WO2011082218A1 - Compositions and method for treatment and prophylaxis of inflammatory bowel disease - Google Patents
Compositions and method for treatment and prophylaxis of inflammatory bowel disease Download PDFInfo
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- WO2011082218A1 WO2011082218A1 PCT/US2010/062339 US2010062339W WO2011082218A1 WO 2011082218 A1 WO2011082218 A1 WO 2011082218A1 US 2010062339 W US2010062339 W US 2010062339W WO 2011082218 A1 WO2011082218 A1 WO 2011082218A1
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- A61K35/74—Bacteria
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- A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
- A61K35/747—Lactobacilli, e.g. L. acidophilus or L. brevis
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- 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
- A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
- A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/74—Bacteria
- A61K35/741—Probiotics
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/74—Bacteria
- A61K35/741—Probiotics
- A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
- A61K35/745—Bifidobacteria
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- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
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- A—HUMAN NECESSITIES
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- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
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- 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
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- A—HUMAN NECESSITIES
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- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- A—HUMAN NECESSITIES
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- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K2035/11—Medicinal preparations comprising living procariotic cells
- A61K2035/115—Probiotics
Definitions
- the present invention relates generally to compositions and methods for the prophylaxis and treatment of inflammatory bowel disease (IBD) due to bacterial infection. More specifically, this invention envisions the use of probiotic formulations in combination with antibiotics to treat IBD symptoms and to reduce the risk of relapse.
- IBD inflammatory bowel disease
- IBD Inflammatory bowel disease
- CD Crohn's disease
- UC ulcerative colitis
- Symptoms of IBD most commonly include fever, vomiting, diarrhea, bloody stool (hematochezia), abdominal pain, and weight loss, but also may include a host of other problems. The severity of symptoms may impair the quality of life of patients that suffer from IBD.
- IBD etiology of IBD
- UC and CD are commonly regarded as autoimmune diseases, with evidence suggesting they are the result of a misdirected immune response.
- the etiology of IBD appears to involve complex interactions of genetic predisposition, environmental factors, disruption of the intestinal microbiome, and an overly aggressive immune response.
- evidence linking the ability of intestinal epithelial cells to modify the mucosal immune response may suggest an invasive bacterial pathway.
- the integrity of the gut epithelial barrier is critical in influencing progression to disease. Imbalance in intestinal microbiota of gut friendly bacteria destroyed by antibiotics as well as opportunistic pathogens are implicating factors as well.
- Additional factors influencing activation may include the unfolded protein response (a result of cellular stress), toll like receptors, invasive bacteria, TNF factors, DNA RNA genetic mutations effecting encoding proteins IL-10R1 -IL10R2, spontaneous mutation of normal gut bacteria, uncontrolled T-cell activation, and enteroinvasive and adherent invasive strains of E. coli bacteria. Disruption in the gut epithelial barrier when bacterial overgrowth overwhelms the body's defense mechanism to cope, the immune/inflammatory response, if left unchecked, often results in chronic inflammation, a precursor to full blown disease. The involvement of luminal bacteria as a cause of chronic inflammation and disease is well documented.
- Trimethoprim- Sulfamethoxazole Therapy of Inflammatory Bowel Disease Gastroenterology, Vol. 96, No. 5, Part 2, p. A1 10.
- sulfamethoxazole -trimethoprin as a first-line therapy, rather than as an adjuvant to immunosuppressant therapy, is not suggested.
- Probiotics are live microbial organisms that beneficially affect the microbiome of the host and treatment of various disorders of the gastrointestinal tract, including IBD, using probiotics is well-known. See, e.g., Schultz M., et al, "Rationale for probiotic treatment strategies in inflammatory bowel disease," Expert Rev. Gastroenterol. Hepatol, 2008 Jun;2(3):337-55.
- treatment of IBD using specific probiotic E. coli strains is disclosed in U.S. Patent No. 7,018,629, to Jacob et al.
- prophylaxis and treatment of IBD with an endogenous strain of Bifidobacterium is described in U.S. Patent Pub. No. 2002/0006432, to Collins et al.
- probiotics alone will not cure IBD, nor will they be a direct cause of remission.
- the invention is premised on the theory that IBD may result from an overactive immune response to invasive or commensal pathogenic bacterial infection in the gastrointestinal tract. Therefore, in IBD cases where pathogenic bacterial infection is suspected, it may be possible to achieve clinical remission of symptoms and prevent relapse with high-dose antibiotics administered for a duration of time sufficient to completely eradicate the bacterial antigen and its spores, allowing for restoration of the gut epithelial barrier.
- the invention also envisions the use of high-dose, selective probiotics to counter the deleterious effects of antibiotic therapy on the natural enteric microflora and promote healing of the mucosa and intestinal epithelial barrier by restoring and maintaining the natural enteric microflora.
- compositions comprising antibiotics and probiotics.
- the antibiotics and probiotics may be combined in a unitary dosage form to improve patient compliance with the treatment protocols.
