Oral Rifamycin SV Composition

Abstract

To provide oral pharmaceutical compositions comprising rifamycin SV, or a pharmaceutically acceptable salt thereof, formulated to obtain an extended-release profile of the rifamycin SV, or a pharmaceutically acceptable salt thereof.SOLUTION: Provided is an oral pharmaceutical composition in the form of a solid dosage form comprising about 600 mg of rifamycin SV, or a pharmaceutically acceptable salt thereof, one or more pharmaceutically acceptable excipients, at least one lipophilic compound, at least one hydrophilic compound, and a gastro-resistant coating, the oral pharmaceutical composition being formulated to release the rifamycin SV, or a pharmaceutically acceptable salt thereof, substantially in the small intestine, and the oral pharmaceutical composition being formulated for controlled release, delayed release, and / or extended release.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] Enteric infections are common diseases caused by colonization of the intestine by foreign pathogens of various origins or by virulence of normally occurring intestinal microorganisms.

[0002] The human intestine is known to be divided into two distinct parts, the proximal and distal parts. - the proximal part, called the "small intestine" or "small bowel", is formed by three segments known cranio-caudally as the duodenum, jejunum and ileum, and is contained between two biological valves, namely the pylorus and the ileocecal valve; - The distal part is called the "large intestine" or "large bowel" and is formed by the colon and the recto-anus (Faller A, Scevola G. Anatomia e Fisiologia del Corpo Umano (Anatomy and Physiology of the Human Body). Vol I. Edizioni Minerva Medica, Turin, 1973, pp. 235-254). This part of the intestine includes several segments known, in order, as the ascending colon, transverse colon, descending colon, sigmoid colon and rectum.

[0003] The two parts, the small intestine and the large intestine, are anatomically and functionally separated by the ileocecal valve, which allows the passage of intestinal contents from the small intestine to the large intestine, but does not allow the passage of intestinal contents from the large intestine to the small intestine under normal conditions.In addition, from the point of view of anatomical structure, the small intestine is quite different from the large intestine, especially from the point of view of function (Non-Patent Document 2: Braga P C. Enteric microflora and its regulation. In Drugs in Gastroenterology. Raven Press, New York, 1991, pp. 501-508), in the small intestine, there is a large absorptive surface and strong peristalsis supported by a specific muscular ring, and in the large intestine, there is a surface epithelium (fenestratum epithelium) and clear and well-ordered crypts.

[0004] Local environmental factors such as pH conditions, nutrients, enzyme presence, and different transit times in each anatomical region determine which microbial species predominate and thus the bacterial concentration in a particular region. The concentration of bacteria in the small intestine is generally much lower than that in the large intestine due to microenvironmental and anatomical differences between regions.

[0005] These many differences in the physio-anatomical features of the small and large intestine explain the characteristic nature of some pathologies that occur at the expense of the small intestine.

[0006] It should be noted that diseases of the digestive system have different etiological pathologies and present various symptoms that allow their diagnosis. The expression "inflammatory bowel disease" or IBD refers to a group of chronic inflammatory bowel pathologies, including mainly ulcerative colitis and Crohn's disease, and should not be confused with "irritable bowel syndrome" or IBS. IBS can be classified and presented as IBS-C (constipation-predominant) or IBS-D (diarrhea-predominant), but in the presentation of IBS-M (mixed), periods of mixed symptoms or alternating with both symptoms may be present in the same individual, and a fourth category IBS-U (unclassified) has also been proposed, although this subcategory may change from individual to individual over time.

[0007] Unlike IBD, IBS is primarily considered a functional disease, since it does not show obvious anatomical disorders of the mucosa. From a purely clinical point of view, IBS is characterized by disturbances in bowel function due to abdominal pain, abdominal distension and altered bowel function (diarrhea, constipation or both). The etiology and pathogenesis of IBS are unknown, but various factors may be responsible for its development. These factors mostly include abnormalities in the regulation of tone and activity of the smooth muscle of the intestinal wall, the effects of bacterial irritants, and psychological and emotional influences. Due to the poor understanding of the pathophysiology and causes of IBS, therapeutic approaches to date have mainly focused on symptom management, maintaining daily function and improving the quality of life of patients. The mainstay of therapeutic interventions to date are pharmacological treatment with antispasmodics and antidiarrheals for diarrhea, prokinetic and high-fiber diets for constipation, and supportive care with low-dose antidepressants to normalize gastrointestinal motility treatments aimed at alleviating the functional symptoms of the disease. Other therapeutic interventions, including advice on lifestyle, dietary modifications and psychological counseling, are also used. However, IBS often does not respond to current treatment options, such as dietary and lifestyle advice, counselling, fibre supplementation, psychotherapy, and / or pharmacotherapy.

[0008] Recently, it has been reported that pregnane X receptor (PXR), a ligand-activated nuclear receptor that senses and responds to various chemical stimuli, including gut microbial metabolites, plays a key role in regulating inflammatory responses in the intestinal epithelium to enhance wound healing and maintain barrier function under inflammatory conditions (Garg A et al in The Journal of Pharmacology and Experimental Therapeutics, 359:91-101, October 2016). In humans, PXR is abundantly expressed in the small intestine, colon, liver, and gallbladder, and to a lesser extent in the stomach. PXR activation can induce metabolic enzymes (e.g., CYP3A4) and affect the pharmacokinetics of xenobiotics and endobiotics. In addition, PXR activation has been shown to attenuate the signaling of nuclear factor kB (NF-kB), a key transcription factor that regulates gene expression of inflammatory cytokines and chemokines. The distribution and function of PXR in the digestive tract suggest that PXR function may play a role in maintaining mucosal homeostasis. Therefore, activation of PXR could potentially contribute to the therapeutic efficacy in IBS patients.

[0009] Inflammation and immune dysregulation contribute to several gastrointestinal (GI) diseases, such as inflammatory bowel disease (IBD), irritable bowel syndrome (IBS) and diverticular disease. Alterations in the reciprocal crosstalk between PXR and NFκB, two key regulators of inflammation, may play a role in the dysregulation of inflammatory mechanisms in IBD and IBS.

[0010] Constant exposure to xenobiotics can not only cause intestinal inflammation and damage, but also impair immune function. In addition to its role in detoxification mechanisms, PXR has been shown to indirectly suppress inflammation through suppression of NFκB activity. NFκB is the master transcription factor regulating gene expression of inflammatory cytokines and chemokines. IBD patients have significantly higher expression of NFκB compared to non-IBD patients. Aberrant activation of NFκB leads to excessive production of proinflammatory cytokines that cause chronic inflammation of the intestine, a major mechanism of IBS.

[0011] Small intestinal bacterial overgrowth (SIBO) is a disturbance of the normal GI flora. In SIBO, the concentration of bacterial organisms in the distal jejunum and ileum increases, disrupting the normal distribution of bacteria. In SIBO, the number and / or variety of bacteria in the small intestine increases. A bacterial count of 10 per ml of proximal jejunal aspirate is considered to be higher than that of 10 per ml of proximal jejunal aspirate. 5 Typically, the bacterial concentration in the small intestine is 10 2 It is less than CFU.

[0012] According to the current view of those skilled in the art, SIBO can result from an underlying disease, such as pancreatic insufficiency, immune deficiency syndrome, diverticulum, previous surgery, scleroderma, autonomic neuropathy in diabetes, enteropathy after radiation therapy, or a combination of these factors. The prognosis of patients with SIBO is usually severe and related to the underlying disease. The resulting malabsorption of nutrients can cause a variety of symptoms. For example, this change in the distribution and concentration of normal GI flora in SIBO alters the metabolism of sugar molecules. Here, sugar molecules are first broken down into short-chain fatty acids (SCFAs), carbon dioxide (CO2) and hydrogen (H2) as part of a fermentation reaction. Most of the CO2 remains in the intestine, causing symptoms of abdominal bloating. The SCFAs generate an osmotic gradient and, in doing so, absorb water into the intestinal lumen, causing symptoms of diarrhea in IBS.

[0013] As a result, there is a significant unmet medical need for more effective treatment of IBS direct jejunal suction measurements and diagnosis of SIBO does not include evaluation of bacterial overgrowth in other less accessible parts of the distal small intestine, which may lead to false-negative results. Less invasive hydrogen breath tests can provide additional information on the extent of SIBO. Although prebiotic and probiotic therapies aimed at restoring natural GI flora have been used empirically by IBS patients for many years, eradication of bacterial overgrowth with antibiotics has not been shown to alleviate IBS symptoms. Broad-spectrum antibiotics, including tetracycline, amoxicillin / clavulanate, metronidazole, and various fluoroquinolones, have been used to reduce bacterial overgrowth and treat IBS. However, these compounds often have systemic side effects. In addition, they may also contribute to the general resistance of bacterial species / strains to antibiotics, especially if used frequently.

[0014] As a result, there is a significant unmet medical need for more effective, locally localized treatments for SIBO and / or IBS.

[0015] Cholera is an acute diarrheal infection caused by ingestion of food or water contaminated with the bacterium Vibrio cholerae. Cholera remains a global threat to public health, especially in third or developing world countries. Researchers estimate that there are approximately 1.3 million to 4 million cases annually, with 21 000 to 143 000 deaths worldwide (M. Ali et al. Updated Burden of Cholera in Endemic Countries. Negl. Trop. Dis 2015, 9(6)). Cholera is endemic or epidemic.

[0016] Cholera is transmitted by the fecal-oral route. The causative organism is acid-sensitive and mostly dies in the stomach, but surviving organisms attach to and colonize the small intestine, where they secrete the potent cholera enterotoxin (CT, also called "choleragen"). Cholera is a highly virulent disease that causes severe acute watery diarrhea affecting both children and adults and can be fatal within hours if untreated.

[0017] Vaccines against cholera exist, but their protection against the cholera bacterium is limited to a few months (Cholera vaccines: WHO position paper-August 2017. Weekly epidemiological record. 92: 477-500. 25 August 2017). Thus, vaccines cannot completely prevent cholera outbreaks in endemic areas. Current treatment of cholera includes rapid rehydration (by mouth or intravenous administration) to replace fluids and electrolytes lost due to watery diarrhea. In addition, antibiotic treatment is recommended, especially for patients who are severely or moderately dehydrated and continue to produce large amounts of stool during rehydration treatment. The choice of antibiotic should be informed by local antibiotic susceptibility patterns. In most countries, doxycycline is recommended as first-line treatment for adults, and azithromycin is recommended as first-line treatment for children and pregnant women. Ampicillin, erythromycin, and fluoroquinolones have also been reported as effective antibiotics for the treatment of cholera. However, in recent years, several reports on multidrug-resistant strains of Vibrio cholerae have been published in the specialized scientific literature (Non-Patent Document 6: T. Shrestha et al. BMC Infectious Diseases (2015) 15:104; Non-Patent Document 7: J Health Popul. Nutr. (2007), 25(2):241-243; Non-Patent Document 8: M. Kitaoka et al. Journal of Medical Microbiology (2011), 60, 397-407).

[0018] Therefore, new antibiotic therapies against cholera are needed that could target the GI tract where Vibrio Cholerae colonizes the host, thus providing a localized maximum concentration of antibiotics where they must act, resulting in a more rapid eradication of the pathogen and a more rapid resolution of symptoms.

[0019] Currently, oral treatment for intestinal infections is + and Gram - Substances with antibacterial activity are used that must have certain properties such as broad spectrum activity against bacteria, resistance to highly acidic environments such as the stomach environment, anti-infective activity independent of the presence of intestinal biomass, adequate duration of intestinal retention, good permeability to infected host cells, and good tolerability (Non-Patent Document 9: Braga P C. Interaction of antibiotics on enteric microflora. In: Drugs in Gastroenterology. Raven Press, New York, 1991, pp. 509-517).

[0020] Treatment with antibacterial agents administered in oral formulations used today has at least two limitations: First, if not adequately protected, the antibacterial agent may lose its efficacy due to enzymatic or degradative inactivation that occurs during passage through the stomach.

[0021] Furthermore, currently available pharmaceutical forms allow the active ingredient to be administered in discrete doses, but release the active ingredient too quickly compared to the time it takes to pass through the digestive tract, allowing the active ingredient to exert its anti-infective effect indiscriminately along the entire gastrointestinal tract.

[0022] Furthermore, antibacterial agents used for disinfection of the digestive tract often do not have a high metabolic rate in order to keep unchanged the therapeutic potential associated with the administration of conventional forms containing antibacterial agents, but must not undergo the phenomenon of metabolic degeneration in order to avoid a weakening of the therapeutic effect associated with the presence of antibacterial agents.

[0023] Therefore, in such cases, a sustained, site-specific form of administration to the small intestine with carry-over to the large intestine, adhering to the passage of a bolus through the gastrointestinal tract, is needed to ensure true efficacy of anti-infective therapy in SIBO, IBS, or cholera.

[0024] Hepatic encephalopathy (HE) is a brain disorder that develops in some patients with liver disease. HE is a complex disease and includes a range of conditions that can range from a subclinical state with no outward signs or symptoms to a severe condition that can cause serious, life-threatening complications. Symptoms are related to progressive dysfunction of the brain and may include personality changes, intellectual disability, memory problems, and loss of consciousness (coma). HE can occur in individuals with acute or chronic liver (hepatic) disease or in individuals (without liver disease) whose liver is bypassed by a portosystemic shunt. Portosystemic shunts are abnormal passageways that allow blood from the gastrointestinal tract to bypass the liver. They may be present at birth (congenital) or acquired during life. HE is caused by toxins that are normally flushed from the body by the liver building up in the blood and eventually traveling to the brain. Many of the symptoms of hepatic encephalopathy are reversible if detected and treated promptly. The exact pathogenesis of HE is not fully understood. It has been theorized that neurotoxic substances, including ammonia and manganese, may gain entry into the brain in the setting of liver failure. In particular, ammonia is produced in the gastrointestinal tract by the breakdown of amines, amino acids, purines, and urea by the bacterial microbiota. Normally, the produced ammonia is detoxified in the liver by conversion to urea via the Krebs-Hensleit cycle. Ammonia is also consumed in the conversion of glutamate to glutamine, a reaction that depends on the activity of glutamine synthetase. Two factors contribute to the hyperammonemia seen in HE in patients with cirrhosis. First, the amount of functioning hepatocytes is reduced, providing less opportunity for ammonia to be detoxified by the above processes. Second, the portosystemic circulation may divert ammonia-containing blood away from the liver and into the systemic circulation.

