WO2009115235A1 - Inhibiteurs de la phosphodiestérase pour le traitement de l’hypertension pulmonaire - Google Patents

Inhibiteurs de la phosphodiestérase pour le traitement de l’hypertension pulmonaire Download PDF

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Publication number
WO2009115235A1
WO2009115235A1 PCT/EP2009/001813 EP2009001813W WO2009115235A1 WO 2009115235 A1 WO2009115235 A1 WO 2009115235A1 EP 2009001813 W EP2009001813 W EP 2009001813W WO 2009115235 A1 WO2009115235 A1 WO 2009115235A1
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WO
WIPO (PCT)
Prior art keywords
use according
pulmonary
aerosol
formulations
pulmonary hypertension
Prior art date
Application number
PCT/EP2009/001813
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English (en)
Inventor
Peter Sandner
Axel Wollenschläger
Dieter Neuser
Original Assignee
Bayer Schering Pharma Aktiengesellschaft
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.)
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Publication date
Application filed by Bayer Schering Pharma Aktiengesellschaft filed Critical Bayer Schering Pharma Aktiengesellschaft
Publication of WO2009115235A1 publication Critical patent/WO2009115235A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles

Definitions

  • the present invention relates to phosphodiesterases (PDEs) and the pharmacology of PDE inhibitors. More particularly, the invention relates to PDE-5 inhibitors including in particular the compound vardenaf ⁇ l and their use for preparation of medicaments administered via inhalation for the treatment of Pulmonary Hypertension (PH).
  • PDEs phosphodiesterases
  • PH Pulmonary Hypertension
  • Pulmonary Hypertension is a severe disease which resulted in the death of the patient within 3 years after the first diagnose, if not or only insufficiently treated.
  • PH refers to a disease characterized by sustained elevations of pulmonary artery pressure (LJ. Rubin, The New England Journal of Medicine, 1997, 336(2), 111).
  • PH is a condition in which the pulmonary artery pressures rises above 20mmHg to >25mmHg and >30 mmHg in rest and exercise respectively.
  • the increased pulmonary resistance leads to an increased incidence of right heart failure.
  • Current treatment of PH depends on the stage and the mechanism of the disease. Typical treatments for pulmonary hypertension include anticoagulation, oxygen supplementation, conventional vasodilator therapy, transplantation and surgical care.
  • Therapeutic agents presently used for the treatment of pulmonary hypertension include e.g. calcium channel blockers and pulmonary vasodilators like endothelin antagonists, prostacyclin receptor agonists but also PDE5 inhibitors and combinations thereof.
  • PDE5 inhibitors like endothelin antagonists, prostacyclin receptor agonists but also PDE5 inhibitors and combinations thereof.
  • PDE5 inhibitors we found when comparing PDE5 inhibitors on the effects of rat pulmonary vessels, that the relaxation was most prominent with Vardenafil, followed by Sildenafil and Tadalaf ⁇ l. This result implies an superior effect of Vardenafil when compared to Sildenafil and Tadalaf ⁇ l.
  • Vardenafil via inhalation in a ten-fold lower dose (30 ⁇ g/kg)
  • the use of vardenafil via inhalation is superior in the treatment for PH if compared to oral administered PDE5 inhibitors and will present a new treatment option for Pulmonary Hypertension.
  • pulmonary hypertension include but is not limited to primary pulmonary hypertension, secondary pulmonary hypertension, familial pulmonary hypertension, sporadic pulmonary hypertension, precapillary pulmonary hypertension, pulmonary arterial, pulmonary artery hypertension, idiopathic pulmonary hypertension, thrombotic pulmonary arteriopathy, plexogenic pulmonary arteriopathy and pulmonary hypertension associated with or related to, left ventricular dysfunction, mitral valvilar disease, constrictivepericarditis, aortic stenosis, cardiomyopathy, mediastinal fibrosis, anomalous pulmonary venous drainage, pulmonary venoocclusive disease, collagen vascular disease, congenital heart disease, congenital heart disease, pulmonary venus hypertension, chronic obstructive pulmonary disease, interstitial lung disease, lung fibrosis, sleep-disordered breathing, alveolarhyperventilation disorder, chronic exposure to high altitude, neonatal lung disease, alveolar-capillary dys
  • Compounds of the invention are administered by inhalation.
  • inhalation or inhaled includes endotracheal and endobronchial administration.
