Microspheres for Controlled Release 3rd Annual Partnership Opportunities in Drug Delivery October 10-11, 2013 Roland Cheung, Associate Scientist

Reducing Injection Frequency

• A solution for all products

• Liposomes: A complex process

Freeze-drying

Storage/Stability

Making

Sizing

Concentration/Purification

Filling

Analysis Labelling & packaging

Filter sterilization

• Microsphere Capabilities at OctoPlus

• Scaling Up Microsphere Products – 1g, 10g, 100g, 1kg and more – Implementation into GMP

PLGA Applications

• Experience in PLGA formulation – Extensive experience with PolyActive microspheres is a strong starting point

for PLGA microspheres

– Many PLGA products are in development for both new and generic market

– Produced several formulations for Toxicity/Animal trial studies

– Working on several PLGA formulations for Ocular diseases

– Several types of processes at scales from grams to kilogram

up to 40% drug load

• Development Routes of PLGA Based Controlled Release Formulations

API soluble in

organic solvents

water miscible: ethyl acetate

non-water miscible: dichloromethane

coacervation extraction & evaporation

API soluble in water

w/o/w: liquid encapsulation

spray drying

s/o/w: solid encapsulation

spray drying coacervation

spray drying (s/o)

coacervation

or

or

water miscible: ethyl acetate

water miscible: ethyl acetate

back-up route preferred route alternative route

• Example of Three-month Peptide Release from PLGA Microspheres

Sustained Release of a Novel Peptide from PLGA Microspheres

0%

10%

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110%

0 20 40 60 80 100

Time (days)

Cum

ulat

ive

Rele

ase

Formulation Round 1

Formulation Round 2 (Optimised)

• Sandostatin LAR generic OctoPlus Octreotide Formulation vs Innovator Sandostatin LAR

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0 5 10 15 20 25 30 35 40Time (days)

Oct

reot

ide

rele

ased

(%)

Sandostatin LAR Depot

OctoPlus Formulation vial 1

OctoPlus Formulation vial2

Ocular Applications Controlled Release Microspheres for Ophthalmic Use

Reducing Injection Frequency in the Eye

• Retinal Diseases – Clinical studies have shown that visual acuity is best

regained under constant anti-VEGF exposure – Current therapies require monthly or bi-monthly injections

www.myretina.com

• OctoPlus’  Microsphere  Experience  in  the  Ocular  Field

– In vivo proof of concept studies and tolerability studies* • Intravitreal injection of controlled release microspheres • Studies performed in rabbits and monkeys • Needle size 27-30G • Injection volume 50 µl

– General study setups used • Single eye & both eyes dosed • Placebo (microspheres) vs. active microspheres • Repeated dosing with active microspheres

* Outsourced or performed at client site

• Injectability

+ 15

• Injectability model: Capped HPLC vial – Provides some backpressure (resembles in vivo situation) – Clear view on quality of injected suspension

• Rule of thumb for injectability:

– Largest particles must be < 1/3 of the inner diameter of the needle

• E.g. If inner diameter is 267 µm (27G) D(0.9) must be < 90 µm

OctoPlus can optimize the PSD for injectability

D(0.5) 30G (ID 178 µm)

27G (ID 267 µm)

25G (ID 318 µm)

60 µm 1% 5% 15%

40 µm 5% 15% 20%

20 µm 15% 15% 20%

Injectable suspension densities at 50 µl injection volume

1% = 10 mg/ml microspheres

• In vitro experience

• History: Proteins and Peptides in PLGA microspheres – Burst release – Irregular release, biphasic – Incomplete release – API degradation during encapsulation procedure – API degradation by acidification

peptide in PLGA in vivo profile

hGH in PLGA in vitro release

0 7 14 21 280

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In Vitro Release of IFN from PolyActiveMicrospheres

Time (days)

µg IF

N re

leas

ed

In Vitro Release of Undisclosed IgG from PolyActive1000PEG80PBT20 Microspheres

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ive

IgG

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ease

(%)

• PolyActive Microspheres for Proteins – No burst release – Near-linear release – Complete release – No API degradation during encapsulation procedure – No API degradation by acidification

• PolyActive Protein Protection

hydrophilic hydrophobic

O-(CH 2 ) 4 -O C C O O

C C O O

(O-CH 2 -CH 2 ) n -O x y

PEG T PBT

• In vitro controlled release of an 80 kDa protein over one year

Mass balance after 12 months Mass balance

0102030405060708090

100

F374-02-001P140A

F374-02-001P140B

F374-02-001P140E

F374-02-001P140F

% o

f ini

tial c

onte

nt

% residual

% release

• Stability of API at physiological conditions (in vitro and in vivo) – Stability at physiological conditions is key to success

– In vitro release studies are performed at pH 7.4 and 37ºC – Stability of API required for duration of release (e.g. 1 wk up to 6 m) – Instability at these conditions may lead to:

• Aggregation no or slow release from the matrix • Fragmentation release rate affected by size of (in-)active fragments

fragments

stable API

aggregates

time

rele

ase

Stability enhancers can be added to the formulation or to the in vitro release medium to mimic or to enhance the in vivo situation

Activity of a Test Protein Released from PolyActive Microspheres Over a Period of 4 Months (n=4)

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% B

ioac

tivity

• Key Development Parameter for CR Products: Long-term API Stability

Vitreous levels Lucentis 0.5 mg

0

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0 10 20 30 40Time (days)

Conc

entra

tion

(ng/

ml)

• Calculation of effective intravitreal level Lucentis – Human PK data: Intraocular

Pharmacokinetics of Ranibizumab Following a Single Intravitreal Injection in Humans. Krohne et al., American Journal of Ophthalmology, Vol.154, Issue 4, October 2012, Pages 682–686

– One compartment PK model – t1/2 = 7.19 days – App. Vd = 8.91 mL

– At  day  30,  vitreal  conc.=  3  μg/ml

after a single ivt dose of 0.5 mg

0 7 14 21 280

50

100

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200

250

In Vitro Release of IFN from PolyActiveMicrospheres

Time (days)

µg IF

N re

leas

ed

dtc

abarelease*)(101

)(

Value Std errora -6.244 3.742b 235.9 7.044c 2.96 0.04896d 0.5432 0.03708R² 0.9919

c2 = inflexion point d = slope

• Modeling the In Vitro Release Profile

Calculated vitreous level Lucentis(1 mg per 6 months)

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Ocu

lar l

evel

(ng/

ml)

Cumulative Theoretical Release of Lucentis

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ive

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ase

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• 1 mg Lucentis Controlled Release is sufficient for 6 months – Monthly dose of unformulated Lucentis = 0.5 mg – Controlled release for 6 months: 1 mg Lucentis needed

• In vivo experience

Cynomolgous toxicity study with PolyActive Ocular toxicity after single injection of placebo PolyActive microspheres (3 months follow-up, intended release duration 6 months)

• Microspheres visible in anterior chamber throughout the study • No adverse events in clinical and histology ocular findings

– No adverse event level @ 3.5 mg microspheres – Minimal to mild amounts of white blood cells in anterior chamber throughout the study (foreign

body reaction), not considered adverse – Minimal intravitreal infiltration of histiocytes in all injected eyes, in one eye focal granulomatous

inflammation at the site of injection, not considered adverse – No rise in IOP