Access the recording: https://bit.ly/2xAaMba Abstract: Long acting injectables (LAI) have been around for decades for the delivery of small molecules and peptides to treat chronic and site-specific diseases. However, when it comes to more sensitive biological therapeutics the classical polylactide and polylactide/glycolide based systems suffer from several limitations (e.g. uncontrolled release kinetics, in situ pH drop, protein degradation) making them unsuitable. The SynBiosys® biodegradable polymeric microparticle technology combines all the features required for LAI formulations for biologics. In two case studies we will showcase sustained release formulations for peptides and proteins and demonstrate their potential via extensive in vitro and in vivo characterization.

1. The life science business of Merck KGaA,
Darmstadt, Germany operates as
MilliporeSigma in the U.S. and Canada.
LONG-ACTING INJECTABLE
MICROPARTICLE FORMULATIONS
A NEW DIMENSION FOR PROTEINS AND PEPTIDES
Webinar
23rd April, 2020

2. The life science business
of Merck KGaA, Darmstadt,
Germany operates as
MilliporeSigma in the U.S.
and Canada

3. Long-Acting Injectable Microparticle Formulations3
Advantages
• Multi-block co-polymers
with phase-separated
morphology
• Hydrophilic amorphous
domains
• Hydrophobic crystalline
domains
• Unlike traditional sustained
release polymers,
SynBiosys® provides a
suitable environment to
maintain protein integrity
and activity.
Long-Acting Injectable Microparticle Formulations
SynBiosys® Technology Plattform
Prepolymer blocks Multi-block copolymer with
unique molecular architecture
Polyethylene
glycol
1,4-butanediol
(chain-extender)
1,4-butanediisocyanate
OHHO
ppCP10C20
(amorphous & hydrophilic)
OHHO
ppLL40
(Crystalline & rigid)
Toolkit Synthesis of multi-block copolymers
Initiators
ε-caprolactoneL-Lactide
Monomers
Chain extender
Customized biodegradable polymers designed for delivery of biologicals

4. Long-Acting Injectable Microparticle Formulations4
Key Questions
➢ Are SynBiosys® polymers and the
microparticle process suitable for
long term release of biologics?
➢ Can biologics be encapsulated and
released structurally intact?
➢ Can drug release kinetics of
biologics be tuned?
➢ Are the in vivo released biologics
structurally intact, biologically
active and therapeutically
effective?
2nd1st
High molecular
weight proteins
Sensitive peptide
Objective
Evaluate the SynBiosys® Technology Platform
of advanced biodegradable drug delivery systems
for sustained release of peptides and
biologicals.
Case Studies
Long-Acting Injectable Microparticle Formulations
Technical Feasibility Study
* https://s3-us-west-2.amazonaws.com/drugbank/protein_structures/full/DB01276.png?1452829397
*

5. Case Study I
Sustained release
microparticle
formulation for a
Sensitive Peptide

6. Cumulative Exenatide Release
0 1 0 2 0 3 0 4 0 5 0 6 0
0
2 5
5 0
7 5
1 0 0
T im e [ d ]
Exenatidecumulativerelease[%]
t o t a l E X T
i n t a c t E X T
Bydureon® shows a typical release
profile of PLGA microspheres
➢ low initial burst
➢ lag-phase
➢ Bulk drug release between days
25-35
➢ 65% of the released Exenatide
remained intact
Bydureon® was used
➢ for validation of the analytical
methods
➢ as a reference formulation
Long-Acting Injectable Microparticle Formulations6
Bydureon®: PLGA-based Exenatide Sustained Release Microparticles
Long-Acting Injectable Microparticle Formulation for a Sensitive Peptide - Exenatide

7. 0 7 1 4 2 1 2 8 3 5 4 2
0
2 5
5 0
7 5
1 0 0
T im e [ d ]
Exenatidecumulativerelease[%]
t o t a l E X T
i n t a c t E X T
Long-Acting Injectable Microparticle Formulations7
4 weeks Formulation (IC-4wF)
✓ Exenatide is compatible with
SynBiosys® polymers and the
microparticle preparation
process yielding monodisperse
particles
✓ Exenatide can be loaded in
microparticles with high EE
(86%)
✓ Exenatide released from
microparticles remains intact
(70-78%)
Cumulative Drug Release – Animal Trial Material (ATM) Formulation
Long-Acting Injectable Microparticle Formulation for a Sensitive Peptide - Exenatide
Mean values of n = 3 are shown ± SD

8. Continuous glucose-lowering effects and reduced HbA1c values demonstrate that the
steadily released peptide is biologically active and in an intact form
Long-Acting Injectable Microparticle Formulations8
Non-fasting blood glucose (NFBG) levels
Long-Acting Injectable Microparticle Formulation for a Sensitive Peptide - Exenatide
0 7 1 4 2 1 2 8 3 5 4 2
- 7 5
- 5 0
- 2 5
0
2 5
5 0
T im e a f t e r a d m i n i s t r a t io n [ d ]
ChangeinNFBG[%]
BYD,P-O,
IC-4wF
BYD
BYD
BYD
I C - 4 w F - 1 x 0 . 8 m g / k g E X T
B y d u r e o n - 4 x 2 . 0 m g / k g E X T
P o ly m e r - o n ly
I C - 4 w F - 1 x 8 . 0 m g / k g E X T
*
**
** *
*
*
* *
* *
* * *
** *
In vivo Studies – Pharmacological Efficacy in Diabetic Rats
% Glycated Hemoglobin A (HbA1c)
N
o
tre
a
tm
e
n
t
P
o
lym
e
r-O
n
lyB
yd
u
re
o
n
(4
x
2
.0
m
g
/kg
)IC
-4
w
F
(1
x
8
.0
m
g
/kg
)IC
-4
w
F
(1
x
0
.8
m
g
/kg
)
0
5
1 0
1 5
BloodHbA1c[%]
d ia b e t icn o n - d i a b e t ic
* *

