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Controlled drug delivery

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  1. Controlled drug delivery Jonathan O’Dwyer John Rasmussen CHEN 641

  2. Overview Normal Application Controlled Application

  3. Chitosan in controlled drug delivery • History • Structure and chemistry • Properties • Applications • Controlled Drug Delivery

  4. Overview

  5. History • Natural polysaccharide found in shells of crustaceans • Discovered in 1859 by Rouget • Chemical structure identified in 1950

  6. Structure and chemistry • Repeat Unit: b 1-4 N-glucosamine (~ 90%) b 1-4 N-acetylglucosamine (~ 10%) • Protonated amino groups at pH < 6.5 (NH3+) • Undergoes homogeneous reactions typical to amines (acylation and Schiff reactions) • Characterized by degreee of deacetylation (DD)

  7. Properties • Soluble at pH < 6.5 • Polycation (protonated amino groups) • Hydrophilic • Low toxicity • Biocompatible • Bioadhesive • Biodegradable • Enzymes present within the large intestines

  8. Applications • Wastewater (removal of metal ions) • Medical (wound dressing) • Health (weightloss supplement) • Membrane (permeability control) • Pharmaceutical (controlled drug delivery)

  9. Controlled Drug Delivery • Delivery form • Powder • Solution • Microparticle (50nm-2mm) • Delivery system • Oral • Injectable • Transdermal • Nasal

  10. Nasal drug delivery obstacles • aMembrane Permeability • Respiratory epithelium • Mucus layer (viscoelastic gel ~ 15mm) • Dense cilia tubules (200/cell) • Goblet cells • bResidence time (typically 10 min) • Mucociliary clearance (MCM) • Amount of mucus • Viscoelastic properties of the mucus • Cilia length, density, and beating frequency

  11. Overcoming obstacles • aPermeability enhancing polymers • Transiently opens paracellular transport pathway • bMicroparticlemucoadhesive polymers • Hydrogen or ionic bonding • Increase residence time (5 hrs & longer) • Increase bioavailability

  12. Chitosan drug release mechanism • Mucoadhesion/Ionic Binding • (+) interacts (-) cell membrane, decreasing MCM ~90% (i.e. increased residence time) • Swelling (hydrophilic) • Increases fluid within matrix forming a gel diffusion layer • Diffusion • Drug passes from the polymer matrix into the external environment

  13. Morphine phase II clinical trial • Pain treatment of cancer patients • Utilizes chitosan microparticles (20-30 mm) loaded with morphine • Microparticles delivered intranasally as powder formulation

  14. Morphine phase II clinical trial • Chitosan microparticle preparation (ChiSysTM) • Chitosan & morphine dissolved in DI-water • Droplets extruded into mineral oil (oil phase) • Emulsify aqueous phase into oil phase • Evaporate aqueous phase (heat forms crosslink) • Separate microparticles from oil phase by centrifugation

  15. Morphine phase II clinical trial • Mathematical modelling • Three models tested • Zero order • First order • Higuchi model (R2 = 0.999) • Describes release from a matrix • Q = k*t1/2 where: Q = amount of drug released per unit area of matrix

  16. Morphine phase II clinical trial • Results • Biphasic pattern • Initial phase • Rapid release • B/C drug on surface and particle defects • Terminal phase • Controlled release • Bioavailability of 70% compared to IV injection • 90% reduction in MCM • 99% of morphine delivered • Non-toxic

  17. Chitosan limitations (+) charged drug repelled by chitosan’s (+) charge • Low encapsulation efficiency for certain drugs due to repulsive forces • Soluble at pH < 6.5 • Highly refined chitosans required

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