Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
  • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
  • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
  • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/12—Antidiarrhoeals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
  • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
  • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

• This invention relates to pharmaceutical compositions and methods of treating gastrointestinal diseases and disorders including irritable bowel syndrome and small intestinal bacterial overgrowth.
• the mucus barrier has an important role in preventing infectious diseases. It provides protection against many intestinal pathogens, including various species of bacteria. Mucus is mainly formed of glycoproteins containing various glycans, but also contains a variety of nonspecific antimicrobial molecules and antibodies targeting specific microbial antigens. Mucus is therefore a major component of innate immunity, and generally prevents pathogens from reaching and persisting on epithelial surfaces within the body. However, some pathogens have evolved to adhere to mucus or to modulate the expression of virulence genes and thereby adapt to the host environment.
• an alteration of mucosal integrity is generally associated with health problems, such as inflammatory bowel diseases, including ulcerative colitis and Crohn's disease.
• health problems such as inflammatory bowel diseases, including ulcerative colitis and Crohn's disease.
• Such changes in the mucosal environment could also be linked to dysbiosis, an abnormal change in the composition of the intestinal microbiota due to Crohn's disease.
• the mucus barrier becomes permeable to bacteria that are able to access the epithelium and therefore cause inflammation, which is why the integrity of the mucus layer is critical for the upkeep of a homeostatic relationship between the intestinal microbiota and its host.
• Bacterial gastroenteritis is usually caused by eating contaminated food, drinking contaminated water, or close contact with an infected person.
• Bacterial enteropathogens include, e.g., enterotoxigenic Escherichia coli (ETEC), enteroaggregative E. coli, and various species of Shigella, Salmonella, Campylobacter, Yersinia, Aeromonas, and Plesiomonas. While most bacterial gastrointestinal illness is short-lived, severe diarrheal illness can lead to serious and sometimes fatal dehydration.
• IBS Irritable Bowel Syndrome
• IBS is characterized by symptoms which include abdominal pain, bloating, and chronic changes in bowel function that may present as diarrhea- predominant (D-IBS), constipation-predominant (C-IBS) or alternate between the two (M-IBS).
• D-IBS diarrhea- predominant
• C-IBS constipation-predominant
• M-IBS alternate between the two
• bacterial infections of the gastrointestinal tract have been linked with the occurrence of IBS. It is theorized that bacteria such as Salmonella spp. or Campylobacter spp. infiltrate the mucosal membrane of the small intestine, often resulting in increased incidence of lasting IBS symptoms.
• Cdt cytolethal distending toxin
• CdtB is the active toxin subunit
• CdtA and CdtC are proposed to collaborate to facilitate the binding and entry of CdtB into mammalian cells.
• rats infected with C. jejuni developed altered stool forms and other symptoms that resemble IBS in humans, whereas rats infected with a mutant form of C. jejuni that lacked CdtB did not.
• Rats directly injected with the CdtB toxin also developed increased bacterial levels in the small bowel, which further supported the hypothesis that CdtB was a key link between infection with pathogens like C. jejuni and the development of PI-IBS.
• food poisoning causes autoimmunity, which triggers neuropathy which triggers small intestinal bacterial overgrowth (SIBO), which leads to irritable bowel syndrome (IBS).
• SIBO small intestinal bacterial overgrowth
• IBS irritable bowel syndrome
• rifaximin is a treatment option for IBS and SIBO because it is not absorbed, or very minimally absorbed, into the body, and therefore has little to no side effects. Resistance does not appear to develop over repeated use.
• mucus In the gastrointestinal (GI) tract, mucus is protective, as it has components that protect the epithelium against pathogens and is also a natural barrier.
• pathogens developed mechanisms to circumvent the protection or even use mucus to their advantage.
• C. jejuni Salmonella, B. fragilis, C. difficile, some strains of E. coli, and many other bacteria can adhere, survive and grow in mucus.
• other non-pathogenic bacteria can also survive and grow in mucus including, Bacteroides sp and Lactobacillus sp (especially reuteri and rhamnosus).
• Rifaximin is a minimally absorbed antibiotic that specifically targets the gastrointestinal tract and is FDA-approved for the treatment of IBS-D. Although treatment with rifaximin is extremely effective, symptom recurrence is common. The mucus layer in the small intestine is viscous, which can render the microbes in the mucus layer inaccessible. Without being limited to any one theory, this inaccessibility may protect certain bacterial species from the effects of rifaximin, thereby facilitating their regrowth and the recurrence of symptoms.
• the reducing agent dithiothreitol can reduce the disulfide bonds linking mucin subunits in mucus. For example, it may be used to reduce mucus viscosity. This led to the hypothesis that using rifaximin in combination with a mucolytic agent would make mucosal bacteria more accessible and thus improve the efficacy of rifaximin in treating IBS symptoms. DTT is not yet approved for use in humans, but the mucolytic agent N-acetylcysteine (NAC) is an approved agent.
• N-acetylcysteine N-acetylcysteine
• Embodiments of the invention described herein include methods of treatment and combination products using an antibiotic, e.g., a rifamycin, such as rifaximin, and a mucolytic, e.g. NAC or DTT, wherein the mucolytic agent facilitates access for the antibiotic to a target microbe (e.g., pathogenic microbes, microbes that make up small intestinal bacterial overgrowth) by diluting the mucus in on the small intestine.
• an antibiotic e.g., a rifamycin, such as rifaximin
• a mucolytic e.g. NAC or DTT
• the invention described herein includes a method for treating a condition, disease or disorder in a subject in need thereof.
• the condition, disease or disorder may include a bacterial infection of the gastrointestinal tract.
• the condition, disease, or disorder may be a gastrointestinal (GI) disease or disorder.
• the GI disease or disorder may include small intestinal bacterial overgrowth (SIBO) or irritable bowel syndrome (IBS).
• IBS may be diarrhea predominant irritable bowel syndrome (IBS-D), mixed irritable bowel syndrome (IBS-M), and constipation predominant irritable bowel syndrome (IBS-C).
• the invention described herein may include a method for inhibiting the growth of or killing microorganisms in one or more regions of a subject’s GI system.
• the invention described herein may include a method of enhancing the efficacy of a rifamycin (e.g., rifaximin) against a condition, disease, or disorder involving a bacterial infection of the GI tract.
• a rifamycin e.g., rifaximin
• such methods may include the administration of a composition comprising a therapeutically effective amount of one or more antibiotics and a mucolytic agent.
