osmotic drug delivery using swellable-core...
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Journal of Controlled Release 94 (2004) 75–89
Osmotic drug delivery using swellable-core technology
A. G. Thombrea,*, L. E. Appelb, M. B. Chidlawb, P. D. Daugheritya, F. Dumonta,L.A.F. Evansa, S.C. Suttona
aPfizer Global R&D, Groton Laboratories, Eastern Point Road, Groton, CT 06340, USAbBend Research, Inc., Bend, OR 97701, USA
Received 1 August 2003; accepted 17 September 2003
Abstract
Swellable-core technology (SCT) formulations that used osmotic pressure and polymer swelling to deliver drugs to the GI
tract in a reliable and reproducible manner were studied. The SCT formulations consisted of a core tablet containing the drug
and a water-swellable component, and one or more delivery ports. The in vitro and in vivo performance of two model drugs,
tenidap and sildenafil, formulated in four different SCT core configurations: homogeneous-core (single layer), tablet-in-tablet
(TNT), bilayer, and trilayer core, were evaluated. In vitro dissolution studies showed that the drug-release rate was relatively
independent of the core configuration but the extent of release was somewhat lower for the homogeneous-core formulation,
particularly under non-sink conditions. The drug-release rate was slower with increasing coating thickness and decreasing
coating permeability, and was relatively independent of the drug loading and the number and size of the delivery ports. The
drug-release rates were similar for the two model drugs despite significant differences in their physicochemical properties.
Tablet-recovery and pharmacokinetic studies conducted in beagle dogs showed that the in vivo release of drug from SCT
formulations was comparable to the in vitro drug release.
D 2003 Elsevier B.V. All rights reserved.
Keywords: Controlled release; In vitro release; In vitro/In vivo correlation; Osmotic pumps
1. Introduction opment of osmotic systems includes seminal contri-
Osmotic systems for controlled drug-delivery ap-
plications are well established, both in human phar-
maceuticals and in veterinary medicine. Several one-
compartment and two-compartment osmotic systems
have been reviewed previously [1–4]. In addition, a
large body of patent literature exists that describes new
and novel osmotic systems [5]. The historical devel-
0168-3659/$ - see front matter D 2003 Elsevier B.V. All rights reserved.
doi:10.1016/j.jconrel.2003.09.009
* Corresponding author. Tel: +1-860-441-8734; fax: +1-860-
715-7668.
E-mail address: [email protected]
(A.G. Thombre).
butions such as the Rose–Nelson pump [6], the
Higuchi–Leeper pumps [7–10], the AlzetR and
OsmetR systems [11], the elementary osmotic pump
[12], and the push-pull or GITSR system [13–15].
Recent advances include the development of the
controlled porosity osmotic pump [16–18] systems
based on asymmetric membranes [19–23], and other
approaches [24–28].
Osmotic drug-delivery systems suitable for oral
administration typically consist of a compressed tablet
core that is coated with a semipermeable membrane
coating. This coating has one or more delivery ports
through which a solution or suspension of the drug is
A.G. Thombre et al. / Journal of Controlled Release 94 (2004) 75–8976
released over time. The core consists of a drug formu-
lation that contains an osmotic agent and a water-
swellable polymer. The rate at which the core absorbs
water depends on the osmotic pressure generated by
the core components and the permeability of the
membrane coating. As the core absorbs water, it
expands in volume, which pushes the drug solution
or suspension out of the tablet through one or more
delivery ports.
The key distinguishing feature of osmotic drug-
delivery systems (compared with other technologies
used in controlled-release formulations) is that they
release drug at a rate that is independent of the pH and
hydrodynamics of the external dissolution medium.
The result is a robust dosage form for which the in
vivo rate of drug release is comparable to the in vitro
rate, producing an excellent in vitro/in vivo correla-
tion. Another key advantage of the present osmotic
systems is that they are applicable to drugs with a
broad range of aqueous solubilities. Depending on
aqueous solubility, the drug is released either as a
solution or as a suspension. Of course, any drug
released as a suspension must dissolve in the in vivo
environment and overcome biological barriers before
it becomes systemically available.
Several mathematical models have been developed
to describe the drug-release kinetics from osmotic
systems [12,16,22,28]. The starting point for all these
models is essentially the same, viz., expressing the
mass delivery rate (dm/dt) from the dosage form as a
product of the total volumetric flow rate (dV/dt) and
the concentration of drug (C) in the solution or
suspension being released. Thus,
dm
dt¼ dV
dtC ð1Þ
For single-core osmotic systems such as the OROSk,
the expression for the volumetric flow rate is derived
from irreversible thermodynamics and is given by
[12]
dV
dt¼ A
hLp rDp � DPð Þ ð2Þ
where Dp and DP are the osmotic and hydrostatic
pressure differences, respectively, across the mem-
brane, Lp is the membrane filtration coefficient, r is
the reflection coefficient, A is the membrane area, and
h is the membrane thickness.
