University of Kentucky UKnowledge Pharmaceutical Sciences Faculty Patents Pharmaceutical Sciences 4-29-2014 Opioid-Ketamine and Norketamine Codrug Combinations for Pain Management Joseph R. Holtman University of Kentucky, [email protected] Peter A. Crooks University of Kentucky, [email protected] Ujjwal Chakraborty University of Kentucky, [email protected] Right click to open a feedback form in a new tab to let us know how this document benefits oy u. Follow this and additional works at: https://uknowledge.uky.edu/ps_patents Part of the Pharmacy and Pharmaceutical Sciences Commons Recommended Citation Holtman, Joseph R.; Crooks, Peter A.; and Chakraborty, Ujjwal, "Opioid-Ketamine and Norketamine Codrug Combinations for Pain Management" (2014). Pharmaceutical Sciences Faculty Patents. 32. https://uknowledge.uky.edu/ps_patents/32 This Patent is brought to you for free and open access by the Pharmaceutical Sciences at UKnowledge. It has been accepted for inclusion in Pharmaceutical Sciences Faculty Patents by an authorized administrator of UKnowledge. For more information, please contact [email protected]. US. Patent Apr. 29, 2014 Sheet 1 017 US 8,710,070 B2 Enhancement of Morphine (MOR) Antinociception with S-Norketamine Taii~Fiick Test intraperiioneal Administration (IP) L i \ i L TAiLFUCKLATENCY(s) O) I MOR (Snig/kg) O _ Q SWNK(3mg/kg) MOR<3mg/kg)+s-NK A 0.75 v 1.5 Q 3 i i i i i 1 i FiG. 1A O 20 4O 60 80 100 120 TIME (min) Enhancement of Morphine (MOR) Antinociception with S-Norketamine (S-NK) Taii~Fiick Test intrathecal Administration (iT) HG- 1B W B * 100 [T-J S_NK 7 ? MOR 80 _ MOR + S-NK 60 ~ * / %MAXIMUMPOSSiBLEEFFECT(%MPE 40 ~ % 20 ~ additive effect 0 __*Ei__,1i...3 MGR - 3 DOSE (mg/kg; iP) Mean 11" SEM (n = 8 rats); * Different from MOR (3 mG/Ko) aione (P<0.05: Dost-hock SNK) US. Patent Apr. 29, 2014 Sheet 2 0f7 US 8,710,070 B2 Enhancement of Morphine (MOR) Antinociception with S-Norketarnine (S-NK) Taii~Flick Test lntrathecal Administration (IT) 14 ~ A Q saline MOR (O?mcg) + S-NK ’0‘; I S'NKUOOmcg) Y 10mcg V 12 ' A MOR(O.5mOQ) 0 5011109 6 ‘ 100mcg ZLu 10 5 8 ~ 6 6 " \ 3 \ u. \I d 4 u IT‘JIRT‘ ? 2 , O i i i \ i l 1"“ 0 3O 60 90 120 150 180 FiG. 2A TIME (min) Enhancement of Morphine (MOR) Antinociception with S-Norketamine (S'NK) Taii~Flick Test SJ intrathecai Administration (1T) FIG“ ZB 2 2*”, 100 » B i».. 0 mE 80 w w S-NK + MOR * LLJ @ 60 ~ / c!) U) 1: g 40 m ,1 E additive effect H :3 E 20 ~*'—"“‘“"—'* “n “Wm M "W >< ,, E<1: n c\@ O S-NK 100 ~ 10 50 100 - MOR — 0.5 0.5 0.5 0.5 30 DOSE (meg) Mean +/— SEM (n = 7-9 rats); * Different from MOR (0.5 mcg) alone (P<0.06; post/hoe SNK) US. Patent Apr. 29, 2014 Sheet 3 0f7 US 8,710,070 B2 Enhancement of Morphine (MGR) Antiallodynia with S~Norketamine (S-NK) Chronic Constriction Nerve Injury (CCi) Intraperitoneai Administration (1P) § 20 C1 , A 6 O saline MOR (1mglkg) + S—NK I [I] MOR (1mg/kg) V 2mg/kg w 15 ~ A S-NK (8mg/kg) <> 4mg/kg LU O 8mg/kg E 5 “1121 e 0 " E i i i i i i i O 20 4O 60 80 100 120 FIG. 3A TiME (min) Enhancement of Morphine (MOR) Antiaiiodynia with S-Norketamine (S-NK) Chronic Constriction Nerve Injury (CC!) HG_ 3B g? lntraperitoneai Administration (1P) <~ B >0(.3 100 .M *— ? 80 e k " E MOR + S'NK w 60 ~ _.i 99 m g 40 @— additive effect T E M~,__m__:_ W-“ .__‘_ D 20 ~ 2 >< g 0 i a? S-NK a - 2 MOR - i 1 DOSE (mg/kg) Mean +/~ SEM- * Different from MOR (1 rng/kg) alone (P<U_05; posbhcc SNK) US. Patent Apr. 29, 2014 Sheet 4 0f 7 US 8,710,070 B2 Enhancement of Morphine (MGR) Antihyperalgesia with S~Norketarnine (S—NK) Chronic Constriotion Nerve Injury (CCI) e Intraperitoneai Administration (IP) O A (—31 II MGR (3mg/kg) I 0 S-NK(1mg/kg) a 300 m MOR (Ems/k9) +' S<NK A 0.01 v 0.1 Q 1 DC I I— e g 200 ~~ 3 <1: 8 > 100 ~ poleC/_ I I I I I F‘G. O 30 60 90 120 TIME (min) Enhancement of Morphine (MOR) Antihyperaigesia with S~Norketamine (S-NK) Chronic Constriotion Nerve Injury (CCI) lntraperitoneai Administration (IP) FIG“ 4B A 120 - E MOR B E [:11 MM f $5 100 " w“ MORI-S—NK * i LU6 80 ~ & LLI * / LU 60 - 55 a '5 40 ~ . C!) O additive effect a. e-_-~___~-_ Mun“ -_W --_~_— ~-~ % 20 v 55E O m E SNK 1 - 001 0,1 1 _ $3 MOR , 3 3 3 3 1O DOSE (mg/Kg) Mean +/~ SEM * Different from MOR (3 mg/kg) alone (P<0005; post-hoe SNK) US. Patent Apr. 29, 2014 Sheet 5 0f7 US 8,710,070 B2 “M g :NFE;L 0 1HNMR US. Patent Apr. 29, 2014 Sheet 6 0f 7 US 8,710,070 B2 Nwm.