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“FORMULATION AND EVALUATION OF A PULSATILE DRUG
DELIVERY SYSTEM CONTAINING A MODEL ANTICANCER
DRUG”
SYNOPSIS FOR
M.PHARM DISSERTATION
SUBMITTED TO
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES
KARNATAKA
BY
CH. RAMAKRISHNA REDDY
I M.PHARM
UNDER THE GUIDANCE OF
Mr. S.J. SHANKAR
Asst.Professor
DEPARTMENT OF PHARMACEUTICS
PES COLLEGE OF PHARMACY
BANGALORE-560050
(2010-2011)
1
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES
KARNATAKA, BANGALORE
ANNEXURE-II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
1.
Name of the candidate and address
CH. RAMAKRISHNA REDDY
1st M. PHARM (PHARMACEUTICS)
PES COLLEGE OF PHARMACY
HANUMANTHANAGAR
BANGALORE-560 050
[email protected]
PERMANENT ADDRESS:
20-6-113, BRINDAVAN NAGAR 3 LINE,
ANJAIAH ROAD,
ONGOLE, 523002,
ANDHRA PRADESH.
PES COLLEGE OF PHARMACY
HANUMANTHA NAGAR
B.S.K.1st STAGE
BANGALORE-560 050
2.
Name of the institution
3.
Course of the study
MASTER OF PHARMACY
(PHARMACEUTICS)
4.
Date of Admission
12th NOVEMBER 2010
5.
Title of the topic:
“FORMULATION AND EVALUATION OF A PULSATILE DRUG
DELIVERY SYSTEM CONTAINING A MODEL ANTICANCER
DRUG”
2
Brief resume of the intended work:
6.1 Need for the study:
Biological processes and functions are organized in space, as a physical anatomy,
and time, as a biological time structure. The latter is expressed by short-, intermediate-, and
long-period oscillations, i.e., biological rhythms. The circadian (24-h) time structure has
been most studied and shows great importance to the practice of medicine and
pharmacotherapy of patients. The phase and amplitude of key physiological and
biochemical circadian rhythms contribute to the known predictable-in-time patterns in the
occurrence of serious and life-threatening medical events, like myocardial infraction and
stroke, and the manifestation and severity of symptoms of chronic diseases, like allergic
rhinitis, asthma,and arthritis.1
The circadian timing system controls drug metabolism and cellular proliferation
over the 24 h through molecular clocks in each cell, circadian physiology, and the
suprachiasmatic nuclei a hypothalamic pacemaker clock that coordinates circadian rhythms.
As a result, both the toxicity and efficacy of over 30 anticancer agents vary by more than
50% as a function of dosing time in experimental models. The circadian timing system also
down regulates malignant growth in experimental models and possibly in cancer patients.2
circadian organisation brings about predictable changes in the body’s tolerance
and tumour responsiveness to anticancer agents, and possibly also for cancer promotion or
growth. The clinical relevance of the chronotherapy principle, ie treatment regimens based
upon circadian rhythms, has been demonstrated in randomised, multicentre trials.
Chronotherapeutic schedules have been used to document the safety and activity of
oxaliplatin against metastatic colorectal cancer and have formed the basis for a new
approach to the medicosurgical management of this disease, which achieved unprecedented
long-term survival. The chronotherapy concept offers further promise for improving current
cancer-treatment options, as well as for optimising the development of new anticancer or
supportive agents.3
Oral dosage forms are known to provide a zero order or first order release in
which the drug is released at a substantially steady rate of release per unit of time.
However, there are instances where maintaining a constant blood level of a drug is not
3
desirable. In such cases a pulsatile drug delivery may be more advantageous. Pulsatile drug
delivery systems can be classified into site-specific systems in which the drug is released at
the desired site within the intestinal tract (e.g., the colon), or time-controlled devices in
which the drug is released after a well-defined time period.4
Current research in the field of drug delivery devices, pulsatile drug delivery
system is the most interesting time and site-specific system. This system is designed for
chronopharmacotherapy. 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 increasing interest in the recent years. In pursuit of
pulsatile release, various design strategies have been proposed, mainly including time
controlling, stimuli induced, externally regulated and multiparticulate formulations. These
systems are beneficial for the drugs having chronopharmacological behavior where night
time dosing is required and for the drug having high first pass metabolism effect and having
specific site of adsorption in gastrointestinal tract.5
Targeting therapeutic delivery to the dynamics of the cross-talk between the
circadian clock, the cell division cycle, and pharmacology pathways represents a new
challenge to concurrently improve the quality of life and survival of cancer patients through
personalized cancer chronotherapeutics.2
6.2 Review of the literature:

