OPTIMISING MEDICINES DEVELOPMENTDR KHULOUD T. AL-JAMALInstitute of Pharmaceutical ScienceKing’s College London

Learning outcomes1. 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

The long road to a new medicine

Examples of “Drug Discovery” at King’sN

CH3

CH3

OH

O

Deferiprone

Iron Chelator – used in thalassemia

N

NH

ON

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

OO

N

RPL-554

Phase II Clinical Trial in COPD

Tablet manufacturing process

Tablet Press

Blistering Machine

Solid oral dosage dissolutionIntact 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 junctionIntercellular 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, 3966-3971Drug 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

OPTIMISING MEDICINES DEVELOPMENTDR KHULOUD T. AL-JAMALInstitute of Pharmaceutical ScienceKing’s College London