RU2793319C2 - Oral rifamycin sv compositions - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: oral pharmaceutical compositions containing rifamycin SV or a pharmaceutically acceptable salt thereof, characterized in that they are formulated at a higher concentration (approximately 600 mg/tablet) and so as to obtain a modified proximal intestinal profile of rifamycin SV or a pharmaceutically acceptable salt thereof, that is, in the small intestine (duodenum, jejunum, and ileum). In one embodiment, the disclosed oral pharmaceutical compositions are used in the prevention and/or treatment of a subject's small bowel bacterial overgrowth syndrome (SIBO) and/or irritable bowel syndrome (IBS), and/or in the treatment of cholera. In one embodiment, the disclosed oral pharmaceutical compositions are used in the prevention and/or treatment of a subject's hepatic encephalopathy, cirrhosis, pouchitis, and/or spontaneous bacterial peritonitis.

EFFECT: in one embodiment, the disclosed oral pharmaceutical compositions are used in the prevention and/or treatment of a subject's non-alcoholic fatty liver disease, non-alcoholic fatty liver, or non-alcoholic steatohepatitis.

16 cl, 4 dwg, 14 tbl, 7 ex

Description

BACKGROUND OF THE INVENTION

Intestinal infections are common diseases caused by the colonization of the intestine by foreign pathogenic agents of various etiologies or caused by intestinal microorganisms that are usually present, becoming virulent.

It is known that the human intestine is divided into two separate parts:

- the proximal part, called "small intestine" or "small intestine", which is formed by three sections known as, in the craniocaudal direction, the duodenum, jejunum and ileum, and is included between two biological valves, namely the pylorus and the ileocecal valve ;

- the distal part, called "large intestine" or "colon", which is formed by the large intestine and rectum (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, in turn, includes several sections known as the ascending colon, transverse colon, descending colon, sigmoid colon, and rectum.

The two parts, small intestine and large intestine, are functionally separated anatomically by the ileocecal valve, which allows intestinal contents to pass from the small intestine to the large intestine, but under normal conditions, and not vice versa. In addition, from an anatomical-structural point of view, the small intestine is also very different from the large intestine and, above all, from a functional point of view (Braga P C. Enteric microflora and its regulation. In Drugs in Gastroenterology . Raven Press, New York, 1991, pp. 501-508), the presence of a large absorptive surface and strong peristalsis supported by specific muscular rings in the small intestine, and the presence of a fenestratal epithelium, as well as clear and regular crypts in the large intestine.

Local environmental factors such as pH conditions, availability of nutrients and enzymes, and differential transit times for each anatomical region determine which microbial species predominate, as well as determining the concentration of bacteria in a particular region. The concentration of bacteria in the small intestine is usually many magnitudes lower than in the large intestine due to the microenvironment and anatomical differences between areas.

These numerous differences between the physio-anatomical characteristics of the small and large intestines explain the special nature of some pathologies arising from the small intestine.

It should be noted that diseases of the digestive system have different etiological pathologies and present different symptoms that allow them to be diagnosed. The expression "inflammatory bowel disease" or IBD refers to a range of chronic inflammatory bowel disorders, including mainly ulcerative colitis and Crohn's disease, which should not be confused with "irritable bowel syndrome" or IBS. IBS can be classified as IBS-C (constipation-dominated) or IBS-D (diarrhea-dominant), although mixed symptoms or alternating periods with both symptoms may be present in the same patient in the presentation of IBS-S (mixed type), and a fourth category of IBS-N (unclassified) has also been proposed, however the subcategory may change for a patient over time.

Unlike IBD, IBS does not show obvious anatomical abnormalities of the mucosa, and is therefore considered a predominantly functional disease. From a purely clinical point of view, IBS is characterized by bowel dysfunction with abdominal pain, bloating, and altered bowel function (diarrhea, constipation, or both). The etiology and pathogenesis of IBS is unknown, but various factors may contribute to its occurrence. These factors often include abnormalities in the regulation of intestinal wall tone and smooth muscle activity, effects of bacterial irritants, and psychological and emotional effects. Because the pathophysiology and causes of IBS are poorly understood, treatment approaches to date have mainly focused on managing symptoms to maintain daily functioning and improve the patient's quality of life. The mainstay of intervention to date is pharmacological treatment with antispasmodics and antidiarrheals for diarrhea, prokinetics and high fiber diets for constipation, and maintenance therapy with low doses of antidepressants to normalize gastrointestinal motility aimed at alleviating the functional symptoms of the disease. Other interventions, including advice on lifestyle and dietary changes, and psychological counseling are also used. However, IBS often does not respond to current treatment options, including dietary and lifestyle advice, counseling, fiber supplementation, psychological therapy, and/or pharmacotherapy.

Recently, the pregnane X receptor (PXR), a ligand-activated nuclear receptor that recognizes and responds to various chemical stimuli, including intestinal microbial metabolites, has been reported to play a key role in the intestinal epithelium by regulating inflammatory responses, enhancing wound healing and maintaining barrier function. in conditions of inflammation (Garg A et al in The Journal of Pharmacology and Experimental Therapeutics, 359:91-101, October 2016). In humans, PXR is most widely expressed in the small intestine, colon, liver, and gallbladder, and to a lesser extent in the stomach. Activation of PXR induces metabolic enzymes (eg CYP3A4) that can influence the pharmacokinetics of xenobiotics and endobiotics. In addition, PXR activation has been shown to attenuate nuclear factor-kB (NF-kB) signaling, a key transcription factor that regulates pro-inflammatory cytokine and chemokine gene expression. The distribution and functions of PXR in the GI tract suggest that PXR function may play a role in maintaining mucosal homeostasis. Thus, PXR activation could potentially contribute to therapeutic effects in patients with IBS.

Inflammation and immune dysregulation contribute to the pathophysiology of a number of gastrointestinal (GI) diseases such as inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), and diverticular disease. Changes in the reciprocal interactions between the two major regulators of inflammation, PXR and NFkB, may play a role in the dysregulation of inflammatory mechanisms in IBD and IBS.

Chronic exposure to xenobiotics is not only capable of causing inflammation and damage to the gut, but can also impair immune function. In addition to its role in detoxification mechanisms, PXR has been shown to indirectly inhibit inflammation by downregulating NFkB activity. NFkB is a major transcription factor that regulates the expression of genes for pro-inflammatory cytokines and chemokines. Patients with IBD have significantly higher NFkB expression compared to patients without IBD. Abnormal activation of NFkB leads to excessive production of pro-inflammatory cytokines that cause chronic inflammation in the gut, the main mechanism of IBS.

Small intestine bacterial overgrowth syndrome (SIBO) is a disorder of the normal microflora of the gastrointestinal tract. In SIBO, the concentration of bacterial organisms in the terminal jejunum and ileum increases and the normal distribution of bacteria is disturbed. In SIBO, there is an increased number and/or type of bacteria in the small intestine. Typical detection is > 10 ⁵ CFU of bacteria per ml of proximal jejunal aspirate, in which, under normal conditions, the concentration of bacteria in the small intestine does not exceed 10 ² CFU.

According to conventional wisdom of one of skill in the art, SIBO may result from an underlying condition such as pancreatic insufficiency, immunodeficiency syndromes, diverticula, history of surgery, scleroderma, diabetic autonomic neuropathy, radiation enteropathy, or a combination of these factors. The prognosis for patients with SIBO is usually serious and related to the underlying condition. As a result, malabsorption of nutrients can lead to a variety of symptoms. For example, this change in the distribution and concentration of the normal microflora of the gastrointestinal tract in SIBO changes the metabolism of sugar molecules, which, as part of the fermentation reaction, initially break down into short-chain fatty acids (SCFA), carbon dioxide (CO ₂ ) and hydrogen (H ₂ ). Most of the CO ₂ remains in the intestines and leads to symptoms of bloating. SCFAs generate an osmotic gradient and thus absorb water into the intestinal lumen, resulting in the symptom of diarrhea in IBS.

As a result, there is a significant unmet medical need for more effective treatments for IBS. Direct measurement of jejunal aspirate and diagnosis of SIBO may lead to false negative results because it does not include assessment of bacterial overgrowth in other less accessible parts of the distal small intestine. A less invasive hydrogen breath test can provide additional information about the degree of SIBO. Although prebiotic and probiotic therapies aimed at restoring the natural microflora of the gastrointestinal tract have been empirically used for many years in patients with IBS, the elimination of bacterial overgrowth with antibiotics has been shown to reduce the symptoms of IBS. A variety of 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. Moreover, especially when used frequently, they can also contribute to general antibiotic resistance in bacterial species/strains.

Therefore, there is a significant unmet medical need for more effective and locally limited treatments for SIBO and/or IBS.

Cholera is an acute diarrheal infection caused by ingestion of food or water contaminated with the bacterium Vibrio cholerae . Cholera remains a global public health threat, especially in third world or developing countries: researchers estimate that between 1.3 and 4.0 million cases and between 21,000 and 143,000 deaths occur annually worldwide (M. Ali et al. Updated Burden of Cholera in Endemic Countries. Negl. Trop. Dis 2015, 9(6)). Cholera transmission can be endemic or epidemic.

Cholera is transmitted by the fecal-oral route. Pathogenic microorganisms are sensitive to acid, and most of them die in the stomach; survivors can adhere to and colonize the small intestine, where they secrete a powerful cholera enterotoxin (CT, also called "cholerogen"). Cholera is an extremely virulent disease that can cause severe, acute, watery diarrhea that affects both children and adults and can lead to death within hours if left untreated.

Although cholera vaccines exist, their protection against V. cholerae is limited to a few months: (Cholera vaccines: WHO position paper-August 2017. Weekly epidemiological record. 92: 477-500. 25 August 2017). Therefore, the vaccine cannot fully protect against cholera outbreaks in endemic areas. Current treatment for cholera involves rapid rehydration (oral or intravenous) to replace fluids and electrolytes lost due to watery diarrhea. In addition, antibiotic treatment is recommended, especially for severely or moderately dehydrated patients who continue to pass large stool volumes during rehydration therapy. The choice of antibiotics should be based on local antibiotic susceptibility patterns. In most countries, doxycycline is recommended as first-line treatment for adults, while azithromycin is recommended as first-line treatment for children and pregnant women. Also ampicillin, erythromycin and fluoroquinolones have been described as effective antibiotics for the treatment of cholera. However, in recent years, several reports of multidrug-resistant strains of V. cholerae have been published in the scientific literature (T. Shrestha et al. BMC Infectious Diseases (2015) 15:104; J Health Popul. Nutr. (2007), 25( 2):241-243, M. Kitaoka et al, Journal of Medical Microbiology (2011), 60, 397-407).

Therefore, there is a need for a new antibiotic therapy in cholera, possibly targeting the gastrointestinal tract where Vibrio Cholerae colonizes the host: this would allow a local maximum concentration of the antibiotic to be obtained where it should act, followed by faster destruction of pathogenic bacteria and faster resolution of symptoms.

Currently, in the oral therapy of intestinal infections, substances with antibacterial activity are used, which must have certain characteristics, such as: a wide spectrum of action against gram + and gram-bacteria, resistance to strongly acidic environments such as the gastric environment, anti-infective activity, independent of presence of intestinal biomass, residence in the intestine for an appropriate period of time, good penetration into the infecting host cell and good tolerance (Braga P C. Interaction of antibiotics on enteric microflora. In: Drugs in Gastroenterology . Raven Press, New York, 1991, pp 509-517).

Therapy with antibacterial agents administered in oral formulations used today has at least two limitations. First, antibacterial agents, if not adequately protected, may lose their effectiveness due to the enzymatic or destructive inactivation that occurs during their passage through the stomach.

In addition, currently used dosage forms, although they allow the administration of the active ingredient in discrete doses, release it too quickly in relation to the time it takes to pass through the digestive tract, so that the active ingredient performs its anti-infective activity haphazardly throughout the gastrointestinal tract. intestinal tract.

In addition, although the antimicrobial agents used for disinfection of the digestive tract do not often have a high metabolic rate, in order to maintain the therapeutic possibility associated with the administration of the traditional form containing antimicrobial agents unchanged, metabolic degradation phenomena should not occur in order to avoid any weakening of the therapeutic efficacy associated with the presence of an antimicrobial agent.

Therefore, in such cases, to ensure the real effectiveness of anti-infective therapy in SIBO, IBS or cholera, there is a need for an extended and site-specific form of administration into the small intestine with possible transfer to the large intestine in accordance with the passage of the bolus within the digestive tract.

Hepatic encephalopathy (HE) is a brain disease that develops in some patients with liver disease. PE is a complex disease that spans a spectrum or continuum of diseases that ranges from a mild condition with no outward signs or symptoms to a severe form that can cause serious, life-threatening complications. Symptoms are associated with progressive brain dysfunction and may include personality changes, intellectual impairment, memory impairment, and loss of consciousness (coma). PE can occur in people with acute or chronic liver disease (hepatic) or in patients whose liver has been bypassed by a portosystemic shunt (without liver disease). A portosystemic shunt is an abnormal vessel that allows blood from the gastrointestinal tract to bypass the liver. They may be present at birth (congenital) or acquired during life. PE occurs when toxins that are normally cleared from the body by the liver accumulate in the blood, eventually reaching the brain. Many of the symptoms of hepatic encephalopathy are reversible with timely detection and treatment. The exact pathogenesis of PE is not fully understood. It is hypothesized that neurotoxic substances, including ammonia and manganese, may enter the brain in liver failure. In particular, ammonia is produced in the gastrointestinal tract during the decomposition of amines, amino acids, purines and urea by bacterial microflora. Normally, produced ammonia is detoxified in the liver by conversion to urea via the Krebs-Henseleit cycle. Ammonia is also used to convert glutamate to glutamine, a reaction that depends on the activity of glutamine synthetase. Two factors contribute to the hyperammonemia that is seen in PE in patients with cirrhosis. Firstly, there is a decrease in the mass of functioning hepatocytes, which leads to a decrease in the likelihood of ammonia detoxification during the above processes. Second, a portosystemic shunt can divert ammonia-containing blood away from the liver and into the systemic circulation.

