FORMULATION AND EVALUATION OF PULSATILE DRUG

DELIVERY SYSTEM

Dissertation Synopsis Submitted

in partial fulfillment of the requirement for the degree of

MASTER OF PHARMACY

To

HIMACHAL PRADESH TECHNICAL UNIVERSITY, HAMIRPUR

By

SAPNA RANA

Under the guidance of

RAJNI M.Pharm.
Assistant Professor

(L.R.INSTITUTE OF PHARMACY)
JABLI –KYAR, P.O. OACHGHAT, SOLAN (HP)
H.P.173223
 CERTIFICATE

This is to certify that project “FORMULATION AND EVALUATION

OF SOLID DISPERSION OF ATORVASTATIN” submitted in partial
fulfillment of the requirement for the award of Degree in Master of
Pharmacy (M. Pharm) of Himachal Pradesh Technical University by
Sapna Rana, Roll No. MP-4010033 to be carried out under my
supervision and guidance.
To the best of my Knowledge data reported is original. The
assistance and help received, during the course of this project has been duly
acknowledged.

Date: Project Guide

Place: Solan Ms.Rajni
 INDEX

S.NO. CONTENTS PAGE NO.

1 INTRODUCTION 4-8

2 DRUG PROFILE 9-12

3 AIM AND OBJECTIVE 13

4 MATERIAL AND EQUIPMENT TO BE USED 14

5 EXPERIMENTAL WORK 15-16

17-19
REFERENCES
6
 PULSATILE DRUG DELIVERY SYSTEM
1. INTRODUCTION
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, which lead to
development of pulsatile system that release a therapeutic agent at a rhythm that ideally
matches the biological requirement of a given disease therapy. Diseases where a constant
drug levels are not preferred, but needs a pulse of therapeutic concentration in a periodic
manner and diseases with established oscillatory rhythm in their pathogenesis includes
asthma, arthritis, duodenal ulcer, cancer, cardiovascular diseases 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. Various techniques are available for the
pulsatile delivery like pH dependent systems, time dependent systems, etc. Pulsatile drug
delivery system providing special and temporal delivery and increasing patient compliance.
Pulsatile drug delivery system is defined as the rapid and transient release of certain
amount of molecules within a short time period immediately after predetermined off-
release periods i.e. lag time. Advantages of the pulsatile drug delivery system are reduced
dose frequency; reduce side effects, drug targeting to specific site like colon and many more.
Now in market varies technologies of pulsatile drug delivery system like OROS, CODAS etc.
are launched by pharmaceutical companies.
Pulsatile system is amongst one of them and gaining a lot
of interest as it is increasing patient compliance by means of providing time- and site-specific
drug delivery system, thus providing special and temporal delivery. A pharmaceutical dosage
form such as a capsule capable of delivering therapeutic agents into the body in a time-
controlled or position-controlled pulsatile release fashion, is composed of a multitude of
multicoated particulates (beads, pellets,granules, etc.) made of one or more populations of
beads. On which cases or circumstance pulsatile drug delivery is used they are listed below.

1) Chronopharmacotherapy of diseases which shows circadian rhythms in their

 pathophysiology.
2) Avoiding the first pass metabolism e.g. protein and peptides.
3) For which the tolerance is rapidly exists.
4) For targetting specific site in intestine e.g. colon,
5) For time programmed administration of hormone and drugs,
6) For drugs having the short half life.

“Chronopharmaceutics” consist of two words chronobiology and pharmaceutics.

Chronobiology is the technical study of biologic rhythms and their fundamental mechanisms.
The term "Chrono" pertains to time and "Biology" is the science of life, thus, chronobiology
concerns with the observation of every metabolic event goes through rhythmic changes in
time that can be measured from seconds to seasons. Typical examples are levels of plasma
testosterone and cortisol, which typically peak in the early morning, and the secretion of
growth hormone, which peaks during sleep. Chronotherapeutics refers to a treatment
method in which in vivo drug availability is timed to match rhythms of disease in order to
optimize therapeutic outcomes and minimize side effects. It is based on the observation that
there is an interdependent relationship between the peak-to through rhythmic activity in
disease symptoms and risk factors, pharmacologic sensitivity, and pharmacokinetics of many
drugs takes into account predictable administration time dependent variation in the
pharmacokinetics of drugs as well as the susceptibility due to temporal organization of
physiochemical process and function of body as circadian and others rhythms. One approach
to increase the efficiency of pharmacotherapy is the administration of drugs at times at which
they are most effective and best tolerated. Chronopharmacokinetics refers to rhythmic
changes in drug bioavailability as well as excretion.
1.1 Advantages of Chronopharmacotherapy
1) It prevents an overdosing of any class ofdrug.
2) It makes the utilization of the drug more appropriate and thus the value of a drug is
increased.
3) It reduces the unnecessary side effects of a drug and helps in caring out the treatment
for only a particular or limited period of time.
There are three types of mechanical rhythms in our body.
They are:
a) Circadian
b) Ultradian
c) Infradian
Circadian
This word comes from Latin word “circa” means about and “dies” means day
Ultrdian
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)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”.
 Figure 1.1. Human circadian time structure.

