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US 2015/0258104 A1 Friedhoff (43) Pub US 20150258104A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0258104 A1 Friedhoff (43) Pub. Date: Sep. 17, 2015 (54) USE OF NORIBOGAINE FOR THE Publication Classification TREATMENT OF PAN (51) Int. Cl. (71) Applicant: psy Rx. Inc., Fort Lauderdale, FL A613 L/55 (2006.01) (52) U.S. Cl. (72) Inventor: Lawrence Friedhoff, River Vale, NJ CPC ...................................... A6 IK3I/55 (2013.01) (US) (73) Assignee: DemeRX, Inc., Fort Lauderdale, FL (US) (57) ABSTRACT (21) Appl. No.: 14/624,276 (22) Filed: Feb. 17, 2015 This invention is directed tO methods of treating pain in O O patients comprising treating patients with noribogaine at a Related U.S. Application Data dosage that provides an average serum concentration of 50 (60) Provisional application No. 61/952,738, filed on Mar. ng/mL to 180 ng/mL, including under conditions where the 13, 2014, provisional application No. 62/005,855, QT interval prolongation does not exceed about 50 millisec filed on May 30, 2014. onds. Patent Application Publication Sep. 17, 2015 Sheet 1 of 9 US 2015/0258104 A1 FIGURE 1 38: 3: . 388: 888&g: 3:38 38 ::. i:::::::::::8:333i:es::::::::::::::::::iises & c. E. s. 3.was... 883r. 3: . 3.& & 8s 3. s & : - 3 8:: : - & 3. 3. 3:38 38: 388 333 333 $ii:::::::: Patent Application Publication Sep. 17, 2015 Sheet 2 of 9 US 2015/0258104 A1 FIGURE 2 3 2. 3. 33 2: 38 g: 3. 33 33.3 83. 3:32 23. ;:3& 8:: Patent Application Publication Sep. 17, 2015 Sheet 3 of 9 US 2015/0258104 A1 S.s S. s c R { f 8. i s N tem sm (u?u) auoo unies Patent Application Publication Sep. 17, 2015 Sheet 4 of 9 US 2015/0258104 A1 FIGURE 4 Time to OST (hr) Patent Application Publication Sep. 17, 2015 Sheet 5 of 9 US 2015/0258104 A1 FIGURES $osio of 83.38: {{SS isior to 38: Rs.33:33. 3 3 ::::::::::: &:::::::::::: 8:33 &:::::::::g::::::33:38 &:::::::::::::::: 383 : s: Box includes values representing 25% - 75% quartiles. Diamond a median crossbar in box = mean; whiskers - values within standard deviation of mid-quartiles. No outliers present. Patent Application Publication Sep. 17, 2015 Sheet 7 of 9 US 2015/0258104 A1 FIGURE 7A Siezsa {ixage in 3888; 3.8 Sears 3:r Fix's 88is sailowing 88sixg 88 triar 88.S: 38sassig338g. :8. FIGURE 7B via & Ci{3-8 ; citatise of the 33 Sixia Scare Cisage first 8ssite isig Rettia itsis : 8ssssseat cut it 8 it's *:::::: &sixgain: 3:3:38 8xieg33i: 3.3 xg 38er;8:33:3& 388 mg Patent Application Publication Sep. 17, 2015 Sheet 9 of 9 US 2015/0258104 A1 FIGURE 9A are Cohor rtriesha: 2 Me-chor: 3 Ma9:a::::: Since after dosing haurs: FIGURE 9B y: 8,3883 & 8, 3.333.2 . .8:8883S kiosia agai& Carssentatis US 2015/0258 104 A1 Sep. 17, 2015 USE OF NORIBOGAINE FOR THE nociceptors are stimulated and Subsequently transmit signals TREATMENT OF PAN through sensory neurons in the spinal cord. The signals are then transmitted to the brain, at which point the individual CROSS-REFERENCE TO RELATED becomes aware of the pain. APPLICATIONS 0007. There are a number of pain categories and classifi 0001. This application claims benefit from U.S. Provi cations, which for example, can be grouped into four catego sional Application No. 61/952,738, filed Mar. 13, 2014, and ries according to the source and related nociceptors: (1) cuta U.S. Provisional Application No. 62/005,855, filed May 30, neous pain; (2) Somatic pain; (3) visceral pain; and (4) 2014, which are hereby incorporated by reference in their neuropathic pain. Other pain classifications include acute entirety. pain and chronic pain. Acute pain is defined as short-term pain or pain with an easily identifiable cause. Acute pain FIELD OF THE INVENTION indicates present damage to tissue or disease and may be “fast' and “sharp' followed by aching pain. Acute pain is 0002 This invention is directed to methods of treating centralized in one area before becoming somewhat spread pain in patients comprising treating patients with nori out. Acute pain generally responds well to medications (e.g., bogaine, noribogaine derivative, or pharmaceutically accept morphine). able salt and/or Solvate thereof at a dosage that provides a 0008 Chronic pain may be medically defined as pain that therapeutic serum concentration. In one embodiment, the has lasted six months or longer. This constant or intermittent average serum concentration is 50 ng/mL to 180 ng/mL, pain has often outlived its purpose because it does not help the including under conditions where the QT interval prolonga body to prevent injury. It is often more difficult to treat than tion does not exceed about 50 milliseconds, and preferably acute pain. Expert care is generally necessary to treat any pain about 30 milliseconds. that has become chronic. In addition, stronger medications are typically used for extended periods in an attempt to con STATE OF THE ART trol the pain. This can lead to drug dependency. For example, 0003) Noribogaine is sometimes referred to as 12-hy opioids are used in some instances for prolonged periods to droxyibogaine. U.S. Pat. No. 2,813,873 claims noribogaine control chronic pain. Drug tolerance, chemical dependency, albeit as “12-O-demethylibogaine' while providing an incor and even psychological addiction may occur. rect structural formula for ibogaine. Noribogaine can be 0009 Debilitating chronic pain affects tens of millions of depicted by the following formula: people annually and costs hundreds of millions of dollars in terms of medication, physical therapy, and lost production. The current methods for treating chronic pain have a limited Success rate and in some cases may result in chemical depen dency. HO C2H5. 