[0025] Initial treatment may be aimed at identifying and eliminating the precipitating event, such as an infection, gastrointestinal bleeding, a particular drug, or renal dysfunction. Such therapy may include medications to treat the infection, medications or procedures to ease or stop bleeding, discontinuation of medications that may be causing the episode, and appropriate therapy for the kidney problem.

[0026] Hepatic encephalopathy is a chronic debilitating complication of cirrhosis. Another complication of cirrhosis is bacterial infection, which is more common in patients with cirrhosis than in the general population, and patients with decompensated cirrhosis are more susceptible to infection than those with compensated disease. Antibiotics are one course of treatment for such infections. In addition, antibiotic prophylaxis is necessary in cirrhotic patients with gastrointestinal bleeding.

[0027] Patients with IBD, especially ulcerative colitis (UC), who have failed available medical therapies or have developed serious, life-threatening complications, must undergo surgery to remove the colon and rectum (proctocolectomy) to resolve the disease. After a patient has a total proctocolectomy, a procedure called an ileal pouch-anal anastomosis (IPAA) is performed. In an IPAA, the ileum, the lowest part of the small intestine, is connected to the anus, creating a structure (pouch) that can store and expel stool. IPAA creates a reservoir of stool in the perineum where the rectum was, restoring the function of the anus by allowing stool to pass through under the patient's voluntary control. Pouchitis is inflammation (swelling) of the pouch that occurs when the pouch becomes irritated and inflamed. Inflammation can cause increased frequency of bowel movements, abdominal cramping or bloating, lower abdominal pain, or sometimes bloody stool. The cause of pouchitis is not entirely clear, but it almost always occurs in people with ulcerative colitis or other forms of colitis, and sometimes in people with familial adenomatous polyposis (FAP), a genetic (hereditary) condition that causes many polyps to form in the colon. Pouchitis is usually treated with a 14-day course of antibiotics. Acute pouchitis (an isolated episode of pouchitis) is generally treated with antibiotics such as metronidazole, rifaximin, or ciprofloxacin, often in conjunction with anti-inflammatory drugs.

[0028] Spontaneous bacterial peritonitis (SBP) is defined as an ascites infection without any obvious surgically treatable cause in the peritoneal cavity. In most cases, occurring in patients with cirrhosis and ascites, the presence of SBP is suspected due to suggestive signs and symptoms such as fever, abdominal pain, or altered mental status, although some patients are asymptomatic and are detected upon paracentesis after admission to the hospital for another reason. Patients suffering from SBP have a poor prognosis, with 1-year mortality ranging from 50% to 90%. SBP may be treated and prevented with antibiotics such as betalactamic antibiotics or quinolones.

[0029] It is now well established that gut microbiota and chronic liver disease are closely related. This association is most evident in the later stages of the disease: liver cirrhosis and liver dysfunction are associated with intestinal bacterial overgrowth, small intestinal motility disorders, increased intestinal permeability, and reduced immune defense, all of which promote bacterial translocation from the intestine to the systemic circulation, leading to infections and exacerbating liver dysfunction in a vicious cycle. Gut dysbiosis (i.e., alterations in the normal saprophytic gut microbiota) is involved in chronic metabolic disorders such as obesity, metabolic syndrome, diabetes, and cardiovascular disease. Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and evolves in the same context as these metabolic diseases. It is therefore not surprising that recent literature highlights the potential role of gut microbiota in the pathophysiology of NAFLD. Nonalcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease that represents an increasing prevalence of metabolic syndrome. Most patients with NAFLD exhibit non-progressive simple fatty liver, i.e. non-alcoholic fatty liver (NAFL). Non-alcoholic steatohepatitis (NASH) is a more severe form of NAFLD broadly defined by the presence of steatosis with inflammation and progressive fibrosis that ultimately leads to cirrhosis and hepatocellular carcinoma (HCC). A subset of NAFLD patients develops NASH through mechanisms that are not well understood. Increasing evidence suggests the existence of a correlation between gut microbiota, bacterial translocation, and NAFLD incidence. Alterations in gut microbiota caused by a high-fat diet may cause the exacerbation of NASH and associated HCC. The development of new therapies is necessary because current treatments for hepatic encephalopathy, cirrhosis, pouchitis, spontaneous bacterial peritonitis, NAFLD, NAFL, and NASH have several drawbacks (low or limited efficacy, complications or side effects outbreaks, recurrence). In particular, bacterial infections play a key role in the pathogenesis of these diseases, so there is a strong demand for new antibiotic treatments that are effective in eradicating infections and limiting systemic exposure to antibiotics.

[0030] US 8,263,120B2 describes controlled and / or programmed release oral pharmaceutical compositions containing at least one rifamycin SV or a pharma- ceutically acceptable salt thereof with antibacterial and / or anti-infective activity, such as rifamycin SV and / or metronidazole, for treating infections of the large intestine, particularly the colon, where a specific bactericidal action is required. In particular, the oral pharmaceutical composition of US 8,263,120B2 releases rifamycin SV or a pharma- ceutically acceptable salt thereof only in the colon, without altering the bacterial flora present in a part of the small intestine, thereby resulting in a local and limited anti-infective effect. [Prior art documents] [Patent documents]

[0031] [Patent Document 1] US 8,263,120B2 [Patent Document 2] WO0076478 [Non-patent literature]

[0032] [Non-Patent Document 1] Faller A, Scevola G. Anatomia e Fisiologia del Corpo Umano (Anatomy and Physiology of the Human Body). Vol I. Edizioni Minerva Medica, Turin, 1973, pp. 235-254 [Non-Patent Document 2] Braga P C. Enteric microflora and its regulation. In Drugs in Gastroenterology. Raven Press, New York, 1991, pp. 501-508 [Non-Patent Document 3] Garg A et al in The Journal of Pharmacology and Experimental Therapeutics, 359:91-101, October 2016

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[0033] Rifamycin SV is currently under development for the treatment of traveler's diarrhea (TD) and infectious colitis. Rifamycin SV or its pharmacologic acceptable salts are formulated in gastroprotective tablets to prevent exposure to the gastric environment, where the acidic pH may compromise the drug's integrity and reduce the antibiotic efficacy of the administered dose. Given that TD and infectious colitis are primarily localized in the last part of the gastrointestinal tract, especially in the colon, premature release of rifamycin SV or its pharmacologic acceptable salts is undesirable to avoid possible exposure to the metabolic effects of enzymes present in the small intestine or stomach, and dilution of the drug in the aqueous fluids of the small intestine should probably also be avoided. [Means for solving the problem]

[0034] The present invention relates to oral pharmaceutical compositions comprising rifamycin SV, or a pharma- ceutical acceptable salt thereof, which are formulated to obtain a sustained release profile of rifamycin SV, or a pharma- ceutical acceptable salt thereof. The sustained release profile of the compositions of the present invention shows release of rifamycin SV, or a pharma- ceutical acceptable salt thereof, beginning in the proximal portion of the intestine, i.e., the small intestine (duodenum, jejunum and ileum), and optionally continuing throughout the large intestine.

[0035] The oral pharmaceutical composition of the present invention is useful for the prevention and / or treatment of diseases or disorders such as cholera or small intestinal bacterial overgrowth (SIBO) and / or irritable bowel syndrome (IBS).

[0036] The oral pharmaceutical composition of the present invention is also useful for the prevention and / or treatment of diseases or disorders such as hepatic encephalopathy, liver cirrhosis, pouchitis, spontaneous bacterial peritonitis, NAFLD, NAFL and / or NASH.

[0037] In one aspect, an oral pharmaceutical composition is provided in the form of a solid dosage form comprising about 600 mg of rifamycin SV or a pharma- ceutical acceptable salt thereof, and one or more pharma- ceutical acceptable excipients, wherein the oral pharmaceutical composition is formulated for controlled release.

[0038] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein, wherein the oral pharmaceutical composition is formulated for sustained release.

[0039] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein, wherein the oral pharmaceutical composition is formulated for delayed release.

[0040] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein, wherein the oral pharmaceutical composition is formulated for delayed release and sustained release.

[0041] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein, wherein the oral pharmaceutical composition is formulated to release Rifamycin SV, or a pharma- ceutical acceptable salt thereof, substantially in the small intestine.

[0042] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein for use in the prevention and / or treatment of small intestinal bacterial overgrowth (SIBO).

[0043] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein for use in the prevention and / or treatment of irritable bowel syndrome (IBS).

[0044] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein for use in the prevention and / or treatment of diarrhea-predominant irritable bowel syndrome (IBS-D).

[0045] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein for use in the prevention and / or treatment of alternating diarrhea-predominant constipation-predominant irritable bowel syndrome (IBS-M).

[0046] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein for use in the prevention and / or treatment of cholera.

[0047] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein for use in the prevention and / or treatment of hepatic encephalopathy.

[0048] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein for use in the prevention and / or treatment of cirrhosis of the liver.

[0049] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein for use in the prevention and / or treatment of pouchitis.

[0050] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein for use in the prevention and / or treatment of spontaneous bacterial peritonitis.

[0051] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein for use in the prevention and / or treatment of NAFLD.

[0052] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein for use in the prevention and / or treatment of NAFL.

[0053] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein for use in the prevention and / or treatment of NASH.

[0054] In one aspect, there is provided a method of treating and / or preventing small intestinal bacterial overgrowth (SIBO) in a subject in need thereof, comprising administering to the subject an effective amount of any of the oral pharmaceutical compositions disclosed herein.

[0055] In one aspect, there is provided a method of treating and / or preventing irritable bowel syndrome (IBS) in a subject in need thereof, the method comprising administering to the subject an effective amount of any of the oral pharmaceutical compositions disclosed herein.

[0056] In one aspect, a method of treating and / or preventing irritable bowel syndrome (IBS) in a subject in need thereof, wherein the IBS is associated with diarrhea-predominant irritable bowel syndrome (IBS-D), is provided.

[0057] In one aspect, a method is provided for treating and / or preventing irritable bowel syndrome (IBS) in a subject in need thereof, wherein the IBS is associated with alternating diarrhea-predominant or constipation-predominant irritable bowel syndrome (IBS-M).

[0058] In one aspect, there is provided a method of treating and / or preventing cholera in a subject in need thereof, the method comprising administering to the subject an effective amount of any of the oral pharmaceutical compositions disclosed herein.

[0059] In one aspect, there is provided a method of treating and / or preventing hepatic encephalopathy in a subject in need thereof, the method comprising administering to the subject an effective amount of any of the oral pharmaceutical compositions disclosed herein.

[0060] In one aspect, there is provided a method of treating and / or preventing cirrhosis in a subject in need thereof, the method comprising administering to the subject an effective amount of any of the oral pharmaceutical compositions disclosed herein.

[0061] In one aspect, there is provided a method of treating and / or preventing pouchitis in a subject in need thereof, the method comprising administering to the subject an effective amount of any of the oral pharmaceutical compositions disclosed herein.

[0062] In one aspect, there is provided a method of treating and / or preventing spontaneous bacterial peritonitis in a subject in need thereof, the method comprising administering to the subject an effective amount of any of the oral pharmaceutical compositions disclosed herein.

[0063] In one aspect, a method for treating and / or preventing NAFLD in a subject in need thereof is provided, the method comprising administering to the subject an effective amount of any of the oral pharmaceutical compositions disclosed herein.

[0064] In one aspect, a method for treating and / or preventing NAFL in a subject in need thereof is provided, the method comprising administering to the subject an effective amount of any of the oral pharmaceutical compositions disclosed herein.

[0065] In one aspect, there is provided a method of treating and / or preventing NASH in a subject in need thereof, the method comprising administering to the subject an effective amount of any of the oral pharmaceutical compositions disclosed herein.

[0066] Unless otherwise defined, all technical terms, notations and other scientific terms used herein are intended to have the meaning commonly understood by those skilled in the art to which this disclosure pertains.In some cases, terms with commonly understood meanings are defined herein for clarity and / or ready reference.Therefore, the inclusion of such definitions herein should not be interpreted as representing a substantial difference to what is commonly understood in the art.

[0067] As used herein, the term "amphiphilic" refers to an affinity for lipids and an affinity for water.

[0068] As used herein, the terms "approximately" and "about" refer to the range of experimental error that may occur in a measurement, for example, an error of 10%, 5%, 2.5%, 2%, or 1%.

[0069] The term "bioequivalence" has the meaning defined in 21 CFR section 314.3 and refers to the absence of significant differences in the rate and extent to which a rifamycin becomes available at the site of drug action when administered under similar conditions at the same molar dose. Two products are considered bioequivalent if the 90% confidence interval of the relevant pharmacokinetic values ​​of a rifamycin observed in a subject when a particular composition is administered to the subject is within about 80% to about 125% of the values ​​observed for the reference product.

[0070] As used herein, the term "cholera" refers to the pathological condition known to those skilled in the art as being caused by infection with the microorganism Vibrio cholerae.

[0071] As used in this specification, the terms "comprising," "having," "including," and "containing" are used interchangeably and should be construed as open-ended terms (i.e., meaning "including but not limited to") and are deemed to provide support for terms such as "consist essentially of," "consisting essentially of," "consist of," or "consisting of."

[0072] As used herein, the terms "consist essentially of" and "consisting essentially of" can be used interchangeably and should be construed as semi-closed terms, meaning that they do not contain other ingredients that would materially affect the basic and novel characteristics of the invention (thus, they may include optional excipients).

[0073] As used herein, the terms "consists of" and "consisting of" can be used interchangeably and should be construed as closed terms.

[0074] The term "core" refers to a matrix, mixture, compressed blend or dispersion of rifamycin SV or a pharma- ceutical acceptable salt thereof, at least one lipophilic compound, at least one hydrophilic compound, and optionally at least one amphiphilic compound and optionally at least one physiologically acceptable excipient.

[0075] The term "delayed release," as used herein in reference to a dosage form, refers to a dosage form that releases drug at a time other than immediately after oral administration of the dosage form to a subject.

[0076] The term "extended release" as used herein with respect to a dosage form refers to a dosage form that is formulated to make a drug available over an extended period of time after oral administration of the dosage form to a subject.

[0077] The term "gastro-resistant coating" as used herein refers to a coating that allows a composition, such as a solid oral dosage form, such as a tablet, to pass through the gastric tract, such as the stomach, without damage, and then dissolves or erodes, or dissolves or erodes substantially or completely, when environmental conditions change, such as when the pH of the gastrointestinal tract changes, thereby releasing the rifamycin SV or a pharma- ceutically acceptable salt thereof, which constitutes the dosage form. The coating may be applied directly to the core.

[0078] As used herein, the term "hydrophilic" refers to an affinity for water.

