<p>Etoposide Amorphous Nanopowder for Improved Oral Bioavailability: Formulation Development, Optimization, in vitro and in vivo Evaluation</p>

Abstract

Introduction: Etoposide refers to a derivative of podophyllotoxin, which plays an important role in the treatment of cancer due to its prominent anti-tumor effect. As a BCS IV drug, etoposide exhibits insufficient aqueous solubility and permeability, thereby limiting its oral absorption. To enhance the oral bioavailability of etoposide, this study developed an amorphous nanopowder. Methods: Based on preliminary screening and experimental design, the stabilizer and preparation process of etoposide nanosuspension were explored. Subsequently, using a Box-Behnken design, the effects of independent factors (ultrasonication time, ratio of two phases and stabilizer concentration) on response variables (particle size and polydispersity index) were studied, and then the formulation was optimized. Finally, nanosuspension was further freeze dried with 1% of mannitol resulting in the formation of etoposide amorphous nanopowder. Results: The optimized etoposide nanopowder showed as spherical particles with an average particle size and polydispersity index of 211.7 ± 10.4 nm and 0.125 ± 0.028. X-ray powder diffraction and differential scanning calorimetry confirmed the ETO in the nanopowder was amorphous. Compared with coarse powder and physical mixture, etoposide nanopowder achieved significantly enhanced saturated solubility and dissolution in various pH environments. The C max and AUC 0-t of etoposide nanopowder after oral administration in rats were respectively 2.21 and 2.13 times higher than the crude etoposide suspension. Additionally, the T max value of nanopowder was 0.25 h, compared with 0.5 h of reference group. Discussion: In the present study, the optimized amorphous nanopowder could significantly facilitate the dissolution and oral absorption of etoposide and might act as an effective delivery method to enhance its oral bioavailability.

Podophyllotoxin Exposure Affects Organelle Distribution and Functions in Mouse Oocyte Meiosis

“…For example, the epimer of POD can result in esophageal squamous cell carcinoma apoptosis by ER stress and increased ROS level ( Kwak et al, 2020 ). Etoposide, a semisynthetic POD derivative, causes focally extensive dilation of the rough ER in the ganglion cell bodies of female CD-1 mice ( Bregman et al, 1994 ; Wang et al, 2020 ). Moreover, Ching001 is the structural analog of POD, which partly induces apoptosis via the activation of the ER stress signaling pathway, showing with increased expression of p-PREK, p-eIF2α, p-JNK, GADD153, and caspase-4 ( Chen et al, 2013 ).…”

Nanocrystal-Loaded Lipid Carriers for Improved Oral Absorption and Anticancer Efficacy of Etoposide: Formulation Development, Transport Mechanism, In Vitro and In Vivo Evaluation

“…ETO-NCs were prepared by the sonoprecipitation-high pressure homogenization method. 1 Briefly, 100 mg of crude etoposide was completely dissolved in 0.5 mL of DMSO. Through sonication (SCIENTZ-IID ultrasonic processor, Scientz Biotechnology Co., Ltd., Ningbo, China), the ETO solution was rapidly added to the aqueous solution containing 0.05% (w/v) CTAB as the stabilizer to obtain the starting ETO suspensions.…”

“…Etoposide concentration in rat plasma was determined by UPLC/MS/MS. 1 2.9. In Vivo Antitumor Effect.…”

“…Due to its significant antitumor properties, it has been approved for the treatment of various cancers, such as small-cell lung cancer. However, ETO belongs to BCS-IV drugs, which limits its oral absorption due to insufficient water solubility and permeability . Nanocrystals (NCs) have become an effective tool for improving the oral absorption of insoluble drugs due to their small particle size and high drug loading capacity.…”

High-Payload Nanosuspension of Centella asiatica Extract for Improved Skin Delivery with No Irritation

“…20 Recently, drug nanocrystal suspension (NS) has been in the spotlight as a promising topical as well as transdermal delivery system for lipophilic pharmaceuticals and cosmetic substances. [21][22][23] Drug nanocrystals are colloidal dispersions of sub-micronized drug particles stabilized using minimal polymeric or amphiphilic stabilizers in a continuous phase. 24,25 A decrease in particle size leads to an increase in surface area, which is favorable for the adhesion of drug particles to biological membranes.…”