Pulsatile drug delivery are the system in which rapid & transient release of an active molecule within a short time period immediately after a predetermined off release period. i.e. lag time The Pulsatile effect i.e. the release of drug as a “pulse” after a lag time has to be designed in such a way that complete and rapid drug release should follow the lag time. Such systems are also called time-controlled as the drug release is independent of the environment.

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Department of Pharmacy (Pharmaceutics) | Sagar savale
Mr. Sagar Kishor SavaleMr. Sagar Kishor Savale
Department of Pharmaceutics
avengersagar16@gmail.com
2015-016

2. • Introduction
• Need for Pulsatile drug delivery
• Advantages
• Methodologies or Approaches
• Recent techniques for Pulsatile System
• Evaluation of pulsatile drug delivery system
• Case studies
• Conclusion
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3. Matrix
Devices
Membrane
Devices
Diffusion-
Controlled
Controlled
Release
Systems
Biodegradable
Systems
Pendant
Chain Systems
Chemically-
Controlled
Solvent-
Activated
Osmotically-
Controlled
Swelling-
Controlled
Rupture-
Controlled
Pulsatile
Delivery
Single
Pulse
Osmotically
Ruptured
Polymer
Dissolution
Erodible
polymer
Multiple
Pulse
Electrically-
Stimulated
Ultrasonically-
Controlled
Magnetically-
Controlled
Temperature-
Controlled
Inflammation
induced
pH-Sensitive
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4.  Pulsatile drug delivery are the system in which rapid & transient
release of an active molecule within a short time period
immediately after a predetermined off release period. i.e. lag
time
 The Pulsatile effect i.e. the release of drug as a “pulse” after a
lag time has to be designed in such a way that complete and
rapid drug release should follow the lag time. Such systems are
also called time-controlled as the drug release is independent of
the environment.
 The system deliver the drugs at:
right time
right place 4

5.  These systems are designed in such a way that there is rapid
and transient release of a certain amount of drug molecule
within a short time period immediately after a certain lag period.
 The lag period may very as per the requirement in disease
condition .The typical graph of pulsatile drug delivery differs
from controlled release is shown in figure.
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6.  Avoiding drug degradation in GIT.
 Drugs which develop biological tolerance.
 Drug with extensive first pass metabolism .
 Drug targeted to specific site in the intestinal tract.
 Chronopharmacotherapy of diseases which shows circadian
rhythms in their pathophysiology.
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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
β-2 agonist, Antihistaminic
Cardiovascular diseases BP is at its lowest during
the sleep cycle and rises
steeply during the early
morning
Nitroglycerin, Calcium
channel blocker, ACE
inhibitors 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

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• Reduced dosage frequency.
• Reduction in dose size.
• Extended daytime or night time activity.
• Improved patient compliance .
• Drug loss is prevented by first pass metabolism.

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• There are innumerable approaches for PDDS. In a
broad point of view methodologies for PDDS can be
categorized in to 3 ways:
I. Time controlled
systems
II. Stimuli induced
systems
III. Hydrogel systems

11. • Osmotic Pressure based systems
• Systems with Rupturable coatings
• Systems with Erodible/swellable coatings
• Capsular systems with polymeric plugs
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12. • The Port System constitute of a gelatin capsule coated with a
semi permeable membrane (e.g., cellulose acetate) housing an
insoluble plug (e.g., lipidic) and an osmotically active agent with
the drug formulation.
• Mechanism
• Upon contact with the aqueous medium, water diffuses across the
semi permeable membrane, resulting in increased inner pressure
that ejects the plug after a lag time.
• The lag time is manipulated controlled by coating thickness.
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14. • These systems depend on the disintegration of the coating for
the release of drug.
• The pressure necessary for the rupture of the coating can be
achieved by the effervescent excipients, swelling agents, or
osmotic pressure.
• An effervescent mixture of citric acid and sodium bicarbonate
was incorporated in a tablet core coated with ethyl cellulose.
• Mechanism: The carbon dioxide gas developed after
penetration of water into the core resulted in a pulsatile release
of drug after rupture of the coating.
• Lag time increases with increasing coating thickness and
increasing hardness of the core tablet.
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16. • Most of the pulsatile drug delivery
systems are
reservoir devices coated with a barrier
layer.
• This barrier erodes or dissolves after a
specific lag period, and the drug is
subsequently released rapidly.
• The time lag depends on the thickness
of the coating layer . 16