[0079] The terms "IBS" and "irritable bowel syndrome" as used hereafter in this specification refer to conditions known to those skilled in the art as functional bowel disorders that can result in abdominal pain, abdominal bloating, and altered bowel function (diarrhea, constipation, or both). As used herein, "IBS" includes IBS-C (constipation-predominant), IBS-D (diarrhea-predominant), IBS-M (mixed), and IBS-U (unclassified).

[0080] As used herein, the term "large intestine" refers to the last part of the gastrointestinal tract or digestive system. The large intestine includes the cecum, colon, rectum, and anal canal.

[0081] The term "lipophilic" as used herein refers to an affinity for lipids and a poor affinity for aqueous fluids.

[0082] The term "matrix" as used herein refers to a macroscopically homogeneous structure, ideally when cut through all of its axes or all of its volumes. The term "homogeneous" does not require that the excipients in the core be homogeneously dispersed or homogeneously mixed, but is meant to describe the absence of distinct layers in the core structure.

[0083] As used herein, the term "mixture" refers to a composition formed or produced by mixing two or more substances where the substances are mixed together but not chemically combined into a new substance.

[0084] The term "modified release" as used herein with respect to dosage refers to a dosage form in which the time and / or location of drug release characteristics are selected to achieve a therapeutic or convenience objective not provided by conventional dosage forms such as solutions or immediate release dosage forms. Modified release solid oral dosage forms include both delayed release and sustained release drug products.

[0085] The term "pharmaceutical acceptable salt" as used herein refers to a salt that has the biological effectiveness and properties of the salified compound and does not produce adverse reactions when administered to a mammal, preferably a human. The pharmaceutical acceptable salt may be an inorganic salt or an organic salt. Examples of pharmaceutical acceptable salts include, but are not limited to, sodium, potassium, magnesium, carbonate, bicarbonate, chloride, bromide, sulfate, hydrogen sulfate, citrate, maleate, fumarate, trifluoroacetate, 2-naphthalenesulfonate, and para-toluenesulfonate. In one embodiment, the pharmaceutical acceptable salt is sodium. Further information regarding pharmaceutical acceptable salts can be found in Handbook of pharmaceutical salts, P. Stahl, C. Wermuth, WILEY-VCH, 127-133, 2008, which is incorporated herein by reference.

[0086] The term "physiologically acceptable excipient" as used herein refers to a substance that has no pharmacological effect of its own and does not cause adverse reactions when administered to a mammal, preferably a human. Physiologically acceptable excipients are well known in the art and are disclosed, for example, in Handbook of Pharmaceutical Excipients, sixth edition 2009, which is incorporated herein by reference.

[0087] The term "rifamycin B" as used herein refers to the compound having Chemical Abstracts No. 13929-35-6 and the chemical name 4-O-(carboxymethyl)rifamycin;[(1,2-dihydro-5,6,17,19,21-pentahydroxy-23-methoxy-2,4,12,16,18,20,22-heptamethyl-1,11-dioxo-2,7-(epoxypentadeca[1,11,13]trienimino)naphtho[2,1-b]furan-9-yl)oxy]acetic acid 21-acetate.

[0088] The term "rifamycin S" as used herein refers to the compound having Chemical Abstracts No. 13553-79-2 and the chemical name 5,17,19,21-tetrahydroxy-23-methoxy-2,4,12,16,18,20,22-heptamethyl-2,7-(epoxypentadeca[1,11,13]trienimino)naphtho[2,1-b]furan-1,6,9,11(2H)-tetraone 21-acetate.

[0089] As used herein, the terms "rifamycin SV" and "rifamycin" are interchangeable and refer to Chemical Abstracts No. 6998-60-3 and the chemical name (2S,12Z,14E,16S,17S,18R,19R,20R,21S,22R,23S,24E)-21-(acetyloxy)-6,9,17,19-tetrahydroxy-23-methoxy-2,4,12,16,18,20,22-heptamethyl-1,11-dioxo-1,2-dihydro-2,7-(epoxypentadeca[1 ,11,13]trienimino)naphtho[2,1-b]furan-5-ol, and (2S,12Z,14E,16S,17S,18R,19R,20R,21S,22R,23S,24E)-5,6,9,17,19-pentahydroxy-23-methoxy-2,4,12,16,18,20,22-heptamethyl-1,11-dioxo-1,2-dihydro-2,7-(epoxypentadeca[1,11,13]trienimino)naphtho[2,1-b]furan-21-yl acetate.

[0090] As used herein, the terms "rifamycin sodium," "rifamycin sodium salt," "sodium rifamycin," "rifamycin SV sodium," "rifamycin SV sodium salt," and "sodium rifamycin SV" are interchangeable and refer to the sodium salt of rifamycin SV having Chemical Abstracts No. 14897-39-3.

[0091] The expression "600 mg of rifamycin SV or a pharma- ceutically acceptable salt thereof" in this specification refers to 600 mg of rifamycin SV as a dry substance (anhydrous), or 600 mg of a pharma- ceutically acceptable salt of rifamycin SV as a dry substance, including, but not limited to, 600 mg of sodium salt of rifamycin SV, or an amount of pharma- ceutically acceptable salt of rifamycin SV equivalent to 600 mg of rifamycin SV as a dry substance (anhydrous). In one embodiment, 600 mg of sodium salt of rifamycin SV as a dry substance corresponds to 582 mg of rifamycin SV as a dry substance. In one embodiment, 600 mg of sodium salt of rifamycin SV corresponds to 582 mg of rifamycin SV and 18 mg of sodium ion.

[0092] As used herein, the terms "prevent," "prevention," and "preventing" refer to the reduction or inhibition of the risk of acquiring or developing a given condition, or the reduction or inhibition of the recurrence or said condition in a subject who is not ill but who is in close proximity or likely to be in close proximity to a person with a disease or disorder.

[0093] The terms "SIBO" and "small intestinal bacterial overgrowth" as used herein refer to a condition known to those skilled in the art as small intestinal bacterial overgrowth, which is a disturbance of normal GI flora. In SIBO, the concentration of bacterial organisms in the distal jejunum and ileum increases, disrupting the normal distribution of bacteria. In SIBO, the number and / or types of bacteria in the small intestine are increased. Over 10 per ml of proximal jejunal aspirate 5 Typically, bacterial counts of ≥ 10 CFU are observed. Under normal conditions, bacterial concentrations in the small intestine are 10 2 It is less than CFU.

[0094] As used herein, the term "small intestine" refers to the region of the gastrointestinal tract between the stomach and the large intestine and refers to the proximal portion of the intestine where most of the final absorption of food occurs. The small intestine has three distinct regions: the duodenum, the jejunum, and the ileum.

[0095] The terms "treat", "treatment" and "treating" as used herein refer to therapeutic treatment. For example, therapeutic treatment includes the reduction or amelioration of the progression, severity and / or duration of a disease or disorder-mediated condition, or the amelioration of one or more symptoms (particularly, one or more identifiable symptoms) of a disease or disorder-mediated condition resulting from the administration of one or more therapies (e.g., one or more therapeutic agents, such as the compositions of the present invention). In certain embodiments, therapeutic treatment includes the improvement of at least one measurable physical parameter of a disease or disorder-mediated condition. In other embodiments, therapeutic treatment includes the inhibition of the progression of a disease or disorder-mediated condition, either physically, e.g., by stabilization of an identifiable symptom, physiologically, e.g., by stabilization of a physical parameter, or both. In other embodiments, therapeutic treatment includes the reduction or stabilization of a disease or disorder-mediated symptom.

[0096] "C max,0-6 ": Maximum plasma concentration achieved in the selected interval (0-6 hours).

[0097] "C max,0-24 ": Maximum plasma concentration achieved in the selected interval (0-24 hours).

[0098] "t max,0-6 ":C max,0-6 Time to achieve it.

[0099] "t max,0-24 ":C max,0-24 Time to achieve it.

[0100] "λz": terminal elimination rate constant calculated after the first dose by log-linear regression using at least three points, if possible.

[0101] "t 1 / 2 ": Half-life calculated after first dose as ln2 / λz, where possible.

[0102] "AUC 0-6 ": Area under the concentration / time curve in the selected interval (0-6 h) calculated by the trapezoidal method.

[0103] "AUC 0-24 ": Area under the concentration / time curve for the selected interval (0-24 h) calculated by the trapezoidal method.

[0104] "AUC 0-∞ ": If possible, AUC 0-6 +C t / λ z (Ct is the last measurable drug concentration) as the area under the concentration-time curve calculated after the first dose and extrapolated to infinity.

[0105] "Cl t / F": Dose / AUC if possible 0-∞ as, total body clearance calculated after the first dose.

[0106] "Clr": Renal clearance calculated as Ae0-6 / AUC0-6 after the first dose.

[0107] "V z / F”: Dosage / λ, if possible z xAUC 0-∞ The apparent terminal volume of distribution was calculated after the first dose as

[0108] "C max,ss,12-18 ": Maximum plasma concentration achieved at steady state over a selected interval (12-18 hours).

[0109] "C min,ss,12-18 ": The minimum plasma concentration achieved at steady state over a selected interval (12-18 hours).

[0110] "AUC ss,12-18 ": Area under the concentration / time curve for the selected interval (12-18 h) at steady state, calculated by the trapezoidal method.

[0111] "AUC ss,0-24 ": Area under the concentration / time curve for the selected interval (0-24 h) at steady state, calculated by the trapezoidal method.

[0112] "t max,ss,12-18 ":C max,ss,12-18 Time to achieve it.

[0113] "C ave,12-18 ":AUC ss,12-18 Mean plasma concentrations over selected intervals (12-18 h) calculated as / τ, where τ is the dosing interval (6 h).

[0114] "PTF% 12-18 ":

[0115]

number

[0116] , the peak-trough fluctuations calculated over the selected interval (12-18 hours).

[0117] "Ae 0-24 ": the total amount of analyte excreted in urine during the selected interval (24 hours).

[0118] "%Ae 0-24 ":(Ae 0-24 Percentage of the amount of analyte excreted in the urine, calculated as (mg / dose x 3) x 100.

[0119] EC 50 Half maximal effective concentration: This refers to the concentration of test compound that elicits a response halfway between the baseline and maximum response.

[0120] I C 50 Half-maximal inhibitory concentration: This refers to the concentration of test compound that inhibits a response halfway between the baseline and maximum response. [Brief description of the drawings]

[0121] [Figure 1]1 shows the mean (±standard deviation (SD)) rifamycin SV concentration (ng / mL) versus time profiles for days 1 and 7 during study treatment of healthy subjects with test rifamycin SV 600 mg coated tablets according to the present invention as reported in the experimental section. 1: rifamycin SV concentration versus time on day 1 (●); 7: rifamycin SV concentration versus time on day 7 (□). [Diagram 2] Rifamycin SV stimulation of PXR transcriptional activity. In this test, rifamycin SV (closed squares) activity is compared to rifaximin (closed triangles) and rifampicin (closed circles), which were used as controls. Data were calculated from three independent experiments. [Diagram 3] Rifamycin SV inhibits NFkB activity (induced by TNFα). The test compares the activity of Rifamycin SV (closed square) with that of Rifaximin (closed triangle), an FDA approved drug for IBS-D. Data calculated from two independent experiments. [Figure 4A] Rifamycin SV (filled squares), rifaximin (filled triangles) or rifampicin (filled circles) inhibition of PMA-induced NFkB transcriptional activity in NFkB reporter cell lines is shown. [Figure 4B] Rifamycin SV (filled squares), rifaximin (filled triangles) or rifampicin (filled circles) inhibition of TNFα-induced NFkB transcriptional activity in NFkB reporter cell lines is shown. [Figure 4C] Rifamycin SV (filled squares), rifaximin (filled triangles) or rifampicin (filled circles) inhibition of LPS-induced NFkB transcriptional activity in NFkB reporter cell lines is shown. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0122] In one embodiment, an oral pharmaceutical composition in the form of a solid dosage form is provided, comprising about 600 mg of rifamycin SV, or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable excipients, the oral pharmaceutical composition being formulated for controlled release. In one embodiment, 600 mg of the sodium salt of rifamycin SV, as a dry substance, corresponds to 582 mg of rifamycin SV, as a dry substance.

[0123] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein, wherein the oral pharmaceutical composition is formulated for sustained release.

[0124] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein, wherein the oral pharmaceutical composition is formulated for delayed release.

[0125] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein, wherein the oral pharmaceutical composition is formulated for delayed release and sustained release.

[0126] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein, wherein the oral pharmaceutical composition is formulated to release Rifamycin SV, or a pharma- ceutical acceptable salt thereof, substantially in the small intestine.

[0127] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein formulated to release rifamycin SV, or a pharma- ceutical acceptable salt thereof, substantially after said solid dosage form has passed through the pylorus passage of the proximal intestine.

[0128] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein further comprising one or more lipophilic compounds, hydrophilic compounds, and amphiphilic compounds.

[0129] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein further comprising one or more lipophilic compounds.

[0130] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein, further comprising one or more hydrophilic compounds.

[0131] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein further comprising one or more amphiphilic compounds.

[0132] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein, further comprising one or more lipophilic compounds and one or more hydrophilic compounds.

[0133] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein further comprising one or more lipophilic compounds and one or more amphiphilic compounds.

[0134] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein further comprising one or more hydrophilic compounds and one or more amphiphilic compounds.

[0135] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein, further comprising a gastro-resistant coating.

[0136] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein, wherein rifamycin SV, or a pharma- ceutically acceptable salt thereof, is released from the solid dosage form when the solid dosage form is placed in an aqueous medium having a pH in the range of about pH 5 to about pH 7.5. In another aspect, there is provided any of the oral pharmaceutical compositions disclosed herein, wherein rifamycin SV, or a pharma- ceutically acceptable salt thereof, is released from the solid dosage form when the solid dosage form is placed in an aqueous medium having a pH in the range of about pH 5 to about pH 7, or about pH 5 to about pH 6.5, or about pH 5 to about pH 6.

[0137] In one aspect, any of the oral pharmaceutical compositions disclosed herein is provided, wherein the solid dosage form comprises a core and a gastro-resistant coating covering the core. In one aspect, the core is a matrix, mixture, compressed blend or dispersion of the components found in the core. In one aspect, the coating is applied directly to the core. In one embodiment, the core may also comprise one or more of microcrystalline cellulose, lactose (such as lactose monohydrate), colloidal silicon dioxide, povidone and / or copovidone, and microcrystalline cellulose.

[0138] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein, wherein administration of one or more of the solid dosage forms to a subject has a t of Rifamycin SV of about 9.50 hours in plasma of the subject. max,0-24 is shown.

