Response Surface Methodology-Guided Development of Hot-Melt-Extruded Cannabidiol Solid Self-Emulsifying Drug Delivery Systems for Enhanced Drug Release and Stability.

Sanil K.; Deshmukh J.; Ashour E. · Pharmaceutics · 2026

**Background & Methods** This is a formulation development study using Response Surface Methodology (RSM) and Central Composite Design to optimize cannabidiol (CBD)-loaded solid self-emulsifying drug delivery systems (S-SEDDSs) processed via hot-melt extrusion (HME). The research evaluated independent variables including oil concentration and surfactant-co-surfactant ratios to identify optimal parameters for enhanced drug release and stability of this lipophilic compound. **Key Findings** • The optimized CBD S-SEDDS formulation achieved 98.15 ± 1.94% drug content and demonstrated 76.6 ± 0.6% in vitro drug release within three hours, representing a 2.7-fold improvement compared to 28 ± 0.9% for pure CBD alone. • The lead formulation demonstrated minimal degradation during stability testing at both 25°C and 40°C storage conditions, indicating robust pharmaceutical stability profile. • RSM-guided formulation optimization combined with HME processing successfully enhanced the solubility and bioavailability potential of CBD, addressing the inherent challenges of this highly lipophilic compound's poor aqueous solubility and extensive first-pass metabolism. **Dosage & Administration** Not reported. This is a preclinical formulation development study without clinical dosing information. **Safety & Adverse Effects** Not reported. The study focused on pharmaceutical development parameters rather than clinical safety assessment or adverse effect monitoring in subjects. **Evidence Quality** This is a formulation optimization study with significant limitations regarding clinical translation. As a laboratory-based pharmaceutical development work, it lacks human clinical data, pharmacokinetic studies, and safety assessments necessary to evaluate therapeutic efficacy or adverse effects. The research represents early-stage preclinical evidence (low-to-moderate quality) demonstrating proof-of-concept for improved CBD delivery through SEDDS technology. While the RSM-guided approach and HME processing are scientifically sound methodologies for formulation optimization, results are limited to in vitro dissolution and accelerated stability testing. Clinical relevance remains unknown without human bioavailability studies, pharmacodynamic assessment, and safety evaluation in relevant patient populations. The study provides valuable pharmaceutical technology development but cannot yet support clinical recommendations for CBD delivery in pain, inflammation, anxiety, schizophrenia, or epilepsy management.

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