• such methods may include the administration of a therapeutically effective amount of one or more antibiotics and a mucolytic agent.
• the one or more antibiotics may include aminoglycosides
• cephalosporins e.g., first generation: cefadroxil, cefazolin, cefalotin or cefalothin, cefalexin; second generation: cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime; third generation: cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibut
• the one or more antibiotics may include a rifamycin.
• the rifamycin may be selected from the group consisting of rifampicin, rifampin, rifabutin, rifapentine, and rifaximin.
• the one or more antibiotics may be selected from the group consisting of a rifaximin, rifamycin, rifampin, penicillin derivative, fluoroquinolone, macrolide, tetracycline, doxycycline, neomycin, and metronidazole.
• the one or more antibiotics may include rifaximin.
• the one or more antibiotics include rifaximin and neomycin.
• the rifamycin may be administered in a dosage of about 25 mg to about 1000 mg.
• the rifamycin is rifaximin and may be administered in a dosage of about 550 mg, 500 mg, 400 mg, 350 mg, 300 mg, 275mg, 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg; or greater than about 550 mg, 500 mg, 400 mg, 350 mg, 300 mg, 275mg, 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg; or less than about 550 mg, 500 mg, 400 mg, 350 mg, 300 mg, 275mg, 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg.
• the mucolytic agent may be selected from the group consisting of selected from the group consisting of dithiothreitol (DTT), N-acetyl cysteine (NAC), acetylcysteine, ambroxol, bromhexine, carbocisteine, erdosteine, mecysteine, and domase alfa.
• the mucolytic agent may be DTT or NAC.
• the mucolytic agent is NAC.
• the mucolytic agent is administered in an amount of about 100 mg to 1200 mg.
• the mucolytic agent is NAC, which may be administered in an amount of 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.
• the one or more antibiotics and mucolytic agent may be administered as one composition or they may be administered as separate compositions in accordance with the methods described herein.
• a mucolytic agent e.g., NAC
• antibiotics e.g., rifaximin
• compositions comprising: one or more antibiotics; and a mucolytic agent.
• antibiotics examples 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., loracarbef), carbapenems (e.g., ertapenem, doripenem, imipenem, cilastatin, meropenem), cephalosporins (e.g., first generation: cefadroxil, cefazolin, cefalotin or cefalothin, cefalexin; second generation: cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime; third generation: cefixime, cefdinir, cefditoren, cefopera
• aminoglycosides e.g
• the one or more antibiotics is selected from the group consisting of rifaximin, rifamycin, rifampin, penicillin derivative, fluoroquinolone, macrolide, tetracycline, doxycycline, neomycin, metronidazole and combinations thereof.
• the penicillin derivative is ampicillin
• the fluoroquinolone is ciprofloxacin
• the macrolide is azithromycin.
• the one or more antibiotics includes rifaximin.
• the one or more antibiotics includes rifaximin and neomycin.
• the one or more antibiotics is rifaximin and the composition comprises 550 mg, 500 mg, 400 mg, 350 mg, 300 mg, 275mg, 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg of rifaximin. In some embodiments, the one or more antibiotic is rifaximin and the composition comprises less than about 550 mg, 500 mg, 400 mg, 350 mg, 300 mg, 275mg, 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg of rifaximin.
• the one or more antibiotic is rifaximin and the composition comprises greater than about 550 mg, 500 mg, 400 mg, 350 mg, 300 mg, 275mg, 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg of rifaximin.
• a therapeutically effective dose of rifaximin in combination with a mucolytic agent, e.g., NAC or DTT
• a mucolytic agent e.g., NAC or DTT
• a mucolytic agent e.g., NAC or DTT
• the increased activity may be greater than about a 10%, 25%, 50%, 75%, 100%, 125%, 150%, 175%, 200%, 225%, 250%, 275%, 300%, 325%, 350%, 375%, 400%, 425%, 450%, 475%, or 500% increase in activity for a rifaximin dosage combined with a mucolytic agent as compared to the same rifaximin dosage without such combination.
• the increased activity may be less than about a 10%, 25%, 50%, 75%, 100%, 125%, 150%, 175%, 200%, 225%, 250%, 275%, 300%, 325%, 350%, 375%, 400%, 425%, 450%, 475%, or 500% increase in activity for a rifaximin dosage combined with a mucolytic agent as compared to the same rifaximin dosage without such combination.
• the increased activity may be about a 10%, 25%, 50%, 75%, 100%, 125%, 150%, 175%, 200%, 225%, 250%, 275%, 300%, 325%, 350%, 375%, 400%, 425%, 450%, 475%, or 500% increase in activity for a rifaximin dosage combined with a mucolytic agent as compared to the same rifaximin dosage without such combination.
• the composition comprises 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg of rifaximin. In some embodiments, the composition comprises greater than about 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg of rifaximin. In some embodiments, the composition comprises less than about 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg of rifaximin.
• An approved dosage of rifaximin is 200 mg for the treatment of Travelers’ diarrhea.
• the composition comprises 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg of rifaximin.
• the one or more antibiotics is rifaximin and neomycin.
• the quantity of rifaximin is 550 mg, 500 mg, 400 mg, 350 mg, 300 mg, 275mg, 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg
• the quantity of neomycin is 500 mg, 500 mg, 400 mg, 350 mg, 300 mg, 275mg, 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg.
• the quantity of rifaximin is less than about 550 mg, 500 mg, 400 mg, 350 mg, 300 mg, 275mg, 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg
• the quantity of neomycin is less than about 500 mg, 500 mg, 400 mg, 350 mg, 300 mg, 275mg, 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg.
• the quantity of rifaximin is greater than about 550 mg, 500 mg, 400 mg, 350 mg, 300 mg, 275mg, 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg
• the quantity of neomycin is greater than about 500 mg, 500 mg, 400 mg, 350 mg, 300 mg, 275mg, 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg.
• the combination of an antibiotic and a mucolytic agent provides vastly increased therapeutic efficacy, and thus, the amount of the antibiotic(s) can be reduced significantly.
• the quantity of rifaximin is 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg
• quantity of neomycin is 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg.
• the quantity of rifaximin is greater than about 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg, and quantity of neomycin is greater than about 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg.
• the quantity of rifaximin is less than about 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg, and quantity of neomycin is less than about 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg.
• the quantity of rifaximin is 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg
• quantity of neomycin is 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg.
• the mucolytic agent is selected from the group consisting of dithiothreitol (DTT), N-acetyl cysteine (NAC), acetylcysteine, ambroxol, bromhexine, carbocisteine, erdosteine, mecysteine, domase alfa and combinations thereof.
