Targeted gastrointestinal tract delivery of probiotic organisms and/or therapeutic agents

Abstract

The present invention relates to the development of a targeted delivery system for the oral delivery of probiotics or therapeutic agent for various indications, including and not limited to active and prophylaxis treatment of Clostridium difficile infection, antibiotic associated diarrhea, irritable bowel syndrome, Crohn's disease, intestinal flora replacement, supplemental flora treatments for patients taking antibiotics, and for restoration of balance and signaling between the intestinal microbiome and the intestinal cells in patients under treatment of metabolic syndrome manifestations, specifically diabetes, insulin resistance, obesity, hyperlipidemia and hypertension. The present invention restores altered probiotic organism imbalances that are characteristic of said diseases among others as well as defines a platform technology development for site specific delivery of probiotic organisms in the GI tract of a mammal, most specifically the ileum and/or right colon of a human subject.

What is claimed is: 
     
         1 . An oral delivery system for delivering a probiotic formulation targeted to the ileum and proximal colon of a subject; the system comprising:
 a core comprising a probiotic formulation wherein the probiotic formulation is included in a biodegradable first capsule that is coated with a first enteric coating that encapsulates the first capsule containing the probiotic formulation, and wherein the an enteric coating solubilizes in a pH of about 6.2 to about 6.5; and   a second capsule sized to include the coated first capsule, wherein the second capsule is fabricated of a biodegradable material and wherein the second capsule is coated with a second enteric coating that solubilizes in a pH of about 7 to 8, wherein the second capsule releases the first capsule in the ileum and once released the first capsule is solubilized in the proximal colon at a pH of about 6.2 to about 6.5 with the release of the probiotic formulation contained therein.   
     
     
         2 . The oral delivery system of  claim 1  wherein the second enteric coating is substantially insoluble at a pH of less than a range of between about 7.0 to about 8.0 and soluble in the pH range of about 7.0 to about 8.0 and wherein the second enteric coating is comprised of one or more compositions selected from the group consisting of copolymers of methacrylic acid and ethyl acrylate, and copolymers of methacrylic acid, methyl acrylate and methyl methacrylate. 
     
     
         3 . The oral delivery system of any one of  claims 1  to  2 , wherein the second capsule releases the first capsule in the ileum and once released the first capsule is solubilized in the proximal colon at a pH of about 6.2 to about 6.5 with the release of the probiotic formulation. 
     
     
         4 . The oral delivery system of any one of  claims 1  to  3 , wherein the probiotic formulation comprises at least one to about 30 species or different strains of bacteria that are normally present in a pre-determined location within the gastrointestinal tract of a subject. 
     
     
         5 . The oral delivery system of  claim 4 , wherein the pre-determined location is the ileum or colon. 
     
     
         6 . The oral delivery system of any one of  claims 1  to  5 , wherein the probiotic formulation comprises a mixture of bacterial genera that is reflective of the mixture of strains derived from the ileum of a normal human, and the number of said organisms released is more than 10 5  and less than 10 12 . 
     
     
         7 . The oral delivery system of any one of  claims 1  to  6 , wherein the release of the probiotic formulation is in at least two sites of the distal end of the gastrointestinal tract including the ileum and colon of a subject and to thereby ameliorate the imbalance of  Clostridium difficile  in a subject suffering from such an imbalance. 
     
     
         8 . The oral delivery system of any one of  claims 1  to  7 , wherein said probiotic formulation comprises a live bacterial suspension selected from the genus  Lactobacillus  and  Bifidobacterium.    
     
     
         9 . The oral delivery system of  claim 8 , wherein the probiotic formulation further comprises the organism  Faecalibacterium prausnitzii  and/or  Bacteroides  thetaiotaomicron. 
     
