Further, we propose developing a corresponding drug product in vivo predictive dissolution (IPD) methodology, based on these classes and subclasses that will be predictive of in vivo performance. While these factors can be complex, in this manuscript we propose a BCS Class II and IV sub-classification with a, b, and c subclasses dependent on the acidic (a), basic (b), or neutral (c) characteristics of the drug in the physiological pH range (~pH < 7.5). Clearly the in vitro dissolution methodology needs further development, relative to the in vivo conditions, in order to be predictive of in vivo oral performance.īCS Class II and IV drug product dissolution in vivo and in vitro is highly dependent on the acidic or basic nature of the drug, the drug solubility and formulation factors, in addition to the in vivo luminal environment. Thus in vivo dissolution is the critical determinant of in vivo absorption, bioavailability (BA) and the subsequent bio-equivalence (BE) determinations. Drugs and drug products within BCS Class II, for example, low solubility and high permeable drugs, would be absorbed completely, if in solution. However, as noted by Butler ( Butler and Dress-man, 2010) it does not capture the most significant physicochemical differences that are critical to dosage form design and performance for BCS Class II and IV drugs/drug products. The criterion for high solubility, high permeability and product dissolution is likely conservative relative to the current in vivo bioequivalence (BE) (80–125%) standard for BCS Class I drugs. The FDA BCS guidance allows biowaivers for BCS Class I drugs based on drug product in vitro dissolution for immediate-release (IR) solid oral dosage forms ( CDER/FDA, 2000). The Biopharmaceutics Classification System (BCS) and the corresponding guidance issued by the FDA categorize drug substances into 4 groups based on aqueous solubility and intestinal membrane permeability ( Amidon et al., 1995). Such a dissolution methodology can be used by development scientists to assess the likelihood of a formulation and dosage form functioning as desired in humans, can be optimized along with parallel human pharmacokinetic studies to set a dissolution methodology for Quality by Design (QbD) and in vitro–in vivo correlations (IVIVC) and ultimately can be used as a basis for a dissolution standard that will ensure continued in vivo product performance. We believe this sub-classification is a step toward developing a more science-based mechanistic in vivo predictive dissolution (IPD) methodology. This BCS sub-classification is particularly important for in vivo predictive dissolution methodology development due to the complex and variable in vivo environment in the gastrointestinal tract, with its changing pH, buffer capacity, luminal volume, surfactant luminal conditions, permeability profile along the gastrointestinal tract and variable transit and fasted and fed states. It is well known that the, p Ka physical property of a drug (API) has a significant impact on the aqueous solubility dissolution of drug from the drug product both in vitro and in vivo for BCS Class II and IV acids and bases, and is the basis, we propose for a sub-classification extension of the original BCS classification. Sub-classification for Classes I and III (high solubility drugs as currently defined) is generally not needed except perhaps in border line solubility cases. In this manuscript we propose a simple extension of the BCS classes to include subspecification of acid (a), base (b) and neutral (c) for classes II and IV. Nevertheless, underneath the simplicity of BCS are many detailed complexities, both in vitro and in vivo which must be evaluated and investigated for any given drug and drug product. The mechanistic base of the BCS approach has, no doubt, contributed to its wide spread acceptance and utility. The classification scheme captures the two most significant factors influencing oral drug absorption solubility and intestinal permeability and it has proven to be a very useful and a widely accepted starting point for drug product development and drug product regulation. The Biopharmaceutics Classification System (BCS) has found widespread utility in drug discovery, product development and drug product regulatory sciences.
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