Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics

What is this patent about?

’866 is related to the field of modified release pharmaceutical formulations, specifically those designed for the delivery of gamma-hydroxybutyrate (GHB). It addresses the clinical need for a once-nightly treatment for narcolepsy symptoms, such as cataplexy and excessive daytime sleepiness, which traditionally require a disruptive middle-of-the-night second dose due to the drug's short half-life and complex absorption characteristics.

The underlying idea behind ’866 is a dual-mechanism delivery system that utilizes a specific ratio of immediate-release and modified-release components to mimic the therapeutic effect of two separate doses. By engineering a formulation that rapidly releases an initial fraction of the drug and then triggers a second rapid release after a specific lag time or pH change, the system achieves high bioavailability and maintains therapeutic blood levels for a full eight hours while ensuring minimal residual drug remains upon waking.

The claims of ’866 focus on a formulation comprising an immediate release portion and a modified release portion of gamma-hydroxybutyrate, combined with distinct acidifying agents and suspending or viscosifying agents. These independent claims specify a precise distribution ratio between the two portions—ranging from 10/90 to 65/35—and require that the auxiliary excipients remain separate from the drug-containing portions to stabilize the release profile and ensure proper pourability after reconstitution in liquid.

In practice, the invention is often implemented as a particulate mixture of IR and MR microparticles. The MR microparticles are typically shielded by a functional coating containing a hydrophobic compound and a pH-sensitive polymer. This coating prevents premature dissolution in the acidic environment of the stomach but allows for a rapid release once the particles reach the higher pH environment of the small intestine, effectively compressing the absorption curve to maximize total drug exposure.

This approach differs from prior art by solving the problem of low bioavailability typically associated with extended-release GHB. While previous attempts resulted in significantly reduced absorption compared to liquid solutions, the ’866 formulation achieves a relative bioavailability of greater than 80%. By incorporating an acidifying agent like malic acid, the formulation also ensures that the drug's release characteristics remain stable for at least 15 minutes after the patient mixes the powder with water, providing a reliable and convenient once-nightly dosing regimen.