KR20050004195A - Novel Combination - Google Patents

Abstract

Combination formulations of a) cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type 5 (PDE5) inhibitors and b) angiotensin converting enzyme (ACE) inhibitors are useful for the treatment of hypertension.

Description

New Combination Formulation {Novel Combination}

Blood pressure (BP) is defined by a number of hemodynamic variables that are considered separately or together. Systolic blood pressure (SBP) is the highest arterial pressure obtained when the heart contracts. Diastolic blood pressure (DBP) is the minimum fluid pressure obtained when the heart relaxes. The difference between SBP and DBP is defined as pulse pressure (PP).

Hypertension, or elevated BP, was defined as SBP greater than 140 mm Hg and / or DBP greater than 90 mm Hg. By this definition, the incidence of hypertension in developed countries is about 20% of the adult population and rises to about 60 to 70% in the population over 60, but a significant proportion of these hypertensive patients are normal BP when measured in a nonclinical setting. Has 60% of this aged hypertensive population has isolated systolic hypertension (ISH). That is, 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 kidney disorders (Fagard, RH, Am. J. Geriatric Cardiology 11 (1), 23-28, 2002, Browns, MJ and Haycock, S. (Drugs 59 (Suppl. 2), 1-12, 2000).

The pathophysiology of hypertension is the subject of ongoing debate. Hypertension is the result of an imbalance between cardiac output and peripheral vascular resistance, and most people with hypertension generally agree that they have abnormal cardiac output and increased peripheral resistance, but it is uncertain which variables change first. Beevers, G., et al., BMJ 322, 912-916, 2001).

Although the majority of drugs, including diuretics, alpha-adrenergic antagonists, beta-adrenergic antagonists, calcium channel blockers, angiotensin converting enzyme inhibitors and angiotensin receptor antagonists, are available in a variety of pharmacological categories, effective hypertension therapy Still not satisfied

ACE inhibitors that block the vasoconstrictive action of the Lenin-Angiotensin-Aldosterone System are recommended as treatment for the first line of hypertension. They are believed to be effective and generally well tolerated without any side effects. The most common side effect is cough, which is reported to account for 10-20% of patients. Other less frequently reported side effects include redness, angioedema, hyperkalemia and functional renal failure.

Phosphodiesterase type 5 is a cyclic guanosine monophosphate-specific phosphodiesterase. Inhibitors of PDE5 reduce the rate of hydrolysis of cGMP and thus potentiate the action of nitric oxide. They have been found to be useful in the treatment of male erectile dysfunction.

The present invention relates to a) inhibitors of cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type 5 (PDE5) and b) angiotensin converting enzyme (ACE) for the treatment of cardiovascular and metabolic diseases, in particular hypertension. To a use of a combination formulation.

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

As used herein, the terms “treating” and “treatment” include palliative, therapeutic and prophylactic treatment. The term "hypertension" includes all diseases characterized by higher than normal blood pressure, such as essential hypertension, pulmonary hypertension, secondary hypertension, isolated systolic hypertension, diabetes-related hypertension, atherosclerosis-related hypertension, and neovascular hypertension, Elevated blood pressure further extends to known risk factors. Thus, the term "treatment of hypertension" includes the treatment or prevention of complications resulting from hypertension and other related comorbidities, including congestive heart failure, angina pectoris, stroke, glaucoma and renal dysfunction (including renal failure). Metabolic diseases include especially metabolic syndrome (also known as X syndrome), diabetes and impaired glucose tolerance (including their complications such as diabetic retinopathy and diabetic neuropathy).

Combination formulations of PDE5 inhibitors and ACE inhibitors, including combination formulations of specific PDE5 inhibitors and specific ACE inhibitors, will then be referred to as combination formulations of the present invention.

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

The term " PDE5 inhibitors " hereafter refers to PDE5 inhibitors for use in the present invention, including all pharmaceutically acceptable salts, solvates and polymorphs of PDE5 inhibitors. Similarly, the term "ACE inhibitor" refers to an ACE inhibitor for use in the present invention, including all pharmaceutically acceptable salts, solvates and polymorphs of the ACE inhibitor.

