(M0930-12-80) Development of Oral Bi-layer Tablet of Ruxolitinib

Purpose: Ruxolitinib is the first Janus kinase (JAK) inhibitor approved for the treatment of moderate to severe myelofibrosis and polycythemia vera. This drug is rapidly absorbed in the gastrointestinal tract, and has a short half-life of approximately 3 hours. Due to the short retention time in the body, it is necessary to take the drug multiple times a day to achieve effective results, which leads to inconvenience in medication for patients. To improve the pharmacokinetics, others have developed an extended release dosage form using high viscosity hydroxypropyl methylcellulose (HPMC). HPMC is easy to handle and is a widely used agent to control extended release, but may cause dose dumping under intragastric pH conditions. Furthermore, due to the drug's high solubility at low pH and its solubility changing in the stomach and intestine under varying pH conditions, Ruxolitinib is not suitable for extended-release control. Here, we present the development of a dual release dosage form of Ruxolitinib to be taken once daily. This dosage form has two layers consisting of an immediate-release and an extended-release layer. For the extended-release layer, polyethylene oxide (PEO, Polyox™) was used to release the drug at a pH-independent zero-order rate.

Methods: Dissolution tests at various pHs to determine the zero-order release pattern of the drug were performed using a PTWS 1220 DSR-M13 (Pharmatest®) instrument under the 50 rpm condition of USP method 2, and the dissolution medium used for the tests was the dissolution medium specified in Method A of the USP extended-release dosage forms. Then, the concentration of the drug released at each time point was measured by HPLC (Agilent 1220) analysis. Linear regression analysis was conducted on the obtained release test data to establish a trend line, and the degree of difference between the measured values and the trend line was evaluated using the coefficient of determination. In-vitro experimental data were evaluated using the DDSolver® program. The non-clinical pharmacokinetic (PK) study was conducted using beagle dogs for three of the several candidate compositions for the extended-release layer. Among the formulations with different PEO, one type with the optimal maximum plasma concentration and area under the curve (AUC) was selected. In the beagle dog PK test, approximately 9 to 1 month old beagles were used as an experimental animal and fasted for 16 hours before administration. The separated plasma samples were analyzed for drug concentration using LC-MS/MS (Agilent 1290 series-Agilent 6495), and PK parameters were analyzed using WinNonlin software. The final selected composition for the extended-release layer and the immediate-release layer were combined at various ratios to create bi-layer tablet formulations. The bi-layer tablets were molded using a single punch tablet press (EK-0, Korsch) by manual compression method. The layer having the greater weight of each layer was first compressed by applying a pre-pressure, and the composition for another layer was added and pressed by a main pressure to prepare a bi-layer tablet. The polyvinyl alcohol (PVA)-based polymer coating solution was dispersed in purified water. Subsequently, the obtained uncoated tablet was coated using Hi-coater (Freund) equipment, completing a film-coated bi-layer tablet. The dissolution tests of the bi-layer tablets were performed using the same method as the test of the single-layer tablet. For the pharmacokinetic (PK) tests of the bi-layer tablets in beagle dogs, the same method as the single-layer tablet was followed. Jakavi 20mg tablet was administered twice daily at 12-hour intervals as a reference drug, and SYO-2101 40mg was administered once daily. After the initial administration followed by a two-week washout period, the drugs were cross administered and the tests were performed under the same conditions. Blood samples obtained through this process were analyzed using the same method as the test of the single-layer tablet.

Results: The coefficient of determination obtained from the linear regression analysis of the dissolution test data of the candidate compositions for the extended-release layer containing PEO was 0.99, while the HPMC formulation had a coefficient of determination of 0.92. Furthermore, it was observed that by maintaining a constant amount of PEO and adjusting its molecular weight, the release rate of the drug can be effectively controlled. The finally selected composition for the extended-release layer and the immediate release layer were combined at various ratios to prepare candidate bi-layer tablets. In the PK tests conducted on beagle dogs, among these candidate compositions, the reference drug showed AUC 2280.2 ng/mL*hr and Cmax 699.1 ng/mL, while the test drug showed AUC 2161.1 ng/mL*hr and Cmax 732.6ng/mL, indicating equivalent levels of maximum plasma concentration and bioavailability.

Conclusion: A dual release bi-layer tablet with a dose of Ruxolitinib 40 mg taken once daily was successfully developed. The PK tests using beagle dogs confirmed equivalence compared to the existing product that requires twice daily administration of 20mg. The development of such a product is expected to greatly improve the medication convenience for patients.