MXPA04010951A

MXPA04010951A - Pharmaceutical combination of pde5 inhibitors with ace inhibitors.

Info

Publication number: MXPA04010951A
Application number: MXPA04010951A
Authority: MX
Inventors: Hughes Bernadette
Original assignee: Pfizer
Priority date: 2002-05-23
Filing date: 2003-05-09
Publication date: 2005-06-08
Also published as: NO20045517L; AU2003223071A1; KR20050004195A; CA2485984A1; WO2003099194A2; EP1506015A2; RU2004133973A; BR0311191A; PA8574201A1; JP2005529927A; PL374198A1; WO2003099194A3; IL164975A0; CN1655820A; UY27816A1; AR040090A1; PE20040514A1; TW200407153A

Abstract

Combinations comprising a) an inhibitor of cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type 5 (PDE5) inhibitor and b) an inhibitor of angiotensin converting enzyme (ACE) are useful for treating hypertension.

Description

New combination The invention relates to the use of a combination of a cyclic guanosine monophosphate-specific phosphodiesterase type 5 (PDE5) inhibitor (G Pc) and b) an angiotensin-converting enzyme (ACE) inhibitor to treat cardiovascular diseases and metabolic, particularly hypertension.

Blood pressure (PS) is defined by a series of hemodynamic parameters taken alone or in combination. Systolic blood pressure (PSS) is the peak blood pressure obtained when the heart contracts. Diastolic blood pressure is the minimum blood pressure obtained when the heart relaxes. The difference between the PSS and the PSD is defined as the pulse pressure (PP).

. Elevated PS hypertension has been defined as PSA of at least 18.7 kPa and / or PSD of at least 12 kPa, according to this definition, the prevalence of hypertension in developed countries. it is approximately 20% of the adult population, increasing to approximately 60-70% in the population of 60 years or older, although a significant fraction of these hypertensive subjects have a normal PS when measured in a non-clinical setting. % of this elderly hypertensive population has isolated systolic hypertension (SAH), specifically have a high PSS and a normal PSD.Hypertension is associated with an increased risk of stroke, myocardial infarction, atrial fibrillation, heart failure, peripheral vascular disease and kidney damage (Fagard, RH, Am. J. Geriatric Cardioloav 1 1 (1), 23-28, 2002; Brown, MJ and Haycock, S., Druqs 59 (Suppl 2), 1-12, 2000).

The pathophysiology of hypertension is the subject of continuous debate. Although it is generally agreed that hypertension is the result of an imbalance between the volume of cardiac output and peripheral vascular resistance, and that most hypertensive subjects have an abnormal cardiac output volume and increased peripheral resistance, there is uncertainty about which parameter changes first (Beevers, G. et al., BJ 322, 9 2-916, 2001).

Despite the large number of drugs available in various pharmacological categories, including diuretics, alpha-adrenergic antagonists, beta-adrenergic antagonists, calcium channel blockers, angiotensin-converting enzyme inhibitors, and receptor antagonists ACE inhibitors, which block the vasoconstrictive action of the renin-angiotensin-aldosterone system, are recommended as first-line therapy for hypertension. They are effective and are generally considered well tolerated. The most common side effect, reported by 10-20% of patients, is cough. Other less frequently reported side effects include rash, angioedema, hyperkalemia, and functional renal failure.

Phosphodiesterase type 5 is a cyclic guanosine monophosphate specific phosphodiesterase. PDE5 inhibitors reduce the hydrolysis rate of G Pc and thus enhance the actions of nitric oxide. They have been found to be useful in the treatment of male erectile dysfunction.

According to a first aspect, the present invention provides the use of a combination comprising a) a PDE5 inhibitor and b) an ACE inhibitor in the manufacture of a medicament for treating diseases, particularly cardiovascular and metabolic diseases, more particularly hypertension.

As used herein, the terms "treat" and "treatment" include palliative, curative and prophylactic treatment. The term "hypertension" includes all diseases characterized by supranormal blood pressure, such as essential hypertension, pulmonary hypertension, "secondary hypertension, systolic hypertension", ischemic hypertension associated with diabetes, hypertension associated with atherosclerosis and renovascular hypertension, and extends further to pathological conditions for which a high blood pressure is a known risk factor., the term "treatment of hypertension" includes the treatment or prevention of complications arising from hypertension, and from other co-associated diseases, including congestive heart failure, angina, stroke, glaucoma and impaired renal function, including renal insufficiency. Metabolic diseases include in particular metabolic syndrome (also known as syndrome X), diabetes and impaired glucose tolerance, including complications thereof, such as diabetic retinopathy and diabetic neuropathy.

Hereinafter, combinations of a PDE5 inhibitor and an ACE inhibitor, including combinations of specific PDE5 inhibitors and specific ACE inhibitors, will be referred to as combinations of the invention.

The combinations of the invention have the advantage that they are more effective, more potent, less toxic or have other properties more desirable than PDE5 inhibitors or ACE inhibitors when used alone to treat hypertension.

