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(12) Patent Application Publication (10) Pub. No.: US 2011/0160273 A1 Buschmann Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2011/0160273 A1 Buschmann Et Al US 2011 0160273A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0160273 A1 Buschmann et al. (43) Pub. Date: Jun. 30, 2011 (54) CO-CRYSTALS OF DULOXETINE AND (30) Foreign Application Priority Data COX-INHIBITORS FOR THE TREATMENT OF PAN May 21, 2008 (EP) .................................. O8384009.O (76) Inventors: Helmut Heinrich Buschmann, Publication Classification Walheim (DE); Lluis Solá (51) Int. Cl. Carandell, Tarragona (ES); Jordi A63L/38 (2006.01) Benet Buchholz, Tarragona (ES); A6II 3/40 (2006.01) Jordi Carles Ceron Bertran, Tarragona (ES); Jesis Ramirez A6IP 25/00 (2006.01) Artero, Tarragona (ES) A6IP 9/02 (2006.01) (52) U.S. Cl. ......................................... 514/423: 514/438 (21) Appl. No.: 12/991,420 (57) ABSTRACT (22) PCT Filed: May 20, 2009 The present invention relates to co-crystals of dulloxetine and (86). PCT No.: PCT/EP2009/003617 co-crystal formers selected from COX-INHIBITORs, pro cesses for preparation of the same and their uses as medica S371 (c)(1), ments or in pharmaceutical formulations, more particularly (2), (4) Date: Mar. 18, 2011 for the treatment of pain. Patent Application Publication Jun. 30, 2011 Sheet 1 of 10 US 2011/O160273 A1 Fig. 1) Patent Application Publication Jun. 30, 2011 Sheet 2 of 10 US 2011/0160273 A1 Aa3 3 8 (sundo) uin Patent Application Publication Jun. 30, 2011 Sheet 3 of 10 US 2011/O160273 A1 - ra'. ....'.....:................ - 'i E. ---, ". it : "g r "put ": m hasi ---O- : : :- s : :. " I sawsaw re s on si " ... orwo "-in- -: ti L ; : " ...i Ei, ii N (, , , -as- T-T gif 2. it. -- ". -- " ... co - ... t - E. " . --- in pri ... " / h i... " ... -- -- --- . r : - ra Patent Application Publication Jun. 30, 2011 Sheet 4 of 10 US 2011/0160273 A1 titae 3% alie LSLE.J. Patent Application Publication Jun. 30, 2011 Sheet 5 of 10 US 2011/0160273 A1 Patent Application Publication Jun. 30, 2011 Sheet 6 of 10 US 2011/O160273 A1 ••••••••••••••~#~~~~~~~~~~~~ Patent Application Publication Jun. 30, 2011 Sheet 7 of 10 US 2011/O160273 A1 Patent Application Publication Jun. 30, 2011 Sheet 8 of 10 US 2011/0160273 A1 : er a ki ret s : - : g lex g Patent Application Publication Jun. 30, 2011 Sheet 9 of 10 US 2011/O160273 A1 ----+---+----- §§? §§## -+------+-------+-------+-------- *• Patent Application Publication Jun. 30, 2011 Sheet 10 of 10 US 2011/0160273 A1 US 2011/O160273 A1 Jun. 30, 2011 CO-CRYSTALS OF OULOXETINE AND 0006 Thus it was the objective of the current invention to COX-INHIBITORS FOR THE TREATMENT provide new means of improving the properties of dulloxetine, OF PAN especially in regard to the treatment of pain, by providing new drugable forms of dulloxetine. 0007 Especially desirable improvements/advantages of the new drugable form would include: 0001. The present invention relates to co-crystals of 0008 improvement of physicochemical properties in dulloxetine and co-crystal formers selected from COX-IN order to facilitate the formulation, the manufacture, or to HIBITORs, processes for preparation of the same and their enhance the absorption and/or the bioavailability: uses as medicaments or in pharmaceutical formulations, 0009 thus more particularly for the treatment of pain. 0.010 being more active when compared to dulloxetine 0002 Pain is a complex response that has been function base or hydrochloride salt; or ally categorized into sensory, autonomic, motor, and affective 0.011 providing a form of dulloxetine with a further components. The sensory aspect includes information about active agent having a beneficial pharmacological effect stimulus location and intensity while the adaptive component in itself, thus allowing for a highly efficient dose/weight may be considered to be the activation of endogenous pain relation of the final active principle or even modulation and motor planning for escape responses. The 0012 allowing the use of a lower therapeutic dose of affective component appears to include evaluation of pain either dulloxetine and the further active agent or of both; unpleasantness and stimulus threat as well as negative emo 0013 having a synergistic effect through the combina tions triggered by memory and context of the painful stimu tion of dulloxetine and the further actice agent in the lus. same new drugable form; or 0003. In general, pain conditions can be divided into 0014 further chronic and acute. Chronic pain includes neuropathic pain 0.015 being easily obtainable, easy to manufacture or and chronic inflammatory pain, for example arthritis, or pain 0016 allowing more flexibility informulating, or facili of unknown origin, as fibromyalgia. Acute pain usually fol tating its formulation, lows non-neural tissue injury, for example tissue