• the mucolytic agent is selected from the group consisting of dithiothreitol (DTT) and N-acetyl cysteine (NAC).
• the mucolytic agent is dithiothreitol (DTT).
• the mucolytic agent is N-acetyl cysteine (NAC).
• the composition comprises 10-20 v/v % of DTT. In various embodiments wherein the mucolytic agent is dithiothreitol (DTT), the composition comprises 5, 10, 15, 20 or 25 v/v % of 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 % of 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 % of DTT.
• the composition comprises 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 v/v % of DTT.
• DTT is available, for example, as a 6.5 mM solution in 100 mM phosphate buffer (pH 7).
• the composition comprises 100-1200mg of N-acetyl cysteine (NAC).
• the composition comprises 50-100mg, 100-200mg, 200-300mg, 300-400mg, 400-500mg, 500-600mg, 600-700mg, 700-800mg, 800-900mg, 900- lOOOmg, 1000-1 lOOmg, 1100-1200mg, 1200-1300mg, 1300-1400mg, or 1400-1500mg of N- acetyl cysteine (NAC) per dose.
• the composition comprises 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, or 1200 mg of N-acetyl cysteine (NAC) per dose. In various embodiments wherein mucolytic agent is N-acetyl cysteine (NAC), the composition comprises greater than about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, or 1200 mg of N-acetyl cysteine (NAC) per dose.
• the composition comprises less than about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, or 1200 mg of N-acetyl cysteine (NAC) per dose.
• NAC N-acetyl cysteine
• the invention described herein provides pharmaceutical compositions including a pharmaceutically acceptable excipient along with a therapeutically effective amount of the one or more antibiotics and mucolytic agent (as one composition or as separate compositions).
• “Pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and desirable, and includes excipients that are acceptable for veterinary use as well as for human pharmaceutical use. Such excipients may be solid, liquid, semisolid, or, in the case of an aerosol composition, gaseous.
• the compounds of the invention described herein may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases.
• pharmaceutically acceptable salts, esters, amides, and prodrugs refers to those carboxylate salts, amino acid addition salts, esters, amides, and prodrugs of the compounds of the invention described herein which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use of the compounds of the invention.
• salts refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the invention described herein. These salts can be prepared in situ during the final isolation and purification of the compounds 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.
• alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium and the like
• nontoxic ammonium, quaternary ammonium, and amine cations including, but not limited to ammonium, tetramethylanunonium, tetraethyl ammonium, methyl amine, dimethyl amine, trimethylamine, triethylamine, ethylamine, and the like.
• esters refers to the relatively nontoxic, esterified products of the compounds of the invention described herein. These esters can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form or hydroxyl with a suitable esterifying agent. Carboxylic acids can be converted into esters via treatment with an alcohol in the presence of a catalyst. The term is further intended to include lower hydrocarbon groups capable of being solvated under physiological conditions, e.g., alkyl esters, methyl, ethyl and propyl esters.
• prodrug refers to compounds that are rapidly transformed in vivo to yield the functionally active compounds disclosed herein.
• a prodrug is a compound that, upon in vivo administration, is metabolized or otherwise converted to the biologically, pharmaceutically or therapeutically active form of the compound.
• a prodrug of the one or more antibiotics as disclosed herein can be designed to alter the metabolic stability or the transport characteristics of one or more antibiotics as disclosed herein, to mask side effects or toxicity, to improve the flavor of a compound or to alter other characteristics or properties of a compound.
• Suitable examples of prodrugs include methyl, ethyl and glycerol esters of the corresponding acid.
• the invention described herein includes methods for treating a gastrointestinal (GI) disease or disorder.
• Various embodiments provide for a method of treating a gastrointestinal (GI) disease or disorder, comprising administering the composition comprising one or more antibiotics and a mucolytic agent.
• Various embodiments provide for a method of treating a gastrointestinal (GI) disease or disorder, comprising administering one or more antibiotics and administering a mucolytic agent.
• the GI disease or disorder is selected from the group consisting of small intestinal bacterial overgrowth (SIBO) or irritable bowel syndrome (IBS).
• irritable bowel syndrome (IBS) is selected from the group consisting of diarrhea predominant irritable bowel syndrome (IBS-D), mixed irritable bowel syndrome (IBS- M), and constipation predominant irritable bowel syndrome (IBS-C).
• the invention described herein includes methods for inhibiting the growth of or killing microorganisms in one or more regions of a subject’s gastrointestinal (GI) system.
• Various embodiments of the invention provide for a method of inhibiting the growth of or killing microorganisms in one or more regions of a subject’s gastrointestinal (GI) system, comprising: administering the composition comprising one or more antibiotics and a mucolytic agent.
• Various embodiments of the invention provide for a method of inhibiting the growth of or killing microorganisms in one or more regions of a subject’s gastrointestinal (GI) system, comprising: administering one or more antibiotics and administering a mucolytic agent.
• the one or more regions of the subject’s GI system is the small intestines.
• the one or more regions of the subject’s GI system is the esophagus, stomach, or colon.
• the microorganism is selected from the group consisting of Proteus, Citrobacter, Aeromonas, Klebsiella, Methanobrevibacter, Eshericia, Salmonella, Lactobacillus, Disulfovibrio, Campylobacter, Bacteroides, Fusobacterium, Bilophila, Shigella, Moraxella, Morganella, Serratia, Enterobacter, Pseudomonas, Acinetobacter, Streptococcus, Veillonella, Prevotella, Paraprevotell, Rothia, Enterobacter, Providencia, Sutterella, Corpococcus, Lachnospira, Roseburia and combinations thereof.
• the microorganism is selected from the group consisting of C. jejuni , Salmonella, B. fragilis, C. difficile, E. coli, Bacteroides sp, Lactobacillus sp (e.g., reuteri and rhamnosus), and combinations thereof.
• the methods described herein may include administering a composition comprising one or more antibiotics and a mucolytic agent. In some embodiments, the methods described herein may include administering one or more antibiotics and a mucolytic agent.
• the composition comprising one or more antibiotics and the mucolytic agent is administered for about 1 week, 2 weeks, 3 weeks. In various embodiments, the composition comprising one or more antibiotics and the 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 for about 1, 2, 3 or 4 times per day. In various embodiments, the composition is administered for about 1 or 2 or 3 times per day.
