Glycan therapeutic agents and related methods

Abstract

Provided is a pharmaceutical composition capable of modulating the abundance of bacterial taxa in the human gastrointestinal microbiota. [Solution] A pharmaceutical composition for use in modulating the abundance of a bacterial taxon in the gastrointestinal microbiota of a human subject, the composition comprising a glycan therapeutic agent in an amount effective to modulate the abundance of the bacterial taxon, wherein i) the glycan therapeutic agent comprises a mixture of branched glycans, wherein the average degree of branching (DB) of the glycans in the agent is at least 0.01, ii) at least 50% of the glycans in the agent have a degree of polymerization (DP) of at least 3 and less than 30 glycan units, and iii) the ratio of alpha-glycosidic bonds to beta-glycosidic bonds present in the glycans in the agent is from about 1:1 to about 5:1.

Description

[Background technology]

[0001] The human microbiome is complex and responds to genetics, age, sex, stress, nutrients, and diet. The microbiota performs many activities and influences the physiology of the host. Changes in the number and species of gut microbiota can alter community function and interactions with the host. A limited number of probiotic bacteria are known in the art and are believed to be beneficial for health. Some associations with effects have been documented when obtained in humans. The substance is a substance that can promote the growth of certain bacteria that are thought to be beneficial to the human host. These substances are considered to be "prebiotic" foods. The results of studies have been conflicting regarding their effectiveness, and the effects on human health have generally been mixed. Therefore, it is believed that it may stimulate beneficial microbiota shifts and improve human health. There is a need for new therapeutic inputs that can improve this. Summary of the Invention

[0002] In one aspect, the present invention provides a method for modulating the abundance of bacterial taxa in the gastrointestinal microbiota of a human subject. The method is characterized in that it is a method for administering to a human subject a bacterial taxon that is effective in modulating the abundance of the bacterial taxon. and administering a pharmaceutical composition comprising a glycan therapeutic agent in an amount of: i) a glycan therapeutic agent; The formulation contains a mixture of branched glycans, and the average branching degree (DB, per residue) of the glycans in the formulation is the branch point) is at least 0.01 (e.g., at least 0.05, or at least 0.1), and ii) at least 50% of the glycans in the formulation are at least 3. and iii) the glycan in the formulation has a degree of polymerization (DP) of the glycan unit of less than The ratio of alpha-glycosidic bonds to beta-glycosidic bonds is about 1:1 to about 1:1 overall. In some embodiments, the bacterial taxon comprises at least a first and a second bacterial taxon. Includes taxa.

[0003] In some embodiments, the formulation comprises branched oligosaccharides. The average degree of branching (DB) in the preparation is at least 0.05 (e.g., at least 0.1). be.

[0004] In some embodiments, at least one, at least two of the glycosidic bonds At least three, at least four, or more independently form 1->2 glycosidic bonds In this case, 1->3 glycosidic bond, 1->4 glycosidic bond, or 1->6 glycosidic bond In some embodiments, one or more, two or more, or three or more glycosidic bonds In some cases, it exists in both alpha and beta configurations.

[0005] In some embodiments, the glycan units are tetroses, pentoses, hexoses, and and heptose, or In some embodiments, the glycan unit comprises at least three or more. Glucose, galactose, arabinose, mannose, fructose, xylose, at least one monosaccharide selected from the group consisting of cocos, rhamnose, and rhamnose; Contains two, at least three, or more.

[0006] In some embodiments, at least one of the glycans in the formulation, e.g., For example, at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or 99% (by weight or number) or virtually all are above a preselected reference level Repeating units of glycan units, e.g., 2, 3, 4, or more glycans In one embodiment, the preselected reference level does not include repeating units of the unit 10, 20, 30, 40, 50, or 60% of the total glycan units of a In an embodiment, from 20 monosaccharide monomers, less than 50% of these 20 monomers The glycans comprised are repeating units of two or three glycan repeats.

[0007] In some embodiments, the glycan therapeutic agent is synthetic and is not a naturally occurring oligosaccharide. or polysaccharide source.

[0008] In some embodiments, the bacterial taxa in the gastrointestinal microbiota of a human subject (e.g., The abundance of the first and second bacterial taxa is at least about 5%, 10%, 25%, At 50%, 75%, 100%, 250%, 500%, 750%, or at least 10 In some embodiments, the modulation is in the gastrointestinal microbiota of a human subject. Increased abundance or abundance of bacterial taxa (e.g., of each of the first and second bacterial taxa) in the includes a decrease.

[0009] In some embodiments, the bacterial taxa (e.g., the first and second bacterial taxa) are symbiotic. In other embodiments, the bacterial taxon (e.g., a first and a second bacterial taxon) ) includes pathogenic bacterial taxa.

[0010] In some embodiments, the bacterial taxa (e.g., the first and second bacterial taxa) are Ak kermansia、Alistipes、Anaerophilum、Bacteroi des、Bilophila、Blautia、Bifidobacterium、Bu tyrivibrio, Campylobacter, Candidatus, Citr obacter、Clostridium、Collinsella、Coprococ cus、Desulfovibrio、Dialister、Dorea、Whole bacter、Enterococcus、Escherichia、Eubacter ium, Faecalibacterium, Fusobacterium, Haemo philus、Klebsiella、Lachnospira、Lactobacillus light、Odoribacter、Oscillospira、Parabacter ides, Peptococcus, Peptostreptococcus, Phas colarctobacterium 、Porphyromonas、Portiera 、Prevotella、Providence、Pseudomonas、Rose buria, Ruminococcus, Salmonella, Shigella, S taphylococcus、Streptococcus、Subdoligranu lum, Vibrio, and Yersinia The active ingredient is the active ingredient(compare 1 part to 3 parts 2) of Prevotel the、Ackermansia、Bacteroides、Clostridium(E rysipelotrichaceae) Clostridium(Clostrid iaceae) 、Bifidobacterium、Aggretibacter、 Clostridium (Peptostreptococcaveae), Parab acteroides, Lactobacillus, and Enterococcus In some embodiments, the bacterial taxon (e.g., the first and second genera) is selected from the group 2 bacterial taxa) are Akkermansia, Bacteroides, and Bifido bacterium, Lactobacillus, and Parabacteroide In some embodiments, the bacterial taxon (e.g., the first and second genera) is selected from the group consisting of: and the second bacterial taxon) are selected from the group of Akkermansia and Blautia. Includes genera.

[0011] In some embodiments, the bacterial taxa (e.g., the first and second bacterial taxa) are from the small intestine. or a taxon that is predominant in the large intestine. In some embodiments, a taxon that is predominant in the small intestine. The dominant bacterial taxa (e.g., the first and second bacterial taxa) are Achromobacter er, Agrobacterium, Blautia, Burkholderia, Co prococcus, Cryocola, Enterococcus, Eubacter ium, Holdemania, Lactococcus, Mycobacterium , Pseudoramibacter, Ralstonia, Sphingomonas A genus selected from the group consisting of Streptococcus, Turicibacter, and In some embodiments, the bacterial taxa that are predominant in the large intestine (e.g., primary and secondary bacterial taxa) are included. The second bacterial taxon) is Anaerotruncus, Akkermansia, Bacillus subtilis, and teroides, Bilophila, Butyricimonas, Odoriba cter, Parabacteroides, Phascolarctobacteri um, Prevotella, and Ruminococcus nothing.

[0012] In some embodiments, the pharmaceutical composition further comprises a polyphenol formulation. In some embodiments, the polyphenol preparation is a plant polyphenol isolated from a plant source material. In some embodiments, the plant source material includes blueberries, cranberries, These include grapes, peaches, plums, pomegranates, soy, red wine, black tea, or green tea.

[0013] In some embodiments, the abundance of a bacterial taxon (e.g., a first and a second bacterial taxon) Modulation of treats microbial incompatibilities, such as those described herein.

[0014] In another aspect, the present invention provides a method for reducing drug- or treatment-induced symptoms in a human subject. The method is characterized by the use of a method for reducing drug- or treatment-induced symptoms in a human subject. Administering an effective amount of a glycan therapeutic agent, wherein i) the glycan therapeutic agent is a branched It contains a mixture of glycans, and the average degree of branching (DB) of the glycans in the preparation is at least 0. 01 (e.g., at least 0.05, or at least 0.1), and ii) in the formulation At least 50% of the glycans have a degree of polymerization (D) of at least 3 and less than 30 glycan units. P), and iii) alpha-glycosidic bond pairs present in the glycans in the formulation. The ratio of beta-glycosidic bonds is from about 1:1 to about 5:1 overall.

[0015] In some embodiments, the drug or treatment-induced symptoms include bloating, diarrhea, vomiting, nausea, vomiting, In some embodiments, the drug or treatment-induced Diarrhea. In some embodiments, the drug- or treatment-induced symptom is constipation.

[0016] In some embodiments, the composition reduces drug-induced symptoms, and the composition In some embodiments, the drug is administered before, simultaneously with, or after administration of the drug. These include antidiabetic drugs, immunosuppressants, antibiotics, chemotherapy drugs, antipsychotics, and proton pump inhibitors. In some embodiments, the drug is a nonsteroidal anti-inflammatory drug (NSAID). The drugs are ciprofloxacin, clindamycin, amoxicillin-clavulanate, and cef Ixime, ephalosporin, fluoroquinolone, azithromycin, clarithromycin erythromycin, tetracycline, azithromycin, irinotecan (Camp tosar), 5-fluorouracil, leucovorin, oxaliplatin, bortezomib , imatinib, lenalidomide, Imbruvica, ipilimumab, pertuzumab, Capecita Bin, docetaxel, lapatinib, erlotinib, carmustine, etoposide, arachnid melphalan, cytarabine, daunorubicin, amsacrine, mitoxantrone, Lanzapine, ranitidine, famotidine, cimetidine, omeprazole, sucralfar esomeprazole, naproxen, diclofenac, indomethacin, ibuprofen ketoprofen, piroxicam, celecoxib, nimesulide, aspirin, metformin The active ingredient is selected from the group consisting of acetaminophen, paroxetine, valproic acid, and clozapine.

[0017] In some embodiments, the composition reduces treatment-induced symptoms, and the treatment is This includes radiation therapy or surgery.

[0018] In some embodiments, the drug or treatment-induced symptoms are caused by the subject during the treatment regimen. In some embodiments, relief of one or more symptoms is indicative of a response to a treatment regimen. In some embodiments, the administration of the compound increases compliance by a subject receiving the compound. The reduction in the level of steroids increases the subject's tolerance to high doses of drugs administered during the treatment regimen. do.

[0019] In another aspect, the invention features a method of modulating microbial diversity in the gastrointestinal tract of a human subject. The composition comprises a glycan therapeutic agent in an amount effective to regulate microbial diversity, ) The glycan therapeutic formulation contains a mixture of branched glycans, and the average branching degree of the glycans in the formulation (DB, branch points per residue) is at least 0.01 (e.g., at least 0.05, or at least 0.1), and ii) at least 50% of the glycans in the formulation are and iii) a degree of polymerization (DP) of at least 3 and less than 30 glycan units in the formulation. The ratio of alpha-glycosidic to beta-glycosidic bonds present in the glycan is In some embodiments, the microbial diversity is between about 1:1 and about 5:1. In some embodiments, the modulation comprises an increase or decrease in microbial diversity.

[0020] In some embodiments, microbial diversity is determined by use of the Shannon diversity index. In some embodiments, In some embodiments, the Shannon diversity is increased or decreased by at least about 5%. The Shannon diversity is increased or decreased by at least about 15%. The Shannon diversity is increased or decreased by at least about 0.3 log-fold. In some cases, Shannon diversity increases or decreases by at least about 0.6 logarithmic factors. In an embodiment, the Shannon diversity is increased or decreased by at least about 1 log-fold.

[0021] In some embodiments, Prevotella, Akkermansia, Bacteria eroides, Clostridium (Erysipelotrichaceae) , Clostridium (Clostridiaceae), Bifidobacte rium, Aggregatibacter, Clostridium (Peptost reptococcaveae), Parabacteroides, Lactobac At least one bacterium selected from the group consisting of the genera Enterococcus, Bacillus, and Enterococcus. The abundance of bacterial taxa is modulated. In some embodiments, Prevotella, A. kkermansia, Bacteroides, Clostridium (Erysi pelotrichaceae), Clostridium (Clostridiaceae) ae), Bifidobacterium, Aggregatibacter, Clos tridium(Peptostreptococcaveae), Parabacte roides, Lactobacillus, and Enterococcus genera The abundance of at least one bacterial taxon selected from the group consisting of:

[0022] In some embodiments, Prevotella, Akkermansia, Bacteria eroides, Clostridium (Erysipelotrichaceae) , Clostridium (Clostridiaceae), Bifidobacte rium, Aggregatibacter, Clostridium (Peptost reptococcaveae), Parabacteroides, Lactobac At least two bacteria selected from the group consisting of the genera Enterococcus, Bacillus, and Enterococcus. The abundance of bacterial taxa is modulated. In some embodiments, Prevotella, A. kkermansia, Bacteroides, Clostridium (Erysi pelotrichaceae), Clostridium (Clostridiaceae) ae), Bifidobacterium, Aggregatibacter, Clos tridium(Peptostreptococcaveae), Parabacte roides, Lactobacillus, and Enterococcus genera The abundance of at least two bacterial taxa selected from the group consisting of:

[0023] In some embodiments, Akkermansia, Bacteroides, Bif Idobacterium, Lactobacillus, and Parabactero The abundance of at least one bacterial taxon selected from the group of genera of ides is modulated. In some embodiments, Akkermansia, Bacteroides, Bifi Lactobacillus, Lactobacillus, and Parabacterioi The abundance of at least two bacterial taxa selected from the group of genera of des is regulated. In some embodiments, the genus is selected from the group consisting of Akkermansia and Blautia. In some embodiments, the abundance of at least one bacterial taxon present in the culture is modulated. The abundance of both the bacterial genera Kkermansia and Blautia is modulated. In some embodiments, modulating microbial diversity treats microbial incompatibility.

[0024] In another aspect, the invention features a method of treating a human subject in need thereof, the method comprising: The method includes: a) identifying a human subject in need of treatment for dysbiosis; and b) administering to the human subject: Administering a pharmaceutical composition comprising a glycan therapeutic agent in an amount effective to treat microbial incompatibility. i) the glycan therapeutic agent comprises a mixture of branched glycans, The average branching degree (DB) of the glycans is at least 0.01 (e.g., at least 0.05, or at least 0.1), and ii) at least 50% of the glycans in the formulation are and iii) a degree of polymerization (DP) of at least 3 and less than 30 glycan units in the formulation. The ratio of alpha-glycosidic to beta-glycosidic bonds present in the glycan is The ratio is approximately 1:1 to 5:1 in the body.

[0025] In some embodiments, the human subject has an infectious disease, disorder, or condition. In some embodiments, the infectious disease, disorder, or condition is Clostridium difficile. Colonic dysplasia infection (CDI), vancomycin-resistant enterococcus (VRE) infection, infectious colitis, and In some embodiments, the infectious disease is selected from the group consisting of C. difficile colitis. The disorder, or condition, is Clostridium difficile-associated diarrhea (CDAD), an antibiotic Antibiotic-associated diarrhea (AAD), antibiotic-induced diarrhea, traveler's diarrhea (TD), pediatric diarrhea, and (acute ) diarrhea selected from the group of infectious diarrheas.

[0026] In some embodiments, the human subject has a metabolic disease, disorder, or condition. In some embodiments, the metabolic disease, disorder, or condition is obesity, (insulin resistance), preglycemia, or The present invention relates to a method for treating diabetes mellitus, which is selected from the group consisting of diabetes, type 2 diabetes, high fasting blood sugar (hyperglycemia), and metabolic syndrome. In some embodiments, the metabolic disease, disorder, or condition is high blood cholesterol, high LDL cholesterol, cardiovascular risk factors selected from the group consisting of high blood pressure (hypertension), high triglyceride levels, and low HDL It is a risk factor.

[0027] In some embodiments, the human subject has an inflammatory disease, disorder, or condition. In some embodiments, the inflammatory disease, disorder, or condition is inflammatory bowel disease (IBD), ulcers, The present invention relates to a method for treating ulcerative colitis, including the treatment of ulcerative colitis, ulcerative colitis, urinary tract infection, and urinary tract infection. In some embodiments, the inflammatory disease, disorder, or condition is irritable bowel syndrome (IBS). ), constipation, diarrhea, dyspepsia, and non-ulcer dyspepsia.

[0028] In some embodiments, the human subject has an autoimmune disease, disorder, or condition. In some embodiments, the autoimmune disease, disorder, or condition is autoimmune arthritis, type 1 diabetes, In some embodiments, the human subject is selected from the group consisting of urinary tract infections, multiple sclerosis, and psoriasis. has an allergy. In some embodiments, the allergy is asthma or atopy Including eczema.

[0029] In some embodiments, the human subject has a neurological disease, disorder, or condition. In some embodiments, the neurological disease, disorder, or condition is autism, hyperammonemia, and hepatic encephalopathy.

[0030] In some embodiments, the treatment further comprises administering a second drug or pharmaceutical agent. In some embodiments, the second drug or pharmaceutical agent is a standard of care drug or In some embodiments, the glycan therapeutic agent and a second drug or pharmaceutical agent The therapeutic effect of a pharmaceutical composition containing the agent is additive. The therapeutic effects of a pharmaceutical composition comprising a therapeutic compound and a second drug or pharmaceutical agent are synergistic. is.

[0031] In some embodiments, the composition is administered daily. The composition is administered daily for a predetermined number of days (treatment period). The duration includes from about 1 day to about 30 days. In some embodiments, the treatment duration is from about 1 month to about 30 days. In some embodiments, the subject receives a single treatment period of about 6 months. In some embodiments, the subject is administered the composition for more than one treatment period. .

[0032] In some embodiments, treating microbial incompatibility treats a disease in a human subject. will be done.

[0033] In another aspect, the present invention provides a method for modulating a functional pathway of the gastrointestinal microbiota in a human subject. The composition comprises a glycan therapeutic agent in an amount effective to regulate a functional pathway. i) the glycan therapeutic formulation contains a mixture of branched glycans, and the average distribution of glycans in the formulation is The divergence factor (DB) is at least 0.01 (e.g., at least 0.05, or at least 0.1), and ii) at least 50% of the glycans in the formulation are at least 3. and having a degree of polymerization (DP) of the glycan unit of less than iii) the alpha-glycosidic vs. beta-glycosidic linkages present in the glycans in the formulation; The ratio of doped bonds is about 1:1 to about 5:1 overall.

[0034] In some embodiments, the functional pathway is an antimicrobial pathway listed in Table 2 by microbiota. It regulates the production of steroids, secondary bile acids, short-chain fatty acids, siderophores, or metabolites. In some embodiments, the antimicrobial agent comprises a bacteriocin or hydrogen peroxide. The short chain fatty acids include formate, butyrate, acetate, propionate, or valerate. In some embodiments, the metabolite is 2-hydroxyisobutyrate, 3-hydroxyisobutyrate, Valerate, 3-methylcrotonylglycine, 3-methylcrotonylglycine, allantoin betaine, formate, mannitol, p-cresol glucuronide, phenylacetyl Glycine, sarcosine, taurine, acetic acid, acetylaldehyde, ascorbic acid, butane Dione, butyric acid, deoxycholic acid, ethylphenyl sulfate, formic acid, indole, isobutyric acid , isovaleric acid, propionic acid, serotonin, succinic acid, succinate, TMAO, tryptophan Contains fan, valeric acid, ursodeoxycholic acid, lactate, lactic acid, or hydrogen peroxide.

[0035] In some embodiments, the functional pathway is an inflammatory or immunoregulatory pathway in a human subject. In some embodiments, the level of inflammatory and immunomodulatory cytokines is modulated. The inhibitors are interleukin-1α (IL-1α), IL-1β, IL-2, IL-4, and IL-1β. -6, IL-8, IL-10, IL-12, IL-13, IL-17A, IL-17F, IL-22, IL-23, tumor necrosis factor (TNF), chemokine (CC motif) ligase and transforming growth factor beta (T GF-β), or interferon gamma (IFN-γ).

[0036] In some embodiments, the functional pathway increases the level of short chain fatty acids in the subject. In some embodiments, an increase in short chain fatty acids may be associated with an increase in regulatory T (Treg) cells by the subject. In some embodiments, the increase in short chain fatty acids induces the production of intestinal or reduces the permeability of plasma endotoxin levels. In some embodiments, an increase in short chain fatty acids In some embodiments, the short chain fatty acid reduces an inflammatory response in a subject. of the families ocaccaceae and / or Lachnospiraceae It is produced by at least one bacterial species.

[0037] In some embodiments, the subject is obese.

[0038] In another aspect, the present invention relates to a method for treating a C. difficile infection in a subject who has previously been administered a drug for the treatment of a C. difficile infection. The present invention relates to a method for preventing recurrence of Clostridium difficile infection in a selected human subject. In one embodiment, the method comprises administering a glycan therapeutic agent in an amount effective to prevent recurrence. i) the glycan therapeutic formulation comprises a mixture of branched glycans, and The average degree of branching (DB) is at least 0.01 (e.g., at least 0.05, or ii) at least 50% of the glycans in the preparation are at least 3 and iii) the glycans in the formulation have a degree of polymerization (DP) of less than 30 glycan units. The ratio of alpha-glycosidic to beta-glycosidic bonds present in the The ratio is 1 to about 5:1.

[0039] In some embodiments, a recurrence is one or more symptoms associated with C. difficile infection. In some embodiments, relapse includes regression of first-line or standard of care drug therapy. Occurs during or after the

[0040] In some embodiments, the drug for the treatment of C. difficile infection is an antibiotic. In some embodiments, the antibiotic is vancomycin, metronidazole, and filariasis. In some embodiments, the composition is selected from the group consisting of C. diff. The drug may be administered simultaneously with or after the administration of a drug for the treatment of a bacterial infection.

[0041] In some embodiments, the composition is administered in combination with a second drug or treatment. In some embodiments, the second drug or treatment comprises an antibiotic. In form, the antibiotics are from the group of vancomycin, metronidazole, and fidaxomicin. is selected from.

[0042] In some embodiments, administration of the composition prevents or alleviates C. difficile infection in a subject. resulting in a reduction in the severity of associated symptoms, but not the population of C. difficile in the subject. In some embodiments, administration of the composition results in the prevention of C. difficile in a subject. resulting in a reduction in the severity of symptoms associated with C. difficile infection in subjects It does not change the level of the ile population.

[0043] In another aspect, the invention features a method of making a pharmaceutical composition, the method comprising: a) combining b) providing a preparation comprising a mixture of synthetic glycans; and c) providing one of the following characteristics of the preparation: and obtaining at least one value for c) degree of polymerization (DP), d) average degree of branching (DB), e) alpha - the ratio of glycosidic bonds to beta-glycosidic bonds, f) i) the number of glycans in the preparation at least 50% have a DP of at least 3 and less than 30 glycan units; and ii) in the formulation The average branching degree (DB) of the glycans is at least 0.01 (e.g., at least 0.05 or at least 0.1), and iii) the alpha present in the glycans in the formulation. - an overall ratio of glycosidic bonds to beta-glycosidic bonds of about 1:1 to about 5:1 The compound may be formulated as a pharmaceutical composition if it meets one or more of the following criteria: Includes and.

[0044] In some embodiments, the method further comprises: a) further characterizing the preparation: i) the glycan units; ii) the ratio of glycan units, or both of these values ​​are obtained. and b) iii) the ratio of glycan units in the preparation is approximately the same as the ratio of input glycan units. If the compound is substantially the same, the compound further comprises formulating the compound as a pharmaceutical composition.

[0045] In some embodiments, the method further comprises: b) further characteristics of the formulation; iv) replenishing the formulation. In the medium, Bacteroides caccae ATCC 43185, Pre Votella copri DSM 18205, Bacteroides thet aiotamicron ATCC 29741, Bacteroides cellu losilyticus DSM 14838, Clostridium scinde ns ATCC 35704, Ruminococcus obeum ATCC 29 714, Clostridium nexile ATCC 27757, and Para bacteroides distasonis ATCC 8503 v) the level of bacterial growth of the selected probiotic strains; dium difficile ATCC BAA-1382, Clostridium difficile ATCC 43255, Enterococcus faeci um ATCC 700221, and Salmonella enterica ATC C 27869, or one or both of these values, and c) the following criteria: vi) at least five vii) the promotion of the growth of commensal strains by the addition of a preparation to the medium; vii) the promotion of the growth of not more than two pathogenic strains and / or the growth of the cells. and, if so, formulating the preparation as a pharmaceutical composition. In some embodiments, step (b) occurs prior to or simultaneously with another step in the process. It is possible.

[0046] In some embodiments, the step of formulating the preparation as a pharmaceutical composition comprises: i) preparing the preparation; ii) removing undesirable constituents from the combination; ii) reducing the volume of the preparation; iii) sterilizing the preparation; iv) mixing the preparation with a pharmaceutically acceptable excipient or carrier. v) mixing the formulation with a second drug or pharmaceutical agent; vi) mixing the formulation vii) formulating the preparation into an aqueous solution or syrup; viii) formulating the preparation into a tablet or pill. and viii) formulating the preparation into a capsule. .

[0047] In some embodiments, the step of formulating the preparation as a pharmaceutical composition comprises: ix) x) packaging the preparation; x) labeling the packaged preparation; and and xi) Selling or offering for sale any packaged and labeled preparation. and one or more of:

[0048] In another aspect, the invention features a method of making a pharmaceutical composition, the method comprising: (i) Glucose, galactose, fucose, xylose, arabinose, rhamnose, and maltose Therapeutic glycan preparations comprising at least one glycan unit selected from the group of glycans (ii) providing a preselected NMR peak or set of NMR peaks; (iii) determining whether preselected peaks or and if a peak or series of peaks is present, formulating the preparation as a pharmaceutical composition. nothing.

[0049] In some embodiments, the peak is a 1H-13C HSQC NMR peak. In some embodiments, the determination is based on the H-C HSQC peaks associated with the pharmaceutical agent. Or to obtain specific values ​​for a set of peaks and, if preselected peaks are present, and formulating the preparation as a pharmaceutical composition.

[0050] In some embodiments, i) for glycans containing glucose, the peak is 5. 42, 92.5;5.21, 92.8;5.18, 93.9;5.08, 97.0;5. 36, 98.4; 5.34, 99.8; 5.38, 100.3; 4.95, 98.6; 4 0.62, 96.6; 4.70, 103.6; 4.49, 103.4 1H shift (pp m) and 13C shift (ppm) QC peaks or corresponding peaks, and ii) for galactose-containing glycans , peaks are 5.37, 92.9; 5.24, 93.1; 5.14, 96.0; 4.96 , 99.3;5.31, 98.7;5.39, 101.4;5.00, 101.8;4. 80, 101.3;4.63, 97.0;4.56, 97.2;4.53, 103.1; 4.43, 104.1 Select from 1H shift (ppm) and 13C shift (ppm) at least one H-C HSQC peak or corresponding peak that is ii) For glycans containing fucose, the peaks were 5.18, 92.9; 5.33; 92.4;5.04, 96.3;4.90, 99.7;4.52, 97.0;4.39, 103.6 A small number selected from 1H shift (ppm) and 13C shift (ppm) iv) xylo- For glycans containing glycans, the peaks were 5.18, 93.0; 5.10, 94.3; 5.34, 98.2; 5.31, 99.6; 5.11, 100.8; 4.91, 99.4 ;4.56, 97.3;4.64, 104.2;4.54, 103.4;4.44, 10 2.6; 4.44, 104.1 1H shift (ppm) and 13C shift (ppm) At least one 1H-13C HSQC peak or corresponding peak selected from v) for arabinose-containing glycans, the peaks are 5.22, 93.2; .13, 93.2; 5.29, 96.0; 5.26, 97.2; 5.12, 96.6; 5 .18, 99.6; 5.06, 99.2; 4.99, 100.0; 5.26, 101.9 ;5.06, 102.1;4.55, 97.4;4.54, 105.2;4.50, 10 5.5; 4.38, 103.9 1H shift (ppm) and 13C shift (ppm) At least one 1H-13C HSQC peak or corresponding peak selected from and vi) for rhamnose-containing glycans, the peaks are 5.21, 93.2; .10, 94.5;4.85, 94.1;5.01, 95.8;5.35, 100.5; 5.15, 102.2; 5.04, 102.9; 4.78, 97.9; 4.71, 99. 0;4.72, 101.0 from 1H shift (ppm) and 13C shift (ppm) Contains at least one selected 1H-13C HSQC peak or corresponding peak , vii) For mannose-containing glycans, the peaks are 5.37, 93.0;5. 16, 94.6;4.88, 94.2;5.39, 101.7;5.24, 101.9; 5.13, 102.8; 5.03, 102.7; 5.24, 105.6; 5.09, 10 8.0;4.88, 94.2;4.89, 100.0;4.70, 101.1 1H At least one 1H-1 shift (ppm) and 13C shift (ppm) Contains 3C HSQC peaks or corresponding peaks.

[0051] In some embodiments, i) for glycans containing glucose, the peak is 5. 42, 92.5;5.21, 92.8;5.18, 93.9;5.08, 97.0;5. 36, 98.4; 5.34, 99.8; 5.38, 100.3; 4.95, 98.6; 4 0.62, 96.6; 4.70, 103.6; 4.49, 103.4 1H shift (pp At least two, at least three, or at least a few selected from the group consisting of 13C shift (ppm) and 13C shift (ppm) At least four or more 1H-13C HSQC peaks or corresponding peaks and ii) for galactose-containing glycans, the peaks are 5.37, 92.9 ;5.24, 93.1;5.14, 96.0;4.96, 99.3;5.31, 98.7 ;5.39, 101.4;5.00, 101.8;4.80, 101.3;4.63, 9 7.0;4.56, 97.2;4.53, 103.1;4.43, 104.1 1H At least two selected from the group consisting of 13C shift (ppm) and 13C shift (ppm), At least three, at least four, or more 1H-13C HSQC peaks or corresponding iii) for glycans containing fucose, the peaks are 5.18, 92.9;5.33, 92.4;5.04, 96.3;4.90, 99.7;4.52, 97.0; 4.39, 103.6 1H shift (ppm) and 13C shift (ppm ) at least two, at least three, at least four, or more selected from or a corresponding peak, and iv) contains xylose. For glycans, the peaks were 5.18, 93.0; 5.10, 94.3; 5.34, 98.2;5.31, 99.6;5.11, 100.8;4.91, 99.4;4.56 , 97.3;4.64, 104.2;4.54, 103.4;4.44, 102.6;4 0.44, 104.1 1H shift (ppm) and 13C shift (ppm) are selected. At least two, at least three, at least four, or more 1H-13 C HSQC peak or corresponding peak, and v) for arabinose-containing glycans In the case of α-glucan, the peaks were 5.22, 93.2; 5.13, 93.2; 5.29, 96.0; 5 .26, 97.2; 5.12, 96.6; 5.18, 99.6; 5.06, 99.2; 4 .99, 100.0; 5.26, 101.9; 5.06, 102.1; 4.55, 97. 4;4.54, 105.2;4.50, 105.5;4.38, 103.9 1H Schiff At least two selected from the group consisting of 13C shift (ppm) and 13C shift (ppm), Three, at least four, or more 1H-13C HSQC peaks or corresponding and vi) for rhamnose-containing glycans, the peaks are 5.21, 9 3.2;5.10, 94.5;4.85, 94.1;5.01, 95.8;5.35, 1 00.5;5.15, 102.2;5.04, 102.9;4.78, 97.9;4.7 1, 99.0; 4.72, 101.0 1H shift (ppm) and 13C shift (ppm) pm), or at least two, at least three, or at least four selected from or more 1H-13C HSQC peaks or corresponding peaks, and vii) mannose For glycans containing , the peaks are 5.37, 93.0; 5.16, 94.6; 4. 88, 94.2; 5.39, 101.7; 5.24, 101.9; 5.13, 102.8 ;5.03, 102.7;5.24, 105.6;5.09, 108.0;4.88, 9 4.2; 4.89, 100.0; 4.70, 101.1 1H shift (ppm) and 1 3C Shift (ppm) Selected from at least two, at least three, at least four It contains one or more 1H-13C HSQC peaks or corresponding peaks.

[0052] In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutic glycan preparation comprising a mixture of branched glycans. The present invention is characterized by an optically active compound having ... ) At least 50% of the glycans in the preparation are of at least 3 and less than 30 glycan units. ii) the glycan preparation has an alpha-glycosidic bond and a beta- -glycosidic bonds present in the glycans in the formulation, and iii) At least one of the bonds is a 1->2 glycosidic bond, a 1->3 glycosidic bond, or a 1- >4 glycosidic bonds, or 1->6 glycosidic bonds, and iv) the glycosidic bond in the preparation The ratio of alpha-glycosidic to beta-glycosidic bonds present in can is approximately 1: The ratio is 1 to about 5:1.

[0053] In some embodiments, at least one, at least two of the glycosidic bonds At least three, at least four, or more independently form 1->2 glycosidic bonds In this case, 1->3 glycosidic bond, 1->4 glycosidic bond, or 1->6 glycosidic bond In some embodiments, one or more, two or more, or three or more glycosidic bonds In some cases, it exists in both alpha and beta configurations.

[0054] In some embodiments, the glycan units are tetroses, pentoses, hexoses, and and heptose, or In some embodiments, the glycan unit comprises at least three or more. Glucose, galactose, arabinose, mannose, fructose, xylose, at least one monosaccharide selected from the group consisting of cocos, rhamnose, and rhamnose; Contains two, at least three, or more.

[0055] In some embodiments, at least one of the glycans in the formulation, e.g., For example, at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or 99% (by weight or number) or virtually all are above a preselected reference level Repeating units of glycan units, e.g., 2, 3, 4, or more glycans In one embodiment, the preselected reference level does not include repeating units of the unit 10, 20, 30, 40, 50, or 60% of the total glycan units of a In an embodiment, from 20 monosaccharide monomers, less than 50% of these 20 monomers The glycans comprised are repeating units of two or three glycan repeats.

[0056] In some embodiments, the glycan therapeutic agent is synthetic and is not a naturally occurring oligosaccharide. or polysaccharide source.

[0057] In some embodiments, the composition further comprises a polyphenol preparation. In some embodiments, the composition further comprises a preparation of probiotic bacteria. In some embodiments, the composition further comprises a drug or therapeutic agent. The composition further comprises a pharmaceutically acceptable excipient.

