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Parenteral Drug Nanodispersions :
Manufacturing, Characterization and In
Vitro/In Vivo Performance Evaluation
Panayiotis P. Constantinides, Ph.D
Biopharmaceutical & Drug Delivery Consulting, LLC
Gurnee, Illinois, USA
Parenterals- 2015, August 17-19, 2015, Chicago, IL
OUTLINE PART I : Overview of Parenteral Drug Nanodispersions
• Particle Size Considerations
• Drug Products on the Market (Doxil® and Abraxane®)
• Engineering and Manufacturing : Impact on Drug Loading
and Release
• Characterization & QbD Aspects
PART II : Case Studies
1. Nanoemulsions : Tocosol™-Paclitaxel
2. Liposomes, Polymeric Micelles : Phospho-Ibuprofen
(NME) ; Solid Lipid Nanoparticles : Phospho-Sulindac (NME)
Conclusions and Future Perspectives
8/18/2015 4 BPDDC LLC www.bpddc.com
PART I
Overview of Parenteral Nanodispersions
Particle Size Considerations
Marketed Drug Products
Engineering, Processing, Characterization
and QbD Aspects
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Nanodimensions of Drug Delivery Nanoparticles Mattheolabakis, G., Rigas B., and Constantinides, P.P. Nanomedicine (2012) 7: 1577-1590
The true nanorange is
narrowly defined as the
1-100 nm particles.
Marketed injectable liposomal
and albumin-bound
nanoparticulate anticancer
drug products, as well as oral
NanoCrystal® drug products
are within the submicron range
(100 – 1000 nm).
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Marketed Parenteral Nanoparticulate Drug Products
• Liposomes
– Abelcet® and Ambisome® (Amphotericin B); DaunoXome®,
(daunorubicin); DOXIL® (doxorubicin), Depocyt® (cytarabine)
• Albumin-Bound Nanoparticles
– Abraxane® (paclitaxel nanosuspension)
• The particle size of these “nanoparticulate” drug products, is in the
range of approx. 100 - 1000 nm and thus above the defined
nanorange (1-100 nm) …..
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((HSPC, CHOL
Nanoparticle Properties and Inter-relationships
Nanoparticles
Morphology Solubility Alterability Bioactivity
Surface Chemistry Charge Biocompatibility
Shape Size Hydrophobicity
Film Forming
Ability Deformability
Toxicity
Dispersed
State Stability
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Nanoparticle Manufacturing Methods
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To
p-D
ow
n
Bo
tto
m-U
p
Energy
Precipitation
Solvent Evaporation
Emulsion-Diffusion
NANOPARTICLES
BULK
SOLUTION
Homogenization Milling
Cryogenic Approaches
• Super-Critical Fluid Technologies
• Spray Freezing into Liquid
• Ultra-rapid Freezing
Growth
Nanoparticle Engineering and Manufacturing and
Impact on Drug Loading and Release
10
Drug
CarrierPreparation
Drug loading
Release
(Release medium)
Solvent, pH, Temperature
Sequence of adding excipients
Loading during or after nanoparticle formation
Type of nanoparticle
Type of polymer/copolymer (MW, functional groups on polymers, charge)
Ratio liquid/solid lipid (SLN)
Nominal drug loading
Type (base vs salt)
Lipophilicity
Functional groups
8/18/2015 BPDDC LLC www.bpddc.com
Lipid Polymorphism with Glycerides : Implications for SLN Mehnert, W. and Mӓder, K. (2001) Adv. Drug Del. Rev. 47 : 165-196; Uner, M. (2006) Pharmazie 61 : 380
supercooled melt
α-modification (less ordered hexagonal form)
β‘-modification (orthorhombic perpendicular form)
β-modification (highly ordered triclinic parallel form)
Low
Thermodynamic
Stability
High
High
Drug Loading
Low
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Methods Used to Monitor Stability of
Nanoparticulate Drugs
Method Measured Parameter(s)
PCS/DLS
Particle size and size distribution
SEM/TEM/AFM
Morphology
Laser Doppler
Electrophoresis
Surface charge/zeta potential
XRD/DSC
Crystallinity
HPLC/FTIR/NMR/MS
Chemical Stability
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In Vitro/Vivo
Performance
Design
Manufacturing
Characterization Nanoparticle
QbD
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QbD is increasingly applied to different types of nanoparticles
PART II
Case Study 1
Nanoemulsions : TOCOSOL-Paclitaxel
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Nanoemulsions : Characteristics
transparent or translucent o/w or w/o droplets with a mean diameter up to 300 nm.
kinetically stable unlike microemulsions which are thermodynamically stable.
