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.
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.
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 pumps
 Matrices with controllable swelling
 diffusion or 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:
Where:
dQ
=
dt
CR
1
1

Pm
Pd
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 Implants
 These 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.
Pre-programmed Delivery Systems
A technique that depend on sequential release of drugs
which fabricated as polymer matrix with multilayer
alternating drug-containing and spacer layers.
 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.
II. System that controlling drug release by
environmental enzymes
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-gDex) and unmodified dextran layers in a silicone tube.
 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 diffusionlimited.
Closed-loop delivery systems
Closed-loop delivery systems are those that are selfregulating.
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 PHmembrane 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 polymerbound 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.