Interfacial tension effects on the properties of PLGA microparticles
Graphical abstract
Introduction
Poly(glycolic acid) (PGA), or polyglycolide, has been known since 1954 as a tough fiber-forming polymer and was developed as the first synthetic absorbable suture in 1962 [1]. The use of poly(l-lactic acid) (PLLA), or poly(l-lactide), in the medical field dates back to 1966 when implanted PLLA powder demonstrated a nontoxic tissue response in guinea pigs and rats [2] and followed with the use of poly(lactic acid) (PLA), or polylactide, as sutures [3] and orthopedic fixation [4] in 1971. The successful development of these materials as surgical sutures and orthopedics led to their expansion as polymeric biomaterials. While PGA suffers from hydrolytic instability and PLA suffers from slow degradation rates, the successful combination of these two has led to poly(lactic-co-glycolic acid) (PLGA), also known as poly(lactide-co-glycolide), being the most widely researched polymer in controlled release drug delivery systems [5].
While PLGA is the most widely used polymer in controlled drug delivery systems, the research efforts to date have led to only three long-acting small molecule PLGA microparticle-based products: Zilretta®, Vivitrol®, and Risperdal Consta®. Arestin® is also a PLGA-based microparticle product approved by the Food and Drug Administration (FDA), but is used for professional subgingival administration into periodontal pockets. The small number of approved long-acting injectable PLGA microparticle products may indicate technical difficulties in their formulation development and subsequent manufacturing.
The basics of PLGA microparticles and implants have been reviewed elsewhere [[6], [7], [8], [9]] and are omitted from this mini-review. The focus of this mini-review is on how understanding the effects of interfacial tension (IFT) during fabrication and drug release may aid in designing better PLGA microparticle drug delivery systems. This mini-review includes the current knowledge about IFT effects on PLGA microparticle drug delivery systems and an overview of strategies for controlling microparticle properties.
Section snippets
Emulsion droplet formation
During PLGA microparticle generation, the droplet deformation from the oil phase or discontinuous phase and possible breakup in flow are controlled by a number of dimensionless numbers, including the Reynolds number (Re), capillary number (Ca), Weber number (We), and viscosity ratio (M):
Emulsifier type
During microparticle formation using the conventional solvent evaporation/extraction approach, an emulsifier is required to ensure droplet stability until the polymer concentration becomes high enough, i.e., enough solvent has been removed from the oil droplet to maintain the particle conformation. The emulsifier plays a significant role in the emulsification. The emulsifier acts to lower the IFT between the discontinuous oil phase and continuous water phase. In the formation of PLGA
Interfacial phenomena in W/O/W systems
As there is a shift in new drug development towards large molecules, developing PLGA microparticles using w/o/w emulsions will become ever more critical. Three main types of w/o/w emulsions have been identified based on the size and number of the internal aqueous droplets: (1) microcapsule, (2) multi-vesicular structure, and (3) matrix or monolithic structure (Fig. 1). Microcapsules usually have one large internal aqueous droplet. In multi-vesicular structures, approximately half of the drops
Solvent effects
PLGA is an all-encompassing term for an extremely broad class of polymers. Each PLGA may have a different L:G ratio, varying between 50:50 and 100:0, molecular weight, polydispersity index, and end-group chemistry. In addition, the manufacturing process of PLGA polymers can also affect the polymer properties through residual catalyst, solvents, and/or monomer.
One route to alter the IFT between the oil and aqueous phases is to select a different solvent or combination of solvents. However, even
Implications on drug release
As previously discussed, the change in IFT between the organic and aqueous phases can affect the organic solvent extraction kinetics from the microparticles and size of the microparticles. These two factors can change the morphology of the microparticles and the drug distribution in the microparticles, both of which play a significant role in the drug release kinetics. The IFT between dichloromethane and water was reduced from approximately 27 mN/m to 5 mN/m when the concentration of ethanol in
Multicomponent systems and block copolymers
In the emulsions and latex fields, it has been recognized for some time that the interfacial properties can dictate the organization of the synthesized particles [62,63]. The IFT between different phases determine the spreading coefficients. The particle morphology is largely determined by the interplay between the spreading coefficients, as different combinations of spreading coefficients may influence the degree of polymer engulfment during the phase separation. The spreading coefficients for
Conclusion
As many PLGA microparticle systems are fabricated and explored, it is important to consider understanding the mechanisms of microparticle preparation, as it is essential in controlling the properties of the microparticles, e.g., drug loading capacity, efficiency, and release kinetics. Controlling these properties requires further mechanistic studies using various PLGAs with different molecular weights, L:G ratios, and end groups for a range of drugs with diverse physicochemical properties. The
CRediT authorship contribution statement
Andrew Otte: Conceptualization, Writing - review & editing. Farrokh Sharifi: Conceptualization, Writing - review & editing. Kinam Park: Conceptualization, Writing - review & editing.
Declaration of Competing Interest
The authors report no declarations of interest.
Acknowledgement
This study was supported by Grant UG3 DA048774 from the National Institute of Drug Abuse and the Showalter Research Trust Fund.
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2021, Journal of Controlled ReleaseCitation Excerpt :For the emulsion extraction method, the manufacturing process begins with the creation of an O/W seed emulsion. The conditions of forming the initial seed emulsion (e.g., mixing point of oil- and water-phases, viscosity of the oil-phase, interfacial tension between two phases, and stirring rate and time) and subsequent solvent extraction (such as the water volume, temperature, and stirring rate) have a significant influence on the final properties [24–26]. Formulations have been traditionally characterized by the drug loading, drug encapsulation efficiency, size distribution, porosity, residual solvent content, surface morphology, and drug release kinetics.