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(12) Patent Application Publication (10) Pub. No.: US 2014/0242169 A1 SESHA (43) Pub US 201402421.69A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0242169 A1 SESHA (43) Pub. Date: Aug. 28, 2014 (54) TAPENTADOL COMPOSITIONS Publication Classification (71) Applicant: GRUENENTHAL GMBH, Aachen (51) Int. Cl. (DE) A63/37 (2006.01) A619/28 (2006.01) (72) Inventor: RAMESH SESHA, WEST WINDSOR, A 6LX3/97 (2006.01) NJ (US) A 6LX3L/95 (2006.01) (52) U.S. Cl. (73) Assignee: GRUENENTHAL GMBH, Aachen CPC ............. A6 IK3I/137 (2013.01); A61 K3I/195 (DE) (2013.01); A61 K9/2866 (2013.01); A61 K 31/197 (2013.01); A61 K9/2853 (2013.01) USPC ............................ 424/468: 514/653: 514/561 (21) Appl. No.: 14/276,377 (57) ABSTRACT 1-1. The present invention provides a method of treating pain and (22) Filed: May 13, 2014 pain related conditions by administering to a patient in need thereof, a therapeutically effective amount of a slow release Related U.S. Application Data Tapentadol Hydrochloride and therapeutically effective (63) Continuation-in-part of application No. 12/786.382 amount of a second analgesic, wherein the second analgesic is filed on May 24, 2010, which is a continuation of gamma-aminobutyric acid (GABA) analogue. The present 2008iii. Spriso.g., iii. N2i comprisinginvention further a therapeutically provides a effectivepharmaceutical amount composition of a slow release Tapentadol Hydrochloride and a therapeutically (60) Provisional application No. 61/004,029, filed on Nov. effective amount of a second analgesic, wherein the second 23, 2007. analgesic is gamma-aminobutyric acid (GABA) analogue. Patent Application Publication Aug. 28, 2014 US 2014/02421.69 A1 søõue?o9.100sSVA I"OIH .......r-ra-re-------------- wo. 203:w ueew US 2014/0242169 A1 Aug. 28, 2014 TAPENTADOL COMPOSITIONS mimic the chemical structure of the neurotransmitter gamma aminobutyric acid (GABA), but is not believed to act on the RELATED APPLICATIONS same brain receptors. Its exact mechanism of action is unknown, but its therapeutic action on neuropathic pain is 0001. This application is a continuation-in-part of U.S. thought to involve Voltage-gated N-type calcium ion chan Nonprovisional patent application Ser. No. 12/786,382, filed nels. on May 24, 2010, now pending, which is, in turn, a continu 0006 Most anti-inflammatory drugs such as non-steroidal ation of International Application PCT/US08/084,423, filed anti-inflammatory drugs (NSAIDs) have been associated on Nov. 21, 2008, which, in turn, claims priority from U.S. with an increased risk of serious upper gastrointestinal com Provisional Patent Application Ser. No. 61/004,029, filed on plications. The risk is believed to be dose dependent and can Nov. 23, 2007, the entire contents of which patent applica be greater when more than one anti-inflammatory drug is tions are incorporated herein by reference. administered. Hence, whenever possible, anti-inflammatory drugs should be administered in mono-therapy. This risk can BACKGROUND OF THE INVENTION be more pronounced in case of non-aspirin non-steroidal anti-inflammatory (NA-NSAID) drugs. Intake of 0002 Tapentadol, 3-(3-Dimethylamino-1-ethyl-2-me NA-NSAIDs as a group has been consistently associated with thyl-propyl)-phenol (compound 1) is a centrally acting anal a four- to five-fold increase in upper gastrointestinal compli gesic with a dual mode of action: g-opioid receptor agonism cations (UGIC). The evidence indicates that the risk is dose and noradrenalinine reuptake inhibition. Its dual mode of dependent. The estimated pooled cardiovascular Relative action provides analgesia at similar levels of more potent Risks (RR) in a recent meta-analysis were 3.0 (95% CI. narcotic analgesics such as hydrocodone, oxycodone, and 2.6-3.4) for low doses, 4.1 (95% CI, 3.6-4.5) for medium morphine with a more tolerable side effect profile. Tapentadol doses, and 6.9 (95% CI, 5.8-8.1) for high doses. Recent was first disclosed in European patent no. EP 693.475 and is research indicates that NA-NSAID as a therapeutic class have a RR of 4.1 (95% CI, 3.6-48). currently under FDA review. 0007 Meloxicam (compound 4), an oxicam derivative, is a member of the enolic acid group of non-steroidal anti inflammatory drugs (NSAIDs). It is reported to be a selective COX-2 inhibitor. Meloxicam is chemically known as 4-hy droxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothi azine-3-carboxamide-1,1-dioxide. It is commercially avail able under the trade name of MOBICR). Meloxicam is indicated for relief of the signs and symptoms of osteoarthri tis and rheumatoid arthritis, pauciarticular or polyarticular course Juvenile Rheumatoid Arthritis in patients 2 years of age and older. 