Mechanism of Implantable Drug Delivery Systems
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Transcript of Mechanism of Implantable Drug Delivery Systems
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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 immuni!ation anticoagulation cancer narcotic antagonists
and insulin delivery (Costantini et al., 2004). "owadays number of drugs have been used for the
implantable drug delivery systems as shown in #able $.
Table 1: Drugs used for the implantable drug delivery
systems
Name of Drugs Purpose
%rogestin&estradiolmegestrolnorgestrel 'ontraception
Ibuprofennapro(enphenylbuta!one %olyarthritis
'yclophosphamidemerchloroethamide 'ancer
Deo(ycortisone Antihypertensive studies
Morphine "arcotic addiction studies
%ilocarpine )laucoma
Non-degradable and biodegradable implant systems
Non-degradable systems
#here are several types of nondegradable implantable drug delivery systems available on the
mar*etplace today but the
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Figure 1: 'ross-
sectional view of ideali!ed nonerodible reservoir and
matri( systems showing diffusion of the drug across the polymer
nondegradable matri( system and reservoir systems are the two most common forms +,igure $.
3. In the polymeric matri( system the drug is dispersed homogeneously inside the matri(
material. Slow diffusion of the drug through the polymeric matri( material provides
sustained release of the drug from the delivery system. #he reservoir-type system on theother hand consists of a compact drug core surrounded by a permeable nondegradable
membrane whose thic*ness and permeability properties can control the diffusion of the drug
into the body.+ #he release *inetics of drug from this system suggest that if theconcentration of the drug within the reservoir is in constant e/uilibrium with the inner
surface of the enclosed membrane the driving force for diffusional release of the agent isconstant and !ero-order release *inetics of the drug from the delivery system is obtained0Ale*ha and )reggrey $1123.#his type of system however has several disadvantages. #he
outer membrane of most of these systems is nondegradable. #herefore after drug has been
released minor surgery is necessary for the removal of the delivery system from the body.
#here is also a possibility that membrane rupture will potentially lead to 4drug dumping5during therapy. Depending on the type of drug involved in the reservoir 4drug dumping5
may result in untoward to(ic side effects from drug plasma concentrations that e(ceed
ma(imum safety levels. #he possibility of 4drug dumping5 has made the reservoir system aless popular method of drug delivery.
In the past nondegradable systems have also been studied for use in the administration of
anticancer drugs such as do(orubicin. Microcapsules containing a nondegradable e(terior and
compressed do(orubicin reservoir interior have been studied. #his type of administration was
compared to biodegradable polymer matrices containing do(orubicin. In such e(periments the
biodegradable polymers did not cause any to(ic reactions within the body and were preferred
over the nonbiodegradable polymers that remained in the body after the drug was released.
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6 Matri( systems are also commonly used as nondegradable implants. #hese systems
consist of uniformly distributed drug throughout a solid nonbiodegradible polymer
0Patel, 2010).
6i*e the reservoir systems matri( systems rely on the diffusion of drug particles through the
nondegradable fibrous networ* of the polymer to obtain sustained release of the drug. 7owever
the *inetic release of drug from these formulations is not constant and depends upon the volume
fraction of the agent in the matri(. #he greater the concentration of the dissolved agent within the
matri( the greater
the release from the system.+2
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 +,igure 8.
Figure 2:
Schematic of a magnetically controlled polymeric drug delivery
system illustrating increased drug release from the system after e(posure
to an oscillating magnetic field
9hen the unit is e(posed to a biological system normal diffusion of the drug due to a
concentration gradient is seen. 7owever upon e(posure to an e(ternal oscillating magnetic field
larger /uantities of drug can be released /uic*ly.+$ #he ma:or advantage of this type of drug
delivery system is the possibility of manipulating the release *inetics of the drug by using
e(ternal magnetic stimuli.+2
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Biodegradable systems
;iodegradable systems have gained much popularity over nondegradable delivery systems.+1$
#wo different types of biodegradable delivery systems are currently available. #he first type a
reservoir system is similar in structure to the nondegradable reservoir type described earlier. #he
mechanism of drug release from both systems is /uite similar.+$? 7owever these bioerodible
systems in contrast contain an e(terior polymeric membrane that degrades at a slower rate than
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the e(pected rate of drug diffusion through the membrane. #herefore the membrane remains
intact while the drug is released completely. @ventually the e(terior polymeric membrane is
degraded in vivo and ultimately eliminated. #he second type of bioerodible system consists of
drug dispersed in a polymer monolithic type which is slowly eroded in vivo by biological
processes at a controlled rate.+$ #he most popular biodegradable polymers currently being
investigated include polyglycolic acid polylactic acid polyglycolic-lactic acid polyaspartic
acid and polycaprolactone.+ #he use of ethyl vinyl acetate copolymer matrices for the delivery
of macromolecular drugs such as insulin has also been studied e(tensively.+$$2 A new form of
lactic acidBlysine copolymer chemically attached to a biologically active peptide is being
developed and tested which could function as a matri( for the mammalian cells.+$1 #his new
copolymer effectively promotes cell adhesion to an otherwise nonadherent surface and this
system will hopefully play a ma:or role in the development of implantable polymers in the
future.+8
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Figure :
Schematic of an insulin implantable pump
%ump systems differ from other implantable systems due to their mechanism of drug delivery.
%ump systems release drugs through a pressure difference generated gradient that results in the
bul* flow of a drug at controllable rates.+88 #o 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 utili!e a fluorocarbon propellant to
administer the drug in vivo. Such pumps were initially developed for the administration of
insulin to diabetic patients. Infusaid 0Infusaid 'orp. Sharon MA SA3 was one of the first
commercially available pumps for this use. "ormally insulin-dependent diabetics re/uire
in:ections once or twice daily.
#his type of dosing results in abnormal pea*s 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 *idney disease.+$8 It is felt that continuous insulin infusion using such pumps may help
eliminate these ris* factors in the diabetic population. #he pump consists of a disc-shaped
canister made of light-weight biocompatible titanium which contains a collapsible welded
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bellow.+8= #he bellow separates the canister interior into two separate chambers. #he first
chamber contains the fluorocarbon propellant and the second contains the insulin formulation+2
+,igure .
