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Mechanism of implantable drug delivery systems.

Most implanted drug delivery systems are based on three basic delivery mechanisms.
Swelling control.
Osmotic pumping.
Diffusion.
In solvent-activated systems a swelling or osmotic mechanism is involved. Applications have
been made in the areas of dentistry, immunization, anticoagulation, cancer, narcotic antagonists,
and insulin delivery

(Costantini et al., 2004).Nowadays,

number of drugs have been used for the

implantable drug delivery systems as shown in Table 1.


Table 1: Drugs used for the implantable drug delivery
systems
Name of Drugs Purpose
Progestin+estradiol,megestrol,norgestrel Contraception
Ibuprofen,naproxen,phenylbutazone Polyarthritis
Cyclophosphamide,merchloroethamide Cancer
Deoxycortisone Antihypertensive studies
Morphine Narcotic addiction studies
Pilocarpine Glaucoma

Non-degradable and biodegradable implant systems


Non-degradable systems
There are several types of nondegradable implantable drug delivery systems available on the
marketplace

today,

but

the

Figure 1: Crosssectional view of idealized nonerodible reservoir and


matrix systems, showing diffusion of the drug across the polymer
nondegradable matrix system and reservoir systems are the two most common forms [Figure 1].
In the polymeric matrix system, the drug is dispersed homogeneously, inside the matrix
material. Slow diffusion of the drug through the polymeric matrix material provides
sustained release of the drug from the delivery system. The reservoir-type system, on the
other hand, consists of a compact drug core surrounded by a permeable nondegradable
membrane whose thickness and permeability properties can control the diffusion of the drug
into the body.[4] The release kinetics of drug from this system suggest that if the
concentration of the drug within the reservoir is in constant equilibrium with the inner
surface of the enclosed membrane, the driving force for diffusional release of the agent is
constant and zero-order release kinetics of the drug from the delivery system is obtained
(Alekha and Greggrey, 1998).This type of system, however, has several disadvantages. The
outer membrane of most of these systems is nondegradable. Therefore, after drug has been
released, minor surgery is necessary for the removal of the delivery system from the body.
There is also a possibility that membrane rupture will potentially lead to drug dumping
during therapy. Depending on the type of drug involved in the reservoir, drug dumping
may result in untoward toxic side effects from drug plasma concentrations that exceed
maximum safety levels. The possibility of drug dumping has made the reservoir system a
less popular method of drug delivery.
In the past, nondegradable systems have also been studied for use in the administration of
3.

anticancer drugs such as doxorubicin. Microcapsules containing a nondegradable exterior and


compressed doxorubicin reservoir interior have been studied. This type of administration was
compared to biodegradable polymer matrices containing doxorubicin. In such experiments, the
biodegradable polymers did not cause any toxic reactions within the body and were preferred
over the nonbiodegradable polymers that remained in the body after the drug was released.

Matrix systems are also commonly used as nondegradable implants. These systems
consist of uniformly distributed drug throughout a solid nonbiodegradible polymer
(Patel, 2010).
Like the reservoir systems, matrix systems rely on the diffusion of drug particles through the
6

nondegradable fibrous network of the polymer to obtain sustained release of the drug. However,
the kinetic release of drug from these formulations is not constant and depends upon the volume
fraction of the agent in the matrix. The greater the concentration of the dissolved agent within the
matrix, the greater
the release from the system.[8]
Another type of nondegradable system is the magnetically controlled release system. In this type
of formulation, small magnetic beads are uniformly dispersed within a polymer [Figure 2].

Figure

2:

Schematic of a magnetically controlled polymeric drug delivery


system illustrating increased drug release from the system after exposure
to an oscillating magnetic field
When the unit is exposed to a biological system, normal diffusion of the drug due to a
concentration gradient is seen. However, upon exposure to an external oscillating magnetic field,
larger quantities of drug can be released quickly.[1] The major advantage of this type of drug
delivery system is the possibility of manipulating the release kinetics of the drug by using
external magnetic stimuli.[8]

Biodegradable systems
Biodegradable systems have gained much popularity over nondegradable delivery systems.[9,10]
The major advantages of biodegradable systems include the fact that the inert polymers, used for
the fabrication of the delivery system, are eventually absorbed or excreted by the body. This
alleviates the need for surgical removal of the implant after the conclusion of therapy thereby
increasing patient acceptance and compliance.[11]
However, developing biodegradable systems is a more complicated task than formulating
nondegradable systems. When fabricating new biodegradable systems, many variables must be
taken into consideration. For instance, the degradation kinetics of the polymer, in vivo, must
remain at a constant rate to maintain sustained release of the drug. Many factors can affect the
rate of degradation of the polymer in the body. Alterations in body pH or temperature can cause a
transient increase or decrease in the degradation rate of the system. The surface area of the
delivery system also plays an important role in its degradation.[12] As the system is eroded, the
surface area of the implantable system decreases. Thus, the change in shape of the drug delivery
system that will occur, in vivo, should be taken into account during the formulation design. In
order to attain a more uniform and constant release, it is necessary to use geometrical shapes
whose surface area does not change as a function of time during erosion.[13] A flattened slabtype shape that has no edge erosion is the shape that approximates most closely a zero-order
release kinetic profile.[14] Some manufactures have also designed systems that contain a
bioerodable inert core coated with the active drug matrix to alleviate the change in surface area
problem encountered during erosion. Another problem that occurs with bioerodable systems is
the slow diffusion of the drug from the polymer matrix.[8] Diffusion of the drug usually occurs
at a slower rate than the bioerosion of the system and is dependent upon the chemical nature of
the polymeric substance utilized in the formulation of the drug delivery system. This becomes a
major challenge to overcome when developing bioerodable systems whose use is intended for
extended release applications or in situations in which the drug has a narrow therapeutic index.
[15]
Two different types of biodegradable delivery systems are currently available. The first type, a
reservoir system, is similar in structure to the nondegradable reservoir type described earlier. The
mechanism of drug release from both systems is quite similar.[16] However, these bioerodible
systems, in contrast, contain an exterior polymeric membrane that degrades at a slower rate than

the expected rate of drug diffusion through the membrane. Therefore, the membrane remains
intact while the drug is released completely. Eventually, the exterior polymeric membrane is
degraded, in vivo, and, ultimately, eliminated. The second type of bioerodible system consists of
drug dispersed in a polymer, monolithic type, which is slowly eroded, in vivo, by biological
processes at a controlled rate.[1] The most popular biodegradable polymers currently being
investigated include polyglycolic acid, polylactic acid, polyglycolic-lactic acid, polyaspartic
acid, and polycaprolactone.[4] The use of ethyl vinyl acetate copolymer matrices for the delivery
of macromolecular drugs such as insulin has also been studied extensively.[17,18] A new form of
lactic acid/lysine copolymer, chemically attached to a biologically active peptide, is being
developed and tested which could function as a matrix for the mammalian cells.[19] This new
copolymer effectively promotes cell adhesion to an otherwise nonadherent surface, and this
system will, hopefully, play a major role in the development of implantable polymers in the
future.[20]
Implantable pump systems
Many different drugs require external control of delivery rate and volume. Such control cannot
be obtained when using biodegradable or nondegradable delivery systems with the exception of
the magnetic-type delivery systems. Pump systems have been used to provide the control needed
in these situations. Recently, due to the availability of advanced microtechnology, it has been
possible to create pump systems small enough to implant, subcutaneously, for drug delivery.[21]
This allows the patient to maintain the control of drug release without the need for an external
pump system. In recent advances, insulin implantable pump systems have been invented and
used for the control of type-1 diabetes as shown in Figure 3.

Figure

3:

Schematic of an insulin implantable pump


Pump systems differ from other implantable systems due to their mechanism of drug delivery.
Pump systems release drugs through a pressure difference generated gradient that results in the
bulk flow of a drug at controllable rates.[22] To date, five different types of implantable pump
systems have been tested including infusion pumps, peristaltic pumps, osmotic pumps, positive
displacement pumps, and controlled release micropumps.
Infusion pumps
Infusion pumps are implantable mechanical systems that utilize a fluorocarbon propellant to
administer the drug, in vivo. Such pumps were initially developed for the administration of
insulin to diabetic patients. Infusaid (Infusaid Corp. Sharon, MA, USA) was one of the first
commercially available pumps for this use. Normally, insulin-dependent diabetics require
injections once or twice daily.
This type of dosing results in abnormal peaks and valleys in blood glucose levels. It is believed
that such poor control of blood glucose levels may lead to diabetic complication such as heart
and kidney disease.[12] It is felt that continuous insulin infusion using such pumps may help
eliminate these risk factors in the diabetic population. The pump consists of a disc-shaped
canister made of light-weight biocompatible titanium which contains a collapsible welded

bellow.[23] The bellow separates the canister interior into two separate chambers. The first
chamber contains the fluorocarbon propellant and the second contains the insulin formulation[8]
[Figure 4].

