In search of the grail: A race for acid suppression. / La búsqueda del Grial: una carrera por la supresión ácida.

Proton pump inhibitors are the reference standards for the treatment of acid-related diseases. Acid suppression in gastroesophageal reflux disease is associated with a high rate of mucosal cicatrization, but symptom response differs among endoscopic phenotypes. Extraesophageal manifestations have a good clinical response in patients that present with abnormal acid exposure (diagnostic test) in the esophagus. Proton pump inhibitors have shown their effectiveness for reducing symptom intensity in nighttime reflux and sleep disorders, improving quality of life and work productivity. That can sometimes be achieved through dose modifications by splitting or increasing the dose, or through galenic formulation. Proton pump inhibitors are not exempt from controversial aspects related to associated adverse events. Technological development is directed at improving proton pump inhibitor performance through increasing the half-life, maximum concentration, and area under the curve of the plasma concentrations through galenic formulation, as well as creating safer and more tolerable drugs. The present review is focused on the mechanisms of action, pharmacokinetic properties, and technological advances for increasing the pharmacologic performance of a proton pump inhibitor.

Development of a stability- indicating HPLC method for simultaneous determination of ten related substances in vonoprazan fumarate drug substance.

Vonoprazan fumarate is a novel potassium-competitive acid blocker for the treatment of acid-related diseases. In the present study, a simple, fast, and economic reversed-phase liquid chromatography (LC) method was developed for the analysis of ten related substances (raw materials, by-products and degradants) in vonoprazan fumarate. The optimized separation was performed on a Phenomenex Kinetex EVO C18 (250mm×4.6mm, 5.0µm) column. The mobile phase consisted of (A) 0.03M sodium phosphate buffer (pH adjusted to 6.5) - methanol - acetonitrile (72:25:3, v/v/v) and (B) 0.03M sodium phosphate buffer (pH adjusted to 6.5) - acetonitrile (30:70, v/v). Detection of the analytes was conducted at 230nm using a UV detector. The stability-indicating ability of this method was demonstrated by carrying out forced degradation studies. Vonoprazan underwent significant degradation when subjected to alkaline and oxidative stress conditions, while the drug proved to be stable to acidic, thermal and photolytic degradation. The degradants did not interfere with the detection of vonoprazan fumarate and its impurities. The performance of this method was validated in accordance to the regulatory guidelines recommended by the International Conference on Harmonisation (ICH) and this validation included specificity, linearity, limit of detection (LOD), limit of quantification (LOQ), accuracy, precision and robustness. The method proposed in this paper could be applied for process development as well as quality assurance of vonoprazan in bulk drug, since no monograph is available in official compendia.

Combining simplicity with cost-effectiveness: Investigation of potential counterfeit of proton pump inhibitors through simulated formulations using thin-layer chromatography.

A simple, accurate and precise high-performance thin-layer chromatographic method has been developed and validated for the analysis of proton pump inhibitors (PPIs) and their co-formulated drugs, available as binary combination. Planar chromatographic separation was achieved using a single mobile phase comprising of toluene: iso-propranol: acetone: ammonia 5.0:2.3:2.5:0.2 (v/v/v/v) for the analysis of 14 analytes on aluminium-backed layer of silica gel 60 FG254. Densitometric determination of the separated spots was done at 290nm. The method was validated according to ICH guidelines for linearity, precision and accuracy, sensitivity, specificity and robustness. The method showed good linear response for the selected drugs as indicated by the high values of correlation coefficients (≥0.9993). The limit of detection and limit of quantiation were in the range of 6.9-159.2ng/band and 20.8-478.1ng/band respectively for all the analytes. The optimized conditions afforded adequate resolution of each PPI from their co-formulated drugs and provided unambiguous identification of the co-formulated drugs from their homologous retardation factors (hRf). The only limitation of the method was the inability to separate two PPIs, rabeprazole and lansoprazole from each other. Nevertheless, it is proposed that peak spectra recording and comparison with standard drug spot can be a viable option for assignment of TLC spots. The method performance was assessed by analyzing different laboratory simulated mixtures and some marketed formulations of the selected drugs. The developed method was successfully used to investigate potential counterfeit of PPIs through a series of simulated formulations with good accuracy and precision.

Assessing the chiral switch: approval and use of single-enantiomer drugs, 2001 to 2011.

OBJECTIVES: A "chiral switch" occurs in the pharmaceutical market when a drug made up of 2 enantiomer forms is replaced with a purified single-enantiomer version, often in the context of a patent expiration. We studied the prevalence of chiral switching in the United States over the past decade, including trends in use of, and expenditures on, these products in Medicaid. STUDY DESIGN: Retrospective analysis. METHODS: We used US Adopted Names prefixes (lev/levo/ar/es/dex/dextro) to identify all single-enantiomer drugs approved from 2001 to 2011. From publicly available US Food and Drug Administration (FDA) approval documents, we extracted the characteristics of the pivotal premarket trials for the single enantiomers. Specifically, we evaluated whether the single enantiomer was directly compared with the precursor racemic drug and whether there was evidence of superior efficacy. We used quarterly drug expenditure data from each state Medicaid program to chart trends in use of, and spending on, the single-enantiomer products and their racemic precursors during the study period. RESULTS: From 2001 to 2011, the FDA approved 9 single-enantiomer products: dexlansoprazole, levoleucovorin, levocetirizine, armodafinil, arformoterol, eszopiclone, escitalopram, dexmethylphenidate, and esomeprazole. Of those 9 drugs, 3 had at least 1 pre-approval randomized trial that included the racemic precursor as a direct comparator, but there was no evidence of superiority of the single enantiomer over the racemic at comparable doses. Between 2001 and 2011, US Medicaid programs spent approximately $6.3 billion on these 9 single-enantiomer drugs. CONCLUSIONS: Recently approved single-enantiomer drugs showed no evidence of superior efficacy over the older racemic precursors in the pivotal trials leading to their approval, and in a majority of cases, they were not directly compared.