WO2020011938A1

WO2020011938A1 - Glucocorticoids for the topical treatment of autoimmune gastritis

Info

Publication number: WO2020011938A1
Application number: PCT/EP2019/068718
Authority: WO
Inventors: Elisabeth ORGLER; Christoph Gasche; Stefanie DABSCH
Original assignee: Medizinische Universität Wien
Priority date: 2018-07-11
Filing date: 2019-07-11
Publication date: 2020-01-16

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.

Description

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, 2011). 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). Despite symptomatic treatment of AIG based on iron infusions, vitamin ! injections and endoscopic surveillance, there is no curative treatment for autoimmune gastritis at this moment. For example, pernicious anaemia can be alleviated by vitamin B_I2 replacement therapy, but this has no impact on the underlying destructive autoimmune disease process (Toh et al, 2012). The effect of immunosuppression by prednisolone was assessed in a mouse model of autoimmune gastritis. It led to remission of the gastric inflammation during therapy, however, withdrawal promptly results in disease recurrence (Biondo et al, 2006). In general, treatment of AIG with glucocorticoid(s) appears not to be recommendable due to the steroid- associated systemic side effects, in particular by long-term administration of systemically effective steroids. Therefore, systemic effects of potential drugs for the treatment of AIG should be avoided, e.g. by a high first pass effect, whereby the concentration of a drug is greatly reduced before it reaches the systemic circulation. Further, development of effective and locally efficient drugs is complicated by the knock of short gastric retention time and the unpredictable rapid gastric rate that may cause partial drug release in the absorption zone of the patient’s body, hence, hampering the efficiency of the dosage.

Hence, the objective of the present invention is the provision of an efficient and locally effective treatment for patients having AIG. In this sense, a suitable drug delivery system may enable a local release of the drug at the topical area to be treated and prolong the retaining ability in the topical area to be treated and would thus improve gastric residence time and efficacy of the drug. Further benefits of such a locally effective drug and its elongated retention ability may be enumerated as: improving activity span for short half-life drugs, increased contact time for the drug to allow for local activity in the topical area to be treated, increased bioavailability of drugs, increased and more efficient absorption for drugs which have specific absorption sites, exclusion of side effects, the ability to reduce the number of dosages per period of time, saving drugs owing to former benefit, minimization or elimination of local and/or systemic side effects, minimization of drug accumulation associated with chronic dosing, improved efficiency and safety of treatment, reduced fluctuation of drug level, and better patient compliance with overall disease management. The advantage to the patient and clinician in having consistent and uniform blood levels of medication over an extended period of time are likewise recognized. Since chronic inflammation and atrophy in AIG patients may increase the risk of developing pernicious anemia, gastric polyps, metaplastic atrophic gastritis (AMAG), gastric cancer, specifically adenocarcinoma, and gastric neuroendocinre tumors, the importance of such a treatment is emerged (Landgren et al, 2011; Hsing et al, 1993). Thereby, further significant risk factors for the development of gastric cancer in autoimmune atrophic gastritis include pernicious anemia, severity of atrophy, intestinal metaplasia, length of disease duration, and age older than 50 years (Park et al., 2013). Therefore, the provision of a treatment of AIG which at the same time reduces the risk of developing gastric cancer is a further objective of the present invention.

The technical problem is solved by provision of the embodiments provided herein below and characterized in the appended claims.

Summary of the Invention

The present invention relates to a composition comprising one or more glucocorticoid(s) for use in the topical treatment of a patient having autoimmune gastritis, wherein the topical area to be treated comprises or is the mucosa of the stomach. Equally provided is a method for topical treatment of a patient having autoimmune gastritis, wherein said method comprises administering a composition comprising one or more glucocorticoid(s) to a patient having autoimmune gastritis, wherein the topical area to be treated comprises or is the mucosa of the stomach.

In particular, the composition of the present invention comprises a carrier. Preferably, the carrier comprises a carrier for oral administration.

In particular preferred aspects of the present invention, the herein provided composition comprises a carrier, which is a controlled and a sustained release carrier for delivery of an effective amount of said one or more glucocorticoid(s) to the topical area of the patient having autoimmune gastritis and release of an effective amount of said one or more glucocorticoid(s) at the topical area. In preferred aspects of the present invention, the carrier is in the form of an oral suspension or an effervescent tablet or a gel. In particularly preferred aspects, the carrier is in the form of a gel.

In further preferred aspects of the present invention, the carrier releases an effective amount of one or more glucocorticoid(s) at the topical area at a time period between 0 and 15 minutes after onset of topical treatment with said composition.

In preferred aspects of the present invention, the one or more glucocorticoid(s) is/ are locally effective at the topical area to be treated.

In preferred aspects of the present invention, autoimmune gastritis in a patient is determined histologically, by the occurrence of gastric inflammation, by the occurrence of destruction of parietal cells, and by a subsequent failure in production of gastric acids, resulting in higher gastrin secretion, and/or increased parietal cell antibody (PCA) and/or anti-intrinsic factor antibody (IFA) levels in a sample of the patient, wherein an increase in PCA or IFA levels and/or a pH increase of gastric juice, compared to a control level is indicative for the patient of having AIG. In particularly preferred aspects of the present invention, autoimmune gastritis in a patient is determined by the PCA level in a sample of the patient, wherein a PCA level above 100 U/ml compared to a control level is indicative for the patient of having active AIG.

In preferred aspects of the present invention, a response to treatment of AIG in a patient is indicated by histological remission, by reduction of gastric inflammation, by suppression of the destruction of parietal cells, by the pH level of gastric juice, specifically serum gastrin, and/or by the PCA and IFA levels, wherein a decrease in PCA/IFA level and/or a decrease of gastric juice pH, specifically reduction in gastrin, compared to a predetermined level or a control is indicative for a response to said treatment. In particularly preferred aspects of the present invention, a response to treatment of AIG in a patient is indicated by reduction of the gastric pH level of gastric juice, preferably reduction of the pH level by more than 2.

In further preferred aspects of the present invention, the one or more glucocorticoid(s) is/are selected from the group consisting of budesonide, flunisolide, triamcinolone acetonide, beclomethasone, dipropionate, dexamethasone sodium phosphate, fluticasone propionate, hydrocortisone, prednisone, prednisolone, mometasone, tipredane, and butixicort. In particularly preferred aspects of the present invention, the glucocorticoide is budesonide. Preferably, the composition is administered in a dose of: 0.01 mg/ml to 10 mg/ml budesonide, more preferably 0.05 mg/ml to 5.0 mg/ml budesonide, more preferably 0.1 mg/ml to 1.0 mg/ml budesonide.

In preferred aspects of the present invention, the composition is administered at an interval of every two days, once a day, twice a day or three times a day, more preferably once a day, or twice a day.

In preferred aspects of the present invention, a delayed stomach emptying of the patient extends the time period of the release of the effective amount of one or more glucocorticoid(s) at the topical area in the patient.

In preferred aspects of the present invention, oral administration of a liquid to the patient is suitable to control the time period in which the effective amount of one or more glucocorticoid(s) at the topical area is released.

In preferred aspects of the present invention, an empty stomach of the patient enhances the therapeutic efficacy of the one or more glucocorticoid(s) at the topical area to be treated.

In preferred aspects of the present invention, the composition further comprises reducing the risk of developing one or more diseases associated with AIG, specifically pernicious anemia (PA), autoimmune metaplastic atrophic gastritis (AMAG), gastric adenocarcinoma or gastric neuroendocrine tumors.

Detailed Description of the Invention

According to the present invention, a composition comprising the one or more glucocorticoid(s) is provided for the topical treatment of patients having AIG, wherein the topical area to be treated comprises or is the mucosa of the stomach.

In this context, the composition and/or method of the present invention relates to a composition comprising one or more glucocorticoid(s) that releases the glucocorticoid(s) in a locally and/or timely controlled manner at the topical area to be treated by using a drug delivery system, particularly a gastroretentive drug delivery system, that delivers the drug at a site-specific area, i.e. the topical area to be treated and/or in a sustained release manner. In this context, the composition of the present invention comprises a carrier, which is a controlled and/or a sustained release carrier, which is suitable for the delivery of an effective amount of said one or more glucocorticoid(s) to the topical area as outlined above and/or wherein the one or more glucocorticoid(s) are released in a sustained manner and are distributed uniformly at the topical area to be treated. In addition, the therapeutic efficacy of the treatment of AIG by the composition of the present invention can be further controlled by considering the physiological condition of the stomach of the patient. In this regard, the duration of the sustained release of glucocorticoid(s) may be extended due to a delayed stomach emptying of the patient and/or controlled by administration of a particular amount of liquid to the patient. The administration of liquid to the patient may further control the local distribution of the composition comprising the one or more glucocorticoid(s) at the topical area to be treated. In addition, the therapeutic efficacy of the one or more glucocorticoid(s) may be enhanced by an empty stomach of the patient at the topical area to be treated as the glucocorticoid(s) of the composition do not interfere with contents in the stomach such as food, thereby facilitating the contact and adsorption of the one or more glucocorticoid(s) the topical area to be treated, i.e. the mucosa of the stomach, preferably the mucosa of the corpus and the fundus.

Delayed stomach emptying is a common symptom of AIG. Thus, a delayed stomach emptying of the patient may extend the time period of the release of the effective amount of one or more glucocorticoid(s) at the topical area to be treated in the patient. The longer residence time in the stomach may be advantageous for the sustained local action of the glucocorticoid(s), wherein a consistent effective amount of glucocorticoid(s) without overdosing may be readily released in a timely controlled manner. In this context, glucocorticoid(s) that are absorbed readily upon release in the stomach may have an improved bioavailability and therapeutic efficacy.

As provided herein, the terms“autoimmune gastritis” and“AIG” are used interchangeably and refer to a chronic inflammatory disease of the stomach with destruction of parietal cells of the gastric body and fimdus that may lead to the atrophy of the mucosa. The terms“parietal cells autoantibodies” and“PCA” are used interchangeably and refer to autoantibodies which are directed against parietal cells of the gastric body and fundus but not in the antrum of the stomach and induce destruction of such by autoimmunity.

Without being bound by theory, chronic atrophic gastritis is not synonymous to AIG since the atrophy of the mucosa is the result of a chronic inflammatory disease independent of etiology, which is mainly Helicobacter pylori gastritis or AIG. Autoimmune antibodies in AIG target parietal cells which are located in the corpus and fimdus but not in the antrum. Thus, in contrast to other gastritis diseases, such as Helicobacter pylori-, stress-, or drug induced gastritis, inflammation and continuous atrophy is restricted to the corpus and the fimdus in AIG. The prevalence of AIG has been estimated to occur in up to 8% of the general population (Toh 2014). AIG is by far more common in women than in men. A majority of diagnosed individuals with the condition are older adults (commonly >60 years of age), although the disease develops at much younger age (between 15 to40 years) but remains asymptomatic.

The terms "composition" and“pharmaceutical composition” are used interchangeably and are to be understood as defining pharmaceutical compositions of which the individual components or ingredients are themselves pharmaceutically acceptable, e.g. where oral administration is foreseen, acceptable for oral use and, where topical administration is foreseen, topically acceptable and also includes combinations thereof, i.e. where oral and topical administration is foreseen, acceptable for oral and topical use. The pharmaceutical composition will be formulated and dosed in a fashion consistent with good medical practice, taking into account the clinical condition of the individual patient, the site of delivery of the pharmaceutical composition, the method of administration, the scheduling of administration, and other factors known to practitioners. The "effective amount" of the pharmaceutical composition for purposes herein is thus determined by such considerations. The skilled person knows that the effective amount of pharmaceutical composition administered to an individual will, inter alia, depend on the nature of the compound.