[0058] In some embodiments, the composition is formulated as a unit dosage form. In some embodiments, the unit dosage form is formulated for oral delivery. The dosage form is formulated to dissolve in an aqueous solution and can be used as a drink, syrup, solution, or suspension. It is administered orally.

[0059] In some embodiments, the unit dosage form is formulated as a delayed release or time-controlled system. In some embodiments, the unit dosage form delivers a therapeutic glycan preparation to a specific region of the gastrointestinal tract. In some embodiments, the specific region of the gastrointestinal tract is the stomach. , small intestine, large intestine, or colon.

[0060] In some embodiments, the compositions modulate the abundance of bacterial genera present in the gastrointestinal tract. In some embodiments, the composition is administered to one or both of the small intestine or the large intestine. In some embodiments, the composition modulates the abundance of bacterial genera present in the Ach romobacter, Agrobacterium, Blautia, Burkhol deria, Coprococcus, Cryocola, Enterococcus, Eubacterium, Holdemania, Lactococcus, Mycob acterium, Pseudoramibacter, Ralstonia, Sphi ngomonas, Streptococcus, and Turicibacter genera The abundance of a bacterial genera that predominates in the small intestine is selected from the group. In this embodiment, the composition comprises Anaerotruncus, Akkermansia, Bacteria eroides, Bilophila, Butyricimonas, Odoribac ter, Parabacteroides, Phascolarctobacteriu large intestine selected from the group consisting of the genera m, Prevotella, and Ruminococcus regulates the abundance of the bacterial genera that predominate in the

[0061] In some embodiments, the unit dosage form contains about 0.1 mL to about 5 mL of a therapeutic glycan formulation. and a therapeutic glycan formulation formulated for oral delivery to deliver the therapeutic glycan formulation to specific regions of the gastrointestinal tract. In some embodiments, the unit dosage form is formulated to release from about 0.1 mg to about Contains 100 mg of therapeutic glycan preparation, formulated for oral delivery and specific for the gastrointestinal tract It is formulated to release a therapeutic glycan compound within the region.

[0062] In some embodiments, the unit dosage form contains about 0.1 mL to about 5 mL of a therapeutic glycan formulation. and the composition is formulated for oral delivery, the composition comprising Bacteroides, Buty yricimonas, Odoribacter, Parabacteroides, P revotella, Anaerotruncus, Phascolarctobact erium, Ruminococcus, Bilophila, Akkermansia , Cryocola, Mycobacterium, Enterococcus, Lac tococcus, Streptococcus, Turicibacter, Blau tia, Coprococcus, Holdemania, Pseudoramibac ter, Eubacterium, Agrobacterium, Sphingomon as, Achromobacter, Burkholderia, and Ralstoni The abundance of a bacterial genera selected from the group a is controlled.

[0063] In some embodiments, the unit dosage form contains about 0.1 mg to about 100 mg of therapeutic glycan. The composition contains a pharmaceutical preparation and is formulated for oral delivery, and the composition contains Bacteroides, B utyricimonas, Odoribacter, Parabacteroides , Prevotella, Anaerotruncus, Phascolarctoba cterium, Ruminococcus, Bilophila, Akkermans ia, Cryocola, Mycobacterium, Enterococcus, L actococcus, Streptococcus, Turicibacter, Bl autia, Coprococcus, Holdemania, Pseudoramib acter, Eubacterium, Agrobacterium, Sphingom onas, Achromobacter, Burkholderia, and Ralsto The abundance of a bacterial genera selected from the group of nia is controlled.

[0064] In some embodiments, the present invention provides a method for treating a bacterial disease comprising administering to a subject a) an amount of a compound effective to modulate the abundance of a bacterial taxon; A glycan therapeutic agent, comprising: i) a mixture of branched glycans; ii) the average branching degree (DB) of the glycans in the preparation is at least 0.01; At least 50% of the glycans in the combination are polymerized with at least 3 and less than 30 glycan units. α-glycosides present in the glycans in the formulation, and iii) A therapeutic preparation having an overall ratio of beta-glycosidic bonds to beta-glycosidic bonds of about 1:1 to about 5:1. and b) polyphenol preparations, probiotic bacterial preparations, drugs or therapeutic agents. and at least a second component selected from the group consisting of a dietary ingredient, c) educational materials, and d) a package. and caging.

[0065] In another aspect, the present invention provides a method for producing saccharides containing glucose, galactose, fucose, xylose, arabinose, at least one glycan unit selected from the group consisting of rhamnose, rhamnose, and mannose; The pharmaceutical composition comprises a therapeutic glycan preparation comprising: glycan units associated with one or more of the 3C HSQC peaks, including i) glucose For glycans containing , the peaks are 5.42, 92.5; 5.21, 92.8; 5. 18, 93.9;5.08, 97.0;5.36, 98.4;5.34, 99.8;5. 38, 100.3;4.95, 98.6;4.62, 96.6;4.70, 103.6; 4.49, 103.4 Select from 1H shift (ppm) and 13C shift (ppm) at least one H-C HSQC peak or corresponding peak that is i) For galactose-containing glycans, the peaks are 5.37, 92.9; 5.24 , 93.1;5.14, 96.0;4.96, 99.3;5.31, 98.7;5.39 , 101.4;5.00, 101.8;4.80, 101.3;4.63, 97.0;4 0.56, 97.2; 4.53, 103.1; 4.43, 104.1 1H shift (pp m) and 13C shift (ppm) QC peak or corresponding peak, and iii) for glycans containing fucose, The peaks were 5.18, 92.9; 5.33, 92.4; 5.04, 96.3; 4.90, 99.7;4.52, 97.0;4.39, 103.6 1H shift (ppm) and 1 At least one 1H-13C HSQC peak selected from 3C shifts (ppm) or a peak corresponding to: iv) for glycans containing xylose, the peak 5.18, 93.0;5.10, 94.3;5.34, 98.2;5.31, 99.6; 5.11, 100.8; 4.91, 99.4; 4.56, 97.3; 4.64, 104. 2;4.54, 103.4;4.44, 102.6;4.44, 104.1 1H Schiff At least one 1H-13 shift (ppm) selected from 1H-13 shift (ppm) and 13C shift (ppm) C HSQC peak or corresponding peak, and v) for arabinose-containing glycans In the case of α-glucan, the peaks were 5.22, 93.2; 5.13, 93.2; 5.29, 96.0; 5 .26, 97.2; 5.12, 96.6; 5.18, 99.6; 5.06, 99.2; 4 .99, 100.0; 5.26, 101.9; 5.06, 102.1; 4.55, 97. 4;4.54, 105.2;4.50, 105.5;4.38, 103.9 1H Schiff At least one 1H-13 shift (ppm) selected from 1H-13 shift (ppm) and 13C shift (ppm) C HSQC peak or corresponding peak, and vi) for rhamnose-containing glycans In the case of α-glucan, the peaks were 5.21, 93.2; 5.10, 94.5; 4.85, 94.1; 5 .01, 95.8; 5.35, 100.5; 5.15, 102.2; 5.04, 102. 9;4.78, 97.9;4.71, 99.0;4.72,101.0 1H shift( at least one 1H-13C selected from 1H-13C shift (ppm) and 13C shift (ppm) vii) for mannose-containing glycans, The peaks were 5.37, 93.0; 5.16, 94.6; 4.88, 94.2; 5. 39, 101.7; 5.24, 101.9; 5.13, 102.8; 5.03, 102. 7;5.24, 105.6;5.09, 108.0;4.88, 94.2;4.89, 1 00.0;4.70, 101.1 1H shift (ppm) and 13C shift (ppm ) at least one 1H-13C HSQC peak or corresponding peak selected from Includes:

[0066] In some embodiments, the pharmaceutical composition comprises glucose, galactose, fucose, At least one selected from the group consisting of xylose, arabinose, rhamnose, and mannose The therapeutic glycan preparation includes one glycan unit, and the preparation is: HSQC peaks containing glycan units associated with two or more of the peaks, i) containing glucose; For the glycan, the peaks were 5.42, 92.5; 5.21, 92.8; 5.18 , 93.9;5.08, 97.0;5.36, 98.4;5.34, 99.8;5.38 , 100.3;4.95, 98.6;4.62, 96.6;4.70, 103.6;4. 49, 103.4 1H shift (ppm) and 13C shift (ppm) selected At least two, at least three, at least four, or more 1H-13C HSQC peak or corresponding peak, and ii) for galactose-containing glycans In the case of α-glucan, the peaks were 5.37, 92.9; 5.24, 93.1; 5.14, 96.0; 4 .96, 99.3; 5.31, 98.7; 5.39, 101.4; 5.00, 101.8 ;4.80, 101.3;4.63, 97.0;4.56, 97.2;4.53, 103 .1;4.43, 104.1 1H shift (ppm) and 13C shift (ppm) At least two, at least three, at least four, or more of the following are selected from the iii) fucose-containing glycoproteins containing H-13C HSQC peaks or corresponding peaks; For Kan, the peaks were 5.18, 92.9; 5.33, 92.4; 5.04, 96 .3;4.90, 99.7;4.52, 97.0;4.39, 103.6 1H shift At least two selected from (ppm) and 13C shift (ppm), and at least 3 One, at least four, or more 1H-13C HSQC peaks or corresponding peaks iv) for glycans containing xylose, the peaks are 5.18, 93. 0;5.10, 94.3;5.34, 98.2;5.31, 99.6;5.11, 100 .8;4.91, 99.4;4.56, 97.3;4.64, 104.2;4.54, 1 03.4;4.44, 102.6;4.44, 104.1 1H shift (ppm) and At least two, at least three, at least Contains four or more 1H-13C HSQC peaks or corresponding peaks, v) For arabinose-containing glycans, the peaks are 5.22, 93.2; 5.13 , 93.2;5.29,96.0;5.26, 97.2;5.12, 96.6;5.18 , 99.6;5.06, 99.2;4.99, 100.0;5.26, 101.9;5. 06, 102.1; 4.55, 97.4; 4.54, 105.2; 4.50, 105.5 4.38, 103.9 1H shift (ppm) and 13C shift (ppm) At least two, at least three, at least four, or more 1H- vi) rhamnose-containing glycans, including a 13C HSQC peak or a corresponding peak; For , the peaks are 5.21, 93.2; 5.10, 94.5; 4.85, 94.1 ;5.01, 95.8;5.35, 100.5;5.15, 102.2;5.04, 10 2.9;4.78, 97.9;4.71, 99.0;4.72, 101.0 1H Schiff At least two selected from the group consisting of 13C shift (ppm) and 13C shift (ppm), Three, at least four, or more 1H-13C HSQC peaks or corresponding vii) for mannose-containing glycans, the peaks are 5.37; 93.0;5.16, 94.6;4.88, 94.2;5.39, 101.7;5.24 , 101.9;5.13, 102.8;5.03, 102.7;5.24, 105.6; 5.09, 108.0; 4.88, 94.2; 4.89, 100.0; 4.70, 101 .1 At least one of 1H shift (ppm) and 13C shift (ppm) Two, at least three, at least four, or more 1H-13C HSQC peaks The peaks include the peaks or corresponding peaks.

[0067] In another aspect, the present invention provides a method for determining the abundance of bacterial taxa in the gastrointestinal microbiota of a human subject. The present invention features a pharmaceutical composition for use in determining the abundance of a bacterial taxon. and i) the glycan therapeutic agent comprises a branched glycan. The average branching degree (DB, branch points per residue) of the glycans in the preparation is is at least 0.01 (e.g., at least 0.05, or at least 0.1); ii) at least 50% of the glycans in the preparation have at least 3 and fewer than 30 glycan units; and iii) alpha-glycols present in the glycans in the formulation. The ratio of glycosidic bonds to beta-glycosidic bonds is from about 1:1 to about 5:1 overall. In some embodiments, the bacterial taxa include at least a first and a second bacterial taxon.

[0068] In some embodiments, the formulation comprises branched oligosaccharides. The average degree of branching (DB) in the preparation is at least 0.05 (e.g., at least 0.1). be.

[0069] In some embodiments, at least one, at least two of the glycosidic bonds At least three, at least four, or more independently form 1->2 glycosidic bonds In this case, 1->3 glycosidic bond, 1->4 glycosidic bond, or 1->6 glycosidic bond In some embodiments, one or more, two or more, or three or more glycosidic bonds In some cases, it exists in both alpha and beta configurations.

[0070] In some embodiments, the glycan units are tetroses, pentoses, hexoses, and and heptose, or In some embodiments, the glycan unit comprises at least three or more. Glucose, galactose, arabinose, mannose, fructose, xylose, at least one monosaccharide selected from the group consisting of cocos, rhamnose, and rhamnose; Contains two, at least three, or more.

[0071] In some embodiments, at least one of the glycans in the formulation, e.g., For example, at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or 99% (by weight or number) or virtually all are above a preselected reference level Repeating units of glycan units, e.g., 2, 3, 4, or more glycans In one embodiment, the preselected reference level does not include repeating units of the unit 10, 20, 30, 40, 50, or 60% of the total glycan units of a In an embodiment, from 20 monosaccharide monomers, less than 50% of these 20 monomers The glycans comprised are repeating units of two or three glycan repeats.

[0072] In some embodiments, the glycan therapeutic agent is synthetic and is not a naturally occurring oligosaccharide. or polysaccharide source.

[0073] In some embodiments, the bacterial taxa in the gastrointestinal microbiota of a human subject (e.g., The abundance of the first and second bacterial taxa is at least about 5%, 10%, 25%, At 50%, 75%, 100%, 250%, 500%, 750%, or at least 10 In some embodiments, the modulation is in the gastrointestinal microbiota of a human subject. Increased abundance or abundance of bacterial taxa (e.g., of each of the first and second bacterial taxa) in the includes a decrease.

[0074] In some embodiments, the bacterial taxa (e.g., the first and second bacterial taxa) are symbiotic. In other embodiments, the bacterial taxon (e.g., a first and a second bacterial taxon) ) includes pathogenic bacterial taxa.

[0075] In some embodiments, the bacterial taxa (e.g., the first and second bacterial taxa) are Ak kermansia, Alistipes, Anaerophilum, Bacteroi Des, Bilophila, Blautia, Bifidobacterium, Bu tyrivibrio, Campylobacter, Candidatus, Citr obacter, Clostridium, Collinsella, Coprococ cus, Desulfovibrio, Dialister, Dorea, Entero bacter, Enterococcus, Escherichia, Eubacter ium, Faecalibacterium, Fusobacterium, Haemo philus, Klebsiella, Lachnospira, Lactobacil lus, Odoribacter, Oscillospira, Parabactero ides, Peptococcus, Peptostreptococcus, Phas colarctobacterium, Porphyromonas, Portiera , Prevotella, Providencia, Pseudomonas, Rose buria, Ruminococcus, Salmonella, Shigella, S Taphylococcus, Streptococcus, Subdoligranu Some include genera selected from the group consisting of serovars, ... In embodiments, the bacterial taxa (e.g., the first and second bacterial taxa) are selected from Prevotel la, Akkermansia, Bacteroides, Clostridium (E rysipelotrichaceae), Clostridium (Clostrid iaceae), Bifidobacterium, Aggregatibacter, Clostridium (Peptostreptococcaveae), Parab acteroides, Lactobacillus, and Enterococcus In some embodiments, the bacterial taxon (e.g., the first and second genera) is selected from the group 2 bacterial taxa) are Akkermansia, Bacteroides, and Bifido bacterium, Lactobacillus, and Parabacteroide In some embodiments, the bacterial taxon (e.g., the first and second genera) is selected from the group consisting of: and the second bacterial taxon) are selected from the group of Akkermansia and Blautia. Includes genera.

[0076] In some embodiments, the bacterial taxa (e.g., the first and second bacterial taxa) are from the small intestine. or a taxon that is predominant in the large intestine. In some embodiments, a taxon that is predominant in the small intestine. The dominant bacterial taxa (e.g., the first and second bacterial taxa) are Achromobacter er, Agrobacterium, Blautia, Burkholderia, Co prococcus, Cryocola, Enterococcus, Eubacter ium, Holdemania, Lactococcus, Mycobacterium , Pseudoramibacter, Ralstonia, Sphingomonas A genus selected from the group consisting of Streptococcus, Turicibacter, and In some embodiments, the bacterial taxa that are predominant in the large intestine (e.g., primary and secondary bacterial taxa) are included. The second bacterial taxon) is Anaerotruncus, Akkermansia, Bacillus subtilis, and teroides, Bilophila, Butyricimonas, Odoriba cter, Parabacteroides, Phascolarctobacteri um, Prevotella, and Ruminococcus nothing.

[0077] In some embodiments, the pharmaceutical composition further comprises a polyphenol formulation. In some embodiments, the polyphenol preparation is a plant polyphenol isolated from a plant source material. In some embodiments, the plant source material includes blueberries, cranberries, These include grapes, peaches, plums, pomegranates, soy, red wine, black tea, or green tea.

[0078] In some embodiments, the abundance of a bacterial taxon (e.g., a first and a second bacterial taxon) Modulation of treats microbial incompatibilities, such as those described herein.

[0079] In another aspect, the present invention provides a method for reducing drug- or treatment-induced symptoms in a human subject. The present invention features a pharmaceutical composition for use in treating drug- or treatment-induced rheumatoid arthritis in a human subject. The method comprises administering a glycan therapeutic agent in an amount effective to reduce the symptoms of the disease, wherein: i) the glycan therapeutic agent is administered in an amount effective to reduce the symptoms of the disease; The glycan therapeutic preparation contains a mixture of branched glycans, and the average branching degree ( DB) is at least 0.01 (e.g., at least 0.05, or at least 0.1 ii) at least 50% of the glycans in the formulation have a molecular weight of at least 3 and less than 30 iii) the degree of polymerization (DP) of the glycan units, and The ratio of sulfo-glycosidic bonds to beta-glycosidic bonds is about 1:1 to about 5:1 overall is.

[0080] In some embodiments, the drug or treatment-induced symptoms include bloating, diarrhea, vomiting, nausea, vomiting, In some embodiments, the drug or treatment-induced Diarrhea. In some embodiments, the drug- or treatment-induced symptom is constipation.

[0081] In some embodiments, the composition reduces drug-induced symptoms, and the composition In some embodiments, the drug is administered before, simultaneously with, or after administration of the drug. These include antidiabetic drugs, immunosuppressants, antibiotics, chemotherapy drugs, antipsychotics, and proton pump inhibitors. In some embodiments, the drug is a nonsteroidal anti-inflammatory drug (NSAID). The drugs are ciprofloxacin, clindamycin, amoxicillin-clavulanate, and cef Ixime, ephalosporin, fluoroquinolone, azithromycin, clarithromycin erythromycin, tetracycline, azithromycin, irinotecan (Camp tosar), 5-fluorouracil, leucovorin, oxaliplatin, bortezomib , imatinib, lenalidomide, Imbruvica, ipilimumab, pertuzumab, Capecita Bin, docetaxel, lapatinib, erlotinib, carmustine, etoposide, arachnid melphalan, cytarabine, daunorubicin, amsacrine, mitoxantrone, Lanzapine, ranitidine, famotidine, cimetidine, omeprazole, sucralfar esomeprazole, naproxen, diclofenac, indomethacin, ibuprofen ketoprofen, piroxicam, celecoxib, nimesulide, aspirin, metformin The active ingredient is selected from the group consisting of acetaminophen, paroxetine, valproic acid, and clozapine.

[0082] In some embodiments, the composition reduces treatment-induced symptoms, and the treatment is This includes radiation therapy or surgery.

[0083] In some embodiments, the drug or treatment-induced symptoms are caused by the subject during the treatment regimen. In some embodiments, relief of one or more symptoms is indicative of a response to a treatment regimen. In some embodiments, the administration of the compound increases compliance by a subject receiving the compound. The reduction in the level of steroids increases the subject's tolerance to high doses of drugs administered during the treatment regimen. do.

[0084] In another aspect, the present invention provides a method for the regulation of microbial diversity in the gastrointestinal tract of a human subject. The present invention features a pharmaceutical composition for the treatment of microbial diseases, the composition comprising a glycoprotein comprising a glycoprotein that is effective in regulating microbial diversity. i) the glycan therapeutic agent comprises a mixture of branched glycans, The average branching degree (DB, branch points per residue) of the glycans in ii) the glycans in the formulation are At least 50% of the glycans have a degree of polymerization (DP) of at least 3 and less than 30 glycan units. and iii) the alpha-glycosidic bond versus the beta-glycosidic bond present in the glycans in the formulation. In some embodiments, the ratio of glycosidic bonds is from about 1:1 to about 5:1 overall. Biodiversity includes bacterial diversity. In some embodiments, modulation is an increase in microbial diversity. This includes addition or decrease.

[0085] In some embodiments, microbial diversity is determined by use of the Shannon diversity index. In some embodiments, In some embodiments, the Shannon diversity is increased or decreased by at least about 5%. The Shannon diversity is increased or decreased by at least about 15%. The Shannon diversity is increased or decreased by at least about 0.3 log-fold. In some cases, Shannon diversity increases or decreases by at least about 0.6 logarithmic factors. In an embodiment, the Shannon diversity is increased or decreased by at least about 1 log-fold.

[0086] In some embodiments, Prevotella, Akkermansia, Bacteria eroides, Clostridium (Erysipelotrichaceae) , Clostridium (Clostridiaceae), Bifidobacte rium, Aggregatibacter, Clostridium (Peptost reptococcaveae), Parabacteroides, Lactobac At least one bacterium selected from the group consisting of the genera Enterococcus, Bacillus, and Enterococcus. The abundance of bacterial taxa is modulated. In some embodiments, Prevotella, A. kkermansia, Bacteroides, Clostridium (Erysi pelotrichaceae), Clostridium (Clostridiaceae) ae), Bifidobacterium, Aggregatibacter, Clos tridium(Peptostreptococcaveae), Parabacte roides, Lactobacillus, and Enterococcus genera The abundance of at least one bacterial taxon selected from the group consisting of:

[0087] In some embodiments, Prevotella, Akkermansia, Bacteria eroides, Clostridium (Erysipelotrichaceae) , Clostridium (Clostridiaceae), Bifidobacte rium, Aggregatibacter, Clostridium (Peptost reptococcaveae), Parabacteroides, Lactobac At least two bacteria selected from the group consisting of the genera Enterococcus, Bacillus, and Enterococcus. The abundance of bacterial taxa is modulated. In some embodiments, Prevotella, A. kkermansia, Bacteroides, Clostridium (Erysi pelotrichaceae), Clostridium (Clostridiaceae) ae), Bifidobacterium, Aggregatibacter, Clos tridium(Peptostreptococcaveae), Parabacte roides, Lactobacillus, and Enterococcus genera The abundance of at least two bacterial taxa selected from the group consisting of:

[0088] In some embodiments, Akkermansia, Bacteroides, Bif Idobacterium, Lactobacillus, and Parabactero The abundance of at least one bacterial taxon selected from the group of genera of ides is modulated. In some embodiments, Akkermansia, Bacteroides, Bifi Lactobacillus, Lactobacillus, and Parabacterioi The abundance of at least two bacterial taxa selected from the group of genera of des is regulated. In some embodiments, the genus is selected from the group consisting of Akkermansia and Blautia. In some embodiments, the abundance of at least one bacterial taxon present in the culture is modulated. The abundance of both the bacterial genera Kkermansia and Blautia is modulated. In some embodiments, modulating microbial diversity treats microbial incompatibility.

[0089] In another aspect, the present invention provides a pharmaceutical composition for use in treating a human subject in need thereof. The present invention features a therapeutic composition for the treatment of microbial incompatibility, which comprises: a) identifying a human subject in need of treatment for microbial incompatibility; and b) administering to the human subject the glycan therapeutic formulation in an amount effective to treat dysbiosis. and administering a pharmaceutical composition comprising: i) the glycan therapeutic agent is a branched glycan; The average branching degree (DB) of the glycans in the preparation is at least 0.01 (e.g., For example, at least 0.05, or at least 0.1), and ii) the glycans in the preparation At least 50% of the glycans have a degree of polymerization (DP) of at least 3 and less than 30 glycan units. and iii) the alpha-glycosidic linkages present in the glycans of the preparation versus beta- The ratio of glycosidic bonds is from about 1:1 to about 5:1 overall.

[0090] In some embodiments, the human subject has an infectious disease, disorder, or condition. In some embodiments, the infectious disease, disorder, or condition is Clostridium difficile. Colonic dysplasia infection (CDI), vancomycin-resistant enterococcus (VRE) infection, infectious colitis, and In some embodiments, the infectious disease is selected from the group consisting of C. difficile colitis. The disorder, or condition, is Clostridium difficile-associated diarrhea (CDAD), an antibiotic Antibiotic-associated diarrhea (AAD), antibiotic-induced diarrhea, traveler's diarrhea (TD), pediatric diarrhea, and (acute ) diarrhea selected from the group of infectious diarrheas.

[0091] In some embodiments, the human subject has a metabolic disease, disorder, or condition. In some embodiments, the metabolic disease, disorder, or condition is obesity, (insulin resistance), preglycemia, or The present invention relates to a method for treating diabetes mellitus, which is selected from the group consisting of diabetes, type 2 diabetes, high fasting blood sugar (hyperglycemia), and metabolic syndrome. In some embodiments, the metabolic disease, disorder, or condition is high blood cholesterol, high LDL cholesterol, cardiovascular risk factors selected from the group consisting of high blood pressure (hypertension), high triglyceride levels, and low HDL It is a risk factor.

[0092] In some embodiments, the human subject has an inflammatory disease, disorder, or condition. In some embodiments, the inflammatory disease, disorder, or condition is inflammatory bowel disease (IBD), ulcers, The present invention relates to a method for treating ulcerative colitis, including the treatment of ulcerative colitis, ulcerative colitis, urinary tract infection, and urinary tract infection. In some embodiments, the inflammatory disease, disorder, or condition is irritable bowel syndrome (IBS). ), constipation, diarrhea, dyspepsia, and non-ulcer dyspepsia.

[0093] In some embodiments, the human subject has an autoimmune disease, disorder, or condition. In some embodiments, the autoimmune disease, disorder, or condition is autoimmune arthritis, type 1 diabetes, In some embodiments, the human subject is selected from the group consisting of urinary tract infections, multiple sclerosis, and psoriasis. has an allergy. In some embodiments, the allergy is asthma or atopy Including eczema.

[0094] In some embodiments, the human subject has a neurological disease, disorder, or condition. In some embodiments, the neurological disease, disorder, or condition is autism, hyperammonemia, and hepatic encephalopathy.

[0095] In some embodiments, the treatment further comprises administering a second drug or pharmaceutical agent. In some embodiments, the second drug or pharmaceutical agent is a standard of care drug or In some embodiments, the glycan therapeutic agent and a second drug or pharmaceutical agent The therapeutic effect of a pharmaceutical composition containing the agent is additive. The therapeutic effects of a pharmaceutical composition comprising a therapeutic compound and a second drug or pharmaceutical agent are synergistic. is.

[0096] In some embodiments, the composition is administered daily. The composition is administered daily for a predetermined number of days (treatment period). The duration includes from about 1 day to about 30 days. In some embodiments, the treatment duration is from about 1 month to about 30 days. In some embodiments, the subject receives a single treatment period of about 6 months. In some embodiments, the subject is administered the composition for more than one treatment period. .

[0097] In some embodiments, treating microbial incompatibility treats a disease in a human subject. will be done.

[0098] In another aspect, the present invention provides a method for modulating functional pathways of the gastrointestinal microbiota of a human subject. The present invention features a pharmaceutical composition for administering to a subject a subject in need thereof, the composition comprising: The glycan therapeutic agent comprises a mixture of branched glycans, The average branching degree (DB) of the glycans in the combination is at least 0.01 (e.g., at least 0 0.05, or at least 0.1), and ii) at least 50% of the glycans in the formulation % have a degree of polymerization (DP) of at least 3 and less than 30 glycan units, and iii) The ratio of alpha-glycosidic to beta-glycosidic bonds present in the glycans in the combination The ratio is about 1:1 to about 5:1 overall.

[0099] In some embodiments, the functional pathway is an antimicrobial pathway listed in Table 2 by microbiota. It regulates the production of steroids, secondary bile acids, short-chain fatty acids, siderophores, or metabolites. In some embodiments, the antimicrobial agent comprises a bacteriocin or hydrogen peroxide. The short chain fatty acids include formate, butyrate, acetate, propionate, or valerate. In some embodiments, the metabolite is 2-hydroxyisobutyrate, 3-hydroxyisobutyrate, Valerate, 3-methylcrotonylglycine, 3-methylcrotonylglycine, allantoin betaine, formate, mannitol, p-cresol glucuronide, phenylacetyl Glycine, sarcosine, taurine, acetic acid, acetylaldehyde, ascorbic acid, butane Dione, butyric acid, deoxycholic acid, ethylphenyl sulfate, formic acid, indole, isobutyric acid , isovaleric acid, propionic acid, serotonin, succinic acid, succinate, TMAO, tryptophan Contains fan, valeric acid, ursodeoxycholic acid, lactate, lactic acid, or hydrogen peroxide.

[0100] In some embodiments, the functional pathway is an inflammatory or immunoregulatory pathway in a human subject. In some embodiments, the level of inflammatory and immunomodulatory cytokines is modulated. The inhibitors are interleukin-1α (IL-1α), IL-1β, IL-2, IL-4, and IL-1β. -6, IL-8, IL-10, IL-12, IL-13, IL-17A, IL-17F, IL-22, IL-23, tumor necrosis factor (TNF), chemokine (CC motif) ligase and transforming growth factor beta (T GF-β), or interferon gamma (IFN-γ).

[0101] In some embodiments, the functional pathway increases the level of short chain fatty acids in the subject. In some embodiments, an increase in short chain fatty acids may be associated with an increase in regulatory T (Treg) cells by the subject. In some embodiments, the increase in short chain fatty acids induces the production of intestinal or reduces the permeability of plasma endotoxin levels. In some embodiments, an increase in short chain fatty acids In some embodiments, the short chain fatty acid reduces an inflammatory response in a subject. of the families ocaccaceae and / or Lachnospiraceae It is produced by at least one bacterial species.

[0102] In some embodiments, the subject is obese.

[0103] In another aspect, the present invention relates to a method for treating a C. difficile infection in a subject who has previously been administered a drug for the treatment of a C. difficile infection. used to prevent recurrence of Clostridium difficile infection in selected human subjects The present invention features a pharmaceutical composition for treating recurrent glaucoma, the composition comprising a glycan in an amount effective to prevent recurrence. The therapeutic agent comprises: i) a glycan therapeutic agent comprising a mixture of branched glycans, The average branching degree (DB) of the glycans is at least 0.01 (e.g., at least 0.05 or at least 0.1), and ii) at least 50% of the glycans in the formulation are having a degree of polymerization (DP) of at least 3 and less than 30 glycan units, and iii) in the formulation The ratio of alpha-glycosidic to beta-glycosidic bonds present in the glycans of The overall ratio is about 1:1 to about 5:1.

[0104] In some embodiments, a recurrence is one or more symptoms associated with C. difficile infection. In some embodiments, relapse includes regression of first-line or standard of care drug therapy. Occurs during or after the

[0105] In some embodiments, the drug for the treatment of C. difficile infection is an antibiotic. In some embodiments, the antibiotic is vancomycin, metronidazole, and filariasis. In some embodiments, the composition is selected from the group consisting of C. diff. The drug may be administered simultaneously with or after the administration of a drug for the treatment of a bacterial infection.

[0106] In some embodiments, the composition is administered in combination with a second drug or treatment. In some embodiments, the second drug or treatment comprises an antibiotic. In form, the antibiotics are from the group of vancomycin, metronidazole, and fidaxomicin. is selected from.

