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IMPLANTABLE CONTROLLED DRUG DELIVERY SYSTEMS. IMPLANTABLE CONTROLLED DRUG DELIVERY SYSTEMS. Implants are very small pellets composed of drug substance only without excipients. They are normally about 2-3 mm in diameter and are prepared in an aseptic manner to be sterile. - PowerPoint PPT Presentation
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Implants are very small pellets composed of drug
substance only without excipients.
They are normally about 2-3 mm in diameter and
are prepared in an aseptic manner to be sterile.
Implants are inserted into a superficial plane
beneath the skin of the upper arm by surgical
procedures, where they are very slowly absorbed
over a period of time.
Implant pellets are used for the administration of
hormones such as testosterone.
IMPLANTABLE CONTROLLED DRUG DELIVERY SYSTEMS
The capsules may be removed by surgical
procedures at the end of the treatment period.
Biocompatibility need to be investigated, such as
the formation of a fibrous capsule around the
implant and, in the case of erosion-based devices
there is the possible toxicity or immunogenicity of
the byproducts of polymer degradation.
The Implantable controlled drug delivery system
achieved with two major challenges.
1) by sustained zero-order release of a therapeutic
agent over a prolonged period of time.
This goal has been met by a wide range of techniques,
including:
Osmotically driven pumpsOsmotically driven pumps
Matrices with controllable swellingMatrices with controllable swelling
diffusiondiffusion or erosion ratesor erosion rates
2) By the controlled delivery of drugs in a pulsatile or
activation fashion.
These systems alter their rate of drug delivery in
response to stimuli including the presence or absence
of a specific molecule, magnetic fields, ultrasound,
electric fields, temperature, light, and mechanical
forces.
Such systems are suitable for release of
therapeutics in non-constant plasma concentrations
as in diabetes.
This goal has been met by two different
methodologies:
A delivery system that releases the drug at a
predetermined time or in pulses of a predetermined
sequence.
A system that can respond to changes in the local
environment.
IMPLANTABLE CONTROLLED DRUG DELIVERY SYSTEMS IN A PULSATILE FASHION
Theoretical pulsatile release from a triggered-system.
IMPLANTABLE CONTROLLED DRUG DELIVERY SYSTEMS
IN A SUSTAINED ZERO-ORDER CONTINUOUS RELEASE
In membrane permeation-type controlled drug
delivery, the drug is encapsulated within a
compartment that is enclosed by a rate-limiting
polymeric membrane.
The drug reservoir may contain either drug
particles or a dispersion of solid drug in a liquid or a
solid type dispersing medium.
The polymeric membrane may be made-up from a
homogeneous or a heterogeneous nonporous
polymeric material or a microporous or
semipermeable membrane.
The drug release by diffusion (dQ/dt) from this type
of implantable therapeutic systems should be constant
and defined by:
dt
dQ=
dm
R
PP
C11
Where:
CR is the drug concentration in the reservoir
compartment and Pm are the permeability coefficients of
the rate-controlling membrane
Pd the permeability coefficients of the diffusion layer
existing on the surface of the membrane, respectively.
Pm and Pd depend on the partition coefficients for the
interfacial partitioning of drug molecules from the
reservoir to the membrane and from the membrane to
the aqueous diffusion layer, respectively.
Example Levonorgestrel ImplantsThese are a set of six flexible, closed capsules
of a dimethylsiloxane/methylvinylsiloxane copolymer,
each containing 36 mg of the progestin
levonorgestrel.
They are inserted through a 2 mm incision in the
mid-portion of the upper arm in a fan-like pattern.
This system provides long-term (up to 5 years)
reversible contraception.
Diffusion of the levonorgestrel through the wall of
each capsule provides a continuous low dose of
progestin.
A technique that depend on sequential release of
drugs which fabricated as polymer matrix with
multilayer alternating drug-containing and spacer
layers.
Pre-programmed Delivery Systems
The polymer matrix is commonly surrounding
impermeable shell, which permitting release of the
entrapped drug only after degradation of this polymer
matrix.
For degradation of this polymer matrix to occur, the
polymer matrix must be susceptible to hydrolysis or
biodegradation by a component in the surrounding
media.
)A) Schematic of a multilayered pulsatile delivery system with one face exposed to the local environment.
(B) Schematic of a cylindrical multilayered delivery system with two open faces.
I.System that controlling drug
release by environmental pH
Using polyanhydrides as the spacer layers and the
drug containing layer as poly[(ethyl glycinate)
(benzly amino acethydroxamate)phosphazene]
(PEBP)
The polyanhydrides and PEBP layers were
compression molded to form a multilayered
cylindrical core, which was then coated with a
poly(lactide-co-1,3-trimethylene carbonate) film over
all surfaces except for one face of the device.
The hydrolysis of PEBP is highly dependent on the
pH of the surrounding media, dissolving much more
rapidly (1.5 days) under neutral and basic conditions
(pH 7.4) but in acidic conditions (pH 5.0) digradad
over 20 days.
