Sharma Ritika et al.

IRJP 2012, 3 (7)

Page 103
INTERNATIONAL RESEARCH JOURNAL OF PHARMACY
www.irjponline.com ISSN 2230 8407
Review Article


PULSATILE DRUG DELIVERY SYSTEM: A REVIEW
Sharma Ritika*, Singh Arjun, Kumar Sunil, Jamil Faraz
Pharmaceutics Research Lab., Vivek College of Technical Education, Bijnor (UP) India

Article Received on: 12/04/12 Revised on: 11/05/12 Approved for publication: 20/05/12

*Email: [email protected]

ABSTRACT
The purpose for this review on pulsatile drug delivery systems (PDDS) is to compile the recent literatures with special focus on the different types and
approaches involved in the development of the formulation. Pulsatile drug delivery system is the most interesting time and site-specific system. 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. Marketed product like
Pulsicap, Ritalin and Pulsys are based on pulsatile release system. The aim of this review is to describe several types of drug delivery systems. This
review also summarizes some current PDDS already available in the market. These systems are useful to several problems encountered during the
development of a pharmaceutical dosage form.
Key words: Pulsatile drug delivery, lag time, Circadian rhythm and time controlled drug release system.

INTRODUCTION
Pulsatile drug delivery system is gaining a lot of interest and
attention now a day. Though most delivery system is
designed for constant drug release over a prolonged period of
time, PDDS are characterized by a programmed drug release,
as constant blood level may not always be desirable. These
systems have a typical mechanism of delivering the drug
rapidly and completely after a lag time
1
. Traditionally, drug
delivery systems have focused on constant/sustained drug
output with the objective of minimizing peaks and valleys of
drug concentrations in the body to optimize drug efficacy and
to reduce adverse effects. A reduced dosing frequency and
improved patient compliance can also be expected for the
controlled/sustained release drug delivery systems, compared
to immediate release preparations
2.
However, in the field of
modern drug therapy, growing attention has lately been
focused on pulsatile delivery of drugs for which conventional
controlled drug-release systems with a continuous release are
not ideal.


Fig. 1. Drug release profile of pulsatile drug delivery systems

Diseases where a constant drug levels are not preferred, but
needs a pulse of therapeutic concentration in a periodic
manner acts as a push for the development of Pulsatile Drug
Delivery Systems
.
In these systems, there is rapid and
transient release of a certain amount of drug molecules within
a short time period immediately after a predetermined off
release period ,i.e lag time
3
. Lag time is defined as the time
between when a dosage form is placed into an aqueous
environment and the time at which the active ingredient
begins to get released from the dosage form
4
.
Chronopharmaceutics consists of two words chronobiology
and pharmaceutics.
Chronobiology is the study of biological rhythms and their
mechanisms. There are three types of mechanical rhythms in
our body. They are :
Circadian: Circa means about and dies means day
Ultradian: Oscillation of shorter duration are termed as
ultradian (more than one cycle per 24 h)
Infradian: Oscillations that are longer than 24 h (less than
one cycle per day)
5
.
Various techniques are available for the pulsatile delivery
like pH dependent systems, time dependent systems, micro-
flora activated systems etc. which can be designed as per the
physiology of disease and properties of the drug molecule
3.
The pulsatile release of an active agent is desirable when
treating diseases that require drug delivery in a manner to
maintain therapeutic levels albeit circadian rhythms
6
. A large
body of literature can be found on oral pulsatile drug delivery
systems, which have been accepted as potentially useful to
the chronotherapy of some common diseases, such as
bronchial asthma, hypertension, angina pectoris, allergic
rhinitis and osteo-/ rheumatoid- arthritis with mainly night or
early morning symptoms
7
.
The shift from conventional sustained release approach to
modern pulsatile delivery of drugs can be credited to the
following reason(s):
First pass metabolism
Some drugs, such as beta blockers, and salicylamide, undergo
extensive first pass metabolism and require fast drug input to
saturatemetabolizing enzymes in order to minimize pre-
systemic metabolism. Thus, a constant/sustained oral method
of delivery would result in reduced oral bioavailability.


