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IMPLANTS
Prepared By..SUSHMITA
M.Pharm
ISFCP
HISTORICAL PERSPECTIVE
1861……….Development of subcutaneously implantable
drug pellet.
Accidental discovery of controlled drug permeation
characteristics of silicon elastomers
Vey small capsule shaped implant containing thyroid
hormone powder released hormone steadily for long
time.
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
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.
IMPLANTS:
Definition: A sterile drug delivery device for
subcutaneous implantation having the ability to
deliver drug at a controlled rate over a
prolonged period of time, comprising a rod
shaped polymeric inner matrix with an
elongated body and two ends.
Implants: Properties
1. Drug release should approach zero-order kinetics
2. Should be
 Biocompatible
 Non-toxic
 Non-mutagenic
 Non-immunogenic
 Non-carcinogenic
1. Should possess a high drug to polymer ratio
2. Should have good mechanical strength
3. Be free of drug leakage
4. Be easily sterilizable
5. Be easy and inexpensive manufacture
6. The rate of drug release can be regulated by the shape and size of
implants, as well as polymer or polymer blend
IMPLANTS :
Advantages:
Controlled drug delivery for over a long time (months/years)
Improve patient compliance
Targeted drug delivery
Decrease side effects
Improve availability of drugs
Disadvantages:
- mini-surgery is needed
- uneasy to simply discontinue the therapy
- local reactions
But usually cannot use implants if:
Who can and cannot use implants
Most women can safely
use implants
•Breastfeeding
6 weeks
or less
•May be
pregnant
•Some other serious
health conditions
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.
APPROACHES
A. Diffusion Controlled System
1. Membrane permeation-controlled system containing
 Non porous membrane
 Microporous membrane
 Semipermeable membrane
2. Matrix diffusion controlled system containing
 Lipophilic polymers
 Hydrophilic swellable polymers
 Porous polymers
3. Microreservoir dissolution controlled system containing
 Hydrophilic reservoir/Lipophilic matrix
 Lipophilic reservoir/hydrophilic matrix
A. Activation Controlled System
A. Osmotic pressure activated
B. Vapor pressure activated
C. Magnetically activated
D. Ultrasound activated
E. Hydrolysis activated
IMPLANTABLE CONTROLLED DRUG DELIVERY SYSTEMS
IN A PULSATILE FASHION
Theoretical pulsatile release from a triggered-system.
DRUG RELEASE MECHANISMS:
 Diffusion controlled devices
 Solvent controlled devices
 Erodible devices
 Regulated release
They are devices with externally-applied trigger to turn release
on/off
i. electrical
ii. mechanical
DIFFUSION CONTROLLED
DEVICES:
 There are two types of diffusion controlled systems:
A- matrix devices
- The drug is either dissolved or dispersed in the polymer. The
drug is released from the matrix by diffusion.
DIFFUSION CONTROLLED
DEVICES:
Advantages:
Simple and convenient to prepare.
Drug dumping is not a problem.
Disadvantages:
Release rate decreases with time.
Matrix is nondegradable, so need another surgery for
removal.
Implants
DIFFUSION CONTROLLED
DEVICES:
B- reservoir devices
- consist of a drug core which can be in powdered or liquid form.
The drug core is surrounded by a non-biodegradable polymeric
material which the drug slowly diffuses through.
Disadvantages
i. Non-degradable implants
ii. Diffusion of large molecules such as proteins through the
polymer is too slow to be effective
iii. Danger of ‘dose dumping’ in barrier systems if membrane is
ruptured
Advantages
Constant release rate with time
DIFFUSION CONTROLLED
DEVICES:
Implants
SOLVENT CONTROLLED
DEVICES:
Solvent controlled release devices are a result of solvent
penetration.
There are two types of solvent controlled systems:
A- osmotic
 Osmotic controlled systems involve an external fluid moving
across a semi-permeable membrane into a region within the
device containing a high concentration of osmotic agents. The
increased volume in the osmotic compartment forces the drug
out through a small orifice.
 Non-bioerodible dosage form
SOLVENT CONTROLLED
DEVICES:
 Osmosis is the movement of
a solvent through a semi-
permeable membrane from a
region of low-solute
concentration to a region of
high-solute concentration.