The degradation products of polyanhydrides create
an acidic environment within the delivery device,
preventing the rapid hydrolysis of the PEBP and
result in slow drug release until all of the
polyanhydride layer has been eroded.
Using hydrogels that have differing susceptibilities
to enzymatic degradation.
Pulsatile release can be achieved with a model
system that uses the enzymatic degradation of
dextran by dextranase to release insulin in a
controlled manner.
A delivery vehicle can be fabricated by covering
poly(ethylene glycol)-grafted (embedded) dextran
(PEG-g-Dex) and unmodified dextran layers in a
silicone tube.
II. System that controlling drug release by environmental enzymes
The drug is loaded into the PEG-g-Dex layers while
dextran is material for the spacer layer.
The introduction of PEG into a dextran solution
containing a drug causes the formation of a two-
phase polymer when the dextran is cross-linked.
The drug is partitioned into the PEG phase,
resulting in drug release that is erosion-limited
instead of diffusion-limited.
Closed-loop delivery systems
Closed-loop delivery systems are those that are
self-regulating.
They are similar to the programmed delivery
devices in that they do not depend on an external
signal to initiate drug delivery.
However, they are not restricted to releasing their
contents at predetermined times. Instead, they
respond to changes in the local environment, such as
the presence or absence of a specific molecule.
Glucose-Sensitive Systems
Several strategies are used for glucose-responsive
drug delivery.
1. pH Dependent systems for glucose-stimulated drug
delivery
2. Competitive binding
1. pH Dependent systems for glucose-stimulated
drug delivery
As insulin is more soluble under acidic conditions,
Incorporating glucose oxidase into a pH-responsive
polymeric hydrogel enclosing insulin solution will
result in a decrease in the pH of the environment
immediately surrounding the polymeric hydrogel in
the presence of glucose as a result of the enzymatic
conversion of glucose to gluconic acid.
)A) Diagram of a glucose-sensitive dual-membrane system.
(B) The membrane bordering the release media responds to increased
glucose levels by increasing the permeability of the membrane
bordering the insulin reservoir.
A copolymer of ethylene vinyl acetate (EVAc)
containing g glucose oxidase immobilized on cross-
linked poly- acrylamide. and insulin solution . the
insulin release rate will be altered in response to
changes in the local glucose concentration.
The release rate of insulin returned to a baseline
level when the glucose was remove.
A dual-membrane system
sensing membrane is placed in
contact with the release media,
while a PH barrier membrane is
positioned between the sensing
membrane and the insulin reservoir.
As glucose diffuses into the hydrogel , glucose
oxidase catalyzes its transport to gluconic acid, thereby
lowering the pH in the microenvironment of the PH
membrane and causing swelling .
Gluconic acid is formed by the interaction of glucose
and glucose oxidase, causing the tertiary amine groups
in the PH- membrane to protonated and induce a
swelling response in the membrane.
Insulin in the reservoir is able to diffuse across the
swollen barrier membrane.
Decreasing the glucose concentration allows the pH of
barrier membrane to increase, returning it to a more
collapsed and impermeable state .
2. Competitive binding methodology depending on the fact that
concanavalin A (Con A) a glucose-binding lectin, can
bind both glycosylated insulin and glucose.
Glycosylated insulin (G-insulin) bound to Con A can
be displaced by glucose, thus release the drug from
system.
In this systems immobilized Con A -Glycosylated
insulin encapsulated with a polymer (sepharose beads
) , release only occurs at sufficiently high glucose
concentration .
as Con A immobilized has a lower binding affinity
for glucose than for G-insulin, preventing release at
low glucose levels.
Hydrogels formed by mixing Con A and (G-insulin)
with copolymers as acrylamide .
hydrogel will undergo a reversible gel–sol phase
transition in the presence of free glucose due to
competitive binding between the free glucose and
Con A.
G-insulin acts as a cross-linker for the Con A chains
due to the presence of four glucose-binding sites on
the molecule, but competitive binding with glucose
disrupts these cross-links, making the material more
permeable and thus increasing the rate of drug
delivery.
Sol–gel phase transition in polymers crosslinked with Con A.
Similar systems have been developed that use the
interaction between an antibody and an antigen to
control the release of a drug in the presence or
absence of the antigen.
A hydrogel held together by the interaction of
polymer-bound antigen to polymer-bound antibody
will swell in the presence of free antigen due to the
competitive binding of bound antibody to free
antigen, reducing the number of crosslinks in the
hydrogel and thus increasing the rate of drug
delivery in proportion to the antigen concentration.
Open-loop Delivery Systems Open-loop delivery systems are not self-regulating,
but require externally generated environmental
changes to initiate drug delivery.
These can include magnetic fields, ultrasound,
electric fields, temperature, light, and mechanical
forces.
