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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
today,
but
the
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:
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:
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 5].
Figure
2-5-0 theke
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
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.
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
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.
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.
drug
delivery
device
was
fabricated
by
positioning
tiny
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.
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.
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
(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
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,
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.
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