WO2015200842A1 - Composition comprenant de la metformine et un modulateur du microbiome - Google Patents

Composition comprenant de la metformine et un modulateur du microbiome Download PDF

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Publication number
WO2015200842A1
WO2015200842A1 PCT/US2015/038088 US2015038088W WO2015200842A1 WO 2015200842 A1 WO2015200842 A1 WO 2015200842A1 US 2015038088 W US2015038088 W US 2015038088W WO 2015200842 A1 WO2015200842 A1 WO 2015200842A1
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Prior art keywords
metformin
beta
glucan
pharmaceutical composition
microbiome
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PCT/US2015/038088
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English (en)
Inventor
Mark L. Heiman
Steve A. Orndorff
Dale R. Pfost
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MicroBiome Therapeutics LLC
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Publication of WO2015200842A1 publication Critical patent/WO2015200842A1/fr

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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
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/733—Fructosans, e.g. inulin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/45—Ericaceae or Vacciniaceae (Heath or Blueberry family), e.g. blueberry, cranberry or bilberry
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers

Definitions

  • compositions comprising an active pharmaceutical agent and at least one microbiome modulator.
  • the disclosure provides pharmaceutical compositions for treating diabetes that contain metformin and at least one microbiome modulator.
  • compositions for treating diabetes that contain metformin and/or various DPP-IV inhibitors and/or SGLT-2 inhibitors and at least one microbiome modulator.
  • compositions that are able to ameliorate the negative side effects associated with small molecule targeted cancer therapy in non-small cell lung cancer (NSCLC) patients. These compositions, when administered in conjunction with the small molecule anti-cancer therapy, are able to decrease the incidence of diarrhea associated with the anti-cancer therapy, as well as manage the hyperglycemia also associated with the anti- cancer therapy.
  • NSCLC non-small cell lung cancer
  • the disclosure also provides for oral dietary supplements, comprising: a therapeutically effective amount of Galega officinalis, or an extract thereof, and a microbiome modulator. Consequently, the disclosure provides for efficacious and“all natural” supplements that are useful for treating diabetes and/or hyperglycemia.
  • type 2 diabetes mellitus also known as adult-onset diabetes
  • the incidence of type 2 diabetes mellitus is disturbing.
  • 90 to 95% have type 2 diabetes.
  • the remaining 10% have type 1 diabetes mellitus or gestational diabetes.
  • Type 2 diabetes is a metabolic disorder that is characterized by hyperglycemia.
  • the classic symptoms of type 2 diabetes are excess thirst, frequent urination, and constant hunger.
  • Obesity is thought to be the primary cause of type 2 diabetes in people who are genetically predisposed to the disease.
  • the increased incidence of obesity in the United States is highly correlated with the increased incidence of type 2 diabetes.
  • Treatment for individuals with type 2 diabetes generally consists of lifestyle alterations comprising: eating well, exercising, and maintaining a healthy weight. If diet and exercise don’t help control an individual’s blood sugar, then diabetic medications or insulin therapy are prescribed.
  • metformin sold by Brisol-Myers Squibb as GLUCOPHAGE ® and GLUCOPHAGE XR®, sold as a liquid formulation by Ranbaxy Laboratories as RIOMET ® , sold by various other corporations as: FORTAMET ® , GLUMETZA ® , OBIMET ® , DIANBEN ® , DIABEX ® , and DIAFORMIN ® ).
  • Metformin is an oral antidiabetic drug in the biguanide class. It is the first-line drug of choice for the treatment of type 2 diabetes mellitus. In particular, metformin is effective in treating type 2 diabetes in overweight and obese people and has been associated with modest weight loss in these patients.
  • metformin has been reported to cause a 20% incidence of diarrhea in diabetic patients taking the drug compared to only 6% of diabetic patients not taking metformin.
  • diarrhea associated with metformin is such a problem that some diabetic patients cannot tolerate the drug.
  • the negative side effects associated with metformin treatment lead to a less than ideal patient compliance with the therapy.
  • the diabetic community is in urgent need of compositions and methods that alleviate the negative side effects, e.g. diarrhea, associated with metformin treatment.
  • compositions and methods that alleviate the negative side effects, e.g. diarrhea, associated with metformin treatment.
  • compositions comprising metformin that are useful for treating type 2 diabetes and which do not suffer from the drawbacks inherent in the current metformin compositions.
  • Particular embodiments of the disclosure comprise metformin formulations that contain one or more“microbiome modulators,” which are defined as compounds that have an effect on the gut associated microbial community or habitat of said community.
  • a microbiome modulator e.g. inulin, and/or beta-glucan, and/or a polyphenolic compound
  • the tolerability to metformin can be defined as a composite index that takes into account various parameters, such as stool consistency, degree of nausea, degree of bloating, etc., and amalgamates all of these parameters into a single “tolerability score.”
  • the compositions of the disclosure lead to better tolerability scores for metformin administration.
  • compositions that are able to ameliorate the negative side effects associated with small molecule targeted cancer therapy in non-small cell lung cancer (NSCLC) patients.
  • NSCLC non-small cell lung cancer
  • these compositions when administered in conjunction with the small molecule anti-cancer therapy, are able to decrease the incidence of diarrhea associated with the anti-cancer therapy, as well as manage the hyperglycemia also associated with the anti- cancer therapy.
  • the compositions of the disclosure comprising metformin and a microbiome modulator are able to reduce many of the negative side effects associated with said NSCLC treatments.
  • compositions comprising a microbiome modulator and an extract from Galega officinalis.
  • the compositions may comprise an indigestible carbohydrate, and/or beta-glucan, and/or at least one polyphenolic compound, along with a therapeutically effective amount of Galega officinalis, or an extract of Galega officinalis.
  • the disclosure provides for“all natural” dietary supplements that comprise at least one microbiome modulator and an effective amount of Galega officinalis, or an extract of Galega officinalis.
  • These dietary supplements can be administered to patients to treat hyperglycemia.
  • the dietary supplements can also be administered to diabetic patients to treat diabetes.
  • compositions of the disclosure comprise a microbiome modulator that is effective at altering the gut associated microbiome of patients administered the composition.
  • the disclosure teaches compositions, comprising: metformin and at least one microbiome modulating compound selected from: a) an indigestible carbohydrate that is fermentable by gastrointestinal microbiota, b) beta-glucan, c) a polyphenolic compound, and/or any combination thereof.
  • compositions and formulations taught herein may comprise metformin and a single microbiome modulating compound selected from the aforementioned a)-c), or the compositions may comprise metformin and any two of the microbiome modulators a)-c), or the compositions may comprise metformin and all three of the microbiome modulators a)-c).
  • compositions taught herein do not suffer from many of the negative side effects associated with current forms of metformin treatment. Specifically, patients treated with compositions of the disclosure comprising metformin and at least one microbiome modulator do not experience the harsh degree of diarrhea normally associated with metformin treatment.
  • the disclosure provides a pharmaceutical composition, comprising:
  • composition comprising metformin and a microbiome modulator may be formulated for oral administration.
  • the pharmaceutical composition may be formulated as a liquid formulation, tablet, pill, capsule, pellet, intravenous solution, or any formulation known to one of skill in the art.
  • the composition may be formulated as a medical food.
  • the composition may also be formulated as an edible product, such as: yogurt, a gummy snack such as a gummy bear, licorice, a food bar, a breakfast bar, an edible bar with a semisolid or gelatinous center, a milkshake, a smoothie, pudding, Jell-OTM, a dessert preparation, a yogurt material packaged in a small tube for individual serving as with Go-GurtTM, and any other edible composition known to one of skill in the art.
  • compositions of the disclosure are formulated with a probiotic composition.
  • the microbiome modulators contained in the compositions of the disclosure could remove competition for the probiotics, because, for example, polyphenols inhibit growth of several microbiota.
  • some of the taught microbiome modulators are considered prebiotics that stimulate growth of most commonly used probiotics. This would be helpful in premixing and preparation of the probiotic, as well as colonization of the probiotic in the colon.
  • the microbiome modulators taught herein protect the mucosal barrier that is home to several probiotics that adhere to this site.
  • the microbiome modulator may be, inter alia, an indigestible carbohydrate that is fermentable by gastrointestinal microbiota, or a dietary beta-glucan, or a dietary polyphenol, or any combination thereof.
  • the microbiome modulators act synergistically when in combination.
  • the combination of metformin with any one of the microbiome modulators leads to a synergistic interaction, which is not observed when metformin is utilized alone.
  • the indigestible carbohydrate may be selected from the group consisting of: inulin, oligofructoses, fructo-oligosaccharides, lactulose, galcto-oligosaccharides, arabinoxylans, resistant starch, xylo-oligosaccharides, xylo-oligosaccharide, polydextrose, soybean oligosaccharides, isomalto-oligosaccharides, gluco-oligosaccharides, palatinose, gentio-oligosaccharides, lactitol, sorbitol, maltitol, xylitol, and mixtures thereof; among others.
  • the dietary beta-glucan may be extracted from a member of the group consisting of: baker’s yeast, oat, barley, wheat, fungi, mushrooms, bacteria, and combinations thereof, among others.
  • the dietary beta-glucan includes (1,3/1,4) beta-glucan extracted from oat.
  • the beta-glucan can be any plant derived beta-glucan.
  • the beta-glucan is a plant derived beta-glucan and not a yeast derived beta-glucan.
  • the beta-glucan is a plant derived beta- glucan and not a fungus derived beta-glucan.
  • the beta-glucan is a plant derived beta-glucan and not a bacterial derived beta-glucan.
  • the dietary polyphenol compounds are extracted from berries and comprise anthocyanins and flavonoids.
  • Sources of polyphenol compounds may include: blueberries, blackberries, chokeberries, elderberries, blackcurrant, raspberries, prunes, grapes, apples, and many others.
  • a composition comprising“a polyphenol,” is to be understood as containing one or more polyphenolic compounds.
  • mixtures of polyphenol compounds can be encompassed by the compositions of the disclosure.
  • Colby s formula to measure synergy
  • E X+Y-(X*Y/100
  • by“synergistic” is intended a component which, by virtue of its presence, increases the desired effect by more than an additive amount.
  • Other compositions comprise one predominant polyphenolic molecule that contributes the most activity to the compositions.
  • FIG. 10 illustrates an example of the polyphenolic compounds that can be contained in a composition of the disclosure.
  • the disclosure provides a liquid pharmaceutical composition for oral administration, comprising:
  • the microbiome modulator is at least one selected from the group consisting of: inulin, beta-glucan, and polyphenol, or any combination thereof.
  • the microbiome modulator may comprise inulin and beta-glucan, or inulin and at least one polyphenol, or beta-glucan and at least one polyphenol, or may comprise all three modulators of inulin, beta-glucan, and at least one polyphenol.
  • the microbiome modulator is at least one selected from the group consisting of: agave inulin, beta-glucan (1,3/1,4) extracted from oat, and a polyphenolic compound extracted from blueberry pomace.
  • the microbiome modulator comprises: agave inulin, beta-glucan (1,3/1,4) extracted from oat, and a polyphenolic compound extracted from blueberry pomace.
  • the therapeutically effective amount of metformin may comprise from about 1 mg to about 1000 mg per dose, or about 100 mg to about 1000 mg per dose, or about 200 mg to about 1000 mg per dose, or about 300 mg to about 1000 mg per dose, or about 400 mg to about 1000 mg per dose, or about 500 mg to about 1000 mg per dose, or about 600 mg to about 1000 mg per dose, or about 700 mg to about 1000 mg per dose, or about 800 mg to about 1000 mg per dose, or about 900 mg to about 1000 mg per dose.
  • the therapeutically effective amount of metformin is selected from the group consisting of: 500 mg per dose, 750 mg per dose, 850 mg per dose, and 1000 mg per dose.
  • the therapeutically effective amount of metformin is 500 mg per 5 mL liquid composition.
  • the pharmaceutically acceptable liquid carrier is purified water.
  • the pharmaceutical composition further comprises: a flavoring agent.
  • the flavoring agent does not increase the blood glucose level of a subject after ingestion thereof.
  • the pharmaceutical composition further comprises: a sugar alcohol or non- nutritive flavoring agent.
  • the therapeutically effective amount of a HCl acid addition salt of metformin is present.
  • the metformin, or its pharmaceutically acceptable salts are in association with a liquid carrier.
  • the liquid form includes: solutions, suspensions, syrups, and emulsions.
  • the liquid carrier is one that is normally utilized as a liquid carrier in pharmaceutical formulations and preparations, except that the liquid carrier, in most embodiments, does not contain excessive alcohol (e.g. ethanol).
  • alcohol e.g. ethanol
  • the liquid carrier may be an aqueous liquid, such as water, a non-aqueous liquid, such as glycols, e.g., propylene glycol or polyethylene glycol, vegetable oil, an oil-in-water emulsion, or a water-in-oil liquid emulsion, or an aqueous dispersion, such as in glycol, liquid polyethylene glycol, vegetable oil, and mixtures thereof.
  • aqueous liquid such as water
  • a non-aqueous liquid such as glycols, e.g., propylene glycol or polyethylene glycol
  • vegetable oil an oil-in-water emulsion
  • a water-in-oil liquid emulsion such as in glycol, liquid polyethylene glycol, vegetable oil, and mixtures thereof.
  • the liquid formulation is syrupy. In some particular embodiments, the viscosity of the liquid formulation is near or greater than 1. In embodiments, the viscosity of the liquid formulation of the disclosure ranges from about 5 to about 50 cps, or from about 10 to about 40 cps, or from about 15 to about 35 cps or is about 25 cps.
  • the density of the liquid formulation is one g/mL or greater, with the maximum value being that value a flowing liquid can have.
  • the density of the liquid at 25°C is between 1 g/mL and 2 g/mL or between 1.05 g/mL and 1.5 g/mL or between 1.1 g/mL and 1.3 g/mL.
  • composition comprising:
  • At least one microbiome modulator selected from: an indigestible carbohydrate, beta-glucan, a polyphenolic compound, or any combination thereof; and c) a pharmaceutically acceptable carrier.
  • the beta-glucan is derived from a plant. In some embodiments, the beta-glucan is not derived from yeast. In particular embodiments, the beta-glucan is (1,3/1,4) beta-glucan extracted from oat.
  • liquid pharmaceutical composition for oral administration comprising:
  • composition comprising:
  • a plant derived microbiome modulator comprises beta-glucan.
  • the plant derived microbiome modulator comprising beta-glucan comprises beta-glucan (1,3/1,4) beta-glucan extracted from oat.
  • the plant derived microbiome modulator comprising beta-glucan further comprises: inulin and/or a polyphenol.
  • the plant derived microbiome modulator comprising beta-glucan further comprises: agave inulin and/or a polyphenol extracted from blueberry pomace.