- one aspect of the invention relates to a multi-layer tablet for the treatment or prophylaxis of inflammatory bowel disease due to pathogenic bacterial infection.
- the multi-layer tablets comprises:
- a delayed-release layer comprising an amount of antibiotic effective to reduce colonization of pathogenic bacteria in the gastrointestinal tract, preferably a combination of:
- an immediate-release layer comprising a probiotic formulation in an amount effective to restore normal microflora colonies in the gut, preferably including at least one strain selected from: Bifidobacterium bifidum;
- the immediate-release layer preferably surrounds the delayed-release layer and releases the probiotic formulation upon contact with gastric fluid in the stomach.
- the delayed-release layer preferably comprises an enteric coating of a polymer which releases the antibiotic primarily in the terminal ileum.
- a method for treatment or prophylaxis of inflammatory bowel disease due to bacterial infection is provided.
- the method is based on the principle that achieving and maintaining remission requires high doses of targeted antibiotics and a duration of treatment sufficient to completely eradicate the offending bacterial antigens and their components. Therefore, the method of the invention may comprise daily administration for extended durations, preferably for a period of at least 120 days, of a composition comprising:
- an amount of antibiotic effective to reduce colonization of pathogenic bacteria in the gastrointestinal tract the antibiotic preferably comprising a combination of sulfamethoxazole and trimethoprim, and
- a probiotic formulation in an amount effective to restore normal microflora colonies in the gut, the probiotic formulation preferably including at least one strain selected from those listed above.
- a preferred therapeutic regimen comprises, in sequential steps:
- a first step for the treatment of active symptoms comprising twice daily administration of about 800 mg of sulfamethoxazole, about 160 mg of trimethoprim, and at least about 20 billion cells of probiotics (for a total daily dose of about 1 ,600 mg of sulfamethoxazole, about 320 mg of trimethoprim, and at least about 40 billion cells of probiotics), for a period from 120 to 180 days, and
- a second step for prophylactic treatment after clinical remission of symptoms comprising once daily administration of about 800 mg of sulfamethoxazole, about 160 mg of trimethoprim, and at least about 20 billion cells of probiotics, for a period from 120 to 180 days.
- ulcerative colitis While ulcerative colitis rarely remits completely, the risk of relapse can be greatly reduced with continued proactive treatment according to the invention, and thus the protocols of the invention provide a new direction for the treatment of inflammatory bowel disease.
- the invention may achieve and maintain remission without incurring the significant toxic side-effects related to steroids and immunosuppressants, and for many patients suffering from chronic inflammation, the invention may mitigate the prospect for colorectal surgery.
- the present invention envisions the treatment or prophylaxis of inflammatory bowel disease, including ulcerative colitis (UC) and Crohn's disease (CD), using antibiotics in combination with probiotics.
- the invention is based on early intervention with targeted antibiotics through control of dosage and duration of treatment, to eradicate invasive or commensal bacterial infection which may allow for restoration of the gut epithelial barrier, with the help of selective probiotics. It is postulated that the immune response may "reset" once the offending antigen is completely eradicated and the immune system is unburdened by toxic immunosuppressants, thus leading to an improved prognosis.
- the method of the invention entails treatment of individuals suffering from UC, CD, or any other form of IBD.
- the UC or CD may be in the active stage or in remission during treatment.
- the treatment is targeted to a patient for whom a clinical diagnosis of IBD, and in particular UC or CD, has been made.
- the patient may be a male, female, adult, geriatric or pediatric patient.
- Veterinary use, particularly for mammals, is also contemplated.
- the invention provides a treatment regimen which involves daily administration of antibiotics and probiotics to a patient in need thereof.
- the administration is preferably oral, but other routes are also contemplated, including for example, rectal administration.
- the treatment is carried out daily for a period of time sufficient to resolve one or more of the symptoms of IBD, which typically will be at least 120 days, preferably at least 150 days, and more preferred still at least 180 days.
- the treatment is preferably carried out for an additional period of time to kill any remaining latent spores in the intestines.
- This additional treatment will typically comprise daily administration, albeit with a fraction of the initial dose, for example, half of the therapeutic dose used in the initial treatment regimen, and typically will be for at least 120 days, preferably at least 150 days, and more preferred still at least 180 days.
- the goal of the follow-on treatment is to reduce the risk of relapse.
- the initial treatment stage when the disease is active, it is preferred to give an oral dose twice daily (B.I.D.). However, once daily, as well as more frequent administration, is contemplated.
- the dosages can be taken, for example, in the morning and before bed, and can be taken with or without a meal.
- the maintenance stage i.e., after a flare-up has resolved, once daily dosing is contemplated, although more or less frequent administration is likewise within the scope of the invention.
- the treatment regimen comprises administration, preferably oral administration, of an antibiotic drug and a probiotic formulation, in amounts effective to reduce colonization of invasive bacteria, such as adherent-invasive Escherichia coli (AIEC) and/or enteroinvasive Escherichia coli (EIEC), Salmonella, and various strains of Shigella in the gastrointestinal tract.
