1. ©
Rogério
Gaspar,
2013
Nanomedicines
within
regulatory
science:
The “nanotechnology revolution”
current
opportuni:es
within
R&D
and
future
developments
for
healthcare
Rogério
Sá
Gaspar
Faculdade
de
Farmácia
da
Universidade
de
Lisboa
&
iMed.UL
(Medicines
Research
Ins:tute,
hDp://www.imed.ul.pt
)
rgaspar@ff.ul.pt
24/10/13
Faculdade
de
Farmácia
da
Ua
Universidade
Lisboa
Faculdade
de
Farmácia
d niversidade
de
de
Lisboa
iMed.UL
(Medicines
Research
Ins:tute)
iMed.UL
(Medicines
Research
Ins:tute)
1

2. Rogério Gaspar
October 24th 2013
Reference
posi:ons
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Vice-­‐Rector
R&D,
University
of
Lisboa
(ULisboa),
Portugal
(2013-­‐
)
General
Council
of
University
of
Lisbon
(UL,
Portugal),
2008-­‐2013
Vice-­‐Dean,
Research
&
Tech
Transfer/
InternaEonal
Affairs
(FFUL).
2012-­‐2013
Head
of
Department
PharmaceuEcal
Technology,
FFUL,
2007-­‐2013
Leader
research
group
“Nanomedicine
&
Drug
Delivery
Systems”
(iMed.UL),
2007-­‐2013
Group
Leader
InTraCell_ADD
(iMed.UL),
2013-­‐
SPCF,
Vice-­‐President
Portuguese
Society
for
PharmaceuEcal
Sciences
(2011-­‐)
FIP,
Vice-­‐chair
Regulatory
Science
Special
Interest
Group
(2011-­‐)
EUFEPS,
ExecuEve
CommiZee
(2009-­‐2013),
VP
for
Science
Policy
in
2011/2012
EUFEPS,
Chair
of
Regulatory
Science
Network
(2011-­‐)
External
Advisory
Board
of
EuroNanoMedNet
(ERA-­‐NET
in
Nanomedicine,
FP7,
EU)
Strategic
Advisory
Board
CIBER-­‐BBN
(Spain)
External
Advisory
Board
of
European
Doctoral
Program
in
Nanomedicine
(NANOFAR)
ScienEfic
Advisory
Board
of
TRANS-­‐INT
(Large
FP-­‐7
project)
ScienEfic
Advisory
Board
of
Z-­‐Cube
(Zambon
group,
Milano,
Italy)
•
Editorial
Board/Interna:onal
Advisory
Board:
Nanomedicine:
Nanotechnology,
Biology,
and
Medicine
(Elsevier),
InternaEonal
Journal
of
Nanomedicine
(Dove
Press),
Drug
Delivery
and
TranslaEonal
Research
(Springer)
(…)
Faculdade
de
Farmácia
da
Universidade
de
Lisboa
iMed.UL
(Medicines
Research
Ins:tute)

3. EUFEPS
Regulatory Science Network
Launched
at
1st
Mee:ng
of
the
Steering
CommiDee
Leiden
(Netherlands),
Saturday
(morning),
January
15th,
2011
Rogério
Gaspar
(chair)
(iMed.UL
&
University
of
Lisboa)
Hans
Linden
(Secretary)
(EUFEPS
Senate
&
EUFEPS
European
Projects)
Daan
Crommelin
(EUFEPS
Senate,
TI
Pharma
&
University
of
Utrecht)
Beatriz
Silva
Lima
(iMed.UL
&
University
of
Lisboa;
EMA-­‐CHMP/ch.SWP)
Bert
Leudens
(MEB,
Netherlands;
EMA-­‐CHMP;
Utrecht
University)
Malcolm
Rowland
(Manchester,
UK
/
EUFEPS
Senate)
Afla
Hincal
(EUFEPS
Senate;
HaceDepe
University,
Ankara)
and
also
invited
observers
from
other
EUFEPS
networks
Faculdade
de
Farmácia
da
Universidade
de
Lisboa
iMed.UL
(Medicines
Research
Ins:tute)

4. The
global
agenda
for
“medicines
research”:
EUFEPS
as
an
indispensable
partner
Rogério Gaspar
October 24th 2013
Environment
&
Pharmaceu:cals
Biotechnology
QbD
&
PAT
Safety
Sciences
Quality
Safety
Sciences
Pharmaco-­‐
kine:cs
Bioavailability
&
Biopharmaceu:cs
PharmacoGene:cs
&
PharmacoGenomics
Faculdade
de
Farmácia
da
Universidade
de
Lisboa
iMed.UL
(Medicines
Research
Ins:tute)

5. Rogério Gaspar
October 24th 2013
The
global
agenda
for
“medicines
research”:
Regulatory
Science
Systems
Approaches:
5
S
Pharmacology
Toxicology
TherapeuEcs
Technologies
Complex
Faculdade
de
Farmácia
da
Universidade
de
Lisboa
iMed.UL
(Medicines
Research
Ins:tute)

6. Rogério Gaspar
October 24th 2013
European
Journal
of
Pharmaceu:cal
Sciences
47
(2012):
979-­‐987,
doi
10.1016/j.ejps.2012.09.020
Faculdade
de
Farmácia
da
Universidade
de
Lisboa
iMed.UL
(Medicines
Research
Ins:tute)

