Drug Delivery

ISSN: 1071-7544 (Print) 1521-0464 (Online) Journal homepage: http://www.tandfonline.com/loi/idrd20

Factors Affecting the Release of Nifedipine from a

Swellable Elementary Osmotic Pump

Ali Nokhodchi, Mohammed N. Momin, Javad Shokri, Mahbobeh Shahsavari

& Parinaz Ahmad Rashidi

To cite this article: Ali Nokhodchi, Mohammed N. Momin, Javad Shokri, Mahbobeh Shahsavari
& Parinaz Ahmad Rashidi (2008) Factors Affecting the Release of Nifedipine from a Swellable
Elementary Osmotic Pump, Drug Delivery, 15:1, 43-48, DOI: 10.1080/10717540701829028

To link to this article: http://dx.doi.org/10.1080/10717540701829028

Published online: 10 Oct 2008.

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 Drug Delivery, 15:43–48, 2008
Copyright

c Informa Healthcare USA, Inc.
ISSN: 1071-7544 print / 1521-0464 online
DOI: 10.1080/10717540701829028

Factors Affecting the Release of Nifedipine from a Swellable

Elementary Osmotic Pump

Ali Nokhodchi and Mohammed N. Momin

School of Pharmacy at Medway, Universities of Greenwich, Kent, England

Javad Shokri, Mahbobeh Shahsavari, and Parinaz Ahmad Rashidi

Drug Applied Research Center and Faculty of Pharmacy, Tabriz University of Medical Sciences,
Tabriz, Iran

trointestinal tract, despite its low water solubility (10 µg/ml),

and the relationship between drug plasma concentrations and
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Oral osmotic devices including an elementary osmotic pump

(EOP) are efficient systems for the delivery of drugs with
high/moderately water-solublility. In this study we designed a new
type of EOP for the efficient delivery of poorly water-soluble and
practically insoluble drugs. In this system, called swellable elemen-
tary osmotic pump (SEOP), drug is released from the delivery ori-
fice in the form of a very fine dispersion of drug in gel which is
ready for dissolution and absorption. Factors affecting the release
of drug from the SEOP containing a poorly water-soluble drug,
nifedipine, were explored extensively. To this end, effect of swelling
and wetting agents, orifice size, concentration of osmotic agent, and
hydrophobic plasticizer were investigated. Interestingly, in the ab-
sence or low concentration of a hydrophobic plasticizer (caster oil),
the osmotic devices did not retain their integrity in dissolution me-
dia. Caster oil in concentration of >1% was necessary for tablets
to retain their integrity during dissolution process. A zero-order
release kinetics for nifedipine was achieved following the effective
optimization of the concentrations of swelling agent, osmotic agent,
wetting agent, and also size of orifice and membrane thickness in
SEOP. The zero-order release lasted for 10 hr at pH 6.8 dissolution
medium. The designed SEOP is suggested as an efficient controlled
delivery system for oral delivery of a poorly water soluble drug
such as nifedipine.
Keywords Nifedipine, Swellable Elementary Osmotic Pump, Zero-
Order Release, Orifice Size, Plasticizer
Nifedipine, a calcium channel blocker of the dihydropyri-
dine type, mainly is used for the treatment of hypertension and
angina pectoris. Nifedipine is a suitable candidate for controlled
release administration due to its short elimination half-life of 2 to
4 hr, its rapid and complete drug absorption over the entire gas-
Received 3 March 2007; accepted 30 April 2007.
Address correspondence to Ali Nokhodchi, School of Phar-
macy at Medway, Universities of Kent and Greenwich, Central
Avenue, Chatham Maritime, Kent, ME4 4TB, England. E-mail:
a.nokhodchi@kent.ac.uk
blood pressure reduction (Grundy and Foster 1996; Bode et al.
1996). Conventional preparation usually is administered two or
three times a day, which will lead to large fluctuation in drug-
plasma concentration and side effects on the human body. Con-
stant plasma level can offer a therapeutic advantage for many
drugs in terms of both efficacy and tolerance of the treatment
(Langer 1998). Once-daily controlled release preparation is of-
ten desirable.
Osmotic systems for controlled drug-delivery applications
are well established, both in human pharmaceuticals and in vet-
erinary medicine. In the 1970s, Theeuwes (1975) introduced
the elementary osmotic pump (EOP) and brought forward its
basic theory. However, the generic EOP is only suitable for the
delivery of moderately solubility drugs. Several one and two-
compartment osmotic systems have been reviewed previously
(Cardinal 2000; Rao et al. 2001; Verma et al. 2000, 20002).
In addition, a large body of patent literature exists that de-
scribes new and novel osmotic systems (Santus and Baker 1995).
The historical development of osmotic systems includes sem-
inal contributions such as the Rose–Nelson pump (Rose and
Nelson 1995), the Higuchi–Leeper pumps (Higuch and Leeper
1973a,b,c; Higuchi and Leeper 1976), the AlzetR and OsmetR
systems (Fara 1985), the EOP (Theeuwes 1975), and the push-
pull or GITSR system (Theeuwes 1978; Cortese and Theeuwes
1982; Wong et al. 1988). Advances include the development
of the controlled porosity osmotic pump (Zentener et al. 1985,
1991; Thombre, Zentner, Himmelstein 1989) systems based on
asymmetric membranes (Amende et al. 2000; Herbig et al. 1995;
Thombre et al. 1999a,b,c), and other approaches [Apple et al.
2002; Curatolo et al. 2001; Eckenhoff, Theeuwes, Urquhart,
1981; Swanson et al. 1987).
In the present study, we tried to design a new EOP like osmotic
system for delivery of an insoluble drug with constant release
rate (zero order release). This device, called swellable elemen-
tary osmotic pump (SEOP), is structurally similar to EOPs but

