JP2019194202A - Compositions for fecal microbiota transplantation and methods for making and using them and devices for delivering them - Google Patents

Abstract

To provide: compositions to be used for gastric, gastrointestinal and/or colonic treatments or lavage, e.g., orthostatic lavage for inducing the purgation of gastrointestinal (GI) tract including colon; and methods for making and using them; compositions, e.g., formulations for the stabilization, amelioration, treatment and/or prevention of constipation, for the treatment of abdominal pain, particularly non-specific abdominal pain, and diarrhea, including diarrhea caused by a side effect of a drug, psychological conditions, diseases or conditions such as Crohn's Disease, a poison, a toxin or an infection, e.g., a toxin-mediated traveler's diarrhea, or C. difficile infection or the pseudo-membranous colitis associated with this infection; and methods for making and using them.SOLUTION: The invention provides a method for producing a pharmaceutical composition comprising viable, non-pathogenic fecal microbiota obtained from a fecal donor. The invention also provides a device for delivering the fecal material to a patient.SELECTED DRAWING: Figure 2

Description

  The present invention relates generally to medicine and gastroenterology, pharmacology and microbiology. In alternative embodiments, the present invention provides compositions, such as formulations or formulations and devices, and methods for making and using the same that are used to implant treated or isolated fecal flora. In an alternative embodiment, the compositions, devices and methods of the present invention can be used for either gastric, gastrointestinal and / or colonic treatment or irrigation. In an alternative embodiment, the compositions, devices and methods of the present invention may be used to expose constipation, Crohn's disease, toxins or toxins or infection, such as toxin-mediated traveler diarrhea; or any bowel disease or Conditions such as inflammatory bowel disease (IBD), Crohn's disease, hepatic encephalopathy, enteritis, colitis, irritable bowel syndrome (IBS), fibromyalgia (FM), chronic fatigue syndrome (CFS), depression, attention Improve and stabilize diseases or conditions such as deficit / hyperactivity disorder (ADHD), multiple sclerosis (MS), systemic lupus erythematosus (SLE), traveler diarrhea, small intestinal bacterial overgrowth, chronic pancreatitis or pancreatic insufficiency, Used to treat and / or prevent. In alternative embodiments, the present invention provides pharmaceuticals and articles of manufacture (articles) for delivering these compositions and formulations to individuals, eg, humans or animals. The present invention also provides a device for delivering fecal material to an individual, eg, a patient.

  The intestinal flora has recently become more important from a therapeutic point of view. It is now recognized that the human flora is an important virtual organ that contains a large number of living microorganisms, rather than just waste material resulting from food digestion. More than 100,000 subspecies exist when the genetically different but often linearly related organisms are further classified by family and subgroup. Waste “material” makes up a certain percentage of the bacterial flora. The bacterial content of the flora actively breaks down or metabolizes unabsorbed substances, many fibers, where bacterial cells grow. Since the bacterial flora is contained in the human body and creates a living component, it is actually configured as a living or virtual organ.

  This virtual organ can be healthy in that it does not contain pathogenic organisms or is not infected or invaded by parasites, bacteria or viruses. When infecting some pathogenic species, such infectious species can produce molecules that affect secretion and can cause pain or parasitize the gut and cause constipation. Intestinal flora or infection of intestinal flora organs can have a significant impact on an individual's health.

  Many of these infections can be acute, such as cholera, but some can be chronic and can actually have a significant impact on the lives of individuals with infectious flora. For example, after antibiotic therapy, some of the bacteriology could be suppressed or eradicated, infectious agents such as Clostridium difficile and other pathogens settled, and passengers in the human flora There is a possibility. These “passengers” are also pathogenic because they can produce toxins such as toxins A and B in C. difficile.

U.S. Patent No. 7,541,091 US Patent Application Publication No. 20110045222 US Patent Application Publication No. 20110008554 US Patent Application Publication No. 201000255231 WO2011 / 033310A1

Grehan et al., J of Clinical Gastroenterology (September 2010)

Definitions The following are some definitions that may be helpful in understanding and describing the present invention. These are intended as general definitions and are in no way intended to limit the scope of the invention to only those terms, but are provided for a better understanding of the following description.

  Unless otherwise specifically stated by context, or explicitly stated to the contrary, integers, steps or elements of the invention described herein as a single integer, step or element are described Apparently encompassing both singular and plural forms of integers, steps or elements.

  Throughout this specification, unless the context dictates otherwise, the term `` includes (subject) '' or variations such as `` include (subject) '' or `` contain '' are described steps or It will be understood that it includes elements or integers or steps or groups of elements or integers, but is not meant to exclude any other steps or elements or integers or groups of elements or integers. Therefore, in the content of this specification, the term “including” means “including mainly, but not necessarily only”.

In a first aspect of the invention, the entire microflora (or substantially whole); treated or untreated fecal flora; substantially or completely from fecal flora, non-fecal flora, non-fecal flora A delivery vehicle, formulation, composition, pharmaceutical preparation, article of manufacture, container or device comprising a purified fecal flora, or a partially, substantially or completely isolated or purified fecal flora. And
(i) Feces substantially or completely purified from whole (or substantially whole) microflora, treated or untreated fecal flora samples, complete or partial fecal flora samples, non-fecal flora faecal material Providing a bacterial flora, or partially, substantially or completely isolated or purified fecal flora; and a delivery vehicle, formulation, pharmaceutical preparation, composition, article of manufacture, container or device;
(ii) substantially or completely from the whole (or substantially whole) of the microflora, the treated or untreated fecal flora sample, the complete or partial fecal flora sample, the non-fecal flora faecal material; Placing the purified fecal flora, or the partially, substantially or completely isolated or purified fecal flora into the delivery vehicle, formulation, composition, pharmaceutical preparation, article of manufacture, container or device; A delivery vehicle, formulation, composition, pharmaceutical preparation, article of manufacture, container or device made by a method comprising:

  In a second aspect of the invention, there is provided an article of manufacture (article) comprising the delivery vehicle, formulation, composition, pharmaceutical preparation, container or device of the first aspect.

In the third aspect of the present invention,
(i) Whole (or substantially whole) microflora; treated or untreated fecal flora sample; full or partial fecal flora sample, feces substantially or completely purified from non-fecal flora faecal material Providing a bacterial flora, or partially, substantially or completely isolated or purified fecal flora; and a delivery vehicle, formulation, pharmaceutical preparation, composition, article of manufacture, container or device;
(ii) substantially or completely purified from the whole (or substantially whole) microbiota, the treated or untreated faecal sample, the complete or partial fecal flora, the non-faecal flora faecal material The fecal flora, or the partially, substantially or completely isolated or purified fecal flora, is placed in the delivery vehicle, formulation, pharmaceutical preparation, composition, article of manufacture, container or device, the container or Creating a substantial or complete anoxic environment in the device, and a method of making a delivery vehicle, formulation, composition, pharmaceutical preparation, article of manufacture, container or device according to the first or second aspect .

In a fourth aspect of the invention, an infection, disease, treatment, addiction or condition having an intestinal dysfunction element or side effect is improved, stabilized, treated and / or prevented, or constipation is improved, treated and / or prevented. Or abdominal pain, nonspecific abdominal pain or diarrhea, drug side effects or psychological conditions or Crohn's disease, toxins, toxins or infection-induced diarrhea, toxin-mediated traveler diarrhea or Clostridium or C. perfringens-Welch welchii) or C. difficile infection or a method for treating pseudomembranous colitis associated with Clostridium infection, comprising:
To an individual in need thereof, the entire microflora (through the delivery vehicle, formulation, composition, pharmaceutical preparation, article of manufacture, container or device of the first aspect or article of manufacture (article) of the second aspect ( Or substantially whole), the treated or untreated fecal flora sample, the complete or partial fecal flora sample, the fecal flora substantially or completely purified from the non-fecal flora fecal material, or Administering a partially, substantially or completely isolated or purified stool flora.

In the fifth aspect of the present invention,
Whole (or substantially whole) microflora; faecal flora partially or substantially or completely isolated or purified; or fecal bacteria substantially or completely purified from non-faecal flora faecal material A delivery vehicle, formulation, composition, pharmaceutical formulation, article of manufacture, container or device comprising a composition comprising a flora is provided.

  In a sixth aspect of the present invention, there is provided a method for ameliorating, stabilizing, treating and / or preventing an infection, disease, treatment, addiction or condition having an intestinal dysfunction element or side effect, wherein the individual is in need thereof. Via the delivery vehicle, formulation, composition, pharmaceutical preparation, article of manufacture, container or device according to the fifth aspect, the entire microflora (or substantially whole), the partly, substantially or completely There is provided a method comprising the step of administering said composition comprising isolated or purified fecal flora, or fecal flora substantially or completely purified from non-fecal flora fecal material.

In a seventh aspect of the invention, a device for delivering fecal material or the composition of the first aspect, comprising:
(a) the device illustrated in FIG. 1B or FIG. 2; or
(b) Devices including:
(i) a bag or container comprising an outlet opening operatively connected to the proximal end of a flexible tube or equivalent;
(ii) an open / close valve or equivalent or obdurator screw top at the distal end of a flexible tube or equivalent and
(iii) a pump or manual pump for moving the material in the bag or container from the distal end or from the open / close valve or equivalent through the flexible tube or equivalent;
(c) A device comprising the device of (a) or (b), further comprising fecal material or the composition of the first aspect is provided.

  In an eighth aspect of the invention, the entire microflora (or substantially whole); treated or untreated fecal flora; substantially or completely purified from fully or partially fecal flora, non-fecal flora material A bag or container comprising the isolated fecal flora, or partially, substantially or completely isolated or purified fecal flora or compositions thereof, wherein the bag or container comprises , Structurally the same or similar to the bag or container of the device of the seventh aspect.

In a ninth aspect of the invention, improving, stabilizing, treating and / or preventing an infection, disease, treatment, addiction or condition having an intestinal dysfunction element or side effect, or reducing or delaying its symptoms, Or improve, treat and / or prevent constipation, abdominal pain, non-specific abdominal pain or diarrhea, drug side effects or psychological conditions or Crohn's disease, diarrhea caused by toxins, toxins or infections, toxin-mediated traveler's diarrhea or Clostridium Or treat C. perfringens-Welch or C. difficile infection or pseudomembranous colitis associated with Clostridium infection, or prevent or reduce or delay its symptoms, or spondyloarthritis, spondyloarthritis or sacroiliac Sacrolileitis (inflammation of one or both sacroiliac joints); nephritic syndrome; with intestinal or intestinal components Inflammatory or autoimmune conditions; lupus; irritable bowel syndrome (IBS or colonic spasm); or colitis; ulcerative colitis or clonal colitis; constipation; autism; degenerative neurological disease; Sclerosis (ALS), multiple sclerosis (MS) or Parkinson's disease (PD); myoclonic dystonia; Steinert disease; proximal myotonic myopathy; autoimmune disease; rheumatoid arthritis (RA) or juvenile idiopathic Arthritis (JIA); chronic fatigue syndrome; benign myalgic encephalomyelitis; chronic fatigue immune dysfunction syndrome; chronic infectious mononucleosis; epidemic myalgic encephalomyelitis; obesity; hypoglycemia, prediabetic syndrome , Type I diabetes or type II diabetes; idiopathic thrombocytopenic purpura (ITP); acute or chronic allergic reactions; skin rash, rash, urticaria or chronic urticaria; and / or insomnia or chronic insomnia, major seizures In a method to improve or treat an individual who has convulsions or small seizures I,
To an individual in need thereof, the entire microflora (or substantially) via the delivery vehicle, formulation, pharmaceutical preparation, article of manufacture, container or device of the first aspect or article of manufacture (article) of the second aspect. The treated or untreated fecal flora sample, the complete or partial fecal flora sample, the fecal flora substantially or completely purified from the non-fecal flora fecal material, or the partial Further comprising administering a substantially or completely isolated or purified fecal flora in a single, repeated or multiple administration, delivery or infusion.

