Stefan Scheuerer

Ibuprofen Extrudate, a Novel, Rapidly Dissolving Ibuprofen Formulation: Relative Bioavailability Compared to Ibuprofen Lysinate and Regular Ibuprofen, and Food Effect on All Formulations

N anti-inflammatory drugs (NSAIDs), including ibuprofen, have been used for decades in the management of a multitude of pain conditions and rheumatic diseases. Their effects include inhibition of prostaglandin synthesis resulting in analgesic, anti-inflammatory, and antipyretic efficacy. Because of a longstanding and favorable safety record as well as proven efficacy in many different populations and indications, the popularity of ibuprofen is ever increasing. The vast majority of indications for pain treatment requires an onset of action as quickly as possible. For an oral administration drug, the time to onset of a desired pharmacological effect depends on many successive steps: dissolution of the formulation, passage to the site of absorption (usually the jejunal parts of the small intestine), permeation through physiological membranes, entry into the portal vein circulation (with potential enteric or hepatic first-pass metabolism), distribution from plasma to the site of action, and interaction with the receptor, which then causes a cascade of events leading to the targeted pharmacological modification. Distribution to other tissues, metabolism, and excretion of the active principle may also affect early availability of the drug at the effector site. For many compounds, the initial rise of the plasma concentration, following oral administration, is critical with regard to time to onset of the desired pharmacological effect. Ibuprofen shows low solubility in aqueous acidic media but is highly permeable through physiological membranes. Bioavailability is close to 100% because of almost complete absorption, but the onset of absorption strongly depends on dissolution and thus on the administered formulation. Different approaches have been made to improve solubility of the active ingredient, such as transferring the substance to a salt (lysinate) or designing a pharmaceutical dosage form that favors a quick release of ibuprofen in the gastrointestinal tract. In the manufacture of ibuprofen extrudate tablets, a special extrusion technology is applied to provide the BRIEF REPORTS/PHARMACOKINETICS

Computational approaches to predict drug metabolism.

Background: Metabolism is one of the key parameters to be investigated and optimized in drug discovery projects. Metabolically unstable compounds or potential inhibitors of important enzymes should be detected as early as possible. As more compounds are synthesized than can be investigated experimentally, powerful computational methods are needed. Objective: We give an overview of state-of-the-art in-silico methods to predict experimental metabolic endpoints with a focus on the applicability in pharmaceutical industry. A macroscopic as well as a microscopic view of the metabolic fate and the interaction with metabolizing enzymes are given. Methods: Ligand-, protein- and rule-based approaches are presented. Conclusion: Although considerable progress has been made, the results of the calculations still need careful inspection. The domain of applicability of the models as well as methodological limitations have to be taken into account.

Novel 6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene analogues as potent and selective 5-HT2C agonists for the treatment of metabolic disorders

The discovery of a novel series of 5-HT(2C) agonists based on a tricyclic pyrazolopyrimidine scaffold is described. Compounds with good levels of in vitro potency and moderate to good levels of selectivity with respect to the 5-HT(2A) and 5-HT(2B) receptors were identified. One of the analogues (7 g) was found to be efficacious in a sub-chronic weight loss model. A key limitation of the series of compounds was that they were found to be potent inhibitors of the hERG ion channel. Some compounds, bearing polar side chains were identified which showed a much reduced hERG liability however these compounds were sub-optimal in terms of their in vitro potency or selectivity.

Discovery of BI 99179, a potent and selective inhibitor of type I fatty acid synthase with central exposure.

Based on a high-throughput screen, cyclopentanecarboxanilides were identified as a new chemotype of non-covalent inhibitors of type I fatty acid synthase (FAS). Starting from initial hits we aimed at generating a tool compound suitable for the in vivo validation of FAS as a therapeutic target. Optimisation yielded BI 99179 which is characterised by high potency, remarkably high selectivity and significant exposure (both peripheral and central) upon oral administration in rats.

Modeling energy intake and body weight effects of a long-acting amylin analogue

The inhibitory effect of anti-obesity drugs on energy intake (EI) is counter-acted by feedback regulation of the appetite control circuit leading to drug tolerance. This complicates the design and interpretation of EI studies in rodents that are used for anti-obesity drug development. Here, we investigated a synthetic long-acting analogue of the appetite-suppressing peptide hormone amylin (LAMY) in lean and diet-induced obese (DIO) rats. EI and body weight (BW) were measured daily and LAMY concentrations in plasma were assessed using defined time points following subcutaneous administration of the LAMY at different dosing regimens. Overall, 6 pharmacodynamic (PD) studies including a total of 173 rats were considered in this evaluation. Treatment caused a dose-dependent reduction in EI and BW, although multiple dosing indicated the development of tolerance over time. This behavior could be adequately described by a population model including homeostatic feedback of EI and a turnover model describing the relationship between EI and BW. The model was evaluated by testing its ability to predict BW loss in a toxicology study and was utilized to improve the understanding of dosing regimens for obesity therapy. As such, the model proved to be a valuable tool for the design and interpretation of rodent studies used in anti-obesity drug development.