Hereinafter, the term "PDE5 inhibitor" means a PDE5 inhibitor for use in the invention, including all pharmaceutically acceptable lysols, solvates and polymorphs of that PDE5 inhibitor. Similarly, the term "ACE inhibitor" means an ACE inhibitor for use in the invention, including all pharmaceutically acceptable salts, solvates and polymorphs of that ACE inhibitor.

The suitability of the PDE5 inhibitor and the ACE inhibitor can be easily determined by evaluating its potency and selectivity using literature procedures followed by evaluation of its toxicity, pharmacokinetics (absorption, metabolism, distribution and elimination), etc. according to standard pharmaceutical practice. Suitable compounds are those that are potent and selective, have no significant toxic effect at the therapeutic dose and are preferably bioavailable after oral administration.

The potency can be defined as a CI5o value, which is the concentration of compound needed to inhibit the enzymatic activity by 50%. The IC5o values for PDE5 inhibitors can be determined using the PDE5 assay described hereinafter. Preferably, PDE5 inhibitors have a Cl50 against PDE5 enzyme less than 100 nM, more preferably less than 50 nM.

The selectivity ratios can be easily determined by an expert, by means of the relationship of the corresponding Cl 50 values for the particular enzymes referred to. The IC5o values for the enzyme PDE3 and PDE4 can be determined using methodology established in the literature, see Ballard S.A. et al .; Journal of Uroloav 159, 2164-2 7, 1998.

Preferably, the PDE5 inhibitors are selective for the PDE5 enzyme. Preferably, they have a selectivity for PDE5 versus PDE3 greater than 100, more preferably greater than 300. More preferably, PDE5 has a selectivity both against PDE3 and PDE4 greater than 100, more preferably greater than 300.

Preferably, the PDE5 inhibitors have a Cl50 versus PDE5 less than 100 nM, and a selectivity to PDE3 of 100 times or greater.

Oral bioavailability refers to the proportion of a drug administered orally that reaches the systemic circulation. The factors that determine the oral bioavailability of a drug are dissolution, membrane permeability and hepatic elimination. Typically, a cascade of selection techniques is used first in vitro and then in vivo to determine oral bioavailability.

The dissolution, the solubilization of the drug by the aqueous contents of the gastrointestinal tract (GIT), can be predicted from in vitro solubility experiments performed at an appropriate pH to mimic the GIT. Preferably, PDE5 inhibitors have a minimum solubility of 50 μ9 / Gp ?. Solubility can be determined by standard procedures known in the art such as those described in Lipinski C.A. et al., Adv. Druq. Deliv. Rev. 23 (1-3), 3-25, 1997.

The membrane permeability designates the passage of a compound through the cells of the GIT.Lipophilicity is a key property in the prediction of this, and is determined by in vitro measurements of log D7f4 using organic solvents and Preferably, the PDE5 inhibitors have a log D7j4 of -2 to +4, more preferably of -1 to + 3. The log D can be determined by standard procedures known in the art such as those described in Stopher, D. McCléan, S .; J. Pharm. Pharmacol .. 42 (2), 144, 1990.

Cell monolayer assays such as Caco2 are substantially added to the prediction of favorable membrane permeability in the presence of efflux transporters such as p-glycoproteins, the so-called Caco2 flux. Preferably, the PDE5 inhibitors have a Caco2 flux greater than 2 x 10"6 cm.s" 1, more preferably greater than 5 x 10"6 cm.s 1. The flow value of Caco2 can be determined by known standard methods. in the art such as those described in Artursson, P. and Agnusson, C, J. Pharm, Sci .. 79 (7), 595-600, 1990.

Metabolic stability refers to the ability of the GIT to metabolize the compounds during the absorption process, or to do so. 10 liver immediately after absorption: the effect of the first step. Test systems such as microsomes, hepatocytes, etc. they are predictive of metabolic lability. Preferably, the PDE5 inhibitors show metabolic stability in the assay system that is proportional to a liver extraction of less than 0.5. Examples of test systems and Data manipulation are described in Obach, R.S .; Curr. Qpin. Druq Pise. (2000).

Due to the interaction of the above processes, additional support can be achieved that a drug will be orally bioavailable in humans by in vivo experiments on animals. The absolute bioavailability is determined in these studies by administering the compound separately or in mixtures orally. For absolute determinations (% bioavailable orally), the intravenous route is also used. Examples of evaluation of oral bioavailability in animals can be found in Ward, K.W. was/.; Drua Met. Disp. 29 (1), 82-87, 2001; Berman, J. et al., J. Med.

Chem. 40 (6), 827-829, 1997 and Han K.S. and Lee, M.G .; Drua Met. Disp. 27 (2), 221-226, 1999.