[0139] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein, wherein three or more administrations of the solid dosage form to a subject result in a C of rifamycin SV of about 2.19±1.94 ng / mL in plasma of the subject. max,0-6 In one aspect, any of the oral pharmaceutical compositions disclosed herein is provided, wherein three or more administrations of the solid dosage form to a subject result in a C of rifamycin SV of greater than about 2.19 ng / mL in plasma of the subject. max,0-6 is shown.

[0140] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein, wherein three or more administrations of the solid dosage form to a subject result in a C of rifamycin SV of about 5.79±4.24 ng / mL in plasma of the subject. max,0-24 In one aspect, any of the oral pharmaceutical compositions disclosed herein is provided, wherein three or more administrations of the solid dosage form to a subject result in a C of rifamycin SV of greater than about 5.79 ng / mL in plasma of the subject. max,0-24 is shown.

[0141] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein, wherein three or more administrations of the solid dosage form to a subject provide an AUC of rifamycin SV of about 3.26±2.85 (ng)(h) / mL in plasma of the subject. 0-6 In one aspect, any of the oral pharmaceutical compositions disclosed herein is provided, wherein three or more administrations of the solid dosage form to a subject result in an AUC of rifamycin SV of greater than about 3.26 (ng)(h) / mL in plasma of the subject. 0-6 is shown.

[0142] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein, wherein three or more administrations of the solid dosage form to the subject result in an AUC of rifamycin SV of about 43.67±20.15 (ng)(h) / mL in plasma of the subject. 0-24 In one aspect, any of the oral pharmaceutical compositions disclosed herein is provided, wherein three or more administrations of the solid dosage form to a subject result in an AUC of rifamycin SV of greater than about 43.67 (ng)(h) / mL in plasma of the subject. 0-24 is shown.

[0143] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein, wherein administration of the oral pharmaceutical composition to a subject results in an AUC and / or C of rifamycin SV in the plasma of the subject that is within about 80% to 125% of the values ​​disclosed herein. max is shown.

[0144] In one aspect, an oral pharmaceutical composition is provided that is bioequivalent to any of the oral pharmaceutical compositions disclosed herein.

[0145] In one aspect, any of the oral pharmaceutical compositions disclosed herein is provided, wherein the urinary excretion rate of rifamycin SV in a subject to which the oral pharmaceutical composition is administered is about 1% or less of the total amount of rifamycin SV, or a pharma- ceutical acceptable salt thereof, administered to the subject.

[0146] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein, wherein the pharmaceutical composition has a solubility in water of at least 2 hours, USP <711> and when placed in a USP dissolution apparatus II conforming to the USP 1.0, the pharmaceutical composition releases about 10% or less of the amount of rifamycin SV, or a pharma- ceutical acceptable salt thereof, that constitutes the pharmaceutical composition, and the dissolution apparatus is operated at pH 1 and 37±0.5. o In another aspect, there is provided any of the oral pharmaceutical compositions disclosed herein, wherein the pharmaceutical composition is administered at a temperature of 1000° C. for 2 hours at 37° C. and 1000 mL of an aqueous solution comprising 0.1 M hydrochloric acid and 0.4% macrogol cetostearyl ether, the aqueous solution being stirred at a speed of 50 rpm. <711> and when placed in a USP dissolution apparatus II conforming to the USP 1.0, the pharmaceutical composition releases about 5% or less, about 2.5% or less, about 2% or less, or about 1% or less of the amount of rifamycin SV or a pharma- ceutical acceptable salt thereof that constitutes the pharmaceutical composition, and the dissolution apparatus is operated at pH 1 and 37±0.5. o At a temperature of 0.5° C., 1000 mL of an aqueous solution containing 0.1 M hydrochloric acid and 0.4% macrogol cetostearyl ether is stirred at a speed of 50 rpm.

[0147] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein, wherein the pharmaceutical composition has a solubility in water of at least 100 mL per hour, <711> and when placed in a USP dissolution apparatus II conforming to the USP 1999 / 1010226, the pharmaceutical composition releases about 20% or less of the amount of rifamycin SV, or a pharma- ceutical acceptable salt thereof, that constitutes said pharmaceutical composition, and the dissolution apparatus is operated at pH 6.4 and 37±0.5. o C, 900 mL of an aqueous buffer solution, said aqueous solution being stirred at a speed of 100 rpm. In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein, wherein the pharmaceutical composition is administered at 100° C. for 1 hour at a temperature of 100° C. <711> and when placed in a USP dissolution apparatus II conforming to USP 6.4, the pharmaceutical composition releases about 15% or less, about 10% or less, about 5% or less, about 2.5% or less, about 2% or less, or about 1% or less of the amount of rifamycin SV, or a pharma- ceutical acceptable salt thereof, that constitutes the pharmaceutical composition, and the dissolution apparatus is operated at pH 6.4 and 37±0.5. oC., containing 900 mL of aqueous buffer, and the aqueous solution is stirred at a speed of 100 rpm.

[0148] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein, wherein the pharmaceutical composition has a solubility in water of at least 3 hours, USP <711> and when placed in a USP dissolution apparatus II conforming to the USP 1999 / 100226 standard, the pharmaceutical composition releases about 20% to about 60% of the amount of rifamycin SV, or a pharma- ceutical acceptable salt thereof, constituting the pharmaceutical composition, and the dissolution apparatus is operated at pH 6.4 and 37±0.5. o C., containing 900 mL of an aqueous buffer solution, and the aqueous solution is stirred at a speed of 100 rpm.

[0149] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein, wherein the pharmaceutical composition has a solubility in water of at least 6 hours, USP <711> and when placed in a USP dissolution apparatus II conforming to the USP 1999 / 1010226, the pharmaceutical composition releases about 50% or more of the amount of rifamycin SV, or a pharma- ceutical acceptable salt thereof, constituting said pharmaceutical composition, and the dissolution apparatus is ... conforming to the USP 1999 / 1010226, the pharmaceutical composition releases about 50% or more of the amount of rifamycin SV, or a pharma- ceutical acceptable salt thereof, o In another aspect, there is provided any of the oral pharmaceutical compositions disclosed herein, wherein the pharmaceutical composition is incubated at 37° C. for 6 hours at 37° C. with 500 mL of aqueous buffer, and the aqueous solution is stirred at a speed of 100 rpm. <711> and when placed in a USP dissolution apparatus II conforming to USP 6.4, the pharmaceutical composition releases about 60% or more, about 70% or more, about 75% or more, about 80% or more, about 85% or more, about 90% or more, or about 95% or more of the amount of rifamycin SV, or a pharma- ceutical acceptable salt thereof, that constitutes the pharmaceutical composition, and the dissolution apparatus is at pH 6.4 and 37±0.5. o C., containing 900 mL of aqueous buffer, and the aqueous solution is stirred at a speed of 100 rpm.

[0150] In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided, wherein the pharmaceutical composition contains about 2% or less by weight of Rifamycin S. In other aspects, any of the oral pharmaceutical compositions disclosed herein are provided, wherein the composition contains about 1.5% or less by weight, about 1.25% or less by weight, about 1% or less by weight, about 0.75% or less by weight, about 0.5% or less by weight, about 0.25% or less by weight, about 0.2% or less by weight, about 0.1% or less by weight, or about 0.05% or less by weight of Rifamycin S.

[0151] In one aspect, any of the oral pharmaceutical compositions disclosed herein is provided, wherein the pharmaceutical composition contains about 1% or less by weight of rifamycin B. In other aspects, any of the oral pharmaceutical compositions disclosed herein is provided, wherein the pharmaceutical composition contains about 0.75% or less by weight, about 0.5% or less by weight, about 0.25% or less by weight, about 0.2% or less by weight, about 0.15% or less by weight, or about 0.1% or less by weight of rifamycin B.

[0152] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein, wherein the pharmaceutical composition contains 10,000 ppm or less of ethanol. In another aspect, there is provided any of the oral pharmaceutical compositions disclosed herein, wherein the pharmaceutical composition contains 7,500 ppm or less, 7,000 ppm or less, 6,000 ppm or less, 5,500 ppm or less, 5,000 ppm or less, or 4,500 ppm or less of ethanol.

[0153] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein, wherein the solid dosage form is administered for 3 months, 25 o C and 60% relative humidity. In another aspect, any of the oral pharmaceutical compositions disclosed herein is provided, wherein the solid dosage form contains less than about 2% by weight of rifamycin S after storage at C and 60% relative humidity. o After storage in a solid dosage form at C and 60% relative humidity, the solid dosage form contains less than about 1%, less than about 0.75%, less than about 0.5%, less than about 0.25%, or less than about 0.1% Rifamycin S by weight.

[0154] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein, wherein the solid dosage form is administered for 1 month, for 40 o C and 75% relative humidity. In another aspect, any of the oral pharmaceutical compositions disclosed herein is provided, wherein the solid dosage form contains less than about 2% by weight of rifamycin S after storage at C and 75% relative humidity. o After storage in a solid dosage form at C and 75% relative humidity, the solid dosage form contains less than about 1.75% by weight, less than about 1.5% by weight, less than about 1.25% by weight, less than about 1% by weight, less than about 0.75% by weight, less than about 0.5% by weight, less than about 0.25% by weight, or less than about 0.1% by weight of Rifamycin S.

[0155] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein, wherein the solid dosage form is administered for 1 month, for 40 o C and 75% relative humidity. In another aspect, any of the oral pharmaceutical compositions disclosed herein is provided, wherein the solid dosage form contains less than 1% by weight of rifamycin B after storage at 40° C. and 75% relative humidity. o After storage in a solid dosage form at C and 75% relative humidity, the solid dosage form contains less than about 0.75% by weight, less than about 0.5% by weight, less than about 0.25% by weight, or less than about 0.1% by weight rifamycin B.

[0156] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein, wherein the solid dosage form is administered for 1 month, 30 o C and 65% relative humidity. In another aspect, any of the oral pharmaceutical compositions disclosed herein is provided, wherein the solid dosage form contains less than 2% by weight of rifamycin S after storage at C and 65% relative humidity. o After storage in solid dosage form at C and 65% relative humidity, the composition contains less than about 1.75%, less than about 1.5%, less than about 1.25%, less than about 1%, less than about 0.75%, less than about 0.5%, less than about 0.25%, or less than about 0.1% by weight of Rifamycin S. All weight percentages of Rifamycin S above are measured with respect to the amount of Rifamycin SV (as labeled claim) present in the composition.

[0157] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein, wherein the solid dosage form is administered for 1 month, 30 o C and 65% relative humidity. In another aspect, any of the oral pharmaceutical compositions disclosed herein is provided, wherein the solid dosage form contains less than 1% by weight of rifamycin B after storage at 4° C. and 65% relative humidity. o After storage in a solid dosage form at C and 65% relative humidity, the solid dosage form contains less than about 0.75% by weight, less than about 0.5% by weight, less than about 0.25% by weight, or less than about 0.1% by weight rifamycin B.

[0158] In the above embodiments, the weight percent of rifamycin S and rifamycin B is expressed as the amount of rifamycin S and rifamycin B, respectively, divided by the amount of the labeled quality description of rifamycin SV in the composition. For example, a composition intended to contain 600 mg of sodium rifamycin SV would have a labeled quality description amount of 600 mg of sodium rifamycin SV. Such a labeled quality description amount of 600 mg of sodium rifamycin SV may or may not correspond to a labeled quality description amount of 582 mg of rifamycin SV.

[0159] In one aspect, any of the oral pharmaceutical compositions disclosed herein is provided, wherein the solid dosage form is contained in a package, and the package comprises a material for protecting the solid dosage form from heat and light. In one aspect, any of the oral pharmaceutical compositions disclosed herein is provided, wherein the package comprises aluminum. In one aspect, any of the oral pharmaceutical compositions disclosed herein is provided, wherein the package comprises an aluminum blister package.

[0160] In one aspect, any of the oral pharmaceutical compositions disclosed herein is provided, wherein the solid dosage form is in the form of a tablet. In one aspect, any of the oral pharmaceutical compositions disclosed herein is provided, wherein the tablet comprises a tablet core and a gastro-resistant coating covering the tablet core. In one aspect, any of the oral pharmaceutical compositions disclosed herein is provided, wherein the gastro-resistant coating comprises one or more of an acrylic acid polymer, an acrylic acid copolymer, a methacrylic acid polymer, and a methacrylic acid copolymer. In one aspect, any of the oral pharmaceutical compositions disclosed herein is provided, wherein the gastro-resistant coating is applied to the tablet core using a coating composition. In one aspect, any of the oral pharmaceutical compositions disclosed herein is provided, wherein the coating composition comprises one or more of an organic solvent and water. In one aspect, any of the oral pharmaceutical compositions disclosed herein is provided, wherein the organic solvent comprises one or more organic alcohols. In one aspect, any of the oral pharmaceutical compositions disclosed herein is provided, wherein the one or more organic alcohols are selected from one or more of ethanol and polyethylene glycol. In one aspect, any of the oral pharmaceutical compositions disclosed herein is provided, wherein the coating composition is substantially free of water. In an aspect, any of the oral pharmaceutical compositions disclosed herein is provided, wherein the coating composition is substantially free of ethanol.

[0161] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein for use in preventing and / or treating the occurrence / recurrence of small intestinal bacterial overgrowth (SIBO).

[0162] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein for use in preventing and / or treating the occurrence / recurrence of irritable bowel syndrome (IBS).

[0163] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein for use in preventing and / or treating the occurrence / recurrence of diarrhea-predominant irritable bowel syndrome (IBS-D).

[0164] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein for use in preventing and / or treating the onset / recurrence of irritable bowel syndrome with alternating diarrhea-predominant constipation (IBS-M).

[0165] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein for use in the prevention and / or treatment of cholera outbreaks / recurrences.

[0166] In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided for use in preventing and / or treating the occurrence / recurrence of hepatic encephalopathy.In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided for use in reducing the risk of overt hepatic encephalopathy (HE) recurrence and / or reducing the risk of breakthrough overt HE recurrence.

[0167] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein for use in preventing and / or treating the development / recurrence of cirrhosis.

[0168] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein for use in preventing and / or treating the occurrence / recurrence of pouchitis.

[0169] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein for use in preventing and / or treating the occurrence / recurrence of spontaneous bacterial peritonitis.

[0170] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein for use in preventing and / or treating the occurrence / recurrence of NAFLD.

[0171] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein for use in preventing and / or treating the occurrence / recurrence of NAFL.

[0172] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein for use in preventing and / or treating the occurrence / recurrence of NASH.

