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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

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Page 1: PolyMorphine: an Innovative Biodegradable Polymer Drug for Extended Pain Relief Kathryn Uhrich November 28, 2012 Department of Chemistry & Chemical Biology

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

Page 2: PolyMorphine: an Innovative Biodegradable Polymer Drug for Extended Pain Relief Kathryn Uhrich November 28, 2012 Department of Chemistry & Chemical Biology

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

Page 3: PolyMorphine: an Innovative Biodegradable Polymer Drug for Extended Pain Relief Kathryn Uhrich November 28, 2012 Department of Chemistry & Chemical Biology

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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Page 4: PolyMorphine: an Innovative Biodegradable Polymer Drug for Extended Pain Relief Kathryn Uhrich November 28, 2012 Department of Chemistry & Chemical Biology

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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Page 5: PolyMorphine: an Innovative Biodegradable Polymer Drug for Extended Pain Relief Kathryn Uhrich November 28, 2012 Department of Chemistry & Chemical Biology

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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Page 6: PolyMorphine: an Innovative Biodegradable Polymer Drug for Extended Pain Relief Kathryn Uhrich November 28, 2012 Department of Chemistry & Chemical Biology

• 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

Page 7: PolyMorphine: an Innovative Biodegradable Polymer Drug for Extended Pain Relief Kathryn Uhrich November 28, 2012 Department of Chemistry & Chemical Biology

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

Page 8: PolyMorphine: an Innovative Biodegradable Polymer Drug for Extended Pain Relief Kathryn Uhrich November 28, 2012 Department of Chemistry & Chemical Biology

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

Page 9: PolyMorphine: an Innovative Biodegradable Polymer Drug for Extended Pain Relief Kathryn Uhrich November 28, 2012 Department of Chemistry & Chemical Biology

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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Page 10: PolyMorphine: an Innovative Biodegradable Polymer Drug for Extended Pain Relief Kathryn Uhrich November 28, 2012 Department of Chemistry & Chemical Biology

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

Page 11: PolyMorphine: an Innovative Biodegradable Polymer Drug for Extended Pain Relief Kathryn Uhrich November 28, 2012 Department of Chemistry & Chemical Biology

• 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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Page 12: PolyMorphine: an Innovative Biodegradable Polymer Drug for Extended Pain Relief Kathryn Uhrich November 28, 2012 Department of Chemistry & Chemical Biology

• Demonstrated that an opioid-based polymer was possible

PolyNalbuphine: Model System

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Page 13: PolyMorphine: an Innovative Biodegradable Polymer Drug for Extended Pain Relief Kathryn Uhrich November 28, 2012 Department of Chemistry & Chemical Biology

• Low yield

• Low Mw

• Difficult to purify

SolutionPolymerization

• High yield

• High Mw

• Pure polymer

PolyMorphine Synthesis

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Page 14: PolyMorphine: an Innovative Biodegradable Polymer Drug for Extended Pain Relief Kathryn Uhrich November 28, 2012 Department of Chemistry & Chemical Biology

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

Page 15: PolyMorphine: an Innovative Biodegradable Polymer Drug for Extended Pain Relief Kathryn Uhrich November 28, 2012 Department of Chemistry & Chemical Biology

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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Page 16: PolyMorphine: an Innovative Biodegradable Polymer Drug for Extended Pain Relief Kathryn Uhrich November 28, 2012 Department of Chemistry & Chemical Biology

• 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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Page 17: PolyMorphine: an Innovative Biodegradable Polymer Drug for Extended Pain Relief Kathryn Uhrich November 28, 2012 Department of Chemistry & Chemical Biology

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

Page 18: PolyMorphine: an Innovative Biodegradable Polymer Drug for Extended Pain Relief Kathryn Uhrich November 28, 2012 Department of Chemistry & Chemical Biology

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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Page 19: PolyMorphine: an Innovative Biodegradable Polymer Drug for Extended Pain Relief Kathryn Uhrich November 28, 2012 Department of Chemistry & Chemical Biology

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

Page 20: PolyMorphine: an Innovative Biodegradable Polymer Drug for Extended Pain Relief Kathryn Uhrich November 28, 2012 Department of Chemistry & Chemical Biology

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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Page 21: PolyMorphine: an Innovative Biodegradable Polymer Drug for Extended Pain Relief Kathryn Uhrich November 28, 2012 Department of Chemistry & Chemical Biology

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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Page 22: PolyMorphine: an Innovative Biodegradable Polymer Drug for Extended Pain Relief Kathryn Uhrich November 28, 2012 Department of Chemistry & Chemical Biology

• 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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Page 23: PolyMorphine: an Innovative Biodegradable Polymer Drug for Extended Pain Relief Kathryn Uhrich November 28, 2012 Department of Chemistry & Chemical Biology

• 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

Page 24: PolyMorphine: an Innovative Biodegradable Polymer Drug for Extended Pain Relief Kathryn Uhrich November 28, 2012 Department of Chemistry & Chemical Biology

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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Page 25: PolyMorphine: an Innovative Biodegradable Polymer Drug for Extended Pain Relief Kathryn Uhrich November 28, 2012 Department of Chemistry & Chemical Biology

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Acknowledgements

• Insert acknowledgements here

Johnson & JohnsonProof-of-Concept Fund