  • liquid pharmaceutical composition for oral administration comprising:
  • a mineral acid and bicarbonate salt both present in sufficient amounts to maintain the pH of the liquid pharmaceutical composition in the range of about 4.0 to about 9.0;
  • the plant derived microbiome modulator is inulin, and/or beta-glucan, and/or a polyphenolic compound derived or extracted from a plant.
  • the beta- glucan is (1,3/1,4) beta-glucan extracted from oat.
  • the plant derived microbiome modulator comprising beta-glucan further comprises: inulin and/or a polyphenol.
  • the plant derived microbiome modulator comprising beta-glucan further comprises: agave inulin and/or a polyphenol extracted from blueberry pomace.
  • the therapeutically effective amount of metformin is selected from the group consisting of: 500 mg per dose, 750 mg per dose, 850 mg per dose, and 1000 mg per dose.
  • the therapeutically effective amount of metformin is 500 mg per 5 mL liquid composition.
  • the pharmaceutically acceptable liquid carrier is purified water.
  • liquid pharmaceutical composition for oral administration further contains a flavoring agent that does not increase the blood glucose level of a subject after ingestion thereof.
  • the liquid pharmaceutical composition for oral administration further contains a sugar alcohol or non-nutritive flavoring agent.
  • the sugar alcohol or non-nutritive flavoring agent can be present in amounts ranging from about: 50% to about 70%, or about 55% to about 65%.
  • the liquid pharmaceutical composition for oral administration comprises a therapeutically effective amount of a HCl acid addition salt of metformin.
  • liquid pharmaceutical composition further comprise alkyl hydroxyethylcellulose.
  • the alkyl hydroxyethylcellulose’s alkyl group may contain from 2 to 10 carbon atoms.
  • the alkyl hydroxyethylcellulose may be present in amounts ranging from about 0.08% to about 0.2% by weight.
  • the polyhydroxy alcohol is present in the composition in an amount ranging from about 15% to about 40% by weight.
  • the polyhydroxy alcohol may contain from 2 to 6 carbon atoms and from 2 to 6 hydroxy groups.
  • the polyhydroxy alcohol is a polymer having a molecular weight ranging from 200 to 2000 daltons and has a repeating unit of 2 to 6 carbon atoms and the repeating unit contains 2 to 6 hydroxy groups.
  • the mineral acid of the composition is hydrochloric acid, nitric acid, or sulfuric acid.
  • the bicarbonate salt of the composition is potassium bicarbonate.
  • a particular embodiment of the composition comprises hydrochloric acid as the mineral acid and potassium bicarbonate as the bicarbonate salt.
  • Also taught herein is a method of minimizing the side effects associated with molecularly targeted treatment in a cancer patient, comprising:
  • a) administering to the cancer patient a pharmaceutical composition comprising: i) a therapeutically effective amount of metformin, or a pharmaceutically acceptable salt thereof;
  • cancer patient is being treated with a compound targeted for treatment of non-small cell lung cancer.
  • the cancer patient is being treated with a compound that is a targeted covalent inhibitor of the cancer-causing mutant forms of epidermal growth factor receptor.
  • the cancer patient is being treated with a compound that is a targeted covalent inhibitor of the initial activating epidermal growth factor receptor mutations.
  • the cancer patient is being treated with a compound that is a targeted covalent inhibitor of the epidermal growth factor receptor T790M resistance mutation.
  • the cancer patient is being treated with a compound with the following structure:
  • the cancer patient is being treated with the hydrobromide salt of a compound with the following structure: .
  • the cancer patient is being treated with CO-1686.
  • the side effect being minimized in the cancer patient is diarrhea or hyperglycemia.
  • the side effect associated with administration of CO-1686 is diarrhea, and the patient experiences less episodes of diarrhea when administered the taught pharmaceutical composition, as compared to the number of episodes of diarrhea experienced by the patient when not administered the taught pharmaceutical composition.
  • the microbiome modulator is at least one selected from the group consisting of: inulin, beta-glucan, polyphenol, and/or any combination thereof.
  • a) administering to the cancer patient a pharmaceutical composition comprising: i) a therapeutically effective amount of metformin, or a pharmaceutically acceptable salt thereof;
  • cancer patient is being treated with CO-1686.
  • the side effect being minimized in the cancer patient is diarrhea. In other aspects, the side effect being minimized is hyperglycemia. In some aspects, both diarrhea and hyperglycemia are minimized in the cancer patient.
  • the cancer patient is being treated with CO-1686 twice per day at an active ingredient concentration per dosage selected from 500 mg, 625 mg, 750 mg, 900 mg, or 1000 mg.
  • the patient is being treated with the taught pharmaceutical composition one or more times per day, e.g. twice per day, three times per day, four times per day, or more.
  • the pharmaceutical composition is administered with a meal.
  • Also taught herein is a method of treating non-small cell lung cancer in a patient in need thereof, comprising administering to said patient:
  • an oral liquid pharmaceutical composition comprising:
  • the microbiome modulator is at least one selected from the group consisting of: inulin, beta-glucan, polyphenol, and combinations thereof. In other embodiments, the microbiome modulator is at least one selected from the group consisting of: agave inulin, beta-glucan (1,3/1,4) extracted from oat, and a polyphenolic compound extracted from blueberry pomace. In yet other embodiments, the microbiome modulator comprises: agave inulin, beta-glucan (1,3/1,4) extracted from oat, and a polyphenolic compound extracted from blueberry pomace.
  • the therapeutically effective amount of metformin is selected from the group consisting of: 500 mg per dose, 750 mg per dose, 850 mg per dose, and 1000 mg per dose.
  • the therapeutically effective amount of metformin is 500 mg per 5 mL liquid composition.
  • the cancer patient is administered CO- 1686 twice per day at an active ingredient concentration per dosage selected from 500 mg, 625 mg, 750 mg, 900 mg, or 1000 mg.
  • a therapeutically effective amount of a HCl acid addition salt of metformin is present in said pharmaceutical composition.
  • Also taught herein is a method of treating non-small cell lung cancer in a diabetic patient in need thereof, comprising: administering to said diabetic patient: a) CO-1686; and b) Metformin-MB.
  • the term“Metformin-MB” is utilized to denote the taught pharmaceutical composition that comprises metformin and at least one microbiome modulator.
  • the diabetic patient has type 2 diabetes.
  • the diabetic patient is administered CO-1686 twice per day at an active ingredient concentration per dosage selected from 500 mg, 625 mg, 750 mg, 900 mg, or 1000 mg, and the diabetic patient is administered Metformin-MB at least once per day, or at least twice per day, or at least three times per day, or at least four times per day, each time with a meal.
  • the disclosure provides for methods of treating diabetes in a patient suffering therefrom, comprising: administering a pharmaceutical composition as taught herein to said patient.
  • the patient suffers from type 2 diabetes.
  • the disclosure provides for methods of treating hyperglycemia in a patient suffering therefrom, comprising: administering a pharmaceutical composition as taught herein to said patient.
  • the patient does not suffer from a high incidence of diarrhea when treated with the pharmaceutical compositions, as taught herein.
  • the patient does not suffer from abdominal pain or bloating when treated with the pharmaceutical compositions of the disclosure.
  • compositions of the disclosure comprise a microbiome modulator that is effective at altering the gut associated microbiome of patients administered the composition.
  • the disclosure teaches compositions, comprising: a DPP-IV inhibitor (generically referred to as a gliptin) and at least one microbiome modulating compound selected from: a) an indigestible carbohydrate that is fermentable by gastrointestinal microbiota, b) beta-glucan, c) a polyphenolic compound, and/or any combination thereof.
  • compositions and formulations taught herein may comprise a DPP-IV inhibitor and a single microbiome modulating compound selected from the aforementioned a)-c), or the compositions may comprise a DPP-IV inhibitor and any two of the microbiome modulators a)-c), or the compositions may comprise a DPP-IV inhibitor and all three of the microbiome modulators a)-c).
  • compositions of the disclosure comprise a microbiome modulator that is effective at altering the gut associated microbiome of patients administered the composition.
  • the disclosure teaches compositions, comprising: a SGLT-2 inhibitor (generically referred to as a gliflozin) and at least one microbiome modulating compound selected from: a) an indigestible carbohydrate that is fermentable by gastrointestinal microbiota, b) beta-glucan, c) a polyphenolic compound, and/or any combination thereof.
  • compositions and formulations taught herein may comprise a SGLT-2 inhibitor and a single microbiome modulating compound selected from the aforementioned a)-c), or the compositions may comprise a SGLT-2 inhibitor and any two of the microbiome modulators a)-c), or the compositions may comprise a SGLT-2 inhibitor and all three of the microbiome modulators a)-c).
  • compositions of the disclosure comprise a microbiome modulator that is effective at altering the gut associated microbiome of patients administered the composition.
  • the disclosure teaches compositions, comprising: both a SGLT-2 inhibitor and a DPP-IV inhibitor and at least one microbiome modulating compound selected from: a) an indigestible carbohydrate that is fermentable by gastrointestinal microbiota, b) beta-glucan, c) a polyphenolic compound, and/or any combination thereof.
  • compositions and formulations taught herein may comprise both a SGLT-2 inhibitor and a DPP-IV inhibitor and a single microbiome modulating compound selected from the aforementioned a)-c), or the compositions may comprise both a SGLT-2 inhibitor and a DPP-IV inhibitor and any two of the microbiome modulators a)-c), or the compositions may comprise both a SGLT-2 inhibitor and a DPP-IV inhibitor and all three of the microbiome modulators a)-c).
  • compositions of the disclosure comprise a microbiome modulator that is effective at altering the gut associated microbiome of patients administered the composition.
  • the disclosure teaches compositions, comprising: metformin and a SGLT-2 inhibitor and a DPP-IV inhibitor and at least one microbiome modulating compound selected from: a) an indigestible carbohydrate that is fermentable by gastrointestinal microbiota, b) beta-glucan, c) a polyphenolic compound, and/or any combination thereof.
  • compositions and formulations taught herein may comprise metformin and a SGLT-2 inhibitor and a DPP-IV inhibitor and a single microbiome modulating compound selected from the aforementioned a)-c), or the compositions may comprise metformin and a SGLT-2 inhibitor and a DPP-IV inhibitor and any two of the microbiome modulators a)-c), or the compositions may comprise metformin and a SGLT-2 inhibitor and a DPP-IV inhibitor and all three of the microbiome modulators a)-c).
  • the compositions of the disclosure comprise a microbiome modulator that is effective at altering the gut associated microbiome of patients administered the composition.
  • compositions comprising: metformin and a SGLT-2 inhibitor and at least one microbiome modulating compound selected from: a) an indigestible carbohydrate that is fermentable by gastrointestinal microbiota, b) beta-glucan, c) a polyphenolic compound, and/or any combination thereof.
  • compositions and formulations taught herein may comprise metformin and a SGLT-2 inhibitor and a single microbiome modulating compound selected from the aforementioned a)-c), or the compositions may comprise metformin and a SGLT-2 inhibitor and any two of the microbiome modulators a)-c), or the compositions may comprise metformin and a SGLT-2 inhibitor and all three of the microbiome modulators a)-c).
  • compositions of the disclosure comprise a microbiome modulator that is effective at altering the gut associated microbiome of patients administered the composition.
  • the disclosure teaches compositions, comprising: metformin and a DPP-IV inhibitor and at least one microbiome modulating compound selected from: a) an indigestible carbohydrate that is fermentable by gastrointestinal microbiota, b) beta-glucan, c) a polyphenolic compound, and/or any combination thereof.
  • compositions and formulations taught herein may comprise metformin and a DPP-IV inhibitor and a single microbiome modulating compound selected from the aforementioned a)-c), or the compositions may comprise metformin and a DPP-IV inhibitor and any two of the microbiome modulators a)-c), or the compositions may comprise metformin and a DPP-IV inhibitor and all three of the microbiome modulators a)-c).
  • Other aspects of the disclosure provide methods for treating diabetes and/or hyperglycemia that contain metformin and/or various DPP-IV inhibitors and/or SGLT-2 inhibitors and at least one microbiome modulator.
  • FIG. 1 is an illustration of the various mechanisms associated with the gut microbial community during dysbiosis.
  • FIG. 2 is a schematic depiction of possible mechanisms of action of various microbiome modulators taught herein.
  • FIG. 3 is an illustration of the contributions of the gastrointestinal (“gut”) microbiome to the development of type 2 diabetes.
  • FIG. 4 is an illustration depicting how an individual’s diet contributes to GI inflammation that is associated with type 2 diabetes.
  • FIG. 5 is an illustration depicting how a microbiome modulator, beta-glucan, can stimulate secretory immunoglobulin A (sIgA) secretion into the GI lumen to protect against consequences of diet-induced inflammation.
  • a microbiome modulator beta-glucan
  • IgA secretory immunoglobulin A
  • FIG. 6 is an expected result illustrating the hypothesized ability of METFORMIN- MB to increase sIgA secretion in a patient compared to a patient receiving the standard metformin formulation that does not comprise, for example, a beta-glucan microbiome modulator.
  • FIG. 7 is an illustration of the relationship of the gastrointestinal (“gut”) microbiome and type 2 diabetes.
  • Metformin hydrochloride is a white to off-white crystalline compound with a molecular formula of C 4 H 11 N 5 •HCl and a molecular weight of 165.63.
  • FIG. 8 illustrates that the development of insulin resistance and ⁇ -cell failure are involved in the development of obesity-associated type 2 diabetes.
  • FIG. 9 illustrates that polyphenols stimulate Acetogens that compete with methanogens and SRB for Hydrogen.
  • FIG. 10 illustrates polyphenol compounds that are present in an example composition according to the disclosure.
  • FIG. 11 illustrates metformin as better tolerated when combined with GIMM (gastrointestinal microbiome modulator) than placebo.
  • Tolerability is a composite score of GI symptoms. A greater tolerability score indicates a better metformin tolerance.
  • FIG. 12A and FIG. 12B illustrate fasting blood glucose levels.
  • Subjects were assigned GIMM (FIG. 12A) or placebo (FIG. 12B).
  • Subjects were instructed to take 500 mg metformin b.i.d. during the initial week of each period and 500 mg metformin t.i.d. during the second week.
  • Subjects were permitted to discontinue metformin dosing if symptoms became intolerable. Days metformin was taken are indicated by the solid symbols.
  • FIG. 13 illustrates the mean observed fasting glucose for subjects taking GIMM during period 1. Bars represent mean ⁇ standard error of the mean (SEM). DETAILED DESCRIPTION
  • the articles“a,”“an,” and“the” may include plural referents unless otherwise expressly limited to one-referent, or if it would be obvious to a skilled artisan from the context of the sentence that the article referred to a singular referent.
  • “About” means plus or minus a percent (e.g., ⁇ 5%) of the number, parameter, or characteristic so qualified, which would be understood as appropriate by a skilled artisan to the scientific context in which the term is utilized.
