Webinar on Novel Dosage

Designs and Medical Devices Nanotechnology--Ovtr a ~adt

of Prog,ess ind Innovation

July 07, 2021

T.iblt' I. The L.nd!Nric ol ~drvg,, del1\fl)' ~ to the aYrWl.

1952 1-firlttw~-rdr-i«hnl,k,gy~ 11• 1

1956 llvM1pn..una.-d111o.~®'jCinh.dff(MDI)
1969 llw&n.1dryp,wdtr1Mil.il)(lll,(Of'I) 111 1
19'1'9 llwfir..11r.1~lp,11c:hTr~15mp• P IJ
1982 llw h R'C'OO\biNnt hWNn INuHn llumulln a• ,~ 1
1984 1lv fif'M ~~ mlmwplwrt \'h•itn>P (~1 )
1986 Thl'fiNQ1l'Ctlon~Dtapeptyf1' 1.:.i1
1989 1lw NM ru.ti.f\all ~ .. r\.omp pn,duct Prc,c-.,,rdw Xl• l~ I
1995 ThrliBtffiA~ppro,,"«dbpot,omcOcmr9 IO I
2005 llwfirstfDA~rwnopanxloi!Ak~ 11-tl
7006 Tlwlir,tFOA.appro,,~bobnolnwdkuw\lmogtnrw PH
Learning Outcomes: :!CU5
2017
TllllfirwffiA-..ppnr,'edJOprw1tdnigSprit.im•
ThefirstFDA-.11Pl'ffl\W~iMPpyKymnffl•
1!71
1~ 1
2017 Th, fir,c FOA..i"J"U''t'd dipbl drug Abibfy "-lyCih!• f~ I

•To identify Global applications of Novel Drug Grng Chan, HZ., Hao Hu, YH and Ocyang D. (2018) A Comprehensive Map of
delivery system (NDDS). FDA•Approved Pharmaceutical products. MDPI Pharma~utics.263

• To discuss common approaches of Novel

Target Drug delivery System.
•To discuss about the FDA Guidelines on the
•
manufacturing of pharmaceutical, cosmetic
and veterinary NDDS products.
'i
Ii
DEFINITION: i
• Novel Drug delivery System (NODS) refers to the rig 11n, 5. Fou~ 1ypn of the 10 11du~ ph;mn~11tic&I r«hnologoK.

approaches, formulations, technologies, Glng cruin, HZ., Hao Hu, YH ,no Ofyans O. (2018) A
Comprehensive M ap ol FOA•A?PrOYed Pharmaceutical
and systems for transporting otoducts. MD91 Pharmaceutlcs.263

a pharmaceutical compound in the body as needed

to safely achieve its desired therapeutic effects. High translational efficacy and clinical
• N DDS is a system for delivery of drug other than success rate
conventional drug delivery system.
Co
• 00 · - ----
!' ti -- ia - • - Cl • - - Con'l'e-ntlonal Drua Tbcrapy
PhannTech1
I . Rapkl and contplele releMe of drua
bnmediale-ly afte-r admln•1ratlon.
2. Al>Mwpdon k lbc rale-UmltJna step
F )A EncoU'agE" 04'V ipme'1t of NO\fel Drug (kr>>>ka).
De ,,er y ,ystem 3. Blood le'l'el nuct:uales (Peak and
Valley).

4. The.re- • rbk or o'l'ennfllkatloa or

.......
under medcatlon al periocb of

5 . Frequent doalna.

_____ . ________ _
6. Plllknl non compl iana-. Therapeutic
,-..1-....-...-.........
__ i:r.,_...,....
_..,. _ _ _ _ _______ _ ...
.,. ____ -....,_flit ~ffkln1cy / C.llure.