7. ©
Rogério
Gaspar,
2013
Personalized
Medicine
&
the
integra:on
of
diagnos:cs
and
therapeu:cs
The
Path
to
Personalized
Medicine
Margaret
A.
Hamburg,
M.D.,
and
Francis
S.
Collins,
M.D.,
Ph.D.
The
New
England
Journal
of
Medicine
June
15,
2010.
The
success
of
personalized
medicine
depends
on
having
accurate
diagnos=c
tests
that
iden=fy
pa=ents
who
can
benefit
from
targeted
therapies.
Increasingly,
however,
the
use
of
therapeuDc
innovaDons
for
a
specific
paDent
is
conDngent
on
or
guided
by
the
results
from
a
diagnosDc
test
that
has
not
been
independently
reviewed
for
accuracy
and
reliability
by
the
FDA.
The
agency's
goal
is
an
efficient
review
process
that
produces
diagnos=c–
therapeu=c
approaches
that
clinicians
can
rely
on
and
allows
companies
that
invest
in
establishing
the
validity
and
usefulness
of
tests
to
make
specific,
FDA-­‐
backed
claims
about
benefits.
New
England
Journal
of
Medicine.
The
Path
to
Personalized
Medicine.
hKp://content.nejm.org/cgi/content/full/NEJMp1006304
Faculdade
de
Farmácia
da
Universidade
armácia
da
Universidade
de
Lisboa
Faculdade
de
F de
Lisboa
24/10/13
iMed.UL
(Research
Ins:tute
for
MResearch
Ind
Pharmaceu:cal
Sciences)
iMed.UL
(Medicines
edicines
a ns:tute)
7
01/02/2013

8. Rogério Gaspar
October 24th 2013
Where
does
nanotechnology
belong
in
the
map
of
science?
Alan
L.
Porter
and
Jan
You=e,
Nature
Nanotechnology,
(September
2009):
534-­‐536
The
posi:on
of
nanoscience
and
nanotechnology
over
a
base
map
of
science.
Each
node
in
this
map15
is
one
of
the
175
subject
categories
in
the
SCI.
The
size
of
each
node
is
propor:onal
to
the
number
of
nanopapers
published
in
journals
in
each
subject
category
during
the
period
January–July
2008.
Loca:on
on
the
axes
in
this
Kamada–Kawai
algorithm
representa:on
has
no
Faculdade
de
Farmácia
da
Universidade
olouring
to
reflect
inherent
meaning:
the
connec:ng
arcs
and
proximity
reflect
similarity
based
on
cross-­‐cita:on
paDerns,
reinforced
by
cde
Lisboa
the
clustering
of
subject
categories
into
macrodisciplines
iMed.UL
(Medicines
Research
Ins:tute)

9. Liposomal
-­‐
lipidic
±
targeEng
and
imaging
agents
Technology
Classes
Rogério Gaspar
in
clinical
trial
or
the
market
October 24th 2013
Polymer
Conjugates
1
drug
polymer-­‐drug
conjugates
±
targe:ng/imaging
agents
PEG
(polymer)
-­‐protein
-­‐aptamer
conjugates
Protein/Ab
Conjugates
2
drugs
combinaEon
therapy
lipidic
drug
mixtures
Block
copolymer
micelles
5-­‐25
nm
60-­‐2
00
drug
maybe
entrapped
or
covalently
bound
±
targe:ng
groups
<1,000
lipidic,
protein
or
polymeric,
inorganic
drug
non
covalently
or
covalent
bound
metallic:-­‐
gold,
silver,
iron
oxide
(polymer
coaEngs
used
to
stabilise)
Crosslinked
(Nano)
Gels
mulElayered
nanoparEcle
nanocapsule,
nanoshell
(NB
many
nanopar:cles
are
not
round)
Nano-­‐sized
drug
crystals
Bioac:ve
Synthe:c
Polymers/Vesicles
Faculdade
de
Farmácia
da
Universidade
de
Lisboa
iMed.UL
(Medicines
Research
Ins:tute)
©Ruth
Duncan,
2010
©R.Duncan
and
R.Gaspar,
2011

10. Liposomal
-­‐
lipidic
±
targeEng
and
imaging
agents
Technology
Classes
Rogério Gaspar
in
clinical
trial
or
the
market
October 24th 2013
Polymer
Conjugates
1
drug
polymer-­‐drug
conjugates
±
targe:ng/imaging
agents
PEG
(polymer)
-­‐protein
-­‐aptamer
conjugates
Protein/Ab
Conjugates
2
drugs
combinaEon
therapy
lipidic
drug
mixtures
Block
copolymer
micelles
5-­‐25
nm
60-­‐2
00
drug
maybe
entrapped
or
covalently
bound
±
targe:ng
groups
<1,000
lipidic,
protein
or
polymeric,
inorganic
drug
non
covalently
or
covalent
bound
metallic:-­‐
gold,
silver,
iron
oxide
(polymer
coaEngs
used
to
stabilise)
Crosslinked
(Nano)
Gels
mulElayered
nanoparEcle
nanocapsule,
nanoshell
(NB
many
nanopar:cles
are
not
round)
Nano-­‐sized
drug
crystals
Bioac:ve
Synthe:c
Polymers/Vesicles
Faculdade
de
Farmácia
da
Universidade
de
Lisboa
iMed.UL
(Medicines
Research
Ins:tute)
©Ruth
Duncan,
2010
©R.Duncan
and
R.Gaspar,
2011

