1. PolyMorphine: an Innovative Biodegradable Polymer Drug for Extended Pain Relief Kathryn Uhrich November 28, 2012 Department of Chemistry & Chemical Biology Rutgers, The State University of New Jersey

2. Pain Acute pain- comes on quickly, can be severe, of short duration Chronic pain- ongoing pain lasting beyond the usual course of acute illness or injury Nociceptive pain demands immediate action Inflammatory pain helps in the healing process Pathological pain characterized by extended discomfort and abnormal sensitivity 2 Pain – an unpleasant sensory and emotional experience associated with actual or potential tissue damage Woolf, C.J. J. Clin. Inv. 2010, 120, 3742-3744; Millan, M.J. Prog. Neutobiol. 1999, 57, 1-164; Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. The National Academies of Press: Washington, DC, 2011. Loss of productivity and daily activity Duration and Intensity Cause

3. Analgesia & Analgesics Analgesia – absence of pain in response to a stimulus that would normally be painful Opioids – compounds that binds to an opioid receptor -Side effects: tolerance, addiction, respiratory depression, somnolence, and gastrointestinal effects (e.g., nausea, vomiting, and constipation) -Short half-life in plasma results in frequent dosing which increase side effects Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. The National Academies of Press: Washington, DC, 2011; Aronson, J. K., Analgesic and Anti-inflammatory Drugs. First ed.; Elsevier: San Diego, CA, 2010 3

4. Why Controlled Drug Release? Plasma drug concentrations proportional to the dose Requires repeated administration Drug is distributed throughout the body Maintain therapeutic levels by a single administration Drug preservation and protection Localize drug delivery Increase patient comfort and improve compliance Ineffective level Toxic level Drug level Therapeutic level Dose t = 0 Dose Time t = n Conventional Administration Controlled Release Koppert, W. Acute Pain 2007, 9, 21; Hagen, N.A. et.al. J. Pain Symptom. Manage. 2005, 29, 80; Vermeire, A. et.al. Int. J. Pharm. 1999, 187, 17;Abouhammoud, H. et.al. Pain 2009, 144, 139; Olsson, B. et.al. Int. J. Pharm. 1995, 119, 223 Drug Delivery Systems 4

5. Biodegradable Delivery Systems Drug is physically incorporated (mixed) into a biocompatible polymer matrix –Drug is protected by the polymer Drug migrates from the polymer to the body –Drug is released in a controlled manner After all drug is released, surgical removal of the polymer is not necessary –Polymer contains labile bonds t = 0 t = n Jain, J. P. et.al. Journal of Controlled Release 2005, 103 (3), 541-563; Dash, A. K. et.al. Journal of Pharmacological and Toxicological Methods 1998, 40 (1), 1- 12; Kipper, M. J. et.al. Biomaterials 2002, 23 (22), 4405-4412; Kumar, N. et.al. Adv Drug Deliv Rev 2002, 54 (7), 889-910. polymer drug 5

6. Physical incorporation of a drug in a polymer-based delivery systems are an improvement to conventional administration Drawbacks: –Incorporate low percentages of drug –High potential for drug separation (accidental or intentional) –Drug is released with a burst Polymeric Drugs can address most of the drawbacks 6 n + Polymerization Drug –Chemically incorporate –Increase drug loading (> 50 % drug) –Prevent accidental/intentional drug separation –Drug released via hydrolytic degradation of the polymer backbone Biodegradable Delivery Systems

7. PolyAspirin PolyAspirin designed to release salicylic acid in a controlled manner Erdmann, L.; Uhrich, K., Biomaterials 2000, 21 (19), 1941-1946; 7 Salicylic acid Acetic acid

8. PolyMorphine: an Innovative Biodegradable Polymer Drug for Extended Pain Relief Goals: Chemical incorporation of morphine into a biodegradable polymer backbone Provide extended analgesia Reduce side effects 8

9. Morphine Morphine is the drug of choice for the treatment of chronic pain Disadvantages: –Short half-life in plasma (3-4 hours) : requires frequent dosing –D evelopment of tolerance : increases the amount of drug needed to obtain the same effect Koppert, W. Acute Pain 2007, 9, 21; Hagen, N.A. et.al. J. Pain Symptom. Manage. 2005, 29, 80; Vermeire, A. et.al. Int. J. Pharm. 1999, 187, 17;Abouhammoud, H. et.al. Pain 2009, 144, 139; Olsson, B. et.al. Int. J. Pharm. 1995, 119, 223 http://www.smartplanet.com/blog/rethinking- healthcare/why-morphine-prevents-ptsd/756 Ineffective level Toxic level Drug level Therapeutic level Dose t = 0 Dose Time t = n 9

10. Morphine Delivery Physical incorporation within a polymer –Orally administrated –Drug effect lasts up to 1 day –Relatively low drug loading (< 30%) –High risk for accidental overdose Olsson, B. et.al. Int. J. Pharm. 1995, 119, 223; Holgado, M.A. et.al. Eur. J. Pharm. Biopharm. 2008, 70, 544; Alvarez-Fuentes, J. et.al. Int. J. Pharm. 1996, 139, 237; Polard, E. et.al. Int. J. Pharm. 1996, 134, 37; Morales, M.E. et.al. J. Control. Release. 2004, 95, 75; Mahkam, M. et.al. Polym. Deg. Stab. 2003, 80, 199; Erdmann, L. et.al. Biomaterials 2000, 21, 1941; Anasrasiou, T.J. et.al. J. Polym. Sci. 2003, 41, 3667 10 Chemical incorporation into the polymer backbone –Implantable –Drug effect can last days to months –Increases drug loading (> 50%) –Drug cannot be physically separated polymer morphine Extended release PolyMorphine

