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IN THIS ISSUEIN THIS ISSUE
From The President………
From The Editor……………
Technical Insights…………
Biomimetic Engineering of PartAaron Anselmo and Samir Mitragotr
i iAtomic Force Microscopy: An Iof Nanoparticles with BiologicaVinod Labhasetwar
Development of Long Acting DAnimals…………………………………Michael Rathbone, Peter Barling, So
Industry Perspectives……
Quality By Design (QbD) RoadmBuket Aksu
505(b)(2): An Industry Insight…Yagna Kumar and Mahalaxmi Andhe
In Vitro In Vivo Correlation for Ankur Raval and Vandana Patravale
CRS News………………………
Controlled Release Socie
Volume 7, February 2015
……………………………………..…......4
……………………………….…….……...6
…………………..….……………….…..…8
ticles: Synthetic Cells ………..………...….9ri
l f d i important Tool for Studying Interactions al Membranes……………………….……..…13
rug Delivery Systems for Companion ……………………………….……………………..19on Teng and Franciska Kim
……………………………………..…….24
map………………………………………..……..25
………………………………………………...……29eria
Stents………………………………………….36
………………………………………..…43
ty Indian Chapter3
Dr. Amarjit Singh
President – CRS Indian Chapter
From the President, Welcome to the Fourteenth International Symposium on Advances in Technology and Business Potential of Drug Delivery Systems. The Symposium aims to address the prime issues in current pharmaceutical research, boost industry-academia relations, and ignite the spark of innovation in our young budding pharmaceutical scientists. A famous quote by Isaac Bickerstaff “Health is the greatest of all possessions; a pale cobbler is better than a sick king” draws attention to the cardinal role of the pharmaceutical fraternity in preserving this possession. It would be an understatement to say that the Indian pharmaceutical industry has grown leaps and bounds over the past few years with India being among the top five emerging pharmaceutical markets in the world. According to McKinsey analysis, the Indian pharmaceutical market is expected to reach 55 billion USD in 2020. This phenomenal growth of the Indian pharmaceutical market can be attributed to superior medical infrastructure, escalation in the occurrence and treatment of chronic diseases, increased health insurance coverage, launches of patented products, and novel market generation in present white spaces. However, there is a need for a strategic shift from generic to innovative research driven products. Unfortunately, the fact that India being a powerhouse of research talent, has not translated into innovative pharmaceutical products at a commensurate pace. It goes without saying that the future growth of the Indian pharmaceutical industry will be fuelled by fruitful collaborations between academia and industry and sound knowledge of regulatory scenario and patient needs. Foreign direct investment and government expenditure on healthcare will definitely play a pivotal role in realising the complete potential of the Indian pharmaceutical fraternity. With these thoughts, I urge the readers of this CRS Newsletter to update themselves with the latest technologies introduced in this edition and take this opportunity proffered by the CRS-Indian Chapter to foster novel ideas and collaborative network, to become the strategic partners of the futuristic pharmaceutical industry.
Prof. Vandana B. Patravale Chief Editor, CRS Newsletter
Priyanka Prabhu Swati Vyas Rashmi Prabhu
Newsletter articles reflect only the views of the authors. Publication of articles within the CRS Newsletter does not constitute endorsement by CRS or its agents of products, services or views expressed herein. No representation is made as to accuracy hereof and the publication is printed subject to errors and omissions. All the E‐mail contributions, views and suggestions, should be directed to the newsletter editor at: vb.patravale@ictmumbai.edu.in; patravale.vb@gmail.com
Cover Page Designed By: SWATI VYAS
Associate Editors
Dear Readers,
It is my great pleasure to welcome you all to the Fourteenth International Symposium on “Advances in technology and Business Potential of New Drug Delivery Systems” organized by ‘Controlled Release Society-Indian Chapter’ at Institute of Chemical Technology which also marks the seventh issue of CRS Newsletter. The prime objective of the newsletter as always is to enlighten the readers with varied content on a gamut of recent topics pertaining to pharmaceutical and biotechnology fields.
The global pharmaceutical market is constantly growing at a burgeoning pace. The ‘Technical Insights’ section aims to keep the readers abreast of the upcoming advancements in the pharmaceutical arena. Prof. Samir Mitragotri, a notable scientist in the field of biomimetic particle engineering provides a peek into the design of biomimetic particles as artificial cells to perform biological functions of real cells. Prof. Vinod Labhasetwar highlights the incredible potential of atomic force microscopy to study nanoparticle-cell interactions. Prof. Michael J. Rathbone throws light on the challenges and approaches for development of long acting formulations for veterinary population. Introducing our readers to the booming topic in pharmaceutical industry is the article on Quality-by-design by Dr. Buket Aksu. Educating our readers about 505 b(2) application in Intellectual Property Rights is Dr. Mahalaxmi Andheria. Addressing the cardinal issue of in vitro in vivo correlation for drug eluting stents is the industry expert Mr. Ankur Raval. The Newsletter has few brain teasers to stimulate your mind in a relaxed way.
The editorial board is immensely thankful to all the authors for giving their valuable time and contributing articles covering various areas of pharmaceutical interest. We also wish to express sincere thanks to our munificent sponsors who have contributed in a colossal way in the making of this Newsletter.
Last but not the least I thank my entire editorial team for their inexorable efforts in making this CRS Newsletter both enlightening and exciting.
The editorial board has enjoyed bringing forth to you the Newsletter and we truly expect that the readers enjoy reading it as much. However, productive suggestions from our readers are always welcome to aid us to embellish the Newsletter.
Prof. Vandana B. Patravale Vice President CRS-IC
TECHNINSIGH
Scientific Reviews
8
ICAL TS
Biomimetic Eof ParticlesCells Cells
Aaron Anselmo anDepartment of Chemical
California, San*Email: samir@en
Introduction An ideal drug
(i) circulate for long periods of time, (itissues and (iii) deliver therapeutics while
Email: samir@en
Various nano‐ and micro‐particles haveideal carriers. However, the translationdelivery systems to the clinic has beenclearance of particles by the immuntargeting of particles to diseased tissueschallenging to synthesize carriers capabchallenging to synthesize carriers capabissues. On the other hand, natural sentities) may be able to perform thePerhaps there is no better carrier than prcells. As an example, red blood cells cirdeliver oxygen throughout the body. Mll bl f h i icells are able to perform their own uniqu
than most sophisticated synthetic dPrimary cells thus provide an interestingfor drug delivery [1‐4]. Unfortunatelymodification required to promote positioften limits the ability of cells to serve asy
Controlled Release Socie
February 2015
Technical Insights
ngineering s: Synthetic
nd Samir Mitragotri*l Engineering, University of nta Barbara, USAngineering ucsb edu
g delivery carrier must:
i) accumulate in targete at these target tissues.
ngineering.ucsb.edu
e been investigated asof particle‐based drugn limited due to rapide system and limiteds. Indeed, it has provenble of addressing these
L-R: Aaron Anselmoand Samir Mitragotrible of addressing these
systems (i.e. biologicaltasks of ideal carriers.rimary circulatory bloodrculate for months andost primary circulatory
k h b
S go
ue tasks that are betterrug delivery systems.platform and paradigmy, the extent of cellve biological outcomesdrug carriers.g
ety Indian Chapter
99Encouraging Research Through Awareness
Controlled Release Society Indian Chapter February 2015 10 Encouraging Research Through Awareness
Recent research has focused on making synthetic
cells so as to combine the advantages of biological
systems, namely the stealth and circulatory
properties, with the advantages of synthetic
systems, namely the abilities to control
biomaterial composition, drug inclusion and the
potential for mass production. Two types of
synthetic cells are of interest, in particular: red
blood cells and platelets. Various synthetic
versions of red blood cells and platelets that mimic
the geometry, structural properties and some of
the biological abilities of their natural counterparts
have been prepared and reported on throughout
literature.
Many different synthesis methods including
photolithographic [5], microfluidic [6] and layer‐
by‐layer (LbL) synthesis [7, 8] have been
investigated for preparing different types of
synthetic cells. Our lab has focused on LbL
synthesis due to the precise control over
biomaterial composition, shape and flexibility LbL
synthesis allows. Synthesis of synthetic cells via
the LbL method involves coating sacrificial particle
templates, either spherical particles or particles
stretched into different shaped templates [9], with
complementary layers of oppositely charged
proteins and polyelectrolytes (Fig. 1, see Table 1
for synthetic cell composition). These proteins and
polyelectrolytes are then cross‐linked in order to
provide sufficient stability and rigidity of the outer
shell prior to dissolution of the sacrificial core
template. Using this method, it is possible to
create both synthetic RBCs and synthetic platelets
that mimic the geometric features of both primary
RBCs and platelets. Synthetic cells also exhibit near
identical flexibility and rigidity of their real cell
counterparts [7, 8].
The synthetic red blood cells created in our lab
(see Table 1 for synthetic red blood cell
composition) were able to perform the same tasks
as their real‐life counterpart in vitro. Primary red
blood cells are responsible for oxygen delivery to
all parts of the body, a necessary biological
function facilitated by their ability to squeeze and
deform through small veins (capillaries) smaller in
diameter than the cell itself. First, synthetic red
blood cells reversibly deform while flowing
through capillaries smaller than their own diamet‐
Figure 1: Synthesis of synthetic cells via the layer‐
by‐layer (LbL) method
er similar to how circulating red blood cells deform
when passing through small capillaries in the body.
Synthetic red blood cells functionalized with
hemoglobin, the protein responsible for oxygen
binding and transfer, were able to bind oxygen to
90% (80% after 1 week of storage) of the capacity
of real red blood cells confirming the ability of
these artificial cells to mimic the biological
functions of their real‐life counterpart. Future
work will be focused on further protein/peptide
alterations of synthetic red blood cells to endow
long‐circulating abilities similar to their real life
counterpart, as has recently been reported in the
literature [10].
Table 1: Particle template, protein and
polyelectrolyte choices for synthesis of LbL
synthetic cells
Using LbL method, our lab has also created
synthetic platelets (see Table 1 for synthetic
platelet composition) which are able to mimic
circulating platelets ability to bind to wound sites.
Materials for LbL Synthetic Cells Synthetic Red Blood Cells Synthetic Platelets
Particle
1 μm Hollow Polystyrene Particles
1‐3 μm Polystyrene Particles Stretched to Oblate Ellipsoids
Templates 3‐7 μm PLGA Particles after 2‐Isopropanol
Treatment
Negatively Charged Bovine Serum Albumin Bovine Serum
Albumin
Proteins/Polyelectrolytes Poly(4‐styrene sulfonate) Actin
Positively Charged Polyallylamine
Hydrochloride
Polyallylamine
Hydrochloride
Proteins/Polyelectrolytes Hemoglobin
Controlled Release Society Indian Chapter February 2015 11Encouraging Research Through Awareness
Circulating platelets are the cells responsible for
binding to damaged endothelium to cause
hemostasis, or the plugging of wounds. Synthetic
platelets were coated with von Willebrand Factor
(vWF), a major protein that contributes to
hemostasis, and were shown to bind and adhere
stronger than real platelets to vWF anti‐ligand
decorated glass slides. During formation of the
hemostatic plug, real platelets bind together and
aggregate to physically form plug on a bleeding
wound. Therefore, high interaction between
synthetic platelets and real platelets is desired. To
simulate this interaction further vWF coated
synthetic platelets or vWF coated PLGA spheres
(control), along with whole human blood
(containing real platelets), were flown over
collagen coated surfaces. Synthetic platelets
(tested at both high and low target‐protein
coating) attached at much higher amount than
controls spheres, effectively confirming the utility
of synthetic platelets in being able to interact with
primary platelets in a clotting situation. Most
recently, we have utilized these synthetic platelets
in an in vivo tail amputation model to determine
whether or not our synthetic cells can perform
hemostasis, or in other words prevent blood loss
following a wound, in an in vivo tail amputation
model. We show that our synthetic platelets that
were functionalized with two distinct wound‐
interacting peptides, and one activated platelet‐
interacting peptide, were able to render up to a
65% percent reduction in bleeding time. In our
study, we systematically investigate the role that
synthetic platelet’s size, shape, and surface
chemistry plays in rendering hemostasis [11].
Table 2: Advantages of LbL synthetic cells over
primary cell delivery systems
Table 2 Synthetic Cells Real Cells
Long shelf‐life
Known expectations
of biological activity
Easily sterilized Proven carriers Advantages Reliable mass‐production
Biodegradable Unparalleled functionality
Not as proven as real cells
in vivo Requires cell modification
Further optimization
needed Short shelf‐life Disadvantages Easily contaminated
Need for blood
typing Need for donors
These recent advances in creating artificial cells
allow the synthesis of both geometrically accurate
artificial cells and also the in vivo application of
these carriers in mimicking the chemical and
biological abilities of real cells. Artificial cells can
potentially address many of the challenges faced
by traditional nanoparticle carriers by mimicking
real cells and their natural ability to perform tasks
necessary for drug delivery (Table 2).
References: 1. J.C. Murciano, S. Medinilla, D. Eslin, E.
Atochina, D.B. Cines, and V.R. Muzykantov.
Prophylactic fibrinolysis through selective
dissolution of nascent clots by tPA‐carrying
erythrocytes. Nat Biotechnol. 21:891‐896
(2003)
2. E.V. Batrakova, S. Li, A.D. Reynolds, R.L.
Mosley, T.K. Bronich, A.V. Kabanov, and H.E.
Gendelman. A macrophage‐nanozyme
delivery system for Parkinson's disease.
Bioconjug. Chem. 18:1498‐1506 (2007)
3. A.C. Anselmo and S. Mitragotri. Cell‐mediated
delivery of nanoparticles: taking advantage of
circulatory cells to target nanoparticles. J
Control Rel. 190:531‐541 (2014)
4. A.C. Anselmo, V. Gupta, B.J. Zern, D. Pan, M.
Zakrewsky, V. Muzykantov, and S. Mitragotri.
Delivering Nanoparticles to Lungs while
Avoiding Liver and Spleen through Adsorption
on Red Blood Cells. ACS Nano. 7:11129‐11137
(2013)
5. T.J. Merkel, S.W. Jones, K.P. Herlihy, F.R.
Kersey, A.R. Shields, M. Napier, J.C. Luft, H.
Wu, W.C. Zamboni, A.Z. Wang, J.E. Bear, and
J.M. DeSimone. Using mechanobiological
mimicry of red blood cells to extend
circulation times of hydrogel microparticles.
Proc. Natl. Acad. Sci. U. S. A. 108:586‐591
(2011)
6. R. Haghgooie, M. Toner, and P.S. Doyle.
Squishy non‐spherical hydrogel microparticles.
Macromol. Rapid Commun. 31:128‐134 (2010)
7. N. Doshi, J.N. Orje, B. Molins, J.W. Smith, S.
Mitragotri, and Z.M. Ruggeri. Platelet mimetic
particles for targeting thrombi in flowing
blood. Adv. Mat. 24:3864‐3869 (2012)
8. N. Doshi, A.S. Zahr, S. Bhaskar, J. Lahann, and
S. Mitragotri. Red blood cell‐mimicking
synthetic biomaterial particles. Proc. Natl.
