WO2015200842A1

WO2015200842A1 - Composition comprising metformin and a microbiome modulator

Info

Publication number: WO2015200842A1
Application number: PCT/US2015/038088
Authority: WO
Inventors: Mark L. Heiman; Steve A. Orndorff; Dale R. Pfost
Original assignee: Microbiome Therapeutics LLC
Current assignee: Microbiome Therapeutics LLC
Priority date: 2014-06-26
Filing date: 2015-06-26
Publication date: 2015-12-30
Anticipated expiration: 2016-12-26

Abstract

The disclosure teaches pharmaceutical compositions and methods of using said pharmaceutical compositions for the treatment of diabetes. The pharmaceutical compositions taught herein are effective at ameliorating the negative side effects associated with both diabetes treatment and also small molecule cancer treatment. In aspects, the pharmaceutical compositions for treating diabetes taught herein comprise metformin and a microbiome modulator. The taught microbiome modulator formulated metformin compositions ameliorate the negative side effects normally encountered in human patients administered the currently available metformin formulations.

Description

IN THE UNITED STATES PATENT & TRADEMARK OFFICE

PCT PATENT APPLICATION COMPOSITION COMPRISING METFORMIN AND A MICROBIOME MODULATOR

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] The present Application is an International Application that claims the benefit of priority to U.S. Provisional Application No. 62/017,340, filed on June 26, 2014, the entire contents of which are hereby incorporated by reference in their entirety.

FIELD

[0002] The disclosure provides pharmaceutical compositions comprising an active pharmaceutical agent and at least one microbiome modulator.

[0003] In particular embodiments, the disclosure provides pharmaceutical compositions for treating diabetes that contain metformin and at least one microbiome modulator.

[0004] Other aspects of the disclosure provide pharmaceutical compositions for treating diabetes that contain metformin and/or various DPP-IV inhibitors and/or SGLT-2 inhibitors and at least one microbiome modulator.

[0005] Also taught herein are 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.

[0006] 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. BACKGROUND

[0007] One of the most prevalent public health issues facing the United States is the overabundance and increasing incidence of diabetes. It is estimated that 25.8 million Americans have diabetes. This is in contrast to a mere 1.5 million Americans with diabetes in 1958. The number and increasing incidence of diabetes in American society is already of epidemic proportions and represents the seventh leading cause of death in the United States.

[0008] Specifically, the incidence of type 2 diabetes mellitus, also known as adult-onset diabetes, in the United States is disturbing. Of the 25.8 million Americans with diabetes, 90 to 95% have type 2 diabetes. The remaining 10% have type 1 diabetes mellitus or gestational diabetes.

[0009] 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. Not surprisingly, the increased incidence of obesity in the United States is highly correlated with the increased incidence of type 2 diabetes.

[0010] 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.

[0011] The most prescribed drug on the market for treatment of type 2 diabetes is called 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^®).

[0012] 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. Bolen S., Feldman L., Vassy J., et al.,“Systematic review: comparative effectiveness and safety of oral medications for type 2 diabetes mellitus,” Ann Intern Med, 2007, Vol. 147(6), pgs. 386-99.

[0013] However, 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. Dandona P., Fonseca V., Mier A., Beckett A.G.,“Diarrhea and metformin in a diabetic clinic,” Diabetes Care, 1983, Vol. 6, pgs. 472-74. In fact, diarrhea associated with metformin is such a problem that some diabetic patients cannot tolerate the drug. Thus, the negative side effects associated with metformin treatment lead to a less than ideal patient compliance with the therapy.

[0014] Therefore, there is a crucial need in the public health sector for compositions and methods that increase patient tolerance to metformin.

[0015] Specifically, the diabetic community is in urgent need of compositions and methods that alleviate the negative side effects, e.g. diarrhea, associated with metformin treatment. SUMMARY OF THE DISCLOSURE

[0016] The present disclosure addresses a great need in the art, by providing for improved compositions and methods for treating diabetes. Specifically, in embodiments, the disclosure provides 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.

[0017] 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.

[0018] In embodiments, patients administered the metformin compositions taught herein comprising a microbiome modulator—e.g. inulin, and/or beta-glucan, and/or a polyphenolic compound—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. Thus, the compositions of the disclosure lead to an increased tolerability to metformin. 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.

[0019] Also taught herein are 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. Thus, 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.

[0020] Also taught herein are 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. Thus, 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.

[0021] In aspects, the compositions of the disclosure comprise a microbiome modulator that is effective at altering the gut associated microbiome of patients administered the composition. In particular embodiments, 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.

[0022] The 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).

[0023] The 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.

[0024] Thus, in an embodiment, the disclosure provides a pharmaceutical composition, comprising:

a) a therapeutically effective amount of metformin, or a pharmaceutically acceptable salt thereof;

b) a microbiome modulator; and c) a pharmaceutically acceptable carrier.

[0025] The pharmaceutical composition comprising metformin and a microbiome modulator may be formulated for oral administration.

[0026] 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. For example, 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-O™, a dessert preparation, a yogurt material packaged in a small tube for individual serving as with Go-Gurt™, and any other edible composition known to one of skill in the art.

[0027] In some aspects, the compositions of the disclosure are formulated with a probiotic composition. In these aspects, 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. Further, 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. Furthermore, the microbiome modulators taught herein protect the mucosal barrier that is home to several probiotics that adhere to this site.

[0028] 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.

[0029] In some aspects, the microbiome modulators act synergistically when in combination. In some aspects, 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. These aforementioned microbiome modulators are not exhaustive, as will be illustrated below and throughout the disclosure.

[0030] For example, 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.

[0031] In embodiments, 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. In certain embodiments, the dietary beta-glucan includes (1,3/1,4) beta-glucan extracted from oat. Thus, in some aspects, the beta-glucan can be any plant derived beta-glucan. In some aspects, the beta-glucan is a plant derived beta-glucan and not a yeast derived beta-glucan. In some aspects, the beta-glucan is a plant derived beta- glucan and not a fungus derived beta-glucan. In some aspects, the beta-glucan is a plant derived beta-glucan and not a bacterial derived beta-glucan.

[0032] In embodiments, 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.

[0033] In embodiments, a composition comprising“a polyphenol,” is to be understood as containing one or more polyphenolic compounds. Thus, mixtures of polyphenol compounds can be encompassed by the compositions of the disclosure. Some mixtures of polyphenolic compounds exhibit synergistic behavior, which can be evaluated by the use of Colby’s formula to measure synergy (i.e. (E) =X+Y-(X*Y/100). Thus, 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.

[0034] Thus, in an embodiment, the disclosure provides a liquid pharmaceutical composition for oral administration, comprising:

b) a microbiome modulator; and

c) a pharmaceutically acceptable liquid carrier.

[0035] In an aspect, the microbiome modulator is at least one selected from the group consisting of: inulin, beta-glucan, and polyphenol, or any combination thereof. For example, 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.

[0036] In another aspect, 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 particular embodiments, the microbiome modulator comprises: agave inulin, beta-glucan (1,3/1,4) extracted from oat, and a polyphenolic compound extracted from blueberry pomace.

[0037] In embodiments, 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.

[0038] In embodiments, 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. A particular embodiment provides that the therapeutically effective amount of metformin is 500 mg per 5 mL liquid composition.

[0039] In aspects, the pharmaceutically acceptable liquid carrier is purified water.

[0040] In aspects, the pharmaceutical composition further comprises: a flavoring agent. In some aspects, the flavoring agent does not increase the blood glucose level of a subject after ingestion thereof.

[0041] In aspects, the pharmaceutical composition further comprises: a sugar alcohol or non- nutritive flavoring agent.

[0042] In particular aspects, the therapeutically effective amount of a HCl acid addition salt of metformin is present.

[0043] In embodiments, the metformin, or its pharmaceutically acceptable salts, are in association with a liquid carrier. The liquid form, as contemplated by the disclosure, includes: solutions, suspensions, syrups, and emulsions. Inasmuch as the pharmaceutical composition is for oral administration, 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). Some embodiments, in which if ethanol is present, comprise ethanol in minimal amounts, e.g., no more than about 1% (v/v) or no more than about 0.5% (v/v).

[0044] 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.

[0045] In some embodiments, 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.

[0046] In embodiments, the density of the liquid formulation is one g/mL or greater, with the maximum value being that value a flowing liquid can have. In some embodiments, 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.

[0047] Also provided herein is a pharmaceutical composition, comprising:

b) 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.

[0048] In some embodiments, 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.

[0049] Also taught herein is a liquid pharmaceutical composition for oral administration, comprising:

a) a therapeutically effective amount of metformin, or a pharmaceutically acceptable salt thereof; b) at least one microbiome modulator selected from: an indigestible carbohydrate, beta-glucan, a polyphenolic compound, or any combination thereof; and c) a pharmaceutically acceptable liquid carrier.

[0050] Also taught herein is a pharmaceutical composition, comprising:

b) a plant derived microbiome modulator; and

c) a pharmaceutically acceptable carrier.

[0051] In aspects, a plant derived microbiome modulator comprises beta-glucan. In aspects, the plant derived microbiome modulator comprising beta-glucan comprises beta-glucan (1,3/1,4) beta-glucan extracted from oat. In some aspects, the plant derived microbiome modulator comprising beta-glucan, further comprises: inulin and/or a polyphenol. In a particular embodiment, the plant derived microbiome modulator comprising beta-glucan, further comprises: agave inulin and/or a polyphenol extracted from blueberry pomace.

[0052] In a particular embodiment, the disclosure provides a liquid pharmaceutical composition for oral administration, comprising:

b) a polyhydroxy alcohol present in an amount of about 15% to about 55% by weight;

c) 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;

d) a plant derived microbiome modulator; and

e) a pharmaceutically acceptable liquid carrier.

[0053] In aspects, the plant derived microbiome modulator is inulin, and/or beta-glucan, and/or a polyphenolic compound derived or extracted from a plant. In aspects, the beta- glucan is (1,3/1,4) beta-glucan extracted from oat. In aspects, the plant derived microbiome modulator comprising beta-glucan, further comprises: inulin and/or a polyphenol. In yet other aspects, the plant derived microbiome modulator comprising beta-glucan, further comprises: agave inulin and/or a polyphenol extracted from blueberry pomace.

[0054] In embodiments, 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.

[0055] In a particular embodiment, the therapeutically effective amount of metformin is 500 mg per 5 mL liquid composition.

[0056] In some embodiments, the pharmaceutically acceptable liquid carrier is purified water.

[0057] Some embodiments provide that the 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.

[0058] Some embodiments provide that the liquid pharmaceutical composition for oral administration further contains a sugar alcohol or non-nutritive flavoring agent. In aspects, 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%.

[0059] In a particular embodiment, the liquid pharmaceutical composition for oral administration comprises a therapeutically effective amount of a HCl acid addition salt of metformin.

[0060] Some embodiments of the 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.

[0061] In some embodiments, 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. In a particular aspect, 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.

[0062] In an aspect, the mineral acid of the composition is hydrochloric acid, nitric acid, or sulfuric acid. In an aspect, 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.

[0063] 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;

ii) a microbiome modulator; and

iii) a pharmaceutically acceptable carrier,

wherein the cancer patient is being treated with a compound targeted for treatment of non-small cell lung cancer.

[0064] In aspects, 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. In other aspects, the cancer patient is being treated with a compound that is a targeted covalent inhibitor of the initial activating epidermal growth factor receptor mutations. In yet other aspects, the cancer patient is being treated with a compound that is a targeted covalent inhibitor of the epidermal growth factor receptor T790M resistance mutation. In a particular aspect, the cancer patient is being treated with a compound with the following structure:

or a pharmaceutically acceptable salt thereof.

