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Drug Elution The Technology AA ‘02

Drug Elution The Technology AA ‘02. Martin T Rothman Barts & The London Trust. 1. Thanks to: Cordis Guidant BSC Cook Biocompatibles My mother As I will forget at the end!!!. The Stent The Coating The Binding The Release The Drug. Drug Elution The Technology.

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Drug Elution The Technology AA ‘02

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  1. Drug ElutionThe TechnologyAA ‘02 Martin T Rothman Barts & The London Trust 1

  2. Thanks to: Cordis Guidant BSC Cook Biocompatibles My mother As I will forget at the end!!!

  3. The Stent The Coating The Binding The Release The Drug Drug ElutionThe Technology

  4. Methods of Stent-mediated Delivery Degradable Reservoir } Coating { Stent COOK CONOR-MEDSYSTEMS IGAKI-TAMAI 2mm } Top- coat } } 5mm Covalent attachment 5mm Sub- layer CORDIS CORDIS (Hepacoat) GUIDANT + + + + + 1mm } } 1mm BOSTON SCIENTIFIC BiodivYsio Matrix LO BiodivYsio Matrix HI Low molecular weight drug High molecular weight drug

  5. The Stent The Coating The Binding The Release The Drug Drug ElutionThe Technology

  6. Current Stent Issues • Metal Content • 316L - <0.03% carbon, • iron 69%, • chromium 18%, • nickel 10% • molybdenum 3% • Nitinol nickel ~55% • titanium ~45% • Tantalum • Surface Finish • Stent Design • flexibility • uniformity of deployment

  7. Device V-Flex Plus™ Coronary Stent • stainless steel, slotted tube • high radial strength and low recoil • diameters: 3.0 or 3.5 mm • length: 16 mm • coated stents have paclitaxel adhered to the abluminal surface using a proprietary process with no polymer.

  8. Biodegradable Stent • Igaki-Tamai Stent • Coil of Poly-l-Latic Acid monopolymer • 0.17 mm thick, zigzag helical coil • 12 mm length, 24% wall coverage • Self-expanding Tamai H et al, Circ 102(4),2000;399-404

  9. Biodegradable Stent Tamai H et al, Circ 102(4),2000;399-404

  10. Biodegradable Stent Tamai H et al, Circ 102(4),2000;399-404

  11. The Stent The Coating The Binding The Release The Drug Drug ElutionThe Technology

  12. Non inflammatory Non thrombogenic Competitive shelf-life Stable for duration of stent lifetime Neutral to drug structure and chemistry Can be sterilised by standard approaches Controlled release (timing and dosage) No limitation on use (tortuosity, etc) Strong clinical data Coating Requirements

  13. Comparison of Coating Thickness

  14. Arterial Side PC coating Drug 1 mm } Targeted drug delivery direct to arterial wall Stent Strut Stent strut cross-section Lumen Side BiodivYsio Drug Delivery Stent- Site-Specific Delivery • Smooth coating • Thrombo-resistant surface

  15. Stability of Coating

  16. Some Coatings Are Not Always Stable Effects of stent expansion and sterilisation on first generation stent coatings Grube E, Cath Lab Digest, 2001, 9(9), 52 Costa, M, TCT Presentation, 2001

  17. Programmable Release Kinetics Coating Uniformity Coating Durability Dosing Efficiency & Repeatability Why use a Carrier Matrix? With Carrier Without Carrier

  18. Blood Contact- In-vitro Uncoated and blood contacted PC coated and blood contacted Adhered and activated platelets Lewis AL, Tolhurst LA & Stratford PW, Biomaterials, 2001, in press

  19. PC is Non-Inflammatory PC Polymer Coated Stent (1 month) ConventionalPolymer Coated Stent (1 month) van der Giessen WJ, et al, Circulation, 1996, 94, 1690 Whelan DM, et al, Heart, 2000, 83, 338

  20. Normal Endothelialisation • PC coating does not affect endothelial-isation • 91% EC coverage within 5 days1 • Fully endothelialised at 30 days2 20mm 1 Whelan DM, et al, Heart, 2000, 83, 338 2 SEM courtesy of Prof I de Scheerder

  21. The Stent The Coating The Binding The Release The Drug Drug ElutionThe Technology

  22. Timing of the Events in Restenosis

  23. Mechanism Of Restenosis • Thrombosis days 0 - 3 • Inflammation days 4 – 8 • Migration/Proliferation days 4 – 8+ • Healing days 8 - 90