. -----•. --"'"--
0 ....... - - ............ -

--
--
7. lncun'l'enlence of patient.
 Advant ages of Conventional Dosage Form : ~
Advantage of NODS
1. Per unit cost of conventiona l dosage form is less
tha n non-immediate release dosage form. • Enhancement of solubility.
2 . More fle x ibility for the physician for adjusting
dosage form in co n ventional dosage form . • Increased bioavailability.
3 . Conventional dosage form can accommodate the
patient variation .
• Protection from toxicity.
4 . N o problems w ith drug havin g too small half life. • Enhancement of pharmacological activity
5 . Potent drugs can 't be formu lated as sus tained
release dosage form . • Enhancement of stability.
• Improved tissue macrophages distribution.
• Sustained delivery.
Drawbacks of conventional dosage forms
• Poo r p a ti e nt complia nce, inc re.ased c ha n ces o f missin g th e
• Protection from physical and chemical
cl os e o f dru g. degradation
• T h e un ava ila ble flu ct u at io n o f dru g co n ce n trat io n m ay lead
to und e r m e d ica ti o n o r ove r m e di ca ti o n .
• A ty pical p eak va.lley p las m a co nce n t ra t io n t ime p ro fil e id
o b ta ined wh ic h m a ke a tta inment o f s tead y s ta te co ndit io n What is drug targeti n
diffic u l t .
- ThC" th C"1,t)X'UtiC' n•spon.k' o f ti dn1g dC"pencls u pon t he i11le1.1C'l k"II of ctr ug
• T he fluc tu a ti o n in drug levels m ay lead to preci p itatio n of 111.:>l« u)("S \\; th c-dl ~II c-..-11 IIIC"1tlU1:t11C" 1·t"lr1 lc"rl biol0$IC'.:l l C"VC" IIIS a l 1~µ 1..:-1
a d ve rse e ffects esp ecia ll y of a drug w it h s m a ll t h e ra p e uti c s itC"S Ill COll t"C" lltn, h cn ckpe n dc- n t II HlllJIC" l"

index wh e neve r ove r m ed ica ti o n occ ur.

Selecti,·e t1 n d e ffect · ,.. a nn acoloiiica lly·acti ve
~ • enn 1ed t n r get(s) 1n lhe r npeu u c co n cen e-
r est" c on e its access t o non·t a r e-et (s) no.-m a l ce llula r linJ n es. t hu s
m i miz m e: toxic e ffects and moxhn iz 1n e: th e 1he1·ope utic i ndex.
Nonconventional Drug

•
Delivery Systems:
What Do They Offer? Normal C ell

Nonna!C.U

T h o, sc, :o l ;. to prud u c"' .. C<> n a11a n 1

1.-v O!'I ,·,r Jru,11: i n 1 ►• ... b<)dy 1lu 11 , ,. hnlco,
• c ,,n1l nu <tu t, l n l ,.av~ n n u • I nfusi o n . ~ Reasons for Drug Targeting
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O t4Ug ins tability

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r
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release dosage for s
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 L i poso m e D rug
A Conve ntlona l llpo some D Et hosome
Co ntent :
Produ c t s
• Drug application (NDA) or
abbrevia ted new drug application
(ANDA) fo r a liposome drug product
Hydfo-ethanok: Guida nce for Indus1ry
aokitlon of drug reviewed by the Center fo r Drug
Evaluation and Research (CDER).
• liposome drug product s:
• (A) Chemistry, manufactu ring, and
controls (CM();
• (B) Human pharmacokinet ics and
bioavailability or, in the case of an
Edge ac tiVator C• .g. single
c::":iE:"'-iSEE.7-: ANDA, bioequiva lence; and
ch•irl surlactant molecule ) -.::::.~ • (C) Labelling in NDAs and ANDAs.

B Tra n sfe rs ome® C Nlosome

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Guida nce for Industry Co ntent :

liiil ..u.s._.rooo&DIIOG
......
Nanotechnology- Over a Decade
of Progress and Innovation
S11 rt'1'.'· or J\"nuom,uerlab tu Cosme,rk
Produces
• Points to Consider in Assessing the
FDA Ap proac h to Safety of Nanomaterials in
• Cosmetic Products
Nanot ec hn ology
• 1. Nanomaterial Characterization
• ~~~o1~~~~ci1~';;rsei~~=:=~~,~~a1,~~~h:~~~~r We intend • a. Physicochemical Properties
our regulatory approach to be adaptive and flexible and to
• b. Impurities
~~~c~~tilia"~~d~:~~~~1!~~ ;~:~:i~t~~,:~~:i~~i~~ r~in\~~t • 2. Toxicology Considerations
of each product and its intended use.
• Particular approaches fo r each product area w ill vary
1 0
~~~°:sd~~~: ~eth,~ ~fia: ~ r°c:J u~~-~hp':{~~j~sgu1~!nsc~ ~~caun~e nts
reflect this approach.
u-11-•--•
r.-_...._ _ _
c_ _ _ ...., ,.. _ _
• a. Routes of Exposure
• b. Uptake and Absorption
• c. Toxicity Testing

• FDA's regulatory policy approach is consistent with relevant l. :'i-tNUI CUl"Xuriu-

____
______________
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__, ...
..,._
.._,_...,_~-
overa rching U.S. JOvernment po licy principles and
supports mnovatlon under appro priate oversight.
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.... ci.-.i • . . . , . _.. (ld''I