1.2 Diseases requiring Pulsatile Drug Delivery

The diseases that are targeted for chronopharmaceutics are those which establish oscillatory
rhythm in their pathogeneisis. These diseases include asthma, arthritis, duodenal ulcer,
cancer, cardiovascular diseases (e.g., hypertension and acute myocardial infarction,
hypercholesterolemia, and ulcer).

Table 1.1 Diseases requiring Pulsatile Drug Delivery

Disease Chronological behavior Drugs used

Peptic ulcer Acid secretion is high in the H2 blockers

afternoon and
at night

Asthma Precipitation of attacks during β2 agonist, Antihistaminics

night or at
early morning hour

Cardiovascular diseases BP is at its lowest during the Nitroglycerin,Calcium

sleep cycle and rises steeply channel blocker, ACE
during the early morning inhibitors, β Blockers etc.
awakening period

Arthritis Pain in the morning and more NSAIDs, Glucocorticoids

pain at night

Diabetes mellitus Increase in the blood sugar Sulfonylurea, Insulin,

level after meal Biguanide

Attention deficit Increase in DOPA level in Methylphenidate

syndrome afternoon
 Hypercholesterolemia Cholesterol synthesis is HMG CoA reductase
generally higher inhibitors
during night than during day
time

1.3 Chronotherapy of cardiovascular diseases

From the various studies, it is formed that the many cardiovascular events including
myocardial infarction, stroke and sudden death occur during the initial hours of morning
activity between 6 AM and 12 noon. And this is much higher during this period that other
timing during the day. BP rises rapidly in the early morning hours, the time when most
individuals wake and begin their day. This rise in BP corresponds to increased secretion of
catecholamine’s and increased plasma rennin activity. Thus, vascular tone and total
peripheral resistance increase in the morning hours, and BP rises as a result. At the same
time, heart rate increases in the late morning or early afternoon. It seems plausible that timing
of certain medical conditions and life-threatening emergencies may parallel these
physiochemical circadian variations. There is an “evil crossing” of many unfavorable events
early in the morning:

1.3.1 Hemodynamic factors:

BP and heart rate, stroke volume and cardiac output, total peripheral resistance, vascular tone,
plasma volume, pulmonary rterial pressure, platelet agregability, blood coagulability, blood
viscosity, serum cholesterol are increased; coronary blood flow, forearm blood flow, renal
flow, glomerular filtration rate, urinary flow, fibrinolysis are decreased.

1.3.2 Neuro-hormonal factors:

Autonomous tone, plasmatic concentrations of: norepinephrine, epinephrine, tyrosine,
dopamine, prorenine, renine, angiotensin I, aldosterone, ACTH, cortisol, endogenous opioids
have increased values; serotonine, natriuretic peptide system, Na excretion, K excretion have
decreased values.
 Figure 1.2. Changing paradigm for targeting blood pressure control.

Figure 1.3. In the early morning, blood pressure and heart rate increase, then augment
the oxygen demand of the heart. The vascular tone and blood coagulability also increase
in the morning. These increases in oxygen demand and decreases in oxygen supply
exaggerate a mismatch of oxygen demand and supply in the morning.

1.4 Conventional antihypertensive/antianginal drugs

1) Any short acting BETA-BLOCKER : Propranolol,sotalol,Metoprolol etc.
2) CALCIUM ANTAGONISTS with sustained release: Verapamil, Diltiazem,
 Amlodipine etc.