- invasive bacteria such as adherent-invasive Escherichia coli (AIEC) and/or enteroinvasive Escherichia coli (EIEC), Salmonella, and various strains of Shigella in the gastrointestinal tract.
- Coli and the number of bacteria in the inflamed region correlates with the severity of bowel inflammation, as well as the fact that animals raised in germ-free environments do not develop colitis. Also, the linkage of Mycobacterium paratuberculosis to UC and CD is highly suggestive in T-cell activation, implicating this bacterium in the etiology of IBD.
- This invention counteracts the action of antibiotics in destroying healthy colonies of microflora in the gut and mitigates the risk of developing opportunistic infection by competing bacteria in the intestine, including Clostridium difficile. Consequently, it is believed that the inventive combination permits a higher dose of antibiotic to be employed for a longer duration than would be possible in the absence of the probiotic mixture. In this manner, not only is it possible to resolve symptoms of IBD, but the treatment allows for the eradication of latent spores, thereby reducing the probability of relapse.
- any antibiotic drug having activity against invasive bacterial infections of the intestines is contemplated to be useful.
- the antibiotic component may have bactericidal and/or bacteriostatic activity against the invasive species.
- Preferred antibiotics will have an activity against at least one bacteria selected from the group consisting of Escherichia coli (E. coli), enterotoxigenic strains of E.
- ETEC that cause bacterial gastroenteritis, indole -positive Proteus species, Proteus mirabilis, Proteus vulgaris, Morganella morganii, Klebsiella species, Enterobacter species, Haemophilus influenzae, Streptococcus pneumoniae, Shigella flexneri, or Shigella sonnei.
- antibiotics having activity against E. Coli, and in particular invasive strains of E. Coli are favored.
- the antibiotic component is active against enterotoxigenic strains of E. coli, adherent- invasive E. coli (AIEC) and/or enteroinvasive E. coli (EIEC) in the gastrointestinal tract.
- the mechanism of action of the antibiotic drug is not important, provided that it is effective in reducing infection of invasive species in the intestines.
- an antibiotic that inhibits folate synthesis in bacteria This pathway involves a multi-step synthesis for the production of tetrahydrofolic acid, an essential coenzyme in many biologic reactions, particularly those relating to the synthesis of amino acids and nucleic acids.
- Useful antibiotic may act on any stage in the bacterial folate synthesis pathway, and may inhibit the bacterial synthesis of one or more intermediates of the tetrahydrofolic synthesis pathway, such as dihydrofolic acid.
- the antibiotic component comprises a drug which inhibits a first step of the tetrahydrofolic synthesis pathway involveing the synthesis of dihydropteroic acid from dihydropteroate diphosphate and para-aminobenzoic acid (PABA), catalyzed by the enzyme dihydropteroate synthetase.
- the antibiotic drug may act as a false-substrate inhibitor of dihydropteroate synthetase and compete with PABA for binding to dihydropteroate synthetase.
- Suitable antibiotics therefore include drugs that are competitive inhibitors of bacterial dihydropteroate synthetase, including para-aminobenzoic acid (PABA) analogs.
- antibacterial sulfonamides namely 4- amino-N-(5-methyl-3-isoxazolyl)benzenesulfonamide, which has the generic name sulfamethoxazole.
- Sulfamethoxazole has the molecular formula of C10H11N3O3S, and the following structure:
- the antibiotic component may also comprise a drug that inhibits the last step in the tetrahydrofolic acid synthesis pathway in bacteria, which involves the conversion of dihydrofolic acid to tetrahydrofolic acid with the enzyme dihydrofolate reductase.
- the antibiotic drug may inhibit the synthesis of tetrahydrofolic acid by, for example, inhibiting the activity of dihydrofolate reductase.
- a suitable compound for inhibiting dihydrofolate reductase is 5-[(3,4,5-trimethoxyphenyl)methyl]- 2,4-pyrimidinediamine, which has the generic name trimethoprim, the molecular formula of C14H18 4O3, and the structure:
- the antibiotic component may comprise at least two drugs that affect distinct steps in the bacterial biosynthesis of tetrahydrofolate.
- Preferred is a combination of a drug that competitively inhibits the activity dihydropteroate synthetase with a drug that inhibits dihydrofolate reductase in bacteria.
- the antibiotic component may include a combination of trimethoprim and sulfamethoxazole.
- the antibiotic component may comprise a combination of trimethoprim and sulfamethoxazole in a weight ratio from about 1 :2 to about 1 :50, preferably from about 1 :3 to about 1 :30, more preferably from about 1 :4 to about 1 :25, even more preferred still from about 1 :5 to about 1 :20.
- the antibiotic component may comprise a combination of trimethoprim and sulfamethoxazole in a ratio of 1 :5.
- the antibiotic component may comprise from about
- the antibiotic component may comprise about 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 1 10 mg, 120 mg, 130 mg, 140 mg, 150 mg, or about 160 mg of trimethoprim.
