Investigating Weak Polypeptide-Cyclodextrin Interactions in Biologic Formulation Development Using Affinity Capillary...

Area of Science:

• Biopharmaceutical Formulation
• Analytical Chemistry
• Pharmacokinetics

Background:

• Protein-excipient interactions are crucial for biopharmaceutical stability and pharmacokinetics (PK).
• Cyclodextrins (CDs) enhance solubility but their weak interactions with polypeptides are poorly understood.
• Relaxin (RLX), a polypeptide with therapeutic potential, exhibits poor solubility and interacts with human serum albumin (HSA).

Purpose of the Study:

• To characterize the weak interactions between relaxin (RLX) and two cyclodextrins (CDs): hydroxypropyl-β-cyclodextrin (HP-β-CD) and sulfobutylether-β-cyclodextrin (SBE-β-CD).
• To evaluate the suitability of SBE-β-CD as an excipient for improving RLX solubility without negatively impacting PK.
• To validate novel analytical methods for assessing weak CD-polypeptide binding.

Main Methods:

• Affinity capillary electrophoresis and flow-induced dispersion analysis (FIDA) were employed to quantify RLX binding affinities.
• Comparative analysis of RLX binding to HP-β-CD and SBE-β-CD.
• In vivo pharmacokinetic (PK) studies in cynomolgus monkeys to confirm the impact of excipient selection.

Main Results:

• Sulfobutylether-β-cyclodextrin (SBE-β-CD) demonstrated a higher binding affinity for RLX compared to hydroxypropyl-β-cyclodextrin (HP-β-CD).
• Both CD interactions with RLX were significantly weaker than RLX's binding to human serum albumin (HSA).
• The chosen analytical methods proved effective for rapid assessment of weak excipient-polypeptide interactions.

Conclusions:

• SBE-β-CD is a promising excipient for enhancing relaxin (RLX) solubility while maintaining favorable pharmacokinetic profiles.
• Affinity capillary electrophoresis and FIDA are valuable tools for characterizing weak cyclodextrin-polypeptide interactions in biopharmaceutical development.
• Understanding these interactions is key to optimizing drug formulation and delivery.