阅读说明：本技术 治疗胃肠疾病和障碍的组合物和方法 (Compositions and methods for treating gastrointestinal diseases and disorders ) 是由 M·皮门特尔 G·G·S·莱特 R·马图尔 A·莱扎伊 W·莫拉莱斯 S·魏茨曼 于 2020-03-18 设计创作，主要内容包括：本文描述了治疗胃肠疾病和障碍诸如肠易激综合征和小肠细菌过度生长的组合物和方法。(Described herein are compositions and methods for treating gastrointestinal diseases and disorders such as irritable bowel syndrome and small intestine bacterial overgrowth.)

1. A method of treating a Gastrointestinal (GI) disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a rifamycin and a therapeutically effective amount of a mucolytic agent.

2. The method of claim 1, wherein said rifamycin is rifaximin.

3. The method of any of the preceding claims, wherein said rifamycin is administered in an oral dose of 25-1000 mg.

4. The method of any one of the preceding claims, wherein the rifamycin is rifaximin administered at an oral dose of 200 mg.

5. The method of any one of the preceding claims, wherein the mucolytic agent is Dithiothreitol (DTT) or N-acetylcysteine (NAC).

6. The method of any of the preceding claims, wherein the duration of treatment is 3 to 15 days.

7. The method of any one of the preceding claims, wherein the gastrointestinal disease or disorder is Irritable Bowel Syndrome (IBS), diarrhea-predominant IBS (IBS-D), constipation-predominant IBS (IBS-C), mixed IBS (IBS-M), or Small Intestine Bacterial Overgrowth (SIBO).

8. The method of any of the preceding claims, wherein the gastrointestinal disease or disorder is diarrhea-predominant irritable bowel syndrome (IBS-D).

9. The method of any one of the preceding claims, wherein the rifamycin is rifaximin in an amount of 200mg and the mucolytic agent is NAC in an amount of 600 mg.

10. A pharmaceutical composition comprising a therapeutically effective amount of a rifamycin and a therapeutically effective amount of a mucolytic agent.

11. The composition of claim 10, wherein said rifamycin is rifaximin.

12. The composition of claim 10 or 11, wherein said rifamycin is an oral unit dosage form comprising 25-1000mg of rifamycin in free or salt form.

13. The composition of any one of claims 10-12, wherein the mucolytic agent is Dithiothreitol (DTT) or N-acetylcysteine (NAC).

14. The composition of any one of claims 10-13, wherein the rifamycin and the mucolytic agent are combined in a tablet or capsule for oral administration.

15. The composition of any one of claims 10-13, wherein said rifamycin and said mucolytic agent are provided in a kit with instructions for use.

16. The composition of claim 14, wherein the rifamycin is rifaximin in an amount of 200mg and the mucolytic agent is NAC in an amount of 600 mg.

17. The composition of claim 15, wherein the rifamycin is an oral unit dosage form comprising 200mg rifaximin and the mucolytic is an oral unit dosage form comprising 600mg NAC.

Technical Field

The present invention relates to pharmaceutical compositions and methods for treating gastrointestinal diseases and disorders, including irritable bowel syndrome and small intestine bacterial overgrowth.

Background

The mucus barrier plays an important role in preventing infectious diseases. It can provide protection against a wide variety of intestinal pathogens, including various bacteria. Mucus is formed primarily from glycoproteins containing various glycans, but also contains various non-specific antibacterial molecules and antibodies to antigens of specific microorganisms. Thus, mucus is a major component of innate immunity, generally preventing pathogens from reaching and residing on epithelial surfaces within the body. However, some pathogens have evolved to adhere to mucus or modulate the expression of virulence genes, adapting to the host environment.

In the case of the gastrointestinal tract, alterations in mucosal integrity are often associated with health problems, such as inflammatory bowel disease, including ulcerative colitis and crohn's disease. This change in mucosal environment may also be associated with dysbiosis, an abnormal change in the composition of the gut microbiota caused by crohn's disease. Once compromised, the mucus barrier becomes permeable to bacteria that are able to enter the epithelium, causing inflammation, which is why the integrity of the mucus layer is essential to maintain a steady-state balance between the gut microbiota and its host.

Bacterial gastroenteritis is generally caused by eating contaminated food, drinking contaminated water or by close contact with infected persons. Bacterial toxins disrupt the cellular mucosa of the gastrointestinal tract (usually the colon), causing diarrhea, watery stools and abdominal cramps, or dysentery (severe diarrhea, often with blood and mucus). Traveller's diarrhea is a common disease caused by exposure to food or water containing pathogenic microorganisms, to which patients have never been exposed before, and thus the immune response is inadequate. Bacterial enteric pathogens include, for example, enterotoxigenic Escherichia coli (ETEC), Enteromorpha agglomerans, and various Shigellas, Salmonella, Campylobacter, Yersinia, Aeromonas, and Plesiomonas. Although most bacterial gastrointestinal diseases are short-lived, severe diarrheal diseases can lead to severe and sometimes fatal dehydration.

Irritable Bowel Syndrome (IBS) is the most common gastrointestinal disorder, with an estimated prevalence of 10% to 15% in the united states. Worldwide estimates of IBS prevalence vary widely, partly due to differences in the diagnostic criteria used (mannine, roman I, roman II, roman III) and the lack of data in less developed areas, but according to the meta-analysis published in 2012 by Lovell and Ford, the combined prevalence of IBS in the nordic study was 12.0%, 15.0% in the southern european study, 7.5% in the middle east study, 17% in the southern asian study, and 21% in the southern american study. Symptoms of IBS include abdominal pain, abdominal distension, and chronic changes in bowel function, which may manifest as diarrhea-predominant (D-IBS), constipation-predominant (C-IBS), or both (M-IBS). The etiology of IBS is not completely understood. However, bacterial infections of the gastrointestinal tract are associated with the development of IBS. Theoretically, bacteria of the genus salmonella or campylobacter penetrate the mucosa of the small intestine, often resulting in an increased incidence of persistent IBS symptoms.

Antibacterial agents generally do not penetrate the mucus layer sufficiently to control infection, but at the same time, the mucus layer provides an important protective effect.

There is a need to improve the treatment of conditions, diseases or disorders associated with bacterial infections of the gastrointestinal tract, such as bacterial gastroenteritis or irritable bowel syndrome.

Summary of The Invention

A key step in understanding the etiology of IBS more accurately is the recognition that acute gastroenteritis may lead to the development of IBS. About 10% of individuals with acute gastroenteritis develop post-infection IBS (PI-IBS), and studies thereafter have shown that PI-IBS may lead to 9% or more cases of IBS. Different bacterial pathogens cause gastroenteritis and PI-IBS, of which Campylobacter jejuni is the most common in the United states. Campylobacter jejuni and other pathogens that cause PI-IBS produce the cytolethal distending toxin (Cdt), a heterotrimeric protein with three subunits, CdtA, CdtB, and CdtC. Where CdtB is an active toxin subunit, CdtA and CdtC are proposed to synergistically promote the binding of CdtB to and into mammalian cells. In early studies, rats infected with campylobacter jejuni developed altered stool morphology and other symptoms similar to IBS in humans, whereas rats infected with campylobacter mutant without CdtB did not. The increased levels of bacteria in the small intestine of rats injected directly with the CdtB toxin further supports that CdtB is a key link in campylobacter jejuni infection and PI-IBS development. In summary, food poisoning can lead to autoimmunity, which can lead to neuropathy, which can lead to Small Intestinal Bacterial Overgrowth (SIBO), which can lead to Irritable Bowel Syndrome (IBS). Without being bound by any one theory, rifaximin is the treatment of choice for IBS and SIBO because it is not absorbed by the body, or is absorbed very little by the body, and therefore has few side effects. Repeated use does not appear to develop resistance.

In the gastrointestinal tract (GI), mucus has a protective effect, since mucus contains components that protect the epithelium from pathogens, and is also a natural barrier. However, some pathogens develop mechanisms to circumvent this protective effect and even to exploit mucus. For example, certain strains of campylobacter jejuni, salmonella, bacteroides fragilis, escherichia coli, and many other bacteria that can adhere survive and grow in mucus. In addition, other non-pathogenic bacteria may also survive and grow in the mucus, including bacteroides and lactobacilli (especially lactobacillus reuteri and lactobacillus rhamnosus).

Rifaximin is the antibiotic with the minimum absorption amount specific to the gastrointestinal tract and is approved by the FDA for the treatment of IBS-D. Although rifaximin treatment is very effective, recurrence of symptoms is common. The mucus layer in the small intestine is viscous, which makes the microorganisms in the mucus layer inaccessible. Without being bound by any one theory, this inaccessibility may protect certain bacteria from rifaximin, thereby promoting their regeneration and recurrence of symptoms.

The reducing agent Dithiothreitol (DTT) can reduce disulfide bonds in mucus that link mucin subunits. For example, it can be used to reduce viscosity of mucus. This leads to the hypothesis that the combined use of rifaximin and mucolytic agents will make mucosal bacteria more accessible, thereby increasing the efficacy of rifaximin in treating IBS symptoms. DTT has not been approved for use in humans, but the mucolytic agent N-acetylcysteine (NAC) is an approved drug.

Embodiments of the invention described herein include methods of treatment and combination products using an antibiotic (e.g., rifamycin, such as rifaximin) and a mucolytic agent (e.g., NAC or DTT), wherein the mucolytic agent facilitates exposure of the antibiotic to a target microorganism (e.g., a pathogenic microorganism that causes overgrowth of small intestine bacteria) by dilution of small intestine mucus.

In embodiments, the invention described herein includes a method of treating a condition, disease, or disorder in a subject in need thereof. In some embodiments, the condition, disease or disorder may include a bacterial infection of the gastrointestinal tract. In some embodiments, the condition, disease or disorder may be a Gastrointestinal (GI) disease or disorder. In some embodiments, the gastrointestinal disease or disorder may include Small Intestinal Bacterial Overgrowth (SIBO) or Irritable Bowel Syndrome (IBS). In some embodiments, the IBS may be diarrhea-predominant irritable bowel syndrome (IBS-D), mixed irritable bowel syndrome (IBS-M), and constipation-predominant irritable bowel syndrome (IBS-C). In embodiments, the invention described herein may include methods for inhibiting the growth of or killing microorganisms in one or more regions of the gastrointestinal system of a subject. In embodiments, the invention described herein may include methods of enhancing the efficacy of a rifamycin (e.g., rifaximin) against a condition, disease, or disorder involving a bacterial infection of the gastrointestinal tract.

