HK1076380A - Pharmaceutical combination of pde5 inhibitors with ace inhibitors - Google Patents

Description

Pharmaceutical combination of a PDE5 inhibitor and an ACE inhibitor

no marking

The present invention relates to the use of a combination of a) an inhibitor of cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type 5 (PDE5) and b) an inhibitor of Angiotensin Converting Enzyme (ACE) for the treatment of cardiovascular and metabolic diseases, in particular hypertension.

Blood Pressure (BP) is defined by a number of hemodynamic parameters, alone or in combination. Systolic Blood Pressure (SBP) is the highest arterial pressure obtained when the heart contracts. Diastolic pressure is the lowest arterial pressure obtained at diastole. The difference between SBP and DBP is defined as Pulse Pressure (PP).

Hypertension or elevated BP is defined as SBP of at least 140mmHg and/or DBP of at least 90 mmHg. With this definition, the prevalence of hypertension in developed countries is about 20% of the adult population, with people aged 60 or older growing to about 60-70%, although most of these hypertensive patients have normal BP when measured in a non-clinical setting. Approximately 60% of these older hypertensive populations have Isolated Systolic Hypertension (ISH), i.e., they have elevated SBP and normal DBP. Hypertension is associated with an increased risk of stroke, myocardial infarction, atrial fibrillation, heart failure, peripheral vascular disease and renal damage (Fagard, RH; am.J. Geriatric Cardiology 11(1), 23-28, 2002; Brown, MJ and Haycock, S; Drugs 59(Suppl 2), 1-12, 2000).

The pathophysiology of hypertension is the subject of constant debate. Although hypertension is generally considered to be the result of an imbalance between cardiac output and peripheral vascular resistance, and most hypertensive patients have abnormal cardiac output and increased peripheral resistance, it remains uncertain which parameter was changed first (Beevers, G et al; BMJ 322, 912-.

Although a large number of drugs have been used in various pharmacological contexts, including diuretics, alpha-adrenergic antagonists, beta-adrenergic antagonists, calcium channel blockers, angiotensin converting enzyme inhibitors, and angiotensin receptor antagonists, the need for effective treatment of hypertension has not yet been met.

ACE inhibitors which block the vasoconstrictive action of the renin-angiotensin-aldosterone system are proposed as first-line treatments for hypertension. They are effective and are generally considered well tolerated. The most common side effect, reported in 10-20% of patients, is cough. Other less reported side effects include rash, angioedema, hyperkalemia, and functional renal failure.

Phosphodiesterase type 5 is cyclic guanosine monophosphate-specific phosphodiesterase. Inhibitors of PDE5 reduce the rate of hydrolysis of cGMP, thereby potentiating the effects 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 for the manufacture of a medicament for the treatment of diseases, in particular cardiovascular and metabolic diseases, more particularly hypertension.

The terms "treatment" and "treat" as used herein include palliative, curative and prophylactic treatment. The term "hypertension" includes all diseases characterized by hyperpiesis, such as essential hypertension, pulmonary hypertension, secondary hypertension, isolated systolic hypertension, hypertension associated with diabetes, hypertension associated with atherosclerosis, and renovascular hypertension, and further extends to conditions where elevated blood pressure is a known risk factor. Thus, the term "treatment of hypertension" includes complications caused by hypertension, and other associated comorbidities, including congestive heart failure, angina, stroke, and impaired renal function, including the treatment or prevention of renal failure. Metabolic diseases include, in particular, metabolic syndrome (also referred to as syndrome X), diabetes and impaired glucose tolerance, including complications thereof such as diabetic retinopathy and diabetic neuropathy.

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

The combination of the invention has the advantage of being more effective, more potent, less toxic, or of having other desirable properties than the separate use of a PDE5 inhibitor or an ACE inhibitor for the treatment of hypertension.

Hereinafter, the term "PDE 5 inhibitor" refers to PDE5 inhibitors, including all pharmaceutically acceptable salts, solvates and polymorphs of the PDE5 inhibitor, for use in the present invention. Likewise, the term "ACE inhibitor" refers to ACE inhibitors for use in the present invention, including all pharmaceutically acceptable salts, solvates, and polymorphs of ACE inhibitors.