[0173] In one embodiment, any of the oral pharmaceutical compositions disclosed herein is provided, wherein the oral pharmaceutical composition is administered to a subject in a daily dose of about 600 mg, about 1200 mg, or about 1800 mg of a pharma- ceutically acceptable salt of rifamycin SV. In one embodiment, any of the oral pharmaceutical compositions disclosed herein is provided, wherein the oral pharmaceutical composition comprises a sodium salt of rifamycin SV, and is administered to a subject in a daily dose equivalent to about 582 mg, about 1164 mg, or about 1746 mg of rifamycin SV.

[0174] In one aspect, any of the oral pharmaceutical compositions disclosed herein is provided, wherein the composition is administered to a subject one, two or three times daily.

[0175] In one aspect, a method of treating and / or preventing small intestinal bacterial overgrowth (SIBO) in a subject in need thereof is provided, comprising administering to the subject an effective amount of any of the oral pharmaceutical compositions disclosed herein.

[0176] In one aspect, a method for treating and / or preventing irritable bowel syndrome (IBS) in a subject in need thereof is provided, comprising administering to the subject an effective amount of any of the oral pharmaceutical compositions disclosed herein.In one aspect, a method for treating is provided in which the IBS is associated with diarrhea-predominant irritable bowel syndrome (IBS-D).In one aspect, a method for treating is provided in which the IBS is associated with alternating diarrhea-predominant or constipation-predominant irritable bowel syndrome (IBS-M).

[0177] In one aspect, a method of treating cholera in a subject in need thereof is provided, comprising administering to the subject an effective amount of any of the oral pharmaceutical compositions disclosed herein.

[0178] In one aspect, a method for the treatment and / or prevention of hepatic encephalopathy in a subject in need thereof is provided, comprising administering to the subject an effective amount of any of the oral pharmaceutical compositions disclosed herein.In one aspect, a method for reducing the risk of overt hepatic encephalopathy (HE) recurrence in a subject in need thereof and / or reducing the risk of sudden overt HE recurrence in a subject in need thereof is provided, comprising administering to the subject an effective amount of any of the oral pharmaceutical compositions disclosed herein.

[0179] In one aspect, a method of treating and / or preventing cirrhosis in a subject in need thereof is provided, comprising administering to the subject an effective amount of any of the oral pharmaceutical compositions disclosed herein.

[0180] In one aspect, a method of treating and / or preventing pouchitis in a subject in need thereof is provided, comprising administering to the subject an effective amount of any of the oral pharmaceutical compositions disclosed herein.

[0181] In one aspect, a method of treating and / or preventing spontaneous bacterial peritonitis in a subject in need thereof is provided, comprising administering to the subject an effective amount of any of the oral pharmaceutical compositions disclosed herein.

[0182] In one aspect, a method for the treatment and / or prevention of NAFLD in a subject in need thereof is provided, comprising administering to the subject an effective amount of any of the oral pharmaceutical compositions disclosed herein.

[0183] In one aspect, a method for the treatment and / or prevention of NAFL in a subject in need thereof is provided, comprising administering to the subject an effective amount of any of the oral pharmaceutical compositions disclosed herein.

[0184] In one aspect, a method of treating and / or preventing NASH in a subject in need thereof is provided, comprising administering to the subject an effective amount of any of the oral pharmaceutical compositions disclosed herein.

[0185] In one embodiment, any of the methods of treatment disclosed herein is provided, wherein an oral pharmaceutical composition is administered to a subject in a daily dose of 600 mg, 1200 mg, or 1800 mg of a pharma- ceutically acceptable salt of rifamycin SV. In one embodiment, any of the oral pharmaceutical compositions disclosed herein is provided, wherein the oral pharmaceutical composition comprises a sodium salt of rifamycin SV and is administered to a subject in a daily dose equivalent to about 582 mg, about 1164 mg, or about 1746 mg of rifamycin SV.

[0186] In one aspect, there is provided any of the methods of treatment disclosed herein, wherein an oral pharmaceutical composition is administered to a subject one, two, three or more times daily.

[0187] In one aspect, there is provided any method of treatment disclosed herein comprising administering to a subject any of the oral pharmaceutical compositions disclosed herein, wherein the oral pharmaceutical composition is administered to the subject three times daily for one or more days. In other aspects, there is provided any method of treatment disclosed herein comprising administering to a subject any of the oral pharmaceutical compositions disclosed herein, wherein the oral pharmaceutical composition is administered to the subject three times a day for 1 or more days, or 2 or more days, or 3 or more days, or 4 or more days, or 5 or more days, or 6 or more days, or 7 or more days, or 8 or more days, or 9 or more days, 10 or more days, or 11 or more days, or 12 or more days, or 13 or more days, 14 or more days, or 15 or more days, or 16 or more days, or 17 or more days, or 18 or more days, or 19 or more days, or 20 or more days, or 21 or more days, or 22 or more days, or 23 or more days, or 24 or more days, or 25 or more days, or 26 or more days, or 27 or more days, or 28 or more days, or 29 or more days, or 30 or more days.

[0188] In one aspect, any method of treatment disclosed herein is provided, comprising administering any of the oral pharmaceutical compositions disclosed herein to a subject, wherein the oral pharmaceutical composition is administered to the subject three times a day for one day.In another aspect, any method of treatment disclosed herein is provided, comprising administering any of the oral pharmaceutical compositions disclosed herein to a subject, wherein the oral pharmaceutical composition is administered to the subject three times a day for 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days.

[0189] In one embodiment, a method of treating a subject with IBS-D is provided, comprising administering to the subject an effective amount of any of the oral pharmaceutical compositions disclosed herein, wherein after administration of the oral pharmaceutical composition to the subject, the subject experiences an improvement in the Bristol Stool Form Scale. In another embodiment, after administration of an effective amount of any of the oral pharmaceutical compositions disclosed herein, the subject experiences a 20% or more, 25% or more, 30% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more reduction in the number of days per week the subject experiences stools that score 6 or 7 on the Bristol Stool Form Scale.

[0190] In one aspect, any of the oral pharmaceutical compositions disclosed herein is provided, wherein the rifamycin SV, or a pharma- ceutically acceptable salt thereof, is rifamycin sodium.

[0191] In one aspect, there is provided any of the uses or methods disclosed herein, wherein the rifamycin SV, or a pharma- ceutically acceptable salt thereof, is rifamycin sodium.

[0192] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein comprising rifamycin SV, or a pharma- ceutically acceptable salt thereof, preferably the sodium salt thereof, formulated to obtain a sustained release profile of rifamycin SV, or a pharma- ceutically acceptable salt thereof.

[0193] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein comprising rifamycin SV, or a pharma- ceutically acceptable salt thereof, preferably the sodium salt thereof, which releases rifamycin SV, or a pharma- ceutically acceptable salt thereof, in the small intestine (duodenum, jejunum, and ileum).

[0194] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein comprising rifamycin SV, or a pharma- ceutically acceptable salt thereof, preferably the sodium salt thereof, which begins release in the small intestine (duodenum, jejunum and ileum) and may continue into the large intestine.

[0195] In one embodiment, rifamycin SV or a pharma- ceutically acceptable salt thereof is released from the composition of the invention starting after dissolution and / or destruction of the gastro-resistant coating in the proximal part of the intestine, i.e., at the beginning of the small intestine. In one embodiment of the invention, rifamycin SV or a pharma- ceutically acceptable salt thereof is released from the composition of the invention only after passage through the pylorus in the proximal part of the intestine, i.e., in the small intestine, starting with dissolution and / or destruction of the gastro-resistant coating. In one embodiment of the invention, rifamycin SV or a pharma- ceutically acceptable salt thereof is released from the composition of the invention when the composition is exposed to a medium having a pH of about 5 to about pH 7.5, preferably about pH 5.5 to about pH 7.0, more preferably about pH 6.0 to about pH 6.5. In a preferred embodiment, rifamycin SV or a pharma- ceutically acceptable salt thereof is released from the composition of the invention when the composition is exposed to a medium having a pH of about 6.4. In one embodiment of the invention, rifamycin SV or a pharma- ceutically acceptable salt thereof is released from the compositions of the invention in an amount greater than 80% over a time period of about 3 to about 12 hours, preferably over a time period of 4 to 11 hours, more preferably over a time period of about 5 to about 10 hours, and even more preferably over a time period of about 5 to about 9 hours. In a preferred embodiment, rifamycin SV or a pharma- ceutically acceptable salt thereof is released from the compositions of the invention in an amount greater than 80% over a time period of about 6 hours. In one embodiment of the invention, rifamycin SV or a pharma- ceutically acceptable salt thereof is released from the compositions of the invention in an amount greater than 80% over a time period of about 3 to about 12 hours when exposed to a medium having a pH of about 5 to about pH 7.5.

[0196] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein, wherein Rifamycin SV, or a pharma- ceutically acceptable salt thereof, is released from the composition of the invention beginning in the small intestine, and optionally continuing to the large intestine.

[0197] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein comprising rifamycin SV, or a pharma- ceutically acceptable salt thereof, preferably the sodium salt thereof, which starts releasing rifamycin SV, or a pharma- ceutically acceptable salt thereof, only after passing through the pylorus, in the proximal part of the intestine, after dissolution and / or destruction of the gastro-resistant coating.

[0198] In one aspect, there is provided any of the oral pharmaceutical compositions disclosed herein comprising rifamycin SV, or a pharma- ceutically acceptable salt thereof, preferably a sodium salt thereof, wherein the rifamycin SV, or a pharma- ceutically acceptable salt thereof, is released when the composition is exposed to a medium having a pH of about 5 to about pH 7.5, preferably about pH 5.5 to about pH 7.0, and more preferably about pH 6.0 to about pH 6.5.

[0199] In one aspect, any of the oral pharmaceutical compositions disclosed herein is provided, which begin to release rifamycin SV, or a pharma- ceutically acceptable salt thereof, from the composition when the composition is exposed to a medium having a pH of about 5.5. In another embodiment, the pharmaceutical composition disclosed herein begins to release rifamycin SV, or a pharma- ceutically acceptable salt thereof, from the composition when the composition is exposed to a medium having a pH of about 6.0. In another embodiment, the pharmaceutical composition disclosed herein begins to release rifamycin SV, or a pharma- ceutically acceptable salt thereof, from the composition when the composition is exposed to a medium having a pH of about 6.4.

[0200] The present invention relates to an oral pharmaceutical composition comprising rifamycin SV, or a pharma- ceutical acceptable salt thereof, preferably the sodium salt thereof, which starts releasing rifamycin SV, or a pharma- ceutical acceptable salt thereof, about 3 hours after administration of the composition and may continue for up to 12 hours, preferably about 3 hours and continues for up to 9 hours.

[0201] Suitable salts of Rifamycin SV according to the present invention may be selected from the sodium or potassium, preferably the sodium salt.

[0202] The oral pharmaceutical composition of the present invention is useful for preventing and / or treating cholera and / or SIBO and / or IBS. In particular, the oral pharmaceutical composition of the present invention is useful for preventing and / or treating IBS-C, IBS-D, IBS-M and / or IBS-U. Preferably, the composition of the present invention is useful for preventing and / or treating IBS-D.

[0203] The oral pharmaceutical composition of the present invention is also useful for the prevention and / or treatment of diseases or disorders such as hepatic encephalopathy, liver cirrhosis, pouchitis, spontaneous bacterial peritonitis, NAFLD, NAFL and / or NASH.

[0204] In one embodiment, the oral pharmaceutical composition according to the invention comprises rifamycin SV or a pharma- ceutical acceptable salt thereof, at least one lipophilic compound, at least one hydrophilic compound, optionally at least one amphiphilic compound and optionally a gastro-resistant coating.

[0205] The dosage of rifamycin SV or a pharma- ceutically acceptable salt thereof in the oral pharmaceutical composition of the present invention, i.e., rifamycin SV or a pharma- ceutically acceptable salt thereof, may be about 400 mg / dose unit to about 2400 mg / dose unit, about 400 mg / dose unit to about 2000 mg / dose unit, about 400 mg / dose unit to about 1500 mg / dose unit, about 400 mg / dose unit to about 1000 mg / dose unit, about 400 mg / dose unit to about 800 mg / dose unit, about 500 mg / dose unit to about 700 mg / dose unit, or about 550 mg / dose unit to about 650 mg / dose unit, preferably about 600 mg of rifamycin SV or a pharma- ceutically acceptable salt thereof in anhydrous form (dry). More preferably, the dosage of rifamycin SV or a pharma- ceutically acceptable salt thereof in the oral pharmaceutical composition of the present invention may be about 600 mg / dose unit of rifamycin SV sodium salt in anhydrous form (dry). All of the above dosage amounts are intended to be in anhydrous form (dry basis).

[0206] In one embodiment, when the oral pharmaceutical composition comprises a sodium salt of rifamycin SV (as a dry substance), the equivalent amount of rifamycin SV (as a dry substance) in the pharmaceutical composition is from about 388 mg / dose unit to about 2328 mg / dose unit, from about 388 mg / dose unit to about 1940 mg / dose unit, from about 388 mg / dose unit to about 1455 mg / dose unit, from about 388 mg / dose unit to about 960 mg / dose unit, from about 388 mg / dose unit to about 776 mg / dose unit, from about 485 mg / dose unit to about 679 mg / dose unit, or from about 533.5 mg / dose unit to about 630.5 mg / dose unit, preferably about 582 mg of rifamycin SV in anhydrous form (dry). More preferably, the dosage of rifamycin SV or a pharma- ceutically acceptable salt thereof in the oral pharmaceutical composition of the present invention is about 600 mg / dose unit of rifamycin SV sodium salt in anhydrous form (dry), which is equivalent to 582 mg / dose unit of rifamycin SV in anhydrous form (dry).All of the above dosages are intended to be in anhydrous form (dry basis).

[0207] In one embodiment, the pharmaceutical composition of the present invention is administered in anhydrous form (dried) in a daily amount ranging from about 600 mg to about 2400 mg, about 600 mg to about 1800 mg, about 600 mg to about 1200 mg, about 800 mg to about 2400 mg, about 600 mg to about 2400 mg, 1200 mg to about 2400 mg, or about 1200 mg to about 1800 mg. In one embodiment, the pharmaceutical composition of the present invention is administered in anhydrous form (dried) in a daily amount ranging from about 600 mg, about 1200 mg, or about 1800 mg.