In certain aspects, the composition of the present invention comprises a carrier, which is a controlled and a sustained release carrier for delivery of an effective amount of said one or more glucocorticoid(s) to the topical area of the patient having autoimmune gastritis and release of an effective amount of said one or more glucocorticoids at the topical area. As used herein, the term“effective amount of said one or more glucocorticoid(s)” as used herein refers to the amount of the one or more glucocorticoid(s) that elicits the biological or medicinal response in the patient suffering from AIG, which includes alleviation of the symptoms of the condition being treated. The therapeutically effective amount can be determined using routine optimization techniques and is dependent upon the particular condition to be treated, the condition of the patient suffering from AIG, the route of administration, the formulation, and the judgment of the practitioner and other factors evident to those skilled in the art. As used herein, the term“delivery of an effective amount of said one or more glucocorticoid(s)” refers to a site specific delivery in the stomach, preferably in the fundus and corpus of the stomach. It is obtained by a locally specific and retaining dosage form as provided by the present invention wherein the one or more glucocorticoid(s) are released by a controlled-release carrier. As used herein, the term“controlled-release carrier” includes components of a controlled drug delivery system and refers to a carrier which releases an efficient amount of the active ingredient in a timely and locally controlled manner to specific site(s) of the topical area to be treated for a sufficient length of time. Thereby, the locally and timely controlled release of the glucocorticoid(s) is achieved by the components included in the composition. In particular, the carrier of the present invention allows, e.g., after oral application, the local bio availability of the active substance, i.e. the glucocorticoid(s), preferably budesonide, in a sufficiently high concentration at the site of inflammation, i.e. the mucosa of the stomach, preferably the mucus of the fundus and corpus of the stomach. This locally controlled stomach targeting concept is preferably achieved by a slow sliding of the composition along the mucosa of the stomach, preferably the fundus and the corpus of the stomach, associated with complete wetting of the surface as well as adhesion of the glucocorticoid(s) to the mucosa of the stomach, preferably to the mucosa of the fundus and/or the corpus of the stomach. By this means, the one or more glucocorticoid(s) of the composition of the present invention are specifically brought to the site of action, i.e. the site of inflammation, and distributed uniformly and completely thereon. In this context, the carrier of the present invention for the treatment of AIG is in a dosage form suitable to counteract the inflammatory processes and changes in the stomach, particularly in the fundus and the corpus of the stomach. Further, such a carrier of the composition of the present invention may be based on a retaining dosage form which functions through a gastroretentive delivery system. A “gastroretentive delivery system” or “sustained release drug delivery system” are used interchangeably and refer to drug delivery systems with prolonged residence time in the stomach for drugs that i) are locally active in the stomach, ii) have an absorption window in the stomach, and/or iii) are unstable in the small intestinal or colonic environment. In addition, commercial gastroretentive systems may exhibit low solubility at high pH values and high solubility at low pH values, such as those pH values found in the stomach of a patient, so that the active ingredient of the composition is specifically dissolved in the stomach. Since AIG patients commonly have an increased pH value in the stomach, the gastroretentive delivery system of the present invention should have a high solubility at such increased pH values in the stomach of AIG patients, preferably at pH values ranging from pH 5 to pH 7.

Various attempts have been made to develop controlled and/or sustained delivery systems, in particular gastroretentive controlled delivery systems, in order to increase the retention of dosage forms in the stomach; and thus to increase the therapeutic efficacy and the local action of the active ingredients of a pharmaceutical composition.

In this context, it is known that certain design parameters are critical to proper drug delivery. Typically, they are: (1) delivering the drug to the target tissue; (2) supplying the drug in the correct temporal pattern for a predetermined period of time; and (3) fabricating a delivery system that provides a drug in the desired spatial and temporal pattern. Controlled release drug delivery systems are intended to utilize these parameters to achieve the aforementioned advantages when compared to conventional pharmaceutical dosing. As provided herein, a controlled release dosage form which remains in the stomach for long periods prolongs the gastric retention time of the composition comprising one or more glucocorticoid(s) so that the drug can be supplied continuously to the absorption site on the stomach. "Controlled-release" is used herein to describe a method and composition for making an active ingredient available to the biological system of a host as described below in more detail. The method of effecting controlled release can be varied. For example, the active ingredient can be associated physically and/or chemically with a surfactant, a chelating agent, etc. Alternatively, the active ingredient can be masked by a coating, a laminate, etc. Regardless of the method of providing the desired release pattern, the present invention contemplates delivery of a controlled-release system which may utilize one or more of the "release" methods and compositions. Factors that need to be considered in the development controlled release drug delivery systems, e.g. in order to increase the retention and/or efficacy of dosage forms in the stomach, include density, size, the amount of liquid in the dosage form and/or the amount of liquid administered together with the dosage form, shape of the dosage form, fed or unfed state, gender, age, disease state of gastric diseases such as diabetes, Crohn’s disease, hypothyroidism, hyperthyroidism, duodenal ulcers and concomitant intake of drug. For example, the density of the dosage forms may be decisive for the gastric residence time since dosage forms having a density lower than that of gastric fluids are floating on the gastric contents, thereby increasing the gastric residence time. A large size of the dosage form may increase gastric residence time because a larger size will not allow the dosage form to quickly pass through the pyloric spincter to intestine. Either round or spherical shaped dosage form may exhibit better property related to other shapes. Gastric retention time of the dosage form is less during fasting condition due to rise in gastric motility. In contrast, high amount of fatty acid and other indigestible polymers slow down the gastric retention time due to variation in gastric motility. As provided herein, the controlled release dosage form of the present may remain in the stomach of an AIG patient for extended periods of time, e.g., due to delayed stomach emptying in these patients. Thus, the gastric retention time of the composition comprising one or more glucocorticoid(s) may be prolonged so that the drug may be supplied continuously to the absorption site on the stomach. As used herein, the composition of the present invention may retain in the stomach, preferably in the fundus and the corpus of the stomach for at least 10 min, preferably for at least 60 min.

The amount of liquid in the dosage form may influence the efficacy of the glucocorticoid(s) of the composition in the stomach, preferably the fundus and the corpus of the stomach. In this sense, a sufficient amount of liquid in the dosage form may be required for complete wetting of the surface of the mucosa. Such a uniform distribution of the composition may be advantageous for the local effect of the active ingredients of the composition at the mucosa since the glucocorticoid(s) are released uniformly and completely to their site of action, i.e. the topical area to be treated. As used herein, the amount of liquid administered in or with the dosage form varies between 2 and 500 ml, preferably between 10 and 100 ml. In this way, distribution of the composition at the mucosa of the stomach, preferably the fimdus and the corpus of the stomach, may be additionally supported, e.g. if the patient rests in a lateral position after administration of the composition. By this means, glucocorticoid(s), such as budenoside, may be released uniformly and completely at the site of action. For example, the release of the minimum amount of a glucocorticoid, such as budesonide, required for an effective amount to be released only in the stomach may be achieved by various methods, for example by swallowing/taking a tablet, such as an effervescent coated tablet, at an empty stomach stage, followed by immediate uptake of 100 to 300 ml water followed by 20 minutes resting at left lateral position. Preferably, the tablet is taken twice a day, preferably every 12 hours. For example, if the tablet is taken twice a day, one tablet is taken in the morning and one tablet in the evening. Controlled release delivery systems including gastroretentive delivery systems can be categorized into floating and non-floating systems. The non-floating systems include, for example, swelling, bioadhesive, expendable and high-density systems.

Floating Drug Delivery Systems (FDDS) have a bulk density lower than gastric fluids and thus remain buoyant in the stomach for a prolonged period of time, without affecting the gastric emptying rate and the drug is released slowly at a desired rate from the system resulting in an increase in the gastric residence time and a better control of fluctuations in the plasma drug concentrations and after complete release of the drug, the residual system is emptied from the stomach.

Based on the buoyancy mechanism, floating systems are classified into effervescent systems and non-effervescent systems. Effervescent systems comprise gas generating systems and volatile liquid containing systems. The mechanism of the gas generating system is the production of C0₂ gas due to the reaction between sodium bicarbonate, citric acid and tartaric acid. The gas produced by the system is entrapped in swollen hydrocolloids of the system resulting in the reduction of density of the system so that it floats on the gastric fluids. Volatile liquid containing systems have an inflatable chamber which contains a liquid, e.g. ether, cyclopentane, that gasifies at body temperature to cause the inflation of the chamber in the stomach. These systems are osmotically controlled systems containing a hollow deformable unit. The non-effervescent floating dosage forms may have swellable cellulose type of hydrocolloids, polysaccharides, and matrix- forming polymers like polycarbonate, polyacrylate, polymeth-acrylate, and polystyrene. It is created by mixing of drug with the gel, followed by swelling by coming in contract with gastric fluid after oral administration and thus maintaining a relative integrity of shape and keeping a density less than one. The dosage form gains its buoyancy owing to air trapped in the swelled up matrix. This swollen up matrix reserves drug and can maintain sustained drug release via gelatinous mass hydroxylpropyl methyl cellulose (HPMC), polyacrylate, polyvinyl acetate, carbopol, agar, sodium alginate, calcium chloride, polyethylene oxide and polycarbonates, which are the most commonly used excipients. Examples for non-effervescent systems include but are not limited to the raft forming systems and bioadhesive systems. Raft forming systems have received much attention for the delivery of antacids and drug delivery for gastrointestinal infections and disorders. The mechanism involved in the raft formation includes the formation of viscous cohesive gel in contact with gastric fluids, wherein each portion of the liquid swells forming a continuous layer called a raft. This raft floats on gastric fluids because of low bulk density created by the formation of C0₂. Usually, the system contains a gel forming agent and alkaline bicarbonates or carbonates responsible for the formation of C0₂ to make the system less dense and float on the gastric fluids. The system contains a gel forming agent (e.g. alginic acid), sodium bicarbonate and acid neutralizer, which forms a foaming sodium alginate gel (raft) when in contact with gastric fluids. The raft thus formed floats on the gastric fluids and prevents the reflux of the gastric contents (i.e. gastric acid) into the esophagus by acting as a barrier between the stomach and esophagus.

Bioadhesive systems bind to the gastric epithelial cell surface or mucus, which extends the retention time of the drug delivery system in the stomach. By this means, bioadhesives may be added to the composition of the present invention in order to increase the viscosity of the composition enabling slow sliding along the mucosa and uniform distribution of the glucocorticoid(s) in the stomach, preferably the fundus and the corpus of the stomach. As provided herein, the terms“bioadhesive” and“mucoadhesive” are used interchangeably and refer to any substance that can adhere to a biological substrate and are particularly capable of being retained on that surface for an extended period of time. Bioadhesives can adhere to different substrates; however, bioadhesives generally adhere to membranes or the mucin layer of those membranes. Preferably, the bioadhesives of the present invention adhere to the mucus of the stomach, preferably the mucus of the fundus and the corpus of the stomach. Thus, bioadhesion refers to the state in which two materials, amongst which one is biological in nature, adhere to each other, preferably for extended periods of time with the help of interfacial forces. As used herein, the term“mucus” refers to a usually clear viscid fluid that may be secreted by mucous membranes in various tissues of the body lining the organs and body cavities, including by the respiratory, gastrointestinal, and reproductive tracts. They contain a connective tissue layer (the lamina propria) above which is an epithelial layer, the surface of which is made moist usually by the presence of a mucus layer. The epithelial may be either single layered, e.g. the stomach, small and large intestines and bronchi, or multilayered/stratified, e.g. in the esophagus and cornea. The former contain goblet cells which secret mucus directly onto the epithelial surfaces: the latter contain, or are adjacent to tissues containing, specialized glands such as salivary glands that secret mucus onto the epithelial surface. Mucus is present either as a gel layer adherent to the mucosal surface of as a luminal soluble or suspended form. The major components of all mucus gels are mucin glycoproteins, lipids, inorganic salts and water, the latter accounting for more than 95% of their weight, making them a highly hydrated system.