- the antibiotic component may comprise from about 200 mg to about 1 ,600 mg of sulfamethoxazole, more typically from about 400 mg to about 800 mg of sulfamethoxazole.
- the antibiotic component may comprise about 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, or about 800 mg of sulfamethoxazole.
- the antibiotic component comprises 80 mg of trimethoprim in combination with 400 mg of sulfamethoxazole.
- the antibiotic component comprises 160 mg of trimethoprim in combination with 800 mg of sulfamethoxazole.
- antibiotic drugs which may be used include, without limitation, vancomycin; amoxicillin; tetracyclines; clarithromycin; clindamycin; a member of the cephlosporin antibiotic family (e.g., cefaclor, cefadroxil, cefixime, cefprozil, ceftriaxone, cefuroxime, cephalexin, loracarbef, and the like); a member of the penicillin family of antibiotics (e.g., ampicillin, amoxicillin/clavulanate, bacampicillin, cloxicillin, penicillin VK, and the like); a member of the fluoroquinolone family of antibiotics (e.g., ciprofloxacin, grepafloxacin, levofloxacin, lomefloxacin, norfloxacin, ofloxacin, sparfloxacin, trovafloxacin, and the like); or a member of the macrolide antibiotic family (
- levofloxacin e.g., 250 mg, 500 mg, or 750 mg
- metronidazole e.g., 250 mg, 500 mg, or 750 mg
- ciprofloxacin e.g., 100 mg, 250 mg, 500 mg, or 750 mg
- amoxicillin e.g., 125 mg, 200 mg, 250 mg, 400 mg, 500 mg, 600 mg, 775 mg, or 875 mg
- erythromycin e.g., 250 mg, 333 mg, or 500 mg
- vancomycin e.g., 125 mg or 250 mg
- clindamycin e.g., 75 mg, 150 mg, or 300 mg
- Each of the forgoing dosages may be administered up to the maximum safe daily dosage for each given drug.
- The may constitute, for example, administration of one, two, three, four, or more of the foregoing doses daily.
- the treatment comprises oral administration of trimethoprim and sulfamethoxazole, optionally in combination with at least one other antibiotic drug selected from the group consisting of levofloxacin, metronidazole, ciprofloxacin, amoxicillin, erythromycin, vancomycin, clindamycin, and combinations thereof.
- the second component of the compositions and treatment methods according to the invention is a probiotic formulation.
- the digestive systems of humans and other mammals include bacteria essential to the health of the gastrointestinal system and overall heath of the individual.
- Beneficial types of bacteria such as lactic acid bacteria, provide various health benefits, including enhancing digestion, nutrient absorption, bowel function, and natural immunity.
- beneficial bacteria may produce vitamins and, moreover, may inhibit the growth of pathogenic microorganisms, such as pathogenic bacteria, viruses, and/or protozoa.
- Beneficial bacteria may inhibit the growth of such undesirable microorganisms, for example, by secreting bacteriocins and/or substances that reduce gastrointestinal tract pH, thereby making the gastrointestinal environment less hospitable to pathogenic microorganisms. Disruption of the balance of the normal intestinal flora can lead to conditions ranging from mild gastrointestinal symptoms to serious infection.
- probiotics useful in the present invention include, without limitation, bacteria selected from the group consisting of Bifidobacterium, Lactobacillus, Streptococcus, Propionibacterium, and Enterococcus , and mixture thereof.
- probiotics include Arthrobacter agilis, Arthrobacter citreus, Arthrobacter globiformis, Arthrobacter leuteus, Arthrobacter simplex, Azotobacter chroococcum, Azotobacter paspali, Azospirillum brasiliencise, Azospriliium lipoferum, Bacillus brevis, Bacillus macerans, Bacillus pumilus, Bacillus polymyxa, Bacillus subtilis, Bacteroides lipolyticum, Bacteroides succinogenes , Brevibacterium lipolyticum, Brevibacterium stationis, Bacillus laterosporus , Bacillus bifidum, Bacillus laterosporus , Bifidophilus infantis, Streptococcus thermophilous , Bifodophilus longum, Bifidobacteria animalis, Bifidobacteria bifidus, Bifidobacteria bre
- the probiotic component comprises cells or spores of at least one strain selected from the group consisting of Bifidobacterium bifidum, Bifidobacterium breve, Bifidobacterium longum, Saccharomyces boulardii, Lactobacillus acidophilus, Lactobacillus bulgaricus, Lactobacillus paracasein, and combinations thereof.
- Commercially available probiotic formulations include Culturelle® from Amerifit Brands, Inc., which contains Lactobacillus GG, and VSL#3® from VSL Pharmaceuticals, Inc. which contains Lactobacillus and Bifidobacterium and is positioned for the treatment of IBD.
