PLGA-based nanomedicines manufacturing: Technologies overview and challenges in industrial scale-up

Nanomedicines based on poly(lactic-co-glycolic acid) (PLGA) carriers offer tremendous opportunities for biomedical research. Although several PLGA-based systems have already been approved by both the Food and Drug Administration (FDA) and the European Medicine Agency (EMA), and are widely used in the clinics for the treatment or diagnosis of diseases, no PLGA nanomedicine formulation is currently available on the global market.

One of the most impeding barriers is the development of a manufacturing technique that allows for the transfer of nanomedicine production from the laboratory to an industrial scale with proper characterization and quality control methods.

This review provides a comprehensive overview of the technologies currently available for the manufacturing and analysis of polymeric nanomedicines based on PLGA nanoparticles, the scale-up challenges that hinder their industrial applicability, and the issues associated with their successful translation into clinical practice.

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Introduction

Nanotechnology is among the most promising Key Enabling Technologies (KETs) that can provide innovative and radical solutions to the unmet needs of society (Soares et al., 2018, Tinkle et al., 2014). Today, nanotechnology touches every aspect of human life, including medicine, giving rise to one of the most important emerging areas of medical health research: nanomedicine (European-Commission, 2020). Nanomedicine involves the use of nanomaterials and nanotechnologies to address challenges in diagnosis, monitoring, control, prevention and treatment of diseases (Agrahari and Hiremath, 2017, Patra et al., 2018, Soares et al., 2018, Tinkle et al., 2014). Nanomedicines formulated as drug delivery systems typically involve active pharmaceutical ingredients that are either encapsulated within or conjugated to nano-size carrier matrices (Murthy, 2007). The carrier material can be based on inorganic (e.g., metal nanoparticles, semi-conductor quantum dots of various sizes and shapes (Biju et al., 2008, Tagit et al., 2015, Tagit et al., 2017, Tagit et al., 2011)) or organic nanostructures, including (and not limited to) polymers (Kumari et al., 2010), dendrimers (Gillies and Frechet, 2005), micelles (Kataoka et al., 2012), liposomes (Alavi et al., 2017), solid lipid nanoparticles (Mukherjee et al., 2009) and polymer-active pharmaceutical ingredient (API) conjugates (Larson and Ghandehari, 2012). These nanomedicines are finely engineered at the nanoscale to introduce various benefits such as protection of therapeutic agents from degradation, increased solubility and bioavailability, improved pharmacokinetics, reduced toxicity, enhanced therapeutic efficacy, decreased API immunogenicity, targeted delivery, and simultaneous diagnostics and treatment options with a single system (Agrahari and Hiremath, 2017, Patra et al., 2018).

To achieve the desired therapeutic efficacy, the nanocarrier should: i) hold the API firmly during transport in the blood compartments, but ii) be able to effectively release the API once it has reached the desired target to exert its pharmaceutical action. In addition, the transporter should iii) be “stealthy” in the blood compartments to effectively evade reticuloendothelial system (RES) screening, but iv) make contact and penetrate the right cells at the target action site (Sun et al., 2012). In this regard, nanocarriers based on poly(lactic-co-glycolic acid) (PLGA) offer tremendous opportunities in terms of design and performance thanks to the various properties of PLGA that make it an ideal nanocarrier (Han et al., 2016, Makadia and Siegel, 2011, Singh et al., 2014). PLGA is a biodegradable and biocompatible polymer with a wide range of degradation times that can be tuned by its molecular weight and copolymer ratio. PLGA is soluble in common solvents including acetone, chlorinated solvents and ethyl acetate, can be processed into almost any shape and size, and can encapsulate molecules of virtually any size (Gentile et al., 2014, Makadia and Siegel, 2011, Södergård and Stolt, 2002). Thus, PLGA polymers have been largely tested as delivery vehicles for drugs, proteins and various other macromolecules such as DNA, RNA and peptides (Jain, 2000, Makadia and Siegel, 2011). In addition to chemical composition and molecular weight of the polymer, the physical properties of the PLGA nanocarrier, such as size, shape, surface area-to-volume ratio, etc., can be ‘tuned’ to obtain the desired release profile (Gentile et al., 2014, Makadia and Siegel, 2011).

With its excellent biocompatibility, tunable degradation and release characteristics, and high versatility, PLGA has been approved for several biomedical applications. In fact, albeit not nano, over 60 PLGA-based drug products with varying properties (i.e., size, shape, etc.) are currently available on the market. Some of the best known PLGA formulations are based on microparticle depot preparations such as Decapeptyl® (the first drug product on the market, based on triptorelin), Lupron Depot® (leuprolide acetate), Nutropin Depot® (somatropin), Suprecur® MP (buserelin acetate), Sandostatin® LAR Depot (octreotide acetate), Somatuline® LA (lanreotide acetate), Trelstar™ Depot (triptorelin pamoate), Vivitrol® (naltrexone) and Risperdal® Consta™ (risperidone). In addition, PLGA-based implants (e.g., Zoladex®, Ozurdex®, Profact® Depot, Durysta™, etc. based on goserelin acetate, dexamethasone, buserelin and bimatoprost, respectively) and even in situ forming implants based on Atrigel® system, i.e. Eligard® (leuprolide acetate), are available (Schwendeman et al., 2014). The already substantial presence of PLGA-based products on the market indicates a promising future also for PLGA-based nanomedicine formulations.