) | 2013-07-25 | 2016-06-30 | Новартис Аг | CYCLIC POLYPEPTIDES FOR TREATMENT OF HEART FAILURE |
SG11201600208RA (en) | 2013-07-25 | 2016-02-26 | Novartis Ag | Bioconjugates of synthetic apelin polypeptides |
KR20170103970A (en) | 2015-01-23 | 2017-09-13 | 노파르티스 아게 | Synthetic Apelin Fatty Acid Conjugate with Improved Half-life |
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BR112019007954A2 (en) * | 2016-10-27 | 2019-07-02 | Damian Pharma Ag | aldosterone synthase inhibitor |
UY38072A (en) | 2018-02-07 | 2019-10-01 | Novartis Ag | COMPOSITIONS DERIVED FROM BUTANOIC ESTER SUBSTITUTED WITH BISPHENYL AS INHIBITORS OF NEP, COMPOSITIONS AND COMBINATIONS OF THE SAME |
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AR127698A1 (en) | 2021-11-23 | 2024-02-21 | Novartis Ag | NAFTYRIDINOONE DERIVATIVES FOR THE TREATMENT OF A DISEASE OR DISORDER |
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-
2001
- 2001-04-10 JP JP2001574092A patent/JP2003530343A/en active Pending
- 2001-04-10 MX MXPA02010091A patent/MXPA02010091A/en not_active Application Discontinuation
- 2001-04-10 CA CA002405895A patent/CA2405895A1/en not_active Abandoned
- 2001-04-10 PE PE2001000328A patent/PE20020082A1/en not_active Application Discontinuation
- 2001-04-10 SK SK1461-2002A patent/SK14612002A3/en unknown
- 2001-04-10 IL IL15208101A patent/IL152081A0/en unknown
- 2001-04-10 AR ARP010101698A patent/AR032316A1/en not_active Application Discontinuation
- 2001-04-10 PL PL01358459A patent/PL358459A1/en not_active Application Discontinuation
- 2001-04-10 WO PCT/EP2001/004116 patent/WO2001076574A2/en not_active Application Discontinuation
- 2001-04-10 AU AU2001273938A patent/AU2001273938B2/en not_active Ceased
- 2001-04-10 EP EP01940317A patent/EP1282410A2/en not_active Withdrawn
- 2001-04-10 AU AU7393801A patent/AU7393801A/en active Pending
- 2001-04-10 BR BR0110079-3A patent/BR0110079A/en not_active IP Right Cessation
- 2001-04-10 KR KR1020027013486A patent/KR20020089437A/en not_active Application Discontinuation
- 2001-04-10 NZ NZ521855A patent/NZ521855A/en unknown
- 2001-04-10 CN CN01807917A patent/CN1422152A/en active Pending
- 2001-04-10 HU HU0301335A patent/HUP0301335A3/en unknown
- 2001-04-10 RU RU2002129569/15A patent/RU2002129569A/en not_active Application Discontinuation
-
2002
- 2002-10-11 NO NO20024920A patent/NO20024920L/en not_active Application Discontinuation
- 2002-10-11 ZA ZA200208204A patent/ZA200208204B/en unknown
Also Published As
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NZ521855A (en) | 2004-10-29 |
AU7393801A (en) | 2001-10-23 |
NO20024920L (en) | 2002-11-27 |
RU2002129569A (en) | 2004-03-27 |
AU2001273938B2 (en) | 2005-03-03 |
AR032316A1 (en) | 2003-11-05 |
NO20024920D0 (en) | 2002-10-11 |
CN1422152A (en) | 2003-06-04 |
SK14612002A3 (en) | 2003-05-02 |
MXPA02010091A (en) | 2003-02-12 |
WO2001076574A2 (en) | 2001-10-18 |
JP2003530343A (en) | 2003-10-14 |
PE20020082A1 (en) | 2002-02-21 |
PL358459A1 (en) | 2004-08-09 |
EP1282410A2 (en) | 2003-02-12 |
IL152081A0 (en) | 2003-05-29 |
KR20020089437A (en) | 2002-11-29 |
HUP0301335A3 (en) | 2006-02-28 |
BR0110079A (en) | 2002-12-31 |
WO2001076574A3 (en) | 2002-04-25 |
HUP0301335A2 (en) | 2003-08-28 |
CA2405895A1 (en) | 2001-10-18 |
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