Acad. Sci. U. S. A. 106:21495‐21499 (2009)
Controlled Release Society Indian Chapter February 2015 12 Encouraging Research Through Awareness
9. J.A. Champion, Y.K. Katare, and S. Mitragotri.
Making polymeric micro‐ and nanoparticles of
complex shapes. Proc. Natl. Acad. Sci. U. S. A.
104:11901‐11904 (2007)
10. P.L. Rodriguez, T. Harada, D.A. Christian, D.A.
Pantano, R.K. Tsai, and D.E. Discher. Minimal
"Self" peptides that inhibit phagocytic
clearance and enhance delivery of
nanoparticles. Science. 339:971‐975 (2013)
11. A.C. Anselmo, C.L. Modery‐Pawlowski, S.
Menegatti, S. Kumar, D.R. Vogus, L.L. Tian, M.
Chen, T.M. Squires, A. Sen Gupta, and S.
Mitragotri. Platelet‐like Nanoparticles:
Mimicking Shape, Flexibility, and Surface
Biology of Platelets To Target Vascular
Injuries. ACS Nano. 8:11243‐11253 (2014)
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Atomic Force MAn Important TStudying InterNanoparticlesBiological MeBiological Me
Vinod LaDepartment of Biomedical E
Institute, Cleveland ClCleveland, O
Introduction Until recently
as an inert component of cell memfunction to act as a supporting matrix fois now very well recognized that lipids
Email: labh
is now very well recognized that lipidsvarious cellular processes including iendocytic process via which nanocinternalized [1]. In addition, it is knownthe lipid profile and hence biophysical plipids in various disease conditions, whd ll idrug transport as well as interacUnderstanding lipid‐drug or lipid‐NP inteuseful in drug discovery as well asnanocarriers for drug delivery applicageneral quest to elucidate biological phebiophysical and physical principles. In tp y p y p pmethods of characterizing cell membranof Atomic force microscopy (AFM) are ver
Biophysical Interaction
model cell membranes are very usnanomaterial interactions because of simnanomaterial interactions because of sim
Controlled Release Socie
February 2015
Technical Insights
Microscopy: Tool for ractions of s with mbranesmbranes
abhasetwarEngineering, Lerner Research linic, 9500 Euclid Avenue, OH 44195, USA
y lipids were considered
brane with a primaryr membrane proteins. Itare actively involved in
hasv@ccf.org
are actively involved inin drug diffusion andcarriers are generallyn that changes occur inproperties of membranehich in turn could alteri i h [2]
Vinod Labhasetwar
ctions with NPs [2].eractions could be veryin designing effectivetions. There is also anomena on the basis ofthis regard, biophysicalg , p yne lipids and sensitivityry useful.
Studies Biomimetic
seful to study drug/mplicity and ability tomplicity and ability to
ety Indian Chapter
1313Encouraging Research Through Awareness
Controlled Release Society Indian Chapter February 2015 14 Encouraging Research Through Awareness
control various parameters. Most commonly used
models are supported lipid bilayers, liposome
membranes, and the lipid monolayers; however,
the suitability of the model to use depends upon
the purpose of investigation [3,4]. In Langmuir
lipid monolayer model, where lipids are
compressed to biological surface pressure (SP=30),
lipid molecule composition, subphase
composition, and temperature can be set to
imitate biological conditions. Therefore, the data
obtained from Langmuir model membrane can be
very relevant and useful in predicting interactions
drugs/NPs with live cells and biodistribution in
vivo. Further, one can analyze the nature of the
interaction from the changes in isotherms or the
change in surface pressure (SP) of the membrane
in the presence of a drug or NPs. The other most
significant advantage of this model is that the lipid
monolayer can be transferred to a substrate
before and after interaction with drugs/NPs for its
characterization using AFM (Figure 1) [5]. In
addition, with AFM, one can also study the domain
structures of membrane lipids before and after
interactions with drug/NPs as well as of the lipids
isolated from different cells such as cancer and
normal cells, which can help in understanding the
biophysical characteristics of cell membrane [6]. In
our study, we have used the above techniques to
study interaction of drugs and NPs of different
physical characteristics [7] and also the lipids
extracted from cancer (drug sensitive and
resistant) [8]. Further, we determined whether
NPs of specific characteristics demonstrate
selectivity interactions with lipids of cancer cells
over normal cells as a strategy for developing
tumor targeted NPs [9].
Interactions With Nanomaterials
Interfacial properties of different nanocarriers –
such as their surface charge [10‐12], the presence
of surface functional groups [13,14], particle size
[15,16], and surface hydrophilicity/hydrophobicity
[17,18] – are known to influence their efficiency in
transporting biotherapeutic agents to target tissue
by affecting their interactions with biological
environment and hence biodistribution and
targeting. However, there is no easy technique to
know how changes in physical/interfacial
characteristics of nanocarriers would affect the
interaction with biological membranes. In the
following sections, we describe our study where
we have demonstrated how changes in
nanocarrier characteristics influence biophysical
interactions with membrane lipids and their
significance in drug delivery.
Effect of size and charge of nanoparticles on
biophysical interactions: For our initial studies, we
used polystyrene NPs of different surface
chemistry and sizes as a model nanomaterial, and
Figure 1: Schematic of Langmuir model to study biophysical interactions of NPs with model
membrane. Interactions can be monitored by change in isotherm and from the Langmuir Schaefer
(LS) film transferred on to a substrate by atomic force microscopy (AFM). Reproduced from Ref (19)
with permission from American Chemical Society (Copyright 2009).
Controlled Release Society Indian Chapter February 2015 15Encouraging Research Through Awareness
changes in the membrane’s SP were used as a
parameter to monitor its interactions with NPs.
The particular effect of NP characteristics on SP,
determined using AFM and π‐A (surface pressure‐
area) isotherm, explained whether the interaction
results in condensation of phospholipids or
penetration of NPs (increase in SP) or their
displacement from the interface into the subphase
(decrease in SP), causing destabilization of the
membrane or no interaction (no change in SP).
Based on the change in SP, the interaction of NPs
with the model endothelial membrane (EMM)
significantly depends on their surface
characteristics and sizes. In general, small
aminated NPs and plain NPs have greater
interactions with the EMM than do carboxylated
and large plain NPs. Interesting observation was
the presence of serum proteins does not seem to
influence the interaction of small NPs (20 nm) with
the membrane irrespective of their surface charge
but large size NPs (60 nm) show different pattern
of interactions with surface charge in the presence
of serum proteins [7]. These results thus suggested
the role of protein corona that is formed around
NPs following interactions with biological fluids on
biophysical interactions with membrane lipids but
the effect depends on physical characteristics of
NPs.
Effect of molecular structure of cationic
surfactant on biophysical interactions of Surface‐
modified Nanoparticles: In this study, we modified
NPs with different polymers and peptides
including cationic surfactants to increase their
interactions with anionic cell membrane. The
important finding was that molecular structure of
cationic surfactants at the NP‐interface influences
the biophysical interactions of NPs with a model
membrane and cellular uptake of NPs. Cationic
surfactants used were of either dichained
(didodecyldimethylammonium bromide [DMAB])
or single chained (cetyltrimethylammonium
bromide [CTAB] and dodecyltrimethylammonium
bromide [DTAB]) forms, the latter two with
different hydrophobic chain lengths. DMAB‐
modified NPs showed a greater increase in SP and
a shift towards higher mean molecular area (mmA)
than CTAB‐ and DTAB‐modified NPs, indicating
stronger interactions of DMAB‐modified NPs with
the EMM. However, analysis of the AFM phase
and height images of the LS films revealed that
both DMAB‐ and CTAB‐modified NPs interacted
with the EMM but via different mechanisms:
DMAB‐modified NPs penetrated the EMM, thus
explaining the increase in SP, whereas CTAB‐
modified NPs anchored onto the EMM’s
condensed lipid domains, and hence did not cause
any significant change in SP. DMAB acquires a
linear configuration because of repulsion between
two hydrophobic acyl chains, which makes one
acyl chain available for anchoring to the NP surface
and other for interaction and penetration through
the membrane [19].
Our recent study with DMAB‐ and CTAB‐modified
poly dl‐lactide co‐glycolide (PLGA) NPs
demonstrated significant difference in the
biomechanics and thermodynamic of interactions
with model membrane [20]. DMAB‐modified NPs
caused membrane bending and also favored
escape from the endosomes than CTAB‐ or
unmodified NPs. From this study, we concluded
that the di‐chained and single‐chained cationic
surfactants on NPs have different mechanisms of
interaction with the cell membrane.
Conventionally, surface charge of NPs is used as a
predictor of NP‐cell interactions. Here we
demonstrated that it is not the charge since all the
surfactants used here imparted cationic charge to
NPs, but the molecular structure of surfactant at
the NP interface determines the extent and
mechanism of interaction with lipid membrane
[19]. This has to do with how surfactant molecules
arrange at the interface and how that
arrangement influences biophysical interactions
(Figure 2).
Peptide‐modified nanoparticles and biophysical
interactions with model membrane:
Functionalization of nanocarriers with cell–
penetrating peptides (CPPs) is one of the
successful strategies to overcome the low cellular
permeability of the encapsulated agents. In our
study, we tested the effects of the TAT peptide
sequence and the amount of peptide conjugated
to NPs on biophysical interactions with EMM, and
the HUVECs were used to determine the uptake of
the encapsulated therapeutic. Ritonavir was
chosen as a model drug since it possesses limited
cellular permeability and transport, attributed
mainly to its P‐gp‐mediated efflux [21]. Our results
demonstrate that the TAT peptide sequence and
Controlled Release Society Indian Chapter February 2015 16 Encouraging Research Through Awareness
Figure 2: Changes in the endothelial model membrane Langmuir‐Schaeffer film morphology following
interactions with different surfactant‐modified NPs. Langmuir‐ Schaffer films were transferred onto silicon
substrate following interaction with NPs for 20 min, and the imaging was carried out using tapping mode
atomic force microscopy in air. a. Endothelial model membrane transferred at SP 30 mN/m. b, c, d, and e are
images of endothelial model membrane following interaction with DMAB‐, CTAB‐, DTAB‐, and PVA‐modified
NPs, respectively. Phase angle scale for all the images 50°. Height scales for the images a, d = 3 nm; b, c, f = 50
nm; e = 200 nm. The section analysis was carried out on AFM height images across the white line. The height
scale for 3‐D height images is 50 nm. Scan size = 2 microns. At least 3‐5 images were scanned to obtain mean
height. Energy minimized conformation of DMAB. Computed minimum energy for the DMAB conformation
shown in (a) is 156.50 K.cal/mole (b) 26.13 K.cal/mole. Minimum energy for different possible geometries of
DMAB was calculated using MM2 molecular mechanics calculation with Chemdraw 3D software. Reproduced
from Ref (19) with permission from American Chemical Society (Copyright 2009).
the amount of TAT conjugated to NPs significantly
affect the biophysical interactions of NPs with the
EMM, and these interactions correlated with the
cellular delivery of the encapsulated drug [22].
The broader significance of the study lies in
optimizing the peptide sequence and the amount
to be conjugated to nanocarriers using biophysical
interaction studies.
Force of interaction of modified nanoparticles
with cell membrane: In this study, we
functionalized PLGA‐NPs with poly‐L‐lysine (PLL) to
determine the effect of this surface modification
on the force of interaction with live cell membrane
and to study how it influences the cellular uptake
and intracellular trafficking of NPs and the delivery
of an encapsulated therapeutic agent. To study the
force of interaction, the AFM probe tips were
coated with NPs and the force of interaction
between these probes and cell membrane was
directly measured using AFM as a function of their
separation distance. Quantification of the force of
interaction demonstrated significant differences in
the relative adhesion force of the two
formulations of NPs with cell surfaces (Figure 3).
The adhesion force measured with unmodified
NPs was 280 pN (maximum) and 20 pN
Controlled Release Society Indian Chapter February 2015 17Encouraging Research Through Awareness
(minimum); the force of functionalized NPs was
1200 pN (maximum) and 50 pN (minimum). To
evaluate the efficiency of surface‐functionalized
NPs for intracellular delivery of therapeutics, NPs
encapsulating the model protein‐horseradish
peroxide (HRP) were prepared. HRP‐loaded,
functionalized NPs demonstrated 10‐fold greater
levels of active HRP enzyme in cells compared to
that with unmodified NPs and protein in solution
[23]. These results suggest that the force of NP‐cell
membrane interactions determined using AFM
provides a measure of the adhesive interaction of
PLGA‐NPs with cell membrane, which further
determines the extent of intracellular delivery of
the encapsulated therapeutic agent. Scanning of
the cell surface also showed the endocytic pit
formed due to internalization of NPs (Figure 3).
Similar technique could be used to determine the
efficacy of a particular targeting ligand (e.g., the
sequence of the targeting or cell‐penetrating
peptides and concentration) based on the force of
interaction with cell membrane. Further, it is
anticipated that the force of interaction with cell
membrane would depend on the membrane
composition. Based on the relative force of
interaction of a nanocarrier with different cell
membranes (e.g., healthy vs. cancer cells), one
may be able to design nanocarrier that targets
specific cell population.
Figure 3: Measurement of force of interaction
between NPs and live cells. AFM tip coated with
NPs was used for interaction study with cells.
Analysis of force distributions for unmodified NPs
and functionalized NPs. Three‐dimensional image
of cell surface showing a typical pit formed on the
surface after incubation with NPs. Figures
reproduced from Ref (23) with permission from
Elsevier B.V. through Rights Link Copyright
Clarence Center.
Concluding Statement AFM provides a sensitive and important tool that
can be explored in various ways to understand
drug/NP interactions with cell membranes.
Understanding such interactions could be of
importance in drug design and development, and
for developing effective nanocarrier systems. A
novel method to quantitatively measure the force
of NP‐cell membrane interactions using AFM offers
unique opportunity towards developing target
cell‐specific nanocarriers. The technique could also
be used to increase our basic understanding of
nanocarrier‐interactions with cell membrane and
their overall role in drug delivery.
Acknowledgements The work described here from authors’ laboratory
is funded by grant R01CA149359 (to V.L.) from the
National Cancer Institute of the National Institutes
of Health.
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lipid environment modulates drug interactions
with the P‐glycoprotein multidrug transporter.
Biochemistry. 38:6887‐6896 (1999)
2. S. Ran, A. Downes, P. E. Thorpe. Increased
exposure of anionic phospholipids on the
surface of tumor blood vessels. Cancer Res.
62:6132‐6140 (2002)
3. G. Brezesinski and H. Mohwald. Langmuir
monolayers to study interactions at model
membrane surfaces. Advances in Colloid and
Interface Science. 100‐102:563‐584 (2003)
4. D. Marsh. Intrinsic curvature in normal and
inverted lipid structures and in membranes.