43
 44 A. NOKHODCHI ET AL.

with different core formulation. In the core of this device, a sig- TABLE 1
nificant amount of water-swellable and gel former polymer(s) as Formulation with different core related parameters
well as suspending agent are used. In these systems, the hydro-
static force produced by osmotic agents and polymer-swelling Swelling agent Suspending agent Osmotic agent
force are employed concurrently for driving the drug out of the (HPMC E50LV) (SLS) (KCl)
system through the orifice. The aim of our present study was F1 15 30 150
to investigate parameters that governing the release of a poorly F2 30 30 150
water soluble drug, nifedipine with a solubility of 10 µg/ml, F3 45 30 150
from SEOPs and presenting a new formulation for zero order F4 60 30 150
delivery of nifedipine. As nifedipine was light sensitive (Shin F5 60 0 150
and Pae 1988; Hayase et al. 1994), all samples were kept in an F6 60 15 150
amber-colored container, wrapped in aluminium foil. F7 60 45 150
F8 60 60 150
F9 60 30 100
MATERIALS AND METHODS
F10 60 30 200
Nifedipine powder was purchased from Zahravi Pharmaceu-
ticals (Tabriz, Iran). Cellulose acetate with 40% acetyl groups Membrane composition was caster oil 1%, PEG 2%, membrane
(Fluka, Switzerland) was used as a semipermeable membrane thickness 90 µm, orifice size 500 µm, and cellulose acetate 5%. The
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(SPM). HPMCs E50LV (Colorcon, England) was used as water-
swellable and gelling agent. KCl (Merck, Germany) and sodium
lauryl sulphate (SLS, Merck, Germany) were applied as osmot-
ically active agent and suspending agent, respectively.
Preparation of Core Tablets
Nifedipine powder was micronized by jet mill (Fritsch FE
80N, Germany) before tableting process. The micronized drug
powder and other core ingredients were mixed and compressed
into convex tablets with 9 mm (diameter) concave punches us-
ing a single punch tableting machine (Korsch, Germany). All
the core formulations contained 30 mg nifedipine and differ-
ent ratios of polymer-suspending agent and osmotic agent. The
composition of different core formulations (F14-F22) is listed
in Table 1. All devices made from these formulations contained
1% caster oil and 2% PEG 300 (as plasticizers) and the thick-
ness of the membrane (cellulose acetate) was 0.13 mm with an
orifice of 650 µm.
amount of nifedipine was 30 mg for all formulations.
Figure 1 shows a schematic diagram of the monolithic os-
motic tablet system. Because of the photosensitivity of nifedip-
ine, all processes such as grinding, mixing and coating steps
were performed in dark condition. The SPM compositions for
different formulations are listed in Table 2.
In Vitro Release Test
All drug release experiments were carried out using a dis-
solution apparatus (Erweka DT-6R, Germany), paddle method,
rotating at 100 rpm at 37◦ C in 900 ml phosphate buffer solu-
tion (pH 6.8). The cells of dissolution tester were covered with
aluminium foil to prevent photodegradation of the drug. Sam-
ples of 5 ml (replaced with fresh medium) were taken at distinct
time intervals and the drug concentration in samples was de-
termined spectroscopically (UV spectrophotometer, Shimadzu
mini 1240, Japan) at a wavelength of 240. The release test was