• the one or more antibiotics and the mucolytic agent are administered for about 1 week, 2 weeks, 3 weeks. In various embodiments, the one or more antibiotics and the mucolytic agent 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 the mucolytic agent are administered for about 1, 2, 3, or 4 times per day. In various embodiments, the one or more antibiotics and the mucolytic agent are administered for about 1 or 2 or 3 times per day.
• antibiotics are as noted above.
• the one or more antibiotics is selected from the group consisting of rifaximin, rifamycin, rifampin, penicillin derivative, fluoroquinolone, macrolide, tetracycline, doxycycline, neomycin, metronidazole and combinations thereof.
• the penicillin derivative is ampicillin
• the fluoroquinolone is ciprofloxacin
• the macrolide is azithromycin.
• the one or more antibiotics is rifaximin.
• the one or more antibiotics is rifaximin and neomycin.
• the one or more antibiotic is rifaximin and the quantity of rifaximin is 550 mg, 500 mg, 400 mg, 350 mg, 300 mg, 275mg, 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg.
• the one or more antibiotic is rifaximin and the quantity of rifaximin less than about 550 mg, 500 mg, 400 mg, 350 mg, 300 mg, 275mg, 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg.
• the one or more antibiotic is rifaximin and the quantity of rifaximin greater than about 550 mg, 500 mg, 400 mg, 350 mg, 300 mg, 275mg, 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg.
• the combination of an antibiotic and a mucolytic agent provides vastly increased therapeutic efficacy, and thus, the amount of the antibiotic can be reduced significantly.
• the quantity of rifaximin is 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg.
• the quantity of rifaximin is 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg.
• the quantity of rifaximin is greater than about 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg. In some embodiments, the quantity of rifaximin is less than about 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg.
• the one or more antibiotics is rifaximin and neomycin.
• the quantity of rifaximin is 550 mg, 500 mg, 400 mg, 350 mg, 300 mg, 275mg, 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg
• the quantity of neomycin is 500 mg, 500 mg, 400 mg, 350 mg, 300 mg, 275mg, 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg.
• the quantity of rifaximin is greater than about 550 mg, 500 mg, 400 mg, 350 mg, 300 mg, 275mg, 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg
• the quantity of neomycin is greater than about 500 mg, 500 mg, 400 mg, 350 mg, 300 mg, 275mg, 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg.
• the quantity of rifaximin is less than about 550 mg, 500 mg, 400 mg, 350 mg, 300 mg, 275mg, 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg
• the quantity of neomycin is less than about 500 mg, 500 mg, 400 mg, 350 mg, 300 mg, 275mg, 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg.
• the combination of an antibiotic and a mucolytic agent provides vastly increased therapeutic efficacy, and thus, the amount of the antibiotic(s) can be reduced significantly.
• the quantity of rifaximin is 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg
• quantity of neomycin is 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg.
• the quantity of rifaximin is greater than about 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg, and quantity of neomycin is greater than about 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg.
• the quantity of rifaximin is less than about 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg, and quantity of neomycin is less than about 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg.
• the quantity of rifaximin is 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg
• quantity of neomycin is 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg.
• the mucolytic agent is selected from the group consisting of dithiothreitol (DTT), N-acetyl cysteine (NAC), acetylcysteine, ambroxol, bromhexine, carbocisteine, erdosteine, mecysteine, dornase alfa and combinations thereof.
• the mucolytic agent is dithiothreitol (DTT).
• the mucolytic agent is N-acetyl cysteine (NAC).
• the DTT may be administered via a composition that comprises 10-20 v/v % of DTT. In various embodiments wherein the mucolytic agent is dithiothreitol (DTT), the DTT may be administered via a composition that comprises 5, 10, 15, 20 or 25 v/v % of DTT. In various embodiments wherein the mucolytic agent is dithiothreitol (DTT), the DTT may be administered via a composition that comprises greater than about 5, 10, 15, 20 or 25 v/v % of DTT.
• the DTT may be administered via a composition that comprises less than about 5, 10, 15, 20 or 25 v/v % of DTT. In various embodiments wherein the mucolytic agent is dithiothreitol (DTT), the DTT may be administered via a composition that comprises 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 v/v % of DTT.
• the NAC may be administered via a composition that comprises 100-1200mg of N-acetyl cysteine (NAC).
• the NAC may be administered via a composition that comprises 50-100mg, 100-200mg, 200-300mg, 300-400mg, 400-500mg, 500-600mg, 600-700mg, 700-800mg, 800-900mg, 900-1000mg, 1000-1 lOOmg, 1100-1200mg, 1200-1300mg, 1300-1400mg, or 1400-1500mg of N-acetyl cysteine (NAC) per dose.
• the NAC may be administered via a composition that comprises 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, or 1200 mg of N-acetyl cysteine (NAC) per dose.
• the NAC may be administered via a composition that comprises greater than about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, or 1200 mg of N-acetyl cysteine (NAC) per dose.
• the NAC may be administered via a composition that comprises less than about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, or 1200 mg of N-acetyl cysteine (NAC) per dose.
• the mucolytic agent dosage may be administered in one unit of a dosage form (e.g., one tablet). In some embodiments, the mucolytic agent dosage may be administered in two or more units of a dosage form (e.g., two, three, four, five, six, or more tablets).
• the GI disease or disorder is small intestinal bacterial overgrowth (SIBO).
• the GI disease or disorder is irritable bowel syndrome
• the GI disease or disorder is diarrhea predominant irritable bowel syndrome (IBS-D).
• the one or more antibiotics is rifaximin, which may be administered according to a quantity as set forth herein.
• the quantity of rifaximin is 550 mg, 500 mg, 400 mg, 350 mg, 300 mg, 275mg, 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg of rifaximin.
• the quantity of rifaximin is 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg of rifaximin. In particular embodiments, the quantity of rifaximin is 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg.
• the combination of an antibiotic and a mucolytic agent provides vastly increased therapeutic efficacy, and thus, the amount of the antibiotic can be reduced significantly.
• the quantity of rifaximin is 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg. In various embodiments wherein the one or more antibiotic is rifaximin the quantity of rifaximin is 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg.
• a method described herein may include administration of about 200 mg of rifaximin and about 600 mg of NAC.
• the rifaximin and NAC may be administered in oral unit dosage form (e.g., tablets) and may be combined in one unit dosage or two or more unit dosages (e.g., one tablet or two or more tablets).
• the GI disease or disorder is mixed irritable bowel syndrome (IBS-M).
• IBS-M mixed irritable bowel syndrome
• the GI disease or disorder is constipation predominant irritable bowel syndrome (IBS-C).