  • “Sustained release” or“controlled release” refers to the release of at least one therapeutic agent, or drug, from a delivery device (e.g. pill, capsule, tablet, etc.) at a predetermined rate. Sustained release implies that the therapeutic agent is not released sporadically, in an unpredictable fashion.
  • the term“sustained release” may include a“burst phenomenon” associated with deployment. In some example embodiments, an initial burst of at least one therapeutic agent may be desirable, followed by a more gradual release thereafter.
  • the release rate may be steady state (commonly referred to as“timed release” or zero order kinetics), that is the at least one therapeutic agent is released in even amounts over a predetermined time (with or without an initial burst phase), or may be a gradient release.
  • sustained release can have substantially no fluctuations in therapeutic agent delivery.
  • the term“patient” refers to an animal who is suffering from a disease or symptom of a disease, for example, hyperglycemia or diabetes.
  • the animal may be a mammal, such as a dog, cat, horse, cow, or human.
  • “Therapeutically effective amount” means a level or amount of an agent needed to treat a condition.
  • a therapeutically effective amount of a therapeutic agent such as metformin, is an amount that is effective in reducing at least one symptom of a diabetic patient.
  • a“therapeutically effective amount” of metformin is meant that amount of metformin, or its pharmaceutically acceptable salt, which either maintains or reduces the concentration of sugar in the blood of the patient, depending upon the severity of the disease.
  • the therapeutically effective amount is determined by an ordinarily skilled artisan, taking into account various considerations, such as: the age of the subject, the weight of the subject, the condition of the subject, the type of subject (i.e., the type of animal), the regimen, the desired result, and the like.
  • microbiome modulator references an agent that is capable of altering the gut associated microbial community of a patient administered the agent or the gut habitat of said community.
  • the microbiome modulators of the disclosure are based on the inventors’ research indicating that the composition of the large populations of bacteria and other microorganisms (collectively referred to as the microbiota, or microbial community) resident in the human GI tract can have a significant impact on health.
  • Microbiome modulators shift the GI microbiota, and their environment, in specific ways to achieve improved health outcomes.
  • the change in the microbial community may involve an increase or decrease in one or more species of the microbial community.
  • the change in the habitat of the gut associated microbial community may comprise an increase or decrease in the“tightness” of a patient’s gut. Furthermore, the change in the habitat of the gut associated microbial community may comprise increased production of small chain fatty acids (SCFAs), increased viscosity in the lumen, protection of a mucus barrier, priming of the GI immune system, sequester of bile salts, impeding glucose absorption, among other habitat alterations discussed herein.
  • SCFAs small chain fatty acids
  • the change may be brought about by a variety of mechanisms as explained in the disclosure.
  • Exemplary microbiome modulators utilized in embodiments of the disclosure include: inulin, beta-glucan, and polyphenolic compounds.
  • Metformin is an oral antihyperglycemic drug used in the management of type 2 diabetes. Metformin has the following structure:
  • metformin N,N-Dimethylimidodicarbonimidic diamide
  • the commercially marketed version of the drug is the HCl acid addition salt, metformin hydrochloride, having the following structure:
  • metformin hydrochloride N,N-Dimethylimidodicarbonimidic diamide hydrochloride
  • Metformin and any of its generic salts can be represented by the following structure:
  • A is the anion of the non-toxic salt of the preferred medicament.
  • Metformin hydrochloride is a white to off-white crystalline compound with a molecular formula of C 4 H 11 N 5 •HCl and a molecular weight of 165.63.
  • Metformin hydrochloride is freely soluble in water and is practically insoluble in acetone, ether, and chloroform.
  • the pKa of Metformin is 12.4.
  • the pH of a 1% aqueous solution of Metformin hydrochloride is 6.68.
  • 3,174,921 discloses various pharmaceutically acceptable salts of metformin, for example: phosphate, sulfate, hydrochloride, salicylate, maleate, benzoate, ethanedisulfonate, fumarate and glycolate; whereas, U.S. Pat. No. 6,031 ,004 discloses metformin salts of dibasic acids, such as fumarate and succinate, wherein the molar ratio of metformin:dibasic acid is 2:1.
  • Metformin can be synthesized according to the following reaction scheme, in which dimethylamine hydrochloride is reacted under heat with 2-cyanoguanidine to yield metformin hydrochloride.
  • metformin hydrochloride tablet USP intended for oral administration and immediate release of active ingredient contains 500 mg, or 850 mg, or 1000 mg metformin hydrochloride.
  • the metformin extended release commercial formulations contain 500 mg and 750 mg metformin hydrochloride.
  • each metformin hydrochloride tablet USP generally contains one of the following inactive ingredients: colloidal silicon dioxide, hypromellose, magnesium stearate, polyethylene glycol, and povidone.
  • GLUCOPHAGE ® contains the inactive ingredients povidone and magnesium stearate and the coating for the 500 mg and 850 mg tables contains hypromellose, whereas the coating for the 1000 mg tablet contains hypromellose and polyethylene glycol.
  • GLUCOPHAGE XR ® 500 mg tablets contain the inactive ingredients sodium carboxymethyl cellulose, hypromellose, microcrystalline cellulose, and magnesium stearate.
  • GLUCOPHAGE XR ® 750 mg tablets contain the inactive ingredients sodium carboxymethyl cellulose, hypromellose, and magnesium stearate.
  • Metformin hydrochloride tablets are comprised of a cohesive white powder which is highly soluble in water (>300 mg/ml at ambient temperature), has a hygroscopicity measured at 95% relative humidity /25° C. of greater than 20% moisture uptake at 6 hours, and a high compaction susceptibility. Accordingly, handling of metformin hydrochloride in a pharmaceutical manufacturing facility can present problems, especially in high humidity environments.
  • metformin hydrochloride salt has a pronounced saline, bitter taste. Accordingly, it is usually marketed as a coated tablet where the coating is designed to mask any unpleasant taste.
  • metformin hydrochloride salt is in the form of scored-divisible tablets, it will not usually have a coating or outer layer to mask the unpleasant taste.
  • taste is of primary concern where the metformin hydrochloride is to be formulated as a chewable tablet or liquid indicated for children or adults who are not able to swallow tablets.
  • the pharmaceutical compositions of the present disclosure are formulated as a tablet.
  • the microbiome modulator is brought into association with the metformin and the normal inactive ingredients and excipients, as aforementioned, and pressed into a tablet as is known by a skilled artisan.
  • the tablets may be larger chewable tablets.
  • the microbiome modulator and metformin formulations may be formed into a tablet using methods known in the art, including a wet granulation method and a direct compression method.
  • the oral tablets are prepared using any suitable process known to the art. See, e.g., Remington's Pharmaceutical Sciences, 18th Edition, A. Gennaro, Ed., Mack Pub. Co. (Easton, Pa. 1990), Chapters 88-91, the entirety of which is hereby incorporated by reference.
  • the active ingredient which in embodiments is metformin and a microbiome modulator, is mixed with pharmaceutically acceptable excipients (e.g., the binders, lubricants, etc. listed above) and compressed into tablets.
  • the dosage form is prepared by a wet granulation technique or a direct compression method to form uniform granulates.
  • the active ingredients can be mixed with the granulate after the granulate is prepared.
  • the moist granulated mass is then dried and sized using a suitable screening device to provide a powder, which can then be filled into capsules or compressed into matrix tablets or caplets, as desired.
  • the tablets are prepared using the direct compression method.
  • the direct compression method offers a number of potential advantages over a wet granulation method, particularly with respect to the relative ease of manufacture.
  • at least one pharmaceutically active agent and the excipients or other ingredients can be sieved through a stainless steel screen, such as a 40 mesh steel screen.
  • the sieved materials can then be charged to a suitable blender.
  • the materials can be blended for an appropriate amount of time, for example 10 minutes.
  • the blend can then be compressed into tablets on a rotary press using appropriate tooling.
  • the tablets of the disclosure comprise metformin and beta- glucan. In other embodiments, the tablets of the disclosure comprise metformin and inulin.
  • the tablets of the disclosure comprise metformin and a polyphenol compound.
  • the tablets of the disclosure comprise metformin and at least one microbiome modulator selected from the group consisting of: inulin, beta-glucan, a polyphenol compound, and any combination thereof.
  • fillers add volume and/or mass to a drug substance, thereby facilitating precise metering and handling thereof in the preparation of dosage forms. Fillers typically also fill out the size of a tablet or capsule, making it practical to produce and convenient for the consumer to use.
  • a filler should typically be inert, compatible with the other components of the formulation, non-hygroscopic, relatively cheap, compactible, and preferably tasteless or pleasant tasting.
  • Plant cellulose pure plant filler
  • Dibasic calcium phosphate is another tablet filler.
  • a range of vegetable fats and oils can be used in soft gelatin capsules.
  • Other examples of fillers include: lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, and magnesium stearate. Sometimes other noted kinds of excipients are in effect doubling in function as fillers.
  • Binders hold the ingredients in a tablet together. Binders ensure that tablets and granules can be formed with required mechanical strength, and give volume to low active dose tablets. Binders are usually saccharides and their derivatives, for instance: (1) Disaccharides: sucrose, lactose; (2) Polysaccharides and their derivatives: starches, cellulose or modified cellulose such as microcrystalline cellulose and cellulose ethers such as hydroxypropyl cellulose (HPC); (3) Sugar alcohols such as xylitol, sorbitol or maltitol; (4) Protein: gelatin; (5) Synthetic polymers: polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), etc.
  • PVP polyvinylpyrrolidone
  • PEG polyethylene glycol
  • Binders are often classified according to their application: Solution binders are dissolved in a solvent (for example water or alcohol can be used in wet granulation processes). Examples include gelatin, cellulose, cellulose derivatives, polyvinylpyrrolidone, starch, sucrose and polyethylene glycol. Dry binders are added to the powder blend, either after a wet granulation step, or as part of a direct powder compression (DC) formula. Examples include cellulose, methyl cellulose, polyvinylpyrrolidone and polyethylene glycol. [0111] Disintegrants expand and dissolve when wet causing the tablet to break apart in the digestive tract, releasing the active ingredients for absorption.
  • a solvent for example water or alcohol can be used in wet granulation processes. Examples include gelatin, cellulose, cellulose derivatives, polyvinylpyrrolidone, starch, sucrose and polyethylene glycol.
  • Dry binders are added to the powder blend, either after a wet granulation step, or as part of a direct
  • disintegrants include crosslinked polymers such as: crosslinked polyvinylpyrrolidone (crospovidone), crosslinked sodium carboxymethyl cellulose (croscarmellose sodium). Another common disintegrant is the modified starch sodium starch glycolate.
  • Lubricants prevent ingredients from clumping together and from sticking to the tablet punches or capsule filling machine. Lubricants also ensure that tablet formation and ejection can occur with low friction between the solid and die wall. Common minerals like talc or silica, and fats, e.g. vegetable stearin, magnesium stearate or stearic acid are the most frequently used lubricants in tablets or hard gelatin capsules. Lubricants are agents added in small quantities to tablet and capsule formulations to improve certain processing characteristics.
  • lubricants There are three roles identified with lubricants as follows: (1) True lubricant role: To decrease friction at the interface between a tablet’s surface and the die wall during ejection and reduce wear on punches and dies; (2) Anti-adherent role: Prevent sticking to punch faces or in the case of encapsulation, lubricants prevent sticking to machine dosators, tamping pins, etc.; (3) Glidant role: Enhance product flow by reducing interparticulate friction.
  • Hydrophilic which are often generally poor lubricants, with no glidant or anti-adherent properties
  • Hydrophobic which are the most widely used lubricants. Hydrophobic lubricants are generally good lubricants and are usually effective at relatively low concentrations. Many also have both anti-adherent and glidant properties. For these reasons, hydrophobic lubricants are used much more frequently than hydrophilic compounds.
  • An example includes magnesium stearate.
  • the pharmaceutical compositions of the present disclosure are formulated as an edible product, such as: yogurt, a gummy snack such as a gummy bear, licorice, a food bar, a breakfast bar, an edible bar with a semisolid or gelatinous center, a milkshake, a smoothie, pudding, Jell-OTM, a dessert preparation, a yogurt material packaged in a small tube for individual serving as with Go-GurtTM, and any other edible composition known to one of skill in the art.
  • metformin is water soluble and has good heat stability, it is not a potent drug. Metformin doses typically needed range from 500mg - 1000mg.
  • the mass of the aforementioned tablet embodiments of the taught pharmaceutical compositions may be larger than a consumer would desire, e.g. ⁇ 8g.
  • the pharmaceutical compositions of the disclosure require a unique delivery system, such as an edible product.
  • these unique delivery systems may be a large capsule or a chewable tablet.
  • the inventors have discovered that they are able to take advantage of the gelling properties of the microbial modulator beta-glucan. Because beta-glucan leads to gelation, this sometimes makes liquid formulations difficult. But, the inventors have surprisingly discovered that this same property aids in formulating something like yogurt, pudding, smoothies, or Jell-OTM. Since metformin should be taken with a meal and compliance is an issue for all drugs to be taken more than 1 time per day, and metformin patients are even less compliant because of GI side effects, the edible product embodiments are a unique solution. Thus, a unique formulation that appears as a desert and lessens the GI side effects could be a real advantage. The present edible product embodiments are particularly great for children with prediabetes or diabetes. In some aspects, the edible products are formulated into a small tube like Go-GurtTM and are easy to carry and store. The edible product embodiments in some aspects do not need to be refrigerated. In some aspects, the edible products are meal replacements.
  • patients administered the aforementioned edible products have less severe diarrhea, less abdominal pain, less bloating, less loose stool, improved OGTT, improved gut tightness with increased sIgA, decreased plasma cholesterol, less nausea, less heartburn, less stomach cramps, and decreased fecal pH, as compared to patients administered a standard metformin formulation that does not comprise a microbiome modulator.
  • Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Its pharmacologic mechanisms of action are different from other classes of oral antihyperglycemic agents. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients with type 2 diabetes or normal subjects and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged, while fasting insulin levels and day-long plasma insulin response may actually decrease.
  • Metformin is effective in the presence of insulin, and its major effect is to decrease hepatic glucose output.
  • metformin increases insulin-mediated glucose utilization in peripheral tissues (such as muscle and liver), particularly after meals, and has an antilipolytic effect that lowers serum free fatty acid concentrations, thereby reducing substrate availability for gluconeogenesis.
  • serum insulin concentrations decline slightly.
  • Metformin also increases intestinal glucose utilization via nonoxidative metabolism, at least in experimental animals.
  • the lactate produced by this process is largely metabolized in the liver as a substrate for gluconeogenesis. The latter effect could protect against hypoglycemia.
  • AMP-activated protein kinase [0122] The molecular mechanisms of metformin action are not fully known. Activation of the enzyme AMP-activated protein kinase (AMPK) appears to be the mechanism by which metformin lowers serum lipid and blood glucose concentrations. Hawley, et al.,“The antidiabetic drug metformin activates the AMP-activated protein kinase cascade via an adenine nucleotide-independent mechanism,” Diabetes, 2002, Vol. 51(8), pgs. 2420-2425.
