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WO2003099194A2 - Nouvelle combinaison - Google Patents

Nouvelle combinaison Download PDF

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Publication number
WO2003099194A2
WO2003099194A2 PCT/IB2003/001889 IB0301889W WO03099194A2 WO 2003099194 A2 WO2003099194 A2 WO 2003099194A2 IB 0301889 W IB0301889 W IB 0301889W WO 03099194 A2 WO03099194 A2 WO 03099194A2
Authority
WO
WIPO (PCT)
Prior art keywords
inhibitor
pde5
hypertension
ace
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2003/001889
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English (en)
Other versions
WO2003099194A3 (fr
Inventor
David Nathan Abraham Fox
Bernadette Hughes
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pfizer Corp Belgium
Pfizer Ltd Great Britain
Pfizer Corp SRL
Original Assignee
Pfizer Corp Belgium
Pfizer Ltd Great Britain
Pfizer Corp SRL
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB0211919A external-priority patent/GB0211919D0/en
Priority claimed from GB0229784A external-priority patent/GB0229784D0/en
Priority to JP2004506721A priority Critical patent/JP2005529927A/ja
Priority to EP03719042A priority patent/EP1506015A2/fr
Application filed by Pfizer Corp Belgium, Pfizer Ltd Great Britain, Pfizer Corp SRL filed Critical Pfizer Corp Belgium
Priority to CA002485984A priority patent/CA2485984A1/fr
Priority to MXPA04010951A priority patent/MXPA04010951A/es
Priority to KR10-2004-7018868A priority patent/KR20050004195A/ko
Priority to AU2003223071A priority patent/AU2003223071A1/en
Priority to BR0311191-1A priority patent/BR0311191A/pt
Publication of WO2003099194A2 publication Critical patent/WO2003099194A2/fr
Publication of WO2003099194A3 publication Critical patent/WO2003099194A3/fr
Priority to IL16497504A priority patent/IL164975A0/xx
Anticipated expiration legal-status Critical
Priority to NO20045517A priority patent/NO20045517L/no
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the 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 treating cardiovascular and metabolic diseases, particularly hypertension.
  • cGMP cyclic guanosine monophosphate
  • PDE5 specific phosphodiesterase type 5
  • ACE angiotensin converting enzyme
  • Blood pressure is defined by a number of haemodynamic parameters taken either in isolation or in combination.
  • SBP stolic blood pressure
  • PP pulse pressure
  • Hypertension or elevated BP
  • SBP SBP of at least 140mmHg and/or a DBP of at least 90mmHg.
  • DBP blood pressure
  • ISH systolic hypertension
  • Hypertension is associated with an increased risk of stroke, myocardial infarction, atrial fibrillation, heart failure, peripheral vascular disease and renal impairment (Fagard, RH; Am. J. Geriatric Cardiology 11 (1), 23-28, 2002; Brown, MJ and Haycock, S; Drugs 59(Suppl 2), 1-12, 2000).
  • hypertension is the result of an imbalance between cardiac output and peripheral vascular resistance, and that most hypertensive subjects have abnormal cardiac output and increased peripheral resistance, there is uncertainty which parameter changes first (Beevers, G et al.; BMJ 322, 912-916, 2001 ).
  • drugs available in various pharmacological categories, including diuretics, alpha-adrenergic antagonists, beta-adrenergic antagonists, calcium channel blockers, angiotensin converting enzyme inhibitors and angiotensin receptor antagonists, the need for effective treatments of hypertension is still not satisfied.
  • ACE inhibitors which block the vasoconstrictive action of the renin-angiotensin- aldosterone system, are recommended as a first-line therapy for hypertension. They are efficacious and generally considered to be well tolerated. The most common side effect, reported by 10-20% of patients, is coughing. Other less frequently reported side effects include rash, angioedema, hyperkalemia and functional renal failure.
  • Phosphodiesterase type 5 is a cyclic guanosine monophosphate-specific phosphodiesterase. Inhibitors of PDE5 decrease the rate of hydrolysis of cGMP and so potentiate the actions of nitric oxide. They have been found to be useful in the treatment of male erectile dysfunction.
  • the present invention provides the use of a combination comprising a) a PDE5 inhibitor and b) an ACE inhibitor in the manufacture of a medicament for treating diseases, particularly cardiovascular and metabolic diseases, more particularly hypertension.
  • the terms “treating” and “treatment” include palliative, curative and prophylactic treatment.
  • hypertension includes all diseases characterised by supranormal blood pressure, 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 for which elevated blood pressure is a known risk factor.
  • treatment of hypertension includes the treatment or prevention of complications arising from hypertension, and other associated co-morbidities, including congestive heart failure, angina, stroke, glaucoma and impaired renal function, including renal failure.
  • Metabolic diseases include in particular metabolic syndrome (also known as syndrome X), diabetes and impaired glucose tolerance, including complications thereof, such as diabetic retinopathy and diabetic neuropathy.
  • combinations of a PDE5 inhibitor and an ACE inhibitor including combinations of specific PDE5 inhibitors and specific ACE inhibitors, will be referred to as combinations of the invention.
  • the combinations of the invention have the advantage that they are more efficacious, more potent, less toxic or have other more desirable properties than PDE5 inhibitors or ACE inhibitors when used alone for treating hypertension.
  • the PDE5 inhibitor means a PDE5 inhibitor for use in the invention, including all pharmaceutically acceptable salts, solvates and polymorphs of that PDE5 inhibitor.