-\w35/0 omion p mwohmvmmm.in"? _// wowdm; LP/528 \/ \I mwmwowmnmdmr _0zO O US. Patent Apr. 29, 2014 Sheet 7 0f 7 US 8,710,070 B2 oomomw“x22 3G- 21,98,,0be».,0?»_.03.b3.Ev.E8.0? mmicmow.wom.oN23Mmowvwo(.6166wewnmEzdamP092mt.mmm.r \0 INNS - m.@vm\$8 3mm1 x8 S| 18 13 wvmuE N.5 US 8,710,070 B2 1 OPIOID-KETAMINE AND NORKETAMINE CODRUG COMBINATIONS FOR PAIN MANAGEMENT 1'6 O X N This application claims priority from US. Provisional m T T \RZ Patent Application No. 61/072,090, ?led Mar. 27, 2008, the O O disclosure of which is hereby incorporated by reference in its entirety. wherein X is nothing, O, S, NH, NR4 (R4:alkyl), (CH2),C (where x:l-20, and the alkane moiety can be linear or FIELD OF THE INVENTION branched), and wherein R2-NiR3 is a norketamine moiety (R3:H) or a ketamine moiety (R3:CH3), and Rl-O is an The present invention relates to the ?eld of pain manage opioid moiety. ment, and more particularly to synergistic codrugs compris ing an opioid and ketamine or norketamine which have been In another embodiment, the present invention provides a combined to form a single chemical codrug entity. When the method of synthesis of a codrug comprising a linker, an codrug is administered it produces a synergistic analgesic opioid and a ketamine or a norketamine, said method com response to pain. prising: a) covalently bonding a ?rst attachment point of the linker to the opioid; b) covalently bonding a second attach BACKGROUND OF INVENTION ment point of the linker to the ketamine or norketamine; and 20 c) recovering the codrug, wherein the norketamine is selected Opioids are any endogenous or exogenous compounds that from the group consisting of S-norketamine, R-norketamine, bind to an opioid receptor. Opioid receptors are localized and racemic norketamine; and wherein the ketamine is primarily in the brain, spinal cord, and gastrointestinal tract. selected from the group consisting of S-ketamine, R-ket There are four broad groups of opioids: endogenous opioid amine, and racemic ketamine. peptides produced in the body; naturally occurring opioid 25 alkaloids such as morphine and codeine; semisynthetic opio In a further embodiment, the present invention provides a ids such as hydrocodone and oxycodone, and synthetic opio method of treatment comprising joining an opioid together ids such as fentanyl and methadone. When opioids bind to with a ketamine or a norketamine using a linker to form a their receptors in the brain and spinal cord they block pain cleavable codrug; and administering an analgesically effec transmission signals from the periphery of the body. Although tive amount of the codrug to a human patient, wherein the opioids are very effective for moderate to severe pain, there 30 norketamine is selected from the group consisting of S-nor are many well known problems associated with opioid ketamine, R-norketamine, and racemic norketamine and therapy. Those problems include serious side effects such as wherein the ketamine is selected from the group consisting of cognitive dysfunction, respiratory depression, nausea/vomit R-ketamine, S-ketamine and racemic ketamine. ing, urinary retention, and constipation. Further, chronic opioid therapy often results in the development of tolerance to 35 BRIEF DESCRIPTION OF THE DRAWINGS the analgesic effect (resulting in dose escalation) as well as physical and psychological dependence. FIG. 1 is a graph illustrating the effect of S-norketamine N-methyl-D-aspartate antagonists are known to be effec and morphine (MOR) combinations, using the tail ?ick test, tive in suppressing the symptoms of opiate withdrawal. The via intraperitoneal administration. FIG. 1A shows tail ?ick anesthetic ketamine is the most potent N-methyl-D-aspartate 40 latencies, and FIG. 1B shows the maximum possible effect. antagonist available in clinical practice. See, for example, FIG. 2 is a graph illustrating the effect of S-norketamine WO/2004/045601. There is a great need for analgesic medications able to and morphine (MOR) via the tail ?ick test, using intrathecal provide high e?icacy pain relief while providing more favor administration. FIG. 2A shows tail ?ick latencies, and FIG. able pharmacokinetics and reducing the possibility of unde 2B shows the maximum possible effect. 45 sirable effects. Therefore, there is a need for a way to admin FIG. 3 is a graph illustrating the effect of morphine (MOR) ister opioids and norketamine to provide a more favorable and with S-Norketamine (S-NK) using chronic constriction nerve pharmacokinetic pro?le.