The term“adhesion” refers to the bond produced by contact between a pressure sensitive adhesive and the surface. In other words, the term“adhesion” refers to the state in which two surfaces are held together by interfacial forces, which may consist of valence forces, interlocking action or both.

The mechanism of bioadhesion is generally divided into two steps: the contact stage and the consolidation stage. The first stage of bioadhesion is characterized by the contact between the bioadhesive and the mucus membrane. In the consolidation step, the bioadhesive materials are activated by the presence of moisture. Moisture plasticizes the system, allowing the bioadhesive molecules to break free and to link up by weak van der Waals and hydrogen bonds.

In certain aspects, the controlled release drug delivery system of the present invention may be a bioadhesive controlled release delivery system. The ability to provide adhesion of a drug delivery system to the gastrointestinal wall specifically may provide longer residence time in a particular organ site, thereby producing an improved effect in terms of local action. Thus, in certain aspects, the one or more glucocorticoid(s) is/ are locally effective at the topical area. Binding of polymers to the mucin/epithelial surface can be divided into three categories: hydration-mediated adhesion, bonding-mediated adhesion and receptor-mediated adhesion. Hydration-mediated adhesion is based on certain hydrophilic polymers that tend to imbibe large amount of water and become sticky, thereby acquiring bioadhesive properties. Bonding- mediated adhesion involves adhesion of polymers to a mucus/epithelial cell surface via various bonding mechanisms, including physical-mechanical bonding and chemical bonding. Physical-mechanical bonds can result from the insertion of the adhesive material into the folds or crevices of the mucosa. Chemical bonds may be either covalent (primary) or ionic (secondary) in nature. Secondary chemical bonds consist of dispersive interactions (i.e., Vander Waals interactions) and stronger specific interactions such as hydrogen bonds. The hydrophilic functional groups responsible for forming hydrogen bonds are the hydroxyl and carboxylic groups. Receptor-mediated adhesion involves certain polymers binding to specific receptor sites on the cell surfaces, thereby enhancing the gastric retention of dosage forms.

A complete and comprehensive theory that can predict adhesion based on the chemical and/or physical nature of a polymer is not yet available. Essentially, there are five theories of adhesion:

1. According to electrostatic theory, adhesion occurrs by means of electron transfer between the mucus and the mucoadhesive system, arising through differences in their electronic structures. The electron transfer between the mucus and the mucoadhesive results in the formation of double layer of electrical charges at the mucus and mucoadhesive interface. The net result of such a process is the formation of attractive forces within this double layer.

2. According to the adsorption theory, after an initial contact between two surfaces, the materials adhere because of surface forces acting between the chemical structures at the two surfaces. When polar molecules or groups are present, they reorientate at the interface. Chemisorption can occur when adhesion is particularly strong. The theory maintains that adherence to tissue is due to the net result of one or more secondary forces (van der Waal’s forces, hydrogen bonding, and hydrophobic bonding).

3. The wetting theory emphasizes the intimate contact between the mucoadhesive polymer and the mucus, and, primarily in liquid systems, it uses interfacial tensions to predict spreading, and subsequent adhesion. Thereby, the wetting theory calculates the contact angle and the thermodynamic work of adhesion.

4. According to the diffusion theory, the mucoadhesive molecules and the glycoproteins of the mucus mutually interact by means of interpenetration of their chains and the building of secondary bonds. For this to take place, the mucoadhesive device has features favoring both chemical and mechanical interactions. For example, molecules with hydrogen bond building groups (- OH, -COOH), an anionic surface charge, high molecular weight, flexible chains and surface-active properties, which help in spreading throughout the mucus layer, can present mucoadhesive properties (Hagerstrom et ah, 2003; Boddupalli et ah, 2010).

5. The fracture theory analyzes the force that is required to separation of two surfaces after adhesion. It is considered to be appropriate for the calculation of the fracture strengths of adhesive bonds involing rigid mucoadhesive materials, and has frequently been applied to the analysis of tensile strength measurements on, for example, microspheres and powder specimens.

Various techniques for the determination of mucoadhesion are known in the art and are fundamental to the development of novel bioadhesive delivery systems (McCarron et al., 2004; Park et al, 1990; McCarron et al, 2005; McCarron et al, 2006; Donnelly et al, 2006). These techniques include tensile test, shear strength, and peel strength. Briefly, in the tensile test, force is perpendicularly applied to the tissue/adhesive interface, during which a state of tensile stress is set up. But during the shear stress, the direction of the forces is reoriented so that it acts along the joint interface. In both tensile and shear modes, an equal pressure is distributed over the contact area. The peel test is based on the calculation of energy required to detach the patch from the substrate. In tensile and shear experiments, the stress is uniformly distributed over the adhesive joint, whereas in the peel strength stress is focused at the edge of the joint. Thus tensile and shear measure the mechanical properties of the system, whereas peel strength measures the resistant of the peeling force. In particular, in vivo mucoadhesive testing methods are known in the art and are used to monitor the mucoadhesion on tissue surface such as the gastrointestinal tract or the buccal cavity. The most common in vivo techniques to monitor mucoadhesion include gastrointestinal transit times of bioadhesive- coated particles and drug release from in situ bioadhesive devices as reported by Ch'ng et al, 2008 and Davis et al, 1985. Magnetic resonance imaging (MRI) is another noninvasive technique that is widely used to detect the time and location of release of bioadhesive formulation as reported by Kremser et al., 2008.

In recent years, many bioadhesive drug delivery systems have been developed, wherein common sites of application where bioadhesive drugs have the ability to deliver pharmacologically active agents include oral cavity, eye conjunctiva, vagina, nasal cavity and gastrointestinal tract (Ahuja et al, 1997). Without being bound by theory, the anatomical differences of the mucus membrane at varying body locations may be decisive for the development bio adhesive drug delivery system outlined as followed. The buccal cavity has a very limited surface area of around 50 cm² and is comprised of three distinct layers - epithelium, basement membrane, and connective tissues. Mucus is secreted by salivary glands, as a component of saliva, forming a 0.1-0.7 mm thick layer. The easy access of the buccal cavity makes it a preferred location for delivering active agents. The site provides an opportunity to deliver pharmacologically active agents systemically by avoiding hepatic first- pass metabolism in addition to the local treatment of the oral lesions. The sublingual mucosa is relatively more permeable than the buccal mucosa due to the presence of large number of smooth muscle and immobile mucosa. Hence, formulations for sublingual delivery are designed to release the active agent quickly while mucoadhesive formulation is of importance for the delivery of active agents to the buccal mucosa, where the active agent has to be released in a controlled manner. This makes the buccal cavity more suitable for bioadhesive drug delivery. Like buccal cavity, nasal cavity also provides a potential site for the development of formulations where bioadhesive polymers can play an important role.

The nasal mucosal layer has a surface area of around 150-200 cm². The nasal cavity is lined with mucous membrane containing columnar cells, goblet cells, and basal cells. Both, keratinized and nonkeratinized epithelial cells are present depending upon location within nasal cavity. The mucus secreted by the submucosal glands and the goblet cells, forming a mucus layer that is approximately 5-20 mth thick. The residence time of a particulate matter in the nasal mucosa varies between 15 and 30 min, which has been attributed to the increased activity of the mucociliary layer in the presence of foreign particulate matter. Due to the continuous formation of tears and blinking of eye lids, there is a rapid removal of the active medicament from the ocular cavity, which results in the poor bioavailability of the active agents. This can be minimized by delivering the drugs using ocular insert or patches. Gastrointestinal tract is also a potential site for the development of bioadhesive based formulations. The various bioadhesive polymers which have been used for the development of oral delivery systems include chitosan, poly(acrylic acid), alginate, poly(methacrylic acid) and sodium carboxymethyl cellulose (Asane et al, 2007). In view of the above, the skilled person is aware of the anatomical differences of the mucus membrane at varying body locations and, therefore, he would consider the different requirements needed for developing bioadhesive drug delivery systems to be used at specific body locations, e.g., the mucosa of the stomach.

In certain aspects, the present invention relates to the composition comprising a carrier. As used herein the term“carrier” refers to the components and thus the property of the controlled release drug delivery system, particularly a gastroretentive drug delivery system. In this context, the carrier of the present invention mediates the locally and timely controlled release of the one or more glucocorticoid(s) of the present invention. The carrier comprises a pharmaceutically acceptable carrier comprising a chemical composition, compound, or solvent with which an active ingredient may be combined and which, following the combination, can be used to administer the active ingredient to a subject. As used herein, "pharmaceutically acceptable carrier" includes, but is not limited to, one or more of the following: excipients; surface active agents; dispersing agents; inert diluents; granulating and disintegrating agents; binding agents; lubricating agents; preservatives; physiologically degradable compositions such as gelatin; aqueous vehicles and solvents; oily vehicles and solvents; suspending agents; dispersing or wetting agents; emulsifying agents, demulcents; buffers; salts; thickening agents; fillers; antioxidants; stabilizing agents; and pharmaceutically acceptable polymeric or hydrophobic materials and other ingredients known in the art. The formulations of the pharmaceutical compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology. In general, such preparatory methods include the step of bringing the active ingredient into association with a carrier or one or more other accessory ingredients, and then, if necessary or desirable, shaping or packaging the product into a desired single- or multi-dose unit. Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for ethical administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and perform such modification with merely ordinary, if any, experimentation. Subjects to which administration of the pharmaceutical compositions of the invention is contemplated include, but are not limited to, humans and other primates, and other mammals. Preferably, subjects are humans. Various types of formulations are available such as tablets, syrups, suspensions, suppositories, injections, transdermal and patches having different types of drug delivery mechanisms. The term“formulation” or“drug formulation” or’’dosage form” as used herein refers to the applied form of a composition containing at least one therapeutic agent or medication, wherein the dosage form may be in the form of a gel, lozenge, pill, tablet, effervescent tablet, capsule, membrane, strip, liquid, patch, film, spray, oral suspension or other form. Thereby, the skilled person in the art is aware of dosage forms which are suitable to be applied for the composition of the present invention. In order to get the desired effect the drug should be delivered to its site of action at such rate and concentration to achieve maximum therapeutic effect and minimum adverse effect. In addition, the drug formulation of the present invention can be any formulation as long as it is compatible with the topical administration of said drug, i.e. the composition comprising the one or more glucocorticoid(s), in accordance with the present invention. As provided herein, the composition comprising the one or more glucocorticoid(s) formulated as a topical composition is delivered to the stomach, preferably the fimdus and the corpus of the stomach. In addition, a formulation may comprise additional, non-active components, such as pharmaceutical excipients, fillers, carrier materials etc. that may be used to modify or improve the drug release, improve its physical and/or chemical stability, dosage form performance, processing, manufacturing, etc.

