sustained release case study in peptide formulation Flashcards
(19 cards)
how to get sustained release profile for protein
use slowly dissolving implant
what material can be used to encapsulate a peptide drug and release it over time
polymer with specific properties
what is LHRH
luteinising hormone releasing hormone
what is goserelin and what does it do
peptide drug/decapeptide agonist of LHRH (binds to the same receptor), mimics LHRH
-boosts then blocks sex hormone release
-initial exposure to goserelin increases release of testosterone or oestrogen
-long term exposure blocks T or O (^) release
-chemical castration due to desensitisation
-treats prostate cancer and early onset puberty
-has to be injected, has 2 hour half life (short)
-requires extended release
how to treat chronic patient without daily injections
use sustained release drug delivery system like injectable depot formulation
describe the delivery concept for LHRH analogues
-single dose that releases goserelin over 3 month period
-using polymer material that dissolves slowly to allow a peptide therapeutic to be liberated continually
name 2 ways to achieve dissolution with diagrams and the problems of the first one, mechanism for second
- high MW water soluble polymer
problems=unreliable bc its dependent on entanglement, most polymer will dissolve quicker than required, glomerular excretion doesnt occur with polymers larger size than threshold,
poor renal excretion at high MW - chemical breakdown of polymer, needs chemical group that hydrolyses
rate anhydrides, esters, amides and orthoesters with diagram on the which is the fastest/slowest rate of hydrolysis
anhydrides>orthoesters>esters>amides
waht is degradation and erosion
degradation=chemical breakdown of polymer chains
erosion=only starts when polymer chains have decreased in MW sufficiently to create enough hydrophilic end groups to drive water solubility
what is the chemical structure of poly(lactic acid) and whats the polymerised dimer called
notes, lactide
effects of stereochemistry on PLA degradation
poly (DL-lactic acid) takes ~1 year to fully degrade, poly (L-lactic acid) takes more than 2 years
poly (DL-lactic acid) is amorphous, lower density, loose packed chains, more rapid water penetration, faster hydrolysis
poly (L-lactic acid) is semi crystalline, dense, low water penetration, slow hydrolysis
draw PLA undergoing bulk erosion (hydrolysis of polymer)
notes
how to tailor PLA degradation kinetics to match clinical needs
add glycolic acid monomer to make co-polymer
waht are the names of the co polymers made from adding glycolic acid to PLA and general structure and compare them
poly(glycolic acid) PGA
poly(lactic acid co glycolic acid) PLGA
-no methyl group as side chain makes it less hydrophobic
-polymerised by ring opening of lactide dimer analogue glycolide
-GA more susceptible to hydrolysis due to lack of hydrophobic methyl group
-so increasing GA in PLGA will increase degradation rate in patient
draw degradation kinetics of PLGA
notes
draw autocatalysis thing and what is the effect of it
device morphology dependent
delivery of LHRH analogue requires constant expose for 3 months, AstraZeneca developed what two medicines and describe them
zoladex
-1 month depot system
-3.6 mg goserelin
-PLGA with 50% DL lactic acid and 50% glycolic acid
-mixture of high and low MW polymer to fine tune controlled release
-cylindrical rod applicator 11 x 1.1 mm, subcutaneous injection
zoladex LA (long acting)
-3 month depot system
-10.8 mg goserelin
-PLGA with 95% DL lactic acid and 5% glycolic acid
-mixture of high and low MW polymer to fine tune controlled release
-cylindrical rod applicator 18 x 1.5 mm, subcutaneous injection
describe the release rates of zoladex and zoladex LA in practise
-dosing is more rapid than predicted from polymer degradation alone
-autocatalytic degradation is pronounced in rod systems
-hydration and fragmentation of rod allows drug to be released by diffusion mechanism before full degradation of polymer
-low MW chains increase early erosion
-plasticisation by lower molar mass components
other drug delivery systems of LHRH
nutropin depot
-long acting dosage form of somatropin, a recombinant human growth hormone (rhGH)
-191 amino acid residues, molar mass 22,125 Da
-formulation is microionised particles of rhGH in PLGA microsphrers
-powder suspended in sterile aq solution before injection
-SC injection 1-2 times per month
bydureon
-PLGAS microparticle delivery sysetm
-exenatide 39 amino acid polypeptide
-synthetic versions of exedin-4, binds to glucagon like peptide1 receptor (GLP-1R)
-weekly injections