HPMC E50LV 15 mg (F1)

Coating and Drilling 70 HPMC E50LV 30 mg (F2)
The tablets were coated with cellulose acetate. Cellulose ac-
Nifedipine Relesaed (%)

60 HPMC E50LV 45 mg (F3)

etate (5 g) and a plasticizer (caster oil) with different concentra- HPMC E50LV 60 mg (F4)
tions were dissolved in 100 ml acetone-ethanol mixture (40:60 50
v/v). The cores were coated by dip coating technique. Coating 40
process was carried out in the same condition for all tablets and
thickness of the coats was periodically controlled using digital 30
micrometer (Mitotoyo, Japan). The membrane thickness of the 20
basic formulations was regulated in the range of 130 ± 10 µm.
Thickness of the empty shells also was measured using digi- 10
tal micrometer after complete dissolution of the contents. For 0
coated tablets, a small orifice was drilled through the one side 0 2 4 6 8 10 12
of each coated tablet by standard mechanical micro drills with Time (h)
various diameters (ranging from 350–800 µm) and orifice diam-
eters were controlled microscopically (Baush & Lomb, Balplan FIG. 1. The effect of swelling agent concentration on the release profile of
microscope, USA). nifedipin from osmotic pumps.
 NIFEDIPINE RELEASE FROM SEOP 45

