Elsevier

Journal of Controlled Release

Volume 146, Issue 2, 1 September 2010, Pages 241-260
Journal of Controlled Release

Issues in long-term protein delivery using biodegradable microparticles

https://doi.org/10.1016/j.jconrel.2010.05.011Get rights and content

Abstract

Recently, a variety of bioactive protein drugs have been available in large quantities as a result of advances in biotechnology. Such availability has prompted development of long-term protein delivery systems. Biodegradable microparticulate systems have been used widely for controlled release of protein drugs for days and months. The most widely used biodegradable polymer has been poly(d,l-lactic-co-glycolic acid) (PLGA). Protein-containing microparticles are usually prepared by the water/oil/water (W/O/W) double emulsion method, and variations of this method, such as solid/oil/water (S/O/W) and water/oil/oil (W/O/O), have also been used. Other methods of preparation include spray drying, ultrasonic atomization, and electrospray methods.

The important factors in developing biodegradable microparticles for protein drug delivery are protein release profile (including burst release, duration of release, and extent of release), microparticle size, protein loading, encapsulation efficiency, and bioactivity of the released protein. Many studies used albumin as a model protein, and thus, the bioactivity of the release protein has not been examined. Other studies which utilized enzymes, insulin, erythropoietin, and growth factors have suggested that the right formulation to preserve bioactivity of the loaded protein drug during the processing and storage steps is important. The protein release profiles from various microparticle formulations can be classified into four distinct categories (Types A, B, C, and D). The categories are based on the magnitude of burst release, the extent of protein release, and the protein release kinetics followed by the burst release. The protein loading (i.e., the total amount of protein loaded divided by the total weight of microparticles) in various microparticles is 6.7 ± 4.6%, and it ranges from 0.5% to 20.0%. Development of clinically successful long-term protein delivery systems based on biodegradable microparticles requires improvement in the drug loading efficiency, control of the initial burst release, and the ability to control the protein release kinetics.

Introduction

The traditional way of delivering a protein drug requires daily, sometimes multiple, injections to achieve its therapeutic effectiveness. To improve patient compliance and convenience, sustained release dosage forms have been developed [1], [2], [3]. In the last three decades, many therapeutic proteins and peptides have been microencapsulated in biodegradable polymers, mainly poly(lactic acid) (PLA), poly(glycolic acid) (PGA), and poly(lactic-co-glycolic acid) (PLGA) [4], [5], [6], [7]. The principle behind using biodegradable polymer is that the release of a loaded protein drug depends mainly on the degradation kinetics of the polymer. Thus, it has been assumed that a loaded protein drug is released gradually following the PLGA degradation kinetics which can be adjusted by changing the lactide/glycolide ratio and molecular weight (MW) [2], [8]. This, however, may not be always true, because other factors of the formulation can also affect the drug release kinetics, and sometimes they are more dominant than the degradation kinetics of a polymer.

An ideal microparticle formulation should have reasonably high protein encapsulation efficiency, loading capacity, and sustained release of the loaded protein with retained bioactivity [2], [9]. The high protein loading and high encapsulation efficiencies are most critical simply due to the extremely high price of therapeutic proteins [9]. For an injectable formulation, the size of microparticles should be small enough for going through a fine needle. Usually, needles of 22–25 gauge (inner diameters of 394–241 µm) are used for quick intravenous infusion as well as intramuscular and subcutaneous injections. Microparticles with the diameter much smaller than that of a needle are preferred, in order to minimize potential blockage of the needle by them. The particle size and size distribution are also important for protein release rate as the total surface area for protein delivery depends on the particle size [10]. Preparing microspheres with all desirable properties has met with only limited success. This article examines the properties of protein-loaded microparticles, in particular, protein loading and release properties from PLGA microparticles.

