Biologics Delivery by inverse Flash NanoPrecipitation: Scalable Routes to Highly Loaded Particles

C. Markwalter, R. Pagels, R. Prud'homme
Princeton University,
United States

Keywords: nanoparticles, microparticles, peptide, protein, drug delivery, controlled release

Summary:

There is a vast unmet need for new approaches to administer the broad array of peptide and protein therapeutics being developed by the pharmaceutical industry. Such “biologics” exhibit many clinical benefits but face barriers to success; chief among them is a typically rapid clearance from the blood stream following IV administration. This means that frequent injections are often required to achieve efficacy, an unappealing prospect for many patients. While chemical modification of the biologic can improve circulation time, this can be a detriment to therapeutic activity. (Mitragotri, 2014) Encapsulation in particulate forms such as nanoparticles or microspheres can protect the biologic from bodily clearance mechanisms while slowly releasing the therapeutic. This controlled release process can lead to reduced injection frequency. However, there are limited techniques to produce these formulations that are universal, scalable, and economical. One solution is inverse Flash NanoPrecipitation. (Pagels, 2015) Inverse Flash NanoPrecipitation (iFNP) relies on a rapid mixing process in special geometries to produce nanoparticles that contain a biologic in an aqueous core and are stabilized by a hydrophobic polymer brush. These nanoparticles are dispersed in an organic solvent and can then be processed into highly loaded microspheres or coated with PEG to form long-circulating nanoparticles. The microspheres are comprised entirely of the nanoparticles, and are assemble through a nanoparticle-in-oil-in-water emulsion. The coated nanoparticle structure consists of a crosslinked hydrophilic polymer core, a hydrophobic polymer shell, and a PEG coating. The iFNP process is universal because it does not rely on specific interactions between the biologic and the formulation excipients. As a continuous process, iFNP can easily be scaled by running the process for longer time periods. The process is economical because it achieves high loadings and encapsulation efficiencies, resulting in less waste of the therapeutic and lower total mass per dose. Coated nanoparticles produced using lysozyme were relatively monodisperse and exhibited controlled, responsive release. Process modifications can tune the rate of release of the biologic, which is dependent on charge interactions and degradation of the hydrophobic layer. Encapsulation efficiency of over 50% at loadings of 30% were possible. Microspheres formed from nanoparticles containing a therapeutic peptide supplied by a pharmaceutical company had encapsulation efficiencies of 95% and higher, with loadings up to 50%. The polymer coating on each individual nanoparticle results in very low process losses and highly tunable release. These results represent true innovation in this field, with typical loadings an order of magnitude smaller for alternative approaches.