peptides in parenteral formulationsrepository.ubaya.ac.id/31197/2/peptides in parenteral...peptides...
TRANSCRIPT
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ChristinaAvantiDepartmentofPharmaceutics
UniversityofSurabaya,Surabaya,Indonesia
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Assoc. Prof. Christina Avanti, PhD
Graduated in Pharmacy at the University of Surabaya , she worked at Sandoz Biochemie Farma Indonesia and did her Master Program in
Cosmetic Formulation at the Department of Pharmaceutics AirlanggaUniversity. She did her PhD at the Department of Pharmaceutical Technology University of Groningen, The Netherlands. She worked
within the Dutch Top Institute Pharma Project entitled “Breaking The Cold Chain of Polypeptide-Based Medicine”. She is now working as a
Senior Researcher and teaching Physical Pharmacy, Formulation, Technology, and Biopharmacy at The School of Pharmacy University
of Surabaya. The overall aim of her work is to achieve a stable peptide/protein formulation to be transported, stored, and used
particularly in tropical developing countries.(Patent: (WO/2010/030180) PEPTIDE FORMULATIONS AND USES THEREOF)
Latest publication:• Stability of lysozyme in aqueous extremolyte solutions during heat
shock and accelerated thermal conditions. Plos One Journal, January 2014, Volume 9, Issue 1, e86244
• The formation of oxytocin dimers is suppressed by the zinc-aspartate-oxytocin complex. J. Pharm. Sci., 2013, DOI
10.1002/jps.23546 (early published online)• Aspartate buffer and divalent metal ions affect oxytocin in
aqueous solution and protect it from degradation. Int. J. Pharm, 2013 , 444(1-2):139-45
DeanofFacultyofPharmacyinUniversityofSurabaya
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Outline
Conclusion
Strategiestoimprovepeptide
stabilityinliquid
formulations
Peptideinstabilityandthepossiblecausesof
degradation
Introduction
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• Peptidesaspotentialdrugs:SuccessfulchemicalsynthesisofoxytocinbyduVigneaud in1953
• overahundredpeptidedrugcandidatesareindevelopmentforawidevarietyofdiseases
• Peptidesdifferfromproteins:smallerandtypicallylackadefinedtertiarystructure
Introduction
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• Aminoacidslinkedtoeachotherbypeptidebonds• Peptidebondoccurswhennitrogenatomononeamino
acidbindstothecarboxylgroupofanotheraminoacid.
Whatispeptideandpeptidebond?
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• Malavolta (2011)Peptidesaremoleculescontainingfewerthan40aminoacidresidues,whileproteinscontain50
residuesormore
• Lee(1991)Aminoacidsjoinedtogetherinchainsof50aminoacidsorlessaredefinedaspeptides,50-100aminoacidsaredefinedaspolypeptides,andover100aminoacidsaredefinedasproteins
DefinitionofPeptide
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Tyr
Lys
Arg
Ser
Trp
Asp
Glu
Gln
Met
AminoAcidBuildingBlock
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• Anumberofhormones,enzymes,antitumoragents,antibioticsandneurotransmittersarepeptides.
• Peptidesregulatemanyphysiologicalprocesses,actingatsomesitesasendocrineorparacrinesignalsandatothersitesasneurotransmittersorgrowthfactors.
• Nowadays,peptidesareusedastherapeuticagentsagainstdiversediseaseareassuchasneurological,endocrinological andhematologicaldisorders
PurposesofPeptides
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Table1Severalpeptide-basedparenteralproductsinthemarketin2010-2013
Genericname
Tradename Supplier Dosageform Shelf-lifeandstoragetemp.
