Combinations of GLP-1 and guanylate cyclase c (GC-c) receptor agonists

Abstract

The present disclosure provides combinations of GLP-1 receptor agonists, and guanylate-cyclase C (GC-C) receptor agonists, and pharmaceutical compositions comprising the same. Also described are methods of making and using the combination, which can be used to treat or prevent of one or more side effects of a GLP-1 receptor agonist.

Description

COMBINATIONS OF GLP-1 AND GUANYLATE CYCLASE C (GC-C) RECEPTOR AGONISTSCROSS REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims priority to and the benefit of U.S. Provisional Application No. 63 / 687,511, filed August 27, 2024, the contents of which are herein incorporated by reference in its entirety.SEQUENCE LISTING

[0002] This application incorporates by reference in its entirety the Sequence Listing XML entitled “223355-553174_ Sequence-listing.xml” (11,556 kilobytes), which was created August 26, 2024, and filed electronically herewith.TECHNICAL FIELD

[0003] New combinations and pharmaceutical compositions for the treatment of one or more side effects of a glucagon-like-peptide-1 (GLP-1) receptor agonist are described and claimed.BACKGROUND

[0004] The management of metabolic syndrome and weight control has become a significant medical concern due to the myriad of comorbidities patients experience. One of the more significant comorbidities in people is the development of diabetes and the associated heart health risk. People suffering from metabolic syndrome, diabetes and / or hypercholesterolemia are often considered for treatment with GLP-1 receptor agonists.

[0005] Commercially several GLP-1 receptor agonists are available for prescription use including semaglutide, liraglutide, as well as others; and, more products targeting glucagon receptor are under development. These GLP-1 receptor agonists have proven quite successful at reducing weight, improving metabolic syndrome and normalizing serum cholesterol.

[0006] Glucagon-like-peptide-1 is a peptide hormone secreted from L-cells that line the intestine. These cells are located throughout the gastrointestinal track and act on the glucagon-like-peptide-1 (GLP-1) receptor, which is expressed fairly ubiquitously throughout the body (e.g., including the pancreas, GI track, heart, lung, and immune cells). When the peptide GLP-1 binds to its cognate receptor — depending on the receptor site — the pharmacodynamic responses range from slowed gastric emptying, reduced appetite and food intake, decreased peptide hormone secretion (e.g., glucagon), as well as generalized slow gastrointestinal transit, which can result in constipation. Accordingly, the overall positivemetabolic effects of the GLP-1 receptor agonist can be compromised because of discontinuation owing to unwanted side effects related to slow gastrointestinal transit.

[0007] In one study of patients taking GLP-1 receptor agonist, nausea, constipation and gastroesophageal reflux – all indicators of delayed gastrointestinal transit – were experienced by 26%, 21%, and 12% of subjects respectively (Digestive Disease Week abstract Mo1918; Cornet et al, May 2023). In addition, 12% of patients taking the GLP-1 in this study experienced abdominal pain and / or bloating. These side effects are quite disturbing to people taking GLP-1 receptor agonists and decreasing or eliminating these unwanted symptoms should result in improved prescription compliance and better clinical outcomes.

[0008] Accordingly, new pharmaceutical compositions and methods to treat and / or reduce the symptoms associated with one or more side effects of a GLP-1 receptor agonist are needed. SUMMARY

[0009] The present disclosure describes a combination comprising: a GLP-1 receptor agonist, and a guanylate-cyclase C (GC-C) receptor agonist.

[0010] In addition, the present disclosure describes a combination comprising: semaglutide and linaclotide, or a pharmaceutically acceptable salt thereof.

[0011] In addition, the present disclosure describes a combination comprising: liraglutide and linaclotide, or a pharmaceutically acceptable salt thereof.

[0012] In addition, the present disclosure describes a combination comprising: semaglutide and a peptide, or a pharmaceutically acceptable salt thereof, having an amino acid sequence of: Cys1Cth2Glu3Leu4Cys5Cys6Asn7Val8Ala9Cys10Tyr11Gly12Cys13(SEQ ID NO: 2); wherein Cth is a cystathionine; wherein Cys1and Cys6; Cys5and Cys13; are connected by disulfide bonds; wherein Cth2and Cys10are connected by a thioether bond; and wherein the peptide has an N-terminus that is optionally acetylated; or a pharmaceutically acceptable salt thereof.

[0013] In addition, the present disclosure describes a combination comprising: liraglutide and a peptide, or a pharmaceutically acceptable salt thereof, having an amino acid sequence of: Cys1Cth2Glu3Leu4Cys5Cys6Asn7Val8Ala9Cys10Tyr11Gly12Cys13(SEQ ID NO: 2); wherein Cth is a cystathionine; wherein Cys1and Cys6; Cys5and Cys13; are connected by disulfide bonds; wherein Cth2and Cys10are connected by a thioether bond; and wherein the peptide has an N-terminus that is optionally acetylated; or a pharmaceutically acceptable salt thereof.

[0014] In addition, the present disclosure describes a combination comprising: semaglutide and plecanatide, or a pharmaceutically acceptable salt thereof.

[0015] In addition, the present disclosure describes a combination comprising: liraglutide and plecanatide.

[0016] In addition, the present disclosure describes a composition comprising combination of: a GLP-1 receptor agonist and a guanylate-cyclase C (GC-C) receptor agonist; and one or more excipients.

[0017] In addition, the present disclosure describes a method of preventing one or more side effects of a GLP-1 receptor agonist in a subject in need thereof, comprising: administering to the subject in need thereof a combination of a GLP-1 receptor agonist and a guanylate-cyclase C (GC-C) receptor agonist.

[0018] In addition, the present disclosure describes a method of preventing one or more side effects of a GLP-1 receptor agonist comprising: (1) identifying a subject being treated with a GLP-1 receptor agonist, wherein the subject is diagnosed with, is suspected of having, is displaying symptoms of, or is confirmed to have one or more side effects of a GLP-1 receptor agonist; and (2) administering to the subject in need thereof a guanylate- cyclase C (GC-C) receptor agonist.

[0019] In addition, the present disclosure describes a method of treating or preventing one or more side effects of a GLP-1 receptor agonist comprising: (a) selecting a subject that is diagnosed with, is suspected of having, is displaying symptoms of, or is confirmed to have one or more side effects of a GLP-1 receptor agonist; and (b) administering to the subject a therapeutically effective amount of a GC-C receptor agonist; wherein the administration of the therapeutically effective amount of the GC-C receptor agonist to the subject results in a reduction in the occurrence or severity of the one or more side effects of the GLP-1 receptor agonist, or a symptom or pain associated thereof, relative to the occurrence or severity of the one or more side effects of the GLP-1 receptor agonist, or a symptom or pain associated thereof, in the subject prior to being administered the therapeutically effective amount of the GC-C receptor agonist.

[0020] In addition, the present disclosure describes a method of treating or preventing one or more side effects of a GLP-1 receptor agonist comprising: (a) selecting a subject that is diagnosed with, is suspected of having, is displaying symptoms of, or is confirmed to have one or more side effects of a GLP-1 receptor agonist; and (b) administering to the subject a therapeutically effective amount of linaclotide, or a pharmaceutically acceptable salt thereof; wherein the administration of the therapeutically effective amount of linaclotide to the subjectresults in a reduction in the occurrence or severity of the one or more side effects of the GLP- 1 receptor agonist, or a symptom or pain associated thereof, relative to the occurrence or severity of the one or more side effects of the GLP-1 receptor agonist, or a symptom or pain associated thereof, in the subject prior to being administered the therapeutically effective amount of linaclotide.

[0021] In addition, the present disclosure describes a method of treating or preventing one or more side effects of a GLP-1 receptor agonist comprising: (a) selecting a subject that is diagnosed with, is suspected of having, is displaying symptoms of, or is confirmed to have one or more side effects of a GLP-1 receptor agonist; and (b) administering to the subject a therapeutically effective amount of a peptide, or a pharmaceutically acceptable salt thereof, having an amino acid sequence of: Cys1Cth2Glu3Leu4Cys5Cys6Asn7Val8Ala9Cys10Tyr11Gly12Cys13(SEQ ID NO: 2); wherein Cth is a cystathionine; wherein Cys1and Cys6; Cys5and Cys13; are connected by disulfide bonds; wherein Cth2and Cys10are connected by a thioether bond; and wherein the peptide has an N-terminus that is optionally acetylated; or a pharmaceutically acceptable salt thereof; wherein the administration of the therapeutically effective amount of linaclotide to the subject results in a reduction in the occurrence or severity of the one or more side effects of the GLP-1 receptor agonist, or a symptom or pain associated thereof, relative to the occurrence or severity of the one or more side effects of the GLP-1 receptor agonist, or a symptom or pain associated thereof, in the subject prior to being administered the therapeutically effective amount of linaclotide.

[0022] In addition, the present disclosure describes a method of treating or preventing one or more side effects of a GLP-1 receptor agonist comprising: (a) selecting a subject that is diagnosed with, is suspected of having, is displaying symptoms of, or is confirmed to have one or more side effects of a GLP-1 receptor agonist; and (b) administering to the subject a therapeutically effective amount of plecanatide, or a pharmaceutically acceptable salt thereof; wherein the administration of the therapeutically effective amount of linaclotide to the subject results in a reduction in the occurrence or severity of the one or more side effects of the GLP- 1 receptor agonist, or a symptom or pain associated thereof, relative to the occurrence or severity of the one or more side effects of the GLP-1 receptor agonist, or a symptom or pain associated thereof, in the subject prior to being administered the therapeutically effective amount of linaclotide.

[0023] In addition, the present disclosure describes a method of treating one or more side effects of a GLP-1 receptor agonist in a subject in need thereof, the method comprising: administering to the subject in need thereof a therapeutically effective amount of thepharmaceutical composition described herein; the liquid pharmaceutical composition described herein; the unit dosage form described herein; or the pharmaceutical rectal foam composition described herein.BRIEF DESCRIPTION OF THE FIGURES

[0024] FIG. 1 shows a diagram of an illustrative Guanylate-cyclase C (GC-C) receptor agonist: linaclotide.DETAILED DESCRIPTION

[0025] Definitions

[0026] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Accordingly, the following terms are intended to have the following meanings:

[0027] As used in the specification and claims, the singular form “a”, “an” and “the” includes plural references unless the context clearly dictates otherwise.

[0028] “Additive” refers to any pharmaceutically acceptable additive. Pharmaceutically acceptable additives include, without limitation, disintegrants, dispersing additives, lubricants, glidants, antioxidants, coating additives, diluents, surfactants, flavoring additives, humectants, absorption promoting additives, controlled release additives, anticaking additives, anti-microbial agents (e.g., preservatives), colorants, desiccants, plasticizers and dyes.

[0029] “Administering” or “administration” or “administer” means to dispense, provide, and / or apply, and refers to any route of administration. For example, administering can refer to, e.g., administration as a suppository, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intracranial, intranasal or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini -osmotic pump, rectal foam, to a subject. Administration can be by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). In some embodiments, parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc. By “co-administer” it is meant that a compound or composition described herein is administered at the same time, just prior to, or just after theadministration of one or more additional agents or therapies, also referred to herein as a “additional agent.’" The combinations of the present disclosure, or a pharmaceutical composition thereof, can be administered alone or can be co-administered to the patient. Coadministration is meant to include simultaneous or sequential administration of each of a compound individually or in combination (more than one compound or agent).

[0030] “Agonist” (e.g., GLP-1 receptor agonist or GC-C receptor agonist) refers to an agent that specifically binds a target (e.g., a receptor) and interacts with said target to cause or promote one or more of the following: (1) stimulates or activates the receptor; (2) enhances, increases or promotes, induces or prolongs an activity, function or presence of the receptor; and / or (3) enhances, increases, promotes or induces the expression of the receptor. In some embodiments, an agonist is an agent that binds to a receptor and alters the receptor state resulting in a biological response that mimics the effect of the endogenous ligand of the receptor. As used herein, the term “agonist” includes partial agonists, full agonists and superagonists. An agonist may be described as a “full agonist” when such agonist which leads to a substantially full biological response (i.e., the response associated with the naturally occurring ligand / receptor binding interaction) induced by receptor under study, or a partial agonist. A “superagonist” is a type of agonist that is capable of producing a maximal response greater than the endogenous agonist for the target receptor, and thus has an activity of more than 100% of the native ligand. In some embodiments, a superagonist can be a synthetic molecule that exhibits greater than 110%, alternatively greater than 120%, alternatively greater than 130%, alternatively greater than 140%, alternatively greater than 150%, alternatively greater than 160%, or alternatively greater than 170% of the response in an evaluable quantitative or qualitative parameter of the naturally occurring form of the molecule when evaluated at similar concentrations in a comparable assay. It should be noted that the biological effects associated with the full agonist may differ in degree and / or in kind from those biological effects of partial or superagonists. In contrast to agonists, antagonists may specifically bind to a receptor but do not result the signal cascade typically initiated by the receptor and may to modify the actions of an agonist at that receptor. Inverse agonists are agents that produce a pharmacological response that is opposite in direction to that of an agonist. Agonist activity can be measured in vitro by various assays know in the art such as, but not limited to, measurement of cell signaling, and the like. Agonist activity can also be measured in vivo by various assays that measure surrogate end points known in the art.

[0031] “Alignment” refers to a method of comparing two or more sequences (e.g., nucleotide, polynucleotide, amino acid, peptide, polypeptide or protein sequences) for thepurpose of determining their relationship to each other. Alignments are typically performed by computer programs that apply various algorithms, however it is also possible to perform an alignment by hand. Alignment programs typically iterate through potential alignments of sequences and score the alignments using substitution tables, employing a variety of strategies to reach a potential optimal alignment score. Commonly-used alignment algorithms include, but are not limited to, CLUSTALW, (see, Thompson J. D., Higgins D. G., Gibson T. J., CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice, Nucleic Acids Research 22: 4673-4680, 1994); CLUSTALV, (see, Larkin M. A., et al., CLUSTALW2, ClustalW and ClustalX version 2, Bioinformatics 23(21): 2947-2948, 2007); Jotun-Hein, Muscle et al., MUSCLE: a multiple sequence alignment method with reduced time and space complexity, BMC Bioinformatics 5: 113, 2004); Mafft, Kalign, ProbCons, and T-Coffee (see Notredame et al., T-Coffee: A novel method for multiple sequence alignments, Journal of Molecular Biology 302: 205-217, 2000). Exemplary programs that implement one or more of the above algorithms include, but are not limited to MegAlign from DNAStar (DNAStar, Inc.3801 Regent St. Madison, Wis.53705), MUSCLE, T-Coffee, CLUSTALX, CLUSTALV, JalView, Phylip, and Discovery Studio from Accelrys (Accelrys, Inc., 10188 Telesis Ct, Suite 100, San Diego, Calif.92121). In some embodiments, an alignment will introduce “phase shifts” and / or “gaps” into one or both of the sequences being compared in order to maximize the similarity between the two sequences, and scoring refers to the process of quantitatively expressing the relatedness of the aligned sequences.

[0032] “Ameliorate” or “amelioration” includes the arrest, prevention, decrease, or improvement in one or more the symptoms, signs, and features of the disease being treated, both temporary and long-term.

[0033] “Binder” refers to” refers to any pharmaceutically acceptable binder that may be used in the practice of the present disclosure. Examples of pharmaceutically acceptable binders include, without limitation, a starch (e.g., corn starch, potato starch and pre- gelatinized starch (e.g., STARCH 1500® and STARCH 1500 LM®, sold by Colorcon, Ltd.) and other starches), maltodextrin, gelatin, natural and synthetic gums such as acacia, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., methylcellulose, hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl cellulose and hydroxypropyl methylcellulose (hypromellose), ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, carboxymethylcellulose, microcrystalline cellulose (e.g. AVICEL™, such as, AVICEL-PH-101™, -103™ and -105™,sold by FMC Corporation, Marcus Hook, PA, USA)), polyvinyl alcohol, polyvinyl pyrrolidone (e.g., polyvinyl pyrrolidone K30), and mixtures thereof.

[0034] “Combination” refers to the result of combining two or more separate components (e.g., a first component and one or more additional components). Thus, as used herein, a “combination” refers to an association of two or more separate components, e.g., the association of a first component (e.g., a first agonist), and one or more additional components (e.g., one or more additional agonists).