Initial treatments may focus on identifying and correcting a triggering event such as infection, gastrointestinal bleeding, certain drugs, or kidney dysfunction. Such treatments may include drugs to treat infections, drugs or procedures to ease or control bleeding, stop using drugs that can cause an attack, and any appropriate therapy for kidney problems.

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

Patients with IBD, especially ulcerative colitis (UC), who have failed with available medical therapy or develop serious life-threatening complications, need to undergo surgery to remove their colon and rectum (proctocolectomy) to correct their disease. After a patient has undergone a total proctocolectomy, a procedure called an ileoanal reservoir anastomosis (IARA) is performed. In IARA, the ileum, or the lowest part of the small intestine, is connected to the anus to create a structure (sac) that can store and expel stool. IARA creates a stool reservoir in the perineum where the rectum used to be and restores the functionality of the anus when the stool passes under the patient's voluntary control. Pouchitis is an inflammation (swelling) of the sac that occurs when the sac becomes irritated and inflamed. The inflammation can cause an increase in bowel frequency, cramping or bloating, pain in the lower abdomen, or sometimes blood in the stool. The cause of pouchitis is not entirely clear, but it almost always occurs in patients with ulcerative colitis or another form of colitis and sometimes in patients with familial adenomatous polyposis (FAP), a genetic (inherited) condition in which many polyps form in the colon. Pouchitis is usually treated with a 14-day course of antibiotics. Acute pouchitis (a single episode of pouchitis) is usually treated with antibiotics such as metronidazole, rifaximin, or ciprofloxacin, often associated with anti-inflammatory drugs.

Spontaneous bacterial peritonitis (SBP) is defined as an infection of ascitic fluid without an obvious intra-abdominal source that can be treated surgically. The presence of SBP, which almost always occurs in patients with cirrhosis and ascites, 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 when they undergo paracentesis after hospitalization for another reason. Patients who suffer from SBP present a dire prognosis and have a one-year mortality rate ranging from 50% to 90%. SBP is treated and can be prevented with antibiotics such as beta-lactam antibiotics or quinolones.

It is now well known that the intestinal microflora and chronic liver disease are closely interrelated. This association is most evident in the later stages of the disease: cirrhosis and liver dysfunction are associated with intestinal bacterial overgrowth, small bowel dysmotility, increased intestinal permeability, and reduced immunological defenses, all of which promote bacterial translocation from the intestine into the systemic circulation, leading to infections, which in turn reinforce liver dysfunction in a vicious circle. Gut dysbiosis (that is, alterations in the normal saprophytic intestinal microflora) is associated with chronic metabolic disorders such as obesity, metabolic syndrome, diabetes, and cardiovascular disease. Non-alcoholic fatty liver disease (NAFLD) is a hepatic manifestation of the metabolic syndrome and therefore develops in the same context as these metabolic diseases. Therefore, it is not surprising that recent literature highlights the potential role of gut dysbiosis in the pathophysiology of NAFLD. Non-alcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease, which is an indicator of the increasing prevalence of metabolic syndrome. Most patients with NAFLD have a non-progressive simple fatty liver, namely non-alcoholic fatty liver (NAFL). Nonalcoholic steatohepatitis (NASH) is a more severe form of NAFLD that is broadly defined by the presence of steatosis with inflammation and progressive fibrosis, eventually leading to cirrhosis and hepatocellular carcinoma (HCC). A subset of patients with NAFLD develop NASH through poorly understood mechanisms. A growing body of evidence suggests a correlation between gut microbiota, bacterial translocation, and incidence of NAFLD. Changes in the gut microbiota resulting from a high-fat diet can cause NASH and exacerbate related HCC. Because current treatments for hepatic encephalopathy, cirrhosis, pouchitis, spontaneous bacterial peritonitis, NAFLD, NAFLD, and NASH have several disadvantages (poor or limited efficacy, occurrence of complications or side effects, relapse), there is a need for new therapies to be developed. . In particular, since bacterial infections play an important role in the pathogenesis of these diseases, there is a significant need for new antibiotic therapies that are effective in eliminating infections and limiting systemic antibiotic exposure.

US 8263120B2 describes controlled and/or programmed release oral pharmaceutical compositions containing at least one rifamycin SV or a pharmaceutically acceptable salt thereof having antimicrobial and/or anti-infective activity, such as rifamycin SV and/or metronidazole, for the treatment of infections. colon, in particular the colon, where their specific sterilizing action is required. In particular, the oral pharmaceutical compositions of US 8263120B2 leave the bacterial flora present in parts of the small intestine intact, releasing rifamycin SV or a pharmaceutically acceptable salt thereof only in the colon, thus providing localized and limited anti-infective efficacy.

Rifamycin SV is currently being developed for the treatment of traveler's diarrhea (TD) and infectious colitis: it was formulated as an enteric tablet to avoid exposure of the intragastric environment to rifamycin SV or its pharmaceutically acceptable salt, where the acidic pH could compromise the integrity of the drug, thereby reducing the effect of the administered dose of antibiotic. Considering that DP and infectious colitis are mainly localized in the last part of the gastrointestinal tract, in particular in the colon, early release of rifamycin SV or its pharmaceutically acceptable salt is undesirable in order to avoid any possible effect on it of the metabolic action of the enzymes present in small intestine or stomach, and dilution of the drug in aqueous fluids of the small intestine may also be avoided.

SUMMARY OF THE INVENTION

The present invention relates to oral pharmaceutical compositions containing rifamycin SV or a pharmaceutically acceptable salt thereof, formulated to obtain a sustained release profile of rifamycin SV or a pharmaceutically acceptable salt thereof. The sustained release profile of the compositions of the present invention demonstrates the release of rifamycin SV, or a pharmaceutically acceptable salt thereof, starting from the proximal intestine, i.e., the small intestine (duodenum, jejunum, and ileum), and may optionally continue throughout the colon.

The oral pharmaceutical compositions of the invention are useful in the prevention and/or treatment of a disease or disorder such as cholera or small intestinal bacterial overgrowth syndrome (SIBO) and/or irritable bowel syndrome (IBS).

The oral pharmaceutical compositions of the invention are also useful in the prevention and/or treatment of a disease or disorder such as hepatic encephalopathy, cirrhosis, pouchitis, spontaneous bacterial peritonitis, NAFLD, NAFLD and/or NASH.

In one aspect, oral pharmaceutical compositions are provided in the form of a solid dosage form containing approximately 600 mg of rifamycin SV or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients wherein the oral pharmaceutical composition is formulated for modified release.

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

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

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

In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided, wherein the oral pharmaceutical composition is formulated to release rifamycin SV or a pharmaceutically acceptable salt thereof substantially in the small intestine.

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

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

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

In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided for use in the prevention and/or treatment of irritable bowel syndrome with intermittent diarrhea and constipation (IBS-S).

In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided for use in the prevention and/or treatment of cholera.

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

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

In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided for use in the prevention and/or treatment of pouchitis.

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

In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided for use in the prevention and/or treatment of NAFLD.

In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided for use in the prevention and/or treatment of NAFLD.

In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided for use in the prevention and/or treatment of NASH.

In one aspect, a method is provided for treating and/or preventing small intestinal bacterial overgrowth syndrome (SIBO) in a subject in need of such treatment, comprising administering to the subject an effective amount of any oral pharmaceutical composition disclosed herein.

In one aspect, a method is provided for the treatment and/or prevention of irritable bowel syndrome (IBS) in a subject in need of such treatment, comprising administering to the subject an effective amount of any oral pharmaceutical composition disclosed herein.

In one aspect, a method is provided for the treatment and/or prevention of irritable bowel syndrome (IBS) in a subject in need of such treatment, in which IBS is predominantly diarrhea (IBS-D).

In one aspect, a method is provided for the treatment and/or prevention of irritable bowel syndrome (IBS) in a subject in need of such treatment, wherein the IBS has alternating diarrhea or constipation predominance (IBS-S).

In one aspect, a method is provided for treating and/or preventing cholera in a subject in need of such treatment, comprising administering to the subject an effective amount of any oral pharmaceutical composition disclosed herein.

In one aspect, a method is provided for treating and/or preventing hepatic encephalopathy in a subject in need of such treatment, comprising administering to the subject an effective amount of any oral pharmaceutical composition disclosed herein.

In one aspect, a method is provided for treating and/or preventing liver cirrhosis in a subject in need of such treatment, comprising administering to the subject an effective amount of any oral pharmaceutical composition disclosed herein.

In one aspect, a method is provided for treating and/or preventing pouchitis in a subject in need of such treatment, comprising administering to the subject an effective amount of any oral pharmaceutical composition disclosed herein.

In one aspect, a method is provided for treating and/or preventing spontaneous bacterial peritonitis in a subject in need of such treatment, comprising administering to the subject an effective amount of any oral pharmaceutical composition disclosed herein.

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

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

In one aspect, a method is provided for treating and/or preventing NASH in a subject in need of such treatment, comprising administering to the subject an effective amount of any oral pharmaceutical composition disclosed herein.

Unless otherwise indicated, all terms, designations and other scientific terminology used in the present description are intended to have the meanings generally understood by a person skilled in the art to which this disclosure pertains. In some instances, terms with common meanings are defined herein for clarity and/or reference; thus, the inclusion of such definitions in this specification should not be construed as representing a significant difference from what is generally understood in the art.

Used in the present description, the term "amphiphilic" refers to the affinity for lipids and affinity for water.

As used herein, the terms "about" and "about" refer to the range of experimental error that can occur in a measurement, such as 10%, 5%, 2.5%, 2%, or 1% error.

The term "bioequivalent" has the meaning defined at 21 C.F.R. Section 314.3 and refers to no significant difference in the rate and extent to which rifamycin becomes available at the drug site of action when administered at the same molar dose and under similar conditions. Two products may be considered bioequivalent if the 90% confidence interval of the corresponding pharmacokinetic values of rifamycin observed in the subject when the composition is administered to the subject is between about 80% and about 125% of the values observed for the reference drug.

Used in the present description, the term "cholera" refers to a pathological condition, known to a person skilled in the art, as caused by infection with the microorganism Vibrio cholerae.

As used herein, the terms "comprising", "having", "including", and "covering" may be used interchangeably and should be construed as non-limiting terms (i.e., meaning "including, but not limited to"), and should be considered as supporting also for terms such as "consisting essentially of", "consisting essentially of", "consisting of", or "consisting of".

As used herein, the terms "consists essentially of", "consisting essentially of" may be used interchangeably and should be construed as semi-closed terms meaning that no other ingredients are included that materially affect the essential and novel features of the invention (therefore, there may be optional excipients included).

Used in the present description, the terms "consists of", "consisting of" can be used interchangeably and should be considered as closed terms.

The term "core" refers to a matrix, mixture, compressed mixture or dispersion of rifamycin SV or a pharmaceutically 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.

As used herein, the term "delayed release" in relation to a dosage form describes a dosage form that releases the drug (or drugs) at a time other than immediately following oral administration of the dosage form to a subject.

Used in the present description, the term "sustained release" in relation to the dosage form describes the dosage form, formulated to ensure the availability of drugs for an extended period of time after oral administration of the dosage form to the object.

As used herein, the term "enteric coating" 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 injury or destruction, and which then dissolves or breaks down or dissolves or breaks down essentially or completely followed by the release of rifamycin SV or its pharmaceutically acceptable salt containing the dosage form, for example, when environmental conditions change, for example, when the pH of the gastrointestinal tract changes. The coating may be applied directly to the core.

Used in the present description, the term "hydrophilic" refers to the affinity for water.

As used herein, the terms "IBS" and "irritable bowel syndrome" refer to conditions known to those skilled in the art as functional bowel disorders that can lead to abdominal pain, bloating, and bowel dysfunction (diarrhea, constipation, or both) . As used herein, the term "IBS" includes IBS-C (constipation-dominated), IBS-D (diarrhea-dominant), IBS-S (mixed) and IBS-N (unclassified).

Used in the present description, the term "colon" refers to the last part of the gastrointestinal tract or digestive system. The large intestine includes the caecum, colon, rectum, and anal canal.

Used in the present description, the term "lipophilic" refers to the affinity for lipids and poor affinity for aqueous liquids.

Used in the present description, the term "matrix" refers to a macroscopically homogeneous structure, when it is ideally cut along all its axes or throughout its volume. The term "homogeneous" does not require that the excipients in the core be uniformly dispersed or uniformly mixed, but is intended to describe the absence of discrete layers in the core structure.

Used in the present description, the term "mixture" refers to a composition formed or obtained by mixing two or more substances, where the substances are mixed, but not chemically combined into a new substance.

As used herein, the term "modified release" in relation to dosage describes a dosage form whose drug release characteristics, period of action and/or localization are chosen to achieve therapeutic or beneficial goals not offered by standard dosage forms, such as a solution or an immediate release dosage form. . Modified release solid oral dosage forms include both delayed and sustained release drugs.

