Parenteral Controlled Release Flashcards
Reasons for development of innovative drug delivery systems for parenteral use
Controlled release- protein and peptide delivery, drug delivery
Targeting: to improve local delivery, increase activity, reduce side effects
First, second and third order targeting
First order: organ specific
Second order: specific cell or disease
Third order: intracellular compartment
Reservoir devices
Drug surrounded by rate controlling polymer membrane, drug release governed by diffusion, water influx initiates drug release, release depends on membrane and drug properties, polymer membranes: silicones, EVA copolymer
E.g. Norplant contraceptive implant 30mcg/day for 5 years
Matrix devices
Drug dispersed in polymeric matrix, drug release governed by diffusion, release decreases over time (drug depleted boundary), polymers include silicone rubbers and methacrylates e.g. cattle growth implant
Biodegradable polymer-based depot formulations used parenterally
Controlled release polymer matrices designed to give zero order release over weeks to months
Controlled release local delivery polymer-matrix discs
Rely on bioerosion or biodegradation
Controlled release depot formulations for the treatment of prostate cancer and advanced breast cancer
Zoladex (goserelin acetate implant) or Lupron Depot
Adverse reactions- rare hypersensitivity
How does goserelin work?
Goserelin acts on the LHRH receptors in the pituitary, in the same way as gonadorelin. Initially causes increase in FSH and LH released, but desensitises to produce less, stopping production of oestrogens and androgens. Can be exploited to treat disorders linked to levels of oestrogen or testosterone.
Mode of action of LHRH analogues
Normally GnRH is released in small pulses every 90 minutes, binds to receptors which group together and are internalised, receptors are resynthesized
Continued exposure causes permanent receptor down-regulation > need a depot formulation for controlled release
Which LHRH analogue?
Naturally occurring LHRH is degraded rapidly in vitro (10 mins)
Goserelin acetate is much more potent than natural hormone due to increased affinity for receptor and stability due to increased residence time
t1/2 = 4.5 hours
Initial aim is a one month controlled release product:
Poly D,L lactide-co-glycolide 50:50 polymers used to make a small rod
Chosen because PLGA known to be safe- biodegradable sutures
In this case the polymer degrades internally and the drug is released by diffusion control
Factors controlling release rate
Particle size
Drug loading
Polymer
Advantages of polymer depot formulations for CR
Can be used as a CR depot to maintain plasma concentrations over long periods
Easy to administer
Good patient compliance
Disadvantages of polymer depot formulations for CR
Drug loading is low so need potent agents
Difficult to remove if adverse events occur
Controlled release local delivery
Gliadel for the treatment of glioblastoma multiforme, local application after surgical removal of the tumour
Rationale for design of gliadel
Wanted to avoid the need for surgical removal of the polymer, needed a surface eroding polymer, needed an anti-tumour agent with a very short half life to avoid neurotoxicity
Erosion controlled polymer matrix system, up to 8 wafers can be implanted in the cavity created when a surgeon removes a brain tumour