  In a tenth aspect of the invention, an infection, disease, treatment, addiction or condition having an intestinal dysfunction element or side effect is improved, stabilized, treated and / or prevented, or constipation is improved, treated and / or prevented. Or abdominal pain, non-specific abdominal pain or diarrhea, drug side effects or psychological conditions or Crohn's disease, venom, toxin or diarrhea caused by infection, Clostridium or C. perfringens-Welch or C Whole microflora (or substantially whole), treated or untreated faecal flora samples, complete or partial fecal bacteria for use in treating pseudomembranous colitis associated with difficile infection or Clostridium infection Flora samples, faecal flora substantially or completely purified from non-fecal flora faecal material, or partially To provide a substantially or completely isolated or purified fecal flora.

  In an eleventh aspect of the invention, an infection, disease, treatment, addiction or condition with an intestinal dysfunction element or side effect is improved, stabilized, treated and / or prevented, or constipation is improved, treated and / or prevented. Or abdominal pain, non-specific abdominal pain or diarrhea, drug side effects or psychological conditions or Crohn's disease, venom, toxin or diarrhea caused by infection, Clostridium or C. perfringens-Welch or C . Whole microflora (or substantially whole), treated or untreated faecal flora samples, complete or partial fecal bacteria in the preparation of a medicament for treating pseudomembranous colitis associated with difficile infection or Clostridium infection Flora samples, fecal flora substantially or completely purified from non-fecal flora faecal material, or Min to provide a substantially or completely the use of isolated or purified fecal flora.

  In a twelfth aspect of the invention, an infection, disease, treatment, addiction or condition having an intestinal dysfunction element or side effect is improved, stabilized, treated and / or prevented, or constipation is improved, treated and / or prevented. Or abdominal pain, non-specific abdominal pain or diarrhea, drug side effects or psychological conditions or Crohn's disease, venom, toxin or diarrhea caused by infection, Clostridium or C. perfringens-Welch or C . Faecal material or whole microflora (or substantially whole), treated or untreated faecal flora sample, complete or partial fecal flora in treating pseudomembranous colitis associated with difficile infection or Clostridium infection Sample, faecal flora substantially or completely purified from non-faecal flora faecal material, or partially Provides the use of a seventh embodiment of the device for delivering a substantially or completely isolated or purified fecal flora.

  In an alternative embodiment, the present invention comprises a delivery vehicle, formulation, container or device comprising treated or untreated fecal flora, or partially, substantially or completely isolated fecal flora. Compositions (including formulations, pharmaceutical compositions, foods, feeds, supplements, articles of manufacture, etc.); and methods of making and using them are provided.

In an alternative embodiment, the present invention provides
(a) (i) a treated or untreated stool sample, or a sample containing the entire (or substantially whole) microflora, or a complete or partial stool flora, or partially, substantially or completely simple Providing a composition comprising isolated or purified fecal flora; and a delivery vehicle, formulation, pharmaceutical preparation, article of manufacture, container or device;
(ii) the treated or untreated stool sample, the partially, substantially or completely isolated or purified fecal flora, the entire microflora (or substantially the whole), or the complete or partial A composition comprising fecal flora, or partially, substantially or completely isolated or purified fecal flora, is placed in the delivery vehicle, formulation, pharmaceutical preparation, article of manufacture, container or device;
Optionally creating a substantial or complete anoxic environment in said delivery vehicle, formulation, pharmaceutical formulation, article of manufacture, container or device;
Optionally, said delivery vehicle, formulation, pharmaceutical preparation, article of manufacture, container or device is said treated or untreated stool sample, or said partially, substantially or completely isolated or purified stool bacteria Treated or untreated fecal flora, whole microflora (or substantially whole), and / or partly, substantially made by a method that is sterile or bacteria-free before the step of entering the flora A delivery vehicle, formulation, pharmaceutical preparation, article of manufacture, container or device comprising a faecal flora isolated on or completely;
(b) incorporating a built-in or clip-on oxygen scavenging mechanism into the delivery vehicle, formulation, pharmaceutical formulation, article of manufacture, container or device; and / or the delivery vehicle, formulation, pharmaceutical preparation, article of manufacture, container Or the device comprises or is coated with an oxygen scavenging material; and / or air in said delivery vehicle, formulation, pharmaceutical preparation, article of manufacture, container or device is completely or substantially nitrogen and / or By being replaced with one or more other inert non-reactive gases, the delivery vehicle, formulation, pharmaceutical formulation, article of manufacture, container or device is substantially or completely oxygen-free (e.g., at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8% or 99.9% anoxic) (A) Delivery vehicle, formulation, pharmaceutical Agents, article of manufacture, container or device;
(c) the delivery vehicle, formulation, pharmaceutical preparation, article of manufacture, container or device partially simulates (creates) a substantial or complete anaerobic environment, (a) or (b) A delivery vehicle, formulation, pharmaceutical preparation, article of manufacture, container or device;
(d) The delivery vehicle of any of (a) to (c), wherein the delivery vehicle, formulation, pharmaceutical preparation, article of manufacture, container or device is manufactured, labeled or formulated for use in humans or animals. , Formulations, pharmaceutical preparations, manufactured articles, containers or devices;
(e) the animal use is for veterinary use, (d) a delivery vehicle, formulation, pharmaceutical preparation, article of manufacture, container or device;
(f) before storage or freezing, spray drying, freeze drying or lyophilization, the stabilizer or glycerol is added to the treated or untreated stool sample, the entire microflora (or substantially whole), or partly, A delivery vehicle, formulation, pharmaceutical preparation, article of manufacture, container or device of any of (a) to (e) that has been added to or mixed with substantially or completely isolated fecal flora ;
(g) the delivery vehicle, formulation, pharmaceutical preparation, article of manufacture, container or device is a solution, suspension, gel, gel tab, semi-solid, tablet, sachet, troche or capsule, or enteral Originally manufactured or formulated as a formulation, or as a solution, suspension, gel, gel tab, semi-solid, tablet, sachet, troche or capsule for final delivery, or enteral formulation A delivery vehicle, formulation, pharmaceutical preparation, article of manufacture, container or device of any of (a) to (f),
(h) by homogenizing, centrifuging and / or filtering coarse particulate matter or non-bacteria material of fecal material or by plasmapheresis, centrifugation, cell trifuge, column chromatography (e.g. affinity chromatography) The stool sample is treated such that the stool microflora is separated from the coarse particulate matter in the stool sample by immunoprecipitation (antibodies immobilized on a solid surface such as a bead or plate). A delivery vehicle, formulation, pharmaceutical preparation, article of manufacture, container or device of any of (a) to (g);
(i) the treated or untreated fecal flora, whole microflora (or substantially whole), or partially, substantially or completely isolated or purified fecal flora is lyophilized, frozen A delivery vehicle, formulation, pharmaceutical preparation, article of manufacture, container or device of any of (a) to (h), which is dry or frozen or processed into a powder;
(j) the fecal flora (e.g., including the whole (or substantially whole) microflora) is initially obtained from an individual screened or tested for disease or infection and / or the fecal flora is normal A delivery vehicle, formulation, pharmaceutical preparation, article of manufacture, container or device of any of (a) to (i) initially obtained from an individual screened as having a healthy or wild-type fecal flora population ;
(k) at least about 90%, 91%, 92%, 93%, 94%, 95%, 96% of the substantially isolated or purified fecal flora or microbiota (or substantially whole), 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8% or 99.9% isolated or pure or about 0.1%, 0.2%, 0.3%, 0.4%, 0.5 Deliver any of (including), (a) to (j), which is an isolate of fecal flora with no more than%, 0.6%, 0.7%, 0.8%, 0.9% or 1.0% non-fecal flora material Vehicle, formulation, pharmaceutical preparation, article of manufacture, container or device; or
(l) The amount of the treated or untreated stool sample, the entire microflora (or substantially the whole), or the partially, substantially or completely isolated or purified stool flora is repeated or Formulated or calibrated for multiple deliveries or infusions, where a repeat or multiple dose, delivery, infusion or implantation protocol may be used daily for the first approximately 10 days, the second Daily for about 10 days, the third includes daily and then the fourth daily, sometimes weekly infusion, and then optionally maintains the weekly infusion until the histology returns to normal. A delivery vehicle, formulation, pharmaceutical preparation, article of manufacture, container or device of any of (a) to (j) is provided.

In an alternative embodiment, the delivery vehicle, formulation, pharmaceutical formulation, article of manufacture, container or device of the invention is:
Saline, medium, antifoam, surfactant, lubricant, acid neutralizer, marker, cell marker, drug, antibiotic, contrast agent, dispersant, buffer or buffer, sweetener, debitter , Flavoring agents, pH stabilizers, acidifying agents, preservatives, desweetening agents and / or coloring agents;
At least one vitamin, mineral and / or dietary supplement (wherein the vitamin may be thiamine, riboflavin, nicotinic acid, pantothenic acid, pyridoxine, biotin, folic acid, vitamin B ₁₂ , lipoic acid, ascorbic acid, vitamin A, vitamin D, vitamin E, vitamin K, choline, carnitine and / or α, β and / or γ carotene); or prebiotic nutrients (wherein prebiotics, in some cases, fecal flora or Contains any component that stimulates the stability, growth and / or activity of fecal bacteria, or optionally polyols, fructooligosaccharides (FOS), oligofructose, inulin, galactooligosaccharides (GOS), xylooligosaccharides (XOS), Polydextrose, monosaccharide, tagatose and / or manno-oligo Further including a included).

  In an alternative embodiment, the present invention provides an article of manufacture (article) comprising a delivery vehicle, formulation, pharmaceutical preparation, product, container or device of the present invention.