Biophys J. 70:2248‐2255 (1996)
5. C. Peetla, A. Stine and V. Labhasetwar.
Biophysical interactions with model lipid
membranes: applications in drug discovery
and drug delivery. Mol Pharmaceutics. 6:1264‐
1276 (2009)
Controlled Release Society Indian Chapter February 2015 18 Encouraging Research Through Awareness
6. C. Peetla, S. Vijayaraghavalu and V.
Labhasetwar. Biophysics of cell membrane
lipids in cancer drug resistance: Implications
for drug transport and drug delivery with
nanoparticles. Adv Drug Deliv Rev. 65:1686‐
1698 (2013)
7. C. Peetla and V. Labhasetwar. Biophysical
characterization of nanoparticle‐endothelial
model cell membrane interactions. Mol
Pharmaceutics. 5:418‐429 (2008)
8. C. Peetla, R. Bhave, S. Vijayaraghavalu, A.
Stine, E. Kooijman and V. Labhasetwar. Drug
resistance in breast cancer cells: biophysical
characterization of and doxorubicin
interactions with membrane lipids. Mol
Pharmaceutics. 7:2334‐2348 (2010)
9. B. Sharma, C. Peetla, I. M. Adjei and V.
Labhasetwar. Selective biophysical
interactions of surface modified nanoparticles
with cancer cell lipids improve tumor
targeting and gene therapy. Cancer Lett.
334:228‐236 (2013)
10. T. H. Chung, S. H. Wu, M. Yao, C. W. Lu, Y. S.
Lin, Y. Hung, et al. The effect of surface charge
on the uptake and biological function of
mesoporous silica nanoparticles in 3T3‐L1 cells
and human mesenchymal stem cells.
Biomaterials. 28:2959‐2966 (2007)
11. M. N. Kumar, S. S. Mohapatra, X. Kong, P. K.
Jena, U. Bakowsky and C. M. Lehr. Cationic
poly(lactide‐co‐glycolide) nanoparticles as
efficient in vivo gene transfection agents. J
Nanosci Nanotechnol. 4:990‐994 (2004)
12. P. R. Lockman, J. M. Koziara, R. J. Mumper and
D. D. Allen. Nanoparticle surface charges alter
blood‐brain barrier integrity and permeability.
J Drug Target. 12:635‐641 (2004)
13. T. S. Hauck, A. A. Ghazani and W. C. Chan.
Assessing the effect of surface chemistry on
gold nanorod uptake, toxicity, and gene
expression in mammalian cells. Small. 4:153‐
159 (2008)
14. J. Pan and S. S. Feng. Targeted delivery of
paclitaxel using folate‐decorated poly(lactide)‐
vitamin E TPGS nanoparticles. Biomaterials.
29:2663‐2672 (2008)
15. L. Balogh, S. S. Nigavekar, B. M. Nair, W.
Lesniak, C. Zhang, L. Y. Sung, et al. Significant
effect of size on the in vivo biodistribution of
gold composite nanodevices in mouse tumor
models. Nanomedicine. 3:281‐296 (2007)
16. Y. Tabata and Y. Ikada. Effect of the size and
surface charge of polymer microspheres on
their phagocytosis by macrophage.
Biomaterials. 9:356‐362 (1988)
17. S. K. Sahoo, J. Panyam, S. Prabha and V.
Labhasetwar. Residual polyvinyl alcohol
associated with poly (D,L‐lactide‐co‐glycolide)
nanoparticles affects their physical properties
and cellular uptake. J Control Rel. 82:105‐114
(2002)
18. M. C. Woodle. Controlling liposome blood
clearance by surface‐grafted polymers. Adv
Drug Rev. 32:139‐152 (1998)
19. C. Peetla and V. Labhasetwar. Effect of
molecular structure of cationic surfactants on
biophysical interactions of surfactant‐
modified nanoparticles with a model
membrane and cellular uptake. Langmuir.
25:2369‐2377 (2009)
20. C. Peetla, S. Jin, J. Weimer, A. Elegbede and V.
Labhasetwar. Biomechanics and
thermodynamics of nanoparticle interactions
with plasma and endosomal membrane lipids
in cellular uptake and endosomal escape.
Langmuir. 30:7522‐7532 (2014)
21. J. Alsenz, H. Steffen and R. Alex. Active apical
secretory efflux of the HIV protease inhibitors
saquinavir and ritonavir in Caco‐2 cell
monolayers. Pharm Res. 15:423‐428 (1998)
22. K. Borgmann, K. S. Rao, V. Labhasetwar and A.
Ghorpade. Efficacy of Tat‐conjugated
ritonavir‐loaded nanoparticles in reducing
HIV‐1 replication in monocyte‐derived
macrophages and cytocompatibility with
macrophages and human neurons. AIDS Res
Hum Retroviruses. 27:853‐862 (2011)
23. J. K. Vasir and V. Labhasetwar. Quantification
of the force of nanoparticle‐cell membrane
interactions and its influence on intracellular
trafficking of nanoparticles. Biomaterials.
29:4244‐4252 (2008)
Development oActing Drug DeSystems for CoAnimalsAnimals
Michael Rathbone*, Peter BarlingInternational Medical University,
Bukit Jalil, 57000, Kua*
Introduction Pets play an
lives of people. They are often revered foon the physical and mental health ofFurthermore, they provide companionshi
*Email: michael_rathb
, y p presponsibility to their owners and famianimals include (but are not limited to) domonkeys and horses. As is the case withthey sometimes need medicines to keepspecific animal requiring any particular ddr g concentration in its blood hich idrug concentration in its blood which witherapeutic benefit. Above the maximutoxic effect may occur, while below the mthe effect will be therapeutically inadequrelease dosage forms such as tablets, capsmultiple dosing is required to maintain twithin the optimum therapeutic raninconvenient to have to administer a druConsequently long acting drug delivery syare being, developed by formulation sciendoing this is generally to ensure that theinduces a slow release of the entrapped dinduces a slow release of the entrapped d
Controlled Release Soci
February 2015
Technical Insights
of Long elivery ompanion
g, Soon Teng and Franciska Kim No. 126, JalanJalil Perkasa 19,
ala Lumpur, Malaysia,
important part in the
or their positive effectstheir human owners.p and instill a sense of
bone@imu.edu.my
pilies. Such companionogs, cats, birds, rabbits,h their human owners,them healthy. For anydrug, there is an idealill achie e a ma im m
Michael Rathbone
ill achieve a maximumm therapeutic level ainimum effective level,uate. With immediate‐sules, and suspensions,the average drug levelnge. It is generallyug frequently to a pet.ystems have been, andntists. The objective ofe resulting formulationrug prolonging therug, prolonging the
iety Indian Chapter
1919Encouraging Research Through Awareness
Controlled Release Society Indian Chapter February 2015 20 Encouraging Research Through Awareness
effective action period after a single dose
administration. The advantages of long acting
dosage forms to the companion animal include the
ease of administration, and a lowering of stress to
the animal and its owner because less time and
effort is required to deliver the overall treatment.
In addition, compliance is potentially increased
and the overall cost of treatment is reduced.
Moreover the dose of administered drug can be
more accurately predicted than if the same drug
were added to, for example, the animal’s food or
water [1].
This article describes some of the long acting
technologies that are currently available for use in
pets, and discusses the challenges faced by
formulation scientists in developing more effective
pharmaceutical products for this purpose.
Long-acting drug delivery formulations These are drug delivery systems which, by virtue of
the excipients, or manufacturing process, or
physical design, provide drug release in a
prolonged manner that is distinct from that of
more conventional dosage forms. They are
formulated to release their medication in a
controlled manner, at a pre‐determined rate, over
an extended duration. They are designed to be
administered once or a few times only, to a
specific location in the body in order to achieve
and maintain optimum therapeutic blood levels of
the drug of choice. Long acting dosage forms can
play an important role in facilitating improvement
in a pet’s health. In conventional formulation,
drugs that are not inherently long‐lasting often
require multiple daily dosing to achieve the
desired therapeutic effect: a commitment which is
often inconvenient to the pet owner, or requires
repeated trips to the veterinarian [2,3].
Challenges in developing long acting dosage treatments for pets
There are many challenges faced by the
formulation scientist is in developing effective long
acting dosage forms for pets. The first is the need
to keep costs at a minimal level because of the
limited budget and resources for veterinary R&D.
The second is the eventual cost of the resulting
product. This results from the resistance of some
pet owners to spend beyond a certain budget on
treatment for their pet. This consideration affects
the design and components of the formulation
(including excipients) and the choice of the
manufacturing process.
Another challenge is to optimize drug dosage and
delivery, considerations which are critical to
achieving clinical efficacy and safety. This is
particularly important when formulating drugs
with a narrow therapeutic index. Increasingly
these days, models of the pharmacokinetics of
drug distribution and metabolism and the
pharmacodynamics of a particular species’
response to a drug have become the basis for
effective dose optimization. Such models are often
very different between different species of pets.
The diversity of breeds poses further challenges,
as large differences in sizes and weights within a
species correlate with variations in anatomy and
physiology. These considerations, together with
seasonal variations and differences in animal
temperaments all need to be taken into account
by the formulation scientist [3,4]. Getting it all
right for a particular species and breed of pet, and
at the right price, poses formidable challenges to
the formulation scientist.
Examples of long acting dosage forms already in use
There are various types of long acting dosage
forms currently available for companion animals.
These include parenterals (injections, implants and
microspheres), collars, spot‐ons and ocular
technologies.
Parenteral long acting dosage forms Drugs given by injection: The main parenteral
routes of drug administration are intramuscular
and subcutaneous. In farm animals, a
subcutaneous route (an injection into the
subcutaneous layer below the skin) is generally
preferable. This is because muscle tissue may be
harvested for food, and a subcutaneous route
avoids the risk that the dosage form or drug might
result in muscle, tissue residue and/or local tissue
damage, thus affecting meat quality. However, in
pets, these considerations are not important
factors, so a route in which the drug is injected
deep into muscle is generally acceptable and has
the advantages of rapidity of drug administration
Controlled Release Society Indian Chapter February 2015 21Encouraging Research Through Awareness
and reliable predictability of the resulting blood
level of the drug. However, the disadvantage of
parenteral injection is that it is almost impossible
to remove the drug once it has been injected
causing problems if there is an allergic reaction or
overdose. In addition, injection sites differ in the
rate of release of a drug. Many factors contribute
to this, including tissue composition, and the rate
of perfusion of nearby blood and lymphatic
vessels.
Recombinant human insulin is often used to treat
diabetes in cats and dogs by a subcutaneous
parenteral depot injection. A depot injection is a
suspension or a solution which precipitates at the
injection site. Delivery of the active drug is
maintained for the period during which the drug
becomes solubilized and released into the
bloodstream. Short‐acting, intermediate‐acting
and long acting insulin preparations are available
for companion animals. ProZincTM is an example of
long acting protamine zinc insulin available for use
in pets (Figure 1).
Implants: Implants have been used extensively for
estrous control in free‐ranging dogs and cats and
to predictably control their oestrous for breeding.
Testosterone implants such as Perlutex Leo®
(which is formulated as polydimethylsiloxane
capsules containing medroxyprogesterone
acetate) has been used to effectively inhibit the
oestrous cycle in free‐ranging dogs in order to
reduce their numbers. This technology is
increasingly gaining popularity as an effective
replacement for surgery to achieve the same
outcome.
Microspheres and microcapsules: Microspheres
and microcapsules are spheres about 1‐1000μm in
diameter in which a drug has been dispersed
(microspheres), or encapsulated in the core
(microcapsules). Microspheres/microcapsules are
easy to administer, and can act as effective
carriers because they can be formulated so the
active drug is released by being leached from the
polymer or by degradation of the polymer matrix.
The drawback of microspheres/microcapsules is
that they have a low drug loading capacity.
Figure 1: ProZinc™ insulin for treatment of
diabetes in cats
Proheart®6 is an example of a microsphere‐
formulated product for use in pets (Figure 2). The
product comprises of two vials, one containing the
active drug and the other a vehicle for constitution
of the microspheres as a sustained release
suspension containing moxidectin (3.4 mg/mL).
This is then administered subcutaneously to
provide prolonged release of moxidectin for 6
months.
Collar long‐acting dosage forms: The flea collar
has been developed to control fleas, ticks and lice
in companion animals. The dose of pest repellent
or insecticide is delivered from a collar that goes
around the neck of a dog or cat. The collar
incorporates active ingredients that leach out of
the collar matrix into the fat layer on the pet’s
skin, and spreads using the pet’s natural skin oil.
The advantages of the flea collar are that it is easy
to fit, and it is waterproof so that it does not need
to be removed while the animal is being showered
or when swimming. Flea collars are widely
available and can control fleas and ticks for 5‐8 months according to the brand. On the down side,
when humans, particularly children, come in
contact with the collar, there is a risk of toxicity,
with a detrimental effect on human health.
Controlled Release Society Indian Chapter February 2015 22 Encouraging Research Through Awareness
Figure 2: ProHeart®6 which prevents heartworm
in dogs
Examples of flea collars include Kiltix, Adams, and
Bob Martin (Figure 3).
Figure 3: The Adams flea and tick collar for large
and small dogs and Bob Martin flea collar for cats
Spot‐on long acting dosage forms: The spot‐on is
another long acting dosage form to kill and
manage fleas, lice, and ticks, or to prevent
heartworm, hookworm, roundworm or whipworm
(Figure 4). The active ingredients in spot‐on
products include fipronil, imidacloprid, selamectin,
ivermectin and moxidectin. They are applied
topically and use the inherent properties of the
drug (aided by the formulation) to partition into
subcutaneous layers of the skin and slowly diffuse
from there into blood to be transported to more
distant sites. Spot‐ons usually last for a month.
The drawback of spot‐on treatments is that the
formulations need to be specifically tailored for
the size and type of the pet. Thus, a product that
has been designed for a large dog may not work
effectively for a smaller dog or vice versa.
Ocular long acting dosage forms: Most of the
ophthalmic drugs formulated for companion
animals use work by penetrating the cornea
through passive diffusion. This process depends
upon the oil/water solubility and partitioning
characteristics of the drug.
Figure 4: Frontline spot‐on for dogs and Bob
Martin spot‐on for cats and kittens to prevent
fleas and ticks
Unfortunately, many drugs do not possess the
ideal physicochemical characteristics to facilitate
their ocular delivery. Therefore, they are often
formulated with excipients such as surfactants
(e.g., benzalkonium chloride) to enhance their
absorption, or combined with organic salts to give
a pro‐drug that has improved solubility. The
frequency of application depends upon the
severity of the condition, the vehicle used and the
duration of action of the drug. Conventional ocular
dosage forms comprise solutions, suspension or
ointments. However alternative long‐acting ocular
delivery systems have also been developed. These
include a delivery system in which a polymeric
membrane holds a reservoir of drug which can be
placed into the conjunctival cul‐de‐sac, permitting
the drug to diffuse out at a predictable rate. This
concept employs a device similar to a soft contact
lens. Pilocarpine and epinephrine are drugs used
for the treatment of glaucoma which have been formulated in this way. The advantage of this type
of delivery system is that it requires placement
into the afflicted eye only once a week and slow
release results in the eye being exposed to a lower
concentration of drug, thus minimizing side
effects. One disadvantage is that at times, the
pet’s third eyelid can catch on the reservoir and
flip it out of the cul‐de‐sac. It is also expensive.
