Transcript Chitosan in controlled drug delivery

Controlled drug delivery
Jonathan O’Dwyer
John Rasmussen
CHEN 641
Overview
Normal
Application
Controlled
Application
Chitosan in controlled drug delivery
History
 Structure and chemistry
 Properties
 Applications
 Controlled Drug Delivery
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Overview
History
Natural polysaccharide found in shells of
crustaceans
 Discovered in 1859 by Rouget
 Chemical structure identified in 1950
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Structure and chemistry
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Repeat Unit: b 1-4 N-glucosamine (~ 90%)
b 1-4 N-acetylglucosamine (~ 10%)
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Protonated amino groups at pH < 6.5 (NH3+)
Undergoes homogeneous reactions typical to
amines (acylation and Schiff reactions)
Characterized by degreee of deacetylation (DD)
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Properties
Soluble at pH < 6.5
 Polycation (protonated amino groups)
 Hydrophilic
 Low toxicity
 Biocompatible
 Bioadhesive
 Biodegradable
 Enzymes present within the large
intestines
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Applications
Wastewater (removal of metal ions)
 Medical (wound dressing)
 Health (weightloss supplement)
 Membrane (permeability control)
 Pharmaceutical (controlled drug delivery)
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Controlled Drug Delivery
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Delivery form
 Powder
 Solution
 Microparticle (50nm-2mm)
Delivery system
 Oral
 Injectable
 Transdermal
 Nasal
Nasal drug delivery obstacles
 aMembrane
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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
Overcoming obstacles
 aPermeability
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enhancing polymers
Transiently opens paracellular transport pathway
 bMicroparticle mucoadhesive
polymers
 Hydrogen or ionic bonding
 Increase residence time (5 hrs & longer)
 Increase bioavailability
Chitosan drug release mechanism
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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
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
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Morphine phase II clinical trial
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TM
Chitosan microparticle preparation (ChiSys )
 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
Morphine phase II clinical trial
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Mathematical modelling
 Three models tested
 Zero order
 First order
2
 Higuchi model (R = 0.999)
 Describes release from a matrix
1/2
 Q = k*t
where: Q = amount of drug released per unit area of
matrix
Morphine phase II clinical trial
 Results
 Biphasic
pattern
 Initial phase
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Rapid release
B/C drug on surface
and particle defects
 Terminal
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phase
Controlled release
 Bioavailability
of 70%
compared to IV injection
 90% reduction in MCM
 99% of morphine delivered
 Non-toxic
Chitosan limitations
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Low encapsulation efficiency for certain drugs due
(+) charged drug repelled
to repulsive forces
by chitosan’s (+) charge
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Soluble at pH < 6.5
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Highly refined chitosans required