In alternative embodiments, the present invention provides a treated or untreated fecal flora, whole microflora (or substantially whole), or partially, substantially or completely isolated or purified fecal bacteria. A method of making a delivery vehicle, formulation, pharmaceutical preparation, article of manufacture, container or device comprising a flora is provided, the method comprising:
(a) (i) a treated or untreated stool sample, or a composition comprising a complete or partial fecal flora, whole microflora (or substantially whole), or partly, substantially or completely simple Providing a separated or purified fecal flora; and a delivery vehicle, formulation, pharmaceutical preparation, article of manufacture, container or device;
(ii) the treated or untreated stool sample, the partially, substantially or completely isolated or purified fecal flora, the entire microflora (or substantially the whole), or the complete or partial A composition comprising fecal flora, or partially, substantially or completely isolated or purified fecal flora, is placed in said delivery vehicle, formulation, pharmaceutical formulation, article of manufacture, container or device and substantially Creating a complete or complete anoxic environment in said container or device;
(b) By incorporating a built-in or clip-on oxygen scavenging mechanism into the delivery vehicle, formulation, container or device, the delivery vehicle, formulation, pharmaceutical preparation, article of manufacture, container or device is substantially or completely And / or the delivery vehicle, formulation, pharmaceutical preparation, article of manufacture, container or device includes or is coated with an oxygen scavenging material; and / or the delivery vehicle, formulation The method of (a), wherein the air in the pharmaceutical formulation, article of manufacture, container or device is completely or substantially replaced by nitrogen and / or one or more other inert non-reactive gases;
(c) the delivery vehicle, formulation, pharmaceutical preparation, article of manufacture, container or device partially simulates (creates) a substantial or complete anaerobic environment, (a) or (b) the method of;
(d) The method of any of (a) to (c), wherein the delivery vehicle, formulation, pharmaceutical formulation, article of manufacture, container or device is manufactured, labeled or formulated for use in humans or animals;
(e) the method of (d), wherein the animal use is for veterinary use;
(f) Before storage or freeze-drying, spray-drying, freezing or freeze-drying, prebiotics, stabilizers or glycerol may be added to the treated or untreated stool sample, or partially, substantially or completely. Any of the methods (a) to (e) added to or mixed with isolated or purified fecal flora;
(g) the delivery vehicle, formulation, pharmaceutical preparation, article of manufacture, container or device is a solution, suspension, gel, gel tab, semi-solid, tablet, sachet, troche or capsule, or enteral Originally manufactured or formulated as a formulation, or as a solution, suspension, gel, gel tab, semi-solid, tablet, sachet, troche or capsule for final delivery, or enteral formulation Any of the methods of (a) to (f),
(h) homogenizing, centrifuging and / or filtering coarse particulate matter or non-bacteria material of fecal material, or plasmapheresis, centrifugation, blood cell separation, column chromatography (e.g. affinity chromatography), The stool sample is treated such that the stool microflora is separated from coarse particulate matter in the stool sample by immunoprecipitation (e.g., antibodies immobilized on a solid surface such as a bead or plate). any method from a) to (g);
(i) The treated or untreated fecal flora, or partially, substantially or completely isolated or purified fecal flora, is freeze-dried, freeze-dried or frozen or processed into a powder. Any of the methods (a) to (h);
(j) screening if said fecal flora was initially obtained from an individual screened or tested for disease or infection and / or if said fecal flora has a normal, healthy or wild type fecal flora population Any of the methods of (a) to (i), obtained initially from the treated individual; or
(k) to the treated or untreated fecal flora, or treated or untreated fecal flora (optionally the entire microflora (or substantially whole), partially, substantially or completely Isolating or purifying isolated or purified fecal flora, or a composition comprising fecal flora substantially or completely purified from non-fecal flora fecal material of the present invention, storage, freezing, freeze drying, Into liquids or solutions used for spray drying, freeze drying, transport, reconstitution and / or delivery,
Saline, medium, antifoam, surfactant, lubricant, acid neutralizer, marker, cell marker, drug, antibiotic, contrast agent, dispersant, buffer or buffer, sweetener, debitter , Flavoring agents, pH stabilizers, acidifying agents, preservatives, desweetening agents and / or coloring agents, and / or at least one vitamin, mineral and / or dietary supplement (where vitamins are sometimes , Thiamine, riboflavin, nicotinic acid, pantothenic acid, pyridoxine, biotin, folic acid, vitamin B ₁₂ , lipoic acid, ascorbic acid, vitamin A, vitamin D, vitamin E, vitamin K, choline, carnitine and / or α, β and / Or containing γ-carotene), and / or prebiotic nutrients (wherein prebiotics are, in some cases, fecal flora or fecal bacterial stability, growth And / or any component that stimulates activity, or optionally polyol, fructooligosaccharide (FOS), oligofructose, inulin, galactooligosaccharide (GOS), xylooligosaccharide (XOS), polydextrose, monosaccharide, tagatose And / or (including a manno-oligosaccharide).
(l) at least about 90%, 91%, 92%, 93%, 94%, 95%, 96% of the whole microflora (or substantially whole), substantially isolated or purified fecal flora, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8% or 99.9% isolated or pure or about 0.1%, 0.2%, 0.3%, 0.4%, 0.5 Any of (a) to (k), which is an isolate of fecal flora having non-fecal flora material of no more than%, 0.6%, 0.7%, 0.8%, 0.9% or 1.0% ; Or
(m) repetitive amounts of the entire microflora (or substantially whole), the treated or untreated faecal sample, or the partially, substantially or completely isolated or purified fecal flora Or formulated or calibrated for multiple deliveries or infusions, where a repeat or multiple dose, delivery, infusion or implantation protocol may be administered daily for the first approximately 10 days, the second Includes daily infusions for about 10 days, 3rd daily, then 4th daily, and sometimes weekly, and then weekly infusions are maintained for more than 2nd until the histology returns to normal , (A) to (l).

  In alternative embodiments, the present invention improves, stabilizes, treats and / or prevents infections, diseases, treatments, addictions or conditions with intestinal dysfunction elements or side effects, or improves, stabilizes, treats constipation And / or prevent, abdominal pain, non-specific abdominal pain or diarrhea, drug side effects or psychological conditions or Crohn's disease, diarrhea caused by toxins, toxins or infections, toxin-mediated traveler diarrhea or Clostridium or C. perfringens -Providing a method of treating pseudomembranous colitis associated with Welch or C. difficile infection or Clostridium infection, the method comprising providing an individual in need thereof a delivery vehicle, formulation, pharmaceutical formulation, article of manufacture of the present invention. Administering a container or device or a product (article) of the invention.

  In an alternative embodiment, the present invention provides a method for ameliorating, stabilizing, treating and / or preventing an infection, disease, treatment, addiction or condition having an intestinal dysfunction element or side effect, the method comprising: Administering to the individual in need the delivery vehicle, formulation, pharmaceutical preparation, article of manufacture, container or device of the invention or the article of manufacture (article) or the contents thereof (e.g. the bacterial flora contained therein). Including.

In an alternative embodiment, the amount of the treated or untreated stool sample, or the partially, substantially or completely isolated or purified stool flora, for repeated or multiple delivery or infusion Or deliver the partially, substantially or completely isolated or purified fecal flora in repeated or multiple infusions,
Here, in some cases, repeated or multiple administration, delivery, infusion or transplantation protocols are performed daily for the first 10 days, daily for the second time for about 10 days, daily for the third time, and then daily for the fourth time. In some cases, weekly infusions are included, and then weekly infusions are maintained for a second or more times, optionally until histology returns to normal.

In an alternative embodiment of the method, the infection, disease, treatment, addiction or condition having an intestinal dysfunction component or side effect is inflammatory bowel disease (IBD), Crohn's disease, hepatic encephalopathy, enteritis, colitis, irritable bowel Syndrome (IBS), fibromyalgia (FM), chronic fatigue syndrome (CFS), depression, attention deficit / hyperactivity disorder (ADHD), multiple sclerosis (MS), systemic lupus erythematosus (SLE), traveler Diarrhea, small intestinal bacterial overgrowth, chronic pancreatitis, pancreatic insufficiency, exposure to toxins or toxins or infection, toxin-borne traveler diarrhea, poisoning, pseudomembranous colitis, Clostridium infection, C. perfringens-welch or Clostridium difficile Infections, neurological conditions, Parkinson's disease, myoclonus dystonia, autism, amyotrophic lateral sclerosis, multiple sclerosis, major or minor seizures. In an alternative embodiment, the amount of the treated or untreated stool sample, or the partially, substantially or completely isolated or purified stool flora, for repeated or multiple delivery or infusion Or deliver said treated or untreated stool sample, or said partially, substantially or completely isolated or purified stool flora in repeated or multiple injections But,
Here, in some cases, repeated or multiple administration, delivery, infusion or transplantation protocols are performed daily for the first 10 days, daily for the second time for about 10 days, daily for the third time, and then daily for the fourth time. In some cases, weekly infusions are included, and then weekly infusions are maintained for a second or more times, optionally until histology returns to normal.

In an alternative embodiment, the present invention provides a delivery vehicle, formulation, pharmaceutical formulation, article of manufacture, container or device comprising:
(a) substantially or completely purified from whole (or substantially whole) microbiota, partially, substantially or completely isolated or purified fecal flora, or non-fecal flora faecal material A composition further comprising an additive or fluid, saline, buffer, buffer or medium or fluid-glucose-cellobiose agar (RGCA) medium;
(b) The composition, container or device, formulation or article of manufacture of (a), wherein the entire microflora (or substantially the whole), or the fecal flora is isolated or purified from human or animal fecal material ;
(c) the entire microbiota (or substantially whole), or fecal flora, is isolated or purified using a method or protocol that includes the use of a centrifuge, blood cell separator, column or immunoaffinity column. Or by a method comprising homogenizing, centrifuging and / or filtering coarse particulate matter or non-bacteria material of fecal material or by plasmapheresis, centrifugation, blood cell separation, column chromatography (e.g. affinity The whole microflora (or substantially whole) or the fecal flora is isolated or purified by chromatography), immunoprecipitation (e.g. antibodies immobilized on a solid surface such as beads or plates), (a ) Or (b) composition, container or device, formulation or article of manufacture;
(d) the whole microflora (or substantially whole), or the fecal flora substantially or completely isolated or purified, or the fecal bacteria substantially or completely purified from non-fecal flora faecal material The composition, container or device, formulation or article of manufacture of any of (a) to (c), wherein the flora is in a substantial or complete anoxic environment in the composition, container or device, preparation or article of manufacture;
(e) the incorporation of a built-in or clip-on oxygen scavenging mechanism into the delivery vehicle, formulation, pharmaceutical formulation, product, container or device substantially converts the composition, container or device, formulation or article of manufacture; And / or the delivery vehicle, formulation, container or device includes or is coated with an oxygen scavenging material; and / or the delivery vehicle, formulation, container or The delivery vehicle, formulation, container or device of (d), wherein the air in the device is completely or substantially replaced by nitrogen and / or one or more other inert non-reactive gases;
(f) Whole microbiota (or substantially whole), substantially or completely isolated or purified fecal flora, or fecal flora substantially or completely purified from non-fecal flora faecal material Is in a substantial or complete anaerobic environment, a composition, container or device, formulation or article of manufacture of any of (a) to (c);
(g) The composition, container or device, formulation of any of (a) to (f), wherein said delivery vehicle, formulation, container or device is manufactured, labeled or formulated for use in humans or animals Or manufactured goods;
(h) the animal use is for veterinary use, the composition, container or device, formulation or article of manufacture of (g);
(i) Before storage or freezing, freeze-drying, spray-drying or freeze-drying, the stabilizer or glycerol is isolated from the whole (or substantially whole) microbial flora, or said partly, substantially or completely. (A) to (h) added to or mixed with a composition comprising purified fecal flora, or non-fecal flora faecal flora substantially or completely purified from fecal material Any composition, container or device, formulation or article of manufacture;
(j) the composition, container or device, formulation or article of manufacture initially as a solution, suspension, gel, gel tab, semi-solid, tablet, sachet, troche or capsule, or as an enteral formulation Manufactured or formulated into, or re-formulated as a solution, suspension, gel, gel tab, semi-solid, tablet, sachet, troche or capsule for final delivery, or as an enteral formulation A composition, container or device, formulation or article of manufacture of any of (a) to (f);
(k) the entire microflora (or substantially the whole), or the partially, substantially or completely isolated or purified fecal flora, or substantially or completely from non-faecal flora fecal material The composition, container or device, formulation or manufactured article of any of (a) to (j), wherein the composition containing the purified fecal flora is freeze-dried, freeze-dried or frozen in powder form;
(l) the entire microbiota (or substantially whole), or the fecal flora initially obtained from an individual screened or tested for disease or infection, and / or the whole microflora (or substantially whole) Or a composition, container or any of (a) to (k), wherein the fecal flora is initially obtained from an individual screened as having a normal, healthy or wild-type fecal flora population Device, formulation or article of manufacture; or
(m) substantially or completely purified from whole (or substantially whole) microflora, said partially, substantially or completely isolated or purified fecal flora, or non-fecal flora faecal material To isolate or purify, store, freeze, freeze-dry, spray-dry, lyophilize, transport, reconstitute and / or deliver the treated or untreated faecal flora to a composition comprising the treated fecal flora To liquid or solution used for:
Saline, medium, antifoam, surfactant, lubricant, acid neutralizer, marker, cell marker, drug, antibiotic, contrast agent, dispersant, buffer or buffer, sweetener, debitter , Flavoring agents, pH stabilizers, acidifying agents, preservatives, desweetening agents and / or coloring agents, and / or at least one vitamin, mineral and / or dietary supplement (where vitamins are sometimes , Thiamine, riboflavin, nicotinic acid, pantothenic acid, pyridoxine, biotin, folic acid, vitamin B ₁₂ , lipoic acid, ascorbic acid, vitamin A, vitamin D, vitamin E, vitamin K, choline, carnitine and / or α, β and / Or γ-carotene), and / or prebiotic nutrients (wherein prebiotics may, in some cases, be the entire microflora (or substantially whole), fecal details Contains any ingredient that stimulates the stability, growth and / or activity of the flora or fecal bacteria, or optionally polyols, fructooligosaccharides (FOS), oligofructose, inulin, galactooligosaccharides (GOS), xylooligosaccharides ( XOS), polydextrose, monosaccharides, tagatose and / or manno-oligosaccharides), the composition, container or device, formulation or article of manufacture of any of (a) to (l);
(n) substantially isolated or purified fecal flora is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5 %, 99.6%, 99.7%, 99.8% or 99.9% isolated or pure or about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8% Any of (a) to (m), including (or including) an entire microflora (or substantially the entire) microflora having 0.9% or 1.0% or less non-fecal flora material A composition, container or device, formulation or article of manufacture; or
(o) repeated amount of the entire microflora (or substantially whole), the treated or untreated faecal sample, or the partially, substantially or completely isolated or purified fecal flora Or formulated or calibrated for multiple deliveries or infusions, where a repeat or multiple dose, delivery, infusion or implantation protocol may be administered daily for the first approximately 10 days, the second Includes daily infusions for about 10 days, 3rd daily, then 4th daily, and sometimes weekly, and then weekly infusions are maintained for more than 2nd until the histology returns to normal , (A) to (l) composition, container or device, formulation or article of manufacture.