Figure !: An implantable propellant driven
pump system during operation
0top3 and during refilling 0bottom3
#he gas pushes the drug through a filter and a flow regulator that provides a constant rate of drug
administration at a given temperature. #he delivery rate is ad:usted by changing the drug
concentration in the pump reservoir.+8 #he advantage of this system involves the fact that no
e(ternal energy source is needed to drive the pump action. 9hen the pump reservoir is refilled
an in:ection of drug through a membrane consisting of a self-sealing silicone rubber and #eflon
septum is administered. #he force of the in:ection 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.+8>
Peristaltic pumps
%eristaltic pumps consist of rotary solenoid-driven systems that run via an e(ternal power source
which is usually a battery.+$ %eristaltic systems li*e 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
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+,igure >. Figure
": 'ross-sectional view of an implantable peristaltic pump showing
all important components
#he advantage of this type of system is that the rate of drug administration can be controlled by
an e(ternal remote control system. #hese 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.
#he osmotic pump also *nown as Oros or the gastrointestinal therapeutic system was first
described by #heeuwes and Eum and released for use by Al!a 'orporation.+8?8 #his pump
consists of a drug reservoir surrounded by a semipermeable membrane. #he surrounding
membrane allows a steady influ( of water and biological fluid into the reservoir through the
process of osmosis. #he hydrostatic pressure built from this influ( causes a steady release of the
drug from an opening in the membrane called the drug portal. #he rate of drug release is
constant or !ero-order until the drug within the reservoir is completely depleted. 'hanging the
rate of drug administration of these systems can only occur by changing the structure of the
semipermeable membrane that re/uires removal of the system.+82
Osmotic pump systems containing hydromorphone have been subcutaneously implanted for the
use of pain management. Cesults have shown that Al!etFs osmotic pumps release 8?8 mgBh of
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hydromorphone to produce stable plasma concentrations of appro(imately =
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independent of the drug formulation dispensed. Drugs of various molecular configurations
including ioni!ed drugs and macromolecules can be dispensed continuously in a variety of
compatible vehicles at controlled rates. #he molecular weight of a compound or its physical and
chemical properties has no bearing on its rate of delivery by A6H@# pumps. 9ater enters into
the salt chamber through semipermeable membrane and causes compression of fle(ible reservoir
and delivery of drug solution.
Fig( !: $l)et osmoti# pump
$ppli#ations
#he al!et pump the enabled to "euroscientist 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.
Al!et pump have proved useful in biotechnology. ,or characteri!ing novel protein peptideFs
such as growth factor while also facilitating e(citing 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. #he system consists of an outer cylindrical titanium alloy reservoir. #his reservoir has
high-impact strength and protects the drug molecules from en!ymes 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. #he
membrane is permeable to water but substantially impermeable to ions. %ositioned ne(t to the
membrane is the osmotic engine. "e(t to the engine is the piston. #he piston is made from
elastomeric materials and serves to separate the osmotic engine from the drug formulation in the
drug reservoir compartment.
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At the distal end of the titanium cylinder is the e(it port. @(it ports can range from simple
straight channels to more complicated design configurations. #he e(it port design must be
coupled to the rheological properties of the drug formulation. Duros implant with diameters up to
mm have been designed resulting in drug formulation volume of the mmJ>mm implant has
a total volume of less than 8
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$3 Duros 6euprolide Implant-the duros leuprolide implant has been designed to provide an
alternative to periodic depot in:ection leuprolide for palliative treatment of advanced prostate
cancer.
83 Salmon calcitonin 0s'#3 has been used for the treatment of osteoporosis and %agetFs disease
where calcitonin inhibits osteoclasic bone resorption and induces calcium upta*e.
=3 Systemic or site-specific administration of a drug. #he preferred site of implantation is
subcutaneous placement in the inside of the upper arm. 9hen implanted a large constant
osmoti# gradient is established between the tissue water and the osmotic engine.
81-$< the*e
In the past drugs were fre/uently administered orally as li/uids or in powder forms. #o avoid
problems incurred through the utili!ation of the oral route of drug administration new dosage
forms containing the drug0s3 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. #herefore drug
delivery systems were developed to optimi!e the therapeutic properties of drug products and
render them more safe effective and reliable. Implantable drug delivery systems 0IDDS3 are an
e(ample of such systems available for therapeutic use. #he study of currently available
implantable drug delivery systems is the main focus of this review. #he ma:or advantages of
these systems contain targeted local delivery of drugs at a constant rate fewer drugs re/uired to
treat the disease state minimi!ation 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 wee* to once a year that in the past re/uired fre/uent daily dosing.
%reliminary studies using these systems have shown superior effectiveness over conventional
methods of treatment. 7owever one limitation of these newly developed drug delivery systems
is the fact that their cost-to-benefit ratio 0costBbenefit3 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 re/uired prior to their use in standard
practice.
INT,D+*TIN
Orally administered drug must be protected against denaturation in the gastrointestinal tract and
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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 en!ymes. #he 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 8 hours. #he main drawbac* of oral dosage form is the long transit time of appro(imately
$8hours through the gastrointestinal tract 0)I#3. If drug cannot be administered orally a
parenteral route of delivery is an alternative. Many proteinsBpeptides and other drugs which are
susceptible to the adverse conditions of )I# are administered intravenously. nfortunately in
intravenous drug administration the duration of drug action is short for ma:ority of
therapeutically active agents and therefore fre/uent in:ections are re/uired.
#he development of in:ectable controlled-release dosage forms is more li*ely 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-L-vis subcutaneously implantable drug delivery
devices offer one uni/ue advantage of a retrievable mechanism +$.
,or integration of various therapeutic agents with different physicochemical characteristics and
for improved mechanism of drug release number of additives is now used. #hus more current
implantables generally contain the therapeutic agent in a rate controlling systems. Implantables
are available in various si!es and shapes. 9hile 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.
,or e(ample 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 re/uire a rapid onset of action. Similarly pulmonary systems such as inhalers re/uire drugs
to be absorbed into the bloodstream from the lungs. Drug delivery by in:ection has other
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disadvantages. %atients must choose between traveling to a treatment site and maintaining a
home supply. ,urthermore the discomfort of fre/uent in:ections leads to poor patient
compliance. ,inally a multiple timed drug-in:ection regimen is complicated to administer and
may re/uire a clinicianFs help.