• exhibit great stability in suspension due to their small droplet size
Ostwald ripening is the primary instability process
• Can be reduced by the addition of a second less soluble oil phase and/or addition of a strongly adsorbed and water insoluble polymeric surfactant
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Nanoemulsions: Emulsification Processes
High-Energy
1. High pressure homogenization
2. Ultrasound energy
Low-Energy
1. Spontaneous
2. Solvent-diffusion
3. Phase inversion temperature (PIT)
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McClements, D.J. (2011) Soft Matter 7 : 2297-2315
Oil-in-Water Microemulsions vs Nanoemulsions
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•
• Can affect the structure and droplet size of ME
• No immediate effect on NE
• Decrease in droplet size for ME
• No effect on NE size
• Same process for ME and spontaneous self- formation of emulsions
• Very Similar
Formulation Process
Temperature
Variations
Dilution with Water
Structural and
Visual Aspects
TOCOSOL Nanoemulsion Manufacturing
Unprocessed Rotor Stator mixed
Tocophilic*
Drug
Mix until all
tocophilic drug
is dissolved
Vitamin E
TPGS/Poloxamer 407
Mix oil phase with
aqueous phase
HP Homogenization
ΔT, ΔP
Sterile Filtration
and Filling
*Lipophilic drug that
is soluble in a tocol
(Vit E)
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Nanoemulsion Stability : TOCOSOL-Paclitaxel Constantinides, P.P. et. al., Pharm. Res. 17, 175-182, 2000
0 5 10 15 20 25 30
40
60
80
100
120
140
160
[D]mean
4°C
[D]mean
25°C
[D]99%
4°C
[D]99%
25°C
Me
an
Dro
ple
t D
iam
ete
r o
r
99
% C
um
ula
tiv
e D
istr
ibu
tio
n (
nm
)
Time (months)
10 100 10000
20
40
60
80
100
62 nm
Volume Distribution:
Particle Size (nm)
Re
lativ
e V
olu
me
Oil
(Vitamin E)
Tocophilic
Drug
(Paclitaxel)
Surfactants
(TPGS, P407)
Paclitaxel potency and levels of degradants were
within specifications throughout the stability study
TOCOSOL
Paclitaxel Loading : 9 mg/ml
8/18/2015 BPDDC LLC www.bpddc.com 19
O
O OH
OHO
O
ONH
O
RAcO
O
3' 1'
OAcOH
6
13
1
10
154
R= C6H5, MW = 853
Solubility < 50 µg/ml It can be filter-sterilized !
Paclitaxel in Blood and Tumor Tissue P.P. Constantinides, A. Tustian and D.R. Kessler, Adv. Drug Del. Rev. 56 (2004) 1243-1255
0
2000
4000
6000
8000
10000
0 10 20 30 40
Time (hr)
Blood
TOCOSOLPaclitaxel
Taxol®
Concentr
ation (
ng/m
L)
0
2000
4000
6000
8000
0 10 20 30 40
Time (hr)
Tumor
TOCOSOLPaclitaxel
Taxol®
Concentr
ation (
ng/g
)
AUCTocosol-P = 2.2 AUC Taxol
Single dose administration of 10 mg/kg to B16 MM-bearing mice
Enhanced TOCOSOL nanoemulsion uptake by tumors due to EPR effect
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PART II
Case Study 2
Liposomes/Polymeric Micelles - Phospho-
Ibuprofen (PI)
Solid Lipid Nanoparticles - Phospho-
Sulindac (PS)
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Phospho-Ibuprofen and Phospho-Sulindac (NMEs)
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S
H2C
O O P
O
OCH2CH
3
OCH2CH
3
O
CH3
F
H3C
Phospho-Ibuprofen (PI)
Phospho-Sulindac (PS)
Diacetyl Phosphate
Butane (spacer)
ester bond
Basil Rigas, WO2009/023631, Anti-inflammatory Compounds and Uses Thereof
Development by Medicon Pharmaceuticals, Setauket, NY
Preparation of Phospho-Ibuprofen Liposomes
Soy PC, DSPE-PEG, Phospho-Ibuprofen
Drug - Lipid Mixture Compounding Chloroform
Thin Lipid Film Formation
Hydration
(MLV)
Extrusion Down Sizing
Free Drug Removal
Solvent Removal
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PBS
Polycarbonate membranes 0.4 and 0.2 µm pore size
Dialysis
P-I Liposomes
Refrigerated under argon and
tested within 1 month after
preparation
Vortexing + Brief Sonication
P-I
Nie, T. et al; (2012) Br. J. Pharmacol.166:991-1001
Preparation of Phospho-Ibuprofen Polymeric Micelles
Phospho-Ibuprofen and PEO-b-PLA in acetone
Drug - Polymer Mixture Compounding PBS
Dialysis Free Drug and Traces of Acetone Removal
Acetone Removal
8/18/2015 BPDDC LLC www.bpddc.com 24
P-I Polymeric Micelles
Refrigerated under argon and tested within
1 month after preparation
P-I
Nie, T. et al; (2012) Br. J. Pharmacol. 166:991-1001
MICELLES LIPOSOMES
P-I
200 nm 50 nm Property Ibuprofen Phospho-
Ibuprofen (P-I)
Partition coefficient (log P) 3.75 5.43
IC50, µM, range
(HT29,HCT116, SW480 colon
cancer cell lines) 748-1,554 28-104
Cell uptake, nmol/mg
protein 0.1 18
Ibuprofen vs Phospho-Ibuprofen (MDC-917) : Physical
Properties and Cytotoxicity Nie, T. et al; (2012) Br. J. Pharmacol. 166:991-1001
8/18/2015 25 BPDDC LLC www.bpddc.com
MDC : Medicon Pharmaceuticals
Soy PC + DSPE-PEG PEO-b-PLA di-
block copolymer Size : 209 ± 16 nm
Z-potential : -15.5 ± 2.6 mV
Size : 78 ± 8 nm
Z-potential : -6.2 ± 0.6 mV
0
50
100
150
200
SW480 HCT116 HT-29
IC50,
µM
2
4-
hr
B
A. Empty Nanocarriers B. Nanocarrier-drug vs Free Drug
In Vitro Cytotoxicity of P-I (MDC-917) Against Colon
Cancer Cell Lines Nie, T. et al; (2012) Br. J. Pharmacol. 166:991-1001
8/18/2015 26 BPDDC LLC www.bpddc.com
Mean ± SD (n=3) Free P-I
Lip P-I
Mic
P-I
0
200
400
600
0 5 10 15 20 25
Tu
mo
r V
olu
me,
mm
3
Treatment, days
Control
P-I
Liposomal P-I
# #
#
#Dose : 100 mg/kg/day i.p.