Sub‐conjuctival delivery involves an injection of a
drug under the bulbar conjunctiva so the drug is
deposited against the sclera. Following
administration, the drug will penetrate via simple
diffusion through the sclera. It has the potential to
increase drug absorption and prolong contact
time. Drugs with low solubility (for instance
corticosteroids) may be provided as a repository
Controlled Release Society Indian Chapter February 2015 23Encouraging Research Through Awareness
lasting days to weeks following subconjuctival
delivery. By this route, water‐soluble products can
also be absorbed into the eye. However, it
requires a perforation of the globe with a needle
and it cannot be used with drugs which have been
found to irritate the animals’ eyes. For small
animals, 0.5mL per site is often safe and effective.
For large animals such as horses, volumes of less
than 1mL can be administered.
Concluding remarks
Many obstacles are faced by formulation scientists
in developing effective long‐acting products for
companion animals. These challenges still need to
be resolved in order to make further progress in
animal health long acting delivery systems. Despite
the challenges, a number of long acting dosage
forms are already available, such as parenteral
injections, microspheres/ microcapsules, implants,
flea collars, and spot‐ons. These products aim to
increase the duration of action of a medication for
the treatment of disease in companion animals.
With the design of more specialized drug carriers
with predicable release profiles, the future for long
acting drug delivery systems for pets looks
promising.
References: 1. M. J. Rathbone. Delivering drugs to farmed
animals using controlled release science and
technology. International e‐Journal of Science,
Medicine & Education. 6(Suppl 1):S118‐S128
(2012).
http://web.imu.edu.my/ejournal/approved/1
6. Review_michael_s118‐s128.pdf
2. M. J. Rathbone and R. Gurny. Controlled
release veterinary drug delivery: Biological
and pharmaceutical considerations, Elsevier,
Holland, 2000.
3. M. J. Rathbone and A. McDowell. Long Acting
Animal Health Drug Products: Fundamentals
and Applications, Advances in Delivery Science
and Technology. Springer, USA, 2012.
4. G. E. Hardee and J. D. Baggot. Development
and Formulation of Veterinary Dosage Forms,
Second Edition, Marcel Dekker, New York,
USA, 1998.
CROSSWORD
Across 7. Popular desiccant 8. Pfizer blockbuster drug for cholesterol
treatment 10. A small device that can be placed in the
artery after angioplasty to ensure that the artery remains open
11. Natural Superdisintegrant 14. A recognizable sign, design or expression
which identifies products or services of a particular source from those of others
15. USP Dissolution Apparatus III 16. Discoverer of liposomes
Down 1. Medicated candy to be dissolved slowly in
the mouth 2. Nicotine chewing gum to aid smoking
cessation 3. A molecule used as an anticoagulant in the
treatment of thrombosis 4. A hormone that stimulates production of red
blood cells and haemoglobin in the bone marrow
5. Artificial sweetener 6. Intravenous fat emulsion 9. Cervical cancer vaccine by GSK 12. A pharmaceutical agent that has been
developed specifically to treat a rare medical condition
13. Type I Glass used in packaging *Answer key on pg 50‐51
INDUSTRUSPERSPE
Technical Reviews
24
RY ECTIVES
Quality By DRoadmapRoadmap
BukeSanta Farma Pharmaceutical
No:16 Sisli, IsEmail: baksu@s
Introduction Today high
pharmaceutical authorization process isefforts and costs. With the incpharmaceutical products, risk control an
d ff l d f h lmore difficult. Rigidity of the regulatdifficulties arising from the implementatare the most important factors explaininindustry in production innovation. Duripharmaceutical industry is trying to adrapidly, has experienced major devep y, p jinformation, quality management systemand has developed modern productionensuring the production quality. Themanufacturers to identify, analyze, correand constantly enhance the production p
In 2002, the Food and Drug Administratiopharmaceutical industry the amendmeManufacturing Practices (cGMP) to imprules that regulate the pharmaceutical pthe pharmaceutical product quality. Interp p q y
Controlled Release S
February 2015
Industrial Perspectives
Design (QbD)
t Aksuls, Okmeydani, BorucicegiSok. stanbul, Turkeyantafarma.com.tr
demand and requests in
s continuously increasingcreasing complexity ofd ensuring the quality get
d f ftory system and fear oftion of new technologies,g the unwillingness of theing the recent years, thedapt itself to innovationselopments in production
Buket Aksu
p pms and risk managementn tools that can assist inese new tools help theect and prevent problems,processes.
on (FDA) introduced to thents in the current Goodprove and modernize theroduct manufacturing andrnational Conference on
Society Indian Chapter
2525Encouraging Research Through Awareness
Controlled Release Society Indian Chapter February 2015 26 Encouraging Research Through Awareness
Harmonization (ICH) is a forum that gathers the
authorities and experts of the pharmaceutical
industry in the United States (US), Japan and
European Union to harmonize the technical
requirements for pharmaceutical products in three
regions, published current guidelines (ICH Q8, Q9,
Q10 and Q11) to bring a new approach which is
called Quality by Design (QbD) to the industry [1].
In this framework, the guideline ICH Q8 was
published in 2005, which introduced the concept
of QbD into the pharmaceutical industry. Later on,
as one of the important steps to define QbD
required a distinction between the critical and
non‐critical product qualities and process
parameters, it was decided that there was a need
to conduct and manage risk assessments, and the
ICH Q9 guideline was thus published. Finally, the
last document of the triple structure, ICH Q10
guideline was published to regulate the quality
management system of pharmaceutical product
manufacturers, which establishes the expectations
from the Pharmaceutical Quality System, and deals
with the ways of their implementation in achieving
compliance with quality standards in design,
quality management, risk assessment and during
the life‐cycle of the product. The studies on
guidelines following the above continued with the
guideline Q11 on manufacture of pharmaceutical
raw materials. In line with these developments, a
better understanding of the QbD approach and its
implementation became very important.
Therefore, in this paper, displaying the QbD
approach, explaining its basic steps and pointing
its benefits was aimed.
Science And Risk Based Approach As defined in ICH Q8 guideline, QbD is a systematic
product development approach that begins with
pre‐defined objectives and emphasized
understanding of the product and process based
on firm science and quality risk management [2].
Two basic components of QbD are quality risk
management and knowledge management.
Risk Based Approach: Adoption of risk based
orientation by the FDA with current Good
Manufacturing Practices (cGMP) is the most
important aspect of twenty first century. FDA has
carried out a pilot study in 2005 including risk‐
rating model. The model is based on a hierarchical
risk assessment and risk filtering method and a
Site Risk Potential (SRP) calculates the site risk as a
function of weighted potentials for each of the
three high level components of site risk, as
product, facility and process. The risk potential for
these three high level components is a function of
the relevant selected risk factors. A sub‐category
set has been defined for each high level
component and each sub‐category comprises of
different risk factors.
Science Based Policies: In the manufacture of a
pharmaceutical product, especially taking into
consideration the financial and ethical pressures
on process development teams carrying out works
to release a new pharmaceutical product to the
market, there is a problem about the idea of
considering the first confirm configuration as the
most suitable one. This situation has resulted in
the authority initiating the process of developing
science‐based policies and standards in order to
support innovation, thus new guidelines have
been generated. Each guideline give incentive for
willing adoption of new technologies in
pharmaceutical manufacturing, by defining
modern, science‐based authorization processes
that allow manufacturers to carry out easier
authorization processes and improvement works.
Qbd Applications Quality of a pharmaceutical product is dependent
on understanding molecule reliability, mechanism
of action and its biology. Understanding, control
and pharmaceutical quality is ensured for
formulation and manufacturing variables, when
QbD is used. Manufacturing process is developed
according to development and fulfilling of
requested features of the molecule; in case
product quality is "designed" rather than "tested".
In the QbD approach, it is possible to use data
obtained from development works carried out to
create a design space for achieving continuous
development and existing information. This way, it
is possible to provide changes in the industry
through change control method, without
confirmation from the authority. Also the most up‐
to‐date pharmaceutical and engineering
information is used during the life‐cycle of the
Controlled Release Society Indian Chapter February 2015 27 Encouraging Research Through Awareness
product. In addition to this, QbD works inside the
design space obtained by considering critical
formulation and process parameters and therefore
no need remains for product quality verification
through final quality test. Processes are adopted
with the help of Design of Experiments (DoE) and
Process Analytical Technology (PAT) instruments
with quality management, in order to create a
product that has the same quality continuously,
and the products are very well understood [3‐5].
With the QbD system, formulation is designed to
meet product quality and the process is designed
to meet critical quality features of the product,
continuously.
Qbd Steps Management of product and process information
is an indispensable component of design and
quality and should be continued throughout the
whole or entire full life‐cycle of the product. In
QbD, it is necessary to ensure flow of information
from development to manufacture and flow back
from manufacture to development and
transparency of information is necessary.
The first step in QbD is determining design
objectives for the product.
Target Product Profile (TPP): Target Product
Profile (TPP) described the general objective of the
pharmaceutical product development program
and provides information about the development
works. In pharmaceutical development, ICH Q8
requires “determining of features critical for
quality of the ready‐made pharmaceutical product,
with regard to intended use and route of
administration and assessment of intended use of
the product and route of administration is carried
out through the TPP” [2]. Many features of TPP are
restricting or determining works of formulation
and process development researchers. Among
them, there are route of administration, form and
amount of dosage, maximum and minimum doses,
presentation of pharmaceutical product and target
patient population [6].
Quality of Target Product Profile (QTPP): Quality
profile of target product, or in other words quality
of target product profile (QTPP) is quantitative
support for clinic safety and efficacy that can be
used for designing and optimizing a formulation or
manufacturing process. In the ICH Q8, QTPP
includes definition of features critical in product
quality in pharmaceutical development, intended
use of the pharmaceutical product and route of
administration [2].
Critical Quality Attributes (CQA): The concept of
criticality can be used to explain any feature,
importance or characteristics of an active
substance, component, raw material, finished
product or device; or any process characteristics,
parameters, conditions or factors in finished
product production.
CQA is defined as physical, chemical, biological and
microbiological features/characteristics that
should be controlled in order to ensure product
quality [2].
Critical Process Parameters (CPPs): The parameter
expresses a characteristic of a system or process
that is measurable or countable. Parameters are
usually considered as features related to
manufacture, such as temperature, mix speed, as
characteristics of equipment or process; on the
other hand, features are considered as
characteristics of materials (such as melting point,
viscosity, sterility). However, it should be kept in
mind that there are no absolute borders between
features and parameters.
Design Space: Realizing the restricting features of
today's pharmaceutical product development
approaches, the FDA, together with the ICH has
supported the concept of "Quality by Design".
Accordingly, design space has started to gain an
important place in the pharmaceutical industry.
Design space is defined as "multi‐dimensional
combinations and interactions of input material
variables (i.e. material features) and process
parameters with proven assured quality".
Boundaries of the design space should be very well
defined. Information should be provided on which
parameters and ranges are included in the design
space. An explanation should be made when
ranges investigated at laboratory scale does not
coincide with the design space. Comprehensive
information about design of experiments and
statistical methods should be included in the
application.
Controlled Release Society Indian Chapter February 2015 28 Encouraging Research Through Awareness
Solutions And Benefits Put Forth By Qbd Primarily QbD applications put forward a win‐win‐
win policy. From the perspective of manufacturers,
better understanding of product/process,
development of more effective processes and less
regulatory requirements are possible. In addition
to these, it allows for understanding critical and
non‐critical parameters in developing design
space, provides opportunity for focusing on
important parameters in product quality in
validation works. As the control range where
product and process are not affected, are better
understood than a range generated only
empirically, a wider validation acceptance criteria
is achieved [7]. Product quality cannot be tested at
the end of manufacturing process using QbD
approach, but quality is designed at product
design phase and quality is embedded in the
product. Rather than controlling quality, quality
assurance is ensured, which is more superior.
Manufacturing implementations with continuously
constant processes have ended with generation of
a full understanding regarding the process; and
process is made dynamic through approaches
based fully on scientific data and implementations
based on previous information and experience,
along with determining and managing critical
points through risk management implementations,
by determining critical points regarding product
and process. Development and innovation are
hindered because of processes and systems that
are not changed. However, with the design space
brought by QbD, flexibilities such as real time
release have become a part of the process.
Because of these changes, operability of the
processes has been proven and reliance on the
system has increased.
Testing of quality in process begins as the process
is halted and testing is removed. Controls have
been carried out based on critical features in the
process and changes made in relation to these
have been managed and the process has been
continuously advanced. As continuous process
improvement has become possible, an approach
implementation has come where process
performance intended for process validation is
continuously monitored, evaluated and adjusted.
Most importantly, other than these, this new
approach has allowed for acting and decision
making with scientific and risk based information.
References: 1. B. Aksu, A. Paradkar, M. de Matas, Ö. Özer, T.
Güneri and P. York. A quality by design
approach using artificial intelligence
techniques to control the critical quality
attributes of ramipril tablets manufactured by
wet granulation. Pharm Dev Technol.
18(1):236‐245 (2013)
2. ICH. Pharmaceutical Development Q8(R2)
(Step 4). Geneva: International Conference on
Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human
Use (ICH)(2009)
3. U.S. Dept. of Health and Human Services,
Guidance for Industry, PAT — A Framework
for Innovative Pharmaceutical Development,
Manufacturing. Food and Drug Administration
Rockville, 2004
4. R. Mhatre and A. S. Rathore. Quality by
Design: An Overview of the Basic Concepts, In,
A. Rathore S, and Mhatre R, (ed) in, Quality by
Design for Biopharmaceuticals: Principles and
Case Studies, John Wiley & Sons, Inc, NJ,
Hoboken (2008)
5. S. K. Singh, T.G. Venkateshwaran, and S. P.
Simmons. Oral Controlled Drug Delivery:
Quality by Design (QbD) Approach to Drug
Development, In, Wen, H and Park K, (ed),Oral
Controlled Release Formulation Design and
Drug Delivery: Theory to Practice, John Wiley
& Sons, Inc, New Jersey, pp 305‐320, 2010
6. R. A .Lionberger, S. L. Lee, L.Lee, A. Raw and L.
X. Yu. Quality by Design: Concepts for ANDAs.
AAPS J.10(2):268‐276 (2008)
7. S. Schmitt. Quality by Design Putting Theory
into Practice,Davis Healthcare International
Publishing, LLC, USA, 2011
EXAMINATION EXAMINATION SPECIFICATIONSPECIFICATION
COPYRIGHT COPYRIGHT INNOVATIONINNOVATION
RESEARCHRESEARCH
505(b)(2): AnInsight
RESEARCHRESEARCH
InsightYagna Kumar and Ma
Intellectual Property DepartmGENBlock, T.T.C.
Mahape, Navi Mu*
Introduction From 1938
Drugs Administration used to approve thsafety studies. Senator Estes Kefauver tr
*Email: mahalaxmiandhe
efficacy requirement, a concept thaindustry fully supported, but could not bof some logical disconnections. In 196sleeping pill, caused birth defects in thouWestern Europe. News reports on the roFDA medical officer, in keeping the druFDA medical officer, in keeping the druaroused public support for stronger drugsame year Kefauver‐Harris Drug Amendensure drug efficacy and greater drug sathe first time, drug manufacturers are rethe effectiveness of their products befo
i i f h d hgeneric version of these new drugs tha1962 could be approved with a "paper(NDA). The paper NDA was based solelyor medical literature; a generic manufacapproved by showing that medical literaabout the chemical, demonstrating t, geffective.
