This document discusses optimizing medicines development. It describes some of the challenges in developing medicines, such as poor solubility, stability, and permeability. It provides examples of drug discovery projects at King's College London targeting conditions like thalassemia, cancer, and COPD. The document also outlines the tablet manufacturing process and discusses formulations like nanoparticles and controlled release designs that can help address challenges with solubility, stability and permeability to improve bioavailability. It compares in vitro and in vivo models for testing these formulations.

1. OPTIMISING MEDICINES
DEVELOPMENT
DR KHULOUD T. AL-JAMAL
Institute of Pharmaceutical Science
King’s College London

2. Learning outcomes
1. Discovery of new and better medicines
2. Describe the problems commonly associated with making
medicines and their bioavailability
3. Explore conventional dosage forms and emerging medicines
4. Describe how pharmaceutical contribute to solving
problems as “scientists”
5. Commonly used drug testing methods

3. The long road to a new medicine

4. Examples of “Drug Discovery”
at King’s
Iron Chelator – used in thalassemia
Anticancer – in phase II clinical trial
(Leukaemia)
Experimental pre-clinical drug entering into Phase I clinical
trial in Pancreatic and Breast Cancer
Phase II ClinicalTrial in
COPD

5. Tablet manufacturing process
Tablet Press
Blistering Machine

6. 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
Diffusion and Absorption
Drug in molecular form

7. Routes of permeation
Unstirred water layer
Drug in solution
Tight junction
Intercellular space
Basement membrane
Blood capillary
Transcellular Paracellular
Apical cell
membrane

8. 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

9. 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

10. Examples of “Nano-carriers”
at King’s DENDRIMERS
VIRAL CORE
PARTICLES
The journal of
biochemistry. 2013,
153, 251-6.
CARBON NANOTUBES
LIPOSOMES
POLYMERIC NANOCAPSULES
HYBRIDS
Proceedings of the National
Academy of Sciences USA,
2010, 107, 3966-3971
Drug Radionuclide siRNA
Proceedings of the National
Academy of Sciences USA, 2011,
108, 10952-7
Nature Materials, 2009, 9, 485–490
Small. 2008, 4, 1406-15
Mol Pharm. 2009, 6, 520-30
Targeting ligand
Hydrophilic drug
Hydrophobic drug

11. In vitro and in vivo models
MONOLAYER
3D SYSTEM and CO-
CULTURE
3D models (Spheroids)
- Targeting + Targeting
Non-
endosomal
Targeted NCNon targeted
NC
IN VIVO TESTING
Blood brain barrier model
Kupffer cells
(liver macrophages) Cancer cells
Endosomal
SPECT/CT FLUORESCENCE

12. OPTIMISING MEDICINES
DEVELOPMENT
DR KHULOUD T. AL-JAMAL
Institute of Pharmaceutical Science
King’s College London