Examples of PDE5 inhibitors for use with the invention are: The pyrazolo [4,3- | pyrimidin-7-ones described in EP-A-0463756, EP-A-0526004 and published international patent applications WO 93/06104, WO 98/49166, WO 99/54333, WO 00/24745, WO 01/27112 and WO 01/27113; the pyrazolo [3,4-d] pyrimidin-4-ones described in EP-A-0995750, EP-A-0995751 and in published international patent application WO 93/07149; the pyrazolo [4,3- /] pyrimidines described in published international patent applications WO 01/18004, WO 02/00660 and WO 02/59126; the quinazolin-4-ones described in the published international patent application WO 93/12095; the [3,2-a] pyrimidin-4-ones described in the published international patent application WO 94/05661; the puriñ-6-ies described "in" the document? -? - 0927 Í8"and in the" application "of published international patent WO 94/00453; hexahydropyrazino [2 ', 1': 6: 1] pyrid [3,4-b] indole-1,4-diones described in published international application WO 95/19978; the imidazo ^ .l-rltl ^^ triazinones described in EP-A-1092719 and in published international patent application WO 99/24433; the bicyclic compounds described in published international application WO 93/07214 and the imidazoquinazolinones described in Rotella D.P. et al. J. Med. Chem. 43 (7 1257-1263, 2000.

The contents of published patent applications and journal articles, and in particular the general formulas of the therapeutically active compounds of the claims and compounds exemplified therein, are incorporated herein by reference in their entirety thereto. .

Further examples of PDE5 inhibitors for use with the invention include: 4-bromo-5- (pyridylmethylamino) -6- [3- (4-chlorophenyl) propoxy] -3 (2f) pyridazinone; monosodium salt of 1- [4 - [(1,3-benzodioxol-5-ylmethyl) amino] -6-chloro-2-quinazolinyl] -4-piperidinecarboxylic acid; (+) - c / s-5) 6a, 7,9,9,9a-hexahydro-2- [4- (trifluoromethyl) phenylmethyl-5-methylcyclopenta [4,5] imidazo [2,1- £ > ] purin-4 (3 / - /) ona; furazlocillin; cs-2-hexyl-5-methyl-3,4,5,6a, 7,8,9,9a-octahydrocyclopenta [4,5] imidazo [2,1-)] purin-4-one; 6-carboxylic acid 3-acetyl-1- (2-chlorobenzyl) -2-propylindole; 6-Acetyl-1- (2-chlorobenzyl) -2-propylindole 6-carboxylate; 4-bromo-5- (3-pyridylmethylamino) -6- (3- (4-chlorophenyl) propoxy) -3- (2 / -) pyridazinone; 1-methyl-5- (5-morpholinoacetyl-2-n-propoxyphenyl) -3-n-propyI-1,6-dihydro-7 - / - pyrazolo [4,3-c /] pyrimidin-7-one; monosodium salt of 1- [4 - [(1,3-benzbdioxol-5-ylmethyl) a7hino] -6¾oró ^ 2-qu Pharmaprojects n ° 4516 (Glaxo Wellcome); Pharmaprojects No. 5051 (Bayer); Pharmaprojects No. 5064 (Kyowa Hakko, see WO 96/26940); Pharmaprojects No. 5069 (Schering Plow); GF-196960 (Glaxo Wellcome); E-8010 and E-4010 (Eisai); Bay-38-3045 & 38-9456 (Bayer) and Sch-51866.

