Volume 7, February 2015 IN THIS ISSUEIN THIS ISSUE · IN THIS ISSUEIN THIS ISSUE ... for drug eluting stents is the industry expert Mr. Ankur Raval. ... imary circulatory blood

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: [email protected]; [email protected]

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


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)


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


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

[email protected]

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



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).


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


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


(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.

References: 1. Y. Romsicki and F. J. Sharom. The membrane

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)


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

[email protected]

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



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


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.


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


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



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


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.


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


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

[email protected]

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



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:


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


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.


(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


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]


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



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, [email protected]

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


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


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.


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.


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


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


CRS NE

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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


February 2015


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.


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.



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”



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.



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



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

Documents

Volume 7, February 2015 IN THIS ISSUEIN THIS ISSUE · IN THIS ISSUEIN THIS ISSUE ... for drug eluting stents is the industry expert Mr. Ankur Raval. ... imary circulatory blood