%ortable infusion systems allow unassisted intravenous administration however these systems
can only administer drugs in li/uid form and re/uire both a transcutaneous catheter and an
e(ternal pump. ,ully implantable drug delivery devices are desirable where alternate forms of
delivery are not preferred or not possible. #hese 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 re/uire drugs to be released continuously to maintain a therapeutic
level for an e(tended time. %ulmonary transdermal intravenous or subcutaneous in:ection or
infusion+8 and implantable systems have been developed for situations where oral drug
delivery is not optimal or feasible+=. 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.
'urrently available drug delivery implants can be divided into two main categories based on
whether they deliver drug in a passive or active manner. %olymer depots are the most common
passive drug delivery systems. #hey 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. 'onventional programmable IDDDs use 8>->-$< years3 of the implant. 7owever in typical
IDDDs medication is typically refilled every $< wee*s by transdermal in:ection into a
subcutaneous refill port 0,igure $.$3+.
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Figure 1(1: The system vie0: $ t0o-pole needle is inserted into the refill port of a drug
delivery devi#e( Inset: $ #lose vie0 of the t0o needle halves maing ele#tri#al #onta#t 0ith
springs inside the septum(
#he overall volume efficiency of an IDDD which is critical to its placement and usability
0particularly in paediatric cases3 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+>. 9hile wireless power transfer is possible for very low-power applications+? D'
recharge capability + offers high current levels and may be more suitable for IDDDs 0,igure
$.83.
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Figure
1(2: $ photo of the front of an assembled mi#rovalve-regulated drug delivery devi#e 0ith
the ba# side refill port sho0n inset34(
Over the last two decades the field of controlled drug delivery has been faced with two ma:or
challenges. One has been achieving sustained !ero-order release of a drug substance over a
prolonged period of time. #his goal has been met by a wide range of techni/ues including
osmotically driven pumps +1 matrices with controllable swelling +$
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2( $D5$NT$6'. F I7P%$NT$B%' D,+6
D'%I5',8 .8.T'7
#he advantages of implantation therapy include.
*onvenien#e:
@ffective concentration of drug in the blood can be maintained for longer period of time by
techni/ues such as continuous intravenous infusion or repeated in:ections. On the other hand
under these treatments patients are regularly re/uired to visit hospital throughout administration
for uninterrupted medical monitoring. A short-acting medicineworsens the condition as the
/uantity of in:ections 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 characteri!ed by a
lower occurrence of infection associated problems in comparison to indwelling catheter-based
infusion system.
Improved drug delivery:
#he drug is distributed locally or in systemic circulation with least interference by metabolic or
biological barriers. ,or e(ample the drug moiety bypassed the )I# and the liver. #he by-passing
effect is beneficial to drugs which are either easily inactivated or absorbed poorly in the )I#
andBor the liver before systemic distribution +$.
*omplian#e:
;y allowing a reduction or complete elimination of patient-involved dosing compliance is
increased hugely. %atient can forget to ta*e a medicine but drug delivery from an implant is not
dependent of patient input. %eriodical refilling is involved in some implantables but despite this
limitation the patient has less involvement in delivering the re/uired medication.
Potential for #ontrolled release:
Implants are available which deliver drugs by !eroorder controlled release *inetics. #he
advantages of !ero order controlled release are
0a3 %ea*s 0to(icity3 and troughs 0ineffectiveness3 of conventional therapy is avoided
0b3 Dosing fre/uency is reduced
0c3%atient compliance is increased.
Potential for bio-responsive release:
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;io-responsive release from implantables is an area of on-going research.
Potential for intermittent release:
Intermittent release can be facilitated by e(ternally programmable pumps. Intermittent release
can facilitate drug release in response to such factors as
0a3 'ircadian rhythms
0b3 ,luctuating metabolic re/uirements
0c3 %ulsatile release of many peptides and proteins.
Fle9ibility:
In the choice of materials methods of manufacture degree of drug loading drug release rate etc.
considerable fle(ibility is possible. ,rom a regulatory viewpoint it is regarded as a new product
and can lengthen the mar*et protection of the drug for an additional > years 0for a new drug
entry3 or = years 0for e(isting drugs3+$2-8$.
(DI.$D5$NT$6'. F I7P%$NT$B%'
D,+6 D'%I5',8 .8.T'7
#he disadvantages of implantables include
Invasive:
#o initiate therapy either a minor or a ma:or surgical procedure is re/uired to initiate therapy.
Appropriate surgical personnel is re/uired for this and may be time-consumingtraumatic. #his
causes some scar formation at the site of implantation and surgeryrelated complications in a very
small number of patients. ncomfortable feeling for the patient wearing the device.
Danger of devi#e failure:
#here is no associated danger with this treatment that the device may for some reason fail to
wor*. #his again re/uires surgical involvement to correct +$.
Termination:
Osmotic pumps and non-biodegradable polymeric implants also are surgically recovered at the
end of therapy. Although surgical recovery is not re/uired in biodegradable polymeric implants.
Its on-going biodegradation ma*es it difficult to end drug delivery or to maintain the accurate
dose at the end of its lifetime.
%imited to potent drugs:
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In order to minimi!e patientFs discomfort the si!e of an implant is usually *ept small. #herefore
most implants have a limited loading capacity so that fre/uently only somewhat potent
medicines such as hormones may be appropriate for delivery by implantable devices.
Bio#ompatibility issues:
'oncerns over body reactions to a foreign substance often increase the issues of biocompatibility
and safety of an implant.
Possibility of adverse rea#tions:
A high concentration of the drug delivered by an implantable device at the implantation site may
produce adverse reactions.
*ommer#ial disadvantages:
An enormous amount of CD investment effort and time is re/uired 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. #hese issues can
attribute to noteworthy delay in the progress mar*eting and price of a new implant +$2-8$.
!( I7P%$NT$B%' D,+6 D'%I5',8 D'5I*'.
!(1 Field of *ontrolled 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 e(ample the cornea. #he field of controlled drug delivery today employs mechanisms
such as transdermal patches polymer implants bioadhesive systems and
microencapsulation+88-8.
!(1(1 Transdermal Pat#hes
#ransdermal patches generally have hollow microneedles made of a biocompatible polymer
through which the drug is delivered below the s*in. #ransdermal patches have numerous
advantages compared with other systems of drug delivery the drugs are not degraded in the )I#
they are painless and they deliver a constant dosage without the need for patientFscompliance+8>. A renowned e(ample for transdermal patches is the nicotine patch.
