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(12) Patent Application Publication (10) Pub. No.: US 2012/0122919 A1 Schutze Et Al US 2012O122919A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0122919 A1 Schutze et al. (43) Pub. Date: May 17, 2012 (54) PHARMACEUTICAL COMPOSITION (30) Foreign Application Priority Data COMBINING TENATOPRAZOLE AND A HISTAMINE H2-RECEPTOR ANTAGONST Oct. 21, 2002 (FR) ...................................... 02/13114 (75) Inventors: Francois Schutze, Saint-Nom-La-Breteche (FR); Suzy Publication Classification Charbit, Creteil (FR); Hervé (51) Int. Cl. Ficheux, Nogent-sur-Marne (FR): A63L/437 (2006.01) Michel Homerin, Courcouronnes A6IPL/04 (2006.01) (FR); Alain Taccoen, Le Chesnay (FR); Nathalie Taccoen, legal representative, La Chesnay (FR); (52) U.S. Cl. ........................................................ S14/303 Yoshio Inaba, Tokyo (JP) (73) Assignees: MTSUBISH PHARMA CORPORATION, Tokyo (JP); (57) ABSTRACT SIDEM PHARMA, Luxembourg (LU) The invention relates to a novel pharmaceutical combination. The inventive pharmaceutical composition, which is intended (21) Appl. No.: 13/297,122 for the treatment of pathologies linked to gastric hyperacidity, (22) Filed: Nov. 15, 2011 comprises a combination of tenatoprazole and one or more O O histamine H2-receptor antagonists preferably selected from Related U.S. Application Data cimetidine, ranitidine, famotidine and nizatidine. The inven (63) Continuation of application No. 10/532,114, filed on tion is particularly suitable for the treatment of duodenal and Jun. 23, 2006, now abandoned, filed as application No. gastric ulcers and the symptoms of, and lesions caused by, PCT/FR2003/003124 on Oct. 21, 2003. gastroesophageal reflux. US 2012/O 122919 A1 May 17, 2012 PHARMACEUTICAL COMPOSITION nist Such as famotidine, with at least two standard antacids COMBINING TENATOPRAZOLE ANDA Such as Sodium bicarbonate and magnesium hydroxide, HISTAMINE H2-RECEPTOR ANTAGONST which display a strong neutralisation potential, and an alu minium hydroxide gel which exhibits weak neutralisation RELATED APPLICATIONS potential. Patent No. FR2,656,528 describes the combination of cimetidine and an antimuscarinic agent, pirenzepine, 0001. The present application is a continuation of U.S. which is presented as diminishing the adverse effects ofcime patent application Ser. No. 10/532,114 filed Jun. 23, 2006, the tidine. contents of which are hereby incorporated by reference in 0011. A study has shown that administering omeprazole their entirety. twice a day and ranitidine in the evening to patients Suffering from gastoesophageal reflux might be useful (Peghini P L. BACKGROUND OF THE INVENTION Katz. PO, Castell DO, “Ranitidine controls nocturnal gastric acid breakthrough on omeprazole : a control study in normal 0002 1. Field of the invention subjects' Gastroenterology (1998) 115(6):1335-9) but other 0003. The present invention concerns a new drug combi studies mention that a treatment comprising administering nation, and more particularly a new pharmaceutical compo omeprazole in the morning and in the evening is more effi sition combining an histamine H2-receptor antagonist and cient than a treatment combining the administration of ome tenatoprazole, for the treatment of diseases related to gastric prazole with that of ranitidine (Cross L. B. Justice LN, “Com hyperacidity, particularly gastric and duodenal ulcers, and bination drug therapy for gastroesophageal reflux disease'. symptoms and lesions related to gastroesophageal reflux. Ann. Pharmacother. (May 2002) 36(5):912-6). In view of Such results, it can be considered that the association of a 0004 2. Description of the Related Art histamine H2-receptor antagonist and a proton pump inhibi 0005. When treating digestive disorders such as dyspep tor has no particular advantage, probably partly because of sia, gastric hyperacidicity, gastritis, etc., the aim is usually to the low elimination half-life of the latter. eliminate the gastric acid which is responsible for damaging 0012. On the contrary, the studies performed by the appli the gastric mucosa. Various medicinal products, such as ant cant have shown that the combination of a specific proton acids, histamine H2-receptor antagonists and proton pump pump inhibitor, i.e. tenatoprazole, and a histamine H2-recep inhibitors have been used for such treatments. tor antagonist procures unexpected effects which compared 0006 Thus histamine H2-receptor antagonists are fre with other proton pump inhibitors and other histamine H2-re quently employed to treat disorders linked to the hypersecre ceptor antagonists, used alone or in combination. More par tion of gastric acid, for example the treatment of gastric ticularly, it has been shown that the combination of tenato ulcers, as they inhibit the secretion of gastric acid. Histamine prazole and