0.0
0.2
0.4
0.6
0.8
Vehicle control P-I Liposomal P-I
Tu
mo
r w
eig
ht,
g
#
#
Antitumor Activity of Liposomal P-I (MDC-917) in
Human Colon Cancer (SW 840)-Bearing Mice Nie, T. et al; (2012) Br. J. Pharmacol. 166:991-1001
8/18/2015 27 BPDDC LLC www.bpddc.com
(Mean ± SEM, n=20)
Preparation of the SLN-PS by Emulsion/Evaporation Zhu et al; Pharm Res (2012) 29 : 3090 - 3101
*Myrj 59 dissolved in water heated to 75 °C under
constant stirring at 700 rpm
Stearic acid + lecithin + PS dissolved in chloroform
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o/w emulsion ice-cold water
Centrifugation at 7,200 g for 1 h, the supernatant was removed and the pellet was
washed twice with deionized water followed by centrifugation. The final pellet was
re-suspended in deionized water, frozen at – 20 °C overnight and freeze-dried.
PS : Phospho-Sulindac
The organic phase was gently injected
into the aqueous phase with a syringe
Stirring for 2.5 h at 1,000 rpm
Stirring continued for another 2 h at 1,000 rpm
*PEG-100 Stearate
SLN-PS In Vitro Characterization Zhu et al; Pharm Res (2012) 29 : 3090 - 3101
8/18/2015 BPDDC LLC www.bpddc.com 29
SLN mean D : 55 nm
A549 : NSCLC cells (wild type) ; H510 : SCLC cells (mutant)
TEM
(cell culture medium)
A549 Xenografts Inhibitory Effect and In Vivo Immunostating Zhu et al; Pharm Res (2012) 29 : 3090 - 3101
8/18/2015 BPDDC LLC www.bpddc.com 30
A549 : NSCLC cells ; urinary F2-isoprostane : oxidative stress marker
tissue sections of A549 xenograft Quantification of cell apoptosis
Tumor Growth
Inhibition
Induction of oxidative stress
Tumor Targeting Mitochondria
Targeting
Conclusions and Future Perspectives
• Parenteral nanodispersions such as liposomes, nanoemulsions, polymeric micelles, and solid lipid nanoparticles: – Constitute enabled formulations of approved drugs or NMEs
with liposomal and nanosuspension drug products on the market (Doxil® and Abraxane®)
• Recent advances with these drug nanocarriers include:
– Improvements in manufacturing and characterization methods, drug product quality and performance.
– At least same efficacy and better tolerance than the earlier systems.
– Enhanced drug loading/release and targeting
• Drivers for future growth and commercialization include :
– funding, patent landscape
– better understanding of stability issues, particularly with
parenteral nanosuspensions and solid lipid nanoparticles
– ongoing need for novel safe drugs and therapies
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Acknowledgements
Liposomes/Polymeric Micelles
Phospho-Ibuprofen (P-I)
Solid Lipid Nanoparticles
Phospho-Sulindac (P-S)
Dr. Basil Rigas and laboratory staff, Stony Brook
University, Medical School, Division of Cancer
Prevention and Medicon Pharmaceuticals,
Setauket, NY
8/18/2015 BPDDC LLC www.bpddc.com 32
Thank You !
8/18/2015 BPDDC LLC www.bpddc.com 33
IVIV Performance
Drug Product Quality
Formulation and Process
Parenteral Drug Nanodispersions
Let us meet again..
We welcome you all to our future conferences of OMICS International
2nd International Conference and Expo on
Parenterals and Injectables
On
October 24-26, 2016 at Istanbul, Turkey http://parenterals-
injectables.pharmaceuticalconferences.com/
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