OPTIMISING MEDICINES DEVELOPMENT DR KHULOUD T. AL-JAMAL Institute of Pharmaceutical Science King’s College London
Learning outcomes Discovery of new and better medicines Describe the problems commonly associated with making medicines and their bioavailability Explore conventional dosage forms and emerging medicines Describe how pharmaceutical contribute to solving problems as “scientists” Commonly used drug testing methods
The long road to a new medicine
Examples of “Drug Discovery” at King’s Anticancer – in phase II clinical trial (Leukaemia) Iron Chelator – used in thalassemia Experimental pre-clinical drug entering into Phase I clinical trial in Pancreatic and Breast Cancer Phase II Clinical Trial in COPD
Tablet manufacturing process Tablet Press Blistering Machine
Solid oral dosage dissolution Intact tablet Disintegration Deaggregation Low rate of dissolution Moderate rate of dissolution Relatively rapid rate of dissolution Diffusion and Absorption Dissolution and diffusion Drug in molecular form Diffusion and Absorption
Routes of permeation Unstirred water layer Drug in solution Tight junction Intercellular space Basement membrane Blood capillary Transcellular Paracellular Apical cell membrane
Problems… Poor aqueous solubility of the drug Poor lipid solubility of the drug Poor chemical and biological stability (e.g. against enzymes, pH) Narrow therapeutic index Poor penetration of the Blood Brain Barrier (BBB) for treatment of brain diseases
Solutions… Addition of co-solvents, solubilisers, micronisations of drug…etc. Chemical modification to facilitate absorption across biological membranes..etc. Enteric coating of tables, encapsulation into nano-carriers…etc. Controlled release formulations Polymeric membrane Drug molecules Hydrophobic core
Examples of “Nano-carriers” at King’s DENDRIMERS Proceedings of the National Academy of Sciences USA, 2010, 107, 3966-3971 CARBON NANOTUBES VIRAL CORE PARTICLES Proceedings of the National Academy of Sciences USA, 2011, 108, 10952-7 Nature Materials, 2009, 9, 485–490 The journal of biochemistry. 2013, 153, 251-6. Drug Radionuclide siRNA LIPOSOMES Small. 2008, 4, 1406-15 Mol Pharm. 2009, 6, 520-30 Targeting ligand Hydrophilic drug Hydrophobic drug POLYMERIC NANOCAPSULES HYBRIDS
In vitro and in vivo models MONOLAYER 3D SYSTEM and CO-CULTURE 3D models (Spheroids) - Targeting + Targeting Non-endosomal Targeted NC Non targeted NC IN VIVO TESTING Blood brain barrier model Kupffer cells (liver macrophages) Cancer cells Endosomal SPECT/CT FLUORESCENCE
OPTIMISING MEDICINES DEVELOPMENT DR KHULOUD T. AL-JAMAL Institute of Pharmaceutical Science King’s College London