Shenkar Plastics ENG.DEP. SUPERVISORS: Professor Hanna Dodiuk Eng. Tehila Efrat

1. Stent based drug delivery system Joint program Allium medical – AorTech Shenkar Plastics ENG.DEP. SUPERVISORS: Professor Hanna Dodiuk Eng. Tehila Efrat Presented by Inbar Freiberg

2. Release of Dexamethasone from Polyurethane Silicone Copolymers (Elast-Eons)coated stents, as a therapy for Prostatitis. Release Dexamethasone Polyurethane Silicone Copolymers (Elast-Eons) stents Prostatitis

3. INTRODUCTION- control drug delivery • Drug/medical device combination products, represent an emerging new trend in implantable therapeutics. • Controlled drug delivery occurs when a polymer, whether natural or synthetic, is combined with a drug or other active agent in such a way that the active agent is released from the material in a predesigned manner.  With traditional tablets or injections the level rises after each administration of the drug and then decreases until the next administration  In controlled drug delivery systems the drug level In the blood remaining constant, between the desired maximum and minimum, for an extended period of time . Reproduced from Ref. [1] Introduction Methodology Results Discussion Conclusions Objectives

4. Normal prostate Infected prostate maycause pain with urination Introduction: Prostatitis An inflammation of the prostate • 1.Chronic Prostatitis/chronic Pelvic Pain Syndrome (CP / CPPS): • 1a.Inflammatory - presence of white blood cells in semen • 1b.Non-inflammatory- absence of white blood cells in semen • 2.Asymptomatic inflammatory prostatitis. www.towerurology.com/handler.cfm?event=pract Introduction Methodology Results Discussion Conclusions Objectives

5. Introduction: Stent “If interventional medicine, using the body's circulatory systemas a "highway" to deliver therapy, worked with devices,it could also work with medicines......”[13] www.jnjgateway.com Introduction Methodology Results Discussion Conclusions Objectives

6. Introduction: Elast-Eon Excellent Excellent mechanical performanceand fatigue resistance Biocompatibility and biostability Silicon Polyurethane Poor long-term biostability, biocompatibility. Poor mechanical performance and fatigue resistance. Biostable Biocompatible Fatigue Resistant Introduction Methodology Results Discussion Conclusions Objectives

7. Introduction: Elast-Eon - Structure Materials Polyurethane Silicon AAA CCC DDD BBB Polyurethane Silicone Copolymers (Elast-Eons) Hard Segment Soft Segment Introduction Methodology Results Discussion Conclusions Objectives

8. Introduction: Elast-Eon 2A 652 545 48% hard 40% hard 45% hard 52% soft 60% soft 55% soft Introduction Methodology Results Discussion Conclusions Objectives

9. Introduction: Dexamethaone Dexamethasone Dexamethasone acetate http://gxwonder.com/Pictures/Dexamethasone.jpg www.chemblink.com/structures/1177-87-3.gif The use of these two kinds of dexamethasone is to examine if there are differences in the way of the releasing regime. Introduction Methodology Results Discussion Conclusions Objectives

10. Dexamethasone has hydrophobic and lipophilic character not soluble in water ALLIUM Ltd. decided  to continue with the project without the Dexamethasone  claiming that the release will be in negligibleamount Results Discussion Conclusions Recommendations Work Process Introduction

11. Dexamethasone-water soluble Cyclodextrin • 2-hydroxypropyl - beta-cyclodextrin is a • water-soluble oligosaccharide. It can be used to dissolve lipophilic drugs, • such as Dexamethasone, in aqueous solutions.[36] • Dexamethasone-water soluble composed of 6% of Dexamethasone and 94% of 2-hydroxypropyl-beta-cyclodextrin 2-hydroxypropyl-beta-cyclodextrin Introduction Methodology Results Discussion Conclusions Objectives