TABLE 2 release behavior of nifedipine from osmotic pumps. To study

Formulations with different semipermeasle membrane (SPM) the effect of core parameters on the release rate of nifidepine,
related parameters (CA 5%, PEG 2%) tablets with various formulations were prepared then coated with
5% cellulose acetate (CA), 1% caster oil, 2% PEG 300, and a
Orifice diameter SPM hydrophobic SPM thickness 500-µm diameter orifice was drilled on one side of the tablet
(µm) plasticizer (%w/w) (µm) surface. The membrane thickness of these formulations was kept
F11 350 1 90 constant (90 µm).
F12 550 1 90
F13 600 1 90 Swelling Agent
F14 650 1 90 HPMC E50LV was selected as the swelling and gelling agent
F15 700 1 90 in osmotic devices of nifedipine. The release profile of the ef-
F16 800 1 90 fect of HPMC concentration on the release rate of nifedipine
F17 500 0.5 90 from osmotic system is shown in Figure 1. The results showed
F18 500 1.5 90 that uniform rate of swelling of the polymer ensured that the
F19 500 2 90 drug is released at a relatively constant rate. Also, the pressure
F20 500 1 40 produced during swelling did not lead to rupture of the sys-
F21 500 1 170 tem. For formulation containing 15 mg HPMC, only 40% of the
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Core composition for formulations F11-F21 was the same as F4
(nifedipine 30 mg, HPMC E50LV 60 mg, SLS 30 mg, KCl 150 mg).
performed at least for 3 tablets and mean and standard deviations
were obtained.
Mathematical Treatments
Dissolution data obtained for various formulations were an-
alyzed by different mathematical and statistical parameters. An
ideal osmotic system should be able to release the majority of
its drug content with constant release rate (zero order kinetic).
Various parameters were used to compare different formula-
tions, mainly, tL (lag time of the drug release from device) and
RSQzero (R square of release data fitted to zero order equation).
Among these formulations, those with tL > 4 hr were rejected
and other formulations were compared in terms of the RSQzero.
tL is the time required to reach steady state release of drugs from
osmotic devices. In fact, tL is the time required for imbibitions of
water through the semipermeable coating, gel forming process,
volume enhancement of the gel, and movement of the formed
gel containing drug particles through the small drug delivery
orifice.
It has been shown that since active material in the tablets does
not induce an osmotic effect due to its poor solubility in water,
an initial lag-time of 1 hr is necessary to moisten the device and
the penetration of water into the core (Zentner et al. 1991). The
time during which it is necessary to moisten the tablets may be
reduced by the addition of a surface-active agent to the coating
material (Zentner et al. 1991).
RESULTS AND DISCUSSION
In the present study, first parameters affecting the release of
nifedipine from the core are discussed. According to the results
obtained in the first section, one of the formulations would be
adopted to investigate the effect of membrane parameters on the
drug was released. When the amount of HPMC was increased
to 30 mg, 56% of the drug released within 10 hr. It we observed
that amount of HPMC had a pronounced effect on release profile
of nifedipine from osmotic systems. However, when the amount
of HPMC was increased from 30 to 45 or 60 mg, no significant
increase in the drug release was observed. HPMC played the
role of thickening agent and elevated the viscosity of the sus-
pension and subsequently prevented precipitation of nifedipine.
The larger the amount of HPMC used, the higher the viscos-
ity of the suspension formed and the higher the stability of the
nifedipine powder.
HPMC E5LV also was an expanding agent; the higher the
amount of the polymer used the greater the expanding force of
core tablet. Therefore, the release rate increased as the amount
of the polymer was increased. The selection of a suitable con-
centration of polymer is crucial when designing the osmotic
pump. Too much polymer will burst the osmotic device and too
little concentration of polymer will produce low viscosity in-
side the device and not thus able to prevent precipitation of the
drug powder inside the device. The visual observation of tablets
at the end of the experiment showed that no crack on the sur-
face of the tablet even with high concentration of HPMC. All
release data also were subjected to zero-order kinetic analysis
and the results showed that core formulations containing 60 mg
HPMC showed higher correlation coefficient for zero-order re-
lease (0.995). Therefore, F4 as a good formulation was adopted
for further investigation.
Wetting Agent
Dissolution profiles of the drug from formulations with dif-
ferent amounts of SLS (0, 15, 30, 45, and 60 mg) are shown in
Figure 2. As indicated in this figure, the presence of SLS in the
core formulation obviously increased the percentage and the re-
lease rate of the drug from the devices. Only small amount of the
drug (14%) was released in the absence of 0 mg SLS after 10 hr.
When the amount of SLS increased to 15 mg, a huge increase
 46 A. NOKHODCHI ET AL.

60 SLS 0 mg (F5) 70
KCL 100 mg (F9)
SLS 15 mg (F6) 60
50 KCl 150 mg (F4)

Nifedipine Released (%)

SLS 30 mg (F4)
50 KCl 200 mg (F10)
Nifedipine Released (%)

40 SLS 45 mg (F7)
SLS 60 mg (F8) 40
30
30
20 20

10 10
0
0
0 2 4 6 8 10 12
0 2 4 6 8 10 12
Time (h)
Time (h)
FIG. 3. The effect of osmotic agent concentration on the release profile of
FIG. 2. The effect of wetting agent concentration on the release profile of
nifedipine from osmotic pumps.
nifedipine from osmotic pumps.
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150 mg KCl (F4). This indicates both these formulations can