[0035] In some embodiments, a combination can be a “mixture.” For example, in some embodiments, a mixture refers to a combination of a first component, and one or more additional components, wherein the first component and the one or more additional components are present together in a single entity (e.g., a single unit). Thus, in some embodiments, a mixture can comprise a first component, and one or more additional components, wherein the first component and the one or more additional components are present in admixture for simultaneous administration. Accordingly, in some embodiments, a combination can refer to the association of a first agonist (e.g., a GLP-1 receptor agonist or a GC-C receptor agonist), and one or more additional agonists (e.g., one or more additional GLP-1 receptor agonists or GC-C receptor agonists); wherein the first agonist and one or more additional agonist are the same or different; and wherein the first agonist and one or more additional agonists are present in a single entity (e.g., an admixture for simultaneous administration).

[0036] In some embodiments, a combination can comprise a first component, and one or more additional components, wherein the first component and the one or more additional components, are present separately (e.g., more than one unit). For example, in some embodiments, a combination can comprise a first component, and one or more additional components, wherein the first component and the one or more additional components may be administered separately, sequentially, simultaneously, concurrently or chronologically staggered.

[0037] Accordingly, in some embodiments, a combination can refer to the association of a first agonist (e.g., a GLP-1 receptor agonist or a GC-C receptor agonist), and one or more additional agonists (e.g., one or more additional GC-C receptor agonists or GLP-1 receptor agonists, respectively); wherein the combination comprises at least a GLP-1 receptor agonist and a GC-C receptor agonist; and wherein the first agonist and one or more additional agonists are present separately (e.g., different units for separate, sequential, simultaneous, concurrent or chronologically-staggered administration). For example, in some embodiments,a combination comprises at least a GLP-1 receptor agonist and a GC-C receptor agonist, wherein the GLP-1 receptor agonist and the GC-C receptor agonist are present separately.

[0038] In some embodiments, a combination can refer to the separate, sequential, simultaneous, concurrent or chronologically-staggered application of two or more separate components (e.g., a first agonist, and one or more additional agonists.

[0039] For example, in some embodiments, a “combination” refers to the result of a simultaneous application of both a first agonist, and one or more additional agonists. Thus, in some embodiments, a “combination” refers to the result of a simultaneous application of both a GLP-1 receptor agonist, and a GC-C receptor agonist.

[0040] In another embodiment, a “combination” refers to the result of a separate application of a first agonist, and one or more additional agonists. For example, in some embodiments, a “combination” refers to the result of a separate application of a GLP-1 receptor agonist, and a GC-C receptor agonist.

[0041] In a further embodiments, a “combination” refers to the result of a sequential application of two or more separate components, e.g., a first application of a first agonist (e.g., a GLP-1 receptor agonist or a GC-C receptor agonist), followed by a second application of one or more additional agonists (e.g., one or more additional GLP-1 receptor agonists or GC-C receptor agonists), wherein the first agonist and one or more additional agonists are the same or different, or vice versa. Where the application is sequential or separate, the delay in applying the second component should not be such as to lose the beneficial effect of the combination.

[0042] “Combination of the present disclosure” refers a combination of a GLP-1 receptor agonist and a GC-C receptor agonist. In one example, in some embodiments, a combination of the present disclosure refers to a combination comprising a GLP-1 receptor agonist, and linaclotide, or a pharmaceutically acceptable salt thereof. In another example, in some embodiments, a combination of the present disclosure refers to a combination comprising a GLP-1 receptor agonist, and plecanatide, or a pharmaceutically acceptable salt thereof. In yet another example, in some embodiments, a combination of the present disclosure refers to a combination comprising a GLP- receptor agonist and a peptide of Formula (I) , or a pharmaceutically acceptable salt thereof.

[0043] “Decreasing” or “decrease” or “decreased” or “reducing” or “reduced” or “a reduction” or “inhibiting” or any variation of these terms, refers to making something (e.g., the amount of pain) less in size, amount, intensity, or degree. For example, in some embodiments, the administration of a therapeutically effective amount of a combination ofthe present disclosure (e.g., a GLP-1 receptor agonist and a GC-C receptor agonist), or a pharmaceutical composition comprising the same, to a patient in need thereof, results in the following effect: a decrease in the number, amount, or severity of one or more side effects of a GLP-1 receptor agonist and / or a pain associated thereof in a patient who has been administered a therapeutically effective amount of a combination of the present disclosure, or a pharmaceutical composition comprising the same; relative to the number, amount, or severity of one or more side effects of a GLP-1 receptor agonist and / or a pain associated thereof experienced by the patient prior to being administered the therapeutically effective amount of a combination of the present disclosure, or a pharmaceutical composition comprising the same. In some embodiments, reducing or decreasing, includes any measurable decrease or complete inhibition to achieve a desired result. For example, there may be a decrease of about 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%, 99%, or more, reduction of a symptom and / or pain compared to normal. About as used herein means within ± 10%, preferably ± 5% of a given value. Thus, in some embodiments, the terms “reduction in one or more side effects,” refers to a decrease or reduction in the number, amount, or severity of a side effect of a GLP-1 receptor agonist experienced by a patient who has received a therapeutically effective amount of a combination of the present disclosure, or a pharmaceutical composition comprising the same, that is at least about 0.1%, at least about 0.2%, at least about 0.3%, at least about 0.4%, at least about 0.5%, at least about 0.6%, at least about 0.7%, at least about 0.8%, at least about 0.9%, at least about 1%, at least about 1.25%, at least about 1.5%, at least about 1.75%, at least about 2%, at least about 2.25%, at least about 2.5%, at least about 2.75%, at least about 3%, at least about 3.25%, at least about 3.5%, at least about 3.75%, at least about 4%, at least about 4.25%, at least about 4.5%, at least about 4.75%, at least about 5%, at least about 5.25%, at least about 5.5%, at least about 5.75%, at least about 6%, at least about 6.25%, at least about 6.5%, at least about 6.75%, at least about 7%, at least about 7.25%, at least about 7.5%, at least about 7.75%, at least about 8%, at least about 8.25%, at least about 8.5%, at least about 8.75%, at least about 9%, at least about 9.25%, at least about 9.5%, at least about 9.75%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, atleast about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, at least about 40%, at least about 41%, at least about 42%, at least about 43%, at least about 44%, at least about 45%, at least about 46%, at least about 47%, at least about 48%, at least about 49%, at least about 50%,at least about 50%, at least about 51%, at least about 52%, at least about 53%, at least about 54%, at least about 55%, at least about 56%, at least about 57%, at least about 58%, at least about 59%, at least about 60%, at least about 61%, at least about 62%, at least about 63%, at least about 64%, at least about 65%, at least about 66%, at least about 67%, at least about 68%, at least about 69%, at least about 70%, at least about 71%, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, or a greater than a 100%, relative to the number, amount, or severity of one or more side effects of a GLP-1 receptor agonist experienced by the patient prior to being administered the therapeutically effective amount of a combination of the present disclosure, or a pharmaceutical composition comprising the same.

[0044] “Excipient” refers to any pharmaceutically acceptable additive, carrier, surfactant, emulsifier, thickener, preservative, solvent, disintegrant, glidant, lubricant, diluent, filler, bulking agent, binder, emollient, stiffening agent, chelating agent, stabilizer, solubilizing agents, dispersing agent, suspending agent, antioxidant, antiseptic, wetting agent, humectant, fragrant, suspending agents, pigments, colorants, isotonic agents, viscosity enhancing agents, mucoadhesive agents, and / or any combination thereof, that can be added to a pharmaceutical composition, preparation, and / or formulation, which may be useful in achieving a desired modification to the characteristics of the pharmaceutical composition, preparation, and / or formulation. Such modifications include, but are not limited to, physical stability, chemical stability, therapeutic efficacy, and / or any combination thereof.

[0045] “Filler” refers to any pharmaceutically acceptable filler that may be used in the practice of the present disclosure. Examples of pharmaceutically acceptable fillers include, without limitation, talc, calcium carbonate (e.g., granules or powder), dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate (e.g., granules or powder), microcrystalline cellulose (e.g., Avicel PH101 or Celphere CP-305), powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch (e.g., Starch 1500), pre-gelatinized starch, lactose, glucose, fructose, galactose, trehalose, sucrose, maltose, isomalt, raffinose, maltitol, melezitose, stachyose, lactitol, palatinite, xylitol, myoinositol, and mixtures thereof.

[0046] “GLP-1 receptor agonist” refers to a substance that can activate glucagon receptor, and interacts with said GLP-1 receptor to cause or promote one or more of thefollowing: (1) stimulates or activates the receptor; (2) enhances, increases or promotes, induces or prolongs an activity, function or presence of the receptor; and / or (3) enhances, increases, promotes or induces the expression of the receptor. In some embodiments, the GLP-1 receptor agonist is an agent that binds to a receptor and alters the receptor state resulting in a biological response that mimics the effect of the endogenous ligand of the receptor. In some embodiments, the GLP-1 receptor agonist can be a partial agonist, a full agonist, or a superagonist. As used herein, the term “agonist” includes partial agonists, full agonists and superagonists. An agonist may be described as a "‘full agonist” when such agonist which leads to a substantially full biological response (i.e., the response associated with the naturally occurring ligand / receptor binding interaction) induced by receptor under study, or a partial agonist. A “superagonist” is a type of agonist that is capable of producing a maximal response greater than the endogenous agonist for the target receptor, and thus has an activity of more than 100% of the native ligand. In some embodiments, a superagonist can be a synthetic molecule that exhibits greater than 110%, alternatively greater than 120%, alternatively greater than 130%, alternatively greater than 140%, alternatively greater than 150%, alternatively greater than 160%, or alternatively greater than 170% of the response in an evaluable quantitative or qualitative parameter of the naturally occurring form of the molecule when evaluated at similar concentrations in a comparable assay.

[0047] “Guanylate-cyclase C (GC-C) receptor agonist” or “GC-C receptor agonist” refers to a substance that can activate guanylate-cyclase C receptor, and interacts with said guanylate-cyclase C receptor to cause or promote one or more of the following: (1) stimulates or activates the receptor; (2) enhances, increases or promotes, induces or prolongs an activity, function or presence of the receptor; and / or (3) enhances, increases, promotes or induces the expression of the receptor. In some embodiments, the GC-C receptor agonist is an agent that binds to a receptor and alters the receptor state resulting in a biological response that mimics the effect of the endogenous ligand of the receptor. In some embodiments, the GC-C receptor agonist can be a partial agonist, a full agonist, or a superagonist. As used herein, the term “agonist” includes partial agonists, full agonists and superagonists. An agonist may be described as a “full agonist” when such agonist which leads to a substantially full biological response (i.e., the response associated with the naturally occurring ligand / receptor binding interaction) induced by receptor under study, or a partial agonist. A “superagonist” is a type of agonist that is capable of producing a maximal response greater than the endogenous agonist for the target receptor, and thus has an activity of more than 100% of the native ligand. In some embodiments, a superagonist can be a synthetic molecule that exhibits greaterthan 110%, alternatively greater than 120%, alternatively greater than 130%, alternatively greater than 140%, alternatively greater than 150%, alternatively greater than 160%, or alternatively greater than 170% of the response in an evaluable quantitative or qualitative parameter of the naturally occurring form of the molecule when evaluated at similar concentrations in a comparable assay.

[0048] “Identity” refers to a relationship between two or more polypeptide sequences or two or more polynucleotide sequences, as determined by comparing said sequences. The term “identity” also means the degree of sequence relatedness between two polypeptide or polynucleotide sequences, as the case may be, as determined by the match between amino acids or bases in the same position in the compared sequences. “Identity” and “similarity” can be readily calculated by any one of the myriad methods known to those having ordinary skill in the art, including but not limited to those described in: Computational Molecular Biology, Lesk, A. M., ed., Oxford University Press, New York, 1988; Biocomputing: Informatics and Genome Projects, Smith, D. W., ed., Academic Press, New York, 1993; Computer Analysis of Sequence Data, Part 1, Griffin, A. M., and Griffin, H. G., eds., Humana Press, New Jersey, 1994:, Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987; and Sequence Analysis Primer, Gribskov, M. and Devereux, J., eds., M Stockton Press, New York, 1991; and Carillo, H., and Lipman, D., SIAM J. Applied Math., 48: 1073 (1988), the disclosures of which are incorporated herein by reference in their entireties. Furthermore, methods to determine identity and similarity are codified in publicly available computer programs. For example in some embodiments, methods to determine identity and similarity between two sequences include, but are not limited to, the GCG program package (Devereux, J., et al., Nucleic Acids Research 12(1): 387 (1984)), BLASTP, BLASTN, and FASTA (Altschul, S. F. et al., J. Molec. Biol.215: 403-410 (1990). The BLAST X program is publicly available from NCBI and other sources (BLAST Manual, Altschul, S., et al., NCBI NLM NIH Bethesda, Md.20894; Altschul, S., et al., J. Mol. Biol. 215: 403-410 (1990), the disclosures of which are incorporated herein by reference in their entireties.

[0049] “Linaclotide” refers to a 14-amino acid peptide consisting of the amino acid sequence set forth in Formula (a):

[0050] The chemical structure of linaclotide (absolute stereochemistry) is shown below in Formula (b):

[0051] Linaclotide can be represented in a linear form using the following three-letter amino acid code: Cys1Cys2Glu3Tyr4Cys5Cys6Asn7Pro8Ala9Cys10Thr11Gly12Cys13Tyr14(SEQ ID NO: 1), wherein Cys1and Cys6; Cys2and Cys10; and Cys5and Cys13, are connected by disulfide bonds; or using the single letter amino acid code: CCEYCCNPACTGCY (SEQ ID NO: 1), wherein Cys1and Cys6; Cys2and Cys10; and Cys5and Cys13, are connected by disulfide bonds. Accordingly, in some embodiments, linaclotide refers to a peptide consisting of the amino acid sequence: Cys1Cys2Glu3Tyr4Cys5Cys6Asn7Pro8Ala9Cys10Thr11Gly12Cys13Tyr14(SEQ ID NO: 1), or a pharmaceutically acceptable salt thereof; wherein Cys1and Cys6; Cys2and Cys10; and Cys5and Cys13, are connected by disulfide bonds.

[0052] The chemical name of linaclotide is L-cysteinyl-L-cysteinyl-L-glutamyl-L- tyrosyl-L-cysteinyl-L-cysteinyl-L-asparaginyl-L-prolyl-L-alanyl-L-cysteinyl-L-threonyl- glycyl-L-cysteinyl-L-tyrosine, cyclic (1-6), (2-10), (5-13)-tris(disulfide).

[0053] The molecular formula of linaclotide is C59H79N15O21S6and its molecular weight is 1526.8. Linaclotide is an amorphous, white to off-white powder. It is slightly soluble in water and aqueous sodium chloride (0.9%). In some embodiments, linaclotide is available under the trade name: “LINZESS,” which comprises linaclotide-coated beads in hard gelatin capsules.

[0054] Linaclotide is a GC-C receptor agonist that acts on the apical surface of epithelial cells surrounding the intestinal lumen to stimulate the receptor guanylate cyclase subtype C (GC-C). By activating GC-C, orally administered linaclotide has been found to increase both intestinal fluid secretion and intestinal transit and to also decrease visceral (abdominal) pain.

[0055] “Molecular weight (MW)” refers to the mass or weight of a molecule, and for proteins is typically measured in “daltons (Da)” or kilodaltons (kDa). In some embodiments, MW can be calculated using sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), gel chromatography, analytical ultracentrifugation, mass spectrometry, or light scattering. In some embodiments, the SDS-PAGE method is as follows: the sample of interest is separated on a gel with a set of molecular weight standards. The sample is run, and the gel is then processed with a desired stain, followed by destaining for about 2 to 14 hours. The next step is to determine the relative migration distance (Rf) of the standards and protein of interest. The migration distance can be determined using the following equation: Rf = (migration distance of the protein) / (Migration distance of the dye front). Next, the logarithm of the MW can be determined based on the values obtained for the bands in the standard; e.g., in some embodiments, the logarithm of the molecular weight of an SDS- denatured polypeptide and its relative migration distance (Rf) is plotted into a graph. After plotting the graph, interpolating the value derived will provide the molecular weight of the unknown protein band.

[0056] “One letter code” means the peptide sequence which is listed in its one letter code to distinguish the various amino acids in the primary structure of a protein: alanine=A, arginine=R, asparagine=N, aspartic acid=D, asparagine or aspartic acid=B, cysteine=C, glutamic acid=E, glutamine=Q, glutamine or glutamic acid=Z, glycine=G, histidine=H, isoleucine=I, leucine=L, lysine=K, methionine=M, phenylalanine=F, proline=P, serine=S, threonine=T, tryptophan=W, tyrosine=Y, and valine=V.

