implants

IMPLANTS

Prepared By..SUSHMITA M.Pharm ISFCP

HISTORICAL PERSPECTIVE1861……….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

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.

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 kinetics2. Should be

Biocompatible Non-toxic Non-mutagenic Non-immunogenic Non-carcinogenic

3. Should possess a high drug to polymer ratio4. Should have good mechanical strength5. Be free of drug leakage6. Be easily sterilizable7. Be easy and inexpensive manufacture8. 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 complianceTargeted drug deliveryDecrease side effectsImprove 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.

APPROACHESA. Diffusion Controlled System1. Membrane permeation-controlled system containing

Non porous membrane Microporous membrane Semipermeable membrane2. 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 SystemA. Osmotic pressure activatedB. Vapor pressure activatedC. Magnetically activatedD. Ultrasound activatedE. 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.


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.


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

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


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.

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.


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.


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.


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


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


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.


Micrographs of gold membranes (a )before and )b( after electrochemical

dissolution


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:

dtdQ

=dm

R

PP

C11

Where: CR is the drug concentration in the reservoir compartment and Pm are the permeability coefficients of the rate-controlling membranePd 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.

implants

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