In one embodiment, the present invention relates to the composition comprising a carrier for oral administration. As used herein, the term“carrier for oral administration” refers to a suitable vehicle, which can be used to form and apply the present compositions to the oral cavity in a safe and effective manner. Such vehicle may include materials such as sodium benzoate, potassium sorbate, ethylenediamine acetic disodium, citric acid, sucrose, methylcellulose, (cassis) flavor, water, other suitable materials, and mixtures thereof. Liquid oral dosage forms are easy to administer as compared to unit solid dosage forms but sustained effect are not achieved due to less residential time in gastrointestinal tract so, due to this problem suitable oral preparations are used to overcome the problems.

Suitable oral preparations may be prepared with aqueous-based solutions such as sodium bicarbonate (e.g., Brioschi®), or in gels and suspensions for topical oral administration. For example, a gel dosage form comprises a liquid before administration and after it converts into gel by various mechanisms in gastric environment so that a sustained release can be achieved. The oral preparations are particularly well-suited for disorders and inflammatory responses involving the mucosa of the stomach. Oral formulations of steroids, such as prednisone (Deltasone), prednisolone (Prelone), dexamethasone (Decadron), and methylprednisolone (Medrol), typically are used to treat inflammation and pain associated with chronic conditions such as rheumatoid arthritis and lupus. The orally administered drug delivery has proven particularly useful and offers several advantages over other drug delivery systems including bypassing hepatic first-pass metabolism, increasing the bioavailability of drugs, improved patient compliance, excellent accessibility, unidirectional drug flux, and improved barrier permeability compared, for example, to intact skin. Oral delivery is currently the gold standard in the pharmaceutical industry where it is regarded as the safest, most convenient and most economical method of drug delivery having the highest patient compliance. Also, solid oral delivery systems do not require sterile conditions and are, therefore, less expensive to manufacture (Nagar et al., 2011).

In certain aspects, the carrier of the present invention is in the form of an effervescent tablet, an oral suspension or a gel.

In some aspects, the carrier of the present invention is in the form of an effervescent tablet. The term“effervescent” refers to those agents which evolve gas, and the bubble or gas generating the action is most often the result of the reaction of a soluble acid source and an alkali metal carbonate or carbonate source. The reaction of these two general classes of compounds produces carbon dioxide gas upon contact with water included in saliva. In other words, the term“effervescence” refers to the reaction of acids and bases producing carbon dioxide. Examples of acids used in this reaction are citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, acid citrates, succinic acid and mixtures thereof. Citric acid is the most commonly used, and it imparts a citrus-like taste to the product. Examples of bases used in the effervescent reaction are sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, magnesium carbonate, sodium glycocarbonate, carboxylysine and mixtures thereof Sodium bicarbonate is very common in effervescent formulas.

Carbonate sources include dry solid carbonate and bicarbonate salts such as sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate, magnesium carbonate and sodium sesequicarbonate, sodium glycine carbonate, L-lysine carbonate, arginine carbonate and amorphous calcium carbonate. Other source of effervescence can be included and the present invention is not limited to those specifically set forth herein. The effervescent tablet may be coated with a thin layer of a rapidly dissolving water soluble polymer or pharmaceutical excipient. A coating of a water soluble excipient results in faster hydration and gas formation than a coating of water soluble polymer. Examples of water soluble pharmaceutical excipients include lactose, sucrose, dextrose, mannitol, xylitol, and the like. As used herein, the carrier may be in the form of an effervescent tablet, in particular in the form of a coated effervescent tablet. A coated effervescent tablet may comprise a core and a coat. For example, a coated effervescent tablet may comprise a core, the core comprising a powder and/or the active agent(s), such as one or more glucocorticoid(s), and an effervescent agent, and a coat. The coat can isolate the core from the environment, thereby protecting the core from oxidation and avoiding parenteral decomposition. In other words, in this context the composition comprising one or more glucocorticoid(s) can be formulated as an effervescent tablet.

After swallowing, tablets are transported to the stomach where they dissolve gradually. Hence, the tablet as used herein may be a tablet that is not orodispersible.

The passage takes variably long in different people, depending on anatomical and physiological factors. The constituents of the tablet start to dissolve in the saliva. Drinking is recommended after swallowing the composition of the present invention in order to minimize dissolving of the tablet in the mouth and oesophagus and to maximize dissolving of the tablet in the stomach, preferably the fundus and the corpus of the stomach. In particular, it may be recommended to drink at least 50-100 ml of liquid, preferably water, in order to minimize dissolving of the tablet in the mouth and oesophagus and to maximize dissolving of the tablet in the stomach, preferably the fundus and the corpus of the stomach. With a dissolved effervescent tablet, the ingredients are evenly distributed in the solution, so that high, localized concentrations cannot occur. This effect may be additionally be supported, e.g. if the patient rests in a lateral position after administration of the composition.

The orally disintegrating property of these tablets is attributable to the ingress of water into the tablet matrix, which creates porous structure and results in disintegration. Hence, the basic approaches to develop effervescent tablets include maximizing the porous structure of the tablet matrix, incorporating the appropriate disintegrating agent and using highly water- soluble excipients in the formulation. In sum, effervescent tablets have the potential to be used for controlled release drug delivery, but coupling of mucoadhesive properties to tablet may have additional advantages, for example, it offers efficient absorption and enhanced bioavailability of the drugs due to a high surface to volume ratio and may facilitate a much more intimate contact with the mucus layer. Further desirable characteristics of the dosage form of an effervescent tablet may include allowance of high drug loading, no requirement of specific packaging, cost effectiveness as minimum number of ingredients are required and good chemical stability as conventional oral solid dosage.

There are several methods for the preparation of effervescent tablets known in the art including but not limited to addition of disintegrants, molding, compaction, spray-drying, freeze-drying or lipophilization, mass extrusion and some special methods are melt granulation, phase transition, and sublimation (Dey et al, 2010; Dobetti 2001; Yang et al, 2004; Ozeki et al, 2003; Radke et al, 2009; Swamy et al, 2008; Abderbary et al, 2004; Kuno et al, 2005; Koizumi et al, 1997; Swamy et al, 2009; Kaushik et al, 2004; Mohire et al, 2009; Chang et al, 2000; Lindgren et al, 1993; Bandari et al 2008; US 6.207.199 (2001); US 6.807.576 (1998); US 6.197.348 (2001). Important ingredients that may be used in the formulation of effervescent tablets include both the pharmacologically active ingredients (drug) and the excipients (additives).

The addition of disintegrants as exipients increase the rate of disintegration and hence the dissolution. Examples for disintegrants include crospovidone, microcrystalline cellulose, sodium starch glycolate, sodium carboxy methyl cellulose, pregelatinzed starch, carboxy methyl cellulose, and modified com starch. Tablets formed by molding process include moistening, dissolving, or dispersing the drugs with a solvent then molding the moist mixture into tablets by applying lower pressure in compression molding, but always lower than the conventional tablet compression. The powder mixture may be sieved prior to the preparation. The preparation by compression is carried out by addition of super disintegrants. Some important super disintegrants used during preparation of effervescent tablets, are crosspovidone and crosscarmellose sodium. During the spray-drying method, effervescent tablets are made up of hydrolyzed or unhydrolyzed gelatin as supporting agent for matrix, mannitol as bulk agent, and sodium starch glycolate or croscarmellose sodium as disintegrating agent. Sometimes in order to improve the disintegration and dissolution, citric acid and sodium bicarbonate are used. Finally, the formulation is spray-dried in a spray drier.

During freeze-drying or lipophilization to prepare the effervescent tablet, the drug may be dissolved or dispersed in an aqueous solution of a carrier. The mixture may be poured into the wells of the preformed blister packs. The trays holding the blister packs are passed through liquid nitrogen freezing tunnel to freeze the drug solution. Then the frozen blister packs are placed in refrigerated cabinets to continue the freeze drying. Finally, the blisters are packaged and shipped. Mass extrusion involves softening the active blend using the solvent mixture of water soluble polyethylene glycol, methanol and expulsion of softened mass through the extruder or syringe to get a cylindrical shape of the product into even segments using heated blade to form tablets.

Resulting tablet dosage forms vary on several parameters like mechanical strength, porosity, dose, stability, taste, mouth feel, dissolution rate and overall bioavailability. Hereby, several drugs categorized into classes can be incorporated in effervescent tablets including the classes but not limited to analgesics and anti-inflammatory agents, antiepileptics, antifungal agents, antimalarial, antigout agents, antihypertensive agents, antibacterial agents, antineoplastic agents, diuretics, antiparkinsonism agents, anxiolytic, sedatives, hypnotics, and neuroleptics, lipid regulating agents, opoid analgesics, corticosteroids, oral vaccines local anaesthetics and nutritional agents. As used herein, the glucocorticoids of the present invention may be incorporated in effervescent tablets by using the methods known in the art as outlined but not limited to the methods described above. Moreover, the skilled person knows how to select suitable parameters for pharmaceutical formulation in order to prepare an effervescent tablet. The term“pharmaceutical formulation” refers to preparations which are in such form as to permit the active ingredients to be effective, and which contains no additional components which are toxic to the subjects to which the formulation would be administered.

As provided herein, the carrier of the present invention may be in the form of an oral suspension. The term“oral suspension” refers to a liquid dosage form wherein the drug is solubilised or suspended into suitable aqueous vehicles and wherein the oral suspension refers to a gastroretentive extended release suspension composition which may be in the form of a suspension or a reconstituted powder for suspension. The powder for suspension may comprise coated cores of active ingredient or a mixture of coated cores of active ingredient, one or more osmogents, one or more gel forming agents and/or one or more gas generating agents, and pharmaceutically acceptable excipients. This powder for suspension may be reconstituted with a pharmaceutically acceptable vehicle or a suspension base to form a gastroretentive extended release suspension composition. The term "suspension base," as used herein, refers to a medium which is used to suspend the coated cores of the active ingredient or to reconstitute the extended release powder for suspension of the active ingredient. The suspension base comprises a pharmaceutically acceptable vehicle, one or more osmogents, and pharmaceutically acceptable excipients. The prior art discloses various approaches for the preparation of extended release liquid compositions. U.S. Patent No. 6,156,340 discloses a controlled release suspension comprising inert cores coated with an active ingredient, which were further coated with two layers of polymers having increasing permeability for water. U.S. Patent No. 7,906, 145 discloses a sustained release suspension of microcapsules in an aqueous liquid phase, wherein each microcapsule comprises a core of an active ingredient and a film coating applied to the core which controls the modified release of the active ingredient in gastrointestinal fluids, comprising a film-forming polymer, a nitrogen-containing polymer, a plasticizer, and a surfactant/lubricant. PCT Publication No. WO 2011/107855 discloses a ready to use sustained release oral suspension comprising inert pellets surrounded by a seal coating, an active ingredient layer surrounding the seal coated inert pellets, and a coating layer comprising a rate- controlling polymer surrounding the active ingredient layer. PCT Publication No. WO 2011/077451 discloses a controlled release suspension comprising an active ingredient loaded core and a polymer dispersion comprising a controlled-release polymer, wherein said suspension has a duration of therapeutic effect for at least about 6 hours to about 30 hours after oral administration. PCT Publication No. WO 2008/122993 discloses a suspension of an active ingredient containing microparticles with at least one coat of a pH-independent polymer. PCT Publication No. WO 2012/063257 and U.S. Publication No. 2008/0118570 disclose controlled release suspensions employing ion-exchange resins.

