USOO8242146 B2 (12) United States Patent (10) Patent No.: US 8.242,146 B2 Klein et al. (45) Date of Patent: Aug. 14, 2012 (54) COMBINATION OF ANSAID AND A PDE-4 Wolda, S.L., “PDE4 inhibitors and chronic obstructive pulmonary INHIBITOR disease”, Emerging Drugs, vol. 5, No. 3, pp. 309-319, (2000). Silva, J.C.R. et al., “Effects of pentoxifylline and nabumetone on the (75) Inventors: Thomas Klein, Constance (DE); serum levels of IL-1B and TNF C in rats with adjuvant arthritis', Hans-Peter Kley, Allensbach (DE) Inflammation Research, vol. 49, pp. 14-19, (2000). Kumar, A. et al., “Analgesic and anti-inflammatory effects of (73) Assignee: Nycomed GmbH, Constance (DE) phosphodiesterase inhibitors'. Indian Journal of Experimental Biol ogy, vol. 38, pp. 26-30. (2000). (*) Notice: Subject to any disclaimer, the term of this Reuter, B.K. et al., “Phosphodiesterase inhibitors prevent NSAID patent is extended or adjusted under 35 entreopathy independently of effects on TNF-C. release'. Am J U.S.C. 154(b) by 1207 days. Physiol, vol. 277, pp. G847-G854, (1999). Sivola, J. et al., “Effects of nonsteroidal anti-inflammatory drugs on (21) Appl. No.: 12/003,129 rat gastric mucosal phosphodiesterase activity'. Agents and Actions, vol. 12, No. 4, pp. 516-520, (1982). (22) Filed: Dec. 20, 2007 Salcedo, J. et al., “Phosphodiesterase 4 Inhibition, A New Mecha nism to Maintain and Promote Gastric and Intestinal Mucosal Integ (65) Prior Publication Data rity Against NSAID-Induced Injury in the Rat', Gastroenterology, US 2008/O255.209 A1 Oct. 16, 2008 vol. 114, No. 4, pp. G1126, Abstract. Tariq, M. et al., “Gastric Antiulcer and cytoprotective effects of Related U.S. Application Data Dipyridamole in rats'. J. Pharmacol. Exp. Ther. vol. 253, No. 3, pp. 944-949 (1990), Abstract 113:71071 American Chemical Society. (62) Division of application No. 10/489,920, filed as Bertrand, et al., “Increase in tumor necrosis factor-O production application No. PCT/EP02/10424 on Sep. 17, 2002, linked to the toxicity of indomethacin for the rat Small intestine'. now abandoned. British Journal of Pharmacology, vol. 124, pp. 1385-1394. (1998). Bouchier-Hayes, et al., “Comparison of the efficacy and tolerability (51) Int. Cl. of diclofenac gel (Voltarol Emulgel) and felbinac gel (Traxam) in the A6 IK3I/44 (2006.01) treatment of soft tissue injuries'. BJCP, vol. 44, No. 8, pp. 319-320, (52) U.S. Cl. ....................................................... S14/352 (1990). Diaz-Granados, et al., “Dextran Sulfate Sodium-Induced Colonic (58) Field of Classification Search ........................ None Histopathology, but not Altered Epithelial Ion Transport, Is Reduced See application file for complete search history. by Inhibition of Phosphodiesterase Activity”, American Journal of Pathology, vol. 156, No. 6, pp. 2169-2177. (2000). (56) References Cited Ding, et al., “Prostaglandin, tumor necrosis factor O. and neutrophils: causative relationship in indomethacin-induced stomach injuries'. U.S. PATENT DOCUMENTS European Journal of Pharmacology, vol. 348, pp. 257-263, (1998). 4,736,024 A 4, 1988 Della Valle et al. Gomez, et al., “Effect of Topical Diflumidone on Ultraviolet-Light 6,174,878 B1 1/2001 Gamache et al. ........ 514,211.12 Induced Erythema'. Dermatologica, vol. 162, pp. 175-182 (1981). 6.410,563 B1 6/2002 Deschenes et al. Häfner, et al., “Additive Effects of Phosphodiesterase-4 Inhibition on FOREIGN PATENT DOCUMENTS Effects of rSP-C Surfactant”, Am J Respir Crit Care Med, vol. 161, CA 2009.730 A1 8, 1990 pp. 1495-1500, (2000). WO 99.06404 A1 2, 1999 Hartmann, et al., “Specific Type IV Phosphodiesterase Inhibitor WO 99/23077 A1 5, 1999 Rolipram Mitigates Experimental Colitis in Mice'. The Journal of WO 01.00229 A1 1, 2001 Pharmacology and Experimental Therapeutics, vol. 292, No. 1, pp. WO O1? 13953 A2 3, 2001 22-30, (2000). WO O1/32127 A2 5, 2001 Hatzelmann, et al., “Anti-Inflammatory and Immunomodulatory WO Of 47880 A1 T 2001 Potential of the Novel PDE4 Inhibitor Roflumilast in Vitro’. The WO O1, 57.036 A1 8, 2001 Journal of Pharmacology and Experimental Therapeutics, vol. 297, WO 01,58441 A1 8, 2001 No. 1, pp. 267-279, (2001). WO 02/060896 A1 8, 2002 WO 02/064584 A1 8, 2002 Primary Examiner — Tracy Vivlemore OTHER PUBLICATIONS Assistant Examiner — Jennifer Berrios Bundschuh, D.S. et al., “In Vivo Efficacy in Airway Disease Models (74) Attorney, Agent, or Firm — The Nath Law Group; of Roflumilast, a Novel Orally Active PDE4 Inhibitor'. Journal of Sheldon M. McGee Pharmacology and Experimental Therapeutics, vol. 297, No. 1, pp. (57) ABSTRACT 280–290, (2001). Dyke, H.J., “Update on the therapeutic potential of PDE4 inhibitors'. The invention relates to the combined use of a PDE4 inhibitor Expert Opin. Investig. Drugs, vol. 11, No. 1, pp. 1-13, (2002). and a conventional NSAID in the treatment of an inflamma Germann, P. et al., “Experimental approaches for the treatment of the tory disease and/or an inflammation-associated disorder acute respiratory distress syndrome in a rat lung lavage model”. while minimizing gastrointestinal side effects, such as gastric Recent Res. Devel. Resp. Critical Care Med., vol. 1, pp. 161-179, (2001). erosions and ulcer, which are frequently associated with the Norman, P., “PDE4 inhibitors 2001. Patent and literature activity use of conventional NSAIDs. A preferred PDE4 inhibitor for 2000–Sep. 2001'. Expert Opin. Ther: Patents, vol. 12, No. 1, pp. this combination is roflumilast or a derivative thereof. A pre 93-111, (2002). ferred conventional NSAID for this combination is Suttorp, N. et al., “Phosphodiesterasen Inhibition und pulmonale diclofenac or a derivative thereof. Strombahn—ein neuer Therapieansatz?'