» SOLUBILITY
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Signifi cant progress has been made over the past two decades to model, predict, and test all of the aforementioned factors. In particular, the introduction and the later widespread use of the Caco-2 cell line for permeability testing as well as the increased sophistication in dissolution testing, has helped improve the precision of predicting the absorption of drugs [3].
Another important milestone has been the introduction of the Biopharmaceutics Classification System (BCS) in 1995 [4] and its widespread use among scientists – including formulation/ drug delivery scientists, pharmacokineticists, pharmacologists, and medicinal chemists, among others – in the process of drug development, thereafter. Today, the BCS concept is also applied to predict the impact of the physiological state of the GI tract and food intake on the bioavailability of drugs [5]. In addition to the BCS, other sophisticated in vitro as well as in silico tools have become available to scientists in the recent past, helping evaluate the suitability of drug candidates, formulations, and delivery systems for oral administration. Building on as well as going beyond pharmacopeial dissolution testing, these modern tools include software packages for the simulation of absorption processes and complex experimental dissolution set-ups like the artificial stomach. Combined uses of dissolution testing in an artificial stomach set- up and computing the data in silico have also been applied more recently [6]. Novel approaches include various important factors, e.g. the prediction of supersaturation and precipitation in the GI- tract, which can be of high relevance. Furthermore, the development of an integrated tool for the prediction of the in vivo performance of oral dosage forms, the “OrBiTo” (Oral Biopharmaceuticals Tool) focused at addressing current gaps in scientists’ toolbox, has been proposed very recently [7].
Today’s increased understanding of absorption processes is the basis for modern development of oral medicines, whether it is applied at early stages of R&D at the pipeline level (portfolio of developmental drugs), the single molecule level (e.g. for the enablement of an specifi c drug), or at the formulation level (e.g. for line-extensions).
Developability of NCEs
Drug discovery today, designing novel drugs for tomorrow, is an important and exciting fi eld. Once a pharmacological target has been identifi ed, early activities comprise the screening of numerous compounds – e.g. from a compound library – in order to determine which ones interact with the target. This process typically results in the identifi cation of so-called hits as one of the fi rst steps in the modern drug discovery process. Subsequent structural optimization of these hits via the hit to lead to candidate to drug sequence takes into account various strategies to increase effi cacy, selectivity, metabolic stability, and, importantly, oral bioavailability of the compounds. Typically it takes about 8-12 years from the initial testing stage via preclinical and clinical development until the new medicine will be available to the patient, and in the process the number of approximately 8,000 compounds will be narrowed down to one marketed drug.
30 | | September/October 2013 - 15TH ANNIVERSARY ISSUE
Figure 1. Drug discovery and developability information (modifi ed from [8])
How to select leads and candidates – and thereby ultimately the novel drug – has been heavily infl uenced by insights from the domain of developability of NCEs [8] in the recent past.
The task at hand – in addition to optimizing the compound’s pharmacological activity – is to increase the probability of successfully moving that very compound from in vitro testing to the bedside. This task can be achieved by carefully designing the physico-chemical and biopharmaceutical properties of the NCE, thereby enhancing its developability. In recent years, a number of models and multi-parametric principles have been established to support exactly that activity.
An earlier milestone in that domain has been the publication of Lipinski’s rule-of-fi ve (RO5) in 1997 [9] and its direct or modifi ed application thereafter. Its increasing importance in the late 90s and its rapid uptake is proven by the fact that in the year 2004 alone, the citations in CAS SciFinder to the original RO5 publication exceeded 1,000 [10]. The original RO5 defi nes four physico-chemical parameters found in a set of orally active drugs which made it into phase II clinical trials:
• • • •
molecular weight ≤500 logP ≤5
H-bond donors ≤5 H-bond acceptors ≤10, and
Over the past 15 years, the knowledge relative to predictors for oral activity of drug candidates has significantly grown, and various changes to the RO5 have been suggested, including the introduction of a rule-of-three for the application in fragment- based drug design [11].
Today, it is widely accepted that a sequential approach of focusing on effi cacy and selectivity, e.g. designing a high affi nity ligand, in a fi rst step and to deal with its drug-like properties only later on, is an inferior strategy to a more holistic approach which includes taking properties like solubility and permeability into account already early on. Furthermore, enzymatic as well as chemical stability are of interest as one looks at the overall developability of compounds.
In practical terms, there are various opportunities at the molecular level to infl uence the developability parameter of solubility, including
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