Sharma Ritika et al. IRJP 2012, 3 (7)
Page 104
Biological tolerance
Continuous release drug plasma profiles are often
accompanied by a decline in the pharmacotherapeutic effect
of the drug, e.g., biological tolerance of transdermal
nitroglycerin.
Special chronopharmacological needs
Circadian rhythms in certain physiological functions are well
established. It has been recognized that many symptoms and
onset of disease occur during specific time periods of the 24
hour day, e.g., asthma and angina pectoris attacks are most
frequently in the morning hours.
Local therapeutic need
For the treatment of local disorders such as inflammatory
bowel disease, the delivery of compounds to the site of
inflammation with no loss due to absorption in the small
intestine is highly desirable to achieve the therapeutic effect
and to minimize side effects.
Gastric irritation or drug instability in gastric fluid
For compounds with gastric irritation or chemical instability
in gastric fluid, the use of a sustained release preparation may
exacerbate gastric irritation and chemical instability in gastric
fluid.
Drug absorption differences in various gastrointestinal
segments
In general, drug absorption is moderately slow in the
stomach, rapid in the small intestine, and sharply declining in
the large intestine. Compensation for changing absorption
characteristics in the gastrointestinal tract may be important
for some drugs. For example, it is rational for a delivery
system to pump out the drug much faster when the system
reaches the distal segment of the intestine, to avoid the
entombment of the drug in the feaces
2
.
METHODOLOGIES FOR PULSATILE DRUG
DELIVERY
Methodologies for the pulsatile drug delivery system can be
broadly classified into three classes;
1. Time controlled
2. Stimuli induced
3. Externally regulated
4. Multipaticulate system
Time controlled pulsatile release system
In time controlled drug delivery systems pulsatile release is
obtained after a specific time interval in order to mimic the
circadian rhythm. Such type of pulsatile drug delivery system
contains two components: one is of immediate release type
and other one is a pulsed release type.
Various methodologies that can be used for time controlled
pulsatile release systems are following:-
Delivery systems with rupturable coating layer


Fig. 2. Schematic diagram of Deliver systems with rutpurable 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 effervescent additives in the reservoir
8
. By
optimizing the system, drug release can be obtained at
specific time interval.
Delivery systems provided with erodible coating layers


Fig. 3. Schematic diagram of Delivery systems 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 optimizing the thickness
of the outer coat
9
.
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.


Fig.4. Schematic diagram of Capsule shaped system provided with
release controlling plug

Pulsatile System Based On Osmosis
Osmotic system consists of capsule coated with the
semipermeable membrane. Inside the capsule there is an
insoluble plug consisting of osmotically active agent and the
drug formulation
10
.
e.g. The Port System
11
.


Fig.5. Schematic diagram of osmosis system

Stimuli induced pulsatile systems
In these systems there is release of the drug after stimulation
by any biological factor like temperature, or any other
chemical stimuli
12
. These systems are further classified as:
Temperature induced systems
Thermo-responsive hydrogel systems have been developed
for pulsatile release. In these systems the polymer undergoes
swelling or deswelling phase in response to the temperature
which modulate drug release in swollen state
1
. Y.H. Bae et al
developed indomethacin pulsatile release pattern in the
Sharma Ritika et al. IRJP 2012, 3 (7)
Page 105
temperature ranges between 20
0
C and 30
0
C by using
reversible swelling properties of copolymers of N-
isopropylacrylamide and butyrylacrylamide
13
.
Chemical stimuli induced Pulsatile system
Glucose-responsive release devices
In case of diabetes mellitus there is insulin 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 gets decreased and
system turns to the deswelling mode thereby decreasing the
insulin release. Examples of the pH sensitive polymers
includes N,Ndimethylaminoethyl methacrylate, chitosan,
polyol etc.
Inflammation-induced pulsatile release
On receiving any physical or chemical stress, such as injury,
fracture etc., inflammation take place at the injured sites.
During inflammation, hydroxyl radicals are produced from
these inflammation-responsive cells .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 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
systems
14
.
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 constants between polymerized antibodies and
naturally derived antibodies towards specific antigens,
reversible gel swelling/deswelling and drug permeation
changes occurs
15
.
pH sensitive drug delivery system
Such type of pulsatile drug delivery system contains 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.