11. 44 marketed Nano-delivery products
Product
Abraxane
Abelcet
Generic
Formulation
Indication
Paclitaxel
Polymeric
nanoparticles
Cancer
chemotherapy
Amphotericin B
Liposomal
formulation
Fungal infections
Manufacturer
Celgene
Elan/Alkermes, Enzon,
Cephalon
Product
Generic
Formulation
Indication
Manufacturer
Solid/lipid
nanoparticles
Osteoarthritis
AlphaRx
Inflexal V
Subunit influenza
vaccine
Virosome
Influenza prophylaxis
Crucell
Paliperidone
Nanocrystal
Antipsychotic
Janssen
Indaflex
Indomethacin
Adagen
Adenosine
deaminase
PEGylation
Enzyme replacement
therapy
Enzon, Sigma-Tau
Invega
Sustenna
AmBisome
Amphotericin B
Liposomal
Formulation
Oral and perioral
infections
Astellas/Gilead
Sciences
Macugen
Pegaptanib
Pegylated anti-vegf
aptamer
OSI Pharmaceuticals/
Pfizer
Amphotec
Amphotericin B
Liposomal
Formulation
Oral and perioral
infections
Three Rivers
Pharmaceuticals/ALZA
Age-related
macular
degeneration
nanocrystal
formulation
Moderate to severe
pain
Cancer chemotherapy
Elan/Alkermes, Pfizer
Doxorubicin
citrate complex
Liposome encapsulated
Avinza
Morphine
sulphate
Myocet
Cephalon/Zeneus
Pharma/ Sopherion
Therapeutics
Glatiramer
acetate
Copolymer of lglutamic
acid, lalanine, l-tyrosine
and l-lysine)
Megace ES
Megestrol acetate
Nanocrystal formulation
Cancer therapy
Multiple sclerosis
Teva Pharmaceuticals
Elan/Alkermes+Par+BristolMyers Squibb
MuGard
Hydrogel mouth
rinse
Nanogel
Head and neck cancers
Access Pharma
Chiesi Farmaceutici
SpA
Naprelan
Nanoxel
Neulasta
Naproxen
Paclitaxel
Filgrastim
Oncospar PEGLasparaginase
Nanocrystal formulation
Polymeric nanoparticles
Pegylation
Pegylation
Arthritis, gout
Cancer chemotherapy
Neutropenia
Elan/Alkermes
Dabur Pharma
Amgen
Enzon/Schering-
Plough
Pegasys
Peginterferon alfa
2a
Pegylation
Copaxone
Curosurf
Poractant alfa
Liposome
Neonatal respiratory
distress
DaunoXome
Daunorubicin
PEGylated liposome
Formulation
Cancer
chemotherapy
Gilead Sciences
DepoCyt
Cytarabine
Sustained-release
Liposomes
Cancer
chemotherapy
SkyePharma/Enzon
Depodur
Morphine
sulphate
Liposome
Pacira
Pharmaceuticals
Pacira
Pharmaceuticals
Diprivan
Propofol
Liposomes
Induction of
anesthesia
AstraZeneca
PegIntron
Peginterferon alfa
2b
Pegylation
Doxorubicin
PEGylated liposome
Formulation
Cancer
chemotherapy
ALZA/ OrthoBiotech/
Schering Plough
Rapamune
Sirolimus
Nanocrystal formulation
Renagel
Sevelamer hcl
Poly (allylamine) resin
Salinum
Potassium,
magnesium,
chlorine
Somavert
Ritalin LA
Doxil/CaelyX
Oncospar
Cancers
Hepatitis B, hepatitis C
Roche/Nektar
Chronic hepatitis C
Schering-Plough
Immunosuppression
Hyperphosphatemia in
hemodialysis
Wyeth Élan/Alkermes
Oral liquid
Xerostomia
Pegvisomant
Polymer protein conjugate
Acromegaly
Pfizer
Methylphenidate
Hcl
Pulsatile release
Nanocrystal formulation
ADHD
Elan/Novartis
Abbott
Abbott Élan/Alkermes
SkyePharma/ First Horizon
Pharmaceuticals/Sciele
Pharma
Elestrin
Elestrin Estradiol
gel
Phosphate
nanoparticles
Menopausal
symptoms
BioSante
Elyzol
Metronidazole
Dental gel
Parodontitis Camurus
Camurus
Emend
Aprepitant
Nanocrystal
Formulation
Anti-emetic
Merck & Co+
Elan/Alkermes
Epaxal
Hepatitis A
vaccine
Virosome technology
Prevention of
Hepatitis A infection
Berna Biotech
Episil
Bioadhesive
barrier
Fluidcrystal
Oral pain
Sinclair/Teva
Survanta
Beractant
Liposome encapsulated
Estrasorb
Estradiol gel
Micellar
Nanoparticles
Menopausal
symptoms
Novavax/Espirit
Pharma
Neonatal respiratory
distress
Tricor
Fenofibrate
Nanocrystal formulation
Lipid reduction
Focalin XR
Dexmethylphen
idate hcl
Nanocrystals
ADHD
Novartis
Élan/Alkermes
Triglide
Fenofibrate
Nanocrystal formulation
Lipid reduction
Fosrenol
Lanthanum
carbonate
Inorganic
Nanoparticles
End-stage renal
disease
Shire
Genexal PM
Paclitaxel
Polymeric micelles
Cancers
Samyang
Verelan/
Verelan
PM
Verapamil
Elan’s SODAS
Hypertension
Multiparticulate technology
Genzyme
Elan/Alkermes Schwarz
Source
BCC
Research
Faculdade
de
Farmácia
da
Universidade
de
Lisboa
iMed.UL
(Medicines
Research
Ins:tute)
01/02/2013