In some embodiments of the methods described herein, such methods may comprise administering a composition comprising a therapeutically effective amount of one or more antibiotics and a mucolytic agent.

In some embodiments of the methods described herein, such methods may comprise administering a therapeutically effective amount of one or more antibiotics and a mucolytic agent.

In some embodiments, the one or more antibiotics can include aminoglycosides (e.g., amikacin, gentamicin, kanamycin, neomycin, netilmicin, streptomycin, tobramycin, paromomycin), ansamycins (e.g., geldanamycin, herbimycin), carbacephems (e.g., chlorocephem), carbapenems (e.g., ertapenem, doripenem, imipenem, cilastatin, meropenem), cephalosporins (e.g., first generation: cefadroxil, cefazolin, cephalothin or cephalothin), cephalexin, second generation: cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, third generation: cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, cefbupirim, ceftizoxime, cefazolin, cefepime, or a, cefepime, or a, cefepime, or a, cefepime, or a, Ceftriaxone; fourth generation: cefepime; and a fifth generation: cephapirin), glycopeptides (e.g. teicoplanin, vancomycin), macrolides (e.g. azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, oleandomycin, telithromycin, spectinomycin), monobactamycin (e.g. aztreonam), penicillins (e.g. amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, flucloxacillin, mezlocillin, methicillin, naphthacillin, oxacillin, penicillin, piperacillin, ticarcillin), antibiotic polypeptides (e.g. bacitracin, colistin, polymyxin b), quinolones (e.g. ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, trovafloxacin), rifamycins (e.g. rifamycin or rifampin, rifabutin, rifapentin, rifaximin), Sulfonamides (e.g., mafenide, chlordol, sulfacetamide, sulfamethylthiazole, sulfamethoxazole, sulfasalazine, sulfisoxazole, trimethoprim sulfisoxazole (trimetrexazole, "tmp-smx"), and tetracyclines (e.g., norcycline, doxycycline, minocycline, oxytetracycline, tetracycline), as well as arsanilipramine, chloramphenicol, clindamycin, lincomycin, ethambutol, fosfomycin, fusidic acid, furazolone, isoniazid, linezolid, metronidazole, mupirocin, nitrofurantoin, platemycin, pyrazinamide, quinonucletin/dalfopristin combination, and tinidazole.

In some embodiments, the one or more antibiotics may include rifamycin. In some embodiments, the rifamycin can be selected from rifamycin, rifampin, rifabutin, rifapentine, and rifaximin. In some embodiments, the one or more antibiotics may be selected from rifaximin, rifamycin, rifampin, penicillin derivatives, fluoroquinolones, macrolides, tetracyclines, doxycycline, neomycin, and metronidazole. In some embodiments, the one or more antibiotics may include rifaximin. In some embodiments, the one or more antibiotics comprise rifaximin and neomycin.

In some embodiments, rifamycin can be administered at a dose of about 25mg to about 1000 mg. In some embodiments, the rifamycin is rifaximin, and can be about 550mg, 500mg, 400mg, 350mg, 300mg, 275mg, 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25 mg; or greater than about 550mg, 500mg, 400mg, 350mg, 300mg, 275mg, 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25 mg; or a dose of less than about 550mg, 500mg, 400mg, 350mg, 300mg, 275mg, 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25 mg.

In some embodiments, the mucolytic agent may be selected from Dithiothreitol (DTT), N-acetylcysteine (NAC), acetylcysteine, ambroxol, bromhexine, carbocisteine, erdosteine, mesteine, and alfacase. In some embodiments, the mucolytic agent may be DTT or NAC. In some embodiments, the mucolytic agent is NAC. In some embodiments, the mucolytic agent is administered in an amount of about 100mg-1200 mg. In some embodiments, the mucolytic agent is NAC, which may be about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, or 1200 mg; or greater than about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, or 1200 mg; or less than about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, or 1200 mg.

In some embodiments, the one or more antibiotics and mucolytic agent may be administered as one composition, or as separate compositions according to the methods described herein.

According to embodiments described herein, administration of a mucolytic agent (e.g., NAC) and one or more antibiotics (e.g., rifaximin) in a single composition, or separately, results in an increase in the therapeutic efficacy of the one or more antibiotics, thereby providing a reduced dosage compared to the use of the one or more antibiotics alone. In addition, mucolytic agents in combination with antibiotics can increase the solubility of the antibiotics described herein compared to the antibiotics used alone.

Detailed Description

All references cited herein are incorporated by reference in their entirety as if fully set forth. Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Singleton et al, Dictionary of Microbiology and Molecular Biology, third edition, revised edition, J.Wiley & Sons (2006, New York, N.Y.); march, Advanced Organic Chemistry Reactions, mechanics and Structure (Advanced Organic Chemistry Reactions, Mechanisms and structures), 7 th edition, J.Wiley & Sons (New York, N.Y., 2013); sambrook and Russel, Molecular Cloning: a Laboratory Manual molecular cloning: a laboratory manual, 4 th edition, cold spring harbor laboratory press (cold spring harbor, n.y., 2012), provides one of ordinary skill in the art with a general guideline for many of the terms used in this application.

One skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. Indeed, the invention is not limited to the methods and materials described. For the purposes of the present invention, the following terms are defined below.

Composition comprising a metal oxide and a metal oxide

Various embodiments of the present invention provide a composition comprising: one or more antibiotics; and a mucolytic agent.

Examples of antibiotics that may be included in the compositions include, but are not limited to, aminoglycosides (e.g., amikacin, gentamicin, kanamycin, neomycin, netilmicin, streptomycin, tobramycin, paromomycin), ansamycins (e.g., geldanamycin, herbimycin), carbacephems (e.g., chlorocephem), carbapenems (e.g., ertapenem, doripenem, imipenem, cilastatin, meropenem), cephalosporins (e.g., first generation: cefadroxil, cefazolin, cephalothin or cephalothin), cephalexin, second generation: cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, third generation: cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, cefbupirim, cefbupirisone, cefuroxime, cefpodoxime, cefuroxime, or, Ceftizoxime, ceftriaxone; fourth generation: cefepime; and a fifth generation: cephapirin), glycopeptides (e.g. teicoplanin, vancomycin), macrolides (e.g. azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, oleandomycin, telithromycin, spectinomycin), monobactamycin (e.g. aztreonam), penicillins (e.g. amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, flucloxacillin, mezlocillin, methicillin, naphthacillin, oxacillin, penicillin, piperacillin, ticarcillin), antibiotic polypeptides (e.g. bacitracin, colistin, polymyxin b), quinolones (e.g. ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, trovafloxacin), rifamycins (e.g. rifamycin or rifampin, rifabutin, rifapentin, rifaximin), Sulfonamides (e.g., mafenide, chlordol, sulfacetamide, sulfamethylthiazole, sulfamethoxazole, sulfasalazine, sulfisoxazole, trimethoprim sulfisoxazole (trimetrexazole, "tmp-smx"), and tetracyclines (e.g., norcycline, doxycycline, minocycline, oxytetracycline, tetracycline), as well as arsanilipramine, chloramphenicol, clindamycin, lincomycin, ethambutol, fosfomycin, fusidic acid, furazolone, isoniazid, linezolid, metronidazole, mupirocin, nitrofurantoin, platemycin, pyrazinamide, quinonucletin/dalfopristin combination, and tinidazole.

In various embodiments, the one or more antibiotics are selected from the group consisting of rifaximin, rifamycin, rifampin, penicillin derivatives, fluoroquinolones, macrolides, tetracyclines, doxycycline, neomycin, metronidazole, and combinations thereof. In various embodiments, the penicillin derivative is ampicillin, the fluoroquinolone is ciprofloxacin, and the macrolide is azithromycin. In various embodiments, the one or more antibiotics comprise rifaximin. In various embodiments, the one or more antibiotics comprise rifaximin and neomycin.

In various embodiments, the one or more antibiotics is rifaximin, and the composition comprises 550mg, 500mg, 400mg, 350mg, 300mg, 275mg, 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25mg rifaximin. In some embodiments, the one or more antibiotics is rifaximin, and the composition comprises less than about 550mg, 500mg, 400mg, 350mg, 300mg, 275mg, 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25mg of rifaximin. In some embodiments, the one or more antibiotics is rifaximin, and the composition comprises greater than about 550mg, 500mg, 400mg, 350mg, 300mg, 275mg, 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25mg of rifaximin.

The currently approved dose of rifaximin for the treatment of diarrhea-predominant IBS is 550 mg. While not wishing to be bound by any particular theory, it is believed that the combination of the antibiotic and the mucolytic agent can greatly improve the therapeutic efficacy, and thus, the amount of antibiotic used can be significantly reduced. In some embodiments, a therapeutically effective dose of rifaximin in the invention described herein (in combination with a mucolytic agent, e.g., NAC or DTT) may be a dose that has increased activity in a subject compared to the same dose of rifaximin provided to a subject that is not in combination with a mucolytic agent, e.g., NAC or DTT. In some embodiments, the increase in activity of rifaximin in combination with a mucolytic agent may be greater than about 10%, 25%, 50%, 75%, 100%, 125%, 150%, 175%, 200%, 225%, 250%, 275%, 300%, 325%, 350%, 375%, 400%, 425%, 450%, 475%, or 500% as compared to the same rifaximin dose without the combination. In some embodiments, the increased activity of rifaximin in combination with a mucolytic agent may be increased by less than about 10%, 25%, 50%, 75%, 100%, 125%, 150%, 175%, 200%, 225%, 250%, 275%, 300%, 325%, 350%, 375%, 400%, 425%, 450%, 475%, or 500% as compared to the same rifaximin dose without the combination. In some embodiments, the increase in activity of rifaximin in combination with a mucolytic agent may be about 10%, 25%, 50%, 75%, 100%, 125%, 150%, 175%, 200%, 225%, 250%, 275%, 300%, 325%, 350%, 375%, 400%, 425%, 450%, 475%, or 500% as compared to the same rifaximin dose without the combination.

