(M1530-01-02) 2-Stage Dissolution Method for Drug Release Testing of Sodium Oxybate Extended-Release Drug Product LUMRYZ^TM

Purpose: A 2-stage dissolution method was developed for quality control testing of an extended-release formulation of sodium oxybate (SO), LUMRYZ^TM, indicated to be taken once at bedtime for the treatment of cataplexy or excessive daytime sleepiness (EDS) in adults with narcolepsy. All previously available SO drug products required twice a night dosing. LUMRYZ^TM has the SO coated onto inert cores made up of microcrystalline cellulose (Cellets), using Polyvinylpyrrolidone (PVP) as binder to form immediate-release (IR) portion of the drug. The controlled-released (CR) portion of the drug is composed of the same Cellets core and drug layer 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 portion (50%) of the dose immediately, and the second pH-dependent portion (50%) of the dose approximately 4 hours later, providing an overall extended-release profile in bioavailability studies.

Methods: The mixture of the IR and CR beads and other excipients (i.e., suspending and acidifying agents), forming LUMRYZ, were tested in USP dissolution Apparatus II, using 0.1N HCl to mimic gastric conditions and after 2 hours switching over to Phosphate Buffer, pH 6.0. The following parameters were tested: Volume (900mL and 1800mL), paddle rotation speed (50rpm, 75rpm and 100rpm) and peak vs. standard vessel. Several different time points were analyzed using HPLC.

Results: The dissolution profile shows immediate release of 50% of the dose ( < 15 min.) and then release of the remaining 50% of the dose between the 2 hour and 4 hour time points. The release specifications are Stage 1 (0.1N HCl): 40-60% release after 15 min and 42-62% after 2 hours, and stage 2 (Phosphate Buffer, pH 6.0): No Less Than 80% release after 4 hours

Conclusion: The 2-stage dissolution development was successful and demonstrated that the release profile under the described dissolution testing conditions provides sufficient discrimination of drug release from LUMRYZ to serve as a manufacturing quality control. The combination of IR beads and CR beads, forming the once at bedtime dosing has the same properties as the twice a night dosing, improving the patient’s quality of life.