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18. • A general -design of such systems consists of an insoluble
capsule body housing a drug and a plug.
• The plug is removed after a predetermined time lag due to
swelling, erosion, or dissolution.
• The Pulsincap® system is an example of such a system
that is made up of a water-insoluble capsule body filled
with drug formulation.
• Upon contact with dissolution medium or gastro-intestinal
fluids, the plug swells, pushing itself out of the capsule
after a time lag. 18

19. • a) Insoluble but permeable and swellable polymers
e.g., polymethacrylates
• b)Erodible compressed polymers
e.g., hydroxypropylmethyl cellulose, polyvinyl
alcohol, polyethylene oxide
• c) Enzymatically controlled erodible polymer
e.g., pectin
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21. • This consists of pellet cores comprising drug and succinic acid
coated with ammonio-methacrylate copolymer USP/NF type B.
• The time lag is controlled by the rate of water influx through the
polymer membrane. The water dissolves acid and the drug in the
core.
• The acid solution in turn increases permeability of the hydrated
polymer film.
• The different types of acids that can be used include succinic acid,
acetic acid, glutaric acid, tartaric acid, maliec acid, or citric acid
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22. • Hydrogel : A polymer network that is not soluble in
water, but is super-absorbent.
• Stimuli responsive hydrogels can absorb or release
their contents based on environmental conditions.
Stimuli include:
• Temperature
• pH
• Ionic Strength
• Presence of certain chemicals
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They are insoluble due to the tie points i.e., physical cross links like entanglement.
Exampels include:
PIPAAm
PEO-PPO-PEO
PLGA-PEO-PLGA grafted co-polymers.

24.  In these systems the polymer undergoes swelling or
deswelling phase in response to the temperature
which modulates drug release in swollen state.
 For example polyN-isopropylacrylamide (PIPAAm)
responds to a specific range of temperature.
 Below 32 C PIPAAm forms a “skinny layer” &
changes to hydrophobic which is impermeable to
water.
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26. ξ
Low pH
High pH
Protect drug
Release drug
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27.  Release of the drug after stimulation by an biological factor or
external stimuli .
 It is classified into two types
stimuli induced pulsatile system
Chemical stimuli induced pulsatile system
i. pH sensitive drug delivery system .
ii. Inflammation-induced system
iii. Glucose responsive insulin release
iv. Drug release from gels responding
to antibody concentration
External stimuli
i.Micro electro release system
ii.Electro Responsive release
iii.Magnetically induced release
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 The system include insulin immobilized in the hydrogel
Glucose
Glucose oxidase
Gluconic acid
Change in pH
Swelling of the polymer
Insulin release

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 Insulin by virtue of its action reduces blood glucose level
& consequently gluconic acid level also get decreased &
system turns to the deswelling mode thereby decreasing
the insulin release.
 Examples of the pH sensitive polymers include N, N-
dimethylaminoethyl methacrylate, chitosan, polyol etc.

30. • Electro responsive pulsatile release
Electrically responsive delivery systems are
prepared from polyelectrolytes (polymers which
contain relatively high concentration of ionisable
groups along the backbone chain) and are thus, pH-
responsive as well as electro-responsive.
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31. • Examples of naturally occurring polymers include
hyaluronic acid, chondroitin sulphate, agarose,
carbomer, xanthan gum and calcium alginate.
• The synthetic polymers are generally acrylate and
methacrylate derivatives such as partially hydrolyzed
polyacrylamide, polydimethylaminopropyl acrylamide
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32. • A micro fabricated device has the ability to store and
release multiple chemical substances on demand.
• Another development in MEMS technology is the
microchip.
• The microchip consists of an array of reservoirs that
extend through an electrolyte-impermeable substrate.
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33. • The microchip consists of an array of reservoirs that
extend through an electrolyte-impermeable substrate.
• The prototype microchip is made of silicon and
contains a number of drug reservoirs, each reservoir
is sealed at one end by a thin gold membrane of
material that serves as an anode in an
electrochemical reaction and dissolves when an
electric potential is applied to it in an electrolyte
solution.
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34. • When release is desired, an electric potential is
applied between an anode membrane and a cathode,
the gold membrane anode dissolves within 10-20
seconds and allows the drug in the reservoir to be
released.
• This electric potential causes oxidation of the anode
material to form a soluble complex with the
electrolytes which then dissolves allowing release of
the drug.
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35. • Dissolution studies.
• Simulated rupture tests with polymer films
• Lag time and drug release of pulsatile capsules
• Water uptake studies with the pulsatile tablets.
• gamma scinitgraphic technology
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37. • The lag time of pulsatile release tablets is defined
as the time when the outer coating starts to rupture.
• The lag time of the pulsatile capsules was
determined by visual observation in a USP paddle
apparatus (medium: phosphate buffer USP pH 7.4,
37°C, and rotation speed 50 rpm).
• We can go either with plcebo or with the drug itself.
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38. • The %water uptake of pulsatile release tablets was
determined in medium-filled containers placed in a
horizontal shaker (100 ml of 0.1 N HCl, 37 0
C, 74 rpm,
n = 3).
• At predetermined time points, the tablets were
removed from the dissolution medium, carefully
blotted with tissue paper to remove surface water,
weighed and then placed back in the medium up to
the time when the coating of the tablet ruptured. The
%water uptake was calculated as follows:
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39. • The %water uptake was calculated as
follows:
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40. gamma scinitgraphic technology
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a b c d
Image (a) was taken immediately
Image (b) was taken at 3 hrs.
Image (c) & (d) at 5 & 6 hrs respectively.