Thus, in various embodiments where the one or more antibiotics is rifaximin, the composition comprises 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25mg rifaximin. In some embodiments, the composition comprises greater than about 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25mg of rifaximin. In some embodiments, the composition comprises less than about 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25mg of rifaximin.

An approved dose of rifaximin is 200mg for the treatment of traveler's diarrhea. While not wishing to be bound by any particular theory, the inventors believe that doses below 200mg may be effective in view of the increased therapeutic efficacy when combined or administered with a mucolytic agent. Thus, in various embodiments where the one or more antibiotics is rifaximin, the composition comprises 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25mg rifaximin.

In various embodiments, the one or more antibiotics are rifaximin and neomycin. In various embodiments, the amount of rifaximin is 550mg, 500mg, 400mg, 350mg, 300mg, 275mg, 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25mg, and the amount of neomycin is 500mg, 400mg, 350mg, 300mg, 275mg, 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25 mg. In some embodiments, the amount of rifaximin is less than about 550mg, 500mg, 400mg, 350mg, 300mg, 275mg, 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25mg, and the amount of neomycin is less than about 500mg, 400mg, 350mg, 300mg, 275mg, 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25 mg. In some embodiments, the amount of rifaximin is greater than about 550mg, 500mg, 400mg, 350mg, 300mg, 275mg, 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25mg, and the amount of neomycin is greater than about 500mg, 400mg, 350mg, 300mg, 275mg, 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25 mg.

As mentioned above, the combination of the antibiotic and the mucolytic agent provides a significantly improved therapeutic efficacy, and thus, the amount of antibiotic used can be significantly reduced. Thus, in various embodiments where the one or more antibiotics are rifaximin and neomycin, the amount of rifaximin is 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25mg and the amount of neomycin is 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25 mg. In some embodiments, the amount of rifaximin is greater than about 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25mg, and the amount of neomycin is greater than about 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25 mg. In some embodiments, the amount of rifaximin is less than about 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25mg, and the amount of neomycin is less than about 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25 mg.

In various embodiments where the one or more antibiotics are rifaximin and neomycin, the rifaximin is in an amount of 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25mg and the neomycin is in an amount of 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25 mg.

In various embodiments, the mucolytic agent is selected from Dithiothreitol (DTT), N-acetylcysteine (NAC), acetylcysteine, ambroxol, bromhexine, carbocisteine, erdosteine, mesteine, alfa-streptokinase, and combinations thereof. In some embodiments, the mucolytic agent is selected from Dithiothreitol (DTT) and N-acetylcysteine (NAC). In various embodiments, the mucolytic agent is Dithiothreitol (DTT). In various embodiments, the mucolytic agent is N-acetylcysteine (NAC).

In embodiments where the mucolytic agent is Dithiothreitol (DTT), the composition comprises 10-20 v/v% DTT. In various embodiments wherein the mucolytic agent is Dithiothreitol (DTT), the composition comprises 5, 10, 15, 20, or 25 v/v% DTT. In various embodiments wherein the mucolytic agent is Dithiothreitol (DTT), the composition comprises greater than about 5, 10, 15, 20, or 25 v/v% DTT. In various embodiments wherein the mucolytic agent is Dithiothreitol (DTT), the composition comprises less than about 5, 10, 15, 20, or 25 v/v% DTT. In various embodiments wherein the mucolytic agent is Dithiothreitol (DTT), the composition comprises 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 v/v% DTT. For example, DTT can be used as a 6.5mM solution in 100mM phosphate buffer (pH 7).

In embodiments where the mucolytic agent is N-acetylcysteine (NAC), the composition comprises 100-1200mg of N-acetylcysteine (NAC). In various embodiments where the mucolytic agent is N-acetylcysteine (NAC), the composition comprises 50-100mg, 100-200mg, 200-300mg, 300-400mg, 400-500mg, 500-600mg, 600-700mg, 700-800mg, 800-900mg, 900-1000mg, 1000-1100mg, 1100-1200mg, 1200-1300mg, 1300-1400mg, or 1400-1500mg of N-acetylcysteine (NAC) per dose. In various embodiments where the mucolytic agent is N-acetylcysteine (NAC), the composition comprises 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, or 1200mg of N-acetylcysteine (NAC) per dose. In various embodiments where the mucolytic agent is N-acetylcysteine (NAC), the composition comprises greater than about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, or 1200mg of N-acetylcysteine (NAC) per dose. In various embodiments where the mucolytic agent is N-acetylcysteine (NAC), the composition comprises less than about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, or 1200mg of N-acetylcysteine (NAC) per dose.

In various embodiments, the invention described herein provides pharmaceutical compositions comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of one or more antibiotics and mucolytic agents (as one composition or as separate compositions). "pharmaceutically acceptable excipient" refers to an excipient that can be used to prepare generally safe, non-toxic, and desirable pharmaceutical compositions, and includes excipients that are acceptable for veterinary use as well as human pharmaceutical use. Such excipients may be solid, liquid, semi-solid, or in the case of a spray composition, may be gaseous.

In certain embodiments, the compounds of the invention described herein may comprise one or more acidic functional groups and, therefore, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term "pharmaceutically acceptable salts, esters, amides, and prodrugs" as used herein refers to carboxylic acid salts, amino acid addition salts, esters, amides, and prodrugs of the compounds of the present invention described herein that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, effective for the intended use of the compounds of the present invention. The term "salt" refers to the relatively non-toxic inorganic and organic acid addition salts of the compounds of the present invention described herein. These salts may be prepared in situ during the final isolation and purification of the compound or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. These may include cations based on alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.

The term "pharmaceutically acceptable ester" refers to the relatively non-toxic esterification product of a compound of the present invention as described herein. These esters can be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound, either in the free acid form or the hydroxy group, with a suitable esterifying agent. The carboxylic acid may be converted to an ester by treatment with an alcohol in the presence of a catalyst. The term is also intended to include lower hydrocarbon groups capable of solvation under physiological conditions, such as alkyl esters, methyl, ethyl and propyl esters.

As used herein, a "pharmaceutically acceptable salt or prodrug" is a salt or prodrug that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject, without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for its intended use.

The term "prodrug" refers to a compound that is rapidly transformed in vivo to yield a functionally active compound disclosed herein. As used herein, a prodrug is a compound that is metabolized or otherwise converted to the biologically, pharmaceutically, or therapeutically active form of the compound upon administration in vivo. Prodrugs of one or more antibiotics disclosed herein can be designed to alter the metabolic stability or transport properties of one or more antibiotics disclosed herein, mask side effects or toxicity, improve the flavor of a compound, or alter other properties or attributes of a compound. Suitable examples of prodrugs include methyl, ethyl and glycerol esters of the corresponding acids.

Method of treatment

In embodiments, the invention described herein includes methods of treating a Gastrointestinal (GI) disease or disorder. Various embodiments provide methods of treating a Gastrointestinal (GI) disease or disorder comprising administering a composition comprising one or more antibiotics and a mucolytic agent. Various embodiments provide methods of treating a Gastrointestinal (GI) disease or disorder comprising administering one or more antibiotics and administering a mucolytic agent.

In some embodiments, the gastrointestinal disease or disorder is selected from Small Intestine Bacterial Overgrowth (SIBO) or Irritable Bowel Syndrome (IBS). In some embodiments, Irritable Bowel Syndrome (IBS) is selected from the group consisting of diarrhea-predominant IBS (IBS-D), mixed IBS (IBS-M), and constipation-predominant IBS (IBS-C).

In embodiments, the invention described herein includes methods for inhibiting or killing the growth of microorganisms in one or more regions of the Gastrointestinal (GI) system of a subject. Various embodiments of the present invention provide methods of inhibiting or killing the growth of microorganisms in one or more regions of the Gastrointestinal (GI) system of a subject, comprising: a composition comprising one or more antibiotics and a mucolytic agent is administered. Various embodiments of the present invention provide methods of inhibiting or killing the growth of microorganisms in one or more regions of the Gastrointestinal (GI) system of a subject, comprising: administering one or more antibiotics and administering a mucolytic agent. In various embodiments, the one or more regions of the gastrointestinal system of the subject is the small intestine. In various embodiments, the one or more regions of the gastrointestinal system of the subject is the esophagus, stomach, or colon.

In various embodiments, the microorganism is selected from the group consisting of proteus, citrobacter, aeromonas, klebsiella, methanobacterium, ehrlichia, salmonella, lactobacillus, thiobacillus, campylobacter, bacteroides, clostridia, bifidobacterium, shigella, moraxella, morganella, serratia, enterobacter, pseudomonas, acinetobacter, streptococcus, vilonola, prevotella, parareilla, rocardia, enterobacter, providencia, sutella, coccus (copocccus), lachnospira, rhoea, and combinations thereof.

In various embodiments, the microorganism is selected from the group consisting of campylobacter jejuni, salmonella, bacteroides fragilis, clostridium difficile, escherichia coli, bacteroides species, lactobacillus species (e.g., lactobacillus reuteri and lactobacillus rhamnosus), and combinations thereof.

In some embodiments, the methods described herein may comprise administering a composition comprising one or more antibiotics and a mucolytic agent. In some embodiments, the methods described herein may comprise administering one or more antibiotics and a mucolytic agent.

In various embodiments, the composition comprising one or more antibiotics and a mucolytic agent is administered for about 1 week, 2 weeks, 3 weeks. In various embodiments, the composition comprising one or more antibiotics and a mucolytic agent is administered for about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days. In various embodiments, the composition is administered about 1, 2, 3, or 4 times per day. In various embodiments, the composition is administered about 1 or 2 or 3 times per day.

In various embodiments, the one or more antibiotics and mucolytic agent are administered for about 1 week, 2 weeks, 3 weeks. In various embodiments, the one or more antibiotics and mucolytic agents are administered for about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days. In various embodiments, the one or more antibiotics and mucolytic agents are administered about 1, 2, 3, or 4 times per day. In various embodiments, the one or more antibiotics and mucolytic agents are administered about 1 or 2 or 3 times per day.

Examples of antibiotics are described above.

In various embodiments, the one or more antibiotics are selected from the group consisting of rifaximin, rifamycin, rifampin, penicillin derivatives, fluoroquinolones, macrolides, tetracyclines, doxycycline, neomycin, metronidazole, and combinations thereof. In various embodiments, wherein the penicillin derivative is ampicillin, the fluoroquinolone is ciprofloxacin, and the macrolide is azithromycin. In various embodiments, the one or more antibiotics is rifaximin. In various embodiments, the one or more antibiotics are rifaximin and neomycin.