[0107] In some embodiments, administration of the composition prevents or alleviates C. difficile infection in a subject. resulting in a reduction in the severity of associated symptoms, but not the population of C. difficile in the subject. In some embodiments, administration of the composition results in the prevention of C. difficile in a subject. resulting in a reduction in the severity of symptoms associated with C. difficile infection in subjects It does not change the level of the ile population. [Brief explanation of the drawings]

[0108] [Figure 1] Representative SEC curve from 16 min to 20.5 min for a glu100 sample showing the average molecular weight at both the leading and trailing edges of the curve and the molecular weight at 10% of maximum absorption. [Figure 2] Representative anomeric region of the 1H-13C HSQC spectrum of the glu100 sample, including signal distribution of alpha- and beta-glycosidic linkages. [Figure 3] Representative anomeric regions of 1H-13C HSQC spectra of a) glu100, b) glu50gal50, and c) gal100 samples showing the additive effect of fingerprint peaks. [Figure 4] Representative GC chromatograms of three representative permethylated and hydrolyzed glycans showing the distribution of regiochemistry, as assigned by comparison with known standards. [Figure 5]Representative partial assignment of peaks in the anomeric region of the H-C HSQC spectrum of a glu100 sample, showing the separation between alpha and beta isomers on the H axis, with the alpha isomer downstream (in this case, H > 4.8 ppm) and the beta isomer upstream (in this case, H < 4.8 ppm). Additionally, terminal and internal sugars can be distinguished on the C axis, with the terminal sugar upstream (in this case, C < 94 ppm for alpha and C < 100 ppm for beta) and the internal sugar downstream (in this case, C > 94 ppm for alpha and C > 100 ppm for beta). [Figure 6] A portion of an exemplary catalyst with a polymer backbone and side chains is shown in Figure 6A. A portion of an exemplary catalyst with side chains bearing acidic groups attached to the polymer backbone by a linker and side chains bearing cationic groups attached directly to the polymer backbone is shown in Figure 6B. [Figure 7] The distance between the microbiota extracted from each mouse one day before and five days after administration of glycan or water, as described in Example 10, was calculated. The greater the distance, the greater the observed change in microbial composition. [Figure 8] Shannon diversity index. The pairwise Wilcoxon test was used to calculate the significance of the observed differences, as described in Example 10. [Figure 9] The relative abundance of sequences assigned to the genus Akkermansia in the phylum Verrucomicrobia is shown in Figure 9A, and the relative abundance of sequences assigned to the genus Blautia in the phylum Firmicutes is shown in Figure 9B. [Figure 10] Kaplan-Meier survival curves following C. difficile infection by treatment group in all short-term treatment groups, as described in Example 12. [Figure 11] Body weight change (mean + / - standard error) 10 days after C. difficile infection in all short-term treatment groups as described in Example 12 [Figure 12]Changes in relative abundance of bacteria by genus from immediately before glycan treatment and C. difficile infection (day -1) to immediately after 6 days of glycan treatment and 4 days of vancomycin treatment (day 6), as described in Example 12. Only genera with an average change of 5% in relative abundance are shown. Only one cage in the water treatment group had surviving animals on day 6. [Figure 13] Predicted relative abundance of the secondary bile acid biosynthetic pathway on day 6 immediately after treatment with glycans or vancomycin, as described in Example 12. Open circles represent cages, and filled circles represent the mean + / - standard deviation. Only cages with animals that developed C. difficile infection on day 0 and survived the infection are shown (n = 4 cages on day 0). (*P < 0.05, Wilcoxon rank sum test). [Figure 14] Logarithmic fold change in alpha diversity (measured by the Shannon index) from day -1 immediately before glycan treatment to day 6 after treatment with glycan or vancomycin in infection with C. difficile, as described in Example 12. Points represent the alpha diversity of a single cage, and the line represents the median alpha diversity. [Figure 15] Percent change in body weight of mice compared to day 0 of the study (mean + / - standard error). In all groups, 2.5% DSS was administered from days 0 to 5, as described in Example 13. Acacia fiber, glu100, and man52glu29gal19 were administered from days -7 to 14 in the treatment groups. [Figure 16] Endoscopy scores measuring colonic inflammation on day 14 of the study, as described in Example 13. Horizontal bars represent median endoscopy scores. **P<0.01, *P<0.05; Wilcoxon rank sum test with Bonferroni correction for multiple hypotheses. [Figure 17]Slopes of percent weight change from day 0 to day 41 in mice treated with glu100 (0.3%; FIG. 17A), man52glu29gal19 (1%; FIG. 17B), and water (both plots), as described in Example 14. The slopes for the glu100- and man52glu29gal19-treated groups were significantly different from the slope for water-treated mice (P<0.001; linear mixed-effects model with a significant interaction between study day and weight change; regression lines are shown with representative shading + / - standard error of the slope). Percent weight change for individual animals is plotted (triangles or circles). [Figure 18] Blood glucose levels on day 39 in mice fed a high-fat diet, a low-fat diet, or a high-fat diet with treatment with glu100 (0.3%) or man52glu29gal19 (1%), as described in Example 14. The upper and lower hinges in the box plots correspond to the first and third quartiles, and the upper and lower whiskers span the maximum and minimum values ​​within 1.5 times the interquartile range, or the distance between the first and third quartiles. Mice were gavaged with 2 g / kg (at a dose rate of 5 mL / kg) glucose in water, and blood glucose levels were assessed 2 hours after administration. The units on the y-axis are glucose (mg / dL). [Figure 19] Epididymal fat pad weights on day 41 as a percentage of total body weight in mice fed a high-fat diet, mice fed a low-fat diet, and mice fed a high-fat diet with treatment with man52glu29gal19 (1%), fos (0.3%, 1%), and glu100 (0.3%), as described in Example 14. DETAILED DESCRIPTION OF THE INVENTION

[0109] The gastrointestinal microbiota in humans is generally stable when the host is in good health. The gastrointestinal microbiota ecosystem is influenced by host age, pathogen infection, stress, diet, and medications. Depending on the disease, including the medical treatment, a state of dysbiosis may occur. Glycan therapeutic agents and pharmaceutical compositions thereof found to be effective in treating inflammatory diseases (and medical food or dietary supplements thereof) preparations, and related methods The formulations of the glycan therapeutic agents and pharmaceutical compositions described herein surprisingly inhibit enterotoxins. It has therapeutic effects on many diseases, disorders, or pathological conditions that may be associated with the underlying disease. Without wishing to be bound by any particularity, the glycan therapeutic agents and pharmaceutical compositions described herein The preparation is designed to produce a desired physiological effect, such as improving health in the host. It is thought to act by modulating the microbiota in the gastrointestinal (GI) tract of the human host. Glycan therapeutics are compounds that bind to certain microbial constituents, which benefit the well-being and health of the host. selectively digested by the microorganisms, thereby inhibiting the activity (e.g., Glycan therapeutic agents can cause specific changes in the gastrointestinal tract, both in the gastrointestinal tract and in the gastrointestinal tract (e.g., function). For example, to enhance or restore the growth of beneficial bacteria and / or to combat pathogenic microorganisms or diseases. Compatible with the indigenous or acquired microbiota, suppressing the growth of microorganisms associated with the disease or condition , may act as a finely tuned regulator.

[0110] The glycan therapeutic agents described herein alter the abundance of important taxa of the gastrointestinal microbiota. The glycan therapeutic agent may mediate the catalysis (and associated functional or genomic changes) of the present composition or Methods are provided that can alter the function of the gastrointestinal microbiota. These changes can be induced, regulated, increased, decreased, or stimulated by a number of important microbiota properties. In some embodiments, modulation can be achieved by: i) responding to perturbations (or microbial incompatibility) ii) the resilience of ecosystems; iii) the diversity of microbiota; iv) the production of metabolic products; and and pathogen colonization, and v) altered metabolic, immune, and other functions of the host. effects, or any combination thereof.

[0111] Treatment and / or management of dysbiosis and diseases potentially associated with dysbiosis of the gastrointestinal microflora or prevention, and / or alleviation of symptoms in a subject in need thereof; and methods, compositions, and kits useful for improving the overall health of a host are described herein. Dosage forms for glycan therapeutic agents are further described herein. In some embodiments, the dosage form is specific for a specific region of the gastrointestinal tract, e.g., the small intestine or large intestine. Pharmaceutical compositions, medications, and the like, including formulations of glycan therapeutic agents, are formulated for targeted delivery. Administration of calfoods, or nutritional supplements, can improve gut dysbiosis, e.g., beneficial bacterial flora. In some embodiments, the present invention may treat or prevent conditions in which the microbiota is perturbed and exhibits dysbiosis. In this case, the disturbances can be alleviated by the use of the glycan therapeutic agents described herein, This results in improved physiological growth and function of both the beneficial microflora and the host. Such treatment or prevention may occur directly, for example, by administering a glycoprotein or a peptide as described herein. Cancer treatments involve the replacement of pathogenic microorganisms with non-pathogenic microorganisms, or the replacement of beneficial or commensal microorganisms. or it may occur indirectly, for example, by increasing the proliferation of The glycan therapeutic agents used may affect the metabolism or other functions of the microbiota and therefore, e.g. For example, the host physiology may be modulated by the effects of one or more downstream metabolites. Administration of the glycan therapeutic agent can improve the overall health of the host and can also improve the overall health of one or more members of the microbial community. maintain a healthy equilibrium in selected ecological niches such as the gastrointestinal tract by influencing can be recovered.

[0112] Generation of Glycan Therapeutic Agents Preparations containing multiple glycans, such as mixtures of oligosaccharides and polysaccharides, can be purified using non-enzymatic catalysts, e.g. No. 8,466,242, which is incorporated herein by reference in its entirety. ) or by other suitable methods. The methods for preparing the polymers and solid supported catalysts described herein can be carried out using WO2 No. 014 / 031956, which is incorporated herein by reference. For example, glycans produced by using a catalyst are different from those produced by an enzymatic reaction. These glycans may be structurally much more diverse than those found in the glycans described above.

[0113] Producing preparations of glycans (e.g., oligosaccharide or polysaccharide compounds) described herein The method also includes the steps of: a) cleaving one or more monosaccharide or disaccharide glycan units or combinations thereof; b) providing a combination of polymerized species having a desired average degree of polymerization. The monosaccharide or disaccharide is reacted with the polymeric catalyst and suitable contacting the polymer with a solvent (e.g., water or a non-aqueous solvent, etc.); and c) polymerization. by isolating and / or recovering at least a portion of the glycan preparation. will be done.

[0114] In some embodiments, the preparation of glycans (e.g., oligosaccharides or polysaccharides) may In some embodiments, the preparation of glycans (e.g., oligosaccharides or polysaccharides) For example, glycan therapeutic agents may be composed of different oligosaccharide species (e.g., For example, different degrees of polymerization and branching and different alpha versus beta glycosidic linkages. In some embodiments, the glycan therapeutic agent comprises a mixture of multiple different They contain various species (e.g., oligosaccharides) in various ratios of 1 × 10 3 , 1×10 4 , 1×10 5 , 1×10 6 , 1×10 7 , 1×10 8 , 1×10 9 , 1×10 10 , 1×10 11 , 1×10 12 , 1×10 13 , 1×10 14 , or more species. The average properties of the therapeutic agent, e.g., degree of polymerization, degree of branching, alpha-glycosidic bond and vein The ratio of tert-glycosidic bonds and the like are described herein.

[0115] In certain embodiments, the starting material (including glycan units) has one or more glycan units. under conditions that promote the formation of the above glycosidic bonds, thereby producing a glycan preparation. In some embodiments, the glycan units are monosaccharides and are contacted with a polymeric catalyst. Suitable polymer catalysts are those which combine acidic monomers and hydroxy groups to form a polymer backbone. ionic monomers, each acidic monomer having at least one Bronsted-Lo wry acid, and each ionic monomer independently contains at least one nitrogen-containing cation In some embodiments, each of the acid groups of the polymer catalyst has a phosphorus-containing cationic group. The monomer may have one Bronsted-Lowry acid, and optionally, this Bronsted In some embodiments, each ion of the polymer catalyst is The cationic monomer has one nitrogen-containing cationic group or one phosphorus-containing cationic group. In some embodiments, at least one ionic monomer of the polymeric catalyst comprises two nitrogen-containing The following schematic diagrams are provided outlining common functional groups: 6a and 6b are shown.

[0116] In certain embodiments, polymer-catalyzed glycans (e.g., oligosaccharides or polysaccharides) are synthesized using a polymer catalyst. The synthesis of sugars is carried out in an aqueous environment. One suitable aqueous solvent is water, which can be obtained from a variety of sources. Generally, water sources with low concentrations of ionic species are preferred, and therefore Such ionic species can reduce the effectiveness of the polymer catalyst. In embodiments, the water contains less than 10% ionic species (e.g., sodium, phosphorus, ammonium, magnesium salts).

[0117] Generally, the polymer catalyst and glycan units are simultaneously or sequentially introduced into the inner chamber of the reactor. The synthesis of glycans (e.g., oligosaccharides or polysaccharides) is carried out in a batch process. For example, in one embodiment, glycan synthesis can be carried out in a batch or continuous process. In a batch process, the contents of the reactor are continuously mixed or blended. In some cases, all or a substantial amount of the product of the reaction is removed (e.g., isolated and / or In one variation, glycan synthesis is carried out in a batch process, The contents of the reactor are initially mixed or blended, but no further physical mixing occurs. In this variation, glycan synthesis is carried out in a batch process, once the contents are further mixed. or if the reactor contents are mixed periodically (e.g., once per hour), or more), and all or a substantial amount of the reactants are removed after a period of time ( For example, isolated and / or recovered).

[0118] In other embodiments, the synthesis of glycans (e.g., oligosaccharides or polysaccharides) is carried out with an average It may be carried out in a continuous process, with continuous flow through the reactor but no explicit mixing. After the introduction of the polymer catalyst and glycan units into the reactor, the contents of the reactor are continuously or Periodically mix or blend to remove less than all of the reactants (e.g., In some variations, glycan synthesis is a continuous process. In this case, the mixture containing the catalyst and the glycan units is not vigorously mixed. , mixing of catalyst and glycan units, redistribution of polymer catalyst sedimentation by gravity, or material This can occur as a result of inert mixing that occurs when the mixture flows through a continuous reactor.

[0119] In some embodiments of the method, the starting materials for the polymerization reaction include one or more monosaccharides, one or more glycan units selected from one or more disaccharides, or a combination thereof In some embodiments of the method, the starting materials for the polymerization reaction are furanose sugars and pyridine. The one or more glycan units are selected from the group consisting of lanose sugars. In this study, the starting materials for the polymerization reaction were tetroses, pentoses, hexoses, or heptoses. In some embodiments of the method, the one or more glycan units are selected from the group consisting of glycans, glycans, and glycans. All starting materials for the polymerization reaction may optionally be in the L- or D-configuration, as desired. either in alpha or beta structure (in the dimer), and / or deoxy - forms of glucose, galactose, arabinose, and the like, as well as any combination thereof saccharides selected from the group consisting of sucrose, mannose, fructose, xylose, fucose, and rhamnose; In some embodiments, the glycan unit is one or more glycan units. one or more of the following groups: pyruvyl, sulfate half ester, phosphate ester, or pyruvyl cyclic acetal group substituted or derivatized with or otherwise, e.g., one derivatized with one or more hydroxyl groups.

[0120] The glycan units used in the methods described herein may contain one or more sugars. In some embodiments, the one or more sugars are monosaccharides, disaccharides, and / or trisaccharides. In some embodiments, the one or more sugars are selected from any mixture of these. , e.g., one or more C5 or C6 monosaccharides. In some embodiments, one or more In other embodiments, one or more sugars are C5 monosaccharides. In other embodiments, one or more sugars are C6 monosaccharides.

[0121] In some embodiments of the method, the starting material for the polymerization reaction is a hybrid glycan. amino sugars, deoxy sugars, imino sugars, sugar acids, short-chain fatty acids, and sugar alcohols to produce The glycan units are one or more glycan units selected from the group consisting of:

[0122] In some embodiments, the starting materials for the polymerization reaction are glycolaldehyde, glycol Ceraldehyde, dihydroxyacetone, erythrose, threose, erythrulose ( erythulose), arabinose, lyxose, ribose, xylose, ribromo Sugar, xylulose, allose, altrose, galactose, glucose, glucose, isopropyl alcohol Dose, mannose, talose, fructose, psicose, sorbose, tagatose, Fucose, fuculose, rhamnose, mannoheptulose, sedoheptulose, neuraminic acid N-acetylneuraminic acid, N-acetylgalactosamine, N-acetylglucosamine amine, fructosamine, galactosamine, glucosamine, sorbitol, glycerol, Erythritol, threitol, arabitol, xylitol, mannitol, sorbitol Examples of suitable saccharides include, but are not limited to, lactic acid, galactitol, fucitol, and lactic acid. One or more glycan units selected from monosaccharides and other carbohydrates.

[0123] In some embodiments, the starting material for the polymerization reaction is acarviosin, N-acetyl Lulactosamine, allolactose, cellobiose, chitobiose, galactose-alf α-1,3-galactose, gentiobiose, isomalt, isomaltose, isomalt Lactulose, kojibiose, lactitol, lactobionic acid, lactose, lactulose , laminaribiose, maltitol, maltose, mannobiose, melibiose, mel Biulose, neohesperidose, nigerose, robinose, rutinose, sambubiose Sugar, sophorose, sucralose, sucrose, sucrose acetate isobutyrate, octadecanoate Acetylsucrose, trehalose, turanose, vicianose, and xylobiose one or more selected from disaccharides and other carbohydrates, including but not limited to: is a glycan unit.

[0124] In some embodiments, the starting materials for the polymerization reaction are amino sugars, deoxy sugars, imino sugars, one or more glycan units selected from monosaccharides, sugar acids, short chain fatty acids, and sugar alcohols do.

[0125] In some embodiments, the glycan units are, for example, hydrochlorides. hlorate, hydroiodate, hydrobromide, phosphorus Acid salts, sulfates, methanesulfates, acetates, formates, tartrates, malates, and citrates Salt, succinate, lactate, gluconate, pyruvate, fumarate, propionate, Salt forms such as aspartate, glutamate, benzoate, and ascorbate (e.g., , and pharmaceutically acceptable salt forms).

[0126] Suitable glycan units include amino sugars, such as acarbose, N-acetylemannoside, N-acetylmuramic acid, N-acetylneuraminic acid, N-acetylethanoic acid Acetylethalosaminuronic acid, Arabinopyra Nosyl-N-methyl-N-nitrosourea, D-fructose-L-histidine, N-glycol Cholylneuraminic acid, ketosamine, kidamycin, mannosamine, 1B-methylseleno- N-acetyl-D-galactosamine, muramic acid, muramyl dipeptide, phosphoribosyl Sialylamine, PUGNAc, Sialyl-Lewis A, Sialyl-Lewis X, Bali Damycin, voglibose, N-acetylgalactosamine, N-acetylglucosamine, Aspartylglucosamine, bacillithiol, daunosamine, desosamine, fructosamine Examples include galactosamine, glucosamine, meglumine, and perosamine.

[0127] Suitable glycan units include deoxy sugars, such as 1-5-ahydroglucitol, Dinose, colitose, 2-deoxy-D-glucose, 3-deoxyglucasone, deoxyglucosone Xylibose, dideoxynucleotides, digitalose, fluooxyglucose, Examples include lumentose and sulfoquinovose.

[0128] Suitable glycan units include imino sugars, e.g., castanospermine, 1-deoxydiisopropylamino These include limumab, iminosugars, miglitol, miglustat, and swainsonine. do.

[0129] Suitable glycan units include sugar acids, such as N-acetylneuraminic acid, N-acetyltauric acid, Acetyltalosamnuronic acid, Aldal Acid, aldonic acid, 3-deoxy-D-manno-oct-2-urosonic acid, glucuronic acid Acid, Glucosamineuronic Acid, Glyceric Acid, N-Glycolylneuraminic Acid, Iduronic Acid Acid, Isosaccharinic Acid, Pangamic Acid, Sialic Acid, Threonic Acid, Uronic Acid, Uronic Acid octanoic acid, xylonic acid, gluconic acid, ascorbic acid, ketodeoxyoctursonic acid, Galacturonic acid, galactosaminuronic acid, mannuronic acid, mannosaminuronic acid, tartaric acid, Mucous acid, sugar acid, lactic acid, oxalic acid, succinic acid, hexanoic acid, fumaric acid, maleic acid, butyric acid, Citric acid, glucosamine acid, malic acid, succinamic acid, sebacic acid, and capric acid etc. are included.

[0130] Suitable glycan units are short chain fatty acids, such as formic acid, acetic acid, propionic acid, butyric acid, Includes isobutyric acid, valeric acid, and isovaleric acid.

[0131] Suitable glycan units are sugar alcohols, e.g., methanol, ethylene glycol, glycol Glycerol, erythritol, threitol, arabitol, ribitol, xylitol , mannitol, sorbitol, galactitol, iditol, volemitol, fusitol maltotriitol, inositol, maltotetriitol, and polyglycitol Includes:

[0132] The glycan units (e.g., sugars) used in the methods described herein are optionally commercially available. It can be obtained from commercially known sources or according to any method known in the art. can be generated.

[0133] Reaction conditions In some embodiments, the glycan unit and the catalyst (e.g., a polymeric catalyst or a solid support) The catalyst is maintained for at least 1 hour, at least 2 hours, at least 3 hours, or at least 4 hours. at least 6 hours, at least 8 hours, at least 16 hours, at least 24 hours, At least 36 hours, or at least 48 hours, or 1 to 24 hours, or 2 to 12 hours , 3 to 6 hours, 1 to 96 hours, 12 to 72 hours, or 12 to 48 hours. can.

[0134] In some embodiments, one or more of the oocytes produced according to the methods described herein are The degree of polymerization of the oligosaccharides can be adjusted over the reaction time. For example, in some embodiments, one or more The degree of polymerization of the oligosaccharides is increased by increasing the reaction time, but in other embodiments In the method, the degree of polymerization of one or more oligosaccharides is decreased by decreasing the reaction time.

[0135] Reaction temperature In some embodiments, the reaction temperature is maintained in the range of about 25°C to about 150°C. In certain embodiments, the temperature is from about 30°C to about 125°C, from about 60°C to about 120°C, or from about 80℃ to about 115℃, about 90℃ to about 110℃, about 95℃ to about 105℃, or about 100℃ ~110℃.

[0136] Amount of glycan units Glycan units used in the methods described herein relative to the amount of solvent used The amount of glycan units used can affect the reaction rate and yield. In certain embodiments, the dry solids content is the percentage of dry solids on a dry weight basis. In some embodiments, the dry solids content of the glycan units refers to the total solids of the slurry. The amount may be from about 5% to about 95% by weight, from about 10% to about 80% by weight, from about 15% to about 75% by weight, or from about 15% to about 75% by weight. % by weight, or about 15% to about 50% by weight.

[0137] Amount of catalyst The amount of catalyst used in the methods described herein can vary, for example, depending on the amount of glycan units. These include the selection of the type of glycan, the concentration of the glycan units, and the reaction conditions (e.g., temperature, time, and pH). In some embodiments, the catalytic glycan unit The weight ratio to Approx. 0.05g / g ~ approx. 1.0g / g, approx. 0.05g / g ~ approx. 0.5g / g, approx. 0.05g / g to about 0.2 g / g, or about 0.1 g / g to about 0.2 g / g.

[0138] solvent In certain embodiments, the catalytic process is carried out in an aqueous environment. A suitable aqueous solvent is water, which can be obtained from a variety of sources. Generally, low concentrations of ionic species are present in the catalyst. It is recommended to avoid water sources containing such ionic species (e.g., sodium, phosphorus, In some cases, the aqueous solvent is water. In embodiments, the water has a viscosity of at least 0.1 megaohm-centimeters, at least 1 megaohm-centimeters, Ohm-centimeters, at least 2 megohms-centimeters, at least 5 megohms Resistivity of ohm-centimeters, or at least 10 megohm-centimeters Has.

[0139] moisture content Furthermore, as the dehydration reaction of the present method progresses, water is transferred to each of the caps of one or more glycan units. In certain embodiments, the methods described herein comprise the reaction The amount of water present in the mixture and / or the ratio of water to monomer or catalyst over a period of time In some embodiments, the method may further comprise monitoring the ratio of (e.g., at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 8 You can remove either 0%, 90%, 95%, 97%, 99%, or 100% of and removing at least some of the water produced in the reaction mixture (e.g., by vacuum filtration). However, the amount of water relative to the monomers used may vary. It should be understood that this may be adjusted based on the reaction conditions and the particular catalyst.

[0140] Any method known in the art may be used, for example, vacuum filtration, vacuum distillation, heating, and and / or may be used to remove water in the reaction mixture by evaporation. In an embodiment, the method includes including water in the reaction mixture.

[0141] In some embodiments, a glycan unit having an acidic and ionic moiety and a catalyst are mixed, forming a reaction mixture, and water being produced in the reaction mixture; and removing at least a portion of the oligosaccharide composition. , as provided herein. In some variations, at least a portion of the water is less than 99% by weight. , less than 90% by weight, less than 80% by weight, less than 70% by weight, less than 60% by weight, less than 50% by weight , less than 40% by weight, less than 30% by weight, less than 20% by weight, less than 10% by weight, less than 5% by weight, or removed to maintain a water content in the reaction mixture of less than 1% by weight.

[0142] In some embodiments, one or more of the oocytes produced according to the methods described herein are The degree of polymerization of the oligosaccharides can be controlled by adjusting or controlling the concentration of water present in the reaction mixture. For example, in some embodiments, the degree of polymerization of one or more oligosaccharides can be adjusted by adjusting the water concentration. In other embodiments, the degree of polymerization of one or more oligosaccharides is increased by decreasing the degree of polymerization. The degree of oxidation is decreased by increasing the water concentration. The water content is adjusted during the reaction to control the degree of polymerization of the oligosaccharide or oligosaccharides produced. .

[0143] In one example, a round-bottom flask equipped with an overhead stirrer and a jacketed short-path condenser was used. The sco- Page 11 11 Page 11 ... 50% (1-10%, 1-20%, 1-30%, 1-40%, 1-60%, 1-70%) One or more of the catalysts described herein may be added. 0.1 to 4 equivalents) can be added to the dry mixture. The slurry is sized to match the contours of the selected round-bottom flask as closely as possible. Use a sized spatula and mix at a low speed (e.g., 10-100 rpm, 50-200 rpm). The mixture can be mixed at a speed of 100-200 rpm. The mixture can be mixed under a vacuum pressure of 10-1000 mbar. heated to 70-180℃ (70-160℃, 75-165℃, 80-160℃) The reaction may be stirred for 30 minutes to 6 hours, and water may be constantly removed from the reaction. The reaction progress can be monitored by HPLC. The solid mass obtained from the reaction is approximately 50%. Sufficient volume of water to make a solution of Brix (grams of sugar per 100g of solution) Once dissolution is complete, the solid catalyst may be removed by filtration and the oleophore may be removed. The copolymer solution can be concentrated, for example, by rotary evaporation, to about 50-75 Brix. Optionally, organic solvents can be used, and water-immiscible solvents can be removed by biphasic extraction, and water-miscible solvents can be removed by biphasic extraction. The miscible solvent can be removed, for example, by rotary evaporation simultaneously with the concentration step.

[0144] Further processing steps Optionally, the preparation may undergo further processing steps. Further processing steps may include, for example, For example, the purification step may include a purification step such as separation, dilution, concentration, filtration, desalting, etc. or ion exchange, chromatographic separation, or decolorization, or any combination thereof. It may include

[0145] bleaching In some embodiments, the methods described herein further comprise a bleaching step. The oligosaccharide or oligosaccharides produced can be separated by, for example, adsorbents, activated carbon, chromatography (e.g. by purification (e.g., using ion exchange resins), hydrogenation, and / or filtration (e.g., microfiltration). The decolorization step may be carried out using any method known in the art, including treatment.

[0146] In certain embodiments, the one or more oligosaccharides produced are subjected to a specific temperature, a specific concentration, and a specific and / or contact with a color-absorbing material for a specific period of time. The mass of color-absorbing material that is contacted with one or more oligosaccharides is determined by the mass of the one or more oligosaccharides. less than 50% by mass of one or more oligosaccharides, less than 35% by mass of one or more oligosaccharides Less than 20%, less than 10% by mass of one or more oligosaccharides, 5% by mass of one or more oligosaccharides less than 2% by mass of one or more oligosaccharides, or less than 1% by mass of one or more oligosaccharides It is full.

[0147] In some embodiments, one or more oligosaccharides are contacted with a color-absorbing substance. In certain embodiments, the one or more oligosaccharides are incubated for less than 10 hours, less than 5 hours, or less than 1 hour. In certain embodiments, one or more of oligosaccharides is contacted with the color-absorbing substance for 1 hour.

[0148] In certain embodiments, the one or more oligosaccharides are heated at temperatures between 20 and 100 degrees Celsius, between 30 and 80 degrees Celsius, Do not expose to color-absorbing materials at temperatures of 0°C, 40-80°C, or 40-65°C. In certain embodiments, one or more oligosaccharides are combined with a material that absorbs color at a temperature of 50 degrees Celsius. and bring it into contact with.

[0149] In one particular embodiment, the color-absorbing material is activated carbon. The absorbing material is powdered activated carbon. In another embodiment, the color absorbing material is ion-exchange In one embodiment, the color-absorbing material is a strongly basic cation exchange resin in chloride form. In another embodiment, the color-absorbing material is cross-linked polystyrene. In yet another embodiment, the color-absorbing material is a cross-linked polyacrylate. In an embodiment, the color-absorbing material is Amberlite FPA91, Amberlite e FPA98, Dowex 22, Dowex Marathon MSA, or D It is owex Optipore SD-2.

[0150] Ion exchange / demineralization In some embodiments, the one or more oligosaccharides produced are treated with salts, minerals, and / or In certain embodiments, the one or more ionic species are contacted with a material to remove other ionic species. The oligosaccharides are run through an anion / cation exchange column pair. The column contains a weakly basic exchange resin in the hydroxide form, and the cation exchange column contains a proton exchange resin. It contains a strongly acidic exchange resin in a hydrated form.

[0151] Separation and concentration In some embodiments, the methods described herein include one or more oligonucleotides produced. In certain variations, isolating one or more oligosaccharides further comprises: For example, techniques including centrifugation, filtration (e.g., vacuum filtration, membrane filtration), and gravity settling. The catalyst may be prepared from at least a portion of one or more oligosaccharides using any method known in the art. In some embodiments, the method further comprises separating at least a portion of the solvent. Isolation of sugars can be achieved by, for example, filtration (e.g., membrane filtration), chromatography (e.g., chromatographies), or the like. fractionation by lithography), differential solubility, and centrifugation (e.g., differential centrifugation). and removing at least one of any unreacted sugars using any method known in the art, including and separating at least a portion of one or more oligosaccharides from the portion.

[0152] In some embodiments, the methods described herein further comprise a concentration step. For example, in some embodiments, isolated oligosaccharides are obtained by evaporation (e.g., vacuum evaporation). In another embodiment, the isolated oligosaccharides are and then undergo a spray drying step to produce an oligosaccharide powder. The isolated oligosaccharides undergo both evaporation and spray drying steps.

[0153] moisture content Furthermore, as the dehydration reaction of the present method progresses, water is introduced into each coupling of one or more sugars. In certain embodiments, the methods described herein further comprise providing in the reaction mixture Monitor the amount of water present and / or the ratio of water to sugar or catalyst over a period of time. In some embodiments, the method may further include (e.g., at least All are approximately 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 9 By eliminating either 5%, 97%, 99%, or 100% removing at least a portion of the water produced in the reaction mixture (e.g., by vacuum filtration); However, the amount of water relative to the sugar will vary depending on the reaction conditions and the particular catalyst used. It should be understood that the amount of HCl may be adjusted based on the medium.

[0154] Any method known in the art may be used, for example, vacuum filtration, vacuum distillation, heating, and and / or may be used to remove water in the reaction mixture by evaporation. In an embodiment, the method includes including water in the reaction mixture.

[0155] In some embodiments, a glycan unit having an acidic and ionic moiety and a catalyst are mixed, forming a reaction mixture, and water being produced in the reaction mixture; and removing at least a portion of the oligosaccharide composition. , as provided herein. In some variations, at least a portion of the water is less than 99% by weight. , less than 90% by weight, less than 80% by weight, less than 70% by weight, less than 60% by weight, less than 50% by weight , less than 40% by weight, less than 30% by weight, less than 20% by weight, less than 10% by weight, less than 5% by weight, or removed to maintain a water content in the reaction mixture of less than 1% by weight.

[0156] In some embodiments, one or more of the oocytes produced according to the methods described herein are The degree of polymerization of the oligosaccharides can be controlled by adjusting or controlling the concentration of water present in the reaction mixture. For example, in some embodiments, the degree of polymerization of one or more oligosaccharides can be adjusted by adjusting the water concentration. In other embodiments, the degree of polymerization of one or more oligosaccharides is increased by decreasing the degree of polymerization. The degree of oxidation is decreased by increasing the water concentration. The water content is adjusted during the reaction to control the degree of polymerization of the oligosaccharide or oligosaccharides produced. .

[0157] Fractionation In some embodiments, the methods described herein further comprise a fractionation step. The prepared and purified oligosaccharides or polysaccharides are then purified, for example, by high performance liquid chromatography. adsorption / desorption (e.g., low-pressure activated carbon chromatography), or filtration (e.g., Molecular weight determination using any method known in the art, including ultrafiltration or diafiltration. In certain embodiments, the glycans prepared and purified can be separated by 0%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, or or >98% were short (DP about 1-2), moderate (DP about 3-10), or long (DP about 11–18) or very long (DP > 18) species are separated into pools representing these species.

[0158] In certain embodiments, the prepared glycans are adsorbed onto a carbonaceous material, followed by: Mixtures of organic solvents in water at concentrations of 1%, 5%, 10%, 20%, 50%, or 100% The material is fractionated by washing with HCl, thereby removing the fractions. In one embodiment, the adsorbent material is activated carbon. In another embodiment, the adsorbent material is a mixture of activated carbon and a volumetric or or by weight, 5%, 10%, 20%, 30%, 40%, or 50% silicon It is a mixture of bulking agents such as algal earth or Celite 545.

[0159] In a further embodiment, the prepared glycans are analyzed using a high performance liquid chromatography system. In certain variations, the glycans prepared are separated by passing them through Ion affinity chromatography, hydrophilic interaction chromatography, including gel permeation and gel filtration The proteins are separated by chromatographic or size exclusion chromatography.

[0160] In other embodiments, low molecular weight materials are removed by filtration methods. In this case, low molecular weight substances are removed by dialysis, ultrafiltration, diafiltration, or tangential flow filtration. In certain embodiments, the filtration is performed in a static dialysis tubing device. In an embodiment, the filtration is performed in a dynamic flow filtration system. Filtration is carried out in a centrifugal force driven filtration centrifuge.

[0161] Characteristics of Glycan Therapeutic Preparations The glycan therapeutic agents described herein may include oligosaccharides and / or polysaccharides. In some embodiments, the glycan therapeutic agent is a homo-oligosaccharide or polysaccharide (or homoglycan). All monosaccharides in a polysaccharide are of the same type. Therapeutic agents consist of monosaccharides that are linked together via single or multiple glycosidic bond types. It may include.

[0162] In some embodiments, the glycan therapeutic agent is a hetero-oligosaccharide or polysaccharide (or hetero- Glycans containing heteropolysaccharides (heteroglycans) contain more than one type of monosaccharide. The agents are of different types that are linked together via single or multiple glycosidic bond types. It may contain monosaccharides.

[0163] Monosaccharides include disaccharides (such as sucrose and lactose) and polysaccharides (such as cellulose and dendritic Glycan therapeutic agents are composed of a single type of monosaccharide (homopolymer or homoglycans) or mixtures (heteropolymers or heteroglycans) Oligosaccharides contain a small number of glycan units (typically 2-9). It is a monosaccharide polymer (in this case, monosaccharides).

[0164] For example, fructooligosaccharides (FOS), found in many vegetables, contain fructose. It consists of short chains of molecules, some of which terminate in glucose molecules. Galactooligosaccharides (GOS) consist of short chains of galactose molecules. , which can only be partially digested by humans. Oligosaccharides are mainly derived from starch or inulin. from the breakdown of natural polymers such as cellulose, from direct extraction from natural materials such as soybeans, or from chemical or is produced by enzymatic synthesis.

[0165] Polysaccharides are long chains of glycan units that are linked together by bonds, such as glycosidic bonds. Polysaccharides are polymeric carbohydrate molecules consisting of 10 or more glycan units. (In this case, monosaccharides). Naturally occurring polysaccharides are C x (H2O) y may have the general formula: In the formula, x is usually a large number, for example, 10 to 2500. Hydrolysis can be performed to produce constituent monosaccharides or monosaccharides suitable for producing the glycans described herein. Glycan units, e.g., monosaccharides, can be used to make oligosaccharides. different forms of, for example, conformers, cyclic forms, acyclic forms, stereoisomers, tautomers, It can exist in anomer and isomeric forms.