Michael H et al., discussed about Rhythmicity in the pathophysiology of disease is
one basis for chronotherapeutics purposeful variation in time of the concentration
of medicines in synchrony with biological rhythm determinants of disease activity
to optimize treatment outcomes. A second basis is the control of undesired effects
of medications, especially when the therapeutic range is narrow and the potential
for adverse effects high, which is the case for cancer drugs. A third basis is to meet
the biological requirements for frequency-modulated drug delivery, which is the
case for certain neuroendocrine peptide analogues. Great progress has been
realized with hydrogels, and they offer many advantages and opportunities in the
design of chronotherapeutic systems for drug delivery via the oral, buccal, nasal,
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subcutaneous, transdermal, rectal, and vaginal routes. Nonetheless, innovative
delivery systems will be necessary to ensure optimal application of
chronotherapeutic interventions. Next generation drug-delivery systems must be
configurable so they (i) require minimal volitional adherence, (ii) respond to
sensitive biomarkers of disease activity that often vary in time as periodic
(circadian rhythmic) and non-periodic (random) patterns to release medication to
targeted tissue(s) on areal time as needed basis, and (iii) are cost-effective.1

Francis L et al., studied the circadian timing system controls drug metabolism and
cellular proliferation over the 24 h through molecular clocks in each cell, circadian
physiology, and the suprachiasmatic nuclei a hypothalamic pacemaker clock that
coordinates circadian rhythms. As a result, both the toxicity and efficacy of over
30 anticancer agents vary bymore than 50%as a function of dosing time in
experimentalmodels. The circadian timing systemalso downregulates malignant
growth in experimental models and possibly in cancer patients. Programmable-intime infusion pumps and rhythmic physiology monitoring devices have made
possible the application of chronotherapeutics to more than 2000 cancer patients
without hospitalization. This strategy first revealed the antitumor efficacy of
oxaliplatin against colorectal cancer. In this disease, international clinical trials
have shown a five-fold improvement in patient tolerability and near doubling of
antitumor activity through the chronomodulated, in comparison to constant-rate,
delivery of oxaliplatin and 5-fluorouracil leucovorin. Here, the relevance of the
peak time, with reference to circadian rhythms, of the chemotherapeutic delivery
of these cancer medications for achieving best tolerability was investigated in 114
patients with metastatic colorectal cancer and in 45 patients with non-small cell
lung cancer. The incidence of severe adverse events varied up to five-fold as a
function of the choice of when during the 24 h the peak dose of the medications
was timed. The optimal chronomodulated schedules corresponded to peak delivery
rates at 1 a.m. or 4 a.m. for 5-fluorouracil–leucovorin, at 1 p.m. or 4 p.m.for
oxaliplatin, and at 4 p.m. for carboplatin.2
5

Nitin S et al., Discussed about the site specific chronotherapeutic drug delivery
systems. Oral dosage forms are known to provide a zero order or first order release
in which the drug is released at a substantially steady rate of release per unit of
time. However, there are instances where maintaining a constant blood level of a
drug is not desirable. In such cases a pulsatile drug delivery may be more
advantageous. Pulsatile drug delivery systems can be classified into site-specific
systems in which the drug is released at the desired site within the intestinal tract
(e.g., the colon), or time-controlled devices in which the drug is released after a
well-defined time period. Environmental factors like pH or enzymes present in the
intestinal tract control the release of a site-controlled system whereas the drug
release from time-controlled systems is controlled primarily by the delivery system
and not by the environment. The delayed liberation of orally administered drugs
has been achieved through a range of formulation approaches, including single or
multiple unit systems provided with release-controlling coatings, capsular devices
andosmotic pumps.3

