This webinar, presented by two world-class experts in polymer based parenteral controlled-release drug delivery technologies, will provide insights into formulation technologies from small molecules up to biologics. There is an increasing interest in long-acting injectables as drugs administered through injection help to increase patient compliance due to reduced frequency of administration while providing the same therapeutic efficiency. Depending from the nature of the drug, the optimum polymer technology is to be selected. Prof. Dr. Mäder focus on how to select the appropriate PLA/PLGA polymer for small drug molecule applications. He will provide an overview of drug delivery systems, most important formulation techniques and appropriate characterization methods along with application examples. Alternative polymer systems are required for peptide and protein controlled-release formulations. Dr. Rob Steendam introduces InnoCore´s SynBioSys® biodegradable polymer system demonstrating excellent safety, control over release kinetics and effective preservation of structural integrity and bioactivity of biologics. InnoCore Pharmaceuticals and SynBioSys® multi-block polymer introduction, challenges in development of controlled-release formulations of biological therapeutics including various examples and development and cGMP manufacturing at InnoCore are key elements of his presentation. In this webinar, you will learn: • drug delivery systems • most important formulation techniques • appropriate characterization methods along with application examples

1. Merck KGaA
Darmstadt, Germany
Polymer based drug delivery systems for parenteral
controlled release: from small molecules to biologics
25th October 2018
Webinar

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

3. 3
Prof. Dr. Karsten Mäder
Part I: General considerations
and DDS for small molecules
Dr. Rob Steendam
Part II: SynBiosys®
- Biodegradable
Polymer Platform for Long-Acting
Injectable Biologics
Polymer based drug delivery systems for parenteral controlled
release: from small molecules to biologics

4. General considerations
and DDSfor
small molecules

5. DDSfor parenteral
controlled release:
Need and challenges

6. 1. … low uptake and high variability of PK after oral administration
2. … rapid excretion and fast metabolism
3. … low concentrations in the desired location
4. … high toxicity
Many drugs show…
SyringeImagefrom
DatabaseCenterforLife
ScienceDBCLS).
PLA / PLGA polymers play a key role
Medical need for injectable DDS with sustained release
6

7. The concept of sustained release with PLA / PLGA
Drug
Polymer
Other excipients
Process
CR-DDS
Slow and constant release
days
Constant drug level
Toxic effects
No effect
7

8. 1. Tunable drug release from days to several months
Less injections, no infusion
2. High drug concentration at the desired location
Better cure
3. Decreased overall dose
Less side effects
Possible benefits of injectables with controlled release
8

9. Systemic effects
 Breast cancer
 Prostate cancer
 Schizophrenia
 Diabetis
 Growth deficiency
 …
Local effects
 Inner eye
 Brain
 Joints
 Ear
 Bone marrow
 …
Application examples
Location specific considerations Mainly intramuscular or
subcutaneous administration
9

10. Selection of polymers
and processes

11. Slower polymer degradation with
1. Molecular weight
2. Ratio lactic / glycolic acid
3. L-lactic acid vs. D,L-lactic acid
4. Polymers with esterified end groups
EXPANSORB®
DLG 50-6A (Acid) DLG 50-6E (Ester)
Polymer selection: PLA/PLGA
L-lactic acid
D-lactic acid
Glycolic acid
COOH
11

12. Drug molecules are different in many aspects
large
medium
poorly water soluble
Risperidone
Dexamethasone
Leuprolide
small
water soluble
5-FUNa-Pamidronate
12
Sensitive

13. Different polymer based DDS
Preformed Implants In-situ forming implants Microparticles
Micro- and Nanocapsules
E.Lehner&K.Mäder
C.Janich&K.Mäder
Micro- and nanofibersNanoparticles
13
J.Zech&K.Mäder

14. 1. Dissolving in
a. Organic solvents (polymers, drugs)
b. Aqueous solvents (drugs)
1. Extrusion
2. Mixing / Shearing
3. Spray Drying
4. …
Commonly used processes to make DDS
Processing
Drug Delivery
System
Excipients
(polymers, surfactants, …)
Drug
 High shear forces
 High temperatures
 Hydrolysis
 Toxic solvents (CH2Cl2)
14
DANGER

15. Preformed Implants
Monolithic
Made by extrusion
In situ forming implants
Formed in vivo
Different principles
(e.g. solvent or
temperature induced)
Microparticles
Multiparticulate
Made by dissolution – dispersion
techniques
Selection of DDS: Implants vs. microparticles
15
Tunable size and release
profile, smaller needles
for injection
Use of organic solvents,
Often burst release,
Danger of particle
aggregation (T>Tg)
Easy
formulation
process
Difficult control of
implant shape,
sometimes injection
of organic solvents
No organic solvents,
better storage stability,
less burst release
Extrusion stress:
(temperature, shear)
Larger needle for injection

