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WO2016178775A1 - Compositions et méthodes d'administration thérapeutique de communautés microbiennes - Google Patents

Compositions et méthodes d'administration thérapeutique de communautés microbiennes Download PDF

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Publication number
WO2016178775A1
WO2016178775A1 PCT/US2016/026130 US2016026130W WO2016178775A1 WO 2016178775 A1 WO2016178775 A1 WO 2016178775A1 US 2016026130 W US2016026130 W US 2016026130W WO 2016178775 A1 WO2016178775 A1 WO 2016178775A1
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Prior art keywords
composition
disease
acid
emulsifying agent
capsule
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PCT/US2016/026130
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English (en)
Inventor
Mark Smith
Gina MENDOLIA
Zain KASSAM
James Burgess
Andrew NOH
Laura BURNS
Dalia WALZER
Anh-thu Elaine VO
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Microbiome Health Research Institute Inc
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Microbiome Health Research Institute Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4875—Compounds of unknown constitution, e.g. material from plants or animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4891—Coated capsules; Multilayered drug free capsule shells

Definitions

  • the present invention relates to compositions for the delivery of microbial communities, and in various embodiments to compositions that are suitable for delivery of microbial communities by the oral route.
  • the compositions are useful for treating diseases or conditions associated with gastrointestinal dysbiosis.
  • the human gastrointestinal tract harbors an abundant and diverse microbial community, also called the microbiota, which is critical for human health.
  • a healthy microbiota provides the human host with multiple benefits, including resistance to pathogen infection, nutrient biosynthesis and absorption, and immune stimulation.
  • a dysbiosis or disruption of the microbiota can result in increased susceptibility to pathogens, altered metabolic profiles, and systemic inflammation or autoimmunity and contribute to a number of diseases.
  • One method for treating gastrointestinal dysbiosis is through manipulation of the composition of the microbiota, through fecal microbiota transplantation or through the addition of pure or mixed cultures of bacteria delivered to the gastrointestinal tract.
  • Fecal microbiota transplantation the most widely used contemporary method involves transplanting the fecal bacteria of a healthy donor to a recipient.
  • transplantation to the upper GI tract is achieved via naso-gastric, naso-duodenal, naso- jejunal intubation, or via esophagogastroduodenoscopy or push enteroscopy. Delivery to the lower GI tract is usually achieved by colonoscopy, sigmoidoscopy, or enema. All of these techniques suffer from shortcomings.
  • upper GI tract administration carries the risks of aspiration-related complications (particularly naso-gastric delivery) and is invasive and uncomfortable to patients.
  • Lower GI tract delivery techniques such as colonoscopy and sigmoidoscopy are also invasive and uncomfortable and are associated with significant costs and risks.
  • Enema delivery is less invasive and expensive, but it is also less effective empirically, and is uncomfortable for many patients.
  • compositions and methods that meet these objectives would be critical for improving the treatment of gastrointestinal dysbiosis, including treatment of recurrent Clostridium difficile infection as well as dysbiosis associated with various chronic diseases.
  • the present invention provides capsules suitable for oral delivery of microbial communities, and which are suitable for fecal matter transplant by the oral route.
  • the capsules comprise microbial communities that have not been dewatered, and thus maintain substantial viability. Further, the capsules provide sufficient room temperature stability, despite delivering an "aqueous-based" sample in a water soluble capsule.
  • the invention provides a composition comprising an aqueous-based sample of intestinal microbial communities (e.g., fecal matter) and an emulsifying agent.
  • the aqueous-based sample of intestinal microbes and the emulsifying agent form a water-in-oil emulsion that is solid at room temperature, but which is liquid at the temperature of the gut.
  • the water-in-oil emulsion is encapsulated within a water-soluble capsule.
  • the composition maintains its structural integrity at room temperature for at least several hours, to at least several days or weeks.
  • the composition of the invention preserves high viability of the encapsulated microorganisms.
  • the intestinal microbial communities are fecal matter derived from a healthy human or animal donor.
  • the intestinal microbial communities are a cocktail of microbial strains grown in pure or mixed culture.
  • the present invention contemplates the use of an emulsifying agent to maintain viability of microbial communities (e.g., without dewatering) while producing capsules that are both water soluble and stable at room temperature.
  • the emulsifying agent is lipid-based, and will be liquid at body temperature and solid at room temperature.
  • the emulsifying agent comprises cocoa butter, with one or more additional agents to adjust its melting point and/or emulsion properties.
  • the emulsion may further comprise an agent that provides cryoprotectant properties, such as glycerol.
  • the present invention provides methods for preventing or treating a disease or condition associated with gastrointestinal dysbiosis.
  • Methods of the invention can treat Clostridium difficile (C. dijf) infection, including relapsing or recurrent C. diff. infection, or Clostridium difficile -associated disease.
  • Methods of the invention can also treat gastrointestinal dysbiosis associated with gastrointestinal diseases (such as inflammatory bowel disease, functional diseases of the GI, autoimmune disease, and malignancies of the GI); hepatic diseases, metabolic diseases, rheumatological diseases, and psychiatric diseases.
  • the gastrointestinal dysbiosis is associated with nosocomial infection and/or a secondary emergent infection.
  • the present invention provides methods for restoring and/or enhancing the microbiota function of a subject.