[0057] “Patient” and “subject” are used herein interchangeably, and refer to any animal (e.g., a mammal, such as a human, a laboratory animal, such as a mouse, rat, rabbit, guinea pig, or other animal models of visceral pain and / or side effects of a GLP-1 receptor agonist, or a domesticated animal, such as a dog, cat, or a domesticated animal, for example, sheep, horses, cattle, pigs and goats). A patient in need of treatment, according to the methods described herein, may be one who is currently taking one or more GLP-1 receptor agonists, or a patient who has been diagnosed with one or more side effects of a GLP-1 receptor agonist, such as those described herein.

[0058] “Peptide” and “protein” and “polypeptide” are used interchangeably herein.

[0059] “Peptide of the present disclosure” refers to a peptide-form of a GLP-1 receptor agonist or a GC-C receptor agonist. For example, in some embodiments, a peptide of the present disclosure can be a peptide-form of a GLP-1 receptor agonist, e.g., a GLP-1receptor agonist. In other embodiments, a peptide of the present disclosure can be a peptide- form of a GC-C receptor agonist, e.g., linaclotide.

[0060] “Pharmaceutically acceptable salts” is meant to include salts of the peptides of present disclosure (e.g., a peptide form of a GLP-1 receptor agonist or a GC-C receptor agonist), which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When peptides of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such peptides with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Non-limiting examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like. Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally- occurring amines and the like, such as arginine, betaine, caffeine, choline, N,N’- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. When peptides of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such peptides with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge, S.M., et al, “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19).

[0061] “Pharmaceutical composition” or “pharmaceutical composition of the present disclosure” refers a pharmaceutical composition comprising a combination of the present disclosure (e.g., a combination comprising a GLP-1 receptor agonist and a GC-C receptoragonist), and one or more excipients. In some embodiments, a pharmaceutical composition of the present disclosure can be formulated in an enteral form; a parenteral form; or a transmucosal form. In other embodiments, a pharmaceutical composition of the present disclosure can be formulated in a suppository form, an enema form, a feeding tube form, or a solution for intraluminal use. In yet other embodiments, a pharmaceutical composition of the present disclosure can be formulated as an enema, a rectal gel, a rectal foam, a rectal aerosol, or a suppository. In such embodiments where the pharmaceutical composition of the present disclosure is formulated as a rectal foam, the terms “pharmaceutical composition” and “pharmaceutical rectal foam composition” are used interchangeably.

[0062] “Side effect(s) of GLP-1 receptor agonists” or “adverse effect(s) of GLP-1 receptor agonists” refer to an adverse, deleterious, and / or unwanted side effect of one or more GLP-1 receptor agonists, and can include, but are not limited to, one or more of slow and / or reduced gastrointestinal transit; constipation; nausea; diarrhea; vomiting; stomach (abdomen) pain; upset stomach; feeling bloated; belching; gas; and heartburn and / or any other side effect of GLP-1 receptor agonists known in the art. Recognition and identification of the side effects of GLP-1 receptor agonists and resultant symptomatology are described herein, and can be performed by those skilled in the art. Methods of identifying the side effects of GLP-1 receptor agonists based on symptomatology are well known in the art, and a variety of methods may be used by one having ordinary skill to confirm the presence of the same. The recognition of the symptoms of one or more adverse effects of GLP-1 receptor agonists present in a subject, is well within the purview of one having ordinary skill in the art, and who can perform suitable clinical, diagnostic, and / or observational or other techniques required. Descriptions of GLP-1 receptor agonists are provided in Wilding et al. Once- Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med 2021; 384:989; Astrup et al. Effects of liraglutide in the treatment of obesity: a randomized, double-blind, placebo-controlled study. Lancet 2009; 374:1606; Astrup et al. Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide. Int J Obes (Lond) 2012; 36:843; Pi-Sunyer et al. A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management. N Engl J Med 2015; 373:11; Wadden et al. Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: the SCALE Maintenance randomized study. Int J Obes (Lond) 2013; 37:1443; and Marso et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2016; 375:311.30; the disclosures of which are incorporated herein by reference in their entireties.

[0063] “Subject” or “patient” are used herein interchangeably, and refer to any animal (e.g., a mammal, such as a human) for whom diagnosis, prognosis, and / or treatment is desired. For example, in some embodiments, a subject can be a mammal, e.g., a human or non-human primate (such as an ape, monkey, orangutan, or chimpanzee), a dog, cat, guinea pig, rabbit, rat, mouse, horse, cattle, or cow. In certain embodiments, a “subject in need thereof" refers to one or more of the following: a subject diagnosed with one or more side effects of a GLP-1 receptor agonist and / or is exhibiting one or more conditions or symptoms associated with one or more side effects of a GLP-1 receptor agonist; a subject who has been diagnosed with or exhibited one or more conditions associated with one or more side effects of a GLP-1 receptor agonist in the past; or a subject who has been deemed at risk of developing one or more side effects of a GLP-1 receptor agonist or one or more conditions associated with one or more side effects of a GLP-1 receptor agonist in the future due to hereditary, lifestyle, and / or environmental factors.

[0064] "Therapeutically effective amount” or “effective amount” or “pharmaceutically effective amount” refer to a nontoxic but sufficient amount of the combination described herein (e.g., a combination comprising a GLP-1 receptor agonist and a GC-C receptor agonist), or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition thereof, to provide the desired biological result, and / or to an amount sufficient to carry out a specifically stated purpose.

[0065] In some embodiments, the term “therapeutically effective amount” refers to an amount of a combination of the present disclosure, or a pharmaceutical composition comprising the same, which is effective to “treat” a disease or condition (e.g., one or more side effects of a GLP-1 receptor agonist) in a subject (e.g., a mammal such as a human), and provides some improvement or benefit to a subject having the disease or condition (e.g., one or more side effects of a GLP-1 receptor agonist). Thus, a “therapeutically effective” amount is an amount that provides some alleviation, mitigation, and / or decrease in at least one clinical symptom of one or more side effects of a GLP-1 receptor agonist. Clinical symptoms associated with the diseases or conditions that can be treated by the methods of the disclosure are well known. Further, therapeutic effects need not be complete or curative, as long as some benefit is provided to the subject. In some embodiments, the term “therapeutically effective” refers to an amount of a therapeutic agent that is capable of alleviation or amelioration of one or more symptoms or conditions; diminishment of extent of condition, disorder or disease; stabilization of the state of condition, disorder or disease; prevention of development of condition, disorder or disease; delay or slowing of condition, disorder or disease onset;amelioration or palliation of the condition, disorder or disease state; limiting the symptoms of the condition, disorder or disease state; reducing the severity of the condition, disorder or disease state and / or any one or more symptoms associated thereof; relieving the pain associated with and / or caused by the condition, disorder or disease state; whether partial or total, in a subject in need thereof

[0066] In some embodiments, a “therapeutically effective amount” can be determined empirically and in a routine manner, in relation to the stated purpose. And, an appropriate therapeutically effective amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation. The actual amount administered and rate and time-course of administration, will depend on the nature and severity of what is being treated. Prescription of treatment, e.g., decisions on dosage etc., is within the responsibility of general practitioners and other medical doctors.

[0067] In some embodiments, a “therapeutically effective amount” can be an amount sufficient for a combination of the present disclosure and / or a pharmaceutical composition comprising the same to accomplish a stated purpose relative to the absence of the peptide of the present disclosure and / or the pharmaceutical composition comprising the same (e.g., achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce a signaling pathway, and / or reduce one or more symptoms of a disease or condition). In one embodiment, an example of a “therapeutically effective amount” is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, condition, or symptom associated thereof (e.g., one or more side effects of treatment with a GLP-1 receptor agonist). In some embodiments, a “reduction” of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s), either in whole or in part.

[0068] In some embodiments, a “therapeutically effective amount” can be an amount that has a prophylactic effect, e.g., an amount of a combination of the present disclosure and / or a pharmaceutical composition comprising the same that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of side effects related to treatment with a GLP-1 receptor agonist . The full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations.

[0069] In some embodiments, a “therapeutically effective amount” can be an amount that results in an increase in activity (e.g., an “activity increasing amount”). In some embodiments, an activity increasing amount can be an amount of a combination of the present disclosure and / or a pharmaceutical composition comprising the same that, when administered to a subject, increases the activity of an enzyme relative to the absence of the combination of the present disclosure and / or the pharmaceutical composition comprising the same.

[0070] “Treatment” or "‘treating” or “treatment of’ a condition, disease or disorder or symptoms associated with a condition, disease or disorder, or symptoms associated with medication taken for a condition, disease or disorder refers to an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions; diminishment of extent of a symptom, condition, disorder or disease; stabilization of the state of a symptom, condition, disorder or disease; prevention of development of a symptom, condition, disorder or disease; ; amelioration or palliation of a symptom, condition, disorder or disease state, and remission; limiting the symptoms of the condition, disorder or disease state; limiting the symptoms of medication taken for a condition, disorder or disease state; reducing the severity of the condition, disorder or disease state and / or any one or more symptoms associated thereof; relieving the pain associated with and / or caused by the condition, disorder or disease state or the medication taken for the condition, disorder or disease state; an increase in the frequency of gastric emptying; an increase in peptide hormone secretion; an increase in the frequency and / or amount of gastrointestinal transit; whether partial or total.

[0071] “Treating” or “reducing” or “inhibiting” or “limiting” or any variation of these terms, refers to making something (e.g., the number of symptoms, severity of symptoms, and / or frequency of symptoms, such as degree / severity of pain and / or frequency of pain) less in size, amount, intensity, or degree. For example, in some embodiments, the administration of a therapeutically effective amount of a combination of the present disclosure and / or a pharmaceutical composition of the present disclosure, to a subject in need thereof, results in the following effect: a decrease in the frequency and / or severity of pain associated with the use of a GLP-1 receptor agonist; a decrease in the frequency and / or severity of an abdominal pain; and / or a decrease in the frequency and / or severity of constipation; and / or decrease in the frequency and / or severity of nausea; diarrhea; vomiting; stomach (abdomen) pain; upset stomach; feeling bloated; belching; gas; or heartbum or any combination thereof; relative tothe number, frequency, and / or severity of these foregoing symptoms and / or pains in the subject prior to having been administered the therapeutically effective amount of the combination of the present disclosure and / or a pharmaceutical composition comprising the same.

[0072] In some embodiments, limiting the symptoms of, reducing the severity of, or treating one or more side effects of a GLP-1 receptor agonist, includes any measurable decrease or complete inhibition to achieve a desired result. For example, there may be a decrease of about 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%, 99%, or more, in the number of symptoms, severity of symptoms, and / or frequency of symptoms (e.g., number, severity, and / or frequency of symptoms and / or pain associated with one or more side effects of a GLP-1 receptor agonist). About as used herein means within ± 10%, preferably ± 5% of a given value.

[0073] Thus, in some embodiments, the terms “limiting the symptoms of,” or “reducing the severity of,” or “treating or preventing one or more side effects of a GLP-1 receptor agonist,” refers to: a decrease or reduction in the frequency and / or severity of a symptom and / or pain associated with one or more side effects of a GLP-1 receptor agonist, when a therapeutically effective amount of a peptide of the present disclosure and / or a pharmaceutical composition of the present disclosure are administered to a subject in need thereof, that is at least about 0.1%, at least about 0.2%, at least about 0.3%, at least about 0.4%, at least about 0.5%, at least about 0.6%, at least about 0.7%, at least about 0.8%, at least about 0.9%, at least about 1%, at least about 1.25%, at least about 1.5%, at least about 1.75%, at least about 2%, at least about 2.25%, at least about 2.5%, at least about 2.75%, at least about 3%, at least about 3.25%, at least about 3.5%, at least about 3.75%, at least about 4%, at least about 4.25%, at least about 4.5%, at least about 4.75%, at least about 5%, at least about 5.25%, at least about 5.5%, at least about 5.75%, at least about 6%, at least about 6.25%, at least about 6.5%, at least about 6.75%, at least about 7%, at least about 7.25%, at least about 7.5%, at least about 7.75%, at least about 8%, at least about 8.25%, at least about 8.5%, at least about 8.75%, at least about 9%, at least about 9.25%, at least about 9.5%, at least about 9.75%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at leastabout 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, at least about 40%, at least about 41%, at least about 42%, at least about 43%, at least about 44%, at least about 45%, at least about 46%, at least about 47%, at least about 48%, at least about 49%, at least about 50%,at least about 50%, at least about 51%, at least about 52%, at least about 53%, at least about 54%, at least about 55%, at least about 56%, at least about 57%, at least about 58%, at least about 59%, at least about 60%, at least about 61%, at least about 62%, at least about 63%, at least about 64%, at least about 65%, at least about 66%, at least about 67%, at least about 68%, at least about 69%, at least about 70%, at least about 71%, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, or a greater than a 100%, relative to the frequency and / or severity of a symptom and / or a pain associated with one or more side effects of a GLP-1 receptor agonist experienced by the subject prior to receiving the therapeutically effective amount of a combination of the present disclosure and / or a pharmaceutical composition of the present disclosure.

[0074] In some embodiments, “treating” can also mean prolonging survival of a subject beyond that expected in the absence of treatment. “Treating” can also mean inhibiting the progression of the condition, disorder or disease, slowing the progression of the condition, disorder or disease temporarily, although in some instances, it involves halting the progression of the condition, disorder or disease permanently. As used herein the terms treatment, treat, or treating refers to a method of reducing the effects of one or more symptoms of a disease or condition. Thus, in some embodiments, treatment can refer to a 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction in the severity of an established disease, condition, or symptom of the disease or condition. For example, a method for treating a disease is considered to be a treatment if there is a 10% reduction in one or more symptoms of the disease in a subject as compared to a control. Thus the reduction can be a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any percent reduction in between 10% and 100% as compared to native or control levels. It is understood that treatment does not necessarily refer to a cure or complete ablation of the disease, condition, or symptoms of the disease or condition. Further, as used herein, references to decreasing, reducing, or inhibiting include a change of 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater as compared to a control level and such terms can include but do not necessarily include complete elimination.

[0075] “Unit dosage form” as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity optionally in association with a pharmaceutical carrier (excipient, diluent, vehicle or filling agent) which, when administered in one or more doses, is calculated to produce a desired effect (e.g., prophylactic or therapeutic effect). Unit dosage forms may be within, for example, ampules and vials, which may include a liquid composition, or a composition in a freeze-dried or lyophilized state; a sterile liquid carrier, for example, can be added prior to administration or delivery in vivo. Individual unit dosage forms can be included in multi-dose kits or containers. Peptides of the present disclosure, and pharmaceutical compositions thereof, can be packaged in single or multiple unit dosage form for ease of administration and uniformity of dosage. The unit dosage form may be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form may be the same or different for each dose.

[0076] Throughout this specification, unless specifically stated otherwise or the context requires otherwise, reference to a single step, composition of matter, group of steps or group of compositions of matter shall be taken to encompass one and a plurality (i.e., one or more) of those steps, compositions of matter, groups of steps or group of compositions of matter.

[0077] Throughout this specification, unless the context requires otherwise, the word “comprise,” or variations such as “comprises” or “comprising,” will be understood to imply the inclusion of a stated step or element or integer or group of steps or elements or integers but not the exclusion of any other step or element or integer or group of elements or integers.

[0078] All patent applications, patents, and printed publications referred to herein are incorporated by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety. And, all patent applications, patents, and printed publications cited herein are incorporated herein by reference in the entireties, except for any definitions, subject matter disclaimers, or disavowals, and except to the extent that the incorporated material is inconsistent with the express disclosure herein, in which case the language in this disclosure controls.

[0079] Guanylate-cyclase C (GC-C) receptor agonists

[0080] “Guanylate-cyclase C (GC-C) receptor agonist” or “GC-C receptor agonist” refers to a substance that can activate guanylate-cyclase C receptor, and interacts with said guanylate-cyclase C receptor to cause or promote one or more of the following: (1) stimulatesor activates the receptor; (2) enhances, increases or promotes, induces or prolongs an activity, function or presence of the receptor; and / or (3) enhances, increases, promotes or induces the expression of the receptor. In some embodiments, the GC-C receptor agonist is an agent that binds to a receptor and alters the receptor state resulting in a biological response that mimics the effect of the endogenous ligand of the receptor. In some embodiments, the GC-C receptor agonist can be a partial agonist, a full agonist, or a superagonist. As used herein, the term “agonist” includes partial agonists, full agonists and superagonists. An agonist may be described as a “full agonist” when such agonist which leads to a substantially full biological response (i.e., the response associated with the naturally occurring ligand / receptor binding interaction) induced by receptor under study, or a partial agonist. A “superagonist” is a type of agonist that is capable of producing a maximal response greater than the endogenous agonist for the target receptor, and thus has an activity of more than 100% of the native ligand. In some embodiments, a superagonist can be a synthetic molecule that exhibits greater than 110%, alternatively greater than 120%, alternatively greater than 130%, alternatively greater than 140%, alternatively greater than 150%, alternatively greater than 160%, or alternatively greater than 170% of the response in an evaluable quantitative or qualitative parameter of the naturally occurring form of the molecule when evaluated at similar concentrations in a comparable assay.

