KR20050013156A - Novel Combination - Google Patents

Abstract

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

Description

New Combination Formulation {Novel Combination}

Blood pressure (BP) is defined by a number of hemodynamic parameters considered alone 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, ie elevated BP, was defined as SBP greater than 140 mm Hg and / or DBP greater than 90 mm Hg. According to this definition, the incidence of hypertension in developed countries is about 20% in the adult population and rises to about 60-70% in the 60-year-old and older population, but when measured in a nonclinical setting, many of these hypertensive subjects had normal BP. Have 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); And Brown, MJ and Haycock, S., Drugs 59 (Suppl. 2), 1-12, 2000).

The pathophysiology of hypertension is the subject of ongoing debate. In general, hypertension is the result of an imbalance between cardiac output and peripheral vascular resistance, and most hypertensive patients agree that they exhibit abnormal cardiac output and increased peripheral resistance, but it is uncertain which parameters 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 (ACE) inhibitors and angiotensin receptor antagonists, are available in a variety of pharmacological categories, effective hypertension therapy Still not satisfied

Angiotensin II receptor antagonists (angiotensin receptor blockers, ARBs) that block the vasoconstrictive action of the renin-angiotensin-aldosterone system are generally more selective than angiotensin converting enzymes acting on the same physiological pathway and are considered to cause fewer side effects. do.

Phosphodiesterase type 5 (PDE5) is a cyclic guanosine monophosphate (cGMP) -specific phosphodiesterase. Inhibitors of PDE5 enhance the action of nitric oxide by reducing the rate of hydrolysis of cGMP. These have been proposed as antihypertensives, but are not yet used as therapeutics in this field. However, they are useful for the treatment of male erectile dysfunction.

The present invention relates to a combination formulation consisting of a) an inhibitor of cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type 5 (PDE5) and b) an inhibitor of angiotensin II receptor antagonist, and in particular for the treatment of hypertension of the combination formulation. It is about use in.

According to a first aspect, the present invention provides the use of a combination formulation comprising a) a PDE5 inhibitor and b) an angiotensin II receptor antagonist 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 a known risk factor. 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, in particular, metabolic syndrome (also known as X syndrome), diabetes and impaired glucose tolerance (including their complications such as diabetic retinopathy and diabetic neuropathy).

The combination formulations of PDE5 inhibitors with angiotensin II receptor antagonists, including combination formulations of specific PDE5 inhibitors with specific angiotensin II receptor antagonists, will now be referred to as combination formulations of the present invention.

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

The term “PDE5 inhibitor” hereinafter refers to a PDE5 inhibitor for use in the present invention, including all pharmaceutically acceptable salts, solvates and polymorphs of the PDE5 inhibitor. Likewise, the term "angiotensin II receptor antagonist" refers to angiotensin II receptor antagonists for use in the present invention, including all pharmaceutically acceptable salts, solvates and polymorphs of angiotensin II receptor antagonists.

The suitability of PDE5 inhibitors and angiotensin II receptor antagonists is facilitated by assessing their efficacy and selectivity using the methods of the literature and then evaluating their toxicity, pharmacokinetics (absorption, metabolism, distribution and elimination) in accordance with standard pharmaceutical practice. Can be determined. Suitable compounds are potent and selective and have no significant toxic effect 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 required to inhibit 50% enzymatic activity. IC ₅₀ values of PDE5 inhibitors can be determined using the PDE5 assay described in the later Test Methods Section. Preferably, the IC ₅₀ for the PDE5 enzyme of the PDE5 inhibitor is 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 for the particular enzyme involved. IC ₅₀ values of PDE3 and PDE4 enzymes can be determined using the methods of established literature (Ballard SA et al., Journal of Urology 159, 2164-2171, 1998).

Preferably, the PDE5 inhibitor is selective for the PDE5 enzyme. Preferably, their selectivity to PDE5 is 100 times higher than PDE3, more preferably 300 times higher. More preferably, the selectivity of PDE5 is 100 times higher, more preferably 300 times higher than both PDE3 and PDE4.

Preferably, the IC ₅₀ for PDE5 of the PDE5 inhibitor is less than 100 nM and the selectivity is 100 times higher than PDE3.