- the probiotic mixture comprises Bifidobacterium bifidum. In one embodiment, the probiotic mixture comprises Bifidobacterium breve. In one embodiment, the probiotic mixture comprises Bifidobacterium longum. In one embodiment, the probiotic mixture comprises Saccharomyces boulardii. In one embodiment, the probiotic mixture comprises Lactobacillus acidophilus. In one embodiment, the probiotic mixture comprises Lactobacillus bulgaricus. In one embodiment, the probiotic mixture comprises Lactobacillus paracasein.
- the dose is from about 1 x 10 to about 1 x 10
- probiotic or from about 1 x 10 to about 1 x 10 cfu of probiotic, per day.
- the probiotic mixture will typically comprise at least 500 million cells or spores, more typically at least 1 billion, preferably at least 5 billion, more preferably at least 10 billion, and more preferred still at least 20 billion cells or spores.
- the dosing is twice daily, up to 40 billion cells or spores or even more will be ingested daily.
- a purified, isolated, and/or genetically altered bacterial strain can be used.
- a strain can be genetically altered in a number of different ways to increase efficacy. Exemplary methods are described in Methods in Cloning Vol. 3, eds. Sambrook and Russell, Cold Spring Harbor Laboratory Press (2001) and references cited therein.
- probiotic bacteria of the present invention can be obtained commercially. A variety of beneficial bacteria are commercially available from American Type Culture Collection Catalogue (Rockville, Md.). Beneficial bacteria can also be obtained by culturing, for example, in liquid, or on solid media, following routine and established protocols, and isolated from the medium by conventional means. Exemplary methods are described in Methods in Cloning Vol. 3, eds. Sambrook and Russell, Cold Spring Harbor Laboratory Press (2001) and references cited therein.
- probiotics include strains of Bifidobacterium isolated from the human gastrointestinal tract, e.g., see WO 00/42168; strains of Bifidobacterium infantis disclosed in U.S. Patent No. 7,195,906; and other bacterial and microbe strains disclosed in U.S. Patent Pub. No. 2008/0241226, the contents of each of which are herein incorporated by reference in their entireties.
- the probiotic is dried. Drying may comprise spray drying, fluid bed drying, or freeze-drying.
- a cell suspension is treated with proteins, maltodextrins, trehalose, and optionally, other stabilizing or freeze -protecting agents like ascorbic acid, to form a viscous paste, which is submitted to freeze-drying.
- the so-obtained material can be grinded to appropriate size in suitable dosage forms.
- the probiotic formulation provide a sufficient number of cells to substantially maintain levels of microflora in the gastrointestinal tract during the course of treatment.
- the levels of microflora in the gastrointestinal tract at the end of the treatment regimen may be, for example, greater than the levels that would otherwise be present at the end of the course of treatment were the probiotic mixture not administered.
- the methods are also useful for reducing the risk of C. difficile infection during antibiotic treatment of IBD.
- probiotics may have ancillary benefits including treatment of abdominal cramps, abdominal discomfort, abdominal distension, antibiotic associated diarrhea (AAD), belching, bloating, celiac disease, cholecystitis, Clostridium difficile associated diarrhea (CD AD), Crohn's disease, constipation (including chronic or functional constipation), diarrhea (including chronic or functional diarrhea), disorders of motility, diverticulitis or diverticular disease, duodenal ulcers, dyspepsia (including functional dyspepsia), erosive esophagitis, excess flatus, gall bladder disease, gastroesophageal reflux disease (GERD), gastroparesis, gastritis, gastric ulcers, halitosis, heartburn, hypersecretory conditions such as Zollinger-Ellison syndrome, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), lactose intolerance, motion sickness, multiple endocrine adenomas, nausea, pain,
- AAD antibiotic associated
- the treatment methods are contemplated to be useful for the treatment, prevention, amelioration, or reduction of symptoms of inflammatory bowel disease. Also provided, are methods for the treatment or prophylaxis of ulcerative colitis (UC) and/or Crohn's disease (CD). The method will find utility in the treatment of UC in either the active stage or during remission to prevent or reduce the probability or occurrence of relapse.
- UC ulcerative colitis
- CD Crohn's disease
- the patient is not administered an immunosuppressant or immunomodulatory drug during the treatment regimen, or if the patient had been on immunosuppressant or immunomodulatory drugs prior to starting the treatment, the levels of immunosuppressant or immunomodulatory drugs are preferably reduced or substantially eliminated during treatment.
- the patient is not administered azathioprine, methotrexate, or 6-mercaptopurine during the treatment regimen or the levels of these drugs are reduced.
- the patient is not administered a TNF-a inhibitor during the treatment regimen. The diminished use of immunosuppressants may result in unhindered DNA/RNA repair mechanisms.
- an aminosalicylate such as mesalamine (5-aminosalicylic acid)
- Mesalamine is marketed in the United States under the names Asacol and Lialda.
- Mesalamine is preferably administered in an mount from about 3.6 g to about 4.8 g daily.
- 9-12 tablets of 400 mg of Asacol (mesalamine) are given daily.
- 3-4 tablets of 1.2 g of Lialda (mesalamine) are given daily.
- the patient is not treated with aminosalicylates.