41. • Spheroidal Oral Drug Absorption System (SODAS)
• Chronotherapeutic Oral Drug Absorption System
(CODAS)
• EURANDs pulsatile and chrono release System
• Magnetic Nanocomposite Hydrogel
• GEOCLOCK® Technology
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42. Technology used Drugs marketed
CODAS Verelan® PM
EURANDS Propranolol hydrochloride (CRR)
GEOCLOCK Lodotra™
PULSYS™ Moxatag™
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43. • Avinash R. Tekade, and Surendra G. Gattani ,
“Development and evaluation of pulsatile drug
delivery system using novel polymer”,
Pharmaceutical Development and Technology, 2009;
14(4): 380–387
• Aim : To develop a PDDS using a plug made up of a
novel material & to show the effect of the plug which
is independent of the ratio of drug as to polymer
taken in the preparation of microspheres.
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44. • Preparation of TPH microspheres
• Microspheres of anhydrous TPH were prepared by solvent evaporation method. Drug
and Eudragit S 100 in various ratios like 2:1, 1:1, 1:1.5 and 1:2 w/w were dissolved in a
sufficient quantity of ethanol. An ethanolic solution of the drug and polymer was then
poured slowly into 100 mL liquid paraffin containing 1% span 80 at 15°C with continuous
stirring at 1000 rpm to form uniform emulsion.
• Preparation of cross-linked gelatin capsules
• A total of 25 mL of 15% (v/v) formaldehyde was taken into a dessicator and a pinch of
potassium perman-ganate was added to it, to generate formalin vapors.
• Preparation of hydrocolloid plug
• Plug for seal-ing the capsule body was prepared by compressing equal amount of DRG
and lactose using 5 mm punches and dies on rotary tablet press keeping varying
thickness and hardness values .
• The joint of the capsule body and cap was sealed with a small amount of the 5% ethyl
cellulose ethanolic solution.The sealed capsules were completely coated by dip
coatingmethod with 5% CAP in 8:2 (v/v) mixture of acetone: ethanol,plasticized with
dibutylphthalate (0.75%)
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47. • PDDS can effectively tackle the chronotherapeutic
problem as it is modulated according to body's
circadian clock giving release of drug after a
specified time lag.
• Plus it can give “a new lease of life” & a “new
therapeutic dimenssion” for existing drug
molecule.
• And a golden future is awaiting for PDDS with
many marketed formulations yet to develop. 47

48. • Tekade AR, Gattani SG. “Development and evaluation of
pulsatile drug delivery system using novel polymer”.
Pharm Dev Tech 2009; 14(4): 380–387.
• Veena S Belgamwar, M.V.Gaikwad, G.B.Patil, S.Surana ,
“Pulsatile drug delivery system” , Asian Journal of
Pharmaceutics - July-September 2008;141-145 .
• A.K. Anal, “Time-Controlled Pulsatile Delivery Systems for
Bioactive Compounds”, Recent Patents on Drug Delivery
& Formulation 2007; 1:73-79 .
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49. • Anita Lalvani,SD Satani,”PULSATILE DRUG DELIVERY
SYSTEM”, Indian journal of pharmaceutical sciences (jul-
2007) 490-497.
• Akihiko Kikuchi, Teruo Okano,” Pulsatile drug release
control using hydrogels”, Advanced Drug Delivery Reviews
54 (2002) 53–77
• Lida E. Kalantzi, Evangelos. Karavas,” Recent Advances in
Oral Pulsatile Drug Delivery “, Recent Patents on Drug
Delivery & Formulation 2009, 3: 49-63
•
• Sharma GS, Srikanth MV, Uhumwangho , “Recent trends
in pulsatile drug delivery systems - A review” International
Journal of Drug Delivery 2 (2010)
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