  24. The Stent The Coating The Binding The Release The Drug Drug ElutionThe Technology Early Action

  25. BiodivYsio Corticosteroid Stent- Programmed Release • PC coating controls drug release • Appropriate timing of delivery for anti-inflammatory action (over first 7 days)

  26. BiodivYsio Matrix LO Drug Loading <1.2k Mwt Solution Drug (>1.2k) Drug (<1.2k) Coating Stent surface

  27. Drug & CoatingBiodivYsio Corticosteroid Stent • Low inflammatory response • Minimal neointimal hyperplasia observed • Minimal inflammatory response induced

  28. Drug & CoatingBiodivYsio Corticosteroid Stent • Normal re-endothelialisation • Endothelialisation unaffected by presence of drug or coating

  29. Pre-stent Post-stent 6-months Case Study 3

  30. The Stent The Coating The Binding The Release The Drug Drug ElutionThe Technology Intermediate Action

  31. Polymer coating Name: TRUECoat Chemical Structure: Backbone structure: C-C bond Low potential for hydrolytic or oxidative chain scission No aromatic component Low risk for chronic toxicity or harmful leachates. Polymer Properties: Thermal: Tg ~ 55-60oC. Tm ~ 165oC Transport: High transport barrier property for moisture vapor diffusion Sterilization compatibility: E-beam Mechanical: Does not crack or rip on the stent surface Polymer Coating - Actinomycin

  32. Top coat Drug coat Primer coat Metal stent Balloon Coating Formulation Overall coating thickness ~ 5 - 6 nm

  33. Drug Uptake into Vessel

  34. The Stent The Coating The Binding The Release The Drug Drug ElutionThe Technology Delayed Action

  35. Matrix metalloproteinases (MMP’s) are secreted by cells to digest extracellular matrix and allow cell to migrate Smoothmuscle cells Cell migration MMP secretion Batimastat Collagen MMP activity Batimastat - An MMP Inhibitor

  36. Batimastat Batimastat - Mode of Action Inflammation Migration Proliferation Restenosis • Smooth muscle cell migration inhibited • Neointimal hyperplasia reduced • Re-endothelialisation unaffected* * From pre-clinical assessment

  37. Timing of the Events in Restenosis

  38. BiodivYsio Batimastat Stent- Sustained Release • PC coating controls • drug release • Appropriate timing • of delivery • Batimastat delivered • over prolonged period • No irreversible drug- • coating interactions In-vitro (top) Extrapolation in-vivo (right) Lewis AL et al, J. Mater. Sci., Mater Med, 2001, in press

  39. ) Ci m ( 1.25 30 (A) (B) stent ) Ci m 1.00 25 20 0.75 Delivered activity ( 15 0.50 Remaining activity on coated 10 0.25 5 0 0.00 0.1 3.0 6.0 72.0 192.0 336.0 0.1 3.0 6.0 72.0 192.0 336.0 (8 d) (14 d) (8 d) (14 d) Time Artery follow - up (Hours) (Hours) Delivery of DNA from the BiodivYsio Matrix HI Stent • (A) 32P-Labeled oligonucleotide elution from the stent • (B) Concomitant intra-tissue delivery of oligonucleotide Leclerc G, et al, unpublished data

  40. Ex-vivo Delivery of Oligo-nucleotides to Rabbit Arteries

  41. Localised Release from Matrix HI

  42. StentChemotherapy Carrier Inert Polymer IV in Cremophor Vehicle Dose 1.0 µg/mm2 110-250 mg/m2 (85µg/16mm stent) Total 1.22 µg/kg 3280 µg/kg ovarian Ca 4250 µg/kg breast Ca Dose from Stent is Over 3000x Less than Chemotherapy Paclitaxel Dose Levels

  43. Adverse (Positive) Remodelling Adverse Hyperplasia (Restenosis) 0 Late Loss (mm) Stent Drug Delivery: Optimising Efficacy and Safety • Conventional Stenting • Restenosis • Repeat procedures • Additional cost • KNOWN PATIENT RISK • Aggressive-drug Stenting • Positive Remodelling • Stent mal-apposition • Late thrombosis? • INCREASED PATIENT RISK?

  44. The future is not the stent, but what is stuck around it……..

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