[0081] In some embodiments, the GC-C receptor agonists of the present disclosure bind to the intestinal guanylate cyclase (GC-C) receptor, a key regulator of fluid and electrolyte balance in the intestine. When stimulated, this receptor, which is located on the apical membrane of the intestinal epithelial surface, causes an increase in intestinal epithelial cyclic GMP (cGMP). This increase in cGMP is believed to cause a decrease in water and sodium absorption and an increase in chloride and potassium ion secretion, leading to changes in intestinal fluid and electrolyte transport and increased intestinal motility. The intestinal GC-C receptor possesses an extracellular ligand binding region, a transmembrane region, an intracellular protein kinase-like region and a cyclase catalytic domain. Proposed functions for the GC-C receptor are fluid and electrolyte homeostasis, the regulation of epithelial cell proliferation and the induction of apoptosis (Shalubhai 2002 Cun Opin Drug Dis Devel 5:261-268).

[0082] Linaclotide

[0083] In some embodiments, a guanylate-cyclase C (GC-C) receptor agonist of the present disclosure is linaclotide.

[0084] Accordingly, in some embodiments, a GC-C receptor agonist of the present disclosure is a peptide having an amino acid sequence that is at least 85% identical, at least 86% identical, at least 87% identical, at least 88% identical, at least 89% identical, at least 90% identical, at least 91% identical, at least 92% identical, at least 93% identical, at least 94% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, at least 99.5% identical, at least 99.6% identical, at least 99.7% identical, at least 99.8% identical, at least 99.9% identical, or 100% identical to the amino acid sequence to the amino acid sequence: Cys1Cys2Glu3Tyr4Cys5Cys6Asn7Pro8Ala9Cys10Thr11Gly12Cys13Tyr14(SEQ ID NO: 1 – single letter amino acid code “CCEYCCNPACTGCY”), wherein Cys1and Cys6; Cys2and Cys10; and Cys5and Cys13, are connected by disulfide bonds; or a pharmaceutically acceptable salt thereof.

[0085] In some embodiments, a GC-C receptor agonist of the present disclosure comprises, consists essentially of, or consists of a peptide having an amino acid sequence: Cys1Cys2Glu3Tyr4Cys5Cys6Asn7Pro8Ala9Cys10Thr11Gly12Cys13Tyr14(SEQ ID NO: 1); wherein Cys1and Cys6; Cys2and Cys10; and Cys5and Cys13, are connected by disulfide bonds; or a pharmaceutically acceptable salt thereof.

[0086] In some embodiments, a GC-C receptor agonist of the present disclosure consists of a peptide having an amino acid sequence: Cys1Cys2Glu3Tyr4Cys5Cys6Asn7Pro8Ala9Cys10Thr11Gly12Cys13Tyr14(SEQ ID NO: 1); wherein Cys1and Cys6; Cys2and Cys10; and Cys5and Cys13, are connected by disulfide bonds; or a pharmaceutically acceptable salt thereof.

[0087] Peptide of Formula (I)

[0088] In some embodiments, a guanylate-cyclase C (GC-C) receptor agonist can be a peptide having an amino acid sequence that is at least 85% identical, at least 86% identical, at least 87% identical, at least 88% identical, at least 89% identical, at least 90% identical, at least 91% identical, at least 92% identical, at least 93% identical, at least 94% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, at least 99.5% identical, at least 99.6% identical, at least 99.7% identical, at least 99.8% identical, at least 99.9% identical, or 100% identical to the amino acid sequence set forth in Formula (I):

[0089] wherein Cth is a cystathionine.

[0090] Cystathionine, which has two α-amino carboxyl groups, designated “1” and “2” in Scheme 1, which can form peptide bonds, as shown below:

[0091] However, to facilitate the use of the three letter amino acid code in describing a peptide sequence, when a cyclic peptide sequence is created by forming a peptide bond with each of the α-amino carboxyl group (designated “1” and “2”) at non-consecutive positions in the peptide sequence which creates a cyclic thioether bridge, the peptide bond formed by the α-amino carboxyl group at position 1 is designated “Cth,” whereas the peptide bond formed by the α -amino carboxyl group at position 2 is designated “Cys.”

[0092] As used herein, “Hcy” represents homocysteine as shown in Scheme 1. As shown in Scheme 1, cystathionine can be viewed as a combination of homocysteine and cysteine, wherein their side chains share a sulfur atom. Therefore, an alternative method of designating a cyclic peptide sequence created by forming a peptide bond with each of the α- amino carboxyl group of cystathionine at non-consecutive positions in the peptide sequence is by designating the peptide linkage formed by the α-amino carboxyl group at position “1” ofScheme 1 as “Hcy” and the peptide linkage formed by the α-amino carboxyl group at position “2” of Scheme 1 “Cys.”

[0093] Thus, it will be readily apparently to those having ordinary skill in the art that a peptide having an amino acid as set forth in Formula (I), comprises four cysteine residues at positions 1, 5, 6, and 13 (i.e., Cys1; Cys5; Cys6; and Cys13), and that these four cysteine residues form two disulfide bonds. Likewise, it will recognized by those having ordinary skill in the art that, as shown in Formula (I) above, a peptide bond is formed, between each of the α-amino carboxyl group (designated “1” and “2” in Scheme 1) at non-consecutive positions in the peptide sequence, which creates a cyclic thioether bridge.

[0094] Accordingly, to facilitate the use of the three letter amino acid code in describing the peptide of Formula (I), when a cyclic peptide sequence is created by forming a peptide bond with each of the α-amino carboxyl group (designated “1” and “2”) at non- consecutive positions in the peptide sequence which creates a cyclic thioether bridge, the peptide bond formed by the α-amino carboxyl group at position 1 is designated “Cth,” whereas the peptide bond formed by the α-amino carboxyl group at position 2 is designated “Cys.”

[0095] Thus, one having ordinary skill in the art will recognize that, when describing the peptide of Formula (I), either as a linear representation of the peptide, or using a structural formula, the cystathionine residue at position 2 can alternatively be represented as a homocysteine (Hcy) moiety in position 2 (Hcy2). And, as those having ordinary skill in the art will recognize, the related des-sulfhydryl cysteine at position 10 (Cys10), due to its chemical structure, can alternatively be represented as an alanine at position 10 (Ala10). Additional descriptions of the linear representations of the peptide of the present disclosure are described herein.

[0096] Those having ordinary skill in the art will recognize that the peptide of Formula (I) can alternatively be represented using a variety of alternative chemical structures known to those in the art. For example, an alternative way of showing the chemical structure for the peptide of Formula (I) is provided below, in Formula (II):

[0097] wherein the cysteine residues at positions 1 and 6, and at 5 and 13 are linked by disulfide bonds; and wherein the cystathionine (Cth) unit at position 2, and the residue at position 10, are linked by an internal sulfide (or thioether) bond.

[0098] A further alternative method of representing the structural formula of the peptide of Formula (I) is shown below in Formula (III), wherein the peptide comprises four cysteine residues that form two disulfide bonds, and a cystathionine (Cth) unit (combining homocysteine and cysteine) providing an internal sulfide (or thioether) bond, with the defined connectivity shown in Formula (III), (i.e., Cys1-Cys6, Cys5-Cys13, Cth2-Cys10).