After combining Eqs. (1) and (2) and making some
simplifying assumptions, the kinetics of drug release
can be derived. Accounting for diffusion in addition to
the osmotic component, applying the equations to
more complex geometries such as layered cores, and
taking into account factors such as hydration of the
polymers, can complicate the expressions for the
drug-delivery rate. However, in most cases, they are
consistent with our intuitive understanding of osmotic
systems, viz., the release rate decreases with increas-
ing membrane thickness and decreasing membrane
permeability.
Osmotic systems can be somewhat complex to
manufacture because (1) the components in the tablet
core may have poor to marginal flow and compression
characteristics; (2) the core may consist of more than
one layer; (3) a solvent-based process is used to apply
the semipermeable membrane coating onto the tablet
cores; and (4) in most systems, a laser-drilling process
is needed to form the delivery port(s). In spite of this
manufacturing complexity, osmotic drug-delivery sys-
tems have been successfully used in many commercial
products.
In this paper, we report the in vitro and in vivo
performance of an osmotic drug-delivery system
known as swellable-core technology (SCT). SCT
was developed as a drug-delivery platform that can
deliver drugs with moderate to poor aqueous solubil-
ity over an 8- to 24-h period. SCT formulations
consist of a core tablet that contains a drug composi-
tion and a water-swellable composition. The drug
composition contains the drug, an entraining polymer
(e.g., polyethylene oxide), and sugars or salts as
osmotic agents. The swellable composition contains
a nonionic polymer (e.g., polyethylene oxide) or an
ionic polymer (e.g., croscarmellose sodium or sodium
starch glycolate), which swells and expands in volume
after absorption of water. The drug composition may
also contain solubilizers, for example, buffering
agents, which solubilize the drug by maintaining a
pH microenvironment that aids in drug dissolution
and absorption. Furthermore, the drug and water-
swellable compositions may contain other ingredients
to improve the flow and compression characteristics
of the blends, aiding in the manufacture of tablets. In
general, the components used in SCT formulations are
safe, commonly used in pharmaceutical products, and
available in pharmaceutical grades.
A.G. Thombre et al. / Journal of Controlled Release 94 (2004) 75–89 77
The drug and water-swellable compositions in SCT
formulations can be designed in various configura-
tions. For example, they can be mixed together
resulting in a uniform homogeneous core, or, they
can be physically separated from each other, resulting
in a layered configuration. The tablet cores are coated
with a film coat of cellulose acetate and polyethylene
glycol from an acetone–water solvent system. The
film coating is then drilled either using a laser or a
mechanical drill or slits are made to produce one or
more exit ports.
To demonstrate the broad applicability of the
technology, formulation parameters such as core com-
position and coating thickness were evaluated using
an acidic and a basic model compound. In addition,
the effect of the tablet core configuration on in vitro
and in vivo performance was systematically studied.
The use of nonionic and ionic swellable polymers was
explored in an effort to achieve complete drug deliv-
eryUi.e., release of the entire amount of active agent
Fig. 1. Schematic diagrams of four SCT formulations: homog
in the tablet core without a significant unreleased
residual. Also, several different delivery-port config-
urations were examined including their number, size,
and placement. The in vivo performance of one of the
model drugs studied is also reported.
2. Methods and materials
Four different core configurations of SCT formu-
lations were evaluated in this study: (1) homogeneous
cores, consisting of a single layer; (2) tablet-in-tablet
(TNT) cores, consisting of a water-swellable central
core surrounded by the drug formulation; (3) bilayer
cores, consisting of a water-swellable layer and a
drug-containing osmotic layer adjacent to each other;
and (4) trilayer cores, consisting of a water-swellable
layer sandwiched between two drug-containing layers.
Schematics of these configurations are shown in Fig.
1. These configurations were chosen because they can
enous core, tablet-in-tablet (TNT), bilayer, and trilayer.
A.G. Thombre et al. / Journal of Controlled Release 94 (2004) 75–8978
be manufactured using equipment that is readily
available in the pharmaceutical industry (bilayer and
trilayer tablet presses are commercially available, as
are presses for compression coating, which can be
used to produce the TNT formulation).
A typical SCT core formulation was 10% model
drug; 29% polyethylene oxide (Polyox WSR-205,
approximate MW 600,000 or Polyox WSR N-80,
approximate MW 200,000, Dow Chemical, Midland,
MI formerly Union Carbide) used as the entraining
polymer; 30% xylitol containing 1.5% carboxymeth-
ylcellulose (Xylitab 200, Xyrofin [UK]) used as the
osmogent/filler; 30% sodium starch glycolate (Explo-
tab, Penwest Pharmaceuticals, Paterson, NY) used as
the water-swellable polymer; and 1% magnesium
stearate (Mallinckrodt, St. Louis, MO) used as the
tablet lubricant. Several variations of the above com-
position were also studied, for example, increased
drug loading (10% and 28%) and substituting cro-
scarmellose sodium (Ac-Di-Sol, FMC, Philadelphia,
PA) or polyethylene oxide (Polyox, WSR Coagulant,
approximate MW 5,000,000, Dow Chemical, former-
ly Union Carbide) as the water-swellable polymer.