The suitability of PDE5 inhibitors and ACE inhibitors can be easily assessed by assessing their efficacy and selectivity using the methods of the literature and then assessing their toxicity, pharmacokinetics (absorption, metabolism, distribution and elimination) according to standard pharmaceutical practices. Can be determined. Suitable compounds are potent, selective, free of significant toxic effects at therapeutic doses, and are preferably bioavailable after oral administration.

Efficacy can be defined as an IC ₅₀ value, which is the concentration of compound needed to inhibit enzyme activity by 50%. IC ₅₀ values of PDE5 inhibitors can be determined using the PDE5 assay described below. Preferably, the PDE5 inhibitor has an IC ₅₀ for PDE5 enzyme of less than 100 nM, more preferably less than ₅₀ nM.

The selectivity ratio can be readily determined by one skilled in the art by the ratio of the corresponding IC ₅₀ value of the particular enzyme involved. IC ₅₀ values of PDE3 and PDE4 enzymes can be determined using established literature methods (Ballard SA et al., Journal of Urology 159, 2164-2171, 1998).

Preferably the PDE5 inhibitor is selective for the PDE5 enzyme. Preferably, they have a selectivity of PDE5 greater than 100 times and more preferably greater than 300 times compared to PDE3. More preferably, PDE5 has a selectivity greater than 100 times and more preferably greater than 300 times compared to PDE3 and PDE4.

Preferably, the PDE5 inhibitor has an IC ₅₀ for PDE5 of less than 100 nM and a selectivity greater than 100 times compared to PDE3.

Oral bioavailability refers to the percentage of orally administered drugs that reach systemic circulation. Factors that determine oral bioavailability of a drug are dissolution, membrane permeability and liver clearance. Typically, oral bioavailability is determined first using selection procedures in vitro and then in vivo techniques.

Dissolution that indicates solubilization of the drug by the aqueous content of the gastrointestinal tract (GIT) can be expected from in vitro solubility experiments performed at appropriate pH to mimic GIT. Preferably the PDE5 inhibitor has a minimum solubility of 50 μg / ml. Solubility is described in Lipinski C. A. et al., Adv. Drug Deliv. Rev. 23 (1-3), 3-25, 1997, by standard procedures known in the art.

Membrane permeability refers to the passage of a compound through the cells of GIT. Affinity is an important property in predicting this and is determined by in vitro Log D _7.4 measurements using organic solvents and buffers. Preferably the PDE5 inhibitor has a Log D _7.4 of -2 to +4, more preferably -1 to +3. Log D is described by Stopper, D. and McClean, S. J. Pharm. Pharmacol. 42 (2), 144, 1990, by standard procedures known in the art.

Cell tomography assays such as Caco2 substantially enhance the prediction of favorable membrane permeability, so-called Caco2 flux, in the presence of effluent transporters such as P-glycoprotein. Preferably, the PDE5 inhibitor has a Caco2 outflow greater than 2 × 10 ⁻⁶ cm · s ⁻¹ , more preferably greater than 5 × 10 ⁻⁶ cm · s ⁻¹ . Caco2 runoff values are described by Arturson, P. and Magnusson, C., J. Pharm. Sci., 79 (7), 595-600, 1990, can be determined by standard procedures known in the art.

Metabolic stability deals with the ability of GIT to metabolize the compound during the absorption process or the liver's ability to metabolize the compound immediately after absorption (first pass action). Analytical systems such as microsomes, hepatocytes and the like are precursors of metabolic instability. Preferably, the PDE5 inhibitor exhibits metabolic stability corresponding to a liver extraction rate of less than 0.5 in the assay system. Examples of analytical systems and data manipulation are described in Obach, R. S. Curr. Opin. Drug Disc. Devel. 4 (1), 36-44, 2001 and Shibata, Y. et al., Drug Met. Disp. 28 (12), 1518-1523, 2000.

Because of the interaction of the methods, additional support that the drug will be orally bioavailable to humans can be obtained by in vivo experiments in animals. Absolute bioavailability in these studies is determined by administering the compounds individually or in mixtures by the oral route. For absolute determination (% oral bioavailability), an intravenous route is also used. Examples of assessing oral bioavailability in animals are described by Ward, K. W. et al., Drug Met. Disp. 29 (1), 82-87, 2001; Berman, J. et al., J. Med. Chem., 40 (6), 827-829, 1997 and by Han K. S. and Lee, M. G., Drug Met. Disp. 27 (2), 221-226, 1999.

