Treatment of chronic cough, breathlessness and dyspnea
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Publication Number
US-11660296-B2
Publication Date
2023-05-30
Expiration Date
Abstract
The present invention relates to methods for treating patients with chronic cough with nalbuphine compositions as well as treating cough, breathlessness, or dyspnea associated with IPF with nalbuphine compositions, wherein the method provides a therapeutic effect in a patient.
Core Innovation
The invention relates to treating idiopathic pulmonary fibrosis (IPF) cough by orally administering an effective amount of nalbuphine or a pharmaceutically acceptable salt or ester thereof to a patient in need. The disclosed approach is directed to IPF-associated chronic cough and related symptoms such as breathlessness and dyspnea, using orally administered nalbuphine formulations, including salts, solvates, or esters.
The invention further describes clinically measurable benefits in IPF patients with cough and breathlessness/dyspnea, including improvements assessed with evaluating respiratory symptoms (E-RS™) breathlessness subscales, Borg dyspnea scale, numerical rating scale (NRS) dyspnea value, modified medical research council (MMRC) dyspnea categories, and PROMIS dyspnea and fatigue scales. It also ties nalbuphine treatment to reduced pulmonary fibrosis progression and reduced hospitalization and acute exacerbations of IPF (AE-IPF), including fewer AE-IPF events.
The document further describes oral nalbuphine titration regimens and extended-release oral dosage forms, including sustained release delivery system concepts. It also characterizes treatment via pharmacokinetic exposure parameters including steady-state plasma levels, AUC (0–24 h), Cmax/Cmin, AUCtau, and titration to steady state, together with a randomized, placebo-controlled crossover clinical study design and daytime cough frequency measured by a digital monitoring approach.
Claims Coverage
The provided claims center on oral treatment of IPF cough with nalbuphine or a pharmaceutically acceptable salt or ester, and the claim set includes multiple dependent refinements. Across the independent claim and dependent features, there are six inventive features comprising quantified cough improvement criteria, pharmacokinetic exposure constraints, a minimum treatment duration, and combination co-administration with specific therapeutic agents.
Oral nalbuphine treatment of IPF cough
Orally administering to a patient in need thereof an effective amount of nalbuphine or a pharmaceutically acceptable salt or ester thereof for treating idiopathic pulmonary fibrosis (IPF) cough.
Quantified daytime cough frequency improvement
After treating a patient, the patient's cough improves as shown by at least a 30% reduction in daytime cough frequency measured with a cough count monitor device compared to before the treating.
Mean Cmax pharmacokinetic constraint
Administering the treatment to a patient results in a mean Cmax between about 5 ng/mL and about 85 ng/mL.
Mean AUCtau pharmacokinetic constraint
Administering the treatment to a patient results in a mean AUCtau between about 40 ng·hr/mL and about 800 ng·hr/mL.
Minimum administration duration
Administering the treatment to a patient for at least one week.
Combination co-administration with nintedanib and/or pirfenidone
Administering nalbuphine or a pharmaceutically acceptable salt or ester together with therapeutic agents selected from nintedanib and pirfenidone.
Overall, the claim coverage centers on oral nalbuphine-based treatment for IPF cough, with dependent refinements that specify quantified improvement in daytime cough frequency, constraints on mean pharmacokinetic exposure, a minimum duration of at least one week, and optional combination co-administration with nintedanib and/or pirfenidone.
Stated Advantages
Reduced pulmonary fibrosis progression.
Reduced hospitalization rate.
Reduced acute exacerbations of IPF (AE-IPF), including fewer AE-IPF events.
Documented Applications
Treatment of idiopathic pulmonary fibrosis (IPF) cough in patients, with cough and breathlessness/dyspnea outcomes assessed using instruments such as E-RS™ breathlessness subscales, Borg dyspnea scale, NRS dyspnea, MMRC categories, and PROMIS dyspnea/fatigue scales.
Use of a randomized, placebo-controlled crossover clinical study design with endpoints including daytime cough frequency measured by a digital monitoring approach and multiple secondary symptom questionnaire measures.
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