• IBS-C constipation predominant irritable bowel syndrome
• the one or more antibiotics is rifaximin and neomycin, which may be administered according to a quantity as set forth herein.
• the quantity of rifaximin is 550 mg, 500 mg, 400 mg, 350 mg, 300 mg, 275mg, 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg
• the quantity of neomycin is 500 mg, 500 mg, 400 mg, 350 mg, 300 mg, 275mg, 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg.
• the combination of an antibiotic and a mucolytic agent provides vastly increased therapeutic efficacy, and thus, the amount of the antibiotic can be reduced significantly.
• the quantity of rifaximin is 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg
• quantity of neomycin is 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg.
• the quantity of rifaximin is 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg
• quantity of neomycin is 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg.
• the invention described herein is also directed to a kit.
• the kit is useful for practicing the inventive method of treating a GI disease or disorder (e.g., SIBO, IBS), and/or inhibiting the growth of or killing microorganism.
• the kit is an assemblage of materials or components, including at least one of the inventive compositions.
• the kit contains a composition including one or more antibiotics and a mucolytic agent, as described above.
• the kit may include one or more antibiotics and a mucolytic agent, as described above.
• kits are configured for the purpose of treating a GI disease or disorder; other embodiments are configured for the purpose of inhibiting the growth of or killing microorganism.
• the kit is configured particularly for the purpose of treating mammalian subjects.
• the kit is configured particularly for the purpose of treating human subjects.
• the kit is configured for veterinary applications, treating subjects such as, but not limited to, farm animals, domestic animals, and laboratory animals.
• Instructions for use may be included in the kit.
• “Instructions for use” typically include a tangible expression describing the technique to be employed in using the components of the kit to effect a desired outcome, such as to treating a GI disease or disorder (e.g., SIBO, IBS), and inhibiting the growth of or killing microorganism.
• the kit also contains other useful components, such as, diluents, buffers, pharmaceutically acceptable carriers, syringes, catheters, applicators, pipetting or measuring tools, bandaging materials or other useful paraphernalia as will be readily recognized by those of skill in the art.
• the materials or components assembled in the kit can be provided to the practitioner stored in any convenient and suitable ways that preserve their operability and utility.
• the components can be in dissolved, dehydrated, or lyophilized form; they can be provided at room, refrigerated or frozen temperatures.
• the components are typically contained in suitable packaging material(s).
• packaging material refers to one or more physical structures used to house the contents of the kit, such as inventive compositions and the like.
• the packaging material is constructed by well-known methods, preferably to provide a sterile, contaminant-free environment.
• the packaging materials employed in the kit are those customarily utilized in treating a GI disease or disorder (e.g., SIBO, IBS), and inhibiting the growth of or killing microorganism.
• the term“package” refers to a suitable solid matrix or material such as glass, plastic, paper, foil, and the like, capable of holding the individual kit components.
• a package can be a plastic bottle used to contain suitable quantities of an inventive composition containing one or more antibiotics and a mucolytic agent, or blister pack containing dosages of one or more antibiotics and the mucolytic agent (as one composition or as separate compositions).
• the packaging material generally has an external label which indicates the contents and/or purpose of the kit and/or its components.
• kits comprising: a composition comprising one or more antibiotics and a mucolytic agent, and instructions for using the composition.
• kits comprising one or more antibiotics and a mucolytic agent, and instructions for using the one or more antibiotics and the mucolytic agent.
• the one or more antibiotics is selected from the group consisting of rifaximin, rifamycin, rifampin, penicillin derivative, fluoroquinolone, macrolide, tetracycline, doxycycline, neomycin, metronidazole and combinations thereof.
• the penicillin derivative is ampicillin
• the fluoroquinolone is ciprofloxacin
• the macrolide is azithromycin.
• the one or more antibiotics is rifaximin.
• the one or more antibiotics is rifaximin and neomycin.
• the one or more antibiotic is rifaximin and the composition comprises 550 mg, 500 mg, 400 mg, 350 mg, 300 mg, 275mg, 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg of rifaximin.
• the kit comprises a composition comprising 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg of rifaximin.
• the quantity of rifaximin is 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg.
• the kit comprises a composition comprising 550 mg, 500 mg, 400 mg, 350 mg, 300 mg, 275mg, 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg, and a composition comprising 500 mg, 500 mg, 400 mg, 350 mg, 300 mg, 275mg, 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg.
• the inventor believes that the combination of an antibiotic and a mucolytic agent provides vastly increased therapeutic efficacy, and thus, the amount of the antibiotic can be reduced significantly.
• the quantity of rifaximin is 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg.
• quantity of neomycin is 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg.
• the quantity of rifaximin is 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg
• quantity of neomycin is 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg.
• the rifaximin and neomycin can be provided in separate compositions or in one composition.
• the mucolytic agent is selected from the group consisting of dithiothreitol (DTT), N-acetyl cysteine (NAC), acetylcysteine, ambroxol, bromhexine, carbocisteine, erdosteine, mecysteine, dornase alfa and combinations thereof.
• the mucolytic agent is dithiothreitol (DTT).
• the mucolytic agent is N-acetyl cysteine (NAC).
• the composition comprises 10-20 v/v % of DTT. In various embodiments wherein the mucolytic agent is dithiothreitol (DTT), the composition comprises 5, 10, 15, 20 or 25 v/v % of 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 % of DTT.
• the composition comprises 100-1200mg of N-acetyl cysteine (NAC).
• the composition comprises 50-100mg, 100-200mg, 200-300mg, 300-400mg, 400-500mg, 500-600mg, 600-700mg, 700-800mg, 800-900mg, 900- lOOOmg, 1000-1 lOOmg, 1100-1200mg, 1200-1300mg, 1300-1400mg, or 1400-1500mg of N- acetyl cysteine (NAC) per dose.
• the composition comprises 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, or 1200 mg of N-acetyl cysteine (NAC) per dose.
• compositions and compounds according to the invention may be formulated for delivery via any route of administration.
• Route of administration may refer to any administration pathway known in the art, including but not limited to aerosol, nasal, oral, transmucosal, transdermal or parenteral.
• Transdermal administration may be accomplished using a topical cream or ointment or by means of a transdermal patch.
• Parenteral refers to a route of administration that is generally associated with injection, including intraorbital, infusion, intraarterial, intracapsular, intracardiac, intradermal, intramuscular, intraperitoneal, intrapulmonary, intraspinal, intrasternal, intrathecal, intrauterine, intravenous, subarachnoid, subcapsular, subcutaneous, transmucosal, or transtracheal.
