US 20110281855A1 (19) United States (12) Patent Application Publication (10) Pub. N0.: US 2011/0281855 A1 SESHA (43) Pub. Date: NOV. 17, 2011

(54) NOVEL AND POTENT A61P 29/00 (2006.01) DOSAGE FORMS A61K 31/38 (2006.01) A61K 31/454 (2006.01) (75) Inventor: RAME SH SESHA; Windsor, N] A 61K 3 1/4 545 (200601) (US) A61P 25/00 (2006.01) A61K 31/439 (2006.01) (73) Assignee: GRUENENTHAL GMBH; A61]; 31/542 (200601) Aachen (DE) (52) us. Cl...... 514/225.5; 514/653; 514/282; (21) Appl_ No. 13/091,871 514/327; 514/226.2; 514/225.8; 514/224.5; 514/431; 514/322; 514/316; 514/329 (22) Filed: Apr. 21, 2011 (57) ABSTRACT Related U's' Apphcatlon Data The present invention provides a dosage form comprising at (63) Continuation of application No, PCT/US2009/ least one form of tapentadol; With or Without a second anal 005866; ?led on Oct, 29, 2009, gesic; and at least one antagonist; Wherein tapentadol _ _ _ _ is present in an optimal or suboptimal amount and the said (60) PrOVlslOnal appl_lc_anon NO' _61/ 191625 > ?led on Oct' antagonist is present in an amount effective to improve the 30’ 2008’ provlslonal apphc_at_lon NO‘ 61/205,312’ e?icacy and or reduce the side effects of tapentadol. The ?led on Jan' 21’ 2009’ provlslonal apphcanon NO' present invention further provides a method of treating pain 61/268,630’ ?led on Jun' 15’ 2009' and pain related conditions by administering to a patient in _ _ _ _ need thereof; a dosage form comprising at least one form of Pubhcatlon Classl?catlon tapentadol; With or Without a second ; and at least (51) Int, Cl, one opioid antagonist; Wherein tapentadol is present in an A61K 31/137 (2006,01) optimal or suboptimal amount and the said antagonist is A61K 31/451 (2006,01) present in an amount effective to improve the e?icacy and or A61K 31/5415 (200601) reduce the side effects of tapentadol. Patent Application Publication Nov. 17, 2011 Sheet 1 0f 17 US 2011/0281855 A1

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NOVEL AND POTENT TAPENTADOL clinical depression, anxiety disorders, obsessive-compulsive DOSAGE FORMS disorder, attention de?cit hyperactivity disorder (ADHD) and chronic neuropathic pain. They act upon tWo neurotransmit RELATED APPLICATIONS ters in the brain that are knoWn to play an important part in [0001] This application claims priority from US. provi mood, namely, serotonin and norepinephrine. Examples of SNRIs include Venlafaxine, duloxetine, milnacipran and des sional patent applications Ser. Nos. 61/197,625 ?led on Oct. venlafaxine etc. 30, 2008, 61/205,312 ?led on Jan. 21, 2009, and 61/268,630 ?led on Jun. 15, 2009, all of Which are incorporated herein by [0008] The drugs acting on 5-HT receptors are usually des reference. ignated as 5-HTagonists. The 5 HT1 agonists are knoWn and used for the treatment of headaches including migraine head FIELD OF THE INVENTION ache. They Were ?rst introduced in the 1990s. While effective at treating individual headaches, they are neither a preventa [0002] The present invention is related to a pharmaceutical tive nor a cure. Triptans include sumatriptan, (Imitrex, Imig dosage form comprising at least one form of tapentadol, With ran), riZatriptan (Maxalt), naratriptan (Amerge, Naramig), or Without a second analgesic, and at least one opioid antago Zolmitriptan (Zomig), eletriptan (Relpax), almotriptan (Ax nist Wherein the said antagonist improves the ef?cacy and to ert, Almogran), and frovatriptan (Frova, Migard). reduce the side effects of tapentadol. The dosage forms [0009] Cyclo-oxygenase-(COX)-inhibiting nitric oxide include immediate release and sloW release dosage forms of donator or “CINODs” have a nitric oxide (NO)-releasing at least one form of tapentadol and least one opioid antagonist group and are also designated No-NSAIDs. These include but Wherein the said tapentadol is in an optimal or suboptimal not limited to naproxcinod among others. amount. [0010] Proton Pump Inhibitors (“PPI”s) are a group of drugs that produce pronounced and long-lasting reduction of BACKGROUND OF THE INVENTION gastric acid production. PPIs structurally are usually benZ [0003] Tapentadol, 3-(3 -Dimethylamino-1-ethyl-2-me imidaZole andbenZimidaZoleilike derivatives. The key PPIs thyl-propyl)-phenol) is a centrally acting analgesic With a include Clinically used proton pump inhibitors: OmepraZole dual mode of action: mu- agonism and nora (brand names: Losec, Prilosec, Zegerid, ocid), LansopraZole drenaline reuptake inhibition. Its dual mode of action pro (brand names: Prevacid, Zoton, Inhibitol), EsomepraZole vides analgesia at similar levels of more potent narcotic anal (brand names: Nexium), PantopraZole (FORMULA 15) gesics such as , , and With (brand names: Protonix, Somac, Pantoloc, PantoZol, Zurcal, a more tolerable side effect pro?le. Tapentadol Was ?rst dis Pan),RabepraZole (brand names: Rabecid, Aciphex, Pariet, closed and claimed in European patent no. EP 693,475, US. Rabeloc. Dorafem: Pat. No. 6,248,737 and US. Pat. RE39,593. The immediate [0011] Despite the bene?ts derived from these pain drugs, release pharmaceutical composition of tapentadol is the sub one area of concern relates to the incidence of unWanted side ject of the United States Food and