[0208] In one embodiment, when an oral pharmaceutical composition comprises a sodium salt of rifamycin SV, the equivalent amount of rifamycin SV as a dry substance in the pharmaceutical composition administered in a daily dose ranges from about 582 mg to about 2328 mg, about 582 mg to about 1746 mg, about 582 mg to about 1146 mg, about 776 mg to about 2328 mg, about 1164 mg to about 2328 mg, or about 1164 mg to about 1746 mg in anhydrous form (dried). In one embodiment, the equivalent amount of rifamycin SV as a dry substance in the pharmaceutical composition of the present invention, such pharmaceutical composition, is administered in a daily dose of about 582 mg or about 1164 mg or about 1746 mg in anhydrous form (dried).

[0209] The preferred dosage of rifamycin SV or a pharma- ceutically acceptable salt thereof in the oral pharmaceutical composition of the present invention, i.e. rifamycin SV or a pharma- ceutically acceptable salt thereof, is about 600 mg / dose unit in anhydrous form (dry) or, if it consists of 600 mg / dose unit of sodium salt of rifamycin SV in anhydrous form (dry), is equivalent to 582 mg / dose unit of rifamycin SV in anhydrous form (dry). It is known that the water content of rifamycin SV or a salt thereof is generally about 12-17%. Therefore, according to the present invention, it refers to rifamycin SV or a pharma- ceutically acceptable salt thereof in anhydrous form (dry). To obtain one of the dosages of rifamycin SV or a pharma- ceutical acceptable salt thereof in anhydrous form as described above, the weighted substance must be corrected by the water content.

[0210] According to one embodiment of the present invention, the weight ratio of the at least one lipophilic compound to the at least one hydrophilic compound is about 1:30 to about 1:90, preferably about 1:66 or about 1:67.

[0211] According to one embodiment of the present invention, the weight ratio of the at least one lipophilic compound to the at least one optional amphiphilic compound is from about 1:1 to about 6:1, preferably about 3:1.

[0212] According to one embodiment of the present invention, the weight ratio of the at least one arbitrary amphipathic compound to the at least one hydrophilic compound is about 1:10 to about 1:30, preferably about 1:20.

[0213] According to one embodiment of the present invention, the weight ratio of rifamycin SV or a pharma- ceutically acceptable salt thereof, preferably its sodium salt, to the at least one lipophilic compound is about 10:1 to about 30:1, preferably about 20:1.

[0214] According to one embodiment of the present invention, the weight ratio of rifamycin SV or a pharma- ceutically acceptable salt thereof, preferably its sodium salt, to the at least one hydrophilic compound is about 1:1 to about 6:1, preferably about 3:1.

[0215] According to one embodiment of the present invention, the weight ratio of rifamycin SV or a pharma- ceutically acceptable salt thereof, preferably its sodium salt, to at least one optional amphipathic compound is about 30:1 to about 90:1, preferably about 60:1.

[0216] According to an embodiment of the present invention, the at least one lipophilic compound may be selected from unsaturated or hydrogenated alcohols (such as cetyl alcohol, stearic alcohol, myristyl alcohol, lauryl alcohol, or oleyl alcohol) or fatty acids, their salts, esters (such as palmitic acid, stearic acid, myristic acid, lauric acid, lauric acid, oleic acid, etc.); fatty acid mono-, di-, or triglycerides such as stearin or their polyethoxylated derivatives; waxes such as beeswax or carnauba wax; ceramides; cholesterol derivatives or mixtures thereof. Stearic acid or one of its salts (such as magnesium stearate) is the preferred at least one lipophilic compound. In another embodiment, the lipophilic compound is an ester of a hydrogenated fatty alcohol. In one embodiment, the lipophilic compound is sodium stearyl fumarate. Optionally, the at least one lipophilic compound has a melting point lower than about 250°C, preferably between about 30 and about 200°C.

[0217] According to another embodiment, the at least one hydrophilic compound is represented by a generally crosslinked or linear polymeric or copolymeric substance known as hydrogel, i.e. a substance that undergoes the so-called "molecular relaxation" when going from a dry state to a hydrated state, i.e. a substance that undergoes a significant increase in mass and weight after a large number of water molecules are coordinated by the polar groups present in the polymer chain.In particular, the at least one hydrophilic compound can be selected from cellulose derivatives and their esters and / or salts, such as hydroxyalkylcelluloses (e.g. hydroxypropylcellulose, hydroxypropylmethylcellulose or sodium hydroxypropylmethylcellulose), alkylcelluloses, carboxyalkylcelluloses (such as sodium carboxymethylcellulose); polyvinyl alcohol; carboxyvinyl derivatives; polysaccharides, such as dextrin, pectin, starch and their derivatives; natural or synthetic gums; alginic acid; polyhydric alcohols, such as xylitol, maltitol, mannitol.Mannitol or sodium carboxymethylcellulose are the preferred at least one hydrophilic compound.More preferably, they are both included in the oral pharmaceutical composition of the present invention.For example, the at least one hydrophilic compound can include starch or sodium starch glycolate. In one embodiment, the at least one hydrophilic compound comprises starch. In one embodiment, the at least one hydrophilic compound comprises sodium starch glycolate.

[0218] According to one embodiment, the composition of the present invention further comprises at least one hygroscopic substance.The presence of at least one hygroscopic substance allows the moisture level of the composition itself to be controlled and / or modified, so as to ensure that Rifamycin SV or its pharma-ceutically acceptable salt is not damaged after storage and / or exposure to moisture.The at least one hygroscopic substance may be selected from mannitol, sorbitol, lactose, maltodextrin or mixtures thereof.Preferably, the at least one hygroscopic substance is mannitol.

[0219] As noted above, rifamycin SV or a salt thereof has a water content of about 12-17%, and therefore there is a further need to maintain or improve the stability of rifamycin SV, or a pharma- ceutically acceptable salt thereof, in the composition itself through contact with other auxiliary substances having a lower content of coordinating water.

[0220] Controlling the moisture content of the composition, in addition to contributing to maintaining or improving the stability profile of rifamycin SV or a salt thereof in the composition, also ensures more suitable compression properties in the case of tablets, producing an acceptable resistance profile to the mechanical stresses of industrial compression procedures.

[0221] The at least one amphiphilic compound that may optionally be used according to the invention includes polar lipids of type I or type II (lecithin, phosphatidylcholine, phosphatidylethanolamine), ceramides, glycol alkyl ethers such as diethylene glycol monomethyl ether (Transcutol®), natural or synthetic gums. Lecithin is the preferred at least one amphiphilic compound in the composition.

[0222] Oral pharmaceutical compositions according to the invention may also contain at least one physiologically acceptable excipient, for example a bioadhesive excipient such as chitosan, polyacrylamide, natural or synthetic gums, acrylic acid polymers and copolymers.

[0223] In any case, it should be noted that the compounds and / or excipients may behave differently in different environments.

[0224] The oral pharmaceutical composition according to the present invention may be prepared according to the more general tablet manufacturing process or method described in WO0076478, which is incorporated herein by reference.

[0225] According to one embodiment, the oral pharmaceutical composition of the present invention may be covered with a gastro-resistant coating (film) which may comprise polymethacrylate, polymers or copolymers of acrylic acid and / or methacrylic acid, or cellulose derivatives such as cellulose acetophthalate. According to a preferred embodiment, the gastro-protective coating comprises polymethacrylates, including but not limited to compounds commercially known as Eudragit S100 (methacrylic acid-methyl methacrylate copolymer) 1:2, Eudragit L100 (methacrylic acid-methyl methacrylate 1:1 copolymer) and / or Eudragit L30 D55 (methyl acrylic acid-ethyl acrylate 1:1 copolymer). According to a preferred embodiment, the gastro-protective coating comprises methacrylic acid-methyl methacrylate 1:1 copolymer (Eudragit L100). According to another preferred embodiment, the gastro-protective coating comprises methyl acrylic acid-ethyl acrylate 1:1 copolymer (Eudragit L30 D55). In one embodiment, the gastro-resistant coating (film) may further comprise one or more of talc, triethyl citrate, titanium dioxide, and one or more compounds that impart color to the oral pharmaceutical composition.

[0226] According to one embodiment, the solvent used for solubilizing the gastro-resistant coating can be organic, aqueous and / or a mixture thereof. The organic solvent can be selected from ethanol, isopropanol, acetone or a mixture thereof. Preferably, the organic solvent is ethanol.

[0227] Surprisingly, the aqueous solvent used to obtain the gastro-resistant coating of the present invention can ensure improved stability of rifamycin SV or its pharma- ceutically acceptable salt in pharmaceutical compositions and reduce the formation of impurities of rifamycin SV or its pharma- ceutical acceptable salt itself. This was found very surprisingly, considering the known reactivity of rifamycin SV or its salt to the presence of water, and such stabilization of rifamycin SV or its pharma- ceutical acceptable salt was not expected to be obtained with the composition of the present invention. In one embodiment, the aqueous gastro-resistant coating ensures that the total impurities are less than about 2.0% by weight after 24 months at 25°C and 60% relative humidity. In another embodiment, the aqueous gastro-resistant coating ensures that the total impurities are less than about 1.5% by weight after 24 months at 25°C / 60% RH.

[0228] In one embodiment, the aqueous gastro-resistant coating ensures that after 36 months at 25° C. and 60% relative humidity, the total impurities are less than about 3.0% by weight. In another embodiment, the aqueous gastro-resistant coating ensures that after 36 months at 25° C. and 60% relative humidity, the total impurities are less than about 2.5% by weight. In another embodiment, the aqueous gastro-resistant coating ensures that after 36 months at 25° C. and 60% relative humidity, the total impurities are less than about 2.0% by weight. The above weight percentages of total impurities are calculated relative to the amount of Rifamycin SV (as the labeled quality statement).

[0229] The gastro-resistant coating of the pharmaceutical composition of the present invention can modulate the onset of release of Rifamycin SV or a pharma- ceutical acceptable salt thereof from the pharmaceutical composition of the present invention disclosed above.

[0230] According to further embodiments, the gastroresistant coating may also optionally include at least one plasticizer, at least one dye, or a mixture thereof.

[0231] The oral pharmaceutical composition of the present invention may be selected from tablets, capsules, granules and / or microgranules, preferably tablets.

[0232] According to an embodiment of the present invention, the oral pharmaceutical composition is a tablet comprising a core and a gastroresistant coating. In another embodiment, the oral pharmaceutical composition is a tablet consisting essentially of a core and a gastroresistant coating. In another embodiment, the oral pharmaceutical composition is a tablet consisting essentially of a core and a gastroresistant coating. In one embodiment, the coating covers the core. In another embodiment, the coating is applied on or directly to the core.

[0233] In one embodiment, the core is a matrix comprising the components found in the cores described herein. In another embodiment, the core is a mixture comprising the components found in the cores described herein. In one embodiment, the core is a compressed blend comprising the components found in the cores described herein. In one embodiment, the core is a dispersion comprising the components found in the cores described herein.

[0234] In one embodiment, the core is a matrix of components comprising those components described herein. In another embodiment, the core is a mixture of components comprising those components described herein. In one embodiment, the core is a compressed blend of components comprising those components described herein. In one embodiment, the core is a dispersion of components comprising those components described herein.

[0235] According to one embodiment, the core may comprise rifamycin sodium SV, ascorbic acid, lecithin, stearic acid, sodium carboxymethylcellulose, mannitol, colloidal anhydrous silica and magnesium stearate. The gastroresistant coating may comprise poly(methacrylic acid-ethyl acrylate 1:1-Eudragit L30 D55) or poly(methacrylic acid-methyl methacrylate 1:1-Eudragit L100), one or more dyes (such as titanium dioxide and ferric oxide), talc, triethyl citrate and optionally PEG6000. The gastroresistant coating may be prepared in aqueous or alcoholic (organic) solution.

[0236] Therefore, one of the advantages of the oral pharmaceutical composition of the present invention is represented by its particular site specificity for the small intestine.Thanks to the particular composition of the present invention, rifamycin SV or its pharma-ceutical acceptable salt is actually released from the composition starting after dissolution and / or destruction of the gastro-resistant coating at the beginning of the proximal part of the intestine, maximizing the therapeutic effect of rifamycin SV or its pharma-ceutical acceptable salt in the part affected by SIBO and / or IBS and / or cholera.

[0237] Another advantage of the oral pharmaceutical composition according to the invention is represented by the possibility of obtaining an improved stabilization of Rifamycin SV or a pharma- ceutically acceptable salt thereof.

[0238] In another embodiment, an oral pharmaceutical composition of the present invention has a dissolution rate of less than about 10% over about 2 hours when measured at pH 1.

[0239] In one embodiment, an oral pharmaceutical composition of the present invention has a dissolution rate of less than about 20% over about 1 hour when measured at about pH 6.4.

[0240] In one embodiment, an oral pharmaceutical composition of the present invention has a dissolution rate of about 20% to about 60% over about 3 hours when measured at about pH 6.4.

[0241] In one embodiment, an oral pharmaceutical composition of the present invention has a dissolution rate of about 80% or greater of Rifamycin SV over a period of about 6 hours when measured at about pH 6.4.

[0242] According to the present invention, dissolution is measured using a USP dissolution apparatus type II equipped with paddles at 100 rpm at 37°±2°C.

[0243] In one embodiment, an oral pharmaceutical composition of the invention has a dissolution rate of less than about 20% in about 1 hour, about 20% to about 60% in about 3 hours, and about 80% or more in about 6 hours, when measured at about pH 6.4 in a USP dissolution apparatus Type II with paddles at 100 rpm at 37°±2° C.

[0244] In some embodiments, rifamycin SV or a pharma- ceutically acceptable salt thereof is released only in the small intestine, thus ensuring complete release of rifamycin SV or a salt thereof, preferably the sodium salt, when necessary to maximize treatment and efficacy.

[0245] In some other embodiments, rifamycin SV or a pharma- ceutically acceptable salt thereof is released beginning in the small intestine and continuing in the large intestine.

[0246] The oral pharmaceutical compositions of the present invention are particularly useful for preventing and / or treating SIBO and / or IBS as they downregulate bacterial overgrowth to normal growth levels.

[0247] The oral pharmaceutical composition of the present invention is particularly useful for the prevention and / or treatment of cholera.

[0248] Thus, in one embodiment, the present invention is a method for preventing and / or treating SIBO, IBS and / or cholera, comprising administering to a subject, preferably a human subject, in need of such prevention and / or treatment an oral pharmaceutical composition of the present invention as described above.

[0249] In one embodiment, the present invention relates to a method for preventing and / or treating IBS-C, IBS-D, IBS-M and / or IBS-U, preferably a method for treating IBS-D, comprising administering an oral pharmaceutical composition of the present invention to a subject, preferably a human subject, in need of prevention and / or treatment of IBS-C, IBS-D, IBS-M and / or IBS-U.