• the compositions may be in the form of solutions or suspensions for infusion or for injection, or as lyophilized powders.
• the pharmaceutical compositions can be in the form of tablets, gel capsules, sugar-coated tablets, syrups, suspensions, solutions, powders, granules, emulsions, microspheres or nanospheres or lipid vesicles or polymer vesicles allowing controlled release.
• the compositions may be in the form of solutions or suspensions for infusion or for injection.
• compositions based on compounds according to the invention may be formulated for treating the skin and mucous membranes and are in the form of ointments, creams, milks, salves, powders, impregnated pads, solutions, gels, sprays, lotions or suspensions. They can also be in the form of microspheres or nanospheres or lipid vesicles or polymer vesicles or polymer patches and hydrogels allowing controlled release.
• These topical- route compositions can be either in anhydrous form or in aqueous form depending on the clinical indication.
• compositions according to the invention can also contain any pharmaceutically acceptable carrier.
• “Pharmaceutically acceptable carrier” as used herein refers to a pharmaceutically acceptable material, composition, or vehicle that is involved in carrying or transporting a compound of interest from one tissue, organ, or portion of the body to another tissue, organ, or portion of the body.
• 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 tissues or organs with which it may come in contact, meaning that it must not carry a risk of toxicity, irritation, allergic response, immunogenicity, or any other complication that excessively outweighs its therapeutic benefits.
• compositions according to the invention can also be encapsulated, tableted or prepared in an emulsion or syrup for oral administration.
• Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition.
• Liquid carriers include syrup, peanut oil, olive oil, glycerin, saline, alcohols 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 sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
• the preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulation, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms.
• a liquid carrier 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 a liquid formulation may be administered directly p.o. or filled into a soft gelatin capsule.
• compositions according to the invention may be delivered in a therapeutically effective amount.
• the precise therapeutically effective amount is that amount of the composition that will yield the most effective results in terms of efficacy of treatment in a given subject. This amount will vary depending upon a variety of factors, including but not limited to the characteristics 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 a given dosage, and type of medication), the nature of the pharmaceutically acceptable carrier or carriers in the formulation, and the route of administration.
• the invention provides:
• composition comprising:
• composition of embodiment 1 wherein the one or more antibiotics is selected from the group consisting of rifaximin, rifamycin, rifampin, penicillin derivative, fluoroquinolone, macrolide, tetracycline, doxycycline, neomycin, metronidazole and combinations thereof.
• the penicillin derivative is ampicillin
• the fluoroquinolone is ciprofloxacin
• the macrolide is azithromycin.
• composition of embodiment 1, wherein the one or more antibiotics is rifaximin.
• composition of embodiment 1, wherein the one or more antibiotic is rifaximin and the composition comprises 550 mg, 500 mg, 400 mg, 350 mg, 300 mg, 275mg, 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg of rifaximin.
• composition of embodiment 1, wherein the one or more antibiotics is rifaximin and neomycin.
• composition of embodiment 1, wherein the mucolytic agent is selected from the group consisting of dithiothreitol (DTT), N-acetyl cysteine (NAC), acetylcysteine, ambroxol, bromhexine, carbocisteine, erdosteine, mecysteine, domase alfa and combinations thereof.
• DTT dithiothreitol
• NAC N-acetyl cysteine
• acetylcysteine ambroxol
• bromhexine bromhexine
• carbocisteine carbocisteine
• erdosteine mecysteine
• domase alfa domase alfa and combinations thereof.
• the composition of embodiment 1, wherein the mucolytic agent is dithiothreitol (DTT).
• DTT dithiothreitol
• NAC N-acetyl cysteine
• the mucolytic agent is dithio
• composition of embodiment 1, wherein the mucolytic agent is N-acetyl cysteine (NAC) and the composition comprises 100-1200mg of N-acetyl cysteine (NAC).
• NAC N-acetyl cysteine
• GI gastrointestinal
• the one or more antibiotics is selected from the group consisting of rifaximin, rifamycin, rifampin, penicillin derivative, fluoroquinolone, macrolide, tetracycline, doxycycline, neomycin, metronidazole and combinations thereof:
• the mucolytic agent is selected from the group consisting of dithiothreitol (DTT), N-acetyl cysteine (NAC), acetylcysteine, ambroxol, bromhexine, carbocisteine, erdosteine, mecysteine, domase alfa and combinations thereof.
• DTT dithiothreitol
• NAC N-acetyl cysteine
• acetylcysteine ambroxol
• bromhexine bromhexine
• carbocisteine carbocisteine
• erdosteine mecysteine
• domase alfa domase alfa and combinations thereof.
• a method of inhibiting the growth of or killing microorganisms in one or more regions of a subject’s gastrointestinal (GI) system comprising:
• the one or more antibiotics is selected from the group consisting of rifaximin, rifamycin, rifampin, penicillin derivative, fluoroquinolone, macrolide, tetracycline, doxycycline, neomycin, metronidazole and combinations thereof.
• a kit comprising:
• composition of embodiment 1 (a) the composition of embodiment 1, and instructions for using the composition, or
• the invention described herein provides a method
• 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) against a condition, disease or disorder involving a bacterial infection of the gastrointestinal tract, the method comprising administering a therapeutically effective amount of a rifamycin (e.g., rifaximin) and a therapeutically effective amount of a mucolytic agent to a subject in need thereof.
• a rifamycin e.g., rifaximin
• rifamycin is selected from rifampicin, rifampin, rifabutin, rifapentine, and rifaximin.
• Any preceding method further comprising administering a therapeutically effective amount of a second antibiotic, e.g., selected from neomycin, clarithromycin, tetracycline, sulfamethoxazole, trimethoprim and metronidazole.
• a second antibiotic e.g., selected from neomycin, clarithromycin, tetracycline, sulfamethoxazole, trimethoprim and metronidazole.
• rifamycin is administered in an oral dosage of 550 mg, 500 mg, 400 mg, 350 mg, 300 mg, 275mg, 250 mg, 225 mg, 200 mg, 175mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg or 25 mg.
• rifamycin is rifaximin administered in an oral dosage of 200 mg three times a day.
• any of the preceding methods, wherein the duration of treatment is three days. Any of the preceding methods, wherein the duration of treatment is fourteen days. Any of the preceding methods wherein the rifamycin is rifaximin administered in an oral dosage of 200 mg two or three times a day for a period of up to fifteen days. Any of the preceding methods wherein the rifamycin is rifaximin administered in an oral dosage of 150 mg two or three times a day for a period of up to fifteen days. Any of the preceding methods wherein the rifamycin is rifaximin administered in an oral dosage of 100 mg two or three times a day for a period of up to fifteen days.
