Insoluble APIs Scaring You? Don’t Be Afraid of Nanotechnology! · Webinar Agenda • Background and nanoparticle drug delivery • Properties of nanosystems • API nanoparticulates

©2018 The Lubrizol Corporation, all rights reserved.

Insoluble APIs Scaring You?

Don’t Be Afraid of Nanotechnology!


On Halloween, Are You Scared Of…


Maybe You Should Be Scared Of….


But For Insoluble APIs, Don’t Be Scared Of…


NanoPharma

The Unseen (Nano-systems)


h Pressure Homogenization

Stealthy

h Pressure Homogenization

Enhanced Permeation and Retention Effect

Colloid Science

NanotoxicityElectrostatic

Ultrasonication

Top-down

The Unknown (Nano-terminology)

h Pressure HomogenizationHigh Pressure

Homogenization

Steric Repulsion

Ostwald Ripening

DVLO theory


“Nanobots will live in our brains in the 2030s”

- Ray Kurzweil, Google

NanoFact or NanoFiction?


Webinar Agenda

• Background and nanoparticle drug delivery

• Properties of nanosystems

• API nanoparticulates

• Equipment used

• Excipients

• Sterilization

• Case studies

• Nanocapsules

• Nanomilling feasibility program – NEW!


API nanoparticle API-loaded nanocapsules• Liposomes• Lipid & polymer nanoparticles• Targeted nanoparticles

Particles ~ 100 – 200 nm

Nanoparticle Drug Delivery


Intrathecal

Ocular

Nasal

Sublingual

Buccal

Oral ingestion

IV

Pulmonary

Topical

Vaginal

Rectal

IM

SubcutaneousImplant

* Fro m Da ta Mo nito r

Routes of Administration

Oral

Injectable

Ophthalmic

Inhalation

Topical

Other


40 – 90%

of NCEs

• Low bioavailability• Fed-fast dependence

Poorly Soluble APIs

Biopharmaceutical Classification System (BCS)


• Amorphous solids

• Solid solutions

• Liquid solutions

• Cyclodextrin complexes

• Co-crystals

• NANOTECHNOLOGY

Delivering Poorly Soluble APIs


• Conceptually simple, practically straightforward

• Liquid form or lyophilized

• Increased bioavailability

• High surface area / high dissolution rate

• Increased solubility

• Reduced fast-fed effect

• Sterile processing feasible

• Enables IV injection of water-insoluble APIs

Advantages of Nanoparticles


0

0.5

1

1.5

2

2.5

3

1 10 100 1000

Rela

tive

So

lub

ility

Particle Radius (nm)

1

10

100

1000

10000

1 10 100 1000 10000

Rela

tive D

issolu

tion R

ate


Smaller particles dissolve faster

due to higher total surface areaSmaller particles have higher solubility

Enhanced Solubility


Enhanced Permeation and Retention Effect


BRAND API DOSAGE FORM INDICATION INNOVATOR

Rapamune® Rapamycin, SirolimusOral Solution

Oral TabletImmunosuppressant Wyeth

Emend® AprepitantOral Suspension

Oral CapsuleAnti-emetic Merck & Co.

Tricor® Fenofibrate Oral Tablet Hypercholesterolemia Abbott Laboratories

Megace ES® Megestrol Oral Suspension Anti-anorexic Par Pharmaceuticals

Triglide® Fenofibrate Oral Tablet Hypercholesterolemia Sciele Pharma Inc.

Avinza®* Morphine Sulphate Oral Capsule Pain King Pharmaceuticals

Focalin XR® Dexmethylphenidate HCl Oral CapsuleAttention Deficit Hyperactivity

DisorderNovartis

Ritalin LA® Methylphenidate HCl Oral Capsule CNS Stimulant Novartis

Zanaflex® Tizanidine HCl Oral Capsule Muscle Relaxant Acorda

Invega Sustenna® Paliperidone Palmitate Intramuscular InjectionSchizophrenia,

Schizoaffective DisorderJanssen Pharma

Ryanodex® Dantrolene Sodium Intravenous Infusion Malignant Hypothermia Eagle Pharmaceuticals

Aristada® Aripiprazole Lauroxil Intramuscular Injection Schizophrenia Alkermes

Commercialized Nanoparticulate Systems

Properties of Nanosystems


Forces Between Particles


Faraday’s gold NPs still suspended after >150 years in the Royal Institution!0.000001

0.00001

0.0001

0.001

0.01

0.1

1

1 10 100 1000

Rela

tive S

edim

enta

tion r

ate


Smaller particles are better suspendeddue to Brownian motion countering gravity

Sedimentation

Stokes Equation


The growth of larger particles at the expense of smaller ones in a polydisperse dispersion

Ostwald Ripening

API Nanoparticles(Suspensions & Powders)


Free surfactant and / or

polymeric stabilizer

Crystalline

drug substance

nanoparticles

Surface bound surfactant and / or polymer stabilizer

API Nanoparticulate Suspensions (NPSs)