12. 18 marketed Pharmaceutical products
Product
Composition
Indication
Company
Rogério Gaspar
October 24th 2013
Annual
Sales
($ Millions)
Abelcet
Amphotericin B/lipid
Fungal infections
Enzon
23
Ambisome
Liposomal
amphotericin B
Fungal infections
Gilead
350
Doxil, Caelyx
Liposomal
doxorubicin
Kaposi’s sarcoma
Ortho, Schering-Plough
360
Depocyt
Liposomal cytarabine
Cancer
Skyepharma
170
Visudyne
Liposomal verteporfin
Age-related macular
degeneration
QLT, Novartis
150
Estrasorb
Estradiol in micelles
Menopause
Novavax
130
Adagen
PEG-adenosine
deaminase
Immunodeficiency
Enzon
33
Neulasta
Oncospar
Pegasys
PEG-GCSF
PEG-asparaginase
PEG- α -interferon 2a
Neutropenia
Leukemia
Hepatitis C
Amgen
Enzon
Nektar, Roche
PEG-Intron
PEG-α -interferon 2b
Hepatitis C
Enzon, Schering-Plough
975
Macugen
Pegylated anti-VEGF
aptamer
Age-related macular
degeneration
OSI Pharmaceuticals, Pfizer
175
Somavert
Copaxone
PEG-HGH
Copolymer of amino-acids
Acromegaly
Multiple sclerosis
Nektar, Pfizer
TEVA
Renagel
Crosslinked
poly(allylamine) resin
Chronic kidney
Disease
Genzyme
575
Megace ES
Nanocrystalline
megestrol acetate
Eating disorders
Elan, Par
55
Rapamune
Nanocrystalline
sirolimus
Immunosuppression
Elan, Wyeth
340
Abraxane
Paclitaxel proteinbound
nanoparticles
Cancer
Abraxis, AstraZeneca
675
Faculdade
de
Farmácia
da
Universidade
de
Lisboa
iMed.UL
(Medicines
Research
Ins:tute)
500
65
1,650
325
3,250
01/02/2013

13. Rogério Gaspar
October 24th 2013
Diagnos:cs
&
Therapeu:cs
Faculdade
de
Farmácia
da
Universidade
de
Lisboa
iMed.UL
(Medicines
Research
Ins:tute)

14. 15 marketed Imaging/diagnostic & biomaterial
Product
Lateral flow tests
Composition
Indication
In vivo Imaging
Iron nanoparticles
Liver tumors
Iron nanoparticles
Liver tumors
Iron nanoparticles
Imaging abdominal
structures
In Vitro Diagnostics
Colloidal gold
Pregnancy, ovulation, HIV
etc
Clinical cell separation
Magnetic nanoparticles
Resovist
Feridex/Endorem
Gastromark/Lumirem
Ceram X duo
Filtek Supreme
Mondial
Premise
Tetric Evoceram
Ostim
Perossal
Vitoss
Acticoat
Pacemaker
Immunodiagnostics
Biomaterials
Nanoparticle composite
Dental filling material
Nanoparticle composite
Dental filling material
Nanoparticle-containing
Dental restoration
dental prosthesis
Nanoparticle composite
Dental repair
Nanoparticle composite
Dental Repair
Nano-hydroxy apatite
Bone defects
Nano-hydroxy apatite
Bone defects
Nano-hydroxy apatite
Bone defects
Silver nanoparticles
Antimicrobial wound care
Active Implants
Fractal electrodes
Heart failure
Rogério Gaspar
October 24th 2013
Company
Schering, Berlin
Advanced Magnetics,
Guerbet
Advanced Magnetics,
Guerbet
British Biocell,
Amersham/GE,
Nymox
Dynal/InVitrogen,
Miltenyl Biotec,
Immunicon
Dentspley
3M Espe
Heraeus Kulzer
Sybron Dental Specialities
Ivoclar Vivadent
Osartis
Aap implantate
Orthovita
Nucryst
Biotronik
Faculdade
de
Farmácia
da
Universidade
de
Lisboa
iMed.UL
(Medicines
Research
Ins:tute)
01/02/2013

