Colonic Drug Delivery Challenges and Oppor tunities - An Overview
Jack Aurora , Naresh Talwar , Vinayak Pathak Director, Pharmaceutical Research and Development, Manager, Formulation Development and
Research Scientist, Pharmascience
Invitro/Invivo Performance Indicators
Can we predict the behaviour of these systems in the GI tract? One of the challenges in the development of such systems is to establish an appropriate in vitro dissolution method that can provide reasonable assurance of in vivo performance. This is because the rationale behind a colon-targeted drug delivery system is quite diverse. Additional factors that complicate the development of such dissolution testing include inadequate understanding of the colon’s hydrodynamics and motility and how they are affected by pathological states.
Conventional US Pharmacopeia (USP) Apparatus I dissolution testing in different buffers is one of the relatively simple and convenient methods routinely used. This method provides essential information primarily on the functionality of the system performance rather than validity of the design selected. A number of alternative or unconventional approaches have also been reported for in vitro performance evaluation of such delivery systems as the modular fermentor, multichamber reactor or simulated human intestinal microbial ecosystems (SHIME) and rotating beads.37 In addition to the complexity of the methods, other factors such as set-up and operating parameters can significantly affect the output of the results.
USP Apparatus 3 (BioDis®) is another recommended method to predict the in vivo performance. This offers multiple advantages, such as using a gradient of media to simulate the passage through different sections in the GI tract, varying hydrodynamic conditions and residence times in different media to simulate motility patterns and passage times under fasting and fed states.
Scintigraphy and magnetic moment imaging studies are other recent techniques to visualise the in vivo targeting properties of such systems. These techniques can provide realtime imaging of the dosage form transit in the GI tract. Such studies are much more expensive and time-consuming but they are complementary to the USP Apparatus 3 system as described above and both these methods together can provide a valuable insight into system performance.
All the above-mentioned procedures are just the tip of the iceberg and, considering the inter- and intra-subject variability of physiological GI tract parameters, further research focus in this area is crucial in both the design and characterisation of the systems.
Summary
The concept of targeting the delivery of specific drugs to colon is quite self explanatory and sufficient scientific rationale is available to support the justification. Various approaches are being researched in attempts to understand and achieve the desired goal of targeting the delivery to a specific organ, the colon. All the available approaches have their own limitations and advantages and extensive research is being focused on these to improve further. Time-dependant systems are not a very practical solution due to variable GI tract transit times but may have a potential role in diseases that are subject to circadian rhythm. On the other hand, pressure-controlled systems hold some promise but currently little is known about the luminal pressures of different regions of GI tract, and at present the commercial manufacturing methods have some unresolved issues to be addressed. The only system available as of today is based on pH but these systems can possibly deliver the drug at the duodenum or may not deliver the drug at all. Further research is ongoing in different labs and it is quite likely that a day is not far off when new, improved polymers will replace the existing available polymers with improved performance. The bacterially activated systems seem to be have the greatest potential as of today as the levels of bacterial enzyme activity is most unique and exploitable in this region. The amylase-based COLAL is the leading product in the later phases of clinical evaluation and has promise for commercial manufacturing.
Another area that still needs to be understood is human physiology and inter-/intra-subject variability. Once this aspect of the human system is understood, the gained knowledge can be applied to focus research on identifying suitable analytical tools that can predict the in vivo performance of the developed system.
At the end of the day the need of today’s business and patient community is to identify the appropriate approach that can result in the delivery of drugs in a safe, effective and less expensive manner with minimum fluctuation in terms of release of drugs at target site. If so, the overall cost of development of such a technology will be practically feasible and commercially viable.