1

10

100

1000

10000

1 10 100 1000 10000

Rela

tive S

urf

ace A

rea


Smaller Particles = Larger Surface Area


Ceramic milling media

Stationary No milling

Optimum speedOptimum milling

Critical speedNo milling

(centrifuging)

Manufacturing: Roll Milling


Manufacturing: High Energy Media Milling

• Wide selection of milling media

• Ceramic, glass, polymeric

• Sterile possible

• Clean in place equipment

• Scalable

• Commercial GMP production


• Scalable

• No media required

• Sterile possible

• Clean in place

Manufacturing: Microfluidization


• Versatile

• Scalable

• Ease of use

• No media

• Metal contamination

• Heat generation

Manufacturing: Ultrasonification


Particle size

Dynamic light scattering

Surface Area Surface charge Sedimentation

Laser Diffraction

Physical Characterization Tools


• Water (purified, possibly sterile)

• Surfactants

• Polymer stabilizers

• Buffers

• Tonicity modifiers

• Cryoprotectants (if lyophilization is envisioned)

• GRAS (generally recognized as safe)

• Ideally used previously in desired ROA

NPS Excipients


• Required for parenteral and ocular formulations

• Terminal Sterilization

• Gamma radiation

• Heat sterilization

• 0.2 micron filtration (requires D90 < ~90 nm)

• Pre-sterilization & aseptic processing (more common)

• Sterilized API & excipients / sterilized equipment

• Heat sterilized API suspension / sterilized equipment

NPS Sterilization

Case Studies


Time / mins

Media

n p

art

icle

siz

e(m

icro

ns) Milling sp e e d , u

Case Study #1

Effect of Milling Speed and Duration:

Griseofulvin

Li et al Pharmaceutics 20;8(2) 17 (2016)


Time / hrs

Pla

sm

a c

on

ce

ntr

atio

n

( n

g / m

L)

5.5 mic ro n

1.8 mic ro n

0.48 mic ro n

0.12 mic ro n (120 nm)

(na no mille d )

Case Study #2

Enhanced Bioavailability:

Aprepitant

Wu et al, Int. J. Pharm, 285, 135 (2004)


Original Suspension Nanocrystal DispersionFe d

Fa ste d

800 mg dose in 20 mL 625 mg dose in 5 mL

Deschamps,B. et al., Intl. J. Nanomed. 4 185 (2009)

Fe d

Fa ste d

Case Study #3

Reduced Fed-Fast Dependence:

Megestrol Acetate

Nanocapsules


Nanocapsule Types

• Liposomes

• Nanoemulsions

• Solid Lipid Nanoparticles

• Nanostructured Lipid Carriers

• Polymer Nanoparticles


• Protects API from environment

• Controls release of API in vivo

• Can be targeted to specific cells and tissue

Advantages of Nanocapsules


• Doxil (Doxorubicin) liposome

• IV chemotherapeutic

Liposomes


Preparation of Solid Lipid Nanoparticles


Nanoparticle Stabilizer Reference

Nanopart

icle

Surf

ace C

harg

e (

zeta

pote

ntial) (

mV

)

Ca tionic AnionicNon- ionic

Interaction of Nanoparticles with Proteins


41

Antibody-coated Lipid Nanoparticles:

Surface Arrayed Therapeutics (SATx™)


42

Fluorescent-labeled

SATx™ Coated with Control IgG1

Fluorescent-labeled

SATx™ Coated with Specific IgG1

Tumor Cells

SATx™ concentrated

In tumor cells

No SATx™

In tumor cells

Specific Cell Targeting


• Made with the same equipment as lipid nanoparticles

• Use API-loaded polymer solution instead of API-loaded lipids

• Biodegradable polymers: PLA, PGA, PLGA, PCL

• API release by biological degradation of particles

• Must be dried to prevent aqueous hydrolysis during storage

Polymer Nanoparticles

PLGA chemical structure


• Nanotechnology is conceptually straightforward

• However, equipment and knowhow IS required for successful development

• Nanotherapeutics successfully commercialized

• Nanotechnology can enable commercialization of insoluble APIs

Summary – Don’t be Afraid!


New! Nanomilling Feasibility Program

SCREENINGDevelop a target product profile and screen your API

for nanomilling with GRAS-approved excipients

CHARACTERIZATIONGenerate particle size distribution and short-term

stability data for each formulation

SCALE-UP & SAMPLINGIdentify promising formulation(s) and provide material for animal PK studies

Particle Sciences is a leader in nanomilling with decades of experience developing nanosuspensions. Visit www.particlesciences.com for more details.

8 Weeks

©2018 The Lubrizol Corporation, all rights reserved. 46

Concept to Commercialization.

We Deliver®

Questions…

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Insoluble APIs Scaring You? Don’t Be Afraid of Nanotechnology! · Webinar Agenda • Background and nanoparticle drug delivery • Properties of nanosystems • API nanoparticulates