• the mucolytic agent is selected from one or more of dithiothreitol (DTT), N-acetyl cysteine (NAC), acetylcysteine, ambroxol, bromhexine, carbocisteine, erdosteine, mecysteine, dornase alfa, thymosin b4, nacystelyn, heparin, dembrexine, guaifenesin, carbocisteine, erdosteine, mecysteine, hyperosmolar saline, mannitol powder, and inhaled surfactants.
• DTT dithiothreitol
• NAC N-acetyl cysteine
• acetylcysteine ambroxol
• bromhexine bromhexine
• carbocisteine erdosteine
• mecysteine mecysteine
• the mucolytic agent hydrolyzes disulfide bonds that link mucin oligomers.
• the mucolytic agent comprises one or more sulfhydryl groups.
• the mucolytic agent is dithiothreitol (DTT) and/or N-acetyl cysteine (NAC).
• DTT dithiothreitol
• NAC N-acetyl cysteine
• any of the preceding methods, wherein the mucolytic agent is dithiothreitol (DTT). Any of the preceding methods, wherein the mucolytic agent is N-acetyl cysteine (NAC).
• DTT dithiothreitol
• NAC N-acetyl cysteine
• the mucolytic agent is administered in a dosage amount of about 100-1200mg.
• any of the preceding methods wherein the rifamycin and the mucolytic agent are present in separate compositions, which are administered simultaneously to a patient. Any of the preceding methods, wherein the rifamycin and the mucolytic agent are present in separate compositions, and wherein the mucolytic agent is administered prior to the rifamycin.
• condition, disease or disorder mediated by degradation or modulation of mucosal tissue or mucous linings is a bacterial, viral or fungal infection.
• condition, disease or disorder mediated by degradation or modulation of mucosal tissue or mucous linings is a bacterial infection.
• the bacterial infection is enterotoxigenic Escherichia coli (ETEC), enteroaggregative E. coli, Shigella spp., Salmonella spp., Campylobacter spp., Yersinia spp., Vibrio spp. Aeromonas spp., Clostridioides spp., and/or Plesiomonas spp.
• ETEC enterotoxigenic Escherichia coli
• enteroaggregative E. coli Shigella spp.
• Salmonella spp. Salmonella spp.
• Campylobacter spp. Campylobacter spp.
• Yersinia spp. Vibrio spp. Aeromonas spp.
• Clostridioides spp. and/or Plesiomonas spp.
• any of the preceding methods wherein the bacterial infection is an E. coli infection. Any of the preceding methods wherein the bacterial infection is a Clostridioides difficile infection. Any of the preceding methods, wherein the condition, disease or disorder is an irritable bowel syndrome (IBS) or small intestine bacterial overgrowth (SIBO).
• IBS irritable bowel syndrome
• SIBO small intestine bacterial overgrowth
• IBS irritable bowel syndrome
• IBS-D diarrhea predominant irritable bowel syndrome
• IBS-C constipation predominant irritable bowel syndrome
• IBS-M mixed irritable bowel syndrome
• condition, disease or disorder is diarrhea predominant irritable bowel syndrome (IBS-D)
• condition, disease or disorder is diarrhea predominant irritable bowel syndrome (IBS-D) and following treatment (e.g., following administering a therapeutically effective amount of a rifaximin and a therapeutically effective amount of NAC to the subject), the subject shows an improvement in stool form and reduction in stool frequency from baseline prior to treatment.
• IBS-D diarrhea predominant irritable bowel syndrome
• condition, disease or disorder is diarrhea predominant irritable bowel syndrome (IBS-D) and following treatment (e.g., following administering a therapeutically effective amount of a rifaximin and a therapeutically effective amount of NAC to the subject), the subject shows a decrease in severity of abdominal pain, e.g., as determined from weekly average visual analog scale (VAS) scores, from baseline prior to treatment.
• IBS-D diarrhea predominant irritable bowel syndrome
• VAS weekly average visual analog scale
• condition, disease or disorder is diarrhea predominant irritable bowel syndrome (IBS-D) and following treatment (e.g., following administering a therapeutically effective amount of a rifaximin and a therapeutically effective amount of NAC to the subject), the subject shows a decrease in urgency or bloating, e.g., as determined from weekly average visual analog scale (VAS) scores, from baseline prior to treatment.
• IBS-D diarrhea predominant irritable bowel syndrome
• VAS weekly average visual analog scale
• condition, disease or disorder is diarrhea predominant irritable bowel syndrome (IBS-D) and following treatment (e.g., following administering a therapeutically effective amount of a rifaximin and a therapeutically effective amount of NAC to the subject), the subject shows a reduction of 3 ⁇ 4 on lactulose hydrogen breath test (LHBT) from baseline prior to treatment.
• IBS-D diarrhea predominant irritable bowel syndrome
• LHBT lactulose hydrogen breath test
• the disclosure further provides a rifamycin and a mucolytic agent for use in combination in a method of treating a condition, disease or disorder involving a bacterial infection of the gastrointestinal tract, e.g., for use in any of Methods 1, et seq.
• the disclosure further 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 a bacterial infection of the gastrointestinal tract, e.g., a medicament for use in any of Methods 1, et seq.
• the present disclosure also provides for a pharmaceutical combination (i.e., Combination 1) comprising a therapeutically effective amount of a rifamycin and a therapeutically effective amount of a mucolytic agent.
• a pharmaceutical combination i.e., Combination 1
• Combination 1 a pharmaceutical combination comprising a therapeutically effective amount of a rifamycin and a therapeutically effective amount of a mucolytic agent.
• combination further comprises and effective amount of neomycin, clarithromycin, tetracycline, sulfamethoxazole, trimethoprim, or metronidazole.
• rifamycin is in an oral unit dosage form comprising 25-1000mg of the rifamycin in free or salt form.
• rifamycin is in an oral unit dosage form in an amount of 550 mg, 500 mg, 400 mg, 350 mg, 300 mg, 275mg, 250 mg,
• the mucolytic agent is selected from one or more of dithiothreitol (DTT), N-acetyl cysteine (NAC), acetylcysteine, ambroxol, bromhexine, carbocisteine, erdosteine, mecysteine, domase alfa, thymosin b4, nacystelyn, heparin, dembrexine, guaifenesin, carbocisteine, erdosteine, mecysteine, hyperosmolar saline, mannitol powder, and inhaled surfactants.
