Design of experiment based formulation optimization of chitosan-coated nano-liposomes of progesterone for effective oral delivery

The aim of this research was to design and develop chitosan-coated nano-liposomes of progesterone for its safe and effective oral delivery through the vesicular system providing sustained drug release, enhanced drug stability in gastro-intestinal (GI) fluid and improved drug absorption leading to better patient compliance. The aqueous solubility of progesterone (poorly soluble drug) was enhanced by hydroxy-propyl-beta-cyclodextrin complexation and the drug-loaded liposomes were prepared by ethanol injection method followed by surface coating with chitosan. Design of experiment-based formulation optimization was performed using Box-Behnken design selecting lipid, cholesterol, and drug content as formulation factors (independent variables) and mean particle size (MPS), polydispersity index (PDI), zeta potential (ZP), entrapment efficiency (EE), drug loading (DL) and cumulative % drug release (CDR) as evaluation parameters (response variables). The optimized formulation was prepared and evaluated for all preferred critical quality attributes which showed 168.3 nm MPS, 0.307 PDI, 24 mV ZP, 53% EE, 7.2% DL, and 76.4% CDR at 24 hours. In-vitro GI drug stability of chitosan-coated liposomes was studied in simulated gastric fluid and simulated intestinal fluid which exhibited 2.12 and 77.3 fold extended half-life, respectively. The ex-vivo GI-drug absorption study demonstrated two-fold rise in progesterone absorption from liposomal formulation. The chitosan-coated liposomes of progesterone which showed sustained drug release following Higuchi model kinetics was found to be a better alternative for oral delivery of progesterone overcoming drawbacks of conventional dosage forms.