Figure 4: An implantable propellant driven


pump system during operation
(top) and during refilling (bottom)
The gas pushes the drug through a filter and a flow regulator that provides a constant rate of drug
administration at a given temperature. The delivery rate is adjusted by changing the drug
concentration in the pump reservoir.[24] The advantage of this system involves the fact that no
external energy source is needed to drive the pump action. When the pump reservoir is refilled,
an injection of drug through a membrane consisting of a self-sealing silicone rubber and Teflon
septum is administered. The force of the injection recompresses the fluorocarbon propellant
thereby recharging the system. In addition to insulin therapy, the use of this pump system in the
delivery of anticoagulant and chemotherapeutic agents has also been investigated.[25]
Peristaltic pumps
Peristaltic pumps consist of rotary solenoid-driven systems that run via an external power source
which is usually a battery.[1] Peristaltic systems, like the infusion pump systems, are filled
through a silicone rubber septum and can be used for several years depending on the life span of
the battery-powered system

[Figure 5].

Figure

5: Cross-sectional view of an implantable peristaltic pump showing


all important components
The advantage of this type of system is that the rate of drug administration can be controlled by
an external remote control system. These systems, however, have proven to be very costly, and,
thus, have not been seen in standard practice to date.
Osmotic pumps
Osmotic pumps have proven to be the most popular type of implantable drug delivery systems.
The osmotic pump, also known as Oros or the gastrointestinal therapeutic system, was first
described by Theeuwes and Yum, and released for use by Alza Corporation.[26,27] This pump
consists of a drug reservoir surrounded by a semipermeable membrane. The surrounding
membrane allows a steady influx of water and biological fluid into the reservoir through the
process of osmosis. The hydrostatic pressure built from this influx causes a steady release of the
drug from an opening in the membrane called the drug portal. The rate of drug release is
constant or zero-order until the drug within the reservoir is completely depleted. Changing the
rate of drug administration of these systems can only occur by changing the structure of the
semipermeable membrane that requires removal of the system.[28]
Osmotic pump systems containing hydromorphone have been subcutaneously implanted for the
use of pain management. Results have shown that Alzets osmotic pumps release 262 mg/h of

hydromorphone to produce stable plasma concentrations of approximately 3040 mg/mL over a


2-week period. This type of delivery system is advantageous over other systems since the initial
burst effect, seen in other forms of degradable or nondegradable matrix systems, does not occur.
[29] The prolonged release of drug at a constant rate has been shown to be effective in the
treatment and management of chronic pain. Therefore, such systems may be used more
extensively in the future.
Positive displacement pumps
Positive displacement pumps have been developed to provide continual insulin delivery in
diabetic patients. Most of these systems utilize piezoelectric disk benders affixed to flexible
tubing. Such pumps are made by first exposing the disks to certain voltages so that they form
spherical surfaces.[30,31] The bellow-type system is then connected to a drug reservoir via a
three-way solenoid driven valve. When exposed to electrical pulses, the valves in the pump open
or close depending on the direction of the pulse. This action causes the release of drug in a
controlled manner based on the rate of the electrical pulse. Other types of positive displacement
pumps using similar designs are currently being developed for the delivery of insulin.[4]

2-5-0 theke

Implantable osmotic pump


They are either for experimental (animal) or for human use,
ALZET
ALZET osmotic pumps are miniature, implantable pumps used for research in mice, rats, and
other laboratory animals. These infusion pumps continuously deliver drugs, hormones, and other
test agents at controlled rates from one day to six weeks without the need for external
connections or frequent handling. Their unattended operation eliminates the need for repeated
nighttime or weekend dosing10. Alzet osmotic pumps Empty reservoir within the core of the
pump is filled with the drug or hormone solution to be delivered and is surrounded by salt
chamber with impermeable layer between them. Mechanism ALZET pumps operate because of
an osmotic pressure difference. The rate of delivery by an Alzet pump is controlled by the water
permeability of the pumps outer membrane. Thus, the delivery profile of the pump is

independent of the drug formulation dispensed. Drugs of various molecular configurations,


including ionized drugs and macromolecules, can be dispensed continuously in a variety of
compatible vehicles at controlled rates. The molecular weight of a compound, or its physical and
chemical properties, has no bearing on its rate of delivery by ALZET pumps. Water enters into
the salt chamber through semipermeable membrane and causes compression of flexible reservoir
and delivery of drug solution.

Fig. 4: Alzet osmotic pump


Applications
The alzet pump the enabled to Neuroscientist to manipulate the central & peripheral nervous
system of an unstrained animal permitting simultaneous study of behavioral of motor & sensory
function also neuro generative disease , drug dependence & tolerance & regulation.
Alzet pump have proved useful in biotechnology. For characterizing novel protein & peptides
such as growth factor, while also facilitating exciting new research in which antisense
oligonucleotides.
For human use Duros
It is a miniature, implantable osmotic pumps for long term, parenteral, delivery of drug in
human. The system consists of an outer cylindrical titanium alloy reservoir. This reservoir has
high-impact strength and protects the drug molecules from enzymes, body moisture, and cellular
components that might deactivate the drug prior to delivery. At one end of the reservoir is
positioned the membrane, constructed from a specially designed polyurethane polymer. The
membrane is permeable to water but substantially 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 in the
drug reservoir compartment.

At the distal end of the titanium cylinder is the exit port. Exit ports can range from simple,
straight channels to more complicated design configurations. The exit port design must be
coupled to the rheological properties of the drug formulation. Duros implant with diameters up to
7mm have been designed , resulting in drug formulation volume of the 4mm*45mm implant has
a total volume of less than 200microlit 11.
Mechanism -Through osmosis, water from the body is slowly drawn through the semipermeable
membrane into the pump by osmotic agent residing in the engine compartment, which expands
the osmotic agent and displaces a piston to dispense small amounts of drug formulation from the
drug reservoir through the orifice.

Fig. 5: Duros

osmotic pump
Compounds delivered using DUROS
Technology
DUROS has the potential to provide more flexibility than competitive products regarding the
types of drugs that can be administered, including proteins, peptides and genes because the drug
dispensing mechanism is independent from the drug substance11.
Applications

1) Duros Leuprolide Implant-the duros leuprolide implant has been designed to provide an
alternative to periodic depot injection leuprolide for palliative treatment of advanced prostate
cancer.
2) Salmon calcitonin (sCT) has been used for the treatment of osteoporosis and Pagets disease
where calcitonin inhibits osteoclasic bone resorption and induces calcium uptake.
3) Systemic or site-specific administration of a drug. The preferred site of implantation is
subcutaneous placement in the inside of the upper arm. When implanted, a large, constant
osmotic gradient is established between the tissue water and the osmotic engine.
29-170 theke

In the past, drugs were frequently administered orally, as liquids or in powder forms. To avoid
problems incurred through the utilization of the oral route of drug administration, new dosage
forms containing the drug(s) were introduced. As time progressed, there was a need for delivery
systems that could maintain a steady release of drug to the specific site of action. Therefore, drug
delivery systems were developed to optimize the therapeutic properties of drug products and
render them more safe, effective, and reliable. Implantable drug delivery systems (IDDS) are an
example of such systems available for therapeutic use. The study of currently available
implantable drug delivery systems is the main focus of this review. The major advantages of
these systems contain targeted local delivery of drugs at a constant rate, fewer drugs required to
treat the disease state, minimization of probable side effects, and better efficacy of treatment.
Due to the development of such sustained release formulations, it is now possible to administer
unstable drugs once a week to once a year that in the past required frequent daily dosing.
Preliminary studies using these systems have shown superior effectiveness over conventional
methods of treatment. However, one limitation of these newly developed drug delivery systems
is the fact that their cost-to-benefit ratio (cost/benefit) is too high which restricts their use over
conventional dosage forms. Some of the most recently discovered implants are in the early
developmental stages and more rigorous clinical testing is required prior to their use in standard
practice.
INTRODUCTION
Orally administered drug must be protected against denaturation in the gastrointestinal tract and