  In an alternative embodiment, the present invention provides a method for ameliorating, stabilizing, treating and / or preventing an infection, disease, treatment, addiction or condition having an intestinal dysfunction element or side effect, the method comprising: Administering to the individual in need the composition, container or device, formulation or article of manufacture of the present invention.

  In an alternative embodiment of the method, the infection, disease, treatment, addiction or condition having an intestinal dysfunction component or side effect is inflammatory bowel disease (IBD), Crohn's disease, hepatic encephalopathy, enteritis, colitis, irritable bowel Syndrome (IBS), fibromyalgia (FM), chronic fatigue syndrome (CFS), depression, attention deficit / hyperactivity disorder (ADHD), multiple sclerosis (MS), systemic lupus erythematosus (SLE), traveler Diarrhea, small intestinal bacterial overgrowth, chronic pancreatitis, pancreatic insufficiency, exposure to toxins or toxins or infection, toxin-borne traveler diarrhea, poisoning, pseudomembranous colitis, Clostridium infection, C. perfringens-welch or Clostridium difficile Infections, neurological conditions, Parkinson's disease, myoclonus dystonia, autism, amyotrophic lateral sclerosis, multiple sclerosis, major or minor seizures.

In an alternative embodiment, the invention provides a method of ameliorating, stabilizing, treating and / or preventing an infection, disease, treatment, addiction or condition having an intestinal dysfunction element or side effect or a method of reducing or delaying its symptoms, Or methods for improving, treating and / or preventing constipation, abdominal pain, non-specific abdominal pain or diarrhea, drug side effects or psychological conditions or Crohn's disease, diarrhea caused by toxins, toxins or infections, toxin-mediated traveler's diarrhea or Clostridium Or a method of treating pseudomembranous colitis associated with C. perfringens-Welch or C. difficile infection or Clostridial infection or spondyloarthritis, spondyloarthritis or sacroiliac (inflammation of one or both sacroiliac joints) ; Nephritic syndrome; lupus, irritable bowel syndrome (IBS or colonic cramps) or ulcerative colitis or clotting Inflammatory or autoimmune conditions with intestinal or intestinal components such as colitis, such as colon colitis; constipation, autism; amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) or Parkinson's disease Degenerative neurological diseases such as (PD); Myoclonus dystonia (e.g. Steinert disease or proximal myotonic myopathy); Autoimmune diseases such as rheumatoid arthritis (RA) or juvenile idiopathic arthritis (JIA); Chronic fatigue syndrome (Including benign myalgic encephalomyelitis, chronic fatigue immune dysfunction syndrome, chronic infectious mononucleosis, epidemic myalgic encephalomyelitis); obesity; hypoglycemia, prediabetic syndrome, type I diabetes or Type II diabetes; idiopathic thrombocytopenic purpura (ITP); acute or chronic allergic reactions such as rash, rash, urticaria or chronic urticaria; and / or insomnia or chronic insomnia, major seizures or minor seizures Prevents convulsions, reduces or delays symptoms Provides a method of improving, stabilizing or treating an individual (e.g., a patient or animal) having or having:
Administering the delivery vehicle, formulation, pharmaceutical preparation, article of manufacture, container or device of the invention or the article of manufacture (article) of the invention in a single, repeated or multiple doses, delivery or infusion to an individual in need thereof Including the steps of:

In alternative embodiments, the amount of whole microflora (or substantially whole), the treated or untreated faecal sample, or the partially, substantially or completely isolated or purified fecal flora Are formulated or calibrated for repeated or multiple delivery or infusion; or the entire microflora (or substantially whole), the treated or untreated stool sample, or the partially, substantially Delivering fecal flora in full or fully isolated or purified, with repeated or multiple injections,
Here, in some cases, repeated or multiple administration, delivery, infusion or transplantation protocols are performed daily for the first 10 days, daily for the second time for about 10 days, daily for the third time, and then daily for the fourth time. In some cases, weekly infusions are included, and then weekly infusions are maintained for a second or more times, optionally until histology returns to normal.

In an alternative embodiment, the present invention provides a device for delivering the composition (including the flora) or the entire microflora (or substantially the entire) of the present invention, or fecal material, the device:
(a) the device illustrated in FIG. 1 or FIG. 2 or an equivalent thereof; or
(b) (1) A bag or container comprising an outlet opening operatively connected to the proximal end of a flexible tube or equivalent
(Wherein the bag or container optionally comprises a gas or oxygen impermeable material,
In some cases, the bag or container is made of a soft material or a material comprising a polyethylene terephthalate polyester film (or including MYLARTM),
In some cases, the bag or container is an (IV-like) intravenous-like bag,
In some cases, the bag or container has an attachment that allows the bag to be suspended from a stand, e.g., installed / suspended on an endoscope,
In some cases, the bag or container is operatively connected to a negative pressure device capable of removing all gas or air from the bag via an on-off valve or equivalent,
In some cases, the bag or container is operatively connected to a fluid supply or storage container for flushing the bag via an outlet opening, via an on-off valve or equivalent, and optionally the fluid The source or storage container is under positive pressure,
In some cases, the flexible tube or equivalent has at least one clip or closure valve or back to prevent backwashing of material from the distal portion to the proximal portion of the tube, or after the tube into the bag or container. Including stop valves);
(2) Open / close valve or equivalent or obturator screw top at the distal end of a flexible tube or equivalent, and optionally a luer lock tip (here) for attachment to a colonoscope or endoscope luer lock port or equivalent In some cases, the luer lock tip is either integrated into the valve or separate from the valve), and in some cases, the enema tube tip for attachment to the enema tube or device or equivalent (where, optionally The enema tube tip is either integrated into the valve or separate from the valve, possibly closing the distal opening when the valve or luer lock tip or enema tip is removed (removed) under pressure Further comprising a safety device or safety clip to); and
(3) A pump or manual pump for moving material in the bag or container from the distal end or from the open / close valve or equivalent through the flexible tube or equivalent; or
(c) the device of (a) or (b) further comprising fecal material or a composition of the present invention.

  In alternative embodiments, the present invention provides for the entire microflora (or substantially whole), or treated or untreated fecal flora, or partially, substantially or completely isolated fecal flora. Or a composition of the invention (e.g., substantially from whole (or substantially whole) microflora, partially, substantially or completely isolated or purified fecal flora, or non-fecal flora faecal material. Or a formulation comprising a composition comprising a fully purified fecal flora), optionally an additive or fluid, saline, buffer, buffer or medium or fluid-glucose-cellobiose agar (RGCA) medium Wherein the bag or container is structurally the same as or different from the bag or container of the device of the present invention (e.g., as illustrated in FIG. 1 or FIG. 2). It is similar, in some cases, the interior of the bag, or a substantial or complete anoxic environment, or internal bag is similar to a substantial or complete anaerobic environment.

  In alternative embodiments, a specific anti-C. Difficile oral antibody (e.g., a chicken) is a composition of the invention (e.g., a partially, substantially or completely isolated or purified fecal flora, or non-fecal bacteria). To isolate or purify, store, freeze, freeze-dry, spray-dry, lyophilize, transport, reconstitute and / or deliver a composition comprising a faecal flora substantially or completely purified from flora fecal material Can be added to the solution used (eg saline, medium, buffer). The combination of the product with these specific anti-C. Difficile oral antibodies enhances the eradication mechanism of the product.

  The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.

  All publications, patents and patent publications mentioned in this specification are hereby expressly incorporated by reference for all purposes.

  The drawings presented herein are illustrative of embodiments of the invention and are not intended to limit the scope of the invention as encompassed by the claims.

FIG. 2 illustrates an exemplary storage device of the present invention as described below. FIG. 2 illustrates an exemplary delivery device of the present invention as described below. FIG. 2 illustrates an exemplary delivery device of the present invention.

  Like reference symbols in the various drawings indicate like elements. Reference will now be made in detail to various exemplary embodiments of the invention, examples of which are illustrated in the accompanying drawings. The following detailed description is provided to give the reader a better understanding of certain details of aspects and embodiments of the invention and should be construed as limiting the scope of the invention. is not.

  In alternative embodiments, the present invention provides compositions comprising treated and / or isolated fecal material for fecal flora transplantation, such as formulations and pharmaceutical preparations, articles of manufacture and containers and delivery vehicles and devices and delivery materials. provide. In one embodiment, the treated and / or isolated fecal material of the invention comprising a fecal flora (eg, bacteria) is transplanted between different individuals, eg, between humans or between animals. In one embodiment, the treated fecal material of the invention is transplanted back into the same individual from which it was collected, e.g. after drug treatment (e.g. antibiotic treatment or chemotherapy), or gastrointestinal (e.g. including the colon) ( GI) Re-growth in the colon after standing irrigation to induce tube swallowing (eg lavage).

  The present invention provides a method of ameliorating, stabilizing or treating bowel disease or infection, the method comprising a delivery vehicle, formulation, article of manufacture or container or device of the present invention; e.g. fecal bacterial formulation therapy, fecal infusion, Using as a fecal transplant or human probiotic infusion (HPI). In alternative embodiments, the present invention provides for any infection, bowel disease or condition with intestinal dysfunction, such as addiction, pseudomembranous colitis, Clostridium difficile infection, inflammatory bowel disease (IBD), Crohn's disease, liver Encephalopathy, enteritis, colitis, irritable bowel syndrome (IBS), fibromyalgia (FM), chronic fatigue syndrome (CFS), depression, attention deficit / hyperactivity disorder (ADHD), multiple sclerosis (MS) ), Systemic lupus erythematosus (SLE), traveler diarrhea, small intestinal bacterial overgrowth, chronic pancreatitis or pancreatic insufficiency, methods of improving, stabilizing, treating or preventing.

  For example, in one embodiment, the antibiotic does not eradicate C. difficile and its spores, so that a delivery vehicle, formulation, article of manufacture or container or device of the invention comprising treated and / or isolated fecal flora is infected or Injection into the colon of a diseased individual, such as a patient or animal, can ameliorate, stabilize or eradicate C. difficile (or pseudomembranous colitis associated with this infection). In an alternative embodiment, the fecal flora obtained from the donor (in treated or isolated form is an alternative embodiment in the delivery vehicle, formulation, article of manufacture or container or device of the invention). Lacking or inappropriate (eg in number or function) of an infected or diseased recipient, including part, substantially all or all of the fecal flora, eg bacteria. Although the present invention is not limited by any particular mechanism of action, in some embodiments it is from donor to recipient that ameliorates or eradicate infection or pseudomembranous colitis associated with this infection. Transfer of part, substantially all or all equivalents of the fecal flora of an infected individual (eg, from person to person).