  • Figure 1A shows the filling of emulsion-based capsules with a multi-channel pipette and a semi-automated capsule loading plate.
  • Figure IB shows emulsion gelling minutes after distribution into the capsule plate.
  • Figure 2 is an illustration showing embodiments of the invention based on a water- in-oil emulsion with cocoa butter. Microbial communities are trapped in aqueous droplets, and shielded from the water-soluble capsule.
  • the first approach involves flash-freezing of an aqueous solution of stool in a glycerol and saline buffer.
  • the aqueous solution preserves the viability of the microbial strains but produces capsules that are highly unstable as the aqueous character of the stool quickly degrades the water-soluble capsules.
  • the physical instability of these capsules complicates mass-production and creates clinical hazards as the capsules can rupture during administration.
  • the second approach involves dewatering of the microbial community through techniques such as lyophilization. However, the dewatering process is physically demanding and significantly reduces the viability of the microbes.
  • the present invention provides stable and effective compositions comprising an aqueous-based sample of microbial communities and an emulsifying agent encapsulated within, for example, a water-soluble capsule.
  • the composition maintains its structural integrity at room temperature for at least 30 minutes, or several hours in various embodiments. In some embodiments, the composition maintains its structural integrity for several days to weeks at room temperature.
  • the composition also preserves the viability of the encapsulated intestinal microbes and in some embodiments effectively delivers the viable microbial community to target sites within the GI.
  • the microbial communities are incorporated as an aqueous- based sample, which means that the communities (e.g., as present in stool) have not been dewatered (e.g., lyophilized).
  • the aqueous-based sample may be at least about 20% water, at least about 40% water, at least about 50% water, at least about 75% water, or at least about 80% water.
  • the aqueous-based sample contains at least 10% solid matter comprising the microbial communities.
  • the composition of the invention employs an emulsifying agent that forms a water- in-oil emulsion with the aqueous sample of microbial communities.
  • the water-in-oil emulsion not only preserves the viability of the microbes but also preserves the integrity of the water-soluble capsule.
  • the emulsifying agent forms a protective hydrophobic layer surrounding dispersed water droplets containing the microbes, thereby providing an aqueous micro environment that protects viability while being substantially shielded from the capsule material.
  • the composition is stable at room temperature (e.g., exhibits no significant degradation) for at least about 2 hours, or at least about 5 hours, or at least about 10 hours, or at least about 1 day, or at least about 2 days, or at least about 1 week, or at least about 2 weeks, or at least about 1 month at room temperature.
  • room temperature means about 25° C.
  • the capsules will maintain integrity and viability indefinitely, for example, for several years.
  • the present invention employs a lipid-based emulsifying agent, which is solid at room temperature, but liquid at the temperature of the gut.
  • the emulsifying agent contains one or more lipid-based materials, optionally with other agents to adjust its physical properties, to achieve a melting point between about 27 and about 36° C.
  • the lipid-based material may have a melting point of from about 28 to about 36°C, from about 28 to about 36°C, from about 30 to about 36°C, from about 32 to about 36° C, or from about 34 to 36° C (e.g., about 35° C).
  • the lipid-based emulsifying agent may include one or more fatty acids including short-chain fatty acids, medium-chain fatty acids, long-chain fatty acids, or very long chain fatty acids.
  • the lipid- based emulsifying agent may include one or more unsaturated fatty acids including, but not limited to, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, linoelaidic acid, a-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, and docosahexaenoic acid.
  • unsaturated fatty acids including, but not limited to, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, linoelaidic acid, a-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, and docosahexaenoic acid.
  • the lipid-based emulsifying agent may include one or more unsaturated fatty acids including, but not limited to, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, and cerotic acid.
  • the lipid-based emulsifying agent includes one or more of a fatty acid selected from arachidic acid, linoleic acid, oleic acid, palmitic acid, palmitoleic acid, and steric acid.
  • the lipid- based emulsifying agent comprises cocoa butter.
  • exemplary lipid-based emulsifying agents may include, for example, lard, duck fat, butter, lanolin, coconut oil, palm kernel oil, palm oil, cottonseed oil, wheat germ oil, soybean oil, olive oil, corn oil, sunflower oil, safflower oil, hemp oil, and canola oil.
  • the emulsion includes a cryoprotectant to preserve viability during storage.
  • the cryoprotectant may operate by increasing the solute concentration in the microbial cells.
  • the cryoprotectant penetrates cells and is non- toxic to the microbes.
  • the compositions may be stored at below 0°C, such as below about 10°C, or below about 20°C, or below about 50°C. In some embodiments, the compositions are stored at about -80°C until use.
  • cryoprotectants which can be used individually or in some combination, include glycerol, dimethylsulfoxide, methanol, ethanol, polyvinyl alcohol, ethylene glycol, propylene glycol, trimethylene glycol, diethylene glycol, polyethylene glycol, polypropylene glycol, polyethylene oxide, mannitol, sorbitol, dulcitol, glucose, xylose, sucrose, lactose, maltose, trehalose, raffinose, dextran, mannan, dextrin, ficoll, gum arabic (acacia), acetamide, methylacetamide, dimethylformamide, dimethylacetamide, succinimide, methylpyrrolidone, polyvinylpyrrolidone, proline, glycine, glutamic acid, aminobutyric acid, glutaric acid, ammonium acetate, EDTA, blood serum, albumins, gelatin, peptones, shell extract, glycoprotein
  • the emulsifying agent is cocoa butter, which is optionally mixed with a co-solvent such as glycerol (or other cryoprotectant) to form an emulsifying solution.
