Issues in long-term protein delivery using biodegradable microparticles
Graphical abstract
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).
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