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
16
. 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 on alginate spheres
17
. 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
application of ultrasonic waves
18
.
Multipaticulate system
Recent trends indicate that multiparticulate drug delivery
systems are especially suitable for achieving controlled or
delayed release oral formulations with low risk of dose
dumping, flexibility of blending to attain different release
patterns as well as reproducible and short gastric residence
time. Such systems are reservoir type with either rupturable
or altered permeability coating and generally housed in
capsular body. The purpose of designing multiparticulate
dosage form is to develop a reliable formulation that has all
the advantages of a single unit formulation and yet devoid of
the danger of alteration in drug release profile and
formulation behaviour due to unit to unit variation
19
.


Fig.6. Hypothetical design of a multiparticulate pulsatile system

DISEASES REQUIRING PULSATILE DRUG
DELIVERY
Circadian rhythm regulates many body functions in humans,
viz., metabolism, behavior, Physiology, sleep patterns,
hormone production, etc. Asthma is one such disease where
pulsatile drug delivery system can be useful. Capillary
resistance and vascular reactivity are higher in the morning
and decrease later in the day. Circadian changes are seen in
normal lung function, which reaches a low in the early
morning hours. Blood pressure is also reported to be high in
the morning and low during night
20
. Platelet aggregability is
increased and fibrinolytic activity is decreased in the
morning, leading to hypercoagulability of the blood
21
. Patient
suffering from rheumatoid arthritis feel more pain in morning
period while patient suffering from osteoarthritis feel less
pain in morning than night
20
. Thus in such disease condition,
release of some drug is ideal in pulse pattern. A single dosage
form provides an first dose of drug followed by one release-
free interval, after which second dose of drug is released,
which is followed by further release-free interval and pulse of
drug release.


Sharma Ritika et al. IRJP 2012, 3 (7)
Page 106
Table 1. Diseases requiring Pulsatile Drug Delivery
Disease Chronological behavior Drugs used
Peptic ulcer Acid secretion is high in
the afternoon and at night
H2 blockers
Asthma Precipitation of attacks
during night or at early
morning hour

2
agonist,
Antihistaminics
Cardiovascular
diseases
BP is at its lowest during
the sleep cycle and rises
steeply during the early
morning awakening
period
Nitroglycerin,
Calcium channel
blocker, ACE
inhibitors,

Blockers etc.
Arthritis Pain in the morning and
more pain at night
NSAIDs,
Glucocorticoids
Diabetes mellitus Increase in the blood
sugar level after meal
Sulfonylurea,
Insulin,
Biguanide
Attention deficit
syndrome
Increase in DOPA level in
afternoon
Methylphenidate
Hypercholesterolemia Cholesterol synthesis is
generally higher during
night than during day time
HMG CoA
reductase
inhibitors

MERITS
2

1.Predictable, reproducible and short gastric residence time.
2.Less inter- and intra-subject variability.
3.Improve bioavailability.
4.Limited risk of local irritation.
5.No risk of dose dumping.
6.Flexibility in design.
7.Improve stability.
LIMITATIONS OF PULSATILE DRUG DELIVERY
SYSTEM
22