Also, in some cases, fillers such as microcrystalline
cellulose (Avicel PH102, FMC) or silicified micro-
crystalline cellulose (Pro-Solv 90, Penwest Pharma-
ceuticals) at a level of up to 30% were added, and the
quantity of other components adjusted appropriately
to improve the tabletting properties of blends.
A typical manufacturing process for SCT formu-
lations was as follows. For small-scale laboratory
batches, the components were blended for 20 min in
a TurbulaR mixer (WAB/Glen Mills, Clifton, NJ)
and the blend was then milled using a Quadro mini-
ComilR 193AS (Quadro Engineering, Waterloo,
Canada), blended again for 20 min, lubricated with
magnesium stearate, and blended for an additional 4
min. The tablets were then compressed using a
Manesty single-station Type ‘‘F’’ tablet press (Man-
esty, Merseyside, UK) with 13/32-in. standard round
concave (SRC) tooling. The average tablet weight
was typically 500 mg and the average tablet hardness
was typically 8 to 10 Kp. The tablet cores were then
sprayed with a coating solution made from 7%
cellulose acetate (CA) (CA 398-10 (Eastman Chem-
ical, Kingsport, TN), 3% polyethylene glycol (PEG)
(PEG 3350, The Dow Chemical), 85% acetone, and
5% water. In some formulations, the CA/PEG ratio
was varied in order to study the effect of the coating
permeability on drug-release performance. A solvent-
ready, explosion-proof side-vented coating pan such
as the Freund HCT 30-EP (Freund Industrial, Japan)
or LDCS-20/30 (Vector Corporation, Marion, IA)
was used to apply the coating. For small batches
of tablet cores, the actives were mixed with placebo
tablets of a slightly different size and coated together
in the same coating pan. The actives were then
separated from the placebos after the coating was
complete. When coated in this manner, the placebo
and actives tended to gain weight at different rates
because, depending on the core weight, either the
placebos or actives had a greater tendency to ‘‘ride’’
on the surface of the tablet bed, which received the
coating spray. The coating weight for the actives was
generally 9% to 10% of the core weight, unless
otherwise specified in Results and discussion or in
the figure legends.
In the case of bilayer tablets, a small quantity
(generally 0.1% by weight) of a red or blue dye was
added to the sweller layer, with appropriate adjust-
ments in the quantity of the other excipients. This
helped to identify the drug layer side after the coating
was completed. Delivery ports were then made on the
drug side of the coated bilayer tablets. In the other
core configurations, the orientation of the tablets
relative to the delivery ports was not important. Two
different types of delivery ports were studied. Holes
were generally 0.9 mm in diameter and drilled,
mechanically or by laser, on the face of the tablet.
Slits were generally 0.9 mm thick and were made
either on the face of the tablet or the land (sometimes
referred to as the band of the tablet). Although, within
reasonable limits, the type and number of delivery
ports were not expected to significantly alter the
osmotic release rate, this variable was studied to
determine whether it influenced the maximum extent
of release and the time lag before the initiation of
release. The number and placement of the holes and
slits are noted within the Results and discussion.
The in vitro and in vivo performance of the four
SCT core configurations was characterized using two
different model drugs, one weak acid and one weak
base. Both model compounds were obtained from
Pfizer Global R&D and their key physicochemical
properties and the extraction solvents used in their
analytical procedure are listed in Table 1. High-
Table 1
Model drugs studied in SCT formulations
Model drug Physico-chemical
properties
Aqueous
solubility
Extraction
solvent
Analytical method
reference
Weak acid
pKa = 3.0
0.001 mg/ml at
pH 5 and 0.2
mg/ml at pH 7.4
Acetone [25,30]
Weak base
pKa = 5.7
(basic)
7.5 mg/ml at pH
4.0 and 0.012
mg/ml at pH 7.4
Acetonitrile
followed by 0.05
M triethylamine
at pH 3
[25]
A.G. Thombre et al. / Journal of Controlled Release 94 (2004) 75–89 79
performance liquid chromatography (HPLC) methods
with ultraviolet (UV) detection were used to quantify
the amount of drug released in dissolution studies; the
specific method varied according to the drug being
studied.
2.1. Dissolution (drug-release) studies
Dissolution studies were conducted using USP
Apparatus 2 (paddles at 100 rpm) with 900 ml
vacuum-degassed medium at 37 jC. The dissolution
medium was 0.1 N HCl (pH 1.2), 0.01 N HCl (pH
2.6), or 0.05 M phosphate buffer (pH 7.5). Depend-
ing on the model drug used, this represented either
sink or non-sink dissolution conditions. For dissolu-
tion under non-sink conditions, the amount of drug
released was determined as follows: At pre-deter-
mined sampling times, the tablets were physically
removed from the dissolution vessel, any extruded
material at or near the exit port(s) was carefully
wiped off, and the residual undelivered drug from
the tablet was extracted for analytical quantification.