  In alternative embodiments, the compositions, such as formulations and pharmaceutical preparations and devices, delivery materials, delivery vehicles, articles of manufacture, containers and devices of the invention require that of the fecal flora (e.g., human flora) component. Can be safely transplanted into an individual, such as an infected, diseased, dying patient, thus providing a consistently safe and still functional bacterial flora for delivery to a recipient or patient.

  In an alternative embodiment, the present invention provides a reliable method for producing a standardized fresh fecal flora that may have a long shelf life. For example, in one embodiment, a delivery vehicle, formulation, pharmaceutical formulation, article of manufacture, container, or device that includes the fecal flora comprises a substantial or complete anoxic environment. In other embodiments, nutrients such as "prebiotic nutrients" (e.g., in dry or liquid form) are prepared from the composition of the invention (e.g., partially, substantially or completely isolated or purified feces). Isolating or purifying, storing, freezing, freeze-drying, spray-drying, freeze-drying, transporting, re-examining the flora, or the composition containing fecal flora substantially or completely purified from non-fecal flora faecal material It can be added to the solution (eg, saline, media, buffer) used to make up and / or deliver. Prebiotic nutrients may be any component that stimulates fecal flora, such as bacterial stability, growth and / or activity; for example, in alternative embodiments, polyols, fructooligosaccharides (FOS), oligofructose, Monosaccharides and / or manno-oligosaccharides such as inulin, galactooligosaccharide (GOS), xylo-oligosaccharide (XOS), polydextrose, tagatose are used as prebiotics for practicing the present invention. In one embodiment, prebiotics are added to prevent “shock” against fecal flora after its isolation or purification, freezing, freeze drying, spray drying, reconstitution in solution, and the like.

  In alternative embodiments, the compositions of the invention, such as delivery vehicles, formulations and pharmaceutical formulations, articles of manufacture or containers or devices, improve C. difficile infection and / or pseudomembranous colitis associated with this infection, for example. And / or contains a large number (e.g., substantially whole) of microbial flora (or substantially whole), or many Bacteroides and / or Firmicutes (e.g., normally found in situ). A high proportion of Bacteroides and / or Fermicutes are present). In alternative embodiments, the compositions of the invention, e.g., delivery vehicles, formulations and pharmaceutical preparations, articles of manufacture or containers or devices, treat colitis (e.g., C. difficile infected pseudomembranous colitis) and constipation. May be available (eg, formulated and / or dosed) for repeated use in individuals having more difficult conditions, such as in patients or animals.

  In an alternative embodiment, the composition of the present invention, e.g., delivery vehicle, formulation and pharmaceutical formulation, article of manufacture or container or device, is selected from a selected bacterial species, e.g., Bacteroides, Pharmicutes, Bacillus-Slingi. Including Bacillus thuringiensis (a bacterium capable of producing a peptide antibiotic against C. difficile). Bacterial species can be isolated by blood cell separation or plasmapheresis.

  In an alternative embodiment, a selected bacterial species, such as Bacteroides, Fermicutes, Bacillus thuringiensis, is added to the composition, such as a delivery vehicle, formulation and pharmaceutical formulation, article of manufacture or container or device, bacteria Can be added as an enriched concentration with bacterial species to contain the wild type.

  In an alternative embodiment, the composition of the present invention is administered in a beverage for oral delivery (e.g., milk) as a stool slurry, saline or buffer suspension (e.g., for an enema suspended in buffer or saline). , Yogurt, shake, flavored beverage or equivalent).

  In alternative embodiments, the compositions of the present invention involve enema products, spray-dried products, reconstituted enemas, small capsule products, small capsule products suitable for administration to children, valve syringes, saline additions Appropriate carrier media such as valve syringes, powder products, powder products in oxygen-deficient sachets suitable for household enema, eg powder products in oxygen-deficient sachets that can be added to valve syringes or enemas or yogurt or milk It can be attached to a provided container and can be formulated, for example, as a spray-dried product in a device that can be directly incorporated and delivered as a child's medication.

  In one embodiment, the composition of the present invention can be delivered directly to the carrier medium via a screw top lid, where fecal material is suspended from the lid, and twisting the lid into the carrier medium. It is released straight.

  In an alternative embodiment, the method of delivering a composition of the invention comprises a beverage (e.g., milk, yogurt, flavored beverage, etc.) via the enema suspended in saline or buffer to the intestine. Includes the use of fecal slurries orally in, via small intestinal infusion via the nasoduodenal tube, via gastrostomy, or by using a colonoscope. In some embodiments, it may be advantageous to deliver via a colonoscope to inject as close as possible to any colon pathology and detect it.

  In an alternative embodiment, the fecal flora used in the methods, compositions and methods of the invention is initially obtained (in whole or in part) from individuals screened or tested for disease or infection, and / or The fecal flora is a normal, healthy, or normal representative "wild-type" fecal flora population; for example, other fecal bacteria such as Bacteroides and / or Fermicutes and / or Bacillus thuringiensis Initially obtained from individuals screened as having normal complement of the flora. In one embodiment, one or more additional (or “complementary”) depending on the deficiency of the bacterial flora (e.g., bacterial) species or species (s) in the donor fecal material or to achieve the desired effect. )) Species, such as Bacteroides, Fermicutes and / or Bacillus thuringiensis species, are added to (or administered with) the product to be delivered at the beginning of the product or at the time of delivery. ), E.g., before administering one or more additional species to an individual (e.g., patient or animal), e.g., when reconstituting a powder, lyophilizate or lyophilized composition for delivery; Alternatively, one or more additional (or “complementary”) species can be co-administered. These additional bacterial flora can be isolated or purified directly from the donor, or can be temporarily expanded (cultured) in vitro prior to addition, or from a pure culture, for example from an ATTC stock. May be derived. For example, some applications use delivery of increased amounts of one or more fecal flora (e.g., bacterial) species, e.g., to achieve a desired effect or therapeutic result, e.g., a product (e.g., a microorganism) Isolate whole phase (or substantially whole), or a composition containing complete or partial fecal flora, or partially, substantially or fully isolated or purified fecal flora) directly from a donor One or more additional (or “supplemental”) species, such as Bacteroides, Pharmicutes and / or Bacillus thuringiensis, which may be prepared from a pure culture, etc. Strengthen (spike).

  In some embodiments, donor selection is very important, eg, to avoid infecting the recipient with another infection or disease. In alternative embodiments, depending on the type of donor and recipient, e.g. human or animal, the donor is at least e.g. retrovirus (e.g. human immunodeficiency virus, HIV); hepatitis A, B, and / or C; cytomegalovirus Test (screen) for Epstein-Barr virus, detectable parasites and / or bacterial pathogens.

  In an alternative embodiment, the present invention provides a fecal flora for transplantation (e.g., the entire biota (or substantially the entire)) that initially includes collection from one or more healthy (e.g., screened) donors. A method of preparing In an alternative embodiment, fresh stool is transported through the stool collection device of the present invention, which in one embodiment includes a suitable container that is suitably oxygen-free (or substantially oxygen-free). An exemplary suitable stool collection device 1 is shown in FIG. 1A. FIG. 1A shows an exemplary container of the present invention containing feces and including a slot 2 for receiving feces. The container can then be placed in bag 3, suitably a disposable leak-proof ziplock / sealing bag.

  In alternative embodiments, the container can be rendered oxygen-free, for example, by incorporating a built-in or clip-on oxygen scavenging mechanism, such as, for example, oxygen scavenging pellets described in US Pat. No. 7,541,091. In other embodiments, the container itself uses an oxygen scavenging material, such as purified and modified layered clay, as an oxygen scavenging iron-performance enhancing support; active iron is dispersed directly in the polymer, such as 02BLOCKTM or equivalent. Manufactured by oxygen scavenging iron, described by In one embodiment, for example, having one or more unsaturated olefinic homopolymers or copolymers; one or more polyamide homopolymers or copolymers; one or more polyethylene terephthalate homopolymers or copolymers; oxygen scavenging activity Use an oxygen scavenging polymer to manufacture the container itself, or to coat the container or to add as pellets, as described in U.S. Patent Application Publication No. 20110045222, which describes a polymer blend exhibiting To do. In one embodiment, for example, a United States describing composition comprising a polyether segment comprising a polyester, a copolyester ether and an oxidation catalyst, wherein the copolyester ether comprises a poly (tetramethylene-co-alkylene ether). As described in patent application publication number 20110008554, oxygen scavenging polymers are used to manufacture the container itself, or to coat the container or add it as pellets. In one embodiment, is the container itself manufactured, for example as described in US 201000255231 which describes an oxygen scavenging film having dispersed iron / salt particles and oxygen scavenging particulates in a polymer matrix? Or oxygen scavenging polymer is used to coat the container or to add as pellets.

  Alternatively, in addition to or in lieu of the oxygen scavenging mechanism, the air in the container is replaced (fully or substantially) with nitrogen and / or other inert non-reactive gas or gases. In an alternative embodiment, the container partially simulates (creates) an anaerobic environment.

  In an alternative embodiment, stool (eg, stool sample) is held in an aesthetically acceptable container that does not leak or smell and still maintains an anaerobic environment. In an alternative embodiment, the container is sterile before receiving the fecal flora.

  In an alternative embodiment, the container is kept below room temperature and refrigerated during most or all of its preparation, transport and / or storage, for example, in a “fecal bank” or at the site of implantation. For example, once delivered to a “processed stool bank”, store in a cold room, cryocontainer or refrigerator to minimize bacterial flora metabolism. In an alternative embodiment, freezing is not performed to prevent destruction of fecal bacterial cells.

  In an alternative embodiment, a stabilizer such as glycerol is added to the material to be collected and / or stored. In one embodiment, the stool is rapidly frozen with liquid nitrogen or any similar coolant so that it can be stored for an extended period of time, for example while waiting for processing.

  In an alternative embodiment, the stool is tested for various pathogens as described above. In an alternative embodiment, once cleared for the infectious agent, it is homogenized and filtered to remove large particles of material. In an alternative embodiment, it is subdivided to the desired volume, for example it may be between 5cc and 3 liters or more. For example, in one embodiment, the container contains 50 grams (g) of stool that may be held in a suitable oxygen resistant plastic, such as a metal coated polyethylene terephthalate polyester film or metal coated MYLAR ™.

  In an alternative embodiment, as shown in FIG.1B, an exemplary therapeutic vehicle (delivery system) 10 and device in which fecal material is retained includes, for example, a manual pump 12 attached to the set. Intravenous (IV-like) donor set 11 provided. Suitably, the bag 11 is a metallized MYLAR ™ that is gas impermeable. When the entire tube of the device is attached to the colonoscopic biopsy channel by the luer lock mechanism 13, the manual pump 12 can easily pump forward the contents of the liquefied feces on top of the plastic device. In this way, a colonoscope or enteroscope will also be the delivery mechanism. In this embodiment, it will typically be placed at any distance to the colon and otherwise into the cecum. In an alternative embodiment, the material is placed above the terminal ileum or, if desired, higher. In an alternative embodiment, this can be injected into the duodenum or lower using an enteroscope. In an alternative embodiment, C. difficile (or pseudomembranous colitis associated with this infection) is ameliorated or eradicated with an injected stool sample or treated stool.

  Another alternative embodiment is shown in FIG. In this embodiment, the therapeutic vehicle / delivery system 20 includes an IV-like bag 21 containing saline (NaCl) 22 and feces / cells 23 of the present invention. In addition to the manual pump 24 and the luer lock 25, the delivery system includes an enema tip 28 with a flushing port 26 (to flush the bag), a clip 27 (to prevent backwash) and a luer lock attachment.