Drug Administration effects caused by these drugs. Thus there is an unmet need to Approved NeW Drug Application number 22-304. develop pharmaceutical dosage forms comprising tapentadol [0004] There are a number of classes of analgesic com such that the dosage forms With enhanced analgesic proper pounds used for treating acute and chronic pain. These ties With as minimal side effects as possible. Hence it is include acetaminophen, NSAIDs such as , meloxi desirable to develop dosage forms With reduced dosages of cam etc, CINODS such as naproxcinod, such as these drugs to alleviate the patients of its side effects Without morphine, , tapentadol, oxycodone etc, GABA ana comprising the extent of pain relief. logues such as and SNRIs such as duloxetine etc. [0012] The use of antagonist to address the potential side [0005] Pregabalin, a GABA analogue, is an anticonvulsant effects and the abuse are knoWn in the art. Opioid antagonists drug used for neuropathic pain, as an adjunct therapy for are entities that modify the response of opioid receptors. partial seizures, and in generaliZed anxiety disorder. Pregaba Opioid antagonists include , , diprenor lin Was designed as a more potent successor to and phine, , , nalinefene, cyclaZacine, it is marketed by P?zer under the trade name Lyrica®. In , pharrnaceutically acceptable salts thereof and general, pregabalin reduces the release of several neurotrans mixtures thereof. mitters, including glutamate, noradrenaline, and sub stance P. [0013] For example, US. Pat. No. 5,866,164 describes a Gabapentin is another GABA analogue similar to Pregabalin dosage system that comprises multiple layers With an opioid and Was initially synthesiZed to mimic the chemical structure analgesic and the second layer comprises an antagonist for of the neurotransmitter gamma-aminobutyric acid (GABA), this opioid analgesic and simultaneously affecting the push but is not believed to act on the same brain receptors. Its exact function. US. Pat. No. 5,472,943 to Crain et al. describes mechanism of action is unknown, but its therapeutic action on methods of enhancing the analgesic potency of bimodally neuropathic pain is thought to involve voltage-gated N-type acting opioid agonists by administering the agonist With an calcium ion channels. It is thought to bind to the (x26 subunit opioid antagonist. US. Pat. No. 6,277,384 purported to pro of the voltage-dependent calcium channel in the central ner vide a dosage form containing a combination of an opioid vous system. agonist and an opioid antagonist in a speci?c ratio, Which [0006] NSAIDs non-steroidal anti-in?ammatory drug brings about a negative effect on administration to an addicted (NSAIDs) include but are not limited to ; Cele person. US. Pat. No. 6,228,863 describes a dosage form coxib; Di?unisal;, ;, ;, ;, containing a combination of an opioid agonist and an opioid Indomethacin;, , and, and used for antagonist, such that the tWo compounds can in each case treating pain. only be extracted together from the dosage form and then [0007] Serotonin Norepinephrine Reuptake inhibitors (SN additional processes required to separate them. US. Pat. No. RIs) are a class of antidepressant used in the treatment of 6,765,010 disclosures relate to compositions and methods US 2011/0281855 A1 Nov. 17, 2011

With tramadol and an opioid antagonist to improve the e?i hydrocodone, , morphine, pharmaceutically accept cacy of tramadol. US. Pat. Application No. 2005/0191244 able salts thereof and mixtures thereof. describes the opioid agonist formulations comprising an opioid agonist, antagonist and gelling agent or an irritant to BRIEF DESCRIPTION OF THE INVENTION prevent the abuse opioid agonist. US. Pat. No. 6,716, 449 describes controlled release opioid agonist and controlled [0016] The objects of the present invention are directed to release opioid antagonist combinations for enhancing the provide dosage forms comprising at least one form of tapen analgesic potency of an opioid agonist and US. Pat. No. tadol and at least one antagoni st and to methods for improving 7,332,142 describes pharmaceutical composition comprising the e?icacy of tapentadol and/or minimiZing its adverse an opioid agonist, an opioid antagonist and an irritant purport effects in a human. The compositions and methods of the to lessen the abuse. US. Pat. No. 6,559,159 to Carroll et al. present invention include immediate release and sloW release describes the use of kappa receptors antagonist for the treat dosage forms of at least one form of tapentadol and at least ment of opioid related addictions. US. Pat. No. 6,309,668 one opioid antagonist Wherein the said tapentadol is in an describes a tablet for oral administration containing tWo or optimal or suboptimal amount. The dosage forms include more layers comprising one or more drugs and one or more those comprising at least one form of tapentadol, at least one gelling agents Within separate layers of the tablet. US. Pat. opioid agonist and a therapeutically effective amount of a No. 6,228,863 teaches the reduction of the abuse potential of second analgesic Wherein the said antagonist improves the oral dosage forms of opioid by selecting the par e?icacy