Arsenic trioxide (ATO) is a promising chemotherapeutic agent, but its clinical application is limited due to its poor pharmacokinetics and dose-limited toxicity. Moreover, the combination of ATO and sec-o-glucosylhamaudol (SOG) can improve the therapeutic effect of hepatoma. In this study, PEGylated magnetic nanographene oxide (PEG@MGO) was used as magnetic carriers to enhance the targeting ability of the drug delivery system. ATO and SOG are loaded on the surface of PEG@MGO nanoparticles through electrostatic interactions. This biocompatible nanocomposite shows magnetic susceptibility, pH sensitivity, and high loading capacity of the drugs. The in vitro cytotoxicity study of human hepatoma cell line (HepG2) cells showed more significant cytotoxicity and obvious synergistic effect between ATO and SOG compared with that of single drug-loaded nanoparticles via MTT assay. In vitro cellular uptake was observed by Prussian blue staining and fluorescently labeling. The results demonstrated a high cellular internalization rate of PEG@MGO. The ATO and SOG co-loaded nanodrug significantly inhibits the growth of tumors in vivo, which might be due to the oxidative stress and proapoptotic effect. This type of multidrug nanocomposite offers a promising alternative for cancer therapy.Graphical A pH-sensitive polyethylene glycol-modified magnetic graphene oxide loaded with ATO and SOG (PEG@MGO@ATO + SOG) was prepared for the magnetically targeted and efficient synergistic-chemo cancer therapy, which exhibited high specificity and good biocompatibility.

Vancomycin (VCM) is an antimicrobial that is recommended for therapeutic drug monitoring (TDM) for maintaining the efficacy and safety of treatment. The trough monitoring has been used to guide VCM dosing regimens. However, newer guidelines recommend the use of area under the curve/minimum inhibitory concentration (AUC/MIC)-guided vancomycin dosing, and there is a need for easier and more frequent measurements of VCM concentrations. Therefore, in this study, we developed a simple and rapid analytical method for measuring urinary VCM by combining solid-phase extraction and fluorescence analysis. Urine samples are easier and less invasive than blood samples. In addition to the therapeutic range of blood VCM, this method was also able to measure 0.01–1 mg/mL, which is the concentration range of urinary VCM. The accuracy of 10, 20, and 30 μg/mL VCM solutions were between 93.18 and 109.76%. The relative standard deviation (RSD) of intra-day and inter-day analysis were less than 6.25% and 6.28%, respectively. Since this method does not use large equipment, it is expected to be better suited for clinical use.

The COVID-19 pandemic has led to increased usage of hand sanitizer products by the public to prevent the spread of COVID-19 and decrease the likelihood of acquiring the disease. The increase in demand has also led to an increase in the number of manufacturers. This work describes the FDA’s Center for Drug Evaluation and Research (CDER) laboratories efforts to develop tests to assess the quality of hand sanitizer products containing ethanol or isopropanol as the primary active ingredient. The products were evaluated for the active ingredient content and determination of the 12 impurities listed in the FDA Hand Sanitizer Temporary Guidance, followed by a spike recovery assay performed to verify the test results. Extensive method development was conducted including an investigation into the stability of ethanol, isopropanol, and the 12 impurities. Stability and kinetic studies confirmed the instability of acetal in acidic liquid hand sanitizer products during spike recovery assay testing. The headspace GC-MS method was validated according to ICH Q2 (R1) guidelines and the spike recovery assay was validated using three concentrations of standards for the drug product. During method application, six liquid hand sanitizer products were tested and all were determined to have ethanol or isopropanol above 70% v/v. Two liquid hand sanitizer products were determined to contain acetaldehyde as an impurity above the FDA recommended safety levels.

The use of a Quality by Design (QbD) approach in the development of pharmaceutical products is known to bring many advantages to the table, such as increased product and process knowledge, robust manufacturing processes, and regulatory flexibility regarding changes during the commercial phase. However, many companies still adhere to a more traditional pharmaceutical process development—in some cases due to the difficulty of going from a theoretical view of QbD to its actual application. This article presents a real-world case study for the development of an industrial pharmaceutical drug product (oral solid dosage form) using the QbD methodology, demonstrating the activities involved and the gains in obtaining systematic process and product knowledge.