The suitability of PDE5 inhibitors and ACE inhibitors can be readily determined by assessing their potency and selectivity using literature methods and then assessing their toxicity, pharmacokinetics (absorption, metabolism, distribution and elimination), and the like, according to standard pharmaceutical procedures. Suitable compounds are those that are effective and selective, that do not have significant toxic effects at therapeutic doses, and that are preferably bioavailable after oral administration.

Efficacy can be defined as IC₅₀Value, i.e. the concentration of compound required to inhibit 50% of the enzyme activity. IC of PDE5 inhibitor₅₀Values can be determined using the PDE5 assay described below. Preferably, the PDE5 inhibitor has an IC for the PDE5 enzyme of less than 100nM, more preferably less than 50nM₅₀。

The selectivity ratio can be readily determined by one skilled in the art by the corresponding IC of the particular enzyme involved₅₀The ratio of the values is determined. IC of PDE3 and PDE4 enzymes₅₀The value can be determined using literature methodsChemical assays, see Ballard SA et al; journal of Urology 159, 2164-2171, 1998.

Preferably, the PDE5 inhibitor is selective for the PDE5 enzyme. Preferably, they are 100, more preferably 300, more selective for PDE5 than for PDE 3. More preferably, PDE5 has a selectivity of 100, more preferably 300, over PDE3 and PDE 4.

Preferably, the IC of PDE5 inhibitors on PDE5₅₀Values less than 100nM and 100-fold higher selectivity than PDE 3.

Oral bioavailability refers to the proportion of an orally administered drug that reaches the systemic circulation. Factors that determine the oral bioavailability of a drug are dissolution, membrane permeability, and liver clearance. Generally, screening performed first in vitro and subsequent in vivo techniques can be used to determine oral bioavailability.

Dissolution, i.e., dissolution of the drug by the aqueous contents of the gastrointestinal tract (GIT), can be predicted from in vitro solubility experiments conducted at a suitable pH to mimic the GIT. Preferably, the PDE5 inhibitor has a minimum solubility of 50 μ g/ml. Solubility can be determined by standard procedures known in the art, as described in Lipinski CA et al, adv. drug Deliv. Rev.23(1-3), 3-25, 1997.

Membrane permeability refers to the flux of compounds through GIT cells. Lipophilicity is a key property to predict this and is in vitro Log D by using organic solvents and buffers_7.4Determined by measurement. Preferably, the PDE5 inhibitor has a Log D of-2- +4, more preferably-1- +3_7.4. Log D can be determined by standard procedures known in the art, as described in Stopher, D and McClean, S; pharm pharmacol.42(2), 144, 1990.

Cell monolayer assays, such as Caco2, are added in large amounts in the presence of efflux transporters, such as P-glycoprotein, also known as Caco2 efflux to predict favorable membrane permeability. Preferably, the PDE5 inhibitor has a potency of greater than 2X 10^-6cm.s^-1More preferably greater than 5X 10^-6cm.s^-1Caco2 stream. Value of Caco2 flowCan be determined by standard procedures known in the art, such as those described in Artursson, P and Magnusson, C; J.pharm.Sci, 79(7), 595-600, 1990.

Metabolic stability refers to the ability of the GIT to metabolize compounds during absorption or the ability of the liver to metabolize compounds immediately after absorption: the first pass effect. Assay systems, such as microsomes, hepatocytes, etc., can predict metabolic instability. Preferably, the PDE5 inhibitor exhibits metabolic stability in the assay system, which corresponds to a liver leaching of less than 0.5. Examples of assay systems and data processing are in Obach, RS; curr. opin. drug disc.devel.4(1), 36-44, 2001 and Shibata, Y et al; drug Met.Disp.28(12), 1518-.

