Excipients for Room Temperature Stable Freeze-Dried Monoclonal Antibody Formulations

Abstract

a b s t r a c tSucrose is a common cryoprotectant and lyoprotectant to stabilize labile biopharmaceuticals during freezedrying and storage. Sucrose-based formulations require low primary drying temperatures to avoid collapse and monoclonal antibody (mAb) containing products need to be stored refrigerated. The objective of this study is to investigate different excipients enabling storage at room temperature and aggressive, shorter lyophilization cycles. We studied combinations of 2-hydroxypropyl-beta-cyclodextrin (CD), recombinant human albumin, polyvinylpyrroldione (PVP), dextran 40 kDa (Dex), and sucrose (Suc) using 2 mAbs. Samples were characterized for collapse temperature (T c ), glass transition temperature of the liquid (T g 0 ) and freeze-dried formulation (T g ), cake appearance, residual moisture, and reconstitution time. Freezedried formulations were stored at 5 C, 25 C, and 40 C for up to 9 months and mAb stability was analyzed for color, turbidity, visible and sub-visible particles, and monomer content. Formulations with CD/ Suc or CD/PVP/Suc were superior to pure Suc formulations for long-term storage at 40 C. When using aggressive freeze-drying cycles, these formulations were characterized by pharmaceutically elegant cakes, short reconstitution times, higher T g 0 , T c , and T g . We conclude that the addition of CD allows for shorter freeze-drying cycles with improved cake appearance and enables storage at room temperature, which might reduce costs of goods substantially.

Stability enhancement in a mAb and Fab coformulation

“…The stability of therapeutic proteins in combination is rarely reported for pharmaceutical products, but there are many examples for which the coformulation with protein-based excipients such as albumin, increased the stability of the pharmaceutical ingredient [37][38][39] . Given that Fab is already known to be relatively stable under the stress conditions, it is possible that the Fab acted in a similar way to that often observed with albumins.…”

Be Aggressive! Amorphous Excipients Enabling Single-Step Freeze-Drying of Monoclonal Antibody Formulations

“…Collapse did not impact protein stability of F S when stored at 40 °C for 3 months. However, we previously found substantial protein degradation for a collapsed 10 mg/mL sucrose-based formulation when stored at 40 °C for 6 months or longer [26].…”

“…T g ’ and T g were determined by differential scanning calorimetry according to Haeuser et al [26]. Measurements were performed using a T zero DSC Q2000 instrument (TA instruments Inc., New Castle, DE, USA).…”

“…HPBCD was able to stabilize an antibody during freeze-drying and supercritical fluid drying comparable to trehalose at a protein to sugar ratio of 1:4 ( w/w ) [23,24]. Additionally, HPBCD could provide protein stability during storage at elevated temperatures superior to sucrose [25,26]. The high T g ’ and the protein stabilizing properties of HPBCD might allow for a high T p during primary drying while resulting in elegant lyophilisates.…”

Comparative study for optimization of folic acid nanoparticles

“…The particle size ranges between 31 nm and 154.62 nm. The particle size results are not exceeding 400 nm throughout 9 months storage which implies good physical stability and is very promising for an easy penetration [36,37]. The particle size values of F2 during this study at RT are slightly larger than in Ref T. Results show less stability, in terms of drug retained, for formulations stored at 25 °C, attributed to introduction of energy into the system leading to particle growth and subsequent aggregation and drug expulsion from NLCs [38].…”