Revolutionizing Sustained Local Drug Delivery

1. Revolutionizing Sustained Local Drug Delivery

2. A unique drug delivery platform � microfilm Legend for Figure �Duration of paclitaxel elution�: Release of paclitaxel from films loaded with 10% (w/w) paclitaxel (n = 3 per each time point) in phosphate buffered saline (just a buffer) at 37�C. ? an �in vitro� assay in a test tube basically, where, at a given time point, the remaining paclitaxel in each film was quantified by HPLC (a chromatographic technique used to separate, identify, and quantify compounds: the film is first dissolved, then the polymer precipitated, and the drug can be separated and the amount is determined in a calibrated process against standards) Legend for Figure �Freedom of locoregional recurrence�: A Kaplan-Meier analysis of freedom from locoreginal recurrence after tumor resection: After a complete resection of the primary tumors, mice were randomly assigned to either local implantation of Pax-loaded film (300 ?g paclitaxel per film), or unloaded film, or local subcutaneous injection of paclitaxel 300 ?g in cremophor/ethanol formulation (Pax-subcu.), or intraperitoneal injection of paclitaxel in cremorphor/ethanol formulation (Pax-ip.). * Freedom from locoregional recurrence in mice following implantation of Pax-loaded films was significantly greater than mice with unloaded film (P = .0001), Pax-ip. (P = .0011), Pax-Subcu. (P = .0003). Symbols represent censored mice due to lung metastases. Kaplan-Meier analysis: estimates the survival function from life-time data, with advantage that the method can take into account "censored" data (compare symbols) Figure tumors: Implantation of Pax-loaded film prevents local recurrence. A) Representative slide showing two large tumors adjacent to unloaded film 16 days after resection of primary tumor. Inset demonstrates tumor cells invading into unloaded film at area indicated by arrow. B) Absence of tumor cells around paclitaxel-loaded film 16 days after resection of primary tumor. Inset demonstrates absence of tumor cell on paclitaxel-loaded film at area indicated by arrow. Original magnification 4x (A, B) or 100x (insets in A, B) ? Primary tumor was created by subcutaneous, dorsal injections of LLC cells (Lewis Lung Carcinoma) Legend for Figure �Duration of paclitaxel elution�: Release of paclitaxel from films loaded with 10% (w/w) paclitaxel (n = 3 per each time point) in phosphate buffered saline (just a buffer) at 37�C. ? an �in vitro� assay in a test tube basically, where, at a given time point, the remaining paclitaxel in each film was quantified by HPLC (a chromatographic technique used to separate, identify, and quantify compounds: the film is first dissolved, then the polymer precipitated, and the drug can be separated and the amount is determined in a calibrated process against standards) Legend for Figure �Freedom of locoregional recurrence�: A Kaplan-Meier analysis of freedom from locoreginal recurrence after tumor resection: After a complete resection of the primary tumors, mice were randomly assigned to either local implantation of Pax-loaded film (300 ?g paclitaxel per film), or unloaded film, or local subcutaneous injection of paclitaxel 300 ?g in cremophor/ethanol formulation (Pax-subcu.), or intraperitoneal injection of paclitaxel in cremorphor/ethanol formulation (Pax-ip.). * Freedom from locoregional recurrence in mice following implantation of Pax-loaded films was significantly greater than mice with unloaded film (P = .0001), Pax-ip. (P = .0011), Pax-Subcu. (P = .0003). Symbols represent censored mice due to lung metastases. Kaplan-Meier analysis: estimates the survival function from life-time data, with advantage that the method can take into account "censored" data (compare symbols) Figure tumors: Implantation of Pax-loaded film prevents local recurrence. A) Representative slide showing two large tumors adjacent to unloaded film 16 days after resection of primary tumor. Inset demonstrates tumor cells invading into unloaded film at area indicated by arrow. B) Absence of tumor cells around paclitaxel-loaded film 16 days after resection of primary tumor. Inset demonstrates absence of tumor cell on paclitaxel-loaded film at area indicated by arrow. Original magnification 4x (A, B) or 100x (insets in A, B) ? Primary tumor was created by subcutaneous, dorsal injections of LLC cells (Lewis Lung Carcinoma)

3. Microfilm: Applicable to several areas Ipriflavone = a �bone builder� � a substance used used to slow down action of osteoclasts (= bone-eroding cells), allowing the osteoblasts (bone-building cells) to build up bone massIpriflavone = a �bone builder� � a substance used used to slow down action of osteoclasts (= bone-eroding cells), allowing the osteoblasts (bone-building cells) to build up bone mass

4. Microfilm can provide new alternatives to cancer treatment Why room for improvement: Lung cancer: Current drugs use Cremophor EL (a castor oil) as exipient (solubilizer), which has been called as a dose limiting agent because of its toxicities. Why room for improvement: Lung cancer: Current drugs use Cremophor EL (a castor oil) as exipient (solubilizer), which has been called as a dose limiting agent because of its toxicities.

5. Potential of Microfilm

6. Commercialization of Microfilms

7. Nanoparticles with breakthrough potential Figure �expansile properties��: Exapansile, paclitaxel-loaded nanoparticles (Pax-exNP) exhibit strongest effect on reduction of tumor mass. MARKETS: Oncology, orthopedics, cardiology, cardiology, endocrinology, Vaccine delivery, Pain therapy, Gene therapy and personalized medicine R&D required: Trafficking, targeting, delivery, safety and toxicity, metabolic studies? Figure �expansile properties��: Exapansile, paclitaxel-loaded nanoparticles (Pax-exNP) exhibit strongest effect on reduction of tumor mass. MARKETS: Oncology, orthopedics, cardiology, cardiology, endocrinology, Vaccine delivery, Pain therapy, Gene therapy and personalized medicine R&D required: Trafficking, targeting, delivery, safety and toxicity, metabolic studies?

8. Nanoparticles: Continue research Prelim data shows nanoparticles loaded with a fluorescent dye. The trace that can be seen results from particles migrating to lymph node (brightest �blob�) Establish biodistribution: includes answering questions like liver accumulation, toxicity, can it cross Blood-brain-barrier? What is the half live of particles in vivo Prelim data shows nanoparticles loaded with a fluorescent dye. The trace that can be seen results from particles migrating to lymph node (brightest �blob�) Establish biodistribution: includes answering questions like liver accumulation, toxicity, can it cross Blood-brain-barrier? What is the half live of particles in vivo

9. Interviews to date IP Analysis FDA Assessment Market Assessment Costs and time to market Research slides Appendix

10. Interviews To date Appendix

11. Interviews To Date

12. Interviews To Date

13. IP analysis Appendix

14. IP - What do we own?

15. IP Landscape � part 1

16. IP Landscape � part 2

18. FDA assessment Appendix

19. FDA Regulatory Approval Issues

20. FDA Regulatory Approval Issues: Office of Combination Products

21. FDA Regulatory Approval Issues: Office of Combination Products

22. Approval as a Drug: FDA New Drug Development Process

23. FDA New Drug Development Process

24. Approval as a Device: FDA New Drug Development Process

25. Market Assessment Appendix

26. Lung Cancer Treatment Potential

27. Orthopedics Potential

28. Cost and time to market Appendix

29. Timeline to Market � Microfilm Start-up

30. Annual Cost Breakdown (Year 1 &2)

31. Cost to Produce

32. Cost to Produce

33. Research slides (will ne included for final presentation) Appendix