- omega-3 fatty acids including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).
- EPA eicosapentaenoic acid
- DHA docosahexaenoic acid
- omega-3 fatty acids daily are taken daily, and more preferably twice daily.
- Other dietary measures are recommended in concert with the treatment regimen, including for example, limiting alcohol and refined sugars, limiting or eliminating gluten, wheat, whey, red meat and dairy products, and limiting fat intake. It also may be desirable to limit or eliminate folic acid and/or iron supplements.
- the dosage of antibiotic can be reduced, and may be cut in half. It is important to continue the therapy, however, to eradicate any latent spores of invasive bacteria. Failure to totally eradicate the offending bacterial pathogen along with lingering spores may contribute to perpetuating a state of chronic inflammation and, consequently, lessen the possibility of remission. Once full clinical remission is noted, the treatment regimen is stopped, but it may be desirable to continue to administer probiotics daily in order to maintain the microflora in the gut and inhibit colonization of invasive species.
- Preferred methods for the treatment or prophylaxis of inflammatory bowel disease comprise daily oral administration to a patient in need thereof for a period of at least 120 days (preferably for 180 days) a dose of about 1 ,600 mg daily of sulfamethoxazole, 320 mg daily of trimethoprim, and a probiotic mixture comprising at least about 40 billion cells.
- the probiotic will preferably comprise at least one strain selected from the group consisting of Bifidobacterium bifidum, Bifidobacterium breve, Bifidobacterium Infantis, Bifidobacterium longum, Saccharomyces boulardii, Lactobacillus acidophilus, Lactobacillus bulgaricus, Lactobacillus paracasein, and combinations thereof.
- the patient is administered 800 mg of sulfamethoxazole twice daily and 160 mg of trimethoprim twice daily for a time sufficient to affect remission of one or more symptoms of inflammatory bowel disease, after which the patient is administered 800 mg of sulfamethoxazole once daily and 160 mg of trimethoprim once daily for a period of at least 90-120 days after the onset of remission.
- the dosing also may be based on the patient's weight.
- adult patients weighing up to 175 pounds, or up to 190 pounds, may be administered two tablets daily, whereas patients over 190 pounds may be administered 21 ⁇ 2 tablets daily, each tablet comprising 800 mg of sulfamethoxazole and 160 mg of trimethoprim.
- This invention has the potential to prevent pathogenic microorganisms from upsetting the balance of normal gut flora and destabilizing the gastrointestinal tract, while eradicating the invasive pathogen.
- the results of treatment may include (1) disruption of the cycle of chronic inflammation allowing for restoration of the gut epithelial barrier; (2) preventing or minimizing translocation of intestinal bacterial to other organs; (3) reversing or preventing side effects of antibiotic therapy; (4) minimizing a causal effect leading to C.
- TNF-a Tumor Necorsis Factor-A
- the sulfamethoxazole, trimethoprim, and probiotic mixture are present in a single dosage form, although it is also possible that the sulfamethoxazole and said trimethoprim are included in a first dosage form and the probiotic mixture is present in a second dosage form.
- the antibiotics and the probiotics are included in separate dosage forms, it is preferred, but not strictly necessary, that they be administered substantially simultaneously.
- the oral dosage form will typically comprise at least about 1 billion cells of probiotics, at least about 2 billion cells of probiotics, at least about 5 billion cells of probiotics, at least about 10 billion cells of probiotics, or at least about 20 billion cells of probiotics, based on the collective number of cells of all species and strains.
- the dosage form comprises about 800 mg of sulfamethoxazole and about 160 mg of trimethoprim, at least about 20 billion cells of probiotic will be included.
- the dosage form may comprise:
- the dosage form comprises about 400 mg of sulfamethoxazole and about 80 mg of trimethoprim, at least about 10 billion cells of probiotic will be included.
- the dosage form may include half the amount of cells listed above for each species.
- the dosage form comprises about 200 mg of sulfamethoxazole and about 40 mg of trimethoprim, at least about 5 billion cells of probiotic will be included, in which case the dosage form may include one quarter of the amount of cells listed above for each species.
- microorganisms that are intended to act in the intestinal tract should be protected against the acidic gastric juice of the stomach.
- Preferred dosage forms include an enteric tablet, capsule, powder or granulate that will survive the stomach and arrive intact in the intestine.
- embedded microorganisms in a carrier or protective matrix may tend to cake due to hygroscopicity, impeding fiowability and reducing storage stability. Techniques for achieving low hygroscopicity and good fiowability in tablets, capsules, and the like, and especially in powdered products involving microorganisms, are described, e.g., in U.S. Patent Pub. No. 2009/0214647, which is incorporated herein by reference in its entirety.
- the oral dosage form may comprise tablets, capsules, powders or sachets, but will typically be in the form a tablet.
- the tablet can be a modified-release tablet, including sustained release and delayed release.
- the dosage form can be designed according to any of the modified release dosage forms known in the art and described, for example, in U.S. Patent No. 7,108,865, the disclosure of which is hereby incorporated by reference, and using any of the carriers, coatings, excipients, and tablet designs in the patent.