pH
ThyrotropinereleasinghormonesTRH/TRF Relefact TRH® Sanovi-
AventisLiquidinj. 2yr15-
25°C6.5
Antibioticpeptides
Daptomycin Cubicin® Novartis Powderforinj. 3yr,2°C–8°C
4-5
Teicoplanin Targocid® Sanofi-Aventis
Powderforinj. 4yr,2-8°C
Plateletaggregatesinhibitors
Eptifibatide Integrilin® GlaxoSmithKline
Liquidforinfusion
3yr,2-8°C 5.35
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SomatostatinanalogOctreotideacetate
Sandostatin® Novartis Liquidinj. 3yr,2-8°C 4.2
VasopressinsandanalogsDesmopressin DDAVP® Ferring Liquidinj. 4yr,2-8°C 4-5
Octostim® Ferring Liquidinj. 4yr,2-8°C 4Minrin® Ferring Liquidinj. 4yr,2-8°C 4
Felypressin Citanest3%Octapressin®
Densply Liquidinj. 3yr,15-25°C 3.5-5.2
Genericname Tradename Supplier Dosageform Shelf-lifeandstoragetemp.
pH
Table1Severalpeptide-basedparenteralproductsinthemarketin2010-2013
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Genericname
Tradename Supplier Dosageform Shelf-lifeandstoragetemp.
pH
OxytocinsOxytocin Syntocinon® Defiante Liquidinj. 4yr,2-8°C 4Carbetocin Pabal® Ferring Liquidinj. 2yr,2-8°C 3.8OxytocinantagonistAtosiban Tractocile® Ferring Liquidinj. 4yr,2-8°C 4.5
Tractocile® Ferring Liquidinj. 4yr2-8°C 4.5
Table1Severalpeptide-basedparenteralproductsinthemarketin2010-2013
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Table1Severalpeptide-basedparenteralproductsinthemarketin2010-2013
Genericname
Tradename Supplier Dosageform Shelf-lifeandstoragetemp.
pH
GNRH/LHRHagonistsGoserelin Zoladex® Div Liquidinj. 3yr,<25°CGonadorelin Relefact
LH-RH®Sanofi-Aventis
Liquidinj. 15-25°C
Triptorelin Decapeptyl-CR®
Ipsen Powderandsolv.forsolforinj.
3yr,2-8°C
Nafarelin Synarel® Pfizer Liquidnasalspray
2yr,<25°C 5-7
Leuprolide Eligard® Sanofi-Aventis
Powderandsolv.forsolforinj.
2yr,2-8°C
Cetrorelix Cetrotide® Serono Powderforinj. 3yr,15-25°C
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Table1Severalpeptide-basedparenteralproductsinthemarketin2010-2013
Genericname
Tradename Supplier Dosageform Shelf-lifeandstoragetemp.
pH
Non-NSAID analgesicZiconotide Prialt® Elan Liquidinj. 3yr,2-8°C 4-5CalcitoninsSalmonCalcitonin
CalcitoninSandoz®
Novartis Liquidinj. 5yr,2-8°C 3-5
Humanparathyroidhormone[hPTH(1–34)]Teriparatide Forsteo® EliLily Liquidinj. 2yr,2-8°CFusioninhibitorofHIV-1withCD4cellsEnfuvirtide Fuzeon® Roche Powderand
solv. solutionforinj.
4yr,2-8°C
ACTHandderivativesCRH/CRF/Corticorelin
CRH-Ferring®
Ferring Powderforinj. 3yr,<25°C
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• Thesensitivitytoenzymaticbreakdown• Thepoorabilitytopassabsorbingmembranestypicallyresultsinapoorbioavailabilityfollowingnon-parenteral administration.
• Thelackofphysicalandchemicalstabilityleadtosignificantdegradationduringprocessingandstorageofthe(aqueous)formulations
Pharmaceuticalpeptides:Challenge
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• buccal,• rectal,• vaginal,• percutaneous,• ocular,• transdermal,• nasal,• pulmonarymanyoftheseroutesofadministrationarestillunderinvestigationandtheymaybeinsufficientlyefficient,especiallywhenarapideffectisdesired.
Non-invasiveroutesforpeptidedrugadministration
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Intravenousadministrationisthemostefficientwaytodeliverpeptidedrugsdirectlyintothesystemiccirculation
most peptide drugs have to be stored and transported at low temperatures
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Chemicaldegradationpathways• hydrolysis,• oxidation,• deamidation .
