Sustained and Controlled Release Drug Delivery Systems

Chapter 15
Sustained- and Controlled-Release Drug-Delivery Systems

Gwen M. Jantzen and Joseph R. Robinson
School of Pharmacy, University of Wisconsin, Madison, Wisconsin
I. INTRODUCTION
Over the past 30 years, as the expense and complica-
tions involved in marketing new drug entities have
increased, with concomitant recognition of the thera-
peutic advantages of controlled drug-delivery, greater
attention has been focused on development of sus-
tained- or controlled-release drug-delivery systems.
There are several reasons for the attractiveness of these
dosage forms. It is generally recognized that for many
disease states, a substantial number of therapeutically
eective compounds already exist. The eectiveness of
these drugs, however, is often limited by side eects or
the necessity to administer the compound in a clinical
setting. The goal in designing sustained- or controlled-
delivery systems is to reduce the frequency of dosing or
to increase eectiveness of the drug by localization at
the site of action, reducing the dose required, or pro-
viding uniform drug delivery.
If one were to imagine the ideal drug-delivery sys-
tem, two prerequisites would be required. First, it
would be a single dose for the duration of treatment,
whether it be for days or weeks, as with infection, or
for the lifetime of the patient, as in hypertension or
diabetes. Second, it should deliver the active entity
directly to the site of action, thereby minimizing or
eliminating side eects. This may necessitate delivery
to specic receptors, or to localization to cells or to
specic areas of the body.
It is obvious that this imaginary delivery system will
have changing requirements for dierent disease states
and dierent drugs. Thus, we wish to deliver the
therapeutic agent to a specic site, for a specic time.
In other words, the objective is to achieve both spatial
and temporal placement of drug. Currently, it is pos-
sible to only partially achieve both of these goals with
most drug-delivery systems.
In this chapter we present the theory involved in
developing sustained- and controlled-release delivery
systems and applications of these systems as ther-
apeutic devices. Although suspensions, emulsions, and
compressed tablets may demonstrate sustaining eects
within the body compared with solution forms of the
drug, they are not considered to be sustaining and are
not discussed in this chapter. These systems classically
release drug for a relatively short period, and their
release rates are strongly inuenced by environmental
conditions.
II. TERMINOLOGY
In the past, many of the terms used to refer to ther-
apeutic systems of controlled and sustained release
have been used in an inconsistent and confusing
manner. Although descriptive terms such as ``timed
release'' and ``prolonged release'' give excellent man-
ufacturer identication, they can be confusing to
health care practitioners. For the purposes of this
chapter, sustained release and controlled release will
represent separate delivery processes. Sustained release
constitutes any dosage form that provides medication
Copyright 2002 Marcel Dekker, Inc.
over an extended time. Controlled release, however,
denotes that the system is able to provide some actual
therapeutic control, whether this be of a temporal
nature, spatial nature, or both. In other words, the
system attempts to control drug concentrations in the
target issue. This correctly suggests that there are
sustained-release systems that cannot be considered
controlled-release systems.
In general, the goal of a sustained-release dosage
form is to maintain therapeutic blood or tissue levels of
the drug for an extended period. This is usually ac-
complished by attempting to obtain zero-order release
from the dosage form. Zero-order release constitutes
drug release from the dosage form that is independent
of the amount of drug in the delivery system (i.e., a
constant release rate). Sustained-release systems gen-
erally do not attain this type of release and usually try
to mimic zero-order release by providing drug in a slow
rst-order fashion (i.e., concentration-dependent).
Systems that are designated as prolonged release can
also be considered as attempts at achieving sustained-
release delivery. Repeat-action tablets are an alter-
native method of sustained release in which multiple
doses of a drug are contained within a dosage form,
and each dose is released at a periodic interval. De-
layed-release systems, in contrast, may not be sus-
taining, since often the function of these dosage forms
is to maintain the drug within the dosage form for
some time before release. Commonly, the release rate
of drug is not altered and does not result in sustained
delivery once drug release has begun. Enteric-coated
tablets are an example of this type of dosage form.
Controlled release, although resulting in a zero-or-
der delivery system, may also incorporate methods to
promote localization of the drug at an active site. In
some cases, a controlled-release system will not be
sustaining, but will be concerned strictly with locali-
zation of the drug. Site-specic systems and targeted-
delivery systems are the descriptive terms used to de-
note this type of delivery control.
The ideal of providing an exact amount of drug at
the site of action for a precise time period is usually
approximated by most systems. This approximation is
achieved by creating a constant concentration in the
body or an organ over an extended time; in other
words, the amount of drug entering the system is
equivalent to the amount removed from the system. All
forms of metabolism and excretion are included in the
removal process: urinary excretion, enterohepatic re-
cycling, sweat, fecal, and so on. Since for most drugs
these elimination processes are rst-order, it can be
said that at a certain blood level, the drug will have a
specic rate of elimination. The idea is to deliver drug
at this exact rate for an extended period. This is re-
presented mathematically as
Rate in = rate out = k
elim
C
d
V
d
where C
d
is the desired drug level, V
d
is the volume of
distribution, and k
elim
is the rate constant for drug
elimination from the body. Often such exacting
delivery rates prove to be dicult to achieve by
administration routes other than intravenous infu-
sion. Noninvasive routes (e.g., oral) are obviously
preferred.
Fig. 1 Drug level versus time prole showing dierences between zero-order controlled release, slow rst-order sustained
release, and release from a conventional tablet or capsule.
Figure 1 shows comparative blood level proles
obtained from administration of conventional, con-
trolled-, and sustained-release dosage forms. The
conventional tablet or capsule provides only a single
and transient burst of drug. A pharmacological eect is
seen as long as the amount of drug is within the ther-
apeutic range. Problems occur when the peak con-
centration is above or below this range, especially for
drugs with narrow therapeutic windows. The slow
rst-order release obtained by a sustained-release pre-
paration is generally achieved by slowing the release of
drug from a dosage form. In some cases this is ac-
complished by a continuous release process; however,
systems that release small bursts of drug over a
prolonged period can mimic the continuous-release
system.
Before treating the various classes of sustained- and
controlled-release drug-delivery systems in this chap-
ter, it is appropriate to note that drug delivery may be
incorporated in other chapters where the various
classes of drug products and routes of administration
are discussed. In addition, the reader is referred to
Chapter 14 on target-oriented drug-delivery systems.
III. ORAL SYSTEMS
Historically, the oral route of administration has been
used the most for both conventional and novel drug-
delivery systems. There are many obvious reasons for
this, not the least of which would include acceptance
by the patient and ease of administration. The types of
sustained- and controlled-release systems employed for
oral administration include virtually every currently
known theoretical mechanism for such application.
This is because there is more exibility in dosage de-
sign, since constraints, such as sterility and potential
damage at the site of administration, axe minimized.
Because of this, it is convenient to discuss the dierent
types of dosage forms by using those developed for
oral administration as initial examples.
With most orally administered drugs, targeting is
not a primary concern, and it is usually intended for
drugs to permeate to the general circulation and per-
fuse to other body tissues (the obvious exception being
medications intended for local gastrointestinal tissue
treatment). For this reason, most systems employed
are of the sustained-release variety. It is assumed that
increasing concentration at the absorption site will
increase the rate of absorption and, therefore, increase
circulating blood levels, which in turn, promotes
greater concentrations of drug at the site of action. If
toxicity is not an issue, therapeutic levels can thus be
extended. In essence, 'drug delivery by these systems
usually depends on release from some type of dosage
form, permeation through the biological milieu, and
absorption through an epithelial membrane to the
blood. There are a variety of both physicochemical and
biological factors that come into play in the design of
such systems.
A. Biological Factors Inuencing Oral Sustained-
Release Dosage Form Design
Biological Half-life
The usual goal of an oral sustained-release product is
to maintain therapeutic blood levels over an extended
period. To achieve this, drug must enter the circulation
at approximately the same rate at which it is elimi-
nated. The elimination rate is quantitatively described
by the half-life (t
1=2
). Each drug has its own char-
acteristic elimination rate, which is the sum of all
elimination processes, including metabolism, urinary
excretion, and all other processes that permanently
remove drug from the bloodstream.
Therapeutic compounds with short half-lives are
excellent candidates for sustained-release preparations,
since this can reduce dosing frequency. However, this
is limited, in that drugs with very short half-lives may
require excessively large amounts of drug in each do-
sage unit to maintain sustained eects, forcing the
dosage form itself to become limitingly large. In gen-
eral, drugs with hall-lives shorter than 2 hours, such as
furosemide or levodopa [1], are poor candidates for
sustained-release preparations. Compounds with long
half-lives, more than 8 hours are also generally not
used in sustaining forms, since their eect is already
sustained. Digoxin, warfarin, and phenytoin are some
examples [1]. Furthermore, the transit time of most
dosage forms in the gastrointestinal (GI) tract (i.e.,
mouth to ileocecal junction) is 8l2 hours making it
dicult to increase the absorptive phase of adminis-
tration beyond this time frame. Occasionally, absorp-
tion from the colon may allow continued drug delivery
for up to 24 hours.
Absorption
The characteristics of absorption of a drug can greatly
aect its suitability as a sustained-release product.
Since the purpose of forming a sustained-release pro-
duct is to place control on the delivery system, it is
necessary that the rate of release is much slower than
the rate of absorption. If we assume that the transit
time of most drugs and devices in the absorptive areas
of the GI tract is about 812 hours, the maximum half-
life for absorption should be approximately 34 hours;
otherwise, the device will pass out of the potential
absorptive regions before drug release is complete.