[0166] In some embodiments, the glycan therapeutic agent is polydisperse, exhibiting a range of degrees of polymerization. (e.g., oligosaccharides or polysaccharides) are produced. Optionally, the preparation can be fractionated, e.g., For example, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98% %, or over 98% of the cases were short (DP approximately 1-2), moderate (DP approximately 3-10), or long (D P ≈11–18) or very long (DP >≈18) species.

[0167] In one embodiment, at least 85%, 90%, or less have a DP of about 3-10. A polydisperse fractionated glycan therapeutic preparation containing 95% intermediate length species is provided. In one embodiment, at least 85%, 90%, or 100% of the cellulose has a DP of about 11-18. provides a polydisperse, fractionated glycan therapeutic preparation containing at least 95% long species; In one embodiment, at least 85%, 90%, or 100% of the cellulose has a DP of about 18-30. A polydisperse fractionated glycan therapeutic preparation containing at least 95% ultralong species is presented. In some embodiments, the medium, long, and extra long fractionated formulations comprise: 0.8:1 to 5:1 or 1:1 to 4:1 alpha-glycosidic bond to beta-glycosidic bond In some embodiments, the fractionated preparation comprises a ratio of about 0.01 to about 1.001 hydroxyl groups. 0.2 or have an average branching degree of about 0.05 to 0.1.

[0168] In some embodiments, the disclosed polymers are used to control the molecular weight distribution of glycans. For example, a large proportion of glycan therapeutic agents, e.g., about 5 5%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or approximately 9 7% are 2-25, 3-25, 4-25, 5-25, 6-25, 7-25, 8-25, 9 ~25, 10~25, 2~30, 3~30, 4~30, 5~30, 6~30, 7~30, having a DP of 8-30, 9-30, or 10-30.

[0169] In one embodiment, the glycan therapeutic agent has a weight ratio of at least 3 and less than 30 glycan units. It has a degree of consistency (DP).

[0170] In some embodiments, about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or approximately 97% are at least 5 and less than 30 In some embodiments, the glycan therapeutic agent has a DP of about 55 glycan units. %, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or approximately 97 % have a DP of at least 8 and less than 30 glycan units. ,Approximately 55%, 60%, 65%, 70%, 75%, 80%, 85% of glycan therapeutic preparations, 90%, 95%, or about 97% have a DP of at least 10 and less than 30 glycan units. In some embodiments, the glycan therapeutic agent comprises about 55%, 60%, 65%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240%, 250%, 260%, 270%, 0%, 75%, 80%, 85%, 90%, 95%, or approximately 97% are 3, 4, 5, 6, 7, 8-10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 Glica In some embodiments, about 55%, 60%, or 70% of the glycan therapeutic agent has a DP of 1000 or more. %, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or approximately 97% is 1 0, 11, 12, 13, 14, 15, 16, 17, 18, 19-20, 21, 22, 23 , 24, 25, 26, 27, 28, 29, 30 glycan units. In some embodiments, the glycan therapeutic agent comprises about 55%, 60%, 65%, 70%, 75%, 80%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240%, 250%, 26 0%, 85%, 90%, 95%, or approximately 97% are 3, 4, 5, 6, 7, 8, 9, 10 DP of ~20, 21, 22, 23, 24, 25, 26, 27, 28 glycan units do.

[0171] In some embodiments, the glycan therapeutic agent comprises one or more glycan units (e.g., glycoproteins). ) with a polymer catalyst (e.g., by combining one or more glycan units (e.g., sugars) with the catalyst). 2, 3, 4, 8, 12, 24, or 48 hours after mixing) DP2 = 0% to 40 %, e.g., less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, or 2% or 10% to 30% or 15% to 25%, DP3=0% to 20%, e.g., Less than 15%, less than 10%, less than 5%; or 5% to 15%, and DP4+=more than 15%, 2 More than 0%, more than 30%, more than 40%, more than 50%, or 15% to 75%, 20% to 40%, or The degree of polymerization (DP) distribution is 25% to 35%.

[0172] Conversion for one or more glycan units (e.g., sugars) in the methods described herein Yields can be determined by methods known in the art, including, for example, high performance liquid chromatography (HPLC). In some embodiments, one or more After mixing the glycan units with the catalyst (e.g., mixing one or more glycan units with the catalyst), Glycans with a DP >1 after 2, 3, 4, 8, 12, 24, or 48 hours (after 2, 3, 4, 8, 12, 24, or 48 hours) of treatment The conversion yield for the formulation is greater than about 50% (e.g., about 55%, 60%, 65%, (greater than 70%, 75%, 80%, 85%, 90%, 95%, or 98%). In some embodiments, after mixing one or more glycan units with a catalyst (e.g., one or more glycan units), 2, 3, 4, 8, 12, 24, or 48 hours after mixing the glycan units with the catalyst) The conversion yield for glycan therapeutic agents with a DP of greater than 30% (e.g., 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, greater than 85%, 90%, 95%, or 98%).

[0173] In one embodiment, about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or about 97% have a DP of at least 2. In embodiments, about 55%, 60%, 65%, 70%, 75%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240%, 250%, 260%, 270%, 280%, %, 85%, 90%, 95%, or about 97% have a DP of at least 3.

[0174] In some embodiments, at least 5%, 10%, 15%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 3 0%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 7 0%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, 99.8% , or at least 99.9%, or even 100%, at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or at least 12 glycan units, 75, 70, 6 5, 60, 55, 50, 45, 40, 35, 30, 25, 20, 19, 18, 17, 16 or a degree of polymerization (DP) of less than 15 glycan units. will be done.

[0175] In some embodiments, at least 5%, 10%, 15%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 3 0%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 7 0%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, 99.8% , or at least 99.9%, or even 100%, have at least 5 and less than 30 glycan units, a degree of polymerization (DP) of at least 8 and less than 30 glycan units, A therapeutic formulation is provided.

[0176] In some embodiments, about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or about 97% is about DP5, DP6, DP 7, DP8, DP9, DP10, DP11, or DP12 do.

[0177] In some embodiments, at least 50%, 60%, 70%, or 80% have at least 3 and less than 30 glycan units, or at least 5 and less than 25 Glycan therapeutic agents having a degree of polymerization of glycan units of less than 10 ... In this form, the average DP of the glycan therapeutic formulation is about DP7 to DP9 or about DP6 to DP1. 0. In some embodiments, these glycan therapeutic agents are 0.8:1 to 5: 1 or a ratio of alpha-glycosidic to beta-glycosidic bonds of 1:1 to 4:1 In some embodiments, the fractionated preparation comprises from about 0.01 to about 0.2 or about 0 It has an average branching degree of 0.05 to 0.1.

[0178] In some embodiments, about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or approximately 97% are approximately 500, 550, 60 0, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800 g / mol , 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600 , 2700, 2800, 2900, 3000, 3100, 3200, 3300, 3400 , 3500, 3600, 3700, 3800, 3900, 4000, 4100, 4200 , 4300, 4400, 4500, 4600, 4700, 4800, 4900, and 50 It has an average molecular weight of less than 00 g / mol.

[0179] In some embodiments, the glycan preparation (e.g., an oligosaccharide or polysaccharide) is linear or Non-branched glycans range from exclusively alpha-linked to exclusively beta-linked structures. The unbranched glycan may contain at least one alpha linkage and at least one vena cava. Branched glycans may contain alpha- or beta-glycosidic bonds. The branch may contain at least one glycan unit linked via a bond to form a branch. The branching rate or degree of branching (DB) can vary, so that approximately second, third, fourth, 5th, 6th, 7th, 8th, 9th, 10th, 15th, 20th, 25th, Every 30th, 35th, 40th, 45th, 50th, 60th, or 70th Each unit contains at least one branch point. For example, animal glycogen contains approximately every 10 units. contains a branch point.

[0180] In some embodiments, the formulation comprises a mixture of branched glycans, and the average degree of branching (DB, Branch points per residue) are 0, 0.01, 0.02, 0.03, 0.04, 0.05, 0 .06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0 0.6, 0.7, 0.8, 0.9, 0.95, 0.99, 1, or 2, In some embodiments, a therapeutic formulation is provided. 1, 0.05, 0.1, 0.2, 0.3, or at least 0.4, In some embodiments, a formulation of the agent is provided. In some embodiments, the average degree of branching is about 0.01 to 0.1 , 0.01-0.2, 0.01-0.3, 0.01-0.4, or 0.01-0.5 A formulation of a glycan therapeutic agent is provided. In some embodiments, the average branching degree is A formulation of a glycan therapeutic agent is provided in which the average branching is not 0. In some embodiments, The degree is at least 0.1 and not less than 0.4 or at least 0.2 and not less than 0.4. A formulation of a glycan therapeutic agent is provided. In some embodiments, a formulation of a glycan therapeutic agent is provided. comprises linear glycans. In some embodiments, the glycan therapeutic agent formulation comprises a branched or containing glycans exhibiting branched branching structures.

[0181] In some embodiments, the average degree of branching (DB) is not 0, but is at least 0.01 , 0.05, 0.1, or at least 0.2, or from about 0.01 to about 0.2 or in the range of about 0.05 to 0.1.

[0182] Some glycans have a reducing end and a non-reducing end, and the saccharide at the reducing end is It actually includes oligosaccharides, whether or not they are reducing sugars. Therefore, most oligosaccharides are referred to herein as having a non-reducing end on the left and a reducing end on the right. Most of the oligosaccharides described herein are designated by the nomenclature for non-reducing saccharides. glycoside name or abbreviation (e.g., Gal or D-Gal), preceded or followed by The bond configuration (alpha or beta), ring bond, and ring position of the reduced saccharide involved in the bond. and then the name or abbreviation of the reducing saccharide (e.g., Glc or D-Glc). The bond between two sugar units (e.g., glycosidic bond, galactosidic bond, glutamic acid bond) Cosidic bonds, etc.) are used interchangeably herein, for example, as 1,4, 1->4, or (1 Each saccharide may be represented as a cyclic form (e.g., a pyranose or a furanoside). For example, lactose has acetal oxygen bridges in the beta orientation. It consists of galactose and glucose in a cyclic form linked by beta(1-4) bonds. It is a disaccharide.

[0183] The linkages between the individual glycan units found in the glycan therapeutic formulation are alpha 1- >2, Alpha 1->3, Alpha 1->4, Alpha 1->6, Alpha 2->1, Lufa 2->3, Alpha 2->4, Alpha 2->6, Beta 1->2, Beta 1-> 3, Beta 1->4, Beta 1->6, Beta 2->1, Beta 2->3, Beta 2-> 4, and beta 2->6.

[0184] In some embodiments, the glycan therapeutic agent contains only alpha linkages. In some embodiments, the glycan therapeutic agent contains only beta linkages. The glycan therapeutic agent comprises a mixture of alpha and beta linkages. In some embodiments, The ratio of alpha-glycosidic to beta-glycosidic bonds in the preparation is approximately 0.1:1. , 0.2:1, 0.3:1, 0.4:1, 0.5:1, 0.6:1, 0.7:1, 0.8 :1, 0.9:1, 1:1, 1.2:1, 1.5:1, 1.7:1, 2:1, 2.2:1 , 2.5:1, 2.7:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1 , or about 10:1.

[0185] In some embodiments, the glycan therapeutic agent comprises a 1->2 glycosidic bond, a 1->3 Glycosidic bond, 1->4 glycosidic bond, 1->5 glycosidic bond, and 1->6 glycosidic bond alpha-glycosidic bonds selected from the group consisting of cosidic bonds and beta-glycosidic bonds In some embodiments, the glycan therapeutic agent comprises at least two or more or at least three alpha and beta 1->2 glycosidic bonds, alpha and beta 1->3 glycosidic bond, alpha and beta 1->4 glycosidic bond, alpha and beta alpha 1->5 glycosidic linkages, and / or alpha and beta 1->6 glycosidic In some embodiments, the glycan therapeutic agent comprises a bond of about 0.8:1, 1:1, of alpha:beta glycosidic bonds in 2:1, 3:1, 4:1, or 5:1 preparations Ratios include, or are in the range of about 0.8:1 to about 5:1 or about 1:1 to about 4:1. This ranges from...

[0186] In some embodiments, formulations of glycan therapeutic agents (e.g., oligosaccharides and polysaccharides) include: It contains a desired mixture of glycan units having alpha or beta configuration, e.g. The formulation of the ricin therapeutic agent may be prepared in any desired ratio, e.g., 1:1, 1:2, 1:3, 1:4, 1: 5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:12, 1:14, 1:16, 1: 18, 1:20, 1:25, 1:30, 1:35, 1:40, 1:45, 1:50, 1: 55, 1:60, 1:65, 1:70, 1:75, 1:80, 1:85, 1:90, 1: 100, 1:150 alpha vs. beta or beta vs. alpha configurations .

[0187] In some embodiments, formulations of glycan therapeutic agents (e.g., oligosaccharides and polysaccharides) include: Substantially all glycan units of alpha or beta configuration, optionally with alternative Approximately 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10% of typical other placements 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 2 Includes 0%.

[0188] In some embodiments, the formulation of the glycan therapeutic agent has an alpha glycosidic bond. At least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15% , 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65% , 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, less In some embodiments, the glycans comprise 99.9%, or even 100% of the glycans. The preparation of the rican therapeutic agent contains at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35 %, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85 %, 90%, 95%, 97%, 98%, 99%, at least 99.9%, or even 1 In some embodiments, the glycan comprises at least 100% glycans having glycosidic bonds. 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or at least 85% of the glycans are alpha- glycosidic bonds, at least 10%, 15%, 20% of which are glycosidic bonds; 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or at least 85% of the glycans are beta-glycosidic, The proportion of sulfo- and beta-glycosidic bonds does not exceed 100%. Formulations of the therapeutic agent are provided.

[0189] In some embodiments, at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 3 %, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35% , 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% , 90%, 95%, 97%, 98%, 99%, at least 99.9%, or even 10 0% is 1->2 glycosidic bond, 1->3 glycosidic bond, 1->4 glycosidic bond, and 1->6 glycosidic linkages. In some embodiments, at least 1%, 2%, or 3% of each of the glycan glycosidic bonds , 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, at least 20%, or 25% are 1->2, 1->3, 1->4, and 1->6 glycosidic bonds. A formulation of a glycan therapeutic agent is provided. Optionally, the formulation of the glycan therapeutic agent is alpha 2- >1, Alpha 2->3, Alpha 2->4, Alpha 2->6, Beta 2->1, Beta beta 2->3, beta 2->4, and beta 2->6 glycosidic bonds. At least 1%, 2%, 3%, 4%, 5%, 6%, 7%, or 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50 %, 55%, 60%, 65%, 70%, 75%, 80%, or at least 85% Included.

[0190] In some embodiments, the formulation of the glycan therapeutic agent comprises alpha 1->2 and alpha 1->3, Alpha 1->2 and Alpha 1->4, Alpha 1->2 and Alpha 1- >6, Alpha 1->2 and Beta 1->2, Alpha 1->2 and Beta 1->3, Lufa 1->2 and Beta 1->4, Alpha 1->2 and Beta 1->6, Alpha 1 ->3 and Alpha 1->4, Alpha 1->3 and Alpha 1->6, Alpha 1-> 3 and Beta 1->2, Alpha 1->3 and Beta 1->3, Alpha 1->3 and Beta Alpha 1->4, Alpha 1->3 and Beta 1->6, Alpha 1->4 and Alpha 1 ->6, Alpha 1->4 and Beta 1->2, Alpha 1->4 and Beta 1->3, Alpha 1->4 and Beta 1->4, Alpha 1->4 and Beta 1->6, Alpha 1->6 and Beta 1->2, Alpha 1->6 and Beta 1->3, Alpha 1->6 and beta 1->4, alpha 1->6 and beta 1->6, beta 1->2 and beta 1->3, Beta 1->2 and Beta 1->4, Beta 1->2 and Beta 1->6, Beta Beta 1->3 and Beta 1->4, Beta 1->3 and Beta 1->6, and Beta at least two glycosidic bonds selected from the group consisting of 1->4 and beta 1->6 The glycan comprises:

[0191] A formulation comprising a branched glycan therapeutic agent containing side chains, which may be the same or different side chains (e.g., For example, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.0 8, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0 For those with DBs of 0.9, 0.95, 0.99, 1, or 2, the side chain is The above beta bonds and alpha bonds, for example, (1-2), (1-3), (1-4), ( 1-6), (2-3), (2-6), or any other suitable bond to the backbone. It is possible.

[0192] In some embodiments, at least one glycan unit is a sugar in the L-form. In some embodiments, a formulation of a therapeutic agent is provided. In some embodiments, a preparation of a glycan is provided, wherein the sugar at position D is in the D-form. The guanine unit is naturally occurring or more common (e.g., D-glucose, D-xylose). When the glycan units are sugars in the L- or D-form, glycan units are sugars in the L- or D-form. Can preparations are provided.

[0193] In some embodiments, formulations of glycan therapeutic agents (e.g., oligosaccharides and polysaccharides) include: Desired ratio, e.g., 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1: 8, 1:9, 1:10, 1:12, 1:14, 1:16, 1:18, 1:20, 1:25 , 1:30, 1:35, 1:40, 1:45, 1:50, 1:55, 1:60, 1:65 , 1:70, 1:75, 1:80, 1:85, 1:90, 1:100, 1:150 L-shape The glycan may contain any desired mixture of L vs. D configurations of glycan units, such as D vs. L or D vs. L configurations. nothing.

[0194] In some embodiments, the formulation of the glycan therapeutic agent optionally contains other forms of Approximately 1%, 2%, 3%, 4% 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, Contains 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% glycans having substantially all L- or D-configuration of the glycan units .

[0195] In some embodiments, at least one glycan unit is a tetrose, pentose, or , hexose, or heptose. , for the formation of glycans (e.g., mixtures of branched oligosaccharides or polysaccharides) of glycan therapeutic agents. Vary the glycan units involved. Examples of monosaccharide glycan units include hexoses, e.g., For example, glucose, galactose, and fructose, as well as pentoses such as xylose. Monosaccharides generally have the chemical formula: C x (H2O) y (wherein, usually, x≧3 Monosaccharides include, for example, diose (2), triose (3), tetrose (4), , pentose (5), hexose (6), and heptose (7) containing carbon atoms They can be classified by the number x. Monosaccharide glycan units can exist in acyclic (open-chain) forms Open-chain monosaccharides with the same molecular graph can exist as two or more stereoisomers. Sugars also undergo nucleophilic addition reactions between a carbonyl group and one of the hydroxyls of the same molecule. The reactants may exist in a cyclic form via a carbon atom closed by one bridging oxygen atom. In these cyclic forms, the ring usually contains five atoms (furanose) or or 6 atoms (pyranose).

[0196] In some embodiments, the glycan therapeutic agent (e.g., oligosaccharides and polysaccharides) is Any desired ratio, for example, for any two glycan units, 1:1, 1:2, 1 :3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:12, 1:1 4, 1:16, 1:18, 1:20, 1:25, 1:30, 1:35, 1:40, 1:4 5, 1:50, 1:55, 1:60, 1:65, 1:70, 1:75, 1:80, 1:8 1:5, 1:90, 1:100, 1:150, etc., optionally for three glycan units, 1: 1:1, 1:2:1, 1:3:1, 1:4:1, 1:5:1, 1:6:1, 1:7:1, 1:8:1, 1:9:1, 1:10:1, 1:12:1, 1:14:1, 1:16:1, 1:18:1, 1:20:1, 1:1:2, 1:2:2, 1:3:2, 1:4:2, 1: 5:2, 1:6:2, 1:7:2, 1:8:2, 1:9:2, 1:10:2, 1:1:3 , 1:2:3, 1:3:3, 1:4:3, 1:5:3, 1:6:3, 1:7:3, 1:8 :3, 1:9:3, 1:10:3, 1:1:4, 1:2:4, 1:3:4, 1:4:4, 1:5:4, 1:6:4, 1:7:4, 1:8:4, 1:9:4, 1:10:4, 1:1 :5, 1:2:5, 1:3:5, 1:4:5, 1:5:5, 1:6:5, 1:7:5, 1 1:8:5, 1:9:5, 1:10:5, etc., and optionally for four glycan units, 1:1 :1:1, 1:2:2:1, 1:3:2:1, 1:4:2:1, 1:5:2:1, 1:6 :2:1, 1:7:2:1, 1:8:2:1, 1:9:2:1, 1:10:2:1, 1: 1:1:2, 1:2:2:2, 1:3:2:2, 1:4:2:2, 1:5:2:2, 1: 6:2:2, 1:7:2:2, 1:8:2:2, 1:9:2:2, 1:10:2:2, etc. For any five glycan units, 1:1:1:1:1, 1:2:2:1:1, etc., any For six glycan units, 1:1:1:1:1:1, 1:1:1:1:1:1:2 etc., for any seven glycan units, 1:1:1:1:1:1:1, 1:1:1: 1:1:1:2, etc., to obtain a desired mixture of glycan units of different monosaccharides, e.g., diose ( 2), triose (3), tetrose (4), pentose (5), hexose (6), or or a mixture of heptose (7).

[0197] In some embodiments, the formulation of the glycan therapeutic agent comprises two, three, four, or five Desired mixtures of different glycan units, such as i) glucose, galactose, arabinose, saccharides selected from the group consisting of rhamnose, mannose, fructose, xylose, fucose, and rhamnose; ii) one or more glycan units selected from the monosaccharides represented by the formula (I), Lulactosamine, allolactose, cellobiose, chitobiose, galactose-alf α-1,3-galactose, gentiobiose, isomalt, isomaltose, isomalt Lactulose, kojibiose, lactitol, lactobionic acid, lactose, lactulose , laminaribiose, maltitol, maltose, mannobiose, melibiose, mel Biulose, neohesperidose, nigerose, robinose, rutinose, sambubiose Sugar, sophorose, sucralose, sucrose, sucrose acetate isobutyrate, octadecanoate Acetylsucrose, trehalose, turanose, vicianose, and xylobiose iii) one or more glycan units selected from disaccharides selected from the group consisting of acarbose, N -acetylemannosamine, N-acetylmuramic acid, N-acetylneuraminic acid, N- Acetylethalosaminuronic acid id), arabinopyranosyl-N-methyl-N-nitrosourea, D-fructose-L- Histidine, N-glycolylneuraminic acid, ketosamine, kidamycin, mannosamine, 1B-Methylseleno-N-acetyl-D-galactosamine, muramic acid, muramyldipep Tide, phosphoribosylamine, PUGNAc, sialyl-Lewis A, sialyl- Lewis X, validamycin, voglibose, N-acetylgalactosamine, N-acetyl Cetylglucosamine, aspartylglucosamine, basilthiol, daunosamine, deso samine, fructosamine, galactosamine, glucosamine, meglumine, and perosamine one or more glycan units selected from amino sugars selected from: Glucitol, cladinose, colitose, 2-deoxy-D-glucose, 3-deoxy-D-glucose Xyglucasone, deoxyribose, dideoxynucleotides, digitalose, fludecanoate a deoxy sugar selected from oxyglucose, sarmentose, and sulfoquinovose; v) one or more glycan units selected from castanospermine, 1-deoxynojirima selected from isine, iminosugars, miglitol, miglustat, and swainsonine one or more glycan units selected from imino acids, N-acetylneuraminic acid, N-acetyl Acetyltalosamnuronic acid, Rudal acid, aldonic acid, 3-deoxy-D-manno-oct-2-urosonic acid, glutamic ... Uronic acid, glucosamine uronic acid, glyceric acid, N-glycolylneuraminic acid, Duronic acid, isosaccharinic acid, pangamic acid, sialic acid, threonic acid, urosonic acid, Uronic acid, xylonic acid, gluconic acid, ascorbic acid, ketodeoxyocturonic acid acid, galacturonic acid, galactosaminuronic acid, mannuronic acid, mannosaminuronic acid, Taric acid, mucic acid, sugar acid, lactic acid, oxalic acid, succinic acid, hexanoic acid, fumaric acid, maleic acid, Butyric acid, citric acid, glucosamine acid, malic acid, succinamic acid, sebacic acid, and caprylic acid vi) one or more glycan units selected from sugar acids selected from phosphoric acid, formic acid, acetic acid; Short-chain fatty acids selected from propionic acid, butyric acid, isobutyric acid, valeric acid, and isovaleric acid one or more glycan units selected from fatty acids, and vii) methanol, ethylene glycol Licorice, glycerol, erythritol, threitol, arabitol, ribitol, Xylitol, mannitol, sorbitol, galactitol, iditol, volemit maltotriitol, maltotetriitol, and poly A mixture of one or more glycan units selected from sugar alcohols selected from glycitols Includes things.

[0198] In some embodiments, the formulation of the glycan therapeutic agent is, for example, hydrochloride (h hydrochlorate, hydroiodate, hydrogen bromide Acid salts, phosphates, sulfates, methanesulfates, acetates, formates, tartrates, and malates , citrate, succinate, lactate, gluconate, pyruvate, fumarate, propyl Salt forms such as benzoate, aspartate, glutamate, benzoate, and ascorbate A glycan unit or a plurality of glycans present in a pharmaceutically acceptable salt form (e.g., a pharmaceutically acceptable salt form). Includes units.

[0199] Exemplary glycans are numbered out of 100 to reflect the proportion of material that the monomers comprise. Therefore, they are described by a three-letter code representing the monomeric sugar moiety. u100" indicates a glycan produced from an input of 100% D-glucose (glycan unit). "glu50gal50" is a 50% D-glucose and 50% D-galactose from an input of lactose (glycan unit) or alternatively lactose dimers (glycan units) As used herein, "glycans" refers to glycans generated from inputs (positions 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, xyl = D-xylose, ara = L-arabinose, gal = D-galactose, gl u = D-glucose, rha = L-rhamnose, fuc = L-fucose, man = D-ma sor = D-sorbitol, gly = D-glycerol, neu = NAc- Ilamic acid.

[0200] In some embodiments, the glycan therapeutic agent is selected from i) to vii) above. Glycan unit A contains 1 glycan unit A, and glycan unit A contains 100% of the glycan unit input. For example, in some embodiments, the glycan therapeutic agent comprises a homo-glycan xyl1 00, rha100, ara100, gal100, glu100, and man100 In some embodiments, the glycan therapeutic agent is selected from homo-glycan fuc 100 and fru100.

[0201] In some embodiments, the formulation of the glycan therapeutic agent is independently of i) to vii) above. The present invention relates to a mixture of two glycan units A and B selected from the group consisting of i) to vii) A and B may be selected from the same or different groups, and A and B may be in any desired ratio (e.g., 100 %, in the range of 1 to 99% A and 99 to 1% B).

[0202] For example, in some embodiments, the glycan therapeutic agent is hetero-glycan ara5 0gal50, xyl75gal25, ara80xyl20, ara60xyl40, ara50xyl50, glu80man20, glu60man40, man60gl u40, man80glu20, gal75xyl25, glu50gal50, man 62glu38, and hybrid glycans glu90sor10 and glu90gly There are 10 to choose from.

[0203] In some embodiments, the formulation of the glycan therapeutic agent is independently of i) to vii) above. The glycan comprises a mixture of three glycan units A, B, and C selected according to the following: A, B, and C are selected according to the following: A, B, and C may be selected from the same or different groups of A, B, and C in any desired ratio. Rate (e.g., not exceeding 100%, 1-99% A, 1-99% B, and 1-99% C range).

[0204] For example, in some embodiments, the glycan therapeutic agent is hetero-glycan xyl7 5glu12gal12, xyl33glu33gal33, glu33gal33fu c33, man52glu29gal19, and the hybrid glycan glu33gal 33neu33 is selected.

[0205] In some embodiments, the formulation of the glycan therapeutic agent is independently of i) to vii) above. The glycan comprises a mixture of four glycan units A, B, C, and D selected according to the following formula: D may be selected from the same or different groups i) to vii), and A, B, C, and D may be any Any desired ratio (e.g., not exceeding 100%, 1 to 99% A, 1 to 99% B, 1 to 99% C and 1 to 99% D).

[0206] In some embodiments, the formulation of the glycan therapeutic agent is independently of i) to vii) above. The present invention relates to a mixture of five glycan units A, B, C, D, and E selected from the group consisting of A, B, C, D, and E. D and E may be selected from the same or different groups i) to vii), and A, B, C, D, and E are any desired ratios (e.g., not exceeding 100%, 1-99% A, 1-99%). % B, 1-99% C, 1-99% D, and 1-99% E) It is possible.

[0207] In some embodiments, at least one glycan unit is selected from the group consisting of glucose, galactose, and the like. sugar, arabinose, mannose, fructose, xylose, fucose, and rhamnose A formulation of a glycan therapeutic agent selected from the group consisting of:

[0208] In some embodiments, the glycan therapeutic agent (e.g., oligosaccharides and polysaccharides) is For example, glucose and galactose, glucose and arabinose, glucose and maize tRNA, glucose and fructose, glucose and xylose, glucose and fructose cose, glucose and rhamnose, galactose and arabinose, galactose and Mannose, galactose and fructose, galactose and xylose, galactose sucrose and fucose, as well as galactose and rhamnose, arabinose and mannose, Arabinose and fructose, arabinose and xylose, arabinose and fucose and arabinose and rhamnose, mannose and fructose, mannose and and xylose, mannose and fucose, and mannose and rhamnose, fructosyl fructose and xylose, fructose and fucose, and fructose and rhamnose , xylose and fucose, xylose and rhamnose, and fucose and rhamnose A desired mixture of glycan units of two different monosaccharides, such as a mixture of saccharides, can be prepared by, for example, :1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:12, 1:14, 1:16, 1:18, 1:20, 1:25, 1:30, 1:35, 1:40, 1:45, 1:50, 1:55, 1:60, 1:65, 1:70, 1:75, Contains in ratios of 1:80, 1:85, 1:90, or 1:100 or their inverse ratios.

[0209] In some embodiments, the glycan therapeutic agent (e.g., oligosaccharides and polysaccharides) is A desired mixture of glycan units of three different monosaccharides, e.g., glucose-containing glycans, For therapeutic formulations, glucose, galactose, and arabinose; glucose, Galactose and mannose; glucose, galactose, and fructose; gluco glucose, galactose, and xylose; glucose, galactose, and fucose; cose, galactose, and rhamnose; glucose, arabinose, and mannose; Glucose, arabinose, and fructose; glucose, arabinose, and xylose glucose, arabinose, and fucose; glucose, arabinose, and ram glucose, mannose, and fructose; glucose, mannose, and kappa Glucose, mannose, and fucose; glucose, mannose, rhamno glucose, fructose, and xylose; glucose, fructose, and fucose glucose, fructose, and rhamnose; glucose, fucose, and rhamnose Mixtures of these oils, for example, 1:1:1, 1:2:1, 1:3:1, 1:4:1, 1:5 :1, 1:6:1, 1:7:1, 1:8:1, 1:9:1, 1:10:1, 1:12:1 , 1:14:1, 1:16:1, 1:18:1, 1:20:1, 1:1:2, 1:2:2 , 1:3:2, 1:4:2, 1:5:2, 1:6:2, 1:7:2, 1:8:2, 1:9 :2, 1:10:2, 1:1:3, 1:2:3, 1:3:3, 1:4:3, 1:5:3, 1:6:3, 1:7:3, 1:8:3, 1:9:3, 1:10:3, 1:1:4, 1:2 :4, 1:3:4, 1:4:4, 1:5:4, 1:6:4, 1:7:4, 1:8:4, 1 :9:4, 1:10:4, 1:1:5, 1:2:5, 1:3:5, 1:4:5, 1:5: Contains ratios such as 1:5, 1:6:5, 1:7:5, 1:8:5, 1:9:5, 1:10:5, etc.

[0210] In some embodiments, the glycan therapeutic agent (e.g., oligosaccharides and polysaccharides) is Containing substantially all diose (2) monosaccharide units, optionally 1%, 2%, 3%, 4% 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% triose (3) tetrose (4); Pentose (5), hexose (6), or heptose (7), or any of these Includes a combination of:

[0211] In some embodiments, the glycan therapeutic agent (e.g., oligosaccharides and polysaccharides) is Containing substantially all triose (3) monosaccharide units, optionally containing 1%, 2%, 3%, 4 % 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% , 16%, 17%, 18%, 19%, or 20% of diose (2), tetroses (4) , pentose (5), hexose (6), or heptose (7), or any of these Includes any combination of

[0212] In some embodiments, the glycan therapeutic agent (e.g., oligosaccharides and polysaccharides) is substantially all tetrose (4) monosaccharide units, optionally 1%, 2%, 3%, 4 % 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% , 16%, 17%, 18%, 19%, or 20% diose (2), triose (3) , pentose (5), hexose (6), or heptose (7), or any of these Includes any combination of

[0213] In some embodiments, the glycan therapeutic agent (e.g., oligosaccharides and polysaccharides) is substantially all pentose (5) monosaccharide units, optionally 1%, 2%, 3%, 4 % 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% , 16%, 17%, 18%, 19%, or 20% diose (2), triose (3) Tetrose (4), hexose (6), or heptose (7), or any of these Includes a combination of:

[0214] In some embodiments, the glycan therapeutic agent (e.g., oligosaccharides and polysaccharides) is Containing substantially all hexose (6) monosaccharide units, optionally containing 1%, 2%, 3%, 4 % 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% , 16%, 17%, 18%, 19%, or 20% diose (2), triose (3) Tetrose (4), pentose (5), or heptose (7), or any of these Includes a combination of:

[0215] In some embodiments, the glycan therapeutic agent (e.g., oligosaccharides and polysaccharides) is substantially all heptose (7) monosaccharide units, optionally 1%, 2%, 3%, 4 % 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% , 16%, 17%, 18%, 19%, or 20% diose (2), triose (3) Tetrose (4), pentose (5), or hexose (6), or any of these Includes a combination of:

[0216] In some embodiments, at least one glycan unit is a furanose sugar. In some embodiments, a formulation of a cancer therapeutic agent is provided. In some embodiments, a preparation of a glycan is provided, wherein the pyranose unit is a pyranose sugar. In some embodiments, the glycan therapeutic agent comprises a mixture of furanose and pyranose sugars. In this formulation, the ratio of furanose sugars to pyranose sugars in the formulation is about 0.1:1, 0.2:1 , 0.3:1, 0.4:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9 :1, 1:1, 1.2:1, 1.5:1, 1.7:1, 2:1, 2.2:1, 2.5:1 , 2.7:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, or approximately 1 The ratio is 0:1.

