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Publication Number
US-12275704-B2
Publication Date
2025-04-15
Expiration Date
Abstract
Provided are certain pharmaceutical formulations of omecamtiv mecarbil and methods for their preparation and use.
Core Innovation
The invention relates to a pharmaceutical formulation comprising omecamtiv mecarbil dihydrochloride salt, or a pharmaceutically acceptable hydrate thereof, for heart failure. The formulation is designed to directly activate cardiac muscle myosin while using a modified or sustained release approach rather than an unmodified release profile.
The formulation includes a control release agent comprising hydroxypropylmethylcellulose and a pH modifying agent comprising fumaric acid, together with a filler and a lubricant. The control release agent and the pH modifying agent are used as formulation components to manage drug release behavior, including minimizing pH-dependent in vitro release as described.
The solid-state form of omecamtiv mecarbil is characterized by XRPD, including omecamtiv mecarbil Form A, Form B, and Form C with specified Cu Kα peak positions. The formulation is associated with complete release within a defined time window, reduced plasma peak-to-trough fluctuation, improved safety and efficacy, and stability under specified storage conditions.
Claims Coverage
The independent claim covers a pharmaceutical formulation built around five required formulation components: omecamtiv mecarbil dihydrochloride salt, or a pharmaceutically acceptable hydrate thereof, a hydroxypropylmethylcellulose-based control release agent, a fumaric-acid-based pH modifying agent, a filler, and a lubricant. Dependent refinements add quantitative w/w ranges and a fumaric-acid-to-active weight ratio constraint, and characterize the active salt or hydrate by XRPD peak positions measured using Cu Kα radiation.
Pharmaceutical formulation with omecamtiv mecarbil dihydrochloride salt hydrate
A pharmaceutical formulation comprising omecamtiv mecarbil dihydrochloride salt or a pharmaceutically acceptable hydrate thereof.
Control release agent comprising hydroxypropylmethylcellulose
A control release agent comprising hydroxypropylmethylcellulose.
pH modifying agent comprising fumaric acid
A pH modifying agent comprising fumaric acid.
Filler and lubricant components
A filler and a lubricant.
Active weight-percent range
The pharmaceutical formulation comprises 12–25% w/w omecamtiv mecarbil dihydrochloride salt, or a pharmaceutically acceptable hydrate, by weight.
Control release agent weight-percent range
The pharmaceutical formulation includes a control release agent at 15–35% w/w.
Fumaric acid weight-percent range
The pharmaceutical formulation comprises 4–11% w/w fumaric acid.
Fumaric acid to active weight ratio constraint
The pharmaceutical formulation is defined by a specified weight ratio of fumaric acid to omecamtiv mecarbil dihydrochloride, or a pharmaceutically acceptable hydrate, ranging from less than 2:1 to 1:1.
XRPD-based crystalline form characterization using Cu Kα radiation
The pharmaceutical formulation contains omecamtiv mecarbil dihydrochloride, or a pharmaceutically acceptable hydrate, with an XRPD pattern exhibiting specified peak positions using Cu Kα radiation.
Overall, the claim coverage centers on a pharmaceutical formulation that combines omecamtiv mecarbil dihydrochloride, or hydrate, with a hydroxypropylmethylcellulose control release agent and a fumaric-acid pH modifying agent, along with a filler and a lubricant. Dependent claims further define component levels through w/w ranges and a fumaric-acid-to-active weight ratio, and characterize the active solid form using XRPD peak positions under Cu Kα radiation.
Stated Advantages
Reduced plasma peak-trough fluctuation.
Improved safety/efficacy.
Stability at 40°C/75% RH for 6 months.
Minimal pH-dependent in vitro release.
Complete release within 24 h.
Documented Applications
Pharmaceutical use for heart failure, including treatment involving direct cardiac myosin activation.
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