Table 1.2 Antihypertensive/antianginal drugs

Drug Bioavailability(%) Half Dose(mg) Solubility pKa
life(hr)
Verapamil 15-30 4-6 40-160 4.47mg/L 8.92
Nifedipine 30-60 2-5 5-20 Insoluble -

Diltiazem 40-60 5-6 30-60 4.65mg/L -

Propranolol 30 3-5 40-480 0.070mg/ml -
Sotalol 60 6-12 160-480 Soluble in 14.1
water
Metoprolol 40-50 3-4 100-400 16.9mg/ml -

1.5 Historic perspective

The first chronotherapeutic agent for hypertension and angina pectoris are controlled onset
extended release verapamil (Covera-HSTM, Pharmacia, Peapack, USA), was recently
developed and marketed to match the chronotherapeutic drug delivery to the circadian B.P.
and myocardial ischemia rhythms. The formulation are wrapping in the entire tablet in a
water soluble delay coat that disintegrated when exposed to gastrointestinal fluids over a 6-8
h period. After administration of the medication at bedtime, very little verapamil would be
absorbed during the night, but by 8- 12 h the patient was likely to awaken because there
would be an abundant delivery of verapamil. This results in several clinical trials this shown
that verapamil is effective in reducing the blood pressure in population which are at high risk
for hypertension and target-organ damage. The Chronotherapeutic Oral Drug Absorption
System (CODAS™) formulation of verapamil was recently developed. Once-daily
administration of the CODAS significantly reduced the morning BP and the formulation is
also taken at bedtime and is used for a multiple-bead pharmaceutical system. Each bead is
coated with a non enteric release-controlling polymer that delays the delivery of verapamil
into the gut for 4-5 h after administration and thereby provides a morning peak concentration
with little adsorption during the night. Onset of myocardial infarction has also increases in
the morning, with 34% events occurring between 6 a.m. and noon. Acute cardiac arrest and
transient myocardial ischemia shows an increased frequency in morning. Covera-HS®,
Procardia XL® (nifedipine) and Verelan PM® are some examples. FDA in 1998 approved
Verelan PM® (verapamil HCl), for hypertension,Schwarz Pharma marketed products, which
was using the chronotherapeutic oral drug absorption system (CODAS) technology, four to
five hours delay in drug delivery followed by an extended drug release is the technical feature
in this. After the drug is administered, peak concentrations arise after 11 hours with trough
concentrations coming around 4 hours post-dose. In 2003, FDA approved a unique graded
extended release diltiazem HCl tablets for the treatment of hypertension and angina with
trade name Cardizem LA® and marketed by Biovail. These tablets made by compressed
beads coated by polymer which giving lag time for appearance of diltiazem in plasma around
3 hours and maximum plasma concentration between eleven to eighteen hours after
administration.

1.6 Methods of Development of Pulsatile Drug Delivery Systems

For pulsatile release purposes, a variety of design strategies have been attempted. Several
coated, capsular and osmotic formulations have been described.
Different approaches of pulsatile systems include:
i. Time controlled systems
ii. Internal stimuli induced systems
iii. Externally regulated systems
iv. Multiparticulate systems.

i. Time controlled systems

In time controlled drug delivery system, drug is released in pulsatile manner after specific time
interval in order to coincide the drug with proper site, thus mimic the circadian rhythm.these
are obtained as follows.

a) By Solubilisation or Erosion of layer

In such systems, the core containing drug is coated with the soluble or erodible polymer as
outer coat and drug release is controlled by the dissolution or erosion of the outer coat. Time
Dependent release of the drug can be obtained by optimizing the thickness of the outer coat.

b) Pulsatile Delivery by Rupture of Membrane

In place of swelling or eroding, these systems are dependent 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 swelling, disintegrants, effervescent excipients, or osmotic pressure. Water
permeation and mechanical resistance of the outer membrane are major factors affecting the
lag time.

c) Capsule based 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.

d) 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.
Figure 1.4. Schematic presentation of time-controlled release technologies according to
relevant formulation strategies.

ii. Internal 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. These systems are further classified in to
temperature induced systems and chemical stimuli induced systems, on the basis of stimulus.
These are of following types
 Temperature –induced pulsatile release
 Thermoresponsive hydrogel systems
 pH sensitive drug delivery system)Inflammation –induced pulsatile
release.
 Glucose-responsive insulin release devices.

iii. Externally regulated pulsatile release system

This system is not self –operated, but instead requires externally generated environmental
changes to initiate drug delivery. These can include magnetic fields, ultrasound, electrical
field, light, and mechanical force. It include
 Magnetic induces release
  Electric field induces release
 Ultrasound induces release
 Light induces release

iv. Multiparticulate system

These systems are reservoir type with either rupturable or altered permeability coating and
generally housed in capsular body. A rupturable pulsatile drug delivery system consists of (i)
a drug core, (ii) a swelling layer, comprising a superdisintegrant and a binder, and (iii)
an insoluble , water-permeable polymeric coating.
 Pulsatile release by Rupturing of membrane
 Pulsatile release by Osmotic Rupture of membrane

Figure 1.5. Hypothetical design of a multiparticulate pulsatile system.

