Polyelectrolyte stabilized multilayered liposomes for oral delivery of paclitaxel

Paclitaxel (PTX) loaded layersome formulations were prepared using layer-by-layer assembly of the polyelectrolytes over liposomes. Stearyl amine was utilized to provide positive charge to the liposomes, which were subsequently coated with anionic polymer polyacrylic acid (PAA) followed by coating of cationic polymer polyallylamine hydrochloride (PAH). Optimization of various process variables were carried out and optimized formulation was found to have particle size of 226 ± 17.61 nm, PDI of 0.343 ± 0.070, zeta potential of +39.9 ± 3.79 mV and encapsulation efficiency of 71.91 ± 3.16%. The developed formulation was further subjected to lyophilization using a universal stepwise freeze drying cycle. The lyophilized formulation was found to be stable in simulated gastrointestinal fluids and at accelerated stability conditions. In vitro drug release studies revealed that layersome formulation was able to sustain the drug release for 24 h; release pattern being Higuchi kinetics. Furthermore, cell culture experiments showed higher uptake of layersomes from lung adenocarcinoma (A549) cell lines as compared to free drug. This was subsequently corroborated by MTT assay, which revealed IC50 value of 29.37 μg/ml for developed layersome formulation in contrast to 35.42 μg/ml for free drug. The in vivo pharmacokinetics studies revealed about 4.07 fold increase in the overall oral bioavailability of PTX as compared to that of free drug. In vivo antitumor efficacy in DMBA induced breast tumor model showed significant reduction in the tumor growth as compared to the control and comparable to that of i.v. Taxol(®). In addition, the toxicity studies were carried out to confirm the safety profile of the developed formulation and it was found to be significantly higher as compared to Taxol(®). Therefore, the developed formulation strategy can be fruitfully exploited to improve the oral deliverability of difficult-to deliver drugs.