15. Rogério Gaspar
October 24th 2013
>70 Nanomedical Products in Clinical trials
Cardiovascular
Diseases
Endocrinology
NCE Brilinta (ticagrelor); AstraZeneca; For the
reduction of thrombotic events in patients with
acute coronary syndrome, Approved July 2011
NCE Afinitor (everolimus); Novartis; For the
treatment of advanced pancreatic
neuroendocrine tumors, Approved May 2011
Immunology
Infectious Diseases
Hematology
Musculoskeletal
AB Actemra (tocilizumab); Genentech; For the
treatment of systemic juvenile idiopathic arthritis,
Approved April 2011
NCE Abstral (fentanyl sublingual tablets);
ProStrakan; For the treatment of breakthrough
cancer pain in opioid-tolerant patients, Approved
January 2011
NCE Abstral (fentanyl sublingual tablets);
ProStrakan; For the treatment of breakthrough
cancer pain in opioid-tolerant patients, Approved
January 2011
NCE Duexis (ibuprofen and famotidine); Horizon
Pharma; For the relief of rheumatoid arthritis and
osteoarthritis and prevention of gastric ulcers,
Approved April 2011
NCEGralise (gabapentin); Abbott; For the
treatment of postherpetic neuralgia, Approved
February 2011
NANO Adcretris (brentuximab vedotin); Seattle
Genetics; For the treatment of Hodgkin
lymphoma and anaplastic large cell lymphoma,
Approved August 2011
NCE Horizant (gabapentin enacarbil);
GlaxoSmithKline; For the treatment of restless
legs syndrome, Approved April 2011
NCE Afinitor (everolimus); Novartis; For the
treatment of advanced pancreatic
neuroendocrine tumors, Approved May 2011
NCE Ferriprox (deferiprone); Apotex; For the
treatment of transfusional iron overload due to
thalassemia, Approved October 2011
AB Benlysta (belimumab); Human Genome
Sciences; For the treatment of systemic lupus
erythematosus, Approved March 2011
NCE Xarelto (rivaroxaban); Bayer; For the
prophylaxis of deep vein thrombosis during knee
or hip replacement surgery, Approved July 2011
NCE Sutent (sunitinib malate); Pfizer ; For the
treatment of pancreatic neuroendocrine tumors,
Approved May 2011
AB Soliris (eculizumab); Alexion; For the
treatment of atypical hemolytic uremic syndrome,
Approved September 2011
NCE
Complera (emtricitabine/rilpivirine/tenofovir
disoproxil fumarate); Gilead; For the treatment of
HIV-1 in treatment-naive adults, Approved August
of 2011
Nephrology
Urology
Dermatology
Plastic Surgery
peptide Firazyr (icatibant); Shire; For the
treatment of acute attacks of hereditary
angioedema, Approved August of 2011
NCE Tradjenta (linagliptin); Boehringer
Ingelheim; For the treatment of type II diabetes,
Approved May 2011
Gastroenterology
NCE Gralise (gabapentin); Abbott; For the
treatment of postherpetic neuralgia, Approved
February 2011
NCE Afinitor (everolimus); Novartis; For the
treatment of advanced pancreatic
neuroendocrine tumors, Approved May 2011
CELL laViv (azficel-T); Fibrocell Science; For the
improvement of nasolabial fold wrinkles in adults,
NCE Dificid (fidaxomicin); Optimer
Pharmaceuticals; For the treatment of
Approved June 2011
Clostridium difficile-associated diarrhea,
Approved May 2011
NANO Sylatron (peginterferon alfa-2b); Merck;
For the treatment of melanoma, Approved April
NCE Duexis (ibuprofen and famotidine); Horizon
Pharma; For the relief of rheumatoid arthritis and
2011
osteoarthritis and prevention of gastric ulcers,
Approved April 2011
NCE Juvisync (sitagliptin and simvastatin);
Merck; For the treatment of type II diabetes,
Approved October 2011
Oncology
NCE
Arcapta (indacaterol maleate inhalation powder);
Novartis; For the treatment of airflow obstruction
resulting from chronic obstructive pulmonary
disease, Approved July 2011
NCE Edarbi (azilsartan medoxomil); Takeda; For
the treatment of hypertension, Approved
February 2011
Neurology
NANO Adcretris (brentuximab vedotin); Seattle
Genetics; For the treatment of Hodgkin
lymphoma and anaplastic large cell lymphoma,
Approved August 2011
NCE Xarelto(rivaroxaban); Bayer; For the
prophylaxis of deep vein thrombosis during knee
or hip replacement surgery, Approved July 2011
Otolaryngology
NCE Vandetanib (vandetanib); Astra
Zeneca; For the treatment of thyroid
cancer, Approved April 2011
Pulmonary
Respiratory Diseases
NCE Daliresp (roflumilast); Forest
Pharmaceuticals; For the treatment of chronic
obstructive pulmonary disease, Approved
February 2011
NBE Nulojix (belatacept); Bristol-Myers Squibb;
For the prevention of organ rejection following
kidney transplant, Approved June 2011
NCE Lazanda (fentanyl citrate) nasal spray;
Archimedes; For the management of
breakthrough cancer pain, Approved June 2011
NCE Lazanda (fentanyl citrate) nasal spray;
Archimedes; For the management of
breakthrough cancer pain, Approved June 2011
NCE Dificid (fidaxomicin); Optimer
Pharmaceuticals; For the treatment of
Clostridium difficile-associated diarrhea,
Approved May 2011
AB Soliris (eculizumab); Alexion; For the
treatment of atypical hemolytic uremic syndrome,
Approved September 2011
NCE Onfi (clobazam); Lundbeck; For the
adjunctive treatment of seizures associated with
Lennox-Gastaut syndrome, Approved October
2011
NCE Sutent (sunitinib malate); Pfizer; For the
treatment of pancreatic neuroendocrine tumors,
Approved May 2011
NCE Oxecta (oxycodone HCl); Pfizer; For the
management of acute and chronic moderate to
severe pain, Approved June 2011
NANO Sylatron (peginterferon alfa-2b); Merck;
For the treatment of melanoma, Approved April
2011
NCE Potiga (ezogabine); Valeant
Pharmaceuticals; For the treatment of partial-
NCE Vandetanib (vandetanib); Astra Zeneca; For
the treatment of thyroid cancer, Approved April
onset seizures, Approved June 2011
2011
NCE Edurant (rilpivirine); Tibotec; For the
treatment of HIV-1, Approved May 2011
Peptide Firazyr (icatibant); Shire; For the
treatment of acute attacks of hereditary
angioedema, Approved August of 2011
Pharmacology
Toxicology
NCE Oxecta (oxycodone HCl); Pfizer;
For the management of acute and
chronic moderate to severe pain,
Approved June 2011
NCE
Arcapta (indacaterol maleate inhalation
powder); Novartis; For the treatment of
airflow obstruction resulting from
chronic obstructive pulmonary disease,
Approved July 2011
NCE Gralise (gabapentin); Abbott; For the
treatment of postherpetic neuralgia, Approved
NCE Viibryd (vilazodone hydrochloride); Clinical
Data; For the treatment of major depressive
NCE Xalkori (crizotinib); Pfizer; For the treatment
of ALK+ non-small cell lung cancer, Approved
February 2011
disorder, Approved January 2011
August of 2011
NCE Daliresp (roflumilast); Forest
Pharmaceuticals; For the treatment of
chronic obstructive pulmonary disease,
Approved February 2011
NCE Incivek (telaprevir); Vertex; For the
treatment of genotype 1 chronic hepatitis C,
Approved May 2011
NCE Xalkori (crizotinib); Pfizer; For the
treatment of ALK+ non-small cell lung
cancer, Approved August of 2011
NBE Nulojix (belatacept); Bristol-Myers Squibb;
For the prevention of organ rejection following
kidney transplant, Approved June 2011
Rheumatology
antibody Yervoy (ipilimumab); Bristol-Myers
Squibb; For the treatment of metastatic
melanoma, Approved March 2011
NCE Zelboraf (vemurafenib); Roche; For the
treatment of BRAF + melanoma, Approved
August of 2011
17 NCE Incivek (telaprevir); Vertex; For the
treatment of genotype 1 chronic hepatitis C,
Approved May 2011
NCE Rectiv (nitroglycerin) ointment 0.4%;
ProStrakan; For the treatment of chronic anal
fissure, Approved June 2011
AB Actemra (tocilizumab); Genentech;
For the treatment of systemic juvenile
idiopathic arthritis, Approved April 2011
NCE
Duexis (ibuprofen and famotidine);
Horizon Pharma; For the relief of
rheumatoid arthritis and osteoarthritis
and prevention of gastric ulcers,
Approved April 2011
Pediatrics
Neonatology
AB Yervoy (ipilimumab); Bristol-Myers Squibb;
For the treatment of metastatic melanoma,
Approved March 2011
AB Actemra (tocilizumab); Genentech;
For the treatment of systemic juvenile
idiopathic arthritis, Approved April 2011
NCE Zelboraf (vemurafenib); Roche; For the
treatment of BRAF + melanoma, Approved
August of 2011
NCE Daliresp (roflumilast); Forest
Pharmaceuticals; For the treatment of
chronic obstructive pulmonary disease,
Approved February 2011
NCE Zytiga (abiraterone acetate); Centocor
Ortho Biotech; For the treatment of prostate
cancer, Approved May 2011
Obstetrics
Gynecology
NCE
Makena (hydroxyprogesterone caproate
injection); Hologic; For the prevention of risk of
preterm birth, Approved February 2011
NCE Sutent (sunitinib malate); Pfizer; For the
treatment of pancreatic neuroendocrine tumors,
Approved May 2011
NCE Victrelis (boceprevir); Merck; For the
treatment of chronic hepatitis C genotype 1,
Approved May 2011
Pharmacology
Toxicology
NCE Oxecta (oxycodone HCl); Pfizer;
For the management of acute and
chronic moderate to severe pain,
Approved June 2011
NCE Victrelis (boceprevir); Merck; For the
treatment of chronic hepatitis C genotype 1,
Approved May 2011
NCE Onfi (clobazam); Lundbeck; For
the adjunctive treatment of seizures
associated with Lennox-Gastaut
syndrome, Approved October 2011
http://www.centerwatch.com/drug-information/fda-approvals/drug-areas.aspx?mp=empty
Faculdade
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01/02/2013

