What is the formulation problem regarding the treatment of prostate cancer?
Requires a sustained release of a peptide therapeutic:
- How to get a sustained release profile? (polymer implant)
- What kind of polymer can encapsulate a drug and release it over time?
- What are the formulation requirements of the drug? (LHRH; luteinizing hormone-releasing hormone agonists)
How does goserelin work? What is it used to treat?
- Decapeptide agonist of LHRH
- Initial exposure to goserelin increases release of testosterone or oestrogen
- Long-term exposure blocks testosterone/oestrogen release; results in chemical castration due to desensitisation
- Treats prostate cancer
What formulation obstacles do goserelin pose?
- Has a 2 hour half-life
- Is a peptide; requires injection
- How to dose patient chronically w/o daily injections? (unpleasant/painful)
What are the different ways of achieving slow drug dissolution?
- High molecular weight water-soluble polymer
• Dense and entangled
• Disentangling gel
• Polymer solid
• Polymer chain in solution
»> Water infiltrates, polymer chain unfolds, releasing drug - Chemical breakdown of the polymer
• Dense and entangled
• Chain scission of polymer chain into smaller fragments
• Dissolution of low molecular weight products
• Soluble fragments
What are the problems with achieving slow drug dissolution from a high molecular weight water-soluble polymer/chemically broken down polymer?
- Unreliable as dependent on entanglement
- Most polymers dissolve quicker than required for goserelin release
- Poor renal excretion of high molecular weight polymer; don’t want polymer to keep circulating
How do we achieve a polymer that slowly breaks down in the body? (required for goserelin slow-release)
- Need a chemical group that hydrolyses (water infiltration to break down polymer chain)
- Anhydrides/Orthoesters/Esters/Peptides (slowest)
What polymer is chosen as a result for slow breakdown in the body to deliver LHRH? What are the requirements of this polymer?
- Polymer must be insoluble
- BUT, low molecular weight degradation products must be water-soluble
»> Polyester
• Water insoluble w/high molar mass; achieved by making v. long polyester chains
• Monomer unit at the end is water-soluble
How does poly(lactic acid) polymerise?
- Polymerised from dimer; lactide
- L, L-Lactide and D, L-Lactide (two chiral centres)
What is the effect of stereochemistry on poly(lactic acid) degradation?
- Poly(DL-lactic acid) takes 1 year to fully degrade
- Poly(L-lactic acid) takes more than 2 years to fully degrade
Explained by crystallinity: • Poly(DL-lactic acid); amorphous - Lower density - Loosely packed chains (can't pack as well) - More rapid water penetration - Faster hydrolysis
• Poly(L-lactic acid); semi-crystalline
- Dense
- Low water penetration (due to crystalline structure)
- Slow hydrolysis (hence > 2 years to hydrolyse)
What is the difference between degradation and erosion?
Degradation:
- Chemical breakdown of polymer chains (into monomer units etc.)
Erosion:
- When polymer chains have decreased in MW sufficiently
- Creating enough hydrophilic end groups to drive water solubility (low MW degradation products)
What is bulk erosion? What polymer undergoes it?
- Don’t need complete breakdown of polymer for drug release
- Water penetration and chain scission more rapid than erosion
- Drug release occurs faster than polymer erosion; some drug can escape when the polymer hydrates (plasticises)
- Degradation, THEN erosion
E.g. poly(lactic acid)
What is the effect of adding glycolic acid to the polylactic acid polymer making a co-polymer?
- Adding glycolic acid (monomer) to PLA forms PLGA; poly(lactic acid-co-glycolic acid)
- The GA component is more susceptible to hydrolysis; lacks a hydrophobic, oily protecting methyl side-chain (which would normally hinder H2O ingress)
- Thus increasing GA content in PLGA speeds up degradation time in the patient; faster release of drug
Why does PLGA 50:50 not follow predicted degradation kinetics of decreasing PGA (poly(glycolic acid)) content?
- PLGA 50:50 degrades faster than PGA 100 as the respective chains do not pack together as well/uniformly; not just about hydrophobicity
- PGA 100 homo-polymer degrades as its chains can pack together nicely (compensating for lack of protecting methyl group)
What is the effect of autocatalysis on polymer degradation (hydrolysis), and how can this be rectified?
- COOH and COH generated from polyester degradation
- Introduces more H+; local acidity enhances hydrolysis rate (H+ can’t diffuse away/escape)
- Build-up of H+ in the middle of the device; THUS long thin rods are used to house the polymer-drug rather than a large bulk
»> Peptides (LHRH, the drug goserelin) are acid-labile (will produce H+) too as well as esters
How does the Astrazeneca preparation Zoladex compare with its sister Zoladex LA?
Zoladex:
- 1 month depot system (shorter)
- 3.6mg goserelin (lower strength)
- PLGA; 50% DL-lactic acid, 50% glycolic acid
- Mix of high and low MW drugs to fine tune controlled release; does not require as much degradation before drug release
- Cylindrical rod of 11 x 1.1 mm (shorter and smaller)
- SC injection
Zoladex LA:
- 3 month depot system
- 10.8mg goserelin
- PLGA 95:5 (a lot more of the hydrophobic DL-lactic acid; only 5% glycolic acid)
- Mix of high and low MW drugs to fine tune controlled release
- Rod of 18 x 1.5 mm
- SC injection (rapid dispersion from SC site when drug escapes)
What are Zoladex/Zoladex LA release rates like in practice?
- Dosing more rapid than predicted from polymer degradation alone; autocatalytic degradation is still pronounced in rod systems
- There is increased local acidity as lactic acid oligomers cannot escape
- But hydration and fragmentation of the rod allows drug release by diffusion mechanism before full diffusion of polymer
- Low MW chains increase early erosion
- Plasticisation by lower molar mass components
How does the pH within PLGA polymers of goserelin change over time?
- Acid is seen to be able to diffuse away from the surface/outside of the polymer, but then is stuck in the middle
- Due to autocatalysis (pH is lower in the middle)