[0250] In another embodiment, the present invention is a method of treating cholera, comprising administering to a subject, preferably a human subject, in need of such treatment an oral pharmaceutical composition of the present invention.

[0251] In another embodiment, the present invention is a method for treating and / or preventing hepatic encephalopathy, cirrhosis, pouchitis and / or spontaneous bacterial peritonitis comprising administering an oral pharmaceutical composition of the present invention to a subject, preferably a human subject, in need thereof.

[0252] In another embodiment, the present invention is a method for treating and / or preventing NAFLD, NAFL and / or NASH, comprising administering an oral pharmaceutical composition of the present invention to a subject, preferably a human subject, in need of such treatment and / or prevention.

[0253] The oral pharmaceutical composition of the present invention preferably contains about 600 mg / dose unit of rifamycin SV or a pharma- ceutically acceptable salt thereof in anhydrous form (i.e., rifamycin SV or a pharma- ceutically acceptable salt thereof, preferably rifamycin SV sodium salt).When the oral pharmaceutical composition of the present invention contains 600 mg / dose unit of rifamycin SV sodium salt in anhydrous form, the equivalent amount of rifamycin SV in anhydrous form is 582 mg / dose unit.

[0254] In one embodiment, the composition is preferably administered according to a dosing regimen of three tablets per day (i.e., three times a day (tid) or all together once a day) to reach an optimal daily dosage of about 1800 mg / day. The tid daily dosing regimen preferably lasts for 14 days, but may last for several months.

[0255] In another embodiment, the oral pharmaceutical composition of the present invention is preferably administered according to a dosing regimen of two tablets per day (i.e., twice a day (bid) or all together once a day) to reach an optimal daily dosage of about 1200 mg / day. The bid daily dosing regimen preferably lasts for 1-4 weeks, preferably 14 days, but may last for several months. EXAMPLES

[0256] The following experimental section describes the invention in detail without limiting its contents in any way.

[0257] Example 1 : Rifamycin sodium 600 mg sustained release coated tablets having the qualitative / quantitative composition disclosed in Table 1 were prepared.

[0258] Organic film coat (gastro-resistant coating)

[0259] [Table 1]

[0260] Rifamycin SV (sodium salt), ascorbic acid, lecithin, stearic acid and a portion of magnesium stearate were mixed in a suitable container until uniformity of dispersion was obtained. Then, mannitol, sodium carboxymethylcellulose and silica were added and the mixture was mixed again. After the addition of magnesium stearate was completed, the powder was compressed in a rotary tablet press to obtain tablet cores. These were then coated in a pan coat unit with Eudragit L100, triethyl citrate, talc, titanium dioxide and red ferric oxide using ethanol as the solvent to apply a gastro-resistant coating layer. The tablets were then polished by adding polyethylene glycol 6000 in an aqueous solution.

[0261] The prepared tablets were evaluated in a dissolution test at pH 1 under the conditions in Table 2:

[0262] [Table 2]

[0263] Dissolution testing was performed by transferring 1000 mL of dissolution medium at pH 1 to a test vessel and warming the solution to 37°C ± 0.5°C. One tablet of the composition was added to the test vessel. After 2 hours, the dissolution medium in each vessel was sampled, filtered, and analyzed using a UV-Visible spectrophotometer against a blank containing dissolution medium.

[0264] At the end of the dissolution time (2 hours), the dissolution medium from each vessel was sampled, filtered, and analyzed against a blank using a UV-Visible spectrophotometer. The amount of Rifamycin SV sodium released from the tablets in the test vessel was calculated using the following formula:

[0265]

number

[0266] The amount of rifamycin SV released from tablets prepared according to Example 1 in a dissolution test at pH 1 is disclosed in Table 3.

[0267] [Table 3]

[0268] The prepared tablets were also evaluated in a dissolution test at pH 6.4 under the conditions in Table 4.

[0269] [Table 4]

[0270] The test solution was prepared by dissolving 6.8 g of monobasic potassium phosphate (KH2PO4) and 0.5 g of NaOH in approximately 400 mL of purified water and diluting to a total volume of 1000 mL with purified water. The standard solution used in the analytical procedure was prepared as a solution of 0.67 mg / mL rifamycin SV WS dissolved in the dissolution medium.

[0271] Dissolution testing was performed by transferring 900 mL of pH 6.4 buffer into the test vessel and warming the solution to 37°C ± 0.5°C. One tablet of the composition was added to the test vessel. At the designated sampling times, the dissolution medium in each vessel was sampled, filtered, and analyzed against a blank containing dissolution medium using a UV-Visible spectrophotometer. The amount of rifamycin SV sodium released from the tablets in the test vessel was calculated using the following formula:

[0272]

number

[0273] The amount of rifamycin SV released from tablets prepared according to Example 1 in a dissolution test at pH 6.4 is disclosed in Table 5.

[0274] [Table 5]

[0275] Stability: A stability study was performed on one batch of tablets manufactured according to Example 1, according to the ICH guidelines for stability studies of new formulations. The tablets were placed at 25° C. / 60% RH. The results are reported in Table 5a below.

[0276] [Table 6]

[0277] Example 2 : Rifamycin sodium 600 mg sustained release coated tablets having the qualitative / quantitative composition disclosed in Table 6 were prepared.

[0278] Water-based film coat (gastro-resistant coating):

[0279] [Table 7]

[0280] Stability: A stability study was performed on one batch of tablets manufactured according to Example 2, according to the ICH guidelines for stability studies of new formulations. The tablets were placed at 25° C. / 60% RH. The results are reported in Table 6a below.

[0281] [Table 8]

[0282] Example 3: In vitro evaluation of the anti-inflammatory properties of Rifamycin SV Inflammation plays a major role in the pathogenesis of IBS, and therefore the ability of rifamycin SV to suppress inflammation was characterized. Evaluation by PXR stimulation and NFkB inhibition was performed in vitro in a cell line mimicking the intestinal environment in the context of IBS.

[0283] Assays to analyze and quantify PXR activity: A nuclear receptor assay system utilizing proprietary human cells engineered to provide constitutive, high-level expression of human PXR was used to determine the EC50 of rifamycin SV agonist activity against PXR.

[0284] This assay product from Indigo Biosciences (PA, USA) utilizes cells expressing a hybrid form of human PXR. The N-terminal sequence encoding the PXR DNA-binding domain (DBD) has been replaced with that of the yeast GAL4-DBD, leaving the native PXR ligand-binding domain (LBD) and other C-terminal domains intact and functional. Ligand interaction activates the receptor and binds it to the GAL4 DNA-binding sequence, which is functionally linked to a resident luciferase reporter gene. Thus, quantifying changes in luciferase activity in treated reporter cells provides a sensitive surrogate measure of changes in PXR activity. The primary use of this reporter assay system is the screening of test samples to quantify the functional activity of agonists or antagonists that can act against human PXR. Increasing concentrations of rifamycin SV were tested compared to rifaximin, and rifampicin was used as the positive control for the assay. Experiments were repeated three times and standard deviations were calculated. EC50 and 95%CI were determined using Prism statistical analysis software, fitting a non-linear curve through the data points expressed as log(agonist) vs response-variable slope (4 parameters). p values ​​were calculated using Prism parametric, paired t test analysis.

[0285] Assays for measuring NFkB activity: The assay measuring the IC50 of rifamycin SV antagonism of the NFkB transcription factor used a similar reporter system as the PXR assay. Indigo Biosciences' NFkB nuclear receptor assay system utilizes human kidney epithelial cells transiently transfected with an NF-kB reporter. NFkB biological activity, measured as transcriptional activity from these reporter cells, requires the same orchestration of all the intracellular molecular interactions and events that can be predicted to occur in vivo.

[0286] Cells were treated in the presence of 30 ng / mL TNFα in antagonist mode to stimulate the NFkB inflammatory cascade. Increasing concentrations of rifamycin SV were tested in comparison to rifaximin. After 24 hours, luminescence, proportional to NFkB transcriptional activity, was quantified. Experiments were repeated twice and standard deviations were calculated. IC50s and 95% CIs were determined using Prism statistical analysis software, fitting a nonlinear curve through the data points expressed as log(inhibitor) vs. response (3 parameters). p-values ​​were calculated using Prism parametric, paired t-test analysis.

[0287] The experimental results showed that rifamycin SV is 200-440 times more potent than rifaximin in stimulating PXR transcriptional activity. In addition, rifamycin SV is 4000 times more potent than rifaximin in inhibiting NFkB transcriptional activity.

[0288] All the data presented show that rifamycin SV is endowed with a strong anti-inflammatory activity far superior to rifaximin. These properties make rifamycin SV a very good candidate for IBS treatment and an ideal substrate for preparations intended to show the relief of symptoms of IBS, especially IBS-D. Of course, to be an effective tool for the healing of patients, rifamycin SV or its pharmacologic acceptable salt must be administered in the appropriate dose and with the ideal delivery rate and range, as confirmed in the above examples directed to ensure that the appropriate amount of rifamycin SV or its pharmacologic acceptable salt is administered to the patient and delivered to the organs capable of exhibiting the appropriate pharmacodynamic activity.

[0289] Example 4: Pharmacokinetic and safety evaluation: The tablets of Example 1 (rifamycin SV sodium 600 mg tablets) were studied in male and female healthy volunteers to evaluate the safety and PK profile obtained after single (on day 1) and multiple (after day 7) dosing of rifamycin SV of the tablets of the invention TID for a cumulative daily intake of 1800 mg / day.

[0290] The primary endpoint of the study was the assessment of the pharmacokinetics of rifamycin SV in plasma and urine after single (day 1) and multiple (day 7) doses of tablets of Example 1 administered to healthy subjects according to a dosing regimen of 600 mg tid (three times a day).

[0291] A secondary endpoint of the study was the evaluation of the safety and tolerability of the tablets of Example 1 administered according to a tid dosing schedule for 14 consecutive days. All study subjects received tablets of Example 1 according to a multiple dosing schedule on days 1 through 14 as follows: - Sodium rifamycin SV 1800 mg, as one 600 mg tablet of Example 1, three times a day (tid) for 7 consecutive days, at 08:00 ± 1 h (before breakfast), 14:00 ± 1 h (before lunch) and 20:00 ± 1 h (before dinner). On each treatment day, the interval between the first and second doses, and between the second and third doses, τ = 6 hours. The interval between the third dose on one day and the first dose on the next day, τ = 12 hours. After discharge on day -8, subjects continued on the same dosing schedule at home through day 14 for a total of 42 doses.

[0292] The pharmacokinetic criteria for evaluation were as follows: - C of plasma rifamycin SV after the first dose of the tablet of Example 4 max,0-6 ,t max,0-6 ,AUC 0-6 ,AUC 0-∞ ,t 1 / 2 ,λ z ,Cl t / F,Cl r and V z / F; - Plasma rifamycin SV C after the first three doses of rifamycin SV 600 mg tablets max,0-24 ,t max,0-24 and AUC 0-24 ; - Plasma rifamycin SV C after the last multiple dose of rifamycin SV 600 mg tablet max,ss,12-18 ,t max,ss,12-18 ,C min,ss,12-18 ,C ave,12-18 ,PTF% 12-18 and AUC ss,12-18 ; -AUC of plasma rifamycin SV after the last 3 doses of rifamycin SV 600mg tablets ss,0-24 ; and - Urinary Ae of Rifamycin SV after the first 3 and last 3 multiple doses of Rifamycin SV 600 mg tablets 0-24 and %Ae 0-24 .

[0293] Pharmacokinetic parameters and results: The mean (+SD) rifamycin SV concentrations (ng / mL) versus time profiles on days 1 and 7 during study treatment with the study formulation are shown in Figure 1.

[0294] The pharmacokinetic parameters of plasma rifamycin SV measured and calculated on days 1 and 7 of treatment are shown below. Median values ​​(range) are shown in Table 7. max Mean ± SD is reported except for (N = 18).

[0295] [Table 9]

[0296] C max,0-6 corresponds to the "peak concentration", i.e., the peak plasma concentration of the drug at the time from 0 to 6 hours after oral administration, and t max,0-6 corresponds to the "time to peak concentration", i.e., the time it takes for the peak plasma concentration of a drug to be reached after oral administration between 0 and 6 hours.

[0297] C max,0-24 corresponds to the "peak concentration", i.e., the peak plasma concentration of the drug in the time period 0-24 h after oral administration, and t max,0-24 corresponds to the "time to peak concentration", i.e., the time it takes for the peak plasma concentration of a drug to be reached from 0 to 24 hours after oral administration.

[0298] AUC corresponds to the "area under the curve", i.e., the integral of the concentration-time curve (after a single dose or after steady state). In particular, AUC0-6 is the area under the curve up to 6 hours, AUC0-24 is the area under the curve up to 24 hours, and AUC0-∞ is the area under the curve to infinity.

[0299] The total amount of rifamycin SV excreted in urine, calculated on days 1 and 7 of treatment, is reported in Table 8 below (mean values ​​± SD are reported).

[0300] [Table 10]

[0301] Safety Results: No serious adverse events were reported, and no subjects discontinued the study due to adverse events. No significant changes in vital signs, BW, ECG, or laboratory parameters were observed after treatment with rifamycin SV. No significant changes in liver or renal function were observed during multiple-dose treatment.

[0302] Conclusion: The PK profile and safety of systemically available rifamycin SV following single and multiple tid administration of rifamycin SV 600 mg tablets were investigated in 18 healthy male and female subjects. Subjects were initially exposed to a daily dose of 1800 mg rifamycin SV for 14 consecutive days. The PK of rifamycin SV was investigated in plasma and urine on days 1 and 7. On day 1, rifamycin SV was quantifiable in plasma levels in all subjects beginning 9 hours after the first dose. On average, rifamycin SV peaked at a median time of 9.5 hours (C max,0-24 On day 7, all subjects had quantifiable levels of rifamycin SV in plasma at each sampling time. Rifamycin SV peaked 2 hours after the first dose on day 7 and then declined to levels similar to those on day 1. After 7 days of tid treatment, absorption of rifamycin SV increased only slightly in rate and extent and showed no significant signs of accumulation. The total amount of rifamycin SV excreted in urine was 0.0033% on day 7.

[0303] Rifamycin SV 600 mg tablets demonstrated an excellent safety profile.

[0304] Example 5 : Activity of rifamycin SV against bacterial strains The efficacy of rifamycin SV and its salts in treating SIBO and / or IBS was verified by evaluation of the MIC (Minimum Inhibiting Concentration) against a specific pathogenic bacterial strain, namely Methanobrevibacter smithii, which is usually present in IBS patients, especially IBS-D patients, in comparison with other antibacterial agents, as shown in Table 9.

