Modified Release Gamma-Hydroxybutyrate Formulations Having Improved Pharmacokinetics
Patent No. US10952986 (titled "Modified Release Gamma-Hydroxybutyrate Formulations Having Improved Pharmacokinetics") was filed by Rtw Investments Lp on May 23, 2019.
What is this patent about?
’986 is related to the field of pharmaceutical formulations, specifically modified-release formulations of gamma-hydroxybutyrate (GHB) for treating conditions like narcolepsy. Current treatments often involve inconvenient twice-nightly dosing of immediate-release sodium oxybate (Xyrem®), which disrupts sleep. Prior attempts at once-nightly modified-release formulations have struggled to achieve comparable bioavailability to the twice-nightly regimen, often requiring higher doses and resulting in significant reductions in drug absorption.
The underlying idea behind ’986 is to create a modified-release GHB formulation that, when taken once at bedtime, closely mimics the pharmacokinetic profile of the standard twice-nightly immediate-release regimen. This is achieved by carefully controlling the in vitro dissolution profile of the formulation, ensuring rapid release of a portion of the drug in acidic conditions (simulating the stomach) followed by rapid release of the remaining drug in a buffered, higher pH environment (simulating the intestines). This biphasic release is key to achieving comparable bioavailability.
The claims of ’986 focus on modified-release GHB formulations, preferably comprising immediate-release and modified-release portions, that meet specific pharmacokinetic or *in vitro* dissolution criteria. Some claims require that a 7.5g dose of the formulation achieves a certain minimum area under the curve (AUC) in a blood concentration vs. time plot. Other claims focus on formulations that release a specified percentage of GHB within certain timeframes in either acidic or buffered dissolution media, as measured by standard USP apparatus.
In practice, the invention uses a combination of immediate-release (IR) and modified-release (MR) microparticles. The MR microparticles are coated with a combination of a polymer containing free carboxylic acid groups (like methacrylic acid copolymers) and a hydrophobic compound with a high melting point (like hydrogenated vegetable oil). The ratio of these components, along with the overall coating thickness, controls the drug release rate. The immediate release portion ensures an initial burst of GHB, while the modified release portion provides a sustained release profile.
The key differentiation from prior approaches lies in the specific dissolution profile achieved by the formulation. Unlike previous modified-release attempts that resulted in reduced bioavailability, ’986's formulation is designed for rapid release in both acidic and buffered environments. This is believed to compress the blood concentration vs. time curve, resulting in a relative bioavailability comparable to or greater than an equipotent dose of an immediate-release liquid solution of sodium oxybate administered twice nightly. The formulation also aims to minimize residual drug content in the bloodstream after eight hours, further improving the safety profile.
How does this patent fit in bigger picture?
Technical landscape at the time
In the mid-2010s when ’986 was filed, modified release formulations were often designed using combinations of immediate release and delayed release components to control drug release. At a time when oral solid dosage forms were typically implemented using coatings and matrix formulations, achieving consistent bioavailability with modified release profiles was a significant challenge. When hardware or software constraints made precise control over dissolution rates non-trivial, complex release mechanisms were often employed to achieve desired pharmacokinetic profiles.
Novelty and Inventive Step
The examiner approved the application because an updated prior art search did not reveal any reference teaching a method of treating a disorder treatable with gamma-hydroxybutyrate in a human in need thereof, where the method involves administering a single daily dose. The examiner concluded that the claimed invention was novel and non-obvious over the prior art of record.
Claims
This patent contains 31 claims, of which claims 1, 10, 11, 12, 13, 22, and 23 are independent. The independent claims generally focus on methods of treating disorders with gamma-hydroxybutyrate, including specific dosages, formulations, and administration protocols, particularly for narcolepsy. The dependent claims generally elaborate on the specifics of the methods, such as timing of administration, mixing procedures, and resulting effects.
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Description
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US10952986
- Application Number
- US16420321
- Filing Date
- May 23, 2019
- Status
- Granted
- Expiry Date
- Aug 24, 2037
- External Links
- Slate, USPTO, Google Patents