!(1(2 Polymer Implants
%olymer implants are biodegradable polymers loaded with the drug molecules. #he polymer
degrades when it comes in interaction with body fluids and in the process releases drug
molecules. #he rate of degradation of the polymer and hence the drug release can be optimi!ed
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by modifying the properties of the polymers. #he polymer material which are most widely used
for these application include but are not restricted to %olyglycolic acid0%)A3 %olylactic
acid0%6A3 %olyurethane and the combinations of these in different proportions.
!(1( Bioadhesives
;ioadhesives are substances which form bonds with biological surfaces. #he most common
substances which are used in this case are polymer hydrogels. #he 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. 7ydrogels are water-swollen polymer networ*s.
#he polymer chains may be held
together by either physical forces or covalent crosslin*s.
;y design of the hydrogel constituents they can be made responsive to their chemical or
physical environment. At a temperature of =>-< P' 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 +8?.
!(1(! 7i#roen#apsulation
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. #here are variety of ways in which
microencapsulation is done. Some of them are use of polymer microspheres liposomes
nanoparticles etc. +8>. #he above devices are Qpassive devicesF and deliver the drug gradually in
very small amounts with precision. ;ut they are not capable of delivering the drug in a non-
linear fashion or Qon demandF. #hey cannot be programmed to deliver drug when re/uired and
stop when not re/uired +88 8=.
!(1(" .ome Important Passive Devi#es
#here are some drug delivery devices which deserve a special mention.
!(1("(1 7i#ro#hip Drug ,eservoirs
#hese devices came out of the lab of Dr. Cobert 6anger lab at MI#. It is one of the very first truly
Micro@lectro Mechanical Systems 0M@MS3based drug delivery systems 0Figure !(13. #he
design incorporates multiple sealed compartments which are opened on demand to deliver dose
of a drug+8. ,abrication of these microchips began by depositing
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silicon nitride layer on one side of the wafer was patterned by photolithography and electron
cyclotron resonance 0@'C3 enhanced reactive ion etching 0CI@3 to give a s/uare device 0$mm (
=mm ( $ mm3 containing =2< s/uare reservoirs. #he silicon nitride served as an etch mas*
for potassium hydro(ide solution at 2>.2P' which anisotropically etched s/uare pyramidal
reservoirs 0Figure !(1 b3 into the silicon along the 0$$$3 crystal planes until the silicon nitride on
the opposite side of the wafer was reached.
Figure !(1(7i#ro#hip drug
reservoir(
!(1("(2 Immuno-isolating *apsules
#hese devices are not drug delivery systems in the conventional sense. #hey deliver insulin in
the body but rather than store it in the device they contain pancreatic islet cells which ma*e
insulin and deliver through the nanoporous membrane of the device.
Microfabrication techni/ues have been applied to create a biocapsule for effective
immunoisolation of transplanted islet cells for the treatment of diabetes+8. #he fabrication of
nanochannels in the membrane structure consists of two steps. ,irst surface micromachining
nanochannels in a thin film on the top of a silicon wafer. Second releasing the membrane by
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etching away the bul* of the silicon wafer underneath the membrane. #hese 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 cytoto(ic cells macrophages
and complement. #he membranes are bonded to a capsule that houses the pancreatic islet cells.
;ecause the difference in the si!e of insulin which must be able to pass freely through the pores
and the si!e of the Ig)immunoglobins which must be e(cluded is only matter of a few
nanometers the highly uniform pore distribution provided by micromachine membranes is
essential for effective immunoisolation and therapeutic effect.
!(1("( Diffusion *hambers
A diffusion chamber from Debiotech Inc. #hey hold a cargo of drugs and are sealed with a
semipermeable membrane. #hese are used for delivering fairly large amount of drugs and in
some cases more than one drug. #he membrane surface area is large compared to the reservoir
resulting in the increased delivery rates. #hese reservoirs are generally not used for long term
delivery+82.
!(1("(! Diffusion *ontrolled Implanted Tubes2-24
#hese use a narrow aperture to provide a slow delivery rate of drugs. #hey are used for long-term
release of highly potent drugs with the release times it the order of years. A good e(ample is the
five-year duration birth control implants based on elastomeric tubes+==. A similar e(ample is
that of the Duros#M osmotic pump from A6HA 'orporation. #his nonbiodegradable
osmotically driven system+8 is intended to enable delivery of small drugs peptides proteins
D"A and other bioactive macromolecules for systemic or tissue-specific therapy. #he DCOSK
implant is a miniature cylinder made from a titanium alloy which protects and stabili!es the drug
inside using A6HARs proprietary formulation technology. 9ater 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. #he delivery can be
over a period of $8 months.
%ums the*e
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Figure !(2Duros
osmoti# pump ;$l)a -7ountain 5ie0< *$< +.$=.
>( T?',$P'+TI* $PP%I*$TIN. F IDD.
#ular disease
"umerous different implantable systems have been estimated to deliversustainedocular delivery.
#hese comprise membrane-controlled devices implantable infusion systems and implantable
silicone devices. Ocular insert 0ocusert3having pilocarpine base and alginic acid in a drug
reservoir surrounded by a release-rate controlling ethylene-vinyl acetate membrane is an
e(ample of the membrane-controlled system+=1-$. #he ocusert system offers an initial rupture
followed by a near !ero order transport of pilocarpine+8 at 8< or < gBh for a span of seven
days. #he device is well tolerated in adults with suitable control of intraocular pressure and
minimal side effects+=-?. 7owever it loo*s to be poorly tolerated in the geriatric patients
where most of the therapeutic re/uirement e(ists.Implantables evaluated for ocular cancer
management include silicone rubber balloon having an antineoplastic agent.
*ontra#eption
"orplant a sub-dermal implant for long-lasting transport of the contraceptive agent
levonorgestrel recently been approved for mar*eting by the ,DA. #he device consists of si(
silicone membrane capsules each having about =? mg of levonorgestrel. #he capsules are placed
sub-dermally on the inside of the upper arm or the forearm in a fan-shaped pattern through atrocar from a single trocar entry point. 'linically "orplant users have a net pregnancy rate of
below $.> in $
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menstruation the progestasert an ethylenevinyl acetate copolymer intrauterine drugreleasing
device which persists for one year and suspensions of in:ectable microspheres or rods composed
of biodegradable polymers+$.