As used herein, the term "pharmaceutically acceptable salts" refers to those salts that have the biological efficacy and properties of a salt compound and that do not cause adverse reactions when administered to a mammal, preferably a human. Pharmaceutically acceptable salts may be inorganic or organic salts; examples of pharmaceutically acceptable salts include, but are not limited to, sodium, potassium, magnesium, carbonate, hydrogen carbonate, chloride, bromide, sulfate, hydrogen sulfate, citrate, maleate, fumarate, trifluoroacetate, 2-naphthalenesulfonate, and p-toluenesulfonate. In one embodiment, the pharmaceutically acceptable salt is sodium. Additional information on pharmaceutically acceptable salts can be found in the Handbook of pharmaceutical salts , P. Stahl, C. Wermuth, WILEY-VCH, 127-133, 2008, which is incorporated herein by reference.

Used in the present description, the term "physiologically acceptable excipient" refers to a substance devoid of any pharmacological effect of its own, which 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.

As used herein, the term "rifamycin B" refers to a chemical compound having CAS 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.

As used herein, the term "rifamycin S" refers to a chemical compound having CAS 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)-tetrona 21-acetate.

As used herein, the terms "rifamycin SV" and "rifamycin" are interchangeable and refer to a chemical compound having CAS 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]trienoimino)naphtho[2,1-b]furan-21-yl acetate.

As used herein, the terms "rifamycin sodium", "rifamycin sodium", "rifamycin sodium", "sodium rifamycin SV", "rifamycin SV sodium", and "rifamycin SV sodium" are used interchangeably and refer to rifamycin SV sodium having CAS No. 14897-39-3.

The expression "600 mg of rifamycin SV or a pharmaceutically acceptable salt thereof" as used herein refers to an amount of 600 mg of rifamycin SV as a dry matter (anhydrous) or 600 mg of a pharmaceutically acceptable salt of rifamycin SV as a dry matter, including, but not limited to, an amount of 600 mg of the sodium salt of rifamycin SV or an amount of a pharmaceutically acceptable salt of rifamycin SV that is equivalent to 600 mg of rifamycin SV in dry matter (anhydrous) form. In one aspect, 600 mg of rifamycin SV sodium on a dry basis is equivalent to 582 mg of rifamycin SV on a dry basis. In one aspect, 600 mg of rifamycin SV sodium is equivalent to 582 mg of rifamycin SV and 18 mg of sodium ions.

As used herein, the terms "prevent", "prevention", and "prophylaxis" refer to reducing or inhibiting the risk of acquiring or developing a given condition, or reducing or inhibiting recurrence or said condition in a subject that is not ill but has been or may be in close proximity. a person with a disease or disorder.

As used herein, the terms "SIBO" and "small intestinal bacterial overgrowth syndrome" hereinafter refer to conditions known to those skilled in the art as small intestinal bacterial overgrowth syndrome, which is a disruption of the normal microflora of the gastrointestinal tract. In SIBO, the concentration of bacterial organisms in the terminal jejunum and ileum increases and the normal distribution of bacteria is disrupted. In SIBO, there is an increased number and/or type of bacteria in the small intestine. Typical detection is > 10 ⁵ CFU of bacteria per ml of proximal jejunal aspirate, in which under normal conditions the concentration of bacteria in the small intestine does not exceed 10 ² .

As used herein, the term "small intestine" refers to the proximal intestine, which is the region of the gastrointestinal tract between the stomach and the large intestine, and where most of the final absorption of food occurs. The small intestine is made up of three distinct regions - the duodenum, jejunum, and ileum.

Used in the present description, the terms "treat", "treatment" and "treating" refer to therapeutic treatment. For example, therapeutic treatment includes ameliorating or reducing the progression, severity, and/or duration of conditions mediated by the disease or disorder, or reducing the intensity of one or more symptoms (in particular, one or more overt symptoms) of conditions mediated by the disease or disorder, resulting in administering one or more treatments (eg, one or more therapeutic agents, such as a composition of the invention). In certain embodiments, the implementation of therapeutic treatment includes reducing the intensity of at least one measurable physical parameter of the condition mediated by the disease or disorder. In other embodiments, the therapeutic treatment comprises inhibiting the progression of the condition mediated by the disease or disorder, either physically, eg, by stabilizing an overt symptom, physiologically, eg, by stabilizing a physical parameter, or both. In other embodiments, the implementation of therapeutic treatment includes the reduction or stabilization of symptoms mediated by the disease or disorder.

"C _max,0-6 ": The maximum plasma concentration achieved in the selected interval (0-6 hours).

"C _max,0-24 ": The maximum plasma concentration achieved in the selected interval (0-24 hours).

"t _max,0-6 ": Time to reach C _max,0-6 .

"t _max,0-24 ": Time to reach C _max,0-24 .

"λz": Terminal elimination rate constant calculated after the first dose, if possible, by logarithmic regression using at least three points.

"t _1/2 ": Half-life calculated after the first dose, if possible, as ln2/λ _z .

"AUC _0-6 ": Area under the concentration/time curve during the selected interval (0-6 hours), calculated using the trapezoidal method.

"AUC _0-24 ": Area under the concentration/time curve during the selected interval (0-24 hours), calculated using the trapezoidal method.

"AUC _0-∞ ": Area under the concentration-time curve, extrapolated to infinity, calculated after the first dose, if possible, as AUC _0-6+ C _t /λ _z , where C _t is the last drug concentration measured.

"Cl _t /F": Total clearance calculated after the first dose, if possible, as Dose/AUC _0-∞ .

"Cl _r ": Renal clearance calculated after the first dose as Ae0-6/AUC0-6.

"V _z /F": Apparent terminal volume of distribution calculated after the first dose, if possible, as Dose/λ _z × AUC _0-∞ .

"C _{max, ss, 12-18} ": The maximum plasma concentration for the selected interval (12-18 hours), achieved at steady state.

"C _min,ss,12-18 ": The minimum plasma concentration for the selected interval (12-18 hours), achieved at steady state.

"AUC _ss,12-18 ": Area under the concentration/time curve during the selected interval (12-18 hours) at steady state, calculated using the trapezoidal method.

"AUC _ss,0-24 ": Area under the concentration/time curve during the selected interval (0-24 hours) at steady state, calculated using the trapezoidal method.

"t _max,ss,12-18 ": Time to reach C _max,ss,12-18 .

"C _ave,12-18 ": Average plasma concentration in the selected interval (12-18 hours), calculated as AUC _ss,12-18 /τ, where τ is the dosing interval (6 hours).

"PTF% _12-18 ": The fluctuation between the maximum and minimum concentrations at steady state, calculated in the selected interval (12-18 hours) as

"Ae _0-24 ": The total amount of analyte excreted in the urine during the selected interval (24 hours).

"%Ae _0-24 ": Percentage of analyte excreted in urine, calculated as (Ae _0-24 /dose × 3) × 100.

EC ₅₀ : Half-Maximum Effective Concentration: refers to the concentration of a test compound that elicits a response equal to half between baseline and maximum response.

IC ₅₀ : Half Maximal Inhibition Concentration: refers to the concentration of a test compound that inhibits a response equal to half between baseline and maximal response.

BRIEF DESCRIPTION OF THE DRAWINGS

); 7: концентрации рифамицина SV в зависимости от времени в день 7 (

).Fig. 1: Mean (± standard deviation (SD)) concentration of rifamycin SV (ng/mL) versus time on Day 1 and Day 7 is shown during treatment in a study of healthy volunteers with an investigational rifamycin SV 600 mg coated tablet according to invention presented in the experimental section. 1: Rifamycin SV concentrations versus time on day 1 (

); 7: Rifamycin SV concentrations versus time per day 7 (

).

) сравнивается с рифаксимином (

) и рифампицином (

) (используется в качестве контроля). Данные были рассчитаны из 3 независимых экспериментов.Fig. 2: Rifamycin SV stimulates PXR transcriptional activity. In this study, the activity of rifamycin SV (

) compared with rifaximin (

) and rifampicin (

) (used as a control). Data were calculated from 3 independent experiments.

) сравнивается с рифаксимином (

), препаратом, получившим одобрение FDA для лечения СРК-Д. Данные были рассчитаны из 2 независимых экспериментов.Fig. 3: Showing rifamycin SV inhibition of NFkB (TNFα-induced) activity. In a study, the activity of rifamycin SV (

) compared with rifaximin (

), an FDA-approved drug for the treatment of IBS-D. Data were calculated from 2 independent experiments.

), рифаксимином (

) или рифампицином (

) транскрипционной активности NFkB, индуцированной PMA (4A), ФНОα (4B) или ЛПС (4C) в репортерной клеточной линии NFkB.Fig. 4A-4C: Rifamycin inhibition of SV is shown (

), rifaximin (

) or rifampicin (

) NFkB transcriptional activity induced by PMA (4A), TNFα (4B) or LPS (4C) in the NFkB reporter cell line.

DETAILED DESCRIPTION

In one aspect, an oral pharmaceutical composition is provided in the form of a solid dosage form containing approximately 600 mg of rifamycin SV or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the oral pharmaceutical composition is formulated for modified release. In one aspect, 600 mg of rifamycin SV sodium on a dry basis is equivalent to 582 mg of rifamycin SV on a dry basis.

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

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

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

In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided, wherein the oral pharmaceutical composition is formulated to release rifamycin SV or a pharmaceutically acceptable salt thereof substantially in the small intestine.

In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided, wherein the oral pharmaceutical composition is formulated to release rifamycin SV or a pharmaceutically acceptable salt thereof substantially after passage of the solid dosage form into the pylorus duct in the proximal colon.

In one aspect, any of the oral pharmaceutical compositions disclosed herein further comprising one or more of a lipophilic compound, a hydrophilic compound, and an amphiphilic compound are provided.

In one aspect, any of the oral pharmaceutical compositions disclosed herein further comprising one or more lipophilic compounds are provided.

In one aspect, any of the oral pharmaceutical compositions disclosed herein further comprising one or more hydrophilic compounds are provided.

In one aspect, any of the oral pharmaceutical compositions disclosed herein further comprising one or more amphiphilic compounds are provided.

In one aspect, any of the oral pharmaceutical compositions disclosed herein further comprising one or more lipophilic compounds and one or more hydrophilic compounds are provided.

In one aspect, any of the oral pharmaceutical compositions disclosed herein further comprising one or more lipophilic compounds and one or more amphiphilic compounds are provided.

In one aspect, any of the oral pharmaceutical compositions disclosed herein further comprising one or more hydrophilic compounds and one or more amphiphilic compounds are provided.

In one aspect, any of the oral pharmaceutical compositions disclosed herein further comprising an enteric coating are provided.

In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided wherein rifamycin SV, or a pharmaceutically 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 other aspects, any oral pharmaceutical compositions disclosed herein are provided wherein rifamycin SV, or a pharmaceutically 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 from about pH 5 to about pH 6.5, or from about pH 5 to about pH 6.

In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided, wherein the solid dosage form comprises a core and an enteric coating that coats the core. In one aspect, the core is a matrix, mixture, compressed mixture or dispersion of the ingredients included in the core. In one aspect, the coating is applied directly to the core. In one embodiment, the core may also contain one or more of microcrystalline cellulose, lactose (such as lactose monohydrate), colloidal silicon dioxide, povidone and/or copovidone, and microcrystalline cellulose.

In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided wherein administration of one or more solid dosage forms to a subject results in a t _max.0-24 of rifamycin SV in the subject's plasma of approximately 9.50 hours.

In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided, wherein administration of three or more solid dosage forms to a subject results in a C _max.0-6 of rifamycin SV in the subject's plasma of approximately 2.19±1.94 ng/mL. . In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided wherein administration of three or more solid dosage forms to a subject exhibits a C _max.0-6 of rifamycin SV in the subject's plasma of greater than about 2.19 ng/mL.

In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided, wherein administration of three or more solid dosage forms to a subject results in _{a Cmax.0-24} of rifamycin SV in the subject's plasma of approximately 5.79 ± 4.24 ng/mL. In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided wherein administration of three or more solid dosage forms to a subject exhibits a C _{max 0-24} of rifamycin SV in the subject's plasma of greater than about 5.79 ng/mL.

In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided wherein administration of three or more solid dosage forms to a subject exhibits an AUC _0-6 of rifamycin SV in the subject's plasma of approximately 3.26±2.85 (ng)(h)/ ml. In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided wherein administration of three or more solid dosage forms to a subject exhibits a subject's plasma AUC _0-6 of rifamycin SV greater than about 3.26 (ng)(h)/mL.

In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided, wherein administration of three or more solid dosage forms to a subject exhibits an AUC of _0-24 rifamycin SV in the subject's plasma of approximately 43.67±20.15 (ng)(h)/ ml. In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided wherein administration of three or more solid dosage forms to a subject exhibits a plasma AUC _0-24 of rifamycin SV in the subject's plasma of greater than about 43.67 (ng)(h)/mL.

In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided, wherein administration of the oral pharmaceutical composition to a subject exhibits an AUC and/or _Cmax of rifamycin SV in the subject's plasma that ranges from about 80% to 125% of the values disclosed in the present description.

In one aspect, oral pharmaceutical compositions are provided that are bioequivalent to any of the oral pharmaceutical compositions disclosed herein.