[0217] In some embodiments, the glycan therapeutic agent (e.g., oligosaccharides and polysaccharides) is For example, a desired ratio, e.g., 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1: 7, 1:8, 1:9, 1:10, 1:12, 1:14, 1:16, 1:18, 1:20, 1:25, 1:30, 1:35, 1:40, 1:45, 1:50, 1:55, 1:60, 1:65, 1:70, 1:75, 1:80, 1:85, 1:90, 1:100, 1:15 0 furanose to pyranose or pyranose to furanose furanose sugar and pyranose Contains any desired mixture of sugars.

[0218] In some embodiments, the formulation of the glycan therapeutic agent comprises substantially all furanose or or pyranose sugars, optionally at 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 1 Contains 9% or 20% typical other sugars.

[0219] In some embodiments, the formulation of the glycan therapeutic agent comprises substantially all pyranose sugars. and in the furanose form in the preparation at about 0.1%, 0.2%, 0.5%, 1% %, 2%, 3%, 4%, or 5% or less of monomeric glycan units. In the form, no more than 3%, 2%, or 1% of the monomeric glycan units in the preparation are It is in the furanose form.

[0220] In some embodiments, the formulation of the glycan therapeutic agent also contains N-acetylgalactosamine. In some embodiments, the glycan preparation is also free of N-acetylglucosamine. In some embodiments, the formulation of the glycan therapeutic agent does not contain lipids and fats. In some embodiments, the formulation of the glycan therapeutic agent does not contain an amino acid. do not have.

[0221] In some embodiments, the formulation of the glycan therapeutic agent does not contain detectable repeating units. In some embodiments, the formulation of the glycan therapeutic agent contains a statistically significant amount of repeating units. In some embodiments, the repeating unit does not include at least 2, 3, 4, 5, or a few It has a DP of at least six glycan units. For example, hyaluronan has two glycosaminoglycans. A reaction consisting of a hydroxybenzoate derivative, glucuronide (glucuronic acid), and N-acetylglucosamine It is a glycosaminoglycan with a complex disaccharide unit. The glycosidic bond is beta(1-> 3) and beta (1->4). Cellulose is bonded together by beta bonds. The presence and amount of repeating units can be determined, for example, by: Total hydrolysis (e.g., to determine the proportion of glycan units), methylation analysis (e.g., to determine the distribution of bond types), and HSQC (e.g., alpha- and beta-glycosylation). (To determine the distribution of cosides) can be used to determine the significance. Statistical methods for determining σ are well known by those skilled in the art.

[0222] Optionally, the monosaccharide or oligosaccharide glycan units of the glycan may be further substituted or derivatized. Derivatized, for example, hydroxyl groups can be etherified or esterified. Glycans (e.g., oligosaccharides or polysaccharides) can be modified saccharide units, e.g., hydroxyl groups. 2'-deoxyribose, where the sila group is removed, and the hydroxyl group is replaced with fluorine. -fluororibose, or N-acetylglucosamine, glucose (e.g., 2'-fluoro The sugars may contain nitrogen-containing forms of the sugars (fluororibose, deoxyribose, and hexose). The degree of substitution (DS, the average number of hydroxyl groups per glycosyl unit) is 1, 2, or 3. , or another suitable DS. In some embodiments, 1%, 2%, 3%, 4% 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of the glycan units are substituted or derivatized In some embodiments, the degree of substitution is such that, for example, a certain percentage is not derivatized, and 1 Some show DS of 1, some show DS of 2, and some show DS of 3, which vary between subunits. A preferred mixture would be, for example, 0-99% of the subunits underivatized and 0-99% of the 0-99% of the subunits exhibit a DS of 1, 0-99% of the subunits exhibit a DS of 2, and 0- 99% of the subunits show a DS of 3, totaling 100%. By adjusting the average number of moles of substituents (molar substitution (MS)) added to the aryl moiety, The distribution of substitutions along the length of the glycan oligosaccharide or polysaccharide chain can be controlled by varying the reaction conditions, This can be controlled by adjusting the reagent type and the extent of substitution. In the present study, the monomer subunits are acetate esters, sulfate half esters, phosphate esters, and is substituted with one or more pyruvyl cyclic acetal groups.

[0223] having a degree of polymerization (DP) of n in the population (denoted herein as DP(n)). The molar percentage of each species was determined using, for example, an Agilent 1260 B equipped with a refractive index (RI) detector. ioInert series instruments and water as the mobile phase, well known to those skilled in the art. Determined by high performance liquid chromatography (HPLC) on various columns. The methodology used is HILIC, metal coordination, and aqueous size-exclusion chromatography, which provides the best isolation of the target species. The chemical properties include, but are not limited to, DP The mole % of (n) is determined by the formula: Percentage of DP(n) = 100*AUC[DP(n)] / AUC[DP(total)] is determined by where AUC is the average activity of the target species as determined by calibration against known standards. It is defined as the area under the concentration curve for the glycosidic bond. %) and beta (%) are measured by nuclear magnetic resonance imaging using various 2D techniques well known to those skilled in the art. The alpha- and beta-isomers are determined by NMR spectroscopy. For example, they can be distinguished by their different shifts in the NMR spectrum, and the molar ratio can be calculated using the formula: Proportion (%) of glycosidic bond (glycoside isomer n) = 100*AUC[shift(isomer n)] / AUC[shift(isomer alpha + isomer beta)], where AUC is the area under the concentration curve for a particular shift value known to represent the desired isomer n. The molar ratio of regiochemical isomers is defined by the formula: Percentage (%) of positional isomer (positional isomer n) = 100 * AUC [shift (positional isomer n)] / AUC[shift (all positional isomers)].

[0224] The relative proportions of monomeric sugars that make up the oligomeric population can be determined, for example, by acid digestion of the oligomeric sample. The sum of the hydroxylations was followed by conversion to alditol acetates, followed by GC analysis against known standards. The concentration is determined by gas chromatographic (GC) analysis of the resulting monomer solution compared to the The molar fraction of monomer (n), where n can be any sugar, is calculated using the formula: Percentage (%) of (sugar n) = 100*AUC[sugar n] / AUC[total of all monomeric sugars ], is determined by.

[0225] In some embodiments, the solubility of the formulation of the glycan therapeutic agent is determined by, for example, charge, structure ( For example, the choice of DP, branching degree, and / or derivatization of the glycan units can be controlled. obtain.

[0226] Glycan therapeutic preparations consisting of certain sugar units uniformly linked in a linear chain are typically Even when the glycan has a low molecular weight with a degree of polymerization (DP) of 20-30, it is insoluble at 23°C. The solubility of the glycan therapeutic agent can be improved by, for example, introducing a (1->6) bond to the glycan. The C-5 to C-6 bond can be adjusted by alternating glycosidic bonds in the The extra degrees of freedom afforded by the substitution of Homoglycans with two types of sugar bonds or heteroglycans with two types of sugars are obtained. are generally more soluble than their homologous polymers. Ionization of linear homoglycans, e.g. The viscosity of the solution is determined by the tertiary structure of the glycans. may vary.

[0227] In some embodiments, the glycan therapeutic agent is highly branched, for example, In some embodiments, the average DB is at least 0.01, 0.05, or 0.1. The glycan therapeutic agent has an average DB of 0.1 to 0.2. The glycan therapeutic agent is highly soluble. In some embodiments, the glycan therapeutic agent is At least 55 Bri at 23°C without obvious solidification or crystallization (final solubility limit) x, 65Brix, 60Brix, 65Brix, 70Brix, 75Brix, 80B In some embodiments, the granules may be concentrated to 85 Brix, or at least 85 Brix. The Lycan Therapeutic Preparation can be dissolved at 23°C (ultimate solubility limit) without any apparent solidification or crystallization. At least about 0.5g / ml, 1g / ml, 1.5g / ml, 2g / ml, 2.5g / ml The concentration may be concentrated to 1, 3 g / ml, 3.5 g / ml, or at least 4 g / ml.

[0228] In some embodiments, the glycan therapeutic agent (e.g., an oligosaccharide) is branched, For example, having an average DB of at least 0.01, 0.05, or 0.1 and at least about 70Brix, 75Brix, 80Brix, or at least about 85Brix or at least about 1 g / ml, 2 g / ml, Or at least about 3 g / ml.

[0229] In some embodiments, the formulation of the glycan therapeutic agent is in deionized water or a suitable buffer. in a buffer solution, e.g., phosphate buffered saline, pH 7.4, or similar physiological pH; At 20°C, at least 0.001g / L, 0.005g / L, 0.01g / L, 0.05 g / L, 0.1g / L, 0.2g / L, 0.3g / L, 0.4g / L, 0.5g / L, 0 .6g / L, 0.7g / L, 0.8g / L, 0.9g / L, 1g / L,5g / L, 10g / L, 20g / L, 30g / L, 40g / L, 50g / L, 100g / L, 200g / L , 300g / L, 400g / L, 500g / L, 600g / L, 700g / L, 800g In some embodiments, the final solubility limit is 900 g / L, 900 g / L, or 1000 g / L. ,Glycan therapeutic agent formulations are more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, 9 Greater than 5%, greater than 96%, greater than 97%, greater than 98%, greater than 99%, or greater than 99.5% soluble , in deionized water or in a suitable buffer, e.g., phosphate buffered saline, pH 7.4, or similar physiological pH) at 20°C, at least 0.001 g / L, 0.005 g / L, 0.01g / L, 0.05g / L, 0.1g / L, 0.2g / L, 0.3g / L, 0.4g / L, 0.5g / L, 0.6g / L, 0.7g / L, 0.8g / L, 0.9g / L, 1g / L, 5g / L, 10g / L, 20g / L, 30g / L, 40g / L, 50g / L, 100g / L, 200g / L, 300g / L, 400g / L, 500g / L, 600 Observed at concentrations above 700g / L, 800g / L, 900g / L, and 1000g / L There is no visible precipitate.

[0230] In some embodiments, the formulation of the glycan therapeutic agent has a desired sweetness. For example, Sucrose (table sugar) is the prototypical sweet substance. The sweetness perception rating of each substance is 1, and other substances are rated relative to this (e.g., Lucrose is rated 1.7 times sweeter than sucrose). The sweetness of the glycan therapeutic preparations ranges from 0.1 to 500,000 compared to sucrose. In some embodiments, the relative sweetness ranges from 0.1, 0.2, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, 10.0, 11.0, 12.0, 13.0, 14.0, 15.0, 16.0, 17.0, 18.0, 1 .2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5 , 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 2 0, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 80, 90, 10 0, 150, 200, 250, 300, 350, 400, 450, 500, 550, 60 0, 650, 700, 750, 800, 850, 900, 950, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000 , 25000, 50000, 75000, 100000, 150000, 200000, 250,000, 300,000, 350,000, 40,000, 450,000, 500,000 or greater than 500,000 (sucrose is scored as 1). In the present invention, the glycan therapeutic agent formulation is mildly sweet or both sweet and bitter.

[0231] In some embodiments, the formulation of the glycan therapeutic agent, for example, substantially DP2+ or is a preparation that is DP3+ (e.g., at least 80%, 90% of DP2+ or DP3+ , or at least 95%, or fractionated preparations) are substantially perceived as sweet. It is not possible to do so, and its relative sweetness is approximately 0, 0.0001, 0.001, 0.001 compared to sucrose. 005, 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0. 7, or about 0.8 (sucrose is scored as 1).

[0232] Identification and characterization of glycan therapeutic agents Optionally, the glycan therapeutic agent can be characterized. For example, the increase in health-promoting bacteria identified in one or more in vitro or in vivo assays to enhance proliferation Preparations of glycan therapeutic agents that inhibit the growth of or microbial pathogens are known in the art. by any method known in the art and further characterized by the methods described herein. Suitable methods are further described in the Examples.

[0233] For glycan therapeutic agents, monomeric building blocks (e.g., monosaccharides or glycans) unit composition), anomeric configuration of side chains, presence and location of substituents, degree of polymerization / molecular weight, and bond The binding patterns can be analyzed by standard methods well known in the art, such as methylation analysis, reduction, etc. Cleavage, hydrolysis, GC-MS (gas chromatography mass spectrometry), MALDI-MS (matrix-assisted laser desorption / ionization mass spectrometry), ESI-MS (electrospray ionization mass spectrometry), spectrometric detection), HPLC (high performance liquid chromatography with ultraviolet or refractive index detection), Electron Microscopy), HPAEC-PAD (High Performance Anthropoietic Chemistry with Pulsed Amperometric Detection) Ion exchange chromatography), CE (capillary electrophoresis), IR (infrared) / It can be identified by techniques such as Raman spectroscopy and NMR (nuclear magnetic resonance) spectroscopy. For polymers, the crystal structure can be determined by, for example, solid-state NMR, FT-IR (Fourier transform), Transform normalized infrared spectroscopy (DIRECT), and WAXS (wide angle X-ray scattering). The distribution and polydispersity of P can be determined, for example, by viscosity measurements and SEC (SEC-HPLC, high performance column chromatography). The heterogeneous groups, end groups, and substituents can be determined by: For example, SEC with labeling, aqueous analysis, MALDI-MS, FT-IR, and NMR To identify the monomeric components of a glycan, for example, acid-catalyzed hydrolysis can be used. Solution, HPLC (High Performance Liquid Chromatography) or GLC (Gas-Liquid Chromatography) Methods such as glycan esterification (after conversion to alditol acetate) can be used. To determine the bonds present, in one example, the polysaccharide is immersed in methyl iodide and a strong base in DMSO. methylation, hydrolysis and reduction to partially methylated alditols are achieved. The acetylation to methylated alditol acetates was performed and the analysis was performed using GL This is done by C / MS (gas-liquid chromatography plus mass spectrometry). In some embodiments, partial depolymerization using acid or enzymes is performed to determine the polysaccharide sequence. The possible structures of polysaccharides are compared with the structures of hydrolyzable oligomers. The anomeric structure is then determined to be one of the possible structures that can form an oligomer. To identify the structure, in one example, the intact polysaccharide or oligosaccharide preparation is subjected to enzymatic analysis. For example, they may be used to treat specific enzymes such as β-galactosidase or α-glucosidase. The product is then contacted with an enzyme that is specific for a particular type of bond, and NMR is used to analyze the product. It is possible.

[0234] For example, the distribution (or average) degree of polymerization (DP) of a glycan therapeutic agent may be, for example, 10 to Samples with a concentration of 100 mg / mL were prepared, for example, as described by Gomez et al. on,Characterization,and Prebiotic Proper ties of Pectic Oligosaccharides from Ora nge Peel Wastes,J Agric Food Chem,2014,6 2:9769), 7.8 x 300 mm BioRad Aminex Agilent equipped with HPX-42A column (or similar) and RI detector Measured by injection into a 1260 BioPure HPLC (or similar) Alternatively, the sample with the concentration can be prepared, for example, as described by Holck et al. ted and non-feruloylated arabino-oligosaccharides arides from sugar beet pectin selectivel y stimulate the growth of bifidobacteria m spp.in human fecal in vitro fermentati ons, Journal of Agricultural and Food Che mistry, 2011, 59(12), 6511-6519), 4 x 250mm Dionex CarboPac PA1 column (or similar) and P Dionex ICS5000 HPLC (or similar) equipped with an AD detector The integration of the resulting spectrum compared to a standard solution of the oligomer is , allowing the determination of the average DP.

[0235] The molecular weight distribution can be measured, for example, by MALDI mass spectrometry. is adjusted for the standardization curve to account for the difference in refractive index between the monomer and oligomer. A Mettler-Toledo sugar refractometer (or similar) was used with the final value It can be measured.

[0236] The distribution of glycosidic regiochemistry can be determined using, for example, standard pulse sequences and a Bruker 50 COSY, HMBC, HSQC, DEPT, and TOCSY analyses were performed using a 0 MHz spectrometer. The peaks can be characterized by a variety of 2D-NMR techniques, including NMR analysis. The spectra can be assigned by correlation to the spectra of naturally occurring polysaccharides of the same chemistry.

[0237] In some embodiments, the relative peak assignments of a sample may be determined based on the concentration and purity of the sample, the solvent, The identity and quality of the solvent (e.g., isotopically labeled solvent) and the pulse sequence used It depends on many factors, including but not limited to: For example, the relative peak assignments of glucose-containing glycans can be calculated using the NMR spectrum. is obtained under similar conditions depending on the factor (e.g., about 0.01 ppm, about 0.0 2 ppm, or about 0.05 ppm). In the present specification, the term "corresponding peak(s)" refers to peaks that are associated with the same sample, e.g. For example, the concentration and purity of the sample, the identity and quality of the isotopically labeled solvent, and the Pulse sequences include, but are not limited to, pulse sequences that are based on a factor (e.g., about 0.0 NMR peaks that differ by about 1 ppm, about 0.02 ppm, or about 0.05 ppm .

[0238] The monomer composition of the oligomer can be determined, for example, by dissolving a known amount of the oligomer in a strong acid at elevated temperature. , which can be measured by the complete hydrolysis method, which allows sufficient time for complete hydrolysis to occur. The concentrations of individual monomers are then used to achieve relative abundance measurements in Holck et al. For this purpose, HPLC or GC methods described herein and well known in the art may be used. Absolute amounts can be measured by averaging the amount of each signal to prevent overlap with any of the critical signals. Measured by spiking the HPLC sample with a selected, known amount of active standard into the detector It can be done.

[0239] The degree of branching in any given population can be calculated, for example, by Hakomori (J. Biochem (Tokyo), 1964, 55, 205) These data allow identification of potential repeating units based on total hydrolysis, average Data from DP and methylation analyses were combined and used for DEPT NMR spectra. Anomeric carbon sequences for these data can be constructed by comparing them. The correlation of signal numbers is reported, for example, by Harding et al. (Carbohydr. Res. 2005) As demonstrated in [340,1107], regular repeat units are used to fill the collected data. Indicates whether it is necessary to fulfill the

[0240] Glycan therapeutic agents (e.g., glucose, galactose, fucose, xylose, arabinose) containing mono- or disaccharide glycan units such as saccharides like ... The preparations are based on the parameters: a) two, three, and four, each representing a different glycosidic bond type; one, four, five, six, seven, or more (e.g., at least four or five) b) presence of diagnostic anomeric NMR peaks, b) about 0.8 to 1 to about 5 to 1 (e.g., alpha bonds); c) alpha-linked to beta-linked ratios of approximately 1:1 to 4:1, generally favoring the alpha-linked to beta-linked type; ,2-, 1,3-, 1,4-, and 1,6-substituted Both have three different glycosidic regiochemistries, as well as 1,2,3-, 1,2,4-, and 1,2, At least two from the list of 6-, 1,3,4-, 1,3,6-, and 1,4,6-substituted or at least three different glycosidic regiochemistries, and d) at least five of each species 0%, 60%, 70%, or at least 80% of at least two, at least three, 3 DP distribution with ~30, or 5-25 DPs, one, two, three, or In some embodiments, the glycan therapeutic agent can be identified using a naturally occurring In some embodiments, the glycan therapeutic The preparations have novel average properties (e.g., DP, .g., .alpha.) that differ from naturally occurring preparations of oligosaccharides. These structural characteristics are defined herein as The glycan therapeutic agents described herein can be quantified by the methods described in. , having at least one, two, three, four, or at least five of the following characteristics: R: (i) Quantitative mass spectrometry measurements, SEC-HPLC, IAC-HPLC, or IEC-H can be identified by PLC, for example, about DP3 to about DP30, or about DP5 to about DP Molecular weight distribution spanning 25 ranges, (ii) For example, explicit identification and definition of signals from alpha and beta glycosides identified by various NMR techniques, including HSQC pulse sequences that allow for quantification Coupling ratios ranging from 0.8:1, 1:1, 2:1, 3:1, 4:1, and 5:1 (approximately Both alpha and beta bonds have In some embodiments of the glycan therapeutic agent, the observed ratio The presence of both alpha- and beta-glycosidic bonds (see Table 6 , the majority of both alpha and beta-linked across the mono- and polysaccharide glycans tested. The presence of a glycosidic acid group generally favors one predominant glycosidic stereochemistry and, optionally, favors the opposing stereochemistry. Unlike naturally occurring oligosaccharide or polysaccharide preparations, which contain only a relatively small fraction of the chemical Become, (iii) Fingerprint NMR process or developed by Hakomori et al. at least one, two, three, or more nucleotides that can be identified by permethylation branch identification Presence of four glycosidic position chemistries. In some embodiments, the glycan therapeutic agent comprises at least At least 0.1%, 0.2%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or at least 10% of 1,2-, 1,3-, 1,4-, and 1,6- Some implementations have one, two, three, or four of the glycosidic bond types. In the form, the glycan therapeutic formulation may contain at least 0.1%, 0.2%, 0.5%, 1%, 2% or more of %, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or at least 10% of 1,2- It has two of the following glycosidic bond types: 1,3-, 1,4-, and 1,6-. In some embodiments, the glycan therapeutic agent comprises at least 0.1%, 0.2%, 0.5% , 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or at least 10% It has three of the following glycosidic bond types: 1,2-, 1,3-, 1,4-, and 1,6-glycosidic bond types. In some embodiments, the glycan therapeutic agent contains at least 0.1%, 0.2% , 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or at least 1,2-, 1,3-, 1,4-, and 1,6-glycosidic bond types account for 10%. In some embodiments, the glycan therapeutic agent further comprises at least one of At least 0.1%, 0.2%, 0.5%, 1%, 2%, 3%, 4%, or at least 5% In some embodiments, the glycan therapeutic agent comprises at least 0.1%, 0.2%, 0.5%, 1%, 2%, 3%, 4%, or at least 5% of ,3,6-, 1,4,6-, or 1,2,4-glycosides Contains at least one, two, or at least three branched bond types. In embodiments, the glycan therapeutic agent is a 1,3,6-, 1,4,6-, or 1,2,4 -glycosides. In some embodiments, the glycosides Can therapeutic preparations contain at least 0.1%, 0.2%, 0.5%, 1%, 2%, 3%, 4% or at least 5% of 1,3,6-, 1,4,6-, or 1,2,4-glycosyl The sugars that do not have a hydroxyl group at a given position X are , 1,X bond type, for example, fucose (6-dehydroxy-galactose) , does not have 1,6-glycosidic bonds, but has 1,2-, 1,3-, and 1,4-glycosidic bonds In some embodiments, the glycan therapeutic agent may have a furanose form. At least 0.1%, 0.2%, 0.5%, 1%, 2%, or at least 3% of the monomer In some embodiments, the glycan therapeutic agent contains multiple glycosyltransferases. The do-position chemistry and the presence of branches (see Figure 4 for three exemplary glycans) , which generally differ from naturally occurring oligosaccharide or polysaccharide preparations that favor specific bond structures. All of these regiochemistries are known to occur in naturally occurring oligosaccharides, but The oligosaccharide preparation of the present invention is a glycan therapeutic agent of some embodiments, It does not include the number and complexity of chemistry. (iv) at least 50%, 60%, 70%, 80%, or at least 90% of the positions Distribution of glycosidic bonds representing all possible combinations of chemistry and stereochemistry. The chemical distribution can be determined by branching analysis, and the stereochemical distribution can be determined by NMR. HSQC-NMR. In some embodiments, the glycan therapeutic agent can be The various peaks in the anomeric region associated with multiplicative combinations of both amine and stereochemistry. In some embodiments, the glycan therapeutic agent is an alpha-1,2-, alpha At least one of alpha-1,3-, alpha-1,4-, and alpha-1,6-glycosides two or at least three, or beta-1,2-, beta-1,3-, beta- At least two of 1,4- and beta-1,6-glycosides or at least In some embodiments, the glycan therapeutic agent comprises alpha-1,2-, alpha-2, alpha-3, alpha-4, alpha-5, alpha-6, alpha-7, alpha-8, alpha-9, alpha-10, alpha-11, alpha-12, alpha-13, alpha-14, alpha-15, alpha-16, alpha-17, alpha-18, alpha-19, alpha-20, alpha All of the alpha-1,3-, alpha-1,4-, and alpha-1,6-glycosides All four, as well as beta-1,2-, beta-1,3-, beta-1,4-, and beta Contains all four of the ter-1,6-glycosides. For example, the glu100 formulation H SQC ensures that the preparation contains all alpha-1,2-, alpha-1,3-, and alpha-1 ,4-, and alpha-1,6-glycosides, as well as all beta-1,2-, beta- It has been shown to contain beta-1,3-, beta-1,4-, and beta-1,6-glycosides. Sugars that do not have a hydroxyl group at a given position X do not have the 1,X bond type, e.g. Fucose (6-dehydroxygalactose) does not have a 1,6-glycosidic bond, , 1,2-, 1,3-, and 1,4-glycosidic bonds. (v) Intrinsic HSQC “fingers” that are a result of the additive nature of the HSQC pulse sequence For any given glycan, the HSQC spectrum shows the specific regiochemical This allows for the identification of peaks that are specific to the bond configuration and stereochemistry. These peaks can be used to identify the regiochemistry and stereochemistry of specific glycosides. The partial spectral assignment of the glu100 preparation is shown, showing the component groups within the glycan. The glycan units (e.g., sugars) exhibit spin isolation in the HSQC pulse sequence, and the polysaccharide The HSQC spectrum of any glycan consisting of is the sum of its individual sugar peaks. A glycan unit component (e.g., a monomer) is a sequence of each of its glycan units (e.g., sugars). For this, HSQC scans showing 4, 5, 6, or more peaks listed in Table 7 were performed. The spectra in Figure 3a-c show the structures of glu100, gal10 This is illustrated by comparing the spectra of formulations of 0 and glu50gal50. do.

[0241] Pharmaceutical compositions, medical foods, and unit dosage forms One or more, two or more, three or more, or four of the characteristics of the formulations described herein A pharmaceutical composition comprising a glycan therapeutic agent meeting one or more of the above criteria (i) to (v), inclusive. Also provided herein are methods for producing the product. Specifically, the method comprises producing a glycan therapeutic agent. and providing, for example, i) the degree of polymerization (DP), ii) the average degree of branching (DB, per residue) branch points), iii) the ratio of alpha-glycosidic to beta-glycosidic bonds, iv ) the identity of the glycan units, and v) the ratio of the glycan units, obtaining values ​​for the above, or three or more characteristics, and determining the desired or predetermined value of the preparation If the criteria are met within the desired range of deviation, a pharmaceutical composition comprising a glycan therapeutic agent and generating

[0242] Formulating the glycan therapeutic agent into a pharmaceutical composition, medical food, or dietary supplement Methods for (i) formulating a pharmaceutical agent into a drug product are well known in the art and include: (ii) packaging the formulation; and (iii) packaging the formulation. (iv) packaging and labeling the compounded preparation. selling or offering for sale the labeled preparation. , two or more, three or more, or four or more. Formulation is well known in the art and involves (i) removing undesirable constituents from the formulation. (ii) reducing the volume of the preparation; and (iii) sterilizing; and (iv) mixing the formulation with a pharmaceutically acceptable excipient or carrier. (v) mixing the formulation with a second drug or pharmaceutical agent; and (vi) ) Formulating the preparation to a suitable consistency, such as an aqueous dilute solution, a syrup, or a solid. and (vii) dispensing the formulation into a suitable dosage form, e.g., a tablet, pill, or capsule. and formulating the compound into a composition comprising one or more, two or more, three or more, or four or more of the following: obtain.

[0243] In some embodiments, the glycan therapeutic agent is a glycan therapeutic agent syrup or powder. For example, in one variation, the glycan may undergo further processing to produce either The therapeutic preparation may be concentrated to form a syrup. Any suitable method known in the art for constricting may be used. In an example, the glycan therapeutic agent is spray dried to form a powder. Any suitable method known in the art for spray drying to form a powder may be used. , can be used.

[0244] Pharmaceutical compositions, medical foods, and dietary supplements comprising glycan therapeutic agents are Provided herein are pharmaceutical compositions, medical fluids, and the like, optionally comprising glycan therapeutic agents. The dietary supplements may contain a second agent, such as a prebiotic and / or In some embodiments, the glycan therapeutic agent further comprises probiotic bacteria. The pharmaceutical compositions, medical foods, and dietary supplements further contain micronutrients. In some embodiments, pharmaceutical compositions, medical foods, and the like, comprising glycan therapeutic agents. The food and dietary supplements do not contain probiotic substances. Pharmaceutical compositions, medical foods, and dietary supplements containing glycan therapeutic preparations are , does not contain prebiotic bacteria. Optionally, further comprising a glycan therapeutic agent; Pharmaceutical compositions, medical foods, and dietary supplements may contain additives such as diluents, binders, disintegrants, dispersants, and the like. one or more additives, including additives, lubricants, glidants, stabilizers, surfactants, flavoring agents, and coloring agents Includes excipients or carriers.

[0245] In some embodiments, the pharmaceutical compositions or medical foods and dietary supplements comprise: glu100, ara100, xyl100, gal100, glu50gal50, g al75xyl25, ara50gal50, man62glu38, ara50xyl 50, man52glu29gal19, or glu33gal33fuc33 Includes can-therapeutic preparations.

[0246] In some embodiments, the pharmaceutical compositions or medical foods and dietary supplements comprise: glu100, ara100, xyl100, glu50gal50, man52glu 29gal19, or glu33gal33fuc33 glycan therapeutic preparations.

[0247] In some embodiments, the pharmaceutical compositions or medical foods and dietary supplements comprise: Contains glycan therapeutic preparations of glu100 and man52glu29gal19.

[0248] In some embodiments, pharmaceutical compositions, medical foods, and the like, comprising glycan therapeutic agents. The dietary supplements (and kits containing them) contain one or more micronutrients. In some embodiments, the micronutrients include trace elements, choline, vitamins, and polyphenols. is selected from the group consisting of:

[0249] In some embodiments, the micronutrient is a trace metal. The elements include boron, cobalt, chromium, calcium, copper, fluoride, iodine, iron, Including, but not limited to, magnesium, manganese, molybdenum, selenium, and zinc It will not be done.

[0250] In some embodiments, the micronutrient is a vitamin. Vitamins include B complex, vitamin B1 (thiamine), vitamin B2 (livfv), Vitamin B3 (niacin), vitamin B5 (pantothenic acid), vitamin B6 Vitamin B6 (pyridoxine, pyridoxal, pyridoxamine), vitamin B7 (biotin), Vitamin B8 (ergodenylic acid), Vitamin B9 (folic acid), Vitamin B12 (cyanocobalamin) Vitamin A (retinol), Vitamin C (ascorbic acid), Vitamin Vitamin D, Vitamin E (tocopherol), Vitamin K, Carotenoids (alpha-carotene , beta-carotene, cryptoxanthin, lutein, lycopene), and zeaxanthin These include, but are not limited to:

[0251] In some embodiments, the micronutrient is a polyphenol. Characterized by having at least one aromatic ring bearing one or more hydroxyl groups. In some embodiments, polyphenols are chemical compounds or molecules that can be synthesized. In some embodiments, the polyphenol is a synthetic or naturally occurring polyphenol. The polyphenols are naturally occurring polyphenols and are derived from plant-source materials. do.

[0252] In some embodiments, the polyphenol is a flavonoid or a catechin. In some embodiments, the flavonoid or catechin is an anthocyanin, a chalcone, a disaccharide, or a hydroxybenzoate. Hydrochalcones, dihydroflavonols, flavanols, flavanones, flavones, flavones In some embodiments, the polyphenol is selected from the group consisting of phenols, isoflavonoids, and isoflavonoids. Le is a lignan.

[0253] In some embodiments, the polyphenol is an alkyl methoxy phenol, alkyl Phenol, curcuminoids, furanocoumarins, hydroxybenzaldehyde, hydroxy Dibenzoketone, hydroxycinnamaldehyde, hydroxycoumarin, hydroxyphenyl Propene, methoxyphenol, naphthoquinone, phenol terpene, and tyrosol In some embodiments, the polyphenol is selected from tannins or tannic acid. is.

[0254] In some embodiments, the polyphenol is a hydroxybenzoic acid, a hydroxycinnamic acid, , hydroxyphenylacetic acid, hydroxyphenylpropanoic acid, and hydroxyphenylpentanoic acid In some embodiments, the polyphenol is selected from stilbene. do.

[0255] In some embodiments, the polyphenol is a polyphenol selected from those listed in Table 5. It is one of these.

[0256] Additionally, if desired, pharmaceutical compositions, medical foods, and nutritional supplements contain therapeutically active agents, prebiotics, and / or probiotics. Alternatively or additionally, the present invention may include a therapeutically active agent, a prebiotic, or a combination thereof. The biotic substance and / or probiotic bacteria may be added separately (e.g., glycoproteins). a pharmaceutical composition of a glycan therapeutic agent, Not as part of a medical food or dietary supplement (e.g., as a co-formulation) In some embodiments, a pharmaceutical composition comprising a glycan therapeutic agent may be administered. , medical foods, and nutritional supplements are not intended to be used in conjunction with a recommended or prescribed diet, e.g. Combined with a diet rich in foods containing probiotics and / or prebiotics These drugs are administered in combination with other drugs and therefore should be administered at a time determined by a doctor or other healthcare professional. Therapeutic agents, prebiotics, and / or probiotics may be used. The bacteria may be administered to modulate the gut microbiome of a subject. In some embodiments, the combined effect (e.g., the number or strength of microbial, genomic, or functional changes) In other embodiments, the combined effects (e.g., microbial, genomic , or in the number or intensity of functional changes) is synergistic.

[0257] In some embodiments, a pharmaceutical composition comprising the glycan therapeutic agent described herein. Compositions, medical foods, and dietary supplements contain prebiotic substances or preparations thereof. The composition further comprises a

[0258] In some embodiments, the prebiotic is a glycan treatment described herein. A subject receiving a pharmaceutical composition, medical food, or dietary supplement, including a pharmaceutical preparation. Prebiotics, when consumed, can be administered to a limited number of specific bacteria in the digestive tract. A beneficial physiological effect on the host by selectively stimulating the desired growth or activity of bacteria. It is a non-digestible substance that can provide beneficial effects (Gibson GR, Roberfroi d M B.Dietary modulation of the human co lonic microbiota: introducing the concept of prebiotics.J Nutr.1995 June;125(6):1 401-12.) Dietary fiber or prebiotics such as prebiotic oligosaccharides (e.g., crystalline cellulose, wheat bran, oat bran, corn fiber, soy fiber, and beet fiber) promote gut function by providing bacteria with fermentable doses of carbohydrates. This further promotes the growth of probiotic and / or commensal bacteria and helps to reduce the risk of these microorganisms in the gastrointestinal tract. Levels of biological populations (e.g., lactobacilli and bifidobacteria) This can increase the bell.