[0065] In another particular aspect, the cancer patient is being treated with the hydrobromide salt of a compound with the following structure:

.

[0066] In embodiments, the cancer patient is being treated with CO-1686.

[0067] In aspects, the side effect being minimized in the cancer patient is diarrhea or hyperglycemia. In aspects, 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.

[0068] In embodiments, the microbiome modulator is at least one selected from the group consisting of: inulin, beta-glucan, polyphenol, and/or any combination thereof.

[0069] Provided herein is also a method of minimizing the side effects associated with CO- 1686 treatment in a cancer patient, comprising:

ii) a microbiome modulator; and

iii) a pharmaceutically acceptable carrier,

wherein the cancer patient is being treated with CO-1686.

[0070] In aspects, 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.

[0071] In an aspect of the method, 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. In an aspect, 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. In some aspects, the pharmaceutical composition is administered with a meal. [0072] Also taught herein is a method of treating non-small cell lung cancer in a patient in need thereof, comprising administering to said patient:

a) CO-1686; and

b) an oral liquid pharmaceutical composition, comprising:

i) a therapeutically effective amount of metformin, or a pharmaceutically acceptable salt thereof;

ii) a microbiome modulator; and

iii) a pharmaceutically acceptable liquid carrier.

[0073] In embodiments, 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.

[0074] In aspects, 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. In a particular aspect, the therapeutically effective amount of metformin is 500 mg per 5 mL liquid composition. In another particular aspect, 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. In an aspect, a therapeutically effective amount of a HCl acid addition salt of metformin is present in said pharmaceutical composition.

[0075] 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. In the specification, the term“Metformin-MB” is utilized to denote the taught pharmaceutical composition that comprises metformin and at least one microbiome modulator.

[0076] In some aspect, the diabetic patient has type 2 diabetes. In particular aspects, 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.

[0077] In aspects, the disclosure provides for methods of treating diabetes in a patient suffering therefrom, comprising: administering a pharmaceutical composition as taught herein to said patient. In particular aspects, the patient suffers from type 2 diabetes.

[0078] In another embodiment, the disclosure provides for methods of treating hyperglycemia in a patient suffering therefrom, comprising: administering a pharmaceutical composition as taught herein to said patient.

[0079] In a further aspect, the patient does not suffer from a high incidence of diarrhea when treated with the pharmaceutical compositions, as taught herein. In another aspect, the patient does not suffer from abdominal pain or bloating when treated with the pharmaceutical compositions of the disclosure.

[0080] In aspects, the compositions of the disclosure comprise a microbiome modulator that is effective at altering the gut associated microbiome of patients administered the composition. In particular embodiments, 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.

[0081] The 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).

[0082] In aspects, the compositions of the disclosure comprise a microbiome modulator that is effective at altering the gut associated microbiome of patients administered the composition. In particular embodiments, 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. [0083] The 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).

[0084] In aspects, the compositions of the disclosure comprise a microbiome modulator that is effective at altering the gut associated microbiome of patients administered the composition. In particular embodiments, 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.

[0085] The 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).

[0086] In aspects, the compositions of the disclosure comprise a microbiome modulator that is effective at altering the gut associated microbiome of patients administered the composition. In particular embodiments, 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.

[0087] The 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). [0088] In aspects, the compositions of the disclosure comprise a microbiome modulator that is effective at altering the gut associated microbiome of patients administered the composition. In particular embodiments, the disclosure teaches 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.

[0089] The 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).

[0090] In aspects, the compositions of the disclosure comprise a microbiome modulator that is effective at altering the gut associated microbiome of patients administered the composition. In particular embodiments, 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.

[0091] The 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).

[0092] 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.

BRIEF DESCRIPTION OF THE FIGURES

[0093] FIG. 1 is an illustration of the various mechanisms associated with the gut microbial community during dysbiosis.

[0094] FIG. 2 is a schematic depiction of possible mechanisms of action of various microbiome modulators taught herein. [0095] FIG. 3 is an illustration of the contributions of the gastrointestinal (“gut”) microbiome to the development of type 2 diabetes.

[0096] FIG. 4 is an illustration depicting how an individual’s diet contributes to GI inflammation that is associated with type 2 diabetes.

[0097] 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.

[0098] 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.

[0099] 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 C₄H₁₁N₅•HCl and a molecular weight of 165.63.

[0100] FIG. 8 illustrates that the development of insulin resistance and ȕ-cell failure are involved in the development of obesity-associated type 2 diabetes.

[0101] FIG. 9 illustrates that polyphenols stimulate Acetogens that compete with methanogens and SRB for Hydrogen.

[0102] FIG. 10 illustrates polyphenol compounds that are present in an example composition according to the disclosure.

[0103] 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.

[0104] 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.

[0105] 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

Definitions

[0106] While the following terms are believed to be well understood by one of ordinary skill in the art, the following definitions are set forth to facilitate explanation of the presently disclosed subject matter.

[0107] The verb“comprise” and its conjugations, are used in the open and non-limiting sense to mean that items following the word are included, but items not specifically mentioned are not excluded.

[0108] As used herein, 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.

[0109] “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.

[0110] Furthermore, since all numbers, values, and expressions referring to quantities used herein, are subject to the various uncertainties of measurement encountered in the art, then unless otherwise indicated, all presented values may be understood as modified by the term “about.”

[0111] Where a numerical range is disclosed herein, then such a range is continuous, inclusive of both the minimum and maximum values of the range, as well as every value between such minimum and maximum values. Still further, where a range refers to integers, every integer between the minimum and maximum values of such range is included. In addition, where multiple ranges are provided to describe a feature or characteristic, such ranges can be combined. That is to say that, unless otherwise indicated, all ranges disclosed herein are to be understood to encompass any and all subranges subsumed therein. For example, a stated range of from“1 to 10” should be considered to include any and all subranges between the minimum value of 1 and the maximum value of 10. Exemplary subranges of the range“1 to 10” include, but are not limited to, 1 to 6.1, 3.5 to 7.8, and 5.5 to 10.

[0112]“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. For example, sustained release can have substantially no fluctuations in therapeutic agent delivery.

[0113] As used herein, 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.

[0114]“Therapeutically effective amount” means a level or amount of an agent needed to treat a condition. Thus, 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.

[0115] For example, 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.

[0116] The term“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. 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 Chemical Structure

[0117] Metformin is an oral antihyperglycemic drug used in the management of type 2 diabetes. Metformin has the following structure:

IUPAC name: N,N-Dimethylimidodicarbonimidic diamide [0118] The free base form of metformin is pharmaceutically useful, but has low stability. For this reason, metformin is administered in the form of a pharmaceutically acceptable acid addition salt.

[0119] The commercially marketed version of the drug is the HCl acid addition salt, metformin hydrochloride, having the following structure:

IUPAC name: N,N-Dimethylimidodicarbonimidic diamide hydrochloride [0120] The commercially marketed version of metformin hydrochloride, may also be represented with the following structural notation:

[0121] Metformin and any of its generic salts can be represented by the following structure:

[0122] In which A is the anion of the non-toxic salt of the preferred medicament.

[0123] Metformin hydrochloride is a white to off-white crystalline compound with a molecular formula of C₄H₁₁N₅•HCl and a molecular weight of 165.63.

[0124] 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.

[0125] Several acid addition salts other than metformin hydrochloride are known, for example, in: U.S. Pat. Nos.: 4,028,402; 4,835,184; 3,903,141; 3,957,853; 3,651,132; International PCT Publication Nos. WO 2005/033067; 2008/093984; 2008/061456; 2009/038396; and 2005/033067, each of which are hereby incorporated by reference in their entireties for all purposes. Also, U.S. Pat. No. 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. Each of these patents is hereby incorporated by reference in their entirety for all purposes.

[0126] For ease of readability, whenever reference is made in the disclosure to“metformin,” this is intended to also entail reference to the pharmaceutically acceptable salt of metformin, as described above.

Metformin Synthesis

[0127] 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.

[0128] Several processes have been reported for the preparation of metformin hydrochloride for example, in: FR 2 322 860 B1; CN100391939 C; IN 189077 A1; and WO 2005/033089, each of which is hereby incorporated by reference in its entirety.

Metformin Commercial Tablet Formulations

[0129] Commercially formulated metformin is often sold as a tablet. The 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.

[0130] In addition, each metformin hydrochloride tablet USP generally contains one of the following inactive ingredients: colloidal silicon dioxide, hypromellose, magnesium stearate, polyethylene glycol, and povidone.

[0131] For example, 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.

[0132] 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.

[0133] 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.

[0134] The currently marketed 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.

[0100] However, where the 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. [0101] 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.

[0102] In such cases, the unpleasant taste of the hydrochloride salt could lead to compliance problems.

Tablet Formulation of Metformin-MB

[0103] In certain aspects, the pharmaceutical compositions of the present disclosure are formulated as a tablet. For instance, 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.

[0104] 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. Typically, 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.

[0105] In embodiments, the dosage form is prepared by a wet granulation technique or a direct compression method to form uniform granulates. Alternatively, 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.

[0106] In an embodiment, 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. For example, in the direct compression method, 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. [0107] In some embodiments, the tablets of the disclosure comprise metformin and beta- glucan. In other embodiments, the tablets of the disclosure comprise metformin and inulin. In yet other embodiments, the tablets of the disclosure comprise metformin and a polyphenol compound. In some embodiments, 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.

[0108] When forming tablets, a person skilled in the art would recognize that when a tablet is being formulated it is necessary to include excipients to fulfill the function of a filler, a binder, a disintegrant, and a lubricant along with the active ingredient.

[0109] Also sometimes called“bulking agents” or“diluents,” 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) is a filler that can be used in tablets or hard gelatin capsules. 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.

[0110] 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. 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. They ensure that when the tablet is in contact with water, it rapidly breaks down into smaller fragments, facilitating dissolution. Examples of 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.

[0112] 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.

[0113] 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.

[0114] There are two major types of lubricants: (1) Hydrophilic, which are often generally poor lubricants, with no glidant or anti-adherent properties; (2) 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.

Edible Product Formulation of Metformin-MB

[0115] In certain aspects, 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-O™, a dessert preparation, a yogurt material packaged in a small tube for individual serving as with Go-Gurt™, and any other edible composition known to one of skill in the art. [0116] Although metformin is water soluble and has good heat stability, it is not a potent drug. Metformin doses typically needed range from 500mg - 1000mg. Consequently, the mass of the aforementioned tablet embodiments of the taught pharmaceutical compositions may be larger than a consumer would desire, e.g. § 8g. Thus, in some aspects, the pharmaceutical compositions of the disclosure require a unique delivery system, such as an edible product. However, these unique delivery systems may be a large capsule or a chewable tablet.

[0117] Furthermore, 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-O™. 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-Gurt™ 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.

[0118] In embodiments, 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 Mechanism of Action

[0119] 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.

[0120] Metformin is effective in the presence of insulin, and its major effect is to decrease hepatic glucose output. In addition, 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. Stumvoll, et al.,“Metabolic effects of metformin in non-insulin dependent diabetes mellitus,” N. Engl. J. Med., 1995, Vol. 333(9), pgs. 550- 554. As a result of the improvement in glycemic control, serum insulin concentrations decline slightly. Wu, et al.,“Effect of metformin on carbohydrate and lipoprotein metabolism in NIDDM patients,” Diabetes Care, 1990, Vol. 13(1), pgs. 1-8.

[0121] 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. Bailey, C.J.,“Biguanides and NIDDM,” Diabetes Care, 1992, Vol. 15(6), pgs. 755-72.