[0099] Notwithstanding their different styles of representing the chemical structure of the peptide of the present disclosure, both Formula (I), Formula (II), and Formula (III) can be used interchangeably. [000100] Acetylated N-terminus [000101] In some embodiments, GC-C receptor agonist can be a peptide having an amino acid sequence that is at least 85% identical, at least 86% identical, at least 87% identical, at least 88% identical, at least 89% identical, at least 90% identical, at least 91% identical, at least 92% identical, at least 93% identical, at least 94% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, at least 99.5% identical, at least 99.6% identical, at least 99.7% identical, at least 99.8% identical, at least 99.9% identical, or 100% identical to the amino acid sequence set forth in Formula (I); wherein peptide of Formula (I) has an acetylated N-terminus. [000102] The chemical structure of the peptide of Formula (I) having an acetylated N- terminus can be represented using Formula (IV):[000103] wherein the cysteine residues at positions 1, 5, 6, and 13 are linked by disulfide bonds; and wherein the cystathionine (Cth) unit at position 2, and the residue at position 10, are linked by an internal sulfide (or thioether) bond. [000104] An alternative method of representing the structural formula of the peptide of Formula (I) having an acetylated N-terminus, is shown below in Formula (V), wherein the peptide comprises four cysteine residues that form two disulfide bonds, and a cystathionine (Cth) unit (combining homocysteine and cysteine) providing an internal sulfide (or thioether) bond, with the defined connectivity shown in Formula (IV), (i.e., Cys1-Cys6, Cys5-Cys13, Cth2-Cys10).[000105] As described above, those having ordinary skill in the art will recognize there are alternative methods for describing the peptide of Formula (I) having an acetylated N- terminus. [000106] For example, in addition to a chemical structure or linear representation, the peptide of Formula (I) having an acetylated N-terminus can be described as follows: Nα- acetyl-{L-hemicystinyl1-[L-homocysteinyl2-L-glutamyl3-L-leucyl4-(L-hemicystinyl5-L- hemicystinyl6}-L-asparagyl7-L-valyl8-L-alanyl9-L-alanyl10]-L-tyrosyl11-glycyl12-L- hemicystine13) acid, cyclic bis-disulfide 1-6, 5-13, thioether 2-10.[000107] Linear representations of the peptide of Formula (I) [000108] Those having ordinary skill in the art will recognize that the peptide set forth in Formula (I):[000109] wherein Cth is a cystathionine; can be linearly represented in a variety of ways. [000110] As described above, cystathionine (Cth), has two α-amino carboxyl groups, designated as positions “1” and “2” in Scheme 1 below, which form peptide bonds:[000111] However, to facilitate the use of the three letter amino acid code in describing a peptide sequence, when a cyclic peptide sequence is created by forming a peptide bond with each of the α-amino carboxyl group (designated “1” and “2”) at non-consecutive positions in the peptide sequence which creates a cyclic thioether bridge, the peptide bond formed by the α-amino carboxyl group at position 1 is designated “Cth,” whereas the peptide bond formed by the α-amino carboxyl group at position 2 is designated “Cys.” [000112] Homocysteine (Hcy) is shown above in Scheme 1; cystathionine can be viewed as a combination of homocysteine and cysteine, wherein their side chains share a sulfur atom. Therefore, an alternative method of designating a cyclic peptide sequencecreated by forming a peptide bond with each of the α-amino carboxyl group of cystathionine at non-consecutive positions in the peptide sequence is by designating the peptide linkage formed by the α-amino carboxyl group at position “1” of Scheme 1 as “Hcy” and the peptide linkage formed by the α-amino carboxyl group at position “2” of Scheme 1 “Cys.” [000113] Thus, it will be readily apparently to those having ordinary skill in the art that a peptide having an amino acid as set forth in Formula (I), comprises four cysteine residues at positions 1, 5, 6, and 13 (i.e., Cys1; Cys5; Cys6; and Cys13), and that these four cysteine residues form two disulfide bonds. Likewise, it will recognized by those having ordinary skill in the art that, as shown in Formula (I) above, a peptide bond is formed, between each of the α-amino carboxyl group (designated “1” and “2” in Scheme 1) at non-consecutive positions in the peptide sequence, which creates a cyclic thioether bridge. [000114] Thus, one having ordinary skill in the art will recognize that, when describing the peptide of Formula (I), either as a linear representation of the peptide, or using a structural formula, the use of Cth at position 2 of Formula (I) can alternatively be represented as a homocysteine (Hcy) moiety a position 2 (Hcy2). And, as those having ordinary skill in the art will recognize that the related des-sulfhydryl cysteine at position 10 (Cys10) of Formula (I), due to its chemical structure, can alternatively be represented as an alanine at position 10 (Ala10). [000115] While the linear representation of the peptide having an amino acid sequence as set forth in Formula (I), shall be linearly represented using a three letter amino acid code, e.g., as follows: Cys1Cth2Glu3Leu4Cys5Cys6Asn7Val8Ala9Cys10Tyr11Gly12Cys13(SEQ ID NO: 2), wherein Cth is a cystathionine residue; and wherein Cys1and Cys6; and Cys5and Cys13; are connected by disulfide bonds; and Cth2and Cys10are connected by a thioether bond; additional descriptions of the linear representations of the peptide of the present disclosure are described herein. [000116] For example, alternatively, in other embodiments, the peptide of the present disclosure can be linearly represented using the one letter amino acid code, e.g., as follows: CXELCCNVACYGC (SEQ ID NO: 2); wherein X is a cystathionine (Cth) residue; and wherein cysteines at positions 1 and 6; and 5 and 13 are connected by disulfide bonds; and the cystathionine at position 2 and the cysteine at position 10 are connected by a thioether bond. [000117] Accordingly, the peptide of Formula (I) can be linearly represented using the following three- or one-letter amino acid codes, all of which are used interchangeably:[000118] Cys1Cth2Glu3Leu4Cys5Cys6Asn7Val8Ala9Cys10Tyr11Gly12Cys13; wherein Cth is a cystathionine; wherein Cys1and Cys6; Cys5and Cys13; are connected by disulfide bonds; and wherein Cth2and Cys10are connected by a thioether bond; [000119] Cys1Hcy2Glu3Leu4Cys5Cys6Asn7Val8Ala9Ala10Tyr11Gly12Cys13; wherein Cth is a cystathionine; wherein Cys1and Cys6; Cys5and Cys13; are connected by disulfide bonds; and wherein Cth2and Cys10are connected by a thioether bond; [000120] CXELCCNVACYGC; wherein X is a cystathionine; wherein the residues at positions 1 and 6, and 5 and 13 are connected by disulfide bonds; and wherein the residues at positions 2 and 10 are connected by a thioether bond; and [000121] CXELCCNVAAYGC; wherein X is a homocysteine; wherein the residues at positions 1 and 6, and 5 and 13 are connected by disulfide bonds; and wherein the residues at positions 2 and 10 are connected by a thioether bond. [000122] In addition, in some embodiments, any of the foregoing linear representations of the peptide of Formula (I) can be described to show an N-terminus acetyl group (i.e. “Ac-)” and / or an unmodified C-terminus (e.g., “-COOH” or “-OH”). Thus, in some embodiments, a peptide of the present disclosure, having an acetylated N-terminus and an unmodified C-terminus, can be linearly represented using the following three- or one-letter amino acid codes, all of which are used interchangeably: [000123] Ac- Cys1Cth2Glu3Leu4Cys5Cys6Asn7Val8Ala9Cys10Tyr11Gly12Cys13- OH; wherein Cth is a cystathionine; wherein Cys1and Cys6; Cys5and Cys13; are connected by disulfide bonds; wherein Cth2and Cys10are connected by a thioether bond; wherein Ac- indicates an acetylated N-terminus; and wherein -OH indicates an unmodified C-terminus; [000124] Ac- Cys1Hcy2Glu3Leu4Cys5Cys6Asn7Val8Ala9Ala10Tyr11Gly12Cys13- OH; wherein Cth is a cystathionine; wherein Cys1and Cys6; Cys5and Cys13; are connected by disulfide bonds; wherein Cth2and Cys10are connected by a thioether bond; wherein Ac- indicates an acetylated N-terminus; and wherein -OH indicates an unmodified C-terminus [000125] Ac-CXELCCNVACYGC-OH (SEQ ID NO: 3); wherein X is a cystathionine; wherein the residues at positions 1 and 6, and 5 and 13 are connected by disulfide bonds; wherein the residues at positions 2 and 10 are connected by a thioether bond; wherein Ac- indicates an acetylated N-terminus; and wherein -OH indicates an unmodified C-terminus. [000126] Ac-CXELCCNVAAYGC-OH (SEQ ID NO: 3); wherein X is a homocysteine; wherein the residues at positions 1 and 6, and 5 and 13 are connected by disulfide bonds; wherein the residues at positions 2 and 10 are connected by a thioether bond; wherein Ac- indicates an acetylated N-terminus; and wherein -OH indicates an unmodified C-terminus.[000127] In some embodiments, a guanylate-cyclase C (GC-C) receptor agonist of the present disclosure can comprise, consist essentially of, or consist of, an amino acid sequence that is at least 85% identical, at least 86% identical, at least 87% identical, at least 88% identical, at least 89% identical, at least 90% identical, at least 91% identical, at least 92% identical, at least 93% identical, at least 94% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, at least 99.5% identical, at least 99.6% identical, at least 99.7% identical, at least 99.8% identical, at least 99.9% identical, or 100% identical to an amino acid amino acid sequence: Cys1Cth2Glu3Leu4Cys5Cys6Asn7Val8Ala9Cys10Tyr11Gly12Cys13(SEQ ID NO: 2), or a pharmaceutically acceptable salt thereof; wherein Cth is a cystathionine; wherein Cys1and Cys6; Cys5and Cys13; are connected by disulfide bonds; and wherein Cth2and Cys10are connected by a thioether bond; or a pharmaceutically acceptable salt thereof. [000128] In some embodiments, a guanylate-cyclase C (GC-C) receptor agonist of the present disclosure can comprise, consist essentially of, or consist of: a peptide having an amino acid sequence that is at least 85% identical, at least 86% identical, at least 87% identical, at least 88% identical, at least 89% identical, at least 90% identical, at least 91% identical, at least 92% identical, at least 93% identical, at least 94% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, at least 99.5% identical, at least 99.6% identical, at least 99.7% identical, at least 99.8% identical, at least 99.9% identical, or 100% identical to an amino acid amino acid sequence: Cys1Cth2Glu3Leu4Cys5Cys6Asn7Val8Ala9Cys10Tyr11Gly12Cys13(SEQ ID NO: 3), or a pharmaceutically acceptable salt thereof; wherein Cth is a cystathionine; wherein Cys1and Cys6; Cys5and Cys13; are connected by disulfide bonds; and wherein Cth2and Cys10are connected by a thioether bond; wherein the peptide has acetylated N-terminus; or a pharmaceutically acceptable salt thereof. [000129] In some embodiments, a GC-C receptor agonist of the present disclosure comprises, consists essentially of, or consists of a peptide having an amino acid sequence: Cys1Cth2Glu3Leu4Cys5Cys6Asn7Val8Ala9Cys10Tyr11Gly12Cys13(SEQ ID NO: 2), or a pharmaceutically acceptable salt thereof; wherein Cth is a cystathionine; wherein Cys1and Cys6; Cys5and Cys13; are connected by disulfide bonds; and wherein Cth2and Cys10are connected by a thioether bond; wherein the peptide has acetylated N-terminus; or a pharmaceutically acceptable salt thereof. [000130] In some embodiments, a GC-C receptor agonist of the present disclosure consists of a peptide having an amino acid sequence: Cys1Cth2Glu3Leu4Cys5Cys6Asn7Val8Ala9Cys10Tyr11Gly12Cys13(SEQ ID NO: 2), or a pharmaceutically acceptable salt thereof; wherein Cth is a cystathionine; wherein Cys1and Cys6; and Cys5and Cys13; are connected by disulfide bonds; and wherein Cth2and Cys10are connected by a thioether bond; or a pharmaceutically acceptable salt thereof. [000131] In some embodiments, a GC-C receptor agonist of the present disclosure comprises, consists essentially of, or consists of a peptide having an amino acid sequence: Cys1Cth2Glu3Leu4Cys5Cys6Asn7Val8Ala9Cys10Tyr11Gly12Cys13(SEQ ID NO: 3), or a pharmaceutically acceptable salt thereof; wherein Cth is a cystathionine; wherein Cys1and Cys6; and Cys5and Cys13; are connected by disulfide bonds; and wherein Cth2and Cys10are connected by a thioether bond; wherein the peptide has acetylated N-terminus; or a pharmaceutically acceptable salt thereof. [000132] In some embodiments, a GC-C receptor agonist of the present disclosure consists of a peptide having an amino acid sequence: Cys1Cth2Glu3Leu4Cys5Cys6Asn7Val8Ala9Cys10Tyr11Gly12Cys13(SEQ ID NO: 3), or a pharmaceutically acceptable salt thereof; wherein Cth is a cystathionine; wherein Cys1and Cys6; Cys5and Cys13; are connected by disulfide bonds; and wherein Cth2and Cys10are connected by a thioether bond; wherein the peptide has acetylated N-terminus; or a pharmaceutically acceptable salt thereof. [000133] Plecanatide [000134] In some embodiments, a guanylate-cyclase C (GC-C) receptor agonist of the present disclosure is plecanatide. [000135] Accordingly, in some embodiments, a GC-C receptor agonist of the present disclosure is a peptide having an amino acid sequence that is at least 85% identical, at least 86% identical, at least 87% identical, at least 88% identical, at least 89% identical, at least 90% identical, at least 91% identical, at least 92% identical, at least 93% identical, at least 94% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, at least 99.5% identical, at least 99.6% identical, at least 99.7% identical, at least 99.8% identical, at least 99.9% identical, or 100% identical to the amino acid sequence to the amino acid sequence: Asn1Asp2Glu3Cys4Glu5Leu6Cys7Val8Asn9Va110Ala11Cys12Thr13Gly14Cys15Leu16(SEQ ID NO: 4 – single letter amino acid code “NDECELCVNVACTGCL”); wherein Cys4and Cys12; and Cys7and Cys15; are connected by disulfide bonds; or a pharmaceutically acceptable salt thereof. [000136] In some embodiments, a GC-C receptor agonist of the present disclosure comprises, consists essentially of, or consists of a peptide having an amino acid sequence: Asn1Asp2Glu3Cys4Glu5Leu6Cys7Val8Asn9Va110Ala11Cys12Thr13Gly14Cys15Leu16(SEQ ID NO: 4); wherein Cys4and Cys12; and Cys7and Cys15; are connected by disulfide bonds; or a pharmaceutically acceptable salt thereof. [000137] In some embodiments, a GC-C receptor agonist of the present disclosure consists of a peptide having an amino acid sequence: Asn1Asp2Glu3Cys4Glu5Leu6Cys7Val8Asn9Va110Ala11Cys12Thr13Gly14Cys15Leu16(SEQ ID NO: 4); wherein Cys4and Cys12; and Cys7and Cys15; are connected by disulfide bonds; or a pharmaceutically acceptable salt thereof. [000138] The present disclosure describes a combination of a GLP-1 receptor agonist, and a guanylate-cyclase C (GC-C) receptor agonist, and methods of using the same. In some embodiments, the methods of the present disclosure are useful for reducing, decreasing or alleviating one or more side effects of GLP-1 receptor agonists (e.g., GLP-1), such as slow and / or reduced gastrointestinal transit; constipation; nausea; diarrhea; vomiting; stomach (abdominal) pain; upset stomach; bloating and / or discomfort or pain associated thereof; belching; gas; heartburn; and / or any other side effect of GLP-1 receptor agonists known in the art. [000139] In some embodiments, the present disclosure describes a method for treating a patient suffering from constipation, wherein said constipation in the patient results from the administration of a GLP-1 receptor agonist (e.g., GLP-1) to the patient. Clinically accepted criteria that define constipation range from the frequency of bowel movements, the consistency of feces and the ease of bowel movement. One common definition of constipation is less than three bowel movements per week. Other definitions include abnormally hard stools or defecation that requires excessive straining (Schiller 2001, Aliment Pharmacol Ther 15:749-763). [000140] In some embodiments, amino acid, non-amino acid, peptide and non-peptide spacers can be interposed between a peptide that is a GC-C receptor agonist and a peptide that has some other biological function, e.g., an analgesic peptide or a peptide used to treat obesity. The linker can be one that is cleaved from the flanking peptides in vivo or one that remains linked to the flanking peptides in vivo. For example, glycine, beta-alanine, glycyl- glycine, glycyl-beta-alanine, gamma-aminobutyric acid, 6-aminocaproic acid, L- phenylalanine, L-tryptophan and glycil-L-valil-L-phenylalanine can be used as a spacer (Chaltin et al.2003 Helvetica Chimica Acta 86:533-547; Caliceti et al.1993 FARMCO 48:919-32) as can polyethylene glycols (Butterworth et al.1987 J. Med. Chem 30:1295-302) and maleimide derivatives (King et al.2002 Tetrahedron Lett. 43:1987-1990). Various other linkers are described in the literature (Nestler 1996 Molecular Diversity 2:35-42; Finn et al.1984 Biochemistry 23:2554-8; Cook et al.1994 Tetrahedron Lett.35:6777-80; Brokx et al. 2002 Journal of Controlled Release 78:115-123; Griffin et al.2003 J. Am. Chem. Soc. 125:6517-6531; Robinson et al.1998 Proc. Natl. Acad. Sci. USA 95:5929-5934. [000141] Any of the aforementioned GC-C receptor agonists can be used in a combination of the present disclosure, e.g., a combination of a GLP-1 receptor agonist and a GC-C receptor agonist, and / or methods of using the same. [000142] GLP-1 receptor agonists [000143] “GLP-1 receptor agonist” refers to a substance that can activate a glucagon receptor, and interacts with said glucagon receptor to cause or promote one or more of the following: (1) stimulates or activates the receptor; (2) enhances, increases or promotes, induces or prolongs an activity, function or presence of the receptor; and / or (3) enhances, increases, promotes or induces the expression of the receptor. In some embodiments, the GLP-1 receptor agonist is an agent that binds to a receptor and alters the receptor state resulting in a biological response that mimics the effect of the endogenous ligand of the receptor. In some embodiments, the GLP-1 receptor agonist can be a partial agonist, a full agonist, or a superagonist. As used herein, the term “agonist” includes partial agonists, full agonists and superagonists. An agonist may be described as a “full agonist” when such agonist which leads to a substantially full biological response (i.e., the response associated with the naturally occurring ligand / receptor binding interaction) induced by receptor under study, or a partial agonist. A “superagonist” is a type of agonist that is capable of producing a maximal response greater than the endogenous agonist for the target receptor, and thus has an activity of more than 100% of the native ligand. In some embodiments, a superagonist can be a synthetic molecule that exhibits greater than 110%, alternatively greater than 120%, alternatively greater than 130%, alternatively greater than 140%, alternatively greater than 150%, alternatively greater than 160%, or alternatively greater than 170% of the response in an evaluable quantitative or qualitative parameter of the naturally occurring form of the molecule when evaluated at similar concentrations in a comparable assay. [000144] In some embodiments, a GLP-1 receptor agonist can be a protein or protein- based. For example, in some embodiments, a GLP-1 receptor agonist can be a compound that contains one or more chains of six or more alpha-amino acids connected by amide linkages, and wherein the one or more chains of amino acids make up at least 40% by mass of the compound's mass. [000145] In some embodiments, a GLP-1 receptor agonist can be non-protein based. For example, in some embodiments, a GLP-1 receptor agonist can be a compound in which nomore than 40% of its mass is made up by one or more chains of six or more alpha-amino acids connected by amide linkages. [000146] In some embodiments, a GLP-1 receptor agonist can activate a glucagon receptor by causing and / or promoting one or more of the following: (1) stimulating or activating the receptor; (2) enhancing, increasing, or promoting, inducing or prolonging an activity, function or presence of the receptor; and / or (3) enhancing, increasing, promoting, or inducing the expression of the receptor; wherein the glucagon receptor is a glucagon-like peptide 1 receptor. An exemplary glucagon-like peptide 1 receptor sequence is provided in NCBI Reference Sequence: NP_002053.3, and has the following amino acid sequence: MAGAPGPLRLALLLLGMVGRAGPRPQGATVSLWETVQKWREYRRQCQRSLTEDPPPATDLFC NRTFDEYACWPDGEPGSFVNVSCPWYLPWASSVPQGHVYRFCTAEGLWLQKDNSSLPWRDLS ECEESKRGERSSPEEQLLFLYIIYTVGYALSFSALVIASAILLGFRHLHCTRNYIHLNLFAS FILRALSVFIKDAALKWMYSTAAQQHQWDGLLSYQDSLSCRLVFLLMQYCVAANYYWLLVEG VYLYTLLAFSVLSEQWIFRLYVSIGWGVPLLFVVPWGIVKYLYEDEGCWTRNSNMNYWLIIR