Dental appli#ation
,or numerous dental applications including local prolonged administration of fluoride
antibacterial and antibioticspolymeric implants have been evaluated. Stannous fluoride was
integrated into different dental cements for sustained release fluoride delivery. Another dispersed
in the hydro(yethyl 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. #he
device about 2 mm long and having 8 mg of fluoride in the core was attached to the buccal
surface of the ma(illary first molar and designed to release mgBday of fluoride for =< days
+-1.
Immuni)ation
%olymeric implants are being evaluated for better immune response to antigens. #he concept
here is to offer pulsatile or continuous administration of the antigen over a prolonged period of
time. 9ise et al. evaluated immuni!ation efficiency of ethylene-vinyl acetate copolymer pellets
having bovine serum albumin as model antigen. #he immune response was comparable to that
achieved by two in:ections of bovine serum albumin in complete ,reundFs ad:uvant 0,reundFs
ad:uvant is an oBw emulsion containing bacteria3.
*an#er
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. 6upron depot produced by #a*eda chemical industries is an implantation system
providingonemonth depot release of leuprolide acetate a synthetic analogue of the gonadotropin-
releasing hormone 0)hC73. #he implant containing biodegradable microspheres made from
polylactic G glycolic copolymer at $$ compositions having $
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"altre(one has been comprehensively evaluated in implant from long term delivery of narcotic
antagonists. "altre(one freebases its hydrochloride or the pamoate acid salt has been formulated
in a various polymers and dosage forms for prolonged narcotic antagonistactivity.
ther appli#ations
Tarious insulin delivery systems have been formulated and evaluated for a biofeedbac* approach
and have been described before.#hese are biofeedbac* controlled system where the drug release
rate is reliant on the bodyFs re/uirement for the drug at a specified time. ,rom a therapeutic
perspective these systems may come closest to reproducing the release from a gland for e(ample
the pancreas. Tarious mechanisms have been employed to attain self-regulated delivery+8 $.
#he above mentioned applications are few e(amples of therapeutic applications of implantable
drug delivery system.
@( F+T+,' P,.P'*T.
At present much research is being conducted in the region of implantable drug delivery systems.
Despite this fact much wor* is still re/uired in the regions of biodegradable and biocompatible
substances the *inetics of drug release and more improvement of present systems before many
of these preparations can be used. In the future scientists remain e(pectant that many of these
systems can be prepared with best !ero-order release *inetics profiles in vivo over long times
allowing for prolonged use in constantly sic* patients."ew medicines are continuously being
prepared. Several of these medications are developed from proteins and peptides which are very
unstable when ta*en through oral route. ;y 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 e(clude the necessity for multiple dosing. It is e(pected 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+>8.
3( *N*%+.IN
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Cecently Implantable drug delivery is one of the technology sectors that often overloo*ed
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 fre/uency of
patient driven dosing and to deliver the compound in targeted manner. Many product utili!ing
implant delivery technologies are being utili!ed 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 to(icity or immunogenicity of the
by-products of polymer degradation. Additionally convenient methods of triggering drug
delivery from the e(ternally controlled delivery systems need to be developed in order for them
to be of practical use. #hese issues coupled with the potential therapeutic benefits of pulsatile
dosing regimens should ensure that the current high level of interest in this area will e(tend 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 mar*et and the number of patents granted in
the recent past. #omorrowFs 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 tas* ahead.
< 82< 818 the*e r o neya :abe..
P$,'NT',$% I7P%$NT.
Implant is an ob:ect or material inserted or grafted into the body for prosthetic therapeutic
diagnostic or e(perimental purposes. Implants are one of the dosage forms used to achieve
effective concentrations for a long time. #herefore the base materials for implants are re/uired to be biocompatible. ;iodegradable and non-biodegradable polymers are often utili!ed as a base
material. "on biodegradable polymers have to be ta*en 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 0%6A3 and poly 0dl-
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lactic acid-co-glycolic acid3 copolymer 0%6)A3 are clinically available as biocompatible and
biodegradable polymers and have been e(amined e(tensively and widely. %6)A and %6A show
a prolonged drug release for $ and = months respectively. Other biodegradable polymer li*e
polyanhydride shows a longer drug release about $ year. "on bio-degradable polymer includes
poly vinyl acetate 0%TA3 etc. Tarious types of implants are available for the drug delivery system
li*e for delivery into eye heart bone cochlea etc.
Implants #lassified as- $.Solid implants-
Solid implants typically e(hibit biphasic release *inetics with initial burst of drug is usually due
to the release of drug deposited on the surface of the implant although !ero order *inetics may be
achieved by. @.g. 'oating 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.
8. In-Situformingimplants-
;iodegradable in:ectable in situ forming drug delivery systems represent an attractive alternative
to microspheres and implants as parenteral depot systems. #he controlled release of bioactive
macromolecules via 0semi-3 solid in situ forming systems has a number of advantages such as
$. @ase of administration
8. 6ess complicated fabrication
=. 6ess stressful manufacturing conditions for sensitive drug molecules.
*NT,%%'D D,+6 D'%I5',8 B8 DIFF+.IN P,*'..
a3 %olymer 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 si!es of implantable drug delivery devices can be
fabricated. An e(ample of this type of implantable drug delivery device is the
Norplantsub dermal implant. "orplantK is a well-*nown contraceptive implant approved
by .S. ,ood and Drug Administration 0,DA3 in $11
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b3 %olymer matri( 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 matri( .#he
dispersion ofdrug solid particle in the polymer matri( can be accomplished by blending
drug solid with a viscous li/uid polymer at room temperature followed by cross lin*ing
of polymer chains or by mi(ing drug solid with a melted polymer dispersion are then
molded or e(cruded to form a drug delivery device of various shapes and si!es. An
e(ample of this type of implantable drug delivery device is the compudose implant.
c3 Membrane-matri( hybrid-type Drug Delivery Devices #his type of implantable
controlled release drug delivery devices is hybrid of the polymer membrane permeation
controlled drug delivery system and polymer matri( diffusion controlled drug delivery
system. It aims to ta*e advantages of the constant drug release *inetics maintained by themembrane permeation-drug delivery system while minimi!ing the ris* of dose dumping
from the reservoir compartment of this type of drug delivery system. An e(ample of type
of implantable drug delivery device is Norplant II sub dermal implant.
d3 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
a/ueous solution of water-miscible polymers forms a homogeneous dispersion of
millions of discrete unreachable microscopic drug reservoir in a polymer matri(.