  • the term “the ACE inhibitor” means an ACE inhibitor for use in the invention, including all pharmaceutically acceptable salts, solvates and polymorphs of that ACE inhibitor.
  • Suitable compounds are those that are potent and selective, have no significant toxic effect at the therapeutic dose, and preferably are bioavailable following oral administration.
  • Potency can be defined as an IC 50 value, being the concentration of compound necessary to inhibit the enzyme activity by 50%.
  • IC 50 values for the PDE5 inhibitors may be determined using the PDE5 assay described hereinafter.
  • the PDE5 inhibitors have an IC 5 o against the PDE5 enzyme of less than 100nM, more preferably less than 50nM.
  • IC 0 values for the PDE3 and PDE4 enzyme may be determined using established literature methodology, see Ballard SA er a/.; Journal of Urology 159, 2164-2171, 1998.
  • the PDE5 inhibitors are selective for the PDE5 enzyme. Preferably they have a selectivity for PDE5 over PDE3 of greater than 100, more preferably greater than 300. More preferably the PDE5 has a selectivity over both PDE3 and PDE4 of greater than 100, more preferably greater than 300.
  • the PDE5 inhibitors have an IC 50 against PDE5 of less than 100nM and a selectivity over PDE3 of greater than 100 fold.
  • Oral bioavailablity refers to the proportion of an orally administered drug that reaches the systemic circulation.
  • the factors that determine oral bioavailability of a drug are dissolution, membrane permeability and hepatic clearance.
  • a screening cascade of firstly in vitro and then in vivo techniques is used to determine oral bioavailablity.
  • the solubilisation of the drug by the aqueous contents of the gastrointestinal tract can be predicted from in vitro solubility experiments conducted at appropriate pH to mimic the GIT.
  • the PDE5 inhibitors Preferably have a minimum solubility of 50 ⁇ g/ml. Solubility can be determined by standard procedures known in the art such as described in Lipinski CA et al.; Adv. Drug Deliv. Rev. 23(1-3), 3-25, 1997.
  • Membrane permeability refers to the passage of a compound through the cells of the GIT. Lipophilicity is a key property in predicting this and is determined by in vitro Log D 7 . 4 measurements using organic solvents and buffer.
  • the PDE5 inhibitors Preferably have a Log D 7 . of -2 to +4, more preferably -1 to +3.
  • the Log D can be determined by standard procedures known in the art such as described in Stopher, D and McClean, S; J. Pharm. Pharmacol. 42(2), 144, 1990.
  • Cell monolayer assays such as Caco2 add substantially to prediction of favourable membrane permeability in the presence of efflux transporters such as P-glycoprotein, so-called Caco2 flux.
  • the PDE5 inhibitors have a Caco2 flux of greater than 2x10 "6 cm.s "1 , more preferably greater than 5x10 "6 cm.s "1 .
  • the Caco2 flux value can be determined by standard procedures known in the art such as described in Artursson, P and Magnusson, C; J. Pharm. Sci, 79(7), 595-600, 1990.
  • Metabolic stability addresses the ability of the GIT to metabolise compounds during the absorption process or the liver to do so immediately post-absorption: the first pass effect.
  • Assay systems such as microsomes, hepatocytes etc are predictive of metabolic lability.
  • the PDE5 inhibitors show metabolic stability in the assay system that is commensurate with an hepatic extraction of less then 0.5. Examples of assay systems and data manipulation 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.
  • PDE5 inhibitors for use with the invention include: 4-bromo- 5-(pyridylmethylamino)-6-[3-(4-chlorophenyl)-propoxy]-3(2/4)pyridazinone; 1 -[4-[(1 ,3- benzodioxol-5- ylmethyl)amiono]-6-chloro-2-quinozolinyl]-4-piperidine-carboxylic acid, monosodium salt; (+)-c/ ' s-5,6a,7,9,9,9a-hexahydro-2-[4-(trifluoromethyl)- phenylmethyI-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- octahydrocycIopent[4,5]-imi
  • Preferred PDE5 inhibitors for use with the invention include:
  • PDE5 inhibitors for use with the invention are selected from the group and pharmaceutically acceptable salts thereof:
  • a particularly preferred PDE5 inhibitor is 5-[2-ethoxy-5-(4-methyl-1 - piperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3- c/]pyrimidin-7-one (sildenafil) (also known as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3- propyl-1 H-pyrazolo[4,3-c lpyrimidin-5-yl)-4-ethoxyphenyI]sulphonyl]-4- methylpiperazine) and pharmaceutically acceptable salts thereof.
  • Sildenafil citrate is a preferred salt.
  • 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, fasidotril, mixanpril, sampatrilat, BMS-189921 , MDL-100240 and Z13752A.
  • dual ACE/NEP inhibitor i.e. a compound that inhibits both ACE and neutral endopeptidase (NEP), such as, for example, omapatrilat, fasidotril, mixanpril, sampatrilat, BMS-189921 , MDL-100240 and Z13752A.
  • PDE5 inhibitors PDE5 inhibitors
  • ACE inhibitors Preferred combinations of PDE5 inhibitors and ACE inhibitors for treating hypertension are:
  • the pharmaceutical combinations of the invention are useful in the treatment of diseases including cardiovascular and metabolic diseases, and they may also be useful in the treatment of other diseases such as thrombosis, and in the management of patients following percutaneous translumenal coronary angioplasty ("post-PTCA patients").
  • the cardiovascular disorder to be treated is hypertension, congestive heart failure, angina, stroke or renal failure. More preferably the cardiovascular disorder is essential hypertension, pulmonary hypertension, secondary hypertension, isolated systolic hypertension, hypertension associated with diabetes, hypertension associated with atherosclerosis, renovascular hypertension, congestive heart failure, angina, stroke or renal failure.