Examples of PDE5 inhibitors for use in the present invention include EP-A-0463756, EP-A-0526004 and WO 93/06104, WO 98/49166, WO 99/54333, WO 00. Pyrazolo [4,3-d] pyrimidin-7-ones as disclosed in / 24745, WO 01/27112 and WO 01/27113; Pyrazolo [3,4-d] pyrimidin-4-ones disclosed in EP-A-0995750, EP-A-0995751 and International Patent Application Publication No. WO 93/07149; Pyrazolo [4,3-d] pyrimidines disclosed in WO 01/18004, WO 02/00660 and WO 02/59126; Quinazolin-4-ones disclosed in International Patent Application Publication No. WO 93/12095; Pyrido [3,2-d] pyrimidin-4-ones disclosed in International Patent Application Publication No. WO 94/05661; Purin-6-ones disclosed in EP-A-1092718 and WO 94/00453; Hexahydropyrazino [2 ', 1': 6,1] pyrido [3,4-b] indole-1,4-dione, disclosed in WO 95/19978; Imidazo [5,1-f] [1,2,4] triazine-ones disclosed in EP-A-1092719 and International Patent Application Publication No. WO 99/24433; Bicyclic compounds disclosed in International Patent Application Publication No. WO 93/07124 and Rotella D. P. et al. Med. Chem. 43 (7), 1257-1263, 2000, the imidazoquinazolinone.

The contents of patent application publications and magazine articles, and in particular the formulas of therapeutically active compounds of the claims and the compounds exemplified therein, are incorporated herein by reference.

Further examples of PDE5 inhibitors for use with the present invention are 4-bromo-5- (pyridylmethylamino) -6- [3- (4-chlorophenyl) -propoxy] -3 (2H) pyrida Xenon; 1- [4-[(1,3-benzodioxol-5-ylmethyl) amino] -6-chloro-2-quinozolinyl] -4-piperidine-carboxylic acid, monosodium salt; (+)-Cis-5,6a, 7,9,9,9a-hexahydro-2- [4- (trifluoromethyl) -phenylmethyl-5-methyl-cyclopent-4,5] imidazo [ 2,1-b] purin-4 (3H) one; Furazlocillin; Cis-2-hexyl-5-methyl-3,4,5,6a, 7,8,9,9a-octahydrocyclopent [4,5] -imidazo [2,1-b] purin-4-one ; 3-acetyl-1- (2-chlorobenzyl) -2-propylindole-6-carboxylate; 3-acetyl-1- (2-chlorobenzyl) -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) pyrimidine- 7-one; 1- [4-[(1,3-benzodioxol-5-ylmethyl) amino] -6-chloro-2-quinazolinyl] -4-piperidinecarboxylic acid, monosodium salt ; Pharmaprojects No. 4516 (Glaxo Wellcome); Pharma Projects No. 5051 (Bayer); Pharma Projects No. 5064 (by Kyowa Hakko; see WO 96/26940); Pharma Projects No. 5069 (Schering Plough); GF-196960 (Glaxo Welcome Inc.); E-8010 and E-4010 (Eisai Corporation); Bay-38-3045 and 38-9456 (Bayer) and Sch-51866.