Implants
Implants
SOLVENT CONTROLLED DEVICES:
 The system consists of an outer cylindrical titanium
alloy reservoir which protects the drug molecules from
enzymes, body moisture, and cellular components.
 At one end of the reservoir is positioned the membrane,
from a polyurethane polymer. The membrane is
permeable to water but impermeable to ions.
 Positioned next to the membrane is the osmotic engine.
 Next to the engine is the piston. The piston is made
from elastomeric materials and serves to separate the
osmotic engine from the drug formulation (may be
either a solution or suspension).
 At the distal end of the titanium cylinder is the exit port.
 Radiation sterilization (gamma) may be utilized to
sterilize the final drug product.
SOLVENT CONTROLLED DEVICES:
 When implanted, a large, constant osmotic gradient is
established between the tissue water and the osmotic
engine which provides a region of high NaCl
concentration.
 In response to the osmotic gradient, water is drawn
across the membrane into the osmotic engine.
 The water imbibed into the osmotic engine expands its
volume, thereby displacing the piston at a controlled,
steady rate.
 This displacement pumps drug formulation from the
drug reservoir through the exit port and into the
patient.
SOLVENT CONTROLLED DEVICES:
Viadur implant delivers leuprolide for the treatment of prostate cancer
SOLVENT CONTROLLED DEVICES:
 Targeted Drug Delivery With Catheterized
Osmotic Pumps:
- Catheters of different designs can be attached to the
exit port of an osmotic pump for targeted drug
delivery.
SOLVENT CONTROLLED DEVICES:
B- swelling
 In swelling controlled systems, a polymer which can hold a
large volume of water is employed. When the device is placed
in an aqueous environment water penetrates the matrix and the
polymer consequently swells and the drug is able to diffuse
through.
 It is nondegradable.
ERODIBLE DEVICES:
 Combination of polymer breakdown and drug diffusion
through matrix releases cargo
Advantage: being injectable and resorbable (no retrieval
surgery)
Disadvantage: therapy difficult to stop once injected due to
difficult recovery of particles
Example: Lupron depot
One month injectable implant containing leuprolide acetate for
treatment of endometriosis and prostatic cancer.
ERODIBLE DEVICES:
 NALTREXONE PELLETS
 Naltrexone pellets block the effects of heroin and other opiates
when inserted under the skin. They gradually release their
medication over time.
 500 mg naltrexone pellets that are replaced every two months,
and 800 mg naltrexone pellets that are replaced every three
months
 DISULFIRAM PELLETS
 treat alcoholism
ELECTRICAL REGULATED
RELEASE:
 Concept
Store drugs in micro-fabricated implants and release them on command
 Advantages
•Protects drugs until release
•Controls the following parameters using
microprocessors:
–Time
–Rate
–Drug combinations
ELECTRICAL REGULATED
RELEASE:
Device features:
•Target: 1+ year implant life
•100 to 400 doses
•Reservoir volume ≥100 nL
•Accommodates solutions, solids
•Individual reservoirs activated electronically
– Each reservoir can contain a different drug or formulation
ELECTRICAL REGULATED
RELEASE:
 E.g. Silicon Microchip
 contained an array of
reservoirs etched in silicon.
The reservoirs were capped
with gold membranes that
could be electrochemically
dissolved in saline with an
applied voltage (through a
wireless signal from outside
the body). At approximately 1
V, gold chloride is formed,
causing the membrane to
dissolve.
ELECTRICAL REGULATED
RELEASE:
Micrographs of gold membranes
)a) before and )b) after electrochemical
dissolution
ELECTRICAL REGULATED
RELEASE:
 The electrothermal mechanism replaced the
electrochemical mechanism at MicroCHIPS for several
reasons:
1- faster operation
2- independence of the membrane material and
surrounding environment
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
C
11
+
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
Implants
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.
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 .
Implants
Implants
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
 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.
Implants
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.
Implants
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
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.

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Implants

  • 2. HISTORICAL PERSPECTIVE 1861……….Development of subcutaneously implantable drug pellet. Accidental discovery of controlled drug permeation characteristics of silicon elastomers Vey small capsule shaped implant containing thyroid hormone powder released hormone steadily for long time.