in the amount of drug release (54% in 10 hr) was observed.
The percentage release was not affected by the increase in the
amount of SLS above 30 mg. We could not establish any direct
relationship between the SLS concentration and the percentage
release. Generally, SLS acts as a wicking agent that is dispersed
throughout the composition and enhances the contact surface
area of drug with incoming aqueous fluid. Thus, the drug might
be released predominantly in a soluble form through the delivery
orifice in the membrane. Comparing the correlation coefficients
of these formulations revealed that an increase in the amount
of SLS from 30 mg (F4) to 60 mg (F8) could not improve cor-
relation coefficient and F4 formulation has the best correlation
coefficient (correlation coefficients were 0.960, 0.995, 0.964,
and 0.990 for F6, F4, F7, and F8, respectively).
Osmotic Agent
One of the main release-controlling factors that must be opti-
mized is the osmotic pressure gradient between inside the com-
partment and the external environment. To this end, different
concentrations of KCl were incorporated into the osmotic core
and their release profiles are represented in Figure 3. Although
the presence of KCl is necessary to induce osmotic pressure for
be used for further development. As the use of high amount
of KCL increases the weight of tablet without any improve-
ment in correlation coefficient, F4 was again adopted for further
investigation.
Orifice Size
To investigate the effect of orifice size, osmotic tablets were
drilled with various orifice sizes ranging from 350–800 µm. Fig-
ure 4 represents the effect of delivery orifice size on the rate of
drug release. The figure shows that an increase in the orifice size
resulted in an increase in release rate of nifedipine. For exam-
ple, after 10 hr the percentage release for the tablets with orifice
size of 350, 500, 650, and 800 was 28.1, 53.8, 57.3 and 89%,
respectively. Kinetics of release data for zero-order showed that
as the size of orifice increases correlation coefficient of zero ki-
netics gets better (correlation coefficients for tablets with orifice
sizes of 350, 500, 650, and 800 µm were 0.984, 0.993, 0.996,
and 0.996, respectively). This indicates that the size of delivery
80 350 micrmeter (F11)
70 500 micrometer (F4)
Nifedipine Released (%)