Physicaldegradation:• adsorption• aggregation
betterunderstandingoftheunderlyingmechanismsofinstabilityofacertainpeptide todesignrationalstrategiesinthedevelopmentprocessofpharmaceuticalstooptimizethestabilityofthepeptideinthefinalformulation
probleminthedevelopmentasactive
pharmaceuticalsNeed
PeptideDegradationPathways
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Peptideinstabilityandthepossiblecausesofdegradation
• Hydrolyticpathways– Chaincleavageofthepeptidebackbone– DeamidationofAsnandGlnresidues– IsomerizationofAspresidues
• Oxidationpathways– Autoxidation– Metal-catalyzedoxidation– Light-inducedoxidation
• β-eliminationreactions• Disulfideexchangereactions• Dimerization,aggregation,andprecipitation
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Deamidation pathwaysofAsn residueviaA.directhydrolysisandB.succinimide mediation
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SelectedoxidationreactionsofMetandHis.(A):methionineoxidationbyperoxidetomethioninesulfoxide inacidicsolution(HA=acid).(B):2-oxo-His,Asn andAsp(adaptedfromLi,et.al,1995).
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Oxytocindegradationpathways
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Strategiestoimprovepeptidestabilityinliquidformulations
Degradationpathway Stabilizationstrategy Aminoacidresidue(s)involved
ChemicalInstabilityAcid/basecatalyzedhydrolysis
pHbufferspeciesco-solvents
SerTrpAsn-ProAsn-Tyr
Deamidation pH3-5increasedsolventviscosity
Asn,Gln
β-elimination Bufferspeciesdivalentmetalions
Cys-Cys
Table 2 Degradation pathways and possible stabilization strategies for peptides including amino acid residues involved in the degradation.
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Degradationpathway Stabilizationstrategy Aminoacidresidue(s)involved
ChemicalInstabilityOxidation pH<7
airexclusionantioxidants
Trp,Met,Cys,Tyr,His
Lightinducedoxidation Protectfromlight TrpMetalinducedoxidation Chelatingagents
PolyolsHis,Cys,Arg,Pro,Met
Disulfideexchange SurfactansPolyolsandsugarsBufferanddivalentmetalions
Cys-Cys
Table 2 Degradation pathways and possible stabilization strategies for peptides including amino acid residues involved in the degradation, continued
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Degradationpathway Stabilizationstrategy Aminoacidresidue(s)involved
PhysicalInstabilityDimerizationandfurtheraggregation
Lowerconcentrationminimalmechanicalstressorganicsolventsalkylsaccharidealkylpolyglycoside
Cys-CysTyr-Tyr
Adsorption surfactanspolymers
HisArg
Table 2 Degradation pathways and possible stabilization strategies for peptides including amino acid residues involved in the degradation, continued
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Conclusion
• In aqueous solutions peptides are often unstable. • Peptides have unique structures that the side chain
of nearly all of the amino acid residues are fully solvent exposed, allowing maximal contact with solvents
• the degradation rates appear to correlate with the degree of solvent exposure.
• Based on knowledge of the peptide’s structure and an understanding of the predominant degradation pathways, the strategies may be developed to achieve adequate stability of the formulation.
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• The degradation pathways of peptides are mainly dependent on the amino acid sequence.
• The most prominent degradation pathways for peptides are hydrolysis, oxidation, and dimerization.
• Formulating peptides in a specific pH with a specific buffer, avoiding oxygen reactive species, and minimizing solvent exposure eliminate chemical degradation.
• Increasing solution viscosity by using sugars or polymers reduces peptide mobility and further decelerates physical degradation.
Conclusion
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Instabilityisthemoststablecharacteristicof
adissolvedpeptide
ChristinaAvanti,2011
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Instabilitiesareanaturalwaytoachievethermodynamicequilibrium
ChristinaAvanti,2012
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