Probiotic recolonisation therapy

• US 8,460,648 B2
• Filed: 07/25/2001
• Issued: 06/11/2013
• Est. Priority Date: 07/25/2000
• Status: Expired due to Term

• Current Assignee: Finch Therapeutics Holdings LLC (Finch Therapeutics Group, Inc.)
• Original Assignee: Thomas Julius Borody
• Inventors: Borody, Thomas Julius
• Primary Examiner(s): Ford, Vanessa L
• Assistant Examiner(s): JACKSON-TONGUE, LAKIA J
• Application Number:
  US10/332,986
• Publication Number:
  US 20040028689A1
• Time in Patent Office: 4,339 Days
• Field of Search: 424/184.1, 424/93.41, 424/167.1, 424/239.1, 424/247.1
• US Class Current: 424/93.3
• CPC Class Codes: A23C 9/123 using only microorganisms of the genus lactobacteriaceae; Yoghurt A23C9/13 takes precedence
• CPC Class Codes: A23C 9/127 using microorganisms of the genus lactobacteriaceae and other microorganisms or enzymes, e.g. kefir, koumiss A23C9/13 takes precedence
• CPC Class Codes: A23C 9/13 using additives
• CPC Class Codes: A23L 2/52 Adding ingredients adding preservatives A23L2/44
• CPC Class Codes: A23L 33/135 Bacteria or derivatives thereof, e.g. probiotics
• CPC Class Codes: A23V 2002/00 Food compositions, function of food ingredients or processes for food or foodstuffs
• CPC Class Codes: A61K 2035/115 Probiotics
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/341 not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
• CPC Class Codes: A61K 31/41 having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
• CPC Class Codes: A61K 31/43 Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula , e.g. penicillins, penems
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 31/545 Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula: , e.g. cephalosporins, cefaclor, or cephalexine
• CPC Class Codes: A61K 31/7034 attached to a carbocyclic compound, e.g. phloridzin
• CPC Class Codes: A61K 31/7048 having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin , digitoxin or digoxin
• CPC Class Codes: A61K 35/24 Mucus; Mucous glands; Bursa; Synovial fluid; Arthral fluid; Excreta; Spinal fluid saliva A61K35/38
• CPC Class Codes: A61K 35/37 Digestive system
• CPC Class Codes: A61K 35/38 Stomach; Intestine; Goblet cells; Oral mucosa; Saliva
• CPC Class Codes: A61K 35/74 Bacteria therapeutic use of a bacterial protein A61K38/00
• CPC Class Codes: A61K 35/741 Probiotics probiotic yeast, e.g. saccharomyces A61K36/06
• CPC Class Codes: A61K 35/742 : Spore-forming bacteria, e.g. Bacillus coagulans, Bacillus subtilis, clostridium or Lactobacillus sporogenes
• CPC Class Codes: A61K 35/744 : Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
• CPC Class Codes: A61K 35/745 : Bifidobacteria
• CPC Class Codes: A61K 35/747 : Lactobacilli, e.g. L. acidophilus or L. brevis
• CPC Class Codes: A61K 35/76 : Viruses; Subviral particles; Bacteriophages
• CPC Class Codes: A61K 36/062 : Ascomycota
• CPC Class Codes: A61K 38/00 : Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/14 : Peptides containing saccharide radicals; Derivatives thereof , e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
• CPC Class Codes: A61K 38/4893 : Botulinum neurotoxin (3.4.24.69)
• CPC Class Codes: A61K 39/00 : Medicinal preparations containing antigens or antibodies materials for immunoassay G01N33/53
• CPC Class Codes: A61K 39/39 : characterised by the immunostimulating additives, e.g. chemical adjuvants
• CPC Class Codes: A61K 45/06 : Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 51/1217 : Dispersions, suspensions, colloids, emulsions, e.g. perfluorinated emulsion, sols
• CPC Class Codes: A61K 9/0031 : Rectum, anus
• CPC Class Codes: A61K 9/0053 : Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/19 : lyophilised , i.e. freeze-dried, solutions or dispersions lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00
• CPC Class Codes: A61K 9/48 : Preparations in capsules, e.g. of gelatin, of chocolate A61K9/0004 takes precedence; bite capsules A61K9/0056
• CPC Class Codes: A61K 9/4891 : Coated capsules; Multilayered drug free capsule shells with drug coating for immediate release A61K9/4808; osmotic devices A61K9/0004
• CPC Class Codes: A61K 9/50 : Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals A61K9/2081 takes precedence; particles with a single coating comprising drug A61K9/167
• CPC Class Codes: A61K 9/5005 : Wall or coating material
• CPC Class Codes: A61K 9/5078 : with drug-free core
• CPC Class Codes: A61P 1/00 : Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/12 : Antidiarrhoeals
• CPC Class Codes: C12N 2795/00032 : Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention relates to pharmaceutical compositions suitable for the treatment of chronic diseases associated with the presence of abnormal or an abnormal distribution of microflora in the gastrointestinal tract of a mammalian host, which compositions comprise viable non-pathogenic or attenuated pathogenic Clostridia. The compositions further comprise one or more additional viable non-pathogenic or attenuated pathogenic microorganisms selected from the group consisting of Bacteroides, Eubacteria, Fusobacteria, Propionibacteria, Lactobacilli, anaerobic cocci, Ruminococcus, E.Coli, Gemmiger, Desullomonas, Peptostreptococcus, and fungi. The present invention also provides pharmaceutical compositions suitable for the treatment of the same chronic diseases comprising viable non-pathogenic or attenuated pathogenic Escherichia coli, at least one strain of viable non-pathogenic or attenuated pathoenic Bacteroides and at least one strain of viable non-pathogenic or attenuated pathogenic microorganism.

