Summary: In this article with Drug Development & Delivery, Dr. Andrew Lewis highlights the growing demand for modified-release (MR) dosage forms that deliver drugs at targeted gastrointestinal sites, maintain plasma concentration, and improve patient compliance. He emphasizes challenges in predicting human pharmacokinetics (PK) from nonclinical models and introduces the design space concept with on-demand manufacturing, applied through the Translational Pharmaceutics platform. This approach allows real-time formulation adjustments during clinical trials, reducing timelines and costs while mitigating development risk. Modified-release technologies like controlled-release, pulsatile, delayed-release, and gastro-retentive systems are evaluated using the Translational Pharmaceutics platform for optimized performance and efficient progression to commercialization.
Modified-release formulations are in high demand, but post challenges in development.
For formulators, they enable drugs to be released in the optimal gastrointestinal (GI) locations to achieve and maintain desirable plasma concentrations for extended periods, avoiding undesirable excursions outside the therapeutic range. For patients, modified-release formulations provide the convenience of infrequent dosing with potentially greater efficacy and fewer side effects than similar, immediate-release delivery systems.
An impressive variety of modified-release formulations are possible, thanks to ongoing technological developments. Strategic selection of excipients and delivery technologies can yield formulations that fulfil very specific performance requirements, such as gastro-retention and sustained-, pulsatile-, or delayed-release formats. Nonetheless, throughout the past 20 years, the fundamental methodology for developing these formulations has stagnated. Initial formulations continue to be founded upon in vitro and preclinical test results, despite evidence that these data correlate poorly with pharmacokinetic (PK) drug performance in humans.
In this article with Drug Development & Delivery, Dr. Andrew Lewis addresses available modified-release formulation technologies, the challenges in modified-release formulation development, and the use of a formulation design-space with on-demand manufacturing. This methodology enables critical-to-performance formulation adjustments during clinical conduct, saving time and cost, and reducing risk in modified-release drug development.
Modified-release formulations and the abundance of modified-release technology: A blessing and a curse
An ever-increasing number of polymers and formulation technologies allow finely tuned control of many aspects of drug release. Selecting and/or combining these technologies offers great potential for optimized oral drug delivery. However, managing all the variables and interpreting in vitro, preclinical, and available human clinical data to define a formulation strategy capable of achieving the desired PK performance is more difficult than many developers expect. Accurate performance prediction is crucial because miscalculations in planning for development or manufacturing are costly and often cause delays.
Off-the-shelf and proprietary polymers help developers achieve their PK goals. Certain polymers are better suited for sustained or delayed release and may be designed to deliver APIs to specific GI target areas, depending on physicochemical, biomechanical, and human physiological factors influencing the site of release. The range of solid dosage forms offers further layers of complexity. This ever-expanding array of tools makes many modified-release formulations possible.
Each delivery format has its own idiosyncrasies. In the first instance, understanding the target PK profile is crucial. What plasma concentration-time profile does the formulation need to deliver? Experience and expertise are then required to select and implement a rational formulation program based on API characteristics, such as solubility, stability in stomach acid, particle size, and bioavailability.
Furthermore, human physiology factors (such as an absorption window, drug transporters, enzymes in the GI tract, and intestinal motility) can impact a product’s performance as it transitions through the intestine. Given these variables, being sure the formulation performs in vivo as it did in vitro can be challenging. A good CDMO can help find the best approach and select a technology to achieve the desired performance.
Continue reading this feature article on the Drug Development & Delivery website for more insight on the best way to predict a formulation’s clinical performance and using a formulation design space to evaluate modified-release technologies.