[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-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. Fullerton et al.,“Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin,” Nat. Med., 2013, Vol. 19(12), pgs. 1649-54. Metformin works through the Peutz-Jeghers protein, LKB1, to regulate AMPK. Shaw et al.,“The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin,” Science, 2005, Vol. 310(5754), pgs. 1642-1646. LKB1 is a tumor suppressor and activation of AMPK through LKB1 may play a role in inhibiting cell growth. Metformin Bioavailability

[0123] The absolute bioavailability of a metformin hydrochloride 500 mg tablet given under fasting conditions is approximately 50% to 60%. Studies using single oral doses of metformin tablets of 500 mg to 1500 mg, and 850 mg to 2550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. 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.

Metformin Distribution

[0124] 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. At usual clinical doses and dosing schedules of metformin hydrochloride tablets, steady state plasma concentrations of metformin are reached within 24 to 48 hours and are generally <1 μg/mL. During controlled clinical trials of metformin hydrochloride, maximum metformin plasma levels did not exceed 5 μg/mL, even at maximum doses. See GLUCOPHAGE XR^® label.

Metformin Metabolism and Elimination

[0125] Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion. Renal clearance (See Table 1. Select Mean (± S.D.) Metformin Pharmacokinetic Parameters Following Single or Multiple Oral Doses of Metformin) is approximately 3.5 times greater than creatinine clearance which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution. See below Table 1 taken from GLUCOPHAGE XR^® label. TABLE 1: Metformin Pharmacokinetic Parameters

Metformin Negative Side Effects

[0126] 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.

[0127] 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.

[0128] The pharmaceutical 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 Combinations

[0129] 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.

[0130] In the United States, 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^®). Generic formulations of metformin/glipizide and metformin/glibenclamide are available.

[0131] Thus, the present pharmaceutical compositions of the disclosure may contain optional active ingredients along with metformin. For example, the compositions may comprise another antihyperglycemic agent.

[0132] The metformin, or salt thereof, may be in combination with one or more antihyperglycemic agents. In a particular embodiment, the compositions comprise: metformin, or a pharmaceutically acceptable salt thereof, and beta-glucan, and glyburide. In another particular embodiment, the compositions comprise: metformin, or a pharmaceutically acceptable salt thereof, and beta-glucan, and glipizide. [0133] The antihyperglycemic agent may be an oral antihyperglycemic agent, e.g., a sulfonyl urea, such as glyburide, glimepiride (disclosed in U.S. Pat. No. 4,379,785, the contents of which are incorporated by reference), glipizide, gluclazide, or chloropropamide, or other known sulfonyl ureas or other antihyperglycemic agents which act on the ATP-dependent channel of the B cells.

[0134] Where present, 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.

[0135] The 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.

[0136] 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).

[0137] The 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.

[0138] The antihyperglycemic agent may be a thiazolinedione oral anti-diabetic agent, which has an insulin sensitivity effect in patients with Type 2 diabetes.

[0139] The 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.

[0140] Where present, 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.

[0141] The 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).

[0142] Where present, 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. [0143] Where present GLP-1 peptides are administered in the liquid oral formulation of the present disclosure.

Metformin Metabolism and Elimination

[0144] Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution. See previous Table 1 taken from GLUCOPHAGE XR^® label.

The Microbiome

[0145] 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.

[0146] Recently, analysis of fecal microbiota showed that patients with type 2 diabetes have a moderate degree of gut microbial dysbiosis, a decrease in the abundance of some universal butyrate producing bacteria, and an increase in various opportunistic pathogens, as well as an enrichment of other microbial functions conferring sulphate reduction and reduction of oxidative stress resistance. Id.

[0147] Other studies showed that obesity, type 2 diabetes, insulin resistance, and the related metabolic syndrome are closely associated with a low-grade inflammation, in which the gut microbiota play a very important role. See, e.g., Cani et al.,“Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet induced obesity and diabetes in mice,” Diabetes, 2008, Vol. 57, pgs. 1470-1481; and Pendyala et al.,“A high-fat diet is associated with endotoxemia that originates from the gut,” Gastroenterology, 2012, Vol. 142, pgs. 1100-1101. [0148] Thus, changes in the human gut microbiome are associated with type 2 diabetes and insulin resistance. The compositions of the present disclosure are capable of having an effect on the gut microbiome of treated individuals. In some embodiments, the taught compositions are capable of causing a shift in the microbial community of treated patients. In some embodiments, the compositions of the present disclosure are capable of having an effect on the GI tract’s environment.

[0149] The shift in the gut associated microbial community, or alteration in the environment of the GI tract, of a treated patient is brought about by the utilization of one or more microbiome modulators contained in the compositions taught herein.

[0150] In particular embodiments, 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.

[0151] The contents of U.S. Application No. 14/238,980, which is a National Stage Entry of International Application No. PCT/US2012/051408, entitled: Composition and use of a formulation to increase the ratio of gastrointestinal microbiota in phylum Bacteriodites to microbiota of Firmuctes phylum, filed on August 17, 2012, are each hereby incorporated by reference in their entireties for all purposes.

Microbiome modulator: Beta-glucan

[0152] Beta-glucans (or“ȕ-Glucans”) are natural polysaccharides that contain only glucose as structural components, and are linked with ȕ-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.

[0153] When 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“Į” (alpha) indicates the etheric oxygen linkage attaches to the anomeric carbon below the ring, and a“ȕ” (beta) indicates the etheric oxygen linkage attaches to the anomeric carbon above the ring (in the standard Haworth projection). Thus, the designation of ȕ(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. Likewise, the designation of ȕ(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.

[0154] Beta-glucans can be isolated from various sources such as: oat, barley, wheat, baker’s yeast, certain fungi, and mushrooms.

[0155] 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. See, Greenway, et al.,“A novel cobiotic containing a prebiotic and an antioxidant augments the glucose control and gastrointestinal tolerability of metformin: a case report,” Beneficial Microbes, 2014, Vol. 5(1), pgs. 29-32, which is hereby incorporated by reference in its entirety for all purposes.

[0156] The below Table 3 illustrates sources of beta-glucan utilized in embodiments of compositions taught herein, along with associated calories contained in the specified quantities.

T^{ABLE 3: Quantity and Calorie Content for} _Beta-Glucan

Microbiome modulator: Indigestible Carbohydrate That is Fermentable by GI

Microbiota

[0157] In an embodiment, the indigestible carbohydrates that are fermentable by gastrointestinal microbiota are the inulins. However, 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.

[0158] 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.

[0159] As aforementioned, 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

[0160] 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.

[0161] 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. [0162] In particular embodiments, 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. 140, pgs. 1764-1768. In some aspects, the 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

[0163] As aforementioned, the term“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.

[0164] The change in the microbial community may involve an increase or decrease in one or more species of the microbial community.

[0165] 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 the mucus barrier, priming of the GI immune system, sequester of bile salts, impeding glucose absorption, among other habitat alterations discussed herein.

[0166] Table 4 below illustrates some of the mechanisms of action of the various exemplary microbiome modulators of the present disclosure.

TABLE 4: Microbiome Modulators and Mechanisms of Action

Compositions Comprising Metformin and a Microbiome modulator

[0167] The pharmaceutical compositions taught herein comprise a therapeutically effective amount of metformin, or its pharmaceutically acceptable salt.

[0168] In particular aspects, the compositions comprise metformin, or its pharmaceutically acceptable salt, and at least one microbiome modulator.

[0169] In still further aspects, the 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.

[0170] In still further aspects, the compositions comprise metformin, or its pharmaceutically acceptable salt, and at least one plant based microbiome modulator.

[0171] In still further aspects, the compositions comprise metformin, or its pharmaceutically acceptable salt, and at least one microbiome modulator not derived from yeast or yeast cells.

[0172] In still further aspects, the 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.

[0174] 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.

[0175] 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.

[0176] 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.

[0177] Oral solutions are liquid preparations for oral use containing one or more active ingredients dissolved in a suitable vehicle.

[0178] 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. In embodiments, the liquid pharmaceutical formulations of the disclosure are formulated as an oral suspension.

[0179] 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.

[0180] 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.

[0181] 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.

[0182] 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.

[0183] In embodiments, the liquid pharmaceutical compositions taught herein comprise a therapeutically effective amount of metformin, or its pharmaceutically acceptable salt, in a liquid carrier.

[0184] Some aspects of the liquid formulations of the disclosure also comprise a microbiome modulator. In particular aspects, the microbiome modulator is at least one selected from the group consisting of: beta-glucan, inulin, and polyphenol.

[0185] In an embodiment, the liquid formulations comprise: metformin and beta-glucan.

[0186] In an embodiment, the liquid formulations comprise: metformin and inulin.

[0187] In an embodiment, the liquid formulations comprise: metformin and at least one polyphenol.

[0188] In an embodiment, the liquid formulations comprise: metformin and beta-glucan and at least one polyphenol. [0189] Additionally, 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.

[0190] The 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.

[0191] In a particular embodiment, the liquid pharmaceutical formulations of the disclosure help prevent the diarrhea side effects normally encountered upon administration of the present commercial embodiments of metformin.

[0192] Other optional ingredients which may be present in the 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.

[0193] Pharmaceutically acceptable carriers are well known and are usually liquids, in which an active therapeutic agent is formulated. In embodiments, 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. Moreover, unless indicated to the contrary, 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).

[0194] 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. [0195] 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.

[0196] In embodiments, the liquid formulation contains polyhydric alcohols. The term 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. When 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.

[0197] 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.

[0198] Examples of said glycols are 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).

[0199] Examples of said triols include glycerin, trimethylol propane, and the like.

[0200] Examples of said polyols include sorbitol, polyvinyl pyrrolidone, and the like.

[0201] 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.

[0202] In a particular embodiment, a polyhydric alcohol is polyethylene glycol. In another particular embodiment, 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. [0203] 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.

[0204] However, as the molecular weight of the polyethylene glycol increases, it becomes more and more viscous and the liquid containing same becomes thicker and more cumbersome to work with. For instance, at the higher molecular weights, the polyethylene glycol begins to adopt more solid-like properties. Furthermore, the greater the molecular weight the less of the polyethylene glycol used in the formulation. Thus, in a particular embodiment, the polyethylene glycol is a mixture of polyethylene glycol of 1000 daltons or less and a polyethylene glycol greater than 1000 daltons.

[0205] It is within the skill of one ordinary skill in the art to mix the various types of polyethylene glycols to obtain a liquid formulation of desired viscosity.

[0206] 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.

[0207] In addition, some embodiments of the liquid formulations comprise alky hydroxyethylcellulose. In embodiments, the 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.

[0208] In a particular embodiment, 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.

[0209] Some embodiments of the liquid formulations comprise a sugar alcohol. As used herein, the term sugar alcohol refers to reduced sugars, such as monosaccharide alcohols and disaccharide alcohols. The monosaccharide alcohols have the formula HO—CH₂ (CHOH)_n— CH₂OH, wherein n is 2—5. They also include tetritols, pentitols, hexitols, and heptitols. [0210] Examples of 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.

[0211] Some embodiments of the 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.

[0212] In a particular embodiment of the present formulation, 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%. In some embodiments, the weight ratio of sweetener to alkyl hydroxyethylcellulose ranges from about 400 to about 800, or from about 500 to about 600. In an embodiment, 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.

[0213] As aforementioned, some embodiments of the 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. As used herein, with respect to this term, 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. Examples include ethylhydroxy ethylcellulose (EHEC) manufactured by Berol Kemi AB under the Bermocoll trade name and hydroxy ethyl cellulose (HEC), modified with a long chain alkyl group, generally termed HMHEC (HM=Hydrophobically Modified) manufactured by Aqualon Cot sold under the trade name Natrosol Plus, and the like.

