Comparison of SynBiosys Urethane-linked Multi-block Copolymer and PLGA Coatings

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1 Comparison of SynBiosys Urethane-linked Multi-block Copolymer and PLGA Coatings Nathan Lockwood Dennis Nduli Joe Tokos Tony Anderson Robert Hergenrother SurModics, Inc. Improving patient lives through technology innovation.

2 SynBiosys TM Urethane-linked Multi-block Copolymers Monomers Pre-polymers Multi-block copolymer + Initiator + Sn Linker 2

3 Urethane-linked Multi-block Copolymers Lactide (LA) Glycolide (GA) -Caprolactone (CL) Monomers Pre-polymers Multi-block copolymer + Initiator + Sn MW ~ Da Linker MW ~ kda H H 1,4-butanediol (BD) H Poly(ethyleneglycol) (PEG) MW ~ Da n H N N 1,4-butanediisocyanate (BDI) 3

4 Urethane-linked Multi-block Copolymers CH 3 NH NH m n oa p q B CH 3 [(GA) - (PEG) - (CL)] BDI [(GA) - (LA)] Four Types of Monomers Glycolide (GA) Lactide (LA) -Caprolactone (CL) Poly(ethylene glycol) (PEG) Polymerization Four Types of Blocks GALA GACL LA GAPEGCL Chain Extension Butanediisocyanate Three Polymer Families GALA LA GACL LA GAPEGCL GALA 4

5 Biodegradable DES coatings Drug elutes from polymer coating Polymer coating degrades Bare metal stent remains Polymer/Drug coating Polymer coating No coating 0 months 1-2 months 3-6 months 5

6 Previous Results Elution of Sirolimus & Degradation in PBS GALA-LA GACL-LA GAPEGCL-GALA % Sirolimus Eluted 6

7 Do urethane-linked multi-block copolymers possess properties distinct from random lactide/glycolide copolymers? 7

8 Multi-block vs. Random Copolymers of PLG Polymer Compositions Multi-block copolymers: GALA block + LA block Random copolymers: LA + GA monomers Match polymers by lactide/glycolide composition Multi-Block Copolymers (GALA-LA) Naming Convention Random Copolymers (LA/GA) wt % LA wt% GA (approx. w:w) wt % LA wt% GA 54% 46% 1:1 LA:GA 54% 46% 77% 23% 3:1 LA:GA 78% 22% 89% 11% 9:1 LA:GA 87% 13% 100% 0% 10:0 LA:GA 100% 0% 8

9 Multi-block vs. Random Copolymers of PLG Evaluations Coated stainless steel stent, 33 wt% sirolimus Suitability for spray coating Blending of polymer/sirolimus Integrity after balloon expansion Controlled release of sirolimus in PBS Degradation in PBS Coated glass slides, polymer only Contact angle (hydrophobicity) Neat polymer Glass transition temperature 9

10 Coating properties Stainless steel stent substrates All polymers suitable for spray coating Conformal coatings Similar coating rates/conditions Comparable coating weights Solubility differences THF suitable for all multi-block copolymers THF not suitable for 1:1 LA:GA random copolymer (poor solubility); performed coating with chloroform Solubility differences noted for high-glycolide polymers: multi-block copolymers more soluble than random copolymers 10

11 Mechanical Properties of Coatings Balloon-Expanded Stents (1:1 LA:GA, 33% Sirolimus, No tie layer) Multi-block Copolymer Random Copolymer Multi-block copolymers and random copolymers of comparable LA:GA exhibit similar mechanical properties 11

12 Elution of Sirolimus from Coatings PBS, ph 7.4, 37 C Multi-block Copolymers 10:0 LA:GA 9:1 LA:GA 3:1 LA:GA 1:1 LA:GA Random Copolymers 10:0 LA:GA 9:1 LA:GA 3:1 LA:GA 1:1 LA:GA % Sirolimus Eluted Time (d) Time (d) Multi-block copolymers release sirolimus faster than random copolymers of comparable LA:GA 12

13 Degradation of Coatings Net Mass Loss PBS, ph 7.4, 37 C 100 Multi-block Copolymers Random Copolymers % Coating Mass Remaining :0 LA:GA 9:1 LA:GA 3:1 LA:GA 1:1 LA:GA Time (d) :0 LA:GA 9:1 LA:GA 3:1 LA:GA 1:1 LA:GA Time (d) Multi-block copolymers degrade faster than random copolymers of comparable LA:GA 13

14 Degradation of Coatings Est. Polymer Loss PBS, ph 7.4, 37 C, Corrected for drug released 100 Multi-block Copolymers Random Copolymers Calculated % Polymer Mass Remaining :0 LA:GA 9:1 LA:GA 3:1 LA:GA 1:1 LA:GA Time (d) :0 LA:GA 9:1 LA:GA 3:1 LA:GA 1:1 LA:GA Time (d) Multi-block copolymers degrade faster than random copolymers of comparable LA:GA 14

15 Do urethane-linked multi-block copolymers possess properties distinct from random PLG copolymers? Yes. Compared to random copolymers of LA/GA, multi-block copolymers of GA/LA exhibited Faster release of sirolimus Faster rates of polymer degradation (mass loss) 15

16 Why the difference? Mixing of components: Confocal Raman microscopy 1:1 LA:GA Random Copolymer 10 µm Multi-block Copolymer Green = Polymer Red = Sirolimus Sirolimus reasonably well mixed in multi-block and random copolymer coatings Some patchiness present in both polymer coatings 16

17 Why the difference? Polymer properties: Hydrophobicity, Glass transition temperature Static Contact Angle ( ) * Multi-block Copolymers Random Copolymers * p<0.05 1:1 3:1 9:1 10:0 LA:GA (w/w) Hydrophobicity generally similar Differences in solubility supports difference observed for 1:1 LA:GA Glass transitions uniformly lower for multi-block copolymers T g ( C) * p<0.05 * * * Multi-block Copolymers Random Copolymers 1:1 3:1 9:1 10:0 LA:GA (w/w) * 17

18 Conclusions Multi-block architecture imparts unique properties to lactide/glycolide-like polymers Faster degradation Faster elution of hydrophobic molecules SynBiosys TM multi-block copolymers show benefits over random copolymers for drug-eluting stent applications Coupling of elution & degradation closely match timeframes desired for biodegradable DES Additional variables for tuning polymer properties and DES formulations (e.g., block ratios) Differences may be due to physical properties of the polymers Glass transitions of multi-block copolymers much lower than random copolymers Blocky architecture likely influences organization of polymer 18