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

Solubility indicative of 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 mimicking GIT. Preferably, the minimum solubility of the PDE5 inhibitor is 50 μg / ml. Solubility is described by Lipinski CA 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, Log D _7.4 of the PDE5 inhibitor is -2 to +4, more preferably -1 to +3. Log D is described in Stopher, 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 expectation of smooth 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 in Artursson, P and Magnusson, C, J. Pharm. Sci., 79 (7), 595-600, 1990, can be determined by standard procedures known in the art.

Metabolic stability addresses the ability of GIT to metabolize a compound during the absorption process or the liver's ability to metabolize a 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 less than 0.5 liver extraction rate in the assay system. Examples of analytical systems and data manipulations are described in Obach, RS, 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 these methods, additional support can be obtained by in vivo experiments in animals that the drug will be orally bioavailable to humans. Absolute bioavailability in these studies is measured by administering the compounds individually or in combination by the oral route. For absolute value measurements (oral bioavailability%), intravenous routes are also used. Examples of assessing oral bioavailability in animals are described by Ward, KW et al., Drug Met. Disp. 29 (1), 82-87, 2001; Berman, J et al., J. 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 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 disclosed in / 24745, WO 00/27848, WO 01/27112, WO 01/98304 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 by Rotella DP et al., J. 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 considered to be incorporated by reference in their entirety.

Further examples of PDE5 inhibitors for use in the present invention are 4-bromo-5- (pyridylmethylamino) -6- [3- (4-chlorophenyl) -propoxy] -3 (2H) pyridazinone ; 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] pyrimidin-5-yl) -4-ethoxyphenyl ] 5- [2-ethoxy-5- (4-methyl-1-piperazinylsulfonyl) phenyl] -1-methyl-3-n-propyl-1, also known as sulfonyl-4-methylpiperazine 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] -3, also known as 5-yl] -3-pyridylsulfonyl} -4-ethylpiperazine -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-propyl, also known as phenyl] sulfonyl] -4-ethylpiperazine -3H-imidazo [5,1-f] [1,2,4] triazin-4-one (vardenafil), ie Examples 20, 19, 337 of WO 99/24433 and 336 compound;

[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);

3- (1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -N- (2- (1-methyl Pyrrolidin-2-yl) ethyl) -4-propoxybenzenesulfonamide (WO 00/27848, see Example 68);

4- (4-chlorobenzyl) amino-6,7,8-trimethoxyquinazolin (Example 11 of International Patent Application Publication No. 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 (Rotella DP et al , J. Med. Chem. 43 (7), 1257-1263, 2000).

More preferred PDE5 inhibitors for use in the present invention

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);

3- (1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -N- (2- (1-methyl Pyrrolidin-2-yl) ethyl) -4-propoxybenzenesulfonamide;

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.

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 angiotensin II receptor antagonists for use in the present invention are candesartan, eprosartan, irbesartan, losarartan, olmesartan, olmesartan, olmeartan There are olmesartan medoxomil, saralasin, telmisartan and valsartan.

Preferred combination formulations of PDE5 inhibitors and angiotensin II receptor antagonists to treat hypertension include sildenafil and candesartan; Sildenafil and eprosartan; Sildenafil and irbesartan; Sildenafil and losartan; Sildenafil and olmesartan; Sildenafil and olmesartan medocsomil; Sildenafil and telmisartan; Sildenafil and valsartan; Tadalafil and candesartan; Tadalafil and eprosartan; Tadalafil and irbesartan; Tadalafil and losartan; Tadalafil and olmesartan; Tadalafil and olmesartan medoxyl; Tadalafil and telmisartan; tadalafil and valsartan; Vardenafil and candesartan; Vardenafil and eprosartan; Vardenafil and irbesartan; Vardenafil and losartan; Vardenafil and olmesartan; Vardenafil and olmesartan medocsomil; Vardenafil and telmisartan; And vardenafil and valsartan.

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 being treated is hypertension, congestive heart failure, angina pectoris, stroke or kidney failure. More preferably, the cardiovascular disorders are 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 tablets, capsules, multiples that may contain flavoring or coloring agents 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 present invention may also be administered as a dispersible or rapid dissolving dosage form or in the form of a high energy dispersion, 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. For example sodium starch glycolate, croscarmellose sodium and certain composite silicates), and granulation binders (e.g. polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), water Excipients such as cross, gelatin and acacia). 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 blended 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 angiotensin II receptor antagonists include various sweeteners or flavorings, colorants, or dyes; Emulsifiers and / or suspending agents; Diluents such as water, ethanol, propylene glycol and glycerin, and mixtures thereof.

