β-Caryophyllene nanoparticles design and development: Controlled drug delivery of cannabinoid CB2 agonist as a strategic tool towards neurodegeneration.

The sesquiterpene β-caryophyllene (BCP) is a structurally singular cannabinoid and a selective agonist of the CB2 receptor, which in addition to being expressed in the CNS, is intrinsically expressed within the immune system and lacks psychoactivity. Nanoencapsulation of BCP can allow its controlled release into the CNS and intranasal administration. Thus, a protocol for nanoencapsulation of BCP was developed and optimized in order to adjust the desired bioactive content and physicochemical parameters. The formulation was assessed regarding nanoparticle size, zeta potential, morphology, pH, osmolarity, stability, and drug release kinetics in vitro. The final composition of the BCP nanoparticles presented in its organic phase (OP) Tween 20 (0.25%), BCP (0.1%), and PEG 400 (5%); and in its aqueous phase (AP) ultrapure water and poloxamer P188 (0.25%). The formulation showed to be suitable for intranasal administration, presenting pH 6.5 and osmolarity of 150 mmol/kg. The mean particle diameter was 147.2 nm, PDI 0.052, and zeta potential of -24.5. The accelerated stability test showed that nanoparticles were stable for up to 1 month, when reversible creaming effect occurred. Besides, it was noted a low rate of particle accumulation and particle size distribution remained unchanged. BCP nanoparticles were shown to be promptly released in physiological medium (up to 60 min). In this work, a formulation containing β-caryophyllene nanoparticles suitable for physiological administration and preclinical tests was successfully developed.