(T1430-01-02) Design and Development of High Drug Loading Commercial Formulation for a Salt Drug Substance with High Propensity of Solid Form Conversion

Purpose: Cedirogant (ABBV-157) was a RoRγt inverse agonist under development for oral treatment of psoriasis. ABBV-157 was an insoluble DCS Class IIb compound with no quantifiable solubility across gastric and intestinal (GI) tract pH range. A high solubility sodium salt was thus identified. However, salt disproportionation was inevitable in vivo especially in gastric pH environment, which eliminated the dissolution advantage of the Na salt. Therefore, formulation design for ABBV-157 aimed to minimize or prevent salt disproportionation in vivo.

Methods: Polymers such as Copovidone are known to inhibit crystallization and reduce salt disproportionation. The difficulties for this approach lie on how to select specific polymer type(s) and the amount. High amount of Copovidone was utilized in FIH capsule formulations and resulted in acceptable in vivo exposure. However, the goal of the commercial tablet formulation was 600 mg size, which necessitated a high drug load formulation leaving no room for incorporation of sufficient Copovidone. The key challenge was to significantly reduce the amount of Copovidone while maintaining desirable oral bioavailability. Another common approach for avoiding acidic gastric environment exposure to the Na salt would have been enteric coat the tablets. This simpler approach was not feasible due to the regional absorption issue. We designed a combination of two approaches to inhibit the disproportionation of ABBV-157 Na salt: (1) Adding sodium carbonate, a basic excipient to increase the surface pH to stabilize the salt; and (2) Incorporating polymers.

Results: The initial tablet formulation with less Copovidone finished with significantly lower bioavailability than FIH capsules in animal models, indicating a need for much stronger crystallization inhibitors. Several systematic polymer screen studies identified HPMC as a superior supersaturation enhancing polymer, but it slowed down the dissolution rate of the tablets. Thus, optimization of HPMC% was necessary. Multiple dissolution methods were thoroughly evaluated, and the two-stage dissolution method was established to correlate with the dog PK data. The two-stage method efficiently screened and finalized the composition combining both PVPVA% and HPMC% as well as sodium carbonate to balance between dissolution rate and maintain supersaturation. The final tablet formulation was selected based on in vitro characterizations and in vivo dog PK results, and advanced to human BE (bioequivalence) studies. The clinical data showed ~20% higher Cedirogant C_max and AUC compared to the FIH capsule formulation.

Conclusion: The high drug loading tablet developed with optimized polymer selections and surface pH modifier has made it possible to realize the dissolution potential of the Na salt and achieved the goal to successfully deliver ABBV-157 to human for late-stage clinical studies with acceptable tablet size.

Acknowledgements: The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication. All authors jointly participated in study design, research, data collection, analysis and interpretation of data, writing, reviewing, and approving the publication. Yi Gao, Hong Yong and Devalina Law are employees of AbbVie and may own AbbVie stock. Deliang Zhou were previously employee of AbbVie and currently employee of Beigene Corporation LTD, and may own stock from both AbbVie and Beigene.