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. 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, but is not limited to these. Modified release and pulsatile release dosage forms may contain one release rate modified excipient or mixtures thereof. Release rate modifying 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 subjects in the body weight range of about 65-70 kg. Those skilled in the art will readily be able to determine the dosage level required for a subject (eg, child and elderly) whose weight is not within this range.

The dosage of the inventive combination formulation included in such formulations will depend on its efficacy, but it can be expected to administer 1 to 500 mg of PDE5 inhibitor and 1 to 300 mg of angiotensin II receptor antagonist 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 20 to 150 mg (eg, 20, 50, 100 and 150 mg) of angiotensin II receptor antagonists and 1 day It may be administered once, 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 subject and the severity of the condition.

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 to 250 mg (e.g. from 10 to 100 mg) of the combination formulation of the present invention, such that one or more than two, if appropriate, are administered at a time. In any case, the physician will determine the actual dosage that will best suit the individual patient, which will depend on the age, weight and response of the particular patient. The dosage is an example of an average case. Of course, there may be separate cases where higher or lower dosage ranges are advantageous, and such cases are 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 in some cases as a single dosage. All references to treatment herein 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 with a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, hydro Fluoroalkane (e.g., 1,1,1,2-tetrafluoroethane (HFA 134A ™) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA ( Are conveniently delivered in the form of aerosol injectors from pressurized vessels, pumps, injectors, nebulizers or nebulizers in the presence or absence of 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 solutions or suspensions of the active compounds, for example using mixtures of ethanol and propellants as solvents, and include lubricants (eg, sorbitan triole) Ate). 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 formulations of the invention and a suitable powder base (eg lactose or starch).

The aerosol or dry powder formulation is preferably arranged such that each metered dose or “puff” contains 1 μg to 50 mg of the combination formulation of the invention for delivery to the patient. The total daily dose for the aerosol will range from 1 μg to 50 mg and may be administered in a single dose or, more commonly, in several portions 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 spray powders. 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.

When topically applied to the skin, the combination formulations of the invention are suspended or dissolved in one or more mixtures selected from, for example, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. It may be formulated as a suitable ointment containing the active compound. 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 modify the solubility, dissolution rate, bioavailability and / or stability of the 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, cyclodextrins can be used as auxiliary additives, for example 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.

Combination formulations of the present invention are the preferred route of administration, oral administration, which is 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.

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

It will be understood 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 angiotensin II receptor antagonist; 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 activities for cyclic guanosine 3 ', 5'-monophosphate (cGMP) and cyclic adenosine 3', 5'-monophosphate (cAMP) phosphodiesterases were characterized by their IC ₅₀ values (enzymes). By determining the concentration of compound required to inhibit the activity by 50%).

Necessary PDE enzymes are essentially described in Ballard SA et al., J. Urology 159 (6), 2164-2171, 1998, essentially in Thampson, WJ et al., Biochemistry 18 (23). , 5228-5237, 1979 may be modified to isolate from a variety of sources including human cavernous body, human and rabbit platelets, human ventricles, human skeletal muscle and bovine retina. In particular, cGMP-specific PDE5 and cGMP-inhibited cAMP PDE3 could 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.

Assays are essentially described in Ballard SA et al., J. Urology 159 (6), 2164-2171, 1998, Thommpson WJ and Appleman MM, Biochemistry 10 (2), 311-316, 1971. ] of the "batch (batch)" used by modifying the method, or armor used by modifying the protocol described by the product code TRKQ7090 / 7100 by the siamese PLL's (Amersham plc) Inc., ^[3 H] - the AMP / GMP cover Can be performed using a flash proximity assay for direct detection of. In summary, scintillation proximity analyzes show the effect of PDE inhibitors at various inhibitor concentrations and small amounts of substrate ([ ³ H] -unlabeled to [ ³ H] -label ratios at concentrations of ˜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 using 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 allow less than 30% substrate conversion, and 50 μl of yttrium silicate SPA beads (3 unlabeled 3 mM each for PDE 9 and PDE 11). Containing click nucleotides). After reclosing the plate and shaking for 20 minutes, the beads were allowed to settle for 30 minutes in the dark and then counted on a TopCount plate reader (Packard, Meriden, Connecticut). Radioactive units are converted to% activity against uninhibited control (100%), plotted against inhibitor concentration, and the IC of the inhibitor using a 'Fit Curve' Microsoft Excel extension. ₅₀ values were obtained.