Due to the interplay of the above processes, it is further supported whether a drug is orally bioavailable in humans can be obtained by performing in vivo experiments in animals. Absolute bioavailability was determined in these studies by administering the compounds by the oral route, either separately or in admixture. For absolute determination (% orally bioavailable), the intravenous route may also be used. Examples of assessing oral bioavailability in animals can be found in Ward, KW, et al; drug met.disp.29(1), 82-87, 2001; berman, J et al; med. chem.40(6), 827-829, 1997 and Han KS and Lee, MG; drug Met.Disp.27(2), 221-226, 1999.

Examples of PDE5 inhibitors useful in the present invention are:

pyrazolo [4, 3-d ] pyrimidin-7-ones as disclosed in EP-A-0463756, EP-A-0526004 and published International patent applications WO93/06104, WO 98/49166, WO 99/54333, WO 00/24745, WO 01/27112 and WO 01/27113; pyrazolo [3, 4-d ] pyrimidin-4-ones as disclosed in EP-A-0995750, EP-A-0995751 and published International patent application WO 93/07149; pyrazolo [4, 3-d ] pyrimidines as disclosed in published international patent applications WO 01/18004, WO 02/00660 and WO 02/59126; quinazolin-4-one disclosed in published international patent application WO 93/12095; pyrido [3, 2-d ] pyrimidin-4-one as disclosed in published international patent application WO 94/05661; purin-6-ones disclosed in EP-A-1092718 and published International patent application WO 94/00453; hexahydropyrazino [2 ', 1': 6, 1] pyrido [3, 4-b ] indole-1, 4-dione; imidazo [5, 1-f ] [1, 2, 4] triazin-one as disclosed in EP-A-1092719 and published International application WO 99/24433; bicyclic compounds disclosed in published international application WO 93/07124 and in Rotella DP et al; med. chem.43(7), 1257-.

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

Other examples of PDE5 inhibitors useful in the present invention include: 4-bromo-5- (pyridylmethylamino) -6- [3- (4-chlorophenyl) -propoxy ] -3(2H) -pyridazinone; 1- [4- [ (1, 3-benzodioxol (dioxol) -5-ylmethyl) amino ] -6-chloro-2-quinazolinyl ] -4-piperidine-carboxylic acid, monosodium salt; (+) -cis-5, 6a, 7, 9, 9, 9 a-hexahydro-2- [4- (trifluoromethyl) -benzyl-5-methyl-cyclopent-4, 5] imidazo [2, 1-b ] purin-4 (3H) one; furacilin; cis-2-hexyl-5-methyl-3, 4, 5, 6a, 7, 8, 9, 9 a-octahydrocyclopenta [4, 5] -imidazo [2, 1-b ] purin-4-one; 3-acetyl-1- (2-chlorophenylmethyl) -2-propylindole-6-carboxylate; 3-acetyl-1- (2-chlorophenylmethyl) -2-propylindole-6-carboxylate; 4-bromo-5- (3-pyridylmethylamino) -6- (3- (4-chlorophenyl) propoxy) -3- (2H) pyridazinone; 1-methyl-5- (5-morpholinoacetyl-2-n-propoxyphenyl) -3-n-propyl-1, 6-dihydro-7H-pyrazolo (4, 3-d) pyrimidin-7-one; 1- [4- [ (1, 3-benzodioxol (dioxol) -5-ylmethyl) amino ] -6-chloro-2-quinazolinyl ] -4-piperidinecarboxylic acid, monosodium salt; pharmaprojects No.4516(Glaxo Welcome); pharmaprojects No.5051 (Bayer); pharmaprojects No.5064 (KyowaHakko; see WO 96/26940); pharmaprojects No.5069(Schering Plough); GF-196960(Glaxo Wellcome); e-8010 and E-4010 (Eisai); bay-38-3045& 38-9456(Bayer) and Sch-51866.