This corresponds to a minimum apparent absorption
rate constant of 0.170.23 h
71
to give 8095% over
this time period [3]. The absorption rate constant is an
apparent rate constant and should, in actuality, be the
release rate constant of' the drug from the dosage
form. Compounds that demonstrate true lower ab-
sorption rate constants will probably be poor candi-
dates for sustaining systems.
The foregoing calculations assume that absorption
of the therapeutic agent occurs at a relatively uniform
rate over the entire length of the small intestine. For
many compounds this is not true. If a drug is absorbed
by active transport or transport is limited to a specic
region of the intestine, sustained-release preparations
may be disadvantageous to absorption. Absorption of
ferrous sulfate, for example, is maximal in the upper
jejunum and duodenum, and sustained-release me-
chanisms that do not release drug before passing out of
this region are not benecial [5].
One method to provide sustaining mechanisms of
delivery for compounds such as these has been to try to
maintain them within the stomach. This allows slow
release of the drug, which then travels to the absorptive
site. These methods have been developed as a con-
sequence of the observation that coadministration of
food results in a sustaining eect [6]. Although admin-
istration of food can create highly variable eects, there
have been methods devised to circumvent this problem.
One such attempt is to formulate low-density pellets,
capsules [7] or tablets [8]. These oat on top of the
gastric juice, delaying their transfer out of the stomach
[9]. The increase in gastric retention results in higher
blood levels for p-aminobenzoic acid, a drug with a
limited GI absorption range [10], but drugs that have
widespread absorption in the intestinal system would
likely not benet froman increase in emptying time [11].
Another approach is that of bioadhesive materials.
The principle is to administer a device with adhesive
polymers having an anity for the gastric surface,
most probably the mucin coat [12]. Bioadhesives have
demonstrated utility in the mouth, eye, and vagina,
with a number of commercially available products. To
date, use of bioadhesives in oral drug delivery is a
theoretical possibility, but no promising leads have
been published.
An alternative to GI retention for drugs with poor
absorption characteristics is to use chemical penetra-
tion enhancers. Membrane modication through che-
mical enhancers has been very well demonstrated for a
variety of tissues in the body, including the gastro-
intestinal tract. Concern about this approach is the
potential toxicity that may arise when protective
membranes are altered. Although there are numerous
safety studies for oral products containing surfactants,
which are known penetration enhancers, there has not
been a denitive safety study in humans using an agent
that is specically present in the formulations as a
penetration enhancer.
Metabolism
Drugs that are signicantly metabolized before ab-
sorption, either in the lumen or the tissue of the
intestine, can show decreased bioavailability from
slower-releasing dosage forms. Most intestinal wall
enzyme systems are saturable. As the drug is released
at a slower rate to these regions, less total. drug is
presented to the enzymatic process during a specic
period, allowing more complete conversion of the drug
to its metabolite. For example, aloprenolol was more
extensively metabolized in the intestinal wall when gi-
ven as a sustained-release preparation [13]. High con-
centrations of dopa-decarboxylase in the intestinal wall
will result in a similar eect for levodopa [14]. If le-
vodopa is formulated in a dosage form with a drug
compound that can inhibit the dopa-decarboxylase
enzyme, the amount of levodopa available for ab-
sorption increases and can sustain its therapeutic ef-
fects. Formulation of these enzymatically susceptible
compounds as prodrugs is another viable solution.
B. Physicochemical Factors Inuencing Oral
Sustained-Release Dosage Form Design
Dose Size
For orally administered systems, there is an upper limit
to the bulk size of the dose to be administered. In
general, a single dose of 0.51.0 g is considered maxi-
mal for a conventional dosage form [15]. This also
holds for sustained-release dosage forms. Those com-
pounds that require a large dosing size can sometimes
be given in multiple amounts or formulated into liquid
systems. Another consideration is the margin of safety
involved in administration of large amounts of a drug
with a narrow therapeutic range.
Ionization, pK
a
, and Aqueous Solubility
Most drugs are weak acids or bases. Since the un-
changed form of a drug preferentially permeates across
lipid membranes, it is important to note the relation-
ship between the pK
a
of the compound and the ab-
sorptive environment. It would seem, intuitively, that
presenting the drug in an uncharged form is advanta-
geous for drug permeation. Unfortunately, the situa-
tion is made more complex by the fact that the drug's
aqueous solubility will generally be decreased by con-
version to an uncharged form. Delivery systems that
are dependent on diusion or dissolution will likewise
be dependent on the solubility of drug in the aqueous
media. Considering that these dosage forms must
function in an environment of changing pH, the sto-
mach being acidic and the small intestine more neutral,
the eect of pH on the release processes must be de-
ned. For many compounds, the site of maximum
absorption will also be the area in which the drug is the
least soluble. As an example, consider a drug for which
the highest solubility is in the stomach and is un-
charged in the intestine. For conventional dosage
forms, the drug can generally fully dissolve in the
stomach and then be absorbed in the alkaline pH of
the intestine. For dissolution- or diusion-sustaining
forms, much of the drug will arrive in the small in-
testine in solid form, meaning that the solubility of the
drug may change several orders of magnitude during
its release.
Compounds with very low solubility (<0.01 mg/mL)
are inherently sustained, since their release over the
time course of a dosage form in the GI tract will be
limited by dissolution of the drug. Examples of drugs
that are limited in absorption by theft dissolution rate
are digoxin [16], griseofulvin [17], and salicylamide [18].
The lower limit for the solubility of a drug to be for-
mulated in a sustained-release systemhas been reported
to be 0.1 mg/mL [19], so it is obvious that the solubility
of the compound will limit the choice of mechanism to
be employed in a sustained-delivery system. Diusional
systems will be poor choices for slightly soluble drugs,
since the driving force for diusion, which is the drug's
concentration in solution, will be low.
Partition Coecient
When a drug is administered to the GI tract, it must
cross a variety of biological membranes to produce a
therapeutic eect in another area of the body. It is
common to consider that these membranes are lipidic;
therefore, the partition coecient of oil-soluble drugs
becomes important in determining the eectiveness of
membrane barrier penetration. Partition coecient is
generally dened as the ratio of the fraction of drug in
an oil phase to that of an adjacent aqueous phase.
Accordingly, compounds with a relatively high parti-
tion coecient are predominantly lipid-soluble and,
consequently, have very low aqueous solubility. Fur-
thermore, these compounds can usually persist in the
body for long periods, because they can localize in the
lipid membranes of cells. Phenothiazines are re-
presentative of this type of compound [20]. Com-
pounds with very low partition coecients will have
diculty penetrating membranes, resulting in poor
bioavailabiity. Furthermore, partitioning eects apply
equally to diusion through polymer membranes. The
choice of diusion-limiting membranes must largely
depend on the partitioning characteristics of the drug.
Stability
Orally administered drugs can be subject to both acid-
base hydrolysis and enzymatic degradation. Degrada-
tion will proceed at a reduced rate for drugs in the solid
state; therefore, this is the preferred composition of
delivery for problem cases. For drugs that are unstable
in the stomach, systems that prolong delivery over the
entire course of transit in the GI tract are benecial;
this is also true for systems that delay release until the
dosage form reaches the small intestine. Compounds
that are unstable in the small intestine may demon-
strate decreased bioavailability when administered
from a sustaining dosage form. This is because more
drug is delivered in the small intestine and, hence, is
subject to degradation. Propantheline [21] and pro-
banthine [22] are representative examples of such
drugs.
C. Oral Sustained- and Controlled-Release
Products
Because of their relative ease of production and cost
compared with other methods of sustained or con-
trolled delivery, dissolution and diusion-controlled
systems have classically been of primary importance in
oral delivery of medication. Dissolution systems have
been some of the oldest and most successful oral sys-
tems in early attempts to market sustaining products.
D. Dissolution-Controlled Systems
It seems inherently obvious that a drug with a slow
dissolution rate will demonstrate sustaining properties,
since the release of drug will be limited by the rate of
dissolution. This being true, sustained-release pre-
parations of drugs could be made by decreasing their
rate of dissolution. The approaches to achieve this
include preparing appropriate salts or derivatives,
coating the drug with a slowly dissolving material, or
incorporating it into a tablet with a slowly dissolving
carrier. Representative products using dissolution-
controlled systems are listed in Tables 1 and 2.
Dissolution-controlled systems can be made to be
sustaining in several dierent ways. By alternating
layers of drug with rate-controlling coats, as shown in
Fig. 2, a pulsed delivery can be achieved, If the outer
layer is a quickly releasing bolus of drug, initial levels
of drug in the body can be quickly established with
pulsed intervals following. Although this is not a true
controlled-release system, the biological eects can be
similar. An alternative method is to administer the
drug as a group of beads that have coatings of dierent
thicknesses (Fig. 3). Since the beads have dierent
coating thicknesses, their release will occur in a pro-
gressive manner, Those with the thinnest layers will
provide the initial dose. The maintenance of drug levels
at later times will be achieved from those with thicker
coatings. This is the principle of the Spansule capsule
marketed by SmithKline Beecham.