In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided, wherein they provide a urinary elimination rate of rifamycin SV in the subject to which the oral pharmaceutical composition is administered, no more than about 1% of the total amount of rifamycin SV, or a pharmaceutically acceptable salt thereof, input to the object.

In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided wherein said pharmaceutical composition releases no more than about 10% of the amount of rifamycin SV or a pharmaceutically acceptable salt thereof, including the pharmaceutical composition when the pharmaceutical composition is placed in a dissolution rate device. II USP corresponding to USP <711> for 2 hours, in which the dissolution rate device contains 1000 ml of an aqueous solution containing 0.1 M hydrochloric acid and 0.4% macrogol cetostearyl ester at pH 1 and a temperature of 37 ± 0 .5°C, and in which the aqueous solution is stirred at a speed of 50 rpm. In other aspects, any of the oral pharmaceutical compositions disclosed herein are provided wherein the pharmaceutical composition releases no more than about 5%, no more than about 2.5%, no more than about 2%, or no more than about 1% of the amount of rifamycin SV or a pharmaceutically acceptable salt thereof, including a pharmaceutical composition, when the pharmaceutical composition is placed in a USP II dissolution rate device conforming to USP <711> for 2 hours, in which the dissolution rate device contains 1000 ml of an aqueous solution containing 0.1 M hydrochloric acid and 0.4% macrogol cetostearyl ester at pH 1 and 37±0.5° C., and in which the aqueous solution is stirred at 50 rpm.

In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided wherein the pharmaceutical composition releases no more than about 20% of the amount of rifamycin SV or a pharmaceutically acceptable salt thereof, including the pharmaceutical composition when the pharmaceutical composition is placed in a dissolution rate device II USP corresponding to USP <711> for 1 hour, in which the dissolution rate device contains 900 ml of aqueous buffer at pH 6.4 and a temperature of 37±0.5°C, and in which the aqueous solution is stirred at a speed of 100 rpm /min In other aspects, any of the oral pharmaceutical compositions disclosed herein are provided wherein the pharmaceutical composition releases no more than about 15%, no more than about 10%, no more than about 5%, no more than about 2.5%, no more than about 2% or no more than about 1% of the amount of rifamycin SV or a pharmaceutically acceptable salt thereof, including the pharmaceutical composition, when the pharmaceutical composition is placed in a USP II dissolution rate device conforming to USP <711> for 1 hour, in in which the dissolution rate device contains 900 ml of an aqueous buffer at pH 6.4 and a temperature of 37±0.5°C, and in which the aqueous solution is stirred at a speed of 100 rpm.

In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided wherein the pharmaceutical composition releases from about 20% to about 60% of the amount of rifamycin SV or a pharmaceutically acceptable salt thereof, including the pharmaceutical composition, when the pharmaceutical composition is placed in a rate-determining device. dissolution II USP corresponding to USP <711> for 3 hours, in which the dissolution rate device contains 900 ml of an aqueous buffer at pH 6.4 and a temperature of 37±0.5°C, and in which the aqueous solution is stirred at a speed 100 rpm

In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided wherein the pharmaceutical composition releases at least about 50% of the amount of rifamycin SV or a pharmaceutically acceptable salt thereof, including the pharmaceutical composition when the pharmaceutical composition is placed in a dissolution rate device II USP corresponding to USP <711> for 6 hours, in which the dissolution rate device contains 900 ml of aqueous buffer at pH 6.4 and a temperature of 37±0.5°C, and in which the aqueous solution is stirred at a speed of 100 rpm /min In other aspects, any of the oral pharmaceutical compositions disclosed herein are provided wherein the pharmaceutical composition releases at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, not less than about 90%, or not less than about 95% of the amount of rifamycin SV or a pharmaceutically acceptable salt thereof, including the pharmaceutical composition, when the pharmaceutical composition is placed in a USP II dissolution rate device conforming to USP <711>, in for 6 hours, in which the dissolution rate device contains 900 ml of an aqueous buffer at pH 6.4 and a temperature of 37±0.5°C, and in which the aqueous solution is stirred at a speed of 100 rpm.

In one aspect, any of the oral pharmaceutical compositions disclosed herein is provided, wherein the pharmaceutical composition contains no more than about 2% by weight of rifamycin S. In other aspects, any of the oral pharmaceutical compositions disclosed herein, wherein the composition contains not more than about 1.5 wt.%, not more than about 1.25 wt.%, not more than about 1 wt.%, not more than about 0.75 wt.%, not more than about 0.5 wt. .%, not more than about 0.25 wt.%, not more than about 0.2 wt.%, not more than about 0.1 wt.%, or not more than about 0.05 wt.% rifamycin S.

In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided wherein the pharmaceutical composition contains no more than about 1 wt % rifamycin B. In other aspects, any of the oral pharmaceutical compositions disclosed herein are provided wherein the pharmaceutical composition contains no more than about 0.75 wt.%, no more than about 0.5 wt.%, no more than about 0.25 wt.%, no more than about 0.2 wt.%, no more than about 0 15 wt.% or not more than about 0.1 wt.% rifamycin B.

In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided, wherein the pharmaceutical composition contains no more than 10,000 ppm ethanol. In other aspects, any of the oral pharmaceutical compositions disclosed herein are provided wherein the pharmaceutical composition contains no more than 7500 ppm, no more than 7000 ppm, no more than 6000 ppm, no more than 5500 ppm ppm, not more than 5000 ppm or not more than 4500 ppm ethanol.

In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided wherein the solid dosage form contains less than about 2% by weight of rifamycin S after storage of the solid dosage form at 25°C and 60% relative humidity for 3 months. In other aspects, any of the oral pharmaceutical compositions disclosed herein are provided wherein the solid dosage form contains less than about 1 wt.%, less than about 0.75 wt.%, less than about 0.5 wt.%, less than than about 0.25 wt.% or less than about 0.1 wt.% rifamycin S after storage of the solid dosage form at 25°C and 60% relative humidity for 3 months.

In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided wherein the solid dosage form contains less than about 2% by weight of rifamycin S after storage of the solid dosage form at 40° C. and 75% relative humidity for 1 month. In other aspects, any of the oral pharmaceutical compositions disclosed herein are provided wherein the solid dosage forms comprise less than about 1.75 wt%, less than about 1.5 wt%, less than about 1.25 wt%. , less than about 1 wt.%, less than about 0.75 wt.%, less than about 0.5 wt.%, less than about 0.25 wt.%, or less than about 0.1 wt.% rifamycin S after storage of the solid dosage form at 40° C. and 75% relative humidity for 1 month.

In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided wherein the solid dosage form contains less than 1 wt% rifamycin B after storage of the solid dosage form at 40° C. and 75% relative humidity for 1 month. In other aspects, any of the oral pharmaceutical compositions disclosed herein are provided wherein the solid dosage forms comprise less than about 0.75 wt%, less than about 0.5 wt%, less than about 0.25 wt%. or less than about 0.1 wt.% rifamycin B after storage of the solid dosage form at 40°C and 75% relative humidity for 1 month.

In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided wherein the solid dosage form contains less than 2 wt% rifamycin S after storage of the solid dosage form at 30° C. and 65% relative humidity for 1 month. In other aspects, any of the oral pharmaceutical compositions disclosed herein are provided wherein the solid dosage forms comprise less than about 1.75 wt%, less than about 1.5 wt%, less than about 1.25 wt%. , less than about 1 wt.%, less than about 0.75 wt.%, less than about 0.5 wt.%, less than about 0.25 wt.%, or less than about 0.1 wt.% rifamycin S after storage of the solid dosage form at 30° C. and 65% relative humidity for 1 month. All of the above wt.% rifamycin S is measured in relation to the amount of rifamycin SV (as indicated in the claims) present in the composition.

In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided wherein the solid dosage form contains less than 1 wt % rifamycin B after storage of the solid dosage form at 30° C. and 65% relative humidity for 1 month. In other aspects, any of the oral pharmaceutical compositions disclosed herein are provided wherein the solid dosage forms comprise less than about 0.75 wt%, less than about 0.5 wt%, less than about 0.25 wt%. or less than about 0.1 wt.% rifamycin B after storage of the solid dosage form at 30°C and 65% relative humidity for 1 month.

In the embodiments described above, the weight % of rifamycin S and rifamycin B is expressed as the amount of rifamycin S and rifamycin B, respectively, divided by the stated amount of rifamycin SV in the composition. For example, a composition intended to include 600 mg of rifamycin SV sodium would have a stated claimed amount of rifamycin SV sodium of 600 mg. This stated claim amount of rifamycin SV sodium of 600 mg may also, or alternatively, correspond to the stated claim amount of 582 mg rifamycin SV.

In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided wherein the solid dosage form is contained in a package, wherein the package contains materials to protect the solid dosage form from heat and light. In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided wherein the package contains aluminum. In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided wherein the package comprises aluminum blister packs.

In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided wherein the solid dosage form is in the form of a tablet. In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided, wherein the tablet comprises a tablet core and an enteric coating coating said tablet core. In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided wherein the enteric 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 are provided wherein an enteric coating is applied to a tablet core using a coating composition. In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided, wherein the coating composition contains one or more of an organic solvent and water. In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided, wherein the organic solvent comprises one or more of one or more organic alcohols. In one aspect, any of the oral pharmaceutical compositions disclosed herein are 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 are provided wherein the coating composition substantially excludes water. In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided wherein the coating composition substantially excludes ethanol.

In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided for use in the prevention/relapse prevention and/or treatment of small intestinal bacterial overgrowth syndrome (SIBO).

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

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

In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided for use in the prevention/relapse prevention and/or treatment of irritable bowel syndrome with alternating diarrhea and constipation (IBS-S).

In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided for use in the prevention/relapse prevention and/or treatment of cholera.

In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided for use in the prevention/relapse prevention and/or treatment of hepatic encephalopathy. In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided for use in reducing the risk of recurrence of overt hepatic encephalopathy (HE) and/or reducing the risk of recurrence of new overt HE.

In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided for use in the prevention/relapse prevention and/or treatment of liver cirrhosis.

In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided for use in the prevention of occurrence/relapse and/or the treatment of pouchitis.

In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided for use in the prevention of occurrence/relapse and/or treatment of spontaneous bacterial peritonitis.

In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided for use in the prevention/relapse prevention and/or treatment of NAFLD.

In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided for use in the prevention/relapse prevention and/or treatment of NAFLD.

In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided for use in the prevention/relapse prevention and/or treatment of NASH.

In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided, wherein the oral pharmaceutical composition is administered to the subject at a daily dose of about 600 mg, about 1200 mg, or about 1800 mg of a pharmaceutically acceptable salt of rifamycin SV. In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided, wherein the oral pharmaceutical composition comprises rifamycin SV sodium and is administered to the subject in a daily dose equivalent to about 582 mg, about 1164 mg, or about 1746 mg of rifamycin SV.

In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided, wherein the composition is administered to a subject once, twice, or three times a day.

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

In one aspect, a method is provided for the treatment and/or prevention of irritable bowel syndrome (IBS) in a subject in need of such treatment, comprising administering to the subject an effective amount of any of the oral pharmaceutical compositions disclosed herein. In one aspect, a method of treatment is provided in which IBS is diarrhea-predominant (IBS-D). In one aspect, a method of treatment is provided wherein IBS has an alternation of diarrhea or constipation predominance (IBS-C).

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

In one aspect, a method is provided for treating and/or preventing hepatic encephalopathy in a subject in need of such treatment, comprising administering to the subject an effective amount of any of the oral pharmaceutical compositions disclosed herein. In one aspect, a method is provided for reducing the risk of recurrence of overt hepatic encephalopathy (HE) in a subject in need of such treatment and/or reducing the risk of recurrence of new overt HE in a subject in need of such treatment, comprising administering to the subject an effective amount of any of an oral pharmaceutical composition, disclosed in the present description.

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

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

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

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

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

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

In one aspect, any of the methods of treatment disclosed herein is provided wherein the oral pharmaceutical composition is administered to the subject at a daily dose of 600 mg, 1200 mg, or 1800 mg of a pharmaceutically acceptable salt of rifamycin SV. In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided, wherein the oral pharmaceutical composition comprises rifamycin SV sodium and is administered to the subject in a daily dose equivalent to about 582 mg, about 1164 mg, or about 1746 mg of rifamycin SV.

In one aspect, any of the methods of treatment disclosed herein is provided, wherein the oral pharmaceutical composition is administered to the subject once, twice, three times, or several times a day.

In one aspect, any of the methods of treatment disclosed herein is provided, comprising administering to the 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. In other aspects, any of the methods of treatment disclosed herein are provided, comprising administering to the 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, or 2 or more, or 3 or more, or 4 or more, or 5 or more, or 6 or more, or 7 or more, or 8 or more, or 9 or more, or 10 or more, or 11 or more, or 12 or more, or 13 or more, or 14 or more, or 15 or more, or 16 or more, or 17 or more, or 18 or more, or 19 or more, or 20 or more, or 21 or more, or 22 or more, or 23 or more, or 24 or more, or 25 or more, or 26 or more, or 27 or more, or 28 or more, or 29 or more, or 30 or more days.

In one aspect, any of the methods of treatment disclosed herein is provided, comprising administering to the 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 day. In other aspects, any of the methods of treatment disclosed herein are provided, comprising administering to the subject any of the oral pharmaceutical compositions disclosed herein, 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.

