Interfacial tension effects on the properties of PLGA microparticles

https://doi.org/10.1016/j.colsurfb.2020.111300Get rights and content

Highlights

  • Interfacial tension effects can impact droplet deformation through drug release.

  • Solvent(s) and emulsifier(s) can alter the drug loading/encapsulation efficiency.

  • Further research on interfacial tension effects can advance the PLGA field.

Abstract

Many types of long-acting injectables, including in situ forming implants, preformed implants, and polymeric microparticles, have been developed and ultimately benefited numerous patients. The advantages of using long-acting injectables include greater patient compliance and more steady state drug plasma levels for weeks and months. However, the development of long-acting polymeric microparticles has been hampered by the lack of understanding of the microparticle formation process, and thus, control of the process. Of the many parameters critical to the reproducible preparation of microparticles, the interfacial tension (IFT) effect is an important factor throughout the process. It may influence the droplet formation, solvent extraction, and drug distribution in the polymer matrix, and ultimately drug release kinetics from the microparticles. This mini-review is focused on the IFT effects on drug-loaded poly(lactic-co-glycolic acid) (PLGA) microparticles.

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):Re=InertialforceViscousforce=ρUdηCa=ViscousforceInterfacialsurfacetension=γ˙ηασorηUσWe=InertialforceInterfacialsurfacetension=ReCa=ρU2ασM=Viscousforce(dispersedphase)Viscousforce(continuouspha

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.

References (68)

  • K. Elkharraz et al.

    Paclitaxel-loaded microparticles and implants for the treatment of brain cancer: preparation and physicochemical characterization

    Int. J. Pharm.

    (2006)
  • F. Ito et al.

    Study of types and mixture ratio of organic solvent used to dissolve polymers for preparation of drug-containing PLGA microspheres

    Eur. Polym. J.

    (2009)
  • Y. Wei et al.

    Fabrication strategy for amphiphilic microcapsules with narrow size distribution by premix membrane emulsification

    Colloids Surf. B Biointerfaces

    (2011)
  • Y. Capan et al.

    Influence of formulation parameters on the characteristics of poly(d,l-lactide-co-glycolide) microspheres containing poly(l-lysine) complexed plasmid DNA

    J. Control. Release

    (1999)
  • S. Mao et al.

    Effects of process and formulation parameters on characteristics and internal morphology of poly(d,l-lactide-co-glycolide) microspheres formed by the solvent evaporation method

    Eur. J. Pharm. Biopharm.

    (2008)
  • J. Garner et al.

    Beyond Q1/Q2: the Impact of manufacturing conditions and test methods on drug release from PLGA-based microparticle depot formulations

    J. Pharm. Sci.

    (2018)
  • A.T. Florence et al.

    Some features of breakdown in water-in-oil-in-water multiple emulsions

    J. Colloid Interface Sci.

    (1981)
  • M.J. Alonso et al.

    Biodegradable microspheres as controlled-release tetanus toxoid delivery systems

    Vaccine

    (1994)
  • C. Pérez-Rodriguez et al.

    Stabilization of α-chymotrypsin at the CH2Cl2/water interface and upon water-in-oil-in-water encapsulation in PLGA microspheres

    J. Control. Release

    (2003)
  • J. Wang et al.

    Stabilization and encapsulation of human immunoglobulin G into biodegradable microspheres

    J. Colloid Interface Sci.

    (2004)
  • L. Chen et al.

    Characterization of PLGA microspheres for the controlled delivery of IL-1α for tumor immunotherapy

    J. Control. Release

    (1997)
  • H. Sah

    Stabilization of proteins against methylene chloride/water interface-induced denaturation and aggregation

    J. Control. Release

    (1999)
  • H. Okada

    One- and three-month release injectable microspheres of the LH-RH superagonist leuprorelin acetate

    Adv. Drug Deliv. Rev.

    (1997)
  • K. Park et al.

    Injectable, long-acting PLGA formulations: analyzing PLGA and understanding microparticle formation

    J. Control. Release

    (2019)
  • S. Skidmore et al.

    Complex sameness: separation of mixed poly(lactide-co-glycolide)s based on the lactide:glycolide ratio

    J. Control. Release

    (2019)
  • S.C. Ayirala et al.

    Solubility, miscibility and their relation to interfacial tension in ternary liquid systems

    Fluid Phase Equilib.

    (2006)
  • A. Rawat et al.

    Effect of ethanol as a processing co-solvent on the PLGA microsphere characteristics

    Int. J. Pharm.

    (2010)
  • H. Sah

    Microencapsulation techniques using ethyl acetate as a dispersed solvent: effects of its extraction rate on the characteristics of PLGA microspheres

    J. Controlled Release

    (1997)
  • J.V. Andhariya et al.

    Development of in vitro-in vivo correlation of parenteral naltrexone loaded polymeric microspheres

    J. Controlled Release

    (2017)
  • J. Shen et al.

    In vitro-in vivo correlation of parenteral risperidone polymeric microspheres

    J. Controlled Release

    (2015)
  • D.K. Sahana et al.

    PLGA nanoparticles for oral delivery of hydrophobic drugs: influence of organic solvent on nanoparticle formation and release behavior in vitro and in vivo using estradiol as a model drug

    J. Pharm. Sci.

    (2008)
  • S. Torza et al.

    Three-phase interactions in shear and electrical fields

    J. Colloid Interface Sci.

    (1970)
  • S.R. Abulateefeh et al.

    Tunable sustained release drug delivery system based on mononuclear aqueous core-polymer shell microcapsules

    Int. J. Pharm.

    (2019)
  • R.K. Kulkarni et al.

    Polylactic acid for surgical implants

    JAMA Surg.

    (1966)
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