Preferred PDE5 inhibitors for use in the present invention include:

5- [ 2-ethoxy-5- (4-methyl-1-piperazinylsulfonyl) phenyl ] -1-methyl-3-n-propyl-1, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one (sildenafil), also known as 1- [ [3- (6, 7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [4, 3-d ] pyrimidin-5-yl) -4-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-propoxyphenyl ] -2- (pyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one (see WO 98/49166);

3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl ] -2- (pyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one (see WO 99/54333);

(+) -3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxy-1 (R) -methylethoxy) pyridin-3-yl ] -2-methyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one, also known as 3-ethyl-5- {5- [ 4-ethylpiperazin-1-ylsulfonyl ] -2- ([ (1R) -2-methoxy-1-methylethyl ] oxy) pyridin-3-yl } -2-methyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one (see WO 99/54333);

5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2- [ 2-methoxyethyl ] -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one, also known as 1- { 6-ethoxy-5- [ 3-ethyl-6, 7-dihydro-2- (2-methoxyethyl) -7-oxo-2H-pyrazolo [4, 3-d ] pyrimidin-5-yl ] -3-pyridylsulfonyl } -4-ethylpiperazine (see WO01/27113, example 8);

5- [ 2-lso-butoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2- (1-methylpiperidin-4-yl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one (see WO01/27113, example 15);

5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2-phenyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one (see WO01/27113, example 66);

5- (5-acetyl-2-propoxy-3-pyridyl) -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-pyridyl) -3-ethyl-2- (1-ethyl-3-azetidinyl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one (see WO 01/27112, example 132);

(6R, 12aR) -2, 3, 6, 7, 12, 12 a-hexahydro-2-methyl-6- (3, 4-methylenedioxyphenyl) -pyrazino [2 ', 1': 6, 1] pyrido [3, 4-b ] indole-1, 4-dione (tadalafil, IC-351), i.e. the compounds of examples 78 and 95 of published International application WO 95/19978, and the compounds of examples 1, 3, 7 and 8;

2- [ 2-ethoxy-5- (4-ethyl-piperazin-1-yl-1-sulfonyl) -phenyl ] -5-methyl-7-propyl-3H-imidazo [5, 1-f ] [1, 2, 4] triazin-4-one (vardenafil), also known as 1- [ [3- (3, 4-dihydro-5-methyl-4-oxo-7-propylimidazo [5, 1-f ] -as-triazin-2-yl) -4-ethoxyphenyl ] sulfonyl ] -4-ethylpiperazine, i.e. the compounds 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-d ] pyrimidin-5-ylmethoxy ] acetic acid (see WO 02/59126, example 1);

4- (4-chlorophenylmethyl) amino-6, 7, 8-trimethoxyquinazoline (example 11 of published International application WO 93/07124 (EISAI)); and

7, 8-dihydro-8-oxo-6- [ 2-propoxyphenyl ] -1H-imidazo [4, 5-g ] quinazoline and 1- [3- [1- [ (4-fluorophenyl) methyl ] -7, 8-dihydro-8-oxo-1H-imidazo [4, 5-g ] quinazolin-6-yl ] -4-propoxyphenyl ] carboxamide (compounds 3 and 14 from Rotella DP et al, J.Med.chem.43(7), 1257-1263, 2000).

More preferred PDE5 inhibitors for use in the present invention are selected from the group consisting of the following and pharmaceutically acceptable salts thereof:

5- [ 2-ethoxy-5- (4-methyl-1-piperazinylsulfonyl) phenyl ] -1-methyl-3-n-propyl-1, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one (sildenafil);

(6R, 12aR) -2, 3, 6, 7, 12, 12 a-hexahydro-2-methyl-6- (3, 4-methylenedioxyphenyl) -pyrazino [2 ', 1': 6, 1] pyrido [3, 4-b ] indole-1, 4-dione (tadalafil, IC-351);

2- [ 2-ethoxy-5- (4-ethyl-piperazin-1-yl-1-sulfonyl) -phenyl ] -5-methyl-7-propyl-3H-imidazo [5, 1-f ] [1, 2, 4] triazin-4-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-d ] pyrimidin-7-one; and

5- (5-acetyl-2-butoxy-3-pyridinyl) -3-ethyl-2- (1-ethyl-3-azetidinyl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] 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-d ] pyrimidin-7-one (sildenafil), also known as 1- [ [3- (6, 7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [4, 3-d ] pyrimidin-5-yl) -4-ethoxyphenyl ] sulfonyl ] -4-methylpiperazine, and pharmaceutically acceptable salts thereof. Sildenafil citrate is a preferred salt.