  • the disorder to be treated is essential hypertension.
  • the disorder to be treated is pulmonary hypertension.
  • the disorder to be treated is secondary hypertension.
  • the disorder to be treated is isolated systolic hypertension.
  • the disorder to be treated is hypertension associated with diabetes.
  • the disorder to be treated is hypertension associated with atherosclerosis. In another particularly preferred embodiment, the disorder to be treated is renovascular hypertension.
  • 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 combination of the invention can 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.
  • the combinations of the invention can 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-, pulsed- or controlled-release applications.
  • the combinations of the invention may also be administered as fast- dispersing or fast-dissolving dosage forms or in the form of a high energy dispersion or as coated particles. Suitable formulations may be in coated or uncoated form, as desired.
  • Such solid pharmaceutical compositions 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 glycollate, 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.
  • 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 glycollate, croscarmellose sodium and certain complex silicates, and
  • Formulation 1 A tablet is prepared using the following ingredients :
  • Active ingredient 50mg is blended with cellulose (microcrystalline), silicon dioxide, stearic acid (fumed) and the mixture is compressed to form tablets.
  • An intravenous formulation may be prepared by combining active ingredient (100mg) with isotonic saline (1000ml)
  • the tablets are manufactured by a standard process, for example, direct compression or a wet or dry granulation process.
  • the tablet cores may be coated with appropriate overcoats.
  • Solid compositions of a similar type may also be employed as fillers in gelatin or HPMC capsules.
  • Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or high molecular weight polyethylene glycols.
  • the PDE5 and ACE inhibitors may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with 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 detailed for immediate release dosage forms together with additional excipients that act as release rate modifiers, these being coated on and/or included in the body of the device.
  • Release rate modifiers include, but are not exclusively limited to, hydroxypropylmethyl cellulose, methyl cellulose, sodium carboxymethylcellulose, ethyl cellulose, cellulose acetate, polyethylene oxide, Xanthan gum, Carbomer, ammonio methacrylate copolymer, hydrogenated castor oil, camauba wax, paraffin wax, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, methacrylic acid copolymer and mixtures thereof.
  • Modified release and pulsatile release dosage forms may contain one or a combination of release rate modifying excipients.
  • Release rate modifying excipients may be present both within the dosage form i.e. within the matrix, and/or on the dosage form, i.e. upon the surface or coating.
  • Fast dispersing or dissolving dosage formulations 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 flavouring, polyethylene glycol, fumed silica, silicon dioxide, sodium starch glycolate, sodium stearyl fumarate, sorbitol, xylitol.
  • dispersing or dissolving as used herein to describe FDDFs are dependent upon the solubility of the drug substance used i.e. where the drug substance is insoluble a fast dispersing dosage form can be prepared and where the drug substance is soluble a fast dissolving dosage form can be prepared.
  • the combinations of the invention can also be administered parenterally, for example, intracavernouslly, intravenously, intra-arterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternally, intracranially, intramuscularly or subcutaneously, or they may be administered by infusion or needleless injection techniques.
  • parenterai administration they are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.
  • the aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary.
  • the dosage of the combination of the invention in such formulations will depend on its potency, but can be expected to be in the range of from 1 to 500mg of PDE5 inhibitor and 1 to 10Omg of ACE inhibitor for administration up to three times a day.
  • a preferred dose is in the range 10 to 100mg (e.g. 10, 25, 50 and 100mg) of PDE5 inhibitor and 5 to 50mg (e.g. 5, 10, 25 and 50mg) of ACE inhibitor which can be administered once, twice or three times a day (preferably once).
  • the precise dose will be as determined by the prescribing physician and will depend on the age and weight of the subject and severity of the symptoms.
  • the daily dosage level of a combination of the invention will usually be from to 5 to 500mg/kg (in single or divided doses).
  • tablets or capsules may contain from 5mg to 250mg (for example 10 to 10Omg) of the combination of the invention for administration singly or two or more at a time, as appropriate.
  • the physician in any event will determine the actual 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 dosages are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited and such are within the scope of this invention.
  • the skilled person will appreciate that the combinations of the invention may be taken as a single dose as needed or desired (i.e. prn). It is to be appreciated that all references herein to treatment include acute treatment (taken as required) and chronic treatment (longer term continuous treatment).