Section snippets

Microencapsulation methods

Understanding the protein loading and release properties requires understanding the microencapsulation methods used for protein drugs. The preparation methods commonly used for making protein-loaded microparticles are listed in Table 1. Compared to double emulsion methods, ultrasonic atomization method, electrospray method, microfluidic method, pore-closing method, thermoreversible-gel method, and microfabrication are relatively new and still under investigation. All methods, except

Characterization of microparticles

Complete characterization of microparticles requires examination of several parameters, and the following parameters are chosen for a comparative study in this review: type of release profile, burst release, particle size, protein loading amount (or capacity), protein encapsulation efficiency, polymer concentration, and protein-encapsulated for study. The summaries of comparison of many different formulations are listed in Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, and the detailed

Future

Currently, there are no standard experimental conditions or no standard formulations that can be used for all different types of proteins. Differences in the tertiary structure, molecular weight, and charge make each protein unique, so that a specific formulation is required for each protein. Optimization of the microsphere preparation process is inherently difficult, because adjustment of one parameter usually results in complicated, often unpredictable, effects on the final microsphere

Acknowledgement

This work was supported in part by NIH through GM067044 and CA129287, and the Korea Research Foundation Grant (KRF-2008-357-D00072).

References (182)

  • H. Tamber et al.

    Formulation aspects of biodegradable polymeric microspheres for antigen delivery

    Adv. Drug Deliv. Rev.

    (2005)
  • R. Liu et al.

    Influence of process parameters on the size distribution of PLA microcapsules prepared by combining membrane emulsification technique and double emulsion–solvent evaporation method

    Colloids Surf. B Biointerfaces

    (2005)
  • R. Liu et al.

    Preparation of insulin-loaded PLA/PLGA microcapsules by a novel membrane emulsification method and its release in vitro

    Colloids Surf. B Biointerfaces

    (2006)
  • F. Ito et al.

    Incorporation of water-soluble drugs in PLGA microspheres

    Colloids Surf. B Biointerfaces

    (2007)
  • M. van de Weert et al.

    The effect of a water/organic solvent interface on the structural stability of lysozyme

    J. Control. Release

    (2000)
  • I.J. Castellanos et al.

    Encapsulation-induced aggregation and loss in activity of gamma-chymotrypsin and their prevention

    J. Control. Release

    (2002)
  • J. Wang et al.

    Stabilization and encapsulation of human immunoglobulin G into biodegradable microspheres

    J. Colloid. Interface Sci.

    (2004)
  • I.J. Castellanos et al.

    Poly(ethylene glycol) as stabilizer and emulsifying agent: a novel stabilization approach preventing aggregation and inactivation of proteins upon encapsulation in bioerodible polyester microspheres

    J. Control. Release

    (2003)
  • B.H. Woo et al.

    Preparation, characterization and in vivo evaluation of 120-day poly(d, l-lactide) leuprolide microspheres

    J. Control. Release

    (2001)
  • M. Sandor et al.

    Effect of lecithin and MgCO3 as additives on the enzymatic activity of carbonic anhydrase encapsulated in poly(lactide-co-glycolide) (PLGA) microspheres

    Biochim. Biophys. Acta

    (2002)
  • C. Thomasin et al.

    Drug microencapsulation by PLA/PLGA coacervation in the light of thermodynamics. 1. Overview and theoretical considerations

    J. Pharm. Sci.

    (1998)
  • C. Thomasin et al.

    Drug microencapsulation by PLA/PLGA coacervation in the light of thermodynamics. 2. Parameters determining microsphere formation

    J. Pharm. Sci.

    (1998)
  • M.J. Blanco-Prieto et al.

    Importance of single or blended polymer types for controlled in vitro release and plasma levels of a somatostatin analogue entrapped in PLA/PLGA microspheres

    J. Control. Release

    (2004)
  • K.G. Carrasquillo et al.

    Non-aqueous encapsulation of excipient-stabilized spray-freeze dried BSA into poly(lactide-co-glycolide) microspheres results in release of native protein

    J. Control. Release

    (2001)
  • S. Freitas et al.

    Ultrasonic atomisation into reduced pressure atmosphere–envisaging aseptic spray-drying for microencapsulation

    J. Control. Release

    (2004)
  • F. Quaglia et al.

    Feeding liquid, non-ionic surfactant and cyclodextrin affect the properties of insulin-loaded poly(lactide-co-glycolide) microspheres prepared by spray-drying

    J. Control. Release

    (2003)
  • G. De Rosa et al.

    How cyclodextrin incorporation affects the properties of protein-loaded PLGA-based microspheres: the case of insulin/hydroxypropyl-beta-cyclodextrin system

    J. Control. Release

    (2005)
  • P. Johansen et al.

    Diphtheria and tetanus toxoid microencapsulation into conventional and end-group alkylated PLA/PLGAs

    Eur. J. Pharm. Biopharm.