Al--6 ■ .. fIM.TM f- ~ - - - - - - ..... ,11

" Considering Whet her an FDA-Regulate d Product .......,...ta._ .. <la... caa6a .. ~ tf U-- ■ 1,t
~adu.-..1--Woftal'l'lllllll(ld?,I) n...aw..
Invo lves t he Applicat ion of Nanot echno logy" . _ . . . . . , , . _ , . _ , . ............ parlff . . ul:I)'

- n.-.w.w."""--"-"-~..,._ • ..a
■ IIIIIUl'l<l,-.adlOl4paaftlk~1JM•dir­
pr<>doa. ....... . _.... -.l(,) 11,-. ■ .. r,r
-.i1.t:i.i1-.w-■o. ait ■ •mm~-•
• (Ref. 1). As described in th at guidance, at t his ti me, w hen con sidering --,c>1..,,.--1111 . . . . . ~...._ .......... li
w het her an FDA-regulated product involves t he ap pl ication of i...••·.........-..-...~--.-,i-1111-..
-•dk9.(M.I)
....,.,..._tf.. w,ol,jb,:~

nanotech nology, FDA w ill ask: • 1')wt1--..IPI. . . .

• (1) w het her a materi al or end product is engineered to have at least Alnll_,.- ..-.•-tlal;d,l1,r..,-..:w.,
one external dimension, or an internal or surface structure, in the
nonoscale range (approximately l nm to 100 nm); and
• (2 ) w het her a mater ial or end product is engineered to exhibit
properties or phenomena, including physical or chemical properties
or biological effects, that are attributable to its dimensian(s), even if
t hese dimensions fall outside t he nanosca le range, up t o one
micrometer (1,000 nm) .
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.io,;..... _ _ _,_ _ _ _ _ , . , _ _ ., . . _
C nld uir~ ror l 11dm1 11

t·~ or l'"• uom.unbh In Food ror An lm11I, $ t... ::5.?-==--:.=:..~.::-..