and or reduces the side effects of tapentadol. ticular opioid agonist and antagonist pair, and the concentra [0017] One object of the present invention is to provide tions of the same such that the antagonist cannot be easily dosage form comprising at least one form of tapentadol and at extracted from the agonist. US. Pat. Nos. 6,277,384, 6,375, least one opioid antagonist, Wherein the said tapentadol is in 957 and 6,475,494 describe oral dosage forms including a an optimal or suboptimal amount and the said antagonist is combination of an orally active opioid agonist and an orally present in an amount to improve the e?icacy and or reduce the active opioid antagonist in a ratio that, When delivered orally, side effects of tapentadol. is analgesically effective but that is aversive in a physically [0018] One object of the present invention is to provide a dependent subject. method of treating pain by administering dosage form com [0014] The prior art doesn’t disclose a dosage form com prising at least one form of tapentadol and at least one opioid prising at least one form of tapentadol and at least one opioid antagonist Wherein the said tapentadol is in an optimal or antagonist Wherein the said tapentadol is in an optimal or suboptimal amount and the said antagonist is present in an suboptimal amount and the said antagonist is in amount effec amount to improve the e?icacy and or reduces the side effects tive to improve the e?icacy and or reduce the side effects of of tapentadol. tapentadol. Similarly, there is no report in the art of a method [0019] One object of the present invention is to provide a of treating pain by administering, to patient in need thereof, a dosage form comprising at least one form of tapentadol and at dosage form comprising at least one form of tapentadol and at least one opioid antagonist Wherein the said dosage form least one opioid antagonist Wherein the said tapentadol is in provides effective pain relief for at least about 12 hours, When an optimal or suboptimal amount and the said antagonist is in administered to a human patient. amount effective to improve the e?icacy and or reduce the [0020] One object of the present invention is to provide a side effects of tapentadol. Similarly the prior art doesn’t dis method of treating pain by administering a dosage form com close a dosage form comprising at least one form of tapenta prising at least one form of tapentadol and at least one opioid dol and at least one opioid antagonist Wherein the said tapen antagonist Wherein the said dosage form provides effective tadol is in an optimal or suboptimal amount and the said pain relief for at least 12 hours, When administered to a human antagonist is in amount effective to improve the ef?cacy and patient. or reduce the side effects of tapentadol, such that the said [0021] One object of the present invention is to provide dosage form provides effective pain relief for at least about 12 dosage form comprising at least one form of tapentadol and at hours, or at least about 24 hours, When orally administered to least one opioid antagonist Wherein the said dosage form a human patient. provides effective pain relief for at about 24 hours, When [0015] Similarly, the prior art discloses neither a dosage administered to a human patient. form comprising at least one form of tapentadol and at least [0022] One object of the present invention is to provide a one opioid antagonist, and a therapeutically effective amount method of treating pain by administering a dosage form com of a second analgesic Wherein the said antagonist improves prising at least one form of tapentadol and at least one opioid the e?icacy and or reduces the side effects of tapentadol nor a antagonist Wherein the said dosage form provides effective method of treating pain and pain related conditions by admin pain relief for about 24 hours, When administered to a human istering to a patient in need thereof, a dosage forms compris patient. ing at least one form of tapentadol and at least one opioid [0023] Still further, the present invention provides a antagonist Wherein the said tapentadol is in an optimal or method for improving the e?icacy of at least form of tapen suboptimal amount and the said antagonist, and a therapeu tadol in a human subject by administering to the human tically effective amount of a second drug Wherein the said subject at least form of tapentadol and at least one opioid antagonist improves the ef?cacy and or reduces the side antagonist effective to improve the ef?cacy of at least form of effects of tapentadol. The second analgesic is selected from a tapentadol, Wherein the said tapentadol is in an optimal or group consisting of an NSAID, Acetaminophen, a GABA suboptimal amount. Preferred opioid antagonists include nal analogue, a Serotonin Norepinephrine reuptake inhibitor trexone, naloxone, or . The e?icacy of at least one (SNRI), a Cyclo-oxygenase-(COX)-inhibiting nitric oxide form oftapentadol may be maintained While one or more side donator, a HT Agonist and a Proton Pump Inhibitor., trama effects are minimiZed Without increasing or decreasing the dol, , faxeladol, axomadol, oxycodone, cumulative daily dose of tapentadol.