In certain aspects, the carrier of the composition comprising one or more glucocorticoid(s) is in the form of a gel. As a liquid or semisolid dosage, gels are typically used where a solid form would affect the patient’s comfort. Certain mucoadhesive polymers comprising the gel, for example, sodium carboxymethylcellulose, carbopol, hyaluronic acid, pectins, xyloglucan, gellan gum, sodium alginate and xanthan gum, undergo a phase change from liquid to semisolid. In particular, the polymer(s) is preferably a water soluble salt of one or more polyuronic acids. The gel forming polymer cross-links with time to form a stable structure. Thus, with the passage of time, the gel forming polymer results in a hycdrodynamically balanced system providing a tortuous diffusion pathway for the drug, thereby resulting in a timely and locally controlled drug release of the glucocorticoid(s) and whereby the matrix is retained in the stomach for an extended period of time. The pharmaceutical composition may also contain other conventional pharmaceutical excipients, for example, water soluble diluents such as lactose, dextrose, mannitol, sorbitol, and the like; water insoluble diluents such as starch, microcrystalline cellulose, powdered cellulose, and the like; or lubricants such as talc, stearic acid or its salt, magnesium stearate, and the like.

There are various mechanisms for gel formulation: physiologically changes (temperature and pH), chemical stimulates (ionic cross linking), physical change in biomaterial (diffusion of solvent and swelling) (US 20020119941; US20110082221; US 20120009275; US 20050063980; US 5360793).

Gel formulation based on swelling may comprise ph dependent gelling and/or temperature dependent gelling. Temperature dependent gelling refers to liquid aqueous solutions before administration, but gel at body temperature. These hydrogels are liquid at room temperature (20°C -25°C) and undergo gelation when in contact with body fluids (35°C -37°C), due to an increase in temperature. This approach exploits temperature-induced phase transition. Some polymers undergo abrupt changes in solubility in response to increase in environmental temperature (lower critical solution temperature, LCST). Examples for such polymers include but are not limited to Pluronics ( poly (ethylene oxide)-poly(propylene oxide)-poly (ethylene oxide)(PEO-PPOPEO) Triblock), polymer networks of poly(acrylic acid) (PAA) and polyacrylamide (PAArn) or poly(acrylamide-co-butyl methacrylate). Such a polymer solution is a free flowing liquid at ambient temperature and gels at body temperature. Polymer networks of poly (acrylic acid) (PAA) and polyacrylamide (PAAm) or poly (acryl amide-co- butyl methacrylate) have positive temperature dependence of swelling (Shah et al, 2012; Neha et al, 2013).

Ph dependent gelling (rbopol®, carbomer or its derivatives, polyvinylacetal diethylaminoacetate (AEA), mixtures of poly (methacrylic acid) (PMA) and poly (ethylene glycol) (PEG)) shows change from sol to gel with change of pH. Swelling of hydrogel increases as the external pH increases in the case of weakly acidic (anionic) groups, but decreases if polymer contains weakly basic (cationic) groups.

Gel formulation based on chemical stimulation and ionic crosslinking comprises certain ion sensitive polysaccharides such as carrageenan, Gellan gum(Gelrite®), pectin, sodium alginate undergoing phase transition in presence of various ions such as K⁺ , Ca²⁺, Mg²⁺, Na⁺. For example, valent cations e.g. Ca²⁺ crosslinks alginate due to the interaction with guluronic acid (Guo et al, 1998). Gel formulation based on chemical stimulation and enzymatic crosslinking comprises certain enzymes which operate efficiently under physiologic conditions without need for potentially harmful chemicals such as monomers and initiators providing a convenient mechanism for controlling the rate of gel formation, which allows the mixtures to be injected before gel formation in situ (Podual et al., 2000).

Gel formulation based on physical mechanisms comprise swelling of polymer by absorption of water causing formation of a gel. Certain biodegradable lipid substances such as myverol (glycerol mono-oleate) form gels under such phenomenon (Esposito and Carratto, 1996; Geraghaty and Attwood, 1997; Motto and Gailloud, 2000).

In certain aspects, the carrier of the composition is a controlled release carrier suitable to release an effective amount of one or more glucocorticoid(s) at the topical area at a time period between 0 and 15 minutes after onset of topical treatment with the composition. The controlled release, e.g. in a timely and/or locally manner, may be additionally supported, e.g. if the patient rests in a lateral position after administration of the composition, as outlined above.

As used herein, the term“controlled release” refers to a drug release profile designed to optimize delivery of the drug to a particular site(s) of absorption such as the stomach while still providing effective treatment over a predetermined extended period of time such as once or twice daily. Further, the term“controlled release” refers to the timely controlled delivery of an effective amount of the one or more glucocorticoid(s) to the topical area to be treated, e.g. the mucosa of the stomach of AIG patient, which is controlled by the dosage form of the carrier of the present invention. Various controlled release methods and formulations are known the art and described above. Common methods of obtaining controlled release systems include but are not limited to polylactides (U.S. Pat. No. 3,773,919, EP 58,481), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate (Sidman et al, 1983), poly (2-hydroxyethyl methacrylate) (Langer et al., 1981, Langer 1982), ethylene vinyl or poly-D-(-)-3- hydroxybutyric acid (EP 133,988).

For example, it is known to fill polymeric capsules with a solid, liquid, suspension or gel containing a therapeutic agent which is slowly released by diffusion through the capsule walls. Heterogeneous matrices, for example compressed tablets, control the release of their therapeutic agents either by diffusion, erosion of the matrix or a combination of both. Other controlled release systems focus on the fabrication of laminates of polymeric material and therapeutic agent which are then formed into a sandwich, relying on diffusion or erosion to control release of the therapeutic agent. Liquid-Liquid encapsulated in a viscous syrup-like solution of polymer, have also been known to be useful in controlling release of the therapeutic agent. Additionally, it is generally known that heterogeneous dispersions or solution of therapeutic agents in water-swellable hydrogel matrices are useful in controlling the release of the agent by slow surface-to-center swelling of the matrix and subsequent diffusion of the agent from the water-swollen part of the matrix. As used herein, the controlled release system comprises the carrier of the present invention in the form of an effervescent tablet, an oral suspension or a gel. Preferably, the controlled release system comprises the carrier of the present invention in the form of a gel. In certain aspects of the invention, the composition comprising the one or more glucocorticoid(s) may comprise effervescent-coating formulations. Such effervescent-coated formulations are known in the art, e.g. as described by Nishimura et al (1983), who shows that an effervescent tablet formulation, coated with hydro xypropyl methylcellulose phthalate as an enteric material, is suitable to disintegrate a composition in the upper part of the intestine. Another Example of an effervescent-coated formulation is disclosed in CN 105663078, which relates to a pharmaceutical preparation of colloidal tartaric bismuth tablets including various disintegrants such as effervescent agents, adhesives, anti-adhesive agents, enteric coating agents and coating agents disintegrated in the lower digestive tract. Further, it is known that this concept of an effervescent-coated formulation can be applied for different target areas, including the stomach, in order to increase the bioavailability of a composition at a specific area as disclosed, e.g., in US 3,91,335 Bl. Coatings applied in thin films to tablets can be used for various reasons; they can for instance modify release of biologically active substances, clarify identification of products, and make tablets easier to swallow. Coating materials are also used for protection of biological active substances from the environment e.g. air, moisture and light. Coating materials which function as moisture barriers and/or protects from oxidation can be found among both pharmaceutically acceptable materials and components used for the preparation of edible films for the food industry. Edible film forming materials have been classified by Bourtoom (International Food Research Journal 15(3): 237- 248 (2008)) into three categories: hydrocolloids (such as proteins, polysaccharides, and alginate), lipids (such as fatty acids, acylglycerol, waxes) and composites (mixtures of the other two classes). One reason to coat tablets is to provide a barrier against moisture and oxygen. Shellac and zein films are examples of coatings that are used in food applications. Zein is the water-insoluble prolamine from com gluten. It is unique in its ability to form odorless, tasteless, clear, hard and almost invisible edible films. Since Zein films are completely safe to ingest, it is the perfect coating for foods and pharmaceutical ingredients. Zein films provide an excellent gas barrier against oxygen at low water contents. Modified cellulose, such as methyl mellulose (MC), hydroxyl propyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC) and carboxymethyl cellulose CMC possess good film forming characteristic; films are generally odorless and tasteless, flexible and moderate protection to moisture and oxygen transmission. Film forming chitosans are clear, tough, flexible and have good oxygen barrier properties. Films produced from high amylose com starch has also been reported to be good oxygen barrier properties. Synthetic polymers may also be used. Polyvinyl alcohol is odorless tasteless and used as a barrier film for food supplement tablets. BASF, has under the trade name Kollicoat, developed a polyvinyl alcohol-polyethylene glycol graft copolymer for instant release coating for tablets which exhibits reliable protection properties for active ingredients against light, oxygen and moisture. Such coatings are known in the art and, for example, disclosed in US20130108745 Al.

In certain aspects of the present invention, the composition of the one or more glucocorticoid(s) may comprise an effervescent-coated formulation of the composition comprising the one or more glucocorticoid(s). Thereby, said effervescent-coated formulation comprising one or more effervescent and a coating agent(s), may improve the bioavailability of the composition and thus absorption of a therapeutically effective amount of the one or more glucocorticoid(s) in the topical area to be treated. In the context of the present invention, the topical area to be treated comprises or is the mucosa of the stomach. Preferably, the topical area to be treated comprises or is the mucosa of the fundus and/or the corpus of the stomach. In particular, the effervescent-coated formulation of the composition comprising the one or more glucocorticoid(s) may use the effervescence as a penetration enhancer for drugs known, or suspected, of having poor bioavailability. Such an enhancement in bioavailability may be, e.g., due to the following mechanisms: reducing the thickness and/or the viscosity of the mucus layer; alteration of the tight junctions between cells, thus promoting absorption through the paracellular route and/or inducing a change in the cell membrane structure, thus promoting transcellular absorption. The composition of the one or more glucocorticoid(s) may include an amount of effervescent agent effective to aid penetration and to promote absorption of the composition in the topical area to be treated.

Effervescent agents of the present invention include but are not limited to dry solid carbonate and bicarbonate salt such as, preferably, sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate, magnesium carbonate and the like.

The coating agent of the effervescent-coated formulation of the composition comprising the one or more glucocorticoid(s) may aid in releasing the drug in a specific area, i.e. the topical area to be treated as provided by the present invention. This site-specific delivery may be promoted by various mechanisms, for example, but not limited to metabolizing the coating agents by enzymes present in a specific part of the area to be treated, thus releasing the drug in that area, e.g. as described in US 6,931,335. In the context of the present invention, the coating agents may be used to prevent the release of the one or more glucocorticoid(s) from the composition before the composition reaches the topical area to be treated. The coating may be used in conjunction with an effervescence to cause the effervescence to occur at the topical area to be treated. No limiting examples of coating agents used in the present invention include but are not limited to cellulose derivatives including cellulose acetate phthalate (CAP); shellac and certain materials sold under the trademark Eudragit™ (various grades may be used in specific combinations) and hydroxypropylmethyl cellulose phthallate. In a preferred embodment of the present invention, the coating agent used in the present invention may comprise hydroxypropylmethyl cellulose phthallate.

In certain aspects, the one or more glucocorticoid(s) is/ are locally effective at the topical area to be treated. By using the controlled drug delivery form of the present invention, i.e. the effervescent-coated formulation, the glucocorticoids may not be transported past the “absorption window” prior to releasing essentially all the drug so that maximum bioavailability may be attained. Targeting the drug to the pathological tissue may be usually preferable for treatment of localized disorders, as the concentration of the drug attained in the diseased tissue or organ may be higher than its systemic concentration, resulting in enhanced effectiveness of the drug in the target organ or tissue, with reduced systemic side effects. In this context, the topical area to be treated comprises or is the mucosa of the stomach. More preferably, the topical area to be treated comprises or is the mucosa of the fundus and/or the corpus of the stomach.