- the antibiotic and probiotic components are compressed with a binder together into a solid core.
- the probiotic component is in a solid core and the antibiotic is contained in a layer surrounding the core.
- the antibiotic component is in a solid core and the probiotic is contained in a layer surrounding the core.
- the tablet may further comprise a water-soluble, water-insoluble, or enteric coating surrounding the outer layer.
- Enteric and other pH-sensitive polymers which are relatively insoluble and impermeable at the pH of the stomach, but which are more soluble and permeable at the pH of the small intestine and colon include polyacrylamides, phthalate derivatives such as acid phthalates of carbohydrates, amylose acetate phthalate, cellulose acetate phthalate, other cellulose ester phthalates, cellulose ether phthalates, hydroxypropylcellulose phthalate, hydroxypropylethylcellulose phthalate, hydroxypropylmethylcellulose phthalate, methylcellulose phthalate, polyvinyl acetate phthalate, polyvinyl acetate hydrogen phthalate, sodium cellulose acetate phthalate, starch acid phthalate, styrene-maleic acid dibutyl phthalate copolymer, styrene-maleic acid polyvinylacetate phthalate copolymer, styrene and maleic acid copolymers, polyacrylic acid derivatives such as acid
- Preferred pH-sensitive polymers include shellac; phthalate derivatives, particularly cellulose acetate phthalate, polyvinylacetate phthalate, and hydroxypropylmethylcellulose phthalate; polyacrylic acid derivatives, particularly polymethyl methacrylate blended with acrylic acid and acrylic ester copolymers; and vinyl acetate and crotonic acid copolymers.
- the antibiotic drug and the probiotic mixture are contained together within a core surrounded by an enteric coating or a delayed release coating.
- a delayed release coating can be, for example, a coating of a water-insoluble polymer such as ethylcellulose which may be impregnated with water-soluble materials that dissolve in the stomach and create pores in the coating.
- only the probiotic component is encapsulated in an enteric coating which releases the probiotic mixture in the small intestine.
- These microcapsules of encapsulated probiotic may be combined in a dosage form with the antibiotic which may or may not be encapsulated in an enteric coating or modified release coating material.
- the antibiotic also may, for example, be provided in the form of microcapsules or the like, with or without a modified-release coating.
- the microcapsules of probiotic and the microcapsules of antibiotic may be charged into a capsules or may be tableted together.
- Such an oral dosage form provides release of the antibiotic drug at a first location and/or time in the gastrointestinal tract and release of the probiotic mixture at a second location and/or time in the gastrointestinal tract.
- the tablet may be an osmotic device comprising a water-insoluble shell having a passage therethrough to permit water from the gut to penetrate the shell and dissolve the carrier contained within the shell, thereby releasing the drug or probiotic contained within the shell.
- the core may comprise a first carrier, proximal to the passage which releases the antibiotic first, and a second carrier distal to the passage which releases the probiotic only after the antibiotic has been substantially released.
- the antibiotic and probiotic may be dispersed in any pharmaceutically acceptable carrier, which may be an immediate release or a slow release carrier.
- the carrier may comprise micro-crystalline cellulose (MCC), dextran, corn starch, flour, talc, sucrose, mannitol, lactose, calcium carbonate, polyvinylpyrrolidone (PVP), polyethylene oxide, hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), polyvinyl alcohol (PVA) or the like.
- MCC micro-crystalline cellulose
- PVP polyvinylpyrrolidone
- HPMC hydroxypropyl methylcellulose
- HPC hydroxypropylcellulose
- PVA polyvinyl alcohol
- the coating may comprise a water-soluble polymer such as polyvinylpyrrolidone (PVP), polyvinylpolypyrrolidone (crospovidone), or polyethylene glycol, or a water insoluble polymer selected from the group consisting of ethers of cellulose, esters of cellulose, cellulose acetate, ethyl cellulose, polyvinyl acetate, neutral copolymers based on ethylacrylate and methylmethacrylate, copolymers of acrylic and methacrylic acid esters with quaternary ammonium groups, pH-insensitive ammonio methacrylic acid copolymers, and mixtures thereof.
- PVP polyvinylpyrrolidone
- crospovidone polyvinylpolypyrrolidone
- polyethylene glycol or a water insoluble polymer selected from the group consisting of ethers of cellulose, esters of cellulose, cellulose acetate, ethyl cellulose, polyvinyl acetate
- the coating may comprise a natural polymer such as methylcellulose, elthylcellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), or a combination therefore.
- HPMC hydroxypropyl methyl cellulose
- HPMC hydroxypropyl methyl cellulose
- HPMC hydroxypropyl cellulose
- a male patient with a clinical diagnosis of chronic ulcerative colitis regularly suffered relapses following a variety of treatments including Asacol, Purinethol, Colazal, Rifaximin, Remicade, Flagyl, Clindamycin, Cyclosporine, Cipro, Cortifoam, and Budesonide.
