ll ( (51) International Patent Classification: Published: A61K9/46 (2006.01) A61K /20 (2006.01) — with international search report (Art. 21(3)) A61K 9/00 (2006.01) A61P 1/04 (2006.01) A61K9/06 (2006.01) A61K 31/58 (2006.01) A61K 9/10 (2006.01) (21) International Application Number: PCT/EP20 19/0687 18 (22) International Filing Date: 11 July 2019 ( 11.07.2019) (25) Filing Language: English (26) Publication Language: English (30) Priority Data: 18182910.2 11 July 2018 ( 11.07.2018) EP (71) Applicant: MEDIZINISCHE UNIVERSITAT WIEN [AT/AT]; Spitalgasse 23, 1090 Wien (AT). (72) Inventors: ORGLER, Elisabeth; Leonhardstralk 3, 8010 Graz (AT). GASCHE, Christoph; Babenbergergasse 20, 3400 Klostemeuburg (AT). DABSCH, Stefanie; Alszeile 84, 1170 Wien (AT). (74) Agent: VOSSIUS & PARTNER (NO 31); Patentanwalte Rechtsanwalte mbB, Siebertstrasse 3, 81675 Munchen (PE). (81) Designated States (unless otherwise indicated, for every kind of national protection available) : AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (84) Designated States (unless otherwise indicated, for every kind of regional protection available) : ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, Cl, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). (54) Title: GLUCOCORTICOIDS FOR THE TOPICAL TREATMENT OF AUTOIMMUNE GASTRITIS (57) Abstract: The present invention relates to compositions comprising one or more glucocorticoid(s)used in the topical treatment of autoimmune gastritisby delivering an effective amount of the glucocorticoid(s) to the topical area to be treated using a gastroretentive drug delivery system that releases the glucocorticoid(s) in a timely and locally controlled manner. Particularly, the topical area to be treated comprises or is the stomach mucosa, preferably the corpus and/or fundus of the stomach and the preferred glucocorticoid is budesonide. GLUCOCORTICOIDS FOR THE TOPICAL TREATMENT OF AUTOIMMUNE GASTRITIS Field of Invention The present invention relates to compositions comprising one or more glucocorticoid(s) used in the topical treatment of autoimmune gastritis by delivering an effective amount of the glucocorticoid(s) to the topical area to be treated using a controlled release drug delivery system that releases the glucocorticoid(s) in a timely and locally controlled manner. Particularly, the topical area to be treated comprises or is the mucosa of the stomach, preferably the mucosa of the corpus and/or fundus of the stomach and the preferred glucocorticoid is budesonide. Background of the Invention Autoimmune gastritis (AIG) is a chronic inflammatory disease of the stomach occurring in up to 8% of the general population and, as the name implies, is characterized by atrophy of the glands in the corpus mucosa caused by the cells of the body's own immune defense system, i.e. with the development of autoantibodies against parietal cells of the gastric body (Toh 2014). These parietal cell autoantibodies (PCA) destroy parietal cells of the corpus and fundus of the stomach leading to an atrophy of the mucosa. Parietal cells are epithelial cells located in the glands of the corpus and fundus but not in the antrum and produce hydrochloric acid and intrinsic factor (Kulnigg-Dabsch 2016). The acidification of the stomach is primarily managed by the gastritic H+/K+ ATPase, the proton pump, which is impaired in AIG (Toh et al, 2000). The decrease and final loss of the parietal cells during progression of the disease results in increased pH of the stomach and loss of intrinsic factor produced by parietal cells. Intrinsic factor is required for uptake of vitamin B I2. Consequently, vitamin B I2 deficiency is a known result of AIG (Kulnigg-Dabsch 2016). Thus, AIG is often associated with impaired absorption of vitamin B I2 and possibly other vitamin and mineral deficiencies, such as folate, and iron deficiency. Patients who developed vitamin B I2 deficiency will suffer from gastrointestinal and neurological complaints such as malabsorption, diarrhea, weight loss, glossitis, peripheral numbness, paresthesia with subsequent development of weakness, and ataxia (Kulnigg-Dabsch 2016). For classification and grading of chronic gastritis including AIG the updated Sydney classification system has been introduced (Dixon et al, 1996). This classification system is used to grade histological parameters, identify topographical distribution and, finally, make a statement about the etiopathogenesis of the gastritis. Of pathogenetic importance is, in the first instance, the differentiation between gastritis with and gastritis without H. pylori infection. In this context, the Sydney System differentiates between the