Different shapes and si!es of drug delivery system by molding or e(trusion. 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 e(ample of this type implantable drug delivery
device is the .yn#hro-7ate implant. It contains drug norgestomet.
8. 'ontrolled drug delivery by activation process
a3 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.
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$l)et osmoti# pump
#he physical or chemical properties of a compound have no influence on the delivery rate
of A6H@#pumps. #he delivery rate of A6H@# 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 fle(ible impermeable reservoir. #he test solution is continuously released through the
flow moderator. A flow modulator is a hollow tubewith an inner diameter of >
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orsilicon elastomers on all sides e(pect one cavity atthe center of the flat surface which
is left uncoated topermit the drug molecules to be delivered through thecavity.
;yapplying an e(ternal magnetic field the drugs areactivated by the electromagnetic
energy to releasefrom the pellet at a much higher rate of delivery.
d3 7ydration activated drug delivery devices
#his 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. #o achieve thisdrug delivery device is often fabricated from ahydrophilic polymer
that becomes swollen uponhydration. Drug molecules are released by diffusingthrough
the polymer matri(. #he hydration activatedimplantable drug delivery device is
e(emplified by the development of the norgestomet releasing 7ydro implant for estrus
synchroni!ation in heifers. #hiswas fabricated by polymeri!ing ethylene
glycolmethacrylate 07ydron S3 in an alcoholic solution that containsnorgestomet a cross-
lin*ing agent 0such asethylene dimethacrylate3 and an o(idi!ing catalyst toform a
cylindrical water swellable 0but insoluble3 7ydron implant.#he 7ydron Implant
technology is based upon specialty blends of hydrogel polymers spun cast into small
tubes measuring in the order of $-inch in length and $B2 inch in diameter.
e3 7ydrolysis activated drug delivery devices#his 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. #o achieve this drugdelivery device is fabricated by depressing a loadingdose of
solid drug in microni!ed form homogeneously through a polymer matri( made from
bioerodible or biodegradable polymer which is thenmolded into a pellet or bead-shaped
implant. #hecontrolled release of the embedded drug particles ismade possible by the
combination of polymer erosionby hydrolysis and diffusion through the polymer matri(.
#he rate of drug release is determined by therate of biodegradation polymer composition
andmolecular weight drug loading and drug-polymerinteraction. #he rate of drug release
from this type of drugdelivery system is not constant and is highlydependent upon the
erosion process of the polymermatri(.
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Ceview perenteral thehe
,'*'NT T'*?N%68 IN I7P%$NT$B%' D,+6 D'%I5',8:
D+,INT7
T'*?N%68
#he DCI"#M biodegradable implant technology is a platform for parenteral delivery of drugs
for periods of wee*s to si( months or more. #he technology is based on the use of biodegradable
polyester e(cipients which have a proven record of safety and effectiveness in approved drug
delivery and medical device products. =
Features:
Superior delivery *inetics. ,le(ibility.
Superior drug loading and stability. ,ully biodegradable.
7istory of safe human use. 'ost effective.
#he D+,IN#M biodegradable implant te#hnology is based on the use of biodegradable
polyesters as e(cipients for implantable drug formulations includes the polymers and
copolymers prepared from glycolide D6-lactide 6-lactide and U-caprolactone.
#he degradation times and physical properties of the biodegradable e(cipient can be engineered
to achieve a wide variety of drug delivery goals by ad:usting monomer composition and
distribution polymer molecular weight and end group chemistry.
#he overall form of the implant is typically a small rod or pellet that can be placed by means of a
needle or trochar. #he composition of the rod or pellet can be monolithic where the drug is
uniformly dispersed throughout the e(cipient. Alternatively reservoir-type designs are also
possible in which the rod or pellet is composed of a drug-rich core surrounded by a rate-
controlling membrane.
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#he drug and e(cipient are mi(ed together and the mi(ture is formed into a fiber rod tablet or
pellet by an e(trusion or molding process. #he rate controlling membrane if re/uired may be
applied during or subse/uent to the core-forming process.>
7anufa#turing:
#ypically melt e(trusion is used at modest temperatures to produce biodegradable implants for
drug delivery. #he active and e(cipient are combined and fed to a melt e(truder to produce a
bul* rod which is then cut to produce the unit dose. ,or coa(ial membrane-controlled implants
two e(truders are operated to simultaneously produce the core and membrane in a continuous
process. ,or particularly heat labile compounds the DCI"#M technology is also compatible
with proprietary manufacturing methods other than e(trusion that ensure drug stability. ;ecause
DCI"#M implants are produced using continuous manufacturing processes batch si!e is
determined by the length of the e(trusion run. Several clinical batches of biodegradable implants
at a batch si!e of more than 8
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manufacture of the Atrigel/ system and its relatively pain-free subcutaneous in:ection into the
body provide significant advantages over both solid implants and microparticles..
#hese include the polyhydro(yacids polyanhydrides polyorthoesters polyesteramides and
others. #he polymers most often used are poly 0dllactide3 lactideBglycolide copolymers and
lactideBcaprolactone copolymers because of their degradation characteristics and their approval
by the ,ood and Drug Administration 0,DA3.2
#he solvents employed in the Atrigel system to dissolve the polymers range from the more
hydrophilic solvents such as dimethyl sulfo(ide N -methyl-8-pyrrolidone 0"M%3 tetraglycol and
glycol furol to the more hydrophobic solvents such as propylene carbonate triacetin ethyl
acetate and ben!yl ben!oate. #he most fre/uently used solvent is "M% because of its solvating
ability and its safetyBto(icology profile.1 $<
7anufa#turing< sterili)ation< and pa#aging
;ecause 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 a/ueous solutions. #herefore the
products currently mar*eted using this technology are filled into plastic syringes and pac*aged
with foil-lined material to protect from moisture. Atri( 6aboratories has developed custom-made
e/uipment 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. #herefore gamma irradiation was evaluated and found
to be a convenient method of terminal sterili!ation of the polymer solution. #here 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 +?.
.#ale-up pro#ess
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#he manufacturing of products with the Atrigel/ system can easily be scaled up to commercial
/uantities. ,irst the polymer is dissolved into the biocompatible solvent using a standard
pharmaceutical product mi(er. 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 mi(er.
