Complexing agent salt formulations of pharmaceutical compounds

Inventors

Becker, Jeffrey • Peterson, Gregg • Wallach, Jason

Abstract

Provided herein are pharmaceutical formulations and pharmaceutical compound salts which utilize complexing agents as counterions. Such formulations and salts are useful for treating a variety of disease and disorders.

Core Innovation

The invention relates to pharmaceutical compositions comprising a cationic pharmaceutical compound, or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof, wherein the cationic pharmaceutical compound comprises a protonated nitrogen atom and is not ketamine, and a substituted cyclodextrin comprising a plurality of anionic functional groups. Substantially all of the plurality of anionic functional groups are deprotonated so that at least one anionic functional group acts as a counterion for the protonated nitrogen atom of the cationic pharmaceutical compound, and the composition uses effective amounts with a molar ratio of the cationic pharmaceutical compound to the substituted cyclodextrin greater than 1:1.

The disclosure describes cyclodextrin-based drug salt and salt-freebase complex formation, including formation of drug-cyclodextrin salt complexes and composition behavior across concentration ranges. The resulting substituted cyclodextrin compositions incorporate protonated nitrogen-containing cationic compounds, and the text characterizes these compositions by formulation into bulk drug substance with target pH and osmolality, together with solution properties.

The disclosed embodiments include specific cyclodextrin excipients such as sulfobutylether-β-cyclodextrin (SBECD), succinylated α-cyclodextrin (SuACD), and carboxymethyl-γ-cyclodextrin (CMGCD), and cationic pharmaceutical compounds paired to form drug-cyclodextrin salt complexes. The compositions are also described in sublingual troche formulations comprising PEG and freebase/cyclodextrin salt mixtures, as well as broadly described pharmaceutical formulation components including sterile injectable aqueous and/or oleaginous suspension components and excipients such as solubilizing agents, stabilizers, preservatives, cryoprotectants, and tonicity-adjusting agents.

Claims Coverage

The independent claims are directed to a pharmaceutical composition and a method of therapy using that composition, plus a further pharmaceutical composition specifying a more stringent osmolality reduction criterion. Across the independent claims, the inventive features center on a non-ketamine cationic pharmaceutical compound with a protonated nitrogen atom, a substituted cyclodextrin with substantially all anionic functional groups deprotonated acting as a counterion, a molar ratio greater than 1:1, and reduced solution osmolality relative to a corresponding sodium-salt comparator.

Across the independent claims, the core inventive structure is a non-ketamine cationic pharmaceutical compound with a protonated nitrogen atom combined with a substituted cyclodextrin having substantially all anionic functional groups deprotonated so that at least one anionic group acts as a counterion. Each claim requires a molar ratio greater than 1:1 and specifies a solution osmolality reduction relative to a corresponding composition prepared using a sodium salt of the substituted cyclodextrin, with thresholds of at least about 10% less or at least about 50 mOsm/kg less.

Stated Advantages

Documented Applications