- the chronic condition persisted for about 35 years, failed to go into prolonged remission, and was characterized by frequent relapse. The patient failed all previous protocols and was facing surgical intervention.
- the patient orally ingested probiotic capsules (40 billion cells daily), along with Omega-3 fish oil capsules (1 ,000 mg daily), 50 mg of 6-mercaptopurine daily, and 12 tablets daily of 400 mg Asacol.
- the colitis symptoms were improved and after 180 days, the patient was in clinical remission.
- tablets of trimethoprim (160 mg) and sulfamethoxazole (800 mg) were administered once daily for an additional 180 days with continued use of probiotics, 6-mercaptopurine, and Omega-3 fish oil.
- the patient has been asymptomatic for over three years.
- Representative tablets according to the invention have the formulation provided in Table 1. These are multi-layer tablets having an immediate-release layer of probiotics around a delayed-release layer of antibiotic.
- the delayed-release layer of antibiotic is encapsulated in an enteric coating which dissolves at a pH of 7 or greater to ensure that the antibiotic is substantially released in the small intestine, and in particular in the terminal ileum, rather than in the stomach.
- the tablets may be full-strength, in which case the treatment protocol recommends twice daily administration, or the tablets may be half-strength, in which case four tablets daily are required during the treatment regimen.
- Lactobacillus paracasein ⁇ 2 billion cells ⁇ 1 billion cells
- Saccharomyces boulardii ⁇ 2.5 billion cells -1.75 billion cells
- a treatment protocol according to the invention includes a first treatment step during the active phase of disease and, after clinical remission, a prophylaxis step to reduce the likelihood of recurrence of symptoms.
- a representative treatment regimen is as follows:
- Treatment 1 full-strength tablet, every 12 hours for 180 days.
- the treatment regimen may be modified if the half-strength tablets are used by administering two of such tablets in place of each full-strength tablet.
- the treatment regimen also allows for decreased levels of immunosuppressants (antimetabolites) and, if it is feasible to do so without adverse reactions, the total elimination of immunosuppressants.
- An anti-inflammatory such as mesalamine (Asacol or Lialda) may also be used in conjunctions with the antibiotic/probiotic therapy. For example, six 400 mg Asacol tablets may be administered twice daily for the duration of the treatment regimen.
- the treatment may further include the following dietary adjustments:
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Priority Applications (9)
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CA2785658A CA2785658C (en) | 2009-12-31 | 2010-12-29 | Compositions and method for treatment and prophylaxis of inflammatory bowel disease |
AU2010339573A AU2010339573B2 (en) | 2009-12-31 | 2010-12-29 | Compositions and method for treatment and prophylaxis of inflammatory bowel disease |
EP10841670.2A EP2519108A4 (en) | 2009-12-31 | 2010-12-29 | Compositions and method for treatment and prophylaxis of inflammatory bowel disease |
US13/517,486 US9138441B2 (en) | 2009-12-31 | 2010-12-29 | Compositions and method for treatment and prophylaxis of inflammatory bowel disease |
MX2012007735A MX348611B (en) | 2009-12-31 | 2010-12-29 | Compositions and method for treatment and prophylaxis of inflammatory bowel disease. |
IL220613A IL220613B (en) | 2009-12-31 | 2012-06-24 | Use of an antibiotic and probiotic formulation in the preparation of a medicament for treatment of inflammatory bowel disease |
US14/857,933 US9492488B2 (en) | 2009-12-31 | 2015-09-18 | Compositions and method for treatment and prophylaxis of inflammatory bowel disease |
US15/292,300 US9649348B2 (en) | 2009-12-31 | 2016-10-13 | Compositions and method for treatment and prophylaxis of inflammatory bowel disease |
US15/592,786 US20170246226A1 (en) | 2009-12-31 | 2017-05-11 | Compositions and method for treatment and prophylaxis of inflammatory bowel disease |
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EP (1) | EP2519108A4 (en) |
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IL (1) | IL220613B (en) |
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US9138441B2 (en) | 2009-12-31 | 2015-09-22 | Ira Milton Trachtman | Compositions and method for treatment and prophylaxis of inflammatory bowel disease |
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US9649348B2 (en) | 2017-05-16 |
MX2012007735A (en) | 2012-09-28 |
EP2519108A4 (en) | 2013-10-16 |
IL220613A0 (en) | 2012-08-30 |
US20170246226A1 (en) | 2017-08-31 |
US9492488B2 (en) | 2016-11-15 |
AU2010339573A1 (en) | 2012-07-19 |
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EP2519108A1 (en) | 2012-11-07 |
US20160000839A1 (en) | 2016-01-07 |
CA2785658A1 (en) | 2011-07-07 |
MX348611B (en) | 2017-06-21 |
AU2010339573B2 (en) | 2014-08-28 |
CA2785658C (en) | 2017-10-24 |
IL220613B (en) | 2018-06-28 |
US20120276201A1 (en) | 2012-11-01 |
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