The amount of drug released was then calculated by
subtracting the amount recovered from the known
initial drug loading, and expressed as a percentage of
the initial drug load. The sample-collection times
were 2, 4, 8, 12, and 24 h for dissolution under non-
sink conditions and 2, 4, 8, 12, 20, and 24 h for
dissolution under sink conditions. For sink condi-
tions, it was assumed that the amount of drug in
solution was representative of the amount of drug
released from the formulation.
2.2. Pharmacokinetic studies in dogs
Regarding all animal studies, the research adhered
to the ‘‘Principles of Laboratory Animal Care’’ [29].
For pharmacokinetic studies, a group of five male
beagle dogs was used and the formulations were
administered in a crossover fashion. The SCT formu-
lations (i.e., homogeneous-core, TNT, bilayer, and
trilayer configurations) were administered to fasted
A.G. Thombre et al. / Journal of Controlled Release 94 (2004) 75–8980
dogs and immediately followed by an oral gavage of
50 ml water. As a control, an immediate-release
suspension or tablet formulation was administered.
After dosing, dogs were returned to metabolism cages
equipped with automated water supplies. They were
fed their normal diet 8 h after dosing on the day of the
study. The dogs remained in the metabolism cages
until all of the tablets had been recovered. Whole
blood samples (3.0 ml) were taken from the jugular
vein of each dog using 5-ml disposable syringes
before dosing and at 1, 2, 3, 4, 6, 8, 12, 16, and 24
h after dosing. The samples were immediately trans-
ferred to heparinized (sodium heparin) Vacutainersk.
Samples were spun in a 5 jC centrifuge at 3000 rpm
for 5 min. The plasma samples were poured into 2-ml
cryogenic plastic tubes. Samples were frozen and
stored in a freezer until they were analyzed for
tenidap, usually within a period of 1 month.
The plasma-concentration-versus-time profiles
were analyzed using standard pharmacokinetic analy-
sis techniques. Peak plasma concentrations (Cmax)
were determined by inspection of the data. The first
occurrence of Cmax was defined as the Tmax. Areas
under the plasma-concentration–time curves (AUC)
and the extrapolated AUC (AUC from the last time
point to l) were calculated by the linear trapezoidal
method using the software program Kineticak (Inna-
Phase, Philadelphia, PA). Pharmacokinetic parameters
were dose-normalized for ease of comparison with the
immediate-release control. Relative bioavailability
(RBA) was defined as the dose-corrected AUC0–l
of the test formulation divided by the dose-corrected
AUC0–l of the immediate-release control formula-
tion (suspension or tablet). The mean in vivo absorp-
tion profiles were calculated by deconvolution of the
plasma-concentration–time profiles and compared to
the in vitro dissolution (drug-release) profile under
sink conditions.
2.3. Tablet-recovery studies in dogs
For tablet-recovery studies, each tablet to be dosed
was marked with a unique symbol using a permanent
marker so that the tablet could be easily identified
when it was recovered. On the day of the study,
beginning at 6 a.m., one tablet was administered to
each dog, immediately followed by an oral gavage of
50 ml of water. This tablet-administration procedure
was repeated at 2-h intervals—at 8 a.m., 10 a.m., and
12 p.m.Uuntil four tablets were dosed to each dog.
Two hours after the last tablets were administered, the
dogs were fed their normal diet. The dogs remained in
metabolism cages until all of the tablets were recovered
from the feces. The recovery times were noted and the
recovered tablets were rinsed, photographed using a
digital camera, and placed in separate plastic vials. The
tablets were kept frozen in a � 20 jC freezer until the
residual (i.e., undelivered) drug content was analyzed.
This procedure had been shown to effectively stop any
further drug release from the tablets.
The residual drug was determined as follows: Each
tablet was removed from its vial and placed in a 250-
ml glass bottle with a screw cap, which contained 200
ml extraction solvent. A Polytron PT3100 mixer
(Kinematica, Littau, Switzerland) was used to extract
the residual drug from the tablets. The contents were
then filtered through a Whatman Autovial polytetra-
fluoroethylene (PTFE) 0.45-Am filter and analyzed
using the HPLC procedure for the specific model drug
being investigated.
3. Results and discussion
3.1. Drug-release mechanism and typical dissolution
profile
The proposed mechanism of drug release from
SCT formulations is as follows. When the coated
SCT tablet is exposed to an aqueous medium, water
diffuses through the film coating because of the
activity gradient of water, hydrating the core. The
solvation of the osmotic agents creates a constant
osmotic-pressure difference between the core contents
and the external environment. The hydration of the
core causes the viscosity of the drug-entraining poly-
mer to decrease, and drug is extruded through the exit
ports via hydrostatic pressure generated by the expan-
sion of the water-swellable composition. After the
drug has been delivered, the tablet shell remains
intact. Depending on its solubility in the external
medium, drug can be released as either a solution or
a suspension. If it is released as a suspension, the drug
composition forms plumes at the delivery ports, which
are dispersed over time by mechanical agitation of the
external medium. This mechanism is consistent with
A.G. Thombre et al. / Journal of Controlled Release 94 (2004) 75–89 81
the performance data on SCT systems discussed in
this paper and also in agreement with the mechanism
of drug release from osmotic systems described in the
literature [12,16,20,22,27].
