MR dosage forms are those dosage forms whose drug release properties are chosen to accomplish therapeutic or convenience objectives not offered by conventional dosage forms such as a solution or an immediate release (IR) dosage form. According to the US Food and Drug Administration (FDA) and US Pharmacopeia, MR solid oral dosage forms comprise delayed and extended release drug products. In addition to the delayed and/or prolonged release characteristics, newer oral MR products may also exhibit pulsatile-release, chrono-release at a predetermined time (e.g., dose release in the morning after administration at bedtime), or targeted delivery (e.g., colonic delivery), etc. Moreover, some of the oral MR products in the marketplace include combinations of IR, delayed release, and/or extended release components. These dosage forms may be designed to deliver drugs in a controlled and predictable manner over a period of time or at a predetermined position in the gastrointestinal (GI) tract.
Several commercial oral MR products have been developed using platform technologies such as hydrophilic matrix tablets, osmotic systems, and multi-particulate tablets. To better predict the in vivo performance of MR products, it is pertinent to understand how the product was designed, the attributes of the technology employed, and the mechanism and kinetics of drug release from the dosage form. Equally important is the understanding of biopharmaceutical properties of the dosage form, such as GI transit and regional absorption of the drug in the GI tract. Biopharmaceutics is focused on the mechanisms behind the absorption of an active drug molecule and its transport to the target site in the body. The key aspects of this process for an orally administered MR formulation intended for systemic absorption may include transit time of the formulation in the GI tract, location of drug released from the formulation, dissolution of the active molecule, permeation through the GI membrane, first pass clearance/pre-systemic metabolism, and intestinal degradation (especially bacteria-mediated reductive degradation in the colon). GI transit course is of special relevance for MR products since formulation design could potentially alter the transit properties, thereby influencing drug absorption. Drug release time course and dissolution profile are the fundamental properties for an MR formulation, which needs to be well understood in order to predict the performance of the product. Intestinal permeability and GI metabolism also deserve special attention for MR formulations in view of regional variations in the GI tract.
In vitro dissolution is one of the most important tests in the development of an MR dosage form, and it is essential to develop and implement in vitro dissolution tests that are capable of predicting in vivo performance whenever possible. However, this can be challenging in the presence of varying physiological conditions (e.g., pH, shear forces, and enzymes) along the GI tract, including food effects and/or ethanol intake. It is further noted that a dissolution method that discriminates between formulations does not always translate into a method that predicts performance in vivo. The development of a predictive dissolution method is commonly dependent upon a number of factors, the most important of which is the matrix and/or technology used to modify the rate of drug release. Consequently, for generic drug development where MR mechanisms are often not the same as the branded product, it is rare that one dissolution method might be useful or predictive for both products.