Examples of ACE inhibitors useful in the present invention include direct acting ACE inhibitors and prodrugs thereof, including alacepril, alindapril, moexipril, benazepril, benazeprilat, captopril, cilonapril, cilazapril, cilazaprilat, delapril, enalapril, enalaprilat, fosinopril, imidapril, indonapril, lisinopril, moexipril, motripril, pentopril, perindopril, quinapril, quinaprilat, ramipril, tranapril, spirapril, temocapril, tepratapine, trandolapril, and zoinopril. Furthermore, the ACE inhibitor may be a "dual ACE/NEP inhibitor", i.e., a compound that inhibits both ACE and Neutral Endopeptidase (NEP), such as, for example, omapatrilat, fastotril, mixanpril, sampatrilat, BMS-189921, MDL-100240, and Z13752A.

Preferred combinations of PDE5 inhibitors and ACE inhibitors for the treatment of 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 moxidepril;

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 moxidepril;

tadalafil and ramipril;

tadalafil and trandolapril;

vardenafil and quinapril hydrochloride;

vardenafil and benazepril hydrochloride;

vardenafil and captopril;

vardenafil and enalapril maleate;

vardenafil and fosinopril;

vardenafil and lisinopril;

vardenafil and moxidepril;

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, but they may also be used in the treatment of other diseases, such as thrombosis, and in the management of patients after percutaneous transluminal angioplasty ("PTCA-post patients").

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

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

The combinations of the invention may be administered alone, but will generally be administered in admixture with a suitable pharmaceutical excipient, diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.

For example, the combinations of the present invention may be administered orally, buccally or sublingually in the form of tablets, capsules, multi-particulates, gels, films, ovules, elixirs, solutions or suspensions, which may contain flavouring or colouring agents, for immediate-, delayed-, modified-, sustained-, pulsatile-or controlled-release applications. The combination of the invention may also be administered in a fast-dispersing or fast-dissolving administration form or in a highly energy-dispersing form or in the form of coated particles. Suitable formulations may be in coated or uncoated form, as desired.

Such 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, potato or tapioca starch), disintegrants such as sodium starch glycolate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, Hydroxypropylmethylcellulose (HPMC), Hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included. The following formulation examples are merely illustrative and are not intended to limit the scope of the present invention. The active ingredients refer to the combinations of the invention.

Preparation 1:

tablets were prepared using the following ingredients: the active ingredient (50mg) was mixed with cellulose (microcrystalline), silicon dioxide, stearic acid (smokable) and the mixture compressed into tablets.

Preparation 2:

intravenous formulations may be prepared by combining the active ingredient (100mg) with isotonic physiological saline (1000 ml).

Tablets are manufactured by standard methods, for example, direct compression or wet or dry granulation. The core of the tablet may be coated with a suitable coating.

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

Modified release and pulsatile release dosage forms may contain excipients such as those described with respect to immediate release dosage forms, as well as other excipients that function as release rate modifying agents, which are encapsulated on and/or contained within the body of the device. Release rate modifiers include, but are not limited to, hydroxypropylmethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, polyethylene oxide, xanthan gum, Carbomer, ammonium-methacrylate copolymer, hydrogenated castor oil, carnauba wax, paraffin wax, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, copolymer of methacrylic acid, and mixtures thereof. Modified release and pulsatile release dosage forms may contain one or a combination of release rate modifying excipients. The release rate modifying excipient may be present both within the administration form, i.e. within the matrix, and/or on the administration form, i.e. on the surface or on the coating.

A fast dispersing or dissolving administration formulation (FDDF) may comprise the following ingredients: aspartame, acesulfame potassium, citric acid, croscarmellose sodium, polyvinylpyrrolidone, ascorbic acid, ethyl acrylate, ethylcellulose, gelatin, hydroxypropyl methylcellulose, magnesium stearate, mannitol, methyl methacrylate, mint flavors, polyethylene glycol, fumed silica, silicon dioxide, sodium starch glycolate, sodium stearyl fumarate, sorbitol, xylitol. The term dispersion or dissolution as used herein describes that FDDF depends on the solubility of the drug used, i.e. if the drug is insoluble, a fast dispersing dosage form can be prepared, and if the drug is soluble, a fast dissolving dosage form can be prepared.