In certain aspects, AIG in a patient is determined histologically, by the occurrence of gastric inflammation, by the occurrence of destruction of parietal cells, and by a subsequent failure in production of gastric acids, resulting in higher gastrin secretion, and/or increased parietal cell antibody (PCA)and/or anti-intrinsic factor antibody (IFA) levels in a sample of the patient, wherein an increase in PCA or IFA levels and/or a pH increase of gastric juice, compared to a control level is indicative for the patient of having autoimmune gastritis.

Histologically, AIG may be determined by inflammatory markers since AIG is characterized by a gastric inflammation of the corpus and the fundus, sustained by a cell-mediated aggression by CD4+CD25- Thl lymphocyte effectors. The main target of immunological injury is the H+/K+-adenosine-triphosphate enzyme (ATPase), a protein of the membrane that coats the secretory canaliculi of the parietal cells and is responsible for the secretion of the hydrogen ions in exchange for the potassium ions (proton pump). Induced by a triggering factor not yet entirely identified, the CD4+CD25- T-cells, together with macrophages and B lymphocytes, infiltrate the submucosa, the lamina propria, and the gastric glands causing the loss of parietal or P/Dl cells. The damage of the corpus and fundus mucosa results in hypo/achlorhydria including failure in production of gastric acids, as a result of destruction of the parietal cells; hypergastrinemia, i.e. higher gastrin secretion, as a result of alteration of the negative feedback mechanism modulated by gastric acidity and governed by somatostatin via paracrine mechanism; malabsorption, which may cause iron-deficiency anemia resistant to oral treatment or vitamin Bi 2-deficiency anemia; presence of circulating autoimmune antibodies directed against the proton pump, parietal cells and the intrinsic factor, a consequence of the effector cytokine action of the T lymphocytes on humoral immunity; reduction of serum levels of pepsinogen and P/Dl cells being destroyed as bystanders of the parietal cells.

The diagnosis of AIG may be made by combined findings of anemia, serological (blood) studies, endoscopic findings, and gastric biopsy diagnosis. Abnormal serological findings include but are not limited to increased serum gastrin, reduced pepsinogen I, anti-parietal cell antibodies, anti- intrinsic factor antibodies, low serum iron, and low vitamin B_I2. Endoscopically, the natural folds in the proximal stomach may appear flattened (‘atrophic’), while the distal or antral part of the stomach appears normal or unaffected. Occasionally, small nodules may be seen in the proximal stomach; which may show carcinoid tumor on biopsy. Biopsies taken from the proximal stomach may show depleted or lost parietal or oxyntic cells (atrophy), increased chronic inflammatory cells (chronic gastritis), intestinal metaplasia, and increased small clusters or hyperplasia of neuroendocrine cells (so-called ECL cells). According to the Sydney system, the diagnosis of gastritis should be based on the separate assessment of at least three samples from the antrum (including the incisura angularis), and two from the gastric body; and any focal lesions should be biopsied too. When such topographically well-defined samples are available, the presence of chronic gastritis with minimal or no active inflammation in the corpus, and a relatively normal antral mucosa in the absence of H. pylori infection should elicit the suspicion of an early autoimmune phenomenon. Since early stages of AIG show often non-specific findings and histological definitions or scores for diagnosis are missing, a study by Kulnigg-Dabsch et al, (2016) found that a cut-off level a PC A of 100 U/ml for the diagnosis of active AIG in patients under 60 years of age is highly accurate for AIG. Thus, in certain aspects, active AIG in a patient is determined by the PC A level in a sample of the patient, wherein a PC A level above 100 U/ml compared to a control level is indicative for the patient of having active autoimmune gastritis.

A frequent clinical presentation of AIG is pernicious anemia (PA), a megaloblastic anemia arising from vitamin B_I2 malabsorption as a consequence of intrinsic factor deficiency or the iron deficiency anemia due to iron malabsorption as a consequence of reduced gastric acid secretion.

Treatment of autoimmune gastritis concerns two separate aspects: Treatment for anemia and early detection of carcinoma and carcinoid in the stomach. Treatment for anemia include substitution for iron and/or vitamin B_I2. Early detection of carcinoma and carcinoid in the stomach involves endoscopic surveillance of gastric mucosa, optimal biopsy tissue procurement, evaluation and removal of the carcinoid nodules.

The term“treatment of patients having autoimmune gastritis” implies that AIG has been diagnosed in a patient/subject. A patient/subject suspected of suffering from AIG may show specific clinical and/or pathological symptoms which a skilled person can attribute to the specific pathological condition occurring in AIG (i.e., diagnose).

In certain aspects of the present invention, a response to treatment of autoimmune gastritis in a patient is indicated by histological remission, by reduction of gastric inflammation, by suppression of the destruction of parietal cells, by the pH level of gastric juice, specifically serum gastrin, and/or by the PCA and IFA levels, wherein a decrease in PCA/IFA level and/or a decrease of gastric juice pH, specifically reduction in gastrin, compared to a predetermined level or a control is indicative for a response to said treatment. In preferred aspects of the present invention, a response to treatment of autoimmune gastritis in a patient is indicated by reduction of the gastric pH level of gastric juice, preferably reduction of the pH level by more than 2. The “treatment” of AIG may, for example, lead to a halt in the progression (e.g., no deterioration of symptoms) or a delay in the progression (in case the halt in progression is of a transient nature only). The“treatment” may also lead to a partial response (e.g., amelioration of symptoms) or complete response (e.g., disappearance of symptoms) of the subject/patient suffering from AIG. Accordingly, the“treatment” of AIG may also refer to an amelioration, which may, e.g., lead to a halt in the progression or a delay in the progression. Such a partial or complete response may be followed by a relapse. It is to be understood that a subject/patient may experience a broad range of responses to a treatment (e.g., the exemplary responses as described herein below). The treatment of a disorder or disease may, inter alia, comprise curative treatment (preferably leading to a complete response and eventually to healing of the disorder or disease) and palliative treatment (including symptomatic relief). Thus, the term“treatment” means obtaining a desired pharmacological and/or physiological effect. The effect may also be prophylactic in terms of completely or partially preventing a disease/medical conditio n/disorder or symptom thereof and/or may be therapeutic in terms of partially or completely curing a disease/medical condition/disorder and/or adverse effect attributed to the disease/medical conditio n/disorder.

As used herein, the term“topical treatment” refers to the application of a pharmaceutical composition at the site of inflammation, i.e., non-systemic administration. In other words, “topical” refers to a localized area of the body or to the surface of a body part of the location of the effect. In this context, a pharmaceutical composition pertains to a particular surface area. As provided herein, the topical area of the composition comprising one or more glucocorticoid(s) used for the topical treatment of AIG comprises or is the mucosa of the stomach. In certain aspects, topical area of the composition comprising one or more glucocorticoid(s) used for the topical treatment of AIG is the mucosa of the stomach. In certain aspects, the topical area of the composition comprising one or more glucocorticoid(s) used for the topical treatment of AIG comprises the mucosa of the fundus and/or the corpus of of the stomach. In certain aspects, topical area of the composition comprising one or more glucocorticoid(s) used for the topical treatment of AIG is the mucosa of the fundus and/or the corpus of the stomach. As provided herein, the glucocorticoid(s) are formulated in a dosage form to be used as topical glucocorticoid(s). For example, topical glucocorticoid(s) may be commonly used to treat inflammatory skin conditions such as atopic eczema, rash and dermatitis. Hydrocortisone and betamethasone are examples of low- and high-potency topical glucocorticoid(s). As provided in certain aspects of the present invention, the one or more glucocorticoid(s) is/ are locally effective at the topical area.

The term“glucocorticoid(s)” and the term“corticosteroid(s)” are used interchangeably and refer to any group of natural isolated or biologically active derivatives of the cortisol secreted from the adrenal cortex or synthetic steroid hormones. Exemplary glucocorticoids include, without limitation, dexamethasone, betamethasone, triamcinolone, triamcinolone acetonide, triamcinolone diacetate, triamcinolone hexacetonide, beclomethasone, dipropionate, beclomethasone dipropionate monohydrate, flumethasone pivalate, diflorasone diacetate, fluocinolone acetonide, fluorometholone, fluorometholone acetate, clobetasol propionate, desoximethasone, fluoxymesterone, fluprednisolone, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, hydrocortisone cypionate, hydrocortisone probutate, hydrocortisone valerate, cortisone acetate, paramethasone acetate, methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, prednisolone, prednisolone acetate, prednisolone sodium phosphate, prednisolone tebutate, clocortolone pivalate, flucinolone, dexamethasone 21 -acetate, betamethasone 17-valerate, isoflupredone, 9-fluorocortisone, 6- hydroxy dexamethasone, dichlorisone, meclorisone, flupredidene, doxibetasol, halopredone, halometasone, clobetasone, diflucortolone, isoflupredone acetate, fluorohydroxyandrostenedione, beclomethasone, flumethasone, diflorasone, clobetasol, cortisone, paramethasone, clocortolone, prednisolone 2l-hemisuccinate free acid, prednisolone metasulphobenzoate, prednisolone terbutate, triamcinolone acetonide 21- palmitate, prednisolone, flurometholone, medrysone, loteprednol, fluazacort, betamethasone, prednisone, methylprednisolone, triamcinolone hexacatonide, paramethasone acetate, diflorasone, fluocinolone and fluocinonide, derivatives thereof, salts thereof, and mixtures thereof.

In certain aspects, the one or more glucocorticoid(s) of the present invention is/are selected from the group consisting of budesonide, flunisolide, triamcinolone acetonide, beclomethasone, dipropionate, dexamethasone sodium phosphate, fluticasone propionate, hydrocortisone, prednisone, prednisolone, mometasone, tipredane, and butixicort. Preferably, the glucocorticoid is budesonide. Suitable pharmaceutically acceptable salts of glucocorticoids include, for example, the aceponate, acetate, butyrate, dipropionate, etabonate, furoate, propionate, and valerate salts thereof. In a preferred aspect of the present invention, the compositions comprising one or more glucocorticoid(s) are selected from the group consisting of budesonide, flunisolide, triamcinolone acetonide, beclomethasone, dipropionate, dexamethasone sodium phosphate, fluticasone propionate, hydrocortisone, prednisone, prednisolone, mometasone, tipredane, and butixicort. Preferably, the glucocorticoid is budesonide. Glucocorticoids which are not specifically disclosed herein but which are useful for the treatment of patients having AIG are expressly included and intended within the scope of the present invention.

