Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics

What is this patent about?

’062 is related to the field of modified release pharmaceutical formulations, specifically focusing on the delivery of gamma-hydroxybutyrate (GHB) for treating narcolepsy. The invention addresses the clinical need for a once-nightly dosing regimen to replace the standard immediate-release liquid solutions, which require patients to wake up in the middle of the night for a second dose. Historically, modified release versions of GHB have suffered from significantly reduced bioavailability and poor pharmacokinetic performance compared to the standard twice-nightly immediate-release protocol.

The underlying idea behind ’062 is that high bioavailability for a once-nightly GHB dose can be achieved by utilizing a dual-mechanism release profile that combines an immediate-release fraction with a modified-release fraction. The key insight is the discovery of a specific relationship between in vitro dissolution and in vivo absorption: by using a pH-dependent trigger combined with a hydrophobic barrier, the formulation can rapidly release the second half of the drug in the upper GI tract. This approach compresses the blood concentration curve to mimic the exposure of two separate doses while ensuring the drug is cleared from the system within eight hours to avoid morning grogginess.

The claims of ’062 focus on a modified release formulation comprising immediate-release and modified-release portions of GHB microparticles. The modified-release portion is defined by a specific coating architecture consisting of a polymer carrying free carboxylic groups and a hydrophobic compound with a melting point of at least 40° C. The independent claims specify that the ratio of the drug between the immediate and modified release portions ranges from 10/90 to 65/35, and the formulation is designed to deliver a total therapeutic dose of 3.0 to 12.0 grams in a single nightly administration.

In practice, the formulation is typically provided as a dry particulate mixture in a sachet that the patient mixes with water before bed. The immediate-release particles provide a rapid initial therapeutic effect, while the modified-release particles remain intact in the acidic environment of the stomach. As the particles move into the higher pH environment of the small intestine, the carboxylic groups on the coating polymer ionize, triggering a rapid secondary release of the remaining drug. This specific combination of methacrylic acid copolymers and hydrogenated vegetable oils ensures that the second fraction is absorbed efficiently before the drug reaches the colon, where GHB absorption is traditionally poor.

This invention differs from prior approaches by avoiding the use of ethylcellulose in the modified-release coating, which often leads to excessively slow release and reduced bioavailability. By optimizing the dissolution trigger to occur between pH 5.5 and 6.97, the formulation achieves a relative bioavailability of greater than 80% compared to twice-nightly immediate-release solutions. This allows for a once-nightly dose that provides equivalent therapeutic coverage for cataplexy and daytime sleepiness without the compliance issues and sleep interruptions associated with multi-dose regimens.