  • PDE5 inhibitor vardenafil relaxed pulmonary vessels of rat more potently then the PDE5 inhibitors sildenafil and tadalafil. This was shown in an organ bath assay using isolated rat pulmonary vessels.
  • the second aspect of the invention is provided by the fact that the Vardenafil applied via inhalation is more potently decreased pulmonary artery pressure then Vardenafil applied orally. This was shown in conscious dogs with telemetric implant in which the pulmonary artery pressure was registered.
  • the compound of the invention can administered by inhalation.
  • Inhaled drugs have the advantage of direct delivery of the active compound to the lung area, producing a faster effect than orally delivered formulations. Also the inhaled dose of drugs is often much lower than than the corresponding oral dose of the same drug to treat the desease. This may reduce unwanted systemic side effects.
  • the aerosol particles or droplets in case of solution aerosols are preferably between 0.5 micrometers and 5 micrometers (MMAD mass median aerodynmic diameter) in size.
  • the aerosol is conveniently generated from a pressurized container, pump, spray or nebuliser with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3- heptafluoropropane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a metering valve to deliver a metered amount.
  • the compound of the invention are administered by inhalation.
  • inhalation or inhaled includes endotracheal and endobronchial administration.
  • solution formulations for nebulization the drug is either dissolved (preferred) or dispersed (i.e., suspension) and applied with a suitable nebulizer.
  • Formulations for nebulization typically contain the drug in dissolved or dispersed form together with suitable excipients to improve solubility, adjust the ph, adjust the tonicity, improve dispersability and increase chemical and/or physical stability of the drug in the formulation. Excipients for such formulations are known to the formulation experts in the field and are accepted by regulatory authorities for this application route.
  • excipients without limitation are solvents such as water, with or without addition of ethanol, surfactants such as polysorbate 20 or polysorbate 80, tonicity modifiers such as sodium chloride, buffering agents such as citrate, phosphate or lactate buffer, stabilizers, i.e, antioxidants such as sodium metabilsulphite, sodium bisulphite or tocopherol, or metal chelators such as ethylendiaminetetraacetic acid.
  • solvents such as water, with or without addition of ethanol
  • surfactants such as polysorbate 20 or polysorbate 80
  • tonicity modifiers such as sodium chloride
  • buffering agents such as citrate, phosphate or lactate buffer
  • stabilizers i.e, antioxidants such as sodium metabilsulphite, sodium bisulphite or tocopherol
  • metal chelators such as ethylendiaminetetraacetic acid.
  • the aerosol formulations are aseptically manufactured or sterilized. They may also contain antimicrobial preservatives.
  • Solutions and dispersion formulations for nebulization are applied utilizing aerosol nebulizer systems that disperse the formulation into the inhalation air of the patient.
  • the droplets of the nebulized solution (dispersion) are typically in the inhalable range (MMAD (mass median aerodynamic diameter) ⁇ 10 ⁇ m, preferrably ⁇ 5 ⁇ m most preferrably ⁇ 3 ⁇ m).
  • MMAD mass median aerodynamic diameter
  • Small doses may be given with specialized nebulizers, that deliver the aerosol within a small number of inhalations.
  • the compound of the invention may also be formulated as dry powder formulation.
  • This formulations are typically applied by the use of dry powder inhalers. Many different type of inhalers are available. Some of which rely on an external energy source for drug dispersion(e.g., electricity, pressured air or gas etc.), others use the inhalation air flow of the patient for dispersion of the drug.
  • an external energy source for drug dispersion e.g., electricity, pressured air or gas etc.
  • Dry powder formulations when administered via a dry powder inhaler provide the active compound dipsersed into the inhalation air of the patient.
  • the particle size of the drug in these cases is in the inhalable range (i.e., the mean aerodynamic diameter MMAD is ⁇ 10 ⁇ m, preferrable ⁇ 5 ⁇ m, most preferrably ⁇ 3 ⁇ m).
  • the MMAD can be determined by the use of cascade impactors.
  • the drug may be incorporated into larger particles with high porosity .
  • the geometric diameter of the particles may be larger than 10 ⁇ m, but because of the high particle porosity, such particles have a low MMAD, which is in the inhalable range.