0010 Numerous treatments have been developed in N attempts to ameliorate pain in its various categories. How N ever, in many cases, treatment requires the use of addictive or H habit-forming Substances (e.g., morphine or methadone). While the prior art suggests that ibogaine at higher doses is 0004 Noribogaine and its pharmaceutically acceptable useful as a treatment for pain, use of ibogaine is associated salts have recently received significant attention as a non with hallucinations and other negative side effects. In the addictive alkaloid useful in treating drug dependency (U.S. United States, ibogaine is classified as a Schedule I controlled Pat. No. 6,348,456) and as a potent analgesic (U.S. Pat. No. Substance. 7.220,737). Such treatment generally requires administration 0011 Noribogaine is a metabolite of ibogaine found in of high doses of noribogaine, typically 0.1 mg to 100 mg per human, dog, rat and monkey. However, the therapeutic dosing kg body weight. of noribogaine for treating pain in humans has not previously 0005 Noribogaine is a metabolite of ibogaine found in been addressed, especially as it relates to dosing protocols human, dog, rat and monkey. While the prior art Suggests that that are effective, as well as safe. Indeed, prior to the instant ibogaine at higher doses is useful as a treatment for addiction, invention, it was uncertainas to whethernoribogaine could be use of ibogaine is associated with hallucinations and other administered at a dose which was therapeutic while at the negative side effects. In the United States, ibogaine is classi same time safe for patients. fied as a Schedule I controlled substance. Noribogaine has 0012. Accordingly, there is a significant need for effective, been Suggested to have a greater and longer lasting activity in non-addictive treatment for pain, such as chronic, debilitat humans than ibogaine for reducing craving for addictive Sub ing, nociceptive pain, that reduces the need for habit-forming stances and treating chemical dependency. U.S. Pat. No. pain relieving drugs. 6,348,456, incorporated by reference herein in its entirety, discloses highly purified noribogaine and teaches that it SUMMARY OF THE INVENTION should be provided at dosages from about 0.01 to about 100 0013 While noribogaine has been disclosed for treatment mg per kg body weight per day to treat addiction, although no of pain, its use in humans is complicated by the fact that the human data was provided showing an effective dose to treat ranges in the prior art are exceptionally broad (0.01 to 1000 drug addiction. mg/kg body weight). Furthermore, human clinical studies 0006 Pain is broadly defined as an unpleasant sensory demonstrate that the lower dosing of noribogaine has minimal experience associated with actual or potential tissue damage, impact on the alleviation of pain in patients. Thus, the previ or described in terms of such damage. The interpretation of ously disclosed broad range has now been found to be insuf sensory pain occurs when peripheral nerve endings called ficient for human therapy at the lower end of this range. US 2015/0258 104 A1 Sep. 17, 2015 0014 Moreover, the use of noribogaine imparts a dose 0019. In some embodiments, the dose of noribogaine, dependent prolongation of the treated patient’s QT interval, noribogaine derivative, or pharmaceutically acceptable salt rendering higher dosing of noribogaine unacceptable. A pro and/or solvate thereof administered to the patient is sufficient longed QT interval is a marker of potential ventricular tach to provide an average serum concentration of 50 ng/mL to 180 yarrhythmia which can result in death. ng/mL or any Subrange or subvalue there between. In a pre 0015 The current invention is predicated on the surprising ferred embodiment, the dose of noribogaine, noribogaine discovery that treatment with a narrow dosage range of nori derivative, or pharmaceutically acceptable salt and/or Solvate bogaine, noribogaine derivative, or pharmaceutically accept thereof administered to the patient provides an average serum able salt and/or solvate thereof, between 0.1 mg/kg body concentration of 80 ng/mL to 100 ng/mL.
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