[0259] Prebiotics include various galactan and carbohydrate-based gums, e.g., osmanthus Examples include ko, guar, carrageen, gellan, lactulose, and konjac. In some embodiments, the prebiotic is galactooligosaccharide. Gotosugar (GOS), lactulose, raffinose, stachyose, lactosucrose, fulvic acid C-oligosaccharides (FOS, e.g., oligofructose or oligofructans), dogs Phosphorus, isomalto-oligosaccharides, xylo-oligosaccharides (XOS), palatinose oligosaccharides Isomaltose oligosaccharides (IMOS), transgalactosylated oligosaccharides (e.g., transgalacto-oligosaccharides), transgalactosylated disaccharides, soybean oligosaccharides Sugars (e.g., soybean oligosaccharides), chitosan oligosaccharides (thioses), gentiooligosaccharides, soybeans and pectic oligosaccharides, glucooligosaccharides, peptin oligosaccharides, palatinose polycondensates, Difructose Anhydride III, Sorbitol, Maltitol, Lactitol, Polyols , polydextrose, linear and branched dextrans, pullulan, Hemicellulose, reduced palatinose, cellulose, beta-glucose, beta-galactose Fructose, beta-fructose, verbascose, galactinol, xylan, inulin , chitosan, beta-glucan, guar gum, gum arabic, pectin, high alginic acid sodium The composition may contain one or more of thorium, and lambda carrageenan, or a mixture thereof.

[0260] Prebiotics are found in certain foods, such as chicory root, Jerusalem artichoke, and dandelion. leaves, garlic, leeks, onions, asparagus, wheat bran, flour, bananas, milk, Yogurt, sorghum, burdock, broccoli, Brussels sprouts, cabbage, cauliflower, It can be found in collard greens, kale, radishes, rutabaga, and miso. In embodiments, the glycan therapeutic agents described herein are rich in prebiotics. Suitable sources of soluble and insoluble fiber are commercially available. It has been done.

[0261] In some embodiments, pharmaceutical compositions, medical foods, and the like, comprising glycan therapeutic agents. Foods and dietary supplements, for example, contain bacteria that are generally recognized as safe (GRAS). Probiotics derived from cultures or known commensal or probiotic microorganisms In some embodiments, the composition further comprises an endogenous commensal microorganism or a preparation thereof. or to maximize the beneficial effects of exogenously administered probiotic microorganisms. , pharmaceutical compositions, medical foods, and dietary supplements containing glycan therapeutic formulations are It is administered to stimulate the growth and / or activity of beneficial bacteria in the intestinal tract.

[0262] Examples of suitable probiotics include Bacteroides, Blautia, Clostridium, Fusobacterium, Eubacterium, Ru minococcus, Peptococcus, Peptostreptococcu s, Akkermansia, Faecalibacterium, Roseburia , Prevotella, Bifidobacterium, Lactobacillus s, Bacillus, Enterococcus, Escherichia, Stre. Genus ptococcus, Saccharomyces, Streptomyces, and and organisms classified as the Christensenellaceae family. Proteases that may be used in the methods and compositions described herein include, but are not limited to: Non-exclusive examples of biotic bacteria include L. acidophilus, Lactoba cillus species, such as L.crispatus, L.casei, L. .rhamnosus, L.reuteri, L.fermentum, L.plant arum, L. sporogenes, and L. bulgaricus, and Bif idobacterum species, e.g., B. lactis, B. anima lis, B. bifidum, B. longum, B. idolescentis, and B. infantis, Saccharomyces boulardii, etc. The yeasts may also be used as probiotics for administration to the gastrointestinal tract, for example, in oral dosage forms or via food. For example, yogurt is suitable as a food supplement containing Lactobacillus buprenorphine. Bacteria such as IgE and Streptococcus thermophilus This product already contains seeds.

[0263] Bacteria that are beneficial in modulating the gastrointestinal microflora include, for example, hydrogen peroxide (H2O2) and bacteria. Organic acid (lactic and acetic) generating or cytotoxic or cytostatic agents, such as osin Bacteriocins can include bacteria that produce them (to inhibit the growth of pathogens). can kill the bacteria involved or have a broader spectrum of activity (e.g. For example, nisin), a small antibacterial peptide.

[0264] Beneficial bacteria include Akkermansia, Anaerofilum, and Bacterio Des, Blautia, Bifidobacterium, Butyrivibrio , Clostridium, Coprococcus, Dialister, Dorea , Fusobacterium, Eubacterium, Faecalibacter ium, Lachnospira, Lactobacillus, Phascolarc tobacterium, Peptococcus, Peptostreptococc us, Prevotella, Roseburia, Ruminococcus, and S One or more of the genus streptococcus and / or Akkermansi a municiphilia, minuta, Clostridium coccoi des, Clostridium leptum, Clostridium scind ens, Dialister invisus, Eubacterium rectal , Eubacterium eligens, Faecalibacterium pr ausnitzii, Streptococcus salivarius, and Str. The bacteria may include one or more of the species Proteococcus thermophiles. In some embodiments, the probiotic or probiotic bacteria include those listed in Table 1. Contains one or more of the following:

[0265] Combined with the glycan therapeutic agent described herein to produce the composition or kit Prebiotic substances and probiotic strains that can be combined are prepared by standard methods. The compounds can be isolated to any level of purity by conventional means known to those skilled in the art, such as distillation. This can be achieved by recrystallization, recrystallization, and chromatography. The cultivated bacteria can be separated by a number of methods, including centrifugation, filtration, or decantation. It can be separated from the culture broth by any method, including but not limited to, or separated from the fermentation broth. The cells were optionally resuspended in water, saline (0.9% NaCl), or any suitable solution. The resulting wet cell mass is washed with a suitable buffer. It can be dried by freeze drying.

[0266] In some embodiments, the probiotic bacteria are freeze-dried vegetative cells. In some embodiments, a preparation of spores from spore-forming probiotic bacteria is used. can be.

[0267] In one embodiment, the pharmaceutical glycan treatment composition comprises prebiotics and probiotics. In one embodiment, the pharmaceutical composition further comprises a partially attenuated viability Probiotics (e.g., 10%, 20%, 30%, 40%, 50%, or more) probiotics consisting solely of non-viable microorganisms (mixtures containing the above non-viable bacteria) The composition comprises microbial membranes and / or microbial proteins isolated and purified from killed microorganisms. The probiotic organism may further comprise a cell wall. The pharmaceutical preparation is prepared as a liquid or semi-solid medium in water or other liquids in which the lab-grown cereals can survive. In another technique, probiotic organisms can be incorporated into the therapeutic composition. The lyophilized powder containing the particulate material or the liquid or semi-solid material can be mixed or blended. may be incorporated into the fee.

[0268] In some embodiments, pharmaceutical compositions, medical foods, and the like, comprising glycan therapeutic agents. The food and dietary supplements may further comprise a second therapeutic agent or a formulation thereof. In some embodiments, the therapeutic agent may be an antibiotic, antibacterial, antiviral, or anti-inflammatory agent (e.g., a cytotoxic agent). Antibiotics include aminoglycosides, e.g., amikacin, gefitinib, and cefotaxime. ampicillin, kanamycin, neomycin, streptomycin, and tobramycin Cephalosporins, such as cefamandole, cefazolin, cephalexin, cef aloglycine, cephaloridine, cephalothin, cephapirin, and cephradine; macroglycemic amides such as erythromycin and troleandomycin; penicillins such as penicillin Nicillin G, amoxicillin, ampicillin, carbenicillin, cloxacillin, diclofenac Xacillin, methicillin, nafcillin, oxacillin, feneticillin, and ticarcillin polypeptide antibiotics, e.g., bacitracin, colistimethate, colistin, polyclonal antibodies; Rimyxin B; Tetracyclines, e.g., chlortetracycline, demeclocycline doxycycline, methacycline, minocycline, tetracycline, and oxalic acid cytetracycline; and miscellaneous antibiotics, e.g., chloramphenicol, chloramphenicol, damycin, cycloserine, lincomycin, rifampin, spectinomycin, These include comycin, viomycin, and metronidazole.

[0269] The glycan therapeutic agents described herein, other therapeutically active agents, prebiotics The steroids, micronutrients, and probiotics may be combined in a single pharmaceutical composition, In other embodiments, the composition may be mixed or admixed with a food, drink, or dietary supplement. These may be contained in separate containers (and / or in various suitable unit dosage forms), but may be combined into one In some embodiments, the formulations or compositions may be packaged together in a kit. The ingredients are not packaged or placed together. For example, the preparations or compositions may be administered together, before, simultaneously with, or after each other. In some embodiments, the formulation or composition is administered to a subject, e.g., in the gastrointestinal tract. They act synergistically in modulating the microbiota.

[0270] In some embodiments, the pharmaceutical composition comprises a w / w, w / v, v / v, or molar % In another embodiment, the pharmaceutical composition comprises 0.1% to 100% of the glycan therapeutic agent. , w / w, w / v, v / v, or mole %, about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17% , 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27% , 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37% , 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47% , 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57% ,58%,59%,60%,61%,62%,63%,64%,65%,66%,67% ,68%,69%,70%,71%,72%,73%,74%,75%,76%,77% , 78%, 79% 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87% ,88%,89%,90%,91%,92%,93%,94%,95%,96%,97% , 98%, 99%, 99.5%, or 100% glycan therapeutic formulation. In some embodiments, the pharmaceutical composition may be present in an amount of about 1 to 90%, about 1 to 90%, or about 1 to 90% by w / w, w / v, v / v, or molar percent. 10-90%, approximately 20-90%, approximately 30-90%, approximately 40-90%, approximately 40-80%, approximately 40-70%, approximately 40-60%, approximately 40-50%, approximately 50-90%, approximately 50-80%, approximately 50-70%, about 50-60%, about 60-90%, about 60-80%, about 60-70%, about 70-90%, approximately 70-80%, approximately 70-90%, approximately 70-80%, approximately 80-90%, approximately 90-96%, approximately 93-96%, approximately 93-95%, approximately 94-98%, approximately 93-99%, or or approximately 90-100% glycan therapeutic preparations.

[0271] Pharmaceutical compositions containing glycan therapeutic agents optionally contain one or more excipients or carriers. The pharmaceutical composition may contain from about 1% to about 90% by w / w, w / v, v / v, or molar percentage. For example, a pharmaceutical composition may contain one or more excipients or carriers such as: In terms of v / v or mole %, approximately 1-90%, 1-75%, 1-60%, 1-55%, 1-5 0%, 1-45%, 1-40%, 1-25%, 1-15%, 1-10%, 10-90%, 10-75%, 10-60%, 10-55%, 10-50%, 10-45%, 10-40 %, 10~25%, 10~15%, 15~90%, 15~75%, 15~60%, 15~ 55%, 15-50%, 15-45%, 15-40%, 15-25%, 25-90%, 2 5~75%, 25~60%, 25~55%, 25~50%, 25~45%, 25~40% , 40~90%, 40~75%, 40~60%, 40~55%, 40~50%, 40~4 5%, 45-90%, 45-75%, 45-60%, 45-55%, 45-50%, 50 ~90%, 50~75%, 50~60%, 50~55%, 55~90%, 55~75%, 55-60%, 60-90%, 60-75%, 75-90% of one or more excipients or carriers It may include a body.

[0272] Medical Food Also provided herein are formulations of glycan therapeutic agents formulated as medical foods. Any of the glycan therapeutic agents described herein includes glycan therapeutic agents It can be formulated as a medical food and pharmaceutical composition.

[0273] Medical foods are subject to the Orphan Drug Act (21 USC 360ee(b)( 3)) Section 5(b)(3). Medical food is, for example, Consumed (ingested) or administered enterally (e.g., as part of a nutritional regimen) under medical supervision by a It is formulated to treat diseases or conditions, such as gastrointestinal microorganisms. Intended for the specific dietary management of microbial dysbiosis or gastrointestinal disorders described herein. Medical food, as used herein, refers to a food that is used to manage symptoms or may be prescribed by a physician solely as part of an overall diet to reduce the risk of a disease or condition Medical foods containing glycan therapeutic preparations are not synthetic Foods that are provided to patients (e.g., by oral intake or enteral feeding through a tube) are formulated and / or processed products, such as those formulated for specialized nutrition , a non-naturally occurring food ingredient used in its natural state. Medical foods may represent a primary component in the management of diseases or conditions of the gastrointestinal tract, e.g., medicinal foods. Medical Food provides a partial or specialized source of food for subjects requiring medical food. In some embodiments, the subject may consume regular food or certain nutrients. Limited or reduced capacity to ingest, digest, absorb, or metabolize. In other embodiments, the subject has other special medically determined nutritional needs and their diet Management cannot be achieved by modification of normal diet alone. Medical foods containing it are taken under medical supervision (which can be active and continued) when necessary. The medical food is administered to a subject who is to receive the medical food. A medical food contains one or more food additives, color additives, GRAS excipients, etc. and other drugs or substances suitable for medical foods. The formulation may be a nutritionally complete or incomplete formulation.

[0274] nutritional supplements Any of the glycan therapeutic agents described herein may be, for example, any of the methods described herein. The composition may be formulated as a dietary supplement for use in the method.

[0275] Dietary supplements are regulated under the Dietary Supplement Health and Education Act of 1994 (DSHEA). Dietary supplements are products taken by mouth that contain "dietary ingredients" that are intended to supplement the diet. The "dietary ingredients" in these products are the glycans described herein. In addition to therapeutic preparations, vitamins, minerals, herbs or other botanicals, amino acids, and one or more of the following substances: enzymes, organ tissues, glands, and metabolic products. The food product may also be an extract or concentrate and may be available in the form of a tablet, capsule, softgel, or gelcap. They can be found in many forms such as cups, liquids, or powders. They are also available in other forms such as bars. If so, the label generally identifies the product as a conventional food or will not be labeled as a meal or a single item in the diet. Supplements must be labeled as dietary supplements, not as general foods. do.

[0276] Dosage form The glycan therapeutic agents described herein can be administered, for example, orally or enterally. The dosage forms described herein can be formulated into any suitable dosage form. It can be produced using

[0277] Dosage forms include, for example, liquids (wash / rinse), gels, creams, ointments, powders, tablets, capsules, etc. in the form of a syringe, repository, disposable applicator, or medical device (e.g., syringe) and may be packets such as any individual containers containing pharmaceutical glycan treatment compositions. For example, unit dosage forms of pharmaceutical glycan therapeutic compositions and methods for using such glycan therapeutic agents Also provided are articles of manufacture such as containers that include labels containing instructions for use in the preparation of the product.

[0278] Orally available forms of the composition include tablets, push-fit capsules made of gelatin, and the like. Capsules are also made of gelatin and plasticizers such as glycerol or sorbitol. Tablets include compressed soft capsules, optionally with one or more accessory ingredients. Compressed tablets can be made by compression or molding. Compressed tablets can optionally contain binders (e.g., polyisoprene). Vidon, gelatin, hydroxypropyl methylcellulose), inert diluents, preservatives, acid Antioxidants, disintegrants (e.g., sodium starch glycolate, cross-linked povidone, cross-linked calcium carbonate) sodium carboxymethylcellulose), or mixed with a lubricant, surfactant, or dispersant The combined active ingredients in a free-flowing form such as powder or granules are compressed in a suitable machine. Molded tablets can be prepared by mixing powdered granules moistened with an inert liquid diluent. The mixture can be made by molding in a suitable machine. , which may optionally be coated or scored, for slow release of the active ingredient therein Alternatively, the drug may be formulated to provide controlled release. The tablets may optionally be enteric coated to provide release in the rectum, colon, or lower intestinal tract. All formulations for oral administration should be administered in dosages suitable for such administration. Push-fit capsules may contain fillers such as lactose, binders such as starches, and / or or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active compound and / or other drugs (e.g. prebiotics or probiotics) in fatty oils, liquid paraffin, or can be dissolved or suspended in a suitable liquid such as liquid polyethylene glycol. Additionally, stabilizers can be added. The cores of the dragees are coated with a suitable coating. For this purpose, a concentrated sugar solution can be used, which can optionally contain arabic acid. Gum, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, or titanium dioxide, a lacquer solution, and a suitable organic solvent or solvent mixture. For the purpose of identifying or characterizing different combinations of doses of active compounds, Dyestuffs or pigments can be added to tablets or dragee coatings.

[0279] Formulations for oral use may also be prepared in which the active ingredient is dissolved in an inert solid diluent, e.g., calcium carbonate. As a hard gelatin capsule mixed with calcium phosphate or kaolin Alternatively, the active ingredient may be dissolved in a water-soluble carrier such as polyethylene glycol, or an oily medium, e.g., Soft gelatin capsules mixed with floral oil, liquid paraffin, or olive oil It can also be presented as

[0280] In one embodiment, the provided glycan therapeutic composition comprises a soft gel formulation. The gel may include a gelatin-based shell surrounding a liquid fill. , plasticizers (e.g., glycerin and / or sorbitol), modifiers, water, pigments, antioxidants The shell can be made of starch or carrageenan. The outer layer may be enteric coated. In one embodiment, a softgel The formulation may comprise an aqueous or oil-soluble fill solution of the composition covered with a layer of gelatin, or It may comprise a suspension.

[0281] A solid formulation for oral use is a formulation in which the glycan therapeutic composition is absorbed in the digestive system. For example, the enteric coating may include an enteric coating that can control the amount of glycan therapy. The pharmaceutical composition is designed not to dissolve in the stomach, but rather to pass to the small intestine and dissolve there. Enteric coatings can be stable at low pH (such as in the stomach) and at higher pH levels. It can be used in enteric coatings. Possible materials include, for example, alginate, cellulose acetate phthalate, plastics, waxes, lac, and fatty acids (e.g., stearic acid, palmitic acid).

[0282] Formulations for oral use may also be presented in liquid form. Liquid preparations may be, for example, aqueous or may be in the form of an oily suspension, solution, emulsion syrup, or elixir, or Presented as a dry product for reconstitution with water or other suitable vehicle before use Such liquid preparations may contain suspending agents such as sorbitol, methylcellulose, Glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose corn starch, aluminum stearate gel, or hydrogenated edible fats, emulsifiers such as lecithin , sorbitan monooleate, gum arabic; non-aqueous vehicles (which may include edible oils), e.g. For example, almond oil, oily esters such as glycerin, propylene glycol, or Ethyl alcohol; preservatives, such as methyl or propyl p-hydroxybenzoate or or sorbic acid, and, if desired, conventional flavorings or colors. In some embodiments, the liquid formulation may contain, for example, an aqueous solution and / or a suspension. Liquid forms of the drug; and polyethoxylated castor oil, alcohol, with or without flavoring. and / or a vehicle containing polyoxyethylated sorbitan monooleate. Each dosage form contains an effective amount of a glycan therapeutic agent and, optionally, a pharmaceutically inactive substance, such as , conventional excipients, vehicles, fillers, binders, disintegrants, pH adjusting substances, buffers, solvents, Dissolving agents, sweeteners, coloring agents, and any other additives that may be included in a pharmaceutical dosage form for administration. Examples of such vehicles and additives are listed in Remington's Pharmaceutical Sciences,17th edition(19 85).

[0283] The pharmaceutical compositions provided herein may be in unit dosage form or multiple dosage form. Form, as used herein, refers to a physically discrete form suitable for administration to a human in need thereof. In one embodiment, the unit dosage form is provided in a package. Each unit dose is , a predetermined quantity of the active ingredient(s) sufficient to produce the desired therapeutic effect, It may be contained together with a pharmaceutical carrier or excipient. Examples of unit dosage forms include ampoules, syringes, etc. and individually packaged tablets and capsules. A unit-dosage form may be administered in fractions or multiples thereof. is a package of multiple identical unit dosage forms in a single container, and is divided into Examples of multiple dose forms include vials, tablets, and the like. Examples include bottles of tablets or capsules, or bottles of pints or gallons. In another embodiment, the multiple dose dosage form comprises different pharmaceutically active agents. For example, a first administration element containing a composition containing a glycan therapeutic agent, and a pre-administration element a second administration element containing an antimicrobial, a therapeutic agent, and / or a probiotic; In this example, a multiple dose dosage form may be provided, which may be in modified release form. In one embodiment, each unit comprises a pair of dosing elements. a first administration element comprising a composition comprising a glycan therapeutic agent, and a probiotic a second administration element containing a steroid, a pharmaceutical agent, a prebiotic, or a combination thereof; A kit containing a plurality of unit doses of the compound is provided, which is in a modified release form. In another embodiment, the kit further comprises a set of instructions.

[0284] In some embodiments, the unit dosage form contains from about 0.001 mg to about 10 g of the glycan therapeutic agent. (e.g., a glycan therapeutic agent disclosed herein). For example, the unit dosage form may contain about 0. 0.001mg to about 9.5g, about 0.005mg to about 9g, about 0.01mg to about 8.5g, about 0.05mg to about 8g, about 0.075mg to about 7.5g, about 0.1mg to about 7g, about 0. 25mg to about 6.5g, about 0.5mg to about 6g, about 0.75mg to about 5.5g, about 1mg ~about 5g, about 2.5mg to about 4.5g, about 5mg to about 4g, about 7.5mg to about 3.5g, Approximately 10mg to approximately 3g, approximately 12.5mg to approximately 2.5g, approximately 15mg to approximately 2g, approximately 17.5m g ~ about 1.5g, about 20mg - about 1g, about 25mg - about 750mg, about 50mg - about 50 It may contain 0 g, or about 75 mg to about 250 mg of the glycan therapeutic agent.

[0285] In certain embodiments, the unit dosage form comprises from about 0.001 mg to about 100 mg, about 0.00 5mg to about 75mg, about 0.01mg to about 50mg, about 0.05mg to about 25mg, about 0 0.1mg to about 10mg, about 0.5mg to about 7.5mg, or about 1mg to about 5mg In other embodiments, the unit dosage form contains about 1 mg to about 100 mg, about 2.5 mg, or a therapeutic agent. mg to about 75 mg, about 5 mg to about 50 mg, or about 10 mg to about 25 mg of glycan therapeutic agent In other embodiments, the unit dosage form contains about 100 mg to about 10 g, about 250 mg to about 10 g, or about 250 mg to about 10 g of a therapeutic agent. Approximately 7.5g, approximately 500mg to approximately 5g, approximately 750mg to approximately 2.5g, or approximately 1g to approximately 2g glycan therapeutics.

[0286] In other embodiments, the unit dosage form contains from about 0.001 mL to about 1000 mL of the glycan therapeutic agent (e.g., a glycan therapeutic agent disclosed herein). For example, the unit dosage form may contain about 0. 001mL ~ approx. 950mL, approx. 0.005mL ~ approx. 900mL, approx. 0.01mL ~ approx. 85 0mL, about 0.05mL to about 800mL, about 0.075mL to about 750mL, about 0.1m L ~ approx. 700mL, approx. 0.25mL ~ approx. 650mL, approx. 0.5mL ~ approx. 600mL, approx. 0 .75mL to approx. 550mL, approx. 1mL to approx. 500mL, approx. 2.5mL to approx. 450mL, approx. 5mL to approx. 400mL, approx. 7.5mL to approx. 350mL, approx. 10mL to approx. 300mL, approx. 1 2.5mL to approx. 250mL, approx. 15mL to approx. 200mL, approx. 17.5mL to approx. 150mL , about 20 mL to about 100 mL, or about 25 mL to about 75 mL of glycan therapeutic agent.

[0287] In certain embodiments, the unit dosage form is from about 0.001 mL to about 10 mL, about 0.005 mL mL ~ approx. 7.5 mL, approx. 0.01 mL ~ approx. 5 mL, approx. 0.05 mL ~ approx. 2.5 mL, approx. 0 0.1mL to approx. 1mL, approx. 0.25mL to approx. 1mL, or approx. 0.5mL to approx. 1mL In other embodiments, the unit dosage form contains from about 0.01 mL to about 10 mL, about 0 0.025mL to approximately 7.5mL, approximately 0.05mL to approximately 5mL, or approximately 0.1mL to approximately 2. In other embodiments, the unit dosage form contains about 0.1 mL to about 10 mL of the glycan therapeutic agent. mL, about 0.25mL to about 7.5mL, about 0.5mL to about 5mL, about 0.5mL to about 2. Contains 5 mL, or about 0.5 mL to about 1 mL of glycan therapeutic agent.

[0288] In some embodiments, the unit dosage form may be, for example, a tablet, a capsule (e.g., a hard capsule), or a combination thereof. tablet, push-fit capsule, or softgel) or softgel is approximately 0.1 inch inches to about 1.5 inches (e.g., about 0.5 inches and about 1 inch), or about 5 mm to about It has a body length of 50 mm (e.g., about 10 mm to about 25 mm). , unit dosage forms such as tablets, capsules (e.g., hard capsules, push-fit capsules, or soft capsule), or soft gel, about 0.05 inches to about 1 inch (e.g. , about 0.1 inches to about 0.5 inches), or about 1 mm to about 25 mm (e.g., about 5 mm The outer diameter is approximately 10 mm.

[0289] Each unit dosage form of glycan therapeutic agent contains approximately 0.01 kcal to approximately 1000 kcal. For example, the unit dosage form may have a value of about 0.01 kcal to about 900 kcal, about 0.0 5kcal ~ approx. 800kcal, approx. 0.1kcal ~ approx. 700kcal, approx. 0.25kcal al~about 600kcal, about 0.5kcal~about 500kcal, about 0.75kcal~ Approximately 400kcal, approximately 1kcal to 300kcal, approximately 5kcal to approximately 200kcal, Alternatively, the caloric value may be from about 10 kcal to about 100 kcal. Therefore, the unit dosage form of the glycan therapeutic agent has a calorie value of 10 kcal to approximately 500 kcal. In another embodiment, the unit dosage form of the glycan therapeutic agent is 50 kcal to about 500 kcal. It has a calorie value of 1.

[0290] In yet other embodiments, the unit dosage form contains from about 0.001 kcal to about 100 kcal, about 0.005kcal ~ approx. 90kcal, approx. 0.01kcal ~ approx. 80kcal, approx. 0.0 25kcal ~ approx. 70kcal, approx. 0.05kcal ~ approx. 60kcal, approx. 0.075k cal ~ approx. 50kcal, approx. 0.1kcal ~ 40kcal, approx. 0.25kcal ~ approx. 3 0kcal, about 0.5kcal to about 25kcal, about 0.25kcal to about 20kcal or may have a caloric value of about 0.1 kcal to about 10 kcal.

[0291] The unit dosage form of the glycan therapeutic agent is dissolved in an aqueous solution (e.g., water, milk, juice, etc.). and administered orally as a drink, syrup, solution, or suspension. For example, a unit dose of the glycan therapeutic agent is formulated for dissolution in an aqueous solution prior to oral administration. packed cubes, packets, lozenges, pills, tablets, capsules, candies, powders, It may include an elixir or concentrated syrup. In other embodiments, a single glycan therapeutic agent may be used. The dosage form dissolves in vivo, e.g., in the mouth, stomach, intestines, or colon of a subject, upon oral administration. cubes, packets, lozenges, pills, tablets, capsules, formulated for dissolution; May include candies, powders, elixirs, or concentrated syrups.

[0292] In some embodiments, the glycan therapeutic composition is administered into the intestine. This is preferred. Indirectly, including oral administration or via oral or nasal tube (nasogastric, nasojejunal) In other embodiments, administration includes rectal administration (including enema). , suppositories, or colonoscopy).

[0293] The dosage forms described herein can be manufactured using processes known to those skilled in the art. For example, for the production of tablets, high shear granulation, low shear granulation, and fluidized bed granulation are used. or formulated for direct compression to provide an effective amount of prebiotics in 1 It can be dispersed evenly in one or more excipients or additives. diluents, binders, disintegrants, dispersants, lubricants, glidants, stabilizers, surfactants, anti-adhesives These include binders, adsorbents, sweeteners, and colorants, or combinations thereof. Diluents, as they are called, are used to increase the bulk of the tablet so that it has a practical size for compression. Non-limiting examples of diluents include lactose, cellulose, microcrystalline Cellulose, mannitol, dry starch, hydrolyzed starch, powdered sugar, talc, sodium chloride Thorium, silicon dioxide, titanium dioxide, dicalcium phosphate dihydrate, calcium sulfate, Binders include calcium carbonate, alumina, and kaolin. Binders provide cohesive properties to tablet formulations. This can be used to help ensure that the tablet remains intact after compression. Non-limiting examples of suitable binders include starches (corn starch and aluminum starch). starch), gelatin, sugars (e.g., glucose, dextrose, sucrose), sugar, lactose, and sorbitol), cellulose, polyethylene glycol, alginate acid, dextrin, casein, methylcellulose, waxes, natural and synthetic rubbers, e.g., thiamin, Gum lagacantha, sodium alginate, gum arabic, xanthan gum, and poly Methacrylic acid, polyvinyl alcohol, hydroxypropyl cellulose, and polyvinyl Lubricants include synthetic polymers such as pyrrolidone. Lubricants can also facilitate tablet manufacture. non-limiting examples include magnesium stearate, calcium stearate, Disintegrants include stearic acid, glyceryl behenate, and polyethylene glycol. Disintegration of the tablet after administration can be aided by additives such as starch, alginate, etc. Acids, cross-linked polymers such as cross-linked polyvinylpyrrolidone, croscarmellose sodium , potassium starch glycolate or sodium starch glycolate, clay, cell cellulose (e.g., carboxymethylcellulose (e.g., carboxymethylcellulose ( CMC), CMC-Na, CMC-Ca), starch, rubber, etc. Non-limiting examples of accelerators include silicon dioxide, talc, etc. Stabilizers are used to inhibit oxidation reactions. It can inhibit or delay drug decomposition reactions. and can be anionic, cationic, amphoteric, or nonionic. Contains stevia extract, aspartame, sucrose, alitame, saccharin, etc. Optionally, the tablet may contain pH buffering agents, preservatives such as antioxidants, wetting agents, or or emulsifiers, solubilizers, coating agents, flavoring agents (e.g., mint, cherry, anise, It may also contain non-toxic supplements such as peach, apricot, licorice, raspberry, and vanilla. The excipients and additives include aluminum acetate, benzyl alcohol, butylparaben, Butylated hydroxytoluene, calcium disodium EDTA, calcium hydrogen phosphate Dihydrate, Dibasic Calcium Phosphate, Tribasic Calcium Phosphate, Candelilla Wax, Calcium Phosphate Nauba wax, hydrogenated castor oil, cetylpyridine chloride, citric acid, colloidal silicon dioxide, Copolyvidone, corn starch, cysteine ​​HCl, dimethicone, disodium hydrogen phosphate Thorium, erythrosine sodium, ethyl cellulose, gelatin, glycerin, mono- Glyceryl leate, glyceryl monostearate, glycine, HPMC phthalate (p thalate), hydroxypropyl cellulose, hydroxypropyl methyl cellulose ferric oxide, red iron oxide, yellow iron oxide, iron oxide or acid Ferric chloride, magnesium carbonate, magnesium oxide, magnesium stearate, methionine methacrylic acid copolymer, methylparaben, silicified microcrystalline cellulose, mineral oil, phosphate , ordinary calcium phosphate, anhydrous calcium phosphate, polaxamer 407, polaxamer 1 88, normal polaxamer, polyethylene oxide, polyoxy 140 stearate, poly Sorbate 80, potassium bicarbonate, sodium sorbate, potato starch, pobi Ingredients: propylene glycol, propylene paraben, propyl paraben, retinyl palmitate Sodium saccharin, selenium, silica, silica gel, fumed silica, benzoate Sodium carbonate, sodium citrate dihydrate, sodium crossmellose Sodium laurate, sodium metabisulfite, sodium propionate, sodium Trisodium Starch, Sodium Starch Glycolate, Sodium Stearyl Fumarate, Sorbic acid, sorbitol, sorbitan monooleate, pregelatinized starch, succinic acid , triacetin, triethyl citrate, vegetable stearin, vitamin A, vitamin E, vitamin The amounts of these excipients and additives may vary depending on the individual formulation. The composition may be appropriately selected based on its relationship to the components of the present invention and the characteristics of the formulation and production method.

[0294] An immediate release formulation of an effective amount of the glycan therapeutic composition provides rapid release of the pharmaceutically active agent (1 hour after administration). The formulation may contain one or more combinations of excipients that allow for controlled release (minutes to 1 hour, etc.). Sustained release (SR), extended release (ER, XR, or XL), sequential continuous release (time- timed-release, controlled-release (CR) (also referred to as sustained release) refers to the release of a drug at a specific desired time point after the dosage form has been administered to a subject. This refers to the release of the glycan therapeutic composition from the dosage form.

[0295] In one embodiment, the controlled release dosage form initiates its release and continues its release over an extended period of time. Release may begin almost immediately or may be continuous. may be obtained, may increase or decrease over time, may be pulsed, may be continuous or intermittent, etc. In one embodiment, a controlled release dosage form allows the drug to follow a desired profile over an extended period of time. In one aspect, controlled release refers to the release of a drug from a composition or dosage form that is released by: A composition or formulation that releases the drug according to a desired profile, where the release occurs after a period of time. refers to the delayed release of a drug from a dosage form.

[0296] Suitable pharmaceutical carriers or vehicles for administration of the compounds provided herein are well suited to the particular administration The composition may comprise any carrier known to those skilled in the art that is suitable for the mode of administration. , one or more components that do not impair the desired action, or that supplement or otherwise enhance the desired action. It may also contain active ingredients.

[0297] In a further aspect, the dosage form can be an effervescent dosage form. Effervescent means that the dosage form is able to absorb water and saliva. It means that when mixed with a liquid containing a certain type of effervescent agent ( or effervescent couple) occurs upon exposure of the effervescent disintegrant to water or saliva in the mouth. The reaction occurs when a soluble acid source reacts with an alkali or monocarbonate to produce a gas. This can be the result of reaction with a source of alkali carbonate. The reaction of these two common compounds It produces carbon dioxide gas upon contact with water or saliva. In addition, effervescent couples (or individual acids and bases separately) can be used as solvent barrier coatings or The couple may be enteric coated. It can also be mixed with previously freeze-dried particles (such as glycan therapeutics). The acid can be anything that is safe to consume, and generally includes food acids, acids, and hydration. Hydrite antacids, e.g., citric acid, tartaric acid, amaryllis Carbonate sources may include those of carboxylic acid, fumaric acid, adipic acid, and succinic acid. carbonates and bicarbonates of, for example, preferably sodium bicarbonate, sodium carbonate, bicarbonate These include potassium carbonate, potassium carbonate, and magnesium carbonate. In one embodiment, citric acid and and sodium bicarbonate are used.