In one aspect, there is provided a method of treating a subject having IBS-D, comprising administering to the subject an effective amount of any of the oral pharmaceutical compositions disclosed herein, wherein the subject experiences an improvement in the Bristol stool shape score after administration of the oral pharmaceutical composition. In other aspects, upon administration of an effective amount of any of the oral pharmaceutical compositions disclosed herein, the subject experiences 20% or more, 25% or more, 30% or more, 40% or more, 45% or more, or 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 per week during which the subject has stool type 6 or 7 on the Bristol stool form scale.

In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided, wherein the rifamycin SV or a pharmaceutically acceptable salt thereof is rifamycin sodium.

In one aspect, any of the uses or methods disclosed herein is provided wherein the rifamycin SV, or a pharmaceutically acceptable salt thereof, is rifamycin sodium.

In one aspect, provided are any of the oral pharmaceutical compositions disclosed herein containing rifamycin SV or a pharmaceutically acceptable salt thereof, preferably the sodium salt, which are formulated to provide a sustained release profile of rifamycin SV or a pharmaceutically acceptable salt thereof.

In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided containing rifamycin SV or a pharmaceutically acceptable salt thereof, preferably the sodium salt, which release rifamycin SV or a pharmaceutically acceptable salt thereof in the small intestine (duodenum, jejunum, and ileum) .

In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided, comprising rifamycin SV or a pharmaceutically acceptable salt thereof, preferably the sodium salt, which initiates the release of rifamycin SV or a pharmaceutically acceptable salt thereof in the small intestine (duodenum, jejunum, and ileum). ) and may continue in the large intestine.

In one embodiment, rifamycin SV or a pharmaceutically acceptable salt thereof is released from the composition of the present invention, starting with the dissolution and/or destruction of the enteric coating at the beginning of the proximal intestine, namely the small intestine. In one embodiment of the present invention, rifamycin SV or a pharmaceutically acceptable salt thereof is released from the composition of the present invention only after passage of the pylorus in the proximal intestine, namely the small intestine, starting with the dissolution and/or destruction of the enteric coating. In one embodiment of the present invention, rifamycin SV, or a pharmaceutically acceptable salt thereof, is released from a composition of the present invention when the composition is exposed to an environment from about pH 5 to about pH 7.5, preferably from about pH 5.5 to about pH 7.0, greater than preferably from about pH 6.0 to about pH 6.5. In a preferred embodiment, rifamycin SV, or a pharmaceutically acceptable salt thereof, is released from the composition of the present invention when the composition is exposed to an environment of approximately pH 6.4. In one embodiment of the present invention, rifamycin SV, or a pharmaceutically acceptable salt thereof, is released from the composition of the present invention in an amount greater than 80% over a period of about 3 to about 12 hours, preferably over a period of 4 to 11 hours, more preferably within a period of time from about 5 hours to about 10 hours, most preferably from about 5 hours to about 9 hours. In a preferred embodiment, rifamycin SV, or a pharmaceutically acceptable salt thereof, is released from the composition of the present invention in an amount greater than 80% over a period of approximately 6 hours. In one embodiment of the present invention, rifamycin SV, or a pharmaceutically acceptable salt thereof, is released from the composition of the present invention in an amount greater than 80% over a period of about 3 to about 12 hours when exposed to an environment of about pH 5 to about pH 7.5.

In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided wherein rifamycin SV, or a pharmaceutically acceptable salt thereof, is released from the composition of the present invention starting in the small intestine and optionally continuing into the colon.

In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided containing rifamycin SV or a pharmaceutically acceptable salt thereof, preferably the sodium salt, which only begin to release rifamycin SV or a pharmaceutically acceptable salt thereof after passage of the pylorus in the proximal intestine after dissolution and/ or destruction of the enteric coating.

In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided comprising rifamycin SV or a pharmaceutically acceptable salt thereof, preferably the sodium salt, wherein rifamycin SV or a pharmaceutically acceptable salt thereof is released when the composition is exposed to an environment of about pH 5 to about pH 7.5, preferably from about pH 5.5 to about pH 7.0, more preferably from about pH 6.0 to about pH 6.5.

In one aspect, any of the oral pharmaceutical compositions disclosed herein are provided wherein release of rifamycin SV or a pharmaceutically acceptable salt thereof from the composition is initiated when the composition is exposed to an environment of approximately pH 5.5. In another embodiment, pharmaceutical compositions wherein release of rifamycin SV or a pharmaceutically acceptable salt thereof begins when the composition is exposed to an environment of approximately pH 6.0. In another embodiment, the pharmaceutical compositions disclosed herein begin releasing rifamycin SV, or a pharmaceutically acceptable salt thereof, when the composition is exposed to an environment of approximately pH 6.4.

The present invention relates to oral pharmaceutical compositions containing rifamycin SV or a pharmaceutically acceptable salt thereof, preferably the sodium salt, which begin to release rifamycin SV or a pharmaceutically acceptable salt thereof approximately 3 hours after administration of the composition and may continue up to 12 hours. Preferably, release begins after about 3 hours and continues up to 9 hours.

Suitable salts of rifamycin SV according to the invention may be selected between sodium or potassium, preferably the sodium salt.

The oral pharmaceutical compositions of the invention are useful in the prevention and/or treatment of cholera and/or SIBO and/or IBS. In particular, the oral pharmaceutical compositions of the invention are useful in the prevention and/or treatment of IBS-C, IBS-D, IBS-C and/or IBS-N; preferably, the compositions of the invention are suitable for the prevention and/or treatment of IBS-D.

The oral pharmaceutical compositions of the invention are also useful in the prevention and/or treatment of diseases or disorders such as hepatic encephalopathy, cirrhosis, pouchitis, spontaneous bacterial peritonitis, NAFLD, NAFLD and/or NASH.

In one embodiment, the oral pharmaceutical compositions of the present invention comprise rifamycin SV or a pharmaceutically acceptable salt thereof, at least one lipophilic compound, at least one hydrophilic compound, optionally at least one amphiphilic compound, and optionally an enteric coating. .

The dosage of rifamycin SV or a pharmaceutically acceptable salt thereof, i.e. rifamycin SV or a pharmaceutically acceptable salt thereof, in the oral pharmaceutical compositions of the invention may be from about 400 mg/dose unit to about 2400 mg/dose unit, from about 400 mg/dose unit to about 2000 mg/dose unit, from about 400 mg/dose unit to about 1500 mg/dose unit, from about 400 mg/dose unit to about 1000 mg/dose unit, from about 400 mg/dose unit to about 800 mg/dose unit, about 500 mg/dose unit to about 700 mg/dose unit or from about 550 mg/dose unit to about 650 mg/dose unit, preferably about 600 mg of rifamycin SV or its pharmaceutically acceptable salt in anhydrous (dried) form. More preferably, the dosage of rifamycin SV or a pharmaceutically acceptable salt thereof in the oral pharmaceutical composition of the invention is about 600 mg/unit dose of rifamycin SV sodium in anhydrous (dried) form. All of the above dosages must be in anhydrous (dry) form.

In one aspect, when the oral pharmaceutical composition contains rifamycin SV sodium (as a dry matter), the equivalent amount of rifamycin SV (as a dry matter) 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 doses up 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 (dried). More preferably, the dosage of rifamycin SV or a pharmaceutically acceptable salt thereof in the oral pharmaceutical composition of the invention is approximately 600 mg/unit dose of rifamycin SV sodium anhydrous (dried), which is equivalent to 582 mg/unit dose of rifamycin SV anhydrous (dried). All of the above dosages must be in anhydrous (dry) form.

In one embodiment, the pharmaceutical compositions of the invention are administered at a daily dose ranging from about 600 mg to about 2400 mg, from about 600 mg to about 1800 mg, from about 600 mg to about 1200 mg, from about 800 mg to about 2400 mg, from about 1200 mg to about 2400 mg, or about 1200 mg to about 1800 mg in anhydrous (dried) form. In one embodiment, the pharmaceutical compositions of the invention are administered in a daily dose of about 600 mg, or about 1200 mg, or about 1800 mg in anhydrous (dried) form.

In one embodiment, when the oral pharmaceutical composition contains rifamycin SV sodium, an equivalent dry matter amount of rifamycin SV in the pharmaceutical composition is administered in a daily dose ranging from about 582 mg to about 2328 mg, from 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 (dried) form. In one embodiment, an equivalent amount of rifamycin SV in dry matter form in the pharmaceutical compositions of the invention, such pharmaceutical compositions are administered in a daily dose of about 582 mg, or about 1164 mg, or about 1746 mg in anhydrous (dried) form.

The preferred dosage of rifamycin SV or a pharmaceutically acceptable salt thereof, i.e. rifamycin SV or a pharmaceutically acceptable salt thereof, in the oral pharmaceutical compositions of the invention is approximately 600 mg/dose anhydrous (dried) or the equivalent of 582 mg/dose anhydrous rifamycin SV ( dried) when the dosage is 600 mg/unit dose of rifamycin SV sodium salt in anhydrous form (dried). It is known that the water content is usually about 12-17% for rifamycin SV or its salts. Therefore, in accordance with the present invention, the inventors refer to rifamycin SV or its pharmaceutically acceptable salts in anhydrous form (dried). In order to obtain one of the dosages of rifamycin SV or its pharmaceutically acceptable salt in anhydrous form as indicated above, the substance to be weighed must be corrected for water content.

In accordance with an embodiment of the invention, the weight ratio of said at least one lipophilic compound to said at least one hydrophilic compound is from about 1:30 to about 1:90, preferably about 1:66 or about 1:67.

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

According to an embodiment of the invention, the weight ratio of said at least one optional amphiphilic compound to said at least one hydrophilic compound is from about 1:10 to about 1:30, preferably about 1:20.

In accordance with an embodiment of the invention, the weight ratio of rifamycin SV or a pharmaceutically acceptable salt thereof, preferably the sodium salt, and said at least one lipophilic compound is from about 10:1 to about 30:1, preferably about 20:1.

In accordance with an embodiment of the invention, the weight ratio of rifamycin SV or a pharmaceutically acceptable salt thereof, preferably the sodium salt, and said at least one hydrophilic compound is from about 1:1 to about 6:1, preferably about 3:1.

In accordance with an embodiment of the invention, the weight ratio of rifamycin SV or a pharmaceutically acceptable salt thereof, preferably the sodium salt, and said at least one optional amphiphilic compound is from about 30:1 to about 90:1, preferably about 60:1.

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

According to another embodiment, the at least one hydrophilic compound is mainly cross-linked or linear polymeric or copolymeric substances, which are known as hydrogels, i.e. substances which, when going from dry to hydrated state, undergo so-called "molecular relaxation" , namely a significant increase in mass and weight after the coordination of a large number of water molecules by the polar groups present in their polymer chains. In particular, at least one hydrophilic agent may be selected from cellulose derivatives and their esters and/or salts, such as hydroxyalkylcelluloses (such as hydroxypropylcellulose, hydroxypropylmethylcellulose or sodium hydroxypropylmethylcellulose), alkylcelluloses, carboxyalkylcelluloses (such as sodium carboxymethylcellulose); polyvinyl alcohols; carboxyvinyl derivatives; polysaccharides such as dextrins, pectins, starches and their derivatives; natural or synthetic gums; alginic acid; polyalcohols such as xylitol, maltitol or mannitol. Mannitol or sodium carboxymethylcellulose is the preferred at least one hydrophilic compound; more preferably, they are both contained in the oral pharmaceutical composition of the present invention. For example, at least one hydrophilic compound may include starch or sodium starch glycolate. In one embodiment, at least one hydrophilic compound contains starch. In one embodiment, at least one hydrophilic compound contains sodium starch glycolate.

According to an embodiment, the compositions of the invention further comprise at least one humectant. The presence of at least one humectant allows the moisture level in the composition itself to be controlled and/or adjusted to ensure that rifamycin SV or a pharmaceutically acceptable salt thereof is not damaged by storage and/or exposure to moisture. The at least one humectant may be selected from mannitol, sorbitol, lactose, maltodextrins, or mixtures thereof. Preferably, at least one humectant is mannitol.

As mentioned above, rifamycin SV or its salts have a water content of approximately 12-17%, and therefore there is an additional need to maintain or improve the stability of this rifamycin SV or its pharmaceutically acceptable salt in the composition itself when interacting with other excipients with a lower content of coordinated water. .

Controlling the water content of the composition, in addition to helping to maintain or improve the stability profile of rifamycin SV or its salts in the composition, also provides more suitable compression characteristics in the case of a tablet, creating an acceptable industrial compression stress profile.

At least one amphiphilic compound which may optionally be used in accordance with the invention includes polar lipids type I or 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.

The oral pharmaceutical composition according to the present invention may also contain at least one physiologically acceptable excipient, for example, bioadhesive excipients such as chitosans, polyacrylamides, natural or synthetic gums, acrylic acid polymers and copolymers.

In any case, it should be noted that the above compounds and/or excipients may have different properties in different environments.

An oral pharmaceutical composition according to the present invention may be prepared according to the more general tableting process or the methods described in WO 0076478, which are incorporated herein by reference.