LPILFAIGVNFLIFVRVICIVVSKLKANLMCKTDIKCRLAKSTLTLIPLLGTHEVIFAFVMD EHARGTLRFIKLFTELSFTSFQGLMVAILYCFVNNEVQLEFRKSWERWRLEHLHIQRDSSMK PLKCPTSSLSSGATAGSSMYTATCQASCS (SEQ ID NO: 5) [000147] In some embodiments, a GLP-1 receptor agonist can be one or more of the following: GLP-1; GLP-1 Eligen; GLP-1(7-36)NH2; GLP-1(7-37); a GLP-1 analog; an acylated GLP-1 analog; a diacylated GLP-1 analog; a dual GLP-1 analog; a GLP1 / glucagon receptor co-agonist; albiglutide (e.g., Syncria®); ARI-2255; ARI-2651; beinaglutide; BHM- 034; MOD-6030; Bydureon®; Byetta®; CAM-2036; CJC-1134-PC; CM-3; CVX-096; DA- 15864; DA-3091; dulaglutide (e.g., Trulicity®); efpeglenatide; elamipretide,; elsiglutide; exenatide; Exenatide-XTEN ; exendin-4; an exendin-4 derivative; an exendin-4 peptide analog; GSK-2374697; langlenatide; Langlenatide / HM-11260C; liraglutide (e.g., Victoza®); lixisenatide (e.g., Lyxumia®); NN-9924; NN-9926; NN-9927; Nodexen; ORMD-0901; PB- 1023; rExendin-4; semaglutide; taspoglutide; TTP-054; TTP-273; or ZYOG-1. [000148] In some embodiments, a GLP-1 receptor agonist of the present disclosure can be used to reduce patient weight, improve metabolic syndrome, and / or normalize serum cholesterol. [000149] In some embodiments, a GLP-1 receptor agonist of the present disclosure can be a glucagon-like-peptide-1 (GLP-1) receptor agonist. Glucagon-like-peptide-1 is a peptide hormone secreted from L-cells that line the intestine. These cells are located throughout the gastrointestinal track and act on a specific glucagon-like-peptide-1 (GLP-1) receptor which is expressed fairly ubiquitously throughout the body, including but not limited to the pancreas,GI track, heart, lung, and immune cells. When the peptide GLP-1 binds to its cognate receptor, the pharmacodynamic responses include slowed gastric emptying, reduced appetite and food intake, decrease peptide hormone secretion like glucagon as well as generalized slow gastrointestinal transit which can result in constipation. Accordingly, the overall positive metabolic effects can be compromised by needing to discontinue the GLP-1 receptor agonist due to unwanted side effects related to slow gastrointestinal transit. [000150] Exemplary descriptions of GLP-1 receptor agonists are provided in U.S. Pat. Nos.11,492,385; 11,046,743; and 10,894,076; the disclosures of which are incorporated herein by reference in their entireties. [000151] Methods of producing GLP-1 receptor and GC-C receptor agonists [000152] Methods of producing proteins, such as GLP-1 receptor agonists and the GC-C receptor agonists, are well known in the art, and there are a variety of techniques available. For example, in some embodiments, proteins can be produced using recombinant methods (e.g., a recombinant expression system). [000153] In other embodiments, a peptide of the present disclosure can be chemically synthesized. [000154] Synthetic peptides and methods regarding the same, can be performed by those having ordinary skill in the art, and / or through the use of commercial vendors (e.g., GenScript®; Piscataway, New Jersey). For example, in some embodiments, chemical peptide synthesis can be achieved using Liquid phase peptide synthesis (LPPS), or solid phase peptide synthesis (SPPS). [000155] In some embodiments, peptide synthesis can generally be achieved by using a strategy wherein the coupling the carboxyl group of a subsequent amino acid to the N- terminus of a preceding amino acid generates the nascent polypeptide chain—a process that is opposite to the type of polypeptide synthesis that occurs in nature. [000156] Exemplary methods of peptide synthesis can be found in Anderson G. W. and McGregor A. C. (1957) T-butyloxycarbonylamino acids and their use in peptide synthesis. Journal of the American Chemical Society.79, 6180-3; Carpino L. A. (1957) Oxidative reactions of hydrazines. Iv. Elimination of nitrogen from 1, 1-disubstituted-2- arenesulfonhydrazides1-4. Journal of the American Chemical Society.79, 4427-31; McKay F. C. and Albertson N. F. (1957) New amine-masking groups for peptide synthesis. Journal of the American Chemical Society.79, 4686-90; Merrifield R. B. (1963) Solid phase peptide synthesis. I. The synthesis of a tetrapeptide. Journal of the American Chemical Society.85, 2149-54; Carpino L. A. and Han G. Y. (1972) 9-fluorenylmethoxycarbonyl amino-protectinggroup. The Journal of Organic Chemistry.37, 3404-9; and A Lloyd-Williams P. et al. (1997) Chemical approaches to the synthesis of peptides and proteins. Boca Raton: CRC Press.278; U.S. Patent Nos: 3,714,140 (filed Mar.16, 1971); 4,411,994 (filed June 8, 1978); 7,785,832 (filed Jan.20, 2006); 8,314,208 (filed Feb.10, 2006); and 10,442,834 (filed Oct., 2, 2015); and United States Patent Application 2005 / 0165215 (filed Dec.23, 2004), the disclosures of which are incorporated herein by reference in their entirety. [000157] Variant Peptides [000158] The present disclosure contemplates variant agonist peptides, e.g., variant GLP-1 receptor agonist and GC-C receptor agonist peptides, which can include one, two, three, four, five, six, seven, eight, nine, or ten (in some embodiments fewer than 5 or fewer than 3 or 2 or fewer) amino acid substitutions. The substitution(s) can be conservative or non- conservative. The naturally-occurring amino acids can be substituted by D-isomers of any amino acid, non-natural amino acids, and other groups. [000159] “Conservative amino acid substitutions” refers to amino acid substitutions in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art. These families include: amino acids with basic side chains (e.g., lysine, arginine, histidine); acidic side chains (e.g., aspartic acid, glutamic acid); polar, negatively charged residues and their amides (e.g., aspartic acid, asparagine, glutamic, acid, glutamine; uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine); small aliphatic, nonpolar or slightly polar residues (e.g., Alanine, serine, threonine, proline, glycine); nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan); large aliphatic, nonpolar residues (e.g., methionine, leucine, isoleucine, valine, cystine); beta-branched side chains (e.g., threonine, valine, isoleucine); aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine); large aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan). [000160] Amino acid substitutions may be made in non-conserved regions that retain function. In general, such substitutions would not be made for conserved amino acid residues or for amino acid residues residing within a conserved motif, where such residues are essential for protein activity. Examples of residues that are conserved and that may be essential for protein activity include, for example, residues that are identical between all proteins contained in an alignment of similar or related toxins to the sequences of the embodiments (e.g., residues that are identical in an alignment of homologs). Examples of residues that are conserved but that may allow conservative amino acid substitutions and stillretain activity include, for example, residues that have only conservative substitutions between all proteins contained in an alignment of similar or related toxins to the sequences of the embodiments (e.g., residues that have only conservative substitutions between all proteins contained in the alignment of the homologs). However, one of skill in the art would understand that functional variants may have minor conserved or non-conserved alterations in the conserved residues. Guidance as to appropriate amino acid substitutions that do not affect biological activity of the protein of interest may be found in the model of Dayhoff, et al., (1978) Atlas of Protein Sequence and Structure (Natl. Biomed. Res. Found., Washington, D.C.), the disclosure of which is incorporated herein by reference. Additional amino acid substitution models are likewise known in the art, e.g., JTT / WAG). [000161] In making such changes, the hydropathic index of amino acids may be considered. The importance of the hydropathic amino acid index in conferring interactive biologic function on a protein is generally understood in the art (Kyte and Doolittle, (1982) J Mol Biol.157(1):105-32). It is accepted that the relative hydropathic character of the amino acid contributes to the secondary structure of the resultant protein, which in turn defines the interaction of the protein with other molecules, for example, enzymes, substrates, receptors, DNA, antibodies, antigens, and the like. [000162] It is known in the art that certain amino acids may be substituted by other amino acids having a similar hydropathic index or score and still result in a protein with similar biological activity, i.e., still obtain a biological functionally equivalent protein. Each amino acid has been assigned a hydropathic index on the basis of its hydrophobicity and charge characteristics (Kyte and Doolittle, ibid). These are: isoleucine (+4.5); valine (+4.2); leucine (+3.8); phenylalanine (+2.8); cysteine / cystine (+2.5); methionine (+1.9); alanine (+1.8); glycine (-0.4); threonine (-0.7); serine (-0.8); tryptophan (-0.9); tyrosine (-1.3); proline (-1.6); histidine (-3.2); glutamate (-3.5); glutamine (-3.5); aspartate (-3.5); asparagine (-3.5); lysine (-3.9) and arginine (-4.5). In making such changes, the substitution of amino acids whose hydropathic indices are within +2 is preferred, those which are within +1 are particularly preferred, and those within +0.5 are even more particularly preferred. [000163] It is also understood in the art that the substitution of like amino acids can be made effectively on the basis of hydrophilicity. U.S. Pat. No.4,554,101, states that the greatest local average hydrophilicity of a protein, as governed by the hydrophilicity of its adjacent amino acids, correlates with a biological property of the protein. [000164] As detailed in U.S. Pat. No.4,554,101, the following hydrophilicity values have been assigned to amino acid residues: arginine (+3.0); lysine (+3.0); aspartate(+3.0.+0.1); glutamate (+3.0.+0.1); serine (+0.3); asparagine (+0.2); glutamine (+0.2); glycine (0); threonine (-0.4); proline (-0.5.+0.1); alanine (-0.5); histidine (-0.5); cysteine (- 1.0); methionine (-1.3); valine (-1.5); leucine (-1.8); isoleucine (-1.8); tyrosine (-2.3); phenylalanine (-2.5); tryptophan (-3.4). [000165] Accordingly, in some embodiments, a conservative amino acid substitution results in the alteration of an amino acid for a similar acting amino acid, or amino acid of like charge, polarity, or hydrophobicity. At some positions, even conservative amino acid substitutions can reduce the activity of the peptide. Among the naturally occurring amino acid substitutions generally considered conservative are:[000166] In some circumstances it can be desirable to treat patients with a variant peptide that binds to and activates, e.g., an intestinal GC-C receptor, but is less active than the non-variant form the peptide. This reduced activity can arise from reduced affinity for the receptor or a reduced ability to activate the receptor once bound or reduced stability of the peptide. [000167] In some embodiments of the GC-C receptor agonists, pairs of Cys residues that normally form a disulfide bond may be replaced, wherein one or both members of the pair can be replaced by homocysteine, 3-mercaptoproline (Kolodziej et al.1996 Int J Pept Protein Res 48:274); β, β dimethylcysteine (Hunt et al.1993 Int J Pept Protein Res 42:249) ordiaminopropionic acid (Smith et al. 1978 J Med Chem 21:117) to form alternative internal cross-links at the positions of the normal disulfide bonds.[000168] Useful receptor agonists can be produced either in bacteria including, without limitation, E. coli or in other existing systems for peptide or protein production(e.g., Bacillus subtilis, baculovirus expression systems using Drosophila Sf9 cells, yeast or filamentous fungal expression systems, mammalian cell expression systems), or they can be chemically synthesized.[000169] In some embodiments, if the peptide or variant peptide is to be produced in bacteria, e.g., E. coli, the nucleic acid molecule encoding the peptide will preferably also encode a leader sequence that permits the secretion of the mature peptide from the cell. Thus, the sequence encoding the peptide can include the pre sequence and the pro sequence of, for example, a naturally -occurring bacterial ST peptide. The secreted, mature peptide can be purified from the culture medium.[000170] The sequence encoding a peptide of the present disclosure is preferably inserted into a vector capable of delivering and maintaining the nucleic acid molecule in a bacterial cell. The DNA molecule may be inserted into an autonomously replicating vector (suitable vectors include, for example, pGEM3Z and pcDNA3, and derivatives thereof). The vector nucleic acid may be a bacterial or bacteriophage DNA such as bacteriophage lambda or Ml 3 and derivatives thereof. Construction of a vector containing a nucleic acid described herein can be followed by transformation of a host cell such as a bacterium. Suitable bacterial hosts include but are not limited to, E. coli, B. subtilis, Pseudomonas. Salmonella. The genetic construct also includes, in addition to the encoding nucleic acid molecule, elements that allow expression, such as a promoter and regulatory sequences. The expression vectors may contain transcriptional control sequences that control transcriptional initiation, such as promoter, enhancer, operator, and repressor sequences. A variety of transcriptional control sequences are well known to those in the art. The expression vector can also include a translation regulatory sequence (e.g., an untranslated 5' sequence, an untranslated 3' sequence, or an internal ribosome entry site). The vector can be capable of autonomous replication or it can integrate into host DNA to ensure stability during peptide production.[000171] The protein coding sequence that includes a peptide of the present disclosure can also be fused to a nucleic acid encoding a polypeptide affinity tag, e.g., glutathione S- transferase (GST), maltose E binding protein, protein A, FLAG tag, hexa-histidine, myc tag or the influenza HA tag, in order to facilitate purification. The affinity tag or reporter fusion joins the reading frame of the peptide of interest to the reading frame of the gene encodingthe affinity tag such that a translational fusion is generated. Expression of the fusion gene results in translation of a single polypeptide that includes both the peptide of interest and the affinity tag. In some instances where affinity tags are utilized, DNA sequence encoding a protease recognition site will be fused between the reading frames for the affinity tag and the peptide of interest.[000172] Genetic constructs and methods suitable for production of immature and mature forms of the peptides and variants of the present disclosure in protein expression systems other than bacteria, and well known to those skilled in the art, can also be used to produce peptides in a biological system.[000173] Mature peptides and variants thereof can be synthesized by the solid-phase method using an automated peptide synthesizer. For example, the peptide can be synthesized on Cyc(4-CH2Bxl)-OCH2-4-(oxymethyl)-phenylacetamidomethyl resin using a double coupling program. Protecting groups must be used appropriately to create the correct disulfide bond pattern. For example, the following protecting groups can be used: t- butyloxycarbonyl (alpha-amino groups); acetamidomethyl (thiol groups of Cys residues B and E); 4-methylbenyl (thiol groups of Cys residues C and F); benzyl (y-carboxyl of glutamic acid and the hydroxyl group of threonine, if present); and bromobenzyl (phenolic group of tyrosine, if present). Coupling is effected with symmetrical anhydride of t- butoxylcarbonylamino acids or hydroxybenzotriazole ester (for asparagine or glutamine residues), and the peptide is deprotected and cleaved from the solid support in hydrogen fluoride, dimethyl sulfide, anisole, and p-thiocresol using 8 / 1 / 1 / 0.5 ratio (v / v / v / w) at 0° C. for 60 min. After removal of hydrogen fluoride and dimethyl sulfide by reduced pressure and anisole and p-thiocresol by extraction with ethyl ether and ethyl acetate sequentially, crude peptides are extracted with a mixture of 0.5M sodium phosphate buffer, pH 8.0 and N,N- dimethylformamide using 1 / 1 ratio, v / v. The disulfide bond for Cys residues B and E is the formed using dimethyl sulfoxide (Tam et al. (1991) J. Am. Chem. Soc. 113:6657-62). The resulting peptide is the purified by reverse-phase chromatography. The disulfide bond between Cys residues C and F is formed by first dissolving the peptide in 50% acetic acid in water. Saturated iodine solution in glacial acetic acid is added (1 ml iodine solution per 100 ml solution). After incubation at room temperature for 2 days in an enclosed glass container, the solution is diluted five-fold with deionized water and extracted with ethyl ether four times for removal of unreacted iodine. After removal of the residual amount of ethyl ether by rotary evaporation the solution of crude product is lyophilized and purified by successive reversephase chromatography.[000174] Intestinal GC-C Receptor Binding Assay [000175] The ability of peptides and other agents to bind to the intestinal GC-C receptor can be tested as follows. Cells of the T84 human colon carcinoma cell line (American Type Culture Collection (Bethesda, Md.) are grown to confluence in 24-well culture plates with a 1:1 mixture of Ham's F12 medium and Dulbecco's modified Eagle's medium (DMEM), supplemented with 5% fetal calf serum. Cells used in the assay are typically between passages 54-60. Briefly, T84 cell monolayers in 24-well plates are washed twice with 1 ml of binding buffer (DMEM containing 0.05% bovine serum albumin and 25 mM HEPES, pH 7.2), then incubated for 30 min at 37° C. in the presence of mature radioactively labeled E. coli ST peptide and the test material at various concentrations. The cells are then washed four times with 1 ml of DMEM and solubilized with 0.5 ml / well 1N NaOH. The level of radioactivity in the solubilized material is then determined using standard methods. [000176] Chromatographic purity [000177] Chromatographic purity of the peptides of the present disclosure may be assessed by performing HPLC under the conditions described herein. For example, in some embodiments, the area under the peptide peak is measured and compared to the total area under all peaks excluding the solvent peak and any non-polypeptide related peaks (i.e., peaks associated with excipients that may be observed in a placebo). [000178] In some embodiments, the chromatographic purity of a peptide in a composition after storage at room temperature or accelerated conditions at a specified time point of storage under accelerated conditions [40ºC / 75% RH] or 12, 18, 24 or more months of storage under room temperature conditions [25 ºC / 60% RH]) can be compared to the chromatographic purity of peptides in a composition at an initial time (e.g., the time when the pharmaceutical composition is released for clinical or patient use (“the release date”)) to provide the chromatographic purity value. [000179] For example, the chromatographic purity of the peptide in a composition is measured after storage for a specified time at, e.g., accelerated conditions (40ºC / 75% RH) and compared to the chromatographic purity of peptide in the composition at the release date. [000180] In some embodiments, the chromatographic purity of the peptide in a composition is measured after storage for a specified time at room temperature conditions (25ºC / 60% RH) and compared to the chromatographic purity of peptide in the composition at the release date. [000181] Pharmaceutically acceptable salts[000182] In some embodiments, pharmaceutically acceptable salts, hydrates, solvates, crystal forms and individual isomers, enantiomers, tautomers, diastereomers and prodrugs of the peptide described herein can be utilized. [000183] In some embodiments, a pharmaceutically acceptable salt of the present disclosure possesses the desired pharmacological activity of the parent compound. Such salts include: acid addition salts, formed with inorganic acids; acid addition salts formed with organic acids; or salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, aluminum ion; or coordinates with an organic base such as ethanolamine, and the like. [000184] In some embodiments, pharmaceutically acceptable salts include conventional toxic or non-toxic salts. For example, in some embodiments, convention non-toxic salts include those such as fumarate, phosphate, citrate, chlorydrate, and the like. In some embodiments, the pharmaceutically acceptable salts of the present disclosure can be synthesized from a parent compound by conventional chemical methods. In some embodiments, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. In some embodiments, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p.1418, the disclosure of which is incorporated herein by reference in its entirety. [000185] In some embodiments, a pharmaceutically acceptable salt can be one of the following: hydrochloride; sodium; sulfate; acetate; phosphate or diphosphate; chloride; potassium; maleate; calcium; citrate; mesylate; nitrate; tartrate; aluminum; or gluconate. [000186] In some embodiments, a list of pharmaceutically acceptable acids that can be used to form salts can be: glycolic acid; hippuric acid; hydrobromic acid; hydrochloric acid; isobutyric acid; lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid (- L); malonic acid; mandelic acid (DL); methanesulfonic acid ; naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinic acid; nitric acid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; proprionic acid; pyroglutamic acid (- L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+ L); thiocyanic acid; toluenesulfonic acid (p); undecylenic acid; a 1-hydroxy-2-naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2-oxoglutaric acid; 4-acetamidobenzoic acid; 4- aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L);benzenesulfonic acid; benzoic acid; camphoric acid (+); camphor- 10-sulfonic acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecylsulfuric acid; ethane- 1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; glucoheptonic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; glutaric acid; or glycerophosphoric acid.