[0298] In another embodiment, the dosage form is in the form of a candy, such as a lollipop or lozenge (e.g., In one embodiment, an effective amount of the glycan therapeutic agent is dispersed in a candy matrix. In one embodiment, the candy base is made of one or more sugars, such as dextrose or In another embodiment, the candy matrix is ​​a sugar-free matrix. There is a wide variation in the choice of specific candy bases. sugar alcohols suitable for use by diabetics (e.g., sorbitol, Sweeteners such as mannitol, or other sweeteners (e.g., those described herein) may be used. The candy base may be very soft and fast dissolving, or hard. The various forms may have advantages in different situations. There will be.

[0299] A candy mass composition containing an effective amount of a glycan therapeutic agent is The candy mass is orally administered to a subject in need thereof, and an effective amount of the candy mass is released as the candy mass dissolves. The lican therapeutic agent can be released into the subject's oral cavity and swallowed. Subjects in need include adults or children.

[0300] The dosage forms described herein may also be prepared by high pressure homogenization, wet or dry ball milling, or or small particle precipitation (e.g., nGimat nanospray). It can also take the form of pharmaceutical particles that are not manufactured by various methods. Another method useful for making a powder formulation is to prepare a solution of the active ingredient and excipients, and then The solution is then precipitated, filtered, and pulverized, or subsequently removed by freeze-drying. and then micronizing the powder to a desired particle size. In one embodiment, the pharmaceutical particles are 3 to 1000 microns, e.g., up to 3, 4, 5, 6, 7, 8, 9, 10, 20, 30 , 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 3 50, 400, 450, 500, 550, 600, 650, 700, 750, 800, 8 In another embodiment, the drug has a final size of 50, 900, 950, or 1000 microns. In another embodiment, the pharmaceutical particles have a final size of 10 to 500 microns. The particles have a final size of 50 to 600 microns. With a final size of 100 to 800 microns.

[0301] In another aspect, the present disclosure provides a method of making the unit dosage forms described herein, The method includes providing a glycan therapeutic agent (e.g., a glycan therapeutic agent described herein). and formulating the glycan therapeutic agent into a unit dosage form (e.g., a unit dosage form described herein). packaging the unit dosage forms and labeling the packaged unit dosage forms. and / or sell the packaged and labeled unit dosage forms; includes offering for sale.

[0302] The unit dosage forms described herein may also be processed. In one embodiment, the processing comprises: Processing the dosage form into a pharmaceutical composition, e.g., by adding a second component, e.g., an excipient or buffer. Formulate with buffer and mix; divide into smaller or larger aliquots; Dispose of in a suitable container, e.g., airtight or liquid-tight; package; label This includes one or more of: combining; shipping or moving to a different location. In an embodiment, this processing includes sorting, selecting, accepting or discarding, releasing or withholding, processing into pharmaceutical compositions, shipping or transferring to a different location to operate, formulate, label, package, and release into commerce. or selling or offering for sale, depending on whether certain thresholds are met. In some embodiments, the processed dosage form includes one or more of the following: The glycan therapeutic agent described herein is included.

[0303] In some embodiments, the processing involves processing the dosage form into a pharmaceutical composition, e.g., Formulating and mixing with a second component, e.g., an excipient or buffer; or dividing into larger aliquots; disposing of in containers, e.g., airtight or liquid-tight containers packaging; integrating labels; shipping or transporting to different locations In one embodiment, this processing includes one or more of: classifying, selecting, selecting, accepting or discarding, releasing or withholding, disposing of pharmaceutical compositions managing, shipping or moving to different locations, formulating, labeling to be sold, packaged, released into commerce, or sold or offered for sale and depending on whether a predetermined threshold is met. In embodiments, an oral dosage form comprising the glycan therapeutic composition is provided, wherein the oral dosage form is a syrup. Syrup is available in approximately 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 8 The syrup may contain about 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 210%, 220%, 230%, 240%, 250%, %, 45%, or 50% liquid, such as water. The solid may comprise a glycan therapeutic composition The solid may contain, for example, about 1 to 96%, 10 to 96%, 20 to 96%, 30 to 96%, 6%, 40-96%, 50-96%, 60-96%, 70-96%, 80-96%, and may be 90 to 96% of the glycan therapeutic composition. In another embodiment, the glycan therapeutic The composition is formulated as a viscous fluid.

[0304] In one embodiment, the composition comprises a foaming component, a neutralizing component, or a water-insoluble dietary fiber. The effervescent components include sodium bicarbonate, sodium carbonate, and calcium carbonate. In one embodiment, the intermediate The Japanese components are citric acid, L-tartaric acid, fumaric acid, L-ascorbic acid, and DL-malic acid. at least one member selected from the group consisting of acetic acid, lactic acid, and anhydrous citric acid In one embodiment, the water-insoluble dietary fiber is selected from the group consisting of crystalline cellulose, wheat bran, and oat bran. Bran, corn fiber, soybean fiber, and beet fiber The formulation may contain at least one member selected from the group consisting of sucrose fatty acid esters, powdered sugar, and fruit. It may contain soup powder and / or seasonings.

[0305] In some embodiments, the dosage form is directed to a specific region(s) of the gastrointestinal tract, such as the small intestine or the large intestine. The pharmaceutical composition is formulated to release a pharmaceutical composition containing a glycan therapeutic agent within the In some embodiments, the dosage form is administered to the cecum, ascending colon, transverse colon, descending colon, sigmoid colon, and / or or rectum, including therapeutic glycan preparations in specific regions of the gastrointestinal tract. The pharmaceutical composition is formulated to release

[0306] In some embodiments, for the pharmaceutical glycan treatment compositions described herein The dosage form is an enzyme-reactive delivery system. For example, a trypsin-reactive polymer The method can be made using a hydrogel cross-linked by peptides that are degraded by synthase. Trypsin is active in the small intestine. Trypsin-responsive delivery systems are used to deliver pharmaceutical groups to the small intestine. In another example, cross-linked albumin can be used to target the delivery of a glycosyl therapeutic composition. Enzyme-digestible hydrogels made of cross-linked poly(vinylpyrrolidone) are used in Pepsi. It is decomposed in the presence of

[0307] In some embodiments, for the pharmaceutical glycan treatment compositions described herein A dosage form is a delivery device that allows sustained retention at a specific site in the gastrointestinal tract. For example: The gastric delivery system allows for sustained release of the pharmaceutical glycan therapeutic composition into the stomach. They are used for pharmaceutical glycan therapeutic compositions that regulate bacteria in the stomach or upper small intestine. It is possible.

[0308] In some embodiments, for the pharmaceutical glycan treatment compositions described herein The dosage forms are mucoadhesive delivery systems that adhere to the mucosal surface of the stomach. They are typically Polymers with many hydrogen-bonding groups, e.g., cross-linked polyacrylic acid, carboxymethyl Sodium cellulose, sodium alginate, carrageenan, Carbopol 934 P, or thiolated polycarbophil.

[0309] In some embodiments, for the pharmaceutical glycan treatment compositions described herein The dosage form is an expanding delivery system that rapidly increases in size within the stomach, slowing down the passage of the pylorus. The stomach system includes a system that expands the stomach. For example, geometric shapes such as tetrahedrons, rings, and disks are used. The shape may be packaged in a gelatin capsule. When the capsule dissolves, the shape expands. The system may include one or more erodible polymers (e.g., hydroxypropyl cellulose). , one or more non-erodible polymers (e.g., polyolefins, polyamides, polyurethanes) The glycan therapeutic agent can then be dispersed within the polymer matrix. The time can be fine-tuned by polymer blends. Alternatively, the polymers can be stabilized at the acidic pH of the stomach. Made from an elastic polymer that dissolves under neutral / alkaline conditions further along the gastrointestinal tract Such polymer formulations may be used when the device leaves the stomach. In addition, it can prevent intestinal obstruction. PA6ACA) and poly(methacrylic acid-co-ethyl acrylate) (EUDRAGIT L 100-55), a supramolecular polymer cross-linked by hydrogen bonds between carboxyl groups. Other systems include a swelling vehicle such as a collagen sponge. For example, a hydrogel matrix (e.g., a swellable core: polyvinylpyrrolidone X L, Carbopol 934P, calcium carbonate) expands 2 to 50 times in the stomach. Porous hydrogel composites expand hundreds of times their original volume within minutes. utilizes gas generation to generate, for example, carbon dioxide surrounded by a hydrophilic membrane. Achieve expansion like an extensible system.

[0310] In some embodiments, for the pharmaceutical glycan treatment compositions described herein The dosage form is a density-controlled delivery system. These systems are designed to float or sink in gastric fluid. This delays their emptying from the stomach. below the pylorus, allowing the device to sink to the fundus of the stomach, thus preventing stomach emptying. Other systems are low density / floating systems. Such devices are e.g. The chamber may contain trapped air or low density materials such as fats, oils, or effervescent powders. Low density can be achieved through swelling, e.g., upon contact with gastric fluids. The hydrocolloid-containing capsule dissolves, and the hydrocolloid expands to form a mucous body. The alternative polymers are chitosan, sodium alginate, and glycerol monooleate. Low density can be achieved through gas evolution. For example, if the tablet is carbonated The optionally charged citric acid generates carbon dioxide after contact with the acidic aqueous medium. The carbon dioxide produced is encapsulated within a gelling hydrocolloid that suspends the system. The colloid contains hydroxypropyl methylcellulose and Carbopol 934P. nothing.

[0311] In some embodiments, for the pharmaceutical glycan treatment compositions described herein The dosage form uses a design that retains the device in the small or large intestine. The specific properties are provided by specific triggering methods, e.g., pH, enzymes, etc. , including systems designed for mucoadhesive and microneedle tablets. Microneedle tablets are pH-responsive. The tablet comprises a drug reservoir spiked with microneedles encapsulated in a hydrophilic coating. When the tablet reaches the desired location in the gastrointestinal tract and the coating dissolves, the microneedles transport the tablet into the gastrointestinal tract. In other embodiments, the microneedle tablets each have a quenching effect, allowing them to be inserted into the lumen of the tube. A capsule consisting of two chemical compartments filled with phosphoric acid and sodium bicarbonate. As the tablet dissolves in the digestive system, the boundary between the two substances erodes, causing them to mix. The resulting mixture is then mixed with the saccharide, undergoing a chemical reaction that pushes the saccharide microneedles through the outer layer of the capsule and into the lumen of the small intestine. The saccharide needle is filled with a drug that is delivered to the adjacent blood vessels as they absorb the saccharide. It can be filled.

[0312] In some embodiments, for the pharmaceutical glycan treatment compositions described herein The dosage form uses a pH-sensitive polymer coating. For example, a pH-dependent polymer (such as or triphasic) are insoluble at low pH levels (e.g., acid resistance in the stomach, pH 1-2) and For example, the pH in the duodenum is approximately 5.5 to 6.2, in the ascending colon it is approximately 5.7, and in the cecum it is approximately 6. .4, about pH 6.6 in the transverse colon, about pH 7.0 in the descending colon, and about 7.2-7.0 in the ileum. 5, or becomes increasingly soluble as the pH increases to about pH 7.5 in the distal small intestine. In one example, TARGIT™ technology delivers pharmaceutical glycan therapeutics within the gastrointestinal (GI) tract. This system can be used for site-specific delivery of therapeutic compositions to the terminal ileum and colon. A pH-sensitive coating is used on injection-molded starch capsules to target the

[0313] In some embodiments, for the pharmaceutical glycan treatment compositions described herein The dosage form is a delayed release or time-controlled system. Such systems are usually Enteric coatings are used that can combine H-sensitive and sustained release functions, e.g. , a core tablet (with rapid release function) containing a glycan therapeutic agent, a compression-coated swellable hydrophobic a hydrophilic polymer layer (e.g., a hydroxypropyl cellulose (HPC) layer), and a sustained release function Three-component ETP (enteric coated sustained release compression coating) The duration of the induction period depends on the weight of the polymer layer and the enteric coating layer. The acid resistance function can be controlled by the acidity or composition.

[0314] In some embodiments, for the pharmaceutical glycan treatment compositions described herein The dosage form is Eudragit® enteric-coated tablets and capsules. Other suitable synthetic polymers include Shellac, ethyl cellulose, acetate phthalate cellulose, cellulose, hydroxypropyl methylcellulose, polyvinyl acetate phthalate, and polyglucose and glutamic acid coatings, such as poly-γ-glutamic acid (γ-PGA). These coatings combine both mucoadhesive and pH-dependent release strategies. To enhance targeted delivery, Eudragits® are It is a methacrylic acid copolymer whose solubility varies depending on the side group composition, depending on the pH. For example, in Eudragit® coated systems, significant drug release Excretion does not occur in the stomach (e.g., at pH 1.4) and small intestine (e.g., at pH 6.3). However, significant drug release can be seen in the ileocecal region at pH 7.8.

[0315] In some embodiments, for the pharmaceutical glycan treatment compositions described herein The dosage form is a microbially derived system, such as a polysaccharide-based delivery system. The delivery system is biodegradable and mucoadhesive, including chitosan and pectin coatings. Other suitable natural polymers include, for example, guar gum, methylparaben ... Nuclein, cyclodextrin, dextran, amylase, chondroitin sulfate, and rho These delivery systems target glycan therapeutics to the small intestine. Guar gum, xanthan gum, chitosan, alginate, etc. The naturally occurring polysaccharide coating enhances the function of the gut microbiota, e.g., enzymes (xylosidases). It is decomposed by enzymes such as CODES, arabinosidase, and galactosidase. (TM) technology can be used to deliver pharmaceutical glycan therapeutic compositions. The system combines a polysaccharide coating with a pH-sensitive coating. In its present form, the system consists of a core tablet coated with three layers of polymer coating. The outer coating is made of Eudragit L. It dissolves in the intestine, exposing the next coating, which is Eudragit E. This layer allows the release of lactulose present in the inner core. Eudragit E is metabolized to short-chain fatty acids that lower the surrounding pH, causing the layer to dissolve. Dissolution of Eudragit E results in exposure of the glycan therapeutic agent. The bacteria are involved in the degradation of polysaccharides released from the core tablet. The degradation of polysaccharides leads to the degradation of the p This can result in the formation of H-lowering organic acids.

[0316] In some embodiments, for the pharmaceutical glycan treatment compositions described herein The dosage form is a pressure-controlled delivery system, which allows higher pressure to be applied to the colon than to the small intestine. For example, ethyl cellulose, which is insoluble in water, is used. For the system, the release of the glycan therapeutic agent occurs due to the lack of water as a result of pressure in the lumen of the colon. The release profile is determined by the thickness of the ethylcellulose capsule. , can be adjusted by varying the capsule size and / or capsule density.

[0317] In some embodiments, for the pharmaceutical glycan treatment compositions described herein The dosage form is a pulsatile colonic targeted delivery system. For example, this system is The capsule used may be a capsule that controls the release of the glycan therapeutic agent. The plug is placed in the cavity. Polyvinyl acetate (HPMC, polymethyl methacrylate, or polyvinyl acetate) is used to When the capsule comes into contact with a fluid, the plug is forced out of the capsule, The release profile is determined by the length of the intersection between the stopper and the capsule body and / or Alternatively, the system may be controlled by changing the point. Another system is the port system. The capsule body is encapsulated in a semipermeable membrane. The insoluble plug contains the osmotically active agent and the glycan therapeutic agent. When the capsule comes into contact with a fluid, the semi-permeable membrane reduces the pressure inside the capsule. This allows for increased fluid inflow, thereby expelling the plug and releasing the glycan therapeutic agent. bring about.

[0318] In some embodiments, for the pharmaceutical glycan treatment compositions described herein The dosage form is an osmotically controlled colon-targeted delivery system. An exemplary system, ORO S-CT is an osmotic unit (up to 5 or 6 capsules) encapsulated in a hard gelatin capsule. This push-pull unit is composed of the impermeable outer membrane and the semi-permeable outer membrane of the intestine. The center of the push-pull is made up of a drug layer and a push layer. The glycan therapeutic agent is released through the semipermeable membrane. The capsule dissolves immediately after administration. In the gastrointestinal tract, the intestinal impermeable membrane prevents water absorption. The enteric coating dissolves in the small intestine (higher pH, >7), allowing water to penetrate the push layer. It expands and forces the glycan therapeutic agent out, flowing into the unit through a semi-permeable membrane.

[0319] In some embodiments, for the pharmaceutical glycan treatment compositions described herein The dosage form may be used to release the glycan therapeutic agent just before reaching the ileocecal valve. "Topil".

[0320] In some embodiments, for the pharmaceutical glycan treatment compositions described herein The dosage form is a rectally administered formulation. For example, an enema is a liquid formulation containing a pharmaceutical glycan treatment. The pharmaceutical composition is introduced into the rectum. The administered volume is typically less than 10 mL. introduces the pharmaceutical glycan treatment composition into the rectum. When the suppository is inserted into the rectum, A solid dosage form that melts or dissolves to release the glycan therapeutic agent. Typical for suppository formulations Typical excipients include cocoa butter, polyethylene glycol, and agar.

[0321] Polyphenol production, synthesis and preparation of extracts Pharmaceutical compositions comprising a glycan therapeutic agent and a polyphenol agent are provided herein. In some embodiments, the pharmaceutical composition comprising the glycan therapeutic agent comprises at least In some embodiments, the glycan therapeutic agent comprises a polyphenol. The biological composition includes a plurality of polyphenols.

[0322] The glycan therapeutic agent formulation and the polyphenol formulation can be produced separately. For example, , glycan therapeutic agent formulations can be synthesized, and polyphenol formulations can be synthesized as described herein. In another example, the glycan therapeutic agent preparation can be synthesized and extracted as a polyphenotype. Preparations of glycols can also be synthesized as described herein. Preparations of cancer treatment agents can be synthesized, and preparations of polyphenols can be prepared by extracting multiple compounds from different sources. Polyphenols and synthetic polyphenols may be included.

[0323] In some embodiments, the preparation of polyphenols comprises an extract containing polyphenols. In another embodiment, the polyphenol preparation is a synthetic polyphenol. Including Nol.

[0324] Pharmaceutical compositions and medical foods may be prepared by any method known in the art. and produced by mixing a preparation of a glycan therapeutic agent with a preparation of polyphenols. In some embodiments, the formulation is 0.000000001:1, 0.0000 0001:1, 0.0000001:1, 0.000005:1, 0.00001:1, 0.0001:1.0.001:1, 0.01:1, 0.1:1, 0.5:1, 1:1, 1:2, 1:5, 1:10, 1:100, 1:1,000, 1:10,000, 1:10 0,000, 1:1000,000 (v / v), (w / w), (w / v), or molar ratio (glycan:polyphenol, polyphenol:glycan)

[0325] In some embodiments, the preparation of polyphenols is a plant, plant part, plant cell, or or extracted from plant products. Examples of plant parts include bark, flowers, petals, trunks, stems, and tubers. Examples of plant products include, but are not limited to, roots, fruits, berries, seeds, nuts, and leaves. Examples include pomace juice, pulp, skins, wort, paste, and slurry. Examples of plants include, but are not limited to, blueberries, cranberries, grapes, and peaches. , plum, pomegranate, soy, red wine, black tea, green tea In some embodiments, the polyphenols are derived from multiple plants, plant parts, or plant products. In some embodiments, the polyphenol extract is extracted from a plurality of plants, The compounds may be combined from plant parts or plant products.

[0326] Polyphenols are found in, for example, cloves, peppermint, star anise, cocoa powder, Dietary fiber containing legumes, celery seeds, black chocolate berries, dark chocolate, and flaxseed , black elderberry, chestnut, common sage, rosemary, spearmint, common Fresh thyme, lowbush blueberries, blackcurrants, capers, black olives , highbush blueberries, hazelnuts, pecans, soy flour, plums, and ginger Green olives, sweet basil, curry powder, sweet cherries, globe artichokes Head, blackberry, roasted soybean, milk chocolate, strawberry, red chicory , red raspberry, coffee, filter, ginger, whole wheat flour, prunes, almonds Black grapes, red onion, green chicory, common thyme, fresh refined Corn flour, soybeans, tempeh, whole grain rye flour, apples, spinach, shallots Tomato, perfume tree, black tea, red wine, green tea, soy yogurt, yellow onion, soy meat, whole grain small Wheat flour, pure apple juice, pure pomegranate juice, premium olive oil, black beans, peaches, pure black Orange juice, cumin, pure grapefruit juice, white beans, cinnamon bark, pure blonde oil Microwave juice, broccoli, red currant, soy tofu, pure lemon juice, whole grain egg Barley flour, apricots, caraway, refined lime flour, asparagus, walnuts, jalapenos Potatoes, Ceylan cinnamon, parsley, nectarines, curly endive, marjoram , sunny lettuce, milk chocolate drink, quince, endive, Soy milk, pure pomelo juice, rapeseed oil, pear, soybean sprouts, green grapes, carrots, vinegar, soybeans Polyphenols, including but not limited to cheese, white wine, and red wine The protein may be extracted from any suitable source, such as foods rich in protein.

[0327] In some embodiments, polyphenols can be extracted from plant juices. In some embodiments, the plant juice is blueberry, blackberry, raspberry, hot kenberry, gooseberry, boysenberry, akaiberry, baneberry, barberry, bearberry Berry, bilberry, chocolateberry, gozentachibana, buffaloberry, chokeberry Lee, lingonberry, elderberry, cranberry, dewberry, currant, falklberry berries, goji berries, gooseberries, grapes, holly berries, huckleberries, ivy berries Lee, Juneberry, Juniperberry, Lingonberry, Loganberry, Mistletoe Appleberry, Nannyberry, Oregon Grape, Persimmon, Pokeberry, Privetberry, Sa -Monberry, strawberry, sugarberry, Thaiberry, thimbleberry, white mulberry, red Juice of mulberry, black mulberry, wineberry, wintergreen, yewberry, or young berry It is a base.

[0328] In some embodiments, the polyphenols are modified, bred, genetically engineered, or otherwise If not, it has been altered, for example to change the composition or amount of polyphenol content. In some embodiments, the plant or plant tissue may be extracted from the plant or plant tissue. , e.g., untreated plants or tissues or those that have not been exposed to polyphenol-inducing agents. or by the plant or plant tissue when compared to a plant or tissue that has not been contacted or to induce or stimulate the production of polyphenols in plants or plant tissues. To increase the relative amount of polyphenols in the plant, the plant or plant tissue is harvested or Before or after isolation, the polyphenol-inducing agent (e.g., a chemical agent or a radiation) may be administered. Treated with, exposed to, or in contact with radiation (e.g., ultraviolet light).

[0329] In some embodiments, pharmaceutical compositions of glycan therapeutic agents are well known in the art. The present invention includes preparations of polyphenols that can be extracted by any known method, for example, by extraction methods The method comprises the following steps: i) drying the source; and ii) milling, grinding, crushing, or blending the source. and iii) extracting the polyphenols from the source. For example, using a solvent.

[0330] The source material may optionally be pretreated with enzymes or treated with enzymes during extraction. Examples of enzymes include, but are not limited to, pectinolytic and cell wall polysaccharide degrading enzymes. .

[0331] The solvent can be any suitable solvent known in the art. For example, the solvent can be: Such solvents include, but are not limited to, methanol, ethanol, acetone, and ethyl acetate. , organic solvent, and optionally aqueous solvent (including water). acid, formic acid, acetic acid, citric acid, hydrochloric acid, tartaric acid, sulfuric acid, or phosphoric acid, etc. The solvent may include, but is not limited to, a mixture of an organic solvent and an acid in any suitable ratio. The solvent may comprise supercritical CO2.

[0332] Extraction can be carried out at temperatures between 0 and 100°C. Extraction methods include maceration and Soxhlet extraction, rotation Evaporation, microwave-assisted extraction, ultrasound-assisted extraction, subcritical water extraction, supercritical fluid extraction, pressurized fluid These include extraction, pressurized liquid extraction, and accelerated solvent extraction.

[0333] In some embodiments, extraction may be performed multiple times on the same source material. Multiple extracts from a material may be combined. In other embodiments, extracts from different source materials may be combined. Multiple extracts may be combined.

[0334] Purification and fractionation of polyphenol extracts can be achieved by i) sequential extraction or liquid-liquid partitioning; ii) ) solid phase extraction, iii) counter-current chromatography, and iv) centrifugation. This can be achieved by any suitable method known in the art, including but not limited to: For sequential extractions, the crude extract may be washed with a non-polar solvent to remove the liquid. Examples of solvents include, but are not limited to, hexane, dichloromethane, and chloroform. For solid phase extraction, the crude extract is washed onto a solid phase binding material to obtain polyphenol-substituted In some embodiments, water-soluble groups such as sugars and organic acids may be separated and / or sugars removed. The soluble constituents are removed with acidic water. Examples of solid phase binding materials are C18, Amberlite XAD-2, XAD-7, XAD-16, Oasis HLB, Silica-based C8, Copoly Mer-based HLB, PH, ENV+, RP-C18, Toyopearl, LH-20, Poly amide resin, and MCX, but are not limited to these. The fraction can be further fractionated by adjusting the elution solvent and solvent pH. Examples of the solvent include ethanol, methanol, acetone, and water, as well as any combination thereof. In some embodiments, the phenolic acid is In some embodiments, the non-polymeric phenol is eluted with acidic ethyl acetate. In some embodiments, the polymerized phenol is separated from water, acetone, ethanol, and and / or methanol. The gin is eluted with acetone and water.

[0335] As an example, proanthocyanidins can be isolated from grape skins. The juice can be collected after it has been pressed and removed from the grape berries. A cetone / water mixture can be used to extract polyphenols from grape skins. The solvent is then removed. Aqueous phase extraction can be performed using, for example, chloroform. ) and the extract may optionally be freeze-dried. The resulting powder may be The proanthocyanidins can be purified using chromatography. The column is washed and eluted with ethanol (ethanol, acetone), and trifluoroacetic acid. The aqueous phase is optionally freeze-dried to produce a proanthocyanidin powder.

[0336] Various methods can be used to characterize the resulting proanthocyanidin mixture. Acid catalysis in the presence of excess phloroglucinol significantly improved the subunit composition, conversion yield, and average The mass distribution of polyphenols can be determined by mass spectrometry. Mass spectrometry is performed by measuring the ion concentration in a suitable solvent (e.g., methanol / acetonitrile). The method consists of dissolving the polyphenols in water and injecting them into an electrosprayer. The spectrum of the elution peaks can be obtained by two columns in series. (For example, TSKgel G3000 Hxl particle size 6um, followed by G2500 Hxl particle size 5um, both 300 x 7.8mm intradermal), dimethylformamide The procedure is carried out under isocratic conditions with a mobile phase of It can be characterized by UV-Vis spectrophotometry. Finally, elemental analysis of C, H, and N can be performed. The powder sample is filled into a tin cup and then heated with an electric current, e.g., Carlo Erba EZ 1108. This can be done by performing the analysis using a spectrometer.

[0337] In some embodiments, the compositions described herein comprise synthetic polyphenols. Polyphenols can be derived from suitable plant sources (e.g., plant extracts) as well as from synthetic Polyphenols can be produced by any chemical, synthetic method known in the art. It can be synthesized through a suitable combination of chemical or biotechnological methods. In embodiments, polyphenols are extracted from natural sources and then subjected to chemical, biochemical, or is modified via bioengineering methods. In some embodiments, synthetic or modified The chemical structures of polyphenols are not found in nature. Examples of chemical modifications include methylation, These include hydroxylation, prenylation, glycosylation, dimerization, and polymerization. Examples of glycosylation include, but are not limited to, glucosides, galactosides, arabinosides, and rhamnosides.

[0338] Methods for chemical synthesis of polyphenols are well known in the art, for example, Qu ideau S et al.“Plant Polyphenols:Chemica l Properties,Biological Activites,and Sy Angewandte Chemie 2011,50,586-6 21. In some embodiments, the polyphenols are bioengineered. Synthesized or modified via methods, e.g., using enzymes to catalyze suitable reactions The reaction can be carried out in cells (e.g., bacteria, yeast, plant cells) or in extracts or lysates. can be induced or obtained from, for example, bacteria, yeast, or plant cells In some embodiments, the specific enzyme is in a suitable buffer system and reacts in a suitable manner. The polyphenols are isolated and used under the conditions described above. are well known in the art and are described, for example, in Cress B et al. flavonoid Production By Genetically Engi Needed Microorganisms”,Natural Products. Springer-Verlag Berlin Heidelberg,2013.1 647-1681, Trantas EA et al. “When Plants P roduce Not Enough Or At All:Metabolic En gineering Of Flavonoids In Microbial Hos ts”, Frontiers in Plant Science 2015, Vol. 6 It is stated as follows.

[0339] Polyphenols can be quantified or measured by any suitable method. In embodiments, the circumferential concentration of a reference standard (e.g., a polyphenol or polyphenols) is The known concentrations are used for comparison of measurements. The methods are Folin-Denis, Folin-Ciocalteau, and permanganate. Acid titration, coloriometry using iron salts, HPLC, substrate precipitation , or quantified via electromagnetic absorbance.

[0340] In some embodiments, the type of polyphenol is quantified. The amine is quantified using electromagnetic absorbance between 490 and 550 nM at one or more pH values. Proanthocyanidins can be detected by colorimetry, substrate precipitation, or protein-binding assays. In another example, tannins can be quantified using iodine, hydroxybenzoates ... potassium chloride, rhodanine, sodium nitrite, or protein binding assays, or In some embodiments, the amount of ionizing radiation can be quantified using a combination of these methods. The method is used for the separation and quantification of polyphenols or polyphenols. If necessary, the polyphenols may be further volatilized, e.g. Alternatively or additionally, polyphenylene ether may be modified prior to gas chromatography. The phenols are quantified via HPLC, optionally using various solid supports and mobile phases. Polyphenols can also be quantified via mass spectrometry (MS). In embodiments, polyphenols are analyzed by HPLC-MS, optionally with various solid supports and transfer media. In some embodiments, the antioxidant capacity of polyphenols is measured. For example, the antioxidant capacity of polyphenols can be measured using the Trolox equivalent antioxidant capacity assay. , Oxygen Radical Absorbance Capacity Assay, Total Radical Trap Antioxidant Parameter Assay, Ferric Ferric Antioxidant powder assay for reduction to cupric ions, antioxidant capacity assay for reduction to cupric ions, or a combination thereof.

[0341] Other methods for phenol extraction, purification, analysis, and quantification are known in the art. It is well known, for example, Dai J. and Mumper RJ, "Plant Phe nolics:Extraction,Analysis and Their Ant ioxidant and anticancer properties”,Mole cules 2010,15(10),7313-7352.

[0342] In some embodiments, polyphenols are selected from the group consisting of phenols, hydroxypropyl ... Optionally, proteins from various sources are used, as described in US Pat. No. 20140328997. , the pH may be changed to extract and / or concentrate.

[0343] In some embodiments, the yield of extracted polyphenols is In some embodiments, the yield of extracted polyphenols is mg / kg of source material. In some embodiments, the yield of extracted polyphenols is g / kg of source. It is a material.

[0344] In some embodiments, the polyphenol formulation includes a flavonoid. In this embodiment, the flavonoid is an anthocyanin, an anthocyanidin, a chalcone, a dihydroxybenzoate, or a hydroxybenzoate. Dorochalcone, dihydroflavonol, flavanol, flavan-3-ol, flavanol Flavones, flavonols, isoflavonoids, proanthocyanidins, condensed tannins In some embodiments, the flavonoid is a monomer. In some embodiments, the flavonoid is a dimer. In some embodiments, the flavonoid is a polymer. Examples of chemical modifications are methylation, hydroxylation, prenylation, and glycosylation. Examples of glycosylation include, but are not limited to, glucosides, galactosides, arabinosides, and the like. Examples of suitable hydroxybenzoates include, but are not limited to, benzoates, rhamnosides, and rhamnosides.

[0345] In some embodiments, the polyphenol formulation includes hydrolyzable tannins, phlorotamarinds, and the like. linnin, lignan, alkoxymethoxyphenol, alkoxyphenol, caramel comoid (c urcumoids), furanocoumarins, hydroxybenzaldehyde, hydroxybenzaldehyde Zoketone, hydroxycinnamaldehyde, hydroxycoumarin, hydroxyphenylpropane phenol, methoxyphenol, naphthoquinone, phenol terpene, tyrosol, arbutin Catechol, pyrocatechol, resorcinol, coumestrol, phenol, fluorine Phosphorus, pyrogallol, phloroglucinol, salvianolic acid, hydroxybenzoic acid, Hydroxycinnamic acid, hydroxyphenylacetic acid, hydroxyphenylpropanoic acid, hydroxy In some embodiments, polyphenols include phenylpentanoic acid, stilbene. In some embodiments, the polyphenol is a dimer. In some embodiments, the polyphenol is a polymer. Polyphenols can be chemically modified. Examples of chemical modifications include methylation, hydroxylation, pre- Examples of glycosylation include, but are not limited to, glycosylation, glycosides, and glycosylation. , galactosides, arabinosides, rhamnosides, but are not limited to these.

[0346] In some embodiments, the extract comprises one or more of a plurality of those listed in Table 5 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60, 70, In some embodiments, the polyphenols include 80, 90, 100 or more polyphenols. Pharmaceutical compositions comprising the glycan therapeutic agents described herein may contain one or more of the compounds listed in Table 5. One or more of the following (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 4 0, 50, 60, 70, 80, 90, 100 or more polyphenols.

[0347] kit Kits are also contemplated. For example, kits may be used to treat gastrointestinal disorders or conditions, such as: Pharmaceutical glycan therapeutic composition in unit dosage form and instructions for use of the glycan therapeutic The kit may include a package insert containing the pharmaceutical glycan treatment composition. The pharmaceutical glycan therapeutic composition is packaged in a suitable package for use by a subject. Any of the compositions described herein may be packaged in the form of a kit. The kit may contain an amount of pharmaceutical compound sufficient for a full course of treatment or for a portion of a course of treatment. a lican therapeutic composition (optionally including prebiotic substances, probiotic bacteria, and / or a second therapeutic agent). Administration of the pharmaceutical glycan treatment composition The amounts may be individually packaged, or the pharmaceutical glycan treatment composition may be bulk packaged. or a combination thereof. Thus, in one embodiment, a kit In suitable packaging, the individual doses correspond to administration points in the treatment regimen. A dose of the glycan therapeutic composition is provided, the dose being packaged in one or more packets. will be done.

