Controlled drug delivery
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Transcript of Controlled drug delivery
Controlled drug delivery
Jonathan O’DwyerJonathan O’Dwyer
John RasmussenJohn Rasmussen
CHEN 641CHEN 641
Overview
NormalNormalApplicationApplication
ControlledControlledApplicationApplication
Chitosan in controlled drug delivery
HistoryHistory Structure and chemistryStructure and chemistry PropertiesProperties ApplicationsApplications
Controlled Drug DeliveryControlled Drug Delivery
Overview
History
Natural polysaccharide found in Natural polysaccharide found in shells of shells of crustaceanscrustaceans
Discovered in 1859 by RougetDiscovered in 1859 by Rouget Chemical structure identified in 1950Chemical structure identified in 1950
Structure and chemistry
Repeat Unit: Repeat Unit: 1-4 N-glucosamine (~ 90%) 1-4 N-glucosamine (~ 90%) 1-4 N-acetylglucosamine (~ 10%) 1-4 N-acetylglucosamine (~ 10%)
Protonated amino groups at pH < 6.5 (NHProtonated amino groups at pH < 6.5 (NH33
++)) Undergoes homogeneous reactions typical to amines Undergoes homogeneous reactions typical to amines
(acylation and Schiff reactions)(acylation and Schiff reactions) Characterized by degreee of deacetylation (DD)Characterized by degreee of deacetylation (DD)
Properties
Soluble at pH < 6.5Soluble at pH < 6.5 PolycationPolycation ( (protonated amino groupsprotonated amino groups)) HydrophilicHydrophilic Low toxicityLow toxicity BiocompatibleBiocompatible BioadhesiveBioadhesive Biodegradable Biodegradable
Enzymes present within the large Enzymes present within the large intestinesintestines
Applications
Wastewater (removal of metal ions)Wastewater (removal of metal ions) Medical (wound dressing)Medical (wound dressing) Health (weightloss supplement)Health (weightloss supplement) Membrane (permeability control)Membrane (permeability control) Pharmaceutical (controlled drug delivery)Pharmaceutical (controlled drug delivery)
Controlled Drug Delivery
Delivery formDelivery form PowderPowder SolutionSolution Microparticle (50nm-2mm)Microparticle (50nm-2mm)
Delivery systemDelivery system OralOral InjectableInjectable TransdermalTransdermal NasalNasal
Nasal drug delivery obstacles aaMembrane PermeabilityMembrane Permeability
Respiratory epithelium Respiratory epithelium Mucus layer Mucus layer
(viscoelastic gel ~ 15(viscoelastic gel ~ 15m)m) Dense cilia tubules (200/cell)Dense cilia tubules (200/cell) Goblet cellsGoblet cells
bbResidence time Residence time (typically 10 min)(typically 10 min) Mucociliary clearance (MCM)Mucociliary clearance (MCM)
Amount of mucusAmount of mucus Viscoelastic properties of the mucusViscoelastic properties of the mucus Cilia length, density, and beating frequencyCilia length, density, and beating frequency
Overcoming obstacles aaPermeability enhancing polymers Permeability enhancing polymers
Transiently opens paracellular transport pathwayTransiently opens paracellular transport pathway
bbMicroparticleMicroparticle mucoadhesive polymersmucoadhesive polymers Hydrogen or ionic bondingHydrogen or ionic bonding
Increase residence time (5 hrs & longer)Increase residence time (5 hrs & longer) Increase bioavailabilityIncrease bioavailability
Chitosan drug release mechanism Mucoadhesion/Ionic BindingMucoadhesion/Ionic Binding
(+) interacts (-) cell membrane, decreasing (+) interacts (-) cell membrane, decreasing MCM ~90% (i.e. increased residence time)MCM ~90% (i.e. increased residence time)
Swelling (hydrophilic)Swelling (hydrophilic) Increases fluid within matrixIncreases fluid within matrix
forming a gel diffusion layerforming a gel diffusion layer DiffusionDiffusion
Drug passes from the polymer Drug passes from the polymer matrix into the external environmentmatrix into the external environment
Morphine phase II clinical trial
Pain treatment of cancer patientsPain treatment of cancer patients Utilizes chitosan microparticles (20-30 Utilizes chitosan microparticles (20-30 m) m)
loaded with morphineloaded with morphine Microparticles delivered intranasally as Microparticles delivered intranasally as
powder formulationpowder formulation
Morphine phase II clinical trial Chitosan microparticle preparation (ChiSysChitosan microparticle preparation (ChiSysTMTM))
Chitosan & morphine dissolved in DI-waterChitosan & morphine dissolved in DI-water Droplets extruded into mineral oil (oil phase)Droplets extruded into mineral oil (oil phase) Emulsify aqueous phase into oil phaseEmulsify aqueous phase into oil phase Evaporate aqueous phase (heat forms crosslink)Evaporate aqueous phase (heat forms crosslink) Separate microparticles from oil phase by Separate microparticles from oil phase by
centrifugationcentrifugation
Morphine phase II clinical trial Mathematical modelling Mathematical modelling
Three models tested Three models tested Zero orderZero order First orderFirst order Higuchi model (RHiguchi model (R22 = 0.999) = 0.999)
Describes release from a matrixDescribes release from a matrixQ = k*tQ = k*t1/2 1/2
where: Q = amount of drug released per unit area of where: Q = amount of drug released per unit area of matrixmatrix
Morphine phase II clinical trial ResultsResults
Biphasic pattern Biphasic pattern Initial phaseInitial phase
Rapid releaseRapid release B/C drug on surface B/C drug on surface
and particle defectsand particle defects Terminal phaseTerminal phase
Controlled releaseControlled release Bioavailability of 70% compared to IV Bioavailability of 70% compared to IV
injectioninjection 90% reduction in MCM90% reduction in MCM 99% of morphine delivered99% of morphine delivered Non-toxicNon-toxic
Chitosan limitations Low encapsulation efficiency for certain drugs due to repulsive Low encapsulation efficiency for certain drugs due to repulsive
forcesforces
Soluble at pH < 6.5Soluble at pH < 6.5
Highly refined chitosans requiredHighly refined chitosans required
(+) charged drug repelledby chitosan’s (+) charge