  • 3. 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 IMPLANTABLE CONTROLLED DRUG DELIVERY SYSTEMS
  • 4. 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.
  • 5. IMPLANTS: Definition: A sterile drug delivery device for subcutaneous implantation having the ability to deliver drug at a controlled rate over a prolonged period of time, comprising a rod shaped polymeric inner matrix with an elongated body and two ends.
  • 6. Implants: Properties 1. Drug release should approach zero-order kinetics 2. Should be  Biocompatible  Non-toxic  Non-mutagenic  Non-immunogenic  Non-carcinogenic 1. Should possess a high drug to polymer ratio 2. Should have good mechanical strength 3. Be free of drug leakage 4. Be easily sterilizable 5. Be easy and inexpensive manufacture 6. The rate of drug release can be regulated by the shape and size of implants, as well as polymer or polymer blend
  • 7. IMPLANTS : Advantages: Controlled drug delivery for over a long time (months/years) Improve patient compliance Targeted drug delivery Decrease side effects Improve availability of drugs Disadvantages: - mini-surgery is needed - uneasy to simply discontinue the therapy - local reactions
  • 8. But usually cannot use implants if: Who can and cannot use implants Most women can safely use implants •Breastfeeding 6 weeks or less •May be pregnant •Some other serious health conditions
  • 9. 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
  • 10. 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.
  • 11. APPROACHES A. Diffusion Controlled System 1. Membrane permeation-controlled system containing  Non porous membrane  Microporous membrane  Semipermeable membrane 2. Matrix diffusion controlled system containing  Lipophilic polymers  Hydrophilic swellable polymers  Porous polymers 3. Microreservoir dissolution controlled system containing  Hydrophilic reservoir/Lipophilic matrix  Lipophilic reservoir/hydrophilic matrix A. Activation Controlled System A. Osmotic pressure activated B. Vapor pressure activated C. Magnetically activated D. Ultrasound activated E. Hydrolysis activated
  • 12. IMPLANTABLE CONTROLLED DRUG DELIVERY SYSTEMS IN A PULSATILE FASHION Theoretical pulsatile release from a triggered-system.
  • 13. DRUG RELEASE MECHANISMS:  Diffusion controlled devices  Solvent controlled devices  Erodible devices  Regulated release They are devices with externally-applied trigger to turn release on/off i. electrical ii. mechanical
  • 14. DIFFUSION CONTROLLED DEVICES:  There are two types of diffusion controlled systems: A- matrix devices - The drug is either dissolved or dispersed in the polymer. The drug is released from the matrix by diffusion.
  • 15. DIFFUSION CONTROLLED DEVICES: Advantages: Simple and convenient to prepare. Drug dumping is not a problem. Disadvantages: Release rate decreases with time. Matrix is nondegradable, so need another surgery for removal.
  • 17. DIFFUSION CONTROLLED DEVICES: B- reservoir devices - consist of a drug core which can be in powdered or liquid form. The drug core is surrounded by a non-biodegradable polymeric material which the drug slowly diffuses through. Disadvantages i. Non-degradable implants ii. Diffusion of large molecules such as proteins through the polymer is too slow to be effective iii. Danger of ‘dose dumping’ in barrier systems if membrane is ruptured Advantages Constant release rate with time
  • 20. SOLVENT CONTROLLED DEVICES: Solvent controlled release devices are a result of solvent penetration. There are two types of solvent controlled systems: A- osmotic  Osmotic controlled systems involve an external fluid moving across a semi-permeable membrane into a region within the device containing a high concentration of osmotic agents. The increased volume in the osmotic compartment forces the drug out through a small orifice.  Non-bioerodible dosage form
  • 21. SOLVENT CONTROLLED DEVICES:  Osmosis is the movement of a solvent through a semi- permeable membrane from a region of low-solute concentration to a region of high-solute concentration.
  • 24. SOLVENT CONTROLLED DEVICES:  The system consists of an outer cylindrical titanium alloy reservoir which protects the drug molecules from enzymes, body moisture, and cellular components.  At one end of the reservoir is positioned the membrane, from a polyurethane polymer. The membrane is permeable to water but impermeable to ions.  Positioned next to the membrane is the osmotic engine.  Next to the engine is the piston. The piston is made from elastomeric materials and serves to separate the osmotic engine from the drug formulation (may be either a solution or suspension).  At the distal end of the titanium cylinder is the exit port.  Radiation sterilization (gamma) may be utilized to sterilize the final drug product.