     
         10 . The oral delivery system of any one of  claims 1  to  9 , wherein the probiotic formulation can be combined with drugs, acetaminophen, foods, nutrients, vitamins, beneficial substances, prebiotics, pH encapsulated glucose, lipids or proteins that release in combination with the probiotics or in a pH of from about 1 to 6 and before the release of the probiotics. 
     
     
         11 . The oral delivery system of any one of  claims 1  to  9 , wherein the probiotic formulation can be co-administered with an antibiotic selected from the group consisting of vancomycin, metronidazole, gentamicin, colistin, fidaxomicin, telavancin, oritavancin, dalbavancin and daptomycin. 
     
     
         12 . The oral delivery system of any one of  claims 1  to  9 , wherein the probiotic formulation is used to modify the course of metabolic syndrome associated diseases selected from the group consisting of obesity and type 2 diabetes; or to repair intestinal dysbiosis associated diseases selected from the group consisting of Antibiotic associated diarrhea (AAD),  Clostridium difficile  associated diarrhea (CDAD) and metabolic syndrome. 
     
     
         13 . The oral delivery system of any one of  claims 1  to  9 , wherein the probiotic formulation is combined with an ileal brake hormone releasing substance active at the ileal brake to stimulate L-cell hormone release and to revise signaling of hormones. 
     
     
         14 . The oral delivery system of any one of  claims 1  to  13 , wherein the first and second biodegradable capsule is fabricated of hydroxypropylmethyl cellulose. 
     
     
         15 . The oral delivery system of any one of  claims 1  to  9 , wherein the probiotic formulation is combined with atorvastatin at a dose of between about 10 mg to about 80 mg, wherein the atorvastatin is released from each dosage unit formulation at between about pH 1.0 to about pH 6.0. 
     
     
         16 . The oral delivery system of any one of  claims 1  to  9 , wherein the probiotic formulation is combined with a with Tumor Necrosis Factor (TNF) antagonist for release at intestinal pH between 7.0 and 7.5, in an amount effective to treat Crohn's disease, Ulcerative colitis or inflammatory bowel disease. 
     
     
         17 . A capsule-in-capsule oral delivery system that delivers desirable probiotics or therapeutic agents to the ileum and/or proximal colon, the system comprising:
 a first capsule containing the desirable probiotics or therapeutic agents, wherein the first capsule is fabricated of a biodegradable material and wherein the first capsule is coated with a first enteric coating that solubilizes in a pH of about 6.2 to about 6.5; and   a second capsule being of a size that can include within its dimensions the coated first capsule, wherein the second capsule is fabricated of a biodegradable material and wherein the second capsule is coated with a second enteric coating that solubilizes in a pH of about 7 to 8, wherein the second capsule releases the first capsule in the ileum and once released the first capsule is solubilized in the proximal colon at a pH of about 6.2 to about 6.5 with the release of the desirable probiotics or therapeutic agents.   
     
     
         18 . The capsule-in-capsule oral delivery system of  claim 17 , wherein the second capsule further comprises desirable probiotics for release in the ileum. 
     
     
         19 . The capsule-in-capsule oral delivery system of  claims 17  to  18 , wherein, the desirable probiotics or therapeutic agents within the capsule system are delivered to the ileum and/or proximal colon without leakage of such probiotics or therapeutic agents in the proximal areas of the gastrointestinal tract positioned before the ileum and/or proximal colon. 
     
     
         20 . The capsule-in-capsule oral delivery system of any one of  claims 17  to  19 , wherein the first and/or second enteric coating is comprised of one or more compositions selected from the group consisting of copolymers of methacrylic acid and ethyl acrylate, and copolymers of methacrylic acid, methyl acrylate and methyl methacrylate. 
     
     
         21 . The capsule-in-capsule oral delivery system of any one of  claims 17  to  20 , wherein the second capsule releases the first capsule in the ileum and once released the first capsule is solubilized in the proximal colon at a pH of about 6.2 to about 6.5 with the release of the desirable probiotics or therapeutic agents. 
     