Fingolimod is an oral agent approved for the treatment of relapsing forms of multiple sclerosis (MS), which has demonstrated efficacy in Phase III trials in patients with relapsing-remitting MS (RRMS). The present study was designed to assess bioequivalence between a fingolimod Test capsule formulation (Teva Argentina, formerly IVAX Argentina S.A.) and a Reference capsule formulation (Novartis Pharma GmbH, Germany). In a single-center, randomized, single-dose, open-label, two-way crossover study under fed conditions, 16 healthy volunteers were randomized to receive a single oral dose of 0.5 mg of the Test and Reference formulations, with a 42-day washout period between administrations. The three pharmacokinetic (PK) parameters employed in the study to assess the bioequivalence between the Test and Reference formulations were maximum plasma concentration (Cmax), time to Cmax (Tmax), and area under the concentration–time curve from time zero to 72 h (AUC0–72). No significant differences between the Test and Reference formulations for any of the three PK parameters were observed. Based on 90% geometric confidence intervals (CIs) within 80% to 125% for both AUC0–72 and Cmax, the Test and Reference formulations were considered bioequivalent.

There has been significant growth in the use of modeling tools to accelerate development and enhance pharmaceutical quality. Among these are empirical and semi-empirical modeling of accelerated stability studies which can be used to predict product shelf-life (Waterman, Pharm Res 24:780–790, 2007; (Wu et al., AAPS Pharm Sci Tech,16:986–991, 2016); (Lavrich, Rapid Development of Robust Stability Models Using Semi-Empirical Design Space, AAPS Webinar, 2016)). These approaches coupled with Lean Stability and Quality by Design (QbD) Analytical Method Development have been discussed at a recent AAPS Workshop (AAPS Workshop, Accelerating Pharmaceutical Development through Predictive Stability Approaches, 2016) with subsequent discussions at a Face-to-Face Focus Group meeting (AAPS, Joint Face-to-Face meeting summary, 6-April, part1, 2017; AAPS, Joint Face-to-Face meeting summary, 6-April, Part II, 2017; Huynh-Ba, et al., Meeting Report, Analytical Approaches to Ensure Product Quality – AAPS Joint Face-to-Face Meeting of the Stability, the Pharmaceutical Impurities, and the CMC Statistics Focus Group, 2017) and the AAPS Annual meeting (AAPS Annual Meeting Sunrise Session, Accelerating Pharmaceutical Development through Predictive Stability Approaches, AAPS Annual Meeting, 2016). A summary/overview and the outcome from the workshop are captured in this publication. The first part focuses on use of Lean Stability Strategies to expedite the development of new chemical entities in early phase development, and to facilitate process, formulation for various dosage forms (solid, liquid, etc.) and product changes throughout development and post-approval. Also, presented, are the global regulatory agencies feedback, challenges and future direction. For Lean Stability and predictive stability approaches to be successful, the methods used must be accurate, precise and consistent across stability time points, analysts, instruments and testing sites, so the data and predictions are meaningful. For both small and large molecules, the use of QbD for analytical method development aids in achieving this goal; and, the second part of this publication discusses such approaches. These approaches are essential to build an overall optimized stability strategy to meet today’s challenges to advance new medicines and enhance quality.

The computer program ASAPprime® has been used successfully for some time to predict the stability of active pharmaceutical ingredients (APIs) in solid-dosage forms. In this study, we have demonstrated that the ASAPprime® program can also be used to predict the slow-down in dissolution of two APIs in an immediate release tablet. The tablets were pre-equilibrated at 25 °C at different relative humidities (30–75 %), sealed in aluminum pouches and stored at temperatures ranging from 50–60 °C for 3, 7 or 14 days. The storage times were selected to encompass the time needed to produce a slowdown in dissolution such that the amount of the two APIs fell below the acceptance criteria of no less than 80 % dissolved in 20 min. Up to 6 months of stability data from a 40 °C/75%RH open dish study were also included in the modeling. The effects of temperature (T in °K) and relative humidity (RH) were then shown to be related to the isoconversion (IC) time by an empirical, modified Arrhenius equations, where IC is the time for the amount dissolved to equal 80 % of the label claim. These studies showed that while the slowdown in dissolution of API 2 was influenced more by the relative humidity than API 1, the overall slowdown in dissolution was more sensitive to changes in temperature than changes in relative humidity. In addition to showing that ASAPprime® could be used to model the effects of temperature and relative humidity on dissolution, the software was also used to demonstrate that no special precautions were necessary to protect the tablets from moisture and they could be stored in Aclar blisters®. It was also shown that the water content of the tablet was not a critical quality attribute and need not be included in the drug product specification.