controlled drug release
DESCRIPTION
Controlled drug release. OBJECTIVES: Gradual release Ability to target an organ. PROBLEM: avoid under and overdosing. TRADITIONAL METHODS. The ideal case is a constant level of drug in body fluid. Classical topic of Pharmacokinetics Two new approaches: - PowerPoint PPT PresentationTRANSCRIPT
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Controlled drug release
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OBJECTIVES:
Gradual release
Ability to target an organ
PROBLEM: avoid under and overdosing
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The ideal case is a constant
level of drug in body fluid
TRADITIONAL
METHODS
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Classical topic of Pharmacokinetics
Two new approaches:
• Microparticle systems: Release from small spherical beads
• Targeting of drug
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MICROPARTICLE SYSTEMS:
Release from small spherical beads,
to control the release kinetics
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First generation materials borrowed from other fields:
o Polyurethanes
oPolysiloxanes
oPMMA
oPolyvynilalcohol
oPolyethylene
oPolyivynilpyrrolidone
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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
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Most recent materials are BIODEGRADABLE POLYMERS:
Polylactic acid (PLA)
o Polyglicolic acid (PGA)
o Copolimers of PLA and PGA
o Polyanhydrides
o Polyorthoesthers
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Materials actually used vary in chemical composition and the type of drug they carry
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POLYMERIC BEADS
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Release Mechanisms
oDIFFUSION
oPARTICLE DEGRADATION
oSWELLING FOLLOWED BY DIFFUSION
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Release Mechanisms
oDIFFUSION
oPARTICLE DEGRADATION
oSWELLING FOLLOWED BY DIFFUSION
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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.
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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).
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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)
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A SIMILAR MECHANISM OPERATES WITH MONOLITHIC MICROBEADS
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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
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RELEASE MECHANISM IN A DOUBLE-WALLMICROBEAD
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In each case by solving the appropriate version of Fick’s equation, the time dependence of the amount of released drug may be evaluated
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Release Mechanisms
oDIFFUSION
oPARTICLE DEGRADATION
oSWELLING FOLLOWED BY DIFFUSION
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Microbeads made of biodegradable polymers
Most polymers degradate by hydrolysis of the polymer chain, yielding biocompatible fragments at lower MW.
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Schematic representation of a bioerodible microbead
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Release from biodegradable systems:
a) Bulk bioerosion
b) Surface bioeresion
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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
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Polyorthoesthers: surface bioerosion, as after 16 weeks the core of the microbead is untouched
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Release Mechanisms
oDIFFUSION
oPARTICLE DEGRADATION
oSWELLING FOLLOWED BY DIFFUSION
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Such systems are unable to release until placed in a suitable biological medium
Release triggered by changes in the environment:
• pH• temperature• ionic strength
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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
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Release systems for diabetes treatment
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HYPERGLYCEMY: increase of sugars in the blood because of reduced insulin secretion
Insulin Glucose
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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)
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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
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Drug Targeting
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Carrier delivering the drug at the chosen siteE.g. magnetic particles With tumors: neoplastic tissues show high permeability to carriers
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A viable system: liposomes
Structures with double layers formed by amfiphilic molecules (surfactants)
Similarity with the cell wall
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Structure of a lipid molecule (lecithin) and of a double lipidic layer (self-assembling structure)
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Various types of lipids and corrisponding self-assembing structures
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A widespread use of surfactants: synthesis of mesoporous
systems
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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
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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)
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LIPOSOMES: fabrication
Coating with a polyethylenglicole (PEG), an inert substance which does not alert the immune system
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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).
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FUNCTIONALIZED LIPOSOMES
(terminal groups with affinity for specific cellular receptors)
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LIPOSOMES MODIFIED TO HAVE A LARGER AFFINITY WITH CANCER CELLS
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Liposome only releases drug when in contact with target!
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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!
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The end