should be capable of absorption across the wall of the stomach or the intestine. After absorption
and upon reaching the portal circulation, it must be resistant to hepatic enzymes. The rate of drug
absorption and elimination should ensure the blood levels within the therapeutic range.
Moreover, the amount of intact drug that reaches the site of action should be sufficiently large to
obtain desired therapeutic effect but insufficient to cause untoward side effects.A controlled drug
action may be achieved by either chemically modifying the drug moiety or by formulating it in a
specific way to control its release. Oral controlled release dosage forms can provide efficacy for
about 24 hours. The main drawback of oral dosage form is the long transit time of approximately
12hours through the gastrointestinal tract (GIT). If drug cannot be administered orally, a
parenteral route of delivery is an alternative. Many proteins/peptides and other drugs, which are
susceptible to the adverse conditions of GIT, are administered intravenously. Unfortunately, in
intravenous drug administration, the duration of drug action is short for majority of
therapeutically active agents and therefore frequent injections are required.
The development of injectable controlled-release dosage forms is more likely to succeed
commercially than alternative routes of delivery, assuming that these dosage forms provide the
desired efficacy and safety. In case of topical drug administration, the percutaneous absorption of
most drugs is limited due to physiological characteristics of the drugs and presence of highly
impermeable stratum corneum.
Implantable drug delivery devices are devoid of aforementioned limitations associated with oral,
intravenous, topical drug administration vis--vis subcutaneously implantable drug delivery
devices offer one unique advantage of a retrievable mechanism [1].
For integration of various therapeutic agents with different physicochemical characteristics and
for improved mechanism of drug release, number of additives is now used. Thus, more current
implantables generally contain the therapeutic agent in a rate controlling systems. Implantables
are available in various sizes and shapes. While oral delivery is considered the preferred method
of administering many drugs, additional methods employing pulmonary, infusion, and
implantable systems have been developed to overcome drug delivery constraints.
For example, many macromolecules are either digested in the gastrointestinal tract or are not
well absorbed into the bloodstream. Oral administration may also not be appropriate for drugs
that require a rapid onset of action. Similarly, pulmonary systems such as inhalers require drugs
to be absorbed into the bloodstream from the lungs. Drug delivery by injection has other

disadvantages. Patients must choose between traveling to a treatment site and maintaining a
home supply. Furthermore, the discomfort of frequent injections leads to poor patient
compliance. Finally, a multiple, timed drug-injection regimen is complicated to administer and
may require a clinicians help.
Portable infusion systems allow unassisted intravenous administration; however, these systems
can only administer drugs in liquid form and require both a transcutaneous catheter and an
external pump. Fully implantable drug delivery devices are desirable where alternate forms of
delivery are not preferred or not possible. These devices allow drugs to be delivered at
efficacious locations and rates without the issue of patient compliance. An advanced implantable
system can be used to precisely control the rate of drug delivery. Some drugs are only therapeutic
when administered in a pulsatile pattern, similar to the way they are produced in the body.
Alternatively, some therapies require drugs to be released continuously to maintain a therapeutic
level for an extended time. Pulmonary, transdermal, intravenous or subcutaneous injection or
infusion[2], and implantable systems have been developed for situations where oral drug
delivery is not optimal or feasible[3]. Implantable drug delivery devices are particularly desirable
where compliance with a prescribed drug regimen is critical. Such devices allow a drug to be
delivered at a specific rate without regular physician or patient intervention.
Currently available drug delivery implants can be divided into two main categories, based on
whether they deliver drug in a passive or active manner. Polymer depots are the most common
passive drug delivery systems. They are designed to maintain a constant diffusion rate of drug
out of the polymer, or they degrade in the body at a particular rate, thereby releasing drug at that
rate. Conventional programmable IDDDs use 25-50% of the implanted device volume for a
battery that is intended to last the entire duration (5-10 years) of the implant. However, in typical
IDDDs medication is typically refilled every 10 weeks by transdermal injection into a
subcutaneous refill port (Figure 1.1)[4].

Figure 1.1: The system view: A two-pole needle is inserted into the refill port of a drug
delivery device. Inset: A close view of the two needle halves making electrical contact with
springs inside the septum.
The overall volume efficiency of an IDDD, which is critical to its placement and usability
(particularly in paediatric cases), can be improved substantially if the conventional battery is
replaced with a smaller battery that is recharged. It is preferable that the recharging occurs in the
same session that the drug reservoir is refilled, although not necessarily at precisely the same
time[5]. While wireless power transfer is possible for very low-power applications[6], DC
recharge capability [7] offers high current levels and may be more suitable for IDDDs (Figure
1.2).

Figure
1.2: A photo of the front of an assembled microvalve-regulated drug delivery device with
the back side refill port shown inset[8].

Over the last two decades, the field of controlled drug delivery has been faced with two major
challenges. One has been achieving sustained zero-order release of a drug substance over a
prolonged period of time. This goal has been met by a wide range of techniques, including
osmotically driven pumps [9], matrices with controllable swelling [10] diffusion [11, 12] or
erosion

rates

[13],

non-uniform

drug

loading

profiles

[14-16],

and

multi-layered

matrices[17].The second of these challenges is the controlled delivery of a therapeutic molecule


or protein in a schematic of a pulsatile or staggered fashion. Two different methodologies have
been heavily investigated as possible solutions to these requirements. One is the fabrication of a
delivery system that releases its payload at a predetermined time or in pulses of a predetermined
sequence. The other is to develop a system that can respond to changes in the local environment.
These systems have been shown to alter their rate of drug delivery in response to stimuli
including the presence or absence of a specific molecule, magnetic fields, electric fields,
ultrasound, light, temperature, and mechanical forces.

2. ADVANTAGES OF IMPLANTABLE DRUG


DELIVERY SYSTEM
The advantages of implantation therapy include.
Convenience:
Effective concentration of drug in the blood can be maintained for longer period of time by
techniques such as continuous intravenous infusion or repeated injections. On the other hand,
under these treatments patients are regularly required to visit hospital throughout administration
for uninterrupted medical monitoring. A short-acting medicineworsens the condition, as the
quantity of injections or the infusion rate needto be increased to maintain a therapeutically
effective level of the drug.
On the other hand, implantation treatment permits patients to get medication outside the hospital
setting with marginal medical observation. Implantation treatment is also characterized by a
lower occurrence of infection associated problems in comparison to indwelling catheter-based
infusion system.
Improved drug delivery:
The drug is distributed locally or in systemic circulation with least interference by metabolic or
biological barriers. For example, the drug moiety bypassed the GIT and the liver. The by-passing
effect is beneficial to drugs, which are either easily inactivated or absorbed poorly in the GIT
and/or the liver before systemic distribution [1].
Compliance:
By allowing a reduction, or complete elimination, of patient-involved dosing compliance is
increased hugely. Patient can forget to take a medicine, but drug delivery from an implant is not
dependent of patient input. Periodical refilling is involved in some implantables but despite this
limitation the patient has less involvement in delivering the required medication.
Potential for controlled release:
Implants are available which deliver drugs by zeroorder controlled release kinetics. The
advantages of zero order controlled release are:
(a) Peaks (toxicity) and troughs (ineffectiveness) of conventional therapy is avoided,
(b) Dosing frequency is reduced,
(c)Patient compliance is increased.
Potential for bio-responsive release:

Bio-responsive release from implantables is an area of on-going research.


Potential for intermittent release:
Intermittent release can be facilitated by externally programmable pumps. Intermittent release
can facilitate drug release in response to such factors as:
(a) Circadian rhythms,
(b) Fluctuating metabolic requirements,
(c) Pulsatile release of many peptides and proteins.
Flexibility:
In the choice of materials, methods of manufacture, degree of drug loading, drug release rate etc.
considerable flexibility is possible. From a regulatory viewpoint, it is regarded as a new product
and can lengthen the market protection of the drug for an additional 5 years (for a new drug
entry) or 3 years (for existing drugs)[18-21].
3.DISADVANTAGES OF IMPLANTABLE
DRUG DELIVERY SYSTEM
The disadvantages of implantables include:
Invasive:
To initiate therapy either a minor or a major surgical procedure is required to initiate therapy.
Appropriate surgical personnel is required for this, and may be time-consuming,traumatic. This
causes some scar formation at the site of implantation and surgeryrelated complications in a very
small number of patients. Uncomfortable feeling for the patient wearing the device.
Danger of device failure:
There is no associated danger with this treatment that the device may for some reason fail to
work. This again requires surgical involvement to correct [1].
Termination:
Osmotic pumps and non-biodegradable polymeric implants also are surgically recovered at the
end of therapy. Although surgical recovery is not required in biodegradable polymeric implants.
Its on-going biodegradation makes it difficult to end drug delivery, or to maintain the accurate
dose at the end of its lifetime.
Limited to potent drugs:

In order to minimize patients discomfort the size of an implant is usually kept small. Therefore
most implants have a limited loading capacity so that frequently only somewhat potent
medicines such as hormones may be appropriate for delivery by implantable devices.
Biocompatibility issues:
Concerns over body reactions to a foreign substance often increase the issues of biocompatibility
and safety of an implant.
Possibility of adverse reactions:
A high concentration of the drug delivered by an implantable device at the implantation site may
produce adverse reactions.
Commercial disadvantages:
An enormous amount of R&D investment, effort and time is required in the development on an
IDDS. If a new material is proposed to formulate an implant its incompatibility and safety must
be carefully evaluated to secure the approval of regulatory organisations. These issues can
attribute to noteworthy delay in the progress, marketing and price of a new implant [18-21].
4. IMPLANTABLE DRUG DELIVERY DEVICES
4.1 Field of Controlled Drug Delivery
Implantable controlled drug delivery methods are also useful to deliver medication to those parts
of the body which are immunologically isolated and regular modes of drug delivery cannot reach
them, for example, the cornea. The field of controlled drug delivery today employs mechanisms
such

as

transdermal

patches,

polymer

implants,

bioadhesive

systems,

and

microencapsulation[22-24].
4.1.1 Transdermal Patches
Transdermal patches generally have hollow microneedles made of a biocompatible polymer
through which the drug is delivered below the skin. Transdermal patches have numerous
advantages compared with other systems of drug delivery: the drugs are not degraded in the GIT,
they are painless, and they deliver a constant dosage without the need for patients
compliance[25]. A renowned example for transdermal patches is the nicotine patch.
4.1.2 Polymer Implants
Polymer implants are biodegradable polymers loaded with the drug molecules. The polymer
degrades when it comes in interaction with body fluids and in the process releases drug
molecules. The rate of degradation of the polymer, and hence the drug release, can be optimized

by modifying the properties of the polymers. The polymer material which are most widely used
for these application include, but are not restricted to, Polyglycolic acid(PGA), Polylactic
acid(PLA), Polyurethane and the combinations of these in different proportions.
4.1.3 Bioadhesives
Bioadhesives are substances which form bonds with biological surfaces. The most common
substances which are used in this case are polymer hydrogels. The principle of operation is
similar to polymer implants in this that they too are loaded with drugs and release drugs at a
specific rate when in contact with body fluids. Hydrogels are water-swollen polymer networks.
The polymer chains may be held
together by either physical forces or covalent crosslinks.
By design of the hydrogel constituents, they can be made responsive to their chemical or
physical environment. At a temperature of 35-40 C it collapses into a denser, more compact
structure due to a switch in the balance of solution and hydrophobic forces as the temperature is
raised [26].
4.1.4 Microencapsulation
Microencapsulation refers to the method of covering the drug molecule with a material which
will prolong the time before the drug is resorbed, so that it will remain in the viable state and will
be released when it reaches the intended destination. There are variety of ways in which
microencapsulation is done. Some of them are use of polymer microspheres, liposomes,
nanoparticles etc. [25]. The above devices are passive devices and deliver the drug gradually in
very small amounts with precision. But they are not capable of delivering the drug in a nonlinear fashion or on demand. They cannot be programmed to deliver drug when required and
stop when not required [22, 23].
4.1.5 Some Important Passive Devices
There are some drug delivery devices, which deserve a special mention.
4.1.5.1 Microchip Drug Reservoirs
These devices came out of the lab of Dr. Robert Langer lab at MIT. It is one of the very first truly
MicroElectro Mechanical Systems (MEMS)based drug delivery systems (Figure 4.1). The
design incorporates multiple sealed compartments, which are opened on demand to deliver dose
of a drug[24]. Fabrication of these microchips began by depositing, 0.12 mm of low stress,
siliconnitride on both sides of prime grade (100) silicon wafers using a vertical tube reactor. The

silicon nitride layer on one side of the wafer was patterned by photolithography and electron
cyclotron resonance (ECR) enhanced reactive ion etching (RIE) to give a square device (17mm x
3mm x 17 mm) containing 34,480 square reservoirs. The silicon nitride served as an etch mask
for potassium hydroxide solution at 85.8C, which anisotropically etched square pyramidal
reservoirs (Figure 4.1 b) into the silicon along the (111) crystal planes until the silicon nitride on
the opposite side of the wafer was reached.

Figure

4.1.Microchip

drug

reservoir.

4.1.5.2 Immuno-isolating Capsules


These devices are not drug delivery systems in the conventional sense. They deliver insulin in
the body but rather than store it in the device they contain pancreatic islet cells which make
insulin and deliver through the nanoporous membrane of the device.
Microfabrication techniques have been applied to create a biocapsule for effective
immunoisolation of transplanted islet cells for the treatment of diabetes[27]. The fabrication of
nanochannels in the membrane structure consists of two steps. First, surface micromachining
nanochannels in a thin film on the top of a silicon wafer. Second, releasing the membrane by

etching away the bulk of the silicon wafer underneath the membrane. These nanopore
membranes are designed to allow the permeability of glucose, insulin, and other metabolically
active products, while at the same time, preventing the passage of cytotoxic cells, macrophages,
and complement. The membranes are bonded to a capsule that houses the pancreatic islet cells.
Because the difference in the size of insulin, which must be able to pass freely through the pores
and the size of the IgGimmunoglobins, which must be excluded, is only matter of a few
nanometers, the highly uniform pore distribution provided by micromachine membranes is
essential for effective immunoisolation and therapeutic effect.
4.1.5.3 Diffusion Chambers
A diffusion chamber from Debiotech Inc. They hold a cargo of drugs and are sealed with a
semipermeable membrane. These are used for delivering fairly large amount of drugs and in
some cases more than one drug. The membrane surface area is large compared to the reservoir
resulting in the increased delivery rates. These reservoirs are generally not used for long term
delivery[28].
4.1.5.4 Diffusion Controlled Implanted Tubes[29-32]
These use a narrow aperture to provide a slow delivery rate of drugs. They are used for long-term
release of highly potent drugs, with the release times it the order of years. A good example is the
five-year duration birth control implants based on elastomeric tubes[33]. A similar example is
that of the DurosTM osmotic pump from ALZA Corporation. This nonbiodegradable,
osmotically driven system[2] is intended to enable delivery of small drugs, peptides, proteins,
DNA and other bioactive macromolecules for systemic or tissue-specific therapy. The DUROS
implant is a miniature cylinder made from a titanium alloy, which protects and stabilizes the drug
inside, using ALZA's proprietary formulation technology. Water enters into one end of the
cylinder through a semi-permeable membrane; the drug is delivered from a port at the other end
of the cylinder at a controlled rate suitable to the specific therapeutic agent. The delivery can be
over a period of 12 months.

Pums theke

Figure

4.2Duros

osmotic pump (Alza -Mountain View, CA, USA).


6. THERAPEUTIC APPLICATIONS OF IDDS
Ocular disease
Numerous different implantable systems have been estimated to deliversustainedocular delivery.
These comprise membrane-controlled devices, implantable infusion systems and implantable
silicone devices. Ocular insert (ocusert)having pilocarpine base and alginic acid in a drug
reservoir surrounded by a release-rate controlling ethylene-vinyl acetate membrane is an
example of the membrane-controlled system[39-41]. The ocusert system offers an initial rupture
followed by a near zero order transport of pilocarpine[42] at 20 or 40 g/h for a span of seven
days. The device is well tolerated in adults, with suitable control of intraocular pressure and
minimal side effects[43-46]. However it looks to be poorly tolerated in the geriatric patients
where most of the therapeutic requirement exists.Implantables evaluated for ocular cancer
management include silicone rubber balloon having an antineoplastic agent.
Contraception
Norplant a sub-dermal implant for long-lasting transport of the contraceptive agent
levonorgestrel recently been approved for marketing by the FDA. The device consists of six
silicone membrane capsules each having about 36 mg of levonorgestrel. The capsules are placed
sub-dermally on the inside of the upper arm or the forearm in a fan-shaped pattern through a
trocar from a single trocar entry point. Clinically, Norplant users have a net pregnancy rate of
below 1.5 in 100 women at 4 years. At the end of 4 years 42 % of the women continued with the
techniquerepresenting acceptability comparable with other techniques. Other polymer-based
systems under study for contraception contain vaginal rings usually composed of silicon rubber
used for 3 to 76 months often with a removal period of one week monthly to allow for

menstruation; the progestasert an ethylenevinyl acetate copolymer intrauterine drugreleasing


device which persists for one year and suspensions of injectable microspheres or rods composed
of biodegradable polymers[41].
Dental application
For numerous dental applications including local prolonged administration of fluoride
antibacterial and antibiotics,polymeric implants have been evaluated. Stannous fluoride was
integrated into different dental cements for sustained release fluoride delivery. Another dispersed
in the hydroxyethyl methacrylate and methyl methacrylate copolymer hydrogel coated with an
outer layer of the same copolymers in different ratio so as to be rate limiting in drug release. The
device, about 8 mm long and having 42 mg of fluoride in the core was attached to the buccal
surface of the maxillary first molar and designed to release 0.5 mg/day of fluoride for 30 days
[47-49].
Immunization
Polymeric implants are being evaluated for better immune response to antigens. The concept
here is to offer pulsatile or continuous administration of the antigen over a prolonged period of
time. Wise et al. evaluated immunization efficiency of ethylene-vinyl acetate copolymer pellets
having bovine serum albumin as model antigen. The immune response was comparable to that
achieved by two injections of bovine serum albumin in complete Freunds adjuvant (Freunds
adjuvant is an o/w emulsion containing bacteria).
Cancer
Silicone rod implants analogous to those used for delivery of levonorgestrone have been
evaluated for delivery ofethinylestradiol or testosterone propionate in persons with prostate
cancer. Lupron depot produced by Takeda chemical industries is an implantation system
providingonemonth depot release of leuprolide acetate, a synthetic analogue of the gonadotropinreleasing hormone (GhRH). The implant containing biodegradable microspheres made from
polylactic glycolic copolymer at 1:1 compositions having 10% leuprolide acetate for the
management of prostate cancer. Zoladexproduced by ICI Pharma provides one month depot
release of goserelin acetate from a biodegradable implantable rod for the management of prostate
cancer.
Narcotic antagonists