  • combinations of the invention can also be administered intranasally or by inhalation and are conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray, atomiser or nebuliser, with or without the use of a suitable propellant, e.g.
  • 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, e.g.
  • Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of the combinations of the invention and a suitable powder base such as lactose or starch.
  • Aerosol or dry powder formulations are preferably arranged so that each metered dose or "puff" contains from 1 ⁇ g to 50mg of a combination of the invention for delivery to the patient.
  • the overall daily dose with an aerosol will be in the range of from 1 ⁇ g to 50mg which may be administered in a single dose or, more usually, in divided doses throughout the day.
  • the combinations of the invention can be administered in the form of a suppository or pessary, or they may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting powder.
  • the combinations of the invention may also be dermally or transdermally administered, for example, by the use of a skin patch, depot or subcutaneous injection. They may also be administered by the pulmonary or rectal routes.
  • the combinations of the invention can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.
  • they can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the combinations of the invention may also be used in combination with a cyclodextrin.
  • Cyclodextrins are known to form inclusion and non-inclusion complexes with drug molecules. Formation of a drug-cyclodextrin complex may modify the solubility, dissolution rate, bioavailability and/or stability property of a drug molecule. Drug-cyclodextrin complexes are generally useful for most dosage forms and administration routes.
  • the cyclodextrin may be used as an auxiliary additive, e.g. as a carrier, diluent or solubiliser.
  • Alpha-, beta- and gamma-cyclodextrins are most commonly used and suitable examples are described in published international patent applications W091/11172, WO94/02518 and WO98/55148.
  • Oral administration of the combinations of the invention is a preferred route, being the most convenient.
  • the drug may be administered parenterally, sublingually or buccally.
  • the combinations of the invention may be used as part of a triple therapy regimen, i.e. a treatment protocol in which the patient is treated with three pharmaceutical agents.
  • the third agent in the triple therapy may be a second PDE5 or ACE inhibitor, or it may be chosen from a third pharmacological group.
  • it may be a neutral endopeptidase inhibitor, an angiotensin II receptor antagonist, a calcium channel blocker such as amlodipine, a statin such as atorvastatin, a beta blocker (i.e. a beta-adrenergic receptor antagonist) or a diuretic.
  • kits for treating hypertension comprising: a) a first pharmaceutical composition comprising a PDE5 inhibitor; b) a second pharmaceutical composition comprising an ACE inhibitor; and c) a container for the compositions;
  • a method of treating hypertension in a subject comprising treating said patient with an effective amount of a combination of the invention.
  • Preferred compounds suitable for use in accordance with the present invention are potent and selective PDE5 inhibitors.
  • In vitro PDE inhibitory activities against cyclic guanosine 3',5'-monophosphate (cGMP) and cyclic adenosine 3',5'-monophosphate (cAMP) phosphodiesterases can be determined by measurement of their IC 5 o values (the concentration of compound required for 50% inhibition of enzyme activity).
  • the required PDE enzymes can be isolated from a variety of sources, including human corpus cavernosum, human and rabbit platelets, human cardiac ventricle, human skeletal muscle and bovine retina, essentially by a modification of the method of Thompson, WJ er a/.; Biochemistry 18(23), 5228-5237, 1979, as described by Ballard SA et al.; J. Urology 159(6), 2164-2171 , 1998.
  • cGMP-specific PDE5 and cGMP-inhibited cAMP PDE3 can be obtained from human corpus cavernosum tissue, human platelets or rabbit platelets; cGMP-stimulated PDE2 was obtained from human corpus cavernosum; calcium/calmodulin (Ca/CAM)-dependent PDE1 from human cardiac ventricle; cAMP-specific PDE4 from human skeletal muscle; and photoreceptor PDE6 from bovine retina.
  • Phosphodiesterases 7-11 can be generated from full length human recombinant clones transfected into SF9 cells.
  • Assays can be performed either using a modification of the "batch” method of Thompson WJ and Appleman MM; Biochemistry 10(2),311-316, 1971 , essentially as described by Ballard SA et al.; J. Urology 159(6), 2164-2171 , 1998, or using a scintillation proximity assay for the direct detection of [ 3 H]-labelled AMP/GMP using a modification of the protocol described by Amersham pic under product code
  • Reactions were initiated with enzyme, incubated for 30-60min at 30°C to give ⁇ 30% substrate turnover and terminated with 50 ⁇ l yttrium silicate SPA beads (containing 3mM of the respective unlabelled cyclic nucleotide for PDEs 9 and 11). Plates were re-sealed and shaken for 20min, after which the beads were allowed to settle for 30min in the dark and then counted on a TopCount plate reader (Packard, Meriden, CT) Radioactivity units were converted to % activity of an uninhibited control (100%), plotted against inhibitor concentration and inhibitor IC 50 values obtained using the 'Fit Curve' Microsoft Excel extension.
  • TopCount plate reader Packard, Meriden, CT
  • SHR spontaneously hypertensive rat

