Extended-release pharmaceutical compositions of Ralinepag

An extended-release pharmaceutical composition comprising ralinepag or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and one or more pharmaceutically acceptable carriers,

• wherein:
• a. the amount of the ralinepag or pharmaceutically acceptable salt, solvate, or prodrug thereof contained in the composition is from about 0.03 mg to about 1.2 mg, and the ralinepag has an average particle size (D90) within about 0.1 μm to 50 μm to facilitate homogeneous dispersion for ultra-low-dose formulations of the ralinepag or pharmaceutically acceptable salt, solvate, or prodrug thereof;
• b. the one or more pharmaceutically acceptable carriers are present in an amount of not less than 85% w/w of the total weight of the pharmaceutical composition;
• and
• c. at least one of the one or more pharmaceutically acceptable carriers comprises one or more release rate-controlling ingredients, wherein the one or more release rate-controlling ingredients is present in an amount not less than about 5% w/w of the total weight of the one or more pharmaceutically acceptable carriers or of the total pharmaceutical composition,
• and wherein the composition:
• a. provides controlled release of the ralinepag or a pharmaceutically acceptable salt, solvate, or prodrug thereof over an extended period of about 8 to 24 hours following oral administration;
• b. when administered orally to a human subject, including with an alcoholic beverage containing up to 40% (v/v) alcohol, provides a 12-hour peak-to-trough plasma concentration ratio of less than about 4.0, and a Tmax greater than about 4 hours;
• c. releases less than about 40% of the ralinepag or pharmaceutically acceptable salt, solvate, or prodrug thereof at 2 hours when tested in 900 mL of aqueous medium using USP Apparatus II at 50 rpm and 37±1° C.;
• d. releases less than about 50% of the ralinepag or pharmaceutically acceptable salt, solvate, or prodrug thereof at 2 hours, more than about 60% at 8 hours, and more than about 80% at 16 hours when tested in 900 mL of aqueous medium containing up to 40% ethanol using USP Apparatus II at 50 rpm and 37±1° C.;
• e. consists of the ralinepag or a pharmaceutically acceptable salt, solvate, or prodrug thereof as sole active ingredient;
• and
• f. provides substantially bioequivalent pharmacokinetic profiles within ±about 25% Cmax and/or AUC, when administered under alcoholic and non-alcoholic conditions, respectively.