[000187] In some embodiments, pharmaceutically acceptable salt can be any organic or inorganic addition salt.[000188] In some embodiments, the salt may use an inorganic acid and an organic acid as a free acid. The inorganic acid may be hydrochloric acid, bromic acid, nitric acid, sulfuric acid, perchloric acid, phosphoric acid, etc. The organic acid may be citric acid, acetic acid, lactic acid, maleic acid, fumaric acid, gluconic acid, methane sulfonic acid, gluconic acid, succinic acid, tartaric acid, galacturonic acid, embonic acid, glutamic acid, aspartic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methane sulfonic acid, ethane sulfonic acid, 4- toluene sulfonic acid, salicylic acid, citric acid, benzoic acid, malonic acid, etc.[000189] In some embodiments, the salts include alkali metal salts (sodium salts, potassium salts, etc.) and alkaline earth metal salts (calcium salts, magnesium salts, etc.). For example, the acid addition salt may include acetate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, edisilate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methyl sulfate, naphthalate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate, trifluoroacetate, aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, zinc salt, etc., and among them, hydrochloride or trifluoroacetate may be used.[000190] In yet other embodiments, the pharmaceutically acceptable salt can be a salt with an acid such as acetic acid, propionic acid, butyric acid, formic acid, trifluoroacetic acid, maleic acid, tartaric acid, citric acid, stearic acid, succinic acid, ethylsuccinic acid, lactobi onic acid, gluconic acid, glucoheptonic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, laurylsulfuric acid, malic acid, aspartic acid, glutaminic acid, adipic acid, cysteine, N- acetylcysteine, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid,hydroiodic acid, nicotinic acid, oxalic acid, picric acid, thiocyanic acid, undecanoic acid, polyacrylate or carboxyvinyl polymer.[000191] In some embodiments, the pharmaceutically acceptable salt can be prepared from either inorganic or organic bases. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, ferrous, zinc, copper, manganous, aluminum, ferric, manganic salts, and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally-occurring substituted amines, and cyclic amines, including isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimelhylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, and the like. Preferred organic bases are isopropylamine, diethylamine, ethanolamine, piperidine, tromethamine, and choline.[000192] In some embodiments, pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977), the disclosure of which is incorporated herein by reference in its entirety.[000193] In some embodiments, the salts of the present disclosure can be prepared in situ during the final isolation and purification of the compounds of the present disclosure, or separately by reacting the free base function with a suitable organic acid. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.[000194] Exemplary descriptions of pharmaceutically acceptable salts is provided in P. H. Stahl and C. G. Wermuth, (editors), Handbook of Pharmaceutical Salts: Properties, Selection and Use, John Wiley & Sons, Aug 23, (2002), the disclosure of which is incorporated herein by reference in its entirety.[000195] COMBINATION THERAPY [000196] The present disclosure describes combinations of GLP-1 receptor agonists, and guanylate-cyclase C (GC-C) receptor agonists.[000197] As used herein, a " combination” refers to the result of combining two or more separate components (e.g., a first component and one or more additional components). Thus, as used herein, a “combination” refers to an association of two or more separate components, e.g., a first agonist and one or more additional component (e.g., one or more additional agonists, wherein said one or more additional agonists are the same or different from the first agonist; or, in the case of a composition, at least two agonists comprising a GLP-1 receptor agonist, and a guanylate-cyclase C (GC-C) receptor agonist, and one or more excipients). Accordingly, in some embodiments, a combination can refer to the association of a first agonist, and one or more additional agonists; wherein the first agonist and one or more additional agonist are the same or different.[000198] In some embodiments, a combination can be a “mixture.” For example, in some embodiments, a mixture refers to a combination of a first component, and one or more additional components, wherein the first component and the one or more additional components are present together in a single entity (e.g., a single unit). Thus, in some embodiments, a mixture can comprise a first component, and one or more additional components, wherein the first component and the one or more additional components are present in admixture for simultaneous administration.[000199] Accordingly, in some embodiments, a combination can refer to the association of a first agonist (e.g., a GLP-1 receptor agonist or a GC-C receptor agonist), and one or more additional agonists (e.g., one or more additional GLP-1 receptor agonists or GC-C receptor agonists); wherein the combination comprises at least a GLP-1 receptor agonist and a GC-C receptor agonist; and wherein the wherein the GLP-1 receptor agonist and the GC-C receptor agonist are present in a single entity (e.g., an admixture for simultaneous administration).[000200] Accordingly, in some embodiments, a combination can refer to the association of a first agonist (e.g., a GLP-1 receptor agonist or a GC-C receptor agonist), and one or more additional agonists (e.g., one or more additional GLP-1 receptor agonists or GC-C receptor agonists); wherein the combination comprises at least a GLP-1 receptor agonist and a GC-C receptor agonist; and wherein the GLP-1 receptor agonist and the GC-C receptor agonist are present separately (e.g., different units for separate, sequential, simultaneous, concurrent or chronol ogi cally -staggered admini strati on).[000201] In some embodiments, a combination can comprise a GLP-1 receptor agonist and a GC-C receptor agonist, wherein the GLP-1 receptor agonist and the GC-C receptor agonist, are present separately (e.g., more than one unit). For example, in some embodiments, a combination can comprise a GLP-1 receptor agonist and a GC-C receptor agonist, wherein the GLP-1 receptor agonist and the GC-C receptor agonist may be administered separately, sequentially, simultaneously, concurrently or chronologically staggered.[000202] Thus, in some embodiments, a combination can refer to the association of a first agonist (e.g., a GLP-1 receptor agonist or a GC-C receptor agonist), and one or more additional agonists (e.g., one or more additional GLP-1 receptor agonists or GC-C receptor agonists); wherein the combination comprises at least a GLP-1 receptor agonist and a GC-C receptor agonist; and wherein the GLP-1 receptor agonist and the GC-C receptor agonist are present separately (e.g., different units for separate, sequential, simultaneous, concurrent or chronologically-staggered administration).[000203] In some embodiments, a combination can refer to the separate, sequential, simultaneous, concurrent or chronologically-staggered administration of a GLP-1 receptor agonist and a GC-C receptor agonist. For example, in some embodiments, a “combination" refers to the result of a simultaneous application of both a GLP-1 receptor agonist and a GC- C receptor agonist.[000204] In another embodiment, a combination of the present disclosure refers to the result of a separate application of a GLP-1 receptor agonist and a GC-C receptor agonist.[000205] In a further embodiments, a combination of the present disclosure refers to the result of a sequential application of a GLP-1 receptor agonist and a GC-C receptor agonist, e.g., a first application of a either a GLP-1 receptor agonist, or a GC-C receptor agonist, followed by a second application of a GC-C receptor agonist or GLP-1 receptor agonist, respectively, or vice versa; thus resulting in a combination of at least a GLP-1 receptor agonist and a GC-C receptor agonist. Where the application is sequential or separate, the delay in applying the second component should not be such as to lose the beneficial effect of the combination.[000206] In some embodiments, a combination of the present disclosure can be present in a single entity, e.g., an admixture for simultaneous administration (a “mixture”). For example, a combination comprising a GLP-1 receptor agonist and a GC-C receptor agonist can be present in a single entity, e.g., an admixture for simultaneous administration (a “mixture”).[000207] In other embodiments, a combination of the present disclosure can further comprise one or more excipients. For example, a combination comprising a GLP-1 receptor agonist and a GC-C receptor agonist can further comprise one or more excipients.[000208] In some embodiments, a combination comprising a GLP-1 receptor agonist and a GC-C receptor agonist is formulated in separate compositions.[000209] In some embodiments, a combination comprising a GLP-1 receptor agonist and a GC-C receptor agonist is formulated in separate compositions, wherein the separate compositions are formulated as admixtures with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of administration, known to the art. In some embodiments, the separate pharmaceutical preparations may be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and / or aromatic substances and the like. They may also be combined where desired with other active agents, e.g., other analgesic agents.[000210] In some embodiments, a combination comprising a GLP-1 receptor agonist and a GC-C receptor agonist is formulated in separate compositions, wherein the separate compositions are formulated using the same excipients or different excipients.[000211] In some embodiments, a combination comprising a GLP-1 receptor agonist and a GC-C receptor agonist is formulated in a single composition.[000212] In some embodiments, a combination comprising a GLP-1 receptor agonist and a GC-C receptor agonist is formulated in a single composition; wherein the single composition is formulated as an admixture with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of administration, known to the art. In some embodiments, the single composition may be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and / or aromatic substances and the like. They may also be combined where desired with other active agents, e.g., other analgesic agents.[000213] In some embodiments, a combination, mixture, or composition comprising a GLP-1 receptor agonist and a GC-C receptor agonist can be applied or administered separately, sequentially, simultaneously, concurrently or chronologically staggered. For example, in some embodiments, a combination comprising a GLP-1 receptor agonist and a GC-C receptor agonist can be applied or administered separately, wherein the first component and the one or more additional components are contained in separate units.[000214] In some embodiments, a combination, mixture, or composition comprising a GLP-1 receptor agonist and a GC-C receptor agonist can be applied or administered sequentially, wherein the first component and the one or more additional components are administered in sequence, for example at an interval or intervals of minutes, hours, days or weeks (wherein the delay in administering the one or more additional components does not lose the beneficial effect of the combination).[000215] In some embodiments, a combination, mixture, or composition comprising a GLP-1 receptor agonist and a GC-C receptor agonist can be applied or administered simultaneously, wherein the first component and the one or more additional components are administered at substantially the same time.[000216] In some embodiments, a combination, mixture, or composition comprising a GLP-1 receptor agonist and a GC-C receptor agonist, can be applied or administered contemporaneously, wherein the GLP-1 receptor agonist and the GC-C receptor agonist are administered closely in time, e.g., the GLP-1 receptor agonist or the GC-C receptor agonist (first component) is administered within from about 30 seconds, to within about one day before or after the GC-C receptor agonist or the GLP-1 receptor agonist, respectively (second component); however, any contemporaneous time is useful given the delay in administering the second component does not lose the beneficial effect of the combination. In someembodiments, when administered contemporaneously, the first component and one and second component are suitably administered at the same locus.[000217] In some embodiments, a combination, mixture, or composition of the present disclosure, comprising at least a GLP-1 receptor agonist and a GC-C receptor agonist can be applied or administered sequentially, wherein the GLP-1 receptor agonist or the GC-C receptor agonist (first component) is applied just prior to, or just after the application the other the GC-C receptor agonist or the GLP-1 receptor agonist, respectively (second component).[000218] In some embodiments, a combination of the present disclosure comprises, consists essentially of, or consists of: one or more GLP-1 receptor agonists, and one or more GC-C receptor agonists.[000219] In some embodiments, a mixture comprises a combination of one or more GLP-1 receptor agonists, and one or more GC-C receptor agonists, and various combinations thereof, wherein the GLP-1 receptor agonist and the GC-C receptor agonist can be blended together in in varying proportions.[000220] In some embodiments, a combination of the present disclosure comprises, consists essentially of, or consists of: one or more GLP-1 receptor agonists, and one or more GC-C receptor agonists; wherein the combination can be provided in the same container, or in different containers.[000221] In some embodiments, a composition of the present disclosure comprises, consists essentially of, or consists of: one or more GLP-1 receptor agonists, one or more GC- C receptor agonists, and one or more excipients.[000222] In some embodiments, an illustrative combination comprises at least two of: (1) one or more GLP-1 receptor agonists, or pharmaceutically acceptable salts thereof; (2) one or more GC-C receptor agonists, or pharmaceutically acceptable salts thereof; and / or (3) any combination thereof; wherein the GLP-1 receptor agonist and the GC-C receptor agonist are present in admixture for simultaneous administration (e.g., present in a single unit).[000223] In some embodiments, an illustrative composition comprises: (1) a GLP-1 receptor agonist and a GC-C receptor agonist, or a pharmaceutically acceptable salt thereof; and (2) at least one excipient (e.g., any of the excipients described herein).[000224] In some embodiments, an illustrative composition comprises: (1) a GLP-1 receptor agonist and a GC-C receptor agonist, or a pharmaceutically acceptable salt thereof; and (2) at least one excipient (e.g., any of the excipients described herein); wherein either of the foregoing (1) or (2) can be used concomitantly, or sequentially.[000225] In some embodiments, a combination comprises a GLP-1 receptor agonist, and aguanylate-cyclase C (GC-C) receptor agonist; wherein GC-C receptor agonist is linaclotide. [000226] Glucagon-like-peptide-1 is a peptide hormone secreted from L-cells that line the intestine; these cells are located throughout the gastrointestinal track and act on a specific glucagon-like-peptide-1 (GLP-1) receptor, which is expressed fairly ubiquitously throughout the body, including but not limited to the pancreas, GI track, heart, lung, and immune cells. When the peptide GLP-1 binds to its cognate receptor the pharmacodynamic responses — depending on the receptor site — include slowed gastric emptying, reduced appetite and food intake, decrease peptide hormone secretion like glucagon as well as generalized slow gastrointestinal transit which can result in constipation. The overall positive metabolic effects can be compromised by needing to discontinue the GLP-1 due to unwanted side effects related to slow gastrointestinal transit.[000227] In one study of patients taking GLP-1 receptor agonist, nausea, constipation and gastroesophageal reflux (all indicators of delayed gastrointestinal transit) were experienced by 26%, 21%, and 12% of subjects, respectively (DDW abstract Mol918; Comet et al, May 2023). In addition, 12% of patients taking the GLP-1 receptor agonist in this study experienced abdominal pain and / or bloating. These side effects of the GLP-1 receptor agonist are quite disturbing to people taking GLP-1 receptor agonists, and decreasing or eliminating these unwanted symptoms should result in improved prescription compliance and better clinical outcomes.[000228] Linaclotide is a peptide that is commercially available to treat irritable bowel syndrome with constipation and chronic idiopathic constipation. Linaclotide works by enhancing intestinal secretion through stimulation of the guanylate C receptor, which then results in improved or accelerated gastrointestinal transit. Linaclotide has also been shown to alleviate abdominal pain and bloating through the guanylate C pathway. Accordingly, the mechanistic effects of linaclotide should have significant clinical benefits in subjects with delayed gastrointestinal transit and potentially reduce or eliminate the symptoms associated with GLP-1 receptor agonists.[000229] There is also a potential benefit for improved pharmacodynamic response by using novel dose administration with linaclotide to enhance the gastrointestinal transit benefit, for example twice daily dosing in patients taking a GLP-1 receptor agonists may be required for optimal gastrointestinal transit and improving symptoms of constipation and abdominal pain.[000230] Accordingly, the present disclosure describes a novel approach for treating the decreased gastrointestinal transit, associated constipation, and / or abdominal pain experienced by subjects taking a GLP-1 receptor agonists, by use of any guanylate cyclase C agonist to improved gastrointestinal motility and decrease associated abdominal pain.[000231] In some embodiments, a combination comprising a GLP-1 receptor agonist and a guanylate-cyclase C (GC-C) receptor agonist can result in significant clinical benefits in subjects with delayed gastrointestinal transit and potentially reduce or eliminate the symptoms associated with GLP-1 receptor agonists alone.[000232] In some embodiments, administering a combination comprising a GLP-1 receptor agonist and a guanylate-cyclase C (GC-C) receptor agonist to a subject in need thereof can result in a reduction of the number and / or severity of side effects of the GLP-1 receptor agonist in the subject, relative to the number and / or severity of side effects of the GLP-1 receptor agonist in the subject prior to receiving the combination.[000233] In some embodiments, administering a combination comprising a GLP-1 receptor agonist and a guanylate-cyclase C (GC-C) receptor agonist to a subject in need thereof can reduce the number and / or severity of side effects of the GLP-1 receptor agonist in the subject, relative to the number and / or severity of side effects of the GLP-1 receptor agonist in a subject that has not been administered the combination.