Abstract
Despite the efficacy and potential therapeutic benefits that poly(lactic-co-glycolic acid) (PLGA) nanomedicine formulations can offer, challenges related to large-scale processing hamper their clinical and commercial development. Major hurdles for the launch of a polymeric nanocarrier product on the market are batch-to-batch variations and lack of product consistency in scale-up manufacturing. Therefore, a scalable and robust manufacturing technique that allows for the transfer of nanomedicine production from the benchtop to an industrial scale is highly desirable. Downstream processes for purification, concentration, and storage of the nanomedicine formulations are equally indispensable. Here, we develop an inline sonication process for the production of polymeric PLGA nanomedicines at the industrial scale. The process and formulation parameters are optimized to obtain PLGA nanoparticles with a mean diameter of 150 ± 50 nm and a small polydispersity index (PDI < 0.2). Downstream processes based on tangential flow filtration (TFF) technology and lyophilization for the washing, concentration, and storage of formulations are also established and discussed. Using the developed manufacturing and downstream processing technologies, production of two PLGA nanoformulations encasing ritonavir and celecoxib was achieved at 84 g/h rate. As a measure of actual drug content, encapsulation efficiencies of 49.5 ± 3.2% and 80.3 ± 0.9% were achieved for ritonavir and celecoxib, respectively. When operated in-series, inline sonication and TFF can be adapted for fully continuous, industrial-scale processing of PLGA-based nanomedicines.
Highlights
Polymeric nanoparticles composed of biodegradable and biocompatible polymers such as poly(lactic-co-glycolic acid) (PLGA) display a promising future for various biomedical and pharmaceutical applications
We developed PLGA nanoparticle manufacturing and downstream processes suitable for industrial scale-up
A Spectrum hollow fiber filter of the MidiKros module family based on modified polyethersulfone material was chosen with a molecular weight cut-off (MWCO) of 750 kDa, fiber ID of 0.5 mm, and 20 cm effective length (D02-E750-05-N)
Summary
Polymeric nanoparticles composed of biodegradable and biocompatible polymers such as poly(lactic-co-glycolic acid) (PLGA) display a promising future for various biomedical and pharmaceutical applications. Based on the preparation method, various impurities that can be toxic are present in the final product [11] These impurities may include organic processing solvents such as dichloromethane (DCM) and dimethyl sulfoxide (DMSO), emulsifiers and stabilizers, monomeric residues, free unbound payloads, and salts. Lab-scale purification of nanoparticles is usually achieved by centrifugation, extraction, or filtration-based techniques Most of these traditional techniques are time-consuming and often lack reproducibility, which can make these processes relatively inefficient [1,11]. As a continuous and gentle process that can significantly reduce membrane clogging compared to other traditional filtration methods, TFF is suitable for downstream processing of nanoparticles at the industrial level [1]. We developed PLGA nanoparticle manufacturing and downstream processes suitable for industrial scale-up. The main reasons for the choice of these substances for large-scale experiments are the low toxicity of the compounds that are to be used in large quantities and their common availability
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