Improving the Oral Delivery of Carmustine Via a Self-Microemulsifying Drug Delivery System

Abstract

Objective: Carmustine (BCNU), a nitrosourea-class chemotherapeutic agent, is extensively utilized in the treatment of high-grade gliomas and brain metastases owing to its efficient penetration across the blood–brain barrier. However, its clinical utility is limited by poor aqueous solubility, rapid degradation, and a short systemic half-life, which hinder the development of effective oral formulations. This study aimed to develop a self-microemulsifying drug delivery system (SMEDDS) to enhance the oral delivery, dissolution, stability, and cytotoxic efficacy of carmustine. Methods: Olive oil, Tween 80, and PEG 400 were found to be the most effective excipients by solubility screening. Pseudo-ternary phase diagram analysis determined a Smix ratio of 2:1 as optimal for forming a stable microemulsion. Six formulations were prepared, and the optimized formulation (F3: 40% oil, 60% Smix) exhibited high drug content (92.08%), rapid emulsification (17–42 s), uniform droplet size (194.29 nm), low polydispersity index (0.263), and highly negative zeta potential (−38.61 mV). Transmission electron microscopy confirmed the presence of spherical nanosized droplets. Results: In vitro dissolution studies in 0.1 N HCl demonstrated rapid, near-complete drug release (>99% within 20 min), compared with negligible release from the pure drug (<20%). The physical appearance, emulsification time, droplet size, zeta potential, and dissolution profiles changed slightly during the course of six months of stability testing in a refrigerator (f₂>50). Additionally, the optimized SMEDDS demonstrated much higher cytotoxicity against U87-MG glioma cells, with an IC50 of 1.1875 µg/ml, compared with 160.95 µg/ml for the pure drug. Conclusion: These findings show that the proposed SMEDDS improves dissolution and in vitro antitumor efficacy while effectively overcoming solubility and stability limitations.