     
         22 . The capsule-in-capsule oral delivery system of any one of  claims 17  to  21 , wherein the desirable probiotics comprise at least one to about 30 different species or strains of bacteria that are normally present in a pre-determined location within the gastrointestinal tract of a subject. 
     
     
         23 . The capsule-in-capsule oral delivery system of any one of  claims 17  to  22  to  24 , wherein the pre-determined location is the ileum or colon. 
     
     
         24 . The capsule-in-capsule oral delivery system of any one of  claims 17  to  23 , wherein the desirable probiotics comprises a mixture of bacterial genera that is reflective of the mixture of strains derived from the ileum of a normal human, and the number of said organisms released is more than 10 5  and less than 10 12 . 
     
     
         25 . The capsule-in-capsule oral delivery system of any one of  claims 17  to  24 , wherein the release of the desirable probiotics is in the distal segments of the gastrointestinal tract including the ileum and colon of a subject and to ameliorate the imbalance of  Clostridium difficile  in a subject suffering from such an imbalance. 
     
     
         26 . The capsule-in-capsule oral delivery system of any one of  claims 17  to  25 , wherein the desirable probiotics comprise a live bacterial suspension selected from the genus  Lactobacillus  and  Bifidobacterium.    
     
     
         27 . The capsule-in-capsule oral delivery system of any one of  claims 17  to  26 , wherein the desirable probiotics further comprises the organism  Faecalibacterium prausnitzii.    
     
     
         28 . The capsule-in-capsule oral delivery system of  claim 17 , wherein the first capsule is coated with the first enteric coating comprises about 10 mg/cm 2  of Eudragit EPO and the second capsule is coated with about 5 mg/cm 2  of Eudragit L100/S100, 75/25 mix. 
     
     
         29 . A method of treating the onset of a gastrointestinal disorder, the method comprising administering to a subject in need of such treatment in a pharmaceutically effective amount of an oral formulation comprising:
 a first capsule containing desirable probiotics having beneficial effects on a gastrointestinal disorder, wherein the first capsule is fabricated of a biodegradable material and wherein the first capsule is coated with a first enteric coating that solubilizes in a pH of about 6.2 to about 6.5; and   a second capsule being of a size that can include within its dimensions the coated first capsule, wherein the second capsule is fabricated of a biodegradable material and wherein the second capsule is coated with a second enteric coating that solubilizes in a pH of about 7 to 8, wherein the second capsule releases the first capsule in the ileum and once released the first capsule is solubilized in the proximal colon at a pH of about 6.2 to about 6.5 with the release of the desirable probiotics.   
     
     
         30 . The method of treating the onset of a gastrointestinal disorder according to  claim 29 , wherein the gastrointestinal disorder is a  Clostridium difficile  disorder. 
     
     
         31 . The method of treating the onset of a gastrointestinal disorder according to any one of  claims 29  to  30 , wherein the oral formulation is in an amount sufficient to alleviate the gastrointestinal disorder in the subject. 
     
     
         32 . The method of treating the onset of a gastrointestinal disorder according to any one of  claims 29  to  31 , wherein the  Clostridium difficile  disorder is associated with one or more of a  Clostridium difficile  infection, an imbalance of  Clostridium difficile  in the ileum or colon of said subject, diarrhea, inflammation, colitis fever or dysbiosis. 
     
     
         33 . The method of treating the onset of a gastrointestinal disorder according to any one of  claims 29  to  32 , wherein said oral formulation comprises a live bacterial suspension selected from the genus  Lactobacillus  and  Bifidobacterium.    
     
     
         34 . The method of treating the onset of a gastrointestinal disorder according to any one of  claims 29  to  33 , wherein the gastrointestinal disorder includes irritable bowel diseases associated with dysbiosis, where the method comprises administering a probiotic formulation targeted to the ileum and right colon in an amount sufficient to alleviate the disorder in said subject. 
     