16. PLGA Microparticles for hydrophobic drugs
Hydrophic drug
PLGA
CH2Cl2
PLGA + Drug
SOLUTION in CH2Cl2
I
II IIa
Spray drying
IIb
Emulsification / solvent
evaporation
o/w-emulsion
(liquid droplets)
CH2Cl2 removal
s/w-suspension
(solid particles)
Addition of
organic liquid:
1.solvent for
CH2Cl2
2.antisolvent
for PLGA
IIc
Coacervation
16

17. PLGA Microparticles for hydrophilic drugs
PLGA CH2Cl2
H2O
PLGA solution
in CH2Cl2
Drug solution
in H2O
W1/O-emulsion
PLGA in o-phase
Drug in w1-phase
CH2Cl2 removal
Suspension
(solid particles)
17
I
II IIa
Spray drying
w1/o/w2-
emulsion
(liquid droplets)
IIb
Emulsification / solvent
evaporation
Addition of
organic liquid:
1.solvent for
CH2Cl2
2.antisolvent
for PLGA
IIc
Coacervation
Hydrophic
drug

18. Understanding and
optimizing thedrug
release

19. Most Important Release Mechanisms
Fredenberg et al.: Int J Pharm. 2011, 415(1-2):34-52
Diffusion
through pores
Diffusion through
the polymer
Osmotic pumping Erosion
19

20. Diffusion
According to Einstein & Smoluchowski:
x2
average = 2 D t
Microparticles / Nanoparticles:
Ratio Diffusion Distance: 1 000 : 1
Ratio Diffusion Time: 1 000 000 : 1
20

21. Polymer Drug D [cm2
/s] Source
PLGA
(Tg > 37°C)
(brittle)
5-FU
8.5*10-12 N. Faisant et al. Int. J.
Pharm. 314 (2006)
189–197
5-FU
5*10-11
to 1*10-13
Siepmann et al. J. Contr.
Rel. 96, 123-134 (2004)
Ibuprofen,
Lidocain
10-11
to 1*10-13
Klose et al. / Int. J.
Pharm. 354 (2008)
95–103
PCL
(Tg < 37°C; rubbary)
Testosterone
estradiol-17β
8.31*10-8
0.728*10-8
Zhang et al, J. Contr.
Rel. 29, (1994),
157-161
Diffusion coefficients in biodegradable polymers
21

22. Average Diffusion lengths: Nano- vs. microparticles
22
D = 2*10-9
cm2
/s D = 2*10-12
cm2
/s
1 s 632 nm 20 nm
10 s 2 µm 63.2 nm
100 s 6.32 µm 200 nm
1000 s (16.7 min) 20 µm
632 nm
10000 s (2.78 h) 63.2 µm 2 µm
100000 s (27.8 h) 200 µm 6.32 µm
1000000 s (11.6 d) 632 µm 20 µm
22

23. Drug Release Might be Quite Complex
Fredenberg et al.:Int J Pharm. 2011, 415(1-2):34-52
23
CAN WE GET CONTROL?
Drug
Carrier
Biological
Environment

24. 1. Autocatalytic degradation with possible very low pH-values (pH2)
2. Larger microparticles degrade faster than smaller
3. Stirring might lead to slower release and degradation
PLGA challenges and surprises
Li, S.M., Garreau, H. & Vert, M. J Mater Sci: Mater Med
(1990) 1: 131.
24

25. Importance of size (I)
100 nm 1 µm 10 µm 100 µm
Phagocytosis
Degradation by lipase
Diffusion controlled release
Autocatalysis
25
Injectability

26. Importance of size (II)
Hydrophilic drug
PLGA microparticles
Smaller
PLGA particles
Larger drug
particles
26

27. DDS Size and shape
PLGA mass and molar mass
Monomer content
Glass transition temperature Tg
Content of water and organic solvents
Drug content and physical state, degradation products
Analytical control of…DrugPLGA
27

28. Control from production to patient
Production Shipping Storage Administration
Avoid:
 High temperatures
 Humidity
 Light
 Mechanical damage
28

29. Drug Release might be quite complex:
Fredenberg et al.:Int J Pharm. 2011, 415(1-2):34-5229

30. Example of optimizing release profile
Market
product
Optimised
formulation
30

31. Summary
and conclusionsPart I

32. Take home message: PLGA and small molecules
Drug release results
Drug release results from interplay between drug, polymer and environment.
Release optimisation
Release optimisation requires appropriate analytical measurements
of important parameters.
Drug release from PLA / PLGA
Drug release from PLA / PLGA might be complex, but not unpredictable!
1
2
3
32

