Margaret S. Landis

Stabilization of Pharmaceuticals to Oxidative Degradation

A guide for stabilization of pharmaceuticals to oxidation is presented. Literature is presented with an attempt to be a ready source for data and recommendations for formulators. Liquid and solid dosage forms are discussed with options including formulation changes, additives, and packaging documented. In particular, selection of and methods for use of antioxidants are discussed including recommended levels.

Hydrolysis in pharmaceutical formulations.

This literature review presents hydrolysis of active pharmaceutical ingredients as well as the effects on dosage form stability due to hydrolysis of excipients. Mechanisms and measurement methods are discussed and recommendations for formulation stabilization are listed.

Discovery of 1-[9-(4-chlorophenyl)-8-(2-chlorophenyl)-9H-purin-6-yl]-4-ethylaminopiperidine-4-carboxylic acid amide hydrochloride (CP-945,598), a novel, potent, and selective cannabinoid type 1 receptor antagonist.

We report the structure-activity relationships, design, and synthesis of the novel cannabinoid type 1 (CB1) receptor antagonist 3a (CP-945,598). Compound 3a showed subnanomolar potency at human CB1 receptors in binding (Ki = 0.7 nM) and functional assays (Ki = 0.12 nM). In vivo, compound 3a reversed cannabinoid agonist-mediated responses, reduced food intake, and increased energy expenditure and fat oxidation in rodents.

Recent Trends in Product Development and Regulatory Issues on Impurities in Active Pharmaceutical Ingredient (API) and Drug Products. Part 2: Safety Considerations of Impurities in Pharmaceutical Products and Surveying the Impurity Landscape

The American Association for Pharmaceutical Scientists (AAPS) Workshop on Predicting and Monitoring Impurities in API and Drug Products: Product Development and Regulatory Issues was held on 13–14 October 2012 at the McCormick Place in Chicago, IL, USA. The goal of the workshop was to discuss control strategies of chemical and physical changes of active pharmaceutical ingredients (API) and drug products in the drug development process. These changes can affect both the safety and efficacy of drugs; therefore, the ability to rapidly predict and assess the potential for drug product performance changes for impurity formation and the associated safety concerns are important parts of speeding the development of innovative drug therapies without compromising quality. The workshop comprised four different sessions. Each session focused on separate fundamental issues to build a comprehensive understanding of the physical and chemical processes that affect drug impurities and drug degradation products, the control of impurities, and the impact of these factors on safety and regulatory areas. Taken together, this comprehensive understanding is used to achieve a more robust development approach that enables predictability with a concomitant assurance of safety and efficacy. Innovative methodologies for development of effective stability control strategies were also presented. This article summarizes sessions 3 and 4 of the American Association for Pharmaceutical Scientists (AAPS) Workshop on Predicting and Monitoring Impurities in API and Drug Products: Product Development and Regulatory Issues and addresses issues of safety considerations of impurities in pharmaceutical products and surveying the impurity landscape. Sessions 1 and 2 of the American Association for Pharmaceutical Scientists (AAPS) Workshop on Predicting and Monitoring Impurities in API and Drug Products: Product Development and Regulatory Issues are summarized in Recent Trends in Product Development and Regulatory Issues on Impurities in active Pharmaceutical Ingredient (API) and Drug Products Part 1: Predicting Degradation Related Impurities and Impurity Considerations for Pharmaceutical Dosage Forms published separately.

Recent Trends in Product Development and Regulatory Issues on Impurities in Active Pharmaceutical Ingredient (API) and Drug Products. Part 1: Predicting Degradation Related Impurities and Impurity Considerations for Pharmaceutical Dosage Forms

The American Association for Pharmaceutical Scientists (AAPS) Workshop on Predicting and Monitoring Impurities in API and Drug Products: Product Development and Regulatory Issues was held on October 13–14, 2012 at the McCormick Place in Chicago, IL, USA. The goal of the workshop was to discuss control strategies of chemical and physical changes of active pharmaceutical ingredients (API) and drug products in the drug development process. These changes can affect both the safety and efficacy of drugs; therefore, the ability to rapidly predict and assess the potential for drug product performance changes for impurity formation and the associated safety concerns are important parts of speeding the development of innovative drug therapies. The workshop consisted of four different sessions. Each session focused on separate fundamental issues to build a comprehensive understanding of the physical and chemical processes that impact drug degradation, the control of impurities and the impact of these factors on safety and regulatory areas. Taken together, this comprehensive understanding is used to achieve a more robust development process that enables predictability with a concomitant assurance of safety and efficacy. Innovative methodologies for development of effective stability control strategies were also presented. This article summarizes Sessions 1 and 2 of the American Association for Pharmaceutical Scientists (AAPS) Workshop on Predicting and Monitoring Impurities in API and Drug Products: Product Development and Regulatory Issues and addresses of predicting degradation related impurities and impurity considerations for pharmaceutical dosage forms. Sessions 3 and 4 of the American Association for Pharmaceutical Scientists (AAPS) Workshop on Predicting and Monitoring Impurities in API and Drug Products: Product Development and Regulatory Issues are summarized in Recent Trends in Product Development and Regulatory Issues on Impurities in Active Pharmaceutical Ingredient (API) and Drug Products Part 2: Safety Considerations of Impurities in Pharmaceutical Products and Surveying the Impurity Landscape published separately.

