1. Pulsatile Drug Delivery
System
(PDDS)

2. Content
 Introduction
 Criteria of Drugs for PDDS
 Different Approaches
 Fabrication
 Recent Advancement
 Marketed Preparations
 Conclusion
 References

3. 1. Introduction
 Why conventional dosage forms???
◦ Advantages (Material, Manufacturing,
Technology, Patient complience)
 Why modified/ controlled dosage forms??
◦ Advantages over conventional dosage forms
( Chronic Treatment, Patient complience, cost of
over all treatment)

4.  What and Why PDDS ? ? ?
 Pulsatile drug delivery system is defined as the rapid and
transient release of certain amount of drug molecules within a
short time period immediately after a predetermined off-
release period, i.e., lag time.
 Pulsatile drug delivery aims to release drug on
programmed pattern i.e. at appropriate time and at
appropriate site of action. NOON
HIGH ALERTNESS
BEST COORDINATION
HIGHEST TESTOSTERONE SECRETION
FASTEST REACTION TIME
BOWEL MOVEMENT LIKELY
MELATONIN SECRETION STOPS GREATEST CVS EFFICIENCY & MUSCLE
STRENGTH
SHARPEST RISE
IN BP
HIGHEST BLOOD PRESSURE
HIGHEST BODY TEMP
LOWEST BODY TEMP
MELATONIN SECRETION STARTS
DEEPEST SLEEP
BOWEL MOVEMENT SUPPRESSED
MIDNIGHT
Circadian

5. Necessity of PDDS
1. Chronopharmacotherapy of diseases which
shows circadian rhythms in their pathophysiology.
1. asthmatic attacks during early morning
2. heart attacks in the middle of the night
3. morning stiffness in arthritis
2. Avoiding the first pass metabolism e.g. protein
and peptides
3. For which the tolerance is rapidly exists (e.g.
Salbutamol sulphate)
4. For targetting specific site in intestine e.g. colon
(e.g Sulfasalazine)
5. For time programmed administration of hormone
and drugs,
6. For drugs having the short half life (e.g ß-
blockers)

6. Advantages
1. Extended daytime or nighttime activity
2. Reduced side effects
3. Reduced dosage frequency
4. Reduction in dose size
5. Improved patient compliance
6. Lower daily cost to patient due to fewer dosage units are
required by the patient in therapy.
7. Drug adapts to suit circadian rhythms of body functions or
diseases.
8. Drug targeting to specific site like colon.
9. Protection of mucosa from irritating drugs.
10.Drug loss is prevented by extensive first pass metabolism

7. Different Approaches
A. PREPLANNED SYSTEMS
I. Pulsatile system based on capsule
II. Pulsatile system based on osmosis
III. Drug delivery system with erodible or soluble
layer
IV. Drug delivery system with rupturable layer
B. STIMULI INDUCED PULSATILE SYSTEMS
I. Temperature induced system
II. Chemically induced System
III. Externally stimuli System

8. A. PREPLANNED SYSTEMS
I. Pulsatile system based on capsule
1. PULSINCAP®
The Pulsincap® system (Scherer DDS, Ltd) is an example of such a
system that is made up of a water insoluble capsule body filled with
drug formulation (McNeil et al., 1990, Wilding et al., 1992 and Saeger
et al. 2004). The body is closed at the open end with a swellable
hydrogel plug.
The length of plug decides lag time.
The plug material consists of insoluble but permeable and swellable
polymers (eg, polymethacrylates), erodible compressed polymers
(eg, hydroxypropylmethyl cellulose, polyvinyl alcohol,
polyethylene oxide) (Krögel et al., 1998), congealed melted
polymers (eg, saturated polyglycolated glycerides, glyceryl
monooleate), and enzymatically controlled erodible polymer (eg,
pectin, agar) (Krögel et al., 1999).

