About OMICS Group...Parenteral Drug Nanodispersions : Manufacturing, Characterization and In...

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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


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).

8/18/2015 BPDDC LLC www.bpddc.com 6

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) …..


((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


Nanoparticle Manufacturing Methods


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


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


In Vitro/Vivo

Performance

Design

Manufacturing

Characterization Nanoparticle

QbD


QbD is increasingly applied to different types of nanoparticles

PART II

Case Study 1

Nanoemulsions : TOCOSOL-Paclitaxel


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


Nanoemulsions: Emulsification Processes

High-Energy

1. High pressure homogenization

2. Ultrasound energy

Low-Energy

1. Spontaneous

2. Solvent-diffusion

3. Phase inversion temperature (PIT)


McClements, D.J. (2011) Soft Matter 7 : 2297-2315

Oil-in-Water Microemulsions vs Nanoemulsions


•

• 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)


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


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


PART II

Case Study 2

Liposomes/Polymeric Micelles - Phospho-

Ibuprofen (PI)

Solid Lipid Nanoparticles - Phospho-

Sulindac (PS)


Phospho-Ibuprofen and Phospho-Sulindac (NMEs)


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


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


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


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


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


(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


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


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


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


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


Thank You !


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/

http://parenterals-injectables.pharmaceuticalconferences.com/



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