Open-loop delivery systems may be coupled to
biosensors to obtain systems that automatically
initiate drug release in response to the measured
physiological demand.
1. Magnetic Field One of the first methodologies to achieve an
externally controlled drug delivery system is the use
of an magnetic field to adjust the rates of drug
delivery from a polymer matrix.
A magnetic steel beads embedded in an EVAc
copolymer matrix that is loaded with the drug.
An oscillating magnetic field ranging from 0.5 to
1000 gauss cause increased rates of drug release.
The rate of release could be altered by changing the
amplitude and frequency of the magnetic field.
The increased release rate was caused by mechanical
deformation due to magnetic movement within the
matrix.
During exposure to the magnetic field, the beads
oscillate (swing) within the matrix, creating compressive
and tensile forces which acts as a pump to (squeezing)
push an increased amount of the drug molecule out of
the matrix.
2. Ultrasound Ultrasound stimulus can be used to adjust drug
delivery by directing the waves at a polymer or
hydrogel matrix.
Where drug release can be increased 27-fold from
an EVAc matrix during exposure to ultrasound.
Increasing the strength of the ultrasound resulted
in a increase in the amount of drug released (1 W/cm
for 30 min).
The principle depends on that sound cavitation
occurred by ultrasonic irradiation at a polymer–liquid
interface forms high-velocity jets of liquid directed at
the polymer surface that are strong enough to
release away material at the surface of the polymer
device, causing an increase in the erosion rate of the
polymer .
Also the sound cavitation enhances mass transport
at a liquid–surface interface.
Electric Field
Electric current signal can be used to activate drug
delivery.
The presence of an electric current can change the
local pH which initiate the erosion of pH-sensitive
polymer and the release of the drug contained in
polymer matrix.
Polymers as poly(methacrylic acid) or poly(acrylic
acid) can be dissolved at pH>5.4
A 5 mA electric current resulted in drug delivery due
to the production of hydroxyl ions at the cathode,
which raised the local pH, disrupting the hydrogen
bonding between the comonomers.
In the absence of the electric stimulus, drug release
was negligible.
Humans can tolerate direct current densities of
under 0.5 mA/cm for up to 10 min; therefore no
visible skin damage was observed.
Temperature
Thermally-responsive hydrogels and membranes can
be used for pulsatile delivery of drugs.
Temperature sensitive hydrogels have a lower critical
solution temperature (LCST), a temperature at which a
hydrogel polymer undergo a phase change. In which
transition of extended coil to the uncross-linked
polymer an can be occurred .
This phase change is based on interactions between
the polymer and the water surrounding the polymer.
Thermally sensitive hydrogel systems can exhibit
both negative controlled release, in which drug
delivery is stoped at temperatures above the LCST,
and positive controlled drug delivery, in which the
release rate of a drug increases at temperatures
above the LCST.
N-Isopropylacrylamide (NIPAAm) is a commonly
used thermosensitive polymer with an LCST of 32 °C.
Thermally sensitive materials exhibiting negative
thermally controlled drug delivery.
When the temperature of the hydrogel is held below its
LCST, the most thermodynamically stable configuration
for the free (non-bulk) water molecules is to remain
clustered around the hydrophobic polymer. When the
temperature is increased over the LCST, the collapse of
the hydrogel is initiated by the movement of the
clustered water from around the polymer into bulk
solution. Once the water molecules are removed from
the polymer, it collapses on itself in order to reduce the
exposure of the hydrophobic domains to the bulk water.
Thermally sensitive materials exhibiting positive
thermally controlled drug delivery.
A copolymer of NIPAAm and acrylamide (AAm) is an
example of such a material. The hydrophilic AAm
increases the LCST of the copolymer as well as
reducing the thickness and density of the outer layer
formed when the temperature of the hydrogel is
raised above its LCST.
Upon collapse, the hydrogel will push out soluble
drug held within the polymer matrix
5. Light
The interaction between light and a material can be
used to adjust drug delivery.
This can be accomplished by combining a material
that absorbs light at a desired wavelength and a
material that uses energy from the absorbed light to
adjust drug delivery.
Near-infrared light has been used to adapt the
release of drugs from a composite material fabricated
from gold nanoparticles and poly(NIPAAm-co-AAm)
When exposed to near-infrared light, the nanoshells
absorb the light and convert it to heat, raising the
temperature of the composite hydrogel above its
LCST (40 °C(. This in turn initiates the
thermoresponsive collapse of the hydrogel, resulting
in an increased rate of release of soluble drug held
within the polymer matrix.
6. Mechanical force
Drug delivery can also be initiated by the
mechanical stimulation of an implant.
Alginate hydrogels can release included drugs in
response to compressive forces of varying strain
amplitudes.
Free drug that is held within the polymer matrix is
released during compression; once the strain is
removed the hydrogel returns to its initial volume.
This concept is similar to squeezing the drug out of
a sponge.