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--- ---..:-
Smooth Gritty

-
"·-:.:~--- ....... ...... ... 1000mg ~400 mg insoluble <SOOmg

~----------. ------
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3.f:JL--,e;,... -=.--·-~.::.·
~~~~£~~
Smart drug delivery nanoplatforms
pH

Enzyme
Rc,odox

.[ empe,a<u , e

I M.:,,gnoti,:;
Developme nt of SPRITAM ®
....,... A co,..s~ic;

! I tgh 1
Formu]ation Aspect
The final fo rm ulation fo r SPRI TAM incl ud es th e labeled strength of
levetirace tam an d th e inactive ingred ients
Colloidal silicon dioxide
Glycerin
Mannitol
Microcrystall ine cellulose
Polysorbate 20, povidone,
5ucralose,
Butylated hydroxyanisole
Narural and artlfictal spearm int navor.

_..,_
These comp onents are commonly used in formula ti ons. Each
com ponen t is USP or NF grade.

--
Advances

-----
r..:.ii,.,....,

~ 3DPRINTINGIN HEALTHCARE

Ad vantage of Zipdose

Support dose loading up to 1000 mg

• "" Allowstheapplicationolenhancedtaste--
mas~in91echmques
 Outline
♦ UnmetNeed
♦ Impedance Spe<troscopy on Electrochemical Mechanism

♦ Problems and Solutions

♦ Impedance Biosens.or
• lnterdlgital Electrode : Bladder cancer biosensor
♦ Future Work

ln~titute of Medical Scie nce and Technology

National Sun Vat-Sen Unh'crslty (NSYSU), Kaohsiung, Taiwan

•
Where is NSYSU
♦ Bladdtr cancer is the 4th
Bladder Cancer commonest cancer amongst

__
men In the western world.
In Southern Taiwan area, the
incidence rate of bladder
/ Kaohsiung cancer Is 10 times.

Recurrence
; 2hr
flight
, rate SO-SO" ......,..
( ., * 1""o-Ol!N nNCINIGel U«uopMfffll
•Mu~Uq,uidCJw«nftOlraphy

"""'
rM, yrlla

II ■
Unmet NEED for
Point-of-Care of Bladder Cancer Diagnosis
'
Easv, Less Sample, Rapid creening, At home

p_e(troscopy on..Electfochemical

,,_,,_,'-d......_ ... ..,o,_~ .. c.

C.:
Double layn ca~itanoc
Solution didet1ric: capacilantt
c..-.1s,,,;~",..,.,nw . .,,.,.,,, Nn -
~ J6,,..., R,.,1 : Soluti<)rl n:,iiittancc,
R. : Rq,rellet\t the antibod y-protein film

✓ Lowpowtr
✓ [1.se lo mini1turi.zalion
✓ l n1egra1ed I.ab-on-chip
✓ Polnt-of-<:are di■ gnosth::s

_,,
Problems and Solutions Fabrication of Immunosensor
Prob1em.s Solutlons - Electrode array
LflottomK IN:l......,l..aJ rr h. SU-I Cui ly l1yt.r ('. lbfl [k<:trodc Layr r and Chip Bond int
♦ Port able De,,Jce fo r point-of- ♦ l ntegrale wilh minia tu rlzed C... ,_ IIU I.,-.

Care read out system I cm rid?

♦ Ion? Conductivity? pH ? ♦ Medium Control

♦ lmmobillza lion? ♦ OEP / Electrodeposltion

♦ Detection Limit? ♦ Na noprobe

♦ Signal I Noise? ♦ Circuit Design

~"-•"""·-.... - - - - - - ~ , ___ _..,._ .....-w... - • - . ·-11-r.,- 1:l

-
-.....irit~-1..-.,. Mof11.•1.,.•1•1'IRl-l1
~.!:a!:_~~~"""°""""'°'""·.,._-c.._~...... ~....n.--l'fl,.. _ _ _ _,,,~_..., _ _

Portable/Miniaturized Immunoassay System

- A prototype of a Por ta ble Impedance Device
AOS933 Integrated circuit (IC} + AOC + OFT(dlscrete Fourier transform)
Design of pre-amplifier and calibration circuit t o im prove accuracy and st ability by
increased signal-noise ratio (SNR) d uring im pedance analysis

•
--- -------------------------,
' ·---1:=====~::::~'
f
'"""""""~"
11ectrodtsurlac:1
N!~SIY
•.
Dltltttrphortsb (OEP)

r r,
Dtltttlon protein, In Cllnltal

II ~~~-~~~·"'~ ··~·
Pal iCD U Url•e

unctionalize Nanoprobes .....

7-Al 20 l Nanopartlclos
FurKtlon Gtflerato, Mlctoscopti

✓ Low-cost
✓
Advantap

Easily to manipulation by OEP

✓tonvtnl,ent detectioft
♦ Bare - Chip
L
♦ Trapping Probes
•-
♦ B locki ng(BSA)
(Z.I
♦ Immunoassay
T24 ce8 Lysate1Z,)
BSA

ental Result - Trapping

♦ Trapping Probes

anoprobes Gal- I antibody/Silane- Al 2O3 NPs ~ DEP

WK6SOOB LCR Meter

- •