Hitesh D et al., discussed about the current research in the field of drug delivery
devices, pulsatile drug delivery system is the most interesting time and sitespecific system. This system is designed for chronopharmacotherapy. 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 increasing interest in the recent years. Diseases
wherein pulsatile drug delivery systems are promising include asthma, peptic
ulcer, cardiovascular diseases, arthritis, attention deficit syndrome in children, and
hypercholesterolemia. In pursuit of pulsatile release, various design strategies have
been proposed, mainly including time controlling, stimuli induced, externally
regulated and multiparticulate formulations. These systems are beneficial for the
drugs having chronopharmacological behavior where night time dosing is required
and for the drug having high first pass metabolism effect and having specific site
of adsorption in gastrointestinal tract.4
6

Akihiko K et al., Discussed about several types of drug delivery systems using
hydrogels are that showed pulsed and/or pulsatile drug delivery characteristics. As
is frequently found in the living body, many vital functions are regulated by pulsed
or transient release of bioactive substances at a specific site and time. Thus it is
important to develop new drug delivery devices to achieve pulsed delivery of a
certain amount of drugs in order to mimic the function of the living systems, while
minimizing undesired side effects. Special attention has been given to the
thermally responsive poly (N-isopropylacrylamide) and its derivative hydrogels.
Thermal stimuli-regulated pulsed drug release is established through the design of
drug delivery devices, hydrogels, and micelles.5

Shraddha S et al., developed hollow calcium pectinate beads for floating-pulsatile
release of diclofenac sodium intended for chronopharmacotherapy. Floating
pulsatile concept was applied to increase the gastric residence of the dosage form
having lag phase followed by a burst release. To overcome limitations of various
approaches for imparting buoyancy, hollow/porous beads were prepared by simple
process of acid-base reaction during ionotropic crosslinking. The floating beads
obtained were porous (34% porosity), hollow with bulk density <1 and had Ft50%
of 14–24 h. In vivo studies by gamma scintigraphy determined on rabbits showed
gastroretention of beads up to 5 h. The floating beads provided expected two-phase
release pattern with initial lag time during floating in acidic medium followed by
rapid pulse release in phosphate buffer.6

Sawada T et al., try to improve the bioavailability of these tablets, the effect of
their core composition of compression-coated tablet on in vivo pharmacokinetics
was investigated. First, the extent of mass reduction of cores in different
compression-coated tablet core formulations was used to establish a new index, the
core erosion ratio. The data show that adding excipients with high water solubility
to the core results in a greater core erosion ratio. And, to elucidate the effect of
core erosion invivo and necroscopy tests were performed on Dogs.The results
suggest that a formulation with a large core erosion ratio can significantly increase
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in vivo drug release from compression-coated tablets, leading to increased drug
absorption from the lower GI tract.7

Atilla A et al., resort to an automaton model describing the transitions through the
successive phases of the cell cycle for optimize the temporal patterning of drug
delivery used in cancer chronotherapy. The model accounts for the progressive
desynchronization of cells due to the variability of the durations of the cell cycle
phases, and for the entrainment of the cell cycle by the circadian clock. Focusing
on the cytotoxic effect of the anticancer drug 5-fluorouracil (5-FU), which kills
cells in the S phase, they compare the effect of continuous infusion of 5-FU with
various circadian patterns of 5-FU administration that peak either at 4 a.m., 10
a.m., 4 p.m., or 10 p.m. The model indicates that the cytotoxic effect of 5-FU is
minimum for the circadian delivery peaking at 4 a.m., and maximum for the
continuous infusion or the circadian pattern peaking at 4 p.m.8