The combinations of the invention may also be administered parenterally, for example intracavernosally, intravenously, intraarterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternally, intracranially, intramuscularly or subcutaneously, or they may be administered by infusion or needle-free injection techniques. For such parenteral administration, they are best used in the form of sterile aqueous solutions which may contain other substances, for example, salts or glucose in sufficient quantities to render the solution isotonic with blood. The aqueous solution should be suitably buffered (preferably to a pH of 3-9) if necessary. Preparation of suitable parenteral formulations under sterile conditions can be readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.

The following levels of administration and other levels of administration herein are relative to a typical human patient having a body weight of about 65-70 kg. The skilled person can readily determine the level of administration required for patients with body weights outside this range, such as children and the elderly.

The administration of the combination of the invention in this formulation depends on its efficacy, but it is contemplated that 1-500mg of the PDE5 inhibitor and 1-100mg of the ACE inhibitor will be administered three times a day. Preferred doses are 10-100mg (e.g., 10, 25, 50 and 100mg) of a PDE5 inhibitor and 5-50mg (e.g., 5, 10, 25 and 50mg) of an ACE inhibitor, which may be administered once, twice or three times a day (preferably once). However, the precise dosage may be determined by the prescribing physician and will depend on the age and weight of the patient and the severity of the symptoms.

When administered orally and parenterally to human patients, the daily administration level of the combination of the invention is generally from 5 to 500mg/kg (single or divided doses).

Thus, a tablet or capsule may comprise from 5mg to 250mg (e.g. 10 to 100mg) of a combination of the invention, suitably administered separately or in two or more doses at a time. In any event, the physician will determine the exact dosage which will be most suitable for any individual patient and it will vary with the age, weight and response of the particular patient. The above doses are exemplary of the general case. There are, of course, instances where higher or lower dosage ranges are acceptable and such are within the scope of this invention. One skilled in the art will recognize that the combination of the invention may be ingested in a single dose (i.e., prn) as needed or desired. It will also be appreciated that all references herein relate to treatment including acute treatment (if required) and chronic treatment (longer lasting treatment).

The combinations of the present invention may also be administered intranasally or by inhalation and are conveniently delivered from a pressurised container, pump, nebulizer, atomizer or nebuliser, in the form of a dry powder inhaler or aerosol spray presentation, with or without the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1, 1, 1, 2-tetrafluoroethane (HFA 134A [ trade mark ]) or 1, 1, 1, 2, 3, 3, 3-heptafluoropropane (HFA 227EA [ trade mark ]), carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurised container, pump, spray, atomiser or nebuliser may contain a solution or suspension of the active compound, for example using a mixture of ethanol and propellant as the solvent, which may also contain a lubricant, for example sorbitan trioleate. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of the combination of the invention and a suitable powder base such as lactose or starch.

Preferably, the aerosol or dry powder formulation is treated so that each metered dose or "puff" contains from 1 μ g to 50mg of the combination of the invention for delivery to a patient. The total daily dose using an aerosol is from 1 μ g to 50mg, which may be administered as a single dose or, more usually, as separate doses throughout the day.

Alternatively, the combination of the invention may be administered in the form of a suppository or pessary, or applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or puff. The combination of the invention may also be administered transdermally or transdermally, for example, by using a skin patch, depot or subcutaneous injection. They may also be administered by the pulmonary or rectal route.

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

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

Oral administration of the combination of the invention is the preferred route, most conveniently. In the case where the subject suffers from a swallowing disorder or suffers from a decrease in absorption of the drug following oral administration, the drug may be administered parenterally, sublingually or buccally.

The combination of the invention can be used as part of a triple therapy, i.e., a treatment regimen for treating a patient with three agents. The third agent in the triple therapy may be a second PDE5 or ACE inhibitor, or it may be selected from the third drug group. For example, it may be a neutral endopeptidase inhibitor, angiotensin II receptor antagonist, calcium channel blocker such as amlodipine, statin such as atorvastatin, beta blocker (i.e. beta-adrenergic receptor antagonist) or diuretic.