Preferred PDE5 inhibitors for use with the invention include: 5- [2-ethoxy-5- (4-methyl-1-p-piperazinylsulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4.3- ( /] pyrimidin-7-one (sildenafil) also known as 1- P-ie-dihydro-l-methyl-y-oxo-S-propyl-IH-pyrazolo ^^ - c ^ pyrimidin-S-yl-ethoxyphenyl] sulfonyl ] -4-methylpiperazine (see EP-A-0463756); 5- (2-ethoxy-5-morpholinoacetylphenyl) -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one ( see EP-A-0526004); 3-Ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2-n-propoxy-phenyl] -2- (pyridn-2-yl) methyl- 2,6-dihydro-7 / - / - pyrazolo [4,3-aflpyrimidn-7-one (see WO 98/49166); 3-etl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxy-ethoxy) pyridin-3-yl] -2- (pyridin-2-yl); l) methyl-2,6-dihydro-7H-pyrrazolo [4,3-d] pyrimidin-7-one (see WO 99/54333); (+) - 3-EtN-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-me pyridyl-3: yl] -2 ^ metii-2 ^ 6-dihydro-7H-pyrazolo [ 4.3 ^., Also known as 3-ethyl-5-. {5- [4-ethylpiperazin-1-ylsulfonyl] -2 - ([(1 R) -2-methoxy-1-methylethyl] oxy) pyridine 3-yl.} -2-methyl-2,6-dihydro-7H-pyrazolo [4,3- (3-pyrimidin-7-o (see WO 99/54333); 5- [2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-etl-2- [2-methoxyethyl] -2,6-dihydro-7H -pyrazolo [4,3-c] pyrimidn-7-one, also known as 1-. { 6-ethoxy-5- [3-ethyl-6,7-dihydro-2- (2-methoxyethyl) -7-oxo-2H-pyrrazolo [4,3-c] pyrimidin-5-yl] -3- pyridylsulfonyl} -4-ethylpiperazine (see WO 01/27113, example 8); 5- [2-isobutoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-ethyl-2- (1-methylpiperidin-4-yl) -2,6-dihydro-7 / - / -pirazolo [4,3-c / lpyrimidin-7-one (see WO 01/27113, example 15); 5- [2-ethoxy-5- (4-ethyl-piperazin-1-ylsulfonyl) -pyridin-3-yl] -3-ethyl-2-phenyl-2,6-d -hydro-7- - prazolo [4,3-d] pyrimid-7-one (see WO 01/27113, example 66); 5- (5-acetyl-2-propoxy-3-pyridinyl) -3-ethyl-2- (1-isopropyl-3-azetidinyl) -2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one (see WO 01/27112, example 124); 5- (5-acetyl-2-butoxy-3-pyridinyl) -3-ethyl-2- (1-ethyl-3-azetidinyl) -2,6-d and h -dro-7H-p¡razolo [ 4.3-c] pyrimidin-7-one (see WO 01/27112, example 132); (6f?, 12aR) -2,3,6,7,12,12a-hexahydro-2-methyl-6- (3,4-methylenedioxyphenyl) -p -razino [2 ', 1': 6 , 1] pyrido [3,4- / 3] indol-1,4-dione (tadalafil, IC-351), specifically the compound of examples 78 and 95 of published international application WO 95/19978, as well as the compound of examples 1, 3, 7 and 8. 2- [2-ethoxy-5- (4-ethylpiperazin-1-yl-1-sulfonyl) phenyl] -5-methyl-7-propyl-3 / - / - imydazo [5,1 - /] [1 > 2,4] triazn-4-one (vardenafil), also known as 1 - [[3- (3,4-dihydro-5-methyl-4-oxo-7-propylimidazo [5,1-] -as-triazin-2-yl) -4-ethoxyphenyl] -sulfonyl] -4-ethylpiperazine, namely the compound of examples 20, 19, 337 and 336 of published international application WO 99/24433; [7- (3-Chloro-4-methoxybenzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-c /] pyrimidin-5-ylmethoxy] acetic acid (see WO 02 / 59126, example 1); 4- (4-chlorobenzyl) amino-6,7,8-trimethoxyquinazoline (example 11 of published international application WO 93/07124 (EISAI)); Y 7,8-dihydro-8-oxo-6- [2-propoxyphenyl] -1H-imidazole [4,5-g] quinazoline and 1- [3- [1 - [(4-fluorophenyl) methyl] -7,8 -dihydro-8-oxo-1 / - / - imidazo [4,5-g] quinazolin-6-yl] -4-propoxyphenyl] carboxamide (compounds 3 and 14 of Rotella DP et al., J. Med. Chem 43 (7), 1257-1263, 2000).

The most preferred PDE5 inhibitors for use with the invention are selected from the following group and pharmaceutically acceptable salts thereof: ~ 5- [2-etc i-5- (4-methyl-1-piperazinylsulfonyl) phenyl] -1 -methyl-3-n-propyl-1,6-dihydro-7 / - / - pyrazolo [4,3-d] pyrimidin-7-one (sildenafil); (6f?, 12af?) -2,3,6,7,12,12a-hexahydro-2-methyl-6- (3,4-methylenedioxyphenyl) -pyrazine [2 ', 1': 6.1] pyrido [3,4-í > ] indole-1,4-dione (tadalafil, IC-351); 2- [2-ethoxy-5- (4-ethylpiperazin-1-yl-1-sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazofS.I-rltl ^^ jtriazin -one (vardenafil); 5- [2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-ethyl-2- [2-methoxyethyl] -2,6-dihydro-7H-pyrazolo [4 , 3-cf] pyrimidin-7-one; and 5- (5-acetyl-2-butoxy-3-pyridinyl) -3-ethyl-2- (1-ethyl-3-azetidinyl) -2,6-dihydro-7H-pyrrazolo [4.3 -c /] pyrimidin-7-one.

A particularly preferred PDE5 inhibitor is 5- [2-ethoxy-5- (4-methyl-1-piperazinylsulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4 , 3-cflpirimidin-7-one (sildenafil) (also known as 1 - [[3- (6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [4.3- /] pyrimidin-5-yl) -4-ethoxyphenyl] sulfonyl] -4-methyl-piperazine) and the pharmaceutically acceptable salts thereof. Sildenafil citrate is a preferred salt.

Examples of ACE inhibitors for use with the invention include both direct acting ACE inhibitors and prodrugs thereof, including alacepril, alindapril, altiopril, benazepril, benazeprilat, captopril, ceronapril, cilazapril, cilazaprilat, delapril, enalapril, enalaprilat , fosinopril, imidapril, indolapril, libenzapril, lisinopril, moexepril, moveltipril, pentopril, perindopril, quinapril, quinaprilat, ramipril, rentiapril, espirapril, temocapril, teprotide, trandolapril and zofenopril. In addition, the ACE inhibitor can be a "dual inhibitor of ACE / NEP", specifically a compound that inhibits both ACE and neutral endopeptidase (NEP), such as, for example omapatrilat, fasidotril, mixanpril, sampatrilat, BMS-189921 , MDL-100240 and Z13752A.