  • the emulsifying solution may include the emulsifying agent (e.g., cocoa butter) and co-solvent (e.g., cryoprotectant, such as glycerol) at a ratio of from about 95:5 to about 50:50, and in various embodiments about 90: 10, about 85: 15, about 80:20, about 75:25, about 70:30: about 65:35; about 60:40, about 55:45, or about 50:50.
  • the aqueous sample of intestinal microbes may be derived from various sources.
  • the intestinal microbes are derived from human or animal feces.
  • the aqueous sample is a sample of human fecal matter from a healthy donor, for preparation of compositions for human use. Other embodiments may employ fecal matter from other animals, for use in compositions intended for veterinary care.
  • the aqueous sample contains a portion of the microbial flora of the intestinal tract of a healthy donor. In some embodiments, the aqueous sample includes the entire microbial flora in the sample.
  • the intestinal microbial community simulates the microbiota of a healthy donor through a synthetic cocktail of microbial strains grown in pure or mixed culture.
  • the composition takes the form of a water-soluble composition that easily dissolves in the digestive tract.
  • the composition can take the form of capsules, softgel capsules, gelatin capsules, microcapsules, including delayed-release formulations and sustained-release formulations that control release of the encapsulated material.
  • Exemplary water-soluble capsules include, but are not limited to, gelatin capsules, hypromellose, and hydroxypropyl methylcellulose (HPMC) capsules.
  • HPMC hydroxypropyl methylcellulose
  • the capsule is acid resistant.
  • compositions can include one or more agents, for example, sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; coloring agents; to provide a palatable preparation.
  • sweetening agents such as fructose, aspartame or saccharin
  • flavoring agents such as peppermint, oil of wintergreen, or cherry
  • coloring agents to provide a palatable preparation.
  • compositions of the invention may additionally include pharmaceutically acceptable excipient or carrier, so long as the viability of the microbes are maintained, as well as the integrity of the capsules at room temperature.
  • excipients include sodium citrate, dicalcium phosphate, etc., and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, silicic acid, microcrystalline cellulose, and Bakers Special Sugar, etc., b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, acacia, polyvinyl alcohol, polyvinylpolypyrrolidone, methylcellulose, hydroxypropyl cellulose (HPC), and hydroxymethyl cellulose etc., c) humectants such as glycerol, etc., d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, al
  • compositions may include co-solvents such as propylene glycol, glycerol, or low molecular weight polyethylene glycols (PEGs).
  • the pharmaceutical composition further includes glycerol.
  • co-solvents such as propylene glycol, glycerol, or low molecular weight polyethylene glycols (PEGs).
  • PEGs low molecular weight polyethylene glycols
  • the pharmaceutical composition further includes glycerol.
  • particular excipients may have two or more functions in the oral dosage form.
  • Various methods may be used to formulate and/or deliver the composition to a location of interest.
  • the compositions described herein may be formulated for delivery to the gastrointestinal tract including the stomach, small intestine, large intestine and rectum including all subsections thereof.
  • the composition is formulated to release (e.g., dissolve) in the small intestine, including one or more of the duodenum, jejunum, and/or the ileum. In some embodiments, the composition is formulated to release (e.g., dissolve) in the large intestine, including one or more of the cecum, the ascending colon, the transverse colon, the descending colon, and/or the sigmoid colon. In some embodiments, the composition dissolves in the stomach. In other embodiments, the composition is formulated so as to not substantially release in the stomach. In various embodiments, the composition may be formulated to have sustained- release profiles, i.e.
  • the composition may be formulated to have a delayed-release profile, i.e. not immediately release the microbial communities upon ingestion; rather, postponement of the release until the composition is lower in the gastrointestinal tract; for example, for release in the small intestine ⁇ e.g., one or more of duodenum, jejunum, ileum) and/or the large intestine ⁇ e.g., one or more of cecum, ascending, transverse, descending or sigmoid portions of the colon, and rectum).
  • a delayed-release profile i.e. not immediately release the microbial communities upon ingestion; rather, postponement of the release until the composition is lower in the gastrointestinal tract; for example, for release in the small intestine ⁇ e.g., one or more of duodenum, jejunum, ileum) and/or the large intestine ⁇ e.g., one or more of cecum, ascending, transverse, descending or sigmoid portions of the colon, and rectum
  • compositions of the present invention may use one or more modified-release coatings such as delayed-release coatings to provide for effective, delayed yet substantial delivery of the microbial communities to the GI tract.
  • a composition can be enteric coated to delay release of the microbes until it reaches the small intestine or the large intestine.
  • the composition may remain essentially intact, or may be essentially insoluble, in gastric fluid.
  • the stability of the delayed- release coating can be pH dependent. Delayed-release coatings that are pH dependent will be substantially stable in acidic environments (pH of about 5 or less), and substantially unstable in near neutral to alkaline environments (pH greater than about 5).
