Post on 13-Jan-2016
description
Controlled drug release
OBJECTIVES:
Gradual release
Ability to target an organ
PROBLEM: avoid under and overdosing
The ideal case is a constant
level of drug in body fluid
TRADITIONAL
METHODS
Classical topic of Pharmacokinetics
Two new approaches:
• Microparticle systems: Release from small spherical beads
• Targeting of drug
MICROPARTICLE SYSTEMS:
Release from small spherical beads,
to control the release kinetics
First generation materials borrowed from other fields:
o Polyurethanes
oPolysiloxanes
oPMMA
oPolyvynilalcohol
oPolyethylene
oPolyivynilpyrrolidone
Second-generation materials chosen for:
CHEMICAL INERTNESS, NO IMPURITY RELEASE, THEIR STRUCTURE, EASE OF PRODUCTION
Poly 2-hydroxymethylmetacrilateoPoly N-vynilpyrrolidoneoPolymethylmetacrilate oPolyvynilalcoholoPolyacrilic AcidoPolyacrilamideoCopolimers polyethilene-vynilacetate.oPolyethilenic glicol
Most recent materials are BIODEGRADABLE POLYMERS:
Polylactic acid (PLA)
o Polyglicolic acid (PGA)
o Copolimers of PLA and PGA
o Polyanhydrides
o Polyorthoesthers
Materials actually used vary in chemical composition and the type of drug they carry
POLYMERIC BEADS
Release Mechanisms
oDIFFUSION
oPARTICLE DEGRADATION
oSWELLING FOLLOWED BY DIFFUSION
Release Mechanisms
oDIFFUSION
oPARTICLE DEGRADATION
oSWELLING FOLLOWED BY DIFFUSION
DIFFUSION takes place when the drug flows through the polymeric material.
Kinetics described by Fick’s law
Either at the MACROSCOPIC scale (e.g. through pores) or at the MOLECULAR scale.
THE DRUG may:
o Be finely dissolved (homogeneous microbead)
o Be finely dispersed into the polymeric matrix (monolithic microbead)
o Constitute an internal nucleus, immersed in a polymeric matrix (reservoir microbead)
o Be embedded in an internal matrix coated externally by a layer of a different polymeric material (double-wall microbeads).
HOMOGENEOUS MICROBEADS
The drug is dissolved inside a NON POROUS polymeric matrix .
Transport involves molecular diffusion through and along the polymeric segments.
Release takes place at the surface (the drug has always the highest concentration at the centre)
A SIMILAR MECHANISM OPERATES WITH MONOLITHIC MICROBEADS
RESERVOIR MICROBEADS
The drug is concentrated at the center with a negative concentration GRADIENT from center to surface
A releasable eccipient with a reverse concentration gradient keeps costant the fraction released
In this way the release rate is practically costant
RELEASE MECHANISM IN A DOUBLE-WALLMICROBEAD
In each case by solving the appropriate version of Fick’s equation, the time dependence of the amount of released drug may be evaluated
Release Mechanisms
oDIFFUSION
oPARTICLE DEGRADATION
oSWELLING FOLLOWED BY DIFFUSION
Microbeads made of biodegradable polymers
Most polymers degradate by hydrolysis of the polymer chain, yielding biocompatible fragments at lower MW.
Schematic representation of a bioerodible microbead
Release from biodegradable systems:
a) Bulk bioerosion
b) Surface bioeresion
Microbeads of a copolymer between polyglicolic and poylactic acids (PLGA) for oral or underskin release: example of bulk erosion.
Original microbeads of PLGA 60:40
PLGA after 133 days in water
Polyorthoesthers: surface bioerosion, as after 16 weeks the core of the microbead is untouched
Release Mechanisms
oDIFFUSION
oPARTICLE DEGRADATION
oSWELLING FOLLOWED BY DIFFUSION
Such systems are unable to release until placed in a suitable biological medium
Release triggered by changes in the environment:
• pH• temperature• ionic strength
Release from microbeads reservoir (a) homogeneous (b) Controlled by swelling
Schematic representation of a release system controlled by swelling: when solvent A penetrates the (vitreous) polymer B, the drug C is released through the newly formed gel
Release systems for diabetes treatment
HYPERGLYCEMY: increase of sugars in the blood because of reduced insulin secretion
Insulin Glucose
insulin secreted by pancreas induces the decrease of glucose from blood
Alterations in diabetes:
1 decrease in utilization of glucose
2 use of alternative energy source (fatty tissue and proteins)
SYSTEMS FOR CONTROLLED RELEASE OF INSULIN
A mechanism often used
Functionalization with glucoso-oxidase (enzyme) of polymers (N,N-dimethyl-aminoethyl-metacrylate or polyacrilamide) impregnated with insulin.
Oxidation reaction of glucose catalyzed by the enzyme causes a decrease in pH with swelling of the polymer and release of insulin
Drug Targeting
Carrier delivering the drug at the chosen siteE.g. magnetic particles With tumors: neoplastic tissues show high permeability to carriers
A viable system: liposomes
Structures with double layers formed by amfiphilic molecules (surfactants)
Similarity with the cell wall
Structure of a lipid molecule (lecithin) and of a double lipidic layer (self-assembling structure)
Various types of lipids and corrisponding self-assembing structures
A widespread use of surfactants: synthesis of mesoporous
systems
C. T. Kresge et al., Nature, 1992, 359, 710-712
Synthetic approach: use of surfactant in the synthesis batch to form large pores MESOPORES
AMORPHOUS SILICA WALLS
SOL-GEL SYNTHESISmesoporous
porosity is controlled by synthesis conditions
Hydrophilic heads pointing outside allow solubility in water
Aqueous phase also present within the liposome
Within the membrane: lipophilic compartment
LIPOSOMES (dimension less than one micron)
LIPOSOMES: fabrication
Coating with a polyethylenglicole (PEG), an inert substance which does not alert the immune system
Because of the presence of both hydrophilic and lipophilic parts, liposomes may carry either POLAR MOLECOLES (within the aqueous phase) or APOLAR MOLECULES (wither the bilayer).
FUNCTIONALIZED LIPOSOMES
(terminal groups with affinity for specific cellular receptors)
LIPOSOMES MODIFIED TO HAVE A LARGER AFFINITY WITH CANCER CELLS
Liposome only releases drug when in contact with target!
Liposomal Delivery in Transdermal Applications
Because of the external layer liposomes may cross lipophilic structures, like those of the skin.
Mechanism of inclusion into the cell!
The end