16. Nanopharmaceu:cals:
overall
view
of
par:culate
carriers
transla:on
Faculdade
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iMed.UL
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Rogério Gaspar
October 24th 2013
16

17. Issues
•
Rogério Gaspar
October 24th 2013
Materials Science
– Challenges arising from new materials (inorganic nanoparticles, nonbiodegradable/ non-biocompatible materials, quantum dots, cationic particles
and dendrimeric structures, carbon nanotubes)
•
Formulation / Technologies
– Adapting existing technologies to new opportunities (e.g. Quality by Design,
Process Analytical Technologies)
•
Translational Research
– Adequacy of non-clinical methodology before first in man use (relevance of,
appropriate toxicityfficcacy biomarkers and barriers related to disease phase and
different routes of administration)
•
Clinical development
– Comparability: non-inferiority versus superiority (risk-benefit management)
•
Market Access
– Comparative pharmacoeconomic assessment
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17

18. Key factors for design
Rogério Gaspar
October 24th 2013
(in respect of specific medical use)
• Materials Science and Formulation (Technology)
• Understanding underlying basic molecular mechanisms
• Integrating anatomo-physiological issues with pathology or disease
state and its progression
• Changes in biological interactions
• Impact in toxicity and efficacy
• Relevance of animal models (In vitro ??! In vivo !!?)
• Differences both in Pharmacokinetics and Pharmacodynamics
• Translational models adapted to specific questions with “nano” (PK/
PD versus specific organ toxicity and differential uptake of particles
– translocation)
• Important issues in clinical development: How to move faster and
safer? Comparability towards specific therapeutic indication?
Faculdade
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19. Rogério Gaspar
October 24th 2013
(a)
Amphiphlic
fullerene
monomer
able
to
self
assemble
(d)
disc
shaped
silicon
microparEcles
(b)
Amphiphilic
carbon
nanotubes
(e)
quantum
dots
(c)
PEGylated
gold
TNF
alpha
(f)
polyglcerol
dendrimers
(h)
Nanoworm
(g)
PRINT
parEcles
(i)
polystyrene
parEcles
containing
Fe3O4
and
with
quantum
dots
on
the
surface
Duncan,
R.
and
Gaspar,
R.
(2011),
Nanomedicine(s)
under
the
microscope,
Molecular
Pharmaceu:cs,
8
(6),
2101–2141,
DOI:
10.1021/mp200394t
Faculdade
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20. Rogério Gaspar
October 24th 2013
(a)
liposome
containing
two
drugs
(b)
polymer
conjugate
containing
two
drugs
(d)
liposome
containing
gold
nanoparEcles
(c)
liposome
containing
a
polymer-­‐drug
conjugate
(e)
disc
shaped
silicon
parEcles
as
mulEstaged
delivery
systems
Duncan,
R.
and
Gaspar,
R.
(2011),
Nanomedicine(s)
under
the
microscope,
Molecular
Pharmaceu:cs,
8
(6),
2101–2141,
DOI:
10.1021/mp200394t
Faculdade
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21. Methodology
Harmonisa:on
versus
Technology
Transfer
Marina
A.
Dobrovolskaia
and
ScoZ
E.
McNeil
–
Immunological
properEes
of
engineered
nanomaterials,
Nature
Nanotechnology,
2:
469-­‐478
(2007)
ScoZ
E.
McNeil
-­‐
NanoparEcle
therapeuEcs:
a
personal
perspecEve
WIREs
Nanomed
Nanobiotechnol
2009
1
264–271
Faculdade
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(Medicines
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Ins:tute)
Rogério Gaspar
October 24th 2013