[0214] 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.

[0215] In some aspects, 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. Preparation of Liquid Metformin Formulations Comprising a Microbiome modulator

[0216] The liquid formulations of the present disclosure may be prepared by any of the known methods of pharmacy.

[0217] In an embodiment, 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.

[0218] In general, the pharmaceutical compositions are prepared by uniformly and intimately mixing these various components with the liquid carrier.

[0219] For example, 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.

[0220] 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.

[0221] It is to be understood that the ingredients used in the present formulation are non- toxic.

Oral Administration

[0222] The compositions of the present disclosure can be formulated for oral administration. As aforementioned, 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.

Quantitative Administration

[0223] In embodiments, the 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.

[0224] In embodiments, the 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.

[0225] In embodiments, the 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. In embodiments, the 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. In particular aspects, the compositions of the present disclosure comprise at least about 1 to 3 grams of inulin per dose.

[0226] In embodiments, the 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 200 mg to 1000 mg total polyphenolics, or 200 mg to 900 mg total polyphenolics, or 200 to 800 mg total polyphenolics, or 200 mg to 750 mg total polyphenolics, or 200 mg to 740 mg total polyphenolics, or 300 mg to 1000 mg total polyphenolics, or 300 mg to 900 mg total polyphenolics, or 300 mg to 800 mg total polyphenolics, or 300 mg to 750 mg total polyphenolics, or 300 mg to 740 mg total polyphenolics, or 400 mg to 1000 mg total polyphenolics, or 400 mg to 900 mg total polyphenolics, or 400 mg to 800 mg total polyphenolics, or 400 mg to 750 mg total polyphenolics, or 400 mg to 740 mg total polyphenolics, or 500 mg to 1000 mg total polyphenolics, or 500 mg to 900 mg total polyphenolics, or 500 mg to 800 mg total polyphenolics, or 500 mg to 750 mg total polyphenolics, or 500 mg to 740 mg total polyphenolics, or 600 mg to 1000 mg total polyphenolics, or 600 mg to 900 mg total polyphenolics, or 600 mg to 800 mg total polyphenolics, or 600 mg to 750 mg total polyphenolics, or 600 mg to 740 mg total polyphenolics. In a particular embodiment, the disclosure provides for compositions comprising approximately at least 731 mg total polyphenolic compounds per dose, said polyphenolic compounds being extracted from blueberry pomace.

[0227] In embodiments, the 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.

[0228] In embodiments, the 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 per dose, or 2000 mg or more of metformin hydrochloride and 1-5 grams of beta-glucan per dose.

[0229] In particular embodiments, the 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.

[0230] In other embodiments, the 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, 1000 mg metformin hydrochloride and 1-5 grams of beta-glucan per 5 mL dose, 1500 mg metformin hydrochloride and 1-5 grams of beta-glucan per 5 mL dose, or 2000 mg or more of metformin hydrochloride and 1-5 grams of beta-glucan per 5 mL dose.

[0231] In other embodiments, 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.

[0232] In other embodiments, 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 5 mL to 10 mL, or 10 mL to 1000 mL, or 10 mL to 500 mL, or 10 mL to 400 mL, or 10 mL to 300 mL, or 10 mL to 200 mL, or 10 mL to 100 mL, or 10 mL to 50 mL, or 10 mL to 40 mL, or 10 mL to 30 mL, or 10 mL to 20 mL.

[0233] In other embodiments, the 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, about 1500 mg to about 2000 mg, or more, of metformin hydrochloride per dose.

[0234] In a particular embodiment, 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.

[0235] Also taught are embodiments 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. Also taught are embodiments 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.

[0236] In a particular embodiment, 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. [0237] Also taught are 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.

[0238] Also taught are embodiments 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.

[0239] Also taught are embodiments 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.

[0240] Also taught are embodiments 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.

[0241] Also taught are embodiments 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.

[0242] The 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.

Various Formulations of the Disclosure

[0244] The below Table 5 recites various formulations of the 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.

TABLE 5

EXAMPLES

Example 1: Preparation of a Base Liquid Metformin Formulation

[0245] In one embodiment, 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.

[0246] According to this embodiment, in 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. 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.

[0247] The resulting product is a base liquid metformin hydrochloride formulation.

[0248] In embodiments, 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. In some aspects, the base liquid metformin hydrochloride formulation is subsequently brought into combination with beta-glucan. In some aspects, the base liquid metformin hydrochloride formulation is subsequently brought into combination with beta-glucan and at least one polyphenolic compound. [0249] In an embodiment, beta-glucan (OATWELL^® 22% manufactured by DSM) is mixed with the base liquid metformin hydrochloride formulation. 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.

[0250] 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. In Example 2, the microbiome modulator (e.g. beta-glucan, inulin, and/or a polyphenolic compound, or any combination thereof) is combined during the initial process of deriving the metformin formulation.

Example 2: Preparation of a Liquid Metformin Formulation Comprising a

Microbiome Modulator

[0251] In embodiments, 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.

[0252] In 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. A microbiome modulator (e.g. beta-glucan, inulin, and/or a polyphenolic compound, or any combination thereof), in an appropriate amount, is slowly added to the Tank at 60 RPM, while the temperature is maintained at 40°C. If 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) 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.

[0253] The resulting product is a liquid metformin hydrochloride formulation comprising a microbiome modulator. As aforementioned, 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

Formulation Comprising Beta-glucan and a Polyphenolic Compound (METFORMIN-MB)

[0254] This is an anticipated human study utilizing a liquid formulation comprising metformin and two microbiome modulators: (1) beta-glucan and (2) at least one polyphenolic compound (METFORMIN-MB) to improve glucose regulation and ameliorate the negative side effects normally associated with metformin treatment.

[0255] In addition to the below study, 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. In some aspects of the proposed study, the composition is formulated as an edible food product.

Study Subjects and Methodology

[0256] The required number of subjects is properly screened to fulfill the necessary qualifications, appropriate laboratory evaluations are performed, measures of positive primary and secondary outcome responses are recorded, adverse events are documented, and patients are adequately followed-up.

Subject Screening and Selection

[0257] 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.

[0258] 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.

[0259] 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.

Study Overview and Expectations

[0260] The study is expected to demonstrate that overweight subjects with impaired fasting blood glucose on an ad libitum diet who take a liquid formulation comprising metformin and beta-glucan and at least one polyphenolic compound, i.e. METFORMIN-MB, either with meal 1 or with meal 2, as well as with meal 3 for 4 weeks, will:

1) Have an increased ratio of Bacteroidetes species to Firmicutes species in fecal samples when samples at the end of study are compared to samples at the onset of study; and when the ratio of species is compared to samples from the patient group administered STANDARD METFORMIN;

2) Have an improved blood glucose and insulin responses to an OGTT by decreasing the areas under the insulin curve (improved insulin sensitivity), particularly at 120 minutes and 180 minutes after consuming glucose;

3) Have a decreased fasting blood glucose value;

4) Have weight loss, loss of body fat, and/or decrease of body fat %;

5) Have increases in GLP-1 and PYY response to the oral glucose challenge and decreases the fasting ghrelin levels at 1 hour after the OGTT and the standardized meal when comparing final values to the initial measurements of the OGTT, and when comparing to those findings of the STANDARD METFORMIN group during the standardized meal;

6) Have decreased stool pH; 7) Have increased stool SCFA;

8) Experience decreased severity of at least one negative side effect selected from the group consisting of: diarrhea, nausea, vomiting, flatulence, asthenia, indigestion, abdominal discomfort, abdominal pain, bloating, heartburn, and headache, as compared to the patients receiving STANDARD METFORMIN.

Study Design

[0261] In this study, 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.

[0262] Some subjects receive 5 mL of a composition 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.

[0263] 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.

[0264] Subjects report weekly for measurements and assessment of any side effects. They are asked to collect a stool sample before initiating the study, as well as at the end of the 4 week treatment period. They are also asked to record any side effects and their frequency (checklist assessment). They are asked to record appetite and satiety during the standardized meal at the 3rd week of intervention. They are provided with the proper paper work to record these.

[0265] 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.

[0266] 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.

[0268] 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.

Appropriate Laboratory Evaluation

[0269] Different tests are performed at the screening of potential participants, at the beginning of the study, and at the end of the 4 week treatment period.

[0270] 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).

[0271] Beginning of Study: Subjects passing the initial screen are evaluated at the beginning of WEEK #1 as follows: a) Fasting blood glucose and insulin levels; b) SMA 20 (Sequential multi-channel analysis with computer-20, a metabolic panel with 20 different analytes), including, uric acid, and liver function tests; c) Triglycerides; d) Cholesterol, including fractions; e) Glycosylated hemoglobin A1 (HgbA1); f) Weight, taken on the same scale each time; g) Body fat% and total body fat, determined by DXA (dual-energy X-ray absorptiometry); h) Height; i) Waist and hip measurements; j) Blood glucose, insulin, GLP- 1, PYY and ghrelin responses to a 75g oral glucose challenge; k) Assessment of appetite and satiety using a visual analog scale; and l) Stool is collected and stored frozen but not analyzed until the end of study.

[0272] End of Study Assessment: All labs aforementioned for the“Beginning of Study” assessment are repeated.

[0273] Additionally, an analysis of the fecal microbiome DNA from both the initial sample and the final sample is conducted.

Expected Results

[0274] This study is expected to demonstrate that METFORMIN-MB:

1) Increases the ratio of Bacteroidetes species to Firmicutes species in fecal samples when samples at the end of study are compared to samples at the onset of study; and when the ratio of species is compared to samples from the patient group administered STANDARD METFORMIN;

2) Improves the blood glucose and insulin responses to an OGTT by decreasing the areas under the insulin curve (improved insulin sensitivity);

3) Decrease fasting blood glucose values

4) Produces weight loss, loss of body fat, and/or decrease of body fat %;

5) Increases GLP-1 and PYY response to the oral glucose challenge and decreases the fasting ghrelin levels at 1 hour after the both the OGTT and the standardized meal when comparing final values to the initial measurements of the OGTT, and when comparing to those findings of the STANDARD METFORMIN group during the standardized meal;

6) Decreases stool pH;

7) Increases stool SCFA;

8) Decreases the severity of at least one negative side effect selected from the group consisting of: diarrhea, nausea, vomiting, flatulence, asthenia, indigestion, abdominal discomfort, abdominal pain, bloating, heartburn, and headache, as compared to the patients receiving STANDARD METFORMIN.

[0275] Some of the hypothesized results of the study are depicted in FIG. 6. The beta-glucan and polyphenolic compound are a strong microbiome modulator that can act synergistically with a biguanide class of compound, such as metformin.

Dosage Regimens and Titration

[0276] 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.

[0277] However, there is no fixed dosage regimen for the management of hyperglycemia in patients with type 2 diabetes with METFORMIN-MB, or any other pharmacologic agent.

[0278] Dosage of METFORMIN-MB must be individualized on the basis of both effectiveness and tolerance, while not exceeding the maximum recommended daily doses. [0279] 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).

[0280] 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.

[0281] During treatment initiation and dose titration, 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.

[0282] 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.

[0283] Short-term administration of METFORMIN-MB may be sufficient during periods of transient loss of control in patients usually well-controlled on diet alone.

Dosing Schedule of METFORMIN-MB in One Embodiment

[0284] Adults: In general, clinically significant responses are sometimes not seen at doses below 1500 mg metformin (15 mL METFORMIN-MB) per day. However, a lower recommended starting dose and gradually increased dosage can be utilized to determine the exact minimum dosage requirement for a particular patient.

[0285] 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.

