International Journal of Pharmaceutics 498 (2016) 82–95 Contents lists available at ScienceDirect International Journal of Pharmaceutics journa l homepage: www.elsevier.com/locate/ijpharm Review Design of PLGA-based depot delivery systems for biopharmaceuticals prepared by spray drying a a,b, Feng Wan , Mingshi Yang * a Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen Ø, Denmark b Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, 110016, China A R T I C L E I N F O A B S T R A C T Article history: Currently, most of the approved protein and peptide-based medicines are delivered via conventional Received 15 September 2015 parenteral injection (intramuscular, subcutaneous or intravenous). A frequent dosing regimen is often Received in revised form 4 December 2015 necessary because of their short plasma half-lives, causing poor patient compliance (e.g. pain, abscess, Accepted 9 December 2015 etc.), side effects owing to typical peak-valley plasma concentration time profiles, and increased costs. Available online 11 December 2015 Among many sustained-release formulations poly lactic-co-glycolic acid (PLGA)-based depot micropar- ticle systems may represent one of the most promising approaches to provide protein and peptide drugs Keywords: with a steady pharmacokinetic/pharmacodynamic profile maintained for a long period. However, the Spray drying development of PLGA-based microparticle systems is still impeded by lack of easy, fast, effective Microencapsulation manufacturing technologies. The aim of this paper is to review recent advances in spray drying, a one- Poly lactic-glycolic acid (PLGA) Sustained release step, continuous microencapsulation process, for manufacturing of PLGA-based depot microparticle Proteins and peptides systems with a focus on the recent efforts on understanding of the role of nozzle design in the microencapsulation of proteins/peptides, and the effect of critical solvent properties and process parameters on the critical quality attributes of the spray-dried microparticles. ã 2015 Elsevier B.V. All rights reserved. Contents 1. Introduction . 82 2. Current production technologies of PLGA-based particle products . 83 3. The spray drying process for production of PLGA-based depot delivery systems . 84 3.1. Atomization of the feed into small droplets . 84 3.2. Droplet drying and particle formation . 85 3.3. Separation of the dry particles from the drying medium . 86 4. Role of critical solvent properties in preparing PLGA microparticles via spray drying . 86 4.1. Effect of solvent properties on the drying kinetics of droplets and the particle formation . 86 4.2. Effect of solvent properties on the characteristics of PLGA microparticles . 88 5. Novel nozzle design for microencapsulation in the spray drying process . 89 5.1. Co-axial ultrasonic atomizer . 91 5.2. Co-axial electrospray . 91 5.3. Three-fluid nozzle . 92 6. Conclusion . 93 Acknowledgements . 93 References . 93 1. Introduction * Corresponding author at: Department of Pharmacy, Faculty of Health and As a result of the development of recombinant DNA technology Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenha- in the past two decades, over 200 biopharmaceutical products are gen Ø, Denmark. on the market with an annual revenue of nearly US $ 167 billion E-mail address: [email protected] (M. Yang). http://dx.doi.org/10.1016/j.ijpharm.2015.12.025 0378-5173/ã 2015 Elsevier B.V. All rights reserved. F. Wan, M. Yang / International Journal of Pharmaceutics 498 (2016) 82–95 83 (Rader, 2013; Walsh, 2010). There are more and more new et al., 2014; Kuno and Fujii, 2011). In addition, PLGA microparticle medicines based on biotechnology rather than organic chemistry. formulations have also been intensively investigated for lung This is because biopharmaceuticals are often less toxic, more administration (Aguiar et al., 2004; Edwards et al., 1997; Jensen specific and have a more predictable in vivo action than small- et al., 2010; Kawashima et al., 1999; Yang et al., 2012a,b). However, molecule drugs (Frokjaer and Otzen, 2005). In spite of this, several no PLGA-based sustained pulmonary delivery system has yet challenges confront pharmaceutical scientists for the efficacious advanced to the clinical trial stage. and safe delivery of proteins and peptides, such as (i) their intrinsic The development of PLGA-based particulate delivery systems is physicochemical instability, (ii) their poor permeability through still impeded by a variety of challenges, including initial burst biological membranes, (iii) their short plasma half-lives (Frokjaer release, incomplete protein release, and poor protein stability and Otzen, 2005; Moeller and Jorgensen, 2008). Hence, most of the during