Design and optimization of DPC-crosslinked HPβCD nanosponges for entrectinib oral delivery: formulation, characterization, and pharmacokinetic studies

• Published in: Future journal of pharmaceutical sciences Vol. 10; no. 1; pp. 101 - 15
• Main Authors: Reddy, Konda Sri Chaya, Bhikshapathi, Darna
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 14.08.2024; Springer Nature B.V; SpringerOpen
• Subjects: Bioavailability; Box–Behnken design; Chromatography; Cross-linker; Diphenyl carbonate; Drug delivery systems; Drug dosages; Entrectinib; Fourier transforms; Hydroxypropyl-β-cyclodextrin; Kinases; Lung cancer; Medicine; Medicine & Public Health; Particle size; Pediatrics; Pharmacokinetics; Scanning electron microscopy; Side effects; Solubility; Spectrum analysis; Tumors; United States > US; Box–Behnken design; Quality by design; Cross-linker; Diphenyl carbonate; Solubility; Entrectinib; Hydroxypropyl-β-cyclodextrin
• ISSN: 2314-7245; 2314-7253
• DOI: 10.1186/s43094-024-00680-8

Background In advanced or metastatic cancers characterized by specific genetic alterations, heightened growth and resistance to conventional therapies are common. Targeted treatments like entrectinib (ENT) precisely inhibit aberrant signaling pathways, potentially enhancing outcomes. The objective of this research is to develop and enhance the effectiveness of entrectinib-loaded nanosponge formulations by utilizing hydroxypropyl-β-cyclodextrin (HPβCD) to improve its oral bioavailability. Results The study employed surface response methodology and Design-Expert® software to optimize key formulation variables such as the molar concentration ratio of the polymer and cross-linker, as well as process variables such as stirring speed and duration. Optimization focused on particle size, polydispersity index, and percentage entrapment efficiency. Validation methods encompassed Fourier transform spectroscopy (FTIR), differential scanning calorimetry (DSC), scanning electron microscopy (SEM), in vitro release studies, and in vivo studies. After optimization, ENT-loaded HPβCD NSPs were formulated with a molar ratio (P:CL) of 0.800 mg, stirred at 3000 rpm for 420 min, achieving a desirability of 0.926. Predicted values for PS (particle size), PdI (polydispersity index), and EE % (entrapment efficiency) were 146.98 nm, 0.263, and 88.29%, respectively. The optimized formulation showed a mean size of 151.8 ± 5.6 nm, PDI of 0.233 ± 0.049, and EE of 87.36 ± 1.61%. Further validation through various analyses confirmed the optimization's efficacy, with notable improvements demonstrated in AUC0-t (6.30-fold) and Cmax (4.10 times) compared to the free drug. Conclusion The findings of the study indicated that nanosponges exhibit promise as an effective carrier for delivering entrectinib, addressing for advance tumor effectively by enhancing release and bioavailability in the treatment of cancer. Highlights Entrectinib (ENT) is an innovative and powerful inhibitor targeting specific genetic alterations in advanced or metastatic cancers. Preclinical investigations have shown strong suppression of receptor tyrosine kinases, such as TRKA/B/C and ROS1, at nanomolar (nM) concentrations using ENT. ENT is categorized under the Biopharmaceutical Classification Systems (BCS) II, with poor solubility and inadequate oral bioavailability. Formulation of ENT HPβCD based nanosponges (NSPs) present a compelling option for drug delivery due to their sustained drug release, enhanced stability, and significant carrying capacity.