This dissolution process can be considered to be
diusion-layer controlled. This is best explained by
considering the rate of diusion fromthe solid surface to
the bulk solution through an unstirred liquid lm as the
rate-determining step. This dissolution process at steady
state is described by the Noyes-Whitney equation:
Table 1 Encapsulated Dissolution Products
Product Active ingredient(s) Manufacturer
Ornade Spansules Phenylpropanolamine SmithKline Beecham
hydrochloride,
chlorpheniramine maleate
Thorazine Spansules Chlorpromazine hydrochloride SmithKline Beecham
Contac 12-hour capsules Phenylpropanolamine SmithKline
hydrochloride, Consumer Products
chlorpheniramine maleate,
atropine sulfate,
scopolamine hydrobromide,
hyoscyamine sulfate
Artane Sequels Trihexyphenidyl hydrochloride Lederle
Diamox Sequels Acetazolamide Lederle
Nicobid Temples Nicotinic acid Rorer
Pentritol Temples Pentaerythritol tetranitrate Rorer
Chlor-Trimeton Repetabs Chlorpheniramine maleate Schering
Demazin Repetabs Chlorpheniramine maleate, Schering
phenylephrine hydrochloride
Polaramine Repetabs Dexchlorpheniramine maleate Schering
Table 2 Matrix Dissolution Products
Product (tablets) Active ingredient(s) Manufacturer
Dimetane Extentabs Brompheniramine maleate Robins
Dimetapp Extentabs Brompheniramine maleate, Robins
phenylephrine hydrochloride,
phenylpropanolamine
hydrochloride
Donnatal Extentabs Phenobarbital, hyoscyamine sulfate, Robins
atropine sulfate, scopolamine
hydrobromide
Quinidex Extentabs Quinidine sulfate Robins
Mestinon Timespans Pyridostigmine bromide ICN
Tenuate Dospan Diethylpropion hydrochloride Merrel
Disophrol Chronotabs Dexbrompheniramine maleate, Schering
pseudoepherine sulfate
dC
dt
= k
D
A(C
s
C) =
D
h
A(C
s
C) (1)
where
dC/dt =dissolution rate
k
D
=dissolution rate constant
D=diusion coecient
C
s
=saturation solubility of the solid
C=concentration of solute in the bulk solution
It can be seen that the dissolution rate constant k
D
is
equivalent to the diusion coecient divided by the
thickness of the diusion layer (D/h).
Equation (1) predicts that the rate of release can be
constant only if the following parameters are constant:
(a) surface area, (b) diusion coecient, (c) diusion
layer thickness, and (d) concentration dierence. These
parameters, however, are not easily maintained con-
stant, especially surface area. For spherical particles,
the change in surface area can be related to the weight
of the particle; that is, under the assumption of sink
conditions, Eq. (1) can be rewritten as the cube-root
dissolution equation:
W
1=3
0
W
1=3
= k
D
t (2)
where k
D
is the cube-root dissolution rate constant and
W
0
and W are the initial weight and the weight of the
amount remaining at time t, respectively.
E. Diusional Systems
Diusion systems are characterized by the release rate
of a drug being dependent on its diusion through an
inert membrane barrier. Usually this barrier is an in-
soluble polymer. In general, two types or subclasses of
diusional systems are recognized: reservoir devices
and matrix devices. These will be considered sepa-
rately.
Reservoir Devices
Reservoir devices, as the name implies, are character-
ized by a core of drug, the reservoir, surrounded by a
polymeric membrane. The nature of the membrane
determines the rate of release of drug from the system.
A schematic description of this process is given in
Fig. 4, and characteristics of the system are listed in
Table 3.
The process of diusion is generally described by a
series of equations that were rst detailed by Fick [23].
The rst of these states that the amount of drug pas-
sing across a unit area is proportional to the con-
centration dierence across that plane. The equation is
given as
J = D
dC
dX
(3)
where the ux J, given in units of amount/area 7time,
D, is the diusion coecient of the drug in the mem-
brane in units of area/time. This is a reection of the
drug molecule's ability to diuse through the solvent
Fig. 3 Schematic representation of a matrix release system.
C
s
is the saturation concentration of drug controlling the
concentration gradient over the distance, h, of the remaining
ghost matrix.
Fig. 2 Two types of dissolution-controlled, pulsed delivery
systems: (A) single bead-type device with alternating drug
and rate-controlling layers; (B) beads containing drug with
diering thickness of dissolving coats.
and is dependent on such factors as molecular size and
charge.
This coecient may be dependent on concentration
[24]; hence, its designation as a coecient and not a
constant, although for the purpose of designing a
pharmaceutical system it is usually considered a con-
stant [25]. dC/dX represents the rate of change in
concentration C relative to a distance X in the mem-
brane.
It is useful to make the assumption that a drug on
either side of the membrane is in equilibrium with its
respective membrane surface. There is, then, an equi-
librium between the membrane surfaces and their
bathing solutions, as shown in Fig. 4. This being so,
the concentration just inside the membrane surface can
be related to the concentration in the adjacent region
by the following expressions:
K =
C
m(0)
C
(d)
at x = 0 (4)
K =
C
m(d)
C
(d)
at x = d (5)
where K is the partition coecient. This coecient
denotes the ratio of drug concentration in the mem-
brane to that in the bathing medium at equilibrium. In
general, a hydrophilic molecule will partition favorably
to the medium, whereas a hydrophobic compound will
preferentially partition to the polymer. C
m
is the con-
centration of drug on the inside surface of the mem-
brane, C
m(d)
the concentration on the outside surface,
and d the thickness of the diusion layer, the diu-
sional path length.
Assuming that D and K are constant, Eq. (3) can be
integrated and simplied to give
J =
DK DC
d
(6)
where DC is the concentration dierence across the
membrane. The other variables are as dened pre-
viously. Drug release will vary, depending on the
geometry of the system. The simplest system to con-
sider is that of a slab, where drug release is from only
one surface, as shown in Fig. 5. In this case, Eq. (6) can
be written as
dM
t
dt
=
ADK DC
d
(7)
where M
t
is the mass of drug released after time t,
dM
t
=dt the steady-state release rate at time t, and A the
surface area of the device. Equations of a similar form
can be written for other geometries, such as spheres or
cylinders [26].
Since the left side of Eq. (7) represents the release rat
of the system, a true controlled-release system with a
zero-order release rate can be possible only if all of the
variables on the right side of Eq. (7) remain constant.
A constant eective area of diusion, diusional path
length, concentration dierence, and diusion coe-
cient are required to obtain a release rate that is con-
stant. These systems often fail to deliver at a constant
rate, since it is especially dicult to maintain all these
Fig. 4 Schematic representation of a reservoir diusional
device. C
m(0)
and C
m(d)
represent concentrations of drug at
inside surfaces of the membrane, and C
(0)
and C
(d)
represent
concentrations in the adjacent regions. (From Ref. 29.)
Table 3 Characteristics of Reservoir Diffusional Systems
Description Drug core surrounded by polymer
membrane that controls release rate
Advantages Zero-order delivery is possible
Release rate variable with polymer type
Disadvantages System must be physically removed
from implant sites
Difficult to deliver high molecular
weight compounds
Generally increased cost per dosage unit
Potential toxicity if system fails
Fig. 5 Diagrammatic representation of the slab congura-
tion of a reservoir diusional system.
parameters constant. The use of a solid drug core re-
servoir results in a constant eective concentration,
that of the solubility of the drug. Often, however, the
polymer may be aected by the bathing medium.
Swelling or contraction of the polymer membrane
causes a change in the diusional path length of the
diusion coecient of the drug through the barrier.
For example, if the polymer swells, the diusion path
length will increase. The ability of the drug to diuse
through the membrane, however, will increase. This is
because the diusion coecient of the drug in the
bathing medium, which has perfused the polymer
during swelling, will be greater than in the unswelled
polymer.
Although the partition coecient is expected to re-
main constant, its magnitude is important. Since this
coecient represents the concentration of drug in the
membrane relative to that in the core, an excessively
high partition coecient will allow quick depletion of
the core and an ineective delivery system. For eec-
tive diusional systems, the partition coecient should
be less than unity. If the value of this coecient is
greater than 1, the surrounding polymer does not re-
present a barrier, and drug release becomes rst-order.
Although diusional systems can provide constant
release at steady state, they will demonstrate Initial
release rates, which may be faster or slower. This de-
pends on the device [27]. For reservoir devices, a sys-
tem that is used relatively soon after construction will
demonstrate a large time in release, since it will take
time for the drug to diuse from the reservoir to the
membrane surface. On the other hand, systems that
are stored will demonstrate a burst eect, since, on
standing, the membrane becomes saturated with
available drug. The magnitude of these eects is de-
pendent on the diusing distance (i.e., the membrane
thickness). Figure 6 gives examples of this phenom-
enon. This plot shows the approach to steady-state
release for a typical reservoir device that has been
stored (burst eect) and for a device that has been
freshly made (time lag).
Reservoir diusional systems have several ad-
vantages over conventional dosage forms. They can
oer zero-order release of drug, the kinetics of which
can be controlled by changing the characteristics of the
polymer to meet the particular drug and therapy con-
ditions. The inherent disadvantages are that, unless the
polymer used is soluble, the system must somehow be
removed from the body after the drug has been re-
leased. This is an important dosage form consideration
with implantable systems. A silicone elastomer re-
servoir has been used to orally deliver iodine through
the water supply to large populations suering from
deciency [28]. For a system such as this, the none-
rodible device poses no signicant problem; however,
the appearance of the drug-depleted matrix in the stool
can often alarm a naive patient.
Another important point to consider is that, in
general, the amount of drug contained in the reservoir
is far greater than the usual dose needed, since the
dosage form is designed to sustain delivery over many
dosing intervals. Any error in production or any ac-
cidental damage to the dosage form that would directly
expose the reservoir core could expose the patient to a
potentially toxic dose of drug. This becomes important
when designing these dosage forms for drugs with
narrow therapeutic ranges or high toxicity. Table 4
gives a representative listing of available products
employing reservoir diusion systems.