  • the dry powder aerosol formulation may consist of the pure micronized drug preferrably in a pelletized form. Pelletization (agglomeration) is done to improve the flow properties of the formulation and thereby improve volumetric metering of the formulation. Excipients such as lactose monohydrate and other sugars may be used to dilute the formulation to an extend, that allows volumetric metering of the desired precision.
  • excipients such as lactose monohydrate and other sugars may consist of a powder with coarse particles classified to a specific particle size.
  • the micronized drug is blended with the carrier and adheres to the surface of the carrier crystals (ordered mixtures).
  • the excipient acts as carrier and provides improved flow properties for exact dosing of the formulation.
  • the particle size of the carrier is typically in the non- inhalable range (for example > 200 ⁇ m).
  • a typical carrier excipient for dry powder aerosols is Lactose monohydrate.
  • the blend is subjected to shear forces (i.e., turbulence) upon which some of the micronized drug is separated from the carrier surface.
  • shear forces i.e., turbulence
  • the patient receives a significant portion of the drug separated from the carrier and dispersed in the inhalation air.
  • the drug is in the inhalable particle size range (MMAE ⁇ 5 ⁇ m, preferrably ⁇ 3 ⁇ m).
  • the emitted mass from the dry powder inhalers is in the range of 10 mg - 20mg per inhalation.
  • higher quantities of powder formulation can be applied to patients (for example up to 50 mg).
  • Multiple inhalations may be given at one administration time point in order to increase the dose of the active compound.
  • KH Krebs-Henseleit
  • ring segments For measurement of isometric tension, ring segments, 2 mm in length, are mounted in a small vessel chamber myograph. Two wires (40 ⁇ m diameter) are introduced through the lumen of the segments and mounted according to the method described by Mulvany and Halpern (Circulation
  • segment contractility is then tested by an initial exposure to a high K + solution (120 mmol/1 K + -KH solution, which is identical to KH solution except that NaCl is replaced by KCl on an equimolar basis).
  • the vessels are than pre-contracted using norpinephrine solution.
  • an accumulative dose response curve of the compound tested is constructed.
  • the stabilized contraction induced by norpinephrine solution is defined as 100% tension.
  • the relaxation is expressed as percentage tension.
  • Dogs are anaesthetized started with a Propofol liquid i.v. injection and maintained with a mixture of isoflurane/fentanyl.
  • telemetric senders from DSI D70 PCPT
  • the pressure catheters are implanted in the pulmonary artery and the aorta respectively allowing registration of blood pressure and pulmonary artery pressure in parallel.
  • the ECG electrodes and the sender is fixed under the skin on the contralateral extremities and the neck of the dog respectively.
  • Postoperatively dogs are treated with a Fentanyl patch (50 ⁇ g/h), Baytril Tablets (75mg/day), Aspirin Tablets (100mg/day) and intramuscular Rimadyl (2mg/kg/day) injection and recovered fully after 3-4 days post surgery.
  • the dogs are trained for measurement of the pulmonary artery pressure, aortic blood pressure and ECG over 3-4 hours.
  • the signals are recorded with PONEMAH physiology platform from DSI registration software. For calculation the collected values in a 5 minutes interval are averaged.
  • Vardenaf ⁇ l is dissolved in citrate-buffered water and nebulized with Ventaneb (Nebu-Tec, Aillesburg Germany) a device also approved for human use and inhaled by the dogs with a mask also used in veterinarian practice.
  • This 30% decrease in pulmonary artery pressure is seen when using the 10-fold higher oral dose.
  • the decrease of the pulmonary artery pressure after vardenafil inhaled lasts over the whole observation period which is 3 hours.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dispersion Chemistry (AREA)
  • Otolaryngology (AREA)
  • Pulmonology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention a trait aux inhibiteurs de la phosphodiestérase 5 (PDE-5) incluant en particulier le composé Vardénafil et à son utilisation pour la préparation de médicaments administrés par inhalation pour le traitement de l’hypertension pulmonaire (PH).
PCT/EP2009/001813 2008-03-20 2009-03-13 Inhibiteurs de la phosphodiestérase pour le traitement de l’hypertension pulmonaire WO2009115235A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP08005250 2008-03-20
EP08005250.9 2008-03-20