Claims

1. A method for the treatment of a chronic disorder associated with the presence of an abnormal or an abnormal distribution of microflora in the gastrointestinal tract of a mammalian host, the chronic disorder selected from the group consisting of:

irritable bowel syndrome, chronic persistent diarrhoea, diarrhoea, flatulence, constipation, and alternating constipation/diarrhoea, which method comprises administering an effective amount of a composition comprising viable non-pathogenic or attenuated pathogenic microorganisms for a period of time sufficient to displace the existing microflora, wherein the composition comprises;

at least two Clostridia selected from among Clostridium bifermentans, Clostridium butyricum and Clostridium innocuum;

at least one Bacteroides selected from among Bacteroides fragilis, Bacteroides thetaiotaomicron and Bacteroides uniformis; and

Escherichia coli; and

wherein lavage or other methods of removal of at least part of the host'"'"'s existing enteric microflora is omitted.

2. A method according to claim 1, further comprising administering Peptostreptococcus productus.

3. A method according to claim 1, further comprising administering one or more additional viable non-pathogenic or attenuated pathogenic microorganisms selected from the group consisting of Bacteroides fragilis ss. vulatus, Eubacterium aerofaciens, Bacteroides fragilis ss. thetaiotaomicron, Peptostreptococcus productus, Bacteroides fragilis ss. distasonis, Fusobacterium prausnitzii, Coprococcus eutactus, Eubacterium aerofaciens, Peptostreptococcus productus, Ruminococcus bromii, Bifidobacterium adolescentis, Gemmiger formicilis, Bifidobacterium longum, Eubacterium siraeum, Ruminococcus torques, Eubacterium rectale, Eubacterium eligens, Bacteroides eggerthii, Clostridium leptum, Eubacterium biforme, Bifidobacterium infantis, Coprococcus comes, Bacteroides capillosus, Ruminococcus albus, Eubacterium formicigenerans, Eubacterium hallii, Eubacterium ventriosum, Fusobacterium russi, Ruminococcus obeum, Clostridium ramosum, Lactobacillus leichmannii, Ruminococcus callidus, Butyrivibrio crossotus, Acidaminococccus fermentans, Eubacterium ventriosum, Bacteroides fragilis ss. fragilis, Coprococcus catus, Eubacterium hadrum, Eubacterium cylindroides, Eubacterium ruminantium, Staphylococcus epidermidis, Eubacterium limosum, Bacteroides praeacutus, Fusobacterium mortiferum, Fusobacterium naviforme, Clostridium innocuum, Propionibacterium acnes, Ruminococcus flavefaciens, Bacteroides fragilis ss. ovatus, Fusobacterium nucleatum, Fusobacterium mortiferum, Escherichia coli, Streptococcus morbiliorum, Peptococcus magnus, Streptococcus intermedius, Ruminococcus lactaris, Eubacterium tenue, Eubacterium ramulus, Bacteroides clostridiiformis ss. clostridliformis, Bacteroides coagulans, Bacteroides oralis, Bacteroides ruminicola ss. brevis, Bacteroides ruminicola ss. ruminicola, Bacteroides splanchnicus or Desuifomonas pigra.

4. A method according to claim 1, further comprising administering fungi.

5. A method according to claim 4, wherein the fungi are Monilia.

6. The method according to claim 1, further comprising administering at least one strain of viable non-pathogenic or attenuated pathogenic Bifidobacterium.

7. A method according to claim 1, further comprising administering one or more additional agents selected from the group consisting of an acid suppressant, an antacid, an H2 antagonist, a proton pump inhibitor.

8. The method according to claim 1, wherein said microorganisms are spores.

9. The method according to claim 1, wherein the composition is lyophilised, pulverised and powdered or a liquid culture.

10. The method according to claim 1, wherein the composition is administered in a form selected from the group consisting of an enteric coated capsule, an enteric coated microcapsule, a reconstituted powder, an enema, a food, a drink.

11. The method according to claim 10, wherein said food is selected from the group consisting of yogurt, a dairy-based product, a soy-based product, or a derivative thereof.

12. The method according to claim 1, wherein the mammalian host is human.

13. The method according to claim 1, wherein administration is by one or more route(s) selected from the group consisting of ingestion, parenteral infusion, enema, per-colonoscope, intubation of the small bowel or orally.

14. The method according to claim 1, wherein the chronic disorder is a gastrointestinal disorder.

15. The method according to claim 1, further comprising an initial treatment regimen of about 10¹⁰ cells per dose administered 3 to 6 times per day for a period sufficient to stabilise the gut flora.

16. The method according to claim 1, wherein said composition comprises viable non-pathogenic or attenuated pathogenic Clostridia and at least one additional bacterial species.

17. The method according to claim 1, wherein said Clostridia is Clostridium innocuum.

18. A method according to claim 1 wherein the irritable bowel syndrome is associated with autism.

19. A method for treatment of a chronic disorder associated with the presence of an abnormal or an abnormal distribution of microflora in the gastrointestinal tract of a mammalian host, the chronic disorder selected from the group consisting of:

irritable bowel syndrome, chronic persistent diarrhea, diarrhea, flatulence, constipation, and alternating constipation/diarrhea, which method comprises administering an effective amount of a composition comprising viable non-pathogenic or attenuated pathogenic microorganisms for a period of time sufficient to displace the existing microflora, wherein the composition comprises;

Clostridium bifermentans, clostridium butyricum and Clostridium innocuum;

Bacteroides fragilis, Bacteriodies thetaiotaomicron and Bacteroides uniformis; and

Escherichia coli;

and wherein lavage or other methods of removal of at least part of the host'"'"'s existing enteric microflora is omitted.