Matrix Devices
A matrix device, as the name implies, consists of drug
dispersed homogeneously throughout a polymer ma-
trix as represented in Fig. 7. In the model, drug in the
outside layer exposed to the bathing solution is dis-
solved rst and then diuses out of the matrix. This
process continues with the interface between the
bathing solution and the solid drug moving toward the
interior. Obviously, for this system to be diusion-
controlled, the rate of dissolution of drug particles
within the matrix must be much faster that the diu-
sion rate of dissolved drug leaving the matrix. Deri-
vation of the mathematical model to describe this
system involves the following assumptions [29,30]: (a) a
pseudo-steady state is maintained during drug release,
(b) the diameter of the drug particles is less than the
Fig. 6 Plot showing the approach to steady state for a re-
servoir device that has been stored for an extended period
(the burst eect curve) and for a device that has been freshly
made (the lag time curve). (From Ref. 29.)
average distance of drug diusion through the matrix,
(c) the bathing solution provides sink conditions at all
times, (d) the diusion coecient of drug in the matrix
remains constant (i.e., no change occurs in the char-
acteristics of the polymer matrix).
The next equations, which describe the rate of re-
lease of drugs dispersed in an inert matrix system, have
been derived by Higuchi [29]. The following equation
can be written based on Fig. 3:
dM
dh
= C
0
dh
C
s
2
(8)
where
dM=change in the amount of drug released per
unit area
dh =change in the thickness of the zone of matrix
that has been depleted of drug
C
0
=total amount of drug in a unit volume of the
matrix
C
s
=saturated concentration of the drug within the
matrix
From diusion theory,
dM=
D
m
C
s
h
dt (9)
where D
m
is the diusion coecient in the matrix.
Equating Eqs. (8) and (9), integrating, and solving for
h gives:
M= [C
s
D
m
(2C
0
C
s
)t[
1=2
(10)
When the amount of drug is in excess of the saturation
concentration, that is, C
0
C
s
,
M= (2C
s
D
m
C
0
t)
1=2
(11)
which indicates that the amount of drug released is a
function of the square root of time. In a similar man-
ner, the drug release from a porous or granular matrix
can be described by
M= D
s
C
a
p
T
(2C
0
pC
a
)t
h i
1=2
(12)
where
p =porosity of the matrix
T=tortuosity
C
a
=solubility of the drug in the release medium
D
s
=diusion coecient in the release medium
This system is slightly dierent from the previous
matrix system in that the drug is able to pass out of the
matrix through uid-lled channels and does not pass
through the polymer directly.
For purposes of data treatment, Eq. (11) or (12) can
be reduce to
M= kt
1=2
(13)
where k is a constant, so that a plot of amount of drug
released versus the square root of time will be linear, if
Table 4 Reservoir Diffusional Products
Duotrate Pentaerythritol tetranitrate Jones
Nico-400 Nicotinic acid Jones
Nitro-Bid Nitroglycerin Marion
Cerespan Papaverine hydrochloride Rho ne-Poulenc Rorer
Nitrospan Nitroglycerin Rorer
Measurin Acetylsalicylic acid Sterling Winthrop
Fig. 7 Matrix diusional system before drug release (time
= 0) and after partial drug release (time = t).
the release of drug from the matrix is diusion-con-
trolled. If this is the case, then, by the Higuchi model,
one may control the release of drug from a homo-
geneous matrix system by varying the following para-
meters [3135]: (a) initial concentration of drug in the
matrix, (b) porosity, (c) tortuosity, (d) polymer system
forming the matrix, and (e) solubility of the drug.
Matrix systems oer several advantages. They are,
in general, easy to make and can be made to release
high molecular weight compounds. Since the drug is
dispersed in the matrix system, accidental leakage of
the total drug component is less likely to occur, al-
though, occasionally, cracking of the matrix material
can cause unwanted release. The primary dis-
advantages of this system are that the remaining ma-
trix ``ghost'' must be removed after the drug has been
released. Also, the release rates generated are not zero-
order, since the rate varies with the square root of time.
A substantial sustained eect, however, can be pro-
duced through the use of very slow release rates, which
in many applications are indistinguishable from zero-
order. The characteristics of the system are summar-
ized in Table 5, and a representative listing of available
products is given in Table 6.
F. Bioerodible and Combination Diusion
and Dissolution Systems
Strictly speaking, therapeutic systems will never be
dependent on dissolution only or diusion only.
However, in the foregoing systems, the predominant
mechanism allows easy mathematical description. In
practice, the dominant mechanism for release will
overshadow other processes enough to allow classi-
cation as either dissolution ratelimited or diusion-
controlled. Bioerodible devices, however, constitute a
group of systems for which mathematical descriptions
of release characteristics can be quite complex. Char-
acteristics of this type of system are listed in Table 7.
A typical system is shown in Fig. 8. The mechanism of
release from simple erodible slabs, cylinders, and
spheres has been described [36]. A simple expression
describing release from all three of these erodible de-
vices is
M
t
M
= 1 1
k
0
t
C
0
a

n
(14)
where n = 3 for a sphere, n = 2 for a cylinder, and
n = 1 for a slab. The radius of a sphere, or cylinder, or
the half-height of a slab is represented by a. M
t
is the
mass of a drug release at time t, and M is the mass
released at innite time. As a further complication,
these systems can combine diusion and dissolution of
both the matrix material and the drug. Not only can
drug diuse out of the dosage form, as with some
previously described matrix systems, but the matrix
itself undergoes a dissolution process. The complexity
of the system arises from the fact that, as the polymer
dissolves, the diusional path length for the drug may
change. This usually results in a moving-boundary
diusion system. Zero-order release can occur only
if surface erosion occurs and surface area does not
change with time. The inherent advantage of such a
system is that the bioerodible property of the matrix
does not result in a ghost matrix. The disadvantages of
these matrix systems are that release kinetics are often
hard to control, since many factors aecting both the
drug and the polymer must be considered.
Another method for the preparation of bioerodible
systems is to attach the drug directly to the polymer by
Table 5 Characteristics of Matrix Diffusion Systems
Description Homogeneous dispersion of solid drug
in a polymer mix
Advantages Easier to produce than reservoir devices
Can deliver high molecular weight
compounds
Disadvantages Cannot obtain zero-order release
Removal of remaining matrix is necessary
for implanted systems
Table 6 Matrix Diffusional Products
Product (tablets) Active ingredient(s) Manufacturer
Desoxyn-Gradumet Methamphetamine hydrochloride Abbott
Fero-Gradumet Ferrous sulfate Abbott
Tral Filmtab Hexocyclium methylsulfate Abbott
PBZ-SR Tripelennamine Geigy
Procan SR Procainamide hydrochloride Parke-Davis
Choledyl SA Oxtriphylline Parke-Davis
a chemical bond [37]. Generally, the drug is released
from the polymer by hydrolysis or enzymatic reaction.
This makes control of the rate of release somewhat
easier. Another advantage of the system is the ability
to achieve very high drug loading, since the amount of
drug placed in the system is limited only by the avail-
able sites on the carrier.
A third type, which in this case utilizes a combina-
tion of diusion and dissolution, is that of a swelling-
controlled matrix [38]. Here the drug is dissolved in the
polymer, but instead of an insoluble or eroding poly-
mer, as in previous systems, swelling of the polymer
occurs. This allows entrance of water, which causes
dissolution of the drug and diusion out of the swollen
matrix. In these systems the release rate is highly de-
pendent on the polymer-swelling rate, drug solubility,
and the amount of soluble fraction in the matrix [39].
This system usually minimizes burst eects, since
polymer swelling must occur before drug release.
G. Osmotically Controlled Systems
In these systems, osmotic pressure provides the driving
force to generate controlled release of drug. Consider a
semipermeable membrane that is permeable to water,
but not to drug. A tablet containing a core of drug
surrounded by such a membrane is shown in Fig. 9.
When this device is exposed to water or any body uid,
water will ow into the tablet owing to the osmotic
pressure dierence. The rate of ow, dV=dt, of water
into the device can be represented as
dV
dt
=
Ak
h(DPDP)
(15)
where
k =membrane permeability
A=area of the membrane
Table 7 Characteristics of Bioerodible Matrix Systems
Description A homogeneous dispersion of drug
in an erodible matrix
Advantages All the advantages of matrix
dissolution system
Removal from implant sites not necessary
Disadvantages Difficult to control kinetics owing to
multiple processes of release
Potential toxicity of degraded polymer
must be considered
Fig. 8 Representation of a bioerodible matrix system. Drug
is dispersed in the matrix before release at time = 0. At time
= t, partial release by drug diusion or matrix erosion has
occurred.
Fig. 9 Diagrammatic representation of two types of osmo-
tically controlled systems. Type A contains an osmotic core
with drug. Type B contains the drug solution in a exible
bag, with the osmotic core surrounding.
h =membrane thickness
DP=osmotic pressure dierence
DP=hydrostatic pressure dierence
These systems generally appear in two dierent
forms, as depicted in Fig. 9. The rst contains the drug
as a solid core together with electrolyte, which is dis-
solved by the incoming water. The electrolyte provides
the high osmotic pressure dierence. The second sys-
tem contains the drug in solution in an impermeable
membrane within the device. The electrolyte surrounds
the bag. Both systems have single or multiple holes
bored through the membrane to allow drug release. In
the rst example, high osmotic pressure can be relieved
only by pumping solution, containing drug, out of the
hole. Similarly, in the second example, the high os-
motic pressure causes compression of the inner mem-
brane, and drug is pumped out through the hole.