Preferred PDE5 inhibitors for use in the present invention include 1-[[3- (6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [4,3-d] pyrimidine 5- [2-ethoxy-5- (4-methyl-1-piperazinylsulfonyl) phenyl] -also known as -5-yl) -4-ethoxyphenyl] sulfonyl-4-methylpiperazine. 1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one (sildenafil) (see EP-A-0463756); 5- (2-ethoxy-5-morpholinoacetylphenyl) -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidine-7- On (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-([(1R) -2-methoxy-1-methylethyl] oxy) pyridin-3-yl} -2 (+)-3-ethyl-5- [5- (4-ethylpiperazine, also known as -methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one -1-ylsulfonyl) -2- (2-methoxy-1 (R) -methylethoxy) pyridin-3-yl] -2-methyl-2,6-dihydro-7H-pyrazolo [4,3 -d] pyrimidin-7-one (see WO 99/54333); 1- {6-Ethoxy-5- [3-ethyl-6,7-dihydro-2- (2-methoxyethyl) -7-oxo-2H-pyrazolo [4,3-d] pyrimidine- 5- [2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl]-, also known as 5-yl] -3-pyridylsulfonyl} -4-ethylpiperazine. 3-ethyl-2- [2-methoxyethyl] -2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one (see WO 01/27113, Example 8) ; 5- [2-iso-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 WO 01/27113, 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 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-dihydro-7H-pyrazolo [4, 3-d] pyrimidin-7-one (see WO 01/27112, Example 132); (6R, 12aR) -2,3,6,7,12,12a-hexahydro-2-methyl-6- (3,4-methylenedioxyphenyl) -pyrazino [2 ', 1': 6,1 ] Pyrido [3,4-b] indole-1,4-dione (tadalafil, IC-351), ie the compounds of Examples 78 and 95 of WO 95/19978, and Example 1 , Compounds of 3, 7 and 8; 1-[[3- (3,4-Dihydro-5-methyl-4-oxo-7-propylimidazo [5,1-f] -as-triazin-2-yl) -4-ethoxy 2- [2-ethoxy-5- (4-ethyl-piperazin-1-yl-sulfonyl) -phenyl] -5-methyl-7-, also known as phenyl] sulfonyl] -4-ethylpiperazine Propyl-3H-imidazo [5,1-f] [1,2,4] triazine-4-one (vardenafil), ie Examples 20, 19, 337 of WO 99/24433 And 336 compounds; [7- (3-Chloro-4-methoxybenzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-ylmethoxy] acetic acid (WO 02/59126) , See Example 1); 4- (4-chlorobenzyl) amino-6,7,8-trimethoxyquinazolin (Example 11 of International Patent Application Publication No. WO 93/07124 (Aisasa)); And 7,8-dihydro-8-oxo-6- [2-propoxyphenyl] -1H-imidazo [4,5-g] quinazoline and 1- [3- [1-[(4-fluoro Phenyl) methyl] -7,8-dihydro-8-oxo-1H-imidazo [4,5-g] quinazolin-6-yl] -4-propoxyphenyl] carboxamide (Lotella et al. Compounds 3 and 14 of J. Med. Chem. 43 (7), 1257-1263, 2000).

More preferred PDE5 inhibitors for use in the present invention are 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) -2,3,6,7,12,12a-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 and their pharmaceutically acceptable salts.

Particularly preferred PDE5 inhibitors are 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) (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 for use in the present invention include alasepril, allindapril, althiopril, benazepril, benaziprilat, captopril, sernaphril, silazapril, silazaprilat, delapril , Enalapril, enalapril, posinopril, imidapril, indolapril, ribenzapril, ricinopril, moexapril, moveltipril, pentopril, perindopril, quinapril, quinapril Direct acting ACE inhibitors and prodrugs thereof, including rats, ramipril, lentiapril, spirapril, temocapril, teprotide, trandolapril and jofenopril are included. In addition, ACE inhibitors are compounds that inhibit both "double ACE / NEP inhibitors", ie, ACE and neutral endopeptidase (NEP) (e.g., omapatrilat, facidotril, micsanpri, tripartilat). , BMS-189921, MDL-100240 and Z13752A).

Preferred combinations of PDE5 inhibitors and ACE inhibitors for the treatment of hypertension include sildenafil and quinapril hydrochloride; Sildenafil and benazepril hydrochloride; Sildenafil and captopril; Sildenafil and enalapril maleate; Sildenafil and posinopril; 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 posinopril; Tadalafil and lisinopril; Tadalafil and moexipril; Tadalafil and ramipril; Tadalafil and trandolapril; Vardenafil and quinapril hydrochloride; Vardenafil and benazepril hydrochloride; Vardenafil and captopril; Vardenafil and enalapril maleate; Vardenafil and posinopril; Vardenafil and ricinopril; Vardenafil and moexipril; Vardenafil and ramipril; And vardenafil and trandolapril.

The pharmaceutical combination formulations of the present invention are useful for the treatment of diseases including cardiovascular and metabolic diseases, which also treat other diseases such as thrombosis and the management of patients undergoing percutaneous transvascular coronary angioplasty (“post-PTCA patients”). Can also be useful.

