Fifty-Eight Years and Counting: High-Impact Publishing in Computational Pharmaceutical Sciences and Mechanism-Based Modeling.

With this issue of the Journal of Pharmaceutical Sciences, we celebrate the nearly 6 decades of contributions to mechanistic-based modeling and computational pharmaceutical sciences. Along with its predecessor, The Journal of the American Pharmaceutical Association: Scientific Edition first published in 1911, JPharmSci has been a leader in the advancement of pharmaceutical sciences beginning with its inaugural edition in 1961. As one of the first scientific journals focusing on pharmaceutical sciences, JPharmSci has established a reputation for publishing high-quality research articles using computational methods and mechanism-based modeling. The journal's publication record is remarkable. With over 15,000 articles, 3000 notes, and more than 650 reviews from industry, academia, and regulatory agencies around the world, JPharmSci has truly been the leader in advancing pharmaceutical sciences.

How Predictable Are Human Stratum Corneum Lipid/Water Partition Coefficients? Assessment and Useful Correlations for Dermal Absorption.

Partition coefficients between human stratum corneum lipids and water (Ksclip/w) are collected or deduced from a variety of sources in a manner that approximately doubles the available data compared to the current state-of-the-art model (Hansen et al., Adv Drug Deliv Rev. 2013;65(2):251-264). An additional datum for water itself in porcine SC that considerably extends the molecular size and lipophilicity range of the data set is considered. The data are analyzed in terms of an extended linear free energy relationship involving octanol/water partition coefficients, Abraham solvation parameters, and a secondary, power law molecular weight dependence. The optimum fit to log Ksclip/w for the full data set reduces the standard error of prediction from 0.50 for a Hansen-like model to 0.39; corresponding multiplicative errors in Ksclip/w are reduced from a factor of 3.1 to one of 2.5. The difference in performance is driven by the water datum, which requires a more complex dependence on molecular size than that afforded by Abraham parameters. In the absence of the water value, the Hansen-like model, which does not include a dependence on molecular size, is essentially optimum. A comparison is presented to fluid-phase phospholipid-water systems, which have a demonstrably different structure-property relationship.

Current challenges in bioequivalence, quality, and novel assessment technologies for topical products.

This paper summarises the proceedings of a recent workshop which brought together pharmaceutical scientists and dermatologists from academia, industry and regulatory agencies to discuss current regulatory issues and industry practices for establishing therapeutic bioequivalence (BE) of dermatologic topical products. The methods currently available for assessment of BE were reviewed as well as alternatives and the advantages and disadvantages of each method were considered. Guidance on quality and performance of topical products was reviewed and a framework to categorise existing and alternative methods for evaluation of BE was discussed. The outcome of the workshop emphasized both a need for greater attention to quality, possibly, via a Quality-By-Design (QBD) approach and a need to develop a "whole toolkit" approach towards the problem of determination of rate and extent in the assessment of topical bioavailability. The discussion on the BE and clinical equivalence of topical products revealed considerable concerns about the variability present in the current methodologies utilized by the industry and regulatory agencies. It was proposed that academicians, researchers, the pharmaceutical industry and regulators work together to evaluate and validate alternative methods that are based on both the underlying science and are adapted to the drug product itself instead of single "universal" method.

Analysis of finite dose dermal absorption data: implications for dermal exposure assessment.

A common dermal exposure assessment strategy estimates the systemic uptake of chemical in contact with skin using the fixed fractional absorption approach: the dermal absorbed dose is estimated as the product of exposure and the fraction of applied chemical that is absorbed, assumed constant for a given chemical. Despite the prominence of this approach there is little guidance regarding the evaluation of experiments from which fractional absorption data are measured. An analysis of these experiments is presented herein, and limitations to the fixed fractional absorption approach are discussed. The analysis provides a set of simple algebraic expressions that may be used in the evaluation of finite dose dermal absorption experiments, affording a more data-driven approach to dermal exposure assessment. Case studies are presented that demonstrate the application of these tools to the assessment of dermal absorption data.

Permeability of fluid-phase phospholipid bilayers: assessment and useful correlations for permeability screening and other applications.

Permeability data (P(lip/w) ) for liquid crystalline phospholipid bilayers composed of egg lecithin and dimyristoylphosphatidylcholine (DMPC) are analyzed in terms of a mathematical model that accounts for free surface area and chain-ordering effects in the bilayer as well as size and lipophilicity of the permeating species. Free surface area and chain ordering are largely determined by temperature and cholesterol content of the membrane, molecular size is represented by molecular weight, and lipophilicity of the barrier region is represented by the 1,9-decadiene/water partition coefficient, following earlier work by Xiang, Anderson, and coworkers. A correlating variable χ = MW(n) σ/(1 -σ) is used to link the results from different membrane systems, where different values of n are tried, and σ denotes a reduced phospholipid density. The group (1 -σ)/σ is a measure of free surface area, but can also be interpreted in terms of free volume. A single exponential function of χ is developed that is able to correlate 39 observations of P(lip/w) for different compounds in egg lecithin at low density, and 22 observations for acetic acid in DMPC at higher densities, spanning nine orders of magnitude to within an rms error for log 10 P(lip/w) of 0.20. The best fit found for n = 0.87 ultimately makes χ much closer to the ratio of molecular to free volumes than surface areas. The results serve as a starting point for estimating passive permeability of cell membranes to nonionized solutes as a function of temperature and cholesterol content of the membrane.