In the system with the bag, or if the hole is large
enough in either system, the hydrostatic dierence
becomes negligible, and Eq. (15) becomes
dV
dt
=
Ak
h(DP)
(16)
indicating that the ow rate of water into the tablet is
governed by permeability, area, and thickness of the
membrane. The rate of drug leaving the orice, dM=dt,
is equivalent to the ow rate of incoming water mul-
tiplied by the solution concentration of drug, C
s
,
within the device:
dM
dt
=
dV
dt
C
s
(17)
Osmotic systems have application in pharmacological
studies, implantation therapies, and oral drug delivery.
In systems with solid drug dispersed with electro-
lyte, the size or number of bored hole(s) are the rate-
limiting factors for release of drug. Quality control of
the manufacture of these systems must be exceptional,
since any variation in boring of the hole, accomplished
with a laser drill, can have a substantial eect on re-
lease characteristics. Most of the orally administered
osmotic systems are of this variety. A variation on this
theme is an osmotic system of similar design without a
hole. The building osmotic pressure causes the tablet to
burst, causing all the drug to be rapidly released [40].
This design is useful for drugs that are dicult to
formulate in tablet or capsule form.
These osmotic systems are advantageous in that
they can deliver large volumes, and some are rellable.
Most important, the release of drug is in theory in-
dependent of the drug's properties [41,42]. This allows
one dosage form design to be used for almost any drug.
Disadvantages are that the systems are relatively ex-
pensive and, for certain applications, require im-
plantation. For drugs that are unstable in solution,
these systems may be inappropriate because the drug
remains in solution form for extended periods before
release. System characteristics are summarized in
Table 8.
H. Ion-Exchange Systems
Ion-exchange systems generally use resins composed of
water-insoluble cross-linked polymers. These polymers
contain salt-forming functional groups in repeating
positions on the polymer chain. The drug is bound to
the resin and released by exchanging with appro-
priately charged ions in contact with the ion-exchange
groups.
Resin
drug
resin
drug
conversely,
Resin
drug
resin
drug
where X
7
and Y
are ions in the GI tract. The free

drug then diuses out of the resin. The drugresin
complex is prepared either by repeated exposure of the
resin to the drug in a chromatography column or by
prolonged contact in solution.
The rate of drug diusing out of the resin is con-
trolled by the area of diusion, diusional path length,
and rigidity of the resin, which is a function of the
amount of cross-linking agent used to prepare the
resin.
This system is advantageous for drugs that are
highly susceptible to degradation by enzymatic pro-
cesses, since it oers a protective mechanism by tem-
porarily altering the substrate. This approach to
Table 8 Characteristics of Osmotically Controlled Devices
Description Drug surrounded by semipermeable
membrane and release governed by
osmotic pressure
Advantages Zero-order release obtainable
Reformulation not required for
different drugs
Release of drug independent of the
environment of the system
Disadvantages Systems can be much more expensive
than conventional counterparts
Quality control more extensive than
most conventional tablets
sustained release, however, has the limitation that the
release rate is proportional to the concentration of the
ions present in the area of administration. Although
the ionic concentration of the GI tract remains rather
constant with limits [15], the release rate of drug can be
aected by variability in diet, water intake, and in-
dividual intestinal content. A representative listing of
ion-exchange products is given in Table 9.
An improvement in this system is to coat the ion-
exchange resin with a hydrophobic rate-limiting poly-
mer, such as ethylcellulose or wax [43]. These systems
rely on the polymer coat to govern the rate of drug
availability.
IV. TARGETED DELIVERY SYSTEMS
Targeted systems represent the next level in state-of-
the-art controlled drug-delivery systems. These systems
address the problem of spatial placement of ther-
apeutic compounds. Since the site of drug action is the
target of these systems, oral administration is generally
not used as a method of delivery. Targeted drug-de-
livery systems have received much attention for cancer
chemotherapy. A very extensive review on this subject
and on novel drugs describes the enormous potential
for the discovery of innovative cancer treatments with
improved ecacy and selectivity for the third millen-
nium [44]. The review focuses on new technologies and
on mechanism-based agents and systems directed to
molecular pathways and targets that are casually in-
volved in cancer formation and progression.
A. Liposomes
Liposomes have been, and continue to be, of con-
siderable interest in drug-delivery systems. A schematic
diagram of their production is shown in Fig. 10.
Liposomes are normally composed of phospholipids
that spontaneously form multilamellar, concentric,
bilayer vesicles, with layers of aqueous media separ-
ating the lipid layers. These systems, commonly re-
ferred to as multilamellar vesicles (MLVs), have
diameters in the range of 15 mm. Sonication of MLVs
results in the production of small unilamellar vesicles
(SUVs), with diameters in the range 0.020.08 mm.
These vesicles are a single, lipid outer layer, with an
aqueous inner core. Large unilamellar vesicles (LUVs)
can also be made by evaporation under reduced pres-
sure, resulting in liposomes with a diameter of 0.1l
mm. Further extrusion of LUVs through a membrane
lter will also result in SUVs.
To use liposomes as delivery systems, drug is added
during the formation process. Hydrophilic compounds
usually reside in the aqueous portion of the vesicle,
whereas hydrophobic species tend to remain in the
lipid proteins. The physical characteristics and stability
of lipsomal preparations depend on pH, ionic strength,
the presence of divalent cations, and the nature of the
phospholipids and additives used [4547].
In general, these vesicle systems demonstrate low
permeability to ionic and polar substances, but this
varies greatly with liposome composition. Those made
with positively charged phospholipids are impermeable
to cations, whereas negatively charged liposomes are
permeable to cations, and both types are readily per-
meated by anions [48]. The degree of saturation or the
length of the phospholipid fatty acid chain will also
greatly aect the solute permeability of the liposomes
[49]. An increase in temperature can also alter perme-
ability [50] by causing the lipids to undergo a phase
transition to a less-ordered, more uid conguration.
Again, the transition is characteristic for diering types
of lipids. This has been employed in a unique targeting
approach by creating an environment of local hy-
pothermia; the liposomes are encouraged to release
their encapsulated cargo in that specied area, for
example, a capillary bed [51,52].
Some proteins, such as those found in serum, are
able to deform, penetrate the bilayer, or remove lipid
components, resulting in changes in liposome perme-
ability [53]. Many additives, such as cholesterol, are
able to inhibit this eect, stabilizing the membrane
structure of the vesicle and limiting cargo leakage [54].
This is achieved by allowing closer lipid packing [55].
The fact that impurities, such as cholesterol or free
Table 9 Ion-Exchange Products
Biphetamine capsules Amphetamine, dextroamphetamine Fisons
Tussionex suspension Hydrocodone, chlorpheniramine Fisons
Ionamin capsules Phenteramine Pennwalt
Delsym solution Dextromethorphan hydrobromide McNeil
fatty acids [56], can dramatically change the perme-
ability and surface charge of liposomes points to the
necessity for strict controls on the quality and purity of
lipids used in liposomal preparation.
Liposomes that remain impermeable to their con-
tents cannot release these compounds without inter-
action with cells. This cellular interaction occurs by
three dierent mechanisms (Fig. 11) [57]. Of these,
fusion and adsorption usually involve drug leakage,
whereas eective drug delivery results from en-
docytosis.
1. Fusion of the liposome with the cell membrane.
For this, the lipid portion of the vesicle becomes
part of the cell wall.
2. Adsorption to the cell wall. For this, transfer of
liposome content must be by diusion through
the lipids of the liposome and the cell mem-
brane.
3. Endocytosis of the vesicle by the cell. The entire
liposomal contents are made available to the
cell.
The advantageous eects of liposomal carrier sys-
tems include protection of compounds from metabo-
lism or degradation, as well as enhanced cellular
uptake. Liposome-mediated delivery of cytotoxic
drugs to cells in culture has resulted in improved po-
tency [58,59]. Prolonged release of encapsulated cargo
has also been demonstrated [60,61]. More recently, li-
posomes with extended circulation half-lives and dose-
independent pharmacokinetics (Stealth liposomes) [62]
have shown promise in delivery of drugs that are
normally very rapidly degraded.
Fig. 10 Schematic representation of a procedure for the production of liposomes.
Liposomes, however, also have inherent dis-
advantages in the areas of stability and uniformity of
production. Once a system has demonstrated merit for
treatment of a particular disease state, the following
must be determined before a formulation is acceptable
for marketing and human use: (a) lipid purity and
stability; (b) drug stability and leakage from the ve-
sicles; (c) lipid-drug cargo interaction; and (d) control
of vesicle size and drug-loading eciency for large-
batch production.
The potential of liposomes in oral drug delivery has
been largely disappointing. However, the use of poly-
mer-coated, polymerized, and microencapsulated li-
posomes have all increased their potential for oral use
[63], and it predicted that a greater understanding of
their cellular processing will ultimately lead to eective
therapies for oral liposomes.
Progress in employing liposomes and nanoparticles
for the targeted delivery of antibiotics over the past 20
years was recently summarized. These systems may
provide stealthy strategies to avoid drug uptake by
mononuclear phagocytes following IV injection, al-
lowing extended systemic presence of the drug and
increased drug concentrations at infected sites while
reducing drug toxicity [64].
Advances in liposome technology that have resulted
in the development of ligand-targeted liposomes cap-
able of selectively increasing the ecacy of carried
agents against receptor-bearing tumor cells have been
extensively reviewed [65]. Receptors for vitamins and
growth factors are attractive targets for ligand-directed
liposomal therapies due to their high expression levels
on various forms of cancer.
