polymorphine: an innovative biodegradable polymer drug for extended pain relief kathryn uhrich...
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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
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
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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
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
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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
Dru
g le
vel
Therapeuticlevel
Doset = 0
Dose Dose Dose Timet = n
ConventionalAdministration
ControlledRelease
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
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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
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• 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
6n
+
Polymerization
Drug
Drug Drug Drug 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
PolyAspirin
• PolyAspirin designed to release salicylic acid in a controlled manner
Erdmann, L.; Uhrich, K., Biomaterials 2000, 21 (19), 1941-1946;
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Salicylic acid Acetic acid
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
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
– Development 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 levelD
rug le
vel
Therapeuticlevel
Doset = 0
Dose Dose Dose Timet = n
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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
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• 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
• 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
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• Demonstrated that an opioid-based polymer was possible
PolyNalbuphine: Model System
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• Low yield
• Low Mw
• Difficult to purify
SolutionPolymerization
• High yield
• High Mw
• Pure polymer
PolyMorphine Synthesis
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Characterization
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Rosario-Meléndez, R. et.al. J. Control. Rel. (2012), doi: 10.1016/j.jconrel.2012.07.033
• 13C-NMR shows that morphine’s structure was preserved
• IR shows the presence of key functional groups
• Comparable viability: cytocompatibility
Characterization
• 13C-NMR shows that morphine’s structure was preserved
Rosario-Meléndez, R. et.al. J. Control. Rel. 2012, 162, 538-544
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• IR shows the presence of key functional groups
Characterization
Rosario-Meléndez, R. et.al. J. Control. Rel. 2012, 162, 538-544
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Cytocompatibility
• Cytocompatibility: comparable viability
*By Roberto Delgado-Rivera
Rosario-Meléndez, R. et.al. J. Control. Rel. 2012, 162, 538-544
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By Roberto Delgado-Rivera
Polymer
PolyMorphine Degradation
• PolyMorphine degradation was studied in vitro mimicking physiological conditions
• HPLC method was developed
• PolyMorphine degrades to release free morphineRosario-Meléndez, R. et.al. J. Control. Rel. 2012, 162, 538-544
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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).
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In collaboration with Dr. Lei Yu and Carolyn Harris
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
Nociceptivepain
Analgesia
hot hothot
Withdrawal reflex(~10 s)
No withdrawal(for 30 s)
Rosario-Meléndez, R. et.al. J. Control. Rel. 2012, 162, 538-544
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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 morphineRosario-Meléndez, R. et.al. J. Control. Rel. 2012, 162, 538-544
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• 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
TF
L (
tim
e)
Non-tolerant TolerantUntreated
Analgesia
After receiving the same treatment
Needs higher dose(not desired)
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• 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
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Rosario-Meléndez, R. et.al. J. Control. Rel. 2012, 162, 538-544
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
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Acknowledgements
• Insert acknowledgements here
Johnson & JohnsonProof-of-Concept Fund