. Altenwegs und Lungenkrankheiten, vol. 22, No. 11, pp. 560-566, (1996). 4 Claims, No Drawings US 8,242,146 B2 1. 2 COMBINATION OF ANSAID AND A PDE-4 The invention thus relates to the combined use of a PDE4 INHIBITOR inhibitor and a conventional NSAID in the treatment of an inflammatory disease and/or an inflammation-associated dis This application is a divisional of U.S. Ser. No. 10/489,920, order while minimizing gastrointestinal side effects, such as filed Mar. 18, 2004 now abandoned, which is a 371 of PCT/ 5 gastric erosions and ulcer, which are frequently associated EP02/10424 filed Sep. 17, 2002, and which claims benefit of with the use of conventional NSAIDs. priority to EP01000473.7 filed Sep. 19, 2001, the disclosure “Combined use” in the context of the invention means the of which is incorporated herein by reference in its entirety for simultaneous, sequential or separate ad-ministration of the all purposes. conventional NSAID on the one hand and of the PDE4 inhibi 10 tor on the other hand. FIELD OF APPLICATION OF THE INVENTION Simultaneous administration includes—aside from the simultaneous uptake of two separate dosage forms containing The invention relates to the combination of certain known the conventional NSAID in the one and the PDE4 inhibitor in active compounds for therapeutic purposes. the other dosage form pharmaceutical compositions con The Substances used in the combination according to the 15 invention are known active compounds from the PDE4-in taining both active ingredients in one single dosage form hibitor class and active compounds from the non-steroidal (fixed unit dose form). anti-inflammatory drug (NSAID) class. Simultaneous administration also includes the oral admin istration of the PDE4 inhibitor during i.v. administration (e.g. KNOWN TECHNICAL BACKGROUND by infusion) of the conventional NSAID, or shortly after intramuscular or intravenous injection of the conventional In the International Patent Application WO01/58441 the NSAID. treating of an inflammatory disease by administering a phos Sequential administration in the context of the invention phodiesterase 4 inhibitor in combination with an inhibitor of means the administration of the conventional NSAID on the prostaglandin synthesis, NSAIDS being exemplary, is dis 25 one hand and of the PDE4 inhibitor on the other hand in closed. separate dosage forms within less than 12 hours, more pref erably within less than one hour, most preferably within 5 DESCRIPTION OF THE INVENTION minutes or less, including regimen where the PDE4 inhibitor is administered first. The use of nonsteroidal anti-inflammatory drugs 30 Separate administration within the context of the invention (NSAIDs) is often associated with the development of gas means the administration of the conventional NSAID on the trointestinal (GI) side effects such as gastric erosions and one hand and of the PDE4 inhibitor on the other hand in ulcer, which limit their widespread clinical use. separate dosage forms within 12 hours or more, including Investigations into the role of several NSAIDs in inhibiting administration regimen where the PDE4 inhibitor is admin the phosphodiesterase 4 and 5 in vitro showed that in partially 35 istered first, and including regimen where e.g. the conven purified or recombinant PDE4 and PDE5, NSAIDs with pref tional NSAID is administered twice or three times daily and erential COX-2 selectivity (for example, nimeSulide INN), the PDE4 inhibitor is administered once or twice daily. CGP28238 Research Code, L-745337 Research Code, Sequential and separate administration also include the and the highly selective drug celecoxib (INN) possess PDE4 oral administration of the PDE4 inhibitor and the i.v. admin and PDE5 activity in the uM range, whereas conventional 40 istration (e.g. by infusion) or intramuscular or intravenous NSAIDs (for example, acetylsalicylic acid, diclofenac (INN) injection of the conventional NSAID. or indometacin (INN) show only minor effects. “Combined use” in the context of the invention also In isolated guinea pig Langendorffhearts, celecoxib selec includes a pharmaceutical product comprising both the con tively increased coronary heart flow at doses consistent with ventional NSAID and the PDE4 inhibitor as discrete separate its inhibitory potency on PDE4 and 5, but had no effect on left 45 dosage forms, in separate containers or e.g.