the drug release, it is clear from Figure 3 that the concentration 60 650 micrometer (F14)
of KCl had no remarkable effect on release rate of nifedipine. 50 800 micrometer (F16)
For example, after 10 hr the percentages of drug release for for-
40
mulations containing 100, 150, and 200 mg KCl were 49, 54,
and 57%, respectively. This indicates that 100 mg KCl is enough 30
to keep constant osmotic pressure for 10 hr. The main reason for 20
a little increase in release rate with an increase in KCl concen- 10
tration is the more KCl incorporated into tablet, the more water
0
was imbibed and the more core formulaton could be liquefied 0 2 4 6 8 10 12
and, as a consequence, more nifedipine was released.
Time (h)
The correlation coefficient of zero-order kinetic showed that
the tablet containing 200 mg KCl (F10) has similar correlation FIG. 4. The effect of the size of delivery orifice on the release profile of
coefficient (0.995) in comparison with the tablets containing nifedipine from osmotic pumps.
 NIFEDIPINE RELEASE FROM SEOP
orifice must be optimized to control the drug release from os-
motic devices. If the size of delivery orifice is too small, zero-
order release will be affected because of development of hydro-
static pressure within the core. This hydrostatic pressure may not
be relieved because of the small orifice size and may lead to de-
formation of delivery system, thereby resulting in unpredictable
drug delivery. However, we showed that if the delivery orifice is
too large solute diffusion from the orifice might take place.
Our results indicate that for the nifedipine osmotic tablets
produced in this study 800 µm is not too large that the solute
diffusion can take place. This is in contrast to other findings
that showed the drug release from osmotic pumps of nifedipine
was not significantly affected by the orifice size between 250–
1410 µm (Lu et al. 2003) or 1000–1500 µm (Liu et al. 2000).
The latter study showed that the release was somewhat rapid with
an orifice diameter of 2200 µm. This may be due to the results
of diffusion from the bigger orifice as mentioned earlier. In the
present study only the drug release was not affected when the
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orifice size was in the range of 500–600 µm (data not shown).
The reason may be that the difference between the orifice sizes
of these two osmotic tablets was not enough to significantly
change the release behavior. A low percentage of release (28%
after 10 hr) was observed at an orifice diameter of 350 µm.
The agglomerated drug in suspension may occlude such a small
orifice, therefore, leading to a low drug release rate.
Hydrophobic Plasticizer
To assess the effect of caster oil concentration on the release
rate of nifedipine from osmotic devices, different concentrations
of caster oil were incorporated into the membrane and release
profiles of these formulations are illustrated in Figure 5. The
results showed that an increase in the concentration of caster oil
(a hydrophobic plasticizer) resulted in a reduction in release rate
of the drug. The highest release rate was observed for the samples
containing 0.5% w/w caster oil and more than 80% of the drug
was released within the first 4 hr. This is due to the presence
of a crack in these formulations. When the concentration of
caster oil was increased from 0.5 to 1% no crack was found in
100
Nifedipine Released (%)
80 Caster oil 0.5% (F17)
Caster oil 1% (F4)
60 Caster oil 1.5% (F18)
Caster oil 2% (F19)
40
20
0 0
0 2 4 6 8 10 12
Time (h)
FIG. 5. The effect of hydrophobic plastisizer on the release profile of nifedip-
ine from osmotic pumps.
47
osmotic devices. This indicates that in order for osmotic devices
to retain their integrity during the release process, at least 1%
caster oil is necessary to be added to the membrane formulation.
Also formulations containing 1% caster oil showed the higher
correlation coefficient.
Membrane Thickness
To assess the role of membrane thickness on the release rate of
nifidipine, the tablets were coated with three different thickness
membranes (40, 90 and 170 µm) and their effect on the release
rate is shown in Figure 6. The figure shows that the thickness
of the membrane has a profound effect on the drug release from
osmotic systems. We can see from equation below that release
rate from osmotic system is inversely proportional to membrane
thickness:
dM A
= Kπ C
dt h
where dM/dt is drug delivery rate, A and h are the membrane area
and thickness respectively, C is the concentration of compound
in the dispersed fluid (soluble fraction of the drug), π is the
osmotic pressure of the system, and K is the equation constant.
It is clear from the equation that release rate from osmotic
devices is inversely proportional to membrane thickness. As the
thickness increased, the resistance of the membrane to water
diffusion increased and the rate of imbibing water decreased. In
turn, the liquefaction rate of the tablet core decreased, resulting
in the drug release rate decreasing. Similar results were obtained
by Liu et al. (2000) for monolithic osmotic tablets of nifedip-
ine where release rates were found to decrease with increase in
membrane thickness from 85 to 340 µm. Contrary to our study,
Lu et al. (2003) did not observe any significant difference in re-
lease rate of naproxen from osmotic tablets coated with different
thicknesses of cellulose acetate (40, 50, and 60 µm). The reason
may be that the difference between the thicknesses of membrane
is not enough to significantly change the release profiles.
40 micrometer (F20)
120
90 micrometer (F4)
100 170 micrometer (F21)
Nifedipine Released (%)
80
60
40
20
0 2 4 6 8 10 12
Time (h)
FIG. 6. The effect of membrane thickness on the release profile of nifedipine
from osmotic pumps.
 48 A. NOKHODCHI ET AL.
The present study also showed that when the membrane thick-
ness was reduced to 40 µm the coating was not able to resist the
pressure within the device. The device cracked and most of drug
was released within the first 4 hr. This indicates that the thickness
of the membrane for nifedipine osmotic pumps containing 1%
caster oil, 2% PEG 300, and 5% cellulose acetate should be kept
above 40 µm. To ensure the coating is able to resist the pres-
sure within the device, membrane thickness was usually kept
above 200 µm (Santus and Baker 1995). However, this may be
problematic in cases in which the drug has low osmotic pressure
because of incomplete/slow drug release take place.
CONCLUSIONS
A SEOP was designed using HPMC E50LV as expanding
agent, KCl as osmotic agent, sodium lauryl sulphate as sus-
pending agent, and caster oil as hydrophobic plasticizer coated
with a cellulose acetate membrane with one orifice drilled on one
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side surface. The SEOP was simple to prepare because there was
no need for a push compartment. The SEOP was optimized by
changing the concentrations of the ingredients and the orifice
size to achieve zero-order release kinetics for the delivery of
the model drug nifedipine. The optimized system was able to
release nifedipine at a zero order kinetics for 10 hr when tested
in pH 6.8 medium.
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