Modified release technologies are increasingly used for enhancing the performance of oral drugs.
For decades, modified-release drug products formed part of a line-extension category and were launched in a strategic way to offer a better product relative to commercial immediate-release (IR) products, thereby extending the life of the brand.
Today, pharma and biotech companies are increasingly considering MR technologies earlier in the development process of a new chemical entity (NCE) to obtain greater differentiation against other products in development or on the market.
This trend of launching superior commercial products with clearer therapeutic benefits is welcomed by all stakeholders including investors, patients, doctors, and payors.
Many drug product improvements can be achieved using MR technologies, including:
- Improved patient compliance - MR technologies can allow for a simpler dosing regimen (e.g. once or twice daily)
- Enhanced pharmacokinetic (PK) profile – MR technologies can be suited to the therapeutic window or to the patient’s needs (e.g. adjusting drug blood levels between daytime and nighttime)
- Reduced side effects - related to a modified PK profile that lowers the Cmax of the drug or its metabolites while maintaining therapeutic plasma levels
The benefits of modified-release products are significant but can come with technical challenges that prevent or complicate their development. Modified-release formulation approaches range in complexity and the formulation selection needs to be based on the properties of the drug substance and the target drug release profile. R&D programs can encounter large delays and cost overruns when the wrong modified-release technology is selected.
Our experience in the development of modified-release products spans controlled release, gastro-retentive, delayed release, pulsatile, and biphasic release technologies.
When evaluating a modified-release product opportunity, we often start with two fundamental questions:
- What is the appropriate MR technology to achieve the therapeutic goal of the drug?
- What is the right development plan to efficiently demonstrate proof-of-concept for the MR product?
A wide variety of MR formulation technologies are available and the majority can be manufactured using common tableting, encapsulation, and coating processes (either pan or fluid bed coating). The specific MR release behavior is also determined by the functional excipients used.
A common approach is to use hydrophilic polymers in a tablet that form a gel matrix in in-vivo that controls drug release out of the matrix. Polymer coatings are also applied either on tablets or multi-particulates (e.g. beads) with functionality that may be pH-dependent, an erodible coat, or a coat that controls drug diffusion through a semi-permeable coat (or orifice). Both the excipients used and the final products are generally non-proprietary.
Among the more complex MR technologies are osmotic tablets (using the approaches described above but sometimes with a small orifice contributing to release-rate control) and gastro-retentive formulations that apply a range of swelling, floating, or adhesion methods to delay gastric-emptying of the dosage form.
A traditional approach to screen and selecting formulation prototypes begins with in vitro testing and animal models, and then a lead prototype or prototypes are selected for clinical testing. This approach and overconfidence in non-clinical to clinical predictions can be flawed when developing oral MR products, because the behavior of the MR formulation is highly dependent on human physiology and this dependence occurs over a longer duration of drug release.
Across more than 100 modified-release product development programs, we have often seen clinical performance of MR products differ considerably from in vitro or animal test predictions, providing a real surprise for the development team, which confirms why non-clinical tests should not be the backbone of an MR product development program.
We have applied our flagship Translational Pharmaceutics® platform for drug development to modified-release drug programs.
We can make formulation adjustments in response to human PK data during the clinical study to accelerate development timelines. To support formulation adjustments during an adaptive clinical study, a formulation design space is defined that allows critical-to-performance parameters, like drug release rate and dose, to be adjusted. The limits of the design space are selected to allow for formulation adjustments if unexpected human PK outcomes are seen. This science-driven approach has been proven to accelerate and derisk drug development, untimely providing clinical benefit to patients.