Review Article

PULSATILE DRUG DELIVERY: CURRENT

SCENARIO
Sachin Survase and Neeraj Kumar*
Department of Pharmaceutics
National Institute of Pharmaceutical Education and Research (NIPER)
Sector- 67, S.A.S. Nagar, Punjab- 160062, India
E-mail: neeraj@niper.ac.in

Pulsatile drug delivery systems (PDDS) are gaining importance as these systems deliver the drug at specific time as per the
pathophysiological need of the disease,resulting in improved patient therapeutic efficacy and compliance. Diseases wherein
PDDS are promising include asthma, peptic ulcer, cardiovascular diseases, arthritis,attention deficit syndrome in children, and
hypercholesterolemia. PDDS can be classified into time controlled systems wherein the drug release is controlled primarily by
the delivery system; stimuli induced PDDS in which release is controlled by the stimuli, like the pH or enzymes present in the
intestinal tract or enzymes present in the drug delivery system and externally regulated system where release is programmed
by external stimuli like magnetism, ultrasound, electrical effect and irradiation. The current article focuses on the diseases
requiring PDDS, methodologies involved for the existing systems, recent update and PDDS product currently available in the
market.

1. Introduction systems is not suitable because of a number of

With the advancement of the technologies in the
pharmaceutical field, drug delivery systems have drawn
an increasing interest over the last few decades.
Nowadays, the emphasis of pharmaceutical galenic
research is turned towards the development of more
efficacious drug delivery systems with already existing
molecule rather going for new drug discovery because
of the inherent hurdles posed in drug discovery and
development process .
1 sustained release dosage form, continuous exposure
Traditionally, drug delivery has meant for getting a
simple chemical absorbed predictably from the gut or
from the site of injection. A second-generation drug
delivery goal has been the perfection of continuous,
constant rate delivery of bioactive agents. However,
living organisms are not ‘‘zero-order’’ in
requirement or response to drugs. They are predictable
resonating dynamic systems, which require different
amounts of drug at predictably different times within
the circadian cycle which will maximize desired and
2
minimize undesired drug effects . Till early nineties
efforts have been made to design the drug delivery
system which will release the drug at fairly constant
rate. In fact these systems turned to be one of the
most successful systems in delivering the drug
3
molecule . But still for many of the drugs, use of such
reasons. This is particularly true in cases where the
drug is subjected to large metabolic degradation.
Due to ‘first pass effect’ there will be reduction in the
bioavailability of the drug because, gradual release
can result in greater degradation. Secondly drugs
with short half-life need to be administered repeatedly
which results in patient non-compliance. Further, in
case of chronic treatment, where the drug is given in
of the drug to body may lead to adverse effect. For
example, diabetes mellitus requires chronic treatment
with sustained release formulations of drugs like
sulfonylurea which will damage the pancreas earlier
than the corresponding immediate release dosage
form. Lastly, drugs which exhibit tolerance should not
their
be delivered at a constant rate, since the drug effect
decreases with time at constant drug level. In addition
drug toxicity increases with time when drug levels
are held constant. In such cases it is preferable to
opt for dosage form which will provide desired
4
concentration of drug at particular time point only .
Nowadays, concept of chronopharmaceutics has
emerged, wherein, research is devoted to the design
and evaluation of drug delivery systems that release
a therapeutic agent at a rhythm that ideally matches

CRIPS Vol. 8 No. 2 April-June 2007 27

Review Article
Table 1. Diseases requiring Pulsatile Drug Delivery

Disease Chronological behavior Drugs used

Peptic ulcer Acid secretion is high in the afternoon and at night H blockers
2

Asthma Precipitation of attacks during night or at early β agonist, Antihistaminics

Cardiovascular diseases
Arthritis
Diabetes mellitus
Attention deficit syndrome
Hypercholesterolemia
2
morning hour
BP is at its lowest during the sleep cycle and Nitroglycerin, Calcium channel
rises steeply during the early morning awakening blocker, ACE inhibitors etc.
period
Pain in the morning and more pain at night NSAIDs, Glucocorticoids
Increase in the blood sugar level after meal Sulfonylurea, Insulin, Biguanide
Increase in DOPA level in afternoon Methylphenidate
Cholesterol synthesis is generally higher HMG CoA reductase inhibitors
during night than during day time

