Modified Release (MR) technologies are increasingly used for enhancing the performance of oral drugs. For decades, MR products formed part of a line-extension category and were launched in a strategic way to offer a better-product relative to a commercial Immediate Release (IR) products and thereby extending the life of the brand. Today however, 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 for ones that are already on the market. This trend in launching superior commercial products with clearer therapeutic benefits which is welcomed by all stakeholders including investors, patients, doctors and payors.
A number of product improvements can be achieved using MR technologies, including:
- Improved patient compliance – associated with a simpler dosing regimen (e.g. once or twice daily)
- Enhanced pharmacokinetic (PK) profile – more suited to the therapeutic window or to match the patient’s needs (e.g. adjusting drug blood levels between day time and night time)
- Reduction in side-effects - related to a modified PK profile that lowers the Cmax of the drug or it’s metabolites while maintaining therapeutic plasma levels
The benefits of MR are significant, but there can often be technical challenges that prevent or complicate the development of an MR drug product. MR formulation approaches range in complexity and the formulation selection should be science-driven, 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 MR technology is selected.
Quotient has extensive experience in the development of modified release products across a variety of different technologies including controlled release, gastro-retentive, delayed release, pulsatile and biphasic release. Deep expertise is essential across multiple-disciplines such as formulation design, manufacturing, biopharmaceutics, gastro-intestinal (GI) physiology and clinical pharmacology, to leverage all the necessary skill-sets to create a successful MR product.
Evaluating an MR product opportunity must address two key questions:
1. What is the appropriate MR technology to achieve the therapeutic goal of the drug?
2. 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 equipment common in the pharmaceutical industry. Tableting, encapsulation and coating processes (either pan or fluid bed coating) support most MR approaches. 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 and/or adhesion methods to delay gastric-emptying of the dosage form.
A traditional approach to screen and select formulation prototypes begins with invitro 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 behaviour of the MR formulation is highly dependent on human physiology and this dependence occurs over a longer duration of drug release.
Translational Pharmaceutics® is a platform that integrates formulation development, real-time manufacturing with clinical testing with an adaptive clinical study design. Applying Translational Pharmaceutics to MR formulation development fixes the limitation of the traditional approach because formulation adjustments can be made in response to human PK data during the clinical study. This integration of “make” and “test” accelerates the generation of human PK data, so both timeline and product performance improvements are delivered. To support formulation adjustments during an adaptive clinical study, a formulation design space is defined that that allows for critical-to-performance parameters to be adjusted within the design space, as part of the clinical protocol. Critical MR variables are typically drug release rate and dose, and the limits of the design space are selected to allow for formulation adjustments if unexpected human PK outcomes are seen.
Quotient has supported over 100 modified release product development programs which have gone on to demonstrate proof-of-concept and in some cases reach the market. 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.
The integrated programs that I described typically has an improved human PK as the primary goal, but additional goals are often built into the program, including in-vivo – in vitro correlation assessment, process scale-up and clinical supply activities. As can be expected, application of more complex drug delivery technologies will add complexity and risk to an R&D program. Thankfully, the science-driven approach of using Translational Pharmaceutics to develop MR products has been proven to accelerate, de-risk and ultimately provide clinical benefit to patients.