Preferably the cardiovascular disorder to be treated is hypertension, congestive heart failure, angina pectoris, stroke or kidney failure. More preferably, the cardiovascular disorder is essential hypertension, pulmonary hypertension, secondary hypertension, isolated systolic hypertension, diabetes related hypertension, atherosclerosis related hypertension and neovascular hypertension, congestive heart failure, angina pectoris, stroke or kidney failure. 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 another particularly preferred embodiment, the disorder to be treated is diabetes related hypertension. In another particularly preferred embodiment, the disorder to be treated is atherosclerosis related hypertension. In another particularly preferred embodiment, the disorder to be treated is neovascular hypertension.

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

Combination formulations of the present invention may be administered alone, but generally in admixture with suitable pharmaceutical excipients, diluents or carriers selected for the intended route of administration and standard pharmaceutical practice.

For example, the combination formulations of the present invention may contain perfumes or colorants, multiple tablets, capsules, multiple, for immediate release, delayed release, modified release, sustained release, pulsatile release or controlled release applications. It may be administered orally, orally or sublingually in the form of particles, gels, membranes, ovules, elixirs, solutions or suspensions. Combination formulations of the invention can also be administered as a dispersible or rapid dissolving dosage form or in the form of high energy dispersions or as coated particles. Suitable formulations may optionally be in the form of coated or uncoated.

Such solid pharmaceutical compositions, e.g. tablets, include microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, glycine and starch (preferably corn, potato or tapioca starch), disintegrants (e.g. Sodium starch glycolate, croscarmellose sodium and optional complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, Excipients such as gelatin and gum arabic). Additionally, glidants 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 present invention. Active ingredient means a combination formulation of the present invention.

Formulation Example 1:

Tablets are prepared using the following ingredients. The active ingredient (50 mg) is combined with cellulose (microcrystalline), silicon dioxide, stearic acid (fumigation) and the mixture is compressed to form tablets.

Formulation Example 2:

Intravenous formulations can be prepared by mixing the active ingredient (100 mg) with isotonic saline (1000 mL).

Tablets can be prepared by standard procedures, for example by direct compression, or by wet or dry granulation processes. The tablet core may be coated with a suitable sheath.

Solid compositions of a similar type can also be used as fillers in gelatin or HPMC capsules. Preferred excipients in this regard are lactose, starch, cellulose, lactose, or high molecular weight polyethylene glycols. For aqueous suspensions and / or elixirs, PDE5 and ACE inhibitors can be mixed with various sweetening or flavoring agents, colorants or dyes, with emulsifiers and / or suspending agents, and with water, ethanol, propylene glycol and glycerin And diluents such as mixtures thereof.

The modified release and pulsatile release dosage forms are those described above for immediate release dosage forms, with additional excipients coated on the body of the device and / or acting as release rate modifiers contained within the body of the device. And may contain the same excipients. Non-limiting examples of release rate modifiers include hydroxypropylmethyl cellulose, methyl cellulose, sodium carboxymethylcellulose, ethyl cellulose, cellulose acetate, polyethylene oxide, xanthan gum, carbomer, ammonio methacrylate copolymer, hydrogenated Castor oil, carnauba wax, paraffin wax, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, methacrylic acid copolymers and mixtures thereof. The modified release and pulsatile release dosage forms may contain one release rate altering excipient or mixtures thereof. Release rate altering excipients may be present in the dosage form, ie in the matrix, and / or on the dosage form, ie on the surface or coating.

Fast dispersible or fast dissolving dosage forms (FDDF) may contain the following ingredients: aspartame, acesulfame potassium, citric acid, croscarmellose sodium, crospovidone, diascorbic acid, ethyl acrylate, ethyl cellulose, gelatin, Hydroxypropylmethyl cellulose, magnesium stearate, mannitol, methyl methacrylate, mint flavor, polyethylene glycol, fumed silica, silicon dioxide, sodium starch glycolate, sodium stearyl fumarate, sorbitol, xylitol. The term dispersion or dissolution as used herein to describe FDDF depends on the solubility of the drug substance used. That is, fast dispersible dosage forms can be prepared if the drug substance is insoluble, and fast dissolving dosage forms can be prepared if the drug substance is soluble.