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WO2009115235A1 true WO2009115235A1 (fr) 2009-09-24

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8574247B2 (en) 2011-11-08 2013-11-05 Shockwave Medical, Inc. Shock wave valvuloplasty device with moveable shock wave generator
WO2014143453A1 (fr) * 2013-03-15 2014-09-18 Henkin Robert I Traitement faisaint intervenir un inhibiteur de la phosphodiestérase
US8968706B2 (en) 2005-04-29 2015-03-03 Robert I. Henkin Methods for diagnosing and treating loss or distortion of taste
EP2944310A1 (fr) 2014-05-16 2015-11-18 Mifcare Inhibiteurs de MIF pour le traitement de l'hypertension pulmonaire aiguë ou chronique
US9719988B2 (en) 2007-01-31 2017-08-01 Cyrano Therapeutics, Inc. Methods for detection of biological substances
WO2018132371A3 (fr) * 2017-01-10 2018-09-07 United Therapeutics Corporation Méthodes et compositions pour le traitement de l'hypertension pulmonaire
US10555940B2 (en) 2008-07-23 2020-02-11 Robert I. Henkin Phosphodiesterase inhibitor treatment
US10598672B2 (en) 2014-02-18 2020-03-24 Cyrano Therapeutics, Inc. Methods and compositions for diagnosing and treating loss and/or distortion of taste or smell
US10912778B2 (en) 2016-12-14 2021-02-09 Respira Therapeutics, Inc. Methods for treatment of pulmonary hypertension
CN116687888A (zh) * 2023-06-02 2023-09-05 苏州易合医药有限公司 伐地那非和达泊西汀复方干粉吸入制剂及其制备方法
US11806314B2 (en) 2013-12-09 2023-11-07 Respira Therapeutics, Inc. PDE5 inhibitor powder formulations and methods relating thereto

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WO2002094219A2 (fr) * 2001-05-24 2002-11-28 Alexza Molecular Delivery Corporation Administration par voie pulmonaire de medicaments contre les troubles de l'erection
WO2006094924A2 (fr) * 2005-03-09 2006-09-14 Boehringer Ingelheim International Gmbh Nouvelles compositions pharmaceutiques a base d'anticholinergiques et d'inhibiteurs de pde 5
WO2006111495A1 (fr) * 2005-04-19 2006-10-26 Nycomed Gmbh Utilisation de roflumilast pour traiter l'hypertension pulmonaire
WO2007134292A2 (fr) * 2006-05-15 2007-11-22 United Therapeutics Corporation Administration de treprostinil utilisant un inhalateur à dose mesurée
WO2008019106A1 (fr) * 2006-08-04 2008-02-14 Artesian Therapeutics, Inc. Méthodes et compositions pour le traitement d'hypertension pulmonaire utilisant une combinaison d'un agent bloquant de canal calcium et un inhibiteur de phosphodiestérase

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002094219A2 (fr) * 2001-05-24 2002-11-28 Alexza Molecular Delivery Corporation Administration par voie pulmonaire de medicaments contre les troubles de l'erection
WO2006094924A2 (fr) * 2005-03-09 2006-09-14 Boehringer Ingelheim International Gmbh Nouvelles compositions pharmaceutiques a base d'anticholinergiques et d'inhibiteurs de pde 5
WO2006111495A1 (fr) * 2005-04-19 2006-10-26 Nycomed Gmbh Utilisation de roflumilast pour traiter l'hypertension pulmonaire
WO2007134292A2 (fr) * 2006-05-15 2007-11-22 United Therapeutics Corporation Administration de treprostinil utilisant un inhalateur à dose mesurée
WO2008019106A1 (fr) * 2006-08-04 2008-02-14 Artesian Therapeutics, Inc. Méthodes et compositions pour le traitement d'hypertension pulmonaire utilisant une combinaison d'un agent bloquant de canal calcium et un inhibiteur de phosphodiestérase