[0305] [Table 11]

[0306] Not surprisingly, rifamycin SV is more effective than other active agents already described as suitable for SIBO and / or IBS treatment.

[0307] The activity of rifamycin SV in the assay of agonism of PXR transcriptional activity compared to the activity of rifaximin and rifampicin is shown in Table 10.

[0308] [Table 12]

[0309] Based on the EC50 values ​​of agonist activity on PXR transcriptional potency, rifamycin SV is 200-440 times more potent than rifaximin and rifampicin. The difference in potency between rifaximin and rifamycin SV in this assay was determined to be statistically significant with a p-value of 0.018. Rifaximin at 30 μM is 2.5 times less potent than rifamycin SV at 0.3 μM. This translates to rifamycin SV being 250 times more potent than rifaximin in stimulating PXR transcriptional activity. Thus, rifamycin SV is confirmed to be effective in inflammatory bowel disease and more potent in stimulating PXR activity (indeed, using a 100 times lower dose). Rifamycin SV has also been shown to be 180 times more potent than rifampicin, which is used as a positive control in the experimental assay.

[0310] Example 6A : Activity of rifamycin and rifaximin in NFkB agonism assays The NFkB agonism effects of rifamycin SV and rifaximin were tested in the assay, and the results are shown in Table 11.

[0311] [Table 13]

[0312] Example 6B : Inhibition of NFkB transcriptional activity in reporter cell lines To establish that NFκB inhibition occurs upon rifamycin-induced PXR activation, reporter cell lines expressing full-length NFκB and carrying a luciferase reporter gene functionally linked to an upstream NFκB gene response element were stimulated with PMA, TNFα or LPS to induce NFκB. Rifamycin or rifaximin were dose-titrated into these stimulated cells. After 24 h of incubation, luminescence associated with NFκB transcriptional activity was quantified. Rifamycin was more potent than rifaximin in antagonizing PMA-induced NFκB activity, with an IC 50 The values ​​are 1.56x10-8 M vs 9.3910 -8 M, showing six-fold higher potency than rifaximin (Figure 4A). Rifamycin also showed an IC 50 The value is 1.48x10 -5 M (Figure 4B) TNFα-induced NFκB activity, with an IC50 value of 3.49x10 -6 Rifaximin antagonized LPS-induced NFκB activity in M ​​(Figure 4C). In stark contrast, rifaximin inhibited neither TNFα- nor LPS-induced NFκB activity up to the highest concentration tested. These results establish a firm correlation between PXR activation and NFκB inhibition by rifaximin, regardless of the inflammatory stimulus.

[0313] Because PXR can indirectly regulate inflammation through inhibition of NFκB, the data indicate that rifamycin induces an alternative or parallel pathway that normalizes intestinal immune function through antagonism of NFκB activity. Rifamycin showed potent antagonism of PMA-, TNFα-, and LPS-induced NFκB activity. PMA avoids induction of NFκB mediated through cell surface receptors by directly activating protein kinase C. Thus, antagonism of PMA-induced NFκB is an indication of potential inhibition of signaling from multiple cell surface receptors. Rifamycin was more potent than rifaximin in antagonizing PMA-induced NFκB. When TNFα receptors were specifically activated to stimulate NFκB, rifamycin potently antagonized TNFα-induced signaling, whereas rifaximin had no effect. More importantly, there was potent inhibition by rifamycin of LPS-induced NFκB, whereas rifaximin had no effect.

[0314] Interestingly, these data indicate that the inhibition of NFκB by rifamycin is stimulus-independent, since rifamycin potently inhibited PMA-, TNFα-, and LPS-induced NFκB, in contrast to rifaximin, which inhibited only PMA-induced NFκB. PMA or diacylglycerol-activated PKC are important for IgE-induced NFκB, which occurs in immune cells such as T cell receptors or T cells and mast cells, respectively. On the other hand, other signaling factors (TRAFs, TNFR-associated factors) are required for TNF- or LPS-induced NFκB, which occurs in colonic epithelial cells. Most importantly, the biological function of NFκB was confirmed in colonic epithelial cells, given its relevance to IBS or IBD. Rifamycin significantly inhibited IL1β-induced synthesis of IL-8, a chemokine regulated by NFκB. These cell-dependent requirements for inducing inflammation imply that the anti-inflammatory potential of rifamycins is broad by acting on a variety of target cells, as dysregulated immune and epithelial cell interactions contribute to the pathogenesis of several GI disorders.

[0315] Example 7 : A Phase II, multicenter, randomized, double-blind, placebo-controlled, proof-of-concept study of the efficacy and safety of a 600 mg tablet of Example 1 in subjects with diarrhea-predominant irritable bowel syndrome (IBS-D).

[0316] Subjects suffering from IBS-D will be randomly assigned (1:1:1) to one of three treatment groups to receive one of the following treatments for 14 consecutive days:

[0317] Treatment Group 1: The tablets of Example 1 are administered to subjects three times daily (tid) according to the following schedule: (a) one tablet of 600 mg in the morning; (b) one tablet of 600 mg in the afternoon; and (c) one tablet of 600 mg in the evening.

[0318] Treatment Group 2: Tablets of Example 1 are administered to subjects twice daily (bid) plus a matching dose of placebo once daily (qd) according to the following schedule: (a) one 600 mg tablet in the morning, (b) one placebo tablet in the afternoon; (c) one 600 mg tablet in the evening.

[0319] Treatment group 3: Placebo tablets will be administered to subjects three times daily (tid) according to the following schedule: (a) one placebo tablet in the morning; (b) one placebo tablet in the afternoon; (c) one placebo tablet in the evening.

[0320] All subjects will take their assigned tablets tid, ideally at the following times: 07:30±2h, 15:30±2h and 23:30±2h, for 14 days. The treatment week will be followed by a 10 week follow-up week.

[0321] The primary endpoint of the study will be the proportion of weekly responders, defined as subjects with weekly reduction in the combined symptom of abdominal pain and stool consistency based on daily assessments. Reduction in abdominal pain will be defined as a reduction in the average weekly abdominal pain score of at least 30% compared to baseline, and reduction in stool consistency will be defined as a reduction of at least 50% in the number of days per week with at least one stool with type 6 or type 7 consistency according to the 7-point Bristol Stool Form Scale compared to baseline 7.

[0322] The Bristol Stool Scale is a graded visualization scale of stool density. It has been validated as a surrogate for gastrointestinal transit time and is used to define "diarrhea" by the European Society for Clinical Microbiology and Infectious Diseases for Clostridium difficile infection (CDI). The parameters of the scale are shown in Table 12.

[0323] Subjects administered a 600 mg tablet of Example 1 two or three times daily according to the above schedule observe relief of abdominal pain as measured as a reduction in the weekly average of abdominal pain score of at least 30% compared to baseline, and a reduction in stool consistency as measured as a 50% or greater reduction in the number of days per week having at least one stool having type 6 or type 7 consistency according to the 7-point Bristol Stool Form Scale compared to baseline 7.

[0324] [Table 14]

[0325] Although the subject matter of the present disclosure has been described and illustrated in some detail with reference to certain exemplary embodiments including various combinations and subcombinations of features, those skilled in the art will readily appreciate other embodiments and variations and modifications thereof that are encompassed within the scope of the present disclosure. Moreover, the description of such embodiments, combinations, and subcombinations is not intended to represent that the claimed subject matter requires features or combinations of features other than those expressly recited in the claims. Accordingly, the scope of the present disclosure is intended to include all modifications and variations encompassed within the spirit and scope of the appended claims.

Claims

1. about 600 mg of rifamycin SV, or a pharma- ceutically acceptable salt thereof; one or more pharma- ceutically acceptable excipients; at least one lipophilic compound selected from unsaturated or hydrogenated alcohols (such as cetyl alcohol, stearic alcohol, myristyl alcohol, lauryl alcohol, or oleyl alcohol) or fatty acids (such as palmitic acid, stearic acid, myristic acid, lauric acid, lauric acid, oleic acid, etc.), their salts, their esters; fatty acid mono-, di-, or triglycerides such as stearin or their polyethoxylated derivatives; waxes such as beeswax or carnauba wax; ceramides; cholesterol; or mixtures thereof; At least one hydrophilic compound selected from hydroxyalkyl cellulose, alkyl cellulose, carboxyalkyl cellulose; polyvinyl alcohol; polysaccharides such as dextrin, pectin, starch, etc.; natural or synthetic gums; alginic acid; polyhydric alcohols such as xylitol, maltitol, or mannitol; a gastro-resistant coating that dissolves and / or breaks down when exposed to an aqueous medium having a pH in the range of pH 5 to pH 6.5; 1. An oral pharmaceutical composition in the form of a solid dosage form comprising:

2. 2. The oral pharmaceutical composition of claim 1, further comprising at least one amphiphilic compound.

3. 3. The oral pharmaceutical composition of claim 1 or 2, wherein the rifamycin SV, or a pharma- ceutically acceptable salt thereof, is released from the solid dosage form when the solid dosage form is placed in an aqueous medium having a pH in the range of about pH 5 to about pH 6.

5.

4. 4. The oral pharmaceutical composition according to claim 1, wherein the solid dosage form comprises a core and a gastro-resistant coating covering the core.

5. Administration of one or more of the solid dosage forms to a subject results in a t of Rifamycin SV of about 9.50 hours in the plasma of the subject. max,0-24 5. The oral pharmaceutical composition according to claim 1 , characterized in that:

6. Three or more administrations of the solid dosage form to a subject A C of about 2.30±2.14 ng / mL of rifamycin SV in the subject's plasma max,0-6 is shown, A C of about 6.23±4.52 ng / mL of rifamycin SV in the subject's plasma max,0-24 is shown, AUC of rifamycin SV of about 3.34±2.96 (ng)(h) / mL in the subject's plasma 0-6 and / or After administration of the three oral pharmaceutical compositions to humans, the AUC of rifamycin SV was approximately 947.92±20.24 (ng)(h) / ml in the plasma of the subject. 0-24 is shown, 6. An oral pharmaceutical composition according to claim 1 ,

7. An oral pharmaceutical composition according to any one of claims 1 to 6, characterized in that the urinary excretion rate of rifamycin SV in a subject to which the oral pharmaceutical composition is administered is 1% or less of the total amount of rifamycin SV or a pharma- ceutical acceptable salt thereof administered to the subject.

8. The pharmaceutical composition releases 10% or less of the amount of rifamycin SV, or a pharma- ceutical acceptable salt thereof, that constitutes the pharmaceutical composition when the pharmaceutical composition is placed in a USP dissolution apparatus II conforming to USP <711> for 2 hours, and the dissolution apparatus is capable of dissolving at pH 1 and 37±0.

5. o 8. An oral pharmaceutical composition according to any one of claims 1 to 7, characterized in that it comprises 1000 mL of an aqueous solution containing 0.1 M hydrochloric acid and 0.4% macrogol cetostearyl ether at a temperature of 35°C, said aqueous solution being stirred at a speed of 50 rpm.

9. The pharmaceutical composition releases about 20% or less of the amount of rifamycin SV, or a pharma- ceutical acceptable salt thereof, that constitutes the pharmaceutical composition when the pharmaceutical composition is placed in a USP dissolution apparatus II conforming to USP <711> for 1 hour, and the dissolution apparatus is operated at pH 6.4 and 37±0.

5. o 9. An oral pharmaceutical composition according to any one of claims 1 to 8, comprising 900 mL of an aqueous buffer solution at a temperature of 0.5 °C, said aqueous solution being stirred at a speed of 100 rpm.

10. When the pharmaceutical composition is placed in a USP dissolution apparatus II conforming to USP <711> for 6 hours, the pharmaceutical composition releases about 50% or more of the amount of rifamycin SV, or a pharma- ceutical acceptable salt thereof, that constitutes the pharmaceutical composition, and the dissolution apparatus is operated at pH 6.4 and 37±0.

5. o 10. The oral pharmaceutical composition according to any one of claims 1 to 9, characterized in that it comprises 900 mL of an aqueous buffer solution at a temperature of 0.5 °C, and the aqueous solution is stirred at a speed of 100 rpm.

11. 11. The oral pharmaceutical composition of claim 1, wherein the pharmaceutical composition contains about 2% by weight or less of rifamycin S or about 1% by weight or less of rifamycin B.

12. 12. The oral pharmaceutical composition according to claim 1, wherein the pharmaceutical composition contains 10,000 ppm or less of ethanol.

13. The solid dosage form comprises: 3 months, 25 o C and 60% relative humidity, containing less than 2% by weight of rifamycin S after storage of said solid dosage form. 3 months, 25 o C and 60% relative humidity after storage of said solid dosage form contains less than 1% by weight of rifamycin B. 1 month, 40 o C and 75% relative humidity, containing less than 2% by weight of rifamycin S after storage of said solid dosage form. 1 month, 40 o C and 75% relative humidity, containing less than 1% by weight of rifamycin B after storage of said solid dosage form. 1 month, 30 o C and 65% relative humidity, or 1 month, 30 o C and 65% relative humidity, containing less than 1% by weight of rifamycin B after storage of said solid dosage form.

13. An oral pharmaceutical composition according to any one of claims 1 to 12.

14. 14. An oral pharmaceutical composition according to any one of claims 1 to 13, characterized in that the solid dosage form is contained in a package, the package comprising a material for protecting the solid dosage form from heat and light.

15. 15. An oral pharmaceutical composition according to any one of claims 1 to 14, characterized in that the solid dosage form is in the form of a tablet.

16. 16. The oral pharmaceutical composition of claim 15, wherein the tablet comprises a tablet core and a gastro-resistant coating covering the tablet core.

17. 17. An oral pharmaceutical composition according to any one of claims 1 to 16 for use in the prevention and / or treatment of irritable bowel syndrome (IBS), diarrhea-predominant irritable bowel syndrome (IBS-D), alternating diarrhea-predominant constipation-predominant irritable bowel syndrome (IBS-M), cholera, hepatic encephalopathy, liver cirrhosis, pouchitis, spontaneous bacterial peritonitis, non-alcoholic fatty liver disease, non-alcoholic fatty liver or non-alcoholic steatohepatitis.

18. 17. The oral pharmaceutical composition according to any one of claims 1 to 16, for use according to claim 17, characterized in that the oral pharmaceutical composition is administered in a daily dose of about 600 mg, about 1200 mg or about 1800 mg.

19. 18. An oral pharmaceutical composition according to any one of claims 1 to 16, for use according to claim 17, characterized in that the composition is administered 1, 2 or 3 times a day.

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