Combination formulations of the present invention may also be administered parenterally, eg, intracavity, intravenous, intraarterial, intraperitoneal, intradural, intraventricular, urethra, intrasternal, intracranial, intramuscular or subcutaneous, or infusion Or by needleless injection techniques. For these parenteral administrations, they are best used in the form of sterile aqueous solutions which may contain sufficient salt or glucose to make other substances, for example, the solution, isotonic with blood. The aqueous solution should be suitably buffered if desired (preferably to pH 3-9). The preparation of suitable parenteral formulations under sterile conditions can be readily carried out by standard pharmaceutical techniques well known to those skilled in the art.

The following dosage levels and other dosage levels are for average human patients with a weight range of about 65-70 kg. Those skilled in the art will readily be able to determine the dosage level required for patients whose weight is not within this range (eg, children and the elderly).

The dosage of the inventive combination formulations included in such formulations will depend on their efficacy, but it can be expected to administer 1 to 500 mg of PDE5 inhibitors and 1 to 100 mg of ACE inhibitors up to three times per day. Preferred dosages range from 10 to 100 mg (eg 10, 25, 50 and 100 mg) of PDE5 inhibitors and 5 to 50 mg (eg 5, 10, 25 and 50 mg) of ACE inhibitors, once a day, It may be administered twice or three times (preferably once). However, the exact dosage will be determined by the prescribing physician and will depend on the age and weight of the patient and the severity of the symptoms.

For oral and parenteral administration to human patients, the daily dosage level of the inventive combination formulation will generally be between 5 and 500 mg / kg (single or multiple administrations).

Thus, tablets or capsules may contain from 5 mg to 250 mg (eg 10 to 100 mg) of the combination formulations of the invention for one or more than two administrations at a time if appropriate. In any case, the physician will determine the actual dosage that will be best suited for the individual patient, which will vary with the age, weight and response of the particular patient. The dosage is an example of an average case. Of course, there may be individual cases where a higher or lower dosage range is advantageous, which is also within the scope of the present invention. Those skilled in the art will appreciate that the combination formulations of the present invention may be taken as needed or as occasional single dose. All references to treatment should be considered to include acute treatment (taken as needed) and chronic treatment (long-term continuous treatment).

Combination formulations of the present invention may also be administered intranasally or by inhalation, and may be administered with a dry powder inhaler, or a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, hydrofluoro Alkanes such as 1,1,1,2-tetrafluoroethane (HFA 134A ™ or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA ™)) It is conveniently delivered in the form of an aerosol injector from a pressurized vessel, pump, injector, nebulizer or nebulizer, with or without carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Pressurized vessels, pumps, injectors, nebulizers or nebulizers may contain a solution or suspension of the active compound, for example using a mixture of ethanol and propellant as solvent, and add a lubricant (eg sorbitan trioleate) It may contain. Capsules and cartridges (eg, made of gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mixture of the combination formulation of the invention and a suitable powder base (eg lactose or starch).

Aerosol or dry powder formulations are preferably arranged such that each metered dose or “puff” contains 1 μg to 50 mg of the combination formulation of the present invention for delivery to a patient. The total daily dose for the aerosol will be between 1 μg and 50 mg, and may be administered once or more generally throughout the day.

Alternatively, the combination formulations of the present invention may be administered in the form of suppositories or pressaries, or may be topically applied in the form of gels, hydrogels, lotions, solutions, creams, ointments or dispersants. Combination formulations of the invention may also be administered dermal or transdermally using, for example, skin patches, depots or subcutaneous injections. They can also be administered by the pulmonary or rectal route.

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

Combination formulations of the present invention can also be used with cyclodextrins. Cyclodextrins are known to form sealed and unsealed complexes with drug molecules. Formation of the drug-cyclodextrin complex can alter the solubility, dissolution rate, bioavailability and / or stability properties of the drug molecule. Drug-cyclodextrin complexes are generally useful for most dosage forms and administration routes. As an alternative to direct complexation with the drug, cyclodextrins can be used as auxiliary additives, such as carriers, diluents or solubilizers. Alpha-, beta- and gamma-cyclodextrins are most commonly used and suitable examples are described in WO 91/11172, WO 94/02518 and WO 98/55148.

Oral administration of the combination formulations of the invention is the preferred route and is the most convenient. In situations where the recipient suffers from swallowing disorders or drug absorption disorders after oral administration, the drug may be administered parenterally, sublingually or orally.