  • AMPK AMP-activated protein kinase
  • AMPK-dependent inhibitory phosphorylation of acetyl-coA carboxylases Acc1 and Acc2 then suppresses lipogenesis and lowers cellular fatty acid synthesis in liver and muscle, which in turn improves insulin sensitivity and reduces blood glucose levels.
  • Metformin works through the Peutz-Jeghers protein, LKB1, to regulate AMPK.
  • LKB1 is a tumor suppressor and activation of AMPK through LKB1 may play a role in inhibiting cell growth.
  • metformin hydrochloride 500 mg tablet given under fasting conditions is approximately 50% to 60%.
  • Food decreases the extent of, and slightly delays the absorption of, metformin, as shown by approximately a 40% lower mean peak plasma concentration (C max ) and 25% lower area under the plasma concentration versus time curve (AUC), and a 35- minute prolongation of time to peak plasma concentration (T max ) following administration of a single 850 mg tablet of metformin with food, compared to the same tablet strength administered fasting. See GLUCOPHAGE XR ® label.
  • V/F The apparent volume of distribution (V/F) of metformin following single oral doses of 850 mg averaged 654 ⁇ 358 L.
  • Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely as a function of time.
  • steady state plasma concentrations of metformin are reached within 24 to 48 hours and are generally ⁇ 1 ⁇ g/mL.
  • maximum metformin plasma levels did not exceed 5 ⁇ g/mL, even at maximum doses. See GLUCOPHAGE XR ® label.
  • Metformin has been reported to cause a 20% incidence of diarrhea in diabetic patients taking the drug compared to only 6% of diabetic patients not taking metformin. See, Diabetes Care, 1983, Vol. 6, pgs. 472-4.
  • metformin Further side effects associated with metformin include: nausea, vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache. See also Table 2 below, taken from GLUCOPHAGE XR ® label and indicating 53.2% of patients taking the metformin drug experienced diarrhea, as compared to only 11.7% of placebo patients.
  • compositions of the present disclosure are able to alleviate one or more of the negative side effects listed in Table 2.
  • TABLE 2 Common Adverse Reactions to Metformin Treatment
  • Metformin is often prescribed to type 2 diabetes patients in combination with other drugs. Several are available as fixed-dose combinations, with the purpose of reducing pill burden and making administration simpler and more convenient. As of 2009, the most popular brand-name combination was metformin with rosiglitazone, sold as AVANDAMET ® by GlaxoSmithKline since 2002. Rosiglitazone actively makes cells more sensitive to insulin, complementing the action of the metformin.
  • metformin is also available in combination with: pioglitazone (ACTOPLUS MET ® ), the sulfonylureas glipizide (METAGLIP ® ) and glibenclamide (known as“glyburide”' in the United States, GLUCOVANCE ® ), the dipeptidyl peptidase-4 inhibitor sitagliptin (JANUMET ® ), and the meglitinide repaglinide (PRANDIMET ® ).
  • pioglitazone ACTOPLUS MET ®
  • MEAGLIP ® sulfonylureas glipizide
  • glibenclamide known as“glyburide”' in the United States, GLUCOVANCE ®
  • JNUMET ® dipeptidyl peptidase-4 inhibitor sitagliptin
  • PRANDIMET ® meglitinide repaglinide
  • compositions of the disclosure may contain optional active ingredients along with metformin.
  • the compositions may comprise another antihyperglycemic agent.
  • the metformin, or salt thereof may be in combination with one or more antihyperglycemic agents.
  • the compositions comprise: metformin, or a pharmaceutically acceptable salt thereof, and beta-glucan, and glyburide.
  • the compositions comprise: metformin, or a pharmaceutically acceptable salt thereof, and beta-glucan, and glipizide.
  • the antihyperglycemic agent may be an oral antihyperglycemic agent, e.g., a sulfonyl urea, such as glyburide, glimepiride (disclosed in U.S. Pat. No.
  • the sulfonyl ureas such as glyburide, glimepiride, glipyride, glipizide, chlorpropamide and gliclazide, and the glucosidase inhibitors acarbose or miglitol, may be employed in formulation amounts and dosing as indicated in the Physician’s Desk Reference.
  • metformin, or salt thereof is preferably employed in a weight ratio to the sulfonylurea in the range from about 50:1 to about 300:1, or from about 75:1 to about 250:1.
  • the antihyperglycemic agent may also be a glucosidase inhibitor, such as acarbose (disclosed in U.S. Pat. No. 4,904,769, the contents of which are incorporated by reference) or miglitol (disclosed in U.S. Pat. No. 4,639,436, the contents of which are incorporated by reference).
  • acarbose Dislosed in U.S. Pat. No. 4,904,769, the contents of which are incorporated by reference
  • miglitol disclosed in U.S. Pat. No. 4,639,436, the contents of which are incorporated by reference.
  • metformin or salt thereof may be employed in a weight ratio to the glucosidase inhibitor within the range from about 2:1 to about 300:1 or from about 25:1 to about 200:1.
  • the antihyperglycemic agent may be a thiazolinedione oral anti-diabetic agent, which has an insulin sensitivity effect in patients with Type 2 diabetes.
  • metformin or salt thereof may be employed in a weight ratio to the thiazolidinedione in an amount within the range from about 0.1:1 to about 75:1 or from about 0.5:1 to about 5:1.
  • the thiazolidinedione anti-diabetic agent may be employed in amounts within the range from about 0.01 to about 2000 mg/day which may be administered in single or divided doses one to four times per day.
  • metformin or salt thereof may also be employed in combination with a non-oral antihyperglycemic agent such as insulin or with glucagon-like peptide-1 (GLP-1) such as GLP-1(1-36) amide, GLP-1(7-36) amide, GLP-1(7-37) (as disclosed in U.S. Pat. No. 5,614,492, the disclosure of which is incorporated herein by reference).
  • GLP-1 glucagon-like peptide-1
  • insulin may be employed in formulations, in the amounts and dosing as indicated by the Physician’s Desk Reference, which is hereby incorporated by reference in its entirety for all purposes.
  • GLP-1 peptides are administered in the liquid oral formulation of the present disclosure.
  • the human gut microbiome appears to be involved in the regulation of metabolic processes, including digestion, absorption, and conversion of indigestible foods or partially digested food ingredients to molecules that may signal physiological host mechanisms.
  • the gut microbiome is a complex ecosystem. A change in the gut microbiome habitat may result in microbiota community shifts and consequential changes in glucose regulation. See Qin et al.,“A metagenome-wide association study of gut microbiota in type 2 diabetes,” Nature, 2012, Vol. 490, pgs. 55-60.
  • compositions of the present disclosure are capable of having an effect on the gut microbiome of treated individuals.
  • the taught compositions are capable of causing a shift in the microbial community of treated patients.
  • the compositions of the present disclosure are capable of having an effect on the GI tract’s environment.
  • the shift in the gut microbial community, or alteration in the environment of the GI tract, of patients treated with the compositions of the disclosure leads to increased tolerance of metformin and decreased incidence of metformin side effects, e.g. diarrhea or any negative side effect of metformin as listed in Table 2.
  • Beta-glucans are natural polysaccharides that contain only glucose as structural components, and are linked with ⁇ -glycosidic bonds. Glycosidic bonds are etheric oxygen bridges that link the monosaccharide units in a polysaccharide, and they are designated by a pair of numbers to indicate which carbons in each of the monosaccharide units are linked.
  • a glycosidic bond involves the number 1 carbon of an aldose monosaccharide (or the number 2 carbon of a ketose monosaccharide)
  • a second designation is needed to indicate the spatial orientation of the etheric oxygen linkage at that carbon (the anomeric carbon).
  • An“ ⁇ ” (alpha) indicates the etheric oxygen linkage attaches to the anomeric carbon below the ring
  • a“ ⁇ ” (beta) indicates the etheric oxygen linkage attaches to the anomeric carbon above the ring (in the standard Haworth projection).
  • the designation of ⁇ (1-3) for a glycosidic linkage indicates that the etheric oxygen bridge between two consecutive monosaccharide units of the polysaccharide connects the number 1 carbon of the first unit to the number 3 carbon of the second unit, and that etheric oxygen bridge attaches to carbon 1 of the first unit from above the ring.
  • the designation of ⁇ (1-6) for a glycosidic linkage indicates that the etheric oxygen bridge between two consecutive monosaccharide units of the polysaccharide connects the number 1 carbon of the first unit to the number 6 carbon of the second unit, and that etheric oxygen bridge attaches to carbon 1 of the first unit from above the ring.
  • Beta-glucans can be isolated from various sources such as: oat, barley, wheat, baker’s yeast, certain fungi, and mushrooms.
  • Beta-glucan is fermented in the colon and its physical properties tend to increase viscosity of the digesta. High digesta viscosity delays gastric emptying and slows digestion and absorption of nutrients.
  • Bioactivities of inulin and beta-glucan in the gastrointestinal (GI) tract are proposed to account for an increase in post-prandial satiety in response to a standard meal, reduce the glucose and insulin response to a breakfast meal, reduce the glycemic index, increase fasting peptide YY and glucagon like peptide-1, decrease ghrelin levels, reduce body weight, and increase insulin sensitivity in humans.
  • Microbiome modulator Indigestible Carbohydrate That is Fermentable by GI
  • the indigestible carbohydrates that are fermentable by gastrointestinal microbiota are the inulins.
  • any indigestible carbohydrate that is fermentable by GI microbiota are envisioned, such as: oligofructoses, fructo-oligosaccharides, lactulose, galcto-oligosaccharides, arabinoxylans, resistant starch, xylo-oligosaccharides, xylo-oligosaccharide, polydextrose, soybean oligosaccharides, isomalto-oligosaccharides, gluco-oligosaccharides, palatinose, gentio-oligosaccharides, lactitol, sorbitol, maltitol, xylitol, and mixtures thereof; among others.
  • Inulins are a group of naturally occurring polysaccharides produced by many types of plants. Further, inulins are water soluble dietary fibers, which increase the abundance of butyrate in the colon through fermentation. Inulin can be included in the compositions taught herein in order to change the gut associated microbial community, or the environment of said microbial community, of a treated patient.
  • bioactivities of inulin and beta-glucan in the gastrointestinal (GI) tract are proposed to account for an increase in post-prandial satiety in response to a standard meal, reduce the glucose and insulin response to a breakfast meal, reduce the glycemic index, increase fasting peptide YY and glucagon like peptide-1, decrease ghrelin levels, reduce body weight, and increase insulin sensitivity in humans.
  • Microbiome modulator Polyphenolic Compounds
  • Polyphenols are a structural class of chemicals characterized by the presence of large multiples of phenol structural units, which can be utilized as microbiome modulators according to the disclosure.
  • Anthocyanins are one type of polyphenolic compound that can be utilized in the present compositions.
  • Anthocyanins are members of the flavonoid group of phytochemicals, widely produced in the plant kingdom, and are water-soluble vacuolar pigments that may appear red, purple, or blue depending upon pH.
  • blueberry pomace extract is utilized in compositions taught herein. Blueberry pomace contains polyphenols and anthocyanins, which are poorly absorbed, but alter the GI microbiome, or its environment, to improve insulin sensitivity in obese insulin-resistant men and women. Stull, et al.,“Bioactives in blueberries improve insulin sensitivity in obese, insulin-resistant men and women,” 2010, Journal of Nutrition, Vol.
  • compositions comprised herein have a total polyphenolics amount of at least about: 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1,000 mg, 2,000 mg, or more. This amount can be made up of one or more specific polyphenols.
  • Microbiome Modulators Mechanism of Action
  • microbiome modulator references an agent that is capable of altering the gut associated microbial community of a patient administered the agent, or the gut habitat of said community.
  • the change in the microbial community may involve an increase or decrease in one or more species of the microbial community.
  • the change in the habitat of the gut associated microbial community may comprise increased production of small chain fatty acids (SCFAs), increased viscosity in the lumen, protection of the mucus barrier, priming of the GI immune system, sequester of bile salts, impeding glucose absorption, among other habitat alterations discussed herein.
  • SCFAs small chain fatty acids
  • Table 4 illustrates some of the mechanisms of action of the various exemplary microbiome modulators of the present disclosure.
  • compositions Comprising Metformin and a Microbiome modulator
  • compositions taught herein comprise a therapeutically effective amount of metformin, or its pharmaceutically acceptable salt.
  • compositions comprise metformin, or its pharmaceutically acceptable salt, and at least one microbiome modulator.
  • compositions comprise metformin, or its pharmaceutically acceptable salt, and at least one microbiome modulator selected from the group consisting of: beta-glucan, inulin, and polyphenol.
  • compositions comprise metformin, or its pharmaceutically acceptable salt, and at least one plant based microbiome modulator.
  • compositions comprise metformin, or its pharmaceutically acceptable salt, and at least one microbiome modulator not derived from yeast or yeast cells.
  • compositions comprise metformin, or its pharmaceutically acceptable salt, and at least one plant based microbiome modulator comprising beta-glucan and not containing beta-glucan derived from a yeast or yeast cell wall.
  • Liquid Formulations of Metformin and a Microbiome modulator [0173]
  • the present disclosure is directed, in one aspect, to a liquid formulation of metformin or its pharmaceutically acceptable salts.
  • This liquid pharmaceutical formulation addresses the aforementioned problems of bitter taste and associated low compliance with certain tablet metformin formulations presently on the market.
  • Liquid preparations for oral use are usually solutions, emulsions, or suspensions containing one or more active ingredients in a suitable vehicle; they may in some cases consist simply of a liquid active ingredient used as such.
  • Liquid preparations for oral use are either supplied in the finished form or, with the exception of oral emulsions, may also be prepared just before issue for use by dissolving or dispersing granules or powder in the vehicle stated on the label.
  • the vehicle for any liquid preparation for oral use is chosen having regard to the nature of the active ingredient and to provide organoleptic characteristics appropriate to the intended use of the preparation.
  • Liquid preparations for oral use may contain suitable antimicrobial preservatives, antioxidants, and other excipients such as dispersing, suspending, thickening, emulsifying, buffering, wetting, solubilizing, stabilizing, flavoring, sweetening agents, and authorized coloring matter.
  • Liquid preparations for oral use may be supplied as multidose or as single-dose preparations. Each dose from a multidose container is administered by means of a device suitable for measuring the prescribed volume.
  • the device is usually a spoon, or a cup, for volumes of 5 mL or multiples thereof, or an oral syringe for other volumes, or for oral drops a suitable dropper.
  • Oral solutions are liquid preparations for oral use containing one or more active ingredients dissolved in a suitable vehicle.
  • Oral suspensions are liquid preparations for oral use containing one or more active ingredients suspended in a suitable vehicle. For oral suspensions containing more than one active ingredient, some of the active ingredients may be in solution. Oral suspensions may show a sediment which is readily dispersed on shaking to give a uniform suspension which remains sufficiently stable to enable the correct dose to be delivered.
