US 20120064156A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0064156A1 Plachetka (43) Pub. Date: Mar. 15, 2012 (54) PHARMACEUTICAL COMPOSITIONS FOR A6II 3/426 (2006.01) THE COORONATED DELVERY OF NSAIDS A6IPL/04 (2006.01) A63L/454 (2006.01) (76) Inventor: John R. Plachetka, Chapel Hill, A6II 3/66 (2006.01) NC (US) A6II 3/4439 (2006.01) A69/48 (2006.01) (21) Appl. No.: 13/215,855 A6IP 29/00 (2006.01) A6IR 9/28 (2006.01) (22) Filed: Aug. 23, 2011 A63L/4545 (2006.01) Related U.S. Application Data (52) U.S. Cl. ......... 424/463; 424/474; 424/475; 514/400; 514/471; 514/370, 514/318: 514/326; 514/165; (60) Division of application No. 12/533,804, filed on Jul. 514/338; 514/161; 514/577 31, 2009, now abandoned, which is a division of appli cation No. 11/129,320, filedon May 16, 2005, which is (57) ABSTRACT a continuation-in-part of application No. 10/158,216, filed on May 31, 2002, now Pat. No. 6,926,907. The present invention is directed to drug dosage forms that release an agent that raises the pH of a patient's gastrointes (60) Provisional application No. 60/294,588, filed on Jun. tinal tract, followed by a non-steroidal anti-inflammatory 1, 2001. drug. The dosage form is designed so that the NSAID is not O O released until the intragastric pH has been raised to a safe Publication Classification level. The invention also encompasses methods of treating (51) Int. Cl. patients by administering this coordinated release, gastropro A6 IK3I/92 (2006.01) tective, antiarthritic/analgesic combination unit dosage form A6 IK 9/30 (2006.01) to achieve pain and symptom relief with a reduced risk of A6 IK 3/4164 (2006.01) developing gastrointestinal damage such as ulcers, erosions A6 IK3I/34 (2006.01) and hemorrhages. NAPROXEN CORE TABLET ENTERIC FILM COAT ACID INHIBITOR COAT Patent Application Publication Mar. 15, 2012 Sheet 1 of 2 US 2012/0064156A1 BARRIER FILM COAT NAPROXEN SODIUM CORE TABET ENERC FM COA ACID INHIBITOR COAT FIG.1 NAPROXEN CORE TABLET ENERIC FILM COAT ACD INHIBOR COAT FIG.2 Patent Application Publication Mar. 15, 2012 Sheet 2 of 2 US 2012/0064156A1 ENTERICFILM- SUBCOAT COAT FIG.3 US 2012/0064156 A1 Mar. 15, 2012 PHARMACEUTICAL COMPOSITIONS FOR with the first dose in a course of treatment since this class of THE COORONATED DELVERY OF NSAIDS drugs is enteric coated to avoid destruction by stomach acid. As a result, absorption is delayed for several hours. Even then, CROSS REFERENCE TO RELATED Some patients fail to respond consistently to drugs of this type APPLICATIONS and suffer from “acid breakthrough which again leaves them Vulnerable to NSAID-associated gastroduodenal damage 0001. The present application is a continuation-in-part of (Aliment. Pharmacol. Ther. 14:709–714 (2000)). Despite a U.S. application Ser. No. 10/158.216, filed on May 31, 2002. significant reduction in gastroduodenal lesions with the con The 216 application claims the benefit of U.S. provisional comitant administration of a proton pump inhibitor during six application No. 60/294,588, filed on Jun. 1, 2001. months of NSAID therapy, up to 16% of patients still develop ulcers, indicating that there remains Substantial room for FIELD OF THE INVENTION improvement (N. Eng. J. Med. 338:727-734 (1998)). Thus, 0002 The present invention is directed to pharmaceutical the addition of a pH sensitive enteric coating to an NSAID compositions that provide for the coordinated release of an could provide additional protection against gastroduodenal acid inhibitor and a non-steroidal anti-inflammatory drug damage not provided by the H2 blocker or PPI alone. In (NSAID). These compositions have a reduced likelihood of addition, although long acting acid inhibitors may reduce the causing unwanted side effects, especially gastrointestinal risk of GI lesions in chronic NSAID users, there are questions side effects, when administered as a treatment for pain, arthri about the safety of maintaining an abnormally elevated pH in tis and other conditions amenable to treatment with NSAIDs. a patient's GI tract for a prolonged period of time (Scand. J. Gastroenterol. Suppl. 178:85-92 (1990)). BACKGROUND OF THE INVENTION 0006 Recognizing the potential benefits of PPIs for the 0003. Although non-steroidal anti-inflammatory drugs are prevention of NSAID-induced gastroduodenal damage, oth widely accepted as effective agents for controlling pain, their ers have disclosed strategies for combining the two active administration can lead to the development of gastroduodenal agents for therapeutic purposes. However, these Suggestions lesions, e.g., ulcers and erosions, in Susceptible individuals. It do not provide for coordinated drug release or for reducing appears that a major factor contributing to the development of intragastric acid levels to a non-toxic level prior to the release these lesions is the presence of acid in the stomach and upper of NSAID (U.S. Pat. No. 5,204,118; U.S. Pat. No. 5,417,980; small intestine of patients. This view is supported by clinical U.S. Pat. No. 5,466,436; and U.S. Pat. No. 5,037,815). In studies demonstrating an improvement in NSAID tolerability certain cases, suggested means of delivery would expose the when patients are also taking independent doses of acid gastrointestinal tract to NSAIDs prior to onset of PPI activity inhibitors (Dig. Dis. 12:210-222 (1994); Drug Safety 21:503 (U.S. Pat. No. 6,365,184). 