2
the biological requirement of a given disease therapy . rhythms. For instance, capillary resistance and vascular
Diseases where a constant drug levels are not reactivity are higher in the morning and decrease
preferred, but needs a pulse of therapeutic later in the day. Platelet aggregability is increased
concentration in a periodic manner acts as a push for and fibrinolytic activity is decreased in the morning,
5
the development of “Pulsatile Drug Delivery Systems ”. leading to a state of relative hypercoagulability of the
6
In these systems, there is rapid and transient release blood . Circadian variations of glucose and insulin in
of a certain amount of drug molecules within a short diabetes have been extensively studied and their
time-period immediately after a predetermined off- clinical importance in case of insulin substitution in
release period. Various techniques are available for type 1 diabetes has been well exploited. Furthermore
the pulsatile delivery like pH dependent systems, time diverse directions of circadian changes in lipid fractions
dependent systems, micro-flora activated systems, etc. in patients and normal subjects may contribute to
which can be designed as per the physiology of alteration in the rhythmicity of other metabolisms and
disease and properties of the drug molecule. The in the blood coagulation system, thus leading to
focus of the present review is primarily on the pulsatile various complications. A circadian rhythm occurs during
drug delivery methodologies and the up coming hepatic cholesterol synthesis. In case of arthritis there
technologies, which are being exploited on an is a circadian rhythm in the plasma concentration of C
industrial scale. - reactive protein and interleukin-6 of patients with
7
rheumatoid arthritis .
2. Diseases requiring pulsatile drug delivery
3. Methodologies for pulsatile drug delivery
Thorough understanding of the disease physiology is
required before designing the pulsatile drug delivery Methodologies for the pulsatile drug delivery system
system. Diseases where rhythmic circadian can be broadly classified into three classes;
organization of the body plays an important role, 1. Time controlled
pharmacokinetics and/or pharmacodynamics of the
2. Stimuli induced
drugs is not constant within 24 h. Table 1 enumerates
various diseases showing such a chronological 3. Externally regulated
behavior. 3.1. Time controlled pulsatile release system
Asthma is one such disease where pulsatile drug In time controlled drug delivery systems pulsatile
delivery system can be useful. Circadian changes are release is obtained after a specific time interval in
seen in normal lung function, which reaches a low order to mimic the circadian rhythm. Such type of
point in the early morning hours. In case of pulsatile drug delivery system contains two
cardiovascular diseases, several functions (e.g. BP, components: one is of immediate release type and
heart rate, stroke volume, cardiac output, blood flow) other one is a pulsed release t ype. Various
of the cardiovascular system are subject to circadian methodologies that can be used for time controlled

28 CRIPS Vol. 8 No. 2 April-June 2007


Drug core
Swellable layer
Outer rupturable coat
Fig. 1. Schematic diagram of Deliver systems with
rutpurable coating layer
pulsatile release systems are discussed in following
section.
3.1.1. Delivery systems with rupturable coating layer
These systems consist of an outer release controlling
water insoluble but permeable coating subject to
mechanically induced rupture phenomenon. Recently
different systems based on hard gelatin capsules and
tablet core were described, all coated by inner
swellable and outer rutpurable layer. The film rupture
may be attained by including swelling, osmotic or
8
effervescent additives in the reservoir . By optimizing
the system, drug release can be obtained at specific
time interval. Sungthongjeen et al developed a tablet
system consisting of core coated with two layers of
swelling and rupturable coatings wherein they used
spray dried lactose and microcrystalline cellulose in
drug core and then core was coated with swelling
polymer croscarmellose sodium and an outer
9
rupturable layer of ethylcellulose . Further Thombre
et al developed osmotic drug delivery using swellable-
core technology wherein formulations consists of a
core tablet containing the drug and a water swellable
10
component, and one or more delivery ports . Fig.1
shows the schematic diagram of delivery systems
with rutpurable coating layer.
3.1.2. Delivery systems provided with erodible coating
layers
In such systems the drug release is controlled by the
dissolution or erosion of the outer coat which is
applied on the core containing drug. Time dependent
release of the active ingredient can be obtained by
11
optimizing the thickness of the outer coat . Sangalli
et al. developed an oral dosage form devised to
release drugs following a programmed time period
after administration based on this concept. System is
composed of a drug-containing core and a hydrophilic
swellable polymeric coating of HPMC which is capable
CRIPS Vol. 8 No. 2 April-June 2007
Review Article
Drug core
Erodible coating layer
Fig. 2. Schematic diagram of Delivery systems with
erodible coating layers
of delaying the drug release through slow interaction
with aqueous fluids12. Fig. 2 shows the schematic
diagram of Delivery systems with erodible coating
layers.
3.1.3. Capsule shaped system provided with release
controlling plug
These systems contain release controlling plug
between immediate release compartment and pulsed
release compartment. On contact with aqueous fluids,
the cap rapidly dissolves thereby releasing the
immediate release component followed by pulsed
release component. The lag time is provided by the
plug which is inserted in to the body. In an approach
used by Jimoh et al, pulsatile release was achieved
by generation of hydrostatic pressure inside the
capsule. A hollow biodegradable capsule of poly(lactic
acid) (PLA) containing the drug along with citric acid
/ sodium bicarbonate and glucose was prepared. Thin
poly(lactide-co-glycolide) (PLGA) membrane (to allow
water penetration inside the capsule) was utilized on
one end. Water penetrates into the capsule through
the thin poly(lactide-co-glycolide) (PLGA) membrane
side, which generates effervescence due to reaction
caused between the citric acid and sodium
bicarbonate, generating carbon dioxide gas that
accumulates in the capsule and finally ruptures the
13, 14
thin membrane .
3.2. Stimuli induced pulsatile systems
In these systems there is release of the drug after
stimulation by any biological factor like temperature,
5
or any other chemical stimuli (Fig.3.) . These systems
are further classified in to temperature induced
systems and chemical stimuli induced system, on the
basis of stimulus.
3.2.1. Temperature induced systems
Thermo-responsive hydrogel systems have been
developed for pulsatile release. In these systems the
29
Review Article
18
copolymer were bound to concanavalin A . These
hydrogels showed a glucose-responsive, sol–gel phase
S* S transition dependent upon the external glucose
Drug concentration. Okano et al developed the system
External
environment delivery based upon the fact that boronic acid moiety forms
P
system reversible bonds with polyol compounds including
D glucose. They used water-soluble copolymers,
containing phenylboronic acid side chains which
S = Internal substrate activated by the stimuli
S* = External stimuli
showed formation of a reversible complex gels with
19
P = A reaction product formed after stimuli polyol compounds such as poly(vinyl alcohol) (PVA) .
D = Drug Such complexes dissociated after the addition of
glucose in a concentration dependent manner
Fig. 3. General scheme for stimuli sensitive pulsatile
drug delivery system 3.2.2.2. Inflammation-induced pulsatile release