  • the delayed-release coating may essentially disintegrate or dissolve in near neutral to alkaline environments such as are found in the small intestine (e.g. one or more of the duodenum, jejunum, and ileum) and/or large intestine (e.g. one or more of the cecum, ascending colon, transverse colon, descending colon, and sigmoid colon).
  • the delayed-release coating includes an enteric agent that is substantially stable in acidic environments and substantially unstable in near neutral to alkaline environments.
  • the delayed-release coating contains an enteric agent that is substantially stable in gastric fluid.
  • the enteric agent can be selected from, for example, solutions or dispersions of methacrylic acid copolymers, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose, and EUDRAGIT®-type polymer (poly(methacrylic acid, methylmethacrylate), hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate, shellac or other suitable enteric coating polymers.
  • the EUDRAGIT®-type polymer include, for example, EUDRAGIT® FS 30D, L 30 D-55, L 100-55, L 100, L 12,5, L 12,5 P, RL 30 D, RL PO, RL 100, RL 12,5, RS 30 D, RS PO, RS 100, RS 12,5, NE 30 D, NE 40 D, NM 30 D, S 100, S 12,5, and S 12,5 P.
  • one or more of EUDRAGIT® FS 30D, L 30 D-55, L 100-55, L 100, L 12,5, L 12,5 P RL 30 D, RL PO, RL 100, RL 12,5, RS 30 D, RS PO, RS 100, RS 12,5, NE 30 D, NE 40 D, NM 30 D, S 100, S 12,5 and S 12,5 P is used.
  • the enteric agent may be a combination of the foregoing solutions or dispersions.
  • the delayed-release coating may degrade as a function of time when in aqueous solution without regard to the pH and/or presence of enzymes in the solution.
  • a coating may comprise a water insoluble polymer. Its solubility in aqueous solution is therefore independent of the pH.
  • pH independent as used herein means that the water permeability of the polymer and its ability to release pharmaceutical ingredients is not a function of pH and/or is only very slightly dependent on pH.
  • Such coatings may be used to prepare, for example, sustained release formulations.
  • Suitable water insoluble polymers include pharmaceutically acceptable non-toxic polymers that are substantially insoluble in aqueous media, e.g., water, independent of the pH of the solution.
  • Suitable polymers include, but are not limited to, cellulose ethers, cellulose esters, or cellulose ether-esters, i.e. , a cellulose derivative in which some of the hydroxy groups on the cellulose skeleton are substituted with alkyl groups and some are modified with alkanoyl groups. Examples include ethyl cellulose, acetyl cellulose, nitrocellulose, and the like.
  • insoluble polymers include, but are not limited to, lacquer, and acrylic and/or methacrylic ester polymers, polymers or copolymers of acrylate or methacrylate having a low quaternary ammonium content, or mixture thereof and the like.
  • insoluble polymers include EUDRAGIT RS®, EUDRAGIT RL®, EUDRAGIT NE®, polyvinyl esters, polyvinyl acetals, polyacrylic acid esters, butadiene styrene copolymers, and the like.
  • the stability of the pharmaceutical composition can be enzyme-dependent. Delayed-release coatings that are enzyme dependent will be substantially stable in fluid that does not contain a particular enzyme and substantially unstable in fluid containing the enzyme. The delayed-release coating will essentially disintegrate or dissolve in fluid containing the appropriate enzyme. Enzyme-dependent control can be brought about, for example, by using materials which release the active ingredient only on exposure to enzymes in the intestine.
  • the stability of the composition can be dependent on the presence of a microbial enzyme present in the gut flora. Accordingly, in various embodiments, the delayed-release coating is degraded by a microbial enzyme present in the gut flora. In an embodiment, the delayed- release coating is degraded by a bacteria present in the small intestine. In another embodiment, the delayed-release coating is degraded by a bacteria present in the large intestine.
  • the present invention also provides for compositions that release multiple doses of the microbial communities along the gastrointestinal tract.
  • the composition and/or formulation can release multiple doses of the microbial communities at different locations along the intestines, at different times, and/or at different pH.
  • the overall release profile of such a formulation may be adjusted using, for example, multiple particle types or multiple layers.
  • the first dose of the microbial communities may be formulated for release in, for example, the small intestine (e.g. , one or more of duodenum, jejunum, ileum), whereas the second dose is formulated for delayed release in, for example, the large intestines (e.g.
  • the first dose of the microbial communities may be formulated for release in, for example, the small intestine (e.g. , one or more of duodenum, jejunum, ileum), whereas the second dose is formulated for delayed release in, for example, another part of the small intestine (e.g. , one or more of duodenum, jejunum, ileum).
  • the first dose of the microbial communities may be formulated for release in, for example, the large intestine (e.g.
  • the composition and/or formulation may release at least one dose, at least two doses, at least three doses, at least four doses, or at least five doses of the microbial communities at different locations along the intestines, at different times, and/or at different pH.
  • each capsule comprises at least about 0.4 grams of stool, or comprises at least about 0.5 grams of stool, or comprises at least about 0.7 grams of stool. In some embodiments, each capsule comprises about 0.5, about 0.6, about 0.7, or about 0.8 grams of stool. Whether capsules deliver microbial communities in the form of stool or in the form of pure or mixed bacterial cultures, each capsule may deliver from about 1 x 10 6 to about 1 x 10 12 bacterial cells. In various embodiments, each capsule delivers from about 1 x 10 8 to about 1 x 10 12 bacterial cells. In some embodiments, each capsule delivers from about 1 x 10 10 to about 1 x 10 12 bacterial cells.