512 (1999); Aliment. Pharmacol. Ther: 12:135-140 (1998); 0007 Attempts to develop NSAIDs that are inherently less Am. J. Med. 104(3A):67S-74S (1998); Clin. Ther: 17:1159 toxic to the gastrointestinal tract have met with only limited 1173 (1995)). Other major factors contributing to NSAID Success. For example, the recently developed cyclooxyge associated gastropathy include a local toxic effect of NSAIDs nase-2 (COX-2) inhibitors show a reduced tendency to pro and inhibition of protective prostaglandins (Can. J. Gastro duce gastrointestinal ulcers and erosions, but a significant risk enterol. 13:135-142 (1999) and Pract. Drug Safety 21:503 is still present, especially if the patient is exposed to other 512. (1999)), which may also make some patients more sus ulcerogens (JAMA 284:1247-1255 (2000): N. Eng. J. Med. ceptible to the ulcerogenic effects of other noxious stimuli. 343:1520-1528 (2000)). In this regard, it appears that even 0004. In general, more potent and longer lasting acid low doses of aspirin will negate most of the benefit relating to inhibitors, such as proton pump inhibitors, are thought to be lower gastrointestinal lesions. In addition, the COX-2 inhibi more protective during chronic administration of NSAIDs tors may not be as effective as other NSAIDs at relieving than shorteracting agents, e.g., histamine H receptorantago Some types of pain and have been associated with significant nists (H-2 blockers) (N. Eng. J. Med. 338:719-726 (1998); cardiovascular problems (JADA 131: 1729-1737 (2000); Am. J. Med 104(3A):56S-61S (1998)). The most likely SCRIP 2617, pg. 19, Feb. 14, 2001): NY Times, May 22, explanation for this is that gastric pH fluctuates widely 2001, pg. C1)). throughout the dosing interval with short acting acid inhibi 0008. Other attempts to produce an NSAID therapy with tors leaving the mucosa Vulnerable for significant periods of less gastrointestinal toxicity have involved the concomitant time. In particular, the pH is at its lowest point, and hence the administration of a cytoprotective agent. In 1998, Searle mucosa is most Vulnerable, at the end of the dosing interval began marketing ArthrotecTM for the treatment of arthritis in (least amount of acid inhibition) and for some time after the patients at risk for developing GI ulcers. This product con Subsequent dose of acid inhibitor. In general, it appears that tains misoprostol (a cytoprotective prostaglandin) and the when a short acting acid inhibitor and an NSAID are admin NSAID diclofenac. Although patients administered Arthro istered simultaneously, NSAID-related mucosal damage tecTM do have a lower risk of developing ulcers, they may occurs before the pH of the gastrointestinal tract can be raised experience a number of other serious side effects such as and after the acid inhibiting effect of the short acting acid diarrhea, severe cramping and, in the case of pregnant inhibitor dissipates. women, potential damage to the fetus. 0005 Although longer lasting agents, such as proton 0009. Another approach has been to produce enteric pump inhibitors (PPIs), usually maintain a consistently coated NSAID products. However, even though these have higher gastroduodenal pH throughout the day, their antisecre shown modest reductions in gastroduodenal damage in short tory effect may be delayed for several hours and may not take term studies (Scand. J. Gastroenterol. 20: 239-242 (1985) and full effect for several days (Clin. Pharmacokinet. 20:38-49 Scand. J. Gastroenterol. 25:231-234 (1990)), there is no con (1991)). Their effect may be diminished toward the end of the sistent evidence of a long term benefit during chronic treat usual dosing interval. Intragastric pH rises particularly slowly ment. US 2012/0064156 A1 Mar. 15, 2012 0010. Overall, it may be concluded that the risk of induc be celecoxib, rofecoxib, lumiracoxib, Valdecoxib, parecoxib, ing GI ulcers is a recognized problem associated with the etoricoxib, CS-502, JTE-522, L-745,337, NS398, aspirin, administration of NSAIDs and that, despite considerable acetaminophen (considered to be an NSAID for the purposes effort, an ideal solution has not yet been found. of the present invention), ibuprofen, flurbiprofen, ketoprofen, naproxen, oxaprozin, etodolac, indomethacin, ketorolac, lor SUMMARY OF THE INVENTION noxicam, meloxicam, piroxicam, droxicam, tenoxicam, 0011.