  • the liquid pharmaceutical formulations of the disclosure are formulated as an oral suspension.
  • Oral emulsions are liquid preparations for oral use containing one or more active ingredients. They are stabilized oil-in-water dispersions, either or both phases of which may contain dissolved solids. Solids may also be suspended in oral emulsions. Oral emulsions may show evidence of phase separation but are readily redispersed on shaking.
  • Oral drops are liquid preparations for oral use that are intended to be administered in small volumes with the aid of a suitable measuring device. They may be solutions, suspensions, or emulsions.
  • Powders for oral solutions, suspensions, or drops are multidose preparations consisting of solid, loose, dry particles of varying degrees of fineness. They contain one or more active ingredients, with or without excipients and, if necessary, authorized coloring matter and flavoring substances. They may contain antimicrobial preservatives and other excipients in particular to facilitate dispersion or dissolution and to prevent caking. After dissolution or suspension in the prescribed liquid, they comply with the requirements for oral solutions, oral suspensions, or oral drops, as appropriate.
  • Granules for oral solutions or suspensions are multidose preparations consisting of solid, dry aggregates of powder particles sufficiently resistant to withstand handling. They contain one or more active ingredients with or without excipients and, if necessary, authorized coloring matter and flavoring substances. They may contain antimicrobial preservatives and other excipients in particular to facilitate dispersion or dissolution and to prevent caking. After dissolution or suspension in the prescribed liquid, they comply with the requirements for oral solutions, or oral suspensions, as appropriate.
  • liquid pharmaceutical compositions taught herein comprise a therapeutically effective amount of metformin, or its pharmaceutically acceptable salt, in a liquid carrier.
  • liquid formulations of the disclosure also comprise a microbiome modulator.
  • the microbiome modulator is at least one selected from the group consisting of: beta-glucan, inulin, and polyphenol.
  • liquid formulations comprise: metformin and beta-glucan.
  • liquid formulations comprise: metformin and inulin.
  • liquid formulations comprise: metformin and at least one polyphenol.
  • the liquid formulations comprise: metformin and beta-glucan and at least one polyphenol.
  • certain embodiments of the liquid formulations of the disclosure comprise: a therapeutically effective amount of metformin, or its pharmaceutically acceptable salts, beta-glucan, and a sweetener that does not increase the blood glucose level of a subject after ingestion thereof.
  • liquid pharmaceutical formulations comprising metformin and beta-glucan are useful for treating hyperglycemia and diabetes. These liquid formulations do not suffer from the bitter taste associated with certain tablet embodiments of metformin. Further, as will be described in more detail below, the liquid formulations of the disclosure also alleviate the negative side effects normally encountered with administration of metformin.
  • liquid pharmaceutical formulations of the disclosure help prevent the diarrhea side effects normally encountered upon administration of the present commercial embodiments of metformin.
  • liquid formulations of the present disclosure include: various liquid carriers, buffers, binding agents, excipients, fillers, diluents, adjuvants, solubilisers, water-miscible co-solvents, flavoring agents, coloring agents, sweeteners, surfactants, thickeners, preservatives, anti-oxidants, wetting agents, anti- foaming agents, polyphenols, fibers, and mixtures thereof.
  • compositions are well known and are usually liquids, in which an active therapeutic agent is formulated.
  • the active therapeutic agent may comprise metformin, or a pharmaceutically acceptable salt thereof.
  • the carrier generally does not provide any pharmacological activity to the formulation, though it may provide chemical and/or biological stability, release characteristics, and the like. Exemplary formulations can be found, for example, in Alfonso R. Gennaro. Remington: The Science and Practice of Pharmacy, 21st Edition. Baltimore, MD: Lippincott Williams & Wilkins, 2006. These formulations include, but are not limited to: saline, water, buffered water, and the like.
  • the liquid carrier is relatively purified. For example, if water is the carrier, it is purified (e.g. RO and/or distilled water and/or deionized water).
  • the liquid compositions presented herein may, in some embodiments, be placed within foodstuffs, such as: beverages, shakes, and the like, as feasible and consumer friendly delivery vehicles.
  • the liquid compositions may comprise a pH ranging from about 4.0 to about 9.0, or from about 4.0 to about 8.0, or from about 4.0 to about 7.0, or from about 5.0 to about 9.0, or from about 5.0 to about 8.0, or from about 5.0 to about 7.0, or from about 6.0 to about 9.0, or from about 6.0 to about 8.0, or from about 6.0 to about 7.0, or approximately 6.68.
  • These pH ranges may be affected by one of ordinary skill in the art using conventional buffer systems, such as critic acid and citrate, and the like.
  • the liquid formulation contains polyhydric alcohols.
  • polyhydric alcohol means any organic polyalcohol containing more than one hydroxy group thereon. It includes propylene glycol, dipropylene glycol, polyethylene glycol, glycerin, butylene glycol, hexylene glycol, polyoxyethylene, polypropylene glycol, sorbitol or other sugar alcohol, ethylene glycol and the like.
  • the polyhydric alcohol is a polymer, such as polyethylene glycol, the number of hydroxy groups thereon is about the same as the number of carbon atoms present. If not a polymer, the alkyl moiety contains 2 to 6 carbons and 2 to 6 hydroxy groups.
  • Such polyhydric alcohols include glycols, triols and polyols having 2, 3, 4, 5, to 6 alcoholic hydroxy groups per molecule or per repeating unit of the polymer.
  • glycols containing 2 to 10 carbon atoms e.g., ethylene glycol, propylene glycol, butylene glycol, and polyethylene glycol (average molecular weight ranging from about 200 to about 8000 daltons or from about 200 to about 6000 daltons or from about 200 to about 2000 daltons).
  • triols examples include glycerin, trimethylol propane, and the like.
  • polyols examples include sorbitol, polyvinyl pyrrolidone, and the like.
  • the polyhydroxy alcohols can be glycols, triols, or polymers, and the like, e.g., alkanes or polymers comprised of repeating alkylene units, wherein the alkanes or repeating alkylene units in the polymers are substituted by at least 3 to 6 hydroxy groups.
  • These polyhydric alcohols may be used either singly or in combination. If used in combination, then two or three different polyhydric alcohols may be used.
  • a polyhydric alcohol is polyethylene glycol.
  • the polyethylene glycol has a molecular weight ranging from about 200 daltons to about 2000 daltons or from about 400 daltons to about 1600 daltons.
  • a polyethylene glycol having a molecular weight greater than 1000 daltons provides a syrupy texture to the liquid formulations that is effective at masking the bitter taste of metformin and its salts.
  • the polyethylene glycol is a mixture of polyethylene glycol of 1000 daltons or less and a polyethylene glycol greater than 1000 daltons.
  • the polyhydric alcohols are present in amounts in the liquid formulation ranging from about 5 to about 55% by weight or from about 15 to about 40% by weight or from about 20% to about 30% by weight. If polyethylene glycol is the polyhydric alcohol, then some embodiments may use a mixture of polyethylene glycol having one polyethylene glycol with a molecular weight greater than 1000 daltons and one polyethylene glycol of 1000 daltons or less. Moreover, some particular embodiments have a ratio of a polyethylene glycol of 1000 daltons or less to the polyethylene glycol of greater than 1000 daltons, said ratio ranging from about 1:1 to about 6:1, or from about 5:1 to about 4:1, or from about 1:2:1 to about 3:1.
  • liquid formulations comprise alky hydroxyethylcellulose.
  • weight ratio of the polyhydric alcohol to alkyl hydroxyethylcellulose ranges from about 50:1 to about 400:1, or from about 100:1 to about 400:1, or from about 200:1 to about 300:1.
  • the weight ratio of metformin, or its pharmaceutically acceptable salt, to polyhydric alcohol ranges from about 1:2 to about 4:1, or from about 1:1 to about 3:1, or from about 1.5:1 to about 2:1.
  • Some embodiments of the liquid formulations comprise a sugar alcohol.
  • sugar alcohol refers to reduced sugars, such as monosaccharide alcohols and disaccharide alcohols.
  • the monosaccharide alcohols have the formula HO—CH 2 (CHOH) n — CH 2 OH, wherein n is 2—5. They also include tetritols, pentitols, hexitols, and heptitols.
  • sugar alcohols include erythritol, theritol, ribitol, arabinitol, xylitol, allitol, dulcitol, glucitol, sorbitol, mannitol, altritol, iditol, maltitol, lactitol, isomalt, hydrogenated starch hydrolysate, and the like.
  • the sugar alcohols, especially the monosaccharide alcohols may be utilized as a racemic mixture or in the D or L form.
  • liquid formulations comprise a non-nutritive flavoring agent or non-nutritive sweetener.
  • the non-nutritive sweeteners are sweet, but are non-caloric. Examples include L-sugars, aspartame, alitame, acesulfame-K, cyclamate, stevioside, glycyrrhiZin, sucralose, neohesperidin, dihydrochalcone, thaumatin saccharin and its pharmaceutically acceptable salts (e.g., calcium), and the like.
  • the sweetener is present in the liquid formulation in amounts ranging from about 40% to about 80% by weight, or from about 50% to about 70%, or from about 55% to about 65%.
  • the weight ratio of sweetener to alkyl hydroxyethylcellulose ranges from about 400 to about 800, or from about 500 to about 600.
  • the ratio of sweetener to metformin, or its pharmaceutically acceptable salt ranges from about 8:1 to about 1:1, or from about 6:1 to about 2:1, or from about 5:1 to about 3:1.
  • liquid formulations comprise alkyl hydroxyethylcellulose. This is produced stepwise or by simultaneous reaction of ethylene oxide and a hydrophobic alkylating reagent known in the art.
  • the alkyl group may contain from 1 to 24 carbon atoms, or from 2 to 15 carbon atoms, or from 2 to 10 carbon atoms, among others.
  • EHEC ethylhydroxy ethylcellulose
  • HMHEC hydroxy ethyl cellulose
  • the alkyl hydroxyethylcellulose in certain embodiments, is present in the liquid formulation in an amount ranging from about 0.01 to about 5% by weight, or from about 0.05 to about 1% by weight, or from about 0.08 to about 0.2% by weight.
  • the weight ratio of alkyl hydroxyethylcellulose to metformin, or its pharmaceutically acceptable salt ranges from about 1:300 to about 1:50, or from about 1:200 to about 1:100.
  • liquid formulations of the present disclosure may be prepared by any of the known methods of pharmacy.
  • the liquid formulations are prepared by a method comprising: bringing into association the metformin and a microbiome modulator, for example: inulin, or beta-glucan, or polyphenol, or combination thereof, with a liquid carrier. Further methods comprise: bringing into association the metformin, microbiome modulator (e.g. inulin, beta- glucan, and/or polyphenol), and one or more of the optional ingredients, with the liquid carrier.
  • a microbiome modulator for example: inulin, or beta-glucan, or polyphenol, or combination thereof.
  • Further methods comprise: bringing into association the metformin, microbiome modulator (e.g. inulin, beta- glucan, and/or polyphenol), and one or more of the optional ingredients, with the liquid carrier.
  • the pharmaceutical compositions are prepared by uniformly and intimately mixing these various components with the liquid carrier.
  • aqueous solutions suitable for oral use can be prepared by dissolving the desired components in water and adding, if desired, additional optional ingredients such as suitable colorants, flavors, stabilizing and thickening agents, and the like, as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided metformin and the beta-glucan in water with viscous material normally used in the pharmaceutical arts to make dispersions, such as natural or synthetic gums, resins, methylcellulose, sodium carboxyethylcellulose, and other well-known suspending agents.
  • compositions of the present disclosure can be formulated for oral administration.
  • the liquid oral formulation of the disclosure does not suffer from the bitter taste inherent with present commercial tablets.
  • the liquid formulated compositions may contain excipients, buffers, diluents, flavors, lubricants, etc.
  • compositions of the present disclosure may comprise from about: 1 mg to 100 mg metformin hydrochloride, or 100 mg to 200 mg metformin hydrochloride, or 200 mg to 300 mg metformin hydrochloride, or 300 mg to 400 mg metformin hydrochloride, or 400 mg to 500 mg metformin hydrochloride, or 500 mg to 600 mg metformin hydrochloride, or 600 mg to 700 mg metformin hydrochloride, or 700 mg to 800 mg metformin hydrochloride, or 800 mg to 900 mg metformin hydrochloride, or 900 mg to 1000 mg metformin hydrochloride, or 1000 mg to 2000 mg metformin hydrochloride, or more, per dose.
  • compositions of the present disclosure may comprise from about: 0.5 g to 100 g beta-glucan, or 0.5 to 50 g beta-glucan, or 0.5 to 25 g beta-glucan, or 0.5 g to 15 g beta-glucan, or 0.5 to 10 g beta-glucan, or 0.5 to 5 g beta-glucan, or at least 0.5 g beta- glucan, or at least 1 g beta-glucan, or at least 2 g beta glucan, or at least 3 g beta-glucan, or at least 4 g beta-glucan, or at least 5 g beta-glucan, per dose.
  • compositions of the present disclosure may comprise from about: 0.5 g to 100 g inulin, or 0.5 g to 50 g inulin, or 0.5 g to 25 g inulin, or 0.5 g to 15 g inulin, or 0.5 g to 10 g inulin, or 0.5 g to 5 g inulin, or 1 g inulin, or 2 g inulin, or 3 g inulin, or 4 g inulin, or 5 g inulin, per dose.
  • compositions of the present disclosure comprise at least about: 0.1 g inulin per dose, or 0.5 g inulin per dose, or 1 g inulin per dose, or 2 g inulin per dose, or 3 g inulin per dose, or 4 g of inulin per dose.
  • the compositions of the present disclosure comprise at least about 1 to 3 grams of inulin per dose.
  • compositions of the present disclosure may comprise from about: 1 mg to 10,000 mg total polyphenolics, or 1 mg to 9,000 mg total polyphenolics, or 1 mg to 8,000 mg total polyphenolics, or 1 mg to 7,000 mg total polyphenolics, or 1 mg to 6,000 mg total polyphenolics, or 1 mg to 5,000 mg total polyphenolics, or 1 mg to 4,000 mg total polyphenolics, or 1 mg to 3,000 mg total polyphenolics, or 1 mg to 2,000 mg total polyphenolics, or 1 mg to 1,000 mg total polyphenolics, or 1 mg to 900 mg total polyphenolics, or 1 mg to 800 mg total polyphenolics, or 1 mg to 750 mg total polyphenolics, or 1 mg to 740 mg total polyphenolics, or 100 mg to 1000 mg total polyphenolics, or 100 mg to 900 mg total polyphenolics, or 100 to 800 mg total polyphenolics, or 100 mg to 750 mg total polyphenolics, or 100 mg to 740 mg total polyphenolics, or 100 mg
  • compositions of the present disclosure are formulated for oral administration and may comprise about: 100 mg metformin hydrochloride per dose, 200 mg metformin hydrochloride per dose, 300 mg metformin hydrochloride per dose, 400 mg metformin hydrochloride per dose, 500 mg metformin hydrochloride per dose, 600 mg metformin hydrochloride per dose, 700 mg metformin hydrochloride per dose, 800 mg metformin hydrochloride per dose, 900 mg metformin hydrochloride per dose, 1000 mg metformin hydrochloride per dose, 1500 mg metformin hydrochloride per dose, or 2000 mg or more of metformin hydrochloride per dose.