[0287] For those patients requiring additional glycemic control, 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.

[0288] Pediatrics: the usual starting dose of METFORMIN-MB for pediatric patients is 500 mg metformin (5 mL METFORMIN-MB) twice a day, given with meals. Dosage increases can be made in increments of 500 mg metformin (5 mL METFORMIN-MB) weekly up to, in embodiments, a maximum of 2000 mg metformin (20 mL METFORMIN-MB) per day, given in divided doses.

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

[0289] This is an anticipated human study utilizing a liquid formulation comprising metformin and beta-glucan and at least one polyphenolic compound (METFORMIN-MB) to minimize diarrhea and hyperglycemia associated with the treatment of non-small cell lung cancer.

Study Subjects and Methodology

[0290] The required number of subjects is properly screened to fulfill the necessary qualifications, appropriate laboratory evaluations are performed, measures of positive primary and secondary outcome responses are recorded, adverse events are documented, and patients are adequately followed-up.

Study Overview and Expectations

[0291] The study is expected to demonstrate that non-small cell lung cancer (NSCLC) patients being treated with a molecularly targeted small molecule can experience relief from the associated diarrhea and hyperglycemia caused from such treatments by administration of METFORMIN-MB. [0292] Specifically, NSCLC patients being treated with the hydrobromide salt of an epidermal growth factor receptor (EGFR) inhibitory compound having the following structure:

referred to as“CO-1686” and manufactured by CLOVIS ONCOLOGY, will experience decreased severity of diarrhea and hyperglycemia if coadministered

METFORMIN-MB in conjunction with the cancer therapy.

Subject Screening

[0293] The subjects must be currently taking CO-1686 for the treatment of NSCLC.

Study Design

[0294] 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.

[0295] 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.

[0296] In this study, 15 subjects consume 5 mL of METFORMIN-MB three times per day, preferably with a meal. The subjects are administered the CO-1686 cancer treatment as is standard for such treatment, e.g. 500 mg, 625 mg, 750 mg, 900 mg, or 1000 mg CO-1686, twice per day.

[0297] In this study, 15 subjects consume 5 mL STANDARD METFORMIN three times per day, preferably with a meal. The subjects are administered the CO-1686 cancer treatment as is standard for such treatment, e.g. 500 mg, 625 mg, 750 mg, 900 mg, or 1000 mg CO-1686, twice per day.

[0298] In this study, 15 subjects consume 5 mL of placebo three times per day, preferably with a meal. The subjects are administered the CO-1686 cancer treatment as is standard for such treatment, e.g. 500 mg, 625 mg, 750 mg, 900 mg, or 1000 mg CO-1686, twice per day.

[0299] Subjects report weekly for measurements and assessment of any side effects. They are asked to collect a stool sample before initiating the study, as well as at the end of the four week treatment period. They are also asked to record any side effects and their frequency (checklist assessment). They are provided with the proper paper work to record these.

Appropriate Laboratory Evaluation

[0300] Beginning of Study: Subjects are evaluated at the beginning of the four week study to ascertain their current level of negative side effects associated with CO-1686 treatment.

[0301] The patients are screened for incidences of: diarrhea, stool firmness, urgency to evacuate, abdominal pain, and hyperglycemia.

[0302] End of Study Assessment: The patients are screened for incidences of diarrhea, stool firmness, urgency to evacuate, abdominal pain, and hyperglycemia.

[0303] Additionally, an analysis of the fecal microbiome DNA from both the initial sample and the final sample is conducted.

Expected Results

A. Negative Side Effects of CO-1686

[0304] Normally, in NSCLC patients being treated with CO-1686, one expects to observe associated negative side effects as depicted below in Table 6 (data obtained from European Lung Cancer Conference, March 2014,“Phase 1 evaluation of CO-1686, an irreversible, mutant-selective inhibitor of EGFR mutations (activating and T790M)” by Heather Wakelee). TABLE 6: Negative Side Effects of CO-1686 in NSCLC Patients

B. METFORMIN-MB vs. STANDARD METFORMIN

[0305] This study is expected to demonstrate that those NSCLC patients being coadministered CO-1686 alongside METFORMIN-MB will have decreased incidences of at least one of: diarrhea, nausea, bloating, urgency to evacuate, abdominal pain, or hyperglycemia, as compared to those NSCLC patients being coadministered CO-1686 alongside STANDARD METFORMIN. That is, the METFORMIN-MB is expected to be able to decrease a negative side effect from Table 6.

[0306] It is expected that the 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.

[0307] We do not expect a complete elimination of diarrhea symptoms, but rather expect to observe a quantifiable decrease in diarrhea, or its associated symptoms, in the patient population administered METFORMIN-MB. We also anticipate that the METFORMIN-MB study group will have decreased abdominal pain and decreased bloating, as compared to the study group administered STANDARD METFORMIN.

C. METFORMIN-MB vs. Placebo

[0308] It is expected that an improvement will be seen in the incidences of diarrhea and hyperglycemia experienced by patients administered the METFORMIN-MB alongside CO- 1686 across all grades, as compared to the placebo group. See Table 6. [0309] Further, we expect patients being administered CO-1686 and METFORMIN-MB to experience less nausea, better appetite, less vomiting, less fatigue, and less myalgia, as compared to the placebo group. See Table 6.

[0310] Consequently, 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

[0311] Besides the aforementioned METFORM-MB study, the inventors also envision co- administering CO-1686 alongside a composition that comprises at least one microbiome modulator (e.g. inulin, beta-glucan, at least one polyphenolic compound), but which does not comprise metformin. 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

Microbiome Modulator

[0312] In embodiments, the disclosure teaches the preparation of a dietary supplement containing Galega officinalis and at least one microbiome modulator

[0313] 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.

[0314] Its name derives from gale (milk) and ega (to bring on), as Galega has been used as a galactogogue in small domestic animals (hence the name“Goat’s rue”). Galega bicolor is a synonym. It is a hardy perennial that blooms in the summer months

[0315] In aspects, 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.

[0316] 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. Further, 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

officinalis and a Microbiome Modulator

[0317] In embodiments, 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.

[0318] 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.

[0320] The inventors expect both the microbiome modulator and the G. officinalis to contribute to postprandial glucose regulation. In embodiments, 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.

[0321] In embodiments, 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. In an embodiment, one dose is consumed in the morning with breakfast and the other dose is consumed in the evening with dinner. At the end of trial, subjects are challenged again with an OGTT.

[0322] In an embodiment, 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.

[0323] 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.

[0324] In embodiments, 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)

[0325] In embodiments, 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

[0326] DPP-IV drugs, or gliptins, 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.

[0327] The disclosure envisions utilization of: Sitagliptin, Vildagliptin, Saxagliptin, Linagliptin, Anagliptin, Teneligliptin, Alogliptin, Gemigliptin, and Dutogliptin among others.

[0328] Other chemicals which inhibit DPP4 include: Berberine, the herbal dietary supplement, and Lupeol, found in mango, red alder (Alnus rubra), and dandelion coffee.

[0329] SGLT2 inhibitor drugs, or gliflozins, 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.

[0330] 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.

[0331] The inventors expect that the 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

[0332] The disclosure envisions utilization of: Canagliflozin, Dapagliflozin, and Empagliflozin.

[0333] In embodiments, the pharmaceutical compositions taught herein may comprise: a microbiome modulator, along with metformin and a gliptin.

[0334] In embodiments, the pharmaceutical compositions taught herein may comprise: a microbiome modulator, along with metformin and a gliptin and a gliflozin.

[0335] In embodiments, the pharmaceutical compositions taught herein may comprise: a microbiome modulator, along with metformin and a gliflozin.

[0336] In embodiments, the pharmaceutical compositions taught herein may comprise: a microbiome modulator, along with a gliptin and a gliflozin.

[0337] The aforementioned compositions are useful for treating diabetes and in some instances demonstrate a synergistic effect.

[0338] The compositions listed above may be administered to a human patient in a therapeutically effective amount to treat said patient for type 2 diabetes.

[0339] 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. Further, 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

[0340] 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.

[0341] The inventors envision conducting human clinical trials, in which a composition comprising: (a) one or more of the aforementioned microbiome modulators (e.g. inulin, ȕ- 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. Example 8: Addition of a Gastrointestinal Microbiome Modulator (GIMM) to

Metformin Improves Metformin Tolerance and Fasting Glucose Levels

[0342] 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. Recently, a mechanism of action for metformin’s reduction of hepatic gluconeogenesis was described to be inhibition of glycerophosphate dehydrogenase, resulting in reduced conversion of lactate and glycerol to glucose. See Madiraju et al.

[0343] Adverse effects of metformin are primarily related to gastrointestinal (GI) intolerance. In a study of 360 newly diagnosed T2D individuals, approximately 88% of participants reported either single or multiple GI symptoms. See Florez et al. The most common GI symptoms were diarrhea (62.1%), heartburn (52.1%), and nausea (47.4%), followed by abdominal pain (35.5%), bloating (35.2%), and retching (21.1%). Constipation was also reported in another study. See Bouchoucha et al. Some mechanisms for these side effects may be attributable to metformin’s actions in the GI tract. These effects are usually mild, dose-related, mitigated by slowing the dose escalation, and cease after dose reduction or drug discontinuation. See Bouchoucha et al. Approximately 5% of study subjects discontinue metformin use due to these events. See Glucophage. [0344] The most serious and sometimes fatal, but rare, side effect is lactic acidosis. This could be attributed to metformin-mediated inhibition of glycerophosphate dehydrogenase. See Madiraju et al. A contributing lactate source may be derived from colonic bacteria. Unabsorbed glucose or glucose polymer delivery to the colon provides a substrate for lactate- producing bacteria such as Lactobacillus species, Streptococcus bovis, Bifidobacterium species, and Eubacterium species. Bacteria produce d- and l-lactic acid, both of which are absorbed into the circulation. See Halperin et al. Accumulation of colonic lactic acid will contribute to some or all of the GI side effects observed in metformin users, especially those consuming diets intensified with starch and sugars. See Gennari et al.

[0345] 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.

[0346] 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.

[0347] Subjects had T2D and either were referred by their Endocrinologist at the LSU Health Sciences Center clinic because they could not tolerate the metformin- associated GI symptoms (n = 6) after titration from 500 mg b.i.d. to 500 mg t.i.d. or responded to a radio advertisement seeking T2D patients who had experienced metformin GI side effects (n =4). The sample size was selected by convenience (Table 9). Inclusion criteria included volunteers with a history of metformin intolerance who were 18 years of age, had a body mass index (BMI) 25 and fasting blood glucose between 100 mg/ dl and 200 mg/dl. 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

[0348] 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.

[0349] 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.

[0350] GIMM (NM504) 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).

[0351] An adaptation of questionnaires validated to evaluate GI symptoms for irritable bowel syndrome¹² was used because it included GI symptoms associated with metformin use in the subject described in the case report and in those referred to the study by their physician. See Greenway et al. Assessments of stool consistency (not applicable, very hard, hard, formed, loose, watery), urgency to evacuate (no need to evacuate within 3h after dosing, need to evacuate within 3 hours, need to evacuate within 2 hours, need to evacuate within 1 hour), daily bowel movements (at least 1 movement every 3-4 days, at least 1 movement every 2 days, at least 1 movement per day, at least 2 movements per day), bloating sensation (not applicable, mild, moderate, severe), flatulence (less than normal, normal, moderately increased, greatly increased), and evacuation completeness (not applicable, incomplete, constipated) were recorded daily. In addition, the King’s Stool Chart was used daily to assess the appearance of fecal output using pictures of feces for the subject to select. See Whelan et al.

