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