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  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Diabetes (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des combinaisons qui contiennent : a) un inhibiteur de phosphodiestérase de type 5 (PDE5) spécifique de la guanosine monophosphate cyclique (GMPc) ; et b) un inhibiteur de l'enzyme de conversion de l'angiotensine (ACE). Ces combinaisons sont utiles pour le traitement de l'hypertension.
PCT/IB2003/001889 2002-05-23 2003-05-09 Nouvelle combinaison Ceased WO2003099194A2 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
AU2003223071A AU2003223071A1 (en) 2002-05-23 2003-05-09 Pharmaceutical combination of PDE5 inhibitors with ACE inhibitors
EP03719042A EP1506015A2 (fr) 2002-05-23 2003-05-09 Combinaison pharmaceutique d'inhibiteurs pde5 et d'inhibiteurs de l'enzyme de conversion de l'angiotensine (ace)
BR0311191-1A BR0311191A (pt) 2002-05-23 2003-05-09 Combinação
JP2004506721A JP2005529927A (ja) 2002-05-23 2003-05-09 新規な組み合わせ
CA002485984A CA2485984A1 (fr) 2002-05-23 2003-05-09 Nouvelle combinaison
MXPA04010951A MXPA04010951A (es) 2002-05-23 2003-05-09 Nueva combinacion.
KR10-2004-7018868A KR20050004195A (ko) 2002-05-23 2003-05-09 신규 조합 제제
IL16497504A IL164975A0 (en) 2002-05-23 2004-11-01 Novel combination
NO20045517A NO20045517L (no) 2002-05-23 2004-12-17 Ny kombinasjon