Preferred combinations of PDE5 inhibitors and inhibitors of ACE to treat hypertension are: sildenafil and quinapril hydrochloride; sildenafil and benazepril hydrochloride; sildenafil and captopril; sildenafil and enalapril maleate; sildenafil and fosinopril; sildenafil and lisinopril; sildenafil and moexipril; sildenafil and ramipril; sildenafil and trandolapril; tadalafil and quinapril hydrochloride; tadalafil and benazepril hydrochloride; tadalafil and captopril; tadalafil and enalapril maleate; tadalafil and fosinopril; tadalafil and lisinopril; tadalafil and moexipril; tadalafil and ramipril; tadalafil and trandolapril; vardenafil and quinapril hydrochloride; virdenafil and benazepriio hydrochloride; vardenafil and captopril; vardenafil and enalapril maleate; vardenafil and fosinopril; vardenafil and lisinopril; vardenafil and moexipril; vardenafil and ramipril; and vardenafil and trandolapril.

The pharmaceutical combinations of the invention are useful in the treatment of diseases including cardiovascular and metabolic diseases, and may also be useful in the treatment of other diseases such as thrombosis, and in the treatment of patients after percutaneous transluminal coronary angioplasty ("patients post-PTCA ").

Preferably, the cardiovascular disorder to be treated is hypertension, congestive heart failure, angina, apoplexy or renal failure. More preferably, the cardiovascular disorder is essential hypertension, pulmonary hypertension, secondary hypertension, isolated systolic hypertension, hypertension associated with diabetes, hypertension associated with atherosclerosis, renovascular hypertension, congestive heart failure, angina, apoplexy or renal insufficiency. In a particularly preferred embodiment, the disorder to be treated is essential hypertension. In another particularly preferred embodiment, the disorder to be treated is pulmonary hypertension. In another particularly preferred embodiment, the disorder to be treated is secondary hypertension. In another particularly preferred embodiment, the disorder to be treated is isolated systolic hypertension. In a particularly preferred embodiment, the disorder to be treated is hypertension associated with diabetes. In another particularly preferred embodiment, the disorder to be treated is hypertension associated with atherosclerosis. In another particularly preferred embodiment, the disorder to be treated is renovascular hypertension.

Preferably, the metabolic disorder to be treated is impaired glucose tolerance or diabetes, including complications thereof, such as diabetic retinopathy and diabetic neuropathy. More preferably, the metabolic disorder is impairment of glucose tolerance, type 1 diabetes, non-insulin dependent diabetes type 2 or insulin-dependent diabetes type 2.

The combination of the invention can be administered alone, but will generally be administered in admixture with a suitable pharmaceutically suitable excipient, diluent or carrier with respect to the intended route of administration and standard pharmaceutical practice.

For example, the combinations of the invention may be administered orally, buccally or sublingually in the form of tablets, capsules, multiparticulates, gels, films, ovules, elixirs, solutions or suspensions, which may contain flavoring or coloring agents, for release applications. immediate, delayed, modified, sustained, pulsed or controlled. The combinations of the invention can also be administered as rapidly dispersing or rapidly dissolving dosage forms or in the form of a high energy dispersion or as coated particles. Suitable formulations can be in coated or uncoated form, as desired.

Said solid pharmaceutical compositions, for example tablets, may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, glycine and starch (preferably corn starch, potato or tapioca), disintegrants such as glycolate. sodium starch, croscarmellose sodium and certain complex silicates, and granulation binders such as poly (vinyl pyrrolidone), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and gum arabic. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.

The following formulation examples are illustrative only, and are not intended to limit the scope of the invention. Active ingredient means a combination of the invention.

Formulation 1: A tablet is prepared using the following ingredients: The active ingredient (50 mg) is mixed with cellulose (microcrystalline), silicon dioxide, stearic acid (fuming) and the mixture is compressed into tablets.

Formulation 2: An intravenous formulation can be prepared by combining the active ingredient (100 mg) with an isotonic saline solution (1000 ml).

The tablets are manufactured by a standard process, for example direct compression or a wet or dry granulation process. The tablet cores may be coated with appropriate coatings.

Solid compositions of a similar type can also be used as fillers in gelatin capsules or HPMC. Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or high molecular weight polyethylene glycols. For aqueous suspensions and / or elixirs, the PDE5 and ACE inhibitors may be combined with various sweetening or flavoring agents, coloring material or dyes, with emulsifying and / or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.

The pulse release and modified release dosage forms may contain excipients such as those detailed for immediate release dosage forms together with additional excipients which act as release rate modifiers, these being coated on and / or included in the body of the delivery. device. Release rate modifiers include, but are not limited to, hydroxypropylmethylcellulose, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, cellulose acetate, poly (ethylene oxide), xanthan gum, carbomer, ammonium and methacrylate copolymer, hydrogenated castor oil, carnauba wax, paraffin wax, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, methacrylic acid copolymer and mixtures thereof. Dosage, modified and pulsed release dosage forms may contain one or a combination of excipients modifying the rate of release. The excipients modifying the rate of release can be present in the dosage form, specifically in the matrix, and / or on the dosage form, specifically on the surface or coating.The dispersion or rapid dissolution (FDDF) dosage formulations may contain the following ingredients: aspartame, potassium acesulfame, citric acid, croscarmellose sodium, crospovidone, diascorbic acid, ethyl acrylate, ethylcellulose, gelatin, hydroxypropylmethylcellulose, magnesium stearate, mannitol, methyl methacrylate, mint flavor, polyethylene glycol, fumed silica, silicon dioxide, sodium starch glycolate, sodium stearyl fumarate, sorbitol, xylitol. The terms "disperse" or "dissolve" as used herein to describe FDDFs depend on the solubility of the drug substance used, namely when the drug substance is insoluble, a fast dispersing dosage form can be prepared, and when the drug substance is soluble, a rapid dissolving dosage form can be prepared.

