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

2. Overview NormalApplication ControlledApplication

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:  1-4 N-glucosamine (~ 90%)  1-4 N-acetylglucosamine (~ 10%)  Protonated amino groups at pH < 6.5 (NH 3 + )  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  a Membrane Permeability  Respiratory epithelium  Mucus layer (viscoelastic gel ~ 15  m)  Dense cilia tubules (200/cell)  Goblet cells  b Residence time (typically 10 min)  Mucociliary clearance (MCM)  Amount of mucus  Viscoelastic properties of the mucus  Cilia length, density, and beating frequency

11. Overcoming obstacles  a Permeability enhancing polymers  Transiently opens paracellular transport pathway  b Microparticle mucoadhesive 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 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  m) loaded with morphine  Microparticles delivered intranasally as powder formulation

14. Morphine phase II clinical trial  Chitosan microparticle preparation (ChiSys TM )  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 (R 2 = 0.999)  Describes release from a matrix  Q = k*t 1/2 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  Low encapsulation efficiency for certain drugs due to repulsive forces  Soluble at pH < 6.5  Highly refined chitosans required (+) charged drug repelled by chitosan’s (+) charge