11. Salicylic acid and similar NSAIDs have structures with 2 different functional groups (1 OH and 1 COOH) Morphine contains 2 OHs Catechol is more similar to morphine (2 OH groups) Nalbuphine used as model compound Salicylic acid Catechol Nalbuphine Polymer Design 11

12. Demonstrated that an opioid-based polymer was possible PolyNalbuphine: Model System 12

13. Low yield Low M w Difficult to purify Solution Polymerization High yield High M w Pure polymer PolyMorphine Synthesis 13

14. Characterization 14 Rosario-Meléndez, R. et.al. J. Control. Rel. (2012), doi: 10.1016/j.jconrel.2012.07.033 13 C-NMR shows that morphine’s structure was preserved IR shows the presence of key functional groups Comparable viability: cytocompatibility

15. Characterization 13 C-NMR shows that morphine’s structure was preserved Rosario-Meléndez, R. et.al. J. Control. Rel. 2012, 162, 538-544 15

16. IR shows the presence of key functional groups Characterization Rosario-Meléndez, R. et.al. J. Control. Rel. 2012, 162, 538-544 16

17. Cytocompatibility Cytocompatibility: comparable viability *By Roberto Delgado-Rivera Rosario-Meléndez, R. et.al. J. Control. Rel. 2012, 162, 538-544 17 By Roberto Delgado-Rivera Polymer

18. PolyMorphine Degradation PolyMorphine degradation was studied in vitro mimicking physiological conditions HPLC method was developed PolyMorphine degrades to release free morphine Rosario-Meléndez, R. et.al. J. Control. Rel. 2012, 162, 538-544 18

19. http://jaxmice.jax.org/images/jaxmicedb/featuredImage/000664_lg.jpg In Vivo Studies Solution or suspension in 5 % Cremophor EL (aq) were used –Cremophor EL is polyethoxylated castor oil and has no effect on behavioral tests Drug dosing: –Free morphine HCl at 10 mg/kg (standard dose) *Higher concentration of morphine after a single administration does not result in an extended analgesic effect –Diacid at 50 mg/kg –PolyMorphine at 200 mg/kg 30 animals in each drug group at the beginning of the study –Adult male C57Bl/6J mice –Most widely used inbred strain Treatments were administered via intraperitoneal injection Rosario-Meléndez, R. et.al. J. Control. Rel. 2012, 162, 538-544; All animal procedures were approved by the Institutional Animal Care and Use Committee (IACUC) at Rutgers University, and consistent with the Guide for the Care and Use of Laboratory Animals (National Institutes of Health, 2011). 19 In collaboration with Dr. Lei Yu and Carolyn Harris

20. Tail-flick Latency Test Tail-flick latency (TFL) test was used to assess nociceptive behavior and morphine sensitivity –Measures response to thermal stimulus –Main end point is a withdrawal response The distal third of the animal’s tail is immersed in a water bath at 49 °C –Baseline response was 10 s –TFL time was recorded with a 30 s cutoff time to avoid tissue damage Nociceptive pain Analgesia hot Withdrawal reflex (~10 s) No withdrawal (for 30 s) Rosario-Meléndez, R. et.al. J. Control. Rel. 2012, 162, 538-544 20

21. Analgesic Effect At the 4h time point, the analgesic effect of free morphine was completely gone The diacid showed a similar time course of analgesic effect as free morphine PolyMorphine maintained strong analgesia over 24h –Analgesic effect was detectable after 3 days 20-times the analgesic window of free morphine Rosario-Meléndez, R. et.al. J. Control. Rel. 2012, 162, 538-544 21

22. Tolerance development with repeated exposure is a well- known side effect of the extended use of morphine –Both in rodent and human Morphine Sensitivity TFL Williams, J.T. et.al. Physiol. Rev. 2001, 81, 299-343; Harrison, L.M. et.al. Peptides, 1998, 19, 1603-1630 Cutoff time TFL (time) Non-tolerant TolerantUntreated Analgesia After receiving the same treatment Needs higher dose (not desired) 22

23. To test morphine sensitivity animals were subjected to an acute morphine dose –10 mg/kg of free morphine in 5 % Cremphor EL in saline –Day 3 and 14 (TFL) All mice showed full responsiveness to acute morphine challenge Morphine Sensitivity 23 Rosario-Meléndez, R. et.al. J. Control. Rel. 2012, 162, 538-544

24. Summary PolyMorphine was synthesized and its physicochemical properties were fully characterized In vitro studies were performed to determine the degradation pathway of the polymer and a key intermediates In vitro cytocompatibility studies showed that PolyMorphine is non-cytotoxic towards fibroblasts When administered in vivo, PolyMorphine provided sustained analgesia for up to 3 days PolyMorphine may offer a desirable option as a long-acting, low abuse liability alternative to conventional opioid analgesics 24

25. 25 Acknowledgements Insert acknowledgements here Johnson & Johnson Proof-of-Concept Fund