Controlled Release Soc
February 2015
Industrial Perspectives
n Industry
ahalaxmi Andheria* ment, Panacea Biotec Ltd, 72/3 Industrial Area,
umbai – 400710
to1962, US Food and
he new drugs based onried for years to add an
ria@panaceabiotec.com
at the research‐basede able to do so because62, thalidomide, a newusands of babies born inole of Dr. Frances Kelsey,ug off the U.S. market,
Yagna Kumar
ug off the U.S. market,g regulation. Thus in thedments was passed toafety [1]. As a result, forequired to prove to FDAore marketing them. A
d f
Mahalaxmi Andheria
at were approved after" new drug applicationy on published scientificcturer could get its drugature had been writtenthat it was safe and
ciety Indian Chapter
2929Encouraging Research Through Awareness
Controlled Release Society Indian Chapter February 2015 30 Encouraging Research Through Awareness
After 1962, though there were 150 drugs that
were off‐patent, but there were very few generics
for this, because as per the new amendments
(Kefauver‐Harris Drug Amendments) a generic
drug manufacturer also required to prove to FDA
the effectiveness of their products before
marketing them, and generic companies simply
could not spend the time and money doing the
clinical trials to get to market, and thus there were
only fifteen "paper NDAs,” post 1962 [2].
This kind of a milieu created an unintentional
advantage for the innovator companies where
they were able to relish the monopoly in the
market without any substantial generic rivalry
even after the expiry of patents. The environment
was conducive for the innovator companies at the
same time inimical to the interests of generic
industry.
Thus the situation ripened to streamline the
approval process of the medicinal products for
human use by balancing benefits for both
innovator companies and the generic industry.
The Hatch - Waxman act and the Approval procedures
As a result of Hatch ‐ Waxman act 1984, United
States Food and Drug Administration (USFDA) in its
regulatory structure included three pathways for
approving medicinal product for the human use by
balancing benefits for both innovator companies
and the generic industry.
(i). New Drug Application (NDA) also known as
505(b)(1) application,
(ii). New Drug Application (NDA) also known as
505(b)(2) application and,
(iii). Abbreviated New Drug Application (ANDA)
also known as 505(j) application.
Here we attempt to provide an outline of the
505(b)(2) process with respect to the
identification, selection, development feasibility,
time lines, cost and other aspects related to
505(b)(2) filing and approval processes.
The 505(b)(2) application The 505(b)(2) application is an intermediate
between 505(b)(1) [an application that contains
full reports of investigations of safety and
effectiveness] and 505(j) [an application that
contains information to show that the proposed
product is identical in active ingredient, dosage
form, strength, route of administration, labeling,
quality, performance characteristics, and intended
use, among other things, to a previously approved
product]. As per 21 U.S.C 355(b)(2), “A 505(b)(2)
application is one for which one or more of the
investigations relied upon by the applicant for
approval were not conducted by or for the
applicant and for which the applicant has not
obtained a right of reference or use from the
person by or for whom the investigations were
conducted".
The comparison of 505(b)(2) applications with
505(b)(1)and 505(j) has been given in Table 1 for
reference [3].
Table 1: Comparison of 505(b)(2) applications
with 505(b)(1) and 505(j)
505(b)(1) 505(b)(2) 505(j)
Regulatory process
Review Timeline 1‐2 years 9 months to
1 year
2.5 to 3
years
Data required for approval
Safety and efficacy
study reports
Yes Depends on
the nature of
application
No
BA/BE study with
RLD
N/A Yes Yes
CMC bridging study
with RLD
N/A Yes Yes
Toxicology bridging
study with RLD
N/A Depends on
the nature of
application
No
Patent and Exclusivity eligibility
Patent listing in OB Yes Yes No
Patent certification N/A Yes Yes
Marketing exclusivity Yes Yes No*
*Except for first to file applicants with P‐IV certification that is eligible for 180 day exclusivity
The 505(b)(2) application expressly permits FDA to
rely, for approval of an NDA, on data not
developed by the applicant, i.e. some of the data
may not be owned by the applicant but may have
a reference to the information in the application of
a full NDA or may be relied on some published
literature or both. The same is dealt in detail
below:
Controlled Release Society Indian Chapter February 2015 31Encouraging Research Through Awareness
Data from published literature: An applicant for a
505(b)(2) application may rely on data from
published literature. This can be called as a
“literature –based 505(b)(2)”. The data from the
literature should be such that the applicant has
not obtained a right of reference for the data,
otherwise, such application qualifies as a 505
(b)(1) application, had the applicant reserved his
right of reference.
Data from the Agency’s(The USFDA) finding of
safety and efficacy of the approved drug: The
505(b)(2) applicant can rely on the Agency’s
finding of safety and efficacy data for a previously
approved drug under section 314.54. This
exclusive provision of relying on reference data
drastically reduces the cost incurred when
compared to that for an NDA involving an NCE.
Hence, such submissions may also prove lucrative
for smaller applicant firms who, in most cases,
may not have the facility, resources and
infrastructure to conduct the study themselves or
lack monetary support in cases of contract
outsourcing.
Types of 505(b)(2) applications [4]
New Chemical Entity (NCE) or New Molecular
Entity (NME): In this, an applicant can submit a
505(b)(2) application for a NCE/NME based on
data revealed by published literature and not from
FDA’s previous findings of safety and efficacy.
Eg: Approval of Bendamustine HCl lyophilized
powder for injection as Treanda® (a Cephalon’s
product) by USFDA was through a 505(b)(2), NCE
application.
Changes to previously approved
drugs/formulation: The approval to a change in
previously approved drug/formulation cannot be
sought through the 505(j) route, however, can be
applied via the 505(b)(2) pathway. The applicant
can rely on the Agency’s safety and efficacy data
for previously approved drugs. The applicant
however, needs to submit additional data for the
matter which makes the application eligible for
505(b)(2), these studies need to be carried out by
the applicant himself or the applicant should
reserve a right of reference on the data which he is
relying upon.
However, section 505(b)(2) applications should not
be submitted for duplicates of approved products
that are eligible for approval under 505(j) (see 21
CFR 314.101(d) (9)).
Some of the below mentioned examples will
provide an insight on various feasible changes to
Reference Listed Drug (RLD) for applying through a
505(b)(2) process:
i. Change in Strength ‐ For example: An application
for a change to a lower or higher strength
ii. Change in Route of administration ‐ For
example: intravenous to intrathecal
iii. Combination product ‐ For example: An
application for a new combination product in
which the active ingredients have been previously
approved individually.
iv. Changes in Formulation ‐ For example: An
application for a proposed drug product that
contains a different quality or quantity of an
excipient(s) than the listed drug where the studies
required for approval are more than those
considered limited confirmatory studies
appropriate to a 505(j) application.
v. Change in Dosing regimen ‐ For example: Twice
daily to once daily
vi. Change in Dosage form ‐ For example: Solid oral
dosage form to transdermal patch
vii. Change in Indication ‐ For example: An
application for an indication which was not
previously approved for a listed drug.
viii. Change in Prescription status from Rx to OTC.
ix. Bioequivalent products ‐ For example: a
505(b)(2) application would be appropriate for a
controlled release product that is bioinequivalent
to a RLD where:1. Such product is at least as
bioavailable as the RLD (unless it has some other
advantage, such as smaller peak/trough ratio); or
2. The pattern of release of the proposed product, although different, is at least as favorable as the
RLD.
505(b)(2) Development Pathway Generally followed principles for the development
of a 505(b)(2) product in an industry setup would
start with identifying an unmet need with the
existing treatment option in a therapeutic class,
identifying the right business opportunity to
design the dosage form that can effectively fulfill
Controlled Release Society Indian Chapter February 2015 32 Encouraging Research Through Awareness
the unmet need or provide significant patient
compliance, followed by selecting the right
molecule in the therapeutic class. The selection of
such opportunity often involves brainstorming
sessions initially involving personnel from Business
Development, Intellectual Property, Clinical and
Formulation Development, followed by some
detailed analysis involving Supply Chain
Management and Regulatory affairs groups.
(i) The Business Development expert estimates the
sales forecast and provides tentative sales
projections. He also estimates possible generic
competition and there by predicting the lifecycle
of the proposed product.
(ii) The Intellectual Property scientist is very crucial
and has a dual role viz (a) to protect the invention
and to safeguard the monopoly of the proposed
product once approved. An IP scientist would pro‐
actively file prosecute and ensure the grant of a
patent in US, comprehensively covering all the
aspects of the invention to prevent other
competitors from circumventing the claims to the
extent possible. He would additionally ensure
listing of such patent(s) in the Orange Book once
the proposed 505(b)(2) is approved by the USFDA.
(b) to provide freedom to operate opinion for such
products in US. This is possible by identifying other
patents filed in US and providing effective
strategies to mitigate the risks associated with
such patents.
If any patent(s) are listed in the Orange Book of
RLD then, the 505(b)(2) application may need to
certify against these patent. In case of Para–IV
certification, IP scientist, based on the product
developed, arranges to obtain a non‐infringement
or invalidation opinion against these patents from
a US attorney, depending on the strategy of filing,
and notify the RLD and Patent holder (collectively
“the innovator”) accordingly as per the provisions
of Hatch‐Waxman Act. On certifying patents with
Para‐IV certification, the 505(b)(2) filer may be
sued by the innovator as per his discretion. IP
scientist collaborates with US attorney to handle
the litigation process.
(iii) The Formulation (R&D) scientist plays an
important role, where he puts all his skills and
expertise to develop and optimize the dosage form
to attain targeted release characteristics both in‐
vitro and in‐vivo and ensures the product meets
safety and efficacy criteria. Typically the process
involves prototype development and product
optimization at lab scale. At this stage, the
scientist in association with clinical group carries
required investigations to establish proof‐of‐
concept (POC). Further the scientist escalates the
lab scale batch and optimizes at a large scale
facility (scale‐up trials) where the batches are
made using higher quantities of drug and
excipients. Finally a Pivotal (Exhibit) batch would
be taken for carrying out the required clinical
investigations. At the same time, the same batch
would be subjected to stability study
investigations under ICH or Agency’s prescribed
conditions. Collating all the data obtained from the
clinical investigations and accelerated stability
study investigations, and in collaboration with
regulatory team a 505(b)(2) dossier would be filed.
Once a project is identified for development, the
formulation scientist follows the regulatory
requirement to develop the product. One
important aspect here is, meeting the time lines.
Developing a 505(b)(2) with in the specified time
period is very vital for effective positioning of the
product in the market and to attain projected
sales. Chasing the timelines by connecting all the
key activities to achieve the goal is a highly
challenging task and often requires extensive
experience, exhibition of extra‐ordinary skills and
knowledge by a formulation scientist.
(iv)The Clinical scientist provides key inputs as to
what kind animal studies, Biostudies or clinical
studies are needed, the study design and the cost
and time involved in such studies in order to take
the proposed project to submission stage. He is
also responsible for successful completion of such
studies.
(v) The Supply Chain or Sourcing personnel
ensures timely and cost effective availability of
API, RLD samples and other materials required for
the development and execution of the project.
(vi) The Regulatory Affairs personnel collate and
evaluate the necessary data and submits the
dossier to the USFDA.
Controlled Release Society Indian Chapter February 2015 33Encouraging Research Through Awareness
(vii) Other stake holders like Quality Control,
Quality Assurance, Production and Project
Management also play an important role in
providing all necessary resources and logistical
support to the formulation scientist to make the
project a success.
The 505(b)(2) development pathway has been
summarized in Fig :1. The average time line for a
development of 505(b)(2) product based on the
complexities rages from 2 to 5 years or more. An
illustrative example is provided in Fig. 2.
Cost estimate from the development to approval of a 505(b)(2) product
Based on the API cost and the technology
involved, which are the major contributors, the
development of a 505(b)(2) product may vary
from 1 million USD to 5 million USD or more. The
regulatory dossier filing cost of 505(b)(2) as per
Prescription Drug User Fee Act (PDUFA) for the
current year 2013 is USD 108,45,50 and is
expected to increase year on year. If a 505(b)(2)
application certifies Para‐IV to the patents listed
for RLD in Orange Book, then based on number of
patents under the suit after the dossier filing, the
litigation expenses may vary from 3 million USD to
5 million USD or more.
Few examples of 505(b)(2) applications There are number of ways to modify conventional
dosage form to qualify as 505(b)(2) products.
Below mentioned are few strategies for the
development of 505(b)(2) products‐
i. IR to ER dosage form: An Extended release (ER)
formulation can be developed for a previously
approved Immediate Release (IR) formulation. An
example of this kind is Altoprev®, an extended
release formulation of Lovastatin developed by
Andrx Labs LLC, which is a 505(b)(2) application of
Mevacor®, an Immediate release formulation of
Lovastatin developed by Merck [5,6].
Figure 1: Development of 505(b)(2) products
ii. Lyophilized to Solution dosage form: ‘Ready to
use’ solutions for injection can be developed for
previously approved lyophilized products. A ‘ready
to use’ solution injectable formulation for
Gemcitabine marketed as “Gemcitabine
hydrochloride Injection solution” developed by Hospira Inc. was approved as a 505(b)(2)
application to “Gemzar®” which is a lyophilized
powder [5,6].
iii. Improved bioavailability product: A 505(b)(2)
application can be submitted for improvement in
bioavailability of Class II and IV drugs. An example
of this strategy is “Antara®(micronized
fenofibrate)” developed by Reliant
Pharmaceuticals and was approved as a 505(b)(2)
Figure 2: Timelines for development of a 505(b)(2) product
Controlled Release Society Indian Chapter February 2015 34 Encouraging Research Through Awareness
application to RLD “Tricor®” ( fenofibrate capsules)
developed by Abbott [5,6].
iv. An NDDS product: A novel drug delivery system
for a previously approved conventional dosage
form can be submitted as a 505(b)(2)application.
As an example, “Marquibo®” is a vincristine
sulfate liposomal injectable formulation developed
by Talon Therapeutics which was approved as a
505(b)(2) application to RLD “Oncovin®”, a
conventional injectable solution formulation of
vincristine sulfate developed by LILLY Pharma
[5,6].
Eligibility of a 505(b)(2) application for patent and exclusivity protection after
approval (refer Table:2) [4]
Exclusivity Protection:
Table 2: Exclusivity protection
Section Exclusivity period Requirement
21 CFR
314.50(j);
314.108(b)
(4) and (5)
3 years
Eg: Onsolis®
NP (New Product)
exclusivity for 3
years granted
Clinical
investigations
other than BA/BE
study was
essential for
approval of
application
21 CFR
314.20‐
316.36
7 years Orphan drug
exclusivity
Section 505A
of the Act
6 month Pediatric
exclusivity
Patent Protection: Under 21 CFR 314.54(a) (1) (v),
a 505(b)(2) application shall contain information
on patents claiming the drug or its method of use
which get listed in Orange Book and is thus eligible
for patent protections.
505(b)(2) & Patent certification A 505(b)(2) applicant has to certify all patents
listed against the previously approved RLD in the
Orange book. At times the applicant have to certify
Para‐IV for OB listed patents against the RLD,
which may call for litigation and thus delay the
approval of the 505(b)(2) application. Further the
applicant needs to provide a statement to the
agency as to whether the listed drug(s) have
received a period of marketing exclusivity (21 CFR
314.108(b)). If a listed drug is protected by
exclusivity, filing or approval of the 505(b)(2)
application may be delayed. In ideal conditions the
total time taken for approval is around 9 ‐12
months from the date of dossier filing.