1. Multiple manufacturing steps in case of Multiparticulate
drug delivery system.
2. Low drug load.
3. Incomplete release.
4. In vivo variability in single unit pulsatile drug delivery
system.
5. Drug dose manipulation in case of child and elder patients
is not possible.
6. Immediate withdrawal of drug is not possible.
RECENT ADVANCES IN THE PULSATILE DRUG
DELIVERY SYSTEM
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, flexibility of blending units with
different release patterns, as well as short and reproducible
gastric residence time
23
. Multiparticulate systems consists
pellets of different release profile which can be of any type
like time dependent, pH dependent, micro flora activated
system as discussed in the previous sections. Site and time
specific oral drug delivery have recently been of great interest
in pharmaceutical field to achieve improved therapeutic
efficacy. Gastroretentive drug delivery system is an approach
to prolong gastric residence time, thereby targeting
sitespecific drug release in upper gastrointestinal (GI) tract.
Floating drug delivery system (FDDS) and bioadhesive drug
delivery are widely used techniques for gastro retention. Low
density porous multiparticulate systems have been used by
researchers for formulation of FDDS. Sharma and Pawar
developed multiparticulate floating pulsatile drug delivery
system using porous calcium silicate and sodium alginate for
time and site specific drug release of meloxicam
24
. Various
pulsatile technologies have been developed on the basis of
methodologies as discussed previously. These includes
OROS technology, CODAS technology, CEFORM
technology, DIFFUCAPS technology, Three-dimensional
printing, timerx etc.

Table 2. Marketed technologies of pulsatile drug delivery
Technology Mechanism Proprietoy name
and dosage form
API Disease Reference
CODAS

Multiparticular pH
dependent system
Verelan

PM; XL
release capsule
Verapamil HCL Hypertension 25
DIFFUCAPS

Multiparticulate system Innopran

; XL
Tablets
Verapamil
HCL,Propranolol HCL
Hypertension 26
Three dimen-
Externally
TheirForm

Externally regulated
system
TheirForm

Diclofenac HCL Inflammation 27

Pulsincap
TM
Rupturable system Pulsincap
TM
Dofitilide Hypertension 28

CURRENT SITUATION AND FUTURE SCOPE
The development of drug products by pulsatile technology is
very challenging since it requires the correct dose to reach the
right site at the appropriate time. However, the novel PDDS
pays more attention on site and time-specificity. It is believed
that in the near future novel PDDS will be explored in the
treatment or management of some other chronic and terminal
disease conditions like 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,
flexibility of blending units with different release patterns, as
well as short and reproducible gastric residence time
29
. Site
and time specific oral drug delivery have recently been of
great interest in pharmaceutical field to achieve improved
therapeutic efficacy. Gastroretentive drug delivery system is
an approach to prolong gastric residence time, thereby
targeting sitespecific drug release in upper gastrointestinal
(GI) tract. Floating drug delivery system (FDDS) and
bioadhesive drug delivery are widely used techniques for
gastro retention. Low density porous multiparticulate systems
have been used by researchers for formulation of FDDS.
Sharma and Pawar developed multiparticulate floating
pulsatile drug delivery system using porous calcium silicate
and sodium alginate for time and site specific drug release of
meloxicam
24
.
CONCLUSION
There is a constant need for new delivery systems that can
provide increased therapeutic benefits to the patients.
Circadian rhythm of the body is an important concept for
understanding the optimum need of drug in the body.
Pulsatile-release formulations have many advantages over
immediate-release formulations. With these formulations,
less-frequent drug administration is possible, and patient
compliance can correspondingly be improved. In this field of
drug delivery, increased attention has recently been focused
Sharma Ritika et al. IRJP 2012, 3 (7)
Page 107
on the potential of systems that are able to release drugs after
a programmable lag phase commencing at administration
time, i.e., in a pulsatile mode. Various methodologies are
employed for developing pulsatile drug delivery like time
controlled PDDS which includes delivery systems with
rupturable coating layer or with erodible coating layers or
with release controlling plug, stimuli induced
PDDS less temperature induced and chemical stimuli induced
systems and externally regulated system. Multiparticulate
systems are useful for treatment of patients; due to their
resulting high efficiency and robustness. There are various
technologies present in the market based on the various
methodolgies. Pulsatile release systems should be promising
in the future. It should be pointed that these drug delivery
systems are still in the early developmental stage and much
research will have to be conducted for such systems become
practical clinical alternatives.
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