10. Advantages :
• Well tolerated in animals and healthy volunteers, and there
were no reports of gastro-intestinal irritation (Saeger et al.,
2004).
Disadvantages :
• Potential problem of variable gastric residence time, which was
overcome by enteric coating the system to allow its dissolution
only in the higher pH region of small intestine (Binns et al., 1996)

11.  Development and evaluation of pulsatile drug delivery
system using novel polymer
The aim of the present investigation was to develop a pulsatile
drug delivery system based on an insoluble capsule body
filled with theophylline microspheres and sealed with a
swellable novel polymer plug isolated from the endosperm
of seeds of higher plant Delonix regia family-Fabaceae.
Theophylline microspheres were prepared by solvent
evaporation method using Eudragit S 100. The swellable
plugs of varying thickness and hardness were prepared by
direct compression, which were then placed in the capsule
opening. The drug delivery system was designed to deliver
the drug at such a time when it was needed most to offer
convenience to the chronic patients of asthma. Formulated
dosage forms were evaluated for an in vitro drug release
study, which showed that the release might be consistent
with a release time expected to deliver the drug to the colon
depending on the thickness and hardness of the hydrogel
plug. Thus, thickness and hardness of the novel polymeric
plug plays an important role in controlling the drug release
from the formulated drug delivery system.

12. II. Pulsatile System Based On Osmosis
Osmotic system consists of capsule coated with the semipermiable
membrane.In this system for development of osmotic pressure
different techniques are used.
Case 1: Osmotic system containing insoluble plug (eg. PORT
system)
Case 2: Osmotic system based on expandable orifice
technology, Linkwitz et al.
elastomer (eg. Styrene-butadiene copolymer)
Case 3: Osmotic capsule containing micropores, Niwa et al

13. Fig. Drug release mechanism from Port Capsule
Step1: Cap dissolves off. immediately or modified release dose is
released.
Step 2: Energy source is activated by controlled permeation of GI
fluid.
Step 3: Time-release plug is expelled.
Step 4: Pulse or Sustained release of second dose.

14. III. Drug delivery system with erodible or soluble
layer
• 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
1. Chronotropic® system
2. Time Clock® system
3. Multilayered Tablet
1. Chronotropic® system
 consists of a drug containing core coated by
hydroxypropylmethyl cellulose (HPMC), a hydrophilic swellable
polymer, which is responsible for a lag phase in the onset of
release (Gazzania et al., 1994 and 1995).
 variability in gastric emptying time can be overcome, and a

15. Chronotropic® system

16. 2. Time Clock® system
 Consists of a solid dosage form coated with lipidic barriers
containing carnauba wax and bees‟ wax along with
surfactants, such as span 80 (Pozzi et al., 1992 and Wilding et
al., 1994).
 After a lag time proportional to the thickness of the film, this
coat erodes or emulsifies in the aqueous environment, and the
core is then available for dispersion.
 The lag time increased with increasing coating thickness
Wax +
Drug Core Surfactant

17. 3. Multilayered Tablet
A release pattern with two pulses was obtained from a three-layered
tablet containing two drug containing layers separated by a drug-free
gellable polymeric barrier layer (Conte et al., 1989 and 1992)
Multilayered Tablet
a. Initial rapid release drug layer
b. Drug – free gellable polymeric barrier layer
c. Second pulse generating drug layer
d. Impermeable ethyl cellulose layer (3 – sided)

18. IV. Drug delivery system with rupturable layer
These systems consist of an outer release controlling water
insoluble but permeable coating subject to mechanically induced
rupture phenomenon.
Ethyl cellulose
Bicarbonate coating
+ Citric acid
+ Drug
Rupturable
polymer layer
Superdisintegrating
agent + Drug

