Polyanion based controlled release system for the GnRH-receptor antagonist degarelix

Area of Science:

• Pharmacology
• Materials Science
• Biochemistry

Background:

• Degarelix is a gonadotropin-releasing hormone receptor antagonist used in prostate cancer treatment.
• Peptide aggregation can affect drug delivery and efficacy.
• Polyanions like alginate and CMC are explored for drug formulation to control release.

Purpose of the Study:

• To investigate the interaction between degarelix and polyanions alginate and carboxymethyl cellulose (CMC).
• To characterize the nano-structure of formed complexes.
• To evaluate the in vitro and in vivo drug release kinetics of degarelix from these complexes.

Main Methods:

• Complex formation via simple mixing of degarelix with alginate or CMC.
• Nano-structure characterization using light and transmission electron microscopy.
• Complexation process monitoring using isothermal titration calorimetry.
• In vitro drug release studies over three months.
• In vivo pharmacokinetic study in Sprague Dawley rats.

Main Results:

• Degarelix and polyanions formed nano-structures of twisted fibers.
• Isothermal titration calorimetry revealed dissolution of peptide self-aggregates followed by complex formation with polyanions acting as templates.
• In vitro release showed only slight differences between complexes and pure degarelix over three months.
• In vivo studies demonstrated similar degarelix plasma concentrations for complex formulations and aqueous solutions after subcutaneous injection.

Conclusions:

• Complexation of degarelix with alginate or CMC forms nano-fibrous structures.
• The process involves polyanions templating the formation of peptide-polymer complexes.
• Drug release and in vivo availability were not significantly enhanced by these complex formulations, suggesting a competition between complex formation and peptide aggregation.