Incentives for 505(b)(2) applicants The 505(b)(2) approval route is a good bargain for
applicants as they can cherish a development
process that eliminates most preclinical studies as
well as safety studies and in certain situations
efficacy studies and can hit the market in relatively
less time, when compared to 505(b)(1) or 505(j)
application. The risk in 505(b)(2) filing is relatively
low since the safety and efficacy of the active
agent has been already established. Further, fewer
clinical requirements (depending on the extent of
studies required) result in reduction of cost for
complete approval process. Product differentiation
can provide significant market potential which
forms the basis for increased 505(b)(2)
applications.
Trends in filing of 505(b)(2) applications The following statistics regarding number of
505(b)(2) applications have been displayed in Fig.
3. The initial period after Hatch Waxman Act saw a
very handful of 505(b)(2) approvals, roughly five
from 1984 to 1996 and another five in 1997 and
1998. The number was seen to increase
substantially post 2002, as can be seen from Fig. 3.
Figure 3: Number of 505(b)(2) NDAs Approved Each Year [7]
Controlled Release Society Indian Chapter February 2015 35Encouraging Research Through Awareness
Table 3 indicates the percentage approval by type
of dosage form [7].
Table 3: Percentage approval by type of dosage
form
Dosage Form % of Total
Capsule DR/ER 6%
Capsule IR 5%
Injection 16%
Ophthalmic 4%
Transdermal Patch 4%
Tablet DR/ER 6%
Tablet IR 29%
Tablet ODT 4%
Topical 10%
Other 16%
DR=Delayed release, ER= Extended release
IR= Immediate release, ODT= Orally disintegrating
tablet
Conclusion In general, 505(b)(2) new drug applications (NDAs)
may be used appropriately to seek approval for a
modification of a previously approved drug
product, such as a change in dosing route, a new
active ingredient, a new or higher amount of an
inactive ingredient or a new indication for use.
Over the years, the 505(b)(2) regulatory pathway
has become very attractive to companies of all
sizes. The approval of 505(b)(2) applications is
nearly doubled compared to traditional 505(b)(1)
applications. This pathway is particularly attractive
to manufacturers transitioning from generic drugs
to innovator products. Due to the similarities to
traditional drug development, these products offer
a low‐risk market entry point. However, there are
unique scientific and regulatory challenges to
developing such products.
References: 1. http://www.fda.gov/AboutFDA/WhatWeDo/H
istory/Milestones/ucm128305.htm
2. G.J. Mossinghoff. Overview of the Hatch‐
Waxman Act and Its Impact on the Drug
Development Process. Food Drug Law J.
54:187‐194 (1999)
3. H.L. Nadler and D. DeGraft‐Johnson.
Demystifying FDA’s 505(b)(2) Drug
Registration Process. Regulatory Focus (2009)
4. Guidance for Industry: Applications Covered
by Section 505(b)(2) (Draft, October 1999).
5. http://www.accessdata.fda.gov/scripts/cder/
ob/default.cfm (Orange Book as available in
Jul 2013)
6. http://www.accessdata.fda.gov/scripts/cder/
drugsatfda/index.cfm?fuseaction=Search.Sear
ch_Drug_Name(Drugs@fda as available in Jul
2013).
7. http://www.contractpharma.com/issues/2010
‐03/view_features/trends‐in‐505‐b‐2‐
approvals/
PHARMA PUZZLE
*Answer key on pg 50‐51
Industrial Perspectives
In Vitro In Vivfor Stents
Ankur Raval*,1 and V1Research and Development
Technologies Pvt. Ltd2Department of PharmaceuticInstitute of Chemical Techno
Introduction During pas
care industry has faced many challenproducts (such as drug eluting impla
ti l t d ti l t t
Institute of Chemical Techno*Email: ankur.me
particulate and nano-particulate systeforming systems) within predefinedresource intensive efforts. Researchersworked towards development of pharmand are collaborating principles of phaand pharmacokinetics to target thebi l i l t f h f l tibiological aspects of such formulationsstages. Such formulations can maintainor tissue levels over extended periodundesirable fluctuations in systemic dreduce multiple dosing frequencies, thcompliance [1]. Drug eluting stents (l t d ithi l tielute drug within vascular tissue
Determination of safety and efficacyimportance during development and esvarious regulatory submissions. Correlduring pharmaceutical development bevivo data (IVIVC) to reduce the de
ti i th f l ti h t i tioptimize the formulation characteristics
Controlled Release So
3636 Encouraging Research Through Awareness
o Correlation
Vandana Patravale2
t Dept., Sahajanand Medical d., Surat, Gujarat, Indiacal Sciences and Technology, ology Matunga Mumbai India
st decades, the health
nges to develop novelants, polymeric micro-
d i it d t
ology, Matunga, Mumbai, Indiaed@sahmed.com
ems and in situ depottimeframe and less
around the globe havemaceutical formulationsarmacy, pharmaceutics,
physicochemical andt id i t l t
Ankur Raval
to avoid issues at latern effective drug plasmads of time, minimizingdrug concentration andhus improving patience(DES) are designed to
t l t
Vandana Patravale
s at a slow rate.y of DES is of primestablishing them duringlations are often usedetween in vitro and inevelopment time ands.
ociety Indian Chapter
February 2015
Controlled Release Society Indian Chapter February 2015 37Encouraging Research Through Awareness
A good correlation is a tool for predicting in vivo
outcomes based on the in vitro data. IVIVC proves
itself an important tool that allows formulation
optimization with fewest possible clinical trials,
freezes dissolution acceptance criteria and can be
used as a surrogate for subsequent bioequivalent
studies and is also recommended by regulatory
agencies.
IVIVC development While many definitions have been proposed for in
vitro‐in vivo correlation, FDA has appropriately
stated IVIVC as a predicative mathematical model
describing the relationship between an in vitro
property of an extended release dosage form
(usually the rate of drug release) and a relevant in
vivo response, e.g., plasma drug levels or amount
of drug absorbed [2]. One of the prime objectives
of drug product development is to have better
understanding of the in vitro and in vivo drug
behavior. By developing an effective IVIVC, in vivo
drug performance can be predicted from its in
vitro implication.
The primary objective of an IVIVC for DES is to
establish a meaningful relationship between in
vitro behavior of a DES product and in vivo
performance of the same product. Often in vitro
drug release data is considered to establish IVIVC
for DES similar to other pharmaceutical products.
In this way IVIVC for DES empowers the in vitro
data to serve as a surrogate marker for in vivo
bioavailability. In general, FDA recommends
following factors for consideration while
establishing IVIVC‐
• Mechanism of drug release from the stent
• Formulation and manufacturing process
factors that influence the release kinetics
• In vitro method conditions (e.g.,
hydrodynamics, media composition)
• In vivo stent deployment factors
While majority of correlation is established based
on the pharmacological aspects of the DES,
mechanical properties of stent structure and
deployment factors are also considered.
IVIVC for drug eluting stent Drug eluting stent is basically a drug device
combination product which has gained remarkable
importance as it has provided effective practical
alternatives for the treatment of coronary artery
diseases. The device part which is generally a
metallic stent provides scaffolding to the artery
and also acts as a platform for drug coating. Figure
1 represents the typical mesh like configuration of
metallic stent. Such stents are designed using
extensive Finite Element Analysis (FEA) and
manufactured by laser micromachining from
seamless metal alloy (commonly SS 316L and Co‐Cr
alloy) tubings. Serpentine struts allow
homogeneous stress distribution within the
structure upon expansion.
Figure 1: Image depicting basic stent structure
Re‐narrowing of the coronary artery also known as
‘restenosis’ occurs after successful stent
implantation due to complex multiple biochemical
reactions and it cannot be controlled by putting a
device alone. This device can only provide
mechanical support to the vessel wall and
prevents elastic recoil, but cannot control the
smooth muscle cell (SMC) migration and
proliferation process. Often stents are coated with
anti‐proliferative, anti‐inflammatory or
antithrombotic agents to minimize the impact of
restenosis process. Controlled drug delivery
systems are formulated by incorporating
therapeutic agents within biocompatible,
biodegradable or non‐degradable polymers. Thin
films of these drug‐polymer formulations can be
created on metallic stents, making them DES.
When such DES are placed at the target area they
start releasing drugs to the surrounding arterial
tissues and due to the drug’s therapeutic activity
restenotic mechanisms involving uncontrolled cell
growth are inhibited. In a way, DES is a
combination of engineering, polymer chemistry,
pharmacology and vascular biology. Therefore,
development of any DES requires all four aspects
to be studied thoroughly in order to understand
the underneath characteristics that governs and
Controlled Release Society Indian Chapter February 2015 38 Encouraging Research Through Awareness
influences the scaffolding property, drug delivery
and ultimate vascular response.
Often development work of DES involves bench
testing to assess various engineering attributes,
analytical testing for total drug content and in vitro
release kinetics and finally establishment of device
safety and efficacy in animals (in‐vitro
biocompatibility, hemocompatibility, toxicity, in‐
vivo pharmacodynamics and pharmacokinetics)
followed by human trials. Generally, for any
pharmaceutical formulation, an in vitro in vivo
correlation is established by studying the in‐vitro
drug dissolution properties and corresponding in
vivo blood plasma levels and its effect on the
human body. For a drug eluting stent, similar kind
of study can be done to establish a correlation of
in vitro drug release and corresponding
pharmacological response. However, study of drug
release properties is not adequate to fully
understand the impact a medical device could
make within the human body. Due to the
incorporation of drug component along with the
device, characterization of such product cannot be
done separately for both parts (device and drug)
as the mechanical aspects of stent structure itself
can also contribute to the device safety and
efficacy. Therefore, an appropriate method for
establishment of in vitro in vivo correlation for
drug eluting stent is to study the mechanical as
well as drug eluting properties of it.
IVIVC considering mechanical attributes: Despite
being a simple mesh like structure, a stent in fact is
a complex mechanical structure made of various
elements designed to withstand various load
conditions. There are certain functional attributes
which determine the stent’s overall capability to
serve its intended purpose. Some of the important
stent properties are: (1) ability to withstand radial
load, (2) fatigue endurance, (3) radial recoil, (4)
longitudinal foreshortening, (5) surface to artery
ratio (6) MRI compatibility (7) corrosion resistance
and (8) device pushability and trackability. Certain
guidelines from International Organization for
Standardization (ISO) like ISO 25539‐2
(Cardiovascular implants ‐ Endovascular devices ‐
Part 2: Vascular stents) specify the general safety
requirements to assess intended purpose, design
characteristics, design and material evaluation for
endovascular prosthesis like cardiac stents. This
guideline exemplifies the various in vitro test
conditions to simulate in vivo conditions for
understanding the performance of stent in actual
practice. However, for each of the mechanical
attribute, American Society for Testing and
Materials (ASTM) has specifically mentioned in
vitro test conditions for evaluation and
interpretation of results which can be
corresponded to an in vivo behavior. For example,
test requirements for fatigue durability test are
specifically mentioned in ‘ASTM 2477 ‐Standard
Test Methods for in vitro Pulsatile Durability
Testing of Vascular Stents’. Using pulsatile fatigue
tester capable of applying cyclic displacement to
the mock artery with the endovascular prosthesis
deployed, approximately 10 years equivalent
cycles can be applied. Physiological conditions of
temperature and pressure should be maintained
throughout the test period. After completion of
pulsatile cycles, zones identified for high
stress/stain should be inspected using scanning
electron microscopy (SEM) or X‐ray equipment for
any deformation or anomalous findings like cracks,
fractures, abrasions etc. Such analysis generates
the data for approximately 10 years of in vivo
device life within 4‐6 months depending up on the
cycle frequency which varies in the range of 50‐70
Hz as applicable to the stent type. Early evaluation
of design utilizing such in vitro tests is very useful
in determination of the design characteristics as
the test outcome can directly be correlated with
the in vivo clinical performance.
Advancements in computer aided simulation
techniques enable researchers and scientists to
use the tools like Finite Element Analysis (FEA) for
analyzing the design and its mechanical behavior prior to prototyping. Guidelines like ‘ASTM
F2514Standard Guide for Finite Element Analysis
(FEA) of Metallic Vascular Stents Subjected to
Uniform Radial Loading’ provide the procedure for
conducting the computer simulation to determine
the stress‐strain behavior of stent structure under
various load conditions. Once the generated stent
model is validated, it can be used to check the
radial recoil, foreshortening and fatigue behavior
prior to prototyping, which greatly reduces
iterations required for design preparation and
subsequent testing.
Controlled Release Society Indian Chapter February 2015 39Encouraging Research Through Awareness
As always, there are some limitations with the
simulation methods, actual prototyping and
assessment yields the real device behavior. For
example, scientists are now correlating the stent
recoil values tested during in vitro examination
and during actual stent implantation in humans.
Often recoil assessment is considered as
engineering testing, but interventional
cardiologists are now performing similar
evaluation in vivo to establish the correlation
between the bench test results and in vivo human
device implantation [3]. Such interpretation also
provides vital insights to stent’s ability to resist
radial collapse pressures. Another important factor
which can be correlated is the stent’s flexibility
and conformability. Under in vitro test conditions,
stent flexibility and conformability can be
measured in terms of 3 point bend test and
analysis of trackability force measurement in
which stent is passed through three dimensional
coronary artery model under simulated laboratory
conditions and track force values are recorded
using a sensitive force gauges. Stent flexibility is its
ability to bend tortuous anatomies during
implantation procedure. Stents with good
flexibility results in achieving low force values
when tested by 3 point bend test and trackability
assessment. With the usage of advance
instruments and softwares, stent conformability is
assessed by many researchers under in vivo
conditions. As many standards and guidelines are
now available from different agencies and
organization like ISO and ASTM, understanding
test requirements and conducting in vitro tests
enables device developer to find out the
performance behavior and correlate it to in vivo
safety and efficacy.
IVIVC considering pharmacology (drug
component): Normally the drug component is
applied on the stents in a form of thin film
coatings. These films should perform two basic
and very important functions of,
(1) Drug elution and
(2) Maintain coating mechanical integrity.
Film integrity is as important for a DES as drug
elution as latter is highly dependent on intactness
of film. Delamination, peeling and damage to thin
film can result in non‐uniform and unpredicted
drug delivery. Erroneous IVIVC can result from
such unreliable data.
Drug eluting stents are designed to deliver drug at
a very slow rate because adequate drug levels are
required at the target site for at least 2‐3 months
to inhibit the SMC proliferation. To estimate drug
release rate at real time scale is very challenging as
DES often contains hydrophobic drug in very less
amount (in microgram levels). Extracting drug
from aqueous media and estimating accurately
even using advanced analytical methods such as
HPLC is a difficult task. This is because of the low
aqueous solubility of hydrophobic drugs. Some
drugs like Sirolimus and its analogs have limited
stability in aqueous buffers (at physiological pH
range) and undergo hydrolytic degradation. Over
the past few years, accelerated in vitro release
methods have received considerable attention in
order to shorten the time required to study real
time drug release for stent base drug eluting
coatings [4]. Many studies have been done using
different surfactants to improve drug solubility in
the aqueous media [5]. These in vitro release
testing methods should have a good
discriminatory power to detect the formulation
changes for serving as good quality control tool.