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YAMAMOTO NORIYUKI ET AL: "Vardenafil (Levitra) reduces pulmonary artery resistance in vitro and in vivo", JOURNAL OF HYPERTENSION, vol. 24, no. Suppl. 6, December 2006 (2006-12-01), & 21ST SCIENTIFIC MEETING OF THE INTERNATIONAL-SOCIETY-OF-HYPERTENSION /5TH ASIAN-PACIFIC CONGRESS OF H; FUKUOKA, JAPAN; OCTOBER 15 -19, 2006, pages 364, XP009115646, ISSN: 0263-6352 *

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11389453B2 (en) 2005-04-29 2022-07-19 Cyrano Therapeutics, Inc. Compositions and methods for treating chemosensory dysfunction
US8968706B2 (en) 2005-04-29 2015-03-03 Robert I. Henkin Methods for diagnosing and treating loss or distortion of taste
US10206927B2 (en) 2005-04-29 2019-02-19 Cyrano Therapeutics, Inc. Compostions and methods for treating chemosensory dysfunction
US9719988B2 (en) 2007-01-31 2017-08-01 Cyrano Therapeutics, Inc. Methods for detection of biological substances
US10555940B2 (en) 2008-07-23 2020-02-11 Robert I. Henkin Phosphodiesterase inhibitor treatment
US8574247B2 (en) 2011-11-08 2013-11-05 Shockwave Medical, Inc. Shock wave valvuloplasty device with moveable shock wave generator
WO2014143453A1 (fr) * 2013-03-15 2014-09-18 Henkin Robert I Traitement faisaint intervenir un inhibiteur de la phosphodiestérase
US11806314B2 (en) 2013-12-09 2023-11-07 Respira Therapeutics, Inc. PDE5 inhibitor powder formulations and methods relating thereto
US11125760B2 (en) 2014-02-18 2021-09-21 Cyrano Therapeutics, Inc. Methods and compositions for diagnosing and treating loss and/or distortion of taste or smell
US10598672B2 (en) 2014-02-18 2020-03-24 Cyrano Therapeutics, Inc. Methods and compositions for diagnosing and treating loss and/or distortion of taste or smell
US11774458B2 (en) 2014-02-18 2023-10-03 Cyrano Therapeutics, Inc. Methods and compositions for diagnosing and treating loss and/or distortion of taste or smell
WO2015173433A1 (fr) 2014-05-16 2015-11-19 Mifcare Inhibiteurs du mif pour le traitement d'urgence ou chronique de l'hypertension pulmonaire
EP2944310A1 (fr) 2014-05-16 2015-11-18 Mifcare Inhibiteurs de MIF pour le traitement de l'hypertension pulmonaire aiguë ou chronique
US10912778B2 (en) 2016-12-14 2021-02-09 Respira Therapeutics, Inc. Methods for treatment of pulmonary hypertension
US11491160B2 (en) 2016-12-14 2022-11-08 Respira Therapeutics, Inc. Methods and compositions for treatment of pulmonary hypertension and other lung disorders
US11491161B2 (en) 2016-12-14 2022-11-08 Respira Therapeutics, Inc. Methods and compositions for treatment of pulmonary hypertension and other lung disorders
WO2018132371A3 (fr) * 2017-01-10 2018-09-07 United Therapeutics Corporation Méthodes et compositions pour le traitement de l'hypertension pulmonaire
CN116687888A (zh) * 2023-06-02 2023-09-05 苏州易合医药有限公司 伐地那非和达泊西汀复方干粉吸入制剂及其制备方法

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