There are a number of approaches to developing a modified-release (MR) formulation, which include traditional polymer matrices, such as a hypromellose matrix (1), and more complex multilayered matrices with or without additional functional excipients (2). There are benefits and restrictions to every approach, which include technology requirements, and applicability to drug type/concentration range. A new MR approach has recently been developed and commercialized by GlaxoSmithKline (GSK) under the trade name of DiffCORE. This article describes the MR approach, its in vivo, in vitro, and industrial commercial performance, and potential benefits of the approach.
What is the background to the MR approach and its technological development?
The approach involves using mechanical drilling of functional film-coated tablets (see Figure 1) to form apertures of known size and position in the film coat. The release rate of the drug can be modified and controlled through altering the exposed surface area and the composition of the tablet core. The manufacture of the tablets utilizes standard manufacturing unit operations (i.e., blending, granulation, and compression). The core formulation and the manufacturing process impact the performance of the final product as it would on any traditional solid dose.
GSK purchased an original patent in 1993, which used a film coating based upon ethylcellulose. While this film coating was a semipermeable coating, when used in the DiffCORE process, it behaves essentially as an impermeable barrier. The coating retards the release of the API from the majority of the core surface area. The apertures in the coating maintain the release rate of the API from the core throughout the entire gastrointestinal tract. This approach was found to be suitable for compounds which had high solubility, primarily weak acids. Weak bases, which at that time formed a large part of the MR portfolio, were found to exhibit reduced release on leaving the gastric environment due to the pH-driven reduction in solubility and thereby availability.
Figure 1: Film-coated tablets with apertures of known size, 2 mm (blue), 3 mm (brown), and 4mm (green).
Using targeted experiments, a new film coating system was developed, which enabled the technology for use with weak bases (3). The increase in potential products that could benefit from the new film-coating system prompted further investment of time and resources to fully explore the capabilities of this technology.
The new coating system developed was an enteric film coat based upon previous research into different detackifiers. For weak bases, this coating initially retards the release of the active material to the drilled apertures while within the high-solubility gastric environment. Upon reaching the higher pH of the intestines, the coating dissociates and becomes soluble. The dissolution of the coat increases the exposed surface area of the core, which increases the availability of the exposed drug substance, thereby compensating for the decreased solubility. By making use of established polymer matrix techniques, the core is formulated to ensure a controlled release rate is maintained.
Further refinements have been made for specific compounds, dependant on the product's pharmacodynamics. The use of a bilayer core enables the combination of an immediate-release (IR) layer and a MR layer. The IR layer reduces the time to reach the minimum therapeutic dose for the patient while the MR layer provides a maintenance dose. This bilayer approach can obviously be extended to combination products though this has not been trialled at this time (4). GSK has several products utilizing this technology under development at various clinical stages, with Lamictal XR (lamotrigine) being the first product commercially available on the market.