The effects of glucocorticoids are widespread and include but are not limited to alterations in carbohydrates, such as increased blood glucose levels, stimulation of amino acid release, maintenance of fluid and electrolyte balance, preservation of normal cardiovascular system function, immune system suppression, and decreased bone formation. Glucocorticoids possess potent anti-inflammatory properties and may be used to treat a variety of inflammatory and autoimmune disorders. Conditions commonly treated with glucocorticoids include asthma; arthritis (eg, rheumatoid arthritis); autoimmune disorders such as lupus, and multiple sclerosis; skin conditions such as eczema and rashes; some types of cancer; and Addison’s disease (insufficient cortisol production) as well as the prevention of organ rejection in transplant recipients. For example, budesonide is a potent glucocorticoid with a high topical activity and low systemic availability in therapeutic doses. Budesonide may be well absorbed from the intestine, have an extensive first pass metabolism and 80 to 90% of an orally given dose may be metabolized in the liver during the first liver pass in healthy subjects. The systemic bioavailability may be about 10%. Further, budesonide may be sometimes used in inhaled form to treat inflammatory diseases or conditions such as asthma, or nasal inflammation, or in other forms, such as by oral delivery or enema, to treat other lower inflammatory lower gastrointestinal diseases or conditions such as Crohn's disease. Flunisolide is a synthetic corticosteroid with anti-inflammatory and anti-allergic properties and is often prescribed as treatment for allergic rhinitis. Triamcinolone acetonide the acetonide salt form of triamcinolone, is a synthetic glucocorticosteroid with immunosuppressive and anti-inflammatory activity used topically in the treatment of various skin disorders. Intralesional, intramuscular, and intra-articular injections are also administered under certain conditions. Beclomethasone dipropionate is the dipropionate ester of a synthetic glucocorticoid with anti-inflammatory and immunomodulating properties. It is used topically as an anti-inflammatory agent and in aerosol form for the treatment of asthma. Fluticasone propionate is the propionate salt form of fluticasone, a synthetic trifluorinated glucocorticoid receptor agonist with antiallergic, anti-inflammatory and antipruritic effects. Hydrocortisone is the main glucocorticoid secreted by the adrenal cortex. Its synthetic counterpart is used, either as an injection or topically, in the treatment of inflammation, allergy, collagen diseases, asthma, adrenocortical deficiency, shock, and some neoplastic conditions. Prednisone is a synthetic anti-inflammatory glucocorticoid derived from cortisone. It is biologically inert and converted to prednisolone in the liver. Mometasone is a pregnadienediol derivative anti allergic agent and anti-inflammatory agent that is used in the management of asthma and allergic rhinitis. It is also used as a topical treatment for skin disorders. Dexamethasone sodium phosphate is a sodium phosphate salt form of dexamethasone, a synthetic adrenal corticosteroid with potent anti-inflammatory properties. In addition to binding to specific nuclear steroid receptors, dexamethasone also interferes with NF-kB activation and apoptotic pathways. Dexamethasone sodium phosphate may be used in the treatment of adrenocortical insufficiency.

According to the present invention, the pharmaceutical composition may incorporate a high dose medicament. In general, the composition of the invention comprises a pharmaceutically effective amount of at least one active drug. This amount, for purposes herein, is that determined by such considerations as are known in the art, and generally means an amount sufficient to prevent, alleviate, treat or cure a disease or disorder. In general, doses of individual steroids are classified as being low dose (7.5 mg/day or less), medium dose (between 7.5 and 30 mg/day), or high dose (greater than 30 mg/day). Steroid doses often are described in terms of equivalent doses of prednisone (e.g., 5 mg of prednisone is equivalent to 4 mg of methylprednisolone) and also in terms of their duration of action, such as short, intermediate, or long acting. An effective amount of the composition comprising one or more glucocorticoid(s) may be administered in a dose range of about 1 pg to about 20 mg, about 1 pg to about 10 mg, about 0.01 mg to about 10 mg, about 0.025 mg to about 10 mg, about 0.05 mg to about 5 mg, about 0.1 mg to about 5 mg, about 0.125 mg to about 5 mg, about 0.25 mg to about 5 mg, about 0.5 mg to about 5 mg, about 0.05 mg to about 2 mg, about 0.1 mg to about 2 mg, about 0.1 mg to about 1 mg, about 0.125 mg to about 2 mg, about 0.25 mg to about 2 mg, about 0.5 mg to about 2 mg, about 10 pg to about 2.5 mg, about 5 pg to about 500 pg, about 5 pg to about 250 pg, about 5 pg to about 130 pg, about 45 pg to about 1000 pg, about 1 pg, about 10 pg, about 16 pg, about 25 pg, about 27.5 pg, about 29 pg, about 32 pg, at least about 25 pg, about 40 pg, about 42 pg, about 45 pg, about 48 pg, about 50 pg, about 55 pg, about 64 pg, about 84 pg, about 96 pg, about 100 pg, about 125 pg, about 128 pg, about 200 pg, about 250 pg, about 400 pg, about 800 pg, about 25 pg to about 66 pg, about 48 pg to about 81 pg, about 73 pg to about 125 pg, about 95 pg, about 35 pg to about 95 pg, about 25 pg to about 125 pg, about 60 pg to about 170 pg, about 1 10 pg, about 170 pg, about 45 pg to about 220 pg, about 45 pg to about 85 pg, about 48 pg to about 82 pg, about 85 pg to about 160 pg, about 140 pg to about 220 pg, about 120 pg to about 325 pg, about 205 pg, about 320 pg, about 325 pg, about 90 mm to about 400 mm, about 95 mm to about 170 mm, about 165 mm to about 275 mm, or about 275 mm to about 400 mm of glucocorticoid. In certain aspects, the composition is administered in a dose of 0.01 mg/ml to 10 mg/ml budesonide, more preferably 0.05 mg/ml to 5.0 mg/ml budesonide, more preferably 0.1 to 1.0 mg/ml glucocorticoid, wherein the glucocorticoid is budesonide.

The administration of the herein provided compositions may, inter alia, comprise an administration twice daily, every day, every other day, every third day, every fourth day, every fifth day, once a week, once every second week, once every third week, once every month, etc. If the composition is administered twice daily, then it may be preferred that the composition is administered at about twelve hour intervals. In certain aspects, the composition is administered at an interval of every three day, every two days, once a day, twice a day or three times a day. Preferably, the composition is administered at an interval of every two days, once a day, twice a day or three times a day, more preferably once a day, or twice a day.

In certain aspects, an empty stomach of the patient enhances the release of the effective amount of one or more glucocorticoids at the topical area. The gastric motility is not uniform, but passes through cycles termed migrating motor complexes (MMC). These MMC last about 2 h in total, but are divided into four phases, of which phase 3 results in the strongest contractions but lasts only about 15 min. Non nutrient liquids are moved quickly from the stomach throughout the MMC, but solids of particle size 2 mm-e.g. partly dissolved drug are only moved into the intestine during the brief phase 3. Thus, gastric emptying rate is an important determinant of oral drug bioavailability and gastrointestinal drug absorption. In this context, most drugs may be best absorbed on an empty stomach. Some common examples include flucloxacillin, phenoxymethylpenicillin or oxytetraxcy cline. If the stomach is not empty, the food could delay the absorption of the drug. Take on an empty stomach means to take the drug within 1 hour before eating or 2 hours after eating. It is recommended and a preferred embodiment of the present invention to treat diseases related to the stomach at an empty stomach stage (e.g., omeprazole [Prilosec®], lanszoprazole [Prevacid®], pantoprazole [Protonix®], or esomeprazole [Nexium®, Vimovo®]). As provided herein, an empty stomach may be particularly advantageous in the topical treatment of AIG by the composition of the present invention since the glucocorticoid can be delivered to the mucosa of the topical area to be treated without hindrance by food or drugs ingested by the patient. In other words, the composition of the present invention which is locally effective may be efficiently delivered to the topical area to be treated in a patient with an empty stomach. Drug-food interactions may also change the bioavailability of a drug. As used herein, the glucocorticoid(s) of the present invention may have an increased bioavailability when administered on an empty stomach.

It has been found that patients with autoimmune gastritis display delayed gastric emptying (Kalkan et al, 2015). In this context, Kalkan et al, (2015) showed that the median gastric emptying half time was reduced in AIG patients and that parameters that affect gastric emptying half time were found as serum gastrin level, chronic inflammation and increase in the degree of the atrophy of the gastric mucosa. Thus, in certain aspects, a delayed stomach emptying of the patient extends the time period of the release of the effective amount of one or more glucocorticoids at the topical area in the patient. In this context, the retention of dosage forms according to the present invention may be increased due to the delayed stomach emptying in AIG patients so that additional administration of medications delaying stomach emptying may not be necessary. Furthermore, it has been reported that the gastric retention of a controlled drug release delivery system comprising 30 mg baclofen can be extended by prohibiting drinking water for 2 hours before dosing and 2 hours thereafter (US 2004/0180088). Thus, in certain aspects, oral administration of a liquid to the patient may be suitable to control the time period in which the effective amount of one or more glucocorticoids at the topical area is released.

Patients with AIG, in particular with pernicious anaemia, may have an increased risk of gastric cancer, specifically autoimmune metaplastic atrophic gastritis (AMAG), and gastric carcinoid tumors (including gastric neuroendocrine tumors), the latter as a result of the associated persistent hypergastrinemia in the presence of achlorhydria due to the severe atrophy with pronounced parietal cell. The most important risk factors besides amenia include severity of atrophy, the presence of intestinal metaplasia, the duration of the disease, and age over 50 years. The incidence of gastric cancer development ranges from 1 to3 % for gastric carcinoma and from 2 to 12.5 % for carcinoid tumors in patients with AIG with or without pernicious anemia. Thus, in certain aspects, the composition for use according to the present invention may further comprise reducing the risk of developing one or more diseases associated with autoimmune gastritis, specifically pernicious anemia (PA), more specifically autoimmune metaplastic atrophic gastritis (AMAG), gastric cancer or gastric neuroendocrine tumors.

The assessment of the extend and location of atrophy can be achieved by the operative link for gastritis assessment (OLGA) staging system for reporting gastritis in terms of stage (the OLGA staging system). Gastritis staging arranges the histological phenotypes of gastritis along a scale of progressively increasing gastric cancer risk, from the lowest (stage 0) to the highest (stage IV). As in H. pylori infection, so too in the autoimmune setting, OLGA stages III to IV have been significantly associated with a higher gastric cancer risk.

As used herein, the terms“comprising” and“including” or grammatical variants thereof are to be taken as specifying the stated features, integers, steps or components but do not preclude the addition of one or more additional features, integers, steps, components or groups thereof. This term encompasses the terms“consisting of’ and“consisting essentially of.”

The term“consisting essentially of’ or grammatical variants thereof when used herein are to be taken as specifying the stated features, integers, steps or components but do not preclude the addition of one or more additional features, integers, steps, components or groups thereof but only if the additional features, integers, steps, components or groups thereof do not materially alter the basic and novel characteristics of the claimed composition, device or method.

Thus, the terms“comprising”/“including”/”having” mean that any further component (or likewise features, integers, steps and the like) can/may be present.

The term“consisting of’ means that no further component (or likewise features, integers, steps and the like) is present.

The term "about" preferably refers to ±10% of the indicated numerical value, more preferably to ±5% of the indicated numerical value, and in particular to the exact numerical value indicated.

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Examples

The following clinical study synopsis further illustrate the present invention but are not construed to limit the scope thereof

Clinical study synopsis: Oral Budesonide Viscous Suspension (BVS) for Autoimmune Gastritis (AIG)

1. Objectives of the Study

The primary objective of this study is to test whether a viscous suspension of oral budesonide reduces destruction of parietal cells in patients with AIG as detected by pH measurement of gastric juice.

Secondary objectives of this study are to test whether budesonide reduces histological inflammation and destruction of parietal cells to investigate if budesonide reduces serum gastrin levels (which inversely relate to gastric acid production) and serum antibody concentration (parietal cell antibodies and intrinsic factor antibodies), to test whether budesonide reduces upper GI symptoms in patients with AIG (score TBD) and to determine the safety and compliance concerning budesonide in patients with AIG.

Descriptive objectives of this study are to investigate whether low budesonide (2mg/day) concentrations are equally effective as 4mg/day), the effect of budesonide by patient’s age (below and above 40 years), and to investigate if budesonide effects differs in the subset of patients with a history of H. pylori infection.