1.7 Recently Available Chronopharmaceutical Technologies

Nowadays pulsatile drug delivery systems are gaining importance in various disease
conditions specifically in cardiovascular diseases 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(Dashevsk & Mohamad, 2006). 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. 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 (Sharma & Pawar, 2006).
 OROS Technology based on osmotic mechanism
 CEFORM Technology
 CONTINR Technology
 DIFFUCAPS Technology-multiparticulate system
 CHRONOTOPIC Technology
 TIME Rx Technology-timed controlled system
 Pulseincap-rupturable system
 CODAS-multiparticulate pH dependent system

Table 1.3 List of the chronopharmaceutical dosage forms marketed and the pulsatile
drug delivery technologies used.

Drug Brand Chronophar Drug release Timing Indications

Name maceutical mechanism of drug for
technology Adminis chronothera-
- tration py
Diltiazem Cardizem CODAS Multiparticulate Bedtime Angina
HCl LA technology pH dependent pectoris/
system hypertension
Molsidomine Coruno Geomatrix Swelling, Morning Angina
technology gelling, erosion pectoris
Verapamil Covera- OROS Osmotic Bedtime hypertension
HCl HS technology regulation
Verapamil Verelan CODAS Multiparticulate Bedtime
HCl PM technology pH hypertension
dependent
system/a
delayed onset of
drug
release
Nifedipine Procardia OROS Osmotic Bedtime Angina
XL technology regulation pectoris/
hypertension
Propranolol CIPLAR DIFFUCAPS Controlled Bedtime Hypertension
HCl technology release/delayed
release
2. REVIEW OF LITERATURE

2.1 Krogel et al.1998; Krogel et al. 1999 works on Capsule based system consists of
pulsincap system, which consists of an insoluble capsule body and swellable and
degradable plugs made of approved substances such as hydrophilic polymers or lipids
.The lag time is controlled by plug, which pushed away by swelling or erosion and
drug is released as a pulse from the insoluble capsule i.e. Pulsincap®. A swellable
hydrogel plug seals the drug contents in to capsule body. When this capsule body
came in to contact with dissolution medium, the hydrogel plug swells, and after the
lag time the plug pushed itself outside the capsule and rapidly released the drug.
Various types of material used for formulation of swellable plug which include
hydroxyl propyl methl cellulose, poly vinyl acetate and poly ethylene oxide.

2.2 Linkwitz et al., developed t system is in the form of capsule from which the drug is
delivered by the capsule’s osmotic infusion of moisture from the body. The delivery
orifice opens intermittently to achieve pulsatile delivery effect. The orifice forms in
the capsule wall, which is constructed of an elastic material, preferably elastomer (eg.
Styrene-butadiene copolymer), which stretches under a pressure differential caused by
the pressure rise inside the capsule.

2.3 Niwa et al., developed a novel capsule made from ethyl cellulose for time-controlled
release of drugs in the colon.Initially, the capsule was prepared by using a gelatin
capsule with ethyl cellulose. The thickness of ethyl cellulose capsule body was varied
and the effect of the wall thickness on the release of the drug in the capsules was
investigated. The ethyl cellulose capsules contained a large number of mechanically
made micropores (400 µm) at the bottom. A swellable layer consisting of low
substituted hydroxy propyl cellulose (L-HPC) was located in the bottom of capsule
body. Above the swellable layer was the drug reservoir which contained mixture of
model drug, fluorescein and a bulking agent, such as lactose and starch. The capsule
was then capped and sealed with a concentrated ethyl cellulose solution.
2.4 Y.H. Bae et al., developed indomethacin pulsatile release pattern in the temperature
ranges between 200C and 300C by using reversible swelling properties of copolymers
of 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.

2.5 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,Hydroxy propylmethy lcellulose phthalate and Hydroxy propyl
methyl cellulose 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).

2.6 Jagdale et al., prepared A tablet system consisting of cores coated with two layers of
swelling and rupturable coatings was prepared and evaluated as pulsatile drug delvery
system.Cores containing Atenolol as model drug were prepared by direct
compression of different ratios of lactose and microcrystalline cellulose and were ten
coated sequentially with an inner swelling layer containing a superdisintegrants
KYRONT314 and an out errupturable layer of ethylcellulose.