Naltrexone has been comprehensively evaluated in implant from long term delivery of narcotic
antagonists. Naltrexone freebases its hydrochloride or the pamoate acid salt has been formulated
in a various polymers and dosage forms for prolonged narcotic antagonistactivity.
Other applications
Various insulin delivery systems have been formulated and evaluated for a biofeedback approach
and have been described before.These are biofeedback controlled system, where the drug release
rate is reliant on the bodys requirement for the drug at a specified time. From a therapeutic
perspective these systems may come closest to reproducing the release from a gland for example
the pancreas. Various mechanisms have been employed to attain self-regulated delivery[2, 41].
The above mentioned applications are few examples of therapeutic applications of implantable
drug delivery system.
7. FUTURE PROSPECTS
At present much research is being conducted in the region of implantable drug delivery systems.
Despite this fact, much work is still required in the regions of biodegradable and biocompatible
substances, the kinetics of drug release, and more improvement of present systems before many
of these preparations can be used. In the future, scientists remain expectant that many of these
systems can be prepared with best zero-order release kinetics profiles, in vivo, over long times,
allowing for prolonged use in constantly sick patients.New medicines are continuously being
prepared. Several of these medications are developed from proteins and peptides which are very
unstable when taken through oral route. By using new types of prolonged-release drug delivery
systems, delivering such drugs at constant rates will be possible over a prolonged period of time
and will exclude the necessity for multiple dosing. It is expected that in the upcoming years,
improvement of new implantable systems will help cost reduction of drug treatment, increase the
effectiveness of drugs, and enhance patient compliance[50-52].
8. CONCLUSION

Recently Implantable drug delivery is one of the technology sectors that often overlooked
in the development of new drug delivery by the formulation, research and development in many
pharmaceuticals. Implanted drug delivery technologies have ability to reduce the frequency of
patient driven dosing and to deliver the compound in targeted manner. Many product utilizing
implant delivery technologies are being utilized for many therapeutics applications such as,
dental, ophthalmic, oncological disease. As with any implanted material, issues of
biocompatibility need to be investigated, such as the formation of a fibrous capsule around the
implant and, in the case of erosion-based devices, the possible toxicity or immunogenicity of the
by-products of polymer degradation. Additionally, convenient methods of triggering drug
delivery from the externally controlled delivery systems need to be developed in order for them
to be of practical use. These issues, coupled with the potential therapeutic benefits of pulsatile
dosing regimens, should ensure that the current high level of interest in this area will extend well
into the future and result in significant advances in the field of controlled drug delivery. A large
number of companies are involved in the development of new drug delivery systems, which is
evident by an increased number of products in the market and the number of patents granted in
the recent past. Tomorrows drugs definitely will be more challenging in terms of the
development of delivery systems, and pharmaceutical scientists will have to be ready for a
difficult task ahead.

40 280 292 theke r o neya jabe..

PARENTERAL IMPLANTS
Implant is an object or material inserted or grafted into the body for prosthetic, therapeutic,
diagnostic, or experimental purposes. Implants are one of the dosage forms used to achieve
effective concentrations for a long time. Therefore the base materials for implants are required to
be biocompatible. Biodegradable and non-biodegradable polymers are often utilized as a base
material. Non biodegradable polymers have to be taken out surgically after completion of the
drug release, resulting in pain and a burden on patients. On the other hand, as biodegradable
polymers disappear spontaneously from the body during or after drug release, their implants are
superior in lowering the burden on patients. In particular, poly-dl-lactic acid (PLA) and poly (dl-

lactic acid-co-glycolic acid) copolymer (PLGA) are clinically available as biocompatible and
biodegradable polymers, and have been examined extensively and widely. PLGA and PLA show
a prolonged drug release for 1 and 3 months, respectively. Other biodegradable polymer like
polyanhydride shows a longer drug release about 1 year. Non bio-degradable polymer includes
poly vinyl acetate (PVA) etc. Various types of implants are available for the drug delivery system
like for delivery into eye, heart, bone, cochlea etc.
Implants classified as- 1.Solid implantsSolid implants typically exhibit biphasic release kinetics, with initial burst of drug is usually due
to the release of drug deposited on the surface of the implant although zero order kinetics may be
achieved by. E.g. Coating the implant drug impermeable material Overall drug release may be
controlled by varying polymer
composition- an increase in the level of lactic acid in a polylactic acid co-glycolic acid
copolymer retards drug release and increase in polymer molecular weight also retards drug
release and prolongs drug effects.
2. In-SituformingimplantsBiodegradable injectable in situ forming drug delivery systems represent an attractive alternative
to microspheres and implants as parenteral depot systems. The controlled release of bioactive
macromolecules via (semi-) solid in situ forming systems has a number of advantages, such as:
1. Ease of administration,
2. Less complicated fabrication,
3. Less stressful manufacturing conditions for sensitive drug molecules.

CONTROLLED DRUG DELIVERY BY DIFFUSION PROCESS


a) Polymer membrane permeation controlled drugdelivery device: In this implantable drug
delivery device the drug reservoir is encapsulated by a rate controlling polymeric
membrane. Different shapes and sizes of implantable drug delivery devices can be
fabricated. An example of this type of implantable drug delivery device is the
Norplantsub dermal implant. Norplant is a well-known contraceptive implant approved
by U.S. Food and Drug Administration (FDA) in 1990.

b) Polymer matrix diffusion-controlled drug delivery devices: In this implantable


controlled-release drug delivery devices the drug reservoir is formed by homogeneous
dispersion of solid particle throughout the a lipophilicor hydrophilic polymer matrix .The
dispersion ofdrug solid particle in the polymer matrix can be accomplished by blending
drug solid with a viscous liquid polymer at room temperature followed by cross linking
of polymer chains or by mixing drug solid with a melted polymer dispersion are then
molded or excruded to form a drug delivery device of various shapes and sizes. An
example of this type of implantable drug delivery device is the compudose implant.
c) Membrane-matrix hybrid-type Drug Delivery Devices: This type of implantable
controlled release drug delivery devices is hybrid of the polymer membrane permeation
controlled drug delivery system and polymer matrix diffusion controlled drug delivery
system. It aims to take advantages of the constant drug release kinetics maintained by the
membrane permeation-drug delivery system while minimizing the risk of dose dumping
from the reservoir compartment of this type of drug delivery system. An example of type
of implantable drug delivery device is Norplant II sub dermal implant.
d) Micro reservoir partition-controlled drug delivery devices: In this implantable controlled
drug, delivery device the drug reservoir, which is a suspension of drug crystals in an
aqueous solution of water-miscible polymers, forms a homogeneous dispersion of
millions of discrete, unreachable, microscopic drug reservoir in a polymer matrix.
Different shapes and sizes of drug delivery system by molding or extrusion. Depending
upon the physicochemical properties of drug and desired properties of drug rate release,
the device can be further coated with a layer of biocompatible polymer to modify the
mechanism and rate of drug release. An example of this type implantable drug delivery
device is the Synchro-Mate implant. It contains drug norgestomet.
2. Controlled drug delivery by activation process

a) Osmotic pressure-activated drug delivery device


In this implantable controlled-release drug delivery device osmotic pressure is used as the
energy sourceto activate and modulate the delivery of drugs, thedrug reservoir, which is
either a solution or asemisolid formulation.