2. Design and Phase of the Study

A single center, randomized, 3-arm, double-blind, phase II clinical study is performed with lOml BVS (0.4mg/ml), lOml BVS (0.2mg/ml) or lOml placebo in AIG patients for 8 weeks. The first visit of the first patient is at Q2, 2019, the first visit o the last patient is at Q3, 2019 and the last visit of the last patient is at Ql, 2020. 100 patients are assessed for eligibility. 60 patients are randomized into 3 groups with 20 patients per group (TBD with statistician, placebo response is expected <5%, BVS >50%, i.e. those below 40 years of age). Randomization ratio is 1 :1 :1. Inclusion criteria for the study are:

Patients with AIG as defined by presence of parietal cell antibodies >100 U/ml, typical histological features and gastric pH >5;

Male or female subjects with the age > 18 and <65 years are included;

Subjects having signed written informed consent prior to inclusion in the study.

Exclusion criteria for the study are:

Presence of H. pylori or eradication within the previous 6 months;

Patients with gastric neoplasia;

Inflammatory Bowel Disease;

Regular use of acetylsalicylic acid: daily use of >l00mg or >300mg more than twice per week in more than 4 weeks within the previous 3 months;

Regular use of NSAIDs or COX-2 inhibitors: More than twice per week in more than 4 weeks within the previous 3 months;

Regular use of proton pump inhibitors, H2 blockers or other pH lowering medication

- Use of acid / pesin supplements (such a Heloacid or Enynorm) within 3 days of the first visit;

- Use of systemic steroids or any immunosuppression in the previous 3 months;

Hypersensitivity to budesonide;

Patients after gastric surgery;

Unwillingness to participate or who is considered incompetent to give an informed consent;

Pregnant or breastfeeding women;

Participation in another clinical study investigating another IMP within 3 month prior to screening;

Renal insufficiency (GFR <30ml/min/l 73m²);

Severe liver disease or liver failure (elevation of liver enzymes above 3xULN);

Current or history of serious psychiatric disorder or alcohol/drug abuse that in the opinion of the investigator may impact the assessment of safety, efficacy or protocol adherence;

Any condition that requires treatment with acetylsalicylic acid, NSAIDs/COX 2 inhibitors or steroids; Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or ability to comply with study procedures, IMP administration and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.

Contaminant medications which are not allowed are:

acetylsalicylic acid: more than 3 doses during the treatment period

use of NSAIDs or COX-2 inhibitors: more than 3 tablets during the treatment period

Any use of proton pump inhibitors, H2 blockers or other pH lowering medication

- Use of acid / pesin supplements (such a Heloacid or Enynorm) within 3 days of the first visit

- Use of oral or parenteral steroids or immunosuppressants more than 3 doses during the treatment period

3. Study periods

3.1 Screening phase: 1-3 weeks

Patients with AIG are identified from a large cohort (Loha for Life) and invited to participate in the study by telephone or email. After informed consent is obtained, medical history and vital signs, concomitant medication, physical examination, body weight and height are assessed together with a pregnancy test. A diary regarding upper GI symptoms is given to the patient. 1 to 3 weeks later the diary is collected, blood (PC A, IF A, Gastrin, CBC, chemistry, TSH, Vitamin B_I2, Ferritin, Transferrin Saturation, pregnancy test) and stool (H. pylori antigen) is sampled, and an upper GI endoscopy with a white light high resolution gastroscope such as Olympus 180 or higher is performed. A minimum of 5 pictures is documented (ora serrata at introduction of scope, gastric body at introduction, gastric antrum with pylorus at introduction, gastric fundus, duodenum). Gastric juice is collected and pH is measured (Method TBI, e.g. pH strips + picture taken with endoscope post procedure. Biopsies of the duodenum, antrum, body and fimdus are collected separately. If a neoplastic lesion is suspected, it should be removed or extra biopsies should be taken. Histology must be negative for neoplasia and H. pylori. A capsule for continuous pH measurement is placed in the gastric body and pH is monitored for 24hours. 3.2 Treatment phase: 8 weeks

Patients are instructed to take lOmL of BVS 0.4mg/ml, or 0.2mg/ml or placebo in the morning

on a fasting stomach and rinse the mouth with water. Further patients are asked not to eat or drink for 30 min. Site visits after 2 and 4 weeks to collect empty containers, compliance check, patients’ diary, check blood parameters (CBC, chemistry, TSH, PCA, IF A, gastrin, pregnancy test) and safety reports, concomitant medication, physical examination and vital signs are assessed.

3.2 End of Treatment

The end of the treatment visit (after 8 weeks of treatment) to collect empty containers, compliance check, patients’ diary, check blood parameters ((PCA, IFA, Gastrin, CBC, chemistry, TSH, Vitamin B_I2, Ferritin, Transferrin Saturation, pregnancy test) and safety reports, concomitant medication, physical examination and vital signs are assessed. Another upper GI endoscopy is performed similar to the screening procedure with picture documentation, gastric juice flushing for pH measurement, biopsies and placement of another capsule for pH monitoring.

3.4 Follow-up visits: 16 weeks

Site visits after 8 and 16 weeks to collect patients’ diary, check blood parameters ((PCA, IF A, Gastrin, CBC, chemistry, TSH, Vitamin B_I2, Ferritin, Transferrin Saturation, pregnancy test) and safety reports, concomitant medication; physical examination and vital signs are assessed.

4. Statistics

Primary endpoint is the number of patients with a reduction of average gastric pH as measured by flushing juice pH and capsule pH of >2 (expected placebo response <5%).

Secondary endpoints are:

Any reduction in gastric pH

Histological changes Reduction in gastrin levels and antibody concentrations during and after treatment compared to the mean of the two pretreatment measurements.

Effect on Upper GI symptoms

Safety and compliance

Differences between high and low dose BVS

- All tests are two-sided and a significance level of 5 % is used.

Claims

1. A composition comprising one or more glucocorticoid(s) for use in the topical treatment of a patient having autoimmune gastritis, wherein the topical area to be treated comprises or is the mucosa of the stomach.

2. The composition for use according to claim 1, wherein the composition comprises a carrier.

3. The composition for use according to claim 1 or 2, wherein the composition comprises a carrier for oral administration.

4. The composition for use according to any of claims 1 to 3, wherein the composition comprises the carrier of claim 2 or 3, which is a controlled and sustained release carrier for delivery of an effective amount of said one or more glucocorticoid(s) to the topical area of the patient having autoimmune gastritis and release of an effective amount of said one or more glucocorticoid(s) at the topical area.

5. The composition for use according to any of claims 2 to 4, wherein the carrier is in the form of an oral suspension or a gel or an effervescent tablet.

6. The composition for use according to any of claims 2 to 5, wherein the carrier is in the form of a gel.

7. The composition according to any of claims 5 or 6, wherein the carrier releases an effective amount of one or more glucocorticoid(s) at the topical area at a time period between 0 and 15 minutes after onset of topical treatment with said composition.

8. The composition for use according to any of the preceding claims, wherein the one or more glucocorticoid(s) is/ are locally effective at the topical area to be treated.

9. The composition for use according to any of the preceding claims, wherein autoimmune gastritis in a patient is determined histologically, by the occurrence of gastric inflammation, by the occurrence of destruction of parietal cells, and by a subsequent failure in production of gastric acids, resulting in higher gastrin secretion, and/or increased parietal cell antibody (PCA) and/or anti-intrinsic factor antibody (IF A) levels in a sample of the patient, wherein an increase in PCA or IFA levels and/or a pH increase of gastric juice, compared to a control level is indicative for the patient of having autoimmune gastritis.

10. The composition for use according to any of the preceding claims, wherein autoimmune gastritis in a patient is determined by the PCA level in a sample of the patient, wherein a PCA level above 100 U/ml compared to a control level is indicative for the patient of having active autoimmune gastritis.

11. The composition for use according to any of the preceding claims, wherein a response to treatment of autoimmune gastritis in a patient is indicated by histological remission, by reduction of gastric inflammation, by suppression of the destruction of parietal cells, by the pH level of gastric juice, specifically serum gastrin, and/or by the PCA and IFA levels, wherein a decrease in PCA/IFA level and/or a decrease of gastric juice pH, specifically reduction in gastrin, compared to a predetermined level or a control is indicative for a response to said treatment.

12. The composition for use according to any of the preceding claims, wherein a response to treatment of autoimmune gastritis in a patient is indicated by reduction of the gastric pH level of gastric juice, preferably reduction of the pH level by more than 2.

13. The composition for use according to any of the preceding claims, wherein the one or more glucocorticoid(s) is/are selected from the group consisting of budesonide, flunisolide, triamcinolone acetonide, beclomethasone, dipropionate, dexamethasone sodium phosphate, fluticasone propionate, hydrocortisone, prednisone, prednisolone, mometasone, tipredane, and butixicort.

14. The composition for use according to any of the preceding claims, wherein the glucocorticoide is budesonide.

15. The composition for use according to claim 14, wherein the composition is administered in a dose of: 0.01 mg/ml to 10 mg/ml budesonide, more preferably 0.05 mg/ml to 5.0 mg/ml budesonide, more preferably 0.1 mg/ml to 1.0 mg/ml budesonide.

16. The composition for use according to any of the preceding claims, wherein the composition is administered at an interval of every two days, once a day, twice a day or three times a day, more preferably once a day, or twice a day.

17. The composition for use according to any of the preceding claims, wherein a delayed stomach emptying of the patient extends the time period of the release of the effective amount of one or more glucocorticoids at the topical area in the patient.

18. The composition for use according to any of the preceding claims, wherein oral administration of a liquid to the patient is suitable to control the time period in which the effective amount of one or more glucocorticoid(s) at the topical area is released.

19. The composition for use according to any of the preceding claims, wherein an empty stomach of the patient enhances the therapeutic efficacy of one or more glucocorticoids at the topical area to be treated.

20. The composition for use according to any of the preceding claims, further comprising reducing the risk of developing one or more diseases associated with autoimmune gastritis, specifically pernicious anemia (PA), more specifically autoimmune metaplastic atrophic gastritis (AMAG), gastric adenocarcinoma or gastric neuroendocrine tumors.

21. A method for topical treatment of a patient having autoimmune gastritis, wherein said method comprises administering a composition comprising one or more glucocorticoid(s) to a patient having autoimmune gastritis, wherein topical area of the topical treatment comprises or is the mucosa of the stomach.

22. The method according to claim 21, wherein the composition comprises a carrier.

23. The method according to claim 21 or 22, wherein the composition comprises a carrier for oral administration.

24. The method according to any of claims 21 to 23, wherein the composition comprises the carrier of claim 22 or 23, which is a controlled and sustained release carrier for delivery of an effective amount of said one or more glucocorticoid(s) to a topical area of the patient having autoimmune gastritis and release of an effective amount of said one or more glucocorticoids at the topical area.

25. The method according to any of claims 22 to 24, wherein the carrier is in the form of an oral suspension or a gel or an effervescent tablet.

26. The method according to any of claims 22 or 24, wherein the carrier is in the form of a gel.

27. The method according to any of claims 22 to 26, wherein the carrier releases an effective amount of one or more glucocorticoids at the topical area at a time period between 0 and 15 minutes after onset of topical treatment with said composition.

28. The method according to any of claims 21 to 27, wherein the one or more glucocorticoid(s) is/are selected from the group consisting of budesonide, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, dexamethasone sodium phosphate, fluticasone propionate, hydrocortisone, prednisone, prednisolone, mometasone, tipredane, and butixicort.

29. The method according to any of claims 21 to 27, wherein the glucocorticoide is budesonide.