Drug delivery to the vessel wall: Coated balloons and the role of the excipient

Transcription

1 Drug delivery to the vessel wall: Coated balloons and the role of the excipient Nathan Lockwood BioInterface SurModics, Inc. 1

2 Evolution of Devices & Therapy: POBA to DCB Balloon angioplasty (POBA) >4 million patients treated annually Dissections Elastic recoil Restenosis caused by cellular proliferation Bare metal stents (BMS) Decreased dissections and elastic recoil Stent thrombosis Intimal hyperplasia (leading to in-stent restenosis) Not a viable option in some sites Drug eluting stents (DES) Decreased cellular proliferation; less in-stent restenosis Late stent thrombosis Drug coated balloons (DCB) Effective treatment without long-term implant Stent fractures and in-stent restenosis Scheinert D, et al. Journal of the American College of Cardiology 2005, 45(2): SurModics, Inc. 2

3 Drug Coated Balloons Angioplasty balloon coated with anti-restenotic drug Paclitaxel (most common) Sirolimus (in development) Used to treat arterial stenosis Coronary Peripheral Lack of implant favors DCB where stenting is difficult or ineffective 2015 SurModics, Inc. 3

4 Drug Coated Balloons: Treatment Durable coating retains drug during transit and upon inflation Minimal Drug Particulates 2015 SurModics, Inc. 4

5 Drug Coated Balloons: Deflation & Retraction Drug is deposited on vessel wall while unused drug is retained on the balloon 2015 SurModics, Inc. 5

6 Efficient Coating Maximizes Drug Transfer Actual DCB Performance (current generation) DISPOSITION OF DEVICE DRUG LOAD Lost During Procedure Retained on Balloon Transferred to Vessel Ideal DCB Performance (future generation) 2015 SurModics, Inc. 6

7 Attributes of an Ideal DCB Coating Cross-section view Facilitate drug retention on balloon during transit Effectively release drug from the balloon to the target lesion site Provide adhesion of the drug to the vessel wall Drug retention upon restoration blood-flow; formation of depot for longterm release Facilitate drug uptake by tissue Excipients can play an important role in achieving these attributes 2015 SurModics, Inc. 7

8 Role of Excipient: Development of a Test System Hypotheses for in-vitro drug adhesion test system Matrigel coatings can mimic the denuded arterial lumen surface Adhesion of drug particles to Matrigel can form a model to elucidate the mechanisms of excipientmediated drug transfer and retention in artery walls 2015 SurModics, Inc. 8

9 Exploring the role of excipient: Methods In vitro test model Suspensions of paclitaxel alone and with excipients Measure deposition on to Matrigel coated surface In vivo test model Balloons coated with paclitaxel and excipient Assess Drug content in tissue (pharmacokinetics) Physical disposition of drug (immunostaining & visualization) Biological effect (histology, CVPath) 2015 SurModics, Inc. 9

10 B. Braun SeQuent Please DCB Role of excipient: Test formulations 100x 5000x Early-generation DCB Crystalline paclitaxel Iopromide (contrast) excipient 2015 SurModics, Inc. 10

11 SurModics SurVeil TM DCB Role of excipient: Test formulations 50x 2000x Development-stage DCB Crystalline paclitaxel Proprietary excipient 2015 SurModics, Inc. This product is not commercially available 11

12 Results In vitro adhesion assays Visualization of Ptx on Matrigel with HCAEC cells SurModics Excipient: nonspecific binding Iopromide: cell-specific binding Cells (dark) Excipient (bright) Cells (dark) Excipient (bright) 2015 SurModics, Inc. 12 Drug Adhesion to Matrigel (µg) Drug Adhesion to Matrigel + HCAE Cells (µg) SurModics excipient SurModics excipient Iopromide Iopromide Excipients promote increased drug adhesion to cells SurModics excipient promotes adhesion to ECM mimic, independent of cells No excipient No excipient

13 Results In vivo drug transfer & retention Ptx concentration 24 hours after balloon treatment (µg/g) Coronary arteries Peripheral arteries SurModics Excipient B. Braun (Iopromide) No excipient Excipients promote drug deposition in the tissue SurModics excipient trends toward higher deposition 2015 SurModics, Inc. 13

14 Results In vivo drug disposition Visualized by immunostaining 24 hours post-treatment Excipients promote adhesion to the vessel wall Transfer with SurModics excipient appears more robust 2015 SurModics, Inc. 14

15 Results: Bioeffect in vivo SurModics Excipient Iopromide (B. Braun) Uncoated (POBA) Histology from CVPath Institute Tissue stained with Movat Pentachrome, 28-days post-treatment Blue/Green Color = Drug Effect Excipients lead to increased biological effect SurModics excipient leads to more uniform biological effect 2015 SurModics, Inc. 15

16 Results: Safety response and bioeffect in vivo 3.0 Score (0-4 scale) Primary markers of drug effect SurModics Excipient-Only B. Braun Uncoated Scored by CVPath Institute Excipients lead to increased biological effect SurModics excipient trends toward stronger effect 2015 SurModics, Inc. 16

17 Conclusions Simple bench-top adhesion assay showed suitability for screening DCB formulations Drug adhesion in vitro showed patterns similar to those observed by staining in vivo Transfer in vitro trended similar to transfer in vivo Excipients in general improve DCB formulations Increase drug transfer to ECM mimics and actual tissue Enhance retention of drug at treatment site May enhance transfer to cells (function of excipient) SurModics excipient further enhances DCB formulations Significant increase in drug adhesion to ECM mimics and cell layers in vitro Increased drug transfer from a DCB in vivo compared to a commercially-available DCB formulation 2015 SurModics, Inc. 17

18 SurModics SurVeil TM DCB PTA platform 4 7 mm x mm Proprietary PhotoLink basecoat Shaft coating Serene hydrophilic coating Uniform drug topcoat Paclitaxel + proprietary excipient 2 µg/mm² drug load 360 coating coverage This product is not commercially available 2015 SurModics, Inc. 18

19 Comparison to Competitive DCBs SurModics SurVeil DCB Competitive DCB #1 Competitive DCB #2 This product is not commercially available 2015 SurModics, Inc. 19

20 SurVeil DCB Delivers More Drug than Competitive DCB 2 µg/mm µg/mm Tissue Concentration (µg/g) SurVeil DCB Competitive DCB 0 0 day 7 day 14 day 21 day 28 day This product is not commercially available 2015 SurModics, Inc. 20

21 Competitive DCB Robust Biological Drug Effect at 28 days SurVeil DCB POBA Control This product is not commercially available 2015 SurModics, Inc. 21

22 Thank you 2015 SurModics, Inc. 22