#he polymer solution is then transferred from the plastic container to the syringe-filling
e/uipment where it is loaded into individual syringes. #he plastic container can then be discarded
and the need for thorough cleaning is eliminated. #he filled syringes are capped and placed into
foil-lined pac*ages to prevent moisture absorption. #he drug is either powder-filled or
lyophili!ed into syringes. If the drug is stable to gamma irradiation then both the drug and
polymer syringe are terminally sterili!ed by this method. If the drug is not stable to gamma
irradiation then the lyophili!ation is carried out under aseptic conditions to give a sterile drug
syringe and the polymer solution is sterili!ed by gamma irradiation. 9ith this type of process
the manufacturing can easily accommodate
the production of several hundred syringes to thousands in one batch $$.
In some cases both the drug and polymer are stable as with the lidocaine hydrochloride product.
7owever 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. 9ith such type of products the drug and polymer solution are maintained in separate
syringes until immediately before use. Atri( has developed proprietary methods to lyophili!e
drugs in plastic syringes that can be coupled with the polymer solution.
Four produ#ts have already been approved by the FD$ using the $trigel te#hnology(
$3 Atrido(K periodontal treatment product
83 AtrisorbK )#C barrier product
=3 AtrisorbK D product with Do(ycycline
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3 Do(yrobeK product
,'6'%/ D'PT T'*?N%68
Ce)elK is one of MacroMedRs proprietary drug delivery systems. #he leading product of
MacroMed Ce)elK employs 8=N 0wBw3 copolymer of poly 0lactide-co-glycolide3-poly
0ethylene glycol3 G poly 0lactide-co-glycolide3 0%6)A-%@)-%6)A3 in phosphate buffer saline.
Cesearch on poly 0lactide-co-glycolide3 and poly 0ethylene glycol3 polymers has resulted in an
e(tensive database for clinical safety and efficacy as components in drug delivery systems.
#hermally reversible gelling materials such as Ce)elK are a uni/ue class of compounds being
developed for parenteral delivery. Ce)elK is a family of polymers that offer a range of gelation
temperatures degradation rates and release characteristics. #he thermal characteristics of
Ce)elK which are in general terms a function of the molecular weight degree of hydrophobicity
and polymer concentration allow the necessary fle(ibility to match a variety of compounds to a
convenient formulation for programmed delivery of active agent.
'9amples of thermosensitive polymers
%oly 0 N isopropylacrylamide3 0%"I%AAM3 poly 0ethylene o(ide3- poly 0propylene o(ide3-poly
0ethylene o(ide3 tribloc* copolymers 0%@O-%%O-%@O3 poly 0ethylene glycol3-poly 0lactic acid3-
poly 0ethylene glycol3 tribloc*s 0%@)-%6A%@)3. #ribloc* %@O-%%O-%@O copolymers
0%luronicsK or %olo(amersK3 show gelation at body temperature at concentrations greater than
$>N 0wBw3.
Pro#edure:
#he synthetic process is well characteri!ed and allows specified gelation temperatures to be
produced based on the starting composition of the poly 0ethylene glycol3 lactide and glycolide
mi(ture. #he components are poly 0ethylene glycol3 lactide and glycolide monomers and the
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catalyst is stannous octoate which results in greater than 1>N yield and more than 11N purity.
A/ueous purification and sterili!ation via filtration or gas-sterili!ation of the lyophili!ed product
is done.$8
$dministration:
%rior to in:ection the product is reconstituted yielding a/ueous Ce)el K as a free-flowing li/uid
below its gelation temperature with a viscosity of V $ poise. ,ollowing in:ection 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.
#he transition occurs without chemical modification of the tribloc* copolymer or active agent
because Ce)el is a physically formed thermally reversible hydrogel.$=
Produ#t +nder #lini#al trials:
MacroMedRs first product n#o6el/ is supplied as a fro!en formulation of paclita(el in ,e6elK
and is entering %hase II trials.
*ytorynT7 is MacroMedRs immunomodulatory locali!ed peri-tumoralBintra-tumoral delivery
system based on a
combination of lympho*ine interleu*in 8 0I6-83 in Ce)elK.
$=
$%&$7', K D'PT#M T'*?N%68
#he Al!amer K Depot#M 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.$$> #he Al!amer K Depot#M
technology consists of a
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biodegradable polymer a solvent and formulated drug particles. #he depot is in:ected
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 re/uire comple( production
processes and harsh solvents that then re/uire removal$? $. Solution depot formulation processes
tend to be simpler typically involving only biocompatible solvents as part of the depot
platform$2.
Initial drug release from microspheres and these earlier-generation depot formulations tends to
be rapid up to >
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.$B', T7 D'PT T'*?N%68
#he SA;@C #M Delivery System is an in:ectable biodegradable delivery system technology that
uses a high viscosity carrier such as sucrose acetate isobutyrate 0SAI;3 solvent and one or more
pharmaceutically acceptable additives.88
In the simplest case the high-viscosity SAI; is formulated as a low-viscosity li/uid by mi(ing
with a pharmaceutically acceptable solvent. #he drug to be delivered is dissolved or dispersed in
the SAI;Bsolvent solution for subse/uent in:ection subcutaneously or intramuscularly. If a water-
soluble solvent such as ethanol is chosen the solvent will diffuse out of the in:ected volume
leaving a viscous depot of SAI; and drug. #he use of a more hydrophobic solvent such as ben!yl
ben!oate gives a less viscous depot with slower solvent diffusion. Sustained drug release occurs
over a period from several hours to several wee*s by diffusion.
In some applications an additive is used to affect release *inetics drug stability or other
performance parameters. SAI; degradation follows drug release.
7anufa#turing:
SAI;-based products are manufactured in a li/uid mi(-and-fill process using conventional tan*s
and stirrers. ,or dispersed drugs particle si!e of the drug must be controlled and particle si!e
reduction is done by milling. 7omogeni!ers have been used to disperse some of the drug
suspensions.
;ecause the SA;@C #M technology is manufactured as a mi(-and-fill li/uid formulation there
have been no specific scale-up problems. #wo issues that must be considered are transferring the
high-viscosity raw material SAI; and the use of organic solvents. #he use of solvents imposes
certain limits on contact surfaces and
re/uires particular attention in selecting tubing and seals.
8= 8.