one or more histamine H2-receptor antagonists H2-receptor antagonists may be chosen from a series of well enables control of gastric acidity which is markedly Superior known products such as cimetidine, ranitidine, famotidine, to that achieved with each of the components used alone, and etc. particularly allows the effective treatment of patients suffer 0007 Proton pump inhibitors have also proved their use ing from Symptoms and lesions related to gastroesophageal fulness in the treatment of gastric and duodenal ulcers. The reflux and refractory to standard therapy with a proton pump first known derivative of this series was omeprazole, inhibitor. described in Patent No. EP 005.129, and endowed with prop SUMMARY OF THE INVENTION erties which inhibit the secretion of gastric acid and is widely 0013 The object of the present invention is therefore a employed as an anti-ulcerative in human therapeutics. Other pharmaceutical composition combining a specific proton proton pump inhibitors include rabeprazole, pantoprazole pump inhibitor, tenatoprazole, with one or more histamine and lanSoprazole, which all exhibit structural analogy and H2-receptor antagonists. belong to the group of pyridinyl-methyl-Sulfinyl-benzimida 0014. A further object of the present invention is a phar Zoles. Tenatoprazole has a similar structure, but of the imida maceutical composition for administration by mouth, com Zopyridine type. These compounds are Sulfoxides presenting prising tenatoprazole and one or more histamine H2-receptor with asymmetry at the level of the sulphur atom, and therefore antagonists, in a form adapted to the treatment of diseases generally take the form of a racemic mixture of two enanti related to gastric hyperacidity, particularly gastric and duode OS. nal ulcers, and the symptoms and lesions of gastroesophageal 0008 Omeprazole has also been envisaged for the treat reflux. ment of gastroesophageal reflux disorders, but its action in 0015. Another object of the invention is the combined use this indication is not entirely satisfactory. Thus studies have of tenatoprazole and at least one histamine H2-receptor shown that its duration of action, like that of other proton antagonist for the treatment of diseases related to gastric pump inhibitors, is insufficient to ensure the efficient treat hyperacidity, particularly gastric and duodenal ulcers, and the ment of nocturnal reflux. symptoms and lesions of gastroesophageal reflux, as well as 0009 Tenatoprazole, or 5-methoxy-2-(4-methoxy-3,5- the combined use of tenatoprazole and at least one histamine dimethyl-2-pyridyl)methylsulfinyl)imidazo[4,5-b]pyridine, H2-receptor antagonist for the manufacture of a medicinal is described in Patent No. EP254.588, together with its prop product intended for the treatment of diseases related to gas erties which inhibit ATPase (H+K) and gastric acid secre tric hyperacidity, particularly gastric and duodenal ulcers, tion. and the symptoms and lesions of gastroesophageal reflux. 0010 Various combinations of active substances belong ing to these categories have also been envisaged with the aim DETAILED DESCRIPTION OF THE PREFERRED of improving their pharmacological effects or attenuating EMBODIMENTS their known adverse effects. For example, U.S. Pat. No. U.S. 0016. According to the invention, tenatoprazole can be 6,090,412 describes a pharmaceutical formulation for oral used in a free or salt form, Such as, for example, a potassium, administration combining a histamine H2-receptor antago magnesium, Sodium or calcium salt. US 2012/O 122919 A1 May 17, 2012 0017. The histamine H2-receptor antagonist employed in been made by Tolman et al. (J. Clin. Gastroenterol., 24(2), the composition of the invention may be selected from cime 65-70, 1997), but this did not enable a judgement as to the tidine, ranitidine, famotidine or nizatidine. superiority of one product over the other. Indeed, different 0018. The ratio between the content in tenatoprazole and criteria must be taken into account, i.e. the time required for that of the histamine H2-receptor antagonist may be between pump regeneration, the period above the minimum concen 1:30 and 1:2, and preferably between 1:20 and 1:5; this ratio tration necessary to inhibit proton pumps. With respect to the may vary as a function of the histamine H2-receptor antago pump regeneration time, it is observed that pumps usually nist chosen. have a half-life of about 30 to 48 hours, and are therefore 0019 Previous studies have shown that amongst both totally renewed every 72 to 96 hours. patients suffering from Symptoms and lesions of gastroesoph 0027. The pharmacokinetic study performed by the claim ageal reflux and healthy Volunteer Subjects, approximately ant showed that, thanks to the unexpected pharmacokinetic 70% of them experienced
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