2.7 Kumar et al., develop colon targeted drug delivery systems for Trimetazidine Hcl
using Chitosan as a carrier. In thi sstudy, investigation of an oral colon specific,
pulsatile device to achieve time or site specific release of Trimetazidine, based on
chronopharmaceutical considerations. The basic design consists of an insoluble hard
gelatine capsule body, filled with chitosan microsphere of trimetazidine and sealed
with a hydrogel plug.The entire device was enteric coated, so that the variability in
gastric emptying time can be overcome and a colon-specific release can be achieved.
2.8 Jagdale et al., developed a novel colon targeted tablet formulation by press coating
rapidly disintegrating tablet of Atenolol with guar gum and Eudragit L-100 as barrier
layer. The entire device was enteric coated so that variability in gastric emptying time
can be overcome and a colon specific release can be achieved. Different ratios of
polymers were selected to achieve suitable lag time for the treatment of angina
pectoris. In-vitro release studies for prepared tablets were carried out for 2 h in 0.1 N
HCl, 3 h in pH 7.4 phosphate buffer and 6 h in simulated colonic fluid. In vitro studies
revealed that the tablet coated with guar gum and Eudragit L-100 have limited drug
release in stomach and small intestinal environment and released maximum amount of
drug in the colonic environment.

2.9 U.Y. Nayak et al., develop pulsatile capsule dosage form of valsartan for controlled
delivery. In the majority of individuals blood pressure rises in the early morning
hours, which lead to serious cardiovascular complications. Formulations with
constant/programmable delivery rates make it possible to deliver drug at definite time
or controlled rate in chronopharmacokinetic studies. The prepared system contained
swellable polymer (L-hydroxypropyl cellulose (L-HPC), xanthan gum, polyethylene
oxide or sodium alginate) together with drug tablet and erodible tablet (L-HPC or
guar gum) in a pre-coated capsule.
3. AIM & OBJECTIVE
The aim of this proposal is to design a pulsatile drug delivery system for chronotherapy of
cardiovascular disease. The primary goal of treatment of an angina/hypertensive patient is to
achieve the maximum reduction in long-term total risk of cardiovascular morbidity and
mortality.
These system would benefit from the release after a lag phase, this may exhibit better drug
profile toward the cardiac disease by comparing a timed-release profile with short lag time of
absorption followed by extended higher blood level in the first six hour compared with a
controlled release tablet product.

3.1 Objectives of the study :

The broad objective of the present research work is to:
i) Development of pulsatile release tablets by direct compression method.
ii) Prepration of single unit pulsatile drug delivery system.
iii) Tablet film coating with pH dependent polymer Eudragit using variable coat
thicknsses.
iv) To study in vitro release of drug and release kinetics.
4. MATERIAL AND METHODS

Table 4.1 List of Materials.

Material Name Quantity(g)
Drug Verapamil,Propanolol,Metoprolol,
Sotalol

Ploymers Eudragit L100,Eudragit S100, Chitosan

Ethyl Cellulose, HPMC, CalciumCMC

Superdisintegrant Cross povidone

Direct Comprissble Micro crystalline cellulose

material Dibasic Calcium phosphate
Diluents Lactose
Glidants Calcium Stearate
Magnesium Stearate
Lubricant Talc
Solvent Acetone
Pet. Ether
Hexane
Pot. Dihydrogen phosphate buffer
Light Liquid Paraffin

4.1 List of Instrument:

 Digital balance.
 Tablet punching machine.
 Dissolution apparatus.
 Disintegration apparatus.
  UV spectrophotometer etc.

4.2 Method:
i) Preformulation studies.
a) Assay
b) Solubility
c) Moisture content
d) Drug polymer compatibility study
e) UV spectra in different solvent
f) Calibration curve at different pH (1.2, 6.8, 7.4)
g) FTIR spectra of drug
ii) Prepration of single unit pulsatile drug delivery system
A) Preparation of core tablets.
a) Wet granulation
b) Direct compression
B) Coating of core tablet with pH dependent polymer Eudragit using variable
coat thicknesses.
C) Evaluation.
a. Compatibilities study by FTIR
b. Micromeric properties
1. Particle size
2. Tapped density
3. Compressibility index
4. True density
5. Flow property
c. Weight variation test
d. Thickness
e. Drug content
f. Hardness
g. Friability
h. Determination of moisture content(LOD)
i. In vitro drug release study and kinetics
j. Accelerated Stability study of optimized formulation.
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