Transcript lezione 7 - drug release

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:
• 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
o Polysiloxanes
o PMMA
o Polyvynilalcohol
o Polyethylene
o Polyivynilpyrrolidone
Second-generation materials chosen for:
CHEMICAL INERTNESS, NO IMPURITY RELEASE,
THEIR STRUCTURE, EASE OF PRODUCTION
Poly 2-hydroxymethylmetacrilate
o Poly N-vynilpyrrolidone
o Polymethylmetacrilate
o Polyvynilalcohol
o Polyacrilic Acid
o Polyacrilamide
o Copolimers polyethilene-vynilacetate.
o Polyethilenic 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
compositi
on
and
the type
of
drug
they carry
POLYMERIC BEADS
Release Mechanisms
o DIFFUSION
o PARTICLE DEGRADATION
o SWELLING
FOLLOWED
DIFFUSION
BY
Release Mechanisms
o DIFFUSION
o PARTICLE DEGRADATION
o SWELLING
FOLLOWED
DIFFUSION
BY
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
microbead)
dissolved
(homogeneous
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 DOUBLEWALLMICROBEAD
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
o DIFFUSION
o PARTICLE DEGRADATION
o SWELLING
DIFFUSION
FOLLOWED
BY
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
o DIFFUSION
o PARTICLE DEGRADATION
o SWELLING FOLLOWED BY
DIFFUSION
Such systems are unable to release until
placed in a suitable biological medium
Release triggered
environment:
• pH
• temperature
• ionic strength
by
changes
in
the
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-aminoethylmetacrylate 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 site
E.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
mesoporous
SOL-GEL SYNTHESIS
Synthetic approach: use of surfactant in the synthesis batch
to form large pores
MESOPORES
porosity is controlled by synthesis conditions
AMORPHOUS SILICA WALLS
C. T. Kresge et al., Nature, 1992, 359, 710-712
LIPOSOMES
(dimension less than one micron)
Hydrophilic
heads
pointing outside allow
solubility in water
Aqueous phase also
present within the
liposome
Within the membrane: lipophilic compartment
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