(T0930-06-37) Developing Lipid Based Nano Drug Delivery System (LBNDDS) of Osimertinib in Combination with Curcumin Using Design of Experiment (DoE) for Enhanced Permeability and Release Effect

Purpose: Osimertinib (OSM), a BCS class III drug, is known to exhibit low permeability [1]. Therefore, the aim of this study was to develop a lipid-based nano drug delivery system (LBNDDS) of OSM in combination with curcumin (CUR) to enhance the permeability and release of Osimertinib.

Methods: The lipid-based nano drug delivery system (LBNDDS) of OSM and CUR was prepared using ethanol injection method. A full factorial design of experiment (DoE) [3factors at 2 levels] was used to evaluate the impact of the process parameters (stirring time) and material attributes (drug and type of stabilizer) on average particle size and entrapment efficiency (EE%) of OSM and CUR nano-preparation using dynamic light scattering (DLS) and UV-spectrophotometry. The in-vitro drug release, and ex-vivo drug permeability was evaluated using dialysis membrane, and Franz diffusion cell respectively.

Results: DLS data showed that the average particle size of LBNDDS batches ranged from 175 nm to 1200 nm. LBNDDS batches of OSM showed entrapment efficiency (EE%) in the range of 65% to 93%. However, a high EE% of OSM was observed when prepared in combination with curcumin ( >90%) (Table 1). Results suggest that the lowest average particle size and highest entrapment efficiency (EE%) was achieved for the batches prepared using tween 80 stirred for 10 minutes (TBO14, size: 176.2 ± 2.6 nm, EE: 86 ± 0.35% and ComTB1, size: 207.3 ± 2.1 nm, EE: 93 ± 0.23%). In vitro drug release study indicates that the LBNDDS batches show higher release than the raw suspension batches. The LBNDDS batch of combined drug (ComTB1) shows a 2-fold higher release of OSM than raw suspension batch of combined drug (ComTB1: 83.3 ± 0.52% and raw OSM in combination: 36.9 ± 0.66%). The OSM only LBNDDS batch (TBO14) shows a ~5-fold higher release of OSM than raw OSM suspension batch (TBO14: 79.8 ± 0.74% and raw OSM: 16 ± 1.02%). Results also suggest that between the two LBNDDS batches (ComTB1 and TBO14), the LBNDDS batch of combined drug (ComTB1: 83.3 ± 0.52%) shows better release of OSM than the OSM only LBNDDS batch (TBO14: 79.8 ± 0.74%) even at a lower concentration of OSM in the combined drug preparation (ComTB1: 0.25mg/mL, TBO14: 0.5mg/mL). The study also exhibits that the raw suspension of combined drug shows a 2-fold higher release of OSM than the raw suspension of OSM only batch even at a low drug concentration (raw OSM in combination: 0.25mg/mL and raw OSM: 0.5mg/mL) (Figure 1a). Ex-vivo permeability study shows that the LBNDDS batches show higher drug permeability than the raw suspension batches. The LBNDDS batch of combined drug (ComTB1) shows a 2-fold higher drug permeability than raw suspension of the combined drug (ComTB1: 0.229 ± 0.0015 mg/mL and raw OSM in combination: 0.102 ± 0.003 mg/mL). The OSM only LBNDDS batch (TBO14) exhibited an 8-fold higher drug permeability than raw OSM suspension batch (TBO14: 0.227 ± 0.0015 mg/mL and raw OSM: 0.027 ± 0.004 mg/mL). Results suggest that between the two LBNDDS batches (ComTB1 and TBO14), there is no significant differences in permeability even at lower drug concentration in LBNDDS batch of combined drug (ComTB1: 0.25mg/mL and TBO14: 0.5mg/mL). The study also indicates that the raw suspension of combined drug shows a 3-fold higher drug permeability of OSM than the raw suspension of only OSM even at a low drug concentration (raw OSM in combination: 0.25mg/mL and raw OSM: 0.5mg/mL) (Figure 1b).

Conclusion: DLS results of LBNDDS batches prepared using ethanol injection method showed particle size ~200 nm and EE% > 90% with tween 80 as stabilizer. The in-vitro and ex-vivo studies suggest that the optimized LBNDDS batches have higher release (ComTB1: 2-fold and TBO14: ~5-fold) and permeability (ComTB1: 2-fold and TBO14: 8-fold) compared to both the raw suspensions. The LBNDDS batch of combined drug has better release and permeability profile even at low drug concentration (0.25mg/mL) compared to that of OSM only LBNDDS batch (0.5mg/mL) which may be due to the use of curcumin which has anti-inflammatory and anti-microbial properties in the combined drug therapy [2]. Further in-vitro cell line studies will be conducted to determine the anti-cancer activity of the optimized LBNDDS batches.

References: 1. K R. Formulation, Optimization and Evaluation of Osimertinib Tablets. J of Chem and Pharm Res. 2019;11(4):1–13.
2. Pandit AP, Joshi SR, Dalal PS, Patole VC. Curcumin as a permeability enhancer enhanced the antihyperlipidemic activity of dietary green tea extract. BMC Complement Altern Med. 2019 Jun 13;19(1):129. doi: 10.1186/s12906-019-2545-1.


Table 1. Average particle size (nm), and Entrapment Efficiency (EE%) of LBNDDS batches prepared using DoE (Mean ± SD, where n = 3).


Figure 1. (a) In-vitro drug release and (b) ex-vivo drug permeability study for the optimized LBNDDS batches and their raw suspension (Mean ± SEM, where n = 3)