Pharmaceutics 5 - Zoladex Case Study

Question 1

What is Goserelin?

Answer 1

A decapeptide agonist of luteinising hormone releasing hormone

Question 2

What happens upon initial exposure to goserelin?

Answer 2

Increases release of testosterone and oestrogen

Question 3

What happens after long-term exposure to goserelin?

Answer 3

Long term exposure blocks testosterone or oestrogen release - chemical castration due to desensitization

Question 4

What is goserelin used for?

Answer 4

To treat prostate cancer and early onset puberty

Question 5

What is the problem with goserelin dosing/administration for chronic treatment?

Answer 5

Goserelin has to be injected by has a half life of 2 hours
How can we dose the patient chronically with daily injections?
Would be painful, expensive and poor compliance

Question 6

What is the drug delivery concept for improving goserelin?

Answer 6

A single dose that releases goserelin over a 3 month period

Using a polymer material that dissolves slowly and reveals new drug reserves continually

Question 7

What are the options to achieve slow dissolution in a goserelin formulation?

Answer 7

1. High molecular weight water soluble polymer; dense and entangled, disentangling gel, polymer solid, polymer chain in solution, drug released over time.
2. Chemical breakdown of the polymer; dense and entangled, chain scission, dissolution of low polymer solid polymer molecular weight products

Question 8

What are the problems with using a high molecular weight soluble polymer for goserelin slow dissolution?

Answer 8

Unreliable and dependent on chain entanglement
Most polymers will dissolve quicker that required for goserelin
What happens to the polymer afterwards? Poor renal excretion at high molecular weight.

Question 9

How can we design polymers that slowly breakdown in the body?

Answer 9

Need a chemical group that hydrolyses over time 
Ester group (susceptible to nucleophilic attack)

Question 10

What is the general rule on rate of hydrolysis?

Answer 10

Anhydrides hydrolysed quickest
Orthoesters
Esters
Peptides (amides) hydrolysed slowest

Question 11

What is the difference between erosion and degradation?

Answer 11

Degradation is 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.
Degredation is the breaking down of longer chains so that they’re more water soluble and then water can egin erosion process.

Question 12

Whats does the effect of stereochemistry of PLA (polylactic acid) have on its degradation?

Answer 12

Poly(DL-lactic acid) takes 1 year to degrade fully
Poly(L-lactic acid) takes 2 years to degrade fully
This is down to its crystallinity.

Question 13

How does the crystallinity of PlLA and PdlLA vary?

Answer 13

Poly(DL-lactic acid) is amorphous so has lower density, loosely packed chains, more rapid water penetration and faster hydrolysis (degredation = 1 year)

Poly(L-lactic acid) is a semi-crystalline structure so is more dense, less water can penetrate and hydrolysis is slower.

Question 14

What is bulk erosion?

Answer 14

The water ingress leads to a constant rate of erosion and then erosion of the hydrated polymer follows. Drug release occurs faster than polymer erosion because drug can be released in the hydration phase.

Question 15

How can poly(lactic acid) degradation kinetics be manipulated?

Answer 15

Changing the rate of H2O ingress is a clinical benefit - adding glycolic acid monomer to make a co-polymer.

Question 16

What affect does the addition of glycolic acid monomers have on the PLA chain?

Answer 16

GA is more susceptible to hydrolysis (due to the lack of protecting methyl group) and therefore increases rate of degradation / reduces degradation time in a patient.

Question 17

Why does 50:50 PGA and PLGA not follow the expected trend in the graph on slide?

Answer 17

50:50 degrades faster than 100% PGA; this is because, despite PGA being more hydrophilic and lacking a protective methyl group it forms a tight protective semi-crystalline structure. Whereas in 50:50, there is still half a chain missing the protective methyl group and it also cannot bind tightly because of the co-polymer properties so it degrades quicker.

Question 18

What is Zoladex?

Answer 18

A 1 month depot system
3.6mg goserelin
PGLA with 50% PdlLA and 50% GA co polymers
Mixture of high and low density weight polymer to fine tune release rate
Cylindrical rod 11 x 1.1mm better for autocatalysis
Subcutaneous injection

Question 19

What is Zoladex LA?

Answer 19

3 month depot system 
10.8mg goserelin
PGLA with 95% PdlLA and 5% GA 
Mixture of high and low molecular weight polymer to fine tune release rate 
Rod 18 x 1.5mm 
Subcutaneous injection

Question 20

What are the release rates of Zoladex and Zoladex LA?

Answer 20

Dosing is more rapid than predicted from polymer degradation alone.
Autocatalytic degradation is pronounced in rod systems.
Hydration and fragmentation of the rod, allows drug to be released by a diffusion mechanism before full degradation of the polymer.
Low molecular weight chains increase early erosion

Question 21

What does autocatalysis cause? How is it seen in evidence?

Answer 21

The centre of the implant rod is acidic due to autocatalysis - the catalysis of the ester gives products carboxylic acids and alcohol.
This makes the local environment acidic and further increases the erosion of polymer /release of goserelin.