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7aret produ#ts:
#he most significant product on the mar*et is %upron/ Depot the leuprolide acetate
microsphere product based on poly0dl-lactide3 0%6A3 and poly0dl-lactide-coglycolide3 0%6)3 for
the treatment of prostate cancer #he microspheres are in:ected using smaller-bore needles
intramuscularly.
&olade9/ again prepared from %6) and used in the treatment of prostate cancer with the
delivery of goserelin. Implants are placed subcutaneously 0S'3 using a relatively large-bore
needle 0$
P, %'$.' T'*?N%68 ;'n#apsulated protein mi#rospheres=
#he %ro6ease delivery system was designed specifically to encapsulate fragile biomolecules and
overcome the problems associated with emulsion encapsulation processes.8?
#he processes used to encapsulate small molecules and peptides typically involve the formation
of emulsions and the generation of an oil-water interface. #he 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 a/ueous solution and protein degradation may occur via water mediated
pathways such as aggregation deamidation hydrolysis and o(idation. 6yophili!ed formulations
of proteins can be stable at ambient temperatures for e(tended periods therefore
%ro6ease technology ta*es advantage of the superior stability of lyophili!ed 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 a/ueous state. In the solid state
water a reactant in many protein degradation pathways is minimi!ed molecular mobility is
reduced and the *inetics of the degradative reactions are retarded significantly. Additionally
there is the opportunity to add e(cipients to enhance the stability of the protein during the
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lyophili!ation process and for storage stability.
Stabili!ing strategies include the addition of salting-out agents sugars and the formation of
reversible metal protein comple(es.8
Prolease manufa#turing pro#ess:
,igure 8. %ro-lease manufacturing process steps.
A li/uid formulation of the protein containing stabili!ing additives or e(cipients is fed into an
atomi!ing no!!le and sprayed into li/uid nitrogen. #he droplets free!e instantaneously as they
come into contact with the li/uid nitrogen.
In the commercial 0%6-process3 process the atomi!ation occurs through an air atomi!er. #his
spray-free!e drying process is used rather than conventional bul* lyophili!ation because it
provides the ability to control the morphology and friability of the lyophili!ed powder.
#he lyophili!ed protein powder is added to the polymer solution and dispersed 0by sonication or
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high-pressure homogeni!ation3 to create a uniform suspension of the powder in the polymer
solution. #he suspension particle si!e achieved after the dispersion is an important variable that
significantly affects the initial release *inetics of the microsphere formulation. #he suspension is
atomi!ed to form droplets these droplets are the precursors of the final microsphere product.
@(traction occurs in the commercial process by transfer of the li/uid nitrogen slurry from the
spray chamber into an e(traction tan* containing cold ethanol.
#he microspheres are collected by filtration and vacuum-dried to produce a free-flowing powder.
#he bul* microspheres may be sieved to facilitate in:ectability before filling sealing and
crimping in glass vials.8
.terili)ation
#he microsphere product cannot be autoclaved because the high temperatures re/uired will
destroy the polymer and protein. )amma irradiation may be an option but e(posure of %6) to
gamma irradiation has been shown to affect the molecular weight of the polymer and may cause
degradation of the encapsulated protein.
#he use of isolation technology enables production of the microsphere product in an aseptic
environment8.
$dministration
#he microspheres may be administered by subcutaneous or intramuscular in:ection.
Wust before administration microsphere powder is dispersed in a viscous a/ueous diluent and
delivered with a hypodermic needle.
7aret produ#ts
#he first approved long-acting formulation of a therapeutic protein Nutropin Depot/
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0)enentech Inc. South San ,rancisco 'A3 is manufactured using the %ro6ease process. 8
D+,./ .7TI* P+7P I7P%$NT
#he DCOSK implant is a sterile nonerodible drug-dedicated osmotically driven system
developed by A6HA 'orporation to provide long-term controlled drug delivery. #he DCOS/
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.
,urthermore continuous administration via the DCOSK system offers the potential for dose-
sparing reductions in overall drug usage.82
Figure : DCOSK Osmotic pump implant
#he DCOSK pump conceptually resembles a miniature syringe in which drug is pushed out in
highly controlled minute dosages. #hrough osmosis water from the body is slowly drawn
through the semi-permeable membrane
into the pump by salt 0osmotic agent3 residing in the engine compartment. #he water drawn into
the engine compartment e(pands the osmotic agent and slowly and continuously displaces a
piston to dispense small amounts of drug formulation from the drug reservoir through the orifice.
#he osmotic engine does not re/uire batteries switches or other electromechanical parts to
operate.
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Features:
D+,./ can be designed to deliver up to $
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Delivery System 0IDDS3 is capable of delivering multiple individual doses.=
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Figure !: @ncapsulated 'ell #echnology
@'# 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. #he current product is ? mm in length roughly the si!e of a grain of rice. > ?
I-5$TIN I7P%$NT(
I-vation Sustained Drug Delivery implant is developed by SurModics 0@den %rairie Minn.3 .
#he I-vation platform offers a great deal of versatility and fle(ibility for formulation and
pharmaco*inetics control. Surmodics is developing a >-mm long helical coil shaped implant
thatFs in:ected into the sclera leaving the coil end coated with drug and a polymer matri( sitting
in the vitreous. #he end cap sits under the con:unctiva but is available for removable when
necessary. #he uni/ue helical design ma(imi!es the surface area available for drug delivery and
ensures secure anchoring of the implant against the sclera *eeping it out of the visual field and
facilitating retrieval. 2
Features of the I-vation Sustained Drug Delivery System
Sustained duration of delivery 0tunable from months to Z 8 years3
#argeted delivery for minimal systemic drug levels
'oating platform compatible with a variety of drugs Cemovable and replaceable
F+T+,' DI,'*TIN. $ND *N*%+.IN.:
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As discussed in this article drugs can be delivered to a patient by many different delivery
systems including oral transdermal in:ection implants etc. Most of the drugs are amenable to
these types of delivery systems. 9ith the se/uencing of the human genome biotechnology
companies are rapidly developing a large number of peptide- and protein-based drugs. It is
e(pected that in the ne(t $< to 8< years protein-and peptide-based drugs will constitute more
than half of the new drugs introduced into the mar*et and more than 2
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A variety of implantable devices based on Micro-@lectro-Mechanical-Systems 0M@MS3
technology has already been demonstrated for chronic illnesses 0%rescott et al. 8
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