A typical drug-release profile obtained with SCT
formulations is described below. There can be a time
lag before the initiation of drug delivery, cor-
responding to the initial ingress of water into the
tablet and hydration of the core. This is followed by
nearly linear release of about 80% to 90% of the
initial drug load. Thereafter, drug-release rate
decreases steadily. Drug delivery from SCT formu-
lations is generally robust, as would be expected of
systems releasing the drug by an osmotic pumping
mechanism.
Visual observations were made to gain insight
into the release mechanism. Fig. 2 shows photo-
graphs of cross-sections of SCT bilayer tablets in a
sequence covering four time points (4, 6, 8, and 20
h) during delivery. In the photographs, the red
material corresponds to the water-swellable compo-
sition and the white material corresponds to the drug
composition. To facilitate comparison, all the tablets
in the photographs are oriented so that the drug-
delivery port is located towards the top. The photo-
graphs clearly show that the core progressively
hydrates and that the volume occupied by the sweller
layer increases with time. The total volume of the
tablet appears to remain essentially unchanged so
that the decrease in the volume of the core occupied
by the drug layer must correspond to the extrusion
(release) of the drug-containing layer through the
delivery port. In the 20-h photograph, a small
amount of white drug-containing material is still
visible inside the tablet. This likely corresponds to
the plateau observed in the drug-dissolution profile,
representing approximately 10% undelivered drug.
The graph in Fig. 2 shows the in vitro dissolution
profile.
3.2. In vitro characterization of SCT formulations
The in vitro drug-release (dissolution) profiles of
tenidap from four SCT formulations (homogeneous,
TNT, bilayer, and trilayer configurations) under sink
and non-sink conditions are shown in Fig. 3. Drug
release under non-sink conditions was studied as
described in Methods and materials. As evident from
the dissolution profiles, the four formulations studied
did not show any significant time lag before the start
of the drug-release phase. As the 2-h time point was
the first sample, the possibility of a short time lag,
such as 0.5 or 1 h, cannot be precluded. Also, the
drug-release profiles from all of the formulations
were virtually identical for the first 4 h. Thereafter,
the homogeneous-core formulation had a slightly
slower release rate compared to the layered core
configurations. Also, compared to the homoge-
neous-core formulation, drug release from the TNT,
bilayer, and trilayer formulations seemed to be more
complete—i.e., a smaller quantity of drug was held
up in the core. This was more apparent in the
dissolution profiles under non-sink conditions. It
should be noted that compared to dissolution under
sink conditions, the experimental data under non-
sink conditions represent fewer tablets and the man-
ual procedure of wiping the drug plume near the
delivery ports was probably intrinsically more vari-
able. It was hypothesized that osmotic delivery was
the major mechanism contributing to drug release
over the first 4 h in the case of the homogeneous-
core SCT followed by a greater contribution by a
diffusive mechanism.
As shown in Fig. 4, varying the number and
position of the delivery ports (slits or holes) in the
tablet coatings did not have an appreciable effect on
the drug-release rate from SCT formulations. In the
case of trilayer SCT tablets containing tenidap with
slits as delivery ports, the dissolution profiles
obtained with tablets that had four or eight slits
were slightly more nonlinear compared to tablets
with only two slits. This is consistent with a
slightly higher diffusive component and lower os-
motic component of overall release in the case of
tablets with a greater number of delivery ports.
There also was a possibly longer time lag before
initiation of drug release in the case of formulations
with fewer slits, which is consistent with a longer
hydration time.
In bilayer sildenafil citrate SCT formulations with
holes instead of slits as delivery ports, the number and
size of the holes in the tablet coatings also did not
appear to have an appreciable effect on the drug-
release rate from SCT formulations. In this case,
however, the effect on the time lag was more pro-
nounced—the extent of time lag decreased with the
Fig. 2. Cross-sectional photographs (a) and in vitro drug release (b) from a bilayer SCT formulation. A red dye was included in the water-
swellable composition. The tablets are oriented so that the drug-delivery port is at the top.
A.G. Thombre et al. / Journal of Controlled Release 94 (2004) 75–8982
number of holes, and, at very early times after the time
lag, the drug release was slightly faster in the case of
formulations with more delivery ports. The longer
time lag seen in formulations with holes compared to
slits is consistent with the much smaller total delivery
port surface area in the case of formulations with
Fig. 3. Effect of (a) sink conditions (pH 7.5) and (b) non-sink
conditions (pH 1.2) on the in vitro dissolution performance of four
SCT formulations containing tenidap.
Fig. 4. Effect of the number and position of drug-delivery ports on
the in vitro dissolution performance of SCT formulations. The top
panel (a) shows dissolution profiles under sink conditions obtained
with tenidap trilayer SCT formulations with slits. The bottom panel
(b) shows dissolution profiles under sink conditions for 2 h followed
by transfer to non-sink conditions obtained with sildenafil citrate
bilayer SCT formulations with holes.