12. OBJECTIVES • This work is aimed, to characterize and to find the drug release profile (Quantity) of Dexamethasone in PBS ( Phosphate buffered saline ) solution, from Polyurethane Silicone Copolymers (Elast-Eons). Notes: • PBS solution simulates human urine controlled at 37°C. • The copolymers are intended to coat stents, as a therapy for Prostatitis (inflammation in the prostate). Introduction Methodology Results Discussion Conclusions Objectives

13. Methodology • Three types of Polyurethane Silicone Copolymers (Elast-Eons) were prepared ( 2A, 545, 652) Each type consist of drug in various concentrations: • Dexamethasone (30%,40% and 50%) • Dexamethasone-water soluble (50%) Samples for Tests Temprature Control UV-Visible Absorption Introduction Methodology Results Discussion Conclusions Objectives

14. Tests Methods • DMTA - dynamic mechanical thermal analysis • Is used to determine the influence of drug concentration in the film, on the mechanical properties of the film. Hence, achieve the optimal mechanical properties. • UV - Visible Absorption • Is used to evaluate the amount of the eluted drug into the PBS solution. UV - Visible Absorption equipment in preparation step . Introduction Methodology Results Discussion Conclusions Objectives

15. Results – DMTA Results • The storage modulus decreases at 37°C from 0.58 x108 (Pa) for the film without drug, to 0.4 x108 Pa for the film with the drug ; Total decreases of 31%. The graphs present the change in the storage modulus as a function of temperature for EE2A EE2A without Dexamethasone EE2A-40% Dexamethasone Introduction Methodology Results Discussion Conclusions Objectives

16. Results - UV Visible Absorption Total released percents of Dexamethasone (%) Eluted from Elast-Eon Films after 11 weeks Introduction Methodology Results Discussion Conclusions Objectives

17. Results - UV Visible Absorption • Dexamethasone has hydrophobic • and lipophilic characters, which makes • it hard to release from any polymer • Matrix in aqueous solutions. • The hydrophobic Dexamethasone tends to interact with the hydrophobic soft segment (silicon). • The free volume of the soft segment (silicon) contributes to the drug ability to be released more easily. Introduction Methodology Results Discussion Conclusions Objectives

18. Results - UV Visible Absorption Total released percent of Dexamethasone water soluble Eluted from Elast-Eon Films, after 3 weeks Introduction Methodology Results Discussion Conclusions Objectives

19. Results - UV Visible Absorption • Dexamethasone-water soluble composed of 6% of Dexamethasone and 94% of 2-hydroxypropyl-beta-cyclodextrin, which is highly hydrophilic. This compound enables Dexamethasone to dissolve betterin the PBS solution. Introduction Methodology Results Discussion Conclusions Objectives

20. Results - UV Visible Absorption Comparison between the release of Dexamethasone and Dexamethasone - water soluble from E2A-50% after 21 days The release amount of Dexamethasone- water soluble is approximately greater ten (10) times more compared to the release amount of Dexamethasone! Introduction Methodology Results Discussion Conclusions Objectives Work Process

21. Conclusions • mechanical performance correlates with drug addition to matrix. Less drug in the matrix give higher mechanical performance. • The higher the percent of the soft segment, greater amount of the drug will be released. • The higher the drug concentration in the Elast-Eon films, greater amount of the drug will be released. • Drug with hydrophilic character will produce more release than drug with hydrophobic character Introduction Methodology Results Discussion Conclusions Objectives

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23. Results - Visual Quality Results • Dexamethasone and Dexamethasone acetateare hydrophobic and lipophilic materials. • "lipophilic" and "hydrophobic" are not synonymous, as can be seen with silicones, which are “hydrophobic “ but not “lipophilic” [35]. • According to the results, Dexamethasone acetate have much lower lipophilic character compared with Dexamethasone. • 30%dex-A, 2A at 40 min at 45ºC and 70ºC for 15 min. 50% dex 2A, 40 min at 45ºC and 70ºC for 15 min. Introduction Methodology Results Discussion Conclusions Objectives