Leda K et al., studied themo responsive hydro gels.Thermoresponsive hydrogels
utilize temperature change as the trigger that determines their gelling behavior
without any additional external factor. These hydrogels have been interesting for
biomedical uses as they can swell in situ under physiological conditions and
provide the advantage of convenient administration.The aqueous polymer
solutions that exhibit transition to gel upon temperature change. Typically,
aqueous solutions of hydrogels used in biomedical applications are liquid at
ambient temperature and gel at physiological temperature. Hydrogels based on
natural polymers are, N-isopropylacrylamide polymers, poly(ethylene oxide)–bpoly(propylene oxide)–b-poly(ethylene oxide) polymers as well as poly(ethylene
glycol)-biodegradable polyestercopolymers.9

Eeckman F et al., developed four thermosensitive copolymers of poly(Nisopropylacrylamide) (PNIPAAm), with phase transition temperature slightly
higher than 37 ◦C, were synthesised and used as time-controlled drug delivery
agents.
For
this
purpose,
compression-coated
tablets
coated
with
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the
thermosensitive copolymers and containing Na2SO4 were prepared and in vitro
dissolution tests were performed at constant physiological temperature, the lag
time before drug release being controlled by the amount of Na2SO4 incorporated
into the form. Due to the salting out effect, the lag time was increased by up to 80–
90% for PNIPAAm-co-NVA and PNIPAAm-co-MVA coated tablets.10

Manuela C et al., synthesised a novel class of microspheric hydrogels by grafting
of N-isopropyacrylamide (NIPAAm) with gelatin. This synthetic approach allows
a modification of the polymeric network composition, producing hydrogels with
suitable physico-chemical properties and a transition temperature higher than
NIPAAm homopolymers. The incorporation of monomers into the network was
confirmed by infrared spectroscopy,and the composition of the polymerization
feed was found to strictly influence the network density and the shape of
hydrogels.11

Jason T et al., studied the performance of a pulsatile capsule delivery system
induced by wet granulation of an erodible HPMC tablet, used to seal the contents
within an insoluble capsule body. Erodible tablets containing HPMC and lactose
were prepared by direct compression (DC) and wet granulation (WG) techniques
and used to seal the model drug propranolol inside an insoluble capsule body.
Dissolution testing of capsules was performed. Physical characterisation of the
tablets and powder blends used to form the tablets was undertaken using a range of
experimental techniques. WG tablets eroded slower and produced longer lag-times
than those prepared by DC; the greatest difference was observed with low
concentrations of HPMC. No anomalous physical characteristics were detected
with either the tablets or powder blends. In conclusion, at low HPMC
concentrations water mobility is at its greatest during the granulation process, such
formulations are therefore more sensitive to processing techniques.12

Jean C, studied the design of optimal (circadian and other period) time-scheduled
regimens for cytotoxic drug delivery by intravenous infusion, a pharmacokinetic–
pharmacodynamic (PK–PD, with circadian periodic drug dynamics) model of
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chemotherapy on a population of tumor cells and its tolerance by a population of
fast renewing healthy cells is presented. The application chosen for identification
of the model parameters is the treatment by oxaliplatin of Glasgow osteosarcoma,
a murine tumor, and the healthy cell population is the jejunal mucosa, which is the
main target of oxaliplatin toxicity in mice. The model shows the advantage of a
periodic time-scheduled regimen, compared to the conventional continuous
constant infusion of the same daily dose, when the biological time of peak infusion
is correctly chosen. Furthermore, it is well adapted to using mathematical
optimization methods of drug infusion flow, choosing tumor population
minimization as the objective function and healthy tissue preservation as a
constraint.13
6.3 Main objectives of the study:

To formulate a pulsatile drug delivery system using various polymers.

To evaluate the prepared pulsatile drug delivery system.

To study the invitro drug release profile of the prepared pulsatile drug
delivery system.
7.

To optimise the dosage form based on various evaluation parameters.

To carryout the invivo drug release studies.