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB0211919.6 2002-05-23
GB0211919A GB0211919D0 (en) 2002-05-23 2002-05-23 Novel combination
GB0229784.4 2002-12-20
GB0229784A GB0229784D0 (en) 2002-12-20 2002-12-20 Novel combination

Publications (2)

Publication Number Publication Date
WO2003099194A2 true WO2003099194A2 (fr) 2003-12-04
WO2003099194A3 WO2003099194A3 (fr) 2004-06-03

Family

ID=29585817

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2003/001889 Ceased WO2003099194A2 (fr) 2002-05-23 2003-05-09 Nouvelle combinaison

Country Status (18)

Country Link
EP (1) EP1506015A2 (fr)
JP (1) JP2005529927A (fr)
KR (1) KR20050004195A (fr)
CN (1) CN1655820A (fr)
AR (1) AR040090A1 (fr)
AU (1) AU2003223071A1 (fr)
BR (1) BR0311191A (fr)
CA (1) CA2485984A1 (fr)
IL (1) IL164975A0 (fr)
MX (1) MXPA04010951A (fr)
NO (1) NO20045517L (fr)
PA (1) PA8574201A1 (fr)
PE (1) PE20040514A1 (fr)
PL (1) PL374198A1 (fr)
RU (1) RU2004133973A (fr)
TW (1) TW200407153A (fr)
UY (1) UY27816A1 (fr)
WO (1) WO2003099194A2 (fr)

Cited By (11)

* Cited by examiner, † Cited by third party
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WO2005011727A1 (fr) * 2003-08-01 2005-02-10 Pfizer Limited Combinaison d'un activateur de cyclase de guanylate soluble et d'un inhibiteur d'ace utile dans le traitement d'un trouble cardio-vasculaire ou metabolique
US7019010B2 (en) 2001-09-27 2006-03-28 Novertis Ag Combinations
JP2007529562A (ja) * 2004-03-25 2007-10-25 ベーリンガー インゲルハイム フェトメディカ ゲゼルシャフト ミット ベシュレンクテル ハフツング 心不全に罹患した哺乳類の心サイズ低下のためのｐｄｅｉｉｉインヒビターの使用
WO2008024494A3 (fr) * 2006-08-24 2008-04-10 Surface Logix Inc Composés de pharmacocinétique améliorée
US8846679B2 (en) 2004-03-08 2014-09-30 Boehringer Ingelheim Vetmedica Gmbh Pharmaceutical composition comprising pimobendan
US8980894B2 (en) 2004-03-25 2015-03-17 Boehringer Ingelheim Vetmedica Gmbh Use of PDE III inhibitors for the treatment of asymptomatic (occult) heart failure
US9107952B2 (en) 2006-11-07 2015-08-18 Boehringer Ingelheim Vetmedica Gmbh Liquid preparation comprising pimobendan
US10071162B2 (en) 2013-07-19 2018-09-11 Boehringer Ingelheim Vetmedica Gmbh Preserved etherified cyclodextrin derivatives containing liquid aqueous pharmaceutical composition
US10172804B2 (en) 2013-12-04 2019-01-08 Boehringer Ingelheim Vetmedica Gmbh Pharmaceutical compositions of pimobendan
US10398705B2 (en) 2012-03-15 2019-09-03 Boehringer Ingelheim Vetmedica Gmbh Pharmaceutical tablet formulation for the veterinary medical sector, method of production and use thereof
US10537570B2 (en) 2016-04-06 2020-01-21 Boehringer Ingelheim Vetmedica Gmbh Use of pimobendan for the reduction of heart size and/or the delay of onset of clinical symptoms in patients with asymptomatic heart failure due to mitral valve disease

