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Formulation and Delivery - Chemical

Mixture of Immediate-Release Beads and Controlled-Release Beads to Form Sodium Oxybate Extended-Release Drug Product (LUMRYZ<sup>TM</sup>)

(M1430-01-02) Mixture of Immediate-Release Beads and Controlled-Release Beads to Form Sodium Oxybate Extended-Release Drug Product (LUMRYZTM)

Monday, October 21, 2024
2:30 PM – 3:30 PM MT

    Presenting Author(s)

  • JV

    Jason Vaughn, Ph.D.

    Sr. Vice President, Technical Operations
    Avadel
    Chesterfield, Missouri, United States

    • Main Author(s)

  • JV

    Jason Vaughn, Ph.D.

    Sr. Vice President, Technical Operations
    Avadel
    Chesterfield, Missouri, United States

    • Co-Author(s)

  • Thorsteinn Thorsteinsson, PhD

    Executive Director Product Development
    Avadel
    Boynton Beach, Florida, United States

  • BS

    BJ Schaefer, BS

    Senior Director, Technical Operations
    Avadel
    Chesterfield, Missouri, United States

  • MF

    Maire Fenton, BS

    Director Program Management
    Avadel
    Chesterfield, Missouri, United States

Purpose: In May 2023, the United States Food and Drug Administration approved LUMRYZTM, an extended-release formulation of sodium oxybate (SO) indicated to be taken once at bedtime for the treatment of cataplexy or excessive daytime sleepiness (EDS) in adults with narcolepsy. All previous SO drug products required twice a night dosing. LUMRYZTM has the SO coated onto inert cores made up of microcrystalline cellulose (Cellets), using Polyvinylpyrrolidone (PVP) as binder to form immediate-release (IR) beads. LUMRYZTM also contains controlled-released (CR) beads, which are composed of the same IR beads onto which a mixture of methacrylic acid copolymers and hydrogenated vegetable oil is layered to provide a pH-dependent release. This combination has a unique release profile that provides the first dose of SO (50%) immediately and the second pH-dependent dose approximately 4 hours later, providing an overall extended-release profile in bioavailability studies.

Methods: The SO and PVP are solubilized in solvents to create a solution. The solution was sprayed onto MCC (Cellets) beads using a Wurster column, to form the IR beads. Half of the IR beads were further coated with a mixture of methacrylic acid copolymers and hydrogenated vegetable oil to form pH-dependent CR beads. The IR and CR beads, in equal amounts, and other excipients (i.e., suspending and acidifying agents) are mixed and drug release was tested in a 2-stage dissolution method. Pharmacokinetic (PK) evaluation was also performed to determine the bioavailability compared to a commercially available twice a night sodium oxybate product. The study was a single dose, open label, randomized, two-way crossover study to compare relative bioavailability of the two products in heathy subjects.

Results: The dissolution profile shows immediate release of 50% of the dose ( < 15 min.) and then the rapid release of the remaining 50% of the dose following the increase in pH. The bioavailability study with 25 volunteers showed that the Cmax of a 6-gram dose was 66 mcg/ml (±31 mcg/ml) and the AUCinf was 282 mcg*h/ml (±30 mcg*h/ml), compared to a Cmax of 77 mcg/ml (±32 mcg/ml) and AUCinf of 273 mcg*h/ml (±28 mcg*h/ml) for a 3-gram dosed twice a night (4 hours apart).

Conclusion: Mixing IR and CR beads is now a proven proprietary technology platform that can provide extended-release properties to drugs that have a high dose and/or are taken multiple times a day. By combining IR beads and CR beads, the once at bedtime dosing has similar pharmacokinetic properties as the twice a night dosing, improving the patient’s quality of life