atrophic gastritis of types A and B, wherein AIG is referred to the “A type” gastritis recognized as a corpus- restricted atrophic gastritis of autoimmune origin, and the “B type” represents the atrophic gastritis that is related to H.pylori infection (Dixon et al, 1996; Sipponen and Price, 201 1). The group of H. pylori-associated gastritis can be further subdivided into forms of gastritis whose morphological distribution patterns usually identify them as sequelae of H. pylori infection, while the group of gastritis unassociated with H. pylori, can be differentiated into autoimmune, chemically induced reactive gastritis, ex-H. pylori gastritis, Helicobacter heilmannii gastritis, Crohn's gastritis and a number of special forms of gastritis. (Stolte et al, 2001). In some cases, AIG does not cause any obvious signs and symptoms. However, some people may experience nausea, vomiting, a feeling of fullness in the upper abdomen after eating, or abdominal pain. The main manifestation of AIG is known to be pernicious anemia. The clinical signs and symptoms of anemia, irrespective of etiology, include shortness of breath, dizziness, tachycardia, lightheadedness, and decreased cognitive and physical function (Kulnigg-Dabsch 2016). In particular, a study by Hershko et al. (2006) further showed that the predominant hematolytic manifestation in patients with AIG is iron deficiency (ID) amenia, a nutritional deficiency caused by an imbalance of iron uptake and iron loss and affecting about 10 to 30 % of women in industrialized nations being in reproductive age. ID is either caused by increased loss of iron due to acute or chronic bleeding, such as gastrointestinal bleeding, augmented menstrual bleeding, or by low absorption of iron. Decreased iron absorption might be due to inflammation at the site of iron uptake, which is found in AIG, wherein the decrease of gastric acid and ascorbic acid contributing to the release of iron-protein-complexes and to reduction of ferric iron are well described (Hershko et al (2007); Aditi et al, (2012)). Symptoms of ID arise independently of amenia-related symptoms, and include fatigue, restless legs syndrome, brittle nails, hair loss, impaired immune function, and impaired wound healing. As for other chronic inflammatory diseases, patients suffering from chronic gastritis including AIG patients have a higher risk of developing carcinoid tumors and gastric adenocarcinomas within the chronically inflamed tissue (Torbenson et al., 2002). In this regard, AIG is considered a "precancerous" condition and it may be responsible for the development of gastric adenocarcinoma or carcinoids. Thereby, a precursor lesion may be induced by the chronic inflammation in AIG patients which may first lead to atrophy of the tissue in the fundus and/or the corpus and subsequently to intestinal metaplasia (Kulnigg-Dabsch 2016). Development of gastric cancer is also known from H. pylori-related gastritis, wherein a major characteristic of the infiltration with inflammatory cells is the typically severe corpus gastritis (Kulnigg-Dabsch 2016; Stolte et al., 2001). With respect to AIG patients, it is also surmised that unknown genetic, metabolic, or environmental triggers may lead to the adenocarcinoma, which is also known from colonic cancer (Correa 1988). The underlying genetic cause of AIG has not been fully identified yet. Studies suggest that the condition may be inherited in an autosomal dominant manner (Nafea 2014). Patients suffering from AIG are likely to have other autoimmune disorders including autoimmune thyroiditis, diabetes type I, Addison’s disease, and vitiligo. Diagnosis of AIG is made through a combination of clinical findings, such as certain blood tests and presence of other autoimmune conditions, and the collection of a biopsy of fundus and/or corpus obtained through endoscopy (Kulnigg-Dabsch 2016). Treatment is based on the signs and symptoms present in each person, but may include iron infusions, vitamin B I2 injections and endoscopic surveillance (Park et al, 2013; Kulnigg-Dabsch 2016). If pernicious anemia is already present at the time of diagnosis, vitamin B I2 injections may be recommended. Iron therapy approaches may include receiving periodic intravenous iron infusion to increase iron stores or a daily dose of oral ferrous glycine sulfate to meet daily iron requirements. In this context, it is recommended that levels of B I2 and iron are routinely monitored in patients suffering from and having suffered from AIG. In some cases, periodic endoscopy may also be recommended due to the increased risk of certain types of cancer (Park et al., 2013; Kulnigg-Dabsch 2016).