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2902009B1 (fr) * 2006-06-13 2012-12-07 Bioprojet Soc Civ Utilisation d'un inhibiteur de vasopeptidase pour le traitement de l'hypertension arterielle pulmonaire

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US4316906A (en) * 1978-08-11 1982-02-23 E. R. Squibb & Sons, Inc. Mercaptoacyl derivatives of substituted prolines
GB9013750D0 (en) * 1990-06-20 1990-08-08 Pfizer Ltd Therapeutic agents
GB9401090D0 (en) * 1994-01-21 1994-03-16 Glaxo Lab Sa Chemical compounds
US6143746A (en) * 1994-01-21 2000-11-07 Icos Corporation Tetracyclic cyclic GMP-specific phosphodiesterase inhibitors, process of preparation and use
DK1049695T3 (da) * 1997-11-12 2002-05-13 Bayer Ag 2-Phenyl-substituerede imidazotriazinoner som phosphodiesterase-inhibitorer
TWI265925B (en) * 1999-10-11 2006-11-11 Pfizer Pyrazolo[4,3-d]pyrimidin-7-ones useful in inhibiting type 5 cyclic guanosine 3',5'-monophosphate phosphodiesterases(cGMP PDE5), process and intermediates for their preparation, their uses and composition comprising them
EA200200240A1 (ru) * 1999-10-11 2002-10-31 Пфайзер Инк. 5-(2-ЗАМЕЩЕННЫЕ-5-ГЕТЕРОЦИКЛИЛСУЛЬФОНИЛПИРИД-3-ИЛ)-ДИГИДРОПИРАЗОЛО[4,3-d]ПИРИМИДИН-7-ОНЫ В КАЧЕСТВЕ ИНГИБИТОРОВ ФОСФОДИЭСТЕРАЗЫ