damage 0017 being highly soluble, thus allowing better disso from Surgery or inflammation, or migraine. lution rates, especially if dissolving in an aqueous physi 0004 (+)-(S)- N-Methyl-N-3-(naphthalene-1-yloxy)- ological Surrounding, or 3-(2-thienyl)-propylamine, having the INN-name Duloxet 0018 reducing hygrosciplicity: ine and being also described as (+)-(S)-Duloxetine or (S)- 0.019 improving stability; Duloxetine is known to be a potent serotonin and 0020 allowing new routes of administration; norepinephrine reuptake inhibitor (SNRI). Duloxetine is mar 0021 also keted for the treatment of a variety of diseases like anxiety and 0022 allowing to combine dulloxetine with a chemi depression but also including pain, especially diabetic periph cally usually non-compatible active agent in the same eral neuropathy. formulation or even in immediate contact, without hav ing to isolate dulloxetine; examples would include an acidic active agents and the acid labile dulloxetine; 7 S 0023 or finally le 0024 minimizing/reducing the side effects, especially the severe side effects, assigned to dulloxetine. 0025 Most desirably the new drugable forms should com i bine more than one, or even most of these advantages. 0026. This objective was achieved by providing new co crystals of dulloxetine. It was found that Duloxetine was able to form Co-crystals with COX-INIBITORs. These co-crys tals show improved properties if compared to dulloxetine Duloxetine? (S)-Duloxetine alone, and also good analgesic activity. The co-crystals thus obtained have a specific Stoichiometry which depends upon the structure of each co-crystal former. Under the proper 0005 Duloxetine is a commonly used drug. The usual circumstance this is also another advantage of these new solid application route is orally with capsules containg dulloxetine drugable forms possibly achieving some modulation of the hydrochloride in enterically coated pellets being applied with pharmacological effects. While APIs (Active Pharmaceutical doses of 20, 30 and 60 mg of active duloxetine. The enteric Ingredients) like dulloxetine in general have been recognized coating is necessary as dulloxetine is acid labile and therefore to form crystalline polymorphs, Solvates, hydrates and amor would have been in danger to become degenerated in the acid phous forms for a number of years, there is little knowledge environment of the stomach. The main side effects, nausea, about which APIs will form co-crystals. Co-crystals are a Somnolence, insomnia and dizzines, are occurring in 10 to specific type of crystalline form which provide a new avenue 20% of the patients. In addition a number of severe side to modulate the API form and thus to modulate API proper effects have been reported. Being as said above a wildly ties. Co-crystals contain an API and at least one other com used drug there is a continuous need to improve its properties ponent which crystallize together. Selection of the other com to achieve a number of effects like improved formulations, ponent helps determine whether a co-crystal will form and higher efficacy, reduction of side effects e.g. through reduc what properties the co-crystal will have. Just as a polymorph, tion of the necessary dosis etc. solvate, hydrate or amorphous form of an API can modulate US 2011/O160273 A1 Jun. 30, 2011 stability, solubility, and hygroscopicity, a co-crystal can not necessarily the case so that there are symptoms of allo modulate those same properties. dynia not connected to neuropathic pain though rendering 0027 Thus the main object of the present invention is a allodynia in some areas broader then neuropathic pain. co-crystal comprising dulloxetine and at least one co-crystal 0034. The IASP further draws the following difference former selected from COX-INHIBITORs. The group of between “allodynia”, “hyperalgesia” and “hyperpathia COX-INHIBITORs include the NSAIDs (Nonsteroidal anti (IASP. Classification of chronic pain, 2'' Edition, IASP Press inflammatory drugs). (2002), 212): 0028 “COX-INHIBITORs are defined by the basis of their activity being inhibition of cyclooxygenase (COX), one of the two activities of prostaglandine endoperoxide synthase (PGHS). PGHS is a key enzyme in the prostaglandin path Allodynia Lowered threshold Stimulus and response mode differ way. Some preferred co-crystal formers in the sense of this Hyperalgesia Increased response Stimulus and response application are those (COX-INHIBITORS/NSAIDs) with a rate are the same carboxylic acid function, with examples including salicy Hyperpathia Raised threshold: Stimulus and response lates, anthranilates, arylacetic acids/arylalkanoic acids, and Increased response rate may be the same or arylpropionic acids, but also including Coxibs. different 0029 “Drugable form (of dulloxetine) as used herein is defined as any form (salt, amorphous
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