Cyclosporin A (CyA) is a good candidate for incorporation in colloidal carriers such as nanoparticles (NP) that would diminish the adverse effects associated with its use under conventional pharmaceutical dosage forms and improve bioavailability after oral administration. In this study a composite rotational experimental design was used to evaluate the joint influence of five formulation variables: temperature of the aqueous phase, needle gauge, volume of the organic phase, and the amounts of polymer and surfactant on the micromeritic characteristics of the CyA-loaded NP obtained by the method of Fessi et al. The percentage of drug encapsulated in the NP was also evaluated for each formulation, and the yield, which was expressed as the ratio between the experimentally measured quantity of drug in the formulation and the theoretical content, was determined because CyA undergoes surface absorption. Potential variables such as stirring speed (500 rpm), final drug concentration (100 micrograms/mL), or injection rates (GRi = 0.379 mL/s) were maintained constant. The ANOVA corresponding to the experimental design showed that the amounts of polymer and surfactant, and the diameter of the needle used in the preparation of NP, significantly affected the percentage of entrapped drug (I2 = 0.8916). The mean particle size was significantly affected by all the formulation variables tested except for the amount of surfactant dissolved in the external aqueous phase (r2 = 0.9518). Neither the yield (mean value of 99.61%) nor the size distribution parameters (polydispersity and coefficient of variation) presented good correlation coefficients for the equations obtained, although some variables showed statistical significance. A second study was carried out to investigate the effects on the drug-loaded NP characteristics of varying the global injection rates (GRi) for the organic phase into the aqueous medium. The results showed a dramatic decrease in both particle size and drug incorporation in the carrier as the rate of mixing increased. From the results of both the experimental design and the second study, a theoretical model for nanoparticle formation is proposed that considers the most significant variables, and an empirical relationship to predict mean particle size is presented. Thus, particle size can be controlled by the injection rates (GRi), the needle gauge, and the polymer concentration.

Cannabinoids, the active components of marijuana and their derivatives, are currently investigated due to their potential therapeutic application for the management of many different diseases, including cancer. Specifically, Δ⁹-Tetrahydrocannabinol (THC) and Cannabidiol (CBD) – the two major ingredients of marijuana – have been shown to inhibit tumor growth in a number of animal models of cancer, including glioma. Although there are several pharmaceutical preparations that permit the oral administration of THC or its analogue nabilone or the oromucosal delivery of a THC- and CBD-enriched cannabis extract, the systemic administration of cannabinoids has several limitations in part derived from the high lipophilicity exhibited by these compounds. In this work we analyzed CBD- and THC-loaded poly-ε-caprolactone microparticles as an alternative delivery system for long-term cannabinoid administration in a murine xenograft model of glioma. In vitro characterization of THC- and CBD-loaded microparticles showed that this method of microencapsulation facilitates a sustained release of the two cannabinoids for several days. Local administration of THC-, CBD- or a mixture (1∶1 w:w) of THC- and CBD-loaded microparticles every 5 days to mice bearing glioma xenografts reduced tumour growth with the same efficacy than a daily local administration of the equivalent amount of those cannabinoids in solution. Moreover, treatment with cannabinoid-loaded microparticles enhanced apoptosis and decreased cell proliferation and angiogenesis in these tumours. Our findings support that THC- and CBD-loaded microparticles could be used as an alternative method of cannabinoid delivery in anticancer therapies.