  • 25. SOLVENT CONTROLLED DEVICES:  When implanted, a large, constant osmotic gradient is established between the tissue water and the osmotic engine which provides a region of high NaCl concentration.  In response to the osmotic gradient, water is drawn across the membrane into the osmotic engine.  The water imbibed into the osmotic engine expands its volume, thereby displacing the piston at a controlled, steady rate.  This displacement pumps drug formulation from the drug reservoir through the exit port and into the patient.
  • 26. SOLVENT CONTROLLED DEVICES: Viadur implant delivers leuprolide for the treatment of prostate cancer
  • 27. SOLVENT CONTROLLED DEVICES:  Targeted Drug Delivery With Catheterized Osmotic Pumps: - Catheters of different designs can be attached to the exit port of an osmotic pump for targeted drug delivery.
  • 28. SOLVENT CONTROLLED DEVICES: B- swelling  In swelling controlled systems, a polymer which can hold a large volume of water is employed. When the device is placed in an aqueous environment water penetrates the matrix and the polymer consequently swells and the drug is able to diffuse through.  It is nondegradable.
  • 29. ERODIBLE DEVICES:  Combination of polymer breakdown and drug diffusion through matrix releases cargo Advantage: being injectable and resorbable (no retrieval surgery) Disadvantage: therapy difficult to stop once injected due to difficult recovery of particles Example: Lupron depot One month injectable implant containing leuprolide acetate for treatment of endometriosis and prostatic cancer.
  • 30. ERODIBLE DEVICES:  NALTREXONE PELLETS  Naltrexone pellets block the effects of heroin and other opiates when inserted under the skin. They gradually release their medication over time.  500 mg naltrexone pellets that are replaced every two months, and 800 mg naltrexone pellets that are replaced every three months  DISULFIRAM PELLETS  treat alcoholism
  • 31. ELECTRICAL REGULATED RELEASE:  Concept Store drugs in micro-fabricated implants and release them on command  Advantages •Protects drugs until release •Controls the following parameters using microprocessors: –Time –Rate –Drug combinations
  • 32. ELECTRICAL REGULATED RELEASE: Device features: •Target: 1+ year implant life •100 to 400 doses •Reservoir volume ≥100 nL •Accommodates solutions, solids •Individual reservoirs activated electronically – Each reservoir can contain a different drug or formulation
  • 33. ELECTRICAL REGULATED RELEASE:  E.g. Silicon Microchip  contained an array of reservoirs etched in silicon. The reservoirs were capped with gold membranes that could be electrochemically dissolved in saline with an applied voltage (through a wireless signal from outside the body). At approximately 1 V, gold chloride is formed, causing the membrane to dissolve.
  • 34. ELECTRICAL REGULATED RELEASE: Micrographs of gold membranes )a) before and )b) after electrochemical dissolution
  • 35. ELECTRICAL REGULATED RELEASE:  The electrothermal mechanism replaced the electrochemical mechanism at MicroCHIPS for several reasons: 1- faster operation 2- independence of the membrane material and surrounding environment
  • 36. 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.
  • 37. 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 C 11 + 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
  • 39. 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.
  • 40. 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
  • 41.  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.
  • 42. )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.
  • 43. 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.
  • 44. 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.
  • 45. 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
  • 46.  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.
  • 47. 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.
  • 48. Glucose-Sensitive Systems Several strategies are used for glucose-responsive drug delivery. 1. pH Dependent systems for glucose-stimulated drug delivery 2. Competitive binding
  • 49. 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.
  • 50. )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.
  • 51.  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.
  • 52. 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.
  • 53.  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 .
  • 56. 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
  • 57.  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.
  • 59. Sol–gel phase transition in polymers crosslinked with Con A.
  • 60. 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.
  • 61. 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.
  • 62. 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.
  • 63. 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.
  • 65. 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).
  • 66. 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.
  • 67. 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
  • 68. 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.
  • 69. 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.
  • 70. 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.
  • 71. 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
  • 72. 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
  • 73. 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)
  • 74. 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.
  • 75. 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.