Purpose:
Monoclonal antibodies (mAbs) are significant biotherapeutic agents for various diseases. Their oral administration is hindered by instability in the gastrointestinal tract (GIT). Lyophilization offers a viable method for stable mAb formulation for oral use. This research discusses the development of a stable oral formulation of mAbs through optimized freeze-drying process.
Method:
mAb formulations were created in buffers of pH 5 (mAb1) and pH 7.4 (mAb2). Bulking agents, stabilizers, and their concentrations were identified for lyophilization. EDTA served as a protease inhibitor to reduce mAb degradation. The lead formulation was established using optimized freezing and drying parameters. Modulated differential scanning calorimetry (MDSC) assessed the glass transition temperature (Tg) and eutectic temperature (Teu). Short-term stability up to 30 days was evaluated through assessments of cake appearance, reconstitution time, moisture content, purity, and related substances.
Results:
Trehalose showed superior cryoprotection as a bulking agent. Increasing trehalose concentration from 10% to 20% lowered the Tg of the lead formulation from -36˚C to -34˚C. The lyophilization cycle was optimized to 72 hours at freezing (-50°C), primary drying (-34°C), and secondary drying (20°C) with a pressure of 72mTorr. Methionine effectively stabilized the lyophilized mAbs, yielding minimal %Impurity. The addition of EDTA to the lead formulation with 20% trehalose did not influence Tg. MDSC findings indicated Tg's significance in maintaining low primary drying temperatures. Moisture content was below 3%. No significant differences in mAb concentrations were noted across various temperatures. However, Lyo-mAb1 exhibited greater stability compared to Lyo-mAb2, as indicated by %Purity data. Both formulations demonstrated %Impurity below 1%, indicating no process-related mAb degradation.
Conclusion:
This study provides critical insights for developing stable lyophilized mAb formulations, addressing stability issues related to enzymatic degradation and acidic pH in the GIT. Furthermore, the lyophilized formulation in enteric-coated capsules presents a promising method for oral mAb delivery.