External stimuli have also been used to further
target liposomes. In one such study magnetite particles
were incorporated in radiolabeled liposomes and a
magnet positioned over the right kidney of a test ani-
mal. The liposomes were selectively targeted to that
kidney in concentrations that were viewed as sig-
nicantly high for relevant clinical applications [66].
Mention should also be made in this section of
niosomes, which are nonionic surfactant vesicles that
have shown promise as inexpensive and chemically
stable alternatives to liposomes [67].
A challenge in designing liposome systems is the
assessment of drug release from such systems in vitro.
Use of agarose gel matrices has been reported as one
approach to evaluate the release kinetics of liposome-
encapsulated materials in the presence of biological
components [68].
B. Prodrugs
A prodrug is a compound resulting from chemical
modication of a biologically active compound that
will liberate the active form in vivo by enzymatic or
hydrolytic cleavage. The primary purpose in forming a
prodrug is to modify the physicochemical properties of
the drug, usually to alter the membrane permeability of
the parent compound. This change in physicochemical
properties of the drug inuences the ultimate locali-
zation of the drug. There are various reasons for for-
mulating a prodrug system. If the parent compound is
insoluble, this can be modied [69]. If it is easily de-
graded, modication can protect the parent compound
from enzymatic of hydrolytic attack. Modications
can also reduce side eects, such as GI irritation [70].
Several drugs are now marketed in the form of a
prodrug; for example, sulindac, a nonsteroidal anti-
inammatory agent, and numerous angiotension-con-
verting enzyme (ACE) inhibitors. The necessary
conversion of prodrug to parent can occur by a variety
of reactions, the most common being hydrolytic clea-
vage [71]. The prodrug ester forms of a hydroxyl or
carboxyl group of the parent compound can be readily
cleaved by blood esterase. Other activation processes
may include biochemical reduction or oxidation.
Fig. 11 Schematic representation of liposome interactions
at a membrane surface.
However the conversion occurs, to achieve sustained
drug action the rate of conversion from prodrug to
active compound should not be too high [72]. Site-
specic, controlled delivery is achieved by the antiviral
prodrug acyclovir, which is converted to active form by
a virus-specic enzyme [73]. Sustained release of ster-
oid prodrugs, especially progestagens and progestagen-
estrogen combinations, have seen a substantial amount
of clinical experience, both as a means of birth control
and as symptomatic menopausal treatment [74].
The concept of the double prodrug (proprodrugs)
may allow more controlled delivery of various prodrug
compounds [75]. For example, if a prodrug shows site-
specic activation but has poor transport properties or
stability problems, it could be converted to a propro-
drug that transported better or is more stable (Fig. 12).
Prodrug systems have been taken even further by in-
cluding as prodrugs polymer prodrugs, in which a drug
is covalently linked to a polymer backbone. This type
of system could encompass a staggering number of
possibilities. Encouraging results have been shown
with mitomycin [76,77], for example. A model, the
Ringsdorf model, has been developed to depict the
ideal drug-delivery system for polymeric prodrugs,
which has all the desired physicochemical properties to
deliver the drug at the desired tissue or intracellular
region [78].
The most serious disadvantage of the prodrug ap-
proach to controlled sustained delivery is that ex-
tensive development must be undertaken to nd the
correct chemical modication for a specic drug. Ad-
ditionally, once a prodrug is formed, it is a new drug
entity and, therefore, requires extensive and costly
studies to determine safety and ecacy.
C. Nanoparticles
Nanoparticles are solid colloidal particles ranging in
size from 10 to 1000 nm. They can be used as drug
carriers, with the drug encapsulated, dissolved, ad-
sorbed, or covalently attached [79,80]. The small size of
the nanoparticles permits administration by in-
travenous injection and also permits their passage
through capillaries that remove larger particles. They
are usually taken up by the liver, spleen, and lungs
[81,82].
Preparation of nanoparticles can be by a variety of
dierent ways. The most important and frequently
used is emulsion polymerization; others include inter-
facial polymerization, solvent evaporation, and deso-
lvation of natural proteins. The materials used to
prepare nanoparticles are also numerous, but most
commonly they are polymers such as poly-
alklcyanoacrylate, polymethylmethacrylate, poly-
butylcyanoacrylate, or are albumin or gelatin.
Distribution patterns of the particles in the body can
vary depending on their size, composition, and surface
charge [8385]. In particular, nanoparticles of poly-
cyanoacrylate have been found to accumulate in cer-
tain tumors [86,87].
There are several possible ways that the drug cargo
can be incorporated into nanoparticles. They may be
bound by polymerization of the nanoparticles in the
presence of drug solution or by absorption of the drug
onto prepolymerized nanoparticles. The drug will be
dispersed in the particle's polymer matrix [88] or ad-
sorbed to the surface, depending on its anity to the
polymer. Drugs used for nanoparticle delivery have
been, for the most part, cytotoxic agents such as dac-
tinomycin (actinomycin D) [89], 5-uorouracil [90,91],
doxorubicin [92,93], and methotrexate [94], but have
also included delivery of bioactive peptides and pro-
teins, for example, growth hormonereleasing factor
[95,96].
Nanoparticles show great promise as devices for the
controlled release of drugs, provided that the choice of
material for nanoparticle formation is made with the
appropriate considerations of the drug cargo, admin-
istration route, and the desired site of action. The use
of nano- and microparticles as controlled drug-delivery
devices has recently been extensively reviewed [97].
Fig. 12 Illustration of prodrug and proprodrug concept.
In addition, biodegradable nanoparticles for sustained
release formulations to improve site-specic drug de-
livery has also been reviewed [98].
D. Resealed Erythrocytes
When red blood cells are placed in hypotonic media,
they swell, which causes rupturing of the membrane
and formation of pores. These pores allow free ex-
change of intra- and extra-cellular components. Re-
adjustment of the solution tonicity to isotonic allows
resealing of the membrane. This technique usually al-
lows encapsulation of up to 25% of the drug or enzyme
in solution [99]. In addition to this method, called the
preswell dilution technique, there are other ways to
form drug-loaded erythrocytes. In the dialysis techni-
que, the red blood cells are placed in dialysis tubes that
are immersed in a hypotonic medium. This results in
retention of cytoplasmic components when the cells are
resealed. Another method involves subjecting the cells
to an intense electric eld, causing pores to form,
which again can be resealed after drug uptake.
The potential advantages of loaded red blood cells
as delivery systems are as follows [100]:
1. They are biodegradable and nonimmunogenic.
2. They can be modied to change their resident
circulation time, depending on their surface
(cells with little membrane damage can circulate
for prolonged periods).
3. Entrapped drug is shielded from immunological
detection and external enzymatic degradation.
4. The system is relatively independent of the
physicochemical properties of the drug (i.e., it
does not require chemical modications).
In general, normally aging erythrocytes and slightly
damaged cells are sequestered in the spleen, whereas
those heavily damaged or modied are removed from
circulation by the liver [101]. This along with a short
storage life of about 2 weeks [102], constitutes the
major drawback of using resealed erythrocytes as drug
carriers.
Before treating the various classes of sustained- and
controlled-release drug-delivery systems in this chap-
ter, it is appropriate to note that drug delivery may be
incorporated in other chapters where the various
classes of drug products and routes of administration
are discussed. In addition the reader is referred to
Chapter 16 on target-oriented drug-delivery systems.
E. Antibody-Targeted Systems
An alternative drug-delivery system makes use of
macromolecular attachment for delivery using im-
munoglobulins as the macromolecule. The obvious
advantage of this system is that it can be targeted to
the site of the antibody specicity. Although this
usually does not provide much of a sustaining me-
chanism, the problem of spatial placement is ad-
dressed. The advantage in this is that far less drug is
used, and side eects can be reduced substantially.
Drugs are linked, covalently or noncovalently, to
the antibody [103] or placed in vesicles such as lipo-
somes or microspheres, and the antibody used to target
the liposome [104,105] (Fig. 13). Covalent attachment
is generally not very ecient and also diminishes the
antigen-binding capacity [106,107]. There are only a
few functional groups available per antibody that can
be used for chemical coupling without aecting the
antibody's binding activity. If conjugation is done
through an immediate carrier molecule, one can in-
crease the drug/antibody ratio [108,109]. Such inter-
mediates have included dextran or poly-l-glutamic
acid [110112].
Many drugs have been conjugated to antibodies or
their fragments, including daunomycin [113], cyclos-
porine [114], platinum [115], chlorambucil [116], and
vindesine [117]. When choosing a drug for this type of
Fig. 13 Diagrammatic representation of two types of antibody-targeted systems. Drug is either covalently linked directly to the
antibody or is contained in liposomes that are targeted by attached antibodies.
delivery, one must consider many facts [118], such as
whether the drug is active extra- or intracellularly, if it
must be cleaved from the antibody to be active, and the
strength and method of coupling.
Immunoliposomesliposomes loaded with drug
cargo that have been surface-conjugated to antibodies
or antibody fragmentshave also been investigated
by a number of researchers. Linkage of antibody to a
liposome can be covalent or noncovalent. Spacers are
used for covalent binding, or the antibody is modied
by attaching an `ànchor group [119] for noncovalent
coupling. The anchor group, which is hydrophobic,
inserts into the bilayer of the liposome, `ànchoring''
the antibody to the vesicle. Numerous antibodylipo-
some combinations have been looked at, delivering
both drugs [120122] and genetic material [123125].