polymer undergoes swelling or deswelling phase in
response to the temperature which modulate drug
15
release in swollen state . Y.H. Bae et al developed
indomethacin pulsatile release pattern in
0 0
temperature ranges between 20 C and 30 C
using reversible swelling properties of copolymers of
16
N-isopropylacrylamide and butyrylacrylamide . Kataoka
et al developed the thermosensitive polymeric micelles
as drug carrier to treat the cancer. They used end-
functionalized poly(N-isopropylacrylamide) (PIPAAm) to
prepare corona of the micelle which showed hydration
and dehydration behavior with changing temperature .
3.2.2. Chemical stimuli induced Pulsatile systems
3.2.2.1. Glucose-responsive insulin release devices
In case of diabetes mellitus there is rhythmic increase
in the levels of glucose in the body requiring injection
of the insulin at proper time. Several systems have
been developed which are able to respond to changes
in glucose concentration. One such system includes
pH sensitive hydrogel containing glucose oxidase
immobilized in the hydrogel. When glucose
concentration in the blood increases glucose oxidase
converts glucose into gluconic acid which changes the
pH of the system. This pH change induces swelling of
the polymer which results in insulin release. Insulin
by virtue of its action reduces blood glucose level
and consequently gluconic acid level also
decreased and system turns to the deswelling mode
thereby decreasing the insulin release. Examples of
the pH sensitive polymers includes
dimethylaminoethyl methacrylate, chitosan, polyol etc.
Obaidat and Park prepared a copolymer of acryl amide
and allyl glucose. The side chain glucose units in the
On receiving any physical or chemical stress, such as
injury, fracture etc., inflammation take place at the
injured sites. During inflammation, hydroxyl radicals
the are produced from these inflammation-responsive cells.
by Yui and co-workers focused on the inflammatory-
induced hydroxyl radicals and designed drug delivery
systems, which responded to the hydroxyl radicals
and degraded in a limited manner. They used
hyaluronic acid (HA) which is specifically degraded by
the hyaluronidase or free radicals. Degradation of HA
via the hyaluronidase is very low in a normal state of
17
health. Degradation via hydroxyl radicals however, is
usually dominant and rapid when HA is injected at
inflammatory sites. Thus, it is possible to treat patients
with inflammatory diseases like rheumatoid arthritis;
using anti-inflammatory drug incorporated HA gels as
new implantable drug delivery systems20.
3.2.2.3. Drug release from intelligent gels responding
to antibody concentration
There are numerous kinds of bioactive compounds
which exist in the body. Recently, novel gels were
developed which responded to the change in
concentration of bioactive compounds to alter their
swelling/deswelling characteristics. Special attention
was given to antigen-antibody complex formation as
the cross-linking units in the gel, since such interaction
are very specific. Utilizing the difference in association
gets
constants between polymerized antibodies and
naturally derived antibodies towards specific antigens,
reversible gel swelling/deswelling and drug permeation
N,N- 21
changes occurs .
3.2.2.4. pH sensitive drug delivery system
Such type of pulsatile drug delivery system contains