In various embodiments, the one or more antibiotics is rifaximin, and the amount of rifaximin is 550mg, 500mg, 400mg, 350mg, 300mg, 275mg, 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25 mg. In some embodiments, the one or more antibiotics is rifaximin, and the amount of rifaximin is less than about 550mg, 500mg, 400mg, 350mg, 300mg, 275mg, 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25 mg. In some embodiments, the one or more antibiotics is rifaximin, and the amount of rifaximin is greater than about 550mg, 500mg, 400mg, 350mg, 300mg, 275mg, 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25 mg.

As described above, the combination of the antibiotic and the mucolytic agent can greatly improve the therapeutic effect, and thus, the amount of the antibiotic can be significantly reduced. Thus, in various embodiments where the one or more antibiotics is rifaximin, the amount of rifaximin is 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25 mg. In various embodiments where the one or more antibiotics is rifaximin, the amount of rifaximin is 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25 mg. In some embodiments, the amount of rifaximin is greater than about 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25 mg. In some embodiments, the amount of rifaximin is less than about 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25 mg.

In various embodiments, the one or more antibiotics are rifaximin and neomycin. In various embodiments, the amount of rifaximin is 550mg, 500mg, 400mg, 350mg, 300mg, 275mg, 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25mg, and the amount of neomycin is 500mg, 400mg, 350mg, 300mg, 275mg, 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25 mg. In some embodiments, the amount of rifaximin is greater than about 550mg, 500mg, 400mg, 350mg, 300mg, 275mg, 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25mg, and the amount of neomycin is greater than about 500mg, 400mg, 350mg, 300mg, 275mg, 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25 mg. In some embodiments, the amount of rifaximin is less than about 550mg, 500mg, 400mg, 350mg, 300mg, 275mg, 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25mg, and the amount of neomycin is less than about 500mg, 400mg, 350mg, 300mg, 275mg, 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25 mg.

As mentioned above, the combination of the antibiotic and the mucolytic agent provides significantly improved therapeutic efficacy, and thus, the amount of antibiotic used can be significantly reduced. Thus, in various embodiments where the one or more antibiotics are rifaximin and neomycin, the amount of rifaximin is 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25mg and the amount of neomycin is 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25 mg. In some embodiments, the amount of rifaximin is greater than about 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25mg, and the amount of neomycin is greater than about 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25 mg. In some embodiments, the amount of rifaximin is less than about 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25mg, and the amount of neomycin is less than about 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25 mg.

In various embodiments where the one or more antibiotics are rifaximin and neomycin, the amount of rifaximin is 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25mg and the amount of neomycin is 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25 mg.

In various embodiments, the mucolytic agent is selected from Dithiothreitol (DTT), N-acetylcysteine (NAC), acetylcysteine, ambroxol, bromhexine, carbocisteine, erdosteine, mesteine, and alfa-streptokinase, and combinations thereof. In various embodiments, the mucolytic agent is Dithiothreitol (DTT). In various embodiments, the mucolytic agent is N-acetylcysteine (NAC).

In embodiments where the mucolytic agent is Dithiothreitol (DTT), DTT may be administered via a composition comprising 10-20 v/v% DTT. In various embodiments where the mucolytic agent is Dithiothreitol (DTT), DTT may be administered via a composition comprising 5, 10, 15, 20, or 25 v/v% DTT. In various embodiments wherein the mucolytic agent is Dithiothreitol (DTT), the DTT may be administered by a composition comprising greater than about 5, 10, 15, 20, or 25 v/v% DTT. In various embodiments wherein the mucolytic agent is Dithiothreitol (DTT), the DTT may be administered by a composition comprising less than about 5, 10, 15, 20, or 25 v/v% DTT. In various embodiments where the mucolytic agent is Dithiothreitol (DTT), the DTT may be administered via a composition comprising 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 v/v% DTT.

In embodiments where the mucolytic agent is N-acetylcysteine (NAC), the NAC may be administered by a composition comprising 100 and 1200mg of N-acetylcysteine (NAC). In various embodiments where the mucolytic agent is N-acetylcysteine (NAC), the NAC can be administered via a composition comprising 50-100mg, 100-200mg, 200-300mg, 300-400mg, 400-500mg, 500-600mg, 600-700mg, 700-800mg, 800-900mg, 900-1000mg, 1000-1100mg, 1100-1200mg, 1200-1300mg, 1300-1400mg, or 1400-1500mg of N-acetylcysteine (NAC) per dose. In various embodiments where the mucolytic agent is N-acetylcysteine (NAC), the NAC may be administered by a composition comprising 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, or 1200mg N-acetylcysteine (NAC) per dose. In various embodiments wherein the mucolytic agent is N-acetylcysteine (NAC), the NAC may be administered via a composition comprising greater than about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, or 1200mg N-acetylcysteine (NAC) per dose. In various embodiments wherein the mucolytic agent is N-acetylcysteine (NAC), the NAC may be administered with a composition comprising less than about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, or 1200mg N-acetylcysteine (NAC) per dose.

In various embodiments, the mucolytic dose may be administered in one unit dosage form (e.g., one tablet). In some embodiments, the dose of mucolytic agent may be administered in two or more unit dosage forms (e.g., two, three, four, five, six, or more tablets).

In various embodiments, the disease or disorder of the gastrointestinal tract is Small Intestine Bacterial Overgrowth (SIBO).

In various embodiments, the gastrointestinal disease or disorder is Irritable Bowel Syndrome (IBS).

In various embodiments, the gastrointestinal disease or disorder is diarrhea-predominant irritable bowel syndrome (IBS-D). In various embodiments where the gastrointestinal disease or disorder is IBS-D, the one or more antibiotics is rifaximin, which can be administered according to the amounts described herein. In various embodiments, the amount of rifaximin is 550mg, 500mg, 400mg, 350mg, 300mg, 275mg, 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25mg rifaximin. In particular embodiments, the amount of rifaximin is 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25mg rifaximin. In particular embodiments, the amount of rifaximin is 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25 mg. As mentioned above, the combination of the antibiotic and the mucolytic agent provides a significantly increased therapeutic efficacy, and thus, the amount of antibiotic can be significantly reduced. Thus, in various embodiments where the one or more antibiotics is rifaximin, the amount of rifaximin is 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25 mg. In various embodiments where the one or more antibiotics is rifaximin, the amount of rifaximin is 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25 mg.

In some embodiments, wherein the gastrointestinal disease or disorder is SIBO or IBS-D, the methods described herein may comprise administering about 200mg rifaximin and about 600mg NAC. In some embodiments, the rifaximin and NAC can be administered in an oral unit dosage form (e.g., a tablet), and can be administered in combination in one unit dose or in two or more unit doses (e.g., one or two or more tablets).

In various embodiments, the gastrointestinal disease or disorder is mixed irritable bowel syndrome (IBS-M).

In various embodiments, the gastrointestinal disease or disorder is constipation-predominant irritable bowel syndrome (IBS-C).

In various embodiments where the gastrointestinal disease or disorder is IBS-C, the one or more antibiotics are rifaximin and neomycin, which can be administered according to the dosages specified herein. In various embodiments, the amount of rifaximin is 550mg, 500mg, 400mg, 350mg, 300mg, 275mg, 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25mg and the amount of neomycin is 500mg, 400mg, 350mg, 300mg, 275mg, 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25 mg. As mentioned above, the combination of the antibiotic and the mucolytic agent provides a significantly increased therapeutic efficacy, and thus, the amount of antibiotic can be significantly reduced. Thus, in various embodiments where the one or more antibiotics are rifaximin and neomycin, the rifaximin is in an amount of 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25mg and the neomycin is in an amount of 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25 mg. In various embodiments where the one or more antibiotics are rifaximin and neomycin, the rifaximin is in an amount of 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25mg and the neomycin is in an amount of 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25 mg.

Medicine box

The invention described herein also relates to kits. The kits can be used to practice the methods of the invention for treating gastrointestinal diseases or disorders (e.g., SIBO, IBS) and/or inhibiting the growth of or killing microorganisms. The kit is a collection of materials or components comprising at least one composition of the invention. Thus, in some embodiments, as described above, the kit comprises a composition comprising one or more antibiotics as described above and a mucolytic agent. In some embodiments, the kit may include one or more antibiotics and a mucolytic agent, as described above.

The exact nature of the components configured in the kits of the present invention will depend on their intended use. For example, some embodiments are configured for treating a gastrointestinal disease or disorder; other embodiments are configured to inhibit the growth of or kill microorganisms. In one embodiment, the kit is particularly configured for the purpose of treating a mammalian subject. In another embodiment, the kit is configured for the purpose of, inter alia, treating a human subject. In further embodiments, the kit is configured for veterinary use, treating subjects such as, but not limited to, farm animals, livestock, and laboratory animals.

The kit may contain instructions for use. "Instructions for use" generally include tangible expressions which describe the techniques employed to achieve the desired result using the kit of parts, for example to treat a disease or disorder of the gastrointestinal tract (e.g., SIBO, IBS) and to inhibit the growth of or kill microorganisms. Optionally, the kit further comprises other useful ingredients readily identifiable by a person skilled in the art, such as diluents, buffers, pharmaceutically acceptable carriers, syringes, catheters, applicators, pipettes or measuring means, bandage materials or other useful means.

The materials or components assembled in the cartridge may be provided to the practitioner in any convenient and suitable manner to maintain their operability and usefulness. For example, the components may be in dissolved, dehydrated or lyophilized form; can be provided at room temperature, refrigerated or frozen temperature. The components are typically contained in a suitable packaging material. As used herein, the phrase "packaging material" refers to one or more physical structures used to contain the contents of a kit, e.g., an inventive composition, etc. The packaging material is manufactured using well known methods, preferably to provide a sterile, non-polluting environment. The packaging material used in the kit is typically used to treat a disease or disorder of the gastrointestinal tract (e.g., SIBO, IBS) and to inhibit the growth of or kill microorganisms. As used herein, the term "package" refers to a suitable solid matrix or material, such as glass, plastic, paper, foil, etc., capable of holding individual cartridge components. Thus, for example, the package may be a plastic bottle for containing an appropriate amount of a composition of the invention containing one or more antibiotics and a mucolytic agent, or a blister pack (as one composition or as a separate composition) containing a dose of one or more antibiotics and a mucolytic agent. The packaging material typically has an external label indicating the contents and/or use of the kit and/or its components.

