Development of anti-angiogenic erlotinib liposomal formulation for pulmonary hypertension: a QbD approach

Pulmonary arterial hypertension (PAH) is the increase in mean pulmonary arterial pressure (> 25 mmHg). The development of the non-reversible plexiform lesions on the arterial walls of the pulmonary arteries has evolved as the reason to increase the pressure. The current treatments are directed towards the vasodilation of the pulmonary arteries via the endothelin, prostacyclin, and NO pathways which provides symptomatic relief. Deeper understanding of the disease leads to the various pathophysiological targets that play an important role in the development of PAH. Out of these, the angiogenetic mechanism of the pulmonary arterial smooth muscle cells has been proved to play an important role in PAH. Targeted therapies by anti-proliferative drugs may lead to the efficient treatment strategies to the root cause of PAH. Erlotinib, a receptor tyrosine kinase inhibitor, which acts on the epidermal growth factor receptor (EGFR), has shown promising results in clinical trials of PAH. The objective of the work has been the development of liposomal formulation of anti-proliferative drug, erlotinib HCl, via Quality by Design (QbD) approach. The liposomal formulation was developed using thin-film hydration technique and characterised for various physicochemical parameters, like particle size, % entrapment efficiency, DSC, FTIR, pXRD, and TEM. In the drug release study, the formulation showed sustained release of erlotinib over 24 h in simulated lung fluid pH 7.4. This developed formulation was evaluated in zebrafish tail fin regeneration assay for its anti-angiogenetic activity. The liposomal formulation inhibited the tail fin regeneration for 14 days indicating anti-angiogenetic activity.