  • compositions of the present disclosure are formulated for oral administration and may comprise about: 100 mg metformin hydrochloride and 1-5 grams of beta-glucan per dose, 200 mg metformin hydrochloride and 1-5 grams of beta-glucan per dose, 300 mg metformin hydrochloride and 1-5 grams of beta-glucan per dose, 400 mg metformin hydrochloride and 1-5 grams of beta-glucan per dose, 500 mg metformin hydrochloride and 1-5 grams of beta-glucan per dose, 600 mg metformin hydrochloride and 1-5 grams of beta-glucan per dose, 700 mg metformin hydrochloride and 1-5 grams of beta- glucan per dose, 800 mg metformin hydrochloride and 1-5 grams of beta-glucan per dose, 900 mg metformin hydrochloride and 1-5 grams of beta-glucan per dose, 1000 mg metformin hydrochloride and 1-5 grams of beta-glucan per dose, 1500 mg metformin hydrochloride and 1-5 grams of beta-glucan
  • compositions of the present disclosure are formulated for oral administration in a liquid carrier, and may comprise about: 100 mg metformin hydrochloride per 5 mL dose, 200 mg metformin hydrochloride per 5 mL dose, 300 mg metformin hydrochloride per 5 mL dose, 400 mg metformin hydrochloride per 5 mL dose, 500 mg metformin hydrochloride per 5 mL dose, 600 mg metformin hydrochloride per 5 mL dose, 700 mg metformin hydrochloride per 5 mL dose, 800 mg metformin hydrochloride per 5 mL dose, 900 mg metformin hydrochloride per 5 mL dose, 1000 mg metformin hydrochloride per 5 mL dose, or 1500 mg metformin hydrochloride per 5 mL dose, or 2000 mg or more of metformin hydrochloride per 5 mL dose.
  • compositions of the present disclosure are formulated for oral administration in a liquid carrier, and may comprise about: 100 mg metformin hydrochloride and 1-5 grams of beta-glucan per 5 mL dose, 200 mg metformin hydrochloride and 1-5 grams of beta-glucan per 5 mL dose, 300 mg metformin hydrochloride and 1-5 grams of beta-glucan per 5 mL dose, 400 mg metformin hydrochloride and 1-5 grams of beta-glucan per 5 mL dose, 500 mg metformin hydrochloride and 1-5 grams of beta-glucan per 5 mL dose, 600 mg metformin hydrochloride and 1-5 grams of beta-glucan per 5 mL dose, 700 mg metformin hydrochloride and 1-5 grams of beta-glucan per 5 mL dose, 800 mg metformin hydrochloride and 1-5 grams of beta-glucan per 5 mL dose, 900 mg metformin hydrochloride and 1-5 grams of beta-glucan per 5 mL dose,
  • the liquid formulation is quantitated for other dosage amounts, such as 10 mL dosage forms. Also envisioned are formulations of 10-100 mL, or 100-200 mL, or 200-300 mL, or 300-350 mL, or 300-400 mL, or 300-500 mL, or about 355 mL, or 100-1,000 mL.
  • the liquid formulation is quantitated for dosage amounts comprising from about: 1 mL to 1000 mL, or 1 mL to 500 mL, or 1 mL to 400 mL, or 1 mL to 300 mL, or 1 mL to 200 mL, or 1 mL to 100 mL, or 1 mL to 50 mL, or 1 mL to 40 mL, or 1 mL to 30 mL, or 1 mL to 20 mL, or 1 mL to 10 mL, or 5 mL to 1000 mL, or 5 mL to 500 mL, or 5 mL to 400 mL, or 5 mL to 300 mL, or 5 mL to 200 mL, or 5 mL to 100 mL, or 5 mL to 50 mL, or 5 mL to 40 mL, or 5 mL to 30 mL, or 5 mL to 20 mL, or or
  • compositions of the present disclosure are formulated for oral administration in a liquid carrier, and may comprise from: about 1 mg to about 1000 mg metformin hydrochloride per dose, about 100 mg to about 1000 mg metformin hydrochloride per dose, about 1 mg to about 100 mg metformin hydrochloride per dose, about 100 mg to about 200 mg metformin hydrochloride per dose, about 200 mg to about 300 mg metformin hydrochloride per dose, about 300 mg to about 400 mg metformin hydrochloride per dose, about 400 mg to about 500 mg metformin hydrochloride per dose, about 500 mg to about 600 mg metformin hydrochloride per dose, about 600 mg to about 700 mg metformin hydrochloride per dose, about 700 mg to about 800 mg metformin hydrochloride per dose, about 800 mg to about 900 mg metformin hydrochloride per dose, about 900 mg to about 1000 mg metformin hydrochloride per dose, about 1000 mg to about 1500 mg metformin hydrochloride per dose
  • the liquid formulations comprise: about 500 mg metformin hydrochloride per dose, or about 750 mg metformin hydrochloride per dose, or about 850 mg metformin hydrochloride per dose, or about 1000 mg metformin hydrochloride per dose. Also taught are embodiments comprising: about 500 mg metformin hydrochloride and about 1-5 grams beta-glucan per dose, or about 750 mg metformin hydrochloride and about 1-5 grams beta-glucan per dose, or about 850 mg metformin hydrochloride and about 1-5 grams beta-glucan per dose, or about 1000 mg metformin hydrochloride and about 1-5 grams beta-glucan per dose.
  • inventions comprising from about 400 mg to about 600 mg metformin hydrochloride per dose, or about 600 mg to about 800 mg metformin hydrochloride per dose, or about 700 mg to about 900 mg metformin hydrochloride per dose, or about 900 mg to about 1100 mg metformin hydrochloride per dose.
  • inventions comprising from about 400 mg to about 600 mg metformin hydrochloride per dose and about 1-5 grams beta-glucan per dose, or about 600 mg to about 800 mg metformin hydrochloride per dose and about 1-5 grams beta-glucan per dose, or about 700 mg to about 900 mg metformin hydrochloride per dose and about 1-5 grams beta-glucan per dose, or about 900 mg to about 1100 mg metformin hydrochloride per dose and about 1-5 grams beta- glucan per dose.
  • the liquid formulations comprise: about 500 mg metformin hydrochloride per 5 mL dose, or about 750 mg metformin hydrochloride per 5 mL dose, or about 850 mg metformin hydrochloride per 5 mL dose, or about 1000 mg metformin hydrochloride per 5 mL dose.
  • liquid formulation embodiments comprising: about 500 mg metformin hydrochloride and about 1-5 grams beta-glucan per 5 mL dose, or about 750 mg metformin hydrochloride and about 1-5 grams beta-glucan per 5 mL dose, or about 850 mg metformin hydrochloride and about 1-5 grams beta-glucan per 5 mL dose, or about 1000 mg metformin hydrochloride and about 1-5 grams beta-glucan per 5 mL dose.
  • inventions comprising: 500 mg metformin hydrochloride and 1-5 grams ⁇ 0.5% beta-glucan per 5 mL dose, or 750 mg metformin hydrochloride and 1-5 grams ⁇ 0.5% beta-glucan per 5 mL dose, or 850 mg metformin hydrochloride and 1-5 grams ⁇ 0.5% beta-glucan per 5 mL dose, or 1000 mg metformin hydrochloride and 1-5 grams ⁇ 0.5% beta-glucan per 5 mL dose.
  • inventions comprising: 500 mg metformin hydrochloride and 1-5 grams ⁇ 1.0% beta-glucan per 5 mL dose, or 750 mg metformin hydrochloride and 1-5 grams ⁇ 1.0% beta-glucan per 5 mL dose, or 850 mg metformin hydrochloride and 1-5 grams ⁇ 1.0% beta-glucan per 5 mL dose, or 1000 mg metformin hydrochloride and 1-5 grams ⁇ 1.0% beta-glucan per 5 mL dose.
  • inventions comprising: 500 mg metformin hydrochloride and 1-5 grams ⁇ 5.0% beta-glucan per 5 mL dose, or 750 mg metformin hydrochloride and 1-5 grams ⁇ 5.0% beta-glucan per 5 mL dose, or 850 mg metformin hydrochloride and 1-5 grams ⁇ 5.0% beta-glucan per 5 mL dose, or 1000 mg metformin hydrochloride and 1-5 grams ⁇ 5.0% beta-glucan per 5 mL dose.
  • inventions comprising: 500 mg metformin hydrochloride and 1-5 grams ⁇ 10.0% beta-glucan per 5 mL dose, or 750 mg metformin hydrochloride and 1-5 grams ⁇ 10.0% beta-glucan per 5 mL dose, or 850 mg metformin hydrochloride and 1-5 grams ⁇ 10.0% beta-glucan per 5 mL dose, or 1000 mg metformin hydrochloride and 1-5 grams ⁇ 10.0% beta-glucan per 5 mL dose.
  • compositions may be administered once a day, twice a day, three times a day, four times a day, five times a day, or more, to a subject in need of such treatment. Furthermore, the compositions may be administered on an as needed basis based upon a subject’s physiological symptoms, such as hyperglycemia. The compositions may be titrated to the individual’s particular glycemic needs, in order to establish a minimum effective daily administrative amount. [0243]
  • the subject in need of such treatment may be a mammal.
  • the subject in need of such treatment may be a companion pet.
  • the subject in need of such treatment may be a human.
  • the subject in need of such treatment may be a patient suffering from hyperglycemia.
  • the subject in need of such treatment may be a patient with high blood sugar.
  • the subject in need of such treatment may be a patient suffering from insulin insensitivity or insulin resistance.
  • the subject in need of such treatment may be a diabetic patient.
  • the subject in need of such treatment may be a patient suffering from type 2 diabetes.
  • microbiome modulators of the disclosure. These microbiome modulators (one, two, or all three) may be combined with at least one agent selected from the group consisting of: metformin, Galega officinalis, a DPP- IV inhibitor, a SGLT-2 inhibitor, or combination thereof.
  • a base liquid metformin formulation can be manufactured according to the method outlined in U.S. Pat. Nos. 6,559,187 and 6,890,957, the contents of each of which are hereby incorporated by reference in their entirety for all purposes.
  • a suitable manufacturing Tank 60 liters of USP purified water can be heated to 40°C. Throughout the process the temperature can be maintained at 40°C. 1.9 kg. of polyethylene glycol is heated to 40° C and Natrosol 250 HX, i.e., hydroxyethylcellulose, (142.5 g) is added to the polyethylene glycol in small quantities and mixed for 30 minutes at 40°C at 60 revolutions per minute on a MagneTek mixer Model #6-962653-41 until homogeneous. The resulting mixture is added slowly to the water in the tank and the contents are mixed at 40°C. Metformin HCL (19 kg) is slowly added to the Tank at 60 RPM, while the temperature is maintained at 40°C.
  • Natrosol 250 HX i.e., hydroxyethylcellulose
  • Calcium saccharin (1.188 kg) is added slowly to the tank and the contents are mixed for 10 minutes at 40 RPM.
  • Citric acid 114 g is added to the tank maintained at 40°C and the contents are mixed at 40 RPM.
  • Potassium benzoate (211.28 g) is added to the tank maintained at 40°C and the contents are mixed at 40 RPM for 10 minutes.
  • Additional polyethylene glycol 9.5 kg is added slowly to the tank maintained at 40°C and the contents are mixed for 30 minutes at 60 RPM.
  • a 70% solution of sorbitol (in water) (w/w) (76 kg) is pumped slowly to the tank maintained at 40°C and the contents are mixed for 20 minutes at 40 RPM.
  • Additional polyethylene glycol (21.85 kg) is pumped into the tank and the contents are mixed for 20 minutes at 40 RPM.
  • a flavor agent 190 g is added to the tank and the contents are mixed for 20 minutes at 40 RPM.
  • the contents of the tank are cooled to 30°C, and additional water is added until the volume is 190 liters.
  • the contents are additionally mixed at 30°C for 60 minutes at 30 RPM.
  • the resulting product is a base liquid metformin hydrochloride formulation.
  • the aforementioned base liquid metformin hydrochloride formulation is subsequently brought into combination with a microbiome modulator, e.g. beta-glucan, inulin, and/or a polyphenolic compound, or combinations thereof.
  • a microbiome modulator e.g. beta-glucan, inulin, and/or a polyphenolic compound, or combinations thereof.
  • the base liquid metformin hydrochloride formulation is subsequently brought into combination with beta-glucan.
  • the base liquid metformin hydrochloride formulation is subsequently brought into combination with beta-glucan and at least one polyphenolic compound.
  • beta-glucan OATWELL ® 22% manufactured by DSM
  • OATWELL ® is an oat beta-glucan and constitutes the main component of the soluble dietary fiber content of oats. Both the 1,3/1,4 and the 1,3/1,6 linked beta-glucan can be utilized depending on the source of the beta- glucan, but oat derived beta-glucan is 1,3/1,4 linked.
  • Example 2 As well be apparent from Example 2, one does not have to start from a base liquid metformin formulation before combining with the microbiome modulator.
  • the microbiome modulator e.g. beta-glucan, inulin, and/or a polyphenolic compound, or any combination thereof
  • the microbiome modulator is combined during the initial process of deriving the metformin formulation.
  • Example 2 Preparation of a Liquid Metformin Formulation Comprising a
  • the liquid metformin formulation comprises a microbiome modulator, e.g. beta-glucan, inulin, and/or a polyphenolic compound, or any combination thereof.
  • the microbiome modulator is brought together with the metformin and liquid carrier in a process as described below.
  • a suitable manufacturing Tank 60 liters of USP purified water can be heated to 40°C. Throughout the process the temperature can be maintained at 40°C. 1.9 kg. of polyethylene glycol is heated to 40° C and Natrosol 250 HX, i.e., hydroxyethylcellulose, (142.5 g) is added to the polyethylene glycol in small quantities and mixed for 30 minutes at 40°C at 60 revolutions per minute on a MagneTek mixer Model #6-962653-41 until homogeneous. The resulting mixture is added slowly to the water in the tank and the contents are mixed at 40°C. Metformin HCL (19 kg) is slowly added to the Tank at 60 RPM, while the temperature is maintained at 40°C.
  • Natrosol 250 HX i.e., hydroxyethylcellulose
  • a microbiome modulator e.g. beta-glucan, inulin, and/or a polyphenolic compound, or any combination thereof
  • a microbiome modulator e.g. beta-glucan, inulin, and/or a polyphenolic compound, or any combination thereof
  • the microbiome modulator utilized is beta-glucan, then the beta-glucan utilized can be OATWELL ® .