  • compositions While a single administration of the compositions, as described below, can be effective for treatment of Clostridium difficile infection, for treatment of chronic medical diseases, multiple treatments may be necessary, including an induction dose and maintenance doses over time.
  • the composition is administered either for induction therapy and/or as maintenance therapy.
  • a patient is treated by first delivering an antibiotic pre-treatment to disrupt/reduce the patient's gastrointestinal biome, followed by induction therapy and maintenance therapy ("Triple Therapy").
  • Antibiotic therapy can facilitate a disruption in the host gastrointestinal microbiome, in turn, enabling a low diversity environment that is ideal for engraftment of newly infused bacteria.
  • the patient receives pre-treatment with a broad-spectrum antibiotic, including but not limited to, individually or in combination, Amoxicillin (and other ⁇ -lactams), Vancomycin, Metronidazole, Ciprofloxacin (and other Fluoroquinolones), Rifampin, Doxycycline, Polymyxins, and Gentamicin (and other Aminoglycosides).
  • a broad-spectrum antibiotic including but not limited to, individually or in combination, Amoxicillin (and other ⁇ -lactams), Vancomycin, Metronidazole, Ciprofloxacin (and other Fluoroquinolones), Rifampin, Doxycycline, Polymyxins, and Gentamicin (and other Aminoglycosides).
  • Induction therapy can be delivered at the beginning of treatment initiation with the compositions described herein or with conventional techniques, and may be repeated if there is an exacerbation of the disease.
  • a high dose of the microbial communities is often desirable to facilitate intestinal engraftment of the newly infused bacteria.
  • Induction therapy may be accomplished with one or more of colonoscopic, enema, nasoenteric, and esophagogastrodudenoscopic delivery routes, or may involve high-dose encapsulated microbial communities (e.g., using compositions of the invention).
  • encapsulated microbial communities may be delivered as maintenance doses.
  • the maintenance dosing regimen can vary, including by microbial dose, frequency of administration, administration interval and length, and microbial payload location, and depending on the disease and biology of the patient.
  • therapy of chronic medical disease may require a dose of about 5 to about 50 unit dosage forms (e.g., capsules) for induction therapy.
  • the composition may be administered in a dose of from about 5 to about 40 capsules per administration.
  • the composition may be administered at a dose of about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, or about 50 dosage units (e.g., capsules) per administration.
  • a patient may be treated with from one to five administrations.
  • a patient is treated with one or two administrations, with each administration including delivery of from about 5 to about 40 dosage units, or from about 10 to about 40 dosage units, or from about 20 to about 40 dosage units (e.g., about 30 dosage units).
  • capsules may be administered daily, or from two to five times weekly, or from one to ten times monthly. Maintenance therapy may proceed for several weeks to several months. For example, maintenance therapy may proceed for about two to about six weeks (e.g., about one month), or may proceed for about two to about six months (e.g., from about 2 to 4 months).
  • An "administration" refers to the dosage units (e.g., capsules) delivered over the course of a single day.
  • the present invention provides methods of treating or preventing a disease or condition associated with gastrointestinal dysbiosis, comprising administering an effective amount of a composition described herein to a subject or a patient need thereof.
  • a disease or condition associated with gastrointestinal dysbiosis comprising administering an effective amount of a composition described herein to a subject or a patient need thereof.
  • Illustrative disorders or conditions that may be associated with dysbiosis include, but are not limited to, the following.
  • the patient has inflammatory bowel diseases (IBD), for example, Crohn's disease, colitis (e.g., ulcerative colitis or microscopic colitis), or pouchitis; or has irritable bowel syndrome or functional dyspepsia.
  • IBD inflammatory bowel diseases
  • the patient has hepatic disease, such as non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), hepatic encephalopathy, primary sclerosing cholangitis (PSC), autoimmune hepatitis, or drug-induced liver injury.
  • the patient has an autoimmune disease such as celiac disease or eosinophilic esophagitis.
  • the patient has a hyperproliferative disease or malignancy of the GI, such as colorectal cancer/polyps, esophageal cancer or Barett's esophagus.
  • the patient has metabolic disease, such as metabolic syndrome, Type 1 or Type 2 diabetes, obesity, malnutrition or undernutrition, or cardiovascular disease (e.g., atherosclerosis).
  • the patient has rheumatologic disease, such as inflammatory arthritis (rheumatoid arthritis or RA, ankylosing spondylitis, psoriatic arthritis, IBD spondyloarthropathy), fibromyalgia, chronic fatigue syndrome, or an autoimmune and connective tissue disorder (e.g., systemic lupus erythematosus, scleroderma, and Sjogren's syndrome).
  • the patient has vasculitis (e.g., polymyalgia rheumatic/giant cell arteritis or polyarteritis nodosa).
  • the patient has a psychiatric disorder such as mood disorder (e.g., depression or bipolar), anxiety disorder (e.g., general anxiety disorder, post-traumatic stress disorder), or developmental disorder (e.g., autism spectrum disorder, attention deficit hyperactivity disorder).