To carry out stability studies according to ICH guidelines.
7.1 Source of data
The data will be obtained from the literature survey, internet source and text books. The
preclinical data of various anti cancer drugs based on chronotherapeutics obtained from
various literatures.
10
7.2 Method of collection of data (including sampling procedures if any)
The experimental work which includes formulation of pulsatile drug delivery systems
by using various polymers, and their evaluation, The data will be collected from
prepared formulations which will be subjected to different evaluation techniques like
DSC, IR, estimation of buyoncy, swelling and erosion studies, drug entrapment
efficiency, disintegration time, in-vitro and in-vivo drug release and stability studies.
7.3 Does the study require any investigation or interventions to be
Conducted on patients or other humans or animals?
YES, ANIMAL STUDIES.
7.4 Has ethical clearance been obtained from your institution in case of
in vivo study?
YES, LETTER ENCLOSED.
11
8.
List of References
1. Michael H, Nicholas A. Chronobiology, drug delivery, and chronotherapeutics.
Adv Drug Deliv Rev. 2007;59:828–51.
2. Francis L, Christian F, Abdoulaye K. Implications of circadian clocks for the
rhythmic delivery of cancer therapeutics. Adv Drug Deliv Rev. 2007;59:1015–
35.
3. Nitin S, Sanjula B, Alka A. Site Specific Chronotherapeutic Drug Delivery
Systems: A Patent Review. Rec Pat Drug Deliv Form. 2009;3:64-70.
4. Hitesh D, Jayvadan K. Chronpharmaceutics, pulsatile drug delivery system as
current trend. Asian J Pharm Sci. 2010;5(5):204-30.
5. Akihiko K, Teruo O. Pulsatile drug release control using hydrogels. Adv Drug
Deliv Rev. 2002;54:53–77.
6. Shraddha S, Praveen S, Aruna K. Development of hollow/porous calcium
pectinate beads for floating-pulsatile drug delivery. Eur J Pharm Biopharm.
2007;65:85–93.
7. Sawada T, Sako K, Fukui M. A new index, the core erosion ratio, of
compression-coated timed-release tablets predicts the bioavailability of
acetaminophen. Int J Pharm. 2003;265:55–63.
8. Atilla A, Francis L, Albert G. A cell cycle automaton model for probing
circadian patterns of anticancer drug delivery. Adv Drug Deliv Rev.
2007;59:1036–53.
9. Leda K, Antonios G. Thermoresponsive hydrogels in biomedical applications.
Eur J Pharm Biopharm. 2008;68:34–45.
12
10. Eeckman F, Moës A, Amighi K. Poly(N-isopropylacrylamide) copolymers for
constant temperature controlled drug delivery. Int J Pharm. 2004;273:109–19.
11. Manuela C, Francesca L, Francesco P. Grafted thermo-responsive gelatin
microspheres as delivery systems in triggered drug release. Eur J Pharm
Biopharm. 2010;76:48–55.
12. Jason T, Alistair C, Alan R. The effect of wet granulation on the erosion
behaviour of an HPMC–lactose tablet, used as a rate-controlling component in
a pulsatile drug delivery capsule formulation. Eur J Pharm Biopharm.
2004;57:541–9.
13. Jean C. Modeling oxaliplatin drug delivery to circadian rhythms in drug
metabolism and host tolerance. Adv Drug Deliv Rev. 2007;59:1054–68.
13
9.
Signature of the candidate:
10.
Remarks of the guide:
11.
Name And Designation of:
11.1 Guide
( CH. RAMAKRISHNA REDDY )
FORWARDED FOR APPROVAL
Mr. S. J. SHANKAR
Asst. Professor
Department of Pharmaceutics,
P.E.S College of Pharmacy,
Bangalore-50.
11.2 Signature
11.3 Co-Guide
NOT APPLICABLE
11.4 Signature
11.5 Head of the department
Dr. MANJULA TALLURI
Professor & Head,
Department of Pharmaceutics,
P.E.S College of Pharmacy,
Bangalore-50.
11.6 Signature
12.
12.1 Remarks of the Principal:
FORWARDED FOR APPROVAL
12.2 Principal
Prof. Dr. S. MOHAN
Principal & director,
P.E.S College of Pharmacy,
Bangalore-50.
12.2 Signature
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