The DEP can modified the probes on the

••
Mo<l"nnlN ll 1"an1,.,urf•~r

~-.,/~~.::t:. ;
<f"' ~~~--
•-,-0-,-0-, • Nanoparticles Nanoprobe
j _L. j -
♦ Fabrication of Oxide antibody

IM•ld""'l'M<l'°"
1,_0H..,OIC)
~ --, ..;:;,..
f......
ll cHo
_. / ' -
30 mio

♦ calculate the antibody

content at NPs surhce by OD -
Fr11quency(Hz)

"
II
 Portable/Miniaturized Immunoassay System nd Discussi D-IRB Clinical Trail
•cooperation with Chi-Mei Hospital_lRB Code: 10404-004
- Accuracy for the portable module
Cu t of Point
Statistical analysis software: SPSS

■
Patient number: 54
lmp,d'"" I MeltrOJ.))
LCR 11,ro, 28 cancer patients
,. Without With

~--
Ot,kt (kll) W•l Disease Disease
26 normal patients
202.64
304.29
401.47
199.82
299.72
399.6S
IJ9
1.50
0.4S
. _..._
, - c-;.~- Normal distribution
■ Norma l Patient
48S.41 499J;3 2.91
c

-
609.79 599.17 1.74 (True Negative, TN)
7 17.80 698.89 2.63

r:=
--- ...
Impedance Variation 0-20%
778.97 799.07 2.58
9 14.24 898.90 USS ■ Cancer Patient
103-0 998.54 J .OS
(True Positive, TP)
lmil!lll 1110 1098.00 1.08
Error Value le" than 2"
lmil!lll 1240 1197.00 J.47
, Impedance Variation 20-50% 40 SO (IO

., Frtqutncy(Hz) Im pedance Va riation (¾ ) 21

discussion esu ts and Discussi D-IRB Clinical Trail

-Difference Concen tration of T24 Cell Lysate of Bladder cancer •u,operat;on w;th Chi-Me; Hospital_ lRB Code: 10404•004

ROC C urve

- c.
Oi,,.,..nt s top• o f lmmunoseslnp
Lr•-•- c,__,.,
11•1--...,,

61Times
J95 Timn ► Discrimination rules of AUC:
• AUC=0.S
(no discrimination )
• 0.7& AUC & 0.8
Difference Concentration
::0.0078-0.2S mg/ml
(acceptable d iscrimination )
llTlmn
• o.s&Auc & o.9
0.0078mg (excell ent discrimination )
::: - pg(< 10-")
Lyute ( > 10,000 proldn) •
For G ■ lecli.n-1 specific protein the
5TimtS
...~ ... ,
i...owr~ •.! ' 1~ Oo.J l~ Qoe:$
• 0 .9& AUC&l.0
(outstanding discrimination)
dettc:Uon llmlltd would bt pgiml Concen1ratlon(mg/ml)
' AUC = 0.863
0 ..

1 - S pt:tlOtUy

Result discussion
-Difference Concentration of Cell Lysate in the Artificial Urine Accuracy - 86% ( excellent)
[)ete,cd(ln of Gal-I l• 1plk_,ed

I
:artifkial aad i ■man urine

Di"1!.-.n11:11ps ,:,( lmmur,o,renrf.,-,g,

Ar,tificialUrin~ .o,tlt+lo! u~,,o • L> - I . 0",.- 1- ) •cooperation with Chi-Mei Hospitol_lRB Code: 10404---004
Protein _ ..,,_,._u•,...o:-.•~l" "'' ..-1

/ ROC C urve
: ,:)
ll!Heftnc1cComeftl1111io11
0.007S--02SonJ/m l

A. nl fll;lsl lfr l■ t: JST~ 1'J

• .r1mu
, . - ,.
28 Tlm e,
·I 1·1
J'\1 11me ■
\
\
► Discrimination rules of AUC:
• AUC =0.S
(no discrimination )
S.2g S9Timl'i • 0 .7& AUC & 0 .8
0.00l21l. KJl 1l'O.
76 Timei,
.,.,}a 11\J ..
AUC. 0 111
(acceptable discrim ination )
-S(l.m,.,
"~ •• ""',., ,-\ N ""MI\I.
Con<:entr~tlon [m g/ml] ••11111\ i"0 .8 & AUC & 0 .9 :
N.!! to!\
]r;.1~0. •~l<lrl,k., , ·u,c;1
: (ex ce llent discrimination) :
04 oe 01 10
1 - M ■ tl
• 0 .9&AUC&l .0
(out standing discrimination)
Resul s-and discussion- Patient urine F19 7 a4'NMP22'0>ROC-

-Signed a Institutional Review Board (lRB) plan with C hi Mei Hospita l

C h1 M e1 1 - Spt.tlntlty

Collected samples for verification

Normal patient Cancer Patient

. . --
lmmediattly
Jlrttrlng

l'r-cu('l-ll"CJ
Jllr
Compariso n
Which Direction to Start?
Approaches of technology innovation

Translation: Technology-Driven Innovation

• Na..,el tectmolog~ with Wood poolen&II app lic.alions
• Availability of s k.ilred pors.armEI with appropriale knowledge- and undarstanding of lh.e market

Research Development Application

BicOesig n: Merket-Dr rYen Innovat ion
• Gaps alld unmet d lnlcal ne-eds
• Well-defined mari,;et ,opporh.milies

Thanks for your attention ! !

chchuang@imst.nsysu.edu.tw
