3rd annual partnership opportunities in drug delivery ...oct 15, 2013 · 3rd annual partnership...
TRANSCRIPT
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%
20%
30%
40%
50%
60%
70%
80%
90%
100%
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
0
10
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30
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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
50
100
150
200
250
In Vitro Release of IFN from PolyActiveMicrospheres
Time (days)
µg IF
N re
leas
ed
In Vitro Release of Undisclosed IgG from PolyActive1000PEG80PBT20 Microspheres
0 25 50 75 100 125 150 1750
10
20
30
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50
60
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100
Time (days)
Cum
ulat
ive
IgG
Rel
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)
0
20
40
60
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0 1 2 3 4 5
Months
% B
ioac
tivity
• Key Development Parameter for CR Products: Long-term API Stability
Vitreous levels Lucentis 0.5 mg
0
10000
20000
30000
40000
50000
60000
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
150
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)
0
1000
2000
3000
4000
5000
6000
7000
8000
0 100 200 300 400Time (days)
Ocu
lar l
evel
(ng/
ml)
Cumulative Theoretical Release of Lucentis
0
20
40
60
80
100
0 100 200 300 400
Time (days)
Cum
ulat
ive
Rele
ase
(%)
• 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