33. SynBiosys®
BiodegradablePolymer Platform
for Long-Acting Injectable
Biologics

34. Marketed PLGA-based parenteral sustained release products
 PLA / PLGA are the
standard polymer
platform of choice
for long-acting
injectables
GelsImplantsmicroparticles
 …. but only for
small molecules
and peptides
There are no marketed PLGA/PLA polymer-based sustained release drug
delivery products of biologicals.34
Image(s) by courtesy of InnoCore Pharmaceuticals

35. Increasing market share protein therapeutics
There is a need for sustained release drug delivery systems
for development of Long-Acting Injectable Biologics
# https://sciex.com/community/blogs/blogs/the-future-of-biologics-
drug-development-is-today
The number of protein-based therapeutics is rapidly increasing
 US$ 140 billion (2016) to grow to US$ 218 billion by 2023 (CAGR 6.5%)
(alliedmarketresearch.com)
35
Image(s) by courtesy of InnoCore Pharmaceuticals

36. Large Peptides and Proteins
Proteins are intrinsically fragile molecules
 Complex 3-dimensional molecules
 Hydrophilic, charged and relatively large size
 Short half-life (t½)
 Oral incompatibility
 Poor stability
Threats for proteins
 High temperatures
 Organic solvents
 Hydrophobic surfaces
 High shear
 Enzymes
 pH changes
Protein degradation
 Unfolding
 Aggregation
 Fragmentation
 Chemical modification
 Loss of biological activity
 Reduced therapeutic efficacy
 Undesired immune response
 Reduced shelf life
Challenges in Formulation of Biologicals
36
Image(s) by courtesy of InnoCore Pharmaceuticals

37. PLGAs are not suitable for sustained release of biologicals
Adsorption
Proteins adsorb to hydrophobic surface of PLGA
Irregular biphasic release kinetics
Degradation controlled release due to rigid polymer
matrix which does not allow protein diffusion
In situ pH drop
Formation of acidic microenvironment due to
accumulation of acidic degradation products ( pH 2)↓
Acylation
Nucleophilic primary amines can interact with
the carboxylic acid end-groups of PLGA or PLGA
degradation products
Sustained release of large peptides and proteins
Peptide acylation in PLGA-
based Sandostatin LAR
Irregular release of Bovine
Serum Albumin from PLGA
Classical PLGA/PLA formulations not suitable for sustained release of
biologicals due to their rigidity and acidic microenvironment formation
Ghassemi et al, Pharm Res (2012) 29:110–120
37

38. BiodegradablePolymeric
Drug Delivery Platform
SynBiosys®

39. SynBiosys®
Hydrophilic Polymer Platform Designed for Delivery of Biologicals
OH
OH
HO
HO
Well-known, clinically-proven safe monomers and chemistry to create
customized multi-block copolymers for delivery of any biological
Monomers
Lactide ε-caprolactone
Prepolymers
(chain-extender)
1,4-butanediisocyanate
Multi-block copolymer
with unique molecular
architecture
Polyethylene glycol 1,4-butanediol
(initiators)
39

40. Hydrophilic Amorphous Domains
 Absorbs water and swells to form
a hydrogel-like structure
− Diffusion-controlled release
Hydrophobic Crystalline Domains
 Physical X-links: provide structural integrity
− Control the degree of swelling
Polymer Matrix Erosion and Degradation
 Degrades through hydrolysis
 No accumulation of acidic degradation products
 No acidic microenvironment / in situ pH drop
Multi-block co-polymers with
phase-separated morphology
 Hydrophilic amorphous domains
 Hydrophobic crystalline domains
SynBiosys®
Designed for Delivery of Large Peptides and Proteins
Unlike traditional sustained release polymers, SynBiosys® provides a
suitable micro-environment to maintain protein integrity and activity40
Image(s) by courtesy of InnoCore Pharmaceuticals

41. Tools to control drug release
 Polymer
− swelling degree
− degradation rate
 Microencapsulation process
Variables for Fine-Tuning
 PEG molecular weight
 PEG content
 Co-monomer type
 Co-monomer weight fraction
 Block ratio
 Molecular weight
SynBiosys®
Control of protein release kinetics by modifying polymer composition
Block ratio
Effect of block ratio of LP10L20-LL40 polymer on BSA release
41
Polymer Grade Block ratio PEG content
Swelling
degree
10LP10L20-LL40 10/90 5 wt.% 1.02
20LP10L20-LL40 20/80 10 wt.% 1.07
30LP10L20-LL40 30/70 15 wt.% 1.15
50LP10L20-LL40 50/50 25 wt.% 1.30
Image(s) by courtesy of InnoCore Pharmaceuticals

