Melt Printing of Polymeric Drug Delivery Microdepots in 2.5D

A facile method for producing polymeric microspheres was developed via “inkjet” printing of polymer melts onto superoleophobic surfaces. Unlike conventional printing, the surface is not wetted, resulting in discrete spherical microspheres (hence 2.5D). Polycaprolactone–based microspheres were prepared with varying amounts of ibuprofen as a model drug. In vitro release studies revealed that one can control the crystal characteristics of both the excipient and the API, resulting to tunable drug–release rates. The technology was further applied towards the controlled delivery of full-spectrum cannabidiol-rich cannabis extract from printed microspheres, exhibiting in-vivo sustained release of the extract, and facilitating significant efficacy in pentylenetetrazol-induced convulsion model in mice.<br/>Microparticle–based polymeric depots are commonly applied toward the sustained release of drugs over prolonged periods, resulting, in reduction of the frequency of injecting drugs and improved pharmacokinetics. Spray-drying and solvent evaporation are the most widespread techniques for producing polymeric microspheres, but they suffer from several downsides stemming from the need of solvent removal, resulting in significant API loss, low encapsulation efficiencies, and low process yields. The use of non-wetting surfaces to produce discrete particles has been previously demonstrated using both hydrogels and polymeric monomers polymerized on the surface.<br/>Herein, we demonstrate the capacity to produce drug delivery microspheres from clinically relevant polymers using a solvent–free, cost-effective, and versatile technique to rapidly print microspheres of polymer melts using non-wetting surfaces with a specialized dispensing valve. Initially, Polycaprolactone (PCL) loaded with a model API–Ibuprofen (IBU). The unique printing process accompanied with an in-depth physical analysis, its resulting microspheres, and the technology’s potential are described hereafter. The use of melt processing to generate microspheres provides a unique opportunity to dive into the effects of the API crystallization, and the excipient crystallization on the API release, as very few studies have addressed the co-influence of the two parameters, and none have linked this with the drug–release profile. Thus, since melt microsphere manufacturing permits regulation over various processing parameters that influence the morphological structure of the resultant spheres, we explored the how the control over protean microsphere morphology, which was found to be largely influenced by the complex interplay between the crystallization behavior of the excipient and the API, resulted in the production of microspheres with differing drug–release kinetics. To further evaluate the clinical prospect of melt printing as a prospect for API encapsulation, whole medicinal cannabis extract microspheres were prepared by melt printing of anticonvulsant cannabis strand oil mixed with polycaprolactone. In vivo subcutaneous injections and pharmacokinetic analysis resulted in elevated serum levels of multiple, major and minor, phytocannabinoids for over 14 days, compared to <i>Cannabis</i> extract injection. A direct analysis of the microspheres retrieved from the injection site gives rise to an empirical model for the release kinetics of the phytocannabinoids as a function of their physical traits. Their long–term efficacy was evaluated via a single administration of the microspheres compared to a single administration of <i>Cannabis</i> extract, in a pentylenetetrazol–induced convulsion model. One week following administration, the microspheres reduce the incidence of tonic-clonic seizures by 40%, increase the survival rate by 50%, and the latency to first tonic–clonic seizures by 170%. These results suggest that a long-term full–spectrum <i>Cannabis</i> delivery system from melt–printed microspheres may provide new form of <i>Cannabis</i> administration and treatments.