A Comparative Study to Evaluate the Effect of Different Carbohydrates on the Stability of Immunoglobulin G during Lyophilization and Following Storage

[...]high-cost cold chains should be ensured for maintaining liquid dosage forms.3,4 Moreover, temperature fluctuation and shear stresses are the most common problems may occur during shipping and storage which directly affect the stability of liquid biopharmaceuticals.5 Therefore, formulation of antibodies with preserved stability during preparation, transportation and shelf time storage is of crucial importance.6 During the past two decades, numerous attempts have been devoted to develop dried pharmaceutical formulations and several drying techniques such as freeze-drying, spray-drying, spray-freeze drying and foam-drying have been evaluated to overcome this issue.7 Amongst the mentioned techniques, freeze-drying or lyophilization is the most popular and commonly used method in pharmaceutical industry.8 Ice crystallization and increasing the concentration of solute lead to major challenges in proteins such as aggregation, fragmentation and conformational alterations.9 Pharmaceutical excipients, particularly sugars, enhance the stability of proteins during both lyophilization process and/or storage time.10,11 Two hypotheses have been suggested to explain the protective effects of sugars. The first opinion describes the ability of sugar molecules to form hydrogen bonds, like water molecules, in the dry state.12 Another one discusses formation of amorphous, rigid and neutral matrix by sugars that decreases the molecular mobility of antibodies during drying.13 Mannitol is a well known sugar that has been repeatedly applied as a bulking agent to create elegant cake and several studies have confirmed that amorphous mannitol can stabilize lyophilized proteins.14,15 Additionally, trehalose as a nonreducing disaccharide has been proved a prominent stabilizer due to its ability to form effective hydrogen bonds with proteins in the absence of water.16 Cyclodextrins (CDs) as circular oligosaccharides are the other category of sugars which are proposed to decrease aggregation of proteins.17 Some reports have claimed that hydroxypropyl beta cyclodextrin (HPßCD) could enhance short-term stability of lyophilized proteins even more than trehalose, sucrose and dextran.18,19 The impact of CDs as aggregation inhibitors for enzymes and various proteins has been thoroughly studied in liquid state;20,21 however, very few studies have investigated the effect of CDs on the stabilization of lyophilized antibodies.