A.G. Thombre et al. / Journal of Controlled Release 94 (2004) 75–89 83
holes, which were made on the tablet surface, while
the slits generally ran the entire thickness of the
tablets (referred to as the ‘‘band’’).
The most straightforward method to modify the
drug-release profile of an SCT formulation is to vary
the coating weight. The effect of coating weight on
release of sildenafil citrate from trilayer and bilayer
SCT tablets is shown in Fig. 5. The drug-release rate
was directly related to the rate that water enters the
tablet core and, as stated earlier, the rate of water
ingress is dependent on the osmotic pressure of the
core and the permeability of the coating. Changing the
coating thickness can alter the permeability of the
coating: the thicker coating has lower water permeabil-
ity. The drug-release profiles show that thicker coatings
not only have slower release rates but also have longer
lag times before the initiation of drug release. This is
explained as follows. Water penetration is slower in
tablets with a thicker coating, which, in turn, results in
a longer time required for sufficient water being present
to fluidize the core so that it can be extruded.
The water permeation through the coating is also
affected by the CA/PEG ratio used in the formulation
of the coating solution. The drug-release profiles in
Fig. 6 show that for the same coating weight, coatings
with higher CA/PEG ratios released drug more slowly
compared to coatings with a lower CA/PEG ratio
consistent with decreasing water permeability as a
function of increasing CA/PEG ratio. However, the
Fig. 5. Effect of coating weight on the in vitro dissolution
performance of SCT formulations containing sildenafil citrate.
The dissolution was conducted under sink conditions (pH 2.0) for 2
h and the tablets were then transferred to non-sink conditions (pH
7.5). The coating formulation was CA/PEG 7/3. The top panel (a)
shows data for the trilayer configuration with ten 900-Am holes on
each tablet face and the bottom panel (b) shows data for the bilayer
configuration with ten 900-Am holes on the drug-layer face.
Fig. 6. Effect of CA/PEG coating ratio on the in vitro dissolution
performance of bilayer SCT formulations containing sildenafil
citrate. The coating weights were equivalent and the dissolution was
conducted under sink conditions (pH 2.0).
A.G. Thombre et al. / Journal of Controlled Release 94 (2004) 75–8984
drug-release profiles in the case of CA/PEG ratios of
7/3 and 6/4 were similar. This indicates that when the
coating permeability is very high, the major resistance
to water ingress may be its transport in the tablet core
rather than its permeation through the coating. Thus,
the CA/PEG ratio of the coating can be used as
another formulation variable (along with the coating
thickness) to control the drug-release rate. Thus, very
thick coatings, which need longer run times in the
coating operation, can be avoided if slower drug
release is desired. Also, very thin coatings, which
may adversely affect the mechanical strength of the
coating and its physical integrity, can be avoided if
faster drug release is desired.
The dependence of drug-release rate on the coating
thickness (i.e., slower drug release with increasing
coating thickness) and on the CA/PEG ratio are
consistent with what is expected of osmotic delivery
systems, i.e., delivery rate directly proportional to
membrane thickness and membrane permeability.
The in vitro dissolution profiles obtained with
tenidap TNT SCT formulations with drug loadings
of 10% and 28% under sink and non-sink conditions
are compared in Fig. 7. The data show that the drug
loading was not a significant factor governing the
drug-release rates from the tablets. Drug release that is
independent of the drug loading is considered a major
attribute contributing to the flexibility of formulation
development. Thus, with SCT formulations, it is
possible to develop multiple tablet strengths relatively
easily by changing only the drug-layer composition
while all other components of the formulation remain
essentially the same.
The breadth of application of SCT was clearly
demonstrated by studying the in vitro release profiles
of the selected model drugs from each of the four SCT
configurations. The in vitro drug-release profiles
obtained with sildenafil citrate formulations are shown
in Fig. 8. A comparison of the drug-release profiles
for tenidap (Fig. 3) and sildenafil citrate (Fig. 8)
Fig. 7. Effect of drug loading on the in vitro dissolution
performance of a TNT SCT formulation containing tenidap. The
top panel (a) shows dissolution data obtained under sink conditions
(pH 7.5) and the bottom panel (b) shows dissolution data obtained
under non-sink conditions (pH 1.2).
Fig. 8. Comparison of the in vitro dissolution performance of SCT
formulations containing sildenafil citrate. The dissolution was
conducted under sink conditions (pH 2) for 2 h and the tablets
were then transferred to non-sink conditions (pH 7.5).
A.G. Thombre et al. / Journal of Cont
indicates that for a given coating, the release profiles
are remarkably similar for the model drugs with a
broad range of physicochemical properties (acids or
bases with a range of aqueous solubility) even though
no attempt was made to optimize the delivery rates or
release durations.
3.3. In vivo characterization of SCT formulations
Two different types of studies were conducted in
beagle dogs to characterize the in vivo performance of
SCT formulations: tablet-recovery studies and phar-
macokinetic studies.