  In an alternative embodiment, the graft material is homogenized and clothed. In alternative embodiments, the treated material can be attached to a container, such as a nasogastric tube or nasoduodenal tube, and the contents can be placed in a bag that can be injected into the stomach, duodenum, or distal jejunum . Alternatively, it can be held in a container, for example a bag that can be attached to an enema tip prepared as an enema.

  In an alternative embodiment, the stool can be homogenized and filtered from coarse particulate matter to produce a stable product that can be separated, frozen or lyophilized and have a long shelf life. Can do. In an alternative embodiment, the microscopic fibers / non-viable material is then separated from the bacteria. Several methods can be used including, for example, repeated filtration using filter sizes that are reduced to the size of bacteria, for example.

  In one embodiment, various filters are used to isolate bacterial species. This is used in WO2011 / 033310A1 by Williams, which uses inferior techniques of filtration with gauze, for example, and inferior to the technique of the present invention to obtain purified bacteria using filtration membranes of various sizes. It is different from the existing technology.

  In one embodiment, a filtration procedure for filtering the entire stool is suitably used to achieve a maximum concentration of approximately 100% bacteria. In one embodiment, the filtration procedure is a two-step procedure that suitably uses a glass fiber depth filter for initial clarification. In one embodiment, stool is filtered under positive pressure. In one embodiment, this would use a combination or sandwich arrangement with a 30 micron PVDF filter. In one embodiment, the sandwich procedure filters the product under positive pressure. Later, in one embodiment, membrane concentration can be used as another step to reduce filtrate volume. In one embodiment, this can be done under a nitrogen cover prior to freeze drying or spray drying.

  Other membranes that can be used for filtration include, but are not limited to, nylon filters, cellulose nitrate filters, PES filters, Teflon filters, mixed cellulose ester filters, polycarbonate filters, polypropylene filters, PVC filters or quartz filters are included. A variety of these combinations can be used to obtain high purity bacteria from which solids and liquids have been removed that are ready for freezing, spray drying or lyophilization.

  Due to freezing, in an alternative embodiment, the bacteria are kept in a liquid to prevent the cells from rupturing upon thawing. This may include various stabilizers such as glycerol and a suitable buffer and / or ethylene glycol. In an alternative embodiment, cryo-protectance uses a final concentration of stabilizer between about 20% and 60%, depending on the stabilizer used; this is otherwise protein structure It helps to stabilize the protein by preventing the formation of ice crystals that would destroy it.

  In alternative embodiments, stabilizers that help reduce the destruction of living bacteria include skim milk, erythritol, arabitol, sorbitol, glucose, fructose and other polyols. Polymers such as dextran and polyethylene glycol can also be used to stabilize fecal bacterial cells.

  By mixing the appropriate amount of bacterial flora with the stabilizer, it can be snap-frozen and kept frozen in the container used to transport it to the appropriate facility to be injected into the patient after thawing. Is possible.

  In alternative embodiments, can the whole microflora (or substantially whole), or isolated and / or treated (e.g., purified or isolated) fecal material and / or bacterial flora be lyophilized or freeze dried? Or the product can be frozen. In an alternative embodiment, freeze drying can produce a powdered form of the product that allows most of the cells to remain viable and can be gently micronized into a powder. The powder or lyophilized or freeze-dried bacterial flora or isolate is then encapsulated into a carrier, such as a tablet, gel tab, pill or capsule, such as an enteric coated capsule, or digestion Can be placed in oil-filled capsules. Alternatively, prior to delivery of the freeze-dried or lyophilized product or powder to an individual, for example, a fluid such as a sterile fluid such as saline, buffer or a medium such as fluid-glucose-cellobiose agar (RGCA) medium. Can be reconfigured in.

  In alternative embodiments, the entire microflora (or substantially the entire), or isolated and / or treated (eg, purified or isolated) fecal material and / or flora can be spray dried. In one embodiment, spray drying is preferred over freeze drying or freeze drying.

  In alternative embodiments, the whole microflora (or substantially the whole), or isolated and / or treated fecal material and / or flora, wild type derived from normal animal (e.g. human) flora Bacteria and / or recombinantly treated bacteria, such as recombinant microorganisms capable of synthesizing proteins, small molecules or carbohydrates with self-defense or ameliorating effects; or given an appropriate signal, such as a chemical delivered by digestion Supplements recombinant microorganisms that can self-destruct.

  In an alternative embodiment, the transplant product (e.g., an isolated or purified fecal flora or composition of the invention comprising the entire (or substantially whole) microflora) is injected by injection, e.g., via the rectum, colostomy. Or from the upper gastrointestinal (Gl) tract or delivered in suppository pills, tablets or encapsulated forms, for example enteric coated graded release capsules or tablets, for example with additives Can be used. In an alternative embodiment, the transplant product is administered as a suppository to obtain a high concentration in the rectum.

  In one embodiment, before, during, and / or after delivery of the transplanted product (e.g., a composition of the invention comprising isolated or purified fecal flora or whole microbiota (or substantially whole)) to an individual. Or in a medium such as a fluid, eg, a sterile fluid such as saline, buffer, or a fluid-glucose-cellobiose agar (RGCA) medium for delivery or during.

  In alternative embodiments, the compositions and methods of the present invention are used to vary various gastrointestinal conditions such as C. difficile infection, C. perfringens-welch and other Clostridium infections, irritable bowel syndrome, constipation, ileum Cystitis, Crohn's disease and microscopic colitis; Improve and stabilize neurological conditions such as Parkinson's disease, myoclonus dystonia, autism, amyotrophic lateral sclerosis and multiple sclerosis, major or minor seizures Prevent, and / or treat. In one embodiment, the neurological condition is treated by encapsulation or frozen material. In an alternative embodiment, patients with colitis require repeated administrations to suppress and ameliorate inflammatory bowel disease and irritable bowel syndrome.

  In alternative embodiments, the crude collected stool is filtered and / or homogenized, and then the bacterial cells are plasmapheresised, centrifuged, blood cell separated, column chromatography (e.g. affinity chromatography), immunoprecipitation (e.g. beads or Separation (eg from a “precipitate” containing fibers) by an antibody immobilized on a solid surface such as a plate. Centrifugation, including the use of a “blood cell separator” (eg, Baxter model MEDIFUGE 1215 ™) is a process that requires centrifugal force to separate the mixture. Is blown out of the rotating plate, while the remaining components move to the axis, and the effect of gravity is enhanced by rotating the flattened product between fast moving glass plates. Centrifugation or blood cell separation can be set up so that cell dilution occurs only at the periphery by centrifugation and is subjected to a rotation cycle.

  In alternative embodiments, wild-type bacterial cells (including, for example, the entire microflora (or substantially the entire)) are separated or purified by, for example, centrifugation, blood cell separation, plasmapheresis, etc., and the cryoprotectant is removed. Use and freeze. In alternative embodiments, the material is then frozen in a container, such as a bag, which can then be used for infusion via a colonoscope, nasal duodenal tube or nasogastric tube. In alternative embodiments, it can be delivered to a facility (eg, a hospital pharmacy) at -20 ° C. or lower, while frozen. Alternatively, the centrifuge material can be lyophilized; and later reconstituted in a liquid, gel, gel tab, pill, capsule or tablet, or as an enema or infusion set, eg via a colonoscope Can be used in suppositories for doing.

  In one embodiment, the cryoprotectant is trehalose. Trehalose can also function as a component in reconstitution or as an additional agent prior to spray drying or freeze drying.

  In alternative embodiments, solutions, gels, gel tabs, pills, capsules or the like comprising a composition of the invention (e.g., isolated or purified fecal flora or whole microflora (or substantially whole)) Tablets are described, for example, as persistent infections, rheumatoid arthritis, systemic lupus erythematosus, autoimmune renal diseases such as nephritis, severe obstruction, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS) and To treat, stabilize, ameliorate or prevent chronic and / or immune conditions such as other conditions long periods of time, for example on a daily basis, for example, 1 week, 2 weeks, 3 weeks or 4 weeks or months It can take more.

Preparation or culture of the entire microflora In an alternative embodiment, the composition (e.g., article of manufacture or formulation) of the present invention is a formulation comprising the entire or substantially the entire microflora of an individual or species, e.g., a human or other mammal. Including formulations, cultures or culture extracts or isolates. In alternative embodiments, the present invention provides compositions and methods for preventing, reducing, ameliorating, stabilizing, or treating various infections, diseases or conditions, or symptoms thereof. They administer these "microflora whole or substantially whole" preparations (e.g. cultures or culture isolates); e.g. spondyloarthropathies, spondyloarthritis or sacroiliac (one or both sacroiliac) Inflammation of the joint); nephritic syndrome; lupus, irritable bowel syndrome (IBS or colonic cramps) or inflammatory or autoimmune conditions with intestinal or intestinal components such as colitis such as ulcerative or clonal colitis; constipation Autism; degenerative neurological diseases such as amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) or Parkinson's disease (PD); myoclonic dystonia (e.g. Steinert disease or proximal myotonicity) Myopathy); Seki Autoimmune diseases such as rheumatoid arthritis (RA) or juvenile idiopathic arthritis (JIA); chronic fatigue syndrome (benign myalgia encephalomyelitis, chronic fatigue immune dysfunction syndrome, chronic infectious mononucleosis, epidemic muscle Including painful encephalomyelitis); obesity; hypoglycemia, prediabetic syndrome, type I or type II diabetes; idiopathic thrombocytopenic purpura (ITP); skin rash, rash, urticaria or chronic urticaria, etc. To prevent, reduce, ameliorate, stabilize, or treat symptoms of acute or chronic allergic reactions; and / or insomnia or chronic insomnia, major or minor seizures Administering a “whole or substantially whole” microbiota preparation.

  In alternative embodiments, the present invention provides, for example, constipation, inflammatory bowel disease (IBD), Crohn's disease, hepatic encephalopathy, enteritis, colitis, irritable bowel syndrome (IBS), fibromyalgia (FM), chronic Fatigue syndrome (CFS), depression, attention deficit / hyperactivity disorder (ADHD), multiple sclerosis (MS), systemic lupus erythematosus (SLE), traveler diarrhea, small intestinal bacterial overgrowth, chronic pancreatitis, pancreatic insufficiency, Toxic or toxin or infection exposure, toxin-borne traveler diarrhea, poisoning, pseudomembranous colitis, Clostridium infection, C. perfringens-Welch or Clostridium difficile infection, neurological condition, Parkinson's disease, myoclonus dystonia, self Prevent, reduce, ameliorate, or treat various infections, diseases or conditions, including autism, amyotrophic lateral sclerosis or multiple sclerosis, major or minor seizures Because, the present invention provides compositions and methods for administering these "whole entire microflora or substantially" preparations.

  Although the present invention is not limited to any particular mechanism of action, the treated or untreated stool sample of the present invention, or the complete or partial stool flora sample of the present invention (eg, “entire or substantially whole microbiota”) Or a partially, substantially or completely isolated or purified fecal flora of the invention that forms colonies in the intestine when injected into a recipient (e.g., a human or mammal) To do. In one embodiment, substantially pure or substantially by filtering human flora and / or by rotation or centrifugation, plasmapheresis, blood cell separation, column chromatography (e.g. affinity chromatography) or immunoprecipitation, etc. Purely or pure fecal flora (eg, “bacteria body”) is extracted to produce (eg, isolate) these fecal flora preparations.