They are also critical in establishing IVIVC and are
desirable to assist in formulation development and
help reduce the regulatory burden of
bioequivalence testing.
Hence, IVIVC considering the drug component is
not a straightforward task just like conventional
pharmaceutical formulations because of following
reasons,
• DES are designed to elute drug directly to
the arterial tissue and not systemically.
• As mentioned earlier IVIVC incorporates
the drug concentration levels in the blood to
establish a relationship with drug release
properties, but with DES, blood levels of drug are
not efficacious.
• Also, as experienced in some DES (like
Taxus Paclitaxel eluting stent), not the entire
coated drug is released from the stent. (Similar to
some SR solid oral dosages)
• Determination of drug amount left on
stent requires an explantation of stent, which is
not possible in humans.
Controlled Release Society Indian Chapter February 2015 40 Encouraging Research Through Awareness
In order to obtain an IVIVC for DES, two sets of
data are collected. The first set of data includes
the in vitro data, usually drug release data as a
function of time using an appropriate drug release
method. Second set of data consists of in vivo drug
amounts extracted from blood, tissues and
remaining amount from explanted stents. A model
which integrates both (i.e., mechanism of drug
release and systemic drug concentration) may
provide a means for developing a physiologically
based PK model for predicting drug disposition and
for establishing relevant mechanism based IVIVC.
A point‐to‐point correlation between in vitro drug
elution and the in vivo tissue uptake of drug is one
to establish a mathematical model for IVIVC,
generally known as level A correlation. In vivo data
are kept fixed while developing such relationships.
Often in vitro release data are modified by fine
tuning the release test conditions to obtain
consistent and meaningful relationship between
the percentage of drug released in vitro and the
fraction of drug released in vivo [6].
For the actual IVIVC of a DES, tissue levels of any
drug are not feasible; instead blood concentration
of drug can be used for studying pharmacokinetic
aspects. In such cases, correlating arterial uptake
of drug from its blood concentration is of major
clinical importance. In one of the study Thakkar et.
al. [7] determined the concentration of Sirolimus
in blood and target blood vessel at various time
intervals using animal model. Level A correlation
has been performed for in vivo release profiles
which showed biphasic pattern of Sirolimus
elution from the stent, i.e., initial burst release
followed by sustained release. Blood flow rate,
metabolism of Sirolimus from arterial tissues and
distribution of Sirolimus from arterial tissue are
the major biological factors which affects Sirolimus
concentration in the vascular tissues.
Studying IVIVC for drug eluting stents:
Selecting an appropriate apparatus
As of now there is no official dissolution apparatus
recommended by USP to study the release profiles
of drug eluting stent like devices. Researchers have
modified existing instruments to simulate the
physiological conditions considering their own
requirements. Preferred apparatus for stent
testing includes, reciprocating disk (USP 7), flow
through cell (USP 4), rotating paddle (USP 2) and
other non‐compendial apparatus. The instruments
that are listed here (refer Figure 2) are used with
some modification to accommodate study of drug
release from stent.
Some important considerations for establishing
appropriate release profile for DES and studying
IVIVC for DES:
a) Establishing in vitro drug release method,
Development of drug release medium
(pH, pKa’s of API, surfactants, hydro‐
alcoholic medium)
Temperature of release medium
Sink conditions
Sampling time points
Apparatus agitation rate
Setting appropriate chromatographic
(HPLC) conditions
b) In vivo data is derived from appropriate
animal models (non‐human subjects) generally
pigs and rabbits.
c) Arterial drug amount is assumed to be
same as amount of drug released in blood.
d) Simultaneous measurement of drug
remaining on stent is to be done at similar time
points.
e) Mass balance of drug to be done as,
Total Drug Content (D) = Drug on Stent (DS) + Drug
in Blood (DB) + Drug in Arterial Tissues (DA)
Figure 2: Some dissolution apparatus for DES (a)
USP‐7 (b) Stent holder for USP‐7 (c) USP‐4 with
flow through cell (d) Stent holding cell for USP‐4
Controlled Release Society Indian Chapter February 2015 41Encouraging Research Through Awareness
If D, DS and DB are known, then we can estimate
the DA. Calculation can be done to find a function
between DA and DB rate of release. The
cumulative amounts of DB+DA can be then
correlated with the in vitro drug release amounts.
Conclusion Developing an IVIVC and applying it appropriately
should make therapeutic sense. While different
correlations can predict the in vivo behavior of any
pharmaceutical products including drug device
combinations like drug eluting stents on the basis
of in vitro data, it is very important to properly
validate the correlation before making any
practical conclusions. IVIVC can become a credible
tool to select the discriminating in vitro test
conditions and to set therapeutically meaningful in
vitro release specifications. If applied correctly, the
IVIVC can save substantial costs and time in drug
product development and regulatory submissions.
References: 1. J. M. Davis, L. Matalon, M.D. Watanabe, and L.
Blake. Depot antipsychotic drugs. Place in
therapy. Drugs. 47:741–773 (1994)
2. The Food and Drug Administration, U.S..
Extended release solid dosage forms:
development, evaluation and application of in
vitro/in vivo correlations. 1997
3. A.D. Abhyankar and A.S. Thakkar. In vivo
assessment of stent recoil of biodegradable
polymer‐coated cobalt‐chromium sirolimus‐
eluting coronary stent system. Indian Heart J.
64:541‐6 (2012)
4. M. Kamberi, S. Nayak, K. Myo‐Min, T.P. Carter,
L. Hancock, and D. Feder. A novel accelerated
in vitro release method for biodegradable
coating of drug eluting stents: Insight to the
drug release mechanisms. Eur J Pharm Sci.
37:217‐22 (2009)
5. A. Raval, A.Parmar,A. Raval, and P. Bahadur.
Preparation and optimization of media using
Pluronic® micelles for solubilization of
sirolimus and release from the drug eluting
stents. Colloids Surf B Biointerfaces. 93:180‐7
(2012)
6. FDA Guidance for Industry, Coronary Drug‐
Eluting Stents ‐ Nonclinical and Clinical
Studies, March 2008
7. A. Thakkar, A. Raval, R. Mandal, S. Parmar, A.
Jariwala, J. Tailor,and A. Mehta. Development
and Evaluation of Drug Eluting Stent Having
Biphasic Release From a Single Layer of
Biodegradable Polymer. J. Med. Devices.7:
011005 (2013)
WORD SEARCH
*Answer key on pg 50‐51
CRS NE
43
EWS
Controlled Release Society Indian Chapter
February 2015 Encouraging Research Through Awareness 44
Glimpses of 13th International Symposium on “Advances in Technology and Business Potential of New Drug Delivery
Systems” held on 22nd and 23rd January 2013 at J. W. Marriott Hotel, Mumbai.
Prof. Sevda Senel delivering her talk at Dignitaries at the Inaugural Ceremony of
13th International Symposium 13th International Symposium
Prof. H. L. Bhalla and Prof. K. K. Singh (R) Prof. Alok Dhawan delivering his talk at
at the Lamp Lighting Ceremony 13th International Symposium
Prof. H. L. Bhalla presenting CRS‐IC Board releasing
Merit Poster Award to Ketan Patel 6th issue of CRS Newsletter
Controlled Release Society Indian Chapter
February 2015
45Encouraging Research Through Awareness
Dr. Sanyog Jain, Associate Professor, National Institute of Pharmaceutical Education and Research (NIPER), Mohali, India was conferred with Bharat Jyoti (The Glory of India) Award, 2013.
Dr. Sanyog Jain, Associate Professor, NIPER, Mohali, India was bestowed with Award for Rising Suns in Asia at 40th Annual Meeting and Exposition of Controlled Release Society, Honolulu, Hawaii, USA, July 21-24, 2013.
Dr. Sanyog Jain, Associate Professor, NIPER, Mohali, India is appointed as Expert member-Radiopharmaceutical Committee (RPC) of Department of Atomic Energy (DAE), Govt. of India (2014).
Dr. Vandana B. Patravale, Professor of Pharmaceutics, Institute of Chemical Technology, Mumbai, India received a prestigious grant of $100,000 for project entitled “Nanovaccine for Brucellosis using Green Technology” from the Bill & Melinda Gates foundation (October 2013).
Dr. Vandana B. Patravale, Professor of Pharmaceutics, Institute of Chemical Technology, Mumbai, India was invited as a Keynote Speaker to deliver a lecture entitled, “Nanostructured Lipid Carriers: Potential as a Vaccine Adjuvant” at the “Vaccine Session” of ‘NanoBio Australia 2014’ conference organized by The University of Queensland held at Brisbane, Australia from 6th to 10th July, 2014.
Dr. Vandana B. Patravale, Professor of Pharmaceutics, Institute of Chemical Technology, Mumbai, India received "Dr. P. D. Patil Best Pharmaceutical Scientist of the year Award - 2014” (November 2014).
Dr. Vandana B. Patravale, Professor of Pharmaceutics, Institute of Chemical Technology, Mumbai, India received “Smt. Chandaben Mohanbhai Patel Industrial Research Award for Women Scientists –2013” by Vividhlaxi Audyogik Samshodhan Vikas Kendra (VASVIK) Apex Committee.
Dr. Vandana B. Patravale, Professor of Pharmaceutics, Institute of Chemical Technology, Mumbai, India was appointed as Convener, Association of Pharmaceutical Teachers of India (APTI), Women forum, (December 2014).
Dr. Padma V. Devarajan, Professor and Head of Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Mumbai, India was conferred with the Prof. C.J. Shishoo Award for Research in Pharmaceutical Sciences, APTI, 2013.
H A L L O F F A M E
Controlled Release Society Indian Chapter February 2015
Encouraging Research Through Awareness 46
Dr. Padma V. Devarajan, Professor and Head of Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Mumbai, India, Member-Board of Scientific Advisors, Controlled Release Society (CRS), Inc, USA.
Dr. Padma V. Devarajan, Professor and Head of Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Mumbai, India was Co-Chair, Drug Delivery and Translational Research, Outstanding Paper Award Committee, Controlled Release Society (CRS), Inc, USA.
Dr. Padma V. Devarajan, Professor and Head of Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Mumbai, India was invited as Guest of Honor and Keynote Speaker at the National Workshop on ‘Advances in Drug Delivery’ organized by Ramanbhai Patel College of Pharmacy, CHARUSAT to deliver a talk on Drug Delivery – Current Scenario and Future Directions, Gujarat, February 2013.
Dr. Padma V. Devarajan, Professor and Head of Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Mumbai, India was invited as Chief guest and Keynote speaker at SVKM’s Dr. Bhanuben Nanavati College of Pharmacy for the graduation ceremony to deliver a talk on “Designer Nanoparticles for Splenotropic Drug Delivery”, Mumbai, July 2013.
Dr. Padma V. Devarajan, Professor and Head of Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Mumbai, India was invited as Key Note Speaker at the DBT- JRF Regional Meeting (Western Region) organized at ICT to deliver a talk on Pharmaceutical Biotechnology- Opportunities and Challenges, Mumbai, November 2013.
Dr. M.S. Nagarsenker, Professor and Head of Pharmaceutics Department at Bombay College of Pharmacy, Mumbai, India, was awarded with Dr. (Mrs.) Manjushree Pal Best Researcher National Award 2013 by Association of Pharmaceutical Teachers of India (APTI).
Dr. M.S. Nagarsenker, Professor and Head of Pharmaceutics Department at Bombay College of Pharmacy, Mumbai, India, was also awarded Prof M. L. Khorana Best Research Paper Award (April 2013) for paper “M. P. Jadhav, M. S. Nagarsenker, R. V. Gaikwad, A. Samad, N. A. Kshirsagar, Formulation and Evaluation of Long Circulating Liposomal Amphotericin B: A Scinti-kinetic Study using Tc in BALB/C Mice. Indian Journal of Pharmaceutical Sciences 2011;73(1):57-64”.
Dr. M.S. Nagarsenker, Professor and Head of Pharmaceutics Department at Bombay College of Pharmacy, Mumbai, India, was Chairman and Convener, Scientific committee, Disso India 2013, Annual conference of Society of Pharmaceutical Dissolution Science, May 6 and 7, Mumbai.
Dr. M.S. Nagarsenker, Professor and Head of Pharmaceutics Department at Bombay College of Pharmacy, Mumbai, India, was Chairman and Convener, Scientific committee, Disso Asia 2014, Annual Conference of Society of Pharmaceutical Dissolution Science, May 5 and 6, Mumbai.
Dr. M.S. Nagarsenker, Professor and Head of Pharmaceutics Department at Bombay College of Pharmacy, Mumbai, India, was invited to attend “Journees Galeniques” annual conference on Transmucosal Drug Delivery, organized by Gattefosse foundation, St. Remy the Provence, France, 10-13th Sept 2014.
Controlled Release Society Indian Chapter
February 2015 47 Encouraging Research Through Awareness
AWARDS Shete, H., Chatterjee, S., De, A., and Patravale, V.B received Best Poster award for poster titled
"Discrepancy in therapeutic efficacy of nanoformulation against different breast cancer cell lines" at the
International Symposium on Drug Discovery for Infectious Disease & Cancer (DDIDC), 16‐17th January,
2013 at ICT, Mumbai, India.
Gugulothu, D. and Patravale V.B. received Best Poster Award for poster titled “Curcumin‐Celecoxib dual
drug loaded pH sensitive nanoparticulate combination therapy: a novel approach for the treatment of
inflammatory bowel disease” at the Thirteenth International Symposium on 'Advances in Technology and
Business Potential of New Drug Delivery Systems' of the Controlled Release Society ‐ Indian Chapter, held
at J. W. Marriot Hotels, Juhu, Mumbai, January, 2013.
Preshita Desai (Student of Dr. Vandana B. Patravale, ICT) received Bombay Technologist Best Postgraduate
Student Award for year 2012‐13, at Institute of Chemical Technology, Mumbai, India, March 2013.
Fernandes, C. and Patravale, V.B. received Best Poster Award (Drug Delivery System Section) for the
poster titled “Impact of drug loading on the anti Parkinsonism effects of lipid formulation of curcumin” at
the 6th International Annual Conference South Asian Chapter of American College of Clinical
Pharmacology, Mumbai, 21st ‐22nd April, 2013.
Mirani, A., Borhade, V., Kate, L., Pathak, S., Sharma, S., and Patravale V.B. received Second Best Poster
Award‐Shared (Drug Delivery System Section) for the poster titled “Bio‐enhanced Atovaquone:
Comparison of solid dispersion and nanosuspension” at the 6th International Annual Conference South
Asian Chapter of American College of Clinical Pharmacology, Mumbai, 21st ‐22nd April, 2013.
Kadwadkar, N., Gugulothu, D., Pathak, S., Sharma, S., and Patravale, V.B. received Second Best Poster
Award‐Shared (Drug Delivery System Section) for the poster titled “Solid lipid nanoparticles of
Arteether/Ellagic acid: A novel combination therapy for treatment of malaria” at the 6th International
Annual Conference South Asian Chapter of American College of Clinical Pharmacology, Mumbai, 21st ‐
22nd April, 2013.
