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(12) Patent Application Publication (10) Pub. No.: US 2005/0249806A1 Proehl Et Al

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US 2005O249806A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0249806A1 Proehl et al. (43) Pub. Date: Nov. 10, 2005 (54) COMBINATION OF PROTON PUMP Related U.S. Application Data INHIBITOR, BUFFERING AGENT, AND NONSTEROIDAL ANTI-NFLAMMATORY (60) Provisional application No. 60/543,636, filed on Feb. DRUG 10, 2004. (75) Inventors: Gerald T. Proehl, San Diego, CA (US); Publication Classification Kay Olmstead, San Diego, CA (US); Warren Hall, Del Mar, CA (US) (51) Int. Cl." ....................... A61K 9/48; A61K 31/4439; A61K 9/20 Correspondence Address: (52) U.S. Cl. ............................................ 424/464; 514/338 WILSON SONS IN GOODRICH & ROSAT (57) ABSTRACT 650 PAGE MILL ROAD Pharmaceutical compositions comprising a proton pump PALO ALTO, CA 94304-1050 (US) inhibitor, one or more buffering agent and a nonsteroidal ASSignee: Santarus, Inc. anti-inflammatory drug are described. Methods are (73) described for treating gastric acid related disorders and Appl. No.: 11/051,260 treating inflammatory disorders, using pharmaceutical com (21) positions comprising a proton pump inhibitor, a buffering (22) Filed: Feb. 4, 2005 agent, and a nonsteroidal anti-inflammatory drug. US 2005/0249806 A1 Nov. 10, 2005 COMBINATION OF PROTON PUMP INHIBITOR, of the Stomach by raising the Stomach pH. See, e.g., U.S. BUFFERING AGENT, AND NONSTEROIDAL Pat. Nos. 5,840,737; 6,489,346; and 6,645,998. ANTI-NFLAMMATORY DRUG 0007 Proton pump inhibitors are typically prescribed for Short-term treatment of active duodenal ulcers, gastrointes CROSS REFERENCE TO RELATED tinal ulcers, gastroesophageal reflux disease (GERD), Severe APPLICATIONS erosive esophagitis, poorly responsive Symptomatic GERD, 0001. This application claims priority to U.S. Provisional and pathological hyperSecretory conditions Such as Application No. 60/543,636 filed Feb. 10, 2004, which is Zollinger Ellison syndrome. These above-listed conditions incorporated herein by reference in its entirety. commonly arise in healthy or critically ill patients of all ages, and may be accompanied by Significant upper gas FIELD OF THE INVENTION trointestinal bleeding. 0002 The present invention is related to pharmaceutical 0008. It is believed that omeprazole, lansoprazole and compositions comprising a proton pump inhibitor, a buffer other proton pump inhibiting agents reduce gastrointestinal ing agent, and a nonsteroidal anti-inflammatory drug. acid production by inhibiting H/K"-ATPase of the parietal cell, which is the final common pathway for gastrointestinal 0.003 Methods for manufacture of the pharmaceutical acid Secretion. See, e.g., Fellenius et al., Substituted Benz compositions and use of the pharmaceutical compositions in imidazoles Inhibit Gastrointestinal Acid Secretion by Block treating disease are disclosed. ing H/K"-ATPase, Nature, 290: 159-161 (1981); Wallmark et al., The Relationship Between Gastrointestinal Acid BACKGROUND OF THE INVENTION Secretion and Gastrointestinal H"/K"-ATPase Activity, J. Biol. Chem., 260: 13681-13684 (1985); and Fryklund et al., 0004 Proton Pump Inhibitors Function and Structure of Parietal Cells. After H/K-AT 0005 Proton pump inhibitors (PPIs) are a class of acid Pase Blockade, Am. J. Physiol., 254 (1988). labile pharmaceutical compounds that block gastric acid Secretion pathways. Exemplary proton pump inhibitors 0009 Proton pump inhibitors have the ability to act as include, omeprazole (Prilosec(R), lansoprazole (Prevacid(R), weak bases which reach parietal cells from the blood and esomeprazole (Nexium(R), rabeprazole (Aciphex(E), panto diffuse into the Secretory canaliculi. There the drugs become prazole (Protonix(R), pariprazole, tenatoprazole, and lemi protonated and thereby trapped. The protonated compound noprazole. The drugs of this class SuppreSS gastrointestinal can then rearrange to form a Sulfenamide which can acid secretion by the specific inhibition of the H/K"- covalently interact with Sulfhydryl groups at critical Sites in ATPase enzyme System (proton pump) at the Secretory the extra cellular (luminal) domain of the membrane-Span Surface of the gastrointestinal parietal cell. Most proton ning H/K-ATPase. See, e.g., Hardman et al., Goodman & pump inhibitors are Susceptible to acid degradation and, as Gilman 's The Pharmacological Basis of Therapeutics, 907 Such, are rapidly destroyed in an acidic pH environment in (9th ed. 1996). As such, proton pump inhibitors are prodrugs the Stomach. Therefore, proton pump inhibitors are often that must be activated within parietal cells to be effective. administered as enteric-coated dosage forms in order to The Specificity of the effects of proton pump inhibiting permit release of the drug in the duodenum after having agents is also dependent upon: (a) the Selective distribution passed through the Stomach. If the enteric-coating of these of H"/K"-ATPase; (b) the requirement for acidic conditions formulated products is disrupted (e.g., during trituration to to catalyze generation of the reactive inhibitor; and (c) the compound a liquid dosage form, or by chewing an enteri trapping of the protonated drug and the cationic Sulfenamide coated granular capsule or tablet), or if a co-administered within the acidic canaliculi and adjacent to the target buffering agent fails to Sufficiently neutralize the gastrointes enzyme. tinal pH, the uncoated drug is exposed to Stomach acid and 0010 Nonsteroidal Anti-Inflammatory Drugs may be degraded. 0011 Nonsteroidal anti-inflammatory drugs (“NSAIDs”) 0006. Omeprazole, a substituted bicyclic aryl-imidazole, are among the most commonly prescribed and used drugs 5-methoxy-2-(4-methoxy-3, 5-dimethyl-2-pyridinyl) world-wide. The ability of NSAIDs to treat inflammatory methylsulfinyl)-1H-benzimidazole, is a proton pump disorders is attributed to their ability to inhibit cyclooxyge inhibitor that inhibits gastrointestinal acid secretion. U.S. nase, the enzyme responsible for biosyntheses of the pros Pat. No. 4,786,505 to Lovgren et al. teaches that a pharma ceutical oral Solid dosage form of omeprazole must be taglandins and certain autocoid inhibitors, including inhibi protected from contact with acidic gastrointestinal juice by tors of lipoxygenase and cyclooxygenase (Such as an enteric-coating to maintain its pharmaceutical activity cyclooxygenase-I and cyclooxygenase-II). and describes an enteric-coated omeprazole preparation con 0012 However, despite the therapeutic benefits of taining one or more Subcoats between the core material and NSAIDs, their use is often limited by an increased risk of the enteric-coating. Non-enteric coated pharmaceutical gastrointestinal Side-effects, in particular upper gastrointes compositions have also been described, which facilitate tinal Side-effects Such as peptic ulceration and dyspeptic immediate release of the pharmaceutically active ingredient Symptoms. For example, Studies have indicated that during into the Stomach and permit Stomach uptake of pharmaceu NSAID treatment, the relative risk of developing a gastric tical agents. Use of non-enteric coated compositions ulcer is increased by a factor of 40-50, the relative risk of involves the administration of one or more buffering agents developing a duodenal ulcer is increased by a factor of 8-10, with an acid labile proton pump inhibitor. The buffering and the relative risk of developing an ulcer complication like agent is thought to prevent Substantial degradation of the bleeding or perforation of the Stomach is increased by a acid labile pharmaceutical agent in the acidic environment factor of 1.5-5. See, e.g., McCarty DSM., Gastroenterology US 2005/0249806 A1 Nov. 10, 2005 1989, 96:662; and Hawkey C., BMJ 1990; 300:278. Fur acid degradation of at least Some of the proton pump thermore, dyspeptic Symptoms are experienced in 30-60% inhibitor in the gastric fluid, and (c) a therapeutically effec of patients on NSAID treatment. See Larkai E. N., Am. J. tive amount of at least one nonsteroidal anti-inflammatory Gas. 1987; 82:1153. Additionally, NSAIDs are typically the drug, are provided herein. Methods are provided for treating prescribed treatment for chronic diseases like rheumatoid gastric acid related disorders and treating inflammatory arthritis and Osteoarthritis, Seen most often in the elderly disorders in a Subject, using pharmaceutical compositions of population. Compliance is especially important in elderly the present invention. Methods are also provided for pre and fragile patients, who have the highest risk of developing venting gastric acid related disorders during long-term a life-threatening complication of NSAID treatment, for administration of NSAID in a subject for the purpose of example bleeding or perforation. It has been reported that reducing the risk of heart attack or certain types of cancers 50% of all peptic ulcer deaths occur in NSAID users, and by administering the Subject pharmaceutical compositions that 68% of these deaths are in patients above the age of 75. of the present invention. See Catford Health Trends 1986, 18:38; and Guess, J. Clin. 0017 Proton pump inhibitors include, but are not limited Epidemiol., 1988, 41:35. to, omeprazole, hydroxyomeprazole, esomeprazole, tenato 0013 Attempts have been undertaken to modify the prazole, lanSoprazole, pantoprazole, rabeprazole, dontopra structure of NSAIDs in order to prevent undesired side Zole, habeprazole, periprazole, ranSoprazole, pariprazole, effects. The new family of NSAIDs which selectively inhibit leminoprazole; or a free base, free acid, Salt, hydrate,
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  • Semantic Query Modeling, Context, Section Detection, and Match Score Maximization