According to an embodiment, the oral pharmaceutical compositions of the invention may be coated with an enteric coating (film) which may contain polymethacrylates, polymers or copolymers of acrylic and/or methacrylic acids, or cellulose derivatives such as cellulose acetate phthalate. According to a preferred embodiment, the enteric coating contains polymethacrylates, including but not limited to compounds known commercially as Eudragit S100 (methacrylic acid/methyl methacrylate copolymer 1:2), Eudragit L100 (methacrylic acid/methyl methacrylate copolymer 1:1) and/ or Eudragit L30 D55 (1:1 copolymer of methylacrylic acid and ethyl acrylate). According to a preferred embodiment, the enteric coating comprises a 1:1 copolymer of methacrylic acid and methyl methacrylate (Eudragit L100). According to another preferred embodiment, the enteric coating comprises a 1:1 copolymer of methylacrylic acid and ethyl acrylate (Eudragit L30 D55). In one embodiment, the enteric 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.

According to an embodiment, the solvent used to solubilize the enteric coating may be organic, aqueous, and/or mixtures thereof. Organic solvents may be selected from ethanol, isopropanol, acetone, or mixtures thereof. Preferably, the organic solvent is ethanol.

It has been surprisingly found that the aqueous solvent used to form the enteric coating of the invention can provide improved stability of rifamycin SV or a pharmaceutically acceptable salt thereof in pharmaceutical compositions by reducing the formation of impurities of rifamycin SV or a pharmaceutically acceptable salt thereof by itself. It was very surprisingly found given the known sensitivity of rifamycin SV or a salt thereof to the presence of water, and it was unexpected that stabilization of such rifamycin SV or a pharmaceutically acceptable salt thereof was obtained in the composition of the present invention. In one embodiment, the aqueous enteric coating provides less than about 2.0 wt.% total impurities after 24 months at 25° C. and 60% relative humidity. In another embodiment, the aqueous enteric coating provides less than about 1.5 wt% total impurities after 24 months at 25°C/60% RH.

In one embodiment, the aqueous enteric coating provides a content of less than about 3.0 wt.% total impurities after 36 months at 25°C and 60% relative humidity. In another embodiment, the aqueous enteric coating provides a content of less than about 2.5 wt.% total impurities after 36 months at 25°C and 60% relative humidity. In another embodiment, the aqueous enteric coating provides less than about 2.0 wt.% total impurities after 36 months at 25°C and 60% relative humidity. The above wt.% total impurities are calculated relative to the amount of rifamycin SV (as indicated in the claims).

The enteric coating of the pharmaceutical compositions of the invention can modulate the onset of release of rifamycin SV or a pharmaceutically acceptable salt thereof from the pharmaceutical compositions of the invention, as disclosed above.

According to a further embodiment, the enteric coating may also optionally contain at least one plasticizer, at least one colorant, or a mixture thereof.

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

According to an embodiment of the invention, the oral pharmaceutical composition is a tablet containing a core and an enteric coating. In another embodiment, the oral pharmaceutical composition is a tablet consisting essentially of a core and an enteric coating. In another embodiment, the oral pharmaceutical composition is a tablet consisting of a core and an enteric coating. In one embodiment, the coating covers the core. In another embodiment, the coating is applied directly to or completely on the core.

In one embodiment, the core is a matrix containing the ingredients found in the core, as described in this application. In another embodiment, the core is a mixture containing the ingredients found in the core, as described in this application. In one embodiment, the core is a compressed mixture containing the ingredients found in the core, as described in this application. In one embodiment, the core is a dispersion containing the ingredients found in the core, as described in this application.

In one embodiment, the core is a matrix of ingredients, where the ingredients contain the ingredients described in this application. In another embodiment, the core is a mixture of ingredients, where the ingredients contain the ingredients described in this application. In one embodiment, the core is a compressed mixture of ingredients, where the ingredients contain the ingredients described in this application. In one embodiment, the core is a dispersion consisting of ingredients, where the ingredients contain the ingredients described in this application.

In accordance with one embodiment, the core may contain sodium rifamycin SV, ascorbic acid, lecithin, stearic acid, sodium carboxymethyl cellulose, mannitol, colloidal anhydrous silica, and magnesium stearate; the enteric coating may contain 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 iron oxide), talc, triethyl citrate and optionally PEG6000. The enteric coating can be prepared in aqueous or alcoholic (organic) solutions.

Therefore, one of the advantages of the oral pharmaceutical composition of the invention is its certain site-specificity in relation to the small intestine. Due to the specific composition of the present invention, rifamycin SV or its pharmaceutically acceptable salt is actually released from the composition, starting with the dissolution and/or destruction of the enteric coating at the beginning of the proximal intestine, maximizing the therapeutic effect of rifamycin SV or its pharmaceutically acceptable salt in the part that is affected by SIBO , and/or IBS, and/or cholera.

Another advantage of the oral pharmaceutical composition of the invention lies in the possibility of obtaining improved stabilization of rifamycin SV or a pharmaceutically acceptable salt thereof.

In another embodiment, the oral pharmaceutical compositions of the present invention have a dissolution rate of less than about 10% over about 2 hours when measured at pH 1.

In one embodiment, the oral pharmaceutical compositions of the present invention have a dissolution rate of less than about 20% over about 1 hour when measured at about pH 6.4.

In one embodiment, the oral pharmaceutical compositions of the present invention have a dissolution rate of from about 20% to about 60% in about 3 hours when measured at about pH 6.4.

In one embodiment, the oral pharmaceutical compositions of the present invention have a dissolution rate greater than or equal to about 80% rifamycin SV in about 6 hours when measured at about pH 6.4.

In accordance with the invention, solubility is measured using a USP type II dissolution rate apparatus equipped with a paddle at 100 rpm at 37°±2°C.

In one embodiment, the oral pharmaceutical compositions of the present invention have a dissolution rate of less than about 20% over about 1 hour, from about 20% to about 60% over about 3 hours, and equal to or greater than about 80% over about 6 hours as measured at approximately pH 6.4 using a USP type II dissolution rate apparatus equipped with a spatula at 100 rpm at 37°±2°C.

In some embodiments, rifamycin SV, or a pharmaceutically acceptable salt thereof, is thus exclusively released in the small intestine, allowing full release of rifamycin SV, or a salt thereof, preferably the sodium salt, where necessary to maximize treatment and efficacy.

In some other embodiments, rifamycin SV, or a pharmaceutically acceptable salt thereof, is released starting from the small intestine and continuing into the large intestine.

The oral pharmaceutical compositions of the invention are most suitable for the prevention and/or treatment of SIBO and/or IBS because they suppress bacterial overgrowth to normal levels of growth.

The oral pharmaceutical compositions of the invention are most suitable for the prevention and/or treatment of cholera.

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

In one embodiment, the present invention is a method for the prevention and/or treatment of IBS-C, IBS-D, IBS-C and/or IBS-N; preferably a treatment for IBS-D comprising administering an oral pharmaceutical composition of the present invention to a subject in need of such treatment, preferably a human.

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

In another embodiment, the present invention is a method of 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 in need of such treatment, preferably a human.

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

The oral pharmaceutical compositions of the invention preferably contain about 600 mg/unit dose of rifamycin SV or a pharmaceutically acceptable salt thereof in anhydrous form (ie rifamycin SV or a pharmaceutically acceptable salt thereof, preferably rifamycin SV sodium salt). When the oral pharmaceutical compositions of the invention contain 600 mg/dose anhydrous rifamycin SV sodium salt, the equivalent amount of rifamycin SV anhydrous is 582 mg/dose unit.

In one embodiment, the compositions are preferably administered according to a dosing regimen of three tablets per day (i.e., tid, three times a day, or all together once a day ) to achieve an optimal daily dose of approximately 1800 mg/day. The indicated tid daily dosing regimen preferably lasts 14 days, but may last for several months.

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

The following experimental section describes the invention in detail without limiting its content in any way.

EXAMPLES

Example 1 : 600 mg rifamycin sodium sustained release coated tablets were prepared having the qualitative-quantitative composition disclosed in Table 1.

Coated with organic film (enteric coating)

Table 1

Ingredients Unit Amount per tablet Core Composition Sodium rifamycin SV ⁽¹⁾ mg 600 ⁽¹⁾ Ascorbic acid mg 30.0 Lecithin mg 10.0 Stearic acid mg 30.0 Sodium carboxymethyl cellulose (Na CMC) mg 200.0 Mannitol mg 215.0 ⁽²⁾ Colloidal Anhydrous Silica mg 20.0 magnesium stearate mg 25.0 Coating composition Copolymer of methacrylic acid and methyl methacrylate (1:1) (Eudragit® L100) mg 41.0 Titanium dioxide mg 11.0 iron oxide red mg 0.6 Talc mg 18.2 triethyl citrate mg 8.2 Polyethylene glycol 6000 mg 1.0 Ethanol ³ -- -- Purified water ³ -- --

⁽¹⁾ as anhydrous (dried) equivalent to approximately 702 mg of rifamycin SV sodium salt in hydrated form, given an average water content of approximately 14.5%.

⁽²⁾ the amount of mannitol is adjusted to compensate for the correction of the sodium amount of rifamycin SV based on water content.

⁽³⁾ Purified water and ethanol are essentially removed during the manufacturing process.

Rifamycin SV (sodium salt), ascorbic acid, lecithin, stearic acid and a portion of magnesium stearate were mixed in a suitable container until a homogeneous dispersion was obtained. Then added mannitol, sodium carboxymethylcellulose and silicon dioxide and the mixture was again stirred; the addition of magnesium stearate was completed and the powder was compressed in a rotary tablet machine to obtain tablet cores. The latter were then coated in a Eudragit L100 coater with triethyl citrate, talc, titanium dioxide and red iron(III) dioxide using ethanol as the enteric coating solvent. The tablets were then polished by adding a small amount of polyethylene glycol 6000 to the aqueous solution.

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

table 2

Tools Dissolution rate device II USP conforming to USP <711>; UV and visible spectrophotometer connected to a PC for data logging Agitator speed 50 rpm Wednesday HCl 0.1M+0.4% macrogol cetostearyl ether Volume 1000 ml average temperature 37±0.5°C Test period 2 hours Wavelength 299 nm Quartz glass cell 0.1 cm

The dissolution test was carried out by transferring 1000 ml of pH 1 dissolution medium into a test vessel and heating 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 of each vessel was withdrawn, filtered and analyzed in comparison with a blank sample containing the dissolution medium using a UV-visible spectrophotometer.

At the end of the dissolution period (2 hours), the dissolution medium of each vial will be aspirated, filtered and analyzed against a blank sample using a UV-visible spectrophotometer. The amount of rifamycin SV sodium released from the tablet in the test vessel was calculated using the formula:

Where:

A _c =Absorption of the sample solution;

R _f = Calibration curve response factor (mg/mL concentration versus absorbance of standard solutions);

1000=Volume of dissolution (ml);

600=Theoretical amount of rifamycin SV sodium (mg/tablet).

The amount of rifamycin SV released from tablets prepared according to Example 1 in a pH 1 dissolution test is disclosed in Table 3:

Table 3

Time Amount of rifamycin SV released from tablet in dissolution medium at pH 1 (% of total rifamycin SV sodium contained in test tablet) 2 hours BUT*

*N/O=not detected within detection limits of the analytical method used.

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

Table 4

Tools Dissolution rate device II USP conforming to USP <711>; UV and visible spectrophotometer connected to a PC for data logging Agitator speed 100 rpm Wednesday Buffer pH 6.4 USP Volume 900 ml average temperature 37±0.5°C Test period 6 hours in pH 6.4 USP buffer Wavelength 314 nm Quartz glass cell 0.1 cm

The test solution was prepared by dissolving 6.8 g of monobasic potassium phosphate (KH ₂ PO ₄ ) and 0.5 g of NaOH in approximately 400 ml of purified water and diluting with purified water to a total volume of 1000 ml. The standard solution for use in the analytical method was prepared as a 0.67 mg/ml solution of rifamycin SV WS in dissolution medium.

The dissolution test was carried out by transferring 900 ml of pH 6.4 buffer into a test vessel and heating the solution to 37°C±0.5°C. One tablet of the composition was added to the test vessel. At a predetermined sampling time, the dissolution medium of each vial was withdrawn, filtered and analyzed against a blank sample containing the dissolution medium using a UV-visible spectrophotometer. The amount of rifamycin SV sodium released from the tablet in the test vessel was calculated using the formula:

Where:

A _c =Absorption of the sample solution;

R _f = Calibration curve response factor (mg/mL concentration versus absorbance of standard solutions);

900=Volume of dissolution (ml);

600=Theoretical amount of rifamycin SV sodium (mg/tablet).

The amounts of rifamycin SV released from tablets prepared according to Example 1 in the pH 6.4 dissolution test are disclosed in Table 5.

Table 5

Time Amount of rifamycin SV released from tablet in dissolution medium at pH 6.4 (% of total rifamycin SV sodium contained in test tablet) 1 hour 2% 2 hours 13% 3 hours 37% 4 hours 58% 6 hours >80% (95%, 96% and 94% based on a three tablet study)

Stability: A stability study was performed on a single batch of tablets made according to Example 1, in accordance with the ICH Guidelines for Stability Studies of New Drugs. The tablets were placed at 25°C/60% RH. The results are presented in Table 5a below.

Table 5a

Moment of time Analysis (mg/tablet) Analysis (% claimed content) Rifamycin S (%) Any other related compounds (%) Total number of related compounds (%) 0 592.0 98.7 <0.02 0.09 0.32 6 months 576.3 96.1 0.06 0.24 0.71 12 months 579.6 96.6 0.07 0.28 1.23 24 months 574.2 95.7 0.07 0.35 1.68 36 months 574.0 95.7 0.11 0.33 2.02

Example 2 : 600 mg rifamycin sodium sustained release coated tablets were prepared having the qualitative-quantitative composition disclosed in Table 6.