     
         35 . The method of treating the onset of a gastrointestinal disorder according to  claim 34  wherein the oral formulation is administered in combination with linaclotide. 
     
     
         36 . The method of treating the onset of a gastrointestinal disorder according to any one of  29  to  35  wherein the oral formulation is administered in combination with statins, linaclotide, ileal brake hormone releasing substances or anti-inflammatory agents. 
     
     
         37 . Use of an oral formulation for preparing a medicament for the treatment of gastrointestinal disorder wherein the oral formulation comprises:
 a first capsule containing a desirable bacteria effective against the gastrointestinal disorder, wherein the first capsule is fabricated of a biodegradable material and wherein the first capsule is coated with an enteric coating that solubilizes in a pH of about 6.2 to about 6.5; and   a second capsule being of a size that can include within its dimensions the coated first capsule, wherein the second capsule is fabricated of a biodegradable material and wherein the second capsule is coated with an enteric coating that solubilizes in a pH of about 7 to 8, wherein the second capsule releases the first capsule in the ileum and once released the first capsule is solubilized in the proximal colon at a pH of about 6.2 to about 6.5 with the release of the desirable bacteria.   
     
     
         38 . An oral delivery system to deliver an oral formulation targeted directly to the ileum and/or colon of a subject with essentially no loss of the oral formulation before reaching at least the ileum, the system comprising:
 a core comprising the oral formulation, wherein the oral formulation comprises probiotics, fecal bacteria for a fecal transplant or a therapeutic agent;   a first enteric coating encapsulating the core, wherein the first coating dissolves in a dissolution pH of about 6.2 to about 6.5;   a second enteric coating encapsulating the first coating, wherein the second coating dissolves in a dissolution pH of about 7 to 8.   
     
     
         39 . The oral delivery system of  claim 38 , further comprising a first biodegradable film layer positioned between the core and first enteric coating. 
     
     
         40 . The oral delivery system of  claim 39 , further comprising a second biodegradable film layer positioned between the first enteric coating and the second enteric coating. 
     
     
         41 . The oral delivery system of  claim 40 , wherein the first and second biodegradable film is hydroxypropylmethyl cellulose. 
     
     
         42 . The oral delivery system of  claim 40 , wherein the first and second biodegradable film is in the form of a tablet or capsule. 
     
     
         43 . The oral delivery system of  claim 42 , wherein the fecal bacteria is administered for a fecal transplant to treat a  Clostridium difficile  associated disorder in a subject suffering from such a disorder. 
     
     
         44 . An oral delivery system that delivers a probiotic formulation targeted to the ileum of a subject; the system comprising:
 a core comprising a probiotic formulation; and   a coating which encapsulates the probiotic formulation, which is substantially insoluble at a pH of less than a range of between about 7.0 to about 8.0 and soluble in the pH range of about 7.0 to about 8.0, and wherein the probiotic formulation is not released until the pH is about 7 and there is essentially no loss of the probiotic formulation through the digestive tract until the delivery systems reaches the ileum.   
     
     
         45 . The oral delivery system of  claim 44 , wherein the coating is comprised of one or more compositions selected from the group consisting of poly(dl-lactide-co-glycolide, chitosan (Chi) stabilized with PVA (poly-vinylic alcohol), a lipid, an alginate, carboxymethylethylcellulose (CMEC), cellulose acetate trimellitiate (CAT), hydroxypropylmethyl cellulose phthalate (HPMCP), hydroxypropylmethyl cellulose, ethyl cellulose, color con, food glaze and mixtures of hydroxypropylmethyl cellulose and ethyl cellulose, polyvinyl acetate phthalate (PVAP), cellulose acetate phthalate (CAP), shellac, copolymers of methacrylic acid and ethyl acrylate, and copolymers of methacrylic acid, methyl acrylate and methyl methacrylate, and copolymers of methacrylic acid and ethyl acrylate to which a monomer of methylacrylate has been added during polymerization,