• DTT dithiothreitol
• NAC N-acetyl cysteine
• acetylcysteine ambroxol
• bromhexine bromhexine
• carbocisteine erdosteine
• mecysteine mecysteine
• domase alfa thymosin
• any of the preceding combinations, wherein the mucolytic agent is dithiothreitol (DTT) and/or N-acetyl cysteine (NAC). Any of the preceding combinations, wherein the mucolytic agent is dithiothreitol (DTT).
• DTT dithiothreitol
• NAC N-acetyl cysteine
• the mucolytic agent is N-acetyl cysteine (NAC).
• rifamycin and the mucolytic agent are present in separate compositions, and wherein the mucolytic agent is administered prior to the rifamycin.
• IBS irritable bowel syndrome
• SIBO small intestine bacterial overgrowth
• any of the preceding combinations wherein the combination is for use in the treatment of small intestine bacterial overgrowth (SIBO). 1.24 Any of the preceding combinations, wherein the rifamycin and the mucolytic agent are in the form of a tablet or capsule.
• mucolytic agent is DTT, and the rifaximin and DTT are combined in a tablet or capsule.
• mucolytic agent is NAC, and the rifaximin and NAC are combined in a tablet or capsule.
• kits with instructions for use, wherein the rifamycin is rifaximin and the mucolytic agent is DTT.
• kits with instructions for use, wherein the rifamycin is rifaximin and the mucolytic agent is NAC.
• kits with instructions for use, wherein the rifamycin is rifaximin in oral dosage form comprising 200 mg rifaximin, and the mucolytic agent is NAC in oral dosage form comprising 600 mg NAC.
• the disclosure further provides a pharmaceutical combination according to
• the disclosure further provides the use of a pharmaceutical combination according to Combination 1, et. seq., in the manufacture of a medicament for use in any of Methods 1.
• the term“comprising” or“comprises” is used in reference to compositions, methods, and respective component(s) thereof, that are useful to an embodiment, yet open to the inclusion of unspecified elements, whether useful or not. 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.).
• the study is a prospective proof-of-concept double-blind (to dose of NAC) clinical trial to determine the efficacy of combined rifaximin and NAC therapy vs. rifaximin alone in decreasing clinical symptoms in subjects with IBS-D.
• Run-In Phase Eligible subjects with IBS-D who consent to participate are recruited. After provision of informed written consent, these subjects undergo baseline testing as described in the Schedule of Activities and complete a daily stool diary for 14 days as well as weekly symptom questionnaires.
• Treatment Phase Subjects are randomized in to one of 3 study arms and receive either:
• Subjects are capable of understanding the requirements of the study, are willing to comply with all the study procedures, and are willing to attend all study visits.
• Acceptable methods of contraception include:
• double barrier methods condom with spermicidal jelly or a diaphragm with spermicide
• hormonal methods e. g. oral contraceptives, patches or medroxyprogesterone acetate
• an intrauterine device IUD with a documented failure rate of less than 1% per year. Abstinence or partner(s) with a vasectomy may be considered an acceptable method of contraception at the discretion of the investigator.
• Female subjects who have been surgically sterilized e.g. hysterectomy or bilateral tubal ligation
• who are postmenopausal total cessation of menses for >1 year
• Demographics and medical history The study staff record the subject’s sex, date of birth, and ethnic origin. Medical history (e.g., previous diagnoses, diseases or surgeries) will be collected. Findings are recorded in REDCap via the medical history questionnaire. Concomitant medications are also b reviewed
• Physical exam including vital signs Complete physical exams are performed by the principal investigator or a physician co-investigator. The general examination includes evaluation of the head, ears, eyes, nose, throat, endocrine, cardiovascular, respiratory, abdomen, skin, neurological, extremities, and musculoskeletal systems. Vital sign measurements, including height, body weight, blood pressure, radial pulse rate, respiratory rate, and temperature will be recorded after the subject has been semi-supine for at least five minutes prior to the test. Abnormalities noted at baseline (Visit 1) are recorded as medical history. Any clinically significant change from baseline are recorded as an adverse event. [0123] Urine pregnancy test: Subjects who are women of childbearing potential are asked to provide a urine sample for pregnancy testing. Pregnancy is considered an Exclusion Criterion.
• Lactulose breath test Subjects are asked to undergo a 24-hour preparatory period just prior to the test. Subjects maintain a bland diet during the first 12 hours and fast during the remaining 12. A baseline breath sample is collected by exhaling into disposable collection bag with a volume of 750 mL. Subjects then consume 10 g lactulose dissolved in water. Subsequent breath samples are collected every 15 minutes over the remainder of the 120-minute test. Breath samples are analyzed for hydrogen, methane, carbon dioxide, and hydrogen sulfide levels immediately after collection via gas chromatograph.
• VAS Clinical Symptom Questionnaires
• Blood draw Blood is drawn by a trained research nurse and collected for complete blood count (CBC), complete metabolic panel (CMP), erythrocyte sedimentation rate (ESR), and, in women of childbearing potential, for serum pregnancy testing. Laboratory analyses is performed in a central clinical laboratory. Reference ranges are supplied by the clinical laboratory and used by the investigator to assess the laboratory results for clinical significance and pathological changes. An additional blood sample is drawn for exploratory cytokines.
• CBC complete blood count
• CMP complete metabolic panel
• ESR erythrocyte sedimentation rate
• Stool collection (optional): At the end of the study visit, subjects are provided with a stool collection kit and asked to obtain a stool sample on the day prior to their next visit. Subjects are instructed to store the sample in the refrigerator and to return it to study staff on their visit the following day. The provision of a stool sample is optional and is used for exploratory analyses of the effects of combined rifaximin and NAC on the gut microbiome.
• Daily stool diary Subjects are asked to complete a daily stool diary at home, using the Bristol Stool Chart as a visual aid, either online or in paper format. Subjects are also asked to use the Dieta mobile application, which includes a stool image capture feature and computer vision technology that objectively classifies stool consistency. [0129] For both rifaximin and NAC, there are no expected adverse effects. While there are side effects that occur in more than 1% of subjects, these are not more common than placebo in the case of rifaximin based on previous clinical trials. As such, these side effects are not “expected”. Adverse events are tracked and reported.
• NAC will demonstrate that NAC increases the activity of rifaximin as compared to rifaximin therapy alone for decreasing clinical symptoms in subjects with IBS-D.

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