(W1130-08-52) Development of Nano Albumin Bound (nab) Paclitaxel Using Scalable High Shear Processing Technology and Comparison of Plasma-Derived and Recombinant Human Serum Albumin

Purpose: Nab-paclitaxel is the only FDA approved formulation utilizing the nab drug delivery technology, which greatly improves the chemotherapeutic efficacy of paclitaxel compared to the solvent-based formulation with significantly reduced toxicity and severe side effects. However, manufacturing nab based nanoparticles remains as a challenge to the pharmaceutical industry. The aim of this study was to develop a manufacturing process of nab-paclitaxel formulated similar to the commercially available products. The study also investigated the applicability of plasma-derived human serum albumin (pdHSA) instead of recombinant HSA (rHSA) to produce the nab-based nanoparticles.

Methods: The nab-paclitaxel nanoparticles were prepared via an emulsion evaporation method. Paclitaxel was solubilized in a water immiscible organic solvent to form the oil phase, which was subsequently emulsified in an HSA aqueous solution using a Microfluidizer® processor. The organic solvent was then removed to allow formation of the nab-paclitaxel nanoparticles. Key formulation and process parameters such as solvent concentration, pre-mixing condition, process pressure and number of cycles were evaluated through design of experiment (DOE) based on the nanoparticle characterization via particle size, zeta potential, encapsulation efficiency and loading capacity analyses.

Results: The most important parameters that affect the final nanoparticle size, size distribution as well as peak area were identified via the coefficient plots obtained from the DOE study (Figure 1a). The information was then used to generate response contour plots to reveal the correlations between each parameter and help determine the optimum conditions (Figure 1b). Using the selected parameters, nab-paclitaxel nanoparticles were successfully produced with both pdHSA and rHSAs. Both HSAs were able to produce nab-nanoparticles within the size range of 130-140 nm (Figure 2a), which was comparable to the reported size for the marketed product. Particle size distribution, zeta potential, drug encapsulation as well as nanoparticle morphology were all very similar for both HSA sources (Figures 2b-d). Single batch replications also generated very similar results, which showed the excellent repeatability and consistency of the Microfluidizer technology (Figure 3).

Conclusion: In summary, nab-paclitaxel nanoparticles were successfully formulated and manufactured using the scalable Microfluidizer high shear technology. Optimal parameters were determined via DOE study. Both pdHSA and rHSA produced similar nab-nanoparticles with desired size, narrow size distribution, moderate colloidal stability and high encapsulation efficiency and are suitable for manufacturing nab-based nanoparticles.

Figure 1-Coefficient (a) and Response Contour (b) Plots of DOE.

Figure 2-Nab-paclitaxel Nanoparticle Size (a), Distribution (b), Encapsulation (c) and Morphology (d).

Figure 3-Nab-paclitaxel Nanoparticle Size and Distribution Repeatability for Both HSA Sources.