  In an alternative embodiment, the composition of the present invention is prepared by culturing the entire (or substantially the entire) microflora co-cultured (e.g., all together without any prior separation of specific bacterial species). To do. In one embodiment, a “microflora whole (or substantially whole) culture” sample is formulated, for example, as a liquid or as a freeze-dried or frozen product. In one embodiment, these formulations do not contain (or are substantially free of) any non-absorbable ingredients that are normally present in non-bacterial flora materials, such as fecal samples, such as raw human feces. In one embodiment, raw (eg, human) stool is produced into a therapeutic agent or formulation.

  In one embodiment, the present invention provides a method of culturing the entire bacterial flora of a mammal, eg, a human, by taking a stool sample from a suitable donor. In one embodiment, a suitable donor is an individual who does not have a pathogen; for example, in one aspect, a sample is taken from a donor that is normal and classified as not containing any pathogen. In one embodiment, bacteria from lean donors can be used to treat obesity in obese patients, either as an independent therapy or in conjunction with other therapies.

  In alternative embodiments, culturing is performed under about 2, 3, 4, 5, 6, 7 or 8 days or more under fully or substantially completely anaerobic conditions. Standard culture procedures can be used, for example using non-selective intestinal microbiota medium (GMM), and in one embodiment, incubation at (human) body temperature of about 36.8 ° C. An atmosphere lacking (or substantially lacking) oxygen and containing nitrogen, carbon dioxide and hydrogen can be used. Various GMMs with varying concentrations of GMM composition can be used.

The colonies or cultured bacterial flora are then collected, for example by scraping with a sterile scraper. The collected colonies or cultured bacterial flora can be frozen, for example, at about -80 ° C. or lower (eg, in a freezer) using, for example, freeze precipitates such as glycerol, cysteine or milk. Such cultures can then be aliquoted and used only once (since re-culture can result in reduced adhesion). In one embodiment, the method may comprise re-culturing in a lipid medium similar to GMM, for example. The entire medium can be frozen again using, for example, glycerol with cysteine; and in one embodiment may remain frozen or freeze-dried. This can produce about 10 ⁸ to about 10 ¹⁰ CFU.

  In alternative embodiments, cultured (e.g., human) bacteria (e.g., “whole or substantially whole microflora”) powder, dried, frozen, freeze dried or liquid or other form of enema, food or food Can be formulated and / or used as a supplement or formulation (e.g. added to yogurt, milk, beverages, flavored beverages or foods) or capsules, tablets, gel tabs etc. (e.g. enteric coated) Delivered (as capsules) to recolonize the intestinal flora, or alternatively, or therapeutically “colonize”.

  In an alternative embodiment, the cultured bacteria are added to a “whole microflora (or substantially whole)” culture or sample or formulation. For example, in one embodiment, the first administration or initial daily formulation comprises only the “whole microbial phase” formulation; while in other embodiments, the first administration or initial daily formulation comprises “microorganisms”. Includes both “total phase” and additional cultured bacteria, such as cultured probiotic bacteria. In alternative embodiments, infrequent formulations or dosing (such as at stepwise short or long intervals, at periodic intervals, or at intervals as determined by the physician or veterinarian depending on the rate of improvement) May include only “whole microbial flora”; in other embodiments, it includes both “whole microbial flora” and additional cultured bacteria, such as cultured probiotic bacteria.

  In alternative embodiments, additional cultured bacteria (e.g., added to the “whole microbial flora”) can be isolated directly from a donor, made from pure culture, etc. to achieve the desired effect or therapeutic result. Bacteroides sp., Fermicutes sp. And / or Bacillus thuringiensis sp. In alternative embodiments, an increased amount of delivery of one or more fecal flora (e.g., bacterial) species is used, e.g., the delivered "whole microflora" product is replaced with one or more additional species, e.g., Bacteroides. Enhance (spike) with genera, Fermicutes and / or Bacillus thuringiensis species.

Multiple or repeated injections or administration In alternative embodiments, treated or untreated stool samples, or partially, substantially or completely isolated or purified stool flora, or “human microorganisms of the invention” A composition of the invention (e.g., an article of manufacture or formulation) comprising a `` culture of the entire phase '', or the entire (or substantially entire) microbial phase, or a combination thereof, for repeated or multiple delivery or infusion Formulate or calibrate. In alternative embodiments of the method of the present invention, for example, faecal flora that is partially or substantially isolated or purified from the entire human microflora, or the entire microflora (or substantially the entire), or These combinations are delivered or administered by repeated or multiple delivery or infusion.

  Accordingly, the present invention treats, stabilizes or ameliorates an intestinal flora infection or condition that is difficult to permanently recover, or treats a condition characterized by an intestinal flora infection that is difficult to permanently recover. Compositions and methods for treatment or amelioration are provided. It has been discovered that multiple infusions can overcome intestinal flora infections or conditions that are difficult to permanently recover. In alternative embodiments, when performing the methods and / or compositions (e.g., articles of manufacture or formulations) of the invention, multiple or repeated fecal flora transplantation (administration, infusion), e.g., pathogenic and / or foreign The causative and progressive bacterial flora infection or chronic condition in individuals with bacterial strains (eg animals or patients) can be overcome.

  Inadequate removal of infectious (eg, pathogenic and / or foreign) bacteria can return the original progressive symptoms. It is known that bacteria do not divide from time to time and many can survive on biofilms on the wet (eg internal) surface of the body. Second, bacteria have spores that can be more difficult to eradicate at intermittent times of spore formation. There are also dormant forms of bacteria that can be intracellular and extracellular, in which case they are even more difficult to eradicate unless the dormant form is divided. Eventually, they may wait for intracellular bacteria until the gut wall cells in which they are present enter the intestinal lumen and reinfect the bacterial flora. In alternative embodiments, multiple or repeated intestinal flora infusions of the methods of the present invention can be performed on viable (e.g., infectious, pathogenic and / or foreign) bacteria that are protected internally, such as cells, biofilms, etc. May or may be required to kill or otherwise inactivate. In an alternative embodiment, multiple or repeated intestinal flora infusions of the methods of the invention migrate to the crypts closer to the lumen where they enter the fecal flow and reconstitute bacterial cells that reinfect the individual or patient. May or may be required to kill or otherwise inactivate.

  In addition, in alternative embodiments, multiple (repeated) or repeated stool flora transplantation (administration, infusion) of the methods and / or compositions (e.g., articles of manufacture or formulations) of the present invention is spondyloarthritis, spondyloarthritis Or sacroiliac (inflammation of one or both sacroiliac joints); nephritis syndrome; lupus, irritable bowel syndrome (IBS or colon spasm) or intestinal or intestinal tract such as colitis such as ulcerative or clonal colitis Inflammatory or autoimmune conditions with components; constipation, autism; degenerative neurological diseases such as amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) or Parkinson's disease (PD); myoclonus dystonia (E.g. Steinert disease or proximal myotonic myopathy); autoimmune diseases such as rheumatoid arthritis (RA) or juvenile idiopathic arthritis (JIA); chronic fatigue syndrome (benign myalgic encephalomyelitis, chronic fatigue immunity) Dysfunction syndrome, chronic infectious mononuclear Including obesity; hypoglycemia, prediabetic syndrome, type I or type II diabetes; idiopathic thrombocytopenic purpura (ITP); skin rash, rash, urticaria Or acute or chronic allergic reactions such as chronic urticaria; and / or prevent, stabilize, reduce or improve symptoms of insomnia or chronic insomnia, major or minor seizures Or an individual having it (eg, a patient).

  In an alternative embodiment, the invention uses a method or composition of the invention comprising repeated infusion of human filtered stool through repeated enema, nasal duodenal (ND) or nasogastric (NG) tract. To execute (implement).

  In alternative embodiments, the methods or compositions of the invention formulate or use various formulations, for example, whether frozen extracted fecal bacterial material is suspended as a flavored beverage or placed in an ND or NG tube Or as an enema.

  In an alternative embodiment, the `` wild type '' that is an extracted bacterium is freeze-dried (optionally after partial, substantial or complete purification and isolation) and formed into a powder; It can be ingested as enteric-coated capsules, tablets, liquids and the like.

  In alternative embodiments, these “product” of the present invention are taken first, daily, then gradually infrequently, and in some embodiments, finally once every few weeks or every month Inject or administer.

  In an alternative embodiment, the cultured bacteria can be used in addition to or in conjunction with the faecal flora that is partially, substantially, or fully purified or isolated. For example, in one embodiment, the first administration or initial daily formulation comprises only partially, mostly, or fully purified or isolated fecal flora, while in other embodiments, the first One administration or initial daily formulation contains, in part, both faecal flora and cultured bacteria, such as cultured probiotic bacteria, either partially or fully purified or isolated. In alternative embodiments, infrequent formulations or dosing (such as at stepwise short or long intervals, at periodic intervals, or at intervals as determined by the physician or veterinarian depending on the rate of improvement) May include only partially, mostly, or completely purified or isolated fecal flora; while in other embodiments, partially, mostly, or completely purified or simply Includes both isolated fecal flora and cultured bacteria; or in other embodiments, includes only cultured bacteria, eg, cultured probiotic bacteria.

  In an alternative embodiment, to achieve the desired effect or therapeutic result, the cultured bacteria may be isolated directly from the donor, or may be made from a pure culture, etc. Tes species and / or Bacillus thuringiensis. In alternative embodiments, an increased amount of delivery of one or more fecal flora (e.g., bacterial) species is used, e.g., the product to be delivered is replaced with one or more additional species, e.g., Bacteroides and / or Potentiates (spikes) with Pharmicutes and / or Bacillus thuringiensis.

  In alternative embodiments, the formulation is incorporated daily or not every day, but instead repeatedly over a long period of time, eg, a fairly high dose, for sufficient efficacy as determined by one skilled in the art. In alternative embodiments, repeated or multiple infusion, administration, or transplantation protocols may include, for example, colitis such as irritable bowel syndrome, ulcerative colitis or clonal colitis, constipation, autism, multiple sclerosis (MS Degenerative neurological diseases such as Parkinson's disease (PD), myoclonus dystonia, rheumatoid arthritis, chronic fatigue syndrome, obesity, diabetes, type II diabetes, idiopathic thrombocytopenic purpura (ITP), autoimmune disease, chronic urticaria and To treat insomnia or chronic insomnia, major seizures or minor seizures, approximately daily infusion for the first 10 days, and then about the second daily separate medication or formulation 10 days, optionally followed by another 3rd daily; then optionally another 4th daily, weekly, or monthly dose or formulation, then optionally histology To return to normal or until other therapeutic parameters or objectives are achieved, and further daily separate dosage or formulation, weekly, includes maintaining a monthly delivery or injection.

  In alternative embodiments, for example, irritable bowel syndrome, colitis such as ulcerative colitis or clonal colitis, constipation, autism, degenerative neurological diseases such as multiple sclerosis (MS), Parkinson's disease (PD), Myoclonus dystonia, rheumatoid arthritis, chronic fatigue syndrome, obesity, diabetes, type II diabetes, idiopathic thrombocytopenic purpura (ITP), autoimmune disease, chronic urticaria and / or insomnia or chronic insomnia, major seizures or To treat minor seizures, repeat or multiple infusions, administration or transplantation, first formulation daily 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 12, 13, 14 or 15 days; second dosing or formulation daily, followed by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 More than a day; then, optionally, a third subsequent dose or formulation is administered daily (e.g., subsequent 1, 2, 3, 4, 5, 6, 7, 8, 9 , 10, 11, 12, 13, 14, or 15 days or longer); then optionally a fourth dose or formulation daily or weekly (e.g., subsequent 1, 2, 3, 4, 5, 6, 7, 8, 9 , 10, 11, 12, 13, 14 or 15 days, weeks, months or more); and then optionally, for example, weekly or monthly until the histology returns to normal or other appropriate parameters for treatment or recovery Maintain the injection. One of ordinary skill in the art, such as a physician or veterinarian, can assess an individual's improvement and determine the correct and appropriate dosing or frequency of administration in this “repeated dose” embodiment of the invention.