42. SynBiosys®
Biocompatible polymer platform and safe degradation products
Extensive ISO-10993 biocompatibility / toxicity data package (summary is available)
In vivo biocompatibility & degradation (implants, microspheres, coatings)
 Various routes of administration: subcutaneous, intramuscular, intra-articular, intravitreal, intracardiac
 Multiple species: rats, rabbits, mini-pigs, pigs, horses, primates
Proven clinical safety – Combo®
sirolimus eluting dual therapy stent:
approved and marketed since 2013 by OrbusNeich
COMBO® is a registered trademark of OrbusNeich42
Monomer Degr. product Excreted as Route
Lactic acid Pyruvic acid CO2 + H2O Urine, breathe
Glycolic acid Pyruvic acid CO2 + H2O Urine, breathe
ε-Caprolactone ω-hydroxy heaxanoic acid ω-hydroxy heaxanoic acid Urine
PEG PEG PEG Urine
1,4-Butanediisocyanate 1,4-Butanediamine (putrescine) 1,4-Butanediamine Urine, breathe
1,4-Butanediol 1,4-Butanediol 1,4-Butanediol Urine

43. SynBiosys®
Versatile portfolio of proprietary Drug Delivery Systems
Microparticles Solid Implants DE Coatings Injectable Gels
SynBiosys biodegradable polymers are suitable for various long-acting
(injectable) sustained release drug delivery systems
43
Image(s) by courtesy of InnoCore Pharmaceuticals

44. SynBiosys®
Microparticles
Proprietary process to manufacture uniformly-sized microparticles
Membrane emulsification
44
Narrow Particle Size Distribution
PARTICLE DIAMETER µM
Image(s) by courtesy of InnoCore Pharmaceuticals

45. SynBiosys®
Microparticles
Unsurpassed injectability due to uniformly-sized microparticles
Drug type Maximum drug dose (mg)a
mg/mL SC (2 mL) IM (4 mL)
Small molecules ≤ 150 ≤ 300 ≤ 600
Peptide ≤ 75 ≤ 150 ≤ 300
Protein/antibody ≤ 60 ≤ 120 ≤ 240
 Smaller needles (less painful injection)
 Reduced immunogenicity due to absence of
undersized (< 10 µm) particles
 High API doses due to highly concentrated
microsphere suspensions (more API)
45 Image(s) by courtesy of InnoCore Pharmaceuticals

46. Casestudies
SynBiosys®
Sustained
releasemicroparticles

47. SynBiosys®
Sustained Release Microparticles of Peptides
Time (Days)
CumulativeReleaseCumulativeRelease
Peptide A
Peptide B
47
Peptide A Peptide B
MW 2.5 kDa 4.5 kDa
Indication Undisclosed Undisclosed
RoA Local injection SubQ injection
Microencapsulation process W/O/W +
lyo (aseptic)
W/O/W +
lyo (aseptic)
Size (d50) ∼ 30 - 70 µm ∼ 30 µm
Drug loading 10-15% 10%
Injection volume 50 µL 0.7 mL
MSP suspension concentration > 20% > 20%
Needle gauge 27 G 27 G
Release duration 5-6 months 2-4 weeks
(Formulati-on)
Image(s) by courtesy of InnoCore Pharmaceuticals

48. Insulin-like growth factor-1 (IGF-1)
MW 7,655 Da
5 wt.% IGF (500 µg/10mg MSP)
SynBiosys®
Sustained Release Microparticles of Proteins
Hepatocyte growth factor (HGF)
MW 69,000 Da
2 wt.% HGF (200 µg HGF/10mg MSP)
Release controlled by block ratio of SynBiosys®
multi-block copolymer
CumulativeRelease
Time (Days)
CumulativeRelease
Time (Days)
48

