Methods for treatment of pulmonary hypertension
Inventors
Weers, Jeffry • ROMERO, ALAIN • SMYTH, HUGH • Curtis, Robert • FROST, Adaani • Xu, Zhen • Shreeniwas, Revati • Donovan, Martin
Assignees
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Publication Number
US-10912778-B2
Publication Date
2021-02-09
Expiration Date
Abstract
Provided herein are methods for treating pulmonary hypertension. The methods include administering to a subject in need thereof an effective amount of a vasodilator, wherein the vasodilator is administered to the subject via inhalation pro re nata using a portable inhaler. In some embodiments, the vasodilator is a PDE5 inhibitor. Pharmaceutical compositions for pro re nata administration of vasodilators are also described.
Core Innovation
The invention relates to treating pulmonary hypertension by administering an effective amount of a vasodilator to a subject in need thereof. The vasodilator is administered via inhalation pro re nata using a portable inhaler, with administration at least 2-30 minutes before physical exertion, to provide rapid-onset benefit associated with pulmonary vascular effects during periods of activity.
The method provides one or both of: a 20% or greater improvement in pulmonary vascular resistance within 20 min of administration; and a decrease in the ratio of pulmonary vascular resistance to systemic vascular resistance (PVR:SVR ratio) in the subject greater than 10%. The disclosure emphasizes acute improvement in exercise tolerance and symptoms, with benefit characterized by hemodynamic measures such as changes in PVR and PVR:SVR ratio.
The disclosure further supports the inhaled administration with dry powder inhaler delivery and performance-oriented formulation features. A portable DPI system is described with a dispersion chamber and a powder deagglomeration mechanism, and vasodilators are deliverable as carrier-based compositions that include micronized drug particles and defined particle-size characteristics.
Claims Coverage
Independent claim 1 covers a PRN inhalation treatment for pulmonary hypertension using a portable inhaler, with timing before physical exertion and specific hemodynamic response thresholds. The independent claim family further refines inventive features for particular vasodilators, quantitative dose and composition ranges, powder particle-size constraints, and portable inhaler dispersion mechanisms.
Portable PRN inhalation vasodilator therapy before exertion
Administering to a subject in need thereof an effective amount of a vasodilator via inhalation pro re nata using a portable inhaler, wherein the vasodilator is administered at least 2-30 minutes before physical exertion.
Rapid improvement in pulmonary vascular resistance
Providing one or both of: a 20% or greater improvement in pulmonary vascular resistance in the subject within 20 min of administration of the vasodilator.
Reduction of PVR:SVR ratio
Providing one or both of: a decrease in the ratio of pulmonary vascular resistance to systemic vascular resistance (PVR:SVR ratio) in the subject greater than 10%.
Vardenafil vasodilator selection
Using vardenafil, or a pharmaceutically acceptable salt or hydrate, as the vasodilator as an inhaled pro re nata portable inhaler therapy.
Vardenafil inhaled nominal dose range
Administering via inhalation a nominal dose of about 0.25 mg to about 2.5 mg of vardenafil to the subject.
Carrier-based vardenafil powder composition concentration
Administering a carrier-based composition with micronized vardenafil particles, wherein vardenafil, or a pharmaceutically acceptable salt or hydrate, is present at about 0.5% to about 3% by weight.
Lactose monohydrate carrier and Dv50 particle-size limits
Administering a carrier-based composition of micronized vasodilator particles with specific Dv50 particle-size limits, wherein the powder base includes coarse crystalline lactose monohydrate and fine crystalline lactose monohydrate carrier particles.
Portable DPI dispersion chamber and oscillating actuator deagglomeration
Providing an inhaler with a dispersion chamber and a reciprocating actuator, wherein airflow through an outlet channel moves air and a carrier-based composition from an inlet into the dispersion chamber and oscillation disperses the composition for delivery to a subject.
Across the independent-method core, the inventive concept is PRN inhaled administration of a vasodilator shortly before exertion using a portable inhaler, with explicitly defined rapid hemodynamic outcomes. Dependent refinements further specify vasodilator selection, dosing and carrier-based powder composition ranges, particle-size characteristics using Dv50 and lactose monohydrate carriers, and a portable DPI dispensing mechanism with a dispersion chamber and actuator-driven powder dispersion.
Stated Advantages
Provides a 20% or greater improvement in pulmonary vascular resistance within 20 min of administration of the vasodilator.
Decreases the ratio of pulmonary vascular resistance to systemic vascular resistance (PVR:SVR ratio) in the subject greater than 10%.
Enables acute improvement of exercise tolerance and symptoms with rapid onset and duration of hours.
Supports administration using a portable inhaler suitable for PRN use before physical exertion.
Documented Applications
Treating pulmonary hypertension by administering an inhaled vasodilator pro re nata using a portable inhaler at least 2-30 minutes before physical exertion.
Using the approach to achieve acute hemodynamic improvement and associated exercise-related outcomes including six-minute walk test and patient-reported outcomes.
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