Coated with water film (enteric coating)

Table 6

Ingredients Unit Amount per tablet Core Composition Sodium rifamycin SV ⁽¹⁾ mg 600.0 ⁽¹⁾ Ascorbic acid mg 30.0 Lecithin mg 10.0 Stearic acid mg 30.0 Sodium carboxymethyl cellulose (Na CMC) mg 200.0 Mannitol ² mg 215.0 ² Colloidal Anhydrous Silica mg 20.0 magnesium stearate mg 25.0 Coating composition Poly(methacrylic acid-ethyl acrylate (1:1) (Eudragit® L30 D55) mg 49.8 ³ Titanium dioxide mg 2.7 iron oxide red mg 0.2 Talc mg 22.2 triethyl citrate mg 5.1 Purified water ⁴ -- --

⁽¹⁾ as anhydrous (dried) equivalent to approximately 702 mg of rifamycin SV sodium salt in hydrated form, given an average water content of approximately 14.5%.

⁽²⁾ the amount of mannitol is adjusted to compensate for the correction of the sodium amount of rifamycin SV based on water content.

⁽³⁾ in anhydrous form.

⁽⁴⁾ purified water is essentially removed during the manufacturing process.

Stability: A stability study was performed on a single batch of tablets made according to Example 2, in accordance with the ICH Guidelines for Stability Studies of New Drugs. The tablets were placed at 25°C/60% RH. The results are presented in Table 6a.

Table 6a

Moment of time Analysis (mg/tablet) Analysis (% claimed content) Rifamycin S (%) Any other related compounds (%) Total number of related compounds (%) 0 592.7 98.8 0.08 0.09 0.45 6 months 590.0 98.3 0.09 0.19 0.73 12 months 586.9 97.8 0.06 0.25 1.12 24 months 588.4 98.1 0.05 0.29 1.22 36 months 583.3 97.2 0.10 0.36 1.48

Example 3: In vitro characterization of the anti-inflammatory properties of rifamycin SV

Inflammation plays a major role in the pathogenesis of IBS, so the ability of rifamycin SV to inhibit inflammation has been characterized. Characterization by PXR stimulation and NFkB inhibition was performed in vitro in cell systems mimicking the intestinal environment in relation to IBS.

Assay to analyze and quantify PXR activity:

A nuclear receptor assay system using proprietary human cells engineered to provide constitutive, high-efficiency expression of human PXR was used to determine the EC50 activity of the PXR agonist rifamycin SV.

This analytical product from Indigo Biosciences (Pennsylvania, USA) uses cells that express a hybrid form of human PXR. The N-terminal sequence encoding the PXR DNA binding domain (DBD) was replaced with yeast GAL4-DBD. The native PXR ligand-binding domain (LBD) and other C-terminal domains remain intact and functional. Ligand interaction activates the receptor, causing it to bind to the GAL4 DNA binding sequence, which is operably linked to the luciferase resident reporter gene. Thus, quantification of changes in luciferase activity in treated reporter cells provides a sensitive surrogate measure of changes in PXR activity. The principal application of this reporter assay system is to screen test samples to quantify any functional activity, either agonist or antagonist, they may have on human PXR. The increase in the concentration of rifamycin SV was tested in comparison with rifaximin. Rifampicin was used as a positive control for the assay. The experiments were repeated 3 times and the standard deviation was calculated. EC50 and 95% CI were determined using Prism statistical analysis software, fitting a non-linear curve over data points expressed as log(agonist) versus response - variable slope (4 parameters). The p value was calculated using the parametric paired t-test of Prism analysis.

Assay to measure NFkB activity:

A similar reporter system was used in the assay to determine the IC50 of antagonism of rifamycin SV to the transcription factor NFkB as in the PXR assay. The Indigo Biosciences Nuclear NFkB Receptor Assay System uses human kidney epithelial cells transiently transfected with the NF-kB reporter. The biological activity of NFkB, measured as the transcriptional activity of these reporter cells, requires the same alignment of all intracellular molecular interactions and phenomena that can be expected to occur in vivo.

Cells were treated in antagonist mode in the presence of 30 ng/ml TNFα to stimulate the NFkB inflammatory cascade. The increase in the concentration of rifamycin SV was tested in comparison with rifaximin. After 24 hours, luminescence was quantified, which is proportional to the transcriptional activity of NFkB. The experiments were repeated 2 times and the standard deviation was calculated. IC50 and 95% CI were determined using Prism statistical analysis software, fitting a non-linear curve over data points expressed as log(inhibitor) versus response (3 parameters). The p value was calculated using the parametric paired t-test of Prism analysis.

Experimental results have shown that rifamycin SV is 200-440 times more effective than rifaximin in stimulating PXR transcriptional activity. In addition, rifamycin SV is also 4000 times more effective than rifaximin in inhibiting NFkB transcriptional activity.

All the data presented show that rifamycin SV has a high anti-inflammatory activity, which is significantly superior to rifaximin. These characteristics make rifamycin SV a very good candidate for the treatment of IBS and an ideal substrate for a formulation intended to alleviate the symptoms of IBS, in particular IBS-D. Of course, to be effective in the recovery of the patient, rifamycin SV or a pharmaceutically acceptable salt thereof must be administered at the correct dose and at the ideal rate and extent of delivery, as provided in the preceding examples, which are intended to ensure that the correct amount of rifamycin SV or its a pharmaceutically acceptable salt was administered to patients and delivered to organs where it could exhibit appropriate pharmacodynamic activity.

Example 4 Pharmacokinetics and Safety Assessment : The tablets of Example 1 (600 mg sodium rifamycin SV tablets) were studied in healthy male and female volunteers to assess the safety of administration and the PK profile obtained after single dose (day 1) and multiple dose (after 7 days) administration of rifamycin SV of the invention in TID tablets for a total daily dose of 1800 mg/day.

The primary endpoint of the study was the evaluation of plasma and urinary pharmacokinetics of rifamycin SV following single (Day 1) and multiple doses (Day 7) tablets of Example 1 administered to healthy subjects according to a dosing regimen of 600 mg t.i.d. (three times a day).

The secondary endpoint of the study was to evaluate the safety and tolerability of the tablets of Example 1 administered according to the dosing regimen t.i.d. for 14 consecutive days. All study participants received the tablets of Example 1 in accordance with the multiple dose regimen from day 1 to day 14 as follows:

- 1800 mg sodium rifamycin SV as one 600 mg tablet of Example 1 3 times a day (t.i.d.) for 7 consecutive days at 0800±1 h (before breakfast), 1400±1 h (before lunch) and 20 :00±1 h (before dinner). Between the 1st and 2nd and between the 2nd and 3rd dose τ=6 h on each day of treatment. Between the 3rd dose of one day and the 1st dose of the next day τ=12 hours.

- after discharge on day 8, the subjects continued treatment according to the same dosing regimen at home until day 14 for 42 administrations in total.

Pharmacokinetic evaluation criteria were as follows:

- C _{max, 0-6} , t _{max, 0-6} , AUC _0-6 , AUC _0-∞ , t _½ , λ _z , Cl _t /F, Cl _r and V _z /F of rifamycin SV in plasma after the first dose tablets of Example 4;

- C _{max, 0-24} , t _{max, 0-24} and AUC _0-24 rifamycin SV in plasma after the first 3 doses of 600 mg rifamycin SV tablets;

- C _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 rifamycin SV in plasma after the last multiple dose of 600 mg rifamycin SV tablets;

- AUC _ss,0-24 of rifamycin SV in plasma after the last 3 doses of 600 mg of rifamycin SV in tablets and

- _Ae0-24 and % _Ae0-24 of rifamycin SV in urine after the first 3 and last 3 multiple doses of 600 mg rifamycin SV tablets.

Pharmacokinetic parameters and results:

The mean (+SD) concentration of rifamycin SV (ng/mL) versus time profiles on day 1 and day 7 during study treatment with the test formulation is shown in FIG. 1.

Plasma pharmacokinetic parameters of rifamycin SV measured and calculated on days 1 and 7 of treatment are shown below; mean±SD is indicated (N=18) except for t _max for which the median (range) is shown in Table 7.

Table 7

Parameter Unit Day 1 Parameter Unit Day 7 _Cmax,0-6 ng/ml 2.19±1.94 Cmax _,ss12-18 ng/ml 2.90±1.73 tmax _,0-6 h 6.00 (4.00-6.00) tmax _,ss12-18 h 12.00 (12.00-18.00) AUC _0-6 (ng)(h)/ml 3.26±2.85 Cmin, ss _ss12-18 ng/ml 1.55±0.39 Cmax _,0-24 ng/ml 5.79±4.24 C _{average,12-18} ng/ml 2.02±0.66 tmax _,0-24 h 9.50 (4.00-24.00) AUC _ss,12-18 (ng)(h)/ml 12.15±3.95 AUC _0-24 (ng)(h)/ml 43.67±20.15 PTF% _12-18 % 59.70±42.48 AUC _ss,0-24 (ng)(h)/ml 80.08±34.09

C _max.0-6 corresponds to "peak concentration", that is, the peak plasma concentration of the drug in the period 0-6 hours after oral administration, and t _max.0-6 corresponds to "time to peak concentration", that is, the time to reach peak plasma concentration in the period 0-6 hours after oral administration of the drug.

C _max,0-24 corresponds to "peak concentration", that is, the peak plasma concentration of the drug in the period 0-24 hours after oral administration, and t _{max, 0-24} corresponds to the time to peak concentration, that is, the time to reach peak concentration in plasma during the period 0-24 hours after oral administration of the drug.

AUC, which corresponds to the "area under the curve", that is, the integral of the concentration-time curve (after a single dose or at steady state). Specifically, 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.

The total amount of rifamycin SV excreted in the urine, calculated on days 1 and 7 of treatment, is shown in Table 8 below (mean ± SD indicated).

Table 8

Ae _0-24 ng 27173.3359±16935.3754 Ae _0-24 ng 59628.8089±24946.1413 %Ae _0-24 % 0.0015±0.0009 %Ae _0-24 % 0.0033±0.0014

Security results:

No severe AEs were reported and no subjects discontinued the study due to AEs. No significant changes in vital signs, body weight, ECG or laboratory parameters were observed after treatment with rifamycin SV. No significant changes in liver or kidney function were observed during multiple dose treatment.

Conclusions:

The PK profile and safety of systemically available rifamycin SV following single and multiple doses of tid 600 mg rifamycin SV tablets were studied in 18 healthy male and female subjects. Subjects were first exposed to a daily dose of 1800 mg of rifamycin SV for 14 consecutive days. The PK of rifamycin SV was assayed in plasma and urine on days 1 and 7. On day 1, plasma levels of rifamycin SV were quantified in all subjects starting 9 hours after the 1st dose. On average, rifamycin SV peaked at a median time of 9.5 hours ( _Cmax.0-24 : 6.23±4.52 ng/ml). On day 7, all subjects had quantifiable plasma levels of rifamycin SV at each sampling point. Rifamycin SV peaked 2 hours after the 1st dose on day 7 and thereafter decreased to levels averaging similar to those on day 1. After 7 days tid of treatment, absorption of rifamycin SV increased slightly in rate and extent and did not show any noticeable signs of accumulation. The total amount of rifamycin SV excreted in the urine was 0.0033% on day 7.

Rifamycin SV 600 mg tablets showed an excellent safety profile.

Example 5 : Activity of rifamycin SV against bacterial strains

The effectiveness of rifamycin SV and its salt in the treatment of SIBO and/or IBS was confirmed by MIC (minimum inhibitory concentration) assessment on a specific pathogenic bacterial strain, i.e. Methanobrevibacter smithii , which is commonly present in IBS patients, especially those with IBS-D, compared with other antibacterial agents, as shown in Table 9.

Table 9

MIC Methanobrevibacter smithii
(DSMZ 11975) Sodium rifamycin SV (Lot No: QRM0030) <1 µg/ml Rifaximin (Batch #: TF10106) 25 µg/ml Neomycin (Code: N0401000 batch 4.0) >100 µg/ml Metronidazole (Code M3761 batch 095K0693) 25 µg/ml

Clearly, rifamycin SV is more effective than other active agents that have already been described as being suitable for the treatment of SIBO and/or IBS.

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

Table 10

Test compound Agonism of PXR transcriptional activity expressed as EC50 molar (95% CI range) Rifamycin SV 6.08 E-09 (values in the nM range) Rifaximin 1.8 E-06 (values in the µM range) Rifampicin (positive control for assay) 1.1 E-06 (values in the μM range)

Based on EC50 values of agonistic activity against PXR transcriptional activity, rifamycin SV is 200-440 times more potent than rifaximin and rifampicin. The difference in efficacy between rifaximin and rifamycin SV in this analysis was determined to be statistically significant, with a p value of 0.018. Rifaximin at 30 µM is 2.5 times less effective than rifamycin SV at 0.3 µM. This means that rifamycin SV is 250 times more effective than rifaximin in stimulating PXR transcriptional activity. Thus, it is confirmed that rifamycin SV is effective in the treatment of inflammatory bowel diseases and more potent in stimulating PXR activity: in fact, the use of the expected dose is 100 times lower. Also shown that rifamycin SV is 180 times more effective than rifampicin used in the experimental analysis as a positive control.

Example 6A : Activity of rifamycin and rifaximin in the NFkB agonism assay.

The NFkB agonism agonism of rifamycin SV and rifaximin was examined in the assay. The results are shown in Table 11.