The obvious advantage to antibody-targeted systems
is that through the use of monoclonal antibodies, which
recognize only the tumor antigen, side eects of cyto-
toxic chemicals on the rest of the body could be greatly
reduced [126,127]. These systems represent a novel and
currently high-interest research area of drug delivery.
Their potential value in the delivery of compounds to
directed targets has generated considerable interest.
V. DENTAL SYSTEMS
Controlled and sustained drug delivery has recently
begun to make an impression in the area of treatment
of dental diseases. Many researchers have demon-
strated that controlled delivery of antimicrobial agents,
such as chlorhexidine [128130], ooxacin [131133],
and metronidazole [134], can eectively treat and
prevent periodontitis. The incidence of dental caries
and formation of plaque can also be reduced by con-
trolled delivery of uoride [135,136]. Delivery systems
used are lm-forming solutions [129,130], polymeric
inserts [132], implants, and patches. Since dental dis-
ease is usually chronic, sustained release of therapeutic
agents in the oral cavity would obviously be desirable.
VI. OCULAR SYSTEMS
The eye is unique in its therapeutic challenges. An ef-
cient mechanism, that of tears and tear drainage,
which quickly eliminates drug solution, makes topical
delivery to the eye somewhat dierent from most other
areas of the body [137]. Usually less than 10% of a
topically applied dose is absorbed into the eye, leaving
the rest of the dose to potentially absorb into the
bloodstream [138], resulting in unwanted side eects.
The goal of most controlled-delivery systems is to
maintain the drug in the precorneal area and allow its
diusion across the cornea. Suspensions and oint-
ments, although able to provide some sustaining eect,
do not oer the amount of control desired [139,140].
Polymeric matrices can often signicantly reduce
drainage [141], but other newer methods of controlled
drug delivery can also be used.
The application of ocular therapy generally includes
glaucoma, articial tears, and anticancer drugs for
intraocular malignancies. The sustained release of ar-
ticial tears has been achieved by a hydro-
xypropylcellulose polymer insert [142]. However; the
best-known application of diusional therapy in the
eye, Ocusert-Pilo, the device shown in Fig. 14, is a
relatively simple structure with two rate-controlling
membranes surrounding the drug reservoir containing
pilocarpine. Thus, a thin, exible lamellar ellipse is
created and serves as a model reservoir device. The unit
is placed in the eye and resides in the lower cul-de-sac,
just below the cornea. Since the device itself remains in
the eye, the drug is released into the tear lm.
The advantages of such a device are that it can
control intraocular pressure for up to a week [143].
Control is achieved with less drug and fewer side ef-
fects, since the release of drug is zero-order. The system
is more convenient, since application is weekly, as
opposed to the four times a day dosing for pilocarpine
solutions. This greatly improves patient compliance
and assures round-the-clock medication, which is of
great importance for glaucoma treatment. The main
disadvantage of the system is that it is often dicult to
retain in the eye and can cause some discomfort.
Another method of delivery of drug to the anterior
segment of the eye that has proved successful is pro-
drug administration [144]. Since the corneal surface
presents an eective lipoidal barrier, especially to hy-
drophilic compounds, it seems reasonable that a pro-
drug that is more lipophilic than the parent drug will
be more successful in penetrating this barrier.
Fig. 14 Schematic diagram of the Ocusert intraocular de-
vice for release of pilocarpine.
One drug that has been formulated in this manner is
dipivalyl epinephrine (Dividephrine), a dipivalyl ester
of epinephrine. Epinephrine itself is poorly absorbed
owing to its polar characteristics and is highly meta-
bolized. The prodrug form is approximately 10 times
as eective at crossing the cornea and produces sub-
stantially higher aqueous humor levels [144,145]. For
another prodrug, phenylephrine pivalate, there is some
possibility that the prodrug itself is therapeutically
active [146,147]. Many other drugs have been deriva-
tized for prodrug ocular delivery: timolol [148,149],
nadolol [150], pilocarpine [151,152], prostaglandin F
2a
[153,154], terbutaline [155], acyclovir [156], vidarabine
[157], and idoxuridine [158,159].
New sustained-release technologies are gaining in
ocular delivery, as in other routes. Liposomes as drug
carriers have achieved enhanced ocular delivery of
certain drugs [160], antibiotics [161163], and peptides
[164]. Biodegradable matrix drug delivery to the ante-
rior segment has also been studied [165,166]. Pro-
longed delivery of pilocarpine can be achieved with a
polymeric dispersion [167] or submicrometer emulsions
[168]. Implantation of polymers containing endotoxin
for neovascularization [169], gancyclovir [170], 5-uro-
uracil [171], and injections of doxorubicin (adriamycin)
[172] have also resulted in sustained delivery. However,
topical ocular delivery is much preferred over implants
and injections.
VII. TRANSDERMAL SYSTEMS
The transdermal route of drug administration oers
several advantages over other methods of delivery. For
some cases, oral delivery may be contraindicated, or
the drug may be poorly absorbed. This would also
include situations for which the drug undergoes a
substantial rst-pass eect [173] and systemic therapy
is desired.
The skin, although presenting a barrier to most drug
absorption, provides a very large surface area for dif-
fusion. Below the barrier of the stratum corneum is an
extensive network of capillaries. Since the venous re-
turn from these capillary beds does not ow directly to
the liver, compounds are not exposed to these enzymes
during absorption [173]. A most notable example of
such a drug is nitroglycerin, which has been adminis-
tered both sublingually and transdermally to avoid
rst-pass metabolism. Other drugs that have seen
success in controlled transdermal delivery are testos-
terone [174], fentanyl [175,176], bupranolol [177], and
clonidine.
Transdermal controlled-release systems can be used
to deliver drugs with short biological half-lives and can
maintain plasma levels of very potent drugs within a
narrow therapeutic range for prolonged periods.
Should problems occur with the system or a change
in the status of the patient require modication of
therapy, the system is readily accessible and easily
removed.
One of the primary disadvantages to this method of
delivery is that drugs requiring high blood levels to
achieve an eect are dicult to load into a transdermal
system owing to the large amount of material required.
These systems would naturally be contraindicated if
the drug or vehicle caused irritation to the skin. Also,
various factors aecting the skin, such as age, physical
condition, and device location, can change the relia-
bility of the system's ability to deliver medication in a
controlled manner. In other words, both the drug and
the nature of the skin can aect the system design.
Current controlled transdermal-release systems can
be classied into four types, as follows, with a re-
presentative product and manufacturer:
1. Membrane permeation-controlled system in
which the drug permeation is controlled by a
polymeric membrane: Transderm-Scop (scopo-
lamine; Ciba-Geigy).
2. Adhesive dispersion-type system, which is si-
milar to the foregoing but lacks the polymer
membrane; instead the drug is dispersed into an
adhesive polymer: Deponit (nitroglycerin;
Wyeth).
3. Matrix diusion-controlled system in which the
drug is homogeneously dispersed in a hydro-
philic polymer; diusion from the matrix con-
trols release rate: Nitrodur (nitroglycerin; key).
4. Microreservoir dissolution-controlled system in
which microscopic spheres of drug reservoir are
dispersed in a polymer matrix: Nitrodisc (ni-
troglycerin; Searle).
Most marketed systems are of the polymeric mem-
brane-controlled type; representative of these is
Transderm-Scop. This product, shown in Fig. 15, is
designed to deliver scopolamine over a period of days
without the side eects commonly encountered when
the drug is administered orally [178]. The system con-
sists of a reservoir containing the drug dispersed in a
separate phase within a highly permeable matrix. This
is laminated between the rate-controlling microporous
membrane and an external backing that is imperme-
able to drug and moisture. The pores of the rate-con-
trolling membrane are lled with a uid that is highly
permeable to scopolamine. This allows delivery of the
drug to be controlled by diusion through the device
and skin. Control is achieved because at equilibrium
the membrane is rate-limiting for drug permeation. To
initiate an immediate eect, a priming dose is con-
tained in a gel on the membrane side of the device.
Another drug that is popular for controlled trans-
dermal release is nitroglycerin. Conventionally, this
drug is administered sublingually, although the dura-
tion of action by this route is quite short. This is ac-
ceptable for acute anginal attacks, but not for
prophylactic treatment. Oral administration has the
disadvantage that large fractions of the dose are lost to
rst-pass metabolism in the liver. Topical ointments
have long been used for prophylactic treatment of
angina, but their duration is only 48 hour and, in
addition, they are not aesthetically acceptable. The
transdermal nitroglycerin devices employ a variety of
systems to provide 24-hour delivery.
An electrochemical method to provide pulsed de-
livery of nitroglycerin, on demand, by the transdermal
route has been described [179]. Transdermal ionto-
phoresis is another technique to provide noninvasive,
continuous, pulsatile, or preprogrammed dosing that,
as disclosed in a review, is showing good promise for
many drugs including some peptides and proteins
[180]. Another promising new approach in transdermal
and transmucosal drug delivery is the use of high-
velocity powder injection. This approach, which uses a
helium gas jet to accelerate ne drug particles (20100
mm diameter) into skin or mucosal sites, has also
recently been reviewed [181]. Yet another new
transdermal system has been developed to deliver nitric
oxide (NO) which is a mediator of a number of bio-
logical processes, including vasodilation, wound heal-
ing, and antimicrobial activity. A chemical generator
of NO is placed on one side of a selective permeable
membrane (to NO but not to the generator chemicals),
with the skin on the other side [182].