[0352] Fasting blood glucose was measured with a glucometer by finger stick each morning before eating and dosing. Data were recorded by the volunteers.

[0353] All calculations and data analyses were performed by a bio-statistician at PBRC using SAS Version 9.4 (SAS Institute, Cary, NC). The data in the text are presented as mean ± standard error of the mean (SEM). The primary outcomes included tolerance of metformin, fasting glucose, and King’s stool chart scores. All outcomes were evaluated by fitting linear models including covariates to account for the crossover design utilized in the study. Least squares means (LS means) of the treatment effects were the output from each model and were compared via 2-sample t tests. P values below .05 were considered statistically significant.

[0354] For the analysis and comparison of metformin tolerability between the treatment groups, 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. For treatment group comparisons, 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. [0355] 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.

[0356] Daily measures of fecal consistency and volume were recorded by the subjects using the King’s stool chart and scored as described by Whelan, Judd, and Taylor. These scores were analyzed with a doubly repeated measures model. Eight females and 2 males volunteered and were either Caucasian (n = 5) or African American (n = 5). Subjects were between the ages of 29 and 71 years. BMI ranged between 26.4 and 47.1 kg/m². Patients had fasting plasma glucose levels ranging from 104 to 178 mg/dl on screening. Eleven T2D subjects were screened, but 1 declined to participate because of scheduling conflicts. Ten subjects were enrolled in the study after providing written consent.

[0357] The volunteers tolerated metformin GI side effects significantly better when the drug was combined with GIMM than in combination with placebo (FIG. 11). Stools tended to be more formed and larger when the volunteers were taking metformin combined with GIMM than when taking metformin with placebo but the difference was not statistically significant (5.4 ± 0.5 vs 4.6 ± 0.5, King’s chart ratings).

[0358] Fasting glucose levels were lower when metformin was combined with GIMM compared to when metformin was combined with placebo, though not statistically significant, during metformin b.i.d. (134.9 ± 6.7 vs 141.5 ± 6.9, mg/dl) and metformin t.i.d. (130.0 ± 14.5 vs 153.0 ± 16.6). There was a statistically significant sequence effect (order of administering GIMM or placebo affected glucose differently). After reviewing glucose levels for particular subjects (FIG. 12A & 12B), we suspect that this may be due to a carryover effect of GIMM on glucose in period 2 due to an inadequate washout period. For this reason, we chose to also compare mean glucose levels only for period 1. The results of this analysis demonstrate that mean fasting glucose was significantly (P < .02) lower with the metformin– GIMM combination (FIG. 13).

[0359] A subset of the participants (n = 6) in this study was identified as metformin- intolerant at baseline based on medical history. To investigate the combination of metformin with GIMM in this population, analyses were carried out only on these participants. More extreme differences in means were observed in all outcomes for the metformin-intolerant participants than for the entire study population, but the results did not change the statistical significance. Fasting glucose decreased more during the period when metformin was combined with GIMM compared to metformin combined with placebo (130.6 ± 6.5 vs 144.1 ± 6.4 mg/dl). The difference between the 2 treatments when comparing only period 1 was statistically significant (115.7 ± 6.7 vs 170.3 ± 9.7 mg/dl; P = .0099). GI symptoms were also lessened and stools were more formed and regular, but these changes were not statistically significant.

[0360] The principal limitation for chronic metformin therapy in some patients is presentation of persistent adverse GI symptoms that may cause patients to discontinue metformin use. The data observed in this pilot clinical trial suggest that a modulator of the GI microbiome could both alleviate metformin-mediated GI symptoms and may improve glucose regulation. Additional clinical trials are necessary to confirm these preliminary findings. This study provides evidence that the reformulated metformin compositions of the disclosure, which reformulate metformin with one or more microbiome modulators, could be attractive new compositions for the treatment of type 2 diabetes. The study provides evidence that the reformulated metformin compositions of the disclosure, which can contain one or more microbiome modulators (e.g. one, two, or all three of the microbiome modulators contained in the tested GIMM formulations), may enable the treatment of more type 2 diabetics than is possible with current metformin formulations on the market. Thus, the metformin compositions of the disclosure are able to expand the patient population that is treatable with metformin.

[0361] There is a paucity of studies investigating the etiology of metformin mediated GI side effects. Inhibition of glycerophosphate dehydrogenase is a recently identified mechanism of action of metformin. See Madiraju et al. This mechanism may be linked not only to serious and rare lactic acidosis, but also to some of the adverse GI symptoms. Bioavailability of metformin is 50%-60% and since efficacious doses range between 1 and 2 g/day with fecal recovery of an oral dose at 20%-30%, there is sufficient metformin to interact with GI microbiota. See Graham et al. Commensal microbiota in the colon such as Bacillus subtilis contain glycerophosphate dehydrogenase that is inhibited by metformin. See Madiraju et al. and Fillinger et al. This could result in an overproduction of d-lactate in the colon. Additional colonic contributions of d-lactate are from organisms such as Lactobacillus species, Streptococcus bovis, Bifidobacterium species, and Eubacterium species that utilize sugars present in the colon. See Stolberg et al. and Hove et al. Furthermore, d-lactate can convert to l-lactate by some colon microbiota, which could contribute to the plasma lactate pool. See Hove et al. [0362] Bile acids are well known to promote colonic fluid and electrolyte secretions, thereby causing diarrhea associated with bile acid malabsorption. See Kelly et al. Metformin may cause GI disturbances by reducing ileal bile salt reabsorption leading to elevated colonic bile salt concentrations. See 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.

[0363] 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.

[0364] Ghrelin is a hormone secreted by the stomach and by the colon that functions to prevent hypoglycemia by stimulating gluconeogenesis. See Li et al. Ghrelin must be acylated with a medium chain fatty acid (MCFA) to activate its receptor (GHS-R1a). See Kojima et al. The acylating enzyme, termed GOAT (ghrelin O-acyltransferase), has a high affinity for MCFAs; however, recent evidence indicates that GOAT can use a SCFA to acylate ghrelin, rendering the hormone inactive. See Kirchner et al. and Matsumoto et al. In addition, SCFAs may act as competitive inhibitors of GOAT. See 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.

[0365] The microbiome of the typical T2D patient appears to be one with an increased production of reactive oxygen species. See Qin et al. This suggests that ingestion of polyphenols with low bioavailability could be beneficial in scavenging the reactive oxygen species. Blueberries contain high antioxidant activity because of antioxidant enzymes, anthocyanins, and flavanols. See Rodriquez-Mateos et al. and Del et al. Most of these polyphenols have poor bio-availability. See Del et al. Since they stay in the colon, they are able to alter the redox state in the intestines and shift communities of GI microbiota. See Hidalgo et al. 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.

[0366] Therapeutic interventions that have mechanisms of actions in the GI microbiome may offer a level of safety that is not attainable by most orally active treatments designed to be absorbed. There is also a reduced potential for a GI modulator to interact with the metabolism of drugs that are orally absorbed. Therefore, we feel that GI microbiome modulators are ideal partners to be used in combination with current and future orally available medications.

[0367] We observed that combining metformin with GIMM permitted 10 T2D subjects, who experienced GI adverse events to metformin, to better tolerate metformin GI side effects than when metformin was combined with placebo. Some subjects could only escalate from 500 mg metformin b.i.d. to t.i.d. while also taking GIMM. This observation is particularly valuable since a slow titration of metformin is presently the only way to reduce metformin- related GI adverse effects. Finally, significantly lower fasting glucose levels were observed when subjects took the metformin-GIMM combination. Larger trials with GIMM– metformin in combination are needed to replicate and expand these findings. Such trials might allow the greater use of metformin in T2D patients and improve treatment of the disease. INCORPORATION BY REFERENCE

[0368] All references, articles, publications, patents, patent publications, and patent applications cited herein are incorporated by reference in their entireties for all purposes.

[0369] However, mention of any reference, article, publication, patent, patent publication, and patent application cited herein is not, and should not be taken as, an acknowledgment or any form of suggestion that they constitute valid prior art or form part of the common general knowledge in any country in the world.

REFERENCES

[0370] U.S. Application No. 14/592,393, entitled: Method to treat diabetes utilizing a gastrointestinal microbiome modulating composition, filed on January 08, 2015.

[0371] U.S. Application No. 14/238,980, which is a National Stage Entry of International Application No. PCT/US2012/051408, entitled: Composition and use of a formulation to increase the ratio of gastrointestinal microbiota in phylum Bacteriodites to microbiota of Firmuctes phylum, filed on August 17, 2012. [0372] US20020009436 Methods and Compositions for Inhibiting Adhesion by Microorganisms

[0373] US20040132164 Methods and Compositions for Inhibiting Adhesion by Microorganisms

[0374] US20050239706 Modulation of the Gastrointestinal Microbiota as a Means to Control Energy Storage in a Subject

[0375] US20070036836 Amino Acid Supplementation for a Healthy Microbiota Ecosystem

[0376] US20070196890 Prebiotic Effect Analysis

[0377] US20080102162 Prebiotic Preparation

[0378] US20080261916 Synergistic Prebiotic Compositions

[0379] US20080274127 Amino Acid Supplementation for a Healthy Microbiota Ecosystem

[0380] US20090142442 Gut Microbiota in Infants

[0381] US20090148414 Novel Composition to Improve Gut Health and Animal Performance and Methods of Making the Same

[0382] US20090170141 Ghrelin O-Acyltransferase (GOAT) Biochemical Assay

[0383] US20100048595 Use of Archaea to Modulate the Nutrient Harvesting Functions of the Gastrointestinal Microbiota

[0384] US20100086527 Synbiotic to Improve Gut Microbiota

[0385] US20100086955 Small Molecule Inhibitors of Ghrelin 0-Acyltransferase

[0386] US20100129816 Microbial Population Analysis

[0387] US20100172874 Gut Microbiome as a Biomarker and Therapeutic Target for Treating Obesity Related Disorder

[0388] US20100254949 Prebiotic Oligosaccharides

[0389] US20100317573 Pediatric Fiber Mixture

[0390] US20110009359 Use of Non-Digestible Carbohydrates for Improving Intestinal Microbiota

[0391] US20110034407 Use of Sphingomyelin and Non-Digestible Carbohydrates for Improving Intestinal Microbiota [0392] US20110123501 Gut Flora and Weight Management

[0393] US20050239706 Modulation of Fiaf and the Gastrointestinal Microbiota as a Means to Control Energy Storage in a Subject

[0394] US20110280840 Compositions and Methods for Treating Obesity and Related Disorders by Characterizing and Restoring Mammalian Bacterial Microbiota

[0395] US20120027724 Methods of Treating Impaired Glucose Metabolism Via Administration of Algal Biomass

[0396] US20120058094 Compositions and Methods for Treating Obesity and Related Disorders by Characterizing and Restoring Mammalian Bacterial Microbiota

[0397] US20120135957 Compositions Containing Mixtures of Fermentable Fibers

[0398] W0/2012/024638A2 Compositions and Methods for Treating Obesity and Related Disorders by Characterizing and Restoring Mammalian Bacterial Microbiota

[0399] W0/2011/107482A9 Method of Diagnostic of Obesity

[0400] W0/2011/103123A2 Reducing Short-Chain Fatty Acids and Energy Uptake in Obese Humans by Managing Their Intestinal Microbial Communities

[0401] W0/2011/022660Al Methods of Diagnosing and Treating Microbiome-Associated Disease Using Interaction Network Parameters

[0402] W0/2008/076696A3 The Gut Microbiome as a Biomarker and Therapeutic Target for Treating Obesity or an Obesity Related Disorder

[0403] EP2102350A2 The Gut Microbiome as a Biomarker and Therapeutic Target for Treating Obesity or an Obesity Related Disorder

[0404] W0/2010/002890A3 Methods of Promoting Weight Loss and Associated Arrays

[0405] W0/2010/151842A2 Methods and Systems for Phylogenetic Analysis

[0406] Peter J. Turnbaugh, Ruth E. Ley, Michael A. Mahowald, Vincent Magrini, Elaine R. Mardis, Jeffrey I. Gordon,“An obesity-associated gut microbiome with increased capacity for energy harvest” Nature 444, 1027-1031, 2006.