9. Case Study II
Sustained release
microparticle
formulation for a
High molecular
Weight Protein

10. 5
4
1
2
Functional cell-based
Assay
Ability of mAbX to inhibit
growth of DiFi colorectal
cancer cells
Fluorescence spectroscopy
Tertiarty structure intergrity
of mAbX
Receptor binding ELISA
Quantification of functional
mAbX
SE-HPLC
Quantification and
aggregation/fragmentation of
mAbX
Circular dichroism spectroscopy
Secondary structure integrity of mAbX
3
Long-Acting Injectable Microparticle Formulations10
Analysis Strategy of mAbX Integrity after in vitro Release (IVR)
Long-Acting Injectable Microparticle Formulation for a Monoclonal Antibody

11. Long-Acting Injectable Microparticle Formulations11
DiFi cells
Formulation
Development
@ Innocore
1
0 1 0 2 0 3 0 4 0
0
1 0 0
2 0 0
3 0 0
4 0 0
5 0 0
6 0 0
T im e a f t e r a d m in is t r a t io n [ d ]
PlasmalevelmAbX[µg/mL]
P o l y m e r - o n l y M S P s s . c .
m A b X - M S P s , 1 m g / m o u s e s . c .
m A b X - M S P s , 2 m g / m o u s e s . c .
m A b X - M S P s , 8 m g / m o u s e s . c .
m A b X - M S P s , 4 m g / m o u s e s . c .
0 5 1 0 1 5 2 0 2 5 3 0 3 5 4 0
0
2 0 0
4 0 0
6 0 0
8 0 0
1 0 0 0
1 2 0 0
1 4 0 0
1 6 0 0
D a y s a f t e r r a n d o m i z a t i o n
RelativeTumorVolume[%]
PK/PD in tumor model
Production
Animal Trial
Material (ATM)
5
Long-Acting Injectable Microparticle Formulation for a Monoclonal Antibody
Proof of Concept along the Pharma Development Path
PK in healthy mice
0 5 1 0 1 5 2 0 2 5 3 0
0
1 0 0
2 0 0
3 0 0
4 0 0
5 0 0
T im e a f t e r a d m in is t r a t io n [ d ]
PlasmalevelmAbX[µg/mL]
8 m g m A b X - M S P s s . c .
1 m g m A b X - M S P s s . c .
4 m g m A b X - M S P s s . c .
In vivo
Studies
6
Cell-based
Activity Assay
4
4 Methods
for Integrity
Testing
3
In vitro
Release
2
0 5 1 0 1 5 2 0 2 5
0
2 0 0
4 0 0
6 0 0
8 0 0
0 . 0
0 . 2
0 . 4
0 . 6
0 . 8
1 . 0
T im e p o in t [ d a y s ]
mAbX[µg/mL]
Fractionfolded
T o t a l m A b X ( S E C )
m A b X F r a c t i o n f o ld e d ( F l . S p e c . )I n t a c t m A b X ( S E C )
I n t a c t m A b X ( E L I S A )
m A b X F r a c t i o n f o ld e d ( C D )
0 5 1 0 1 5 2 0 2 5
0
2 0
4 0
6 0
8 0
1 0 0
T im e p o in t [ d a y s ]
mAbXcumulativerelease[%]
I n t a c t m A b X
T o ta l m A b X

12. Long-Acting Injectable Microparticle Formulations12
Conclusion
✓ SynBiosys® polymers and the microsphere encapsulation process are compatible
with sensitive peptides and with high molecular weight proteins such as
monoclonal antibodies.
✓ Linear release of peptide and monoclonal antibody from weeks to several months
in vitro.
✓ In vitro released monoclonal antibody with high structural integrity as confirmed
by five orthogonal methods.
✓ Immunogenic potential of SynBiosys®-based peptide and protein microparticles is
very low.
✓ Controlled Release of biologically active and therapeutically effective peptide and
monoclonal antibody was demonstrated in vivo.
Long-Acting Injectable Microparticle Formulation

13. Legal Disclaimer
10
The typical technical data above serve to generally characterize the excipient. These values are not meant
as specifications and they do not have binding character. The product specification is available separately
at: www.emdmillipore.com
We provide information and advice to our customers on application technologies and regulatory matters to
the best of our knowledge and ability, but without obligation or liability. Existing laws and regulations are
to be observed in all cases by our customers. This also applies in respect to any rights of third parties.
Our information and advice do not relieve our customers of their own responsibility for checking the
suitability of our products for the envisaged purpose.

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their respective owners. Detailed information on trademarks is available via publicly accessible resources.
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