Alzet osmotic pump


The physical or chemical properties of a compound have no influence on the delivery rate
of ALZETpumps. The delivery rate of ALZET pumps iscontrolled by the water
permeability of the outermembrane. In short, water from the environmententers the pump
through the semipermeablemembrane into the osmotic layer, which causescompression of
the flexible, impermeable reservoir. The test solution is continuously released through the
flow moderator. A flow modulator is a hollow tubewith an inner diameter of 500 microns.
Solutions and even high molecular weight compounds can effectively flow through the
flow moderator ofALZET pumps.

b) Vapor pressure activated drug delivery devices


In this implantable controlled release drug delivery device vapor pressure is used as the
power source to activate the controlled delivery of drugs. The drug reservoir, which is a
solution formulation, is contained inside an infusate chamber. By a freely movable
bellows the infusate chamber is physically separated from the vapor pressure chamber,
which contains the vaporizable fluid, such as fluorocarbon. The fluorocarbon vaporizes at
body temperature and creates a vapor pressure that pushes the bellows to move upward
and forces the drug solution in theinfusate chamber to deliver the drug.
A typical example of drugs that can be given by this type of infusion pump are morphine
for patient suffering from intensive pain of terminal cancer, heparin for anticoagulation
treatment and insulin for the treatment of diabetes.
c) Magnetically activated drug delivery devices
In this implantable controlled release drug delivery device electromagnetic energy is used
as the power source to control the rate of drug delivery. A magnetic wave triggering
mechanism is incorporated into the drug delivery device, and drug can be triggered to
release at varying rates depending upon the magnitude and the duration of
electromagnetic energy applied. This sub dermallyimplantable, magnetically modulated
hemispherical

drug

delivery

device

was

fabricated

by

positioning

tiny

donutshapedmagnet at the center of a medicated polymer matrix that contains a


homogenous dispersion of a drug with polymer. The external surface of the hemispherical
pellet is further coated with a pure polymer, such as ethylene vinyl acetate copolymer

orsilicon elastomers, on all sides, expect one cavity atthe center of the flat surface, which
is left uncoated topermit the drug molecules to be delivered through thecavity.
Byapplying an external magnetic field the drugs areactivated by the electromagnetic
energy to releasefrom the pellet at a much higher rate of delivery.
d) Hydration activated drug delivery devices
This type of implantable controlled release drug delivery device releases drug molecules
uponactivation by hydration of the drug delivery device bytissue fluid at the implantation
site. To achieve thisdrug delivery device is often fabricated from ahydrophilic polymer
that becomes swollen uponhydration. Drug molecules are released by diffusingthrough
the polymer matrix. The hydration activatedimplantable drug delivery device is
exemplified by the development of the norgestomet releasing Hydro implant for estrus
synchronization

in

heifers.

Thiswas

fabricated

by

polymerizing

ethylene

glycolmethacrylate (Hydron S) in an alcoholic solution that containsnorgestomet, a crosslinking agent (such asethylene dimethacrylate), and an oxidizing catalyst toform a
cylindrical water swellable (but insoluble) Hydron implant.The Hydron Implant
technology is based upon specialty blends of hydrogel polymers spun cast into small
tubes measuring in the order of 1-inch in length and 1/8 inch in diameter.

e) Hydrolysis activated drug delivery devices


This type of implantable controlled release drug delivery device is activated to release
drug moleculesupon the hydrolysis of the polymer base by tissuefluid at the implantation
site. To achieve this drugdelivery device is fabricated by depressing a loadingdose of
solid drug, in micronized form, homogeneously through a polymer matrix made from
bioerodible or biodegradable polymer, which is thenmolded into a pellet or bead-shaped
implant. Thecontrolled release of the embedded drug particles ismade possible by the
combination of polymer erosionby hydrolysis and diffusion through the polymer matrix.
The rate of drug release is determined by therate of biodegradation, polymer composition
andmolecular weight, drug loading, and drug-polymerinteraction. The rate of drug release
from this type of drugdelivery system is not constant and is highlydependent upon the
erosion process of the polymermatrix.

Review perenteral thehe


RECENT TECHNOLOGY IN IMPLANTABLE DRUG DELIVERY:
DURINTM TECHNOLOGY
The DURINTM biodegradable implant technology is a platform for parenteral delivery of drugs
for periods of weeks to six months or more. The technology is based on the use of biodegradable
polyester excipients, which have a proven record of safety and effectiveness in approved drug
delivery and medical device products. 3
Features:
Superior delivery kinetics. Flexibility.
Superior drug loading and stability. Fully biodegradable.
History of safe human use. Cost effective.
The DURINTM biodegradable implant technology is based on the use of biodegradable
polyesters as excipients for implantable drug formulations, includes the polymers and
copolymers prepared from glycolide, DL-lactide, L-lactide, and -caprolactone.
The degradation times and physical properties of the biodegradable excipient can be engineered
to achieve a wide variety of drug delivery goals by adjusting monomer composition and
distribution, polymer molecular weight, and end group chemistry.
The overall form of the implant is typically a small rod or pellet that can be placed by means of a
needle or trochar. The composition of the rod or pellet can be monolithic, where the drug is
uniformly dispersed throughout the excipient. Alternatively, reservoir-type designs are also
possible in which the rod or pellet is composed of a drug-rich core surrounded by a ratecontrolling membrane.

The drug and excipient are mixed together, and the mixture is formed into a fiber, rod, tablet, or
pellet by an extrusion or molding process. The rate controlling membrane, if required, may be
applied during or subsequent to the core-forming process.5
Manufacturing:
Typically, melt extrusion is used at modest temperatures to produce biodegradable implants for
drug delivery. The active and excipient are combined and fed to a melt extruder to produce a
bulk rod, which is then cut to produce the unit dose. For coaxial, membrane-controlled implants,
two extruders are operated to simultaneously produce the core and membrane in a continuous
process. For particularly heat labile compounds, the DURINTM technology is also compatible
with proprietary manufacturing methods other than extrusion that ensure drug stability. Because
DURINTM implants are produced using continuous manufacturing processes, batch size is
determined by the length of the extrusion run. Several clinical batches of biodegradable implants
at a batch size of more than 2000 doses are successfully prepared. 4
ATRIGEL DRUG DELIVERY TECHNOLOGY
The Atrigel system is a proprietary delivery system that can be used for both parenteral and sitespecific drug delivery. It consists of biodegradable polymers dissolved in a biocompatible carrier.
When the liquid polymer system is placed in the body using standard needles and syringes, it
solidifies upon contact with aqueous body fluids to form a solid implant 6
Atrix Laboratories has continued to develop the technology and to extend its use to a large
number of both drug delivery and medical device applications.
The manufacturing process for the Atrigel system is not complicated in that the first step is the
dissolution of the polymer into a biocompatible solvent. The drug is next added to the solution
where it dissolves or forms a suspension. This drug/ polymer mixture is then easily and
conveniently injected into the body where it forms a solid implant inside the tissue. The ease of

manufacture of the Atrigel system and its relatively pain-free subcutaneous injection into the
body provide significant advantages over both solid implants and microparticles.7.
These include the polyhydroxyacids, polyanhydrides, polyorthoesters, polyesteramides, and
others. The polymers most often used are poly (dllactide), lactide/glycolide copolymers, and
lactide/caprolactone copolymers because of their degradation characteristics and their approval
by the Food and Drug Administration (FDA).8
The solvents employed in the Atrigel system to dissolve the polymers range from the more
hydrophilic solvents such as dimethyl sulfoxide, N-methyl-2-pyrrolidone (NMP), tetraglycol, and
glycol furol to the more hydrophobic solvents such as propylene carbonate, triacetin, ethyl
acetate, and benzyl benzoate. The most frequently used solvent is NMP because of its solvating
ability and its safety/toxicology profile.9, 10
Manufacturing, sterilization, and packaging
Because the Atrigel system is a somewhat viscous polymer solution, it is not as easy to fill into
vials and aspirate into syringes at the time of use as normal aqueous solutions. Therefore, the
products currently marketed using this technology are filled into plastic syringes and packaged
with foil-lined material to protect from moisture. Atrix Laboratories has developed custom-made
equipment to fill a variety of plastic syringes with the polymer solutions within narrow fill
volumes.
Although an Atrigel polymer solution can be sterile-filtered, this is not the preferred method
because of the viscosity of the solution. Therefore, gamma irradiation was evaluated and found
to be a convenient method of terminal sterilization of the polymer solution. There is some loss in
polymer molecular weight during gamma irradiation, but this is compensated for by using a
polymer with a slightly higher molecular weight initially [6].
Scale-up process

The manufacturing of products with the Atrigel system can easily be scaled up to commercial
quantities. First, the polymer is dissolved into the biocompatible solvent using a standard
pharmaceutical product mixer. More recently, the polymer has been dissolved in the solvent by
simply loading the two components into a sterile plastic container and placing it on a roll mixer.
The polymer solution is then transferred from the plastic container to the syringe-filling
equipment where it is loaded into individual syringes. The plastic container can then be discarded
and the need for thorough cleaning is eliminated. The filled syringes are capped and placed into
foil-lined packages to prevent moisture absorption. The drug is either powder-filled or
lyophilized into syringes. If the drug is stable to gamma irradiation, then both the drug and
polymer syringe are terminally sterilized by this method. If the drug is not stable to gamma
irradiation, then the lyophilization is carried out under aseptic conditions to give a sterile drug
syringe, and the polymer solution is sterilized by gamma irradiation. With this type of process,
the manufacturing can easily accommodate
the production of several hundred syringes to thousands in one batch11.
In some cases, both the drug and polymer are stable as with the lidocaine hydrochloride product.
However, because the drug and polymer are in solution, degradation of both components and
reactions between the two may occur somewhat faster with some formulations than in a dry,
solid state. With such type of products, the drug and polymer solution are maintained in separate
syringes until immediately before use. Atrix has developed proprietary methods to lyophilize
drugs in plastic syringes that can be coupled with the polymer solution.
Four products have already been approved by the FDA using the Atrigel technology.
1) Atridox periodontal treatment product
2) Atrisorb GTR barrier product
3) Atrisorb D product with Doxycycline