3.3.1. Tablet-recovery studies
The results from the tablet-recovery study for
tenidap SCT formulations are given in Fig. 9, which
shows the in vitro and in vivo release profiles for each
of the four SCT formulations. In this and other tablet-
recovery studies, the in vivo release profiles were
constructed from the tablet-recovery data and the in
vitro release profiles were generated from tablet
dissolution data under sink conditions. In general,
the results of the tablet-recovery study were consistent
with the in vitro results for the four formulations and
provided strong evidence that the formulations re-
leased the drug as intended throughout the delivery
duration.
The tablet-recovery studies are important because
they offer direct evidence of the in vivo release of the
drug from the SCT formulations. Thus, the data offer
compelling evidence that the in vivo performance of
the SCT formulations, particularly the layered formu-
lations, was as expected from their in vitro drug-
release characteristics. It is important to note that this
performance attribute of SCT is a characteristic of the
technology and not dependent on the physicochemical
properties of the particular drug being studied. How-
ever, one drawback of the experimental technique is
that the total amount of time that a particular tablet
rolled Release 94 (2004) 75–89 85
Fig. 9. Comparison of the in vitro and in vivo release from SCT formulations containing tenidap. The in vitro drug-release data were obtained
from dissolution studies under sink conditions. The in vivo drug-release data were obtained from tablet-recovery studies and an analysis of the
residual undelivered drug.
A.G. Thombre et al. / Journal of Controlled Release 94 (2004) 75–8986
spends in the GI tract of the dog cannot be controlled
with great accuracy and depends on a variety of
factors. In the tenidap studies, some tablets had
relatively short GI residence times, which allowed
characterization of the amount released in vivo at
early times.
3.3.2. Pharmacokinetic studies
The mean dose-normalized plasma tenidap concen-
tration-versus-time profiles following administration
of the four SCT formulations in beagle dogs are
shown in Fig. 10. Data for an immediate-release
control formulation are included for comparison.
The data for the SCT formulations are corrected for
the actual amount of drug delivered, as determined by
residual analysis of recovered tablets. The pharmaco-
kinetic parameters are summarized in Table 2.
The mean AUC(0–l) was 328 Ag h/ml (21% CV)
for the homogeneous-core formulation; 388 Ag h/ml
(38% CV) for the TNT formulation; 221 Ag h/ml
(28% CV) for the bilayer formulation; and 289 Ag h/
ml (43% CV) for the trilayer formulation. These
values were not statistically different from each other
(P> 0.05) as determined by the Tukey’s Honest
Significant Difference (HST) test–post hoc ANOVA.
All four of the SCT formulations had longer Tmax
values than the immediate-release suspension. The
Tmax for the immediate-release suspension was
1.1F 0.6 hours, whereas the Tmax values were
9.2F 2.4, 7.8F 4.3, 6.6F 2.2, and 9.6F 4.6 h for
Fig. 10. Mean dose-normalized profiles for plasma concentration
versus time in beagle dogs following administration of an
immediate-release suspension formulation and four SCT formula-
tions containing tenidap.
A.G. Thombre et al. / Journal of Controlled Release 94 (2004) 75–89 87
the homogeneous-core, TNT, bilayer, and trilayer
formulations. Compared to the IR formulation, the
homogeneous-core and trilayer SCT formulations
were significantly longer, P= 0.045 and P= 0.030,
respectively. Compared to the IR formulation, there
was a trend towards a longer Tmax, 6.6 and 7.8 h,
respectively, for the bilayer and TNT formulations,
and they were not statistically different from each
other. Likewise, the Cmax values for the four for-
mulations were not statistically different (P>0.05),
with values of 20.7 Ag/ml (15% CV), 17.6 Ag/ml
(23% CV), 13.8 Ag/ml (33% CV), and 17.3 Ag/ml
Table 2
Comparative summary of pharmacokinetic data obtained with four
SCT formulations containing tenidap
Homogeneous TNT Bilayer Trilayer
AUC(0 –l) (Ag h/ml)
(CV%)
328
(21.1)
288
(37.6)
221
(28.1)
289
(42.9)
Cmax (ug/ml)
(CV%)
20.7
(14.9)
17.6
(22.5)
13.8
(32.8)
17.3
(25.1)
Tmax (h)
(S.D.)
9.2
(2.4)
7.8
(4.3)
6.6
(2.2)
9.6
(4.6)
RBA (%)
(S.D.)
73.8
(25.1)
72.8
(25.9)
53.0
(17.6)
69.0
(21.0)
AUC (0–l) and Cmax are reported as geometric means with CV%;
Tmax and RBA are reported as arithmetic average with standard
deviations.
(25% CV) for the homogeneous-core, TNT, bilayer,
and trilayer formulations, respectively.
The in vivo release appeared consistent with the
respective in vitro release data for the four SCT
formulations. The RBAs were not statistically differ-
ent, with values of 73.8F 25.1%, 72.8F 25.9%,
53.0F 17.6%, and 69.0F 21.0% for the homoge-
neous-core, TNT, bilayer, and trilayer formulations,
respectively.