Pharmacokinetics and metabolism studies on the glucagon-like peptide-1 (GLP-1)-derived metabolite GLP-1(9-36)amide in male Beagle dogs

Abstract 1. Glucagon-like peptide-1 (GLP-1)(7-36)amide is a 30-amino acid peptide hormone that is secreted from intestinal enteroendocrine L-cells in response to nutrients. GLP-1(7-36)amide possesses potent insulinotropic actions in the augmentation of glucose-dependent insulin secretion. GLP-1(7-36)amide is rapidly metabolized by dipeptidyl peptidase-IV to yield GLP-1(9-36)amide as the principal metabolite. Contrary to the earlier notion that peptide cleavage products of native GLP-1(7-36)amide [including GLP-1(9-36)amide] are pharmacologically inactive, recent studies have demonstrated cardioprotective and insulinomimetic effects with GLP-1(9-36)amide in mice, dogs and humans. 2. In the present work, in vitro metabolism and pharmacokinetic properties of GLP-1(9-36)amide have been characterized in dogs, since this preclinical species has been used as an animal model to demonstrate the in vivo vasodilatory and cardioprotective effects of GLP-1(9-36)amide. A liquid chromatography tandem mass spectrometry assay was developed for the quantitation of the intact peptide in hepatocyte incubations as opposed to a previously reported enzyme-linked immunosorbent assay. Although GLP-1(9-36)amide was resistant to proteolytic cleavage in dog plasma and bovine serum albumin (t1/2 > 240 min), the peptide was rapidly metabolized in dog hepatocytes with a t1/2 of 110 min. Metabolite identification studies in dog hepatocytes revealed a variety of N-terminus cleavage products, most of which, have also been observed in human and mouse hepatocytes. Proteolysis at the C-terminus was not observed in GLP-1(9-36)amide. 3. Following the administration of a single intravenous bolus dose (20 µg/kg) to male Beagle dogs, GLP-1(9-36)amide exhibited a mean plasma clearance of 15 ml/min/kg and a low steady state distribution volume of 0.05 l/kg, which translated into a short elimination half life of 0.05 h. Following subcutaneous administration of GLP-1(9-36)amide at 50 µg/kg, systemic exposure of GLP-1(9-36)amide as ascertained from maximal plasma concentrations and area under the plasma concentration–time curve from zero to infinity was 44 ng/ml and 32 ng h/ml, respectively. The subcutaneous bioavailability of GLP-1(9-36)amide in dogs was 57%. 4. Our findings raise the possibility that the cardioprotective effects of GLP-1(9-36)amide in the conscious dog model of pacing-induced heart failure might be due, at least in part, to the actions of additional downstream metabolites, which are obtained from proteolytic cleavage of the peptide backbone in the parent compound in the liver.

Discovery of spirocyclic-diamine inhibitors of mammalian acetyl CoA-carboxylase.

A novel series of spirocyclic-diamine based, isoform non-selective inhibitors of acetyl-CoA carboxylase (ACC) is described. These spirodiamine derivatives were discovered by design of a library to mimic the structural rigidity and hydrogen-bonding pattern observed in the co-crystal structure of spirochromanone inhibitor I. The lead compound 3.5.1 inhibited de novo lipogenesis in rat hepatocytes, with an IC50 of 0.30 μM.

Commentary: Why Pharmaceutical Scientists in Early Drug Discovery Are Critical for Influencing the Design and Selection of Optimal Drug Candidates

This commentary reflects the collective view of pharmaceutical scientists from four different organizations with extensive experience in the field of drug discovery support. Herein, engaging discussion is presented on the current and future approaches for the selection of the most optimal and developable drug candidates. Over the past two decades, developability assessment programs have been implemented with the intention of improving physicochemical and metabolic properties. However, the complexity of both new drug targets and non-traditional drug candidates provides continuing challenges for developing formulations for optimal drug delivery. The need for more enabled technologies to deliver drug candidates has necessitated an even more active role for pharmaceutical scientists to influence many key molecular parameters during compound optimization and selection. This enhanced role begins at the early in vitro screening stages, where key learnings regarding the interplay of molecular structure and pharmaceutical property relationships can be derived. Performance of the drug candidates in formulations intended to support key in vivo studies provides important information on chemotype-formulation compatibility relationships. Structure modifications to support the selection of the solid form are also important to consider, and predictive in silico models are being rapidly developed in this area. Ultimately, the role of pharmaceutical scientists in drug discovery now extends beyond rapid solubility screening, early form assessment, and data delivery. This multidisciplinary role has evolved to include the practice of proactively taking part in the molecular design to better align solid form and formulation requirements to enhance developability potential.

Design of Clinical Studies in Early Development

There is growing philosophy in the realm of drug discovery that rapid feedback from strategic and tactical early clinical studies is one of the most vital components to optimizing the cycle of successful drug design. The current early development paradigms however do not always support the rapid relay of this vital clincal information to early drug discovery teams. Several industrial, government and academic initiatives are underway to improve the efficiency of the discovery to clinical information feedback loop, thereby increasing the number of drug therapies ultimately commercialized. Success will lie in early, proactive clinical biomarker and diagnostics identification and/or co-development, an early and sustained focus on predictive model development, application of early, adaptive clinical design strategies, and the use of fully integrated information technology (IT) and knowledge management (KM) systems.