30 CRIPS Vol. 8 No. 2 April-June 2007

 Review Article
Table 2. Marketed technologies of pulsatile drug delivery

Technology Mechanism Proprietory name API Disease Reference

and dosage form

® ®
OROS Osmotic Covera-HS ; XL Verapamil HCl Hypertension 28
mechanism tablet

® ®
CODAS Multiparticular Verelan PM; XL Verapamil HCl Hypertension 29
pH dependent release capsule
system

® ®
DIFFUCAPS Multiparticulate Innopran ; XL Verapamil HCl, Hypertension 30
system tablets Propranolol HCl

®
Three dimen- Externally TheirForm Diclofenac sodium Inflammation 31
®
sional printing regulated system

TM TM
Pulsincap Rupturable system Pulsincap Dofetilide Hypertension 32

two components one is of immediate release type
and other one is pulsed release which releases the
drug in response to change in pH. In case of pH
dependent system advantage has been taken of the
fact that there exists different pH environment at
different parts of the gastrointestinal tract. By selecting
the pH dependent polymers drug release at specific
location can be obtained. Examples of pH dependent
polymers includes cellulose acetate phthalate,
polyacrylates, sodium carboxymethylcellulose. These
polymers are used as enteric coating materials so as
to provide release of drug in the small intestine. Yang
et al developed pH-dependent delivery system of
nitrendipine in which they have mixed three kinds of
pH dependent microspheres made up of acrylic resins
Eudragit E-100, Hydroxypropylmethylcellulose phthalate
and Hydroxypropylmethylcellulose acetate succinate
as pH dependent polymers. In one of the study carried
out by Mastiholimath et al attempt was made to
deliver theophylline into colon by taking the advantage
of the fact that colon has a lower pH value (6.8) than
that of the small intestine (7.0–7.8). So, by using the
mixture of the polymers, i.e. Eudragit L and Eudragit
S in proper proportion, pH dependent release in the
colon was obtained .
22
3.3. Externally regulated systems
For releasing the drug in a pulsatile manner, another
way can be the externally regulated systems in which
drug release is programmed by external stimuli like
magnetism, ultrasound, electrical effect and irradiation.
Magnetically regulated system contain magnetic beads
in the implant. On application of the magnetic field,
drug release occurs because of magnetic beads.
Saslawski et al. developed different formulation for
in vitro magnetically triggered delivery of insulin based
23
on alginate spheres . In case of ultrasonically
modulated systems, ultrasonic waves causes the
erosion of the polymeric matrix thereby modulating
drug release. Miyazaki et al evaluated the effect of
ultrasound (1 MHz) on the release rates of bovine
insulin from ethylenevinyl alcohol copolymer matrices
and reservoir-type drug delivery systems in which
they found sharp drop in blood glucose levels after
24
application of ultrasonic waves . Also irradiation with
light rays the desired drug release pattern. Mathiowitz
et al developed photochemically controlled delivery
systems prepared by interfacial polymerization of
polyamide microcapsules. For this purpose,
azobisisobutyronitrile (AIBN), a substance that
photochemically emanates nitrogen gas, was
incorporated. Due to exposure of azobisisobutyronitrile
to light, causing release of nitrogen and an increase
in the pressure which ruptures the capsules thereby
25
releasing the drug .
4. Recent advances in the pulsatile drug
delivery
Nowadays pulsatile drug delivery systems are gaining
importance in various disease conditions specifically
in diabetes where dose is required at different time
intervals. Among these systems, multi-particulate
systems (e.g. pellets) offer various advantages over
single unit which include no risk of dose dumping,

CRIPS Vol. 8 No. 2 April-June 2007 31

Review Article
flexibility of blending units with different release 7. References
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26
residence time . Multiparticulate systems consists 8
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have been developed on the basis of methodologies
as discussed previously. These includes OROS
® 11. Gazzaniga A, Paluga L, Foppoli A, et al. (2007)
technology, CODAS
®
technology, CEFORM
®
technology, Eur. J. Pharm. and Biopharm. (In Press)
® ®
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®
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995
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32 CRIPS Vol. 8 No. 2 April-June 2007


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