[0348] In one embodiment, the pharmaceutical glycan treatment composition is contained in a single container or in two, three or more containers. , four, five, or more than five containers in bulk. For example, each container may contain , a pharmaceutical glycan therapeutic composition sufficient for a specific treatment program carried out for one month If more than one bulk container is provided, the bulk containers shall be suitably grouped together. Packaged to provide a pharmaceutical glycan therapeutic composition sufficient for all or part of the treatment period. The container(s) may be provided to a subject in need of treatment or to a device, e.g., an administration station. The device may be labeled with labeling information useful to a physician administering a treatment protocol, such as a schedule. .

[0349] The pharmaceutical glycan treatment composition may contain other suitable substances, such as those described herein. It may be packaged with probiotic bacteria, prebiotic substances, or other substances. The other substance(s) are packaged separately from the pharmaceutical glycan therapeutic composition. or may be mixed with a pharmaceutical glycan treatment composition, or a combination thereof Thus, in one embodiment, the kit may comprise a series of treatments or part of a series of treatments. All components intended for use in, for example, pharmaceutical glycan therapeutic compositions, and optionally buffers, excipients, probiotics, prebiotics, or treatments. In one embodiment, the pharmaceutical glycan treatment composition comprises a dosage form containing a pharmaceutical agent. Packaged in a cage or set of packages, and containing additional components, e.g. Biotic bacteria, prebiotics, or therapeutic agents are pharmaceutical glycan therapeutic compositions It is packaged separately from the items.

[0350] The kit includes documentation, e.g., instructions, expected results, testimonials, explanations, warnings, clinical data, In one embodiment, the kit may further include a label, instructions for use, and / or information for medical professionals. Contains labeling or other information indicating that the product is to be used only under the direction of a healthcare professional. A vessel may be a spoon, syringe, bottle, cup, applicator, or other measuring or serving object. The device may further include a

[0351] Methods for modulating microbial taxa, genomes, and functional states of the microbiome Bacterial taxa (e.g., 1, 2, 3, 4, 5) in the gastrointestinal microbiota of human subjects Methods for regulating the abundance of one or more taxa are provided herein. These methods involve administering to a human subject a glycoprotein in an amount effective to modulate the abundance of the taxon. The method further comprises administering a pharmaceutical composition containing a therapeutic compound to treat the ulcerative colitis. When a therapeutic agent is administered, it is relatively effective (or from one time point to another) in other taxa. The increase may be at least 5%, 10%, 25%, 50%, 75% , 100%, 250%, 500%, 750% increase or at least 1000% increase The abundance of bacterial taxa may also be affected by other taxa when a glycan therapeutic agent is administered. may decrease relatively (or relatively from one point in time to another), and this decrease may be at least Both 5%, 10%, 25%, 50%, 75%, 85%, 90%, 95%, 96%, 97% , 98%, 99%, or at least 99.9% reduction. In embodiments, dysbiosis is achieved by shifting the microbiota and increasing one or more undesirable taxa. Administration of a glycan therapeutic agent increases the number of desired taxa and / or enhances the number of desired taxa. Modulating the abundance of desirable and / or undesirable bacterial taxa in the elephant gastrointestinal microbiota , thereby treating dysbiosis.

[0352] In some embodiments, the glycan therapeutic agent is selected from one or more bacteria, for example, bacteria found in the gastrointestinal tract. May contain Bacteroides, Odoribacter, Parabacter oides, Alistipes, Blautia, Clostridium, Copr ococcus, Dorea, Eubacterium, Lachnospira, Ro seburia, Ruminococcus, Faecalibacterium, Os The growth of bacteria belonging to the genera cillospira and Subdoligranulum In some embodiments, the amount of glycoprotein in the glycoprotein can be adjusted (e.g., increased or decreased). The cannabinoid therapeutic agent may be selected from the group consisting of one or more bacteria, e.g., bacteria thought to be associated with healthy gastrointestinal conditions, For example, Akkermansia, Anaerofilum, Bacteroides, Blautia, Bifidobacterium, Butyrivibrio, Clo stridium, Coprococcus, Dialister, Dorea, Fus obacterium, Eubacterium, Faecalibacterium, Lachnospira, Lactobacillus, Phascolarctoba cterium, Peptococcus, Peptostreptococcus, P Revotella, Roseburia, Ruminococcus, and Strep one or more of the genera Tococcus and / or Akkermansia m uniciphilia, Christensenella minuta, Clost ridium coccoides, Clostridium leptum, Clos tridium scindens, Dialister invisus, Eubac terium rectal, Eubacterium eligens, Faecal ibacterium prausnitzii, Streptococcus sal ivarius, and the seed sac of Streptococcus thermophilus The proliferation of one or more of these can be modulated (eg, increased or decreased).

[0353] In some embodiments, the glycan therapeutic agent is Prevotella, Akkerma nsia, Bacteroides, Clostridium (Erysipelotr ichaceae), Clostridium (Clostridiaceae), Bi fidobacterium, Aggregatibacter, Clostridiu m(Peptostreptococcaveae), Parabacteroides At least one selected from the group consisting of Lactobacillus, Lactobacillus, and Enterococcus can also regulate (e.g., increase or decrease) the growth of two bacterial taxa. Exemplary glycan therapeutic agents include glu100, ara100, glu50gal50, and g lu33gal33fuc33, and in some embodiments, the glycan therapeutic agent is 2 It is possible to regulate the growth of two bacterial taxa: Akkermensia and Blautia. An exemplary glycan therapeutic agent is xyl100.

[0354] In some embodiments, the glycan therapeutic agent is intended to improve the composition and activity (or These factors result in selective changes for both the host's health and its function, which in turn have beneficial effects on the host's health. In some embodiments, the glycan therapeutic agent is selected from one or a limited number of latent proteins present in the gastrointestinal tract. It is a selective substrate for potentially beneficial bacteria and stimulates their growth and / or metabolic activity. In some embodiments, the glycan therapeutic agent inhibits the growth of gastrointestinal microorganisms in certain bacteria. The composition of the flora can be changed to a higher or lower composition. In this form, the glycan therapeutic agent inhibits the growth and / or selection of gastrointestinal bacteria associated with health and well-being. In one example, the glycan therapeutic compositions described herein selectively stimulate the targeting activity of the glycan. Decrease the abundance or relative number or density of pathogenic bacteria.

[0355] The relationship between microbiota and their hosts is not just symbiotic (harmless coexistence); In many cases, there is a symbiotic relationship: the subject can survive without the microbiota, but the microorganisms For example, fermenting unused energy substrates, training the immune system, and killing pathogenic cells. Preventing bacterial growth, regulating intestinal development, providing vitamins (biotin and They perform various useful functions (e.g., producing vitamins, etc.) guez-Bello MG and Blaser MJ,2008 Micro bes Infect, 10(9):1072-1076). Bacterial taxa include Bacteroides, Odoribacter, and Parabacter. eroides, Alistipes, Blautia, Clostridium, Co prococcus, Dorea, Eubacterium, Lachnospira, Roseburia, Ruminococcus, Faecalibacterium, The genera Oscillospira and Subdoligranulum are included. Akkermansia, Anaerophilum, Bacteroides, Bl autia, Bifidobacterium, Butyrivibrio, Clost ridium, Coprococcus, Dialister, Dorea, Fusob acterium, Eubacterium, Faecalibacterium, La chnospira, Lactobacillus, Phascolarctobact erium, Peptococcus, Peptostreptococcus, Pre votella, Roseburia, Ruminococcus, and Strepto The genus coccus and / or Akkermansia municiphili a, Christensenella minuta, Clostridium coc coides, Clostridium leptum, Clostridium sc indens, Dialister invisus, Eubacterium rec tal, Eubacterium eligens, Faecalibacterium prausnitzii, Streptococcus salivarius, and Some bacteria, such as Streptococcus thermophilus species The genera and species are thought to be associated with the health of the gastrointestinal tract.

[0356] However, for example, infections and diseases associated with disease states without necessarily requiring a causative agent. and / or by inducing inflammation and / or bacteria, which, under certain conditions, can cause disease. Potentially pathogenic species and pests reside in ecological niches. In the form of disease-related bacteria that can be modulated by the glycan therapeutic agents described herein, The pests, or pathogens, are Bilophila, Campylobacter, C. andidatus, Citrobacter, Clostridium, Collin sella, Desulfovibrio, Enterobacter, Enteroc occus, Escherichia, Fusobacterium, Haemophi lus, Klebsiella, Lachnospiraceae, Peptostre ptococcus, Porphyromonas, Portiera, Providence ncia, Pseudomonas, Salmonella, Shigella, Sta. phylococcus, Streptococcus, Vibrio, and Yersi The species is selected from the group consisting of the genus nia.

[0357] In some embodiments, the glycans may be modulated by the therapeutic agents described herein. The disease-associated bacterium, pesticide, or pathogen is Bilophila wadswor thia, Campylobacter jejuni, Citrobacter fa rmer, Clostridium difficile, Clostridium p erfringens, Clostridium tetani, Collinsell aerofaciens, Enterobacter hormaechei, En terococcus faecalis, Enterococcus faecium , Escherichia coli, Fusobacterium varium, F usobacterium nucleatum, Haemophilus parai nfluenzae, Klebsiella pneumonia, Peptostre ptococcus stomatis, Porphyromonas asaccha rolytica, Pseudomonas aeruginosa, Salmonel la bongori, Salmonella enteric, Shigella b. oydii, Shigella dysenteriae, Shigella flex neri, Shigella sonnei, Staphylococcus aure us, Streptococcus infantarius, Vibrio chol era, and Yersinia enterocolitica species will be done.

[0358] In some embodiments, the glycans may be modulated by the therapeutic agents described herein. Disease-associated bacteria, pesticides, or pathogens are primarily found in one or more specific regions of the gastrointestinal tract. It can exist.

[0359] For example, Listeria, Entamoeba histolytica, Bala ntidium coli, Basidiobolus ranarum, Trypan osoma cruzi, Clostridium botulinum, Fascio la hepatica, Histoplasma capsulatum, Rotav irus, Schistosoma mansoni, Schistosoma jap onicum, and Schistosoma mekongi, Shigella, Br achyspira aalborgi, Serpulina pilosicoli, Trichuris trichiura and Yersinia enterocol Disease-related bacteria, pesticides, or pathogens such as Ibacterium itica, are present in the large intestine (colon). Mainly present.

[0360] Vibrio, Yersinia enterocolitica, Yersinia pseudotuberculosis, Clostridium perfring ens, Capillaria philippinensis, Cryptospor idium parvum, Cyclospora cayetanensis, and C. Disease-associated bacteria, pests, or pathogens, such as the MV virus, reside primarily in the small intestine. There is.

[0361] Disease-associated bacteria such as Campylobacter and Salmonella, Bionts, or pathogens, reside primarily in the large and small intestines.

[0362] Other examples include CMV virus, Bacillus anthracis, and Candida , Cryptosporidium, EBV (Epstein-Barr virus), G iardia lamblia, Helicobacter pylori, Helic obacter felis, Helicobacter fennelliae, He licobacter cinaedi, Mycobacterium avium, H erpes varicella zoster, Histoplasma, and Tox Disease-related bacteria, pests, or pathogens such as eoplasma, reside primarily in the stomach. There is.

[0363] A healthy microbiome can protect against potential pathogens or diseases, for example by strengthening the intestinal barrier. By competitive exclusion of disease-associated bacteria and by inhibiting the growth of bacterial pathogens and disease-associated bacteria Healthy microbial communities produce antibacterial substances, including bacteriocins and acids, which protect the host. It can exert a direct antibacterial effect on pathogens and disease-related bacteria through the production of otter PD,et al.2005 Nat Rev,3:777-788,S ervin AL,2004 FEMS Microbiol Rev,28:405 -440). Antibacterial substances are used alone to inhibit the growth of pathogenic or disease-associated bacteria. The healthy bacterial community acts to prevent pathogens and pathogens from entering the gastrointestinal lumen. The adhesion of both of these toxins can be reduced.

[0364] In some embodiments, the glycan therapeutic agent is one or more bacterial taxa present in the gastrointestinal tract. , which may be found in the gastrointestinal tract, Bacteroides, Odoribacter , Parabacteroides, Alistipes, Blautia, Clost ridium, Coprococcus, Dorea, Eubacterium, Lac hnospira, Roseburia, Ruminococcus, Faecalib Acterium, Oscillospira, and Subdoligranulum It can regulate (e.g., increase or decrease) the growth of bacteria belonging to the genus. In some embodiments, the glycan therapeutic agent is a glycan that inhibits one or more bacterial taxa, for example, a healthy gastrointestinal condition. Bacteria thought to be associated with, e.g., Akkermansia, Anaerofilu m, Bacteroides, Blautia, Bifidobacterium, Bu tyrivibrio, Clostridium, Coprococcus, Diali ster, Dorea, Fusobacterium, Eubacterium, Fae calibacterium, Lachnospira, Lactobacillus, Phascolarctobacterium, Peptococcus, Peptos treptococcus, Prevotella, Roseburia, Rumino coccus, and Streptococcus genera, and / or Akkermansia municiphilia, Christensenell a minuta, Clostridium coccoides, Clostridi um leptum, Clostridium scindens, Dialister invisus, Eubacterium rectal, Eubacterium eligens, Faecalibacterium prausnitzii, Str. eptococcus salivarius, and Streptococcus th Modulating (e.g., increasing or decreasing) the growth of one or more species of Helicobacter pylori In some embodiments, the glycan therapeutic agent can be one or more bacterial taxa. group, taxa of the phylum Verrucomicrobia, e.g., the genus Akkermansia The proliferation of taxa can be modulated (e.g., increased or decreased).

[0365] In some embodiments, the growth of one or more bacterial taxa predominantly present in the small intestine is modulated. (e.g., increased or decreased). For example, the glycan therapeutic agent can be, for example, Actinob acteria, Firmicutes (Bacilli, Clostridia), and and Proteobacteria (Alphaproteobacteria, Beta proteobacteria) that are primarily present in the small intestine. Regulates 5, 6, 7, 8, 9, 10, or more bacterial taxa. In some embodiments, the glycan therapeutic agent is selected from the group consisting of Cryocola, Mycobacteriu m, Enterococcus, Lactococcus, Streptococcus , Turicibacter, Blautia, Coprococcus, Holdem ania, Pseudoramibacter Eubacterium, Agroba cterium, Sphingomonas, Achromobacter, Burkh One or more bacteria predominantly present in the small intestine selected from the genera olderia, and Ralstonia Above (2, 3, 4, 5, 6, 7, 8, 9, 10, or more) bacteria Regulate taxa.

[0366] In some embodiments, the glycan therapeutic agent is one or more bacterial classes that are predominantly present in the large intestine. Regulating (e.g., increasing or decreasing) the growth of a population. For example, glycan therapeutic agents can be used to For example, Bacteroidetes, Firmicutes (Clostridia), V errucomicrobia, and Proteobacteria (Deltapro teobacteria) that are primarily present in the large intestine (two, three, four, five, Regulates several bacterial taxa (six, seven, eight, nine, ten, or more). In embodiments, the glycan therapeutic agent is Bacteroides, Butyricimona s, Odoribacter, Parabacteroides, Prevotella , Anaerotruncus, Phascolarctobacterium, Rum Selected from the genera Inococcus, Bilophila, and Akkermansia One or more (two, three, four, five, six, seven, eight, nine, 10 or more) bacterial taxa.

[0367] In some embodiments, the glycan therapeutic agent is, for example, Actinobacteria. , Bacteroides, Bacilli, Clostridia, Mollicut es, Alpha Proteobacteria, and Verrucomicrobial modulate the growth of one or more bacterial taxa that are predominantly present in the cecum, such as a decreases).

[0368] In some embodiments, the glycan therapeutic agent is, for example, Actinobacteria. , Bacteroides, Bacilli, Clostridia, Fusobact eria, Beta Proteobacteria, Delta / Epsilon P roteobacteria, Gamma Proteobacteria, and Ver The growth of one or more bacterial taxa predominantly present in the ascending colon, such as rucomicrobia, was investigated. To change (e.g., increase or decrease).

[0369] In some embodiments, the glycan therapeutic agent is, for example, Actinobacteria. , Bacteroides, Clostridia, Mollicutes, Fusob Proteobacteria, and Gamma Proteobacteria in the traverse colon Regulating (e.g., increasing or decreasing) the growth of one or more bacterial taxa primarily present.

[0370] In some embodiments, the glycan therapeutic agent is, for example, Bacteroides, Cl ostridia, Mollicutes, Fusobacteria, Delta / E psilon Proteobacteria, and Verrucomicrobia, etc. modulate the growth of one or more bacterial taxa that are predominantly present in the descending colon of decreases).

[0371] In some embodiments, the glycan therapeutic agent is, for example, Actinobacteria. , Bacteroides, Bacilli, Clostridia, Mollicut es, Alpha Proteobacteria, Beta Proteobacte One or more cells that are predominantly present in the sigmoid colon, such as sigmoid colon, sigmoid colon, and ... Regulating (e.g., increasing or decreasing) the growth of fungal taxa.

[0372] In some embodiments, the glycan therapeutic agent is, for example, Bacteroides, Cl Ostridia, Mollicutes, Alpha Proteobacteria , Gamma Proteobacteria, and Verrucomicrobia, etc. modulate (e.g., increase or decrease) the growth of one or more bacterial taxa that are predominantly present in the rectum of do).

[0373] In some embodiments, the glycan therapeutic agent is one or more (e.g., 1, 2, 3, 4, 5 , 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 2 0, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 80, 90, 10 0, 150, 200, or more than 200) endosymbiotic microbial taxa, or e.g., Al istipes, Akkermansia, Anaerophilum, Bacteroi Des, Blautia, Bifidobacterium, Butyrivibrio , Clostridium, Coprococcus, Dialister, Dorea , Fusobacterium, Eubacterium, Faecalibacter ium, Lachnospira, Lactobacillus, Odoribacte r, Oscillospira, Parabacteroides, Phascolar ctobacterium, Peptococcus, Peptostreptococcus cus, Prevotella, Roseburia, Ruminococcus, St. Exogenously administered bacteria, including Reptococcus, and Subdoligranulum Modulates (e.g., stimulates / increases) the growth of probiotic bacterial taxa of various genera (or inhibit / reduce).

[0374] In some embodiments, the glycan therapeutic agent is one or more (e.g., 1, 2, 3, 4, 5 , 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 2 0, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 80, 90, 10 0, 150, 200, or more than 200) endosymbiotic or symbiotic microbial taxa, or For example, gastrointestinal health-related disorders that can be regulated by the glycan therapeutic agents described herein. Akkermansia, Anaerofilum, Bacteriolytics Des, Blautia, Bifidobacterium, Butyrivibrio , Clostridium, Coprococcus, Dialister, Dorea , Fusobacterium, Eubacterium, Faecalibacter ium, Lachnospira, Lactobacillus, Phascolarc tobacterium, Peptococcus, Peptostreptococc us, Prevotella, Roseburia, Ruminococcus, and Streptococcus and of the species Akkerm ansia municiphilia, Christensenella minut a, Clostridium coccoides, Clostridium lept um, Clostridium scindens, Dialister invisu s, Eubacterium rectal, Eubacterium eligens , Faecalibacterium prausnitzii, Streptococcus cus salivarius, and Streptococcus thermophi Exogenous bacterial taxa, including, but not limited to, bacterial taxa selected from the group consisting of the genera of ectobiotics, Probiotics of various genera that are administered topically modulate the growth of bacterial taxa (e.g., (increase / increase or decrease / increase).

[0375] In some embodiments, the glycan therapeutic agent is one or more of the compounds listed in Table 1 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 1 7, 18, 19, 20, 25, 30, 35, 40, 45, 50, or more than 50) genera, species , or substantially increase the relative representation of a phylogenetic clade (or the entire gastrointestinal community) or substantially decrease) proliferation (and number) of Table 1 provides a genus-level listing of the microbial constituents of the gastrointestinal tract. .

[0376] In some embodiments, the glycan therapeutic agent is one or more of the compounds listed in Tables 1, 3, and 4. Above (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 1 5, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, or 50 (super) OTU, genus, species, or phylogenetic clade total gastrointestinal community, large intestinal community, or Proliferation in the small intestinal community, for example, substantially increases total number or relative representation.

[0377] In some embodiments, the glycan therapeutic agent is one or more of the compounds listed in Tables 1, 3, and 4. Above (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 1 5, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, or 50 (super) OTU, genus, species, or phylogenetic clade total gastrointestinal community, large intestinal community, or The proliferation, e.g., total number or relative representation, in the small intestinal community is substantially reduced.

[0378] In some embodiments, the glycan therapeutic agent is one or more of the compounds listed in Tables 1, 3, and 4. Above (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 1 5, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, or 50 (super) OTU, genus, species, or phylogenetic clade total gastrointestinal community, large intestinal community, or Proliferation in the small intestinal community, for example, substantially increases and decreases total numbers or relative representation.

[0379] In some embodiments, selected populations that can utilize glycan therapeutic agents as a food source. Glycan therapeutic agents that are substrates only in selected bacterial populations are provided herein. The degradation of glycan therapeutics exerts beneficial effects on the health of the host. , which can utilize glycan therapeutic agents as a food source and confer health benefits to the host. The growth and / or viability of a selected number of microbial genera, species, or strains in the gut microbiota. In certain embodiments, the selective stimulation of the biological activity of the glycan therapeutic agent The effect is due to the selective stimulation of the growth of beneficial bacteria in the gastrointestinal tract. Such increases and decreases in abundance of microbial proteins "normalize" the resident microbiota, e.g., promote healthy The increase or decrease may be sufficient to restore the state or balance. The ratio of the glycan present in a human subject prior to ingestion of the therapeutic composition, or the pharmaceutical glycan therapeutic composition The prebiotic index (PI) is the value calculated for the control group that does not use the prebiotic. It can be used as a proxy for the effectiveness of the glycan therapeutic agents described in PI. is (Bifidobacteria / total bacteria) + (Lactobacilli / total bacteria) ) - (Bacteroides / total bacteria) - (Clostridia / total bacteria) (Palframan et al, 2003, Lett Appl Micro Biol 37:281-284). In some embodiments, Eubac The ratio of Eubacterium rectale / total bacteria may also be considered. Sodium rectale produces butyrate, which is beneficial to the intestinal barrier in adults.

[0380] For example, stimulation of the growth of certain bacterial taxa lowers colonic pH and increases the production of short-chain fatty acids. Increases cell proliferation, prevents the growth and adhesion of pathogenic microorganisms (barrier effect), and prevents the growth of potentially carcinogenic amination It may increase the metabolism of the compound and / or increase the production of the vitamin.

[0381] In some embodiments, certain side effects are absent or may be reduced, for example, bloating, discomfort, and Substantial reduction in symptoms of fermentation, such as increased gas formation, which can cause bloating and / or bloating Glycan therapeutics that can be digested by the microbiota (e.g., by hydrocarbon fermentation) Therapeutic agents are provided herein.

[0382] In certain embodiments, the proportions of certain bacterial taxa or their relative abundances are , can be shifted. Such a shift can be achieved in a subject prior to administration of the pharmaceutical glycan treatment composition. The ratio of the present amount to the present amount of glycan present in the present invention is measured relative to a control group that does not use the pharmaceutical glycan therapeutic composition. obtain.

[0383] In some embodiments, the glycan therapeutic agent is one or a limited number of glycans present in the gastrointestinal tract. It is a selective substrate for a number of potentially beneficial bacterial taxa, supporting their growth and / or Stimulates metabolic activity. In some embodiments, the glycan therapeutic agent is specific to specific bacterial taxa. In this case, the composition of the gastrointestinal microbiota can be changed to a higher or lower composition. In some embodiments, the glycan therapeutic agent is a gastrointestinal bacterial taxon associated with health and well-being. Selectively stimulates proliferation and / or selective activity of the population.

[0384] administering to a subject in need thereof a pharmaceutical glycan treatment in an amount effective to regulate microbial diversity; In some embodiments, the glycan composition is administered to a subject. Administration of the therapeutic agent can occur in the gastrointestinal tract (or specifically in the large or small intestine) of a human subject. The diversity is modulated (e.g., increased or decreased) by the administration of an effective amount of glycoproteins. It may increase or decrease when the therapeutic agent is administered.

[0385] In some embodiments, the glycan therapeutic agent increases diversity. In this state, the glycan therapeutic agent reduces diversity. Exemplary glycans that regulate microbial diversity The therapeutic agents are glu100, ara100, xyl100, glu50gal50, and Contains glu33gal33fuc33.

[0386] In some embodiments, dysbiosis can shift the microbiota to reach an unsettling state. To achieve this, glycan therapeutic agents can be administered to increase or decrease microbial diversity. In some embodiments, microorganisms can be isolated from the gut and used to treat microbial incompatibility. Biodiversity declined, resulting in the proliferation of Akkermansia, Blautia, and Bacteroides s, Bifidobacterium Lactobacillus, and Paraba cteroides, one or more, two or more, three or more, or four or more bacterial classes The presence of the group increases.

[0387] Microbial diversity can be assessed using techniques known in the art, including analysis of 16S rDNA sequences as described herein. Diversity can be measured by any suitable method known in the art. The Shannon entropy, the number of observed OTUs, the Chao1 index, etc. In some embodiments, the glycan therapeutic agent may be expressed as a Shannon index. Regulating diversity within the microbial community of the gastrointestinal tract, for example, which can be expressed using entropy (e.g., increase or decrease).

[0388] In some embodiments, the glycan therapeutic agent is selected from microbial diversity and related Shannon Entropy. Peaks are set to 0.0001%, 0.0005%, 0.001%, 0.005%, 0.01%, 0 .05%, 0.1%, 0.5%, 1%, 5%, 10%, 50%, 100%, 500%, 1 In some embodiments, the glycan is increased by 0, 5,000%, 5,000%, or 10,000%. Therapeutic agents increase microbial diversity and associated Shannon entropy by (logarithmic) 1x, 2x, 3x, 4x, 5x, 6x, 7x, 8x, 9x, 10x, 20x, 30x, 40x, 50x, 60 fold, 70-fold, 80-fold, 90-fold, 100-fold, or more increase. In this study, glycan therapeutics reduced microbial diversity and associated Shannon entropy by 0.0001%. ,0.0005%,0.001%,0.005%,0.01%,0.05%,0.1%, 0.5%, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 8 In some embodiments, the reduction is 0%, 90%, or 99% or more. The rican therapeutic agent increased microbial diversity and associated Shannon entropy by (logarithmic) 1x, 2x, and 2x. x, 3x, 4x, 5x, 6x, 7x, 8x, 9x, 10x, 20x, 30x, 40x, 5 It can decrease by 0x, 60x, 70x, 80x, 90x, 100x, or more.

[0389] In some embodiments, the glycan therapeutic agent is selected from microbial diversity and related Shannon Entropy. At least 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 3 Increase by 0%, 35%, 40%, 45%, or at least 50%.

[0390] In some embodiments, the glycan therapeutic agent is selected from microbial diversity and related Shannon Entropy. Peaks should be at least (logarithmically) 0.2x, 0.3x, 0.4x, 0.5x, 0.8x, 1x, Increase by 1.2x, 1.5x, 1.8x, or at least 2x.

[0391] In some embodiments, the glycan therapeutic agent is selected from microbial diversity and related Shannon Entropy. At least 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 3 0%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or less At least 75% reduction.

[0392] In some embodiments, the glycan therapeutic agent is selected from microbial diversity and related Shannon Entropy. Peaks should be at least (logarithmically) 0.2x, 0.3x, 0.4x, 0.5x, 0.8x, 1x, A decrease of 1.2x, 1.5x, 1.8x, 2x, 3x, 4x, or at least 5x.

[0393] Some of the methods described herein involve modulating host immune and intestinal epithelial cell function. The glycan therapeutic agent can be, for example, administered to improve the host's ability to fight infection. Although immune function can be upregulated to improve immune function, downregulation of immune function can lead to allergic reactions. The regulated beneficial bacteria may be able to prevent the onset of disease or enteritis. The production of anti-inflammatory substances and cytoprotective proteins, as well as cytokine-induced intestinal epithelial cell It can stimulate intestinal epithelial cell responses, including the prevention of cell apoptosis.

[0394] Bacteria induce both pro- and anti-inflammatory responses from host (mammalian) cells. and different bacterial species can elicit different host responses. Glycan therapeutics can be used to alter bacterial populations to elicit desired host responses. The host response may occur through direct interaction with the bacteria or through secreted or excreted proteins. It can be regulated through indirect interactions via bacteria...

Claims

1. A pharmaceutical composition comprising a glycan therapeutic agent for use in treating a disease, disorder or condition associated with microbial incompatibility in a human subject in need of treatment of a previously identified microbial incompatibility, i) the glycan therapeutic agent comprises a mixture of branched glycans, and the average branching degree (DB) of the glycans in the agent is at least 0.05; ii) at least 50% of the glycans in the formulation have a degree of polymerization (DP) of at least 3 and less than 30 glycan units; and iii) the ratio of alpha-glycosidic to beta-glycosidic bonds present in the glycan is between 1:1 and 5:1; The composition, wherein the glycan unit comprises at least one of the monosaccharides selected from the group consisting of glucose, galactose, arabinose, mannose, fructose, xylose, fucose, and rhamnose, and the disease, disorder, or condition is enteritis.

2. 2. The composition for use according to claim 1, wherein the intestinal inflammation is inflammatory bowel disease (IBD).

3. The composition for use according to claim 2, wherein the IBD is ulcerative colitis (UC) or Crohn's disease (CD).

4. The composition for use according to claim 1 , wherein the colitis is microscopic colitis.

5. 10. The composition for use according to claim 1, wherein the treatment further comprises administering a second drug or pharmaceutical agent.

6. 6. The composition for use according to claim 5, wherein the second drug or pharmaceutical agent is a standard of care drug or agent.

7. The composition for use according to any one of claims 1 to 6, wherein the composition is administered daily.

8. The composition for use according to any one of claims 1 to 7, wherein the composition is administered daily for a given number of days (treatment period).

9. 9. The composition for use according to claim 8, wherein the subject is administered the composition during a single treatment period or for more than one treatment period.

10. 10. The composition for use according to any one of claims 1 to 9, wherein at least two, or at least three of the glycosidic bonds independently comprise a 1->2 glycosidic bond, a 1->3 glycosidic bond, a 1->4 glycosidic bond, or a 1->6 glycosidic bond.

11. The composition for use according to any one of claims 1 to 10, wherein the glycan therapeutic agent is synthetic and not isolated from a natural oligosaccharide or polysaccharide source.

12. The composition is formulated in a unit dosage form; (i) the unit dosage form may be formulated for oral delivery, or (ii) The composition for use according to any one of claims 1 to 11, wherein the unit dosage form is formulated to be dissolved in an aqueous solution and may be administered orally as a drink, syrup, solution or suspension.

13. 2. The composition for use according to claim 1, comprising at least one glycan unit selected from the group consisting of glucose, galactose, fucose, xylose, arabinose, rhamnose, and mannose, wherein the formulation comprises a glycan unit associated with one or more of the following 1H-13C HSQC peaks: (i) for glycans containing glucose, the peak comprises at least one of or corresponding to 1H-13C HSQC peaks selected from 5.42, 92.5; 5.21, 92.8; 5.18, 93.9; 5.08, 97.0; 5.36, 98.4; 5.34, 99.8; 5.38, 100.3; 4.95, 98.6; 4.62, 96.6; 4.70, 103.6; 4.49, 103.4 1H shifts (ppm) and 13C shifts (ppm); (ii) for galactose-containing glycans, the peak comprises at least one of or corresponding to 1H-13C HSQC peaks selected from 5.37, 92.9; 5.24, 93.1; 5.14, 96.0; 4.96, 99.3; 5.31, 98.7; 5.39, 101.4; 5.00, 101.8; 4.80, 101.3; 4.63, 97.0; 4.56, 97.2; 4.53, 103.1; 4.43, 104.1 1H shifts (ppm) and 13C shifts (ppm); (iii) for glycans containing fucose, the peak comprises at least one of or corresponding to 1H-13C HSQC peaks selected from 5.18, 92.9; 5.33, 92.4; 5.04, 96.3; 4.90, 99.7; 4.52, 97.0; 4.39, 103.6 1H shifts (ppm) and 13C shifts (ppm); (iv) for glycans containing xylose, the peak comprises at least one of or a corresponding peak selected from 5.18, 93.0; 5.10, 94.3; 5.34, 98.2; 5.31, 99.6; 5.11, 100.8; 4.91, 99.4; 4.56, 97.3; 4.64, 104.2; 4.54, 103.4; 4.44, 102.6; 4.44, 104.1 1H shifts (ppm) and 13C shifts (ppm); (v) for arabinose-containing glycans, the peak comprises at least one of or corresponding to 1H-13C HSQC peaks selected from 5.22, 93.2; 5.13, 93.2; 5.29, 96.0; 5.26, 97.2; 5.12, 96.6; 5.18, 99.6; 5.06, 99.2; 4.99, 100.0; 5.26, 101.9; 5.06, 102.1; 4.55, 97.4; 4.54, 105.2; 4.50, 105.5; 4.38, 103.9 1H shifts (ppm) and 13C shifts (ppm); (vi) for rhamnose-containing glycans, the peak comprises at least one of the following 1H-13C HSQC peaks or corresponding peaks selected from: 5.21, 93.2; 5.10, 94.5; 4.85, 94.1; 5.01, 95.8; 5.35, 100.5; 5.15, 102.2; 5.04, 102.9; 4.78, 97.9; 4.71, 99.0; 4.72, 101.0 1H shifts (ppm) and 13C shifts (ppm); (vii) For mannose-containing glycans, the peak comprises at least one of or a corresponding peak to 1H-13C HSQC peaks selected from 5.37, 93.0; 5.16, 94.6; 4.88, 94.2; 5.39, 101.7; 5.24, 101.9; 5.13, 102.8; 5.03, 102.7; 5.24, 105.6; 5.09, 108.0; 4.88, 94.2; 4.89, 100.0; 4.70, 101.1 1H shifts (ppm) and 13C shifts (ppm).

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