Combination formulations of the present invention can be used as part of a triple therapy, ie, a treatment protocol for treating a patient with three pharmaceutical agents. The third agent of the triple therapy may be a second PDE5 or ACE inhibitor, or may be selected from a third pharmacological group. For example, it may be a neutral endopeptidase inhibitor, angiotensin II receptor antagonist, calcium channel blocker (e.g. amlodipine), statins (e.g. atorvastatin), beta blocker (i.e., beta-adrenergic receptor antagonist). ) Or diuretics.

It will be appreciated that the present invention comprises further aspects of the following i) to iii) and that the embodiments described above for the first aspect extend to these aspects:

i) a pharmaceutical combination formulation of the invention (for simultaneous, separate or sequential administration) for treating hypertension;

ii) a) a first pharmaceutical composition comprising a PDE5 inhibitor; b) a second pharmaceutical composition comprising an ACE inhibitor; And c) a container for treating hypertension, comprising a container for the composition;

iii) treating a subject with high blood pressure, comprising treating the patient with an effective amount of a combination formulation of the present invention.

Method

Preferred compounds suitable for use according to the invention are potent and selective PDE5 inhibitors. In vitro PDE inhibitory activity against cyclic guanosine 3 ', 5'-monophosphate (cGMP) and cyclic adenosine 3', 5'-monophosphate (cAMP) phosphodiesterases showed their IC ₅₀ values (enzyme activity). By determining the concentration of compound required to inhibit 50%).

Necessary PDE enzymes are described in Ballard et al. As described in Urology 159 (6), 2164-2171, 1998, humans are essentially modified by methods of Thompson (WJ) et al., Biochemistry 18 (23), 5228-5237, 1979. It can be isolated from a variety of sources including cavernous bodies, human and rabbit platelets, human ventricles, human skeletal muscles and bovine retinas. In particular, cGMP-specific PDE5 and cGMP-inhibited cAMP PDE3 can be obtained from human cavernous tissue, human platelets or rabbit platelets; cGMP-stimulated PDE2 was obtained from human cavernous bodies; Calcium / calmodulin (Ca / CAM) -dependent PDE1 was obtained from human ventricles; cAMP-specific PDE4 was obtained from human skeletal muscle; Photoreceptor PDE6 was obtained from the bovine retina. Phosphodiesterase 7-11 can be generated from full length human recombinant clones transfected into SF9 cells.

The assay is essentially a ballad et al. J. Variation of the "batch" method of Thompson and Appleman MM (Biochemistry 10 (2), 311-316, 1971) as described in Urology 159 (6), 2164-2171, 1998]. Using a flash proximity assay for the direct detection of [ ³ H] -labeled AMP / GMP, or using a modification of the protocol described by product Amersham plc with product code TRKQ7090 / 7100. Can be performed. In summary, the effect of PDE inhibitors in flash proximity assays is determined by the ratio of [ ³ H] -unlabeled to [ ³ H] -labeled at various inhibitor concentrations and small amounts of substrate (~ 1/3 K _m or less). Phosphorus cGMP or cAMP) was investigated by analyzing a fixed amount of enzyme to be IC ₅₀ ≒ K _i . The final assay volume was brought to 100 μl with assay buffer [20 mM Tris-HCl, pH 7.4, 5 mM MgCl ₂ , 1 mg / ml bovine serum albumin]. The reaction was initiated by enzyme, incubated at 30 ° C. for 30-60 minutes to achieve less than 30% substrate conversion, and 50 μl of yttrium silicate SPA beads (3 mM individual unlabeled cyclic nucleotides for PDE 9 and PDE 11). Containing). After reclosing the plate and shaking for 20 minutes, the beads were allowed to settle for 30 minutes in the dark and then counted in a TopCount plate reader (Packard, Meriden, Connecticut). Radioactive units were converted to% active against uninhibited control (100%), plotted against inhibitor concentration, and inhibitor IC ₅₀ values were obtained using a 'Fit Curve' Microsoft Excel extension. .