4) Doxyrobe product
REGEL DEPOT TECHNOLOGY
ReGel is one of MacroMed's proprietary drug delivery systems. The leading product of
MacroMed, ReGel, employs 23% (w/w) copolymer of poly (lactide-co-glycolide)-poly
(ethylene glycol) poly (lactide-co-glycolide) (PLGA-PEG-PLGA) in phosphate buffer saline.
Research on poly (lactide-co-glycolide) and poly (ethylene glycol) polymers has resulted in an
extensive database for clinical safety and efficacy as components in drug delivery systems.
Thermally reversible gelling materials, such as ReGel, are a unique class of compounds being
developed for parenteral delivery. ReGel is a family of polymers that offer a range of gelation
temperatures, degradation rates, and release characteristics. The thermal characteristics of
ReGel, which are in general terms a function of the molecular weight, degree of hydrophobicity,
and polymer concentration, allow the necessary flexibility to match a variety of compounds to a
convenient formulation for programmed delivery of active agent.
Examples of thermosensitive polymers
Poly (Nisopropylacrylamide) (PNIPAAM), poly (ethylene oxide)- poly (propylene oxide)-poly
(ethylene oxide) triblock copolymers (PEO-PPO-PEO), poly (ethylene glycol)-poly (lactic acid)poly (ethylene glycol) triblocks (PEG-PLAPEG). Triblock PEO-PPO-PEO copolymers
(Pluronics or Poloxamers) show gelation at body temperature at concentrations greater than
15% (w/w).
Procedure:
The synthetic process is well characterized and allows specified gelation temperatures to be
produced based on the starting composition of the poly (ethylene glycol), lactide, and glycolide
mixture. The components are poly (ethylene glycol), lactide, and glycolide monomers, and the

catalyst is stannous octoate, which results in greater than 95% yield and more than 99% purity.
Aqueous purification and sterilization via filtration or gas-sterilization of the lyophilized product
is done.12
Administration:
Prior to injection, the product is reconstituted yielding aqueous ReGel as a free-flowing liquid
below its gelation temperature with a viscosity of < 1 poise. Following injection, the physical
properties of the polymer rapidly undergo a reversible phase change that results in hydrophobic
polymer-polymer interactions and the formation of a water insoluble biodegradable implants.
The transition occurs without chemical modification of the triblock copolymer or active agent
because ReGel is a physically formed thermally reversible hydrogel.13
Product Under clinical trials:
MacroMed's first product, OncoGel, is supplied as a frozen formulation of paclitaxel in ReGel
and is entering Phase II trials.
CytorynTM is MacroMed's immunomodulatory localized peri-tumoral/intra-tumoral delivery
system based on a
combination of lymphokine interleukin 2 (IL-2) in ReGel.
13
ALZAMER DEPOTTM TECHNOLOGY
The Alzamer DepotTM technology was designed to offer sustained delivery of therapeutic
agents, including proteins, peptides, other biomolecules, and small-molecular-weight
compounds, for up to a month with
minimal initial drug burst, and bioerosion of the dosage form. 14,15 The Alzamer DepotTM
technology consists of a

biodegradable polymer, a solvent, and formulated drug particles. The depot is injected
subcutaneously, and drug is released by diffusion from the system while water and other
biological fluids diffuse in. At the later stages of release, the polymer degrades, further
contributing to drug release. Microspheres, however, typically require complex production
processes and harsh solvents that then require removal16, 17. Solution depot formulation processes
tend to be simpler, typically involving only biocompatible solvents as part of the depot
platform18.
Initial drug release from microspheres and these earlier-generation depot formulations tends to
be rapid; up to 50% of the drug can be released upon injection. In contrast, Alzamer DepotTM
technology (ALZA Corporation, Mountain View, CA) uses biocompatible solvents of low water
miscibility, which help control the initial drug release. In addition, this type of depot is easy to
process and can be stored with the protein particles
preformulated into the gel, enhancing convenience of use
19, 20, 21.
Formulation development
Alzamer DepotTM technology consists of the biodegradable polymer polylactic glycolic acid
(PLGA), a biocompatible solvent of low water miscibility (e.g., benzyl benzoate), and
formulated drug particles. Protein stability is maintained by isolating the drug in a solid particle.
This particle is suspended in the non-aqueous polymer/solvent depot to prevent premature
exposure to water. Drug release can be adjusted by varying the initial formulation and drug
loading, as well as the injection volume of the preloaded syringe.
Pre-clinical evaluation
To date, more than 100 different Alzamer DepotTM formulations have been tested in rats. No
remarkable adverse clinical observations or systemic signs of toxicity have been noted.

SABERTM DEPOT TECHNOLOGY


The SABERTM Delivery System is an injectable, biodegradable delivery system technology that
uses a high viscosity carrier such as sucrose acetate isobutyrate (SAIB), solvent and one or more
pharmaceutically acceptable additives.22
In the simplest case, the high-viscosity SAIB is formulated as a low-viscosity liquid by mixing
with a pharmaceutically acceptable solvent. The drug to be delivered is dissolved or dispersed in
the SAIB/solvent solution for subsequent injection subcutaneously or intramuscularly. If a watersoluble solvent such as ethanol is chosen, the solvent will diffuse out of the injected volume
leaving a viscous depot of SAIB and drug. The use of a more hydrophobic solvent such as benzyl
benzoate gives a less viscous depot with slower solvent diffusion. Sustained drug release occurs
over a period from several hours to several weeks by diffusion.
In some applications, an additive is used to affect release kinetics, drug stability, or other
performance parameters. SAIB degradation follows drug release.
Manufacturing:
SAIB-based products are manufactured in a liquid mix-and-fill process using conventional tanks
and stirrers. For dispersed drugs, particle size of the drug must be controlled, and particle size
reduction is done by milling. Homogenizers have been used to disperse some of the drug
suspensions.
Because the SABERTM technology is manufactured as a mix-and-fill liquid formulation, there
have been no specific scale-up problems. Two issues that must be considered are transferring the
high-viscosity raw material SAIB and the use of organic solvents. The use of solvents imposes
certain limits on contact surfaces and
requires particular attention in selecting tubing and seals.
23, 24.

Market products:
The most significant product on the market is Lupron Depot, the leuprolide acetate
microsphere product based on poly(dl-lactide) (PLA), and poly(dl-lactide-coglycolide) (PLG) for
the treatment of prostate cancer, The microspheres are injected using smaller-bore needles,
intramuscularly.
Zoladex, again prepared from PLG and used in the treatment of prostate cancer with the
delivery of goserelin. Implants are placed subcutaneously (SC) using a relatively large-bore
needle (1016 gauge).25
PRO LEASE TECHNOLOGY (Encapsulated protein microspheres)
The ProLease delivery system was designed specifically to encapsulate fragile biomolecules and
overcome the problems associated with emulsion encapsulation processes.26
The processes used to encapsulate small molecules and peptides typically involve the formation
of emulsions and the generation of an oil-water interface. The amphipathic nature of proteins
causes them to accumulate at the interface; potentially disrupting their three-dimensional
structure and resulting in loss of biological activity. Additionally, the protein is usually
encapsulated as an aqueous solution and protein degradation may occur via water mediated
pathways such as aggregation, deamidation, hydrolysis, and oxidation. Lyophilized formulations
of proteins can be stable at ambient temperatures for extended periods; therefore,
ProLease technology takes advantage of the superior stability of lyophilized protein formulations
by encapsulating the protein in the solid state.
One of the main reasons for the loss of protein integrity and stability during emulsion-based
encapsulated processes is that the protein is encapsulated in the aqueous state. In the solid state,
water, a reactant in many protein degradation pathways, is minimized, molecular mobility is
reduced, and the kinetics of the degradative reactions are retarded significantly. Additionally,
there is the opportunity to add excipients to enhance the stability of the protein during the

lyophilization process and for storage stability.


Stabilizing strategies include the addition of salting-out agents, sugars, and the formation of
reversible metal protein complexes.27
Prolease manufacturing process:

Figure 2. Pro-lease manufacturing process steps.


