Problem Based Learning:

Polymers in Advanced Drug Delivery

Dr Georgina Marsh
Problems to solve:

• Delivery of LHRH agonists requires constant exposure for 3 months

• Treatment of interstitial gliomas with carmustine causes excessive

damage to the bone marrow

• Daily injections of filgrastim are required during chemotherapy.

• How can contraceptive products for developing countries deliver

drug for years?

• Can we overcome the poor long-term health of Type I Diabetics?

• Treatment of Heroine Addiction with Naltrexone is poor due to poor

compliance
New Skills 1:

• Mechanisms of polymer biodegradation

• Factors affecting kinetics of polymer biodegradation
• Structure of poly(lactic acid) and related polymers
• Structure of polyanhydrides
• Structure and function of PEG
• Mechanisms of drug release from biostable polymers
• Concept of stimuli responsive drug delivery systems
Things you need to know that I won’t explain

• What is a polymer?
• How do you calculate or measure the molecular
weight of a polymer?
• How does pH affect the dissociation of weak
acids and weak bases?
Problem 1: Delivery of LHRH Agonists

• Goserelin is a decapeptide agonist of luteinising

hormone releasing hormone.
• Initial exposure to goserelin increases release of
testosterone or oestrogen
• Long-term exposure blocks testosterone or oestrogen
release. CHEMICAL CASTRATION due to
desensitisation.
• Used to treat prostate cancer (>50k deaths in US per
year) and early onset puberty.
• But goserelin has to be injected and has a 2 hour half-life
• How do you chronically expose the patient without
daily injections?
Delivery Concept for LHRH Analogues

• A single dose that releases goserelin over 3 month

period
• Use a polymer material that dissolves slowly to
allow a peptide therapeutic to be liberated
continually.

=
Achieving Slow Dissolution

• Option 1
• High molecular weight water-soluble polymer

Dense and entangled

Disentangling gel Polymer chain in solution
polymer solid
Achieving Slow Dissolution

• Option 2
• Chemical breakdown of the polymer

Dense and entangled Chain scission of Dissolution of low

polymer solid polymer molecular weight products
Problems with Option 1

• Unreliable as dependent on entanglement

• Most polymers will dissolve quicker than

required for goserelin

• What happens to the polymer after dissolution?

• Poor renal excretion at high mw
Designing polymers that slowly breakdown in
the body

• Need a chemical group that hydrolyses

Ester group
Other degradable-link polymers

General rule on rate of hydrolysis

Anhydrides Orthoesters Esters Amides (peptides)

Poly(sebacic anhydride) Poly(glycolic acid)

Goserelin!

Note - not all polyesters are rapidly degradable – PET!

Designing polymers that slowly breakdown in
the body

• Polymer must be water-insoluble but low molecular weight

degradation products must be water soluble.
Water insoluble

Water
swellable

Water soluble

• Degradation is the chemical breakdown of polymer chains

• Erosion only starts when polymer chains have decreased in

molecular weight sufficiently to create enough hydrophilic end
groups to drive water solubility.
Poly(lactic acid) and related polymers

• Chemical structure

• Polymerised from dimer called lactide

Effect of stereochemistry on PLA degradation
• Poly(DL-lactic acid) (PDLLA) takes approx 1 year to fully degrade
• Poly(L-lactic acid) (PLLA) takes more than 2 years to fully
degrade

• Explained by crystallinity.
• PLLA is semi-crystalline

• PDLLA is amorphous
PLA undergoes bulk erosion

• Water penetration and chain scission is more rapid that

erosion

Hydrated
Polymer Polymer

Water Water

• Note: drug release occurs faster than polymer erosion as

some drug can escape when the polymer hydrates
 Tailoring PLA degradation kinetics to match clinical need

• Add glycolic acid monomer to make a co-polymer

Poly(glycolic acid) - PGA Poly(lactic acid-co-glycolic acid)

Usually polymerised by ring PLGA
opening of lactide dimer analogue,
glycolide

• GA component is more susceptible to hydrolysis due to lack of

protecting methyl group
• Therefore, increasing GA in PLGA should increase degradation rate,
(decreasing degradation time) in the patient
Degradation Kinetics of PLGA

1 year

Time to Predicted
complete degradation
degradation kinetics
in body

Note: LA is
6 months
in DL form

Actual All polymer

3 months in small
degradation
kinetics particle
morphology

PGA PLGA 50:50 PLGA 65:35 PLGA 85:15 PDLLA

Polymer
Type
A further complication
• Effect of autocatalysis

Autocatalysis

• Note: this effect will be device morphology dependent

Delivery of LHRH Analogues requires constant
exposure for 3 months

• Astrazeneca developed Zoladex and Zoladex LA

• Excellent review in Clinical Pharmacokinetics 2000, 39 (1),

27-48 Ian Cockshott
Zoladex

• 1 month depot system

• 3.6 mg goserelin
• PLGA with 50% DL-lactic acid and 50% glycolic
acid
• Mixture of high and low molecular weight
polymer to fine tune controlled release.
• Cylindrical rod of 11 x 1.1 mm
• Subcutaneous injection
Zoladex release kinetics
Zoladex LA

• 3 month depot system

• 10.8mg goserelin
• PLGA with 95% DL-lactic acid and 5% glycolic
acid
• Mixture of high and low molecular weight
polymer to fine tune controlled release.
• Rod of 18 x 1.5 mm
• Subcutaneous injection
Zoladex LA release and testosterone suppression
Why do Zoladex LA and Zoladex release doses
more rapidly than predicted from polymer
degradation

• 1. Autocatalytic degradation is pronounced in

rod systems
• 2. Hydration and fragmentation of the rod
allows drug to release by a diffusion mechanism
before full degradation of the polymer.
• 3. Low molecular weight chains increase early
erosion