Modified Release Gamma-Hydroxybutyrate Formulations Having Improved Pharmacokinetics

Patent No. US12263150 (titled "Modified Release Gamma-Hydroxybutyrate Formulations Having Improved Pharmacokinetics") was filed by Flamel Ireland Ltd on Jun 28, 2024.

’150 is related to the field of modified-release pharmaceutical formulations , specifically those containing gamma-hydroxybutyrate (GHB). GHB, particularly in the form of sodium oxybate, is used to treat narcolepsy symptoms like excessive daytime sleepiness and cataplexy. Current treatments often involve immediate-release formulations requiring twice-nightly dosing, which is inconvenient and can disrupt sleep. The challenge lies in creating a once-nightly formulation with comparable bioavailability to the existing twice-nightly regimen, while also minimizing side effects and maintaining consistent drug levels throughout the night.

The underlying idea behind ’150 is to achieve a modified-release profile for GHB that mimics the pharmacokinetic benefits of a twice-nightly immediate-release regimen but with the convenience of a single dose. This is accomplished by combining immediate-release and modified-release components in a single formulation. The modified-release portion is designed to delay and then sustain the release of GHB, ensuring therapeutic levels are maintained throughout the night without causing excessive initial peaks or residual drug levels in the morning.

The claims of ’150 focus on a method of treating disorders treatable with gamma-hydroxybutyrate, specifically using a pharmaceutical formulation containing a combination of calcium, potassium, and magnesium salts of gamma-hydroxybutyric acid . The method involves initiating a low dose, maintaining it for at least a week, and then gradually increasing the dose until the desired therapeutic effect is achieved, without further escalation once effective.

In practice, the invention uses a combination of immediate-release and modified-release particles. The immediate-release portion provides an initial dose of GHB, while the modified-release portion, coated with a pH-sensitive polymer and a hydrophobic compound, delays and sustains the release. This dual-release mechanism aims to provide a pharmacokinetic profile that closely matches the twice-nightly immediate-release regimen, but with the convenience of a single dose.

This approach differs from prior attempts at once-nightly GHB formulations, which often suffered from reduced bioavailability or undesirable pharmacokinetic profiles. By carefully controlling the release rate and timing through the specific combination of immediate and modified release components, ’150 seeks to optimize the therapeutic effect while minimizing side effects and improving patient compliance. The use of calcium, potassium, and magnesium salts may also contribute to a more balanced physiological effect compared to sodium-only formulations.

How does this patent fit in bigger picture?

Technical landscape at the time

In the mid-2010s when ’150 was filed, modified release formulations were commonly designed to address issues such as bioavailability and dosing frequency. At a time when achieving desired drug release profiles often required complex multi-component systems, techniques for controlling drug release based on pH and time were well-established. When formulating modified release dosage forms, it was non-trivial to balance immediate and extended release characteristics to optimize drug absorption and minimize side effects.

Novelty and Inventive Step

The examiner approved the patent because the prior art, specifically Liang et al. and Allphin et al., did not disclose or suggest the specific combination of salts (calcium, potassium, and magnesium) of gamma-hydroxybutyrate (GHB) in a single, once-nightly dosage for administration to a human subject, nor did they teach the up-titration of the dose as claimed. While Liang et al. taught reducing a twice-nightly dosage regimen to a single dose and Allphin et al. taught pharmaceutical compositions comprising mixed salts of GHB, neither reference combined these elements in the manner claimed in the present application. The examiner stated that there was no motivation or guidance from the prior art to combine these features, thus the obviousness rejection was withdrawn.

Claims

This patent contains 19 claims, with claims 1 and 11 being independent. The independent claims are directed to methods of treating disorders treatable with gamma-hydroxybutyrate using a specific pharmaceutical formulation and dosage regimen. The dependent claims generally elaborate on or further define elements of the independent claims, such as dosage amounts, specific disorders, and methods of administration.

Key Claim Terms New

Definitions of key terms used in the patent claims.

Term (Source)	Support for Specification	Interpretation
Calcium salt of gamma-hydroxybutyric acid (Claim 1, Claim 11)	“Sodium oxybate is also known as sodium 4-hydroxybutanoate, or gamma-hydroxybutyric acid sodium salt, and has the following chemical structure: Sodium oxybate is marked commercially in e United States as Xyrem®. The product is formulated as an immediate release liquid solution that is taken once immediately before bed, and a second time approximately 2.5 to 4 hours later, in equal doses.”	A salt form of gamma-hydroxybutyric acid where the cation is calcium.
Ceasing any further up-titrating upon effect (Claim 1)	“When initiating treatment with sodium oxybate, careful titration up to an adequate level is essential both to obtain positive results and avoid adverse effects. The recommended starting dose is 4.5 g divided into 2 equal doses of 2.25 g, the first taken at bedtime and the second taken 2.5 to 4 hours later. The starting dosage can be decreased to 3.0 g/day or increased to as high as 9.0 g/day in increments of 1.5 g/day (0.75 g per dose). Two weeks are recommended between dosage adjustments to optimize reduction of daytime symptoms and minimize side effects.”	Stopping the gradual increase of the dosage when the desired therapeutic outcome is achieved.
Magnesium salt of gamma-hydroxybutyric acid (Claim 1, Claim 11)	“Sodium oxybate is also known as sodium 4-hydroxybutanoate, or gamma-hydroxybutyric acid sodium salt, and has the following chemical structure: Sodium oxybate is marked commercially in e United States as Xyrem®. The product is formulated as an immediate release liquid solution that is taken once immediately before bed, and a second time approximately 2.5 to 4 hours later, in equal doses.”	A salt form of gamma-hydroxybutyric acid where the cation is magnesium.
Potassium salt of gamma-hydroxybutyric acid (Claim 1, Claim 11)	“Sodium oxybate is also known as sodium 4-hydroxybutanoate, or gamma-hydroxybutyric acid sodium salt, and has the following chemical structure: Sodium oxybate is marked commercially in e United States as Xyrem®. The product is formulated as an immediate release liquid solution that is taken once immediately before bed, and a second time approximately 2.5 to 4 hours later, in equal doses.”	A salt form of gamma-hydroxybutyric acid where the cation is potassium.
Up-titrating the once-nightly dosage (Claim 1)	“When initiating treatment with sodium oxybate, careful titration up to an adequate level is essential both to obtain positive results and avoid adverse effects. The recommended starting dose is 4.5 g divided into 2 equal doses of 2.25 g, the first taken at bedtime and the second taken 2.5 to 4 hours later. The starting dosage can be decreased to 3.0 g/day or increased to as high as 9.0 g/day in increments of 1.5 g/day (0.75 g per dose). Two weeks are recommended between dosage adjustments to optimize reduction of daytime symptoms and minimize side effects.”	Gradually increasing the amount of the pharmaceutical formulation administered each night.

Litigation Cases New

US Latest litigation cases involving this patent.

Case Number	Filing Date	Title
1:25-cv-00435	Apr 8, 2025	Avadel Cns Pharmaceuticals, Llc V. Jazz Pharmaceuticals, Inc.
1:25-cv-00405	Apr 1, 2025	Avadel Cns Pharmaceuticals, Llc V. Jazz Pharmaceuticals, Inc.

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US12263150

FLAMEL IRELAND LTD

Application Number: US18759320
Filing Date: Jun 28, 2024
Status: Granted
Expiry Date: Jul 21, 2037
External Links: Slate, USPTO, Google Patents

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