The combinations of the invention can also be administered parenterally, for example intracavernous, intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular or subcutaneous, or they can be administered by infusion or needleless injection techniques. For such parenteral administration, they are preferably used in the form of a sterile aqueous solution which may contain other substrates, for example enough salts or glucose to make it an ideal solution with the blood. The aqueous solutions should be suitably buffered (preferably at a pH of 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is easily accomplished by standard pharmaceutical techniques well known to those skilled in the art.

The following dosage levels and other dosage levels herein are for the average human subject with a weight range of approximately 65 to 70 kg. The skilled person will be able to easily determine the dosage levels required for a subject whose weight is outside this range, such as children and the elderly.

The dosage of the combination of the invention in said formulations will depend on its potency, but can be expected to be in the range of 1 to 500 mg of PDE5 inhibitor and 1 to 100 mg of ACE inhibitor for administration up to three times a day . A preferred dose is in the range of 10 to 100 mg (for example 10, 25, 50 and 100 mg) of PDE5 inhibitor and 5 to 50 mg (for example, 5, 10, 25 and 50 mg) of inhibitor of ACE, which can be administered once, twice or three times a day (preferably once). However, the precise dose will be determined by the prescribing physician, and will depend on the age and weight of the subject and the severity of the symptoms.

For oral and parenteral administration to human patients, the daily dosage level of a combination of the invention will be approximately 5 to 500 mg / kg (in single or divided doses). -. - - Thus, the tablets or capsules may contain from 5 mg to 250 mg (for example from 10 to 100 mg) of the combination of the invention for administration of one or two or more at a time, as appropriate. The doctor will determine in any case the actual dosage that will be the most appropriate for each individual patient, and will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the middle case. There may, of course, be individual cases where smaller or larger dosage ranges are required, and these are within the scope of this invention. The skilled person will appreciate that the combinations of the invention can be taken as a single dose as needed or desired (namely prn). It is appreciated that all references herein to treatment include acute treatment (taken when required) and chronic treatment (continuous longer-term treatment).

The combinations of the invention can also be administered intranasally or by inhalation, and are conveniently released in the form of a dry powder inhaler or an aerosol spray presentation from a pressure pack, pump, spray, atomizer or nebulizer, with or without the use of a suitable propellant, for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1, 1, 1, 2-tetrafluoroethane (HFA 134A [trademark]) or 1, 1, 1, 2,3,3,3-heptafluoropropane (HFA 227EA [trademark]), carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosing unit can be determined by providing a valve to open a bottle. it may contain a solution or suspension of the active compound, for example using a mixture of ethanol and the propellant as solvent, which may additionally contain a lubricant, for example sorbitan trioleate. Capsules and cartridges (prepared for example from gelatin) for use in an inhaler or insufflator can be formulated to contain a powder mixture of the combinations of the invention and a suitable powder base such as lactose or starch.

Aerosol or dry powder formulations are preferably arranged so that each measured or "burst" dose contains from 1 μg to 50 mg of a combination of the invention for delivery to the patient. The total daily dose with an aerosol will be in the range of 1 μ? to 50 mg, which can be administered in a single dose or, more usually, in divided doses throughout the day.

Alternatively, the combinations of the invention can be administered in the form of a suppository or pessary, or they can be administered topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or fine powder. The combinations of the invention can also be administered dermally or transdermally, for example using a dermal patch, a reservoir or a subcutaneous injection. They can also be administered pulmonarily or rectally.

For topical administration to the skin, the combinations of the invention can be formulated in the form of a suitable ointment containing the active compound suspended or dissolved, for example, in a mixture of one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene-polyoxypropylene compound, emulsifying wax and water. Alternatively, they can be formulated as a suitable, suspended or dissolved lotion or cream, for example, in a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, Cetearyl alcohol, 2-octyldodecane, benzyl alcohol and water.

The combinations of the invention can also be used in combination with a cyclodextrin. Cyclodextrins are known to form inclusion and non-inclusion complexes with drug molecules. The formation of a drug-cyclodextrin complex can modify the solubility, dissolution rate, bioavailability properties and / or stability of a drug molecule. Drug-cyclodextrin complexes are generally useful for most dosage forms and routes of administration. As an alternative to direct complexation with the drug, the cyclodextrin can be used as an auxiliary additive, for example as a carrier, diluent or solubilizer. Alpha-, beta- and gamma-xtrines are the most commonly used, and suitable examples are described in published international patent applications WO 91/11172, WO 94/02518 and WO 98/55148.