VIII. VAGINAL AND UTERINE SYSTEMS
Sustained- and controlled-release devices for drug de-
livery in the vaginal and uterine areas are most often
for the delivery of contraceptive steroid hormones. The
advantages in administration by this routeprolonged
release, minimal systemic side eects, and an increase
in bioavailabilityallow for less total drug than with
an oral dose. First-pass metabolism that inactivates
many steroid hormones can be avoided [183,184].
One such application is the medicated vaginal ring
[185]. Therapeutic levels of medroxyprogesterone have
been achieved at a total dose that was one-sixth the
required oral dose [186]. Ring delivery devices have
several problems that have limited their usevaginal
wall erosion and ring expulsion, to name a few. Mi-
crocapsules have also recently been useful for vaginal
and cervical delivery [187]. Local progesterone release
from this dosage form can alter cervical mucus to in-
terfere with sperm migration [188]. Other steroids have
also attained sustained delivery by an intracervical
system [189]. The sustained release of progesterone
from various polymers given vaginally have also been
found useful in cervical ripening and the induction of
labor [190192]. A possible new use of the vaginal
route is for long-term delivery of antibodies. When
various antibodies, including monoclonal IgG and
IgM, were administered from polymer vaginal rings in
test animals, antibody concentrations remained high
over 30 days in vaginal secretions and detectable in
blood and tissues, suggesting the route as a reasonable
approach to achieve sustained mucosal and systemic
antibody levels [193].
A more common contraceptive device is the in-
trauterine device (IUD). The rst type of intrauterine
device used was undedicated. These have received in-
creased attention since the use of polyethylene plastics
and silicone rubbers [194196]. These materials had the
ability to resume their shape following distortion. Be-
cause they are unmedicated, these IUDs cannot be
classieds as sustained-release products. It is believed
that their mechanism of action is due to local en-
dometrial responses, both cellular and cytosecretory
Fig. 15 Schematic diagram of a transdermal device for the
delivery of scopolamine.
[197]. Initial investigations of these devices led to the
conclusion that the larger the device, the more eective
it was in preventing pregnancy. Large devices, how-
ever, increased the possibility of uterine cramps,
bleeding, and expulsion of the device.
Eorts to improve IUDs have led to the use of
medicated devices. Two types of agents are generally
usedcontraceptive metals and steroid hormones. The
metal device is exemplied by the CU-7, a poly-
propylene plastic device in the shape of the number 7.
Copper is released by a combination of ionization and
chelation from a copper wire wrapped around the ver-
tical limb. This system is eective for up to 40 months.
The hormone-releasing devices have a closer re-
semblance to standard methods of sustained release
because they involve the release of a steroid compound
by diusion [198,199]. The Progestasert, a reservoir
system, is shown in Fig. 16. Progesterone, the active
ingredient, is dispersed in the inner reservoir, sur-
rounded by an ethylene/vinyl acetate copolymer
membrane. The release of progesterone from this sys-
tem is maintained almost constant for 1 year. The ef-
fects of release are local, with none of the systematic
side eects observed with orally administered contra-
ceptives [200207].
IX. INJECTIONS AND IMPLANTS
One of the most obvious ways to provide sustained-
release medication is to place the drug in a delivery
system and inject or implant the system into the body
tissue. The concept of such delivery methods is not
new, but the technology applied is contemporary.
Administration of these systems often requires surgical
implantation or specialized injection devices. The fact
that these systems are in constant contact with exposed
tissue components places certain requirements on the
systems and their polymer composition.
In general, the materials used must be biocompa-
tible, that is, the polymers themselves must not cause
irritation at the implantation site or promote infectien
or sterile abscess. The most common polymers used are
hydrogels, silicones, and biodegradable materials [208].
Hydrogels have the advantageous property of being
able to retain large amounts of water within their
structure without dissolving [209]. This high aqueous
content makes them very compatible with living tissues
but unfortunately allows low molecular weight sub-
stances to diuse out quickly. Cross-linking agents can
be used to reduce this diusional loss and to provide
structural rigidity, but this can increase the frictional
irritation of the hydrogel with its surrounding tissue.
Subcutaneous implantation is currently one of the
most utilized routes to investigate the potential of
sustained-delivery systems. This is because favorable
absorption sites are available and removal of the device
can be accomplished at any time. Surgery is often re-
quired and in itself can be considered a disadvantage,
as is the fact that once implanted, the delivery rate of
the drug is usually xed until the device is removed.
The development of implants has a long history,
starting initially with investigations on implanted sili-
cone devices. The most notable new implantable pro-
duct is Norplant, a contraceptive device releasing
levonorgestrel for up to 5 years [210]. This product is
implanted subdermally and requires only a local an-
esthetic. A variety of other drugs have also been used,
including thyroid hormones, steroids, cardiovascular
agents [211213], insulin [215], and nerve growth factor
[216].
Sustained-release injections, subcutaneous and in-
tramuscular, have been investigated in a variety of
dierent formulations [217,218]. Injections of degrad-
able microspheres have eciently prolonged delivery
of numerous drugs [219222], even antigenic sub-
stances and vaccines to produce immunity [223,224].
Some implantation devices have extended well be-
yond the classic diusional systems and have included
not only bioerodible devices, but also implantable
therapeutic systems that can be activated. There are
devices activated by change in osmotic pressure to
deliver insulin [225], morphine release trigger by va-
por pressure [226], and pellets activated by magnetism
Fig. 16 Schematic diagram of the Progestasert intrauterine
device for the release of progesterone.
to release their encapsulated drug load [227]. Such
external control of an embedded device would elim-
inate many of the disadvantages of most implanted
delivery systems.
In the delivery of therapeutic proteins, although
recent advances in transdermal and oral delivery have
been signicant, logarithmic increases in the bioa-
vailability of these drugs must be achieved to make
them candidates for commercialization by these
routes. Therefore, in the years immediately ahead,
protein delivery for commercial products will likely be
limited to injection forms, depot systems, and pul-
monary administration [228]. As a result a great deal
of research is now directed to such areas as increasing
the functionalization of polymer carrier material
surfaces to meet the demands of the biological host
system [229]. Included in this general approach are
adherent bilayer hydrogels carrying proteins for intra-
arterial delivery [230]. Another approach involves the
chemical modication of proteins to facilitate their
formulation into or conjugation with the parenteral
polymeric carriers [231].
X. OTHER TARGETED SITES
Sites along the small intestine and in the colon are in-
creasingly becoming specic locations for drug delivery.
A wide variety of transporters are found in the intestine
and are involved in the transport of dietary nutrients.
These transporters, located in the brush border mem-
brane and basolateral membrane, exhibit unique sub-
strate specicities. The development of prodrugs that
target intestinal transporters has been successful in
some cases, and the intestinal peptide transporter is
used to increase the bioavailability of several peptido-
mimetic drugs. Recent advances in gene cloning and
molecular biology techniques are making it possible to
study the characteristics and distribution of transpor-
ters at a molecular level. This eld and the promise for
targeting specic intestinal transporters in drug delivery
has recently been comprehensively reviewed [232].
The colon represents an important and challenging
target site in the gastrointestinal tract to provide more
eective treatments for ulcerative colitis, Crohn's dis-
ease, and colorectal cancer. In addition, colonic de-
livery of vermicides and diagnostic agents is enhanced.
Special ``superenteric'' polymer coatings continue to be
investigated; these transit not only to the stomach, but
also to the small intestine before releasing all or most
of their `èncapsulated'' drug [233,244]. Several very
comprehensive reviews on colonic drug targeting have
been published [235,236]. Various prodrug conjugates
of 5-aminosalicylic acid have also been used to deliver
that drug to the colon for site-specic release [237].
Another very important site for drug delivery is the
central nervous system (CNS). The blood-brain barrier
presents a formidable barrier to the eective delivery of
most agents to the brain. Interesting work is now ad-
vancing in such areas as direct convective delivery of
macromolecules (and presumably in the future
macromolecular drug carriers) to the spinal cord [238]
and even to peripheral nerves [239]. For the interested
reader, the delivery of therapeutic molecules into the
CNS has also been recently comprehensively reviewed
[240].
Polymers have historically been the key to the
great majority of drug-delivery systems. It is expected
that this will be the case in the foreseeable future.
A class of polymers growing in importance in this
regard are phase-transition polymers. These materials
undergo physical changes, which may, for example,
trigger drug release in response to external stimuli
(pH, temperature including microwave response, light
sources, chemicals including metabolites, electric
current, magnetic eld, etc.). The signicance of these
polymers is that they may not only dictate where a
drug is delivered, but when and at what time intervals
it is released. A paper has summarized these polymers
and their applications to modulated drug delivery
[241].
XI. CONCLUSIONS
The space limitations of a text such as this do not
permit a complete discourse on all of the sustained and
controlled mechanisms available for possible drug
delivery. Instead an attempt has been made to cover as
completed as possible the major and currently mar-
keted types, of drug delivery while also providing some
insights into likely future advances. Sustained and
controlled drug-delivery systems are becoming more
the norm rather than the exception in modem phar-
maceutical development, to enhance and even optimize
drug product eectiveness, reliability, and safety.
Current research in this area involves numerous new
and novel systems, many of which have strong ther-
apeutic potential. Furthermore, many if not most of
the drugs that will derive from the biotechnology sci-
entic revolution in the years and decades ahead will
require the application of eective and innovative
drug-delivery technology. The future of this area is
limited only by the imagination of those who choose to
become involved in the eld.
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Sustained and Controlled Release Drug Delivery Systems

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Chapter 15

Sustained- and Controlled-Release Drug-Delivery Systems

are ions in the GI tract. The free

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