22. Rogério Gaspar
October 24th 2013
Technology
(science-­‐based)
strategies
• Con:nuous
manufacturing
– Batch
vs
conEnuous
– Quality
by
Design
(QbD)
&
Process
AnalyEcal
Technologies
(PAT)
– Microfluidic
processes
for
purposely
engineered
manufacturing
of
nanosystems
• PRINT
technologies
– ModulaEon
of
shape
and
size
– AutomaEon
/
roboEzaEon
of
manufacturing
processes
– CustomizaEon
/
adequacy
of
manufacturing
to
specific
clinical
needs
• Integra:on
of
ICT
with
pharmaceu:cals
– Increased
complexity
in
order
to
find
adequate
medical
intervenEon
– IntegraEon
of
pharmaceuEcals
with
other
health
technologies
– NanotheranosEcs
Faculdade
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23. Rogério Gaspar
October 24th 2013
Faculdade
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iMed.UL
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24. Rogério Gaspar
October 24th 2013
Hook,
A.
L.,
Chang,
C.
Y.,
Yang,
J.,
Scurr,
D.
J.,
Langer,
R.,
Anderson,
D.
G.,
et
al.
Polymer
Microarrays
for
High
Throughput
Discovery
of
Biomaterials.
J.
Vis.
Exp.
(59),
e3636,
doi:
10.3791/3636
(2012).
Faculdade
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25. Rogério Gaspar
October 24th 2013
Belliveau
et
al,
Molecular
Therapy–Nucleic
Acids
(2012)
1,
e37;
doi:10.1038/mtna.2012.28
Leung
et
al,
Journal
of
Physical-­‐Chemistry,
J.
Phys.
Chem.
C
2012,
116,
18440−18450,
doi.org/10.1021/jp303267y
Faculdade
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26. Rogério Gaspar
October 24th 2013
Faculdade
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27. Intracellular
trafficking
modula:on
for
advanced
drug
delivery
Rogério Gaspar
October 24th 2013
Cellular
Uptake
and
Intracellular
Trafficking
of
AnEsense
and
siRNA
OligonucleoEdes
Rudolph
L.
Juliano,
Xin
Ming
and
Osamu
Nakagawa,
Bioconjugate
Chemistry,
2011,
dx.doi.org/10.1021/bc200377d
Endocytosis
and
Intracellular
Trafficking
as
Gateways
for
Nanomedicine
Delivery:
OpportuniEes
and
Challenges
Ruth
Duncan
and
Simon
C.
W.
Richardson,
Molecular
PharmaceuEcs
2012,
dx.doi.org/10.1021/mp300293n
Faculdade
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28. Rogério Gaspar
October 24th 2013
Challenges
from
metas:sa:on
and
recurrence
Klopp
AH,
Lacerda
L,
et
al.
(2010)
Mesenchymal
Stem
Cells
Promote
Mammosphere
FormaEon
and
Decrease
E-­‐Cadherin
in
Normal
and
Malignant
Breast
Cells.
PLoS
ONE
5(8):
e12180.
doi:10.1371/journal.pone.0012180
Murielle
Mimeault
and
Surinder
K.
Batra,
New
promising
drug
targets
in
cancer-­‐
and
metastasis-­‐iniEaEng
cells,
Drug
Discovery
Today,
15(9/1)
354-­‐364
(2010)
Faculdade
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29. Rogério Gaspar
October 24th 2013
Salva:,
A.
et
al.
Nature
Nanotech.
8,
137–143
(2013).
Gaspar
R,
Nanopar:cles:
Pushed
off
target
with
proteins.
Nat
Nanotechnol.
2013
Feb;8(2):79-­‐80.
doi:
10.1038/nnano.2013.11.
24/10/13
Faculdade
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Assembly
London
de
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da
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Research
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29

