Despite the fact that a significant percentage of the population is unable to swallow tablets and capsules, these dosage forms continue to be the default standard. These oral formulations fail many patients, especially children, because of large tablet or capsule size, poor palatability, and lack of correct dosage strength. The clinical result is often lack of adherence and therapeutic failure. The American Association of Pharmaceutical Scientists formed a Pediatric Formulations Task Force, consisting of members with various areas of expertise including pediatrics, formulation development, clinical pharmacology, and regulatory science, in order to identify pediatric, manufacturing, and regulatory issues and areas of needed research and regulatory guidance. Dosage form and palatability standards for all pediatric ages, relative bioavailability requirements, and small batch manufacturing capabilities and creation of a viable economic model were identified as particular needs. This assessment is considered an important first step for a task force seeking creative approaches to providing more appropriate oral formulations for children.

This review starts with an introduction on the theoretical aspects of biopharmaceutics and developments in this field from mid-1950s to late 1970s. It critically addresses issues related to fundamental processes in oral drug absorption such as the complex interplay between drugs and the gastrointestinal system. Special emphasis is placed on drug dissolution and permeability phenomena as well as on the mathematical modeling of oral drug absorption. The review ends with regulatory aspects of oral drug absorption focusing on bioequivalence studies and the US Food and Drug Administration and European Medicines Agency guidelines dealing with Biopharmaceutics Classification System and Biopharmaceutic Drug Disposition Classification System. (C) 2013Wiley Periodicals, Inc. and the American Pharmacists Association

Unveil the properties of a two-stage design (TSD) for bioequivalence (BE) studies. A TSD with an upper sample size limit (UL) is described and analyzed under different conditions using Monte Carlo simulations. TSD was split into three branches: A, B1, and B2. The first stage included branches A and B1, while stage two referred to branch B2. Sample size re-estimation at B2 relies on the observed GMR and variability of stage 1. The properties studied were % BE acceptance, % uses and % efficiency of each branch, as well as the reason of BE failure. No inflation of type I error was observed. Each TSD branch exhibits different performance. Stage two exhibits the greatest % BE acceptances when highly variable drugs are assessed with a low starting number of subjects (N-1) or when formulations differ significantly. Branch A is more frequently used when variability is low, drug products are similar, and a large N-1 is included. BE assessment at branch A is very efficient. The overall acceptance profile of TSD resembles the typical pattern observed in single-stage studies, but it is actually different. Inclusion of a UL is necessary to avoid inflation of type I error.

Purpose: The purpose of this work was to assess the colloidal stability of novel milk-based formulations. Methods: Milk-based formulations were prepared in situ by adding into milk alkaline- or ethanolic-drug solutions containing an array of drugs namely; ketoprofen, tolfenamic acid, meloxicam, tenoxicam and nimesulide, mefenamic acid, cyclosporine A, danazol and clopidogrel besylate. The produced formulations were characterized by means of dynamic lightscattering, zeta-potential studies, atomic force microscopy, fluorescence spectroscopy, Raman spectroscopy complemented with ab initio calculations and stability studies. Results: The presence of the drugs did not induce significant changes in most cases to the particle size and zeta-potential values of the emulsions pointing to the colloidal stability of these formulations. Raman spectroscopy studies revealed interactions of the drugs and the milk at the intermolecular level. Complementary analysis with ab initio calculations confirmed the experimental observations obtained by Raman spectroscopy. Finally the produced drug containing alkaline/ethanolic solutions exhibited stability over a period of up to 12 months. Conclusions: The current data demonstrate that milk is a promising drug carrier. (C) 2013 Elsevier B. V. All rights reserved.

Assessment of bioequivalence (BE) for highly variable drugs is challenging. As within-subject variability increases, it becomes more difficult to prove BE, unless a large number of subjects is recruited. In order to face this problem, several approaches have been proposed. Among them, scaled BE limits (BEL) have recently attracted special attention because the European Medicines Agency and the US Food and Drug Administration adopted scaled approaches. Scaled BELs expand with variability using specific mathematical functions while include additional regulatory criteria in some cases. The aim of this study is twofold: (1) to provide a deeper insight into the dependence of scaled BELs on variability and (2) to unveil the underlying mathematical relationships. The comparative analysis of these BELs is implemented through algebraic manipulations and graphic illustrations. Special emphasis is placed on the ``absolute change{''} of each BEL and the ``relative change,{''} reflecting the portion of the relative to the maximum expansion of a BEL. This analysis reveals the causal differences between the different BELs on the mode of ``absolute{''} and ``relative{''} change. The results derived from this study are in agreement with the observed different performances of the various scaled BE approaches. (C) 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:296-301, 2013

Generics are usually considered to exhibit comparable in vivo properties in terms of efficacy and safety and for this reason are intended to be interchangeable with the reference product. The aim of this study is to provide a quantitative picture of the switchability problem between two generics and to introduce the concept of conditional probability of bioequivalence (BE) acceptance. Monte Carlo simulations were performed to examine all possible relationships between the tested products. Four types of percent BE acceptances are defined and evaluated: (a) % BA1, when generic T-1 is compared to the R product, (b) % BA2, in cases of comparison of generic T-2 with the R product, (c) % BA21, when generic T-2 is compared to another generic T-1, and finally (d) % BA21C which is the conditional probability of percent bioequivalence acceptance of generic T(2)versus another generic T-1 given that both T-1 and T-2 are declared bioequivalent to the same R formulation. The simulations were expanded to study concomitantly the performance of T-1 and T-2 when compared to the same R formulation. In each case, the 2 x 2 cross-over design was used and evaluation of BE was based on the classic BE limits (0.80-1.25) and the stricter BE limits (0.90-1.11) for narrow therapeutic index (NTI) drugs. A number of 24 and 48 subjects were assumed to participate in the simulated trials, while the coefficient of variation for the within-subject variability (CVw) was 20% and 40%. A number 40,000 BE trials were simulated under each condition. The T-1/R and T-2/R ratios ranged from 0.80 to 1.25 using a step of 0.05. Even though two generics (T-1 and T-2) can be declared bioequivalent to the same R product, this does not ensure that they are always mutually bioequivalent. On the contrary, two generic products which differ substantially from the R product can still have a high probability to be truly interchangeable. The two generics (T-1 and T-2) can be switched from one to another when the T-1/R and T-2/R ratios are close to the same value, the CVw of the drug is low, and each BE study of T-1-R and T-2-R was conducted using a relatively large number of subjects. In the same context, two generic NTI drugs which differ more than 10% from the R product can still be declared bioequivalent to one another depending on the relative T-1/R and T-2/R ratios. Switchability between generics assessed at the 0.90-1.11 interval is safer, but not always ensured. (C) 2013 Elsevier B.V. All rights reserved.

Fractals have been very successful in quantifying nature's geometrical complexity, and have captured the imagination of scientific community. The development of fractal dimension and its applications have produced significant results across a wide variety of biomedical applications. This review deals with the application of fractals in pharmaceutical sciences and attempts to account the most important developments in the fields of pharmaceutical technology, especially of advanced Drug Delivery nano Systems and of biopharmaceutics and pharmacokinetics. Additionally, fractal kinetics, which has been applied to enzyme kinetics, drug metabolism and absorption, pharmacokinetics and pharmacodynamics are presented. This review also considers the potential benefits of using fractal analysis along with considerations of nonlinearity, scaling, and chaos as calibration tools to obtain information and more realistic description on different parts of pharmaceutical sciences. As a conclusion, the purpose of the present work is to highlight the presence of fractal geometry in almost all fields of pharmaceutical research. (C) 2013 Elsevier B.V. All rights reserved.