  • mood disorder e.g., depression or bipolar
  • anxiety disorder e.g., general anxiety disorder, post-traumatic stress disorder
  • developmental disorder e.g., autism spectrum disorder, attention deficit hyperactivity disorder.
  • the patient has one or more of colonic polyps, cysts, diverticular disease, constipation, intestinal obstruction, malabsorption syndrome, ulceration of the mucosa, and diarrhea. Additional diseases, disorders and conditions which are suitable for treatment with the compositions and methods of the invention are described in Table 3 of WO 2014/121298, the entire contents of which are hereby incorporated by reference.
  • the patient has an infectious diseases of the intestine, for example, C. difficile infection (CDI) and/or a C. difficile -associated disease, nosocomial infection, secondary emergent infection, amebiasis, intestinal tuberculosis, or parasitic disorder.
  • CDI C. difficile infection
  • the present invention provides methods for treating or preventing a C. difficile infection (CDI) and/or a C. difficile -associated disease, comprising administering an effective amount of a composition described herein to a subject or a patient need thereof.
  • the CDI or C. difficile-associated disease comprises one or more of: C. difficile diarrhea (CDD), C. difficile intestinal inflammatory disease, colitis, pseudomembranous colitis, fever, abdominal pain, dehydration and disturbances in electrolytes, megacolon, peritonitis, and perforation and/or rupture of the colon.
  • the disease or condition associated with gastrointestinal dysbiosis is treated or prevented in the context of initial onset or relapse/recurrence (e.g. due to continued or restarted antibiotic therapy).
  • the present composition or formulation may be administered upon the first symptoms of recurrence in the patient.
  • symptoms of recurrence include, in a mild case, about 5 to about 10 watery bowel movements per day, no significant fever, and only mild abdominal cramps while blood tests may show a mild rise in the white blood cell count up to about 15,000 (normal levels are up to about 10,000), and, in a severe case, more than about 12 watery stools per day, nausea, vomiting, high fever (e.g. about 102-104°F), rectal bleeding, severe abdominal pain (e.g. with tenderness), abdominal distention, and a high white blood count (e.g. of about 15,000 to about 40,000).
  • the methods of the present invention are used to treat a subject or patient who is suffering from, or is susceptible to, a disease or condition associated with gastrointestinal dysbiosis.
  • the patient may be undergoing or has undergone an initial and/or adjunctive therapy that renders the patient susceptible to a disease or condition associated with gastrointestinal dysbiosis.
  • the patient is undergoing treatment, or has undergone treatment, with an antibiotic.
  • the patient may have taken an antibiotic during the past about 30 or so days and/or have an immune system that is weak (e.g. from a chronic illness).
  • the patient may have recently been in the hospital, including in an intensive care unit.
  • the methods and uses of the present invention treat or prevent a nosocomial infection and/or a secondary emergent infection and/or a hospital acquired infection (HAI).
  • HAI hospital acquired infection
  • the administration regimen comprises a dose of from 1 to about 50 unit dosage forms (e.g., capsules) per administration.
  • each administration for induction therapy may include a dose of from 5 to 40 capsules, such as a dose of about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, or about 50 dosage units (e.g., capsules) per administration.
  • a patient may be treated with from one to five administrations of induction therapy in some embodiments.
  • capsules are administered at a dose of from about 1 to 5 capsules, preferably from about 1 to 3 times per day, or 1 to about 7 capsules per week.
  • administration of the composition of the invention restores and/or enhances the intestinal microbiota of the subject or patient.
  • the composition of the invention may be administered in combination with an additional therapeutic agent.
  • the additional therapeutic agent is an anti -inflammatory agent such as steroidal anti-inflammatory agents or non-steroidal anti-inflammatory agents (NSAIDs).
  • NSAIDs non-steroidal anti-inflammatory agents
  • Steroids, particularly the adrenal corticosteroids and their synthetic analogues, are well known in the art.
  • corticosteroids include, without limitation, hydroxyltriamcinolone, alpha-methyl dexamethasone, beta-methyl betamethasone, beclomethasone dipropionate, clobetasol valerate, desonide, desoxymethasone, dexamethasone, diflorasone diacetate, diflucortolone valerate, fluadrenolone, fluclorolone acetonide, flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortine butylester, fluocortolone, fluprednidene (fluprednylidene) acetate, flurandrenolone, halcinonide, methylprednisolone, triamcinolone acetonide, cortisone, cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate, fluradrenolone aceton
  • NSAIDS that may be used in the present invention, include but are not limited to, salicylic acid, acetyl salicylic acid, methyl salicylate, glycol salicylate, salicylmides, benzyl-2,5-diacetoxybenzoic acid, ibuprofen, fulindac, naproxen, ketoprofen, etofenamate, phenylbutazone, and indomethacin.
  • the additional therapeutic agent is an antidiarrheal agent.
  • Antidiarrheal agents suitable for use in the present invention include, but are not limited to, DPP-IV inhibitors, natural opioids, such as tincture of opium, paregoric, and codeine, synthetic opioids, such as diphenoxylate, difenoxin and loperamide, bismuth subsalicylate, lanreotide, vapreotide and octreotide, motiln antagonists, COX2 inhibitors like celecoxib, glutamine, thalidomide and traditional antidiarrheal remedies, such as kaolin, pectin, berberine and muscarinic agents.