0003. The traditional formulations of tapentadol for oral 0008 Naproxen (compound 5) is another non-steroidal administration lead to a rapid release of the drug in the gas anti-inflammatory drug (NSAID) commonly used for the trointestinal tract and hence its analgesic action begins rap reduction of mild to moderate pain, fever, inflammation and idly. However, a rapid reduction in the analgesic activity is stiffness caused by conditions such as osteoarthritis, rheuma observed. Therefore, treatment with tapentadol requires toid arthritis, psoriatic arthritis, gout, ankylosing spondylitis, repeated administration of the pharmaceutical composition at injury (like fractures), menstrual cramps, tendonitis, bursitis, relatively short intervals, often as high as four to ten times and the treatment of primary dysmenorrhea. Naproxen, daily, to maintain the required concentration of active ingre chemically known as (+)-(S)-2-(6-methoxy-naphthalen-2-yl) dient in the patient’s blood plasma. The need for repeated propanoic acid, and naproxen Sodium are marketed under dosing can lead to errors in administration and inability to various trade names including: Aleve, AnaproX, Naprogesic, maintain desirable concentration in the plasma, which are Naprosyn, Naprelan, and Synflex. There have also been detrimental to patient compliance and the therapeutic objec reports of naproxen producing disturbances in the gas tives, particularly if the condition is chronic pain or a pain trointestinal tract, like other NSAIDs. Additional NSAIDs related condition. Accordingly, there is an unmet need to have include but are not limited to compound 6, Diclofenac; com slow or controlled release pharmaceutical compositions for pound 7, Celecoxib; compound 8. Diflunisal; compound 9. oral administration of the active ingredient, tapentadol. Fur Etodolac; compound 10, Fenoprofen; compound 11, Ibupro ther, there is a need for compositions suitable for long term fen, compound 12, Indomethacin; compound 13, Ketoprofen, treatment of pain and pain related conditions particularly and compound 14, Ketorolac. because Such conditions persist among aged populations of the Society. 0004 Pregabalin (compound 2), a gamma-aminobutyric 15 acid (GABA) analogue, is an anticonvulsant drug which is OCH used as an adjunct therapy for partial seizures, for neuropathic pain, and in generalized anxiety disorder. Pregabalin was designed as a more potent Successor to gabapentin and it is marketed by Pfizer under the trade name Lyrica(R). Recent HO studies have shown that pregabalin is effective at treating chronic pain in disorders such as fibromyalgia and spinal cord injury. 0005 Gabapentin (compound 3) is another GABA ana logue similar to Pregabalin and was initially synthesized to US 2014/0242169 A1 Aug. 28, 2014 0009 Tramadol (compound 15) is a centrally acting syn other NSAIDs may cause gastrointestinal side effects espe thetic opioid analgesic. It is chemically (t) cis-2-(dimethy cially if used repeatedly. See, e.g., M. J. S. Langman, Am. J. lamino) methyl-1-(3-methoxyphenyl)cyclo-hexanol hydro Med. 84 (Suppl. 2A): 15-19, 1988); P. A. Insel in “Goodman chloride. A commercially available form is the hydrochloride and Gilman's The Pharmacological Basis of Therapeutics.” salt as Ultram tablets. Tramadol has been used for the man Gilman AG, Rall TW. Nies AS, et al. (eds). Pergamon Press, agement of moderate to moderately severe pain in adults. 8th Ed., 1990, Chapter 26, pp. 664-668. Tramadol is a non-NSAID analgesic that is not believed to 0014 Neuropathic pain is believed to be caused by a pri cause the increased risk of stomach ulceration and internal mary lesion or dysfunction in the nervous system. Neuro bleeding associated with non-steroidal anti inflammatory pathic pains have been categorized as peripheral neuropathic drugs (NSAID). However, it still has some commonly pain, due to lesion of the peripheral nervous system and reported side effects including nausea, constipation, dizzi central pain following lesions of the central nervous system. ness, headache, drowsiness, and Vomiting. Other reported The prevalence of neuropathic pain is estimated to be about side effects include itching, Sweating, dry mouth, diarrhea, 1%. Neuropathic pain has been shown to be therapy resistant. rash, visual disturbances, and vertigo. Thus, it would be desir However, a number of agents have been used to treat neuro able to prevent or reduce these side effects by prescribing pathic pain including NSAIDs, opioids, antidepressants, anti lower doses of tramadol without compromising pain relief. convulsants, excitatory amino acid antagonists, GABAergic 0010 Literature reports indicate that NSAIDs such as agonists, Substance Pantagonists, etc. Low doses of carbam naproxen can inhibit the excretion of sodium and lithium. azepine and amitriptyline have been recommended for neu Hence it is desirable to control their dosage to alleviate side ropathic pain in general. The side effects of GABA agonists effects inpatients without comprising the extent of pain relief. Such as gabapentin, pregabalin, etc. have been documented in Similarly, dizziness, Somnolence, dry mouth, edema, blurred the literature. Hence, it is desirable to reduce their dosage to vision, weight gain, and “thinking abnormal” (primarily dif alleviate the patients of its side effects without comprising the ficulty with concentration/attention) were more commonly extent of pain relief. reported by subjects treated with GABA analogues like pre 0015.
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