    (1999)
  • M.J. Blanco-Prieto et al.

    In vitro and in vivo evaluation of a somatostatin analogue released from PLGA microspheres

    J. Control. Release

    (2000)
  • B. Bittner et al.

    Recombinant human erythropoietin (rhEPO) loaded poly(lactide-co-glycolide) microspheres: influence of the encapsulation technique and polymer purity on microsphere characteristics

    Eur. J. Pharm. Biopharm.

    (1998)
  • H.R. Costantino et al.

    Relationship between encapsulated drug particle size and initial release of recombinant human growth hormone from biodegradable microspheres

    J. Pharm. Sci.

    (2004)
  • X.M. Lam et al.

    Encapsulation and stabilization of nerve growth factor into poly(lactic-co-glycolic) acid microspheres

    J. Pharm. Sci.

    (2001)
  • J.L. Cleland et al.

    Development of poly-(d,l-lactide–coglycolide) microsphere formulations containing recombinant human vascular endothelial growth factor to promote local angiogenesis

    J. Control. Release

    (2001)
  • C. Berkland et al.

    Precise control of PLG microsphere size provides enhanced control of drug release rate

    J. Control. Release

    (2002)
  • C. Berkland et al.

    Controlling surface nano-structure using flow-limited field-injection electrostatic spraying (FFESS) of poly(d,l-lactide-co-glycolide)

    Biomaterials

    (2004)
  • S. Freitas et al.

    Flow-through ultrasonic emulsification combined with static micromixing for aseptic production of microspheres by solvent extraction

    Eur. J. Pharm. Biopharm.

    (2005)
  • S. Freitas et al.

    Continuous contact- and contamination-free ultrasonic emulsification—a useful tool for pharmaceutical development and production

    Ultrason. Sonochem.

    (2006)
  • S. Freitas et al.

    Microencapsulation by solvent extraction/evaporation: reviewing the state of the art of microsphere preparation process technology

    J. Control. Release

    (2005)
  • Y. Yeo et al.

    A new process for making reservoir-type microcapsules using ink-jet technology and interfacial phase separation

    J. Control. Release

    (2003)
  • Y. Yeo et al.

    A new microencapsulation method using an ultrasonic atomizer based on interfacial solvent exchange

    J. Control. Release

    (2004)
  • Y. Xu et al.

    Electrospray encapsulation of water-soluble protein with polylactide. Effects of formulations on morphology, encapsulation efficiency and release profile of particles

    Int. J. Pharm.

    (2006)
  • A. Gomez et al.

    Production of protein nanoparticles by electrospray drying

    J. Aerosol Sci.

    (1998)
  • H.K. Kim et al.

    Biodegradable polymeric microspheres with “open/closed” pores for sustained release of human growth hormone

    J. Control. Release

    (2006)
  • S.E.A. Gratton et al.

    Nanofabricated particles for engineered drug therapies: a preliminary biodistribution study of PRINT™ nanoparticles

    J. Control. Release

    (2007)
  • L.C. Glangchai et al.

    Nanoimprint lithography based fabrication of shape-specific, enzymatically-triggered smart nanoparticles

    J. Control. Release

    (2008)
  • G. Acharya et al.

    The hydrogel template method for fabrication of homogeneous nano/microparticles

    J. Control. Release

    (2010)
  • K.S. Jaganathan et al.

    Development of a single dose tetanus toxoid formulation based on polymeric microspheres: a comparative study of poly(d,l-lactic-co-glycolic acid) versus chitosan microspheres

    Int. J. Pharm.

    (2005)
  • J.M. Pean et al.

    NGF release from poly(d,l-lactide-co-glycolide) microspheres. Effect of some formulation parameters on encapsulated NGF stability

    J. Control. Release

    (1998)
  • J.B. Herrmann et al.

    The effect of particle microstructure on the somatostatin release from poly(lactide) microspheres prepared by a W/O/W solvent evaporation method

    J. Control. Release

    (1995)
  • G. Wei et al.

    The release profiles and bioactivity of parathyroid hormone from poly(lactic-co-glycolic acid) microspheres

    Biomaterials

    (2004)
  • Cited by (316)

    • Injectable systems for long-lasting insulin therapy

      2023, Advanced Drug Delivery Reviews
    View all citing articles on Scopus
    View full text