(616b) Increasing the Hydrophobicity of Biologic Active Pharmaceutical Ingredients By Generating Insoluble Salt Forms to Enable Continuous Nanoprecipitation and Encapsulation

Pulmonary delivery of antibiotics that are effective against
Pseudomonas aeruginosa in patients
with cystic fibrosis is limited due to the presence of a thick layer of
pulmonary mucus, through which antibiotic diffusion is severely hindered.
Mucus-penetrating nanoparticles (NPs) offer a promising delivery vehicle for
such antibiotics, as the NPs’ diffusivity in mucosal layers is significantly
faster than that of the antibiotics. However, the majority of nanofabrication
processes are batch processes, which present issues in scalability. We have
previously shown that polyethylene glycol (PEG)-surface-coated nanoparticles
(NPs) made via Flash NanoPrecipitation (FNP), a block-copolymer directed
self-assembly technique, can penetrate pulmonary mucus. Significantly, FNP is a
continuous nanofabrication technique, which offers advantages in scalability
over traditional batch processes. In order to encapsulate a hydrophilic
antibiotic within NPs via FNP, we employ hydrophobic ion-pairing to increase
the drug’s hydrophobicity temporarily and make it more suitable for the
precipitation process. Sixteen ion-pairing reagents (IPs) were screened and
used to successfully encapsulate a variety of hydrophilic compounds and
proteins, such as gentamicin, polymyxin, and
lysozyme, into mucus-penetrating PEG-coated NPs. In addition, IP compositions
were varied to tune both drug encapsulation efficiencies (> 95%) and drug
release rates (up to 7 days). Thus, the mucus-penetrating nanodelivery
system developed herein offers new options for managing Pseudomonas aeruginosa pulmonary infections in patients with cystic
fibrosis. 

Schematic of Flash NanoPrecipitation used to simultaneously
ion-pair a hydrophilic active pharmaceutical ingredient and encapsulate it into
a nanoparticle.

Release rates of polymyxin NPs.
Fraction of polymyxin B released over time when using
1:1 API to IP charge ratio for various IPs.