[0407] Peter J. Turnbaugh, Micah Hamady, Tanya Yatsunenko, Brandi L. Cantarel, Alexis Duncan, Ruth E. Ley, Mitchell L. Sogin, William J. Jones, Bruce A. Roe, Jason P. Affourtit, et al.“A core gut microbiome in obese and lean twins,” Nature 457, 480-484,2008. [0408] Ruth E. Ley, Fredrik Backhed, Peter Turnbaugh, Catherine A. Lozupone, Robin D. Knight, and Jeffrey I. Gordon,“Obesity alters gut microbial ecology,” PNAS 102:11070- 11075,2005.

[0409] Peter J. Turnbaugh, Ruth E. Ley, Michael A. Mahowald, Vincent Magrini, Elaine R. Mardis & Jeffrey I. Gordon,“An obesity-associated gut microbiome with increased capacity for energy harvest,” Nature 444: 1027-1031, 2006.

[0410] Andrew L. Goodman, George Kallstrom, Jeremiah J. Faith, Alejandro Reyes, Aimee Moore, Gautam Dantas, and Jeffrey I. Gordon,“Extensive personal human gut microbiota culture collections characterized and manipulated in gnotobiotic mice,” PNAS 108: 6252- 6257, 2011

[0411] Peter J. Turnbaugh, Vanessa K. Ridaura, Jeremiah J. Faith, Federico E. Rey, Rob Knight, and Jeffrey I. Gordon,“The Effect of Diet on the Human Gut Microbiome: A Metagenomic Analysis in Humanized Gnotobiotic Mice,” Sci Transl Med 1: 1-10,2009.

[0412] Justin L. Sonnenburg, Jian Xu, Douglas D. Leip, Chien-Huan Chen, Benjamin P. Westover, Jeremy Weatherford, Jeremy D. Buhler, and Jeffrey I. Gordon,“Glycan Foraging in Vivo by an Intestine-Adapted Bacterial Symbiont,” Science 307: 1955-1959, 2005.

[0413] Glenn R. Gibson, Hollie M. Probert, Jan VanLoo, Robert A. Rastall and Marcel B. Roberfroid,“Dietary modulation of the human colonic microbiota: updating the concept of prebiotics,” Nutr. Res. Rev. 17: 259-275, 2004.

[0414] Carlotta De Filippo, Duccio Cavalieri, Monica DiPaola, Matteo Ramazzotti, Jean Baptiste Poullet, Sebastien Massart, Silvia Collini, Giuseppe Pieraccini, and Paolo Lionetti, “Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa,” PNAS 107: 14691-14696, 2010.

[0415] Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. 1999,“Ghrelin is a growth-hormone-releasing acylated peptide from stomach,” Nature 402: 656-60.

[0416] Carine D Vriese, Francoise Gregoire, Roger Lema-Kisoka, Magali Waelbroeck, Patrick Robberecht and Christine Delporte,“Ghrelin Degradation by Serum and Tissue Homogenates: Identification of the Cleavage Sites,” Endocrinol 145: 1 4997-5005, 2005.

[0417] Carlotta Gauna, Rosalie M. Kiewiet,Joop A.M. J. L. Janssen, Bedette van de Zande, Patrie J.D. Delhanty,Ezio Ghigo, Leo J. Hofland,Axel P. N. Themmen, and Aart Jan van der Lely,“Unacylated ghrelin acts as a potent insulin secretagogue in glucose-stimulated conditions,” Am J Physiol Endocrinol Metab 293: E697-E704, 2007.

[0418] Gutierrez, J.A. et al.,“Ghrelin octanoylation mediated by an orphan lipid transferase” Proc Natl Acad Sci USA 105, 6320-5 (2008).

[0419] Yang, J., Brown, M.S., Liang, G., Grishin, N.V. & Goldstein, J.L.,“Identification of the acyltransferase that octanoylates ghrelin, an appetite-stimulating peptide hormone,” Cell132, 387-96 (2008).

[0420] Matsumoto M, Hosoda H, Kitajima Y, Morozumi N, Minamitake Y, Tanaka S, Matsuo H, Kojima M, Hayashi Y, Kangawa K.,“Structure-activity relationship of ghrelin: pharmacological study of ghrelin peptides,” Biochem Biophys Res Commun. 2001 Sep 14;287(1):142-6.

[0421] Kirchner, H., Gutierrez, J.A., Solenberg, P.J., Pfluger, P.T., Czyzyk, T.A., Willency, J.A., Schurmann, A., Joost, H.G., Jandacek, R.J., Hale, J.E., et al.,“GOAT links dietary lipids with the endocrine control of energy balance,” (2009). Nat. Med. 15 (7), 741-745.

[0422] Yvette van Kooyk and Gabriel A Rabinovich,“Protein-glycan interactions in the control of innate and adaptive immune responses,” Nat Immunol 9: 593-601, 2008.

[0423] Claudine Manach, Augustin Scalbert, Christine Morand, Christian Remesy, and Liliana Jimenez,“Polyphenols: food sources and bioavailability,” Am J Clin Nutr, 79:727- 47, 2004.

[0424] Kathrin Kahle, Michael Kraus, Wolfgang Scheppach, Matthias Ackermann, Friederike Ridder,and Elke Richling,“Studies on apple and blueberry fruit constituents: do the polyphenols reach the colon after ingestion?,” Mol. Nutr. Food Res. 50: 418-423, 2006.

[0425] R. Puupponen-Pimia, L. Nohynek, C. Meier, M. Kahkonen, M. Heinonen, A. Hopia, and K.-M. Oksman-Caldentey,“Antimicrobial properties of phenolic compounds from berries,” J Appl Microbial 90: 494-507, 2001.

[0426] R. Puupponen-Pimia, L. Nohynek, S. Hartmann-Schmidlin, M. Kahkonen, M. Heinonen, K. Maatta-Riihinen and K.-M. Oksman-Caldentey,“Berry phenolics selectively inhibit the growth of intestinal pathogens,” J Appl Microbial 98: 991-1000, 2005.

[0427] U.S. Department of Agriculture, Agricultural Research Service. 2010. USDA National Nutrient Database for Standard Reference, Release 23. Nutrient Data Laboratory Home Page, http://www.ars.usda.gov/nutrientdata. [0428] A.J. Stull, K.C. Cash, W. D. Johnson, C. M. Champagne, and W. T. Cefalu, “Bioactives in Blueberries Improve Insulin Sensitivity in Obese, Insulin-Resistant Men and Women,” J. Nutr. 140: 1764-1768,2010.

[0429] 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.

[0430] L. Agot Lia, G. Hallmans, A. Sandberg, B. Sundberg, P. Aman, and H. Andersson, “Oat Beta glucan increases bile acid excretion and a fiber-rich barley fraction increases cholesterol excretion in ileostomy subjects,” Am J Clin Nutr 1995;62:1245-51.

[0431] American Diabetes Association. Diabetes Care. 2012;35(suppl. 1):Sll-S63.

[0432] Dandona P, Fonseca V, Mier A, Beckett AG,“Diarrhea and metformin in a diabetic clinic,” Diabetes Care. 1983:6:472-4.

[0433] M. Rajili6-Stojanovi6, E. Biagi1, H.G.H.J. Heilig, K. Kajander, R.A. Kekkonen, S. Tims, and W.M. de Vos.“Global and Deep Molecular Analysis of Microbiota Signatures in Fecal Samples from Patients with Irritable Bowel Syndrome,” Gastroenterology 2011 Nov;141(5):1792-801.

[0434] T.J. Borody and A. Khoruts, “Fecal microbiota transplantation and emerging applications,” Nature Reviews Gastroenterology and Hepatology 9, 88-96, 2012.

[0435] A. Vrieze, E. van Nood, F. Holleman, J. Salojarvi, R.S. Kootte, J.F.W.M. Bartelsman, G.M. Dallinga-Thie, M.T. Ackermans, M.J. Serlie, R. Oozeer, M. Denien, A. Druesne, J.E.T. van Hylckama Vlieg, V.W. Bloks, A.K. Groen, H.G.H.J. Heilig, E.G. Zoetendal, E.S. Stroes, W.M. de Vos, J.B.L. Hoekstra, M. Nieuwdorp,“Transfer of Intestinal Microbiota from Lean Donors Increases Insulin Sensitivity in Subjects with Metabolic Syndrome,” Gastroenterology (2012), doi:10.1053/j.gastro.2012.06.031.

[0436] M. Oresic, T. Seppanen-Laakso, L. Yetukmi, F. Backhed, and V. Hanninen,“Gut microbiota affects lens and retinal lipid composition,” Experimental Eye Research 89 (2009) 604-607.

[0437] M. Rolando and M. Zierhut, “The Ocular Surface and Tear Film and Their Dysfunction in Dry Eye Disease,” Survey of Ophthalmology 45, Suppl2, S203-S210, 2001. [0438] Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycaemia in type 2 diabetes, 2015: a patient-centered approach. Update to a position statement of the American

[0439] Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2015; 38:140-149.

[0440] Graham GG, Punt J, Arora M, et al. Clinical pharmacokinetics of metformin. Clin Pharmacokinet. 2011;50:81-98.

[0441] Zhou G, Meyers R, Li Y, et al. Role of AMP-activated protein kinase in mechanism of metformin. J Clin Invest. 2001;108:1167-1174.

[0442] Madiraju AK, Erion DM, Rahimi Y, et al. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycero phosphate dehydrogenase. Nature. 2014;510:542-546.

[0443] Florez H, Luo J, Castillo-Florez S, et al. Impact of metformin-induced gastrointestinal symptoms on quality of life and adherence in patients with type 2 diabetes. Postgrad Med.2010;122:112-120.

[0444] Bouchoucha M, Uzzan B, Cohen R. Metformin and digestive disorders. Diabetes Metab. 2011;37:90-96.

[0445] Glucophage (metformin hydrochloride) and Glucophage XR (extended-release) prescribing information. Bristol, NJ: Bristol-Myers Squibb; 2009.

[0446] Halperin ML, Kamel KS. D-lactic acidosis: turning sugar into acids in the gastrointestinal tract. Kidney Int. 1996;49:1-8.

[0447] Gennari FJ, Weise WJ. Acid-base disturbances in gastrointestinal disease. Clin J Am Soc Nephrol. 2008;3:18618.

[0448] Greenway F, Wang S, Heiman M. A novel cobiotic containing a prebiotic and an antioxidant augments the glucose control and gastrointestinal tolerability of metformin: a case report.Beneficial Microbes. 2014;5:29-32.

[0449] Gordon S, Ameen V, Bagby B, Shahan B, Jhingran P, Carter E. Validation of irritable bowel syndrome global improvement scale: an integrated symptom end point for assessing treatment efficacy. Dig Dis Sci. 2003;48:1317-1323.

[0450] Whelan K, Judd PA, Taylor MA. Assessment of fecal output in patients receiving enteral tube feeding: validation of a novel chart. Eur J Clin Nutr. 2004;58:1030-1037.