    Semantic Query Modeling, Context, Section Detection, and Match Score Maximization

    DutchHatTrick: Semantic query modeling, ConText, section detection, and match score maximization. Martijn Schuemie* Dolf Trieschnigg† Edgar Meij‡ ErasmusMC University of Twente University of Amsterdam [email protected] [email protected] [email protected] Introduction This report discusses the collaborative work of the ErasmusMC, University of Twente, and the University of Amsterdam on the TREC 2011 Medical track. Here, the task is to retrieve patient visits from the University of Pittsburgh NLP Repository for 35 topics. The repository consists of 101,711 patient reports, and a patient visit was recorded in one or more reports. Because the training set provided by the track organization was small and not made available until quite late in the competition, we decided to create a small training set ourselves. Not only did this allow us to test several ideas before submitting runs to TREC, it also led to several insights into the data. One finding was that synonyms are widely used. Query expansion was therefore deemed essential to achieve a reasonable performance. Query expansion has been used before in Information Retrieval (IR), and is often divided into statistical and knowledge-based query expansion. Statistical query expansion uses data derived from the corpus itself, and a well-known example is pseudo-relevance feedback [1]. In contrast, we investigated knowledge-based query expansion, which uses a knowledge base such as an ontology or a dictionary to find related terms. This type of query expansion has not always proven to be successful. For instance, Hersh et al. [2] found a decrease in overall search performance when using the Unified Medical Language System (UMLS) [3] to find related terms.