Jain, S., Basu, H., Joshi, M., Pathak, S., Sharma, S., and Patravale, V.B. received Second Best Poster Award
(Preclinical Section) for the poster titled “Selective Uptake of Nanostructured Lipid Carriers by Malaria
Infected Red Blood Cells” at the 6th International Annual Conference South Asian Chapter of American
College of Clinical Pharmacology, Mumbai, 21st ‐22nd April, 2013.
Namrata Kadwadkar, student of Dr. V.B. Patravale, ICT, Mumbai, India was selected for Novartis Biocamp,
Hyderabad, July 2013.
Preshita Desai, student of Dr. V.B. Patravale, ICT, Mumbai, India received Visiting fellowship for a tenure
of 2 months at the Center for Pharmaceutical Engineering Science, University of Bradford, UK under the
UKIERI (UK‐India Education and Research Initiative) collaborative project entitled, “Process analytics
enabled green technologies for processing of poorly soluble drugs” funded by British council. Project title:
Hot melt extrusion assisted solid dispersions for oral bioenhancement of poorly bioavailable drugs (August
– October 2013).
A proposal for a non‐invasive vaccine for brucellosis using green technology conceptualized by Swati Vyas
and Priyanka Prabhu (Students of Dr. Vandana B. Patravale), ICT, Mumbai, India received a prestigious
grant of $100,000 for project entitled “Nanovaccine for Brucellosis using Green Technology” from the Bill
& Melinda Gates foundation (October 2013).
Swati Vyas, Ronak Bhuptani, Soniya Jain, Amit Mirani, and Preshita Desai (Students of Dr. Vandana B.
Patravale), ICT, Mumbai, India were selected in Biotechnology Entrepreneurship Student Team (BEST)
Workshop sponsored by Department of Biotechnology (DBT), Ministry of Science and Technology,
Government of India and managed and administered by Association of Biotechnology Led Enterprises,
ABLE – India, Bangalore, India, October 2013.
Controlled Release Society Indian Chapter
February 2015 48 Encouraging Research Through Awareness
Pol, A., Mirani, A., Kadwadkar, N., Singhal, R., and Patravale, V.B. received the Best Poster Award for the
poster titled “Super Critical extraction method optimization of Seabuckthorn (SBT) berry oil: Exploiting its
role in anti‐ageing” at the OMICS Group of conference: Pharmacognosy, Phytochemistry& Natural
Products, Hyderabad, October 21‐23, 2013.
Shete, H., Prabhu, R. and Patravale, V.B. received Veneto Nanotech Prize (Winner of the second edition of
the Cadini Prize) for the poster titled “Influence of newly synthesized Mono‐Guanidine heterolipid based
cationic Nanocarriers in treatment of melanoma tumour in C57BL/6 mice” at the NanotechItaly, 2013 in
Venice –Mestre, Italy.
Shete, H. and Patravale, V.B. received Best Poster award for the poster titled “Lymphtarg for tamoxifene:
Potential in breast cancer treatment” at the "Workshop on Advances in Biomaterials and
Nanobiotechnology (ICT‐NANOBIO2013)" held at the Institute of Chemical Technology, Matunga, Mumbai
(November, 2013).
Shete, H., Desai, P., Vanage, G., and Patravale, V.B. received First prize for poster titled, “In vivo
investigation of anticancer activity and treatment associated toxicity of tamoxifen‐loaded cationic
lipomer” at 65th Indian Pharmaceutical Congress, Delhi, India, December 2013.
Patale, R., Desai, P. and Patravale, V.B. won First Poster award for the poster titled “Development of
mathematical model to predict release of a water soluble drug from tamarind seed polysaccharide
matrices” at the National Seminar on "Software in Drug Discovery and Development", Kolhapur,
India, January, 2014.
Gite, S., Mirani, A. and Patravale, V.B. won Second Poster Award for the poster titled “Design Expert: An
Integration of Software Solution for Nanoformulation Experimentations" at the National Seminar on
"Software in Drug Discovery and Development", Kolhapur, India, January, 2014.
Desai, P., Hassan, P., and Patravale, V.B. received First prize for poster entitled, “SANS investigation of a
micellar drug delivery system formed by a novel antioxidant‐ lipid bioconjugate” at Conference on
Neutron Scattering 2014, Pune, India, February 2014.
Swati Vyas (Student of Dr. Vandana B. Patravale, ICT) received Bombay Technologist Best Postgraduate
Student Award for year 2013‐14, Institute of Chemical Technology, Mumbai, India, March 2014.
Preshita Desai (Student of Dr. Vandana Patravale, ICT) was selected as top 20 research students from all
over the world for Merck Serono Innovation Cup 2014, Darmstadt, Germany, July 2014.
Desai, P., Kulkarni, C., Gokarna, V., Deshpande, V., Paradkar, A., and Patravale, V.B. received First prize for
poster entitled, “Green approach towards bioenhanced curcumin: process analytical technology (PAT)
enabled scale up studies of curcumin solid solution using hot melt extrusion” at 1st International
Conference on Industrial Pharmacy (ICIP) 2014, Kuantan, Malaysia, August 2014.
Gite, S., Mirani, A., Kundaikar, H., Velhal, S., Degani, M.S., Bandivdekar, A., and Patravale, V.B. received
Excellent Poster Award for the poster titled “Comparison of Phytopolyphenols as gp120‐CD4 Binding
Inhibitor: In Silico & In Vitro Screening” at the 5th Indo‐Japanese International Joint Symposium on
Overcoming Intractable Infectious Diseases Prevalent in Asian Countries, September, 2014 in Tokyo,
Japan.
Mirani, A., Kundaikar, H., Velhal, S., Degani, M.S., Bandivdekar, A., and Patravale, V.B. received Excellent
Poster Award for the poster titled “Evaluation Of Punicalin And Punicalagin As GP 120‐CD4 Binding
Inhibitor: In Silico & In Vitro Screening” at the 5th Indo‐Japanese International Joint Symposium on
Overcoming Intractable Infectious Diseases Prevalent in Asian Countries, September, 2014 in Tokyo,
Japan.
Desai, P., Bacchav, B.K., Bochre, M.B., Degani, M.S., and Patravale, V.B. received Excellent Poster Award
for the poster titled “Pharmaceutical Co‐Crystal Of Atovaquone: A Systemic Approach Towards Solubility
Enhancement” at the 5th Indo‐Japanese International Joint Symposium on Overcoming Intractable
Infectious Diseases Prevalent in Asian Countries, September, 2014 in Tokyo, Japan.
Agrawal, A., Gugulothu, D., Pathak, S., Sharma, S., and Patravale, V.B. received Excellent Poster Award for
the poster titled “Solid Lipid Nanoparticles of Ellagic Acid: A Novel Modality for the Treatment of Malaria”
Controlled Release Society Indian Chapter
February 2015 49 Encouraging Research Through Awareness
at the 5th Indo‐Japanese International Joint Symposium on Overcoming Intractable Infectious Diseases
Prevalent in Asian Countries, September, 2014 in Tokyo, Japan.
Sudeep Pukale, a student of Dr. Vandana Patravale, ICT, Mumbai, India won First Prize in poster
competition for poster titled “Polymeric Nanoparticulate Delivery of Curcumin‐Ellagic acid: Synergistic
Potential for Inflammatory Bowel Disease Therapy” at the conference on Advances in Pharmaceutical
Technology and its Business Potential organized by Yadavrao Tasgaonkar College of Pharmacy (YTCP),
Mumbai.
Sudeep Pukale, a student of Dr. Vandana Patravale, ICT, Mumbai, India got 3rd prize in Pharmawiz
competition conducted at Institute of Chemical Technology (ICT), Mumbai.
Sudeep Pukale, a student of Dr. Vandana Patravale, ICT, Mumbai, India got 1st prize in Industrially Defined
Problem (IDP) ‐Vortex for proposal of innovative and cost effective sanitary pads for rural women
conducted by Institute of Chemical Technology (ICT), Mumbai.
Preshita Desai (Student of Dr. Vandana Patravale, ICT) was declared as recipient of Ranbaxy Science
Scholar Award ‐ 2014 in the field of Pharmaceutical Sciences, November 2014.
Desai, P., Kulkarni, C., Paradkar, A., and Patravale, V.B. received Young innovator in Bioprocessing Award
(2nd Place) for research work entitled, “Bioenhanced ellagic acid solid solution: a systematic green
approach” at Bioprocessing India 2014 conference, Mumbai, India, December 2014.
Ankit Agrawal, student of Dr. V.B. Patravale, ICT, Mumbai, India received the prestigious “Prime Minister’s
Fellowship” for doctoral Research. This is a joint initiative of CII, Science & Engineering Research Board
(SERB) and Sahajanand Medical Technologies Pvt. Ltd. as an Industry partner.
Harshad Harde (Student of Dr. Sanyog Jain, NIPER) received CEFIPRA fellowship award by “Centre Franco‐
Indien pour la Promotion de la Recherche Avancée”, India to attend European School on Nanosciences
and Nanotechnologies (ESONN 2013), Grenoble, France from Aug 25, 2013 to Sep 14, 2013.
Amit Jain (Student of Dr. Sanyog Jain, NIPER) won 2013 AAPS Lipid based drug delivery graduate student
award.
Ashish Agrawal (Student of Dr. Sanyog Jain, NIPER) won Punjab Young Scientist Award‐2013, by Punjab
Science Academy at 17th Punjab Science Congress.
Sumit Arora (Student of Dr. Sanyog Jain, NIPER) received 2014 Endeavour Research Fellowship,
Department of Education, Australian Government.
Sumit Arora (Student of Dr. Sanyog Jain, NIPER) received DADD Scholarship 2014 for pursuing part of Ph.D.
work at Max Planck Institute, Germany.
Kaushik Thanki (Student of Dr. Sanyog Jain, NIPER) won Mike How Award 2014 for expressing unique
passion in the field of Industrial Pharmacy by Industrial Pharmacy Section (IPS), International
Pharmaceutical Federation (FIP). Award facilitated at 74th FIP World Congress, Bangkok during August 31
to September 04, 2014.
Kaushik Thanki (Student of Dr. Sanyog Jain, NIPER) won 2014 AAPS Lipid based drug delivery graduate
student award.
Pranatharthiharan, S., Patel, M. and Devarajan, P. were awarded certificate of merit for poster titled
“Efficacy study of pullulan anchored stealth DOX nanoformulations in fibrocarcinoma mouse model” at
the Thirteenth International Symposium on 'Advances in Technology and Business Potential of New Drug
Delivery Systems' of the Controlled Release Society ‐ Indian Chapter, held in January, 2013.
Pranatharthiharan, S., Patel, M. and Devarajan, P. won second prize in “Preclinical section” for oral
presentation entitled “Role of Carbohydrate based Ligands on the cytotoxicity and cell uptake of
Doxorubicin nanoformulations” at 6th International annual conference South Asian Chapter of American
College of Clinical Pharmacology, Mumbai, 21st ‐22nd April, 2013.
Dalvi, B., Benival, D. and Devarajan, P. won second prize in “Preclinical section” for poster presentation
entitled “PES Lopinavir nanoparticles: A promising approach to target multiple HIV reservoirs” at 6th
International annual conference South Asian Chapter of American College of Clinical Pharmacology,
Mumbai, 21st ‐22nd April, 2013.
Controlled Release Society Indian Chapter
February 2015 50 Encouraging Research Through Awareness
Soni, M., Shelkar, N., Gaikwad, R., Samad, A., Devarajan, P. and Vanage, G. won second prize in “Preclinical
section” for poster presentation entitled “Genotoxicity and Mutagenicity evaluation of Buparvaquone
Solid Lipid Nanoparticles” at 6th International annual conference South Asian Chapter of American College
of Clinical Pharmacology, Mumbai, 21st ‐22nd April, 2013.
Malode, V. and Devarajan, P. won second prize for poster entitled “Modified USP Dissolution Apparatus II
for Dissolution Testing of Buccal Tablets of Rivastigmine Hydrogen Tartrate” at First International
Conference, Disso India 2013 in Mumbai, 3‐4 May, 2013.
Bhagyashree Dalvi and Sandhya Pranatharthiharan, students of Dr. Padma V. Devarajan, ICT, were
selected for Novartis Biocamp, Hyderabad, July 2013.
Pranatharthiharan, S. and Devarajan P. won second prize for poster presentation titled
“Asialoglycoprotein receptor mediated hepatocyte targeted delivery of polymeric nanoparticles of
Doxorubicin” in NIPICON 2014, January 23‐25, 2014 at Nirma University, Ahmedabad.
Dalvi, B. and Devarajan, P. won first prize for poster presentation titled “Design of surface functionalized
nanoparticles with a novel targeting ligand (TL) for macrophage targeting” in Rasayanam 2014, 3‐4 March
2014 held at ICT, Mumbai.
Chawla, S. and Devarajan, P. won second prize for poster titled “Nano diagnostic approach for blood group
detection” in 7th International Conference organized by South Asian Chapter of American College of
Clinical Pharmacology on “Clinical Pharmacology‐Translational Research: Patient to Public Health”,17‐20
April 2014, held at Nehru Centre, Worli, Mumbai.
Pranatharthiharan, S. and Devarajan, P. won consolation prize for poster titled “Carbohydrate anchored
stealth doxorubicin nanoformulations with improved efficacy in fibrosarcoma mouse model” in Indo‐US
Workshop on nanoengineering in medicine, December 17‐19, 2014 at AIIMS, Delhi.
ANSWERKEYWORD SEARCH
PHARMA PUZZLE
B R U C E L L O S I S 10 3 14 17 2 15 1
E P I L E P S Y 5 7 9
B O T U L I S M
Controlled Release Society Indian Chapter
February 2015 51 Encouraging Research Through Awareness
I M P E T I G O 16 8 4 6 11
M I G R A I N E 13 12
M U L T I P L E 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
CROSSWORD
Across
7. SILICA GEL—Popular dessicant 8. LIPITOR—Pfizer blockbuster drug for cholesterol treatment 10. STENT—A small device that can be placed in the artery after angioplasty to ensure that the artery
remains open 11. EMCOSOY—Natural Superdisintegrant 14. TRADEMARK—A recognizable sign, design or expression which identifies products or services of a
particular source from those of others 15. RECIPROCATING CYLINDER—USP Dissolution Apparatus III 16. BANGHAM—Discover of liposomes
Down
1. LOZENGE—Medicated candy to be dissolved slowly in the mouth 2. NICORETTE—Nicotine chewing gum to aid smoking cessation 3. HEPARIN—A molecule used as an anticoagulant in the treatment of thrombosis 4. ERYTHROPOIETIN—A hormone that stimulates production of red blood cells and haemoglobin in the
bone marrow 5. SUCRALOSE—Artificial sweetener 6. LIPOSYN—Intravenous fat emulsion 9. CERVARIX—Cervical cancer vaccine by GSK 12. ORPHAN DRUG—A pharmaceutical agent that has been developed specifically to treat a rare medical
condition 13. BOROSILICATE—Type I Glass used in packaging
CRYPTOGRAM Science investigates religion interprets. Science gives man knowledge which is power; religion gives man
wisdom which is control.
S Y P H I L I S
S C L E R O S I S
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