It will be appreciated that the present invention covers the following further aspects, and that the embodiments described in detail above with respect to the first aspect extend to these aspects:

i) a pharmaceutical combination of the invention for use in the treatment of hypertension (for simultaneous, separate or sequential administration);

ii) 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 container of the composition;

iii) a method of treating hypertension in a patient, which comprises treating said patient with an effective amount of a combination of the invention.

Assay method

Preferred compounds suitable for use in the present invention are potent and selective inhibitors of PDE 5. In vitro PDE inhibitory Activity on 3 ', 5' -cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) phosphodiesterase can be determined by measuring their IC₅₀Value determination (concentration of compound required for 50% inhibition of enzyme activity).

The required PDE enzymes can be isolated from a variety of sources, including human cavernosa, human and rabbit platelets, human ventricles, human skeletal muscle, and bovine retina, primarily by Thompson, WJ et al; biochemistry 18(23), 5228-5237, 1979, e.g., Ballard SA et al; improvements to the methods described in J.Urology 159(6), 2164-2171, 1998. In particular, cGMP-specific PDE5 and cGMP-inhibited cAMP PDE3 can be obtained from human cavernous body tissue, human platelets, or rabbit platelets; cGMP-stimulated PDE2 was obtained from human sponge; calcium/calmodulin (Ca/CAM) -dependent PDE1 is derived from the human ventricle; cAMP-specific PDE4 is derived from human skeletal muscle; photoreceptor PDE6 is derived from bovine retina. Phosphodiesterase 7-11 can be produced from a full-length human recombinant clone transfected into SF9 cells.

Assays may use Thompson WJ and Appleman MM; biochemistry 10(2), 311-316, 1971, mainly by Ballard SA et al; improvement of the "batch" method of J.Urology 159(6), 2164-2171, 1998 or improvement of the protocol described by Amersham plc using the direct detection [2 ] using the product code TRKQ7090/7100³H]Scintillation proximity assay of labeled AMP/GMP. In summary, for scintillation proximity assays, the effect of PDE inhibitors is studied by determining the amount of enzyme (cGMP or cAMP, 3: 1 ratio, unlabeled to [, [2 ]) in the presence of various inhibitor concentrations and small amounts of substrate³H]-label, -1/3Km or less concentration) such that IC₅₀Ki. With assay buffer [20mM Tris-HCl pH7.4, 5mM MgCl₂1mg/ml bovine serum albumin]The final assay volume was replenished to 100. mu.l. The reaction was started using an enzyme, incubated at 30 ℃ for 30-60min, giving < 30% substrate turnover, and stopped with 50. mu.l of yttrium silicate SPA beads (containing 3mM each unlabelled cyclic nucleotide of PDE 9-11). The plates were sealed again and shaken for 20min, after which the beads were allowed to settle in the dark for 30 min and then counted on a TopCount plate reader (Packard, Meriden, CT). Conversion of the radioactivity units to% activity of unlabeled control (100%) versus inhibitor concentration and IC obtained using 'Fit curve' Microsoft Excel extension₅₀Values are plotted.

Animal research

The efficacy of the combination of the invention has been demonstrated in an animal model of human hypertension using enalapril as a representative ACE inhibitor and 5- [ 2-ethoxy-5- (4-methyl-1-piperazinylsulfonyl) phenyl ] -1-methyl-3-n-propyl-1, 6-dihydro-7H-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.

Animal(s) production

Spontaneous Hypertensive Rats (SHR) are widely used as a model of human hypertension. Male SHR (20-22 weeks old) mesenteric, hind leg and renal blood flow, aortic blood pressure and heart rate were measured using a Doppler flow probe as disclosed (Gardiner, SM et al; Br. J. Pharmacol.132 (8), 1625-.

Medicine

Solutions of enalapril (7.5 μ g/mL), PDE5 inhibitor (200 μ g/mL), and enalapril in combination with PDE5 inhibitor (7.5 μ g/mL +200 μ g/mL) were infused over the experimental period at a rate of 0.4 mL/h. Control animals received compound vehicle; isotonic saline adjusted to pH4 with hydrochloric acid.