Oral administration of the combinations of the invention is a preferred route, since it is the most convenient. In circumstances in which the recipient suffers a swallowing disorder or an altered absorption of drug after oral administration, the drug may be administered via the para-oral route. sublingual or buccal . . . · .. - The combinations of the invention can be used as part of a triple therapy regimen, namely a treatment protocol in which the patient is treated with three pharmaceutical agents. The third agent in the triple therapy can be a second PDE5 or ACE inhibitor, or it can be chosen from a third pharmacological group. For example, it can be a neutral endopeptidase inhibitor, an angiotensin II receptor antagonist, a calcium channel blocker such as amlodipine, a statin such as atorvastatin, a beta blocker (specifically a beta-adrenergic receptor antagonist) or a diuretic .

It will be appreciated that the invention covers the following additional aspects and that the embodiments specified hereinabove for the first aspect extend to these aspects: i) a pharmaceutical combination of the invention (for simultaneous, separate or sequential administration) to treat hypertension; i) a kit for treating hypertension, the kit comprising: a) a first pharmaceutical composition comprising a PDE5 inhibitor; b) a second pharmaceutical composition comprising an ACE inhibitor; and c) a package for the compositions; a procedure for treating hypertension in a subject that | - Test The preferred compounds suitable for use according to the present invention are potent and selective PDE5 inhibitors. The in vitro inhibitory activities of PDE5 against phosphodiesterases of 3 ', 5'-cyclic guanosine monophosphate (cGMP) and 3'5'-cyclic adenosine monophosphate (A Pc) can be determined by measuring their Cl50 values ( concentration of compound necessary for a 50% inhibition of the enzymatic activity).

The required PDE enzymes can be isolated from a number of sources, including human cavernous body, human and rabbit platelets, human cardiac ventricle, human skeletal muscle and bovine retina, essentially by a modification of the Thompson, W.J. et al .; Biochemistry 18 (23), 5228-5237, 1979, as described in Ballard, SA, er a /., J. Uroloqy 159 (6), 2164-2171, 1998. In particular, PDE5 specific for GMPC and PDE3 can be obtained of cAMP inhibited by cGMP from human cavernous body tissue, human platelets or rabbit platelets; PDE2 stimulated by cGMP was obtained from the human cavernous body; calcium / calmodulin (Ca / CAM) -dependent PDE1 of human cardiac ventricle; cAMP-specific PDE4 of human skeletal muscle; and the PDE6 of bovine retina photoreceptor. Phosphodiesterases 7-11 can be generated from whole human recombinant clones transfected into SF9 cells.

^ The tests can be performed; using a modification of the "batches" procedure of Thompson, W.J and Appleman, M.M .; Biochemistry 10 (2), 31 1-316, 1971, essentially as described in Ballard, S.A. et al .; J. Uroloqy 159 (6), 2164-2171, 1998, or using a proximity scintillation assay for direct detection of AMP / GMP labeled with [3H] using a modification of the protocol described by Amersham foot with product code TRKQ7090 / 7100 In summary, for the proximity scintillation assay, the effect of PDE inhibitors was investigated by assaying a fixed amount of enzyme in the presence of varying concentrations of inhibitor and low substrate (cGMP or cAMP in a 3: 1 ratio of unlabeled to marked with [3H] at a concentration of -1/3 Km or less) such that IC50 «K¡. The final assay volume was completed at 100 μ? with assay buffer [20 mM Tris-HCl, pH 7.4, 5 mM MgCl 2, 1 mg / ml bovine serum albumin]. Reactions were initiated with enzyme, incubated for 30-60 minutes at 30 ° C providing <30% substrate exchange and were finished with 50 μ? of yttrium silicate in SPA beads (containing at 3 mM concentration to the respective unlabeled cyclic nucleotide for PDE9 and 11). The plates were resealed and shaken for 20 minutes, after which the beads were allowed to settle for 30 minutes in the dark and then counted in a TopCount plate reader (Packard, Merlden, CT). The radioactivity units were converted to% activity of an uninhibited control (100%), plotted against the inhibitor concentration, and IC50 values of inhibitor were obtained using the Microsoft Excel extension "curve fitting".

Animal study The efficacy of the combinations of the invention in an animal model of human hypertension using enalapril as a representative ACE inhibitor and 3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2- methoxyethoxy) pyridin-3-yl] -2- (pyridin-2-yl) methyl-2,6-dihydro-7 - / - pyrazolo [4,3-d] pyrimidin-7-one (the compound of Example 4 of published international patent application WO 99/54333) as a representative PDE5 inhibitor.

Animals The spontaneously hypertensive rat (SHR) is a widely used model of human hypertension. Doppler flow probes were provided to male SHR (20-22 weeks of age) for measurement of mesenteric, posterior and renal blood flow, aortic blood pressure and heart rate according to published procedures (Gardiner, SM et al., Br. J. Pharmacol., 132 (8), 1625-1629, 2001).

Drugs Solutions of enalapril (7.5 μg ml), PDE5 inhibitor (200 μg / ml) and a combination of enalapril and PDE5 inhibitor (7.5 μg / ml + 200 μg / ml) at a rate of 0 were infused. , 4 ml / h during the experimental period. Control animals received vehicle of the compound; isotonic saline solution adjusted to pH 4 with hydrochloric acid.

