Pulsatile Drug Delivery System: A Promising
Delivery System
Pragya Baghel*, Amit Roy, Shashikant Chandrakar, Sanjib Bahadur
Columbia Institute of Pharmacy, Vil. Tekari, Near Vidhan Sabha, Raipur (C.G) 493 111
ABSTRACT:
Pulsatile drug delivery system is
nowadays gaining a lot of interest as they deliver the drug at right site of
action at the right time and in the right amount. These systems are designed
according to the circadian rhythm of the body, and the drug is released rapidly
and completely as a pulse after a lag time. Products follow the sigmoid release
profile characterized by a time period. Theses follow chronopharmacological
behavior, where nocturnal dosing is required, and for drugs that show the
first-pass effect. Various systems like capsular system, osmotic system, and
single multiple unit system based on the use of soluble or erodible polymer
coating and use of rupturable membrane. Diseases
where in PDDS are promising include asthma, peptic ulcers, cardiovascular
ailments, arthritis and attention deficit syndrome in children and
hypercholesterolemia.
KEYWORDS: Pulsatile drug delivery, Chronopharmacology, Circadian Rhythm, Sigmoidal
Release
INTRODUCTION:
Conventional controlled release drug
delivery systems are based on single- or multiple-unit reservoir or matrix
systems, which are designed to provide constant or nearly constant drug levels
over an extended period of time. 1
In the body under physiological
conditions, many vital functions are regulated by transient release of
bioactive substances at a specific time and site. Thus, to mimic the function
of living systems and in view of emerging chronotherapeutic
approaches, pulsatile delivery, which is meant to
release a drug following programmed lag phase, has attracted increasing
interest in recent years.2 In recent years, temporal control of drug
delivery has been of interest to achieve improved drug therapies. Pulsatile drug delivery system has the advantage of
avoiding drug tolerance or matching the chronotherapeutic
needs. The oral pulsatile release system was mainly
for the treatment of disease symptoms such as hypertension, ischemic, heart
disease, asthma and rheumatoid arthritis that exhibit circadian rhythms. The
required amount of drug should be released from the drug delivery system at the
required time of night or early morning.3
Pulsed or pulsatile
drug release is defined as the rapid and transient release of a certain amount
of drug molecules within a short time-period immediately after a predetermined
off-release period. Pulsatile release is commonly
found in the body, for example during hormone release, in which a baseline
release is combined with pulsed, one-shot type release within a short time
range. For this mode of delivery it is assumed that constant plasma drug levels
are not preferred and an optimal therapeutic effect comes from a periodically
fluctuating drug concentration.4
Pulsatile drug delivery system (PDDS) is
based on principle of rapid release of a certain amount of drug within short
time period after a predetermined off-release period, lag time. Such novel drug
delivery has been attempted for (i) chronopharmacotherapy of diseases which show circadian
rhythms in their pathophysiology (ii) avoiding degradation of active
ingredients in upper GI tract, e.g. proteins and peptides (iii) for time programmed administration of
hormones and many drugs such as isosorbide dinitrate, respectively to avoid suppression of normal
secretion of hormones in body that can be hampered by constant release of
hormone from administered dosage form and development of resistance (iv) to
avoid pharmacokinetic drug–drug interactions between concomitantly administered
drugs, etc.5
Several approaches to pulsatile
drug delivery exist. Most systems contain a drug reservoir, surrounded by a
barrier which either erodes or dissolve, or ruptures. With eroding or
dissolving systems, a potential problem is the retardation and therefore not
immediate drug release after the loss of the barrier function or a premature
release, seen in particular with highly water-soluble drugs. Capsular-shaped
systems are more independent from the nature of the content, for example, the Pulsincap system, which consists of an insoluble capsule
body and a swellable plug. One drawback of this
system was the use of a non approved plug material. This problem was overcome
with devices of similar shape comprising insoluble capsule shells and swellable or degradable plugs made of approved substances,
such as hydrophilic polymers or lipids. However, these capsular systems require
special equipment and manufacturing steps and, therefore, large-scale production
is complicated. In addition, larger non-degradable single-unit devices could
become critical with regard to GI-accumulation.6
Pulsatile drug release profiles are
interesting for the treatment of several diseases including hypertension,
bronchial asthma, myocardial infarction, angina pectoris, rheumatic disease,
and ulcer disease. Pulsatile release DDS allow the
adaptation of drug therapies to chronopharmacological
needs.7 Controlled release systems displaying pulsatile
release are mainly based on polymeric materials. These systems can be
classified into one pulse, double pulse and mixed pulse systems. Most pulsatile systems are reservoir systems and usually covered
with a barrier. This barrier can be dissolved, eroded or removed at a
predetermined period of time after which the drug is dissolved and rapidly
released.8
Fig. 1. Schematic representation of pulsatile
drug delivery system.8
Chronotherapeutical devices based on osmotic pumps
have been developed by MaGruder and Cutler Time
controlled coating systems were also developed by Ueda and Narisawa,
including single and multiple unit dosage forms. The major problem with these
formulations is that they concern complicated and not industrially scalable
systems.9
Among single unit and multi particulate
system, Multiparticulate systems (e.g. pellets) offer
various advantages over single unit. These include no risk of dose dumping,
flexibility of blending units with different release patterns, as well short
and reproducible gastric residence time.10
For pulsatile
release purposes, a variety of design strategies have been attempted. Several
coated, capsular and osmotic formulations have indeed been described. In the
present article, the main oral pulsatile delivery
systems proposed are surveyed with regard to the relevant formulation
characteristics and release performance.