30. Rogério Gaspar
October 24th 2013
(a)
biological
phenomena
that
can
theore:cally
influence
nanomedicine
fate
solution properties
escape through pores,
fenestrations, between cells
across cells
rate
of
flow
pressure
mmHg
unstirred layer
diffusion
convecEon
biological barriers
cells, membranes, gels, metabolic degradation,
protein interaction
endothelial cells
penetraEon
through
extracellular
matrix
or
a
mucin
barrier
glycocalyx
cellular
uptake
and
membrane
interac:on
receptor
docking,
endocytosis,
exocytosis,
cytosolic
delivery
Duncan,
R.
and
Gaspar,
R.
(2011),
Nanomedicine(s)
under
the
microscope,
Molecular
Pharmaceu:cs,
8
(6),
2101–2141,
DOI:
10.1021/mp200394t
Faculdade
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31. General approaches to NanoDDS design
Rogério Gaspar
October 24th 2013
Petros
and
DeSimone,
Strategies
in
the
design
of
nanopar:cles
for
therapeu:c
applica:ons,
Nature
Reviews
in
Drug
Discovery
,
9(8):
615-­‐627
(2010)
Alnylam,
media-­‐kit
at
hDp://www.alnylam.com/News-­‐and-­‐Events/Media-­‐Kit.php
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32. Clinical
Trials
Heidi
Ledford,
“4
ways
to
fix
the
Clinical
trial”,
Nature,
477
(29
September
2011):
526-­‐528
Faculdade
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iMed.UL
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Rogério Gaspar
October 24th 2013

33. Rogério Gaspar
October 24th 2013
Quan:ta:ve
Systems
Pharmacology
Quan:ta:ve
and
Systems
Pharmacology
in
the
Post-­‐genomic
Era:
New
Approaches
to
Discovering
Drugs
and
Understanding
Therapeu:c
Mechanisms
-­‐
An
NIH
White
Paper
by
the
QSP
Workshop
Group
–
October,
2011
Faculdade
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34. Rogério Gaspar
October 24th 2013
Current and future regulatory challenges
• combination therapy
– The trend for reformulation of old APIs, with advantages of
combined administration on the same delivery system (issues on
quality/stability, PK/PD, clinical, IP, market access)
• potential theranostic approaches
– Combined system that is able to localize to the target
pathophysiology and deliver an appropriate therapeutic agent
(both diagnostic and therapeutic functions)
• “follow-on” products
– A number of unresolved problems will arise if preventive action is
not taken on matters related to old products, previously not
classified as nanoparticles that are in fact colloidal nanoparticulate
systems
Faculdade
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35. Rogério Gaspar
October 24th 2013
AAPS
J,
2013
(In
Press)
Faculdade
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36. Rogério Gaspar
October 24th 2013
Faculdade
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iMed.UL
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37. Rogério Gaspar
October 24th 2013
New
areas
for
pharmaceu:cal/health
R&D:
Advanced
Therapies
Adapted
from
Patrick
Celis
(EMEA),
April
3rd,
2009
Faculdade
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38. Rogério Gaspar
October 24th 2013
Nanomedicine
NOW
?
"Converging
today’s
Building
Blocks
to
Ethical
Medicine
-­‐
When
is
Nanomedicine
'NOW'?”
...
the
answer
is
basically...
• it
is
already
here
(for
the
last
30
years)
and
• it
will
improve
clinical
management
performance
– integra:ng
now
diagnos:cs
and
therapeu:cs
under
the
same
technology
plaxorms,
– allowing
a
beZer
performance
by
the
healthcare
system
• ...personalised
(subpopulaEon-­‐driven)
medicine
as
one
of
the
examples...
Faculdade
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39. Pharmaceutical Sciences beyond 2020 –
The rise of a new era in healthcare
Faculdade
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40.
Intracellular
Trafficking
Modula:on
for
Advanced
Drug
Delivery
Bioorganic
Chemistry|Pedro
Góis
Chemical
Biology
and
Toxicology|
Maria
H.
Ribeiro
HIV
Evolu:on,
Epidemiology
and
Preven:on|
Nuno
Taveira
Host-­‐Pathogen
Interac:ons
|
Elsa
Anes
Innova:ve
Plaxorms
for
Non-­‐parenteral
Delivery
Systems
|
Helena
Cabral
Marques
Intracellular
Trafficking
Modula:on
for
Advanced
Drug
Delivery|
Rogério
Gaspar
Medicinal
Chemistry
|
Rui
Moreira
Metabolism
and
Gene:cs
|
Isabel
Tavares
de
Almeida
Molecular
and
Cell
Biology
of
Eukaryo:c
Systems
|Cecília
Rodrigues
Molecular
Microbiology
and
Biotechnology
(M2B)
|
João
Gonçalves
Natural
Products
Chemistry
|
Maria
José
Umbelino
Ferreira
Nanostructured
Systems
for
Overcoming
Biological
Barriers
and
Immune
Response
Modula:on
|
António
José
Almeida
Neuron
Glia
Biology
in
Health
and
Disease
|
Dora
Brites
Pharmacoepidemiology
and
Social
Pharmacy
|
Afonso
Cavaco
Pharmacological
Sciences
|
Beatriz
Silva
Lima
Rogério Gaspar
October 24th 2013
Rogério
Gaspar
(Group
Leader)
Bárbara
Mar:ns
Luisa
Corvo
Mafalda
Videira
Helena
Florindo
Liana
C.
Silva
(Ciência/FCT)
Ana
M.
Saraiva
(BPD/FCT)
Joana
Silva,
PhD
student
(BD/FCT)
Ana
Raquel
Varela,
PhD
Student
(BD/FCT)
Diana
Rafael,
PhD
student
(BD/FCT)
Eva
Zupancic,
PhD
student
(BD/FCT)
Ana
Cláudia
Carreira,
PhD
student
(BD/FCT)
Carina
Peres,
PhD
student
(BD/FCT)
João
Conniot,
PhD
student
(BD/FCT)
Nuno
Mar:nho,
PhD
student
(BD/FCT)
Vanessa
Gameiro
Sainz,
PhD
student
(BD/FCT)
Andreia
Giro
dos
Santos,
PhD
student,
Research
Fellow
Faculdade
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