title: Physical Properties and Effect in a Battery of Safety Pharmacology Models for Three Structurally Distinct Enteric Polymers Employed as Spray-Dried Dispersion Carriers.
abstract: Establishing a wide therapeutic index (TI) for pre-clinical safety is important during lead optimization (LO) in research, prior to clinical development, although is often limited by a molecules physiochemical characteristics. Recent advances in the application of the innovative vibrating mesh spray-drying technology to prepare amorphous solid dispersions may offer an opportunity to achieve high plasma concentrations of poorly soluble NCEs to enable testing and establishment of a wide TI in safety pharmacology studies. While some of the amorphous solid dispersion carriers are generally recognized as safe for clinical use, whether they are sufficiently benign to enablein vivopharmacology studies has not been sufficiently demonstrated. Thus, the physical properties, and effect in a battery ofin vivosafety pharmacology models, were assessed in three classes of polymers employed as spray-dried dispersion carriers. The polymers (HPMC-AS, Eudragit, PVAP) displayed low affinity with acetone/methanol, suitable for solvent-based spray drying. The water sorption of the polymers was moderate, and the degree of hysteresis of HPMC-AS was smaller than Eudragit and PVAP indicating the intermolecular interaction of water-cellulose molecules is weaker than water-acrylate or water-polyvinyl molecules. The polymer particles were well-suspended without aggregation with a mean particle size less than 3 μm in an aqueous vehicle. When tested in conscious Wistar Han rats in safety pharmacology models (n= 6-8/dose/polymer) investigating effects on CNS, gastrointestinal, and cardiovascular function, no liabilities were identified at any dose tested (30-300 mg/kg PO, suspension). In brief, the polymers had no effect in a modified Irwin test that included observational and evoked endpoints related to stereotypies, excitation, sedation, pain/anesthesia, autonomic balance, reflexes, and others. No effect of the polymers on gastric emptying or intestinal transit was observed when measured using a barium sulfate tracer material. Finally, in telemetry-instrumented rats the polymers had no effect on acute or 24-h mean blood pressure and heart rate values at doses up to 300 mg/kg. Thus, the properties of the three enteric polymers are appropriate as spray-dried dispersion carriers and were benign in a battery of safety pharmacology studies, demonstrating their applicability to enablein vivosafety pharmacology profiling of poorly soluble molecules during LO.
authors: Cardiometabolic Diseases Research, Boehringer Ingelheim Pharmaceuticals Inc. Ridgefield, CT, USA.
authors: Ryan M
authors: RM
authors: Fryer
authors: Small Molecule Discovery Research, Boehringer Ingelheim Pharmaceuticals Inc. Ridgefield, CT, USA.
authors: Mita
authors: M
authors: Patel
authors: Cardiometabolic Diseases Research, Boehringer Ingelheim Pharmaceuticals Inc. Ridgefield, CT, USA.
authors: Xiaomei
authors: X
authors: Zhang
authors: Drug Discovery Support, Boehringer Ingelheim Pharmaceuticals Inc. Biberach, Germany.
authors: Katja S
authors: KS
authors: Baum-Kroker
authors: Cardiometabolic Diseases Research, Boehringer Ingelheim Pharmaceuticals Inc. Ridgefield, CT, USA.
authors: Akalushi
authors: A
authors: Muthukumarana
authors: Small Molecule Discovery Research, Boehringer Ingelheim Pharmaceuticals Inc. Ridgefield, CT, USA.
authors: Brian
authors: B
authors: Linehan
authors: Small Molecule Discovery Research, Boehringer Ingelheim Pharmaceuticals Inc. Ridgefield, CT, USA.
authors: Yin-Chao
authors: YC
authors: Tseng
keywords: amorphous solid dispersion; drug discovery; safety pharmacology; spray-dried dispersion