Various embodiments provide kits comprising: compositions comprising one or more antibiotics and a mucolytic agent, and instructions for using the compositions.

Various embodiments provide kits comprising one or more antibiotics and mucolytic agents, and instructions for using the one or more antibiotics and mucolytic agents.

Examples of antibiotics are described above.

In various embodiments, the one or more antibiotics are selected from the group consisting of rifaximin, rifamycin, rifampin, penicillin derivatives, fluoroquinolones, macrolides, tetracyclines, doxycycline, neomycin, metronidazole, and combinations thereof. In various embodiments, wherein the penicillin derivative is ampicillin, the fluoroquinolone is ciprofloxacin, and the macrolide is azithromycin. In various embodiments, the one or more antibiotics is rifaximin. In various embodiments, the one or more antibiotics are rifaximin and neomycin.

In various embodiments, the one or more antibiotics is rifaximin, and the composition comprises 550mg, 500mg, 400mg, 350mg, 300mg, 275mg, 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25mg rifaximin.

As described above, the inventors believe that the combination of the antibiotic and the mucolytic agent may greatly improve the therapeutic efficacy, and thus, the amount of the antibiotic used may be significantly reduced.

Thus, in various embodiments where the one or more antibiotics is rifaximin, the kit comprises a composition comprising 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25mg rifaximin. In various embodiments where the one or more antibiotics is rifaximin, the amount of rifaximin is 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25 mg.

In various embodiments where the one or more antibiotics are rifaximin and neomycin, the kit comprises a composition comprising 550mg, 500mg, 400mg, 350mg, 300mg, 275mg, 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25mg, and a composition comprising 500mg, 400mg, 350mg, 300mg, 275mg, 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25 mg. As noted above, the inventors believe that the combination of the antibiotic and the mucolytic provides significantly improved therapeutic efficacy and, therefore, the amount of antibiotic can be significantly reduced. Thus, in various embodiments where the one or more antibiotics are rifaximin and neomycin, the amount of rifaximin is 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25 mg. The neomycin is present in an amount of 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg or 25 mg. In various embodiments where the one or more antibiotics are rifaximin and neomycin, the rifaximin is in an amount of 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25mg and the neomycin is in an amount of 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25 mg. The rifaximin and neomycin may be provided in separate compositions or in one composition.

In various embodiments, the mucolytic agent is selected from Dithiothreitol (DTT), N-acetylcysteine (NAC), acetylcysteine, ambroxol, bromhexine, carbocisteine, erdosteine, mesteine, and alfa-streptokinase, and combinations thereof. In various embodiments, the mucolytic agent is Dithiothreitol (DTT). In various embodiments, the mucolytic agent is N-acetylcysteine (NAC).

In embodiments where the mucolytic agent is Dithiothreitol (DTT), the composition comprises 10-20 v/v% DTT. In various embodiments wherein the mucolytic agent is Dithiothreitol (DTT), the composition comprises 5, 10, 15, 20, or 25 v/v% DTT. In various embodiments wherein the mucolytic agent is Dithiothreitol (DTT), the composition comprises 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 v/v% DTT.

In embodiments where the mucolytic agent is N-acetylcysteine (NAC), the composition comprises 100-1200mg of N-acetylcysteine (NAC). In various embodiments where the mucolytic agent is N-acetylcysteine (NAC), the composition comprises 50-100mg, 100-200mg, 200-300mg, 300-400mg, 400-500mg, 500-600mg, 600-700mg, 700-800mg, 800-900mg, 900-1000mg, 1000-1100mg, 1100-1200mg, 1200-1300mg, 1300-1400mg, or 1400-1500mg of N-acetylcysteine (NAC) per dose. In various embodiments where the mucolytic agent is N-acetylcysteine (NAC), the composition comprises 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, or 1200mg of N-acetylcysteine (NAC) per dose.

Route of administration

In various embodiments, the compositions and compounds according to the present invention may be formulated for delivery via any route of administration. The "route of administration" may refer to any route of administration known in the art, including but not limited to aerosol, nasal, oral, transmucosal, transdermal, or parenteral administration.

"transdermal" administration may be accomplished using topical creams or ointments or transdermal patches.

By "parenteral" is meant a route of administration typically associated with injection, including intraorbital, infusion, intraarterial, intracapsular, intracardiac, intradermal, intramuscular, intraperitoneal, intrapulmonary, intraspinal, intrasternal, intrathecal, intrauterine, intravenous, subarachnoid, subcapsular, subcutaneous, transmucosal, or transtracheal injection. By parenteral route, the composition may be in the form of a solution or suspension for infusion or injection, or in the form of a lyophilized powder.

By enteral route, the pharmaceutical composition may be in the form of tablets, gel capsules, dragees, syrups, suspensions, solutions, powders, granules, emulsions, microspheres or nanospheres or lipid vesicles or polymersomes allowing controlled release. By parenteral route, the composition may be in the form of a solution or suspension for infusion or injection.

By topical route, compositions based on the compounds of the invention can be formulated for the treatment of the skin and mucous membranes in the form of ointments, creams, milks, salves, powders, impregnated pads, solutions, gels, sprays, lotions or suspensions. They may also be in the form of microspheres or nanospheres or lipid vesicles or polymer patches and hydrogels that allow controlled release. These topical route compositions may be in anhydrous or aqueous form, depending on the clinical indication.

By the ocular route, it may be in the form of eye drops.

The composition according to the invention may further comprise any pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or carrier that is involved in carrying or transporting a compound of interest from one tissue, organ, or part of the body to another tissue, organ, or part of the body. For example, the carrier may be a liquid or solid filler, diluent, excipient, solvent or encapsulating material, or a combination thereof. Each component of the carrier must be "pharmaceutically acceptable" in that it must be compatible with the other ingredients of the formulation. It must also be suitable for use in contact with any tissue or organ with which it may come into contact, meaning that it must not be at risk of toxicity, irritation, allergic response, immunogenicity, or any other complication that unduly outweighs its therapeutic benefit.

The compositions according to the invention may also be encapsulated, tableted or prepared as emulsions or syrups for oral administration. Pharmaceutically acceptable solid or liquid carriers may be added to improve or stabilize the composition, or to facilitate preparation of the composition. Liquid carriers include syrup, peanut oil, olive oil, glycerol, saline, alcohol and water. Solid carriers include starch, lactose, calcium sulfate, dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin. The carrier may also include a slow release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax.

The formulations are prepared according to conventional pharmaceutical techniques including grinding, mixing, granulating and tableting (if necessary) for tableting; or ground, mixed and filled for use in hard gelatin capsules. When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension. Such liquid preparations may be administered orally directly or filled into soft gelatin capsules.

The composition according to the invention may be delivered in a therapeutically effective amount. The exact therapeutically effective amount is that amount of the composition that will produce the most effective result in terms of the therapeutic efficacy of the intended subject. This amount will vary depending on a variety of factors including, but not limited to, the nature of the therapeutic compound (including activity, pharmacokinetics, pharmacodynamics, and bioavailability), the physiological condition of the subject (including age, sex, disease type and stage, general physical condition, responsiveness to the indicated dose and drug type), the nature of the pharmaceutically acceptable carrier or carriers in the formulation, and the route of administration. One skilled in the clinical and pharmacological arts will be able to determine a therapeutically effective amount by routine experimentation, for example, by monitoring the subject's response to administration of the compound and adjusting the dosage accordingly. For more guidance, see Remington: the Science and Practice of Pharmacy, Remington: pharmaceutical sciences and practices (Gennaro ed., 20 th edition, Williams and Wilkins, Pa., USA) (2000).

Thus, in certain embodiments, the present invention provides:

1) a composition comprising:

(a) one or more antibiotics; and

(b) a mucolytic agent.

2) The composition of embodiment 1, wherein said one or more antibiotics are selected from the group consisting of rifaximin, rifamycin, rifampin, penicillin derivatives, fluoroquinolones, macrolides, tetracyclines, doxycycline, neomycin, metronidazole, and combinations thereof.

3) The composition of embodiment 2 wherein the penicillin derivative is ampicillin, the fluoroquinolones are ciprofloxacin, and the macrolides are azithromycin.

4) The composition of embodiment 1, wherein the one or more antibiotics is rifaximin.

5) The composition of embodiment 1, wherein the one or more antibiotics is rifaximin, and the composition comprises 550mg, 500mg, 400mg, 350mg, 300mg, 275mg, 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25mg rifaximin.

6) The composition of embodiment 1, wherein the one or more antibiotics are rifaximin and neomycin.

7) The composition of embodiment 1, wherein said mucolytic agent is selected from the group consisting of Dithiothreitol (DTT), N-acetylcysteine (NAC), acetylcysteine, ambroxol, bromhexine, carbocisteine, erdosteine, mesteine, alfa-streptokinase, and combinations thereof.

8) The composition of embodiment 1, wherein the mucolytic agent is Dithiothreitol (DTT).

9) The composition of embodiment 1, wherein the mucolytic agent is N-acetylcysteine (NAC).

10) The composition of embodiment 1, wherein the mucolytic agent is Dithiothreitol (DTT) and the composition comprises 10-20 v/v% DTT.

11) The composition of embodiment 1, wherein the mucolytic agent is N-acetylcysteine (NAC) and the composition comprises 100-1200mg of N-acetylcysteine (NAC).

12) A method of treating a Gastrointestinal (GI) disease or disorder comprising

(a) Applying the composition of embodiment 1, or

(b) Administering one or more antibiotics and administering a mucolytic agent.

13) Example Error! A method of Reference source not found comprising administering the composition of embodiment 1.

14) Example Error! A method of Reference source not found, comprising:

(a) administering one or more antibiotics; and

(b) a mucolytic agent is administered.

15) Example Error! A method of Reference source not found, wherein said gastrointestinal disease or disorder is Small Intestine Bacterial Overgrowth (SIBO).

16) Example Error! A method of Reference source not found, wherein the gastrointestinal disease or disorder is Irritable Bowel Syndrome (IBS).