19.  Process and Formulation Variables Affecting the
Performance of a Rupturable Capsule‐Based Drug Delivery
System with Pulsatile Drug Release
 The objective of this study was to optimize several process and
formulation parameters, which influence the performance of a
rupturable, pulsatile drug delivery system. The system consisted
of a drug‐containing hard gelatin capsule, a swelling layer of
croscarmellose (Ac‐Di‐Sol®) and a binder, and an outer
ethylcellulose coating. Polyvinyl pyrrolidone (Kollidon 90F) was
superior to HPMC and HPC as a binder for the swelling layer
with regard to binding (adherence to capsule) and
disintegration properties of the swelling layer. The
capsule‐to‐capsule uniformity in the amount of swelling layer and
outer ethylcellulose coating, which significantly affected the lag
time prior to rupture of the capsule, was optimized by decreasing
the batch size, and by increasing the rotational pan speed and the
distance between the spray nozzle and the product bed. The type
of baffles used in the coating pan also affected the layering
uniformity. Fully‐filled hard gelatin capsules had a shorter lag time
with a higher reproducibility compared to only half‐filled capsules,
because the swelling pressure was directed primarily to the outer
ethylcellulose coating and not to the inner capsule core. Stability
studies revealed that the lag time of the capsules was stable over
a 240‐day period when the moisture content was kept unchanged.

20. B. STIMULI INDUCED PULSATILE SYSTEMS
I. Temperature induced system
 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. Eg.
1) Y.H. Bae et al developed indomethacin pulsatile release
pattern in the temperature ranges between 20oC and 30oC by
using reversible swelling properties of copolymers of N-
isopropylacrylamide and butyrylacrylamide.
2) Kataoka et al developed the thermosensitive polymeric micelles
as drug carrier to treat the cancer. They used endfunctionalized
poly(N-isopropylacrylamide) (PIPAAm) to prepare corona of the
micelle which showed hydration and dehydration behavior with
changing temperature.

21. I. Chemical induced system
 There has been much interest in the development of stimuli-
sensitive delivery systems that release a therapeutic agent in
presence of specific enzyme or protein.
 One prominent application of this technology has been
development of a system that can autonomously release insulin in
response to elevated blood glucose levels.
1. pH dependent system GLUCOSE GLUCONIC
ACID
Glucose oxidase
immobilized on cross linked
polyacrylamide
INSULIN
N, N- diethylaminoethyl
methacrylate and 2-hydroxypropyl
methacrylate (DEA-HPMA) formed
the barrier membrane

22. III. Externally stimuli System
 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.
a) Magnetically Stimulated
b) Ultrasonically Stimulated
c) Photo Stimulated
d) Electrically Stimulated

23. Evaluation Parameters
◦ Hardness
◦ Friability
◦ Weight uniformity
◦ Swelling index
◦ Thickness of layer
◦ Drug release profile
◦ Coating uniformity

24. Recent Advancement in
PDDS
1. ACCU-BREAK™ Technology
Accu-Break Pharmaceuticals, Inc. and
Azopharma Product Development Group, Inc.
Accu-Break tablets are manufactured on
commercially available multilayer
compression equipment. Accu-Break™
Technology is divided in to two types ACCU-
B™ Technology and ACCU-T™ Technology.

25. II.SODAS® Technology
 SODAS® (Spheroidal Oral Drug Absorption
System) is Elan‟s Multiparticulate drug delivery
system. Based on the production of controlled
release beads, the SODAS® technology is
characterized by its inherent flexibility, enabling
the production of customized dosage forms
that respond directly to individual drug
candidate needs.
 Elan‟s SODAS® Technology is based on the
production of uniform spherical beads of 1-2
mm in diameter containing drug plus excipients
and coated with product specific controlled
release polymers.
 The most recent regulatory approvals for a
SODAS® based system occurring with the
launch of once-daily oral dosage forms of
Avinza™, Ritalin® LA and Focalin® XR.

26. III. IPDAS® Technology
 The Intestinal Protective Drug Absorption System
(IPDAS® Technology) is a high density multiparticulate
tablet technology, intended for use with GI irritant
compounds.
 Once an IPDAS® tablet is ingested, it rapidly
disintegrates and disperses beads containing a drug in
the stomach, which subsequently pass into the
duodenum and along the gastrointestinal tract in a
controlled and gradual manner, independent of the
feeding state.
 Release of active ingredient from the multiparticulates
occurs through a process of diffusion through the
polymeric membrane. micromatrix of polymer/active
ingredient formed in the extruded/spheronized
multiparticulates.
 Naprelan®, which is marketed in the United States and
Canada, employs the IPDAS® technology. This
innovative formulation of naproxen sodium.