Animal experiment

Enalapril as a representative ACE inhibitor, and 3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) -pyridine-3- as a representative PDE5 inhibitor Il] -2- (pyridin-2-yl) methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one (implementation of international patent application WO 99/54333 Compound of Example 4) was used to demonstrate the efficacy of the inventive combination formulation in an animal model of human hypertension.

animal

Spontaneous hypertension rats (SHR) are a widely used model of human hypertension. Mesenteric, hepatic and renal blood flow in male SHR (20-22 weeks old) according to published methods (Gardiner, SM, et al., Br. J. Pharmacol, 132 (8), 1625-1629, 2001). Doppler flow probes for the measurement of aortic blood pressure and heart rate were installed.

drug

A solution of enalapril (7.5 μg / ml), PDE5 inhibitor (200 μg / ml), and a combination formulation of enalapril and PDE5 inhibitor (7.5 μg / ml + 200 μg / ml) was 0.4 mL / h throughout the experimental period. It was injected at the rate of. Control animals received an isotonic saline adjusted to pH 4 with an excipient compound, ie hydrochloric acid.

protocol

Basic hemodynamic variables were recorded. Animals (n = 7 or 8 / group) were randomized and then treated with drug solution by continuous infusion over 4 days. Changes in hemodynamic variables were monitored daily for 7 hours during the experiment. The summary results, expressed as differences from excipient reactions, are shown in the table below.

Aid Enalapril PDE5 inhibitors Combination formulation Total change in mean BP (mmHg) -2.4 -12.1 -17.8 Change in mesenteric conductivity (%) +22.4 +22.1 +48.1 % Change in stretch conductivity +14.2 -0.8 +34.2 % Change in aortic conductivity +3.7 +19.8 +30.1

In particular, the results of renal conductivity demonstrate that the two agents included in the combination formulation can produce an effect that is greater than the sum of their individual effects.

Claims (13)

Palliative, treatment of hypertension, congestive heart failure, angina pectoris, stroke, diabetes, and impaired glucose tolerance, including essential hypertension, pulmonary hypertension, secondary hypertension, isolated systolic hypertension, diabetes-related hypertension, atherosclerosis-related hypertension and neovascular hypertension Use of a combination formulation of a cyclic guanosine monophosphate specific phosphodiesterase type 5 (PDE5) inhibitor and an angiotensin converting enzyme (ACE) inhibitor to prepare a medicament for therapeutic or prophylactic treatment. The use of claim 1, wherein the IC ₅₀ value of the PDE5 inhibitor is less than 100 nM. The use according to claim 2, wherein the IC ₅₀ value of the PDE5 inhibitor is less than ₅₀ nM. The method of claim 1, 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); (6R, 12aR) -2,3,6,7,12,12a-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. The method of claim 4, wherein the PDE5 inhibitor is 5- [2-ethoxy-5- (4-methyl-1-piperazinylsulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-di Hydro-7H-pyrazolo [4,3-d] pyrimidin-7-one (sildenafil) or a pharmaceutically acceptable salt thereof. 6. Use according to claim 5, wherein the PDE5 inhibitor is sildenafil citrate. The method according to any one of claims 1 to 6, wherein the ACE inhibitor is benazepril, captopril, silazepril, enalapril, enalapril, posinopril, ricinopril, moexapril, Uses selected from perindopril, quinapril, ramipril and trandolapril, and pharmaceutically acceptable salts thereof. 8. The method of claim 7, wherein the combination formulation of PDE5 inhibitor and ACE inhibitor is sildenafil citrate and quinapril hydrochloride; Sildenafil citrate and benazepril hydrochloride; Sildenafil citrate and captopril; Sildenafil citrate and enalapril maleate; Sildenafil citrate and posinopril; Sildenafil citrate and ricinopril; Sildenafil citrate and moexipril; Sildenafil citrate and ramipril; And sildenafil citrate and transdolapril. Use according to claim 1, wherein the medicament is for the treatment of hypertension. A pharmaceutical composition comprising a cyclic guanosine monophosphate specific phosphodiesterase type 5 (PDE5) inhibitor and an angiotensin converting enzyme (ACE) inhibitor. A pharmaceutical formulation for treating hypertension for simultaneous, individual or sequential administration comprising a cGMP specific phosphodiesterase type 5 (PDE5) inhibitor and an angiotensin converting enzyme (ACE) inhibitor. a) a first pharmaceutical composition comprising a PDE5 inhibitor; b) a second pharmaceutical composition comprising an ACE inhibitor; And c) a container for the composition. A method of treating hypertension in a subject, comprising concurrent, individual or sequential treatment of the patient with an effective amount of a PDE5 inhibitor and an ACE inhibitor.