17) Example Error! A method of Reference source not found, wherein the gastrointestinal disease or disorder is diarrhea-predominant irritable bowel syndrome (IBS-D).

18) Example Error! A method of Reference source not found, wherein said gastrointestinal disease or disorder is irritable bowel syndrome mixed (IBS-M).

19) Example Error! A method of Reference source not found, wherein the gastrointestinal disease or disorder is constipation-predominant irritable bowel syndrome (IBS-C).

20) Example Error! A method of Reference source not found, wherein said one or more antibiotics are selected from the group consisting of rifaximin, rifamycin, rifampin, a penicillin derivative, a fluoroquinolone, a macrolide, a tetracycline, doxycycline, neomycin, metronidazole, and combinations thereof:

21) example Error! The method of Reference source not found, wherein said one or more antibiotics is rifaximin.

22) Example Error! The method of Reference source not found, wherein the one or more antibiotics is rifaximin, and the composition comprises 550mg, 500mg, 400mg, 350mg, 300mg, 275mg, 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25mg rifaximin.

23) Example Error! The method of Reference source not found, wherein said one or more antibiotics are rifaximin and neomycin.

24) Example Error! Reference source not found, wherein the mucolytic agent is selected from the group consisting of Dithiothreitol (DTT), N-acetylcysteine (NAC), acetylcysteine, ambroxol, bromhexine, carbocisteine, erdosteine, mesteine, alpha-streptokinase, and combinations thereof.

25) Example Error! The method of Reference source not found, wherein said mucolytic agent is Dithiothreitol (DTT).

26) Example Error! The method of Reference source not found, wherein said mucolytic agent is N-acetylcysteine (NAC).

27) Example Error! A method of Reference source not found, wherein the mucolytic agent is Dithiothreitol (DTT), and the composition comprises 10-20 v/v% DTT.

28) Example Error! Reference source not found, wherein the mucolytic agent is N-acetylcysteine (NAC), and the composition comprises 100-1200mg of N-acetylcysteine (NAC).

29) A method of inhibiting or killing the growth of microorganisms in one or more regions of the Gastrointestinal (GI) system of a subject, comprising:

(a) applying the composition of embodiment 1, or

(b) Administering one or more antibiotics and administering a mucolytic agent.

30) Example Error! The method of Reference source not found, wherein the one or more regions of the gastrointestinal system of the subject is the small intestine.

31) Example Error! A method of Reference source not found comprising administering the composition of embodiment 1.

32) Example Error! A method of Reference source not found, comprising:

(a) administering the one or more antibiotics; and

(b) administering the mucolytic agent.

33) Example Error! The method of Reference source not found, wherein said one or more antibiotics are selected from the group consisting of rifaximin, rifamycin, rifampin, a penicillin derivative, a fluoroquinolone, a macrolide, a tetracycline, doxycycline, neomycin, metronidazole, and combinations thereof.

34) Example Error! The method of Reference source not found, wherein said one or more antibiotics is rifaximin.

35) Example Error! The method of Reference source not found, wherein the one or more antibiotics is rifaximin, and the composition comprises 550mg, 500mg, 400mg, 350mg, 300mg, 275mg, 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25mg rifaximin.

36) Example Error! The method of Reference source not found, wherein said one or more antibiotics are rifaximin and neomycin.

37) Example Error! A method of Reference source not found, wherein said mucolytic agent is selected from the group consisting of Dithiothreitol (DTT), N-acetylcysteine (NAC), acetylcysteine, ambroxol, bromhexine, carbocisteine, erdosteine, mesteine, alpha-favasase, and combinations thereof.

38) Example Error! The method of Reference source not found, wherein said mucolytic agent is Dithiothreitol (DTT).

39) Example Error! The method of Reference source not found, wherein said mucolytic agent is N-acetylcysteine (NAC).

40) Example Error! A method of Reference source not found, wherein the mucolytic agent is Dithiothreitol (DTT), and the composition comprises 10-20 v/v% DTT.

41) Example Error! Reference source not found, wherein the mucolytic agent is N-acetylcysteine (NAC), and the composition comprises 100-1200mg of N-acetylcysteine (NAC).

42) A kit, comprising:

(a) the composition of embodiment 1 and instructions for using the composition, or

(b) One or more antibiotics and mucolytics, and instructions for using the one or more antibiotics and mucolytics.

In particular embodiments, the invention described herein provides a method (i.e., method 1) of treating a condition, disease, or disorder involving a bacterial infection of the gastrointestinal tract, or enhancing the efficacy of a rifamycin (e.g., rifaximin) for a disease or condition involving a bacterial infection of the gastrointestinal tract, the method comprising administering to a subject in need thereof a therapeutically effective amount of a rifamycin (e.g., rifaximin) and a therapeutically effective amount of a mucolytic agent.

For example, the invention described herein provides the following embodiments of method 1:

1.1 method 1, wherein said rifamycin is selected from the group consisting of rifamycin, rifampicin, rifabutin, rifapentine, and rifaximin.

1.2 method 1, wherein the rifamycin is rifaximin.

1.3 any of the above methods further comprises administering a therapeutically effective amount of a second antibiotic, for example, selected from the group consisting of neomycin, clarithromycin, tetracycline, sulfamethoxazole, trimethoprim, and metronidazole.

1.4 of any one of the above methods, wherein the rifamycin is administered an oral dose of 25-1000mg once, twice, or three times daily.

1.5 any of the above methods, wherein the rifamycin is administered at an oral dose of 550mg, 500mg, 400mg, 350mg, 300mg, 275mg, 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25 mg.

1.6 of any one of the above methods, wherein the rifamycin is rifaximin, administered three times daily at an oral dose of 200 mg.

1.7 of any one of the above methods, wherein the duration of treatment is from 3 to 15 days.

1.8 of any one of the above methods, wherein the duration of treatment is 3 days.

1.9 of any one of the above methods, wherein the duration of treatment is 14 days.

1.10 any one of the above methods, wherein the rifamycin is rifaximin, administered orally at a dose of 200mg, twice or three times daily for 15 days.

1.11 of any one of the above methods, wherein the rifamycin is rifaximin, and the oral dose is 150mg, twice or three times daily for 15 days.

1.12 of any one of the above methods, wherein the rifamycin is rifaximin, administered orally at a dose of 100mg, twice or three times daily for 15 days.

1.13 of any one of the above methods, wherein the mucolytic agent is selected from one or more of Dithiothreitol (DTT), N-acetylcysteine (NAC), acetylcysteine, ambroxol, bromhexine, carbocisteine, erdosteine, mestane, alfa-streptokinase, thymosin beta 4, nacystelyn, heparin, denbromcline, guaiacol, carbocisteine, erdosteine, mesteine, hypertonic saline, mannitol powder, and an inhalation surfactant.

1.14 of any one of the above methods, wherein the mucolytic agent hydrolyzes the disulfide bonds linking the mucin oligomers.

1.15 of any one of the above methods, wherein the mucolytic agent comprises one or more sulfhydryl groups.

1.16 of any one of the above methods, wherein the mucolytic agent is Dithiothreitol (DTT) and/or N-acetylcysteine (NAC).

1.17 of any one of the above methods, wherein the mucolytic agent is Dithiothreitol (DTT).

1.18 of any one of the above methods, wherein the mucolytic agent is N-acetylcysteine (NAC).

1.19 of any one of the above methods wherein the mucolytic agent is administered at a dose of about 100-.

1.20 of any one of the above methods, wherein the mucolytic agent and the antibacterial agent are in the form of a single composition.

1.21 any one of the above methods, wherein the rifamycin and the mucolytic agent are present in separate compositions and are administered to the patient simultaneously.

1.22 of any one of the above methods, wherein the rifamycin and mucolytic agent are present in separate compositions, and wherein the mucolytic agent is administered prior to the rifamycin.

1.23 the method above, wherein the mucolytic agent is administered no more than 24 hours prior to the administration of the rifamycin.

1.24 the above method, wherein the mucolytic agent is administered no more than 12 hours prior to the administration of the rifamycin.

1.25 of any one of the above methods, wherein the condition, disease or disorder mediated by degradation or modulation of mucosal tissue or mucosa is a bacterial, viral or fungal infection.

1.26 of any one of the above methods, wherein the condition, disease or disorder mediated by degradation or modulation of mucosal tissue or mucosa is a bacterial infection.

1.27 of any one of the above methods, wherein the bacterial infection is a gram negative bacterium.

1.28 of any one of the above methods, wherein the bacterial infection is enterotoxigenic escherichia coli (ETEC), enteroaggregative escherichia coli, shigella species, salmonella species, campylobacter species, yersinia species, vibrio species, aeromonas species, clostridium species, and/or orthomonas species.

1.29 any one of the above methods, wherein the bacterial infection is an escherichia coli infection.

1.30 of any one of the above methods, wherein the bacterial infection is a clostridium difficile infection.

1.31 of any one of the above methods, wherein the condition, disease or disorder is Irritable Bowel Syndrome (IBS) or Small Intestine Bacterial Overgrowth (SIBO).

1.32 of any of the above methods, wherein the condition, disease or disorder is Irritable Bowel Syndrome (IBS), such as diarrhea-predominant IBS (IBS-D), constipation-predominant IBS (IBS-C), or mixed IBS (IBS-M).

1.33 of any one of the above methods, wherein the condition, disease or disorder is diarrhea-predominant irritable bowel syndrome (IBS-D).

1.34 of any of the above methods, wherein the condition, disease or disorder is diarrhea-predominant irritable bowel syndrome (IBS-D), and after treatment (e.g., administration of a therapeutically effective amount of rifaximin and a therapeutically effective amount of NAC to the subject), the subject has improved stool morphology and reduced stool frequency compared to baseline prior to treatment.

1.35 of any one of the above methods, wherein the condition, disease, or disorder is diarrhea-predominant irritable bowel syndrome (IBS-D), and after treatment (e.g., administration of a therapeutically effective amount of rifaximin and a therapeutically effective amount of NAC to a subject), the subject has a decreased severity of abdominal pain as compared to pre-treatment baseline, e.g., as determined by a weekly average Visual Analog Scale (VAS) score.