 Imp roved Drug De live ry Systems - enhance penetration of
Hyaluronic Acid -chitosan-latanoprost the drug, lead ing to better ocular availability.
Nanoparticle for Improved Ocu lar Drug ► .J,frequency of administration
Delivery
Ana M arie L. Rubenicia , PhD ► .J,drug concentration with adequate therapeutic
effect paired with lower adverse effect profile

► .J,reduce t he use of BAC (eye irritant) as a

preservat ive an d penetration enhancer
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OINTMENT
NIOSOMES
DISCOME..s
PHARMACOSOMl!S
INS€RT

Prostagla ndin Analog: Latanoprost OCULAR DELIVERY

SYSTEMS
Lowering of IOP
POLYMERIC
Tr ■ ~I
NANOPARTICLE
Trobocula, meehWOfk CONT ACT UHJU
• CHITOSAN
M:LERAL PLUGS
Schlomm·a canal CYCLOO _ A_. GltN ■ Oa.LIVIERV • HYALURONI
MtcR0~ .-01.9
Ep,acleral VUtn&
. . ClltO ■Mla..ltON:J ACID
NANO IU,..RNJtON
Uvaosclerill outflow
Aqueous

CohAry body
~ humor lnflo""

Hyalu ronic acid-chitosa n-lata noprost

Vun,ouahody
Nanoparticles ( .c.,.1 or 1 ) Drug

De livery System
► enhanced corneal contact
time and permeability
Eye irritation and other adverse effects cou ld be

,- ---~-
corneal ► prolonged and controlled
rea sons for patient noncompliance.c:=:=====-=== Hyalu ron ic ~•-= permeation drug action
medication regimen . Ad d •chito~a n-
la t anopr0$l ► convenience of a drop, but wm
Link
localize and maintain drug activity
N anQpartic les
at Its site of action

► a basis for decreasing the

amount of BAC as prese rvative
and penetration enhancer

Why conventional eye drops may require higher doses,

frequent administration and penetration enhancers?
LM:rimal
...... 0
-
overflow/ dilution
reflex blinking
short tear turnover rate
.
.
Ingredient

Chitosan (CS)

Tripolyphosphate
(TPP)

Latanoprost
F- Composition
Description (Use)

Positively charged mucoadheslve

and penetration enhancer polymer

Anionic cross-linking agent

Drug substance that reduces

IOP pressure
·-
lo-,.....
.,..-...
.·· JR,o·•
____
~·
.....:.
.1 ..
_,

,
corneal/conjunctival
barrier
Hyaluronlc acid Negatively charged substrate
(HA) for CD44 receptors and ·~
muooadhesive oolvmer
nasolacrimal drainage
limit the contact time of
ophthalmic solutions to about 1-2
min and their bioavailability is
0 generally less than 10%
(Ma KH & Hadzlja BW,. 2013)
 HA-CS-Iatan Composition Research Design

IDrug Content

HA-CS-latanoprost NPs Mucoadhesion and Drug : Sterility Test

Penetration Enhance ment Drainace controlled by mucus
turnover rate

IEye Irritation Test

...
SJ'u~d
_. t
lgrc!blc4111,
\.,

,.
j

a ,
Research Design

Research Design
Preparat ion ;md Ophm1zation of NP by
the Ionic Gelat,on Method
CS TP P - 2 1, J 1, 4 1 !i 1, 6 1,8 1
lntraocular Pressure Reduction Activity
Preparation and Optimization of HA-
CS-latanoprost NP
CS.HA - 7 .1, 10 1, 20.1

(Particle s ize (nm)

Partlcle size (nm)
Polydispe rsi bility lnde.x: Polydispersibil ity Index
RESULTS
z eta potential (mV) Zeta potentia l (m V)
Dynamic Light Scattering Dynam ic Light Scattering
Melhod using Malvern
Zetasizer
Method using Ma lvern
Zetasizer
hi n-1, op l'I clE. co lloida l
di spersion, ·. TP , 2:1. 3:1, 4:1, 5:1, 6:1 and 8:1.
¾ Entrap ment Effic iency
% Entrapment Effi ciency
Dynamic Dialysis
Dynamic Dialysis Tech nique . Technique, High
High Performance Liqu id Performance Liquid
Chromatography Chromatography

Research Design

Scanning Electron Microscopy HA-C lat o st co lloidal dispersion,

C hemical Integ rity Analysis
, 7:1. 10:1, and 20:1
Hl1hH t amount of HA-
Infrared Spectroscopy most turbid

In Vitro Drug Release

Membrane Diffus ion Tecnlque, HPLC

Mucln-partlcle Method, Malvern Zetaslzer

 Eh ,i:t
of the ratio o CS and TPP on the pa rt icle si2e, polydispe rs ibili t y index
