Enhancing Cannabidiol Apparent Solubility and Oral Delivery: Self-assembled Nanomicelles of Amphiphilic Block Copolymer with γ-Polyglutamic Acid-grafted Cholesterol.

Purpose: Cannabidiol (CBD) exhibits antiepileptic, anticonvulsant, and anticancer effects. However, its clinical value is limited by poor oral absorption, low water solubility, and poor stability. Therefore, this study aimed to prepare a novel nanomicelles (NMs) to improve the above aspects of CBD.

Methods: The amphiphilic polymer was synthesized by selecting γ -polyglutamic acid (γ-PGA) and cholesterol (CHOL) as hydrophilic and hydrophobic materials respectively. The optimal preparation process for CBD/(γ-PGA-g-CHOL) NMs was obtained through single-factor and orthogonal tests. The particle size, potential, stability, morphology, apparent solubility and in vitro drug release behavior of the drug-loaded NMs were characterized. Cytotoxicity, uptake and transport experiments on Caco-2 cells and in vivo pharmacokinetics studies in rats were performed for in vitro and in vivo oral absorption of the drugs.

Results: The optimal parameters were a dosage of 2 mg, blank NM concentration of 5 mg/mL, an organic/aqueous ratio of 1:5, and a stirring time of 6 h. The NMs showed pH-sensitive release behavior, with particle size 163.1 ± 2.3 nm, zeta potential -16.5 ± 1.7 mV, encapsulation rate 84.46% ± 0.35%, and drug loading 8.78% ± 0.28%. They were spherical by SEM, stable at 25 ℃ and 37 ℃, and their apparent solubility increased 424-fold. The NMs were biocompatible and improved CBD absorption in uptake/transport tests. Orally administered NMs showed lower apparent clearance value (CL/F), and higher C_max and AUC than those in the free CBD group.

Conclusions: These findings reveal potential of the delivery system, γ-PGA-g-CHOL NMs, to improve the stability of CBD and enhance its apparent solubility and systemic exposure.