1.36 of any one of the above methods, wherein the condition, disease, or disorder is diarrhea-predominant irritable bowel syndrome (IBS-D), and after treatment (e.g., after administration of a therapeutically effective amount of rifaximin and a therapeutically effective amount of NAC to the subject), the subject exhibits a sense of urgency for defecation or a reduction in abdominal distension as compared to pre-treatment baseline, e.g., as determined by a weekly mean Visual Analog Scale (VAS) score.

1.37 of any one of the above methods, wherein the condition, disease or disorder is diarrhea-predominant irritable bowel syndrome (IBS-D), and after treatment (e.g., administration of a therapeutically effective amount of rifaximin and a therapeutically effective amount of NAC to the subject), the subject has a decrease in Lactulose Hydrogen Breath Test (LHBT) as compared to pre-treatment baseline.

1.38 of any one of the above methods, wherein the condition, disease or disorder is Small Intestine Bacterial Overgrowth (SIBO).

1.39 of any one of the above methods, wherein the rifamycin and mucolytic agent are independently in the form of a tablet or capsule.

1.40 of any one of the above methods, wherein the rifamycin and mucolytic agent are each in the form of a tablet or capsule comprising an enteric coating layer.

1.41 of any one of the above methods, wherein the rifamycin and mucolytic agent are combined in a single tablet or capsule.

1.42 of any one of the above methods, wherein the rifamycin and mucolytic agent are combined in a tablet or capsule comprising an enteric coating layer.

1.43 of any one of the above methods, wherein the rifamycin is rifaximin and the mucolytic agent is DTT.

1.44 of any one of the above methods, wherein the rifamycin is rifaximin and the mucolytic agent is DTT, wherein the rifaximin and DTT are combined in a tablet or capsule.

1.45 any one of the above methods, wherein the rifamycin is rifaximin and the mucolytic agent is NAC.

1.46 of any one of the above methods, wherein the rifamycin is rifaximin and the mucolytic agent is NAC, wherein the rifaximin and NAC are combined in a tablet or capsule.

1.47 of any one of the above methods, wherein the rifamycin is 200mg of rifaximin and the mucolytic agent is 600mg of NAC administered orally three times daily for up to 15 days. 1.48 of any one of the above methods, wherein the rifamycin and the mucolytic agent are administered in any one of combination 1, and the like.

The present disclosure also provides rifamycin and a mucolytic agent for combined use in a method of treating a condition, disease, or disorder involving a bacterial infection of the gastrointestinal tract, e.g., for any one of method 1, and the like.

The present disclosure also provides the use of an antibacterial agent and a mucolytic agent in the manufacture of a medicament for use in a method of treating a condition, disease or disorder involving bacterial infection of the gastrointestinal tract, e.g., a medicament for use in any of method 1, etc.

Thus, in various embodiments, the present invention also provides a pharmaceutical combination (i.e., combination 1) comprising a therapeutically effective amount of a rifamycin and a therapeutically effective amount of a mucolytic agent. For example, the present disclosure provides the following combinations:

1.1 combination 1, wherein the rifamycin is selected from rifamycin, rifampicin, rifabutin, rifapentine, or rifaximin.

1.2 any of the above combinations, wherein the combination further comprises an effective amount of neomycin, clarithromycin, tetracycline, sulfamethoxazole, trimethoprim, or metronidazole.

1.3 wherein the rifamycin is rifaximin.

1.4 of any combination of the above, wherein the rifamycin is in an oral unit dosage form comprising 25-1000mg of rifamycin in free or salt form.

1.5 of any combination of the above, wherein the rifamycin is in an oral unit dosage form comprising 550mg, 500mg, 400mg, 350mg, 300mg, 275mg, 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 75mg, 50mg, or 25 mg.

1.6 of any combination of the above, wherein the rifamycin is rifaximin in an oral unit dosage form of 200 mg.

1.7 of any combination above, wherein the rifamycin is rifaximin in a 550mg oral unit dosage form.

1.8 of any combination of the above, wherein the mucolytic agent is selected from the group consisting of Dithiothreitol (DTT), N-acetylcysteine (NAC), acetylcysteine, ambroxol, bromhexine, carbapenem, epothitine, methylcysteine, dornase alpha, thymosin beta 4, nanocysteine, heparin, des-amino acid, guaiacol, carbopenicillin, epothitine, methylcysteine, hypertonic saline, mannitol powder, and an inhalation surfactant.

1.9 of any one of the combinations above, wherein the mucolytic agent is Dithiothreitol (DTT) and/or N-acetylcysteine (NAC).

1.10 of any combination above, wherein the mucolytic agent is Dithiothreitol (DTT).

1.11 of any combination of the above, wherein the mucolytic agent is N-acetylcysteine (NAC).

1.12 of any combination of the above, wherein the mucolytic agent is administered at a dose of about 100 and 1200 mg.

1.13 of any combination of the above, wherein the mucolytic agent and the rifamycin are in the form of a single composition.

1.14 of any combination of the above, wherein the rifamycin and the mucolytic agent are in separate compositions for simultaneous administration to the patient.

1.15 of any combination above, wherein the rifamycin and the mucolytic agent are in separate compositions, and wherein the mucolytic agent is administered prior to the rifamycin.

1.16 the above combination, wherein the mucolytic agent is administered no more than 24 hours prior to the administration of the rifamycin.

1.17 the combination above, wherein the mucolytic agent is administered no more than 12 hours prior to the rifamycin.

1.18 of any one of the above combinations, wherein the combination is for use in the treatment of Irritable Bowel Syndrome (IBS) or Small Intestine Bacterial Overgrowth (SIBO).

1.19 of any one of the above combinations, wherein the combination is for use in the treatment of Irritable Bowel Syndrome (IBS).

1.20 of any one of the above combinations, wherein the combination is for use in the treatment of diarrhea-predominant irritable bowel syndrome (IBS-D).

1.21 any combination of the above, wherein the combination is for use in the treatment of constipation-predominant irritable bowel syndrome (IBS-C).

1.22 of any combination of the above, wherein the combination is for use in the treatment of mixed irritable bowel syndrome (IBS-M).

1.23 of any one of the above combinations, wherein the combination is for use in the treatment of Small Intestine Bacterial Overgrowth (SIBO).

1.24 of any combination of the above, wherein the rifamycin and the mucolytic agent are in the form of a tablet or capsule.

1.25 of any combination of the above, wherein the rifamycin and the mucolytic agent are in the form of a tablet or capsule comprising an enteric coating layer.

1.26 of any combination above, wherein the rifamycin is rifaximin, the mucolytic agent is DTT, and the rifaximin and DTT are combined in a tablet or capsule.

1.27 of any combination above, wherein the rifamycin is rifaximin, the mucolytic agent is NAC, and the rifaximin and NAC are combined in a tablet or capsule.

1.28 of any combination of the above, wherein the rifamycin is 200mg of rifaximin, the mucolytic agent is 600mg of NAC, and the rifaximin and NAC are combined in a tablet or capsule.

1.29 of any combination of the above, wherein said rifamycin and said mucolytic agent are provided in a kit with instructions for use.

1.30 of any combination of the above, wherein said rifamycin and said mucolytic agent are provided in a kit with instructions for use, wherein said rifamycin is rifaximin and said mucolytic agent is DTT.

1.31 of any combination of the above, wherein the rifamycin and the mucolytic agent are provided in a kit with instructions for use, wherein the rifamycin is rifaximin and the mucolytic agent is NAC.

1.32 of any combination of the above, wherein the rifamycin and the mucolytic agent are provided in a kit with instructions for use, wherein the rifamycin is in an oral dosage form comprising 200mg rifaximin and the mucolytic agent is in an oral dosage form comprising 600mg NAC.

1.33 for any of the foregoing combinations of any of method 1, etc.

The present disclosure further provides a pharmaceutical combination according to combination 1 or the like, for use in any one of method 1 or the like.

The present disclosure further provides the use of a pharmaceutical combination according to combination 1 or the like in the manufacture of a medicament for use in any of method 1.

Various embodiments of the present invention are described in the above detailed description of the invention. While these descriptions directly describe the above embodiments, it is to be understood that modifications and/or variations to the specific embodiments shown and described herein may be envisioned by those skilled in the art. Any such modifications or variations that fall within the scope of this specification are intended to be included therein. It is the intention of the inventors that the words and phrases in the specification and claims be given the ordinary and customary meaning to the skilled artisan, unless otherwise indicated.

The foregoing description, at the time of filing, has presented various embodiments of the invention known to the applicant and is intended for the purposes of illustration and description. It is not intended to be exhaustive or to limit the invention to the precise form disclosed, and many modifications and variations are possible in light of the above teaching. The described embodiments are intended to explain the principles of the invention and its practical application and to enable others skilled in the art to utilize the invention in various embodiments and with various modifications as are suited to the particular use contemplated. Therefore, it is intended that the invention not be limited to the particular embodiments disclosed for carrying out this invention.

While particular embodiments of the present invention have been shown and described, it will be obvious to those skilled in the art that, based upon the teachings herein, changes and modifications may be made without departing from this invention and its broader aspects and, therefore, the appended claims are to encompass within their scope all such changes and modifications as are within the true spirit and scope of this invention. It will be understood by those within the art that, in general, terms used herein are generally intended as "open" terms (e.g., the term "including" should be interpreted as "including but not limited to," the term "having" should be interpreted as "having at least," the term "includes" should be interpreted as "includes but is not limited to," etc.).

As used herein, the terms "comprising" or "comprises" are used in reference to compositions, methods, and respective components thereof that are useful for the embodiments but may include unspecified elements, whether or not useful. It will be understood by those within the art that, in general, terms used herein are generally intended as "open" terms (e.g., the term "including" should be interpreted as "including but not limited to," the term "having" should be interpreted as "having at least," the term "includes" should be interpreted as "includes but is not limited to," etc.). Although the invention is described and claimed herein using the open-ended term "comprising" as a term such as comprising, including, or having synonyms, the invention or embodiments thereof may also be described using alternative terms (e.g., "consisting of or" consisting essentially of).

Examples

The following examples are provided to better illustrate the claimed invention and should not be construed as limiting the scope of the invention. To the extent that specific materials are mentioned, they are used for illustrative purposes only, and are not intended to limit the invention. Those skilled in the art may develop equivalent means or reactants without losing the ability of the invention and without departing from the scope of the invention.

