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OPTIMISING MEDICINES DEVELOPMENT
DR KHULOUD T. AL-JAMALInstitute of Pharmaceutical ScienceKing’s College London
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
Examples of “Drug Discovery” at King’sN
CH3
CH3
OH
O
Deferiprone
Iron Chelator – used in thalassemia
N
NH
O
N
NH
O
O O
OCH3 H3CO
SJG-136
Anticancer – in phase II clinical trial(Leukaemia)
O
MeO
N
N
O
H
NH
O
N
N
O
HN
NH3CO
O
KMR-28-39
Experimental pre-clinical drug entering into Phase I clinical trial in Pancreatic and Breast Cancer
NH
O
H2NNN
O
O
O
N
RPL-554
Phase II Clinical Trial in COPD
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
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
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, 10952-7Nature Materials, 2009, 9, 485–
490
Small. 2008, 4, 1406-15 Mol Pharm. 2009, 6, 520-30
Targeting ligand
Hydrophilic drug
Hydrophobic drug
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