  • Calcium saccharin (1.188 kg) is added slowly to the tank and the contents are mixed for 10 minutes at 40 RPM.
  • Citric acid 114 g
  • Potassium benzoate (211.28 g) is added to the tank maintained at 40°C and the contents are mixed at 40 RPM for 10 minutes.
  • Additional polyethylene glycol (9.5 kg) is added slowly to the tank maintained at 40°C and the contents are mixed for 30 minutes at 60 RPM.
  • a 70% solution of sorbitol (in water) (w/w) (76 kg) is pumped slowly to the tank maintained at 40°C and the contents are mixed for 20 minutes at 40 RPM.
  • Additional polyethylene glycol (21.85 kg) is pumped into the tank and the contents are mixed for 20 minutes at 40 RPM.
  • a flavor agent (190 g) is added to the tank and the contents are mixed for 20 minutes at 40 RPM.
  • the contents of the tank are cooled to 30°C, and additional water is added until the volume is 190 liters.
  • the contents are additionally mixed at 30°C for 60 minutes at 30 RPM.
  • the resulting product is a liquid metformin hydrochloride formulation comprising a microbiome modulator.
  • the liquid metformin hydrochloride formulation may comprise beta-glucan, and/or inulin, and/or a polyphenolic compound, or any combination thereof.
  • Example 3 Treatment of a Diabetic Patient Population with a Liquid Metformin
  • the inventors also envision a study that comprises a formulation of metformin and at least one microbiome modulator chosen from inulin, beta- glucan, and at least one polyphenolic compound.
  • the composition is formulated as an edible food product.
  • a total of 30 subjects is selected, 15 are assigned to treatment with a liquid formulation comprising metformin and two microbiome modulators: (1 ) beta-glucan and (2) at least one polyphenolic compound (METFORMIN-MB) and 15 are assigned to STANDARD METFORMIN, which does not contain the two microbiome modulators of beta-glucan and the polyphenolic compound.
  • a liquid formulation comprising metformin and two microbiome modulators: (1 ) beta-glucan and (2) at least one polyphenolic compound (METFORMIN-MB) and 15 are assigned to STANDARD METFORMIN, which does not contain the two microbiome modulators of beta-glucan and the polyphenolic compound.
  • the subjects must be healthy men and women between the ages of 18 and 70 with a BMI between 25 and 35 and fasting blood glucose between 100 and 125mg/dl and a stable weight over 2 months.
  • Excluded subjects include those that: a) take medications affecting glucose, b) take medications affecting insulin, c) take medications affecting body weight, d) take medications affecting bacterial flora, e) have intestinal disease or a recent history of intestinal disease, f) have had surgery on stomach or intestine, g) are hypothyroid, h) are pregnant, i) have heart disease.
  • treated subjects consume 5 mL of a liquid formulation comprising metformin at an active concentration of 500 mg/5 mL and beta-glucan in a concentration from about 1 gram to about 5 gram per 5 mL and at least one polyphenolic compound present in an amount of at least 700 mg.
  • the liquid formulation comprising metformin and beta- glucan and at least one polyphenolic compound is termed METFORMIN-MB.
  • compositions comprising only metformin in a standard liquid formulation at an active concentration of 500 mg/5mL and lacking the about 1 gram to about 5 grams of beta-glucan and lacking the at least one polyphenol.
  • This liquid formulation is termed STANDARD METFORMIN and can be acquired as RIOMET ® from Ranbaxy Laboratories, Inc.
  • Subjects are administered the liquid formulations in 5 mL dosages orally within 1 hour prior to consumption of either meal 1 or meal 2, and meal 3 each day.
  • Subjects selected for participation are allowed an ad libitum diet and are given an evaluation sheet to assess their appetite and satiety before and after a meal.
  • Foods excluded include alcohol.
  • Low calorie or joule liquids are stressed in place of high calorie or joule liquids such as fruit juices, milk, sweet tea (tea with sugar), regular soft drinks, coffee with sugar, etc.
  • the subjects are randomly assigned to either METFORMIN-MB or STANDARD METFORMIN treatment groups. Both the experimenter and the subjects are blinded to who receive the METFORMIN-MB or STANDARD METFORMIN. [0267] The subjects are encouraged to consume either treatment during either breakfast or lunch and during dinner.
  • Subjects are given a 4 week supply of either METFORMIN-MB or STANDARD METFORMIN at the onset and are instructed to orally take the entire 5 mL dosage with either meal 1 or 2, as well as another 5 mL dosage with meal 3.
  • Screening Subjects are screened to exclude hypothyroidism, pregnancy, and heart disease. The following tests can suffice for this: T4 (thyroxin), T3 (triiodotyronine), TSH (thyroid stimulating hormone), urine pregnancy test, blood pressure & ECG (electrocardiogram).
  • beta-glucan and polyphenolic compound are a strong microbiome modulator that can act synergistically with a biguanide class of compound, such as metformin.
  • the aforementioned experiment utilized a dosage of 1000 mg metformin per day and about 0.5-10 grams beta-glucan (i.e. 5 mL METFORMIN-MB with meal 1 or 2 and also meal 3) and at least about 700 mg of a polyphenol.
  • METFORMIN-MB Dosage of METFORMIN-MB must be individualized on the basis of both effectiveness and tolerance, while not exceeding the maximum recommended daily doses.
  • the maximum recommended daily dose of METFORMIN-MB is, in particular embodiments, 2550 mg metformin (25.5 mL METFORMIN-MB) in adults and 2000 mg metformin (20 mL METFORMIN-MB) in pediatric patients (10-16 years of age).
  • METFORMIN-MB can be given in divided doses with meals. METFORMIN-MB can be started at a low dose, with gradual dose escalation, to permit identification of the minimum dose required for adequate glycemic control of the patient.
  • fasting plasma glucose should be used to determine the therapeutic response to METFORMIN-MB and identify the minimum effective dose for the patient. Thereafter, glycosylated hemoglobin should be measured at intervals of approximately three months.
  • the therapeutic goal should be to decrease both fasting plasma glucose and glycosylated hemoglobin levels to normal or near normal by using the lowest effective dose of METFORMIN-MB, either when used as monotherapy or in combination with sulfonylurea or insulin.
  • monitoring of blood glucose and glycosylated hemoglobin will also permit detection of primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication, and secondary failure, i.e., loss of an adequate blood glucose lowering response after an initial period of effectiveness.
  • Short-term administration of METFORMIN-MB may be sufficient during periods of transient loss of control in patients usually well-controlled on diet alone.
  • a starting dose of METFORMIN-MB can be 500 mg metformin (5 mL METFORMIN-MB) twice a day or 850 mg metformin (8.5 mL METFORMIN-MB) once a day, given with meals. Dosage increases can be made in increments of 500 mg (5 mL METFORMIN-MB) weekly or 850 mg metformin (8.5 mL METFORMIN-MB) every 2 weeks, up to a total of 2000 mg metformin (20 mL METFORMIN-MB) per day, given in divided doses. [0286] Patients can also be titrated from 500 mg metformin (5 mL METFORMIN-MB) twice a day to 850 mg metformin (8.5 mL METFORMIN-MB) twice a day after 2 weeks.
  • METFORMIN-MB may be given, in embodiments, to a maximum daily dose of 2550 mg metformin (25.5 mL METFORMIN-MB) per day. Doses above 2000 mg metformin (20 mL METFORMIN-MB) may be better tolerated given three times a day with meals.
  • Example 4 Treatment of a Non-Small Cell Lung Cancer Patient with METFORMIN- MB to Minimize Diarrhea and Hyperglycemia Associated with Molecularly Targeted Cancer Therapy
  • NSCLC non-small cell lung cancer
  • EGFR epidermal growth factor receptor
  • a total of 45 subjects is selected and 15 are assigned to treatment with a liquid formulation comprising metformin and beta-glucan and at least one polyphenolic compound (METFORMIN-MB) and 15 are assigned to STANDARD METFORMIN and 15 are given a placebo.
  • a liquid formulation comprising metformin and beta-glucan and at least one polyphenolic compound (METFORMIN-MB) and 15 are assigned to STANDARD METFORMIN and 15 are given a placebo.
  • Each study group continues to receive its recommended dosages of CO-1686, e.g. 500 mg, 625 mg, 750 mg, 900 mg, or 1000 mg CO-1686, twice per day. Though we expect to utilize a twice per day (b.i.d) dosage regime in the experiment, we also envision conducting experiments where the CO-1686 is administered once per day, or three times per day (t.i.d.), or more.
  • the patients are screened for incidences of: diarrhea, stool firmness, urgency to evacuate, abdominal pain, and hyperglycemia.
  • End of Study Assessment The patients are screened for incidences of diarrhea, stool firmness, urgency to evacuate, abdominal pain, and hyperglycemia.
  • METFORMIN-MB study group will not only have improved hyperglycemia control (which should also be associated with the STANDARD METFORMIN group), but this improved hyperglycemia control will not involve the normal diarrhea side effect that is expected to occur in the STANDARD METFORMIN study group.
  • METFORMIN-MB is an excellent choice for co-administration with CO-1686, as METFORMIN-MB’s ability to decrease the negative side effects, e.g. hyperglycemia and diarrhea, associated with CO-1686 treatment will lead to increased compliance among the NSCLC patient population taking CO-1686
  • composition that comprises at least one microbiome modulator (e.g. inulin, beta-glucan, at least one polyphenolic compound), but which does not comprise metformin.
  • microbiome modulator e.g. inulin, beta-glucan, at least one polyphenolic compound
  • the inventors predict that the composition will alleviate at least one negative symptom from Table 6.
  • Example 5 Preparation of a Dietary Supplement Containing Galega officinalis and a
  • the disclosure teaches the preparation of a dietary supplement containing Galega officinalis and at least one microbiome modulator
  • Galega officinalis commonly known galega, goat’s-rue, French lilac, Italian fitch, or professor-weed, is an herbaceous plant in the Faboideae subfamily. It is native to the Middle East, but it has been naturalized in Europe, western Asia, and western Pakistan. The plant has been extensively cultivated as a forage crop, an ornamental, a bee plant, and as green manure. However, the plant has proved too toxic for widespread agricultural use, with the potential to induce tracheal frothing, pulmonary oedema, hydrothorax, hypotension, paralysis and death.
  • Galega bicolor is a synonym. It is a hardy perennial that blooms in the summer months
  • the dietary supplements taught herein contain Galega officinalis and at least one microbiome modulator selected from an indigestible carbohydrate, and/or beta- glucan, and/or at least one polyphenolic compound, or any combination thereof.
  • the below Table 7 illustrates compositions of the disclosure containing Galega officinalis and at least one microbiome modulator.
  • the Table 7 provides the ranges of the microbiome modulators that may be present with the Galega officinalis.
  • the Galega officinalis may be present in any form, including: an extract, crude ground plant material, particulate plant material, powder, a concentrate, a solution, a purified form of the plant material, or any other embodiment known to one of skill in the art.
  • the below compositions in Table 7 may be formulated in any manner previously discussed in the disclosure, for example as a: pill, capsule, oral unit dosage form, edible food product, etc. TABLE 7
  • the dietary supplements taught herein containing Galega officinalis and at least one microbiome modulator selected from an indigestible carbohydrate, and/or beta-glucan, and/or at least one polyphenolic compound, or any combination thereof, are useful for treating hyperglycemia and/or diabetes, and in particular type 2 diabetes.
  • the inventors envision conducting a human clinical trial in which a composition comprising Galega officinalis and at least one microbiome modulator selected from an indigestible carbohydrate, and/or beta-glucan, and/or at least one polyphenolic compound, or any combination thereof, is given to human patients suffering from type 2 diabetes. [0319] The inventors expect that said trial will demonstrate that the type 2 diabetes in the treated patients will be effectively managed. That is, the inventors anticipate that the patients administered the dietary supplement will experience improved glucose control.
  • postprandial glucose regulation is evaluated with an oral glucose tolerance test (OGTT). OGTT is performed in the morning after an overnight fast. A blood sample is taken at the clinic for measurements of fasting glucose and insulin levels. The subject then consumes 75 g of glucose, and blood samples are taken at 30, 60, 120, and 180 minutes after consuming the glucose.
  • OGTT oral glucose tolerance test
  • the acute study design is to select subjects for a trial who take an oral antidiabetic (OAD) medication, such as metformin.
  • Subjects are withdrawn from their OAD for two weeks and would begin the trial with a baseline OGTT.
  • Subjects are then treated with the microbiome modulator and the G. officinalis for a period of at least two weeks, or in another embodiment for a period of at least four weeks.
  • a dose of the microbiome modulator and G. officinalis is administered to a group of subjects in one or two doses twice per day. Another group of subjects will receive a placebo in one or two doses twice per day.
  • one dose is consumed in the morning with breakfast and the other dose is consumed in the evening with dinner.
  • subjects are challenged again with an OGTT.
  • the microbiome modulator dose is administered at between 1 g and 5 g.
  • the G. officinalis is administered between 10 g and 20 g of an extract. Comparisons are made between the dose groups of the data from the OGTTs at four weeks of treatment. In embodiments, comparisons are made, within the subjects, between the OGTT data obtained at baseline and at the end of four weeks of treatment.
  • the inventors expect the area under the curve for blood glucose to exhibit a dose-dependent response for the G. officinalis.
  • the inventors also expect the blood glucose levels determined 120 and 180 minutes after consuming glucose to be significantly lower in the treated subjects versus the subjects receiving the placebo.
  • the inventors expect the data to demonstrate an improved oral glucose tolerance, and accordingly a better postprandial glucose regulation which is expected to be a consequence of increased insulin sensitivity and lower glucose adsorption.
  • a 90 day trial would further measure hemoglobin A1c.
  • the inventors expect A1c values to be significantly reduced in the treated subjects versus the subjects receiving placebo, which is expected to be a consequence of greater glycemic control.
  • Example 7 Combination of Microbiome Modulator with: Biguanides, and/or DPP-IV Inhibitors (gliptins), and/or SGLT-2 Inhibitors (gliflozins)
  • the pharmaceutical compositions taught herein may comprise: a microbiome modulator, along with a therapeutic agent selected from the group consisting of: a biguanide (e.g. metformin), dipeptidyl peptidase type IV inhibitors (DPP-IV), sodium glucose co-transporter 2 inhibitors (SGLT2), and any combination thereof
  • a biguanide e.g. metformin
  • DPP-IV dipeptidyl peptidase type IV inhibitors
  • SGLT2 sodium glucose co-transporter 2 inhibitors
  • DPP-IV drugs are a class of oral hypoglycemics that block DPP-4. They can be used to treat diabetes mellitus type 2.
  • the first agent of the class (Sitagliptin) was approved by the FDA in 2006. Glucagon increases blood glucose levels, and DPP-4 inhibitors reduce glucagon and blood glucose levels.