27. IV. CODAS™ Technology
 Elan‟s drug delivery technology can be
tailored to release drug after a predetermined
delay. The CODAS™ drug delivery system
enables a delayed onset of drug release,
resulting in a drug release profile that more
accurately compliments circadian patterns.
 Elan‟s Verelan® PM represents a
commercialized product using the CODAS™
technology. The Verelan® PM formulation
was designed to begin releasing Verapamil
approximately four to five hours post
ingestion. This delay is introduced by the
level of release-controlling polymer applied to
the drug-loaded beads.

28. V. PRODAS® Technology
 Programmable Oral Drug Absorption System
(PRODAS® Technology) is a multiparticulate
technology, which is unique in that it
combines the benefits of tabletting
technology within a capsule.
 The PRODAS® delivery system is presented
as a number of minitablets combined in a
hard gelatin capsule. Very flexible, the
PRODAS® technology can be used to pre-
program the release rate of a drug. It is
possible to incorporate many different
minitablets, each one formulated individually
and programmed to release drug at different
sites within the gastro-intestinal tract. It is
also possible to incorporate minitablets of
different sizes so that high drug loading is
possible.

29. VI. TMDS Technology
 TMDS (Time Multiple Action Delivery system)
Technology provide control release rate of multiple
ingredient within single tablet in programme
manner. TMDS Technology allows for more than
one active ingredient in a single tablet formulation
provide multiple release profile over extended
period of time.
VII. DMDS Technology
 DMDS (Dividable Multiple Action Delivery System)
is designed to provide greater dosing flexibility that
improve product efficacy and reduces side effects.
Traditional controlled release tablet often lose their
controlled release mechanism of delivery once it
broken. But DMDS technology allows tablet to be
broken down in half so that each respective portion
of the tablet will achieve exactly the same release
profile as the whole tablet. This allows the patient
and physician to adjust the dosing regimen
according to the clinical needs without

30. VIII. PMDS Technology
 PMDS (Programmed Multiple-action
Delivery System) technology is designed to
provide for the multi-phasic delivery of any
active ingredient in a more controlled
fashion as compared to typical controlled
release technologies.
 This technology allows us to overcome one
of the technical challenges in the
development of multi-particulate dosage
forms – achieving acceptable uniformity
and reproducibility of a product with a
variety of release rates. It is designed to
provide greater dosing flexibility that
improves product efficacy and may reduce

31. IX. GEOCLOCK® Technology
 SkyePharma developed a new oral drug
delivery technology, Geoclock®; that allows the
preparation of chronotherapy-focused press-
coated tablets.
 Geoclock® tablets have an active drug inside
an outer tablet layer consisting of a mixture of
hydrophobic wax and brittle material in order to
obtain a pH-independent lag time prior to core
drug delivery at a predetermined release rate.
This dry coating approach is designed to allow
the timed release of both slow release and
immediate release active cores by releasing
the inner table first after which time the
surrounding outer shell gradually disintegrates.
 Using this novel technology, SkyePharma has
been developing Lodotra™, a rheumathoid
arthritis drug, on behalf of Nitec Pharma.
Lodotra™ will deliver the active pharmaceutical
ingredient at the most suitable time of day to

32. X. GEOMATRIX™ Technology
 The Geomatrix™ technology is applied to
achieve customised levels of controlled
release of specific drugs and can achieve
simultaneous release of two different drugs
and different rates from a single tablet.
 The controlled release is achieved by
constructing a multilayered tablet made of
two basic key components; 1) hydrophilic
polymers such as hydroxypropyl
methycellulose (HPMC) and 2) surface
controlling barrier layers.
 SkyePharma manufactures several
Geomatrix™ products for its partners, which
include Sular® for Sciele, ZYFLO CR™ for
Critical Therapeutics, Coruno® for
Therabel, diclofenac-ratiopharm® uno for
ratiopharm and Madopar DR® for Roche.