Scheme(s)

Baseline hemodynamic parameters were recorded. Animals were then treated at random by continuous infusion with drug solution for 4 days (n-7 or 8/group). Changes in hemodynamic parameters were monitored daily over a 7h study period. The summary results, expressed as the difference in reaction to the excipient, are given in the table below.

	Treatment of
				Enalapril	PDE5 inhibitors	Combination of
	Total change in mean BP	-2.4	-12.1				-17.8
Change in mesenteric conductance (%)				+22.4	+22.1	+48.1
	Change in renal conduction (%)	+14.2	-0.8				+34.2
Change in aortic conductance (%)				+3.7	+19.8	+30.1

As a result, particularly for renal conduction, it was demonstrated that the combination of two agents can produce a greater effect than the sum of their respective effects.

Claims (13)

1. Use of a combination of an inhibitor of cyclic guanosine monophosphate specific phosphodiesterase type 5 (PDE5) and an inhibitor of Angiotensin Converting Enzyme (ACE) for the preparation of a medicament for the 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 of claim 1, wherein the PDE5 inhibitor has an IC of less than 100nM₅₀The value is obtained.

3. The use of claim 2, wherein the PDE5 inhibitor has an IC of less than 50nM₅₀The value is obtained.

4. Use according to any preceding claim, wherein the PDE5 inhibitor is selected from

5- [ 2-ethoxy-5- (4-methyl-1-piperazinylsulfonyl) phenyl ] -1-methyl-3-n-propyl-1, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one (sildenafil);

(6R, 12aR) -2, 3, 6, 7, 12, 12 a-hexahydro-2-methyl-6- (3, 4-methylenedioxyphenyl) -pyrazino [2 ', 1': 6, 1] pyrido [3, 4-b ] indole-1, 4-dione (tadalafil);

2- [ 2-ethoxy-5- (4-ethyl-piperazin-1-yl-1-sulfonyl) -phenyl ] -5-methyl-7-propyl-3H-imidazo [5, 1-f ] [1, 2, 4] triazin-4-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-d ] pyrimidin-7-one; and

5- (5-acetyl-2-butoxy-3-pyridinyl) -3-ethyl-2- (1-ethyl-3-azetidinyl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

And pharmaceutically acceptable salts thereof.

5. The use of claim 4, wherein the PDE5 inhibitor is 5- [ 2-ethoxy-5- (4-methyl-1-piperazinylsulfonyl) phenyl ] -1-methyl-3-n-propyl-1, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one (sildenafil) or a pharmaceutically acceptable salt thereof.

6. The use of claim 5 wherein the PDE5 inhibitor is sildenafil citrate.

7. The use according to any preceding claim wherein the ACE inhibitor is selected from the group consisting of benazepril, captopril, cilazapril, enalapril, enalaprilat, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril and trandolapril and pharmaceutically acceptable salts thereof.

8. The use according to claim 7, wherein the combination of a PDE5 inhibitor and an ACE inhibitor is selected from the group consisting of

Sildenafil citrate and quinapril hydrochloride;

sildenafil citrate and benazepril hydrochloride;

sildenafil citrate and captopril;

sildenafil citrate and enalapril maleate;

sildenafil citrate and fosinopril;

sildenafil citrate and lisinopril;

sildenafil citrate and moxidepril;

sildenafil citrate and ramipril; and

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 an inhibitor of cyclic guanosine monophosphate specific phosphodiesterase type 5 (PDE5) and an inhibitor of Angiotensin Converting Enzyme (ACE).

11. A pharmaceutical composition for simultaneous, separate or sequential administration for the treatment of hypertension comprising an inhibitor of cGMP-specific phosphodiesterase type 5 (PDE5) and an inhibitor of Angiotensin Converting Enzyme (ACE).

12. 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 container for said composition.

13. A method of treating hypertension in a patient, comprising treating said patient with an effective amount of a PDE5 inhibitor and an ACE inhibitor simultaneously, separately or sequentially.