  In alternative embodiments, these exemplary protocols will also be cultured probiotics that will be swept into the intestine with waves that can address the problems of biofilm spores, dormancy morphology and intracellular bacteria It can also be used to inject or ingest bacteria.

  In summary, in an alternative embodiment, the present invention treats and stabilizes intestinal flora infections that are difficult to permanently recover by repeatedly injecting the fecal flora described herein multiple times. Compositions and methods are provided for treating or ameliorating a condition characterized by or associated with intestinal flora infection that is difficult to ameliorate or ameliorate, or to be permanently recovered or controlled. In an alternative embodiment, the fecal microflora transplant compositions and methods of the present invention are effective in the more difficult conditions listed above, in addition to those in which Clostridium, such as C. difficile, is an infectious agent. In an alternative embodiment, repeated or repeated infusion is important to obtain healing, stabilization or long-term remission.

Devices for Delivering Compositions of the Invention The present invention also provides devices for delivering the compositions of the invention, for example an exemplary delivery device is illustrated in FIG. 1B. In an alternative embodiment, the device of the present invention may also comprise or consist of:
(b) (1) A bag or container comprising an outlet opening operatively connected to the proximal end of a flexible tube or equivalent
(Wherein the bag or container optionally comprises a gas or oxygen impermeable material;
In some cases, the bag or container is made of a soft material or a material comprising a polyethylene terephthalate polyester film (or including MYLARTM),
In some cases, the bag or container is an (IV-like) intravenous-like bag,
In some cases, the bag or container has an attachment that allows the bag to be suspended from a stand, e.g., installed / suspended on an endoscope,
In some cases, the bag or container is operatively connected to a negative pressure device capable of removing all gas or air from the bag via an on-off valve or equivalent,
In some cases, the bag or container is operatively connected to a fluid supply or storage container for flushing the bag via an outlet opening, via an on-off valve or equivalent, and optionally the fluid The source or storage container is under positive pressure,
In some cases, the flexible tube or equivalent is at least one clip or closure 25 valve or to prevent backwashing of material from the distal portion of the tube to the proximal portion, or from the back of the tube to the bag or container or Including check valve);
(2) Open / close valve or equivalent or obturator screw top at the distal end of a flexible tube or equivalent, and optionally a luer lock tip (here) for attachment to a colonoscope or endoscope luer lock port or equivalent In some cases, the luer lock tip is built into the valve or separate from the valve), and in some cases, the enema tube tip (optionally here, for attachment to the enema tube or device or equivalent) The enema tip is either built into the valve or separate from the valve,
Optionally further comprising a safety device or safety clip to close the distal 5 opening when the valve or luer lock tip or enema tip is released (removed) under pressure); and
(3) A pump or manual pump for moving the material in the bag or container from the distal end or from the open / close valve or equivalent through the flexible tube or equivalent.

  In an alternative embodiment, the device of the present invention is a treated or untreated fecal flora, or a partially, substantially or completely isolated fecal flora, or a composition of the present invention, eg, a portion In particular, fecal flora substantially or completely isolated or purified, or fecal flora substantially or completely purified from non-fecal flora fecal material, optionally with additives or fluids, Further included is a composition further comprising saline, buffer, buffer or medium or fluid-glucose-cellobiose agar (RGCA) medium.

  In one embodiment, the present invention provides a treated or untreated fecal flora, or a partially, substantially or completely isolated fecal flora, or a composition of the present invention, such as partially Including fecal flora substantially or completely isolated or purified, or fecal flora substantially or completely purified from non-fecal flora fecal material, optionally with additives or fluids, saline, Provided is a bag or container comprising a composition further comprising a buffer, buffer or medium or fluid-glucose-cellobiose agar (RGCA) medium, said bag or container structurally with the bag or container of the device of the invention. Bags that are the same or similar and that include an outlet opening that is operatively connected to the proximal end, such as, for example, a soft tube or equivalent described herein. It is a container.

  The invention will be further described with reference to the following examples; however, this should not be construed as limiting the invention to such examples.

(Example)
(Example 1)
Exemplary Methods of the Invention One exemplary procedure of the invention involves 5-10 days of treatment with an enema containing the treated or isolated fecal flora of the invention originally derived from a healthy donor. Alternatively, the patient can recover after only one treatment.

  In one embodiment, the best choice for the donor is a close relative tested for a broad set of bacterial and parasitic factors. Enemas are prepared and administered in a hospital environment to ensure all necessary precautions. An exemplary probiotic infusion of the present invention can also be administered via a nasogastric tube to deliver bacteria directly to the small intestine. These two methods can be combined to achieve the desired result. Until one year after the procedure, normal examination should be required.

  In one embodiment, prior to medical treatment, a self-fecal sample is obtained from a patient and stored in a refrigerator, lyophilized, freeze-dried, or the like. Subsequently, if the patient develops an infection, eg, C. difficile infection, the sample is prepared (extracted) with saline and filtered. The filtrate can be freeze-dried and the resulting solid can be encapsulated in a capsule, such as an enteric coated capsule. Administration of the capsule can regenerate the patient's own colonic flora and eradicate infections such as C. difficile. In one embodiment, the sample is delivered to the duodenum via a nasal probe.

  In one embodiment, the method of the present invention collects fresh human flora (feces) from a healthy donor, transports it to a central laboratory, processes it for long life, checks for pathogens, Maintain temperature control to reduce bacterial metabolic activity, control for oxygen-shock, develop homogenized standardized flora storage facility, transport flora to remote hospitals, eg acute Treatment of patients with pseudomembranous colitis, severe C. difficile infection, sepsis or other comparable conditions.

  In one embodiment, the product of the present invention is a modified stool composition. Anaerobic that can collect feces and extract air with materials that adsorb or absorb oxygen to the maximum extent, or exhaust and fill with nitrogen or inert or other gases that do not impair anaerobic flora Need to be quickly placed in a container. It must be kept in an aesthetically acceptable container that does not leak feces and does not leak gas causing an anaerobic situation. Once delivered to the central “bank”, stool can be stored in a cold room to reduce metabolism, but cannot be frozen to prevent hydrostatic expansion of bacterial cells contained in the stool.

  In one embodiment, antioxidants and / or materials such as glycerol are added to help stabilize bacteria at low temperatures and prevent them from being destroyed during storage and transport.

  In one embodiment, the product is stored / contained as a volume between about 10 cc to 3 liters of stool or by volume. In one embodiment, it is stored (as) in a 300 cc container (or quantity) and a suitable oxygen resistant material such as plastic, oxygen resistant or gas impermeable polyethylene terephthalate polyester film (e.g. metal coated form) or Hold in metal-coated MYLAR (TM) or aluminum-coated MYLAR (TM), which can be attached to the pump via a donation set that should be attached to the colonoscope, via the colonoscope to the distal small intestine Or administered into the upper colon / terminal ileum to overcome Clostridium difficile infection.

Central flora supply laboratory or “bank”
In one embodiment, the laboratory functions to supply the human flora as follows:
1. Collect feces in special containers and keep them anaerobically at low temperatures until they reach the central flora processing unit.
2. In processing unit, add special additives including glycerol, if possible antioxidants and other special preservatives, keep at low temperature, homogenize, proper but gas impervious Dispense into intravenous-like bags with somewhat thicker products such as polyethylene terephthalate polyester film or aluminum-coated MYLAR ™. This prevents oxygen from entering, nitrogen escape, and odor detection by the administration staff. The bag is then stored at a temperature that will not freeze the bacteria and is ready to be transported in a cooler to the hospital where the fecal transplant is performed.
3. Supply the bag with an attached donation set so that it is not handled by hospital staff. It is fitted with a “blood type” pump with a check valve. (IV-like) The intravenous-like bag has an attachment that allows the bag to be suspended from an IV fluid stand and can be placed / suspended on an endoscope. The endoscopist then removes the obdulator screw top, attaches it to the luer lock tip on the endoscopic luer lock port, and passes through the biopsy forceps channel to the colonoscope or endoscope tip Inject with. If the tip comes off under pressure, install a safety device. The product then flows out of the “donor set” with the pressure mechanism associated with the donor set, and air is expelled, and once the air is expelled from the tube, the dosing pump is then used to administer only feces into the patient's colon For example, flush with some saline.
4. The endoscopy operator then removes the colonoscope and “lowers the head / lifts the feet” of the patient to absorb air and liquid and prevent the patient from defecation prematurely. In this way, for example, as described by Grehan et al. In J of Clinical Gastroenterology (September 2010), the bacteria recover temperature and begin to attach themselves to the intestinal wall.

  Several embodiments of the invention have been described. However, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims.

1 Fecal collection device
2 slots
3 bags
10 Therapeutic vehicle (delivery system)
11 Intravenous (IV) delivery set
12 Manual pump
13 Luer lock mechanism
20 Therapeutic vehicle / delivery system
21 IV bag
22 Saline (NaCl)
23 Feces / cells of the invention
24 Manual pump
25 Lure lock
26 Flushing port
27 clips
28 Enema tip

Claims (16)

A method for producing a pharmaceutical composition for administration to a human comprising a living non-pathogenic fecal flora from a fecal donor comprising:
Receiving a stool sample from the donor in a stool microbiota donation bank, wherein the donor is a pre-screened donor for an infectious agent and the stool sample is in a stool collection device;
Mixing the stool sample with a liquid to form a mixture, the liquid comprising a buffer and a cryoprotectant;
Homogenizing and filtering the mixture to separate fibers from the bacterial flora to produce a filtrate containing the microflora of the stool sample; and formulating the filtrate as a pharmaceutical composition;
Including a method. A method for producing a pharmaceutical composition for administration to a human comprising a living non-pathogenic fecal flora from a fecal donor using a stool microbiota donation bank comprising:
Receiving a stool sample from a donor at the stool microbiota donation bank, wherein the stool sample is in a stool collection device;
Testing the stool sample for pathogens;
Mixing the stool sample with a liquid to form a mixture, the liquid comprising a buffer, a cryoprotectant, and an antioxidant;
Homogenizing and filtering the mixture to produce a filtrate comprising an antioxidant and the microflora of the stool sample, wherein the filtration results in separation of fibers from the microflora;
Formulating the filtrate as a pharmaceutical composition; and
Delivering the pharmaceutical composition from a faecal flora providing bank to a facility for administration to a person;
Including a method.   The method according to claim 1 or 2, wherein the cryoprotectant is selected from the group consisting of glycerol, polyethylene glycol, trehalose, skim milk, erythritol, arabitol, sorbitol, glucose, fructose, and combinations thereof.   The method according to claim 1 or 2, wherein the cryoprotectant comprises trehalose.   The method of claim 1 or 2, wherein the filtrate comprises cysteine.   3. The method of claim 1 or 2, further comprising lyophilizing the microbiota prior to encapsulation.   The method according to claim 1 or 2, wherein the microflora is encapsulated in a carrier.   The method according to claim 1 or 2, wherein the carrier is selected from the group consisting of tablets, gel tabs, pills and capsules.   The method according to claim 1 or 2, further comprising the step of freezing the filtrate.   The method according to claim 1 or 2, wherein the encapsulated microflora is frozen for storage.   3. A method according to claim 1 or 2, wherein the encapsulated microflora is in a graded release capsule.   The method of claim 1 or 2, wherein the stool collection device comprises an oxygen scavenging material.   3. The method of claim 1 or 2, wherein the mixture, filtrate, or both are maintained in at least 95% anoxic environment.   The method according to claim 1 or 2, further comprising adding one or more cultured bacteria to the filtrate.   3. A method according to claim 1 or 2, comprising repeated filtration while reducing the filter size.   Receiving a second stool sample from a second donor in the stool microbiota-providing bank; and processing the second stool sample to produce an antioxidant and a microbiota of the second stool sample The method of claim 2, further comprising producing an object.