Protocol Hemodynamic baseline parameters were recorded. The animals were randomly pooled (n = 7 or 8 / group) and then treated with the drug solution by continuous infusion for 4 days. Changes in hemodynamic parameters were monitored during the study period for 7 hours each day. The summary results expressed as difference with respect to the response of the vehicle are presented in the following table.

Treatment Enalapril Combination Inhibitor PDE5 Total change in mean SP (kPa) -0.3 -1.6 -2.4 Change in conductance +22.4 +22.1 +48.1 mesenteric (%) Change in Renal conductance (%) +14.2 -0.8 +34.2 Change in aortic conductance (%) +3.7 +19.8 +30.1 The results, for renal conductance in particular, show that the two agents in combination can produce an effect that is greater than the sum of their individual effects.

Claims

1. The use of a cyclic guanosine monophosphate-specific phosphodiesterase type 5 (PDE5) inhibitor combination and an angiotensin-converting enzyme (ACE) inhibitor for the preparation of a medicament for palliative, curative or prophylactic treatment of hypertension, including essential hypertension, pulmonary hypertension, secondary hypertension, isolated systolic hypertension, hypertension associated with diabetes, hypertension associated with atherosclerosis and renovascular hypertension, congestive heart failure, angina, stroke, diabetes and impaired glucose tolerance.

2. The use according to the_ rei indicaciórTL | , _emel.jjUjB¾el, inhibidpr = detFDE5 has a Cl50 value of less than 100 nM. '"*" "_

3. The use according to claim 2, wherein the PDE5 inhibitor has an IC50 value of less than 50 nM.

4. The use according to any of the preceding claims, wherein the PDE5 inhibitor is selected from 5- [2-ethoxy-5- (4-methyl-1-piperazinylsulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7 y-pyrazolo [4,3-c ( 1-rimidin-7-one (sildenafil) (6 ^, 123 /?) - 2,3,67 ^ 2,123-? T? 3 ??? G? -2 ^ ???? - 6- (3,4 -? t ??????? (_ ????? T ???) - pyrazino [2 ', 1': 6,1] pyrido [3,4- £>] indole-1, 4 -dione (tadalafil); 2- [2-ethoxy-5- (4-ethylpiperazin-1-yl-1-sulfonyl) phenyl] -5-methyl-7-propyl-3 / - / - imidazo [5, 1 - | [1, 2, 4] triazin-4-one (vardenafil); 5- [2-ethoxy-5- (4-ethi-piperazin-1-ylsulfonyl) pyridin-3-yl] -3-etl-2- [2-methoxyethyl] -2 , 6-dihydro-7 / - -pyrazolo [4,3-of] pyrimidin-7-one; Y 5- (5-acetyl-2-butoxy-3-pyridinyl) -3-ethyl-2- (1-ethyl-3-azetidini!) - 2,6-d pyrazolo [4,3- /] pyrimidin-7- ona; and the pharmaceutically acceptable salts thereof.

5. The use according to claim 5T-5- [2-ethoxy-5- (4: methyl-1-piperazin-sulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7 / - / - ~ pyrazolo [4,3-c-pyrimidin-7-one (sildenafil) or a pharmaceutically acceptable salt thereof.

6. The use according to claim 5, wherein the PDE5 inhibitor is sildenafil citrate.

7. The use according to any of the preceding claims, wherein the ACE inhibitor is selected from benazepri, captopril, cilazepril, enalapril, enalaprilat, fosinopril, lisinopril, moexepril, perindopril, quinapril, ramipril and trandolapril and the pharmaceutically acceptable salts thereof .

8. The use according to claim 7, wherein the combination of the PDE5 inhibitor and the ACE inhibitor is selected from sildenafil citrate and quinapril hydrochloride; sildenafil citrate and benazepril hydrochloride; sildenafil citrate and captopril; sildenafil citrate and enalapril maleate; Sildenafinyl citrate and fosinopril; sildenafil citrate and lisinopril; sildenafil citrate and moexipril; Sildenafil citrate and ramipril; Sildenafil citrate and trandolapril.

9. The use according to claim 1, wherein the medicament is for the treatment of hypertension. - ------ =

10. A pharmaceutical composition comprising a phosphodiesterase type 5 (PDE5) inhibitor specific for cyclic guanosine monophosphate and an angiotensin converting enzyme (ACE) inhibitor.

11. A pharmaceutical combination for simultaneous, separate or sequential administration for treating hypertension, comprising a phosphodiesterase inhibitor of type 5 (PDE5) specific for cGMP and an inhibitor of angiotensin converting enzyme (ACE).

12. A kit for the treatment of hypertension, the kit comprising: a) a first pharmaceutical composition comprising a PDE5 inhibitor; b) a second pharmaceutical composition comprising an ACE inhibitor; and c) a package for the compositions;

13. A method of treating hypertension in a subject comprising treating the said patient simultaneously, separately or sequentially with an effective amount of a PDE5 inhibitor and an ACE inhibitor. New combination SUMMARY Combinations comprising a) a phosphodiesterase inhibitor of type 5 (PDE5) specific for cyclic guanosine monophosphate (cGMP) and b) an angiotensin converting enzyme (ACE) inhibitor are useful for treating hypertension.