  • natural opioids such as tincture of opium, paregoric, and codeine
  • synthetic opioids such as diphenoxylate, difenoxin and loperamide, bismuth subsalicylate, lanreotide, vapreotide and octreotide, motiln antagonists
  • COX2 inhibitors like cele
  • the additional therapeutic agent is a probiotic.
  • Probiotics suitable for use in the present invention include, but are not limited to, Saccharomyces boulardii; Lactobacillus rhamnosus GG; Lactobacillus plantarum 299v; Clostridium butyricum M588; Clostridium difficile VP20621 (non-toxigenic C.
  • Lactobacillus casei Lactobacillus acidophilus
  • Lactobacillus casei Lactobacillus acidophilus
  • Actimel Combination of Lactobacillus casei, Lactobacillus bulgaricus, Streptococcus thermophilus (Actimel)
  • Lactobacillus acidophilus Bifidobacterium bifidum
  • Florajen3 combination of Lactobacillus acidophilus, Lactobacillus bulgaricus delbrueckii subsp.
  • the present invention provides methods for producing the compositions described herein.
  • the method includes an initial step of obtaining an aqueous sample of an intestinal microbial community.
  • the aqueous sample is human feces or is derived from human feces.
  • the aqueous sample is a cocktail of microbial strains.
  • the aqueous sample of intestinal microbial community (as already described) is mixed with an emulsifying agent to form a water-in-oil emulsion.
  • the mixing is conducted at about 37°C, such that the emulsifying agent is in liquid form.
  • the emulsifying agent is cocoa butter
  • a co- solvent e.g., cryoprotectant
  • glycerol in some embodiments, to form an emulsifying solution which is then mixed with the aqueous sample of microbial community.
  • the emulsifying solution may include the emulsifying agent (e.g.
  • the aqueous sample is mixed with the emulsifying agent or with the emulsifying solution at a ratio of from about 10: 1 to about 5: 1 (w/v), such as about 9: 1 (w/v), about 8: 1 (w/v), about 7: 1 (w/v), about 6: 1 (w/v), or about 5: 1 (w/v).
  • the emulsion is subsequently added into a capsule.
  • the capsule is selected from a gelatin capsule, a hydroxypropyl methylcellulose (HPMC) capsule, acid- resistant hypromellose capsule, or a lipid-based microcapsule.
  • HPMC hydroxypropyl methylcellulose
  • the aqueous sample is filtered before mixing with the emulsifying agent.
  • the water-in-oil emulsion is filtered before being added to the capsule.
  • composition includes anaerobes.
  • methods of the invention are conducted under anaerobic conditions.
  • anaerobic conditions are achieved by using a buffer that is sparged with an inert gas in advance of the introduction of the microbial community to remove dissolved oxygen.
  • the method may further include supplementation with a reducing agent such as cysteine to eliminate oxygen introduced during processing.
  • the composition produced in accordance with the methods described herein may be stored at -80°C prior to use.
  • the composition may be administered to a patient within about 1 day, within about 20 hours, within about 15 hours, within about 10 hours, within about 5 hours, within about 2 hours, or within about 1 hour of thawing.
  • This example describes a protocol for producing orally-administered capsules containing fecal microbiota.
  • Donors deposited stool in a commode, sealed the lid, and placed the collection container in a resealable LDPE plastic bag (Ri-Pac 2GN or similar) as secondary containment.
  • the donors were trained to avoid contamination during collection.
  • the sealed sample collection container was transferred from the donor to a qualified technician to process the fecal sample within one hour of passage.
  • a technician measured the mass of the sample, subtracting the tare weight of the collection container. Subsequently, the sample was transferred to a UV-sterilized biosafety cabinet and cleaned with a sporicidal agent. The sample was not exposed to any other materials or processes in the production facility. The stool sample was transferred to a sterile filter bag within the biosafety cabinet. The filter bag fitted around the collection commode entirely such that there was no risk of any material escaping during the transfer process. All stool materials were added to the same side of the membrane in the filter bag.
  • An autoclaved solution including 80% cocoa butter (Jedwards International, Inc., B3025-C) and 20% glycerol was preheated to 37°C in a water bath, and added to the filter bag in a ratio of 1 g stool: 1 mL solution.
  • the sample solution sealed inside the filter bag was then introduced to a homogenizer blender for 90 seconds to mix the materials.
  • the cocoa butter-glycerol solution created a water-in-oil (w/o) emulsion when mixed with stool, which had an aqueous character.
  • the homogenized sample solution inside the filter bag was then introduced to a water bath at 37°C for 5 minutes.
  • Cocoa butter is solid at room temperature and has a melting point of 35°C ⁇ 1°C.
  • This temperature is also the temperature in the colon and as such is expected to be a suitable temperature for the colonic bacterial populations present in the stool.
  • the filtered sample solution was transferred to a reservoir using a power pipette.
  • a capsule filler machine (CapsulCN, CN-240CL; or similar) was prepared with the corresponding number of empty gelatin capsules (Capsuline, F05592; or similar).