Animal research

Candesartan as a representative angiotensin II receptor antagonist, and 3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) -pyridine- as a representative PDE5 inhibitor 3-yl] -2- (pyridin-2-yl) methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one (International Patent Application Publication WO 99/54333 The compound of example 4 of the present invention) 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 human hypertension model. Anesthetized male SHR (250-450 g) was surgically prepared to measure systolic, diastolic and mean arterial blood pressure. The cannula was inserted into the jugular vein and the carotid artery. The trachea was also intubated to facilitate breathing. After 60 minutes of postoperative stabilization period, arterial blood pressure and heart rate were recorded via a pressure transducer and a PoNeMah data acquisition system.

drug

A solution of candesartan (0.02 μg / kg / min), PDE5 inhibitor (15.6 μg / kg / min), and a combination formulation of PDE5 inhibitor and candesartan (15.6 μg / kg / min + 0.02 μg / kg / min) Injection was appropriately at a rate of 0.5 ml / h. Control animals received compound vehicle (5% DMSO, 10% PEG200, 85% water for injection (volume / volume)).

protocol

Basic hemodynamic parameters were recorded. Animals (n = 6 / group) were randomly extracted and then primed injections of vehicle or PDE5 inhibitor for 60 minutes. At this point, these groups were further randomly extracted to either i) administer vehicle alone or PDE5 inhibitors alone, ii) candesartan alone, or iii) a combination formulation of candesartan and PDE5 inhibitors. . Changes in mean arterial blood pressure were monitored during the study. Summary data expressed as changes in mean arterial pressure for vehicle treated animals are shown in the table below.

Aid Candesartan (0.02 μg / kg / min) PDE5 inhibitor Combination formulation Mean arterial blood pressure change (mmHg) on vehicle basis -3.2 -7.4 -32.6

This data demonstrates that the effect of the combination formulation belonging to the MAP of 32.6 mmHg is significantly greater than the sum of the two individual effects (7.4 mmHg for PDE5 inhibitors and 3.2 mmHg for candesartan) (p = 0.058).

Claims (13)

Essential hypertension, pulmonary hypertension, secondary hypertension, isolated systolic hypertension, diabetic hypertension, atherosclerosis-related combination of cyclic guanosine monophosphate specific phosphodiesterase type 5 (PDE5) inhibitors and angiotensin II receptor antagonists Use in the manufacture of a medicament for the palliative, therapeutic or prophylactic treatment of hypertension, congestive heart failure, angina pectoris, stroke, diabetes, and impaired glucose tolerance, including hypertension and neovascular hypertension. The use of claim 1, wherein the IC ₅₀ value of the PDE5 inhibitor is less than 100 nM. The use according to claim 1 or 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); 3- (1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -N- (2- (1-methyl Pyrrolidin-2-yl) ethyl) -4-propoxybenzenesulfonamide; 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 Use selected from hydro-7H-pyrazolo [4,3-d] pyrimidin-7-one (sildenafil) and pharmaceutically acceptable salts thereof. 6. Use according to claim 5, wherein the PDE5 inhibitor is sildenafil citrate. The method of claim 1, wherein the angiotensin II receptor antagonist is candesartan, eprosartan, irbesartan, losartan, olmesar Use selected from olmesartan, olmesartan medoxomil, saralasin, telmisartan and valsartan, and pharmaceutically acceptable salts thereof. 8. The method of claim 7, wherein the combination formulation of PDE5 inhibitor and angiotensin II receptor antagonist is sildenafil citrate and candesartan; Sildenafil citrate and eprosartan; Sildenafil citrate and irbesartan; Sildenafil citrate and losartan; Sildenafil citrate and olmesartan; Sildenafil citrate and olmesartan medoxomil; Sildenafil citrate and telmisartan; And sildenafil citrate and valsartan. 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 II receptor antagonist. A pharmaceutical combination formulation for treating hypertension for simultaneous, separate or sequential administration comprising a cGMP specific phosphodiesterase type 5 (PDE5) inhibitor and an angiotensin II receptor antagonist. a) a first pharmaceutical composition comprising a PDE5 inhibitor; b) a second pharmaceutical composition comprising angiotensin II receptor antagonist; And c) a container for the composition. A method of treating hypertension in a subject, comprising concurrently, separately or sequentially treating the patient with an effective amount of a PDE5 inhibitor and an angiotensin II receptor antagonist.