1.
Delivery systems based on
release-controlling coatings
Coatings with differing
compositions are applied to solid cores that contain the active ingredient in
order to defer the onset of its release. Erodible devices are provided with
hydrophilic polymeric coatings of adequate thickness. When exposed to aqueous
media, these undergo swelling, dissolution and/or erosion phenomena that result
in a delayed release of the drug from the core formulation. Lag time is
basically programmed by selecting the appropriate polymer and coating level.
2.
Delivery systems based on
release-controlling plugs
A number of capsular systems
were described from which pulsatile delivery was
obtained through the timely ejection of a hydrophilic matrix plug sealing the
drug formulation in an impermeable capsule body. Upon contact with aqueous
fluids, a rapid dissolution of the gelatin cap would occur and the plug could
indeed undergo a gradual swelling process until expulsion from the body, thus
allowing the drug to be delivered. The lag phase prior to release coincided
with the time needed for plug removal, and its duration depended on the
physical-chemical nature, size and position of the plug itself.
3.
Delivery systems based on
osmotic pumping
Osmotic pumping was relied on to
develop a once-a-day controlled-onset extended-release (COER-24) formulation of
verapamil hydrochloride. In accordance with the OROS®
Push–PullTM technology, COER-24 consisted of a
bipartite core tablet including an expanding polymeric compartment and a drug
compartment. The core was entirely coated by a semi-permeable film with laser
drilled orifices connecting the drug tablet with the outer medium. A
hydrophilic coat was interposed between the core and the outer membrane to
further prolong the dela preceding the onset of
release. Upon water ingress, the active ingredient dissolved and the push
compartment started swelling. As a result, the drug solution was pumped out at
a constant rate through the orifices of the semipermeable
film. Sustained release of verapamil was demonstrated
to occur after lag times of 4–6 h, and a good in vitro–in vivo correlation was
assessed.11
The majority of existing pulsatile release systems can be classified into two
categories, time-controlled system and stimuli-induced systems. Time-controlled
release systems can only release at pre-programmed time points, whereas
stimuli-induced pulsatile release systems are more
easily manipulated. Stimuli-induced systems have been developed based on
thermal, chemical, and electrical stimuli. However, systems based on thermal
stimuli are particularly convenient since they can be designed and operated
without significantly affecting other critical parameters of the system.12
Pulsatile drug delivery systems are
characterized by two release phases, a first phase with no or little drug being
released, followed by a second phase, during which the drug is released
completely within a short period of time after the lag-time. The release can be
either time- or site-controlled. The release from the first group is
essentially determined by the system, while the release from the second group
is primarily controlled by the biological environment in the gastrointestinal
tract (e.g. pH or enzymes)13. The simplest pulsatile
formulation corresponds to the press-coated tablets comprised of two layers.
Solid dosage film coating has been used for more than 30 years in
pharmaceutical technology. The disadvantage of such formulations is that the
rupture time cannot be adjusted as it is strongly correlated with the
physicochemical properties of the polymer.14
There are many other such systems under pulsatile release which are discussed below:
Pre-Programmed
Drug Delivery System
These systems are designed to release drug
in pulses governed by the device fabrication and ideally, independent of the
environment. The release mechanisms employed include bulk erosion of the
polymer in which drug release by diffusion is restricted, surface erosion of
layered devices composed of alternating drug-containing and drug-free layers, osmotically controlled rupture and enzymatic degradation of
liposomes.
-
Bulk-eroding systems
-
Surface eroding systems
-
Osmotically controlled systems
-
Enzymatically activated liposomes
Closed-loop
delivery systems
Closed-loop delivery systems are those that
are self-regulating. They are similar to the programmed delivery devices in
that they do not depend on an external signal to initiate drug delivery.
However, they are not restricted to releasing their contents at predetermined
times. Instead, they respond to changes in local environment, such as the
presence or absence of a specific molecule
-
Glucose sensitive systems
Open loop delivery
systems
Open-loop delivery systems are not
self-regulating, but instead require externally generated environmental changes
to initiate drug delivery. These can include magnetic fields, ultrasound,
electric field, temperature, light and mechanical force.15
-
Magnetic Field
-
Ultrasound
-
Temperature
-
Electric Field
-
Light
-
Mechanical force
CONCLUSION:
Pulsatile drug delivery system is found
to be a better delivery system that has proved to be shown better and improved
patient compliance, by delivering the drug at right time, right place and in
right amount. Patients suffering from chronic diseases such as asthma, heart
diseases etc. holds a promising benefit by such delivery system.
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Received on 15.05.2013
Modified on 20.06.2013
Accepted on 02.07.2013
© A&V Publication all right reserved
Research Journal of Pharmaceutical Dosage Forms and Technology. 5(3):
May- June, 2013, 111-114