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7019010B2 (en) 2001-09-27 2006-03-28 Novertis Ag Combinations
WO2005011727A1 (fr) * 2003-08-01 2005-02-10 Pfizer Limited Combinaison d'un activateur de cyclase de guanylate soluble et d'un inhibiteur d'ace utile dans le traitement d'un trouble cardio-vasculaire ou metabolique
US8846679B2 (en) 2004-03-08 2014-09-30 Boehringer Ingelheim Vetmedica Gmbh Pharmaceutical composition comprising pimobendan
US8859554B2 (en) 2004-03-08 2014-10-14 Boehringer Ingelheim Vetmedica Gmbh Packaging assembly for pharmaceutical composition including pimobendan
US8846680B2 (en) 2004-03-08 2014-09-30 Boehringer Ingelheim Vetmedica Gmbh Pharmaceutical composition comprising pimobendan
US10537588B2 (en) 2004-03-25 2020-01-21 Boehringer Ingelheim Vetmedica Gmbh Use of pimobendan for the reduction of heart size in mammals suffering from heart failure
US10117869B2 (en) 2004-03-25 2018-11-06 Boehringer Ingelheim Vetmedica Gmbh PDE III inhibitors for treatment of asymptomatic heart failure
US8980894B2 (en) 2004-03-25 2015-03-17 Boehringer Ingelheim Vetmedica Gmbh Use of PDE III inhibitors for the treatment of asymptomatic (occult) heart failure
JP4932700B2 (ja) * 2004-03-25 2012-05-16 ベーリンガー インゲルハイム フェトメディカ ゲゼルシャフト ミット ベシュレンクテル ハフツング 心不全に罹患した哺乳類の心サイズ低下のためのｐｄｅｉｉｉインヒビターの使用
US9463199B2 (en) 2004-03-25 2016-10-11 Boehringer Ingelheim Vetmedica Gmbh Use of PDE III inhibitors for the reduction of heart size in mammals suffering from heart failure
US11413285B2 (en) 2004-03-25 2022-08-16 Boehringer Ingelheim Vetmedica Gmbh PDE III inhibitors for treatment of asymptomatic heart failure
US9889148B2 (en) 2004-03-25 2018-02-13 Boehringer Ingelheim Vetmedica Gmbh Use of pimobendan for the reduction of heart size in mammals suffering from heart failure
JP2007529562A (ja) * 2004-03-25 2007-10-25 ベーリンガー インゲルハイム フェトメディカ ゲゼルシャフト ミット ベシュレンクテル ハフツング 心不全に罹患した哺乳類の心サイズ低下のためのｐｄｅｉｉｉインヒビターの使用
US8853394B2 (en) 2006-08-24 2014-10-07 Surface Logix, Inc. Pharmacokinetically improved compounds
WO2008024494A3 (fr) * 2006-08-24 2008-04-10 Surface Logix Inc Composés de pharmacocinétique améliorée
US9107952B2 (en) 2006-11-07 2015-08-18 Boehringer Ingelheim Vetmedica Gmbh Liquid preparation comprising pimobendan
US10639305B2 (en) 2006-11-07 2020-05-05 Boehringer Ingelheim Vetmedica Gmbh Liquid preparation comprising pimobendan
US9616134B2 (en) 2006-11-07 2017-04-11 Boehringer Ingelheim Vetmedica Gmbh Liquid preparation comprising pimobendan
US10398705B2 (en) 2012-03-15 2019-09-03 Boehringer Ingelheim Vetmedica Gmbh Pharmaceutical tablet formulation for the veterinary medical sector, method of production and use thereof
US10071162B2 (en) 2013-07-19 2018-09-11 Boehringer Ingelheim Vetmedica Gmbh Preserved etherified cyclodextrin derivatives containing liquid aqueous pharmaceutical composition
US11185590B2 (en) 2013-07-19 2021-11-30 Boehringer Ingelheim Vetmedica Gmbh Preserved etherified cyclodextrin derivatives containing liquid aqueous pharmaceutical composition
US12357696B2 (en) 2013-07-19 2025-07-15 Boehringer Ingelheim Vetmedica Gmbh Preserved etherified cyclodextrin derivatives containing liquid aqueous pharmaceutical composition
US10172804B2 (en) 2013-12-04 2019-01-08 Boehringer Ingelheim Vetmedica Gmbh Pharmaceutical compositions of pimobendan
US10537570B2 (en) 2016-04-06 2020-01-21 Boehringer Ingelheim Vetmedica Gmbh Use of pimobendan for the reduction of heart size and/or the delay of onset of clinical symptoms in patients with asymptomatic heart failure due to mitral valve disease
US12011441B2 (en) 2016-04-06 2024-06-18 Boehringer Ingelheim Vetmedica Gmbh Pimobendan for the reduction of heart size and/or the delay of onset of clinical symptoms in patients with asymptomatic heart failure due to mitral valve disease

Also Published As

Publication number Publication date
WO2003099194A3 (fr) 2004-06-03
RU2004133973A (ru) 2005-09-10
AU2003223071A1 (en) 2003-12-12
CA2485984A1 (fr) 2003-12-04
NO20045517L (no) 2004-12-17
AR040090A1 (es) 2005-03-16
JP2005529927A (ja) 2005-10-06
IL164975A0 (en) 2005-12-18
PE20040514A1 (es) 2004-08-24
EP1506015A2 (fr) 2005-02-16
PA8574201A1 (es) 2003-12-19
TW200407153A (en) 2004-05-16
CN1655820A (zh) 2005-08-17
KR20050004195A (ko) 2005-01-12
PL374198A1 (en) 2005-10-03
UY27816A1 (es) 2003-12-31
MXPA04010951A (es) 2005-06-08
BR0311191A (pt) 2005-03-01

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