  • the mechanism of DPP-4 inhibitors is to increase incretin levels (GLP-1 and GIP), which inhibit glucagon release, which in turn increases insulin secretion, decreases gastric emptying, and decreases blood glucose levels.
  • the disclosure envisions utilization of: Sitagliptin, Vildagliptin, Saxagliptin, Linagliptin, Anagliptin, Teneligliptin, Alogliptin, Gemigliptin, and Dutogliptin among others.
  • DPP4 Other chemicals which inhibit DPP4 include: Berberine, the herbal dietary supplement, and Lupeol, found in mango, red alder (Alnus rubra), and dandelion coffee.
  • SGLT2 inhibitor drugs are a new class of drugs indicated for the treatment of type 2 diabetes.
  • SGLT2 is a low-affinity, high capacity glucose transporter located in the proximal tubule in the kidneys. It is responsible for 90% of glucose reabsorption. Inhibition of SGLT2 leads to the decrease in blood glucose due to the increase in renal glucose excretion.
  • the mechanism of action of this new class of drugs also offers further glucose control by allowing increased insulin sensitivity and uptake of glucose in the muscle cells, decreased gluconeogenesis and improved first phase insulin release from the beta cells.
  • the gliflozins exhibit side effects such as metabolic acidosis or ketoacidosis, which is increasingly reported in patients using this new class of drugs.
  • a patient’s microbiome is thought to contribute to the acidosis. Fermenting bacteria, those that utilize glucose, express SGLTs. Some bacteria generate ketones and the SGLT-2 inhibitors may positively select for these bacteria in the microbiome, thus increasing the amount of ketone-producing bacteria.
  • Ketones are small neutral molecules that are rapidly absorbed into the bloodstream. This selection process thought to be driven by SGLT-2 inhibitors may contribute to ketoacidosis or could be the principle etiology of the ketoacidosis, especially if the patient consumes large quantities of dietary proteins.
  • microbiome modulator will select for fermenters of glucose in the microbiome, and expect that the polyphenol antioxidants will select for acetogens and against methanogens and sulfur-reducing bacteria. The inventors further expect that the microbiome modulator will retard the absorption of ketones into the bloodstream.
  • the combination of the presently described microbiome modulator with SGLT- 2 inhibitors may mitigate a dangerous side effect of this new class of OAD drugs
  • the disclosure envisions utilization of: Canagliflozin, Dapagliflozin, and Empagliflozin.
  • the pharmaceutical compositions taught herein may comprise: a microbiome modulator, along with metformin and a gliptin.
  • the pharmaceutical compositions taught herein may comprise: a microbiome modulator, along with metformin and a gliptin and a gliflozin.
  • the pharmaceutical compositions taught herein may comprise: a microbiome modulator, along with metformin and a gliflozin.
  • the pharmaceutical compositions taught herein may comprise: a microbiome modulator, along with a gliptin and a gliflozin.
  • compositions are useful for treating diabetes and in some instances demonstrate a synergistic effect.
  • compositions listed above may be administered to a human patient in a therapeutically effective amount to treat said patient for type 2 diabetes.
  • the below Table 8 illustrates compositions of the disclosure containing at least one microbiome modulator and at least one active therapeutic agent selected from: metformin, and/or a gliptin, and/or a gliflozin.
  • the Table 8 provides the ranges of the microbiome modulators that may be present with the metformin, and/or gliptin, and/or gliflozin.
  • the below compositions in Table 8 may be formulated in any manner previously discussed in the disclosure, for example as a: pill, capsule, oral unit dosage form, edible food product, etc. TABLE 8
  • Metformin and the SGLT-2 inhibitors are contraindicated for those with compromised renal clearance. This is partly because of an increased accumulation of lactic acid and the serious problem of acidosis. Since a significant amount of d-lactate is derived from the microbiome and the microbiome modulator compositions of the disclosure (comprising, e.g. inulin and/or beta-glucan and/or a polyphenolic compound) should reduce that by stimulating fermentation of sugars to short-chain fatty acids, a combination of the SGLT-2 drugs with the microbiome modulators of the disclosure may open up the use of this class of drugs for diabetics with partial kidney failure and those with decreased renal clearance.
  • composition comprising: (a) one or more of the aforementioned microbiome modulators (e.g. inulin, ⁇ - glucan, and/or at least one polyphenol) and (b) one or more of: metformin, a gliptin, and a gliflozin, are administered to a type 2 diabetic patient to improve said diabetes in the patient.
  • microbiome modulators e.g. inulin, ⁇ - glucan, and/or at least one polyphenol
  • metformin, a gliptin, and a gliflozin are administered to a type 2 diabetic patient to improve said diabetes in the patient.
  • GIMM Gastrointestinal Microbiome Modulator
  • Metformin Improves Metformin Tolerance and Fasting Glucose Levels
  • Metformin is the first-line pharmacological therapy for type 2 diabetes (T2D). See Inzucchi et al. The fasting glucose-lowering activity of metformin is equal to or better than that of other oral agents without inducing hypoglycemia or weight gain. Metformin may be successfully combined with all other currently used glucose-lowering agents, including insulin. Metformin is best tolerated when taken with a meal and the most common effective dose is 1500-2000 mg/day, with a maximum of 2550 mg/day. See Graham et al. A well- accepted mechanism of action for metformin is the activation of hepatic AMP-activated protein kinase (AMPK). See Zhou et al.
  • AMPK hepatic AMP-activated protein kinase
  • the GI microbiome reported to be present in T2D patients is characterized by microbiota enriched in bacteria that harvest sugars. See Qin et al.
  • Other functional changes suggested by bacterial dysbiosis in T2D are boosted metabolism of branched-chain amino acids that are associated with increased methane metabolism, increased xenobiotic degradative metabolism, and stimulation of sulphate reduction.
  • a microbiome modulator to shift the GI microbiome of someone with T2D toward 1 characterized in healthy individuals was developed.
  • the modulator contains purified food ingredients to stimulate blooms of competing commensal microbiota that generate short chain fatty acids (SCFA) instead of lactic acid, retard absorption of small molecules by increasing the viscosity of luminal contents, fortify the mucosal barrier, sequester bile acids and salts, and deliver a potent antioxidant to combat the increased demand of oxidative stress.
  • SCFA short chain fatty acids
  • the sample size was selected by convenience (Table 9).
  • BMI body mass index
  • Exclusion criteria included pregnancy, nursing, taking proton pump inhibitors, taking antibiotics within the 3 previous months, or taking insulin. Twelve subjects from the clinic demonstrated interest to participate but only 6 of the referred showed for screening, qualified and were enrolled. Two of 6 subjects responding to radio advertisements did not qualify. One subject dropped out after screening but before commencing treatment because of scheduling conflicts and was replaced. Patients withdrew from diabetes medications for 2 weeks prior to entry into the study. Table 9
  • a 2-period crossover study design was used with 2 treatment sequences, either placebo in period 1 followed by the GIMM in period 2 or vice versa. Study periods lasted for 2 weeks, with a 2-week washout period between. Each subject was randomly assigned to 1 of the treatment sequences. All subjects received daily doses of metformin. During the first week of each study period, subjects took 500 mg along with their assigned GIMM/placebo treatment with breakfast and with dinner. In the second week, subjects took 500 mg metformin (t.i.d.), with GIMM or placebo consumed along with the first and third daily metformin doses. Subjects were permitted to discontinue metformin dosing if it became intolerable.
  • Metformin, GIMM, and placebo were dispensed by the Pennington Biomedical Research Center (PBRC) pharmacist. Metformin was administered in tablets. GIMM and placebo were provided by MicroBiome Therapeutics (Broomfield, CO) in sealed, coded pouches to make them indistinguishable. Volunteers were instructed to empty the entire content of a pouch into 6 ounces of water, mix, and drink along with the tablet.
  • PBRC Pennington Biomedical Research Center
  • GIMM is a combination of 3 purified food ingredients that are generally recognized as safe (GRAS) by the FDA. Inulin (3.79 g) from agave, beta-glucan (2.03 g) from oats, and polyphenols from blueberry pomace (anthocyanins [162.5 mg]; total polyphenolics [723.99 mg]) were blended with inactive food ingredients (14.2 g) at Merlin Development Inc (Minneapolis, MN) to create a pleasant tasting, readily dissolvable powder. A placebo was developed in parallel to offer a powder that was indistinguishable in color and taste but substituted cellulose (8.7 g) for the total dietary fiber content of NM504 (8.7 g).
  • a composite tolerability score was calculated using participant ratings of severity of 4 GI symptoms (stool consistency, urgency to evacuate, bloating sensation, and flatulence). The symptom ratings were combined into a single score for each participant using a weighted sum, with weights derived using principal components analysis (PCA). Using PCA for constructing the tolerability score ensures that this particular weighted sum of the symptom ratings accounts for more variation in the data than any other combination of the symptoms. Although this score has not been validated for use in determining tolerability, the construction and statistical properties of the score are sound. The scores are such that a higher score indicates a higher tolerability.
  • PCA principal components analysis
  • a linear mixed model was used with non-baseline-adjusted tolerability score as the response. Covariates included in the model were period and sequence effects from the crossover design. Group mean tolerability scores, adjusted for these covariates were compared using a 2-sample t test.
  • Measures of fasting glucose were recorded daily throughout the study. The observed glucose levels while participants were actively taking metformin were included in the analysis. Due to the nature of the design, a doubly repeated measures model was utilized, with the period of the crossover being the first level of repeated measures and days within period being the second level.
  • the metformin compositions of the disclosure are able to expand the patient population that is treatable with metformin.
  • d-lactate can convert to l-lactate by some colon microbiota, which could contribute to the plasma lactate pool. See Hove et al.
  • Bile acids are well known to promote colonic fluid and electrolyte secretions, thereby causing diarrhea associated with bile acid malabsorption.
  • Metformin may cause GI disturbances by reducing ileal bile salt reabsorption leading to elevated colonic bile salt concentrations.
  • Scarpello et al. The GIMM contains beta-glucan, which is an oligosaccharide resistant to human digestion. Viscous beta-glucan encapsulates or sequesters bile acids in the colonic contents. See Kim et al.
  • Beta-glucan and inulin are oligosaccharides that are both metabolized in the colon by microbiota in the Bacteroides and Prevotella genera. See Bolam et al. The end products of this fermentation are short chain fatty acids (SCFAs) that activate free fatty acid receptors (FFAR3 and FFAR4) in the colon, resulting in secretion of peptide YY (PYY), glucagon-like peptide-1 (GLP-1), and GLP-2. See Covington et al. and Karaki et al. Both PYY and GLP-1 signal satiety. GLP-1 also decreases gastric emptying and increases insulin release. GLP-1 analogs are used to treat T2D and oral drugs that block rapid degradation of endogenous GLP-1 are also widely used to treat T2D.
  • SCFAs short chain fatty acids
  • FFAR3 and FFAR4 free fatty acid receptors
  • GLP-1 glucagon-like peptide-1
  • Ghrelin is a hormone secreted by the stomach and by the colon that functions to prevent hypoglycemia by stimulating gluconeogenesis.
  • Ghrelin must be acylated with a medium chain fatty acid (MCFA) to activate its receptor (GHS-R1a).
  • MCFA medium chain fatty acid
  • GGS-R1a The acylating enzyme, termed GOAT (ghrelin O-acyltransferase)
  • GOAT ghrelin O-acyltransferase
  • SCFAs may act as competitive inhibitors of GOAT.
  • Fukumori et al. Therefore, generation of SCFAs could contribute to reduce blood glucose levels via production of an inactive ghrelin or lower active ghrelin levels.
  • GIMM Each dose of GIMM is developed to contain the same polyphenolic mass as that found in 2 cups of blueberries. Blueberry consumption is shown to improve insulin sensitivity in men and women. See Stull et al. The sugars are removed from the blueberry extract used in GIMM, which should further improve the effect on carbohydrate metabolism. Although we did not measure insulin sensitivity in the present study, we observed a greater improvement of fasting blood glucose levels in subjects taking GIMM with metformin compared to those taking a placebo-metformin combination.
  • GI microbiome modulators are ideal partners to be used in combination with current and future orally available medications.
  • EP2102350A2 The Gut Microbiome as a Biomarker and Therapeutic Target for Treating Obesity or an Obesity Related Disorder
  • K.B.M.S Islam, S. Fukiya, M. Hagio, N. Fujii, S. Ishizuka,T. Ooka, Y. Ogura, T. Hayashi, A.Yokota,“Bile Acid is a Host Factor that Regulates the Composition of the Cecal Microbiota in Rats,” Gastroenterology (2011), doi:10.1053/j.gastro.2011.07.046.25.
  • ADA Diabetes Association
  • EASD European Association for the Study of Diabetes
  • Glucophage metalformin hydrochloride
  • Glucophage XR extended-release
  • Halperin ML Kamel KS. D-lactic acidosis: turning sugar into acids in the gastrointestinal tract. Kidney Int. 1996;49:1-8.
  • Fukumori R Sugino T
  • Hasegawa Y et al.
  • Plasma ghrelin concentration is decreased by short chain fatty acids in wethers. Domest Anim Endocrinol. 2011;41:50-55.

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Abstract

La présente invention concerne des compositions pharmaceutiques et des procédés d'utilisation de ces compositions pharmaceutiques pour le traitement du diabète. Les compositions pharmaceutiques décrites ici sont efficaces pour améliorer les effets secondaires négatifs associés à la fois au traitement du diabète et au traitement du cancer à petites molécules. Dans certains aspects, les compositions pharmaceutiques pour le traitement du diabète de l'invention comprennent de la metformine et un modulateur du microbiome. Les compositions de formulation de metformine et de modulateur du microbiome améliorent les effets secondaires négatifs qui apparaissent normalement chez des patients humains auxquels ont été administrées des formulations de metformine actuellement disponibles.
PCT/US2015/038088 2014-06-26 2015-06-26 Composition comprenant de la metformine et un modulateur du microbiome WO2015200842A1 (fr)

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WO2018161077A1 (fr) * 2017-03-03 2018-09-07 The Regents Of The University Of California Méthodes de traitement de pathologies associées à une barrière intestinale semi-perméable
US10119116B2 (en) 2016-07-28 2018-11-06 Bobban Subhadra Devices, systems and methods for the production of humanized gut commensal microbiota
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US11938158B2 (en) 2021-11-22 2024-03-26 Solarea Bio, Inc. Methods and compositions for treating musculoskeletal diseases, treating inflammation, and managing symptoms of menopause
US11980647B2 (en) 2018-09-05 2024-05-14 Solarea Bio, Inc. Methods and compositions for treating musculoskeletal diseases, treating inflammation, and managing symptoms of menopause
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US11938158B2 (en) 2021-11-22 2024-03-26 Solarea Bio, Inc. Methods and compositions for treating musculoskeletal diseases, treating inflammation, and managing symptoms of menopause

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