49. Bioactivity of IGF-1 is preserved
 IGF-1 signal transduction pathway
 Activity of released IGF-1 assayed in vitro
 A431 was used as reporter cell line
 Signal transduction pathway activation was
analyzed 10 min after IGF-1 addition
Structural integrity of IGF-1 is preserved
 SDS-PAGE
 IGF-1 released after different time points was
structurally fully intact
 no formation of fragments or aggregated IGF-1
SynBiosys®
Microparticles
Protein Integrity and Bioactivity
1 2 3 4 5 6 7 8 9 10
IGF-1
CBB-stain
37
25
20
15
10
5
KDa Marker 1 2 3 4 5 6 7 8 9 10
IGF-1
CBB-stain
37
25
20
15
10
5
KDa Marker
37
25
20
15
10
5
KDa Marker
-- pAKT
-- pIGF-1 R
0 0.78 1.563.126.25 12.5 ng/ml
-- β-actin
Protein maintains structure and activity after microencapsulation
and subsequent release from SynBiosys®
microparticles49
Image(s) by courtesy of InnoCore Pharmaceuticals

50. SynBiosys®
Microparticles
Examples of SynBiosys®
-based Long Acting Injectable Biologics
50
Therapy / indication Drug molecule Formulation type
Route of
Administration
Ocular disease Protein Microparticle Intravitreal
Sexual dysfunction Protein Microparticle SubQ
Ischemic heart disease IGF-1 / HGF Microparticle Intra-arterial
Diabetes GLP-1 analogue Microparticle SubQ
Cancer Antibody Microparticle SubQ / IM
Prostate cancer Goserelin Solid implant SubQ
Cancer Peptide Microparticle SubQ / IM
Osteoarthritis Protein Microparticle Intra-articular

51. Development & cGMP
manufacturing services

52. Sustained release solutions from Small Molecules to Large Proteins
Small MoleculesSmall Molecules PeptidesPeptides ProteinsProteins
< 1 kDa< 1 kDa 1 – 10 kDa1 – 10 kDa > 10 kDa> 10 kDa
A versatile portfolio of polymers and DDS to formulate
any API into a fit for purpose Drug Product
52
EXPANSORB® is a registered trademark
of Groupe PCAS, Longjumeau, France
SynBiosys® is a registered trademark of Innocore
Pharmaceuticals, Groningen, Netherlands

53. Collaboration and Development Services
Preclinical development and cGMP manufacturing
53
API
&
TPP
R&D
Feasibility study
GLP
Optimization &
Scale-up
Clinical
Trials
Commercial
Manufacturing
& Sales
Merck KGaA / InnoCore CooperationPARTNER
Polymer Supply
Drug
Delivery
System
 Optimization
 Process scale-up
 Analytical
validation
 Production of
GLP tox material
GMP
Production CTM
 Tech Transfer
 cGMP production
clinical supplies
 QC testing
 Batch release
 Stability studies
 Analytical
development
 Polymer
 Formulation
development
 ATM prodution
POC in vivo
PK/PD studies
GLP tox
studies
Phase I/II
clinical studies
Manufacturing
Partner/CMO
Mark. & Sales
PARTNER
PARTNER

54. Summary and
conclusionsPart 2

55. Unique biodegradable polymer platform for long-acting injectable biologics
 Sustained release of biologicals for up to 6 months
 Preservation of integrity and bioactivity
 Excellent injectability (small needles) and high API doses due to uniformly sized microparticles
 Safe and clinically validated platform
Development services from PoC up to cGMP manufacturing of clinical supplies
Proven track record in effectively working with partners to formulate their biological
therapeutics into unique and commercially viable drug delivery products
Partnering and business opportunities
 Chronic and site-specific diseases
 Small molecules – peptides - recombinant proteins, etc
 New therapies, new RoA, repurposing of existing API, supergenerics
 Effective patent protection > 2038
SynBiosys®
Key features SynBiosys®
Microparticle Technology Proposition
55

56. Summary

57. Take Home Message
Parenteral Controlled Release of Small Molecules and Biologics
57
controlled drug release results from the interplay between drug, polymer and environment.
release optimization requires appropriate analytical measurements of important parameters.
the Synbiosys technology is a unique multiblock copolymer platform for sustained release of biologics.
PLA/ PLGA polymers and Synbiosys technology together deliver the tools to formulate any API into a fit for purpose
drug product.
4
With this webinar we demonstarted that:
3
2
1

58. Part II:
SynBiosys®
- Biodegradable Polymer
Platform for Long-Acting Injectable
Biologics
Part I:
General considerations and DDS
for small molecules
Dr. Rob SteendamProf. Dr. Karsten Mäder
The vibrant M is a trademark of Merck KGaA, Darmstadt, Germany or its affiliates. All other trademarks are the property of their respective owners.
Detailed information on trademarks is available via publicly accessible resources.
© 2018 Merck KGaA, Darmstadt, Germany and/or its affiliates. All Rights Reserved.
Contact person
Dr. Judit HuarteCiganda
judit.huarte-ciganda@emdgroup.com