ReviewOn the importance and mechanisms of burst release in matrix-controlled drug delivery systems
Introduction
In recent years, the study of controlled release of drugs and other bioactive agents from polymeric devices has attracted many researchers from around the world. Controlled drug delivery applications include both sustained delivery over days/weeks/months/years and targeted (e.g., to a tumor, diseased blood vessel, etc.) delivery on a one-time or sustained basis [1]. Controlled release formulations can be used to reduce the amount of drug necessary to cause the same therapeutic effect in patients. The convenience of fewer and more effective doses also increases patient compliance [2]. Over the years of controlled release research, different systems, ranging from coated tablets and gels to biodegradable microspheres and osmotic systems, have been explored experimentally and computationally to get predesigned release profiles. In many of the controlled release formulations, immediately upon placement in the release medium, an initial large bolus of drug is released before the release rate reaches a stable profile. This phenomenon is typically referred to as ‘burst release.’ As shown in Fig. 1, burst release leads to higher initial drug delivery and also reduces the effective lifetime of the device. Because burst release happens in a very short time compared to the entire release process, it has not been specifically investigated in most published results, and it has been ignored in most mathematical models. However, among the plethora of controlled release publications, burst phenomena have been observed and studied [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15]. Several researchers [3], [4], [5], [6] have observed burst release without giving advanced explanations; some [7], [8], [9], [10], [11] tried to find the mechanisms of burst and prevent it technologically; and some [10], [12], [13] have made an effort to include burst in models to simulate the release process. At the opposite end of spectrum, burst release has been utilized to deliver drugs at high release rates as part of the drug administration strategy [14].
Section snippets
Significance of burst release
Normally short in duration, burst release is worth thorough study due to the high release rates that can be reached in the initial stages after activation. The burst effect can be viewed from two perspectives: it is often regarded as a negative consequence of creating long-term controlled release devices, or, in certain situations, rapid release or high initial rates of delivery may be desirable (Table 1).
Burst release may be the optimal mechanism of delivery in several instances. One of the
Causes of burst release
Although the importance of burst release has been realized as controlled release research is developed to higher levels, publications referring to burst as their specific topic are rare. A number of research papers [5], [6], [7], [8], [9], [10], [11], [12], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33] have observed burst release experimentally and a few [10], [12], [17], [24], [28], [30], [31] have put forth theories to explain it in
Prevention of burst release
Although favorable in some limited situations, under most of the circumstances in drug delivery, burst release is considered a negative effect. The importance of avoiding burst release can be seen in the number of publications focused on developing methods to prevent or minimize the burst effect in a wide range of polymer/drug systems. A system for controlled release would be ideal if it could be processed in a single step to include high drug loading and have no burst release. Several advanced
Modeling
Polymeric drug delivery systems can be designed to work by a variety of mechanisms. According to these mechanisms, Langer [49] categorized the systems into diffusion-controlled, chemically controlled, swelling-controlled, and magnetically controlled devices. Among these, diffusion-controlled and swelling-controlled systems have been widely studied not only experimentally, but also by establishing both simple and complex mathematical models. Significantly absent from most of the models is the
Summary
Although the burst effect has been reported in numerous publications in our field, much of the research has focused on methods to prevent burst but little has been done to elucidate the mechanisms of burst release. Understanding of the burst effect during controlled release is still limited but knowledge continues to grow as researchers realize both the economic and therapeutic importance of the burst period. For many applications, small burst quantities may be acceptable, as long as the burst
Acknowledgements
The authors express gratitude to the University of Alabama College of Engineering and Department of Chemical Engineering for supporting the work leading to this paper.
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