(P OI), zeta potential (ZP), and entra pment ef ficiency (EE) of th e prepa red
na no particles
Code for LP cs TPP ........ MEAN ""-a. MEAN ...... M EAN ......
CS:TPP mcglmL mg /ml mg/ml PARTICLE PDI ZP % EE
SIZE (mV)
(nm)

F2:1 50 0.5 482±259 0.316±ooos 1 7.43 ±0.55 6 8 ±195

F3: 1 50 0.33 199J:.< .25 0 .274.t0.0l4 2 7.7\h 0.27 6 4 .t. 2.45

F4: 1 50 025 249 13,98 0. 299c!0.035 34 .9 7~0.!6 5 8 J 1.02

F5:1 50 0.2 289±4,-30 O.3S5±0.012 35-.63±2.51 Slci2.12

F6:1 50 0.17 294±.$ 18 0 .427±0082 37.47,..0.3 1 3 &3 19

FS:1 50 0 .1 25 54 &? .46 0 .623o-0 124 37.53±0.06 25"'.1.76

Effect of the ratio of CS an HA on t he part icl e size, polyd ispersibil ity index (POI )
, zeta pot en ti al (ZP) and entrapmen t efficiency (EE) of the prepared NPs

Code LP cs Tl'P HA ...... MEAN...... MEAN ~ MEAN...... II EE

CS:HA mcg/mL mglm mg/ml mg/ml PARTICLE ZE TA
L SIZE POTENTIAL
(nm) (mVJ
F7: 1 50 0.33 0. 15 3661.7.99 0 .4 S910.coo 2S .2?J.o.92 66 c2. 27 rT -IASpKUaolKACJ.IMaftOt>ro,il Nanopa,!lde

F10: 1 50 0.33 0.10 4 16,1,7.76 O.519,i,().027 31.33±040 57,-, 1.88

F20:1 50 0.33 0.05 314:0.6J O.43L-o.012 29.87±0.51 68±o.47

•Data a re pre5ented a5 mea n± SD; n • 6; % EE .i. SE, n =9 .

P.irticle sii e: SD 10 500 nm - suit able size ranee fordru_g loaded NPs
PDI: > 0.7 - nonunifor mity ofparticle size distribu tion.
Zeta pale nt ial: ~30 mV - preven t pa rtic le aRs regatio n
% Eotrament Efficiency - nearest to 100%

Scan ning electron microscopy at 15,000 and 20,000

resolu t ion of chitosan- latanoprost soluti on only, ~P
?\IF fom t

-
_L~ .,~;~... ·-...
el,

Scanning electron microscopy at 15,000 and 35,000

The drug r~lease profil e of and :S- latanoprost NPs
of (3:1 CS: TPP
formulation).

ma

0 ~

row o, el of Latanoprost from HA-CS-latanoprost

Scanning electron microscopy at 15,0CXl and
35,000 of HA-CS-latanoprost NPs ( NPs Hiu,..... .c,_.. M _ ..,_,.., fl .... . . o, ......... _,,,_,. HA.C 1$-
,..........,_, u..~ NP•
).
 Mean Zeta Potentials of the HA-CS-lata noprost NPs without the Comparison of the mean treatment effects of Plain Latanoprost, Xa lata n, and HA-CS-
latanoprost NP eve drcps on the IOP on the first day of treat ment (day 3
r )_. _ _ _ __
Mucin and with Mucin
ZetaPotulli ■ljmV)

N I Mlt1lrrium I Mulmum IMem I Std D~11

3 I 31.5, I 33.11 I J2U3 1 o.493

l I · '1.87 I •-5.]2 1-5.0TI I 0.228

Day 3 - first day of treatment (there is no

carry over effect)
For~ulated HA-CS-latanoprost NPs eye drops
prepared in E.L. Laboratories, Inc.,
Da ily mea n IOP ±SD measure of Plai n Latanoprost, Xalatan, and
Hf:-CS-latanoprost NP eye drops.

Determinations of Appropr iateness, Volume, pH,

Particl e Size, Latanoprost Content, and Sterility.
Osmolarity of 280 mOsmole/L
Temp Ap,p,of>f-l•loon,oH Volume
lr,1
pH P;irticleSile Lo1t ;mopr 051 Ste rility
Conclusion
....t,lt.-, 1... , t.d 6.2to6.5

30±2 ° C
"''"M
whrt•, 1u, b, d 6.48 271:14.99 100 sterile
The IOP reducing test shows t hat the form ulat ion of latanoprost with
wM.ior, chitosan and hyaluronic acid is more effective in reducing t he IOP
whrl•,tur Di d
-M 6.46 287±4.93 100.3 sterile
than by drug alone in normal rabbits. These results could serve as a
whh•,ti.,r Did 6.48 271±4.99 100 sterile basis that HA-CS-latanoprost NP formu lation cou ld improve and
"'"'M susta in drug concentration in the act ive site, thus could aid in the
...
wh rt.,no, Di d 6.48 286±3.02 99.96 sterile
w hiti""'
4Dt2 ° C whitf., nnbod , 271 ±4.99 100 sterile formulation of latanoprost eye drops with decrea sed or no
whit•,tu11>id
benzalkonium HCI as an irritant preservative and penetration
6.37 281±1.82 99.48 st•rlla-