Table 11

Test compound Antagonism of NFkB activity
IC50 molar (95% CI range) Rifamycin SV 2.3 E-08=23 nM Rifaximin 8.3 E-05=83 µM

Example 6B : Inhibition of NFkB transcriptional activity in a reporter cell line.

To establish that NFκB inhibition occurs after rifamycin-induced PXR activation, a reporter cell line expressing full-length NFκB and carrying a luciferase reporter gene operably linked to upstream elements of the NFκB genetic response was stimulated with either PMA, TNFα, or LPS to induce NFκB. Rifamycin or rifaximin was dosed to these stimulated cells. After a 24-hour incubation, luminescence was quantified, correlating with the transcriptional activity of NFκB. Rifamycin was more effective than rifaximin in antagonizing PMA-induced NFκB activity with IC ₅₀ values of 1.56 × 10 ^-8 M versus 9.39 × 10 ^-8 M, respectively, which is 6-fold higher than that of rifaximin ( Fig. 4A). Rifamycin also antagonized TNFα-induced NFκB activity with an IC ₅₀ value of 1.48 × 10 ^-5 M (Fig. 4B) and LPS-induced NFκB activity with an IC ₅₀ value of 3.49 × 10 ^-6 M (Fig. 4C ). In contrast, rifaximin did not inhibit TNFα- or LPS-induced NFκB activity to the highest concentration tested. These results establish a strong correlation between PXR activation and NFκB inhibition by rifamycin, independent of the inflammatory stimulus.

Because PXR can indirectly regulate inflammation through NFκB inhibition, the data indicate that rifamycin induces an alternative or parallel pathway to normalize gut immune function through antagonism of NFκB activity. Rifamycin showed strong antagonism against PMA, TNFα- and LPS-induced NFκB activity. PMA bypasses NFκB induction, which is mediated through cell surface receptors by directly activating protein kinase C. Thus, PMA-induced NFκB antagonism is indicative of potential inhibition of signaling from multiple cell surface receptors. Rifamycin was more effective than rifaximin in antagonizing PMA-induced NFκB. When the TNFα receptor was specifically activated to stimulate NFκB, rifamycin effectively antagonized TNFα-induced signaling, while rifaximin was ineffective. More importantly, there was strong inhibition of LPS-induced NFκB by rifamycin, while rifaximin was ineffective.

Interestingly, these data indicate that NFκB inhibition by rifamycin is stimulus independent, as rifamycin effectively inhibited PMA, TNFα, and LPS-induced NFκB, in contrast to rifaximin, which only inhibited PMA-induced NFκB. PMA or diacylglycerol-activated PKC is important for the T cell receptor or IgE-induced NFκB, which occurs in immune cells such as T cells and mast cells, respectively. On the other hand, TNF or LPS-induced NFκB, which occurs in colonic epithelial cells, requires other signaling factors (TRAFs, TNFR-associated factors). More importantly, for its relevance in IBS or IBD, the biological function of NFκB has been confirmed in colonic epithelial cells. Rifamycin significantly inhibited IL1β-induced synthesis of the NFκB-regulated chemokine IL-8. These cell-dependent requirements for inducing inflammation imply that by acting on various target cells, the anti-inflammatory potential of rifamycin is broad, since deregulated immune and epithelial cellular interactions contribute to the pathogenesis of several gastrointestinal diseases.

Example 7 : Phase II, multicenter, randomized, double-blind, placebo-controlled pilot study of the clinical efficacy and safety of 600 mg tablets of Example 1 in subjects with diarrhea-predominant irritable bowel syndrome (IBS-D).

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

Treatment group 1:

The tablets of Example 1 will be administered to the subject three times a day (t.i.d.) according to the following schedule: (a) one 600 mg tablet in the morning; (b) one 600 mg tablet in the afternoon and (c) one 600 mg tablet in the evening.

Treatment group 2:

The tablets of Example 1 will be administered to the subject twice daily (b.i.d.) plus the corresponding placebo daily (q.d.) according to the following schedule: (a) one 600 mg tablet in the morning; (b) placebo tablet in the afternoon and (c) one 600 mg tablet in the evening.

Treatment group 3:

The placebo tablets will be administered to the subject three times a day (t.i.d.) according to the following schedule: (a) one placebo tablet in the morning; (b) one placebo tablet in the afternoon and (c) one placebo tablet in the evening.

All facilities will take the prescribed t.i.d. within 14 days, ideally at the following times: 07:30±2 h, 15:30±2 h, and 23:30±2 h. Weeks of treatment will be followed by ten (10) weeks of follow-up.

The primary endpoint of the study will be the proportion of respondents who were defined weekly as subjects who experienced weekly improvement in the combination of abdominal pain and stool consistency based on their daily ratings. Abdominal pain relief is defined as a decrease in the average weekly abdominal pain score of at least 30% from baseline, and improvement in stool consistency is defined as a 50% or more decrease in days per week with at least one a type of stool that has a consistency of type 6 or 7, compared with a baseline of 7 according to the 7-point Bristol stool shape scale.

The Bristol Stool Shape Scale is a graduated visual scale for stool density. It is approved as a measure of the transit time of food through the gastrointestinal tract and is used to define "diarrhea" by the European Society for Clinical Microbiology and Infectious Diseases in Clostridium difficile infection (CDI). The scale parameters are described in Table 12.

Subjects administered the 600 mg tablet of Example 1 twice or thrice daily according to the above schedule will experience a reduction in abdominal pain, measured as a reduction in mean weekly abdominal pain score of at least 30% from baseline. level and improvement in stool consistency, measured as a 50% or more reduction in the number of days per week with at least one stool that has a type 6 or 7 consistency, compared with a baseline level of 7 according to the 7-point Bristol Scale stool shapes.

Table 12

Type Description 1 Separate hard lumps like nuts 2 Sausage shaped but lumpy 3 In the shape of a sausage, but with a ribbed surface 4 Sausage or snake shape, smooth and soft 5 Soft little balls with smooth edges 6 Loose particles with jagged edges, mushy stools 7 Watery, no solid particles, completely liquid

While the subject matter of this disclosure has been described and shown in some detail with reference to certain illustrative embodiments, including various combinations and subcombinations of features, those skilled in the art will readily appreciate other embodiments and variations and modifications thereof that fall within the scope of this disclosure. Furthermore, descriptions of such embodiments, combinations, and subcombinations are not intended to convey that the claimed subject matter requires features or combinations of features other than those expressly stated in the claims. Accordingly, the scope of this disclosure is intended to include all modifications and variations covered by the spirit and scope of the following appended claims.

Claims (28)

1. An oral pharmaceutical composition for modified release, including sustained and/or delayed release, of rifamycin SV or a pharmaceutically acceptable salt thereof, wherein the composition is in the form of a solid dosage form containing approximately 600 mg of rifamycin SV or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable acceptable excipients, wherein the oral pharmaceutical composition contains an enteric coating containing a 1:1 copolymer of methacrylic acid and methyl methacrylate or a copolymer of methacrylic acid and ethyl acrylate 1:1, and additionally contains: 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, their salts, esters (such as palmitic, stearic, myristic, lauric , lauryl or oleic acid); mono-, di- or triglycerides of fatty acids or their polyethoxylated derivatives such as stearin; waxes such as beeswax or carnauba wax; ceramides; cholesterol derivatives or mixtures thereof; at least one hydrophilic compound selected from cellulose derivatives and their esters and/or salts, such as hydroxyalkylcelluloses (such as hydroxypropylcellulose, hydroxypropylmethylcellulose or sodium hydroxypropylmethylcellulose), alkylcelluloses, carboxyalkylcelluloses (such as sodium carboxymethylcellulose); polyvinyl alcohols; carboxyvinyl derivatives; polysaccharides such as dextrins, pectins, starches and their derivatives; natural or synthetic gums; alginic acid; polyhydric alcohols such as xylitol, maltitol or mannitol; And at least one amphiphilic compound containing type I or II polar lipids (lecithin, phosphatidylcholine, phosphatidylethanolamine), ceramides, glycol alkyl ethers such as diethylene glycol monomethyl ether (Transcutol®), natural or synthetic gums, wherein the oral pharmaceutical composition is formulated to release rifamycin SV or its pharmaceutically acceptable salt essentially in the small intestine, where the release of rifamycin SV or its pharmaceutically acceptable salt begins in the small intestine and may optionally continue in the large intestine. 2. An oral pharmaceutical composition according to claim 1, wherein the oral pharmaceutical composition is formulated to release rifamycin SV or a pharmaceutically acceptable salt thereof substantially after passage of the solid pylorus dosage form into the proximal intestine. 3. An oral pharmaceutical composition according to claim 1 or 2, wherein rifamycin SV or a pharmaceutically 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. An oral pharmaceutical composition according to any one of the preceding claims, wherein the solid dosage form comprises a core and an enteric coating covering the core. 5. An oral pharmaceutical composition according to any one of the preceding claims, wherein administration of one or more solid dosage forms to the subject exhibits a t _{max. 0-24} of rifamycin SV in the subject's plasma of approximately 9.50 hours. 6. An oral pharmaceutical composition according to any one of the preceding claims, wherein the administration of three or more solid dosage forms to the subject shows a _Cmax.0-6 of rifamycin SV in the subject's plasma of approximately 2.30 ± 2.14 ng/ml, shows C _{max, 0-24} rifamycin SV in the plasma of the object is approximately 6.23 ± 4.52 ng / ml, indicates an AUC _0-6 of rifamycin SV in subject plasma of approximately 3.34±2.96 (ng)(h)/mL and/or shows subject plasma AUC _0-24 of rifamycin SV of approximately 947.92±20.24 (ng)(h)/mL following administration of three oral pharmaceutical compositions to a human. 7. An oral pharmaceutical composition according to any one of the preceding claims, wherein it provides a urinary elimination rate of rifamycin SV from the subject to which the oral pharmaceutical composition is administered, no more than about 1% of the total amount of rifamycin SV or a pharmaceutically acceptable salt thereof administered to the subject. 8. An oral pharmaceutical composition according to any one of the preceding claims, wherein said pharmaceutical composition releases no more than 10% of the amount of rifamycin SV or a pharmaceutically acceptable salt thereof, including the pharmaceutical composition when the pharmaceutical composition is placed in a USP dissolution rate II device according to USP <711>, for 2 hours, in which the dissolution rate device contains 1000 ml of an aqueous solution containing 0.1 M hydrochloric acid and 0.4% macrogol cetostearyl ester at pH 1 and a temperature of 37±0.5°C, and in which the aqueous solution is stirred at a speed of 50 rpm. 9. An oral pharmaceutical composition according to any one of the preceding claims, wherein the pharmaceutical composition releases no more than about 20% of the amount of rifamycin SV or a pharmaceutically acceptable salt thereof, including the pharmaceutical composition when the pharmaceutical composition is placed in a USP dissolution rate II device according to USP <711>, for 1 hour, in which the dissolution rate device contains 900 ml of an aqueous buffer at pH 6.4 and a temperature of 37±0.5°C, and in which the aqueous solution is stirred at a speed of 100 rpm. 10. An oral pharmaceutical composition according to any one of the preceding claims, wherein the pharmaceutical composition releases at least about 50% of the amount of rifamycin SV or a pharmaceutically acceptable salt thereof, including the pharmaceutical composition when the pharmaceutical composition is placed in a USP dissolution rate II device according to USP <711>, for 6 hours, in which the dissolution rate device contains 900 ml of an aqueous buffer at pH 6.4 and a temperature of 37±0.5°C, and in which the aqueous solution is stirred at a speed of 100 rpm. 11. Oral pharmaceutical composition according to any one of the preceding paragraphs, where the pharmaceutical composition additionally contains no more than about 2 wt. % rifamycin S or not more than about 1 wt. % rifamycin B. 12. An oral pharmaceutical composition according to any one of the preceding claims, wherein the pharmaceutical composition further comprises not more than 10,000 ppm ethanol. 13. Oral pharmaceutical composition according to any one of the preceding paragraphs, where the solid dosage form contains less than 2 wt. % rifamycin S after storage of the solid dosage form at 25°C and 60% relative humidity for 3 months, contains less than 1 wt. % rifamycin B after storage of the solid dosage form at 25°C and 60% relative humidity for 3 months, contains less than 2 wt. % rifamycin S after storage of the solid dosage form at 40°C and 75% relative humidity for 1 month, contains less than 1 wt. % rifamycin B after storage of the solid dosage form at 40°C and 75% relative humidity for 1 month, contains less than 2 wt. % rifamycin S after storage of the solid dosage form at 30°C and 65% relative humidity for 1 month, contains less than 1 wt. % rifamycin B after storage of the solid dosage form at 30°C and 65% relative humidity for 1 month. 14. An oral pharmaceutical composition according to any one of the preceding claims, wherein the solid dosage form is contained in a package, where the package contains materials for protecting the solid dosage form from heat and light. 15. An oral pharmaceutical composition according to any one of the preceding claims, wherein the solid dosage form is in the form of a tablet. 16. An oral pharmaceutical composition according to claim 15, wherein the tablet comprises a tablet core and an enteric coating covering said tablet core. 17. Oral pharmaceutical composition according to any one of paragraphs. 1-16 for use in the prevention and/or treatment of small bowel bacterial overgrowth syndrome (SIBO), irritable bowel syndrome (IBS), diarrhea-predominant irritable bowel syndrome (IBS-D), irritable bowel syndrome with alternating diarrhea and constipation (SRK-S).

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