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.


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]


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


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


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.


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.


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).


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.


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.


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


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.


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