enhancer. These cha racte ristics of drug delivery are an advantage for

,.
whil.o,,rur Di d U9:t0.49 ' 6.48 271±4.99 100 sterih~
eye drops especially those for long term use such as glaucoma
whlt♦,IU r b, d 9.s.l -t0.l'll5 296 ±1.5!:I 99.74 st,nile medications, because it cou ld improve patient compliance as well.
"''"M

Ocular Irritation Study ____ .....................

----· ...- . ._.
Publlutions
Pro c:e ed l , .. g~

According to Scores for Grading the Severity of Ocular Ab s t:ra cts f r o m t:h c 4
t_h
A s ion Co n ferc n co In
Lesions/Grading System in the Ocular Irritation Test the scored value Phormac e ut:i ca l Sc i e n ces ( A s i a Pharm I V)

was zero from day 1 to 7 of treatment with the HA-CS LP NP

formulation, then after 24 hrs, 48 hrs, 72 hrs and 7 days from the 7th
day of treatment.

~~=-::.-=--==:
-· ~~:...~ u :.:::r~;r=
:::::::..- ~::;..."'-:=~~.:':~~=:::::.::

lntraocular Pressure Reduction Activity

Measu re IOP usingTonoCa re hand held, wireless,
noncontact tonometer (Keeler Ltd., Windsor, UK), at time
interval of 2 houn fa r 12 houn from Barn to 8pm.

Each time interval has 8 data points per treatment.

Each data point hH S, rep,eated meHurement:s

J
Mean IOP {40 IOP measurements) for each
treatment eve,v time interval was computed .

Data Analysis
 NEURODEGENERATIVE
DRUG DISCOVERY SYSTEM AGAINST DISORDERS
NEURODEGENERATIVE DISORDERS: Alzheimer's disease (AD
A MANUFACTURING CHALLANGE
Parkinson's disease (PD)

DR. PRASHANT TIWARI

COPS, DSU, BANGALORE, INDIA
• Multiple sclerosis (MS)

Wilson's disease(WD)

Amyotrophic lateral sclerosis (ALS)

Huntington's disease (HD)

OUTLINE TREATMENT STRATEGI

• Introduction
, Cholinesterase inhibitors
• NDD Donepezil, Galantamine, Rivastigmine & Tacrine

, NM DA type glutamate receptor antagonist- Memantine

• Current therapy
, Piracetam : GABA derivative has no GABA like activity. It
• Recent advances in selectively Improves efficiency of hi gher telencephallc neurons
• Citicoline: Derived from choline and cytidi ne, involved in
pharmacotherapy biosynthesis of leci thin
, Improve cerebral function by increasing blood flow to the brain a nd
enhancing cerebral metabolism
• Manufacturing

NEURODEGENERATIVE
Challenges , Antioxidant therapies??

EMERGING
•
DISORDERS TARGET BASED
• Neurodegenerative diseases are a hete rogeneous THERAPIES
1. Secretase inhibitors
group of di sorde rs t hat are characterized by the
2. lmmunotberapy
progressive degeneration of the structure and
J. Neprilysin
function of the central neivous system
4. Altering BBB transport
or peripheral nervous system s. Inhibition of Aj3 aggregation

6. Antioxidants

7. Statins
• In curabl e and leads to debi li tating condi tion s

•
8. Dim ebon
• Cogn iti ve di sa bility, Ataxia a nd deme ntia
• 9. Estroge ns

The Blood Brain Barrier

--
Normal Blood Ve ssels vs.

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mul faceted diff s s
• HIStory of 11-d targe! p,edlct1on
Magnetic
Nanopartkles
Liposomes
Recent focus on slngle~ta~t efforts

. .. ... for multl•phenotypfc dlsea~

Id ntiflcatlon of rep, s nta
phenotyplc screens or CNS d sonlers
Gold
opartlcles
P n tratlon ol e blood- brain b;irrier

~
Ml gallon of to le side-effects

Svstem c lack of anlmal models lch

Dendrimers accurately represent comple
diseases
POO<' tran latlon b tw mod I nd
. , Nanocapsules
Solid lipid humans
Nanoparticles
Nanoshells
Objecdve endpoints for social and
cotnltlvo conditions
Lowt'r th~ shold for sld f'ffPctS fO<
CNS drugs

Dru Di co r C cl

Biotechnology
Companies

linu-.11
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Nanastructures and Devlen

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