As shown in Fig. 11, results from the absorption
analysis showed apparent biphasic absorption profiles,
with a lag period of about 1 h followed by a burst of
accelerated absorption that lasted 1 to 2 h. The burst
was present in all the absorption profiles obtained in
dogs given the homogeneous-core and TNT formula-
tions; however, only two of the data sets for the
bilayer tablets and one of the data sets for the trilayer
tablets displayed this burst. The accelerated release
was followed by a period of slower absorption, which
lasted several hours. Three of the bilayer-tablet data
sets and two of the trilayer-tablet data sets did not
show the burst. These last data sets showed nonlinear
decreasing absorption over 8 to 10 h.
During the period of apparent accelerated release,
the mean rate of drug absorbed for the homogeneous-
core, TNT, bilayer, and trilayer tablets expressed as
a percentage of drug absorbed were 25.8F 11.7,
35.2F 5.5, 37.5 and 54.9%/h, respectively, with mean
release rates of 8.4F 1.24, 12.8F 4.91, 7.5, and 15.6
mg/h, respectively. These data are shown in Table 3.
Fig. 11. Mean absorption profiles in beagle dogs following
administration of four different SCT formulations containing
tenidap. The drug-absorption profiles were calculated by deconvo-
lution of the plasma-concentration profiles.
Table 3
Comparative summary of deconvolution results obtained for four SCT formulations containing tenidap
Dog Homogeneous core TNT Bilayer Trilayer Homogeneous core TNT Bilayer Trilayer
Drug absorbed during accelerated-absorption period (%/h) Drug absorbed during accelerated-absorption period (mg/h)
36188 41.0 34.2 43.4 10.2 8.7 9.3
36189 34.7 43.6 9.0 11.8
36190 20.9 30.6 8.2 13.2
36288 19.8 30.6 31.6 54.9 7.6 9.3 5.8 15.6
36249 12.5 37.3 7.0 21.0
Mean 25.8F 11.7 35.2F 5.5 37.5 54.9 8.4F 1.2 12.8F 4.9 7.5 15.6
Dog Homogeneous core TNT Bilayer Trilayer Homogeneous core TNT Bilayer Trilayer
Drug absorbed during slower-absorption period (%/h) Drug absorbed during slower-absorption period (mg/h)
36188 5.6 4.9 2.9 4.8 1.4 1.3 0.6 2.3
36189 4.5 6.3 12.3 8.2 1.2 1.7 2.6 2.0
36190 7.7 10.2 12.5 12.3 3.0 4.4 3.0 3.4
36238 13.9 5.0 3.7 3.5 5.3 1.5 0.7 1.0
36249 7.6 6.2 8.4 8.6 4.2 3.5 3.5 3.7
Mean 7.8F 3.7 6.5F 2.1 8.0F 4.6 7.5F 3.4 3.0F 1.8 2.5F 1.4 2.1F1.4 2.5F 1.1
A.G. Thombre et al. / Journal of Controlled Release 94 (2004) 75–8988
During the subsequent period of slower absorption,
the rate of drug absorbed was 7.8F 3.7, 6.5F 2.1,
8.0F 4.6, and 7.5F 3.45%/h for the homogeneous-
core, TNT, bilayer, and trilayer tablets, respectively.
Further, the mean release rates for the four formu-
lations were 3.0F 1.8, 2.5F 1.4, 2.1F1.4, and
2.5F 1.1 mg/h, respectively.
When compared with the extent of in vitro drug
release, the SCT tablet configurations appeared to
have similar in vivo release durations: approximately
80% of the drug was absorbed by 8 to 10 h. There
were insufficient data to state definitely whether the
apparent accelerated-absorption rate was an artifact of
regional solubility and permeability or a function of
the formulation.
4. Conclusions
Swellable-core technology (SCT) represents a
broadly applicable oral osmotic drug-delivery plat-
form for the controlled release of drugs. The formu-
lations consist of a drug-containing composition and a
water-swellable composition, which can be designed
in several different core configurations. SCT formu-
lations use components that are safe and commonly
used in pharmaceutical products, and are available in
pharmaceutical grades. The processes for manufactur-
ing SCT formulations are somewhat more complex
than for other controlled-release technologies such as
hydrophilic matrix tablets, but have precedence in the
pharmaceutical industry.
Drug-release from SCT formulations can be con-
trolled by the composition of the core and perme-
ability of the membrane coating. The in vitro drug
delivery from SCT formulations was extremely ro-
bust—independent of external pH and hydrodynam-
ics, insensitive to number, position, and size of the
drug-delivery ports, and relatively independent of the
drug itself. These attributes translate to an extremely
predictable in vivo performance as demonstrated for
one drug. The drug release rates from SCT formu-
lations can be easily tailored to a particular applica-
tion by controlling the osmotic agent in the core and
the permeability of the membrane coating. A major
advantage of SCT systems is that they allow rapid
progression of exploratory drug candidates since
prototype formulations can be developed and pro-
gressed rapidly into clinical studies to achieve proof
of concept.
Acknowledgements
We acknowledge S.M. Herbig for his continued
support for work in the area of osmotic drug delivery
and D. Supplee for her help in assembling this
manuscript.
A.G. Thombre et al. / Journal of Controlled Release 94 (2004) 75–89 89
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