33. XI. PULSYS™ Technology
 MiddleBrook™ (Earlier known as Advancis
Pharmaceuticals) Pharmaceuticals
developed PULSYS™, an oral drug delivery
technology that enables once daily pulsatile
dosing. The PULSYS™ dosage form is a
compressed tablet that contains pellets
designed to release drug at different regions
in the gastro-intestinal tract in a pulsatile
manner.
 PULSYS™ Technology‟s Moxatag™ tablet
contain Amoxicillin is designed to deliver
amoxicillin at lower dose over a short
duration therapy in once daily formulation.
Advancis have also demonstrated that by
preclinical studies which improved
bactericidal effect for amoxicillin when deliver
in pulsatile manner as compared to standard
dosing regimen even against resistant

34. XII. IntelliMatrixTM Technology
 IntelliPharmacetical is a pharmaceutical technology
development company with a suite of proprietary
tablet technologies.
 IntelliMatrixTM drug delivery platform is unique
composition of several different „intelligent‟
polymers such as hydroxy ethylcellulose and a
channel former as Lactose.
XIII. Eurand’s pulsatile and chrono release System
 Eurand‟s Time controlled pulsatile release system is
capable of providing one or more rapid release pulses
at predetermined lag times, such as when
chronotherapy is required, and at specific sites, such
as for absorption along the GI tract.
 Eurand has created a circadian rhythm release
(CRR) dosage form for a cardiovascular drug,
Propranolol hydrochloride, with a four-hour delay in
release after oral administration. Administered at
bedtime, Propranolol is released after the initial delay
such that maximum plasma level occurs in the early
morning hours, when the Patient is most at risk.

35. XIV. Banner’s VersetrolTM Technology
 VersetrolTM Technology is novel innovative
technology that provides time controlled
release for wide range of drug. In this
technology drug is incorporated in lipophilic or
hydrophilic matrix and that is than incorporated
in soft gelatin capsule shell. This technology is
versatile because depending on
physiochemical properties of drug either
emulsion or suspension can be developed. For
lipophilic drugs suspension formulation is
preferred while for hydrophilic drugs emulsion
form is utilized. By applying combination of
lipophilic and hydrophilic matrices desire
release profile can be achieved.

36. XV. Magnetic Nanocomposite Hydrogel
 Magnetic nanocomposite of temperature
responsive hydrogel was used as remote
controlled pulsatile drug delivery.
Nanocomposites were synthesized by
incorporation of superparamagnetic Fe3O4
particles in negative temperature sensitive
poly (N-isopropylacrylamide) hydrogels. High
frequency alternating magnetic field was
applied to produce on demand pulsatile drug
release from nanocomposite hydrogel.
Nanocomposite hydrogel temperature
increase above LCTS so, result in to
accelerated collapse of gel. Hence
Nanocomposites hydrogel are one type of
On-Off device where drug release can be turn
on by application of alternative magnteic field.

37. Marketed Products :

38. Conclusion
 It can be concluded that pulsatile drug delivery
systems offer a solution for delivery of drugs
exhibiting chronopharmacological behavior, extensive
first-pass metabolism, necessity of night-time
dosing, or absorption window in GIT.
 A variety of systems based on single or multiple units
are developed for pulsatile release of drug.
 One major challenge will be to obtain a better
understanding of the influence of the biological
environment on the release performance of pulsatile
delivery systems in order to develop simple systems
based on approved excipients with a good in vitro-in
vivo correlation.

39. References
1. Ramesh D. Parmar, et al. “Pulsatile Drug Delivery
Systems: An Overview”, International Journal of
Pharmaceutical Sciences and Nanotechnology,
Volume 2, Issue 3, Oct – Dec 2009.
2. JIGAR D. PATEL, et al. “PULSATILE DRUG
DELIVERY SYSTEM: AN "USER-FRIENDLY"
DOSAGE FORM”, JPRHC, Volume 2, Issue 2, April
2010, 204-215.
3. Roland A. Bodmeier, et al. “Drug Delivery: Pulsatile
Systems”
4. Recent Techniques For Oral Time Controlled
Pulsatile Technology, The Internet Journal of Third
World Medicine™ ISSN: 1539-4646