the production process, storage, and drug release process. approved protein and peptide-based medicines are delivered via a The total body of literature in the area is immense and the reader is needle (intramuscularly, subcutaneous or intravenous) because of referred to the excellent review articles (Fredenberg et al., 2011; the assured bioavailability. However, a frequent dosing regimen is Giteau et al., 2008; Schwendeman et al., 2014; Weert et al., 2000; often necessary because of their short plasma half-lives, which Wischke and Schwendeman, 2008). In addition, for the protein and further causes poor patient compliance (e.g. pain, abscess, etc.), peptide drugs, the lack of easy, fast, effective microencapsulation unwanted side effects, and increased costs. technologies represents one of the major hurdles for commerciali- Vast efforts have been focused on the development of novel zation of proteins-loaded PLGA particulate delivery systems strategies for extending the duration of proteins and peptides in (Kumar and Palmieri, 2010). The complexity of the production vivo, including delivery of biopharmaceuticals via sustained- process can not only increase the risk of protein denaturation, but release drug delivery systems (Cun et al., 2015; Shi and Li, 2005; also make the sterilization of products difficult, often eventually Yang et al., 2012a), and modification of proteins and peptides via resulting in the commercial failure of the products (Desai and chemical approaches such as PEGylation, acetylation, and protein Schwendeman, 2013; Shi and Li, 2005). For example, the first FDA fusion (Beals and Shanafelt, 2006; Yang and Frokjaer, 2009), etc. To approved injectable protein depot (Nutropin Depot, produced by date, peptides/proteins with chemical modification are typically Cryogenic spray-drying technology) was finally discontinued by limited to weekly dosing, in contrast, it is possible to obtain the one the manufacturers due to the complexity of the manufacturing to three months of pharmacological effect with polymer based process (Desai and Schwendeman, 2013). Currently, there are a few sustained-release systems (Schwendeman et al., 2014). Among production technologies available for preparation of PLGA based them, poly lactic-co-glycolic acid (PLGA)-based particulate deliv- depot delivery systems, which have been reviewed elsewhere ery systems may represent one of the most promising approaches. (Wan et al., 2013b; Ye et al., 2010; Yeo et al., 2001). In this review PLGA, a copolymer that is synthesized through random ring- we will focus on the spray drying process to design PLGA-based opening co-polymerization of two different monomers, the cyclic depot delivery systems for proteins and peptides. Especially, we dimers (1,4-dioxane-2,5-diones) of glycolic acid and lactic acid, has will discuss the role of nozzle design and solvent properties in the been approved by the US FDA and European Medicine Agency spray drying process, which influence the PLGA microparticle (EMA) (Wischke and Schwendeman, 2008). It is now commercially formation process and critical quality attributes of the product. available with different molecular weights and copolymer compositions and the properties of the polymer can be tailored 2. Current production technologies of PLGA-based particle by varying the molecular weight, L:G ratio, PLA stereochemistries, products end-group functionalization, and PEGylation. The general trends are summarized in Table 1. To date, PLGA-based particle systems A variety of microencapsulation methods have been developed have been investigated to deliver various biopharmaceutical over past decades, including emulsion methods (Cui et al., 2005; agents (e.g. leuprolide, octreotide, sCT, rhGH, insulin, rhEPO, Cun et al., 2008), phase separation (coacervation) (Nihant et al., DGR, VEGF, BDNF, rhEGF, INF-a2b, vaccines, siRNA, etc.) via 1995; Nihant et al., 1994), spray drying (Mok and Park, 2008; Wan injection routes (i.e. intravenous, subcutaneous or intramuscular et al., 2014a,b), spray freeze drying (SFD) (Bi et al., 2008; Saluja injection) (Bertram et al., 2010; Cun et al., 2010; Desai and et al., 2010), electrospray (ES) drying (Bohr et al., 2015, 2012) and Schwendeman, 2013; Geng et al., 2008; Han et al., 2001; He et al., supercritical fluid technology (SCF) (Casettari et al., 2011; Salmaso 2006; Jensen et al., 2010; Park and Na, 2009; Takada et al., 2003; et al., 2009). The features of the current widely used microencap- Ungaro et al., 2009; Wang et al., 2004; Zhang et al., 2008). In the sulation technologies are summarized in Table 3. last two decades, several products based on PLGA depots have been Nowadays, emulsion methods, coacervation and spray