Example 1

(1) The same patient duodenal aspirate sample was vortexed and divided into two portions: (i) rifaximin and DTT (rifaximin dose: 0.01g/mL) were added; (ii) rifaximin was added and DTT was not added (rifaximin dose: 0.01 g/mL). Culturing: blood agar was cultured aerobically and MacConkey, and blood agar was cultured anaerobically. It was observed that the sample with DTT improved the dissolution of rifaximin. Rifaximin did not penetrate mucus in samples without DTT. The results are shown in tables 1a and 1b below.

(2) The same patient duodenal aspirate sample was vortexed and divided into two portions: (i) rifaximin and DTT (rifaximin dose: 0.1g/mL) were added; (ii) rifaximin was added and DTT was not added (rifaximin dose: 0.1 g/mL). Culturing: MacConkey aerobic culture and blood agar anaerobic culture. It was observed that the DTT sample improved the dissolution of rifaximin. The results are shown in tables 1a and 1b below.

(3) The same patient duodenal aspirate sample was vortexed and divided into two portions: (i) rifaximin and DTT (rifaximin dose: 0.01g/mL) were added; (ii) rifaximin was added and DTT was not added (rifaximin dose: 0.01 g/mL). Culturing: MacConkey aerobic culture and blood agar anaerobic culture. Again, DTT improved the dissolution of rifaximin. Rifaximin did not penetrate mucus in samples without DTT. The results are shown in tables 1a and 1b below.

(4) The same patient duodenal aspirate sample was vortexed and divided into two portions: (i) rifaximin and DTT (rifaximin dose: 0.1g/mL) were added; (ii) rifaximin was added and DTT was not added (rifaximin dose: 0.1 g/mL). Culturing: MacConkey aerobic culture and blood agar anaerobic culture. DTT improved the dissolution of rifaximin. Rifaximin did not penetrate mucus in samples without DTT. The results are shown in tables 1a and 1b below.

Table 1a.

Table 1b.

The results indicate that DTT improves the dissolution of rifaximin. Aspirated samples treated with DTT and rifaximin together showed a reduction in bacterial CFU/mL compared to rifaximin alone. In all experiments, DTT also improved the rifaximin effect on anaerobes. The improvement of rifaximin plus DTT on gram-negative bacteria was species specific (tests #1 and #3 showed efficacy. test # 2: no efficacy).

Example 2-evaluation of the efficacy and safety of rifaximin and N-acetylcysteine (NAC) combination in adult diarrhea-associated irritable bowel syndrome patients

The objectives and endpoints of this study are summarized below:

the study is a prospective proof-of-concept double blind (to NAC dose) clinical trial aimed at determining the efficacy of rifaximin and NAC combination therapy with rifaximin monotherapy in alleviating clinical symptoms in IBS-D subjects.

The study is a single-center, open label test consisting of 3 stages:

an import phase: eligible subjects for IBS-D who agreed to participate were enrolled. After providing informed written consent, these subjects followed the activity scheduleThe table was subjected to baseline testing and completed as a 14 day daily stool diary and weekly symptom questionnaire.

Stage of treatment: subjects were randomized to one of 3 study arms and received either:

rifaximin 550mg is taken orally three times a day for 14 days,

or

Rifaximin 200mg plus placebo is taken orally three times a day for 14 days,

or

Rifaximin 200mg plus N-acetylcysteine (600mg) was administered orally three times daily for 14 days.

Subjects completed a daily stool diary for 14 days of treatment and a weekly symptom questionnaire.

Follow-up phase: after completion of treatment, subjects received the same repeat examinations as at the baseline examination. The subject then completed a daily stool diary and weekly symptom questionnaire for a 28-day period. At the end of this period, subjects completed one study end visit and performed additional repeat exams as specified in the activity schedule.

The entry criteria for this study are as follows:

male or female subject aged 18-75 years (including 18 years and 75 years)

The IBS-D roman HI criteria are met, and in order to advance to the treatment stage, the following requirements are met:

the average score for IBS-related abdominal pain is greater than or equal to 3. The abdominal pain score was based on the subject's responses to the following daily questions: "what do you score in the 0-10 point range for your specific IBS abdominal pain symptoms, were you the most severe IBS-related abdominal pain in the last 24 hours? "0" means you are not painful at all; "10" means the most severe pain you can imagine. "

The average score for IBS-related bloating was greater than or equal to 3 points. The abdominal distension score is based on the subject's responses to the following daily questions: "is you scoring in the 0-6 point range for your IBS bloating symptoms, how painful your IBS-related bloating was in the last 24 hours? 0 is not at all; 1 ═ almost no; 2 ═ a bit; medium 3; 4, it is painful; 5, suffering; 6 is very painful. "

Stool consistency is 6 (hairy, ragged, mushy stools) or 7 (watery stools, no solid pieces; complete liquid) using the Bristol stool form scale (BSS) for at least 2 days per week. Stool was scored using BSS as follows: 1 ═ individual hard pieces like nuts (difficult to pass through); 2, the sausage is shaped like sausage but is blocky; 3, the sausage is like a sausage, but the surface of the sausage is provided with cracks; 4, like sausage or snake, smooth and soft; 5 ═ soft spots with sharp edges (easy to pass); 6, the pieces of hairy antler are ragged and have irregular edges and are pasty excrement; water-like stool without solid fragments; is entirely liquid.

Must complete the colonoscopy within the past 10 years

Subjects were able to understand study requirements, were willing to follow all study procedures, and were willing to attend all study visits.

Consent was given to use of acceptable contraceptive methods during participation in the study. Acceptable methods of contraception include:

double barrier methods (condoms with spermicidal jelly or diaphragms with spermicidal agents),

hormonal methods (e.g. oral contraceptives, patches or medroxyprogesterone acetate),

the annual failure rate recorded is lower than 1% of the intrauterine devices (IUDs).

Investigators considered abstinence or partner vasectomy to be an acceptable method of contraception.

Female subjects that are surgically sterilized (e.g., hysterectomy or bilateral tubal ligation) or postmenopausal (complete cessation of menses for > 1 year) will not be considered "women with fertility potential".

All subjects will provide written informed consent for Institutional Review Board (IRB) approval prior to the initiation of any study-related activities.

Exclusion criteria were as follows:

previous use of rifaximin for treating IBS symptoms

Any oral antibiotic has been used within the past two months

Subjects with a history of bowel surgery (except appendectomy or cholecystectomy)

Subjects with known pelvic floor dysfunction

Pregnancy

Mother giving milk

Uncontrolled/uncontrolled gross disease that can interfere with research procedures

History of intestinal obstruction

History of inflammatory bowel disease or celiac disease

History of HIV

Cirrhosis of the liver

IBS-C/Chronic idiopathic constipation

Poorly controlled diabetes or thyroid disorders

History of anorectal radiotherapy/surgery

History of prostatitis

Known to be allergic or hypersensitive to rifaximin, rifamycin or NAC

Currently, treatment with Eluzadoline (EIuxadoline) or opioids is used

Current treatment with warfarin or cyclosporine

Any occurrence of exclusion criteria during the study is the basis for discontinuation of the study by the subject.

Demographics and medical history: investigators recorded the subject's gender, date of birth, and race. A history of the disease (e.g., past diagnosis, disease or surgery) will be collected. The findings were recorded in REDCap by a medical history questionnaire. Accompanying medication was also examined.

Physical examination including vital signs: a complete physical examination is performed by the primary researcher or physician co-researcher. General examinations included the evaluation of the head, ears, eyes, nose, throat, endocrine, cardiovascular, respiratory, abdominal, skin, nervous, extremity and musculoskeletal systems. Before examination, vital sign measurements including height, weight, blood pressure, radial pulse rate, respiratory rate, and body temperature were recorded after the subject was semi-supine for at least 5 minutes. Abnormalities found at baseline check-up (visit 1) were recorded as a medical history. Any clinically significant change was recorded as an adverse event compared to the baseline examination.

Urine pregnancy test: female subjects with fertility potential are asked to provide urine samples for pregnancy tests. Pregnancy is considered as the exclusion criterion.

Lactulose breath test: subjects were asked to undergo a 24 hour preparation period prior to the trial. Subjects remained on a flat diet for the first 12 hours and fasted for the remaining 12 hours. The baseline breath sample was collected by expiration into a disposable collection bag with a capacity of 750 mL. Then, the subject consumed 10g of lactulose dissolved in water. During the remaining 120 minute tests, subsequent breath samples were taken every 15 minutes. Immediately after collection, the breath samples were analyzed for hydrogen, methane, carbon dioxide and hydrogen sulfide content by gas chromatography.

Clinical symptoms questionnaire (VAS): the baseline symptoms questionnaire was completed. Symptom severity was recorded using a Visual Analog Scale (VAS) with a score ranging from 0 (no symptoms) to 100 (most severe symptoms). The online survey and database may be populated using a secure, web-based application for building and managing online surveys and databases, or may be populated in paper form.

Blood drawing: blood was drawn by a trained research nurse, blood was collected for Complete Blood Count (CBC), complete metabolic assay (CMP), Erythrocyte Sedimentation Rate (ESR), and serum pregnancy tests were performed on women with fertility potential. Laboratory analyses were performed at a central clinical laboratory. Reference ranges are provided by clinical laboratories and are used by researchers to assess clinical significance and pathological changes in laboratory results. An additional blood sample was drawn for exploratory cytokine detection.

Stool collection (optional): at the end of the study visit, subjects were provided with a stool collection kit and asked to take stool samples the day before the next visit. Subjects were instructed to store the samples in a refrigerator and return the samples to the investigator at the next visit. Providing a stool sample is optional for exploratory analysis of the effect of rifaximin and NAC combination on gut microbiology.

Daily stool diary: subjects were asked to complete a stool diary per order at home using Bristol stool images in online or paper form as a visual aid. Subjects were also asked to objectively classify stool consistency using a diet mobile application that included stool image capture functionality and computer vision techniques.

Neither rifaximin nor NAC had the expected adverse effects. Although more than 1% of subjects showed side effects, according to previous clinical trials rifaximin side effects were not more frequent than placebo. Thus, these side effects are not "expected". Adverse events are tracked and reported.

The improvement of the primary, secondary and tertiary endpoints identified above was evaluated and reported.

After completion of the study, it is expected that the combination of rifaximin and NAC will demonstrate that NAC enhances rifaximin activity and reduces clinical symptoms in IBS-D subjects compared to rifaximin monotherapy.