[0451] Fillinger S, Boschi-Muller S, Azza S, Dervn E, Branlant G, Aymerich S. Two glyceraldehyde-3-phosphate dehydroge- nases with opposite physiological roles in a nonphotosynthetic bacterium. J Biol Chem. 2000;275:14031-14037. [0452] Stolberg L, Rolfe R, Gitlin N, et al. d-Lactic acidosis due to abnormal gut flora: diagnosis and treatment of two cases. N Engl J Med. 1982;306:1344-1348.

[0453] Hove H, Mortensen PB. Colonic lactate metabolism and d-lactic acidosis. Dig Dis Sci. 1995;40:320-330.

[0454] Kelly OB, Mroz MS, Ward JB, et al. Ursodeoxycholic acid attenuates colonic epithelial secretory function. J Physiol. 2013;591(pt 9):2307-2318.

[0455] Scarpello JH, Hodgson E, Howlett HC. Effect of metformin on bile salt circulation and intestinal motility in type 2 diabetes metllitus. Diabet Med. 1998;15:651-656.

[0456] Kim HJ, White PJ. Interactional effects of ȕ-glucan, starch, and protein in heated oat slurries on viscosity and in vitro bile acid binding. J Agric Food Chem. 2012;60:6217-6222.

[0457] Bolam DN, Sonnenburg JL. Mechanistic insight into polysaccharide use within the intestinal microbiota. Gut Microbes. 2011;2:86-90.

[0458] Covington DK, Briscoe CA, Brown AJ, Jayawickreme CK. The G-protein-coupled receptor 40 family (GPR40-GPR43) and its role in nutrient sensing. Biochem Soc Trans. 2006;34:770-773.

[0459] Karaki S, Mitsui R, Hayashi H, et al. Short-chain fatty acid receptor, GPR43, is expressed by enteroendocrine cells and mucosal mast cells in rat intestine. Cell Tissue Res.2006;324:353-360.

[0460] Li RL, Sherbet DP, Elsbernd DL, Goldstein JL, Brown MS, Zhao TJ. Profound hypoglycemia in starved, ghrelin-deficient mice is caused by decreased gluconeogenesis and reversed by lactate or fatty acids. J Biol Chem. 2012;287:17942-17950.

[0461] 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.

[0462] Wang SY, Chen H, Ehlenfeldt MK. Antioxidant capacities vary substantially among cultivars of rabbiteye blueberry (Vaccinium ashei Reade). Int J Food Sci Tech. 2011;46:2482- 490.

[0463] Rodriquez-Mateos A, Cifuentes-Gomez T, Tabatabaee S, Lecras C, Spencer JPE. Procyanidin, anthocyanin, and chlo- rogenic acid contents of highbush and lowbush blueberries. J. Agric Food Chem. 2012;60:5772-5778.

[0464] Del BC, Ciappellano S, Klimis-Zacas D, et al. Anthocyanin absorption, metabolism, and distribution from a wild blue- berry-enriched diet (Vaccinium angustifolium) is affected by diet dyration in the Sprague-Dawley rat. J Agric Food Chem. 2010;58:2491-2497. [0465] Hidalgo M, Oruna-Concha MJ, Kolida S, et al. Metabolism of anthocyanins by human gut microflora and the influence on gut bacterial growth. J Agric Food Chem. 2012;60:3882-3890.

[0466] Stull AJ, Cash KC, Johnson WD, Champagne CM, Cefalu WT. Bioactives in blueberries improve insulin sensitivity in obese, insulin-resistant men and women. J Nutr. 2010;140:1764-1768.

Claims

CLAIMS What is claimed is:

1. A pharmaceutical composition for oral administration, comprising:

b) a microbiome modulator; and

c) a pharmaceutically acceptable carrier.

2. The pharmaceutical composition of claim 1, wherein the microbiome modulator is at least one selected from the group consisting of: an indigestible carbohydrate fermentable by gastrointestinal microbiota, beta-glucan, and a polyphenolic compound.

3. The pharmaceutical composition of claim 1, wherein the microbiome modulator is at least one selected from the group consisting of: inulin, beta-glucan extracted from a plant, and a polyphenolic compound extracted from a berry.

4. The pharmaceutical composition of claim 1, wherein the microbiome modulator is at least one selected from the group consisting of: inulin, beta-glucan extracted from oat, and a polyphenolic compound extracted from blueberry.

5. The pharmaceutical composition of claim 1, wherein the microbiome modulator comprises: beta-glucan and a polyphenolic compound.

6. The pharmaceutical composition of claim 1, wherein the microbiome modulator comprises: beta-glucan (1,3/1,4) extracted from oat and a polyphenolic compound extracted from blueberry pomace.

7. The pharmaceutical composition of claim 1, wherein the composition is formulated as an oral unit dosage form.

8. The pharmaceutical composition of claim 1, wherein the composition is formulated as a tablet, pill, pellet, capsule, powder, lozenge, granule, solution, suspension, emulsion, syrup, elixir, oral liquid preparation, edible food product, prebiotic, probiotic, beverage, food bar, smoothie, shake, or yogurt.

9. The pharmaceutical composition of claim 1, wherein the composition is formulated as an oral unit dosage form and further comprises one or more optional agents selected from sweetening agents, flavoring agents, coloring agents, preserving agents, time delay or delay disintegration materials, standard oral vehicles, suitable carriers, excipients, or diluents.

10. The pharmaceutical composition of claim 1, wherein the composition is formulated as an oral unit dosage form and is suitable for administration to a human in need thereof.

11. The pharmaceutical composition of claim 1, wherein 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.

12. The pharmaceutical composition of claim 1, wherein a therapeutically effective amount of a HCl acid addition salt of metformin is present.

13. The pharmaceutical composition of claim 1, wherein the microbiome modulator comprises: beta-glucan present in an amount of at least about 1 gram and a polyphenolic compound present in an amount of at least about 500 mg.

14. The pharmaceutical composition of claim 1, wherein the microbiome modulator comprises: beta-glucan and a polyphenolic compound that act synergistically.

15. A method of treating diabetes or hyperglycemia in a patient suffering therefrom, comprising: administering the pharmaceutical composition according to claim 1 to said patient.

16. The method of claim 15, wherein said patient suffers from type 2 diabetes.

17. A method of minimizing the negative side effects associated with molecularly targeted treatment in a cancer patient, comprising:

a) administering to the cancer patient the pharmaceutical composition according to claim 1, wherein the cancer patient is being treated with a compound targeted for treatment of non-small cell lung cancer.

18. The method of claim 17, wherein 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.

19. The method of claim 17, wherein the cancer patient is being treated with a compound that is a targeted covalent inhibitor of the initial activating epidermal growth factor receptor mutations.

20. The method of claim 17, wherein the cancer patient is being treated with a compound that is a targeted covalent inhibitor of the epidermal growth factor receptor T790M resistance mutation.

21. The method of claim 17, wherein the cancer patient is being treated with a compound with the following structure:

or a pharmaceutically acceptable salt thereof.

22. The method of claim 17, wherein the cancer patient is being treated with the hydrobromide salt of a compound with the following structure:

.

23. The method of claim 17, wherein the cancer patient is being treated with CO-1686.

24. The method of claim 17, wherein the side effect being minimized is diarrhea.

25. The method of claim 17, wherein the side effect being minimized is hyperglycemia.

26. The method of claim 23, wherein the side effect associated with administration of CO-1686 is diarrhea, and wherein said patient experiences less episodes of diarrhea when administered the pharmaceutical composition according to claim 1, as compared to the number of episodes of diarrhea experienced by said patient when not administered the pharmaceutical composition according to claim 1.

27. A dietary supplement for oral administration, comprising:

a) a therapeutically effective amount of Galega officinalis, or an extract thereof; and

b) a microbiome modulator.

28. The dietary supplement of claim 27, wherein the microbiome modulator is at least one selected from the group consisting of: an indigestible carbohydrate fermentable by gastrointestinal microbiota, beta-glucan, and a polyphenolic compound.

29. The dietary supplement of claim 27, wherein the microbiome modulator is at least one selected from the group consisting of: inulin, beta-glucan extracted from a plant, and a polyphenolic compound extracted from a berry.

30. The dietary supplement of claim 27, wherein the microbiome modulator is at least one selected from the group consisting of: inulin, beta-glucan extracted from oat, and a polyphenolic compound extracted from blueberry.

31. The dietary supplement of claim 27, wherein the microbiome modulator comprises: beta-glucan and a polyphenolic compound.

32. The dietary supplement of claim 27, wherein the microbiome modulator comprises: beta-glucan (1,3/1,4) extracted from oat and a polyphenolic compound extracted from blueberry pomace.

33. The dietary supplement of claim 27, wherein the supplement is formulated as a tablet, pill, pellet, capsule, powder, lozenge, granule, solution, suspension, emulsion, syrup, elixir, oral liquid preparation, edible food product, prebiotic, probiotic, beverage, food bar, smoothie, shake, or yogurt.

34. A pharmaceutical composition for oral administration, comprising:

a) a therapeutically effective amount of at least one active agent selected from the group consisting of: metformin, a DPP-IV inhibitor, and a SGLT-2 inhibitor, or combination thereof;

b) a microbiome modulator; and

c) a pharmaceutically acceptable carrier.

35. The pharmaceutical composition of claim 34, wherein the microbiome modulator is at least one selected from the group consisting of: an indigestible carbohydrate fermentable by gastrointestinal microbiota, beta-glucan, and a polyphenolic compound.

36. The pharmaceutical composition of claim 34, wherein the microbiome modulator is at least one selected from the group consisting of: inulin, beta-glucan extracted from a plant, and a polyphenolic compound extracted from a berry.

37. The pharmaceutical composition of claim 34, wherein the microbiome modulator is at least one selected from the group consisting of: inulin, beta-glucan extracted from oat, and a polyphenolic compound extracted from blueberry.

38. The pharmaceutical composition of claim 34, wherein the microbiome modulator comprises: beta-glucan and a polyphenolic compound.

39. The pharmaceutical composition of claim 34, wherein the microbiome modulator comprises: beta-glucan (1,3/1,4) extracted from oat and a polyphenolic compound extracted from blueberry pomace.

40. The pharmaceutical composition of claim 34, wherein the composition is formulated as an oral unit dosage form.

41. The pharmaceutical composition of claim 34, wherein the composition is formulated as a tablet, pill, pellet, capsule, powder, lozenge, granule, solution, suspension, emulsion, syrup, elixir, oral liquid preparation, edible food product, prebiotic, probiotic, beverage, food bar, smoothie, shake, or yogurt.

42. The pharmaceutical composition of claim 34, wherein the composition is formulated as an oral unit dosage form and further comprises one or more optional agents selected from sweetening agents, flavoring agents, coloring agents, preserving agents, time delay or delay disintegration materials, standard oral vehicles, suitable carriers, excipients, or diluents.

43. The pharmaceutical composition of claim 34, wherein the composition is formulated as an oral unit dosage form and is suitable for administration to a human in need thereof.

44. The pharmaceutical composition of claim 34, wherein metformin and a DPP-IV inhibitor are present.

45. The pharmaceutical composition of claim 34, wherein metformin and a SGLT-2 inhibitor are present.

46. The pharmaceutical composition of claim 34, wherein metformin, a DPP-IV inhibitor, and a SGLT-2 inhibitor are present.

47. The pharmaceutical composition of claim 34, wherein a DPP-IV inhibitor is present.

48. The pharmaceutical composition of claim 34, wherein a DPP-IV inhibitor and a SGLT-2 inhibitor are present.

49. The pharmaceutical composition of claim 34, wherein a SGLT-2 inhibitor is present.

50. A method of treating diabetes or hyperglycemia in a patient suffering therefrom, comprising: administering the pharmaceutical composition according to claim 34 to said patient.