IMPLANTABLE%20CONTROLLED%20DRUG%20DELIVERY%20SYSTEMS

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IMPLANTABLE CONTROLLED DRUG DELIVERY SYSTEMS
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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.

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• 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.

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• 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

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• 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.

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IMPLANTABLE CONTROLLED DRUG DELIVERY SYSTEMS IN
A PULSATILE FASHION
Theoretical pulsatile release from a
triggered-system.
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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.

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• The drug release by diffusion (dQ/dt) from this
  type of implantable therapeutic systems should be
  constant and defined by

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.
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• 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.

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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.
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• 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.

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)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.
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• 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)phosphazen
  e (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.

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• 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.

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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-g-Dex) and unmodified dextran layers in a
  silicone tube.

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• 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.

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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.

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Glucose-Sensitive Systems Several strategies are
used for glucose-responsive drug delivery. 1. pH
Dependent systems for glucose-stimulated drug
delivery 2. Competitive binding
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• 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.

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)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.
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• 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.

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• 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.

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• 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 .

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• 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.

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• Hydrogels formed by mixing Con A and (G-insulin)
  with copolymers as acrylamide .
• hydrogel will undergo a reversible gelsol 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.

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Solgel phase transition in polymers crosslinked
with Con A.
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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.
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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.

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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.

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• 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.

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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).

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• The principle depends on that sound cavitation
  occurred by ultrasonic irradiation at a
  polymerliquid 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 liquidsurface interface.

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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 pHgt5.4

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• 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.

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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.

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• 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.

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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.
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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
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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)

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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.
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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.