A liquid formulation of the protein, containing stabilizing additives or excipients, is fed into an
atomizing nozzle and sprayed into liquid nitrogen. The droplets freeze instantaneously as they
come into contact with the liquid nitrogen.
In the commercial (PL-process) process, the atomization occurs through an air atomizer. This
spray-freeze drying process is used rather than conventional bulk lyophilization because it
provides the ability to control the morphology and friability of the lyophilized powder.
The lyophilized protein powder is added to the polymer solution and dispersed (by sonication or

high-pressure homogenization) to create a uniform suspension of the powder in the polymer


solution. The suspension particle size achieved after the dispersion is an important variable that
significantly affects the initial release kinetics of the microsphere formulation. The suspension is
atomized to form droplets; these droplets are the precursors of the final microsphere product.
Extraction occurs in the commercial process, by transfer of the liquid nitrogen slurry from the
spray chamber into an extraction tank containing cold ethanol.
The microspheres are collected by filtration and vacuum-dried to produce a free-flowing powder.
The bulk microspheres may be sieved to facilitate injectability before filling, sealing, and
crimping in glass vials.27
Sterilization
The microsphere product cannot be autoclaved because the high temperatures required will
destroy the polymer and protein. Gamma irradiation may be an option, but exposure of PLG to
gamma irradiation has been shown to affect the molecular weight of the polymer and may cause
degradation of the encapsulated protein.
The use of isolation technology enables production of the microsphere product in an aseptic
environment27.
Administration
The microspheres may be administered by subcutaneous or intramuscular injection.
Just before administration, microsphere powder is dispersed in a viscous aqueous diluent and
delivered with a hypodermic needle.
Market products
The first approved long-acting formulation of a therapeutic protein, Nutropin Depot

(Genentech Inc., South San Francisco, CA), is manufactured using the ProLease process. 27
DUROS OSMOTIC PUMP IMPLANT
The DUROS implant is a sterile, nonerodible, drug-dedicated, osmotically driven system
developed by ALZA Corporation to provide long-term, controlled drug delivery. The DUROS
implant offers an alternative to other methods of biomolecule delivery. It provides long-term,
controlled delivery without the need for patient intervention. In addition, it is small, is inserted
subcutaneously during procedure, and can be removed to discontinue therapy immediately.
Furthermore, continuous administration via the DUROS system offers the potential for dosesparing reductions in overall drug usage.28

Figure 3: DUROS Osmotic pump implant


The DUROS pump conceptually resembles a miniature syringe in which drug is pushed out in
highly controlled, minute dosages. Through osmosis, water from the body is slowly drawn
through the semi-permeable membrane
into the pump by salt (osmotic agent) residing in the engine compartment. The water drawn into
the engine compartment expands the osmotic agent and slowly and continuously displaces a
piston to dispense small amounts of drug formulation from the drug reservoir through the orifice.
The osmotic engine does not require batteries, switches or other electromechanical parts to
operate.

Features:
DUROS can be designed to deliver up to 1,000 mg of concentrated drug from months to one
year.

The engine can generate pressure sufficient to deliver highly concentrated, viscous and nonwater-based drug formulations.

The system can be engineered to accurately deliver a drug formulation at dosing rates down to
1/100 of a drop per day on a continuous basis.

The titanium shell of the system protects the drug formulation inside from contact with body
fluids, thus protecting it from degradation by enzymes, water and clearance processes within the
body.

The delivery rate is typically designed to be constant 10% for better than 95% of its drug
content.

The delivery rate in vivo is equal to the delivery rate in vitro where the delivery rate can be
controlled for quality.
Application:
The potential of the DUROS technology, licensed from ALZA, was demonstrated by the Food
and Drug Administrations approval in March 2000 of ALZA Corporations Viadur product for
the treatment of prostate cancer, the first product utilizing the DUROS platform.29
MEMS AND NEMS BASED IMPLANTABLE DRUG DELIVERY TECHNOLOGY
MEMS and NEMS (Micro and Nano based electromechanical system) Implantable Drug

Delivery System (IDDS) is capable of delivering multiple individual doses. 30 This product
controls the release of potent therapeutic compounds that might otherwise require frequent
injections. The system will provide stable, hermetic storage of therapeutic drugs, such as proteins
and peptides, in solid, liquid, or gel form. Because discrete doses are stored individually,
multiple-drug regimens of pulsatile or continuous release are possible. Drugs, implanted in
MEMS based IDDS, are organic or inorganic molecules, including proteins, nucleic acids,
polysaccharides and synthetic organic molecules, having a bioactive effect, for example,
anaesthetics,

vaccines,

chemotherapeutic

agents,

hormones,

metabolites,

sugars,

immunomodulators, antioxidants, ion channel regulators, and antibiotics.31,32

ENCAPSULATED CELL TECHNOLOGY


Encapsulated Cell Technology (ECT) is patented core technology developed by Neurotech. ECT
enables the controlled, continuous delivery of biologics directly to the back of the eye,
overcoming a major obstacle in the treatment of retinal disease 44, 45. Conventional approaches to
therapy are limited by the absence of an acceptable means of sustained protein delivery across
the blood-retinal barrier. While therapeutic agents can be injected directly into the eye, this is an
impractical approach if regular administration is required.

Figure 4: Encapsulated Cell Technology


ECT implants consist of cells that have been genetically modified to produce a desired
therapeutic factor that are encapsulated in a section of semi-permeable hollow fiber membrane
with a suture loop at one end to anchor the implant to the sclera in the vitreo-retinal body inside
the
eye. The current product is 6 mm in length, roughly the size of a grain of rice. 44, 45 46
I-VATION IMPLANT.
I-vation Sustained Drug Delivery implant is developed by SurModics (Eden Prairie, Minn.) 44, 47.
The I-vation platform offers a great deal of versatility and flexibility for formulation and
pharmacokinetics control. Surmodics is developing a 5-mm long, helical coil shaped implant
thats injected into the sclera, leaving the coil end, coated with drug and a polymer matrix, sitting
in the vitreous. The end cap sits under the conjunctiva, but is available for removable when
necessary. The unique helical design maximizes the surface area available for drug delivery, and
ensures secure anchoring of the implant against the sclera, keeping it out of the visual field and
facilitating retrieval. 48
Features of the I-vation Sustained Drug Delivery System
Sustained duration of delivery (tunable: from months to > 2 years)
Targeted delivery for minimal systemic drug levels
Coating platform compatible with a variety of drugs Removable and replaceable
FUTURE DIRECTIONS AND CONCLUSIONS:

As discussed in this article, drugs can be delivered to a patient by many different delivery
systems, including oral, transdermal, injection, implants, etc. Most of the drugs are amenable to
these types of delivery systems. With the sequencing of the human genome, biotechnology
companies are rapidly developing a large number of peptide- and protein-based drugs. It is
expected that in the next 10 to 20 years, protein-and peptide-based drugs will constitute more
than half of the new drugs introduced into the market, and more than 80% of these protein drugs
will be antibodies. These biopharmaceuticals (proteins, peptides, carbohydrates, oligonucleotides, and nucleic acids in the form of DNA) present drug delivery challenges because
these are often large molecules that degrade rapidly in the blood stream. Moreover, they have a
limited ability to cross cell membranes and generally cannot be delivered orally. Such molecules
will be much more difficult to deliver via conventional routes, and injections may be the only
means of delivery. The routes of administration will be dictated by the drug, disease state, and
desired site of action. Some sites are easy to reach such as the nose, the mouth, and the vagina.
Others sites are more challenging to access, such as the brain. Gene therapy is also likely to be
one of the most exciting growth sectors as biotech companies become involved in drug delivery.
In conclusion, the market for drug delivery systems has come a long way and will continue to
grow at an impressive rate. Todays drug delivery technologies enable the incorporation of drug
molecules into new delivery systems, thus providing numerous therapeutic and commercial
advantages. A large number of companies are involved in the development of new drug delivery
systems, which is evident by an increased number of products in the market and the number of
patents granted in the recent past. Tomorrows drugs definitely will be more challenging in terms
of the development of delivery systems, and pharmaceutical scientists will have to be ready for a
difficult task ahead.
Article 28 theke

A variety of implantable devices based on Micro-Electro-Mechanical-Systems (MEMS)


technology has already been demonstrated for chronic illnesses (Prescott, et al. 2006). These
devices also show great potential for treatment of a number of pathologies in emergency
situations without the assistance of a physician or medical practitioner.
Actively controlled devices provide advantages over passive release devices, as the drug delivery
process can be controlled actively after implantation and even engaged telemetrically, as opposed
to passive devices that depend on the degradation chemistry of the specific device materials in
the intended implantation region. Active devices based on MEMS technology have been
previously investigated and proven successful for in vivo use in multiple clinical applications.
Such active devices are based on MEMS technology, such as micro-pumps (Nguyen, et al. 2002),
electro-chemical or electrical degradation of membranes for multiple-reservoir drug delivery
chips (Santini, et al. 1999; Grayson, et al. 2003).
MEMS technology allowed the successful miniaturization of micro-pumps for drug delivery,
providing for active delivery of fluids from single or multiple reservoirs. The low delivery rates,
low reliability due to the dependence on mechanical moving parts in fluids, and high power
consumption are among the prime limitations of an implantable drug delivery device that relies
on micro-pumps. Drug delivery devices characterized by multiple-reservoir architectures and
based on electrical actuation mechanisms provide a more reliable platform. These devices
typically can also rely on electro-thermal actuation to rupture a reservoir sealing membrane as a
result of an applied electrical potential, allowing the drugs inside of reservoirs to freely diffuse
into the region of interest (Maloney, et al. 2005; Grayson, et al. 2005).
Elman theke