QbD aided development of ibrutinib-loaded nanostructured lipid carriers aimed for lymphatic targeting: evaluation using chylomicron flow blocking approach

Ibrutinib (IBR) is the choice of drug for the treatment of chronic lymphocytic leukaemia (CLL) and mantle cell lymphoma (MCL). IBR has low oral bioavailability of 2.9% owing to its high first pass metabolism. Present study was aimed to develop the nanostructured lipid carriers (NLC) using glyceryl monostearate (GMS) as solid lipid and Capryol™ PGMC as liquid lipid. Plackett-Burman design (PBD) was applied to screen the significant factors; furthermore, these significant factors were subjected to optimisation using Central Composite design (CCD).

The size, poly dispersity index (PDI) and entrapment efficiency (E.E.) of the developed NLC were 106.4 ± 8.66 nm, 0.272 ± 0.005 and 70.54 ± 5.52% respectively. Morphological evaluation using transmission electron microscope (TEM) and field emission scanning electron microscope (FESEM) revealed spherical particles. Furthermore, differential scanning calorimetry (DSC) indicates the formation of molecular dispersion of drug in the melted lipid matrix while Powder X-Ray Diffraction (PXRD) studies reveal the absence of crystalline drug peaks in the formulation diffractogram. In-vivo pharmacokinetics of NLC displayed an increase in C_max (2.89-fold), AUC_0-t (5.32-fold) and mean residence time (MRT) (1.82-fold) compared with free drug.

Furthermore, lymphatic uptake was evaluated by chylomicron flow blocking approach using cycloheximide (CXI). The pharmacokinetic parameters C_max, AUC_0-t and MRT of NLC without CXI were 2.75, 3.57 and 1.30 folds higher compared with NLC with CXI. The difference in PK parameters without CXI indicates significant lymphatic uptake of the formulation. Hence, NLC can be a promising approach to enhance the oral bioavailability of drugs with high first-pass metabolism.

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Article Information: Nagarjun Rangaraj, Sravanthi Reddy Pailla, Saurabh Shah, Shubham Prajapati & Sunitha Sampathi; Drug Delivery and Translational Research, 2020.