  • the type of filler machine used and the number of gelatin capsules depended on the size of the stool sample. As shown in Figures 1A and IB, samples were aliquotted (750 uL) with a micropipette directly into the empty capsules using sterile, filter pipette tips.
  • the cocoa butter surrounded the water droplets, providing each droplet with a hydrophobic protection layer. This preserved the aqueous environment around the stool droplets and protected the gelatin capsule from aqueous attack and degradation. Accordingly, the capsule formulation described herein extended the window during which capsules may be administrated without risk of leakage or structural compromise. Providers were instructed to administer the capsules within 60 minutes of thawing to preserve bacterial cell viability.
  • Capsules which were produced in accordance with the protocol described in Example 1 were clinically evaluated for the prevention and treatment of recurrent C. diff infections. Specifically, a 52-year old women with a background history of chronic bacterial vaginosis was diagnosed with recurrent Clostridium difficile-associated diarrhea, suffering from 10-12 loose bowel movements per day (modified Horn Index 4). She had been treated with standard antibiotic therapy, including 2 vancomycin tapers, but experienced 4 confirmed episodes of recurrent C. difficile infection after discontinuing antibiotics. She did not have any contraindications to encapsulated FMT administration, and antibiotics were discontinued 48 hours prior to the planned capsule administration.
  • a clear food diet was undertaken the day of capsule treatment, and a fast for 2-hours employed prior to planned ingestion of 30 FMT capsules. Additionally, the patient fasted for another 1-hour post-FMT capsule administration. The same protocol was applied the next day with administration of 30 FMT capsules and an identical diet protocol.
  • Capsules which were produced in accordance with the protocol described in Example 1 were clinically evaluated in a multi-center, cluster randomized dose-finding study. The study aimed to evaluate the safety and resolution rate of diarrhea in patients suffering 3 or more recurrences of Clostridium diffiicile-associated diarrhea and failing to maintain cure after standard oral vancomycin therapy, using high and low dose capsule treatments. High dose treatments were defined as 30 pills daily for two consecutive days while low dose treatments were defined as 30 pills daily for one day only.
  • Patients were treated at two academic hospitals, one of which was randomized to high-dose capsules, and the other two low-dose capsules. Patients at both sites were first pre-treated with oral proton pump inhibitors daily for 48 hours to decrease gastric acid production and maintain microbial viability. Non-responders at either site were treated with a rescue therapy of high dose capsules.

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Abstract

La présente invention concerne des compositions destinées à l'administration de communautés microbiennes. L'invention concerne également des méthodes d'utilisation des compositions pour le traitement d'une maladie ou d'un état associé à la dysbiose gastro-intestinale.
PCT/US2016/026130 2015-05-01 2016-04-06 Compositions et méthodes d'administration thérapeutique de communautés microbiennes Ceased WO2016178775A1 (fr)

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WO2018057747A1 (fr) * 2016-09-21 2018-03-29 Finch Therapeutics, Inc. Compositions pharmaceutiques et procédés d'administration de compositions microbiennes
CN108741030A (zh) * 2018-05-29 2018-11-06 中国热带农业科学院南亚热带作物研究所 一种富含Omega-7的水溶性坚果油微胶囊及其制备方法
WO2018218211A1 (fr) 2017-05-26 2018-11-29 Animal Microbiome Analytics, Inc. Produits et procédés d'administration thérapeutique de micro-organismes à des animaux non humains
WO2019043051A1 (fr) 2017-08-29 2019-03-07 Chr. Hansen A/S Capsules stables comportant un microbiote fécal ou une culture de micro-organismes
WO2020212297A1 (fr) * 2019-04-15 2020-10-22 Institut D'investigacions Biomèdiques August Pi I Sunyer (Idibaps) Composition de microbiote fécal vivant stable à long terme
CN115916235A (zh) * 2020-04-15 2023-04-04 九米特生物制药有限公司 包含d-氨基酸的拉瑞唑来衍生物

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018057747A1 (fr) * 2016-09-21 2018-03-29 Finch Therapeutics, Inc. Compositions pharmaceutiques et procédés d'administration de compositions microbiennes
WO2018218211A1 (fr) 2017-05-26 2018-11-29 Animal Microbiome Analytics, Inc. Produits et procédés d'administration thérapeutique de micro-organismes à des animaux non humains
WO2019043051A1 (fr) 2017-08-29 2019-03-07 Chr. Hansen A/S Capsules stables comportant un microbiote fécal ou une culture de micro-organismes
CN108741030A (zh) * 2018-05-29 2018-11-06 中国热带农业科学院南亚热带作物研究所 一种富含Omega-7的水溶性坚果油微胶囊及其制备方法
CN108741030B (zh) * 2018-05-29 2021-08-17 中国热带农业科学院南亚热带作物研究所 一种富含Omega-7的水溶性坚果油微胶囊及其制备方法
WO2020212297A1 (fr) * 2019-04-15 2020-10-22 Institut D'investigacions Biomèdiques August Pi I Sunyer (Idibaps) Composition de microbiote fécal vivant stable à long terme
EP4609873A3 (fr) * 2019-04-15 2025-11-12 Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS) Composition de microbiote fécal vivant stable à long terme
CN115916235A (zh) * 2020-04-15 2023-04-04 九米特生物制药有限公司 包含d-氨基酸的拉瑞唑来衍生物

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