[000234] In some embodiments, administering a combination comprising a GLP-1 receptor agonist and a guanylate-cyclase C (GC-C) receptor agonist to a subject in need thereof can result in a reduction of the number and / or severity of side effects of the GLP-1 receptor agonist in the subject, relative to the number and / or severity of side effects of the GLP-1 receptor agonist in the subject prior to receiving the combination; wherein the side effects are one or more of slowed gastric emptying; reduced appetite and / or food intake; decreased peptide hormone secretion (e.g., glucagon); slow gastrointestinal transit; constipation; and / or any abdominal pain associated thereof.[000235] In some embodiments, administering a combination comprising a GLP-1 receptor agonist and a guanylate-cyclase C (GC-C) receptor agonist to a subject in need thereof can reduce the number and / or severity of side effects of the GLP-1 receptor agonist in the subject, relative to the number and / or severity of side effects of the GLP-1 receptor agonist in a subject that has not been administered the combination; wherein the side effects are one or more of slowed gastric emptying; reduced appetite and / or food intake; decreased peptide hormone secretion (e.g., glucagon); slow gastrointestinal transit; constipation; and / or any abdominal pain associated thereof.[000236] In some embodiments, administering a combination comprising a GLP-1 receptor agonist and a guanylate-cyclase C (GC-C) receptor agonist to a subject in need thereof can result in an increase in the level of gastrointestinal motility, and / or decrease in the level of associated abdominal pain in the subject, relative to the level of gastrointestinal motility and / or the level of associated abdominal pain in the subject prior to receiving the combination.[000237] In some embodiments, administering a combination comprising a GLP-1 receptor agonist and a guanylate-cyclase C (GC-C) receptor agonist to a subject in need thereof can result in an increase in the level of gastrointestinal motility, and / or decrease in the level of associated abdominal pain in the subject, relative to the level of gastrointestinal motility and / or the level of associated abdominal pain in a subject that has not been administered the combination.[000238] As describe herein, combination therapy can be achieved by administering two or more agents, e.g., a GLP-1 receptor agonist (e.g., a GLP-1 receptor agonist) and a guanylate-cyclase C (GC-C) receptor agonist (e.g., linaclotide), each of which is formulated and administered separately, or by administering the two or more agents in a single formulation. Other combinations are also encompassed by combination therapy. For example, two agents can be formulated together and administered in conjunction with a separate formulation containing a third agent. While the two or more agents in the combination therapy can be administered simultaneously, they need not be. For example, administration of a first agent (or combination of agents) can precede administration of a second agent (or combination of agents) by minutes, hours, days, or weeks. Thus, the two or more agents can be administered within minutes of each other or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14 days of each other or within 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks of each other. In some cases even longer intervals are possible. While in many cases it is desirable that the two or more agents used in a combination therapy be present in within the patient’s body at the same time, this need not be so.[000239] In some embodiments, the combination therapy can also include two or more administrations of one or more of the agents (e.g., a GLP-1 receptor agonist and a GC-C receptor agonist) used in the combination. For example, if agent X and agent Y are used in a combination, one could administer them sequentially in any combination one or more times, e.g., in the order X-Y-X, X-X-Y, Y-X-Y, Y-Y-X, X-X-Y-Y, etc.[000240] The agents (e.g., a GLP-1 receptor agonist and a GC-C receptor agonist), alone or in combination, can be combined with any pharmaceutically acceptable carrier or medium. Thus, they can be combined with materials that do not produce an adverse, allergic or otherwise unwanted reaction when administered to a patient. The carriers or mediums used can include solvents, dispersants, coatings, absorption promoting agents, controlled release agents, etc.[000241] In some embodiments, the agents (e.g., a GLP-1 receptor agonist and a GC-C receptor agonist) either in their free form or as a salt can be combined with a polymer such as polylactic-glycoloic acid (PLGA), poly-(I)-lactic-glycolic-tartaric acid (P(I)LGT) (WO 01 / 12233), polyglycolic acid (U.S. 3,773,919), polylactic acid (U.S. 4,767,628); poly(M- caprolactone) to create a sustained release formulation. Such formulations can be used for implants that release a peptide or another agent over a period of a few days, a few weeks or several months depending on the polymer, the particle size of the polymer, and the size of the implant (see, e.g., U.S. 6,620,422). Other sustained release formulations are described herein, and in EP 0 467 389 A2, WO 93 / 241150, U.S. 5,612,052; WO 97 / 40085, WO 94 / 155587, U.S. 5,672,659, U.S. 5,893,985, U.S. 5,134,122, U.S. 5,192,741, U.S. 5,192,741, and U.S. 5,445,832. In such sustained release formulations microparticles of peptide are combined with microparticles of polymer. One or more sustained release implants can be placed in the large intestine, the small intestine or both.[000242] In some embodiments, the agents (e.g., a GLP-1 receptor agonist and a GC-C receptor agonist) can be administered, e.g., by intravenous injection, intramuscular injection, subcutaneous injection, or by other routes. The agents can be administered orally, e.g., as a tablet, gel, paste, slurry, liquid, powder or in some other form. Orally administered compositions can include binders, flavoring agents, and humectants. The agents can be included in dentifrices or oral washes. Thus, oral formulations can include abrasives and foaming agents. The agents can also be administered transdermally or in the form a suppository.[000243] In some embodiments, the agents (e.g., a GLP-1 receptor agonist and a GC-C receptor agonist) can be a free acid or base, or a pharmacologically acceptable salt thereof. Solids can be dissolved or dispersed immediately prior to administration or earlier. In some circumstances the preparations include a preservative to prevent the growth of microorganisms. The pharmaceutical forms suitable for injection can include sterile aqueous or organic solutions or dispersions which include, e.g., water, an alcohol, an organic solvent, an oil or other solvent or dispersant (e.g., glycerol, propylene glycol, polyethylene glycol, andvegetable oils). Pharmaceutical agents can be sterilized by filter sterilization or by other suitable means. [000244] Suitable pharmaceutical compositions in accordance with the present disclosure will generally include an amount of the active compound(s) with an acceptable pharmaceutical diluent or excipient, such as a sterile aqueous solution, to give a range of final concentrations, depending on the intended use. The techniques of preparation are generally well known in the art, as exemplified by Remington's Pharmaceutical Sciences (18th Edition, Mack Publishing Company, 1995). [000245] In some embodiments, the agents (e.g., a GLP-1 receptor agonist and a GC-C receptor agonist) described herein and combination therapy agents can be packaged as a kit that includes single or multiple doses of two or more agents, each packaged or formulated individually, or single or multiple doses of two or more agents packaged or formulated in combination. Thus, one or more agents can be present in first container, and the kit can optionally include one or more agents in a second container. The container or containers are placed within a package, and the package can optionally include administration or dosage instructions. A kit can include additional components such as syringes or other means for administering the agents as well as diluents or other means for formulation. [000246] Additional methods and formulations are described in the sections below. [000247] PHARMACEUTICAL COMPOSITIONS [000248] As used herein, “v / v” or “% v / v” or “volume per volume” refers to the volume concentration of a solution (“v / v” stands for volume per volume). Here, v / v can be used when both components of a solution are liquids. For example, when 50 mL of ingredient X is diluted with 50 mL of water, there will be 50 mL of ingredient X in a total volume of 100 mL; therefore, this can be expressed as “ingredient X 50% v / v.” Percent volume per volume (% v / v) is calculated as follows: (volume of solute (mL) / volume of solution (100 mL)); e.g., % v / v = mL of solute / 100 mL of solution. [000249] As used herein, “w / w” or “% w / w” or “weight per weight” or “% wt / wt” refers to the weight concentration of a solution, i.e., percent weight in weight (“w / w” stands for weight per weight). Here, w / w expresses the number of grams (g) of a constituent in 100 g of solution or mixture. For example, a mixture consisting of 30 g of ingredient X, and 70 g of water would be expressed as “ingredient X 30% w / w.” Percent weight per weight (% w / w) is calculated as follows: (weight of solute (g) / weight of solution (g)) x 100; or (mass of solute (g) / mass of solution (g)) x 100.[000250] As used herein, “w / v” or “% w / v” or “weight per volume” refers to the mass concentration of a solution, i.e., percent weight in volume (“w / v” stands for weight per volume). Here, w / v expresses the number of grams (g) of a constituent in 100 mL of solution. For example, if 1 g of ingredient X is used to make up a total volume of 100 mL, then a “1% w / v solution of ingredient X” has been made. Percent weight per volume (% w / v) is calculated as follows: (Mass of solute (g) / Volume of solution (mL)) x 100. [000251] The present disclosure contemplates combinations, mixtures, and compositions comprising, consisting essentially of, or consisting of, a combination of a GLP- 1 receptor agonist and a GC-C receptor agonist as described herein. The preparation of a pharmaceutical composition that contains a peptide of the present disclosure will be known to those of skill in the art in light of the present disclosure, as exemplified by Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, Moreover, for animal (e.g., human) administration, it will be understood that preparations should meet sterility, pyrogenicity, general safety, and purity standards. [000252] Formulations may be employed in admixtures with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of administration, known to the art. The pharmaceutical preparations may be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and / or aromatic substances and the like. They may also be combined where desired with other active agents. e.g., other analgesic agents. [000253] In some embodiments, a combination of the present disclosure may be administered as a pharmaceutical composition in which the one or more peptides are admixed with an appropriate pharmaceutically acceptable carrier, diluent, excipient, vehicle, or carrier. [000254] In some embodiments, a pharmaceutical composition can comprise, consist essentially of, or consist of, a GLP-1 receptor agonist and a GC-C receptor agonist, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier. [000255] In some embodiments, the pharmaceutical compositions of the present disclosure may be administered parenterally, or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous,intramuscular, intrasternal injection or infusion techniques. Methods of administration are described in detail below. [000256] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a combination of a GLP-1 receptor agonist and a GC-C receptor agonist; and one or more excipients. [000257] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a combination of a GLP-1 receptor agonist and a GC-C receptor agonist; wherein the GC-C receptor agonist is a peptide having an amino acid sequence that is at least 85% identical, at least 86% identical, at least 87% identical, at least 88% identical, at least 89% identical, at least 90% identical, at least 91% identical, at least 92% identical, at least 93% identical, at least 94% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, at least 99.5% identical, at least 99.6% identical, at least 99.7% identical, at least 99.8% identical, at least 99.9% identical, or 100% identical to the amino acid sequence to the amino acid sequence: Cys1Cys2Glu3Tyr4Cys5Cys6Asn7Pro8Ala9Cys10Thr11Gly12Cys13Tyr14(SEQ ID NO: 1), wherein Cys1and Cys6; Cys2and Cys10; and Cys5and Cys13, are connected by disulfide bonds; or a pharmaceutically acceptable salt thereof; and one or more excipients. [000258] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a combination of a GLP-1 receptor agonist and a GC-C receptor agonist; wherein the GC-C receptor agonist is a peptide having an amino acid sequence that is at least 85% identical, at least 86% identical, at least 87% identical, at least 88% identical, at least 89% identical, at least 90% identical, at least 91% identical, at least 92% identical, at least 93% identical, at least 94% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, at least 99.5% identical, at least 99.6% identical, at least 99.7% identical, at least 99.8% identical, at least 99.9% identical, or 100% identical to an amino acid amino acid sequence: Cys1Cth2Glu3Leu4Cys5Cys6Asn7Val8Ala9Cys10Tyr11Gly12Cys13(SEQ ID NO: 2), or a pharmaceutically acceptable salt thereof; wherein Cth is a cystathionine; wherein Cys1and Cys6; Cys5and Cys13; are connected by disulfide bonds; and wherein Cth2and Cys10are connected by a thioether bond; or a pharmaceutically acceptable salt thereof; and one or more excipients. [000259] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a combination of a GLP-1 receptor agonist and a GC-C receptor agonist; wherein the GC-C receptor agonist is a peptide having an amino acid sequence that is at least 85% identical, at least 86% identical, at least 87% identical, at least 88% identical,at least 89% identical, at least 90% identical, at least 91% identical, at least 92% identical, at least 93% identical, at least 94% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, at least 99.5% identical, at least 99.6% identical, at least 99.7% identical, at least 99.8% identical, at least 99.9% identical, or 100% identical to an amino acid amino acid sequence: Cys1Cth2Glu3Leu4Cys5Cys6Asn7Val8Ala9Cys10Tyr11Gly12Cys13(SEQ ID NO: 3), or a pharmaceutically acceptable salt thereof; wherein Cth is a cystathionine; wherein Cys1and Cys6; Cys5and Cys13; are connected by disulfide bonds; and wherein Cth2and Cys10are connected by a thioether bond; or a pharmaceutically acceptable salt thereof; and one or more excipients. [000260] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a combination of a GLP-1 receptor agonist and a GC-C receptor agonist; wherein the GC-C receptor agonist is a peptide having an amino acid sequence that is at least 85% identical, at least 86% identical, at least 87% identical, at least 88% identical, at least 89% identical, at least 90% identical, at least 91% identical, at least 92% identical, at least 93% identical, at least 94% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, at least 99.5% identical, at least 99.6% identical, at least 99.7% identical, at least 99.8% identical, at least 99.9% identical, or 100% identical to the amino acid sequence to the amino acid sequence: Asn1Asp2Glu3Cys4Glu5Leu6Cys7Val8Asn9Va110Ala11Cys12Thr13Gly14Cys15Leu16(SEQ ID NO: 4); wherein Cys4and Cys12; and Cys7and Cys15; are connected by disulfide bonds; or a pharmaceutically acceptable salt thereof; and one or more excipients. [000261] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a combination of a GLP-1 receptor agonist and a GC-C receptor agonist and one or more excipients; wherein the GC-C receptor agonist is a peptide having an amino acid sequence that is at least 85% identical, at least 86% identical, at least 87% identical, at least 88% identical, at least 89% identical, at least 90% identical, at least 91% identical, at least 92% identical, at least 93% identical, at least 94% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, at least 99.5% identical, at least 99.6% identical, at least 99.7% identical, at least 99.8% identical, at least 99.9% identical, or 100% identical to the amino acid sequence to the amino acid sequence: Cys1Cys2Glu3Tyr4Cys5Cys6Asn7Pro8Ala9Cys10Thr11Gly12Cys13Tyr14(SEQ ID NO: 1), wherein Cys1and Cys6; Cys2and Cys10; and Cys5and Cys13, are connected by disulfide bonds; or a pharmaceutically acceptable salt thereof.[000262] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a combination of a GLP-1 receptor agonist and a GC-C receptor agonist; wherein the GC-C receptor agonist is a peptide having an amino acid sequence that is at least 85% identical, at least 86% identical, at least 87% identical, at least 88% identical, at least 89% identical, at least 90% identical, at least 91% identical, at least 92% identical, at least 93% identical, at least 94% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, at least 99.5% identical, at least 99.6% identical, at least 99.7% identical, at least 99.8% identical, at least 99.9% identical, or 100% identical to an amino acid amino acid sequence: Cys1Cth2Glu3Leu4Cys5Cys6Asn7Val8Ala9Cys10Tyr11Gly12Cys13(SEQ ID NO: 2), or a pharmaceutically acceptable salt thereof; wherein Cth is a cystathionine; wherein Cys1and Cys6; Cys5and Cys13; are connected by disulfide bonds; and wherein Cth2and Cys10are connected by a thioether bond; or a pharmaceutically acceptable salt thereof; and one or more excipients. [000263] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a combination of a GLP-1 receptor agonist and a GC-C receptor agonist; wherein the GC-C receptor agonist is a peptide having an amino acid sequence that is at least 85% identical, at least 86% identical, at least 87% identical, at least 88% identical, at least 89% identical, at least 90% identical, at least 91% identical, at least 92% identical, at least 93% identical, at least 94% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, at least 99.5% identical, at least 99.6% identical, at least 99.7% identical, at least 99.8% identical, at least 99.9% identical, or 100% identical to an amino acid amino acid sequence: Cys1Cth2Glu3Leu4Cys5Cys6Asn7Val8Ala9Cys10Tyr11Gly12Cys13(SEQ ID NO: 3), or a pharmaceutically acceptable salt thereof; wherein Cth is a cystathionine; wherein Cys1and Cys6; Cys5and Cys13; are connected by disulfide bonds; and wherein Cth2and Cys10are connected by a thioether bond; or a pharmaceutically acceptable salt thereof; and one or more excipients. [000264] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a combination of a GLP-1 receptor agonist and a GC-C receptor agonist; wherein the GC-C receptor agonist is a peptide having an amino acid sequence that is at least 85% identical, at least 86% identical, at least 87% identical, at least 88% identical, at least 89% identical, at least 90% identical, at least 91% identical, at least 92% identical, at least 93% identical, at least 94% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, at least 99.5% identical, at least 99.6% identical, at least 99.7% identical, at least 99.8% identical, at least 99.9%identical, or 100% identical to the amino acid sequence to the amino acid sequence: Asn1Asp2Glu3Cys4Glu5Leu6Cys7Val8Asn9Va110Ala11Cys12Thr13Gly14Cys15Leu16(SEQ ID NO: 4); wherein Cys4and Cys12; and Cys7and Cys15; are connected by disulfide bonds; or a pharmaceutically acceptable salt thereof; and one or more excipients. [000265] In some embodiments, a pharmaceutical composition comprises a combination comprising a GLP-1 receptor agonist and a GC-C receptor agonist; and an excipient; wherein the amount of the GLP-1 receptor agonist ranges from about 0.000001% w / w to about 99.99999% w / w of the total composition, or from about 0.01% to about 99.99%; from about 0.02% to about 99.98%; from about 0.03% to about 99.97%; from about 0.04% to about 99.96%; from about 0.05% to about 99.95; from about 0.06% to about 99.94%; from about 0.07% to about 99.93%; from about 0.08% to about 99.92%; from about 0.09% to about 99.91%; from about 1% to about 99%; from about 2% to about 98%; from about 3% to about 97%; from about 4% to about 96%; from about 5% to about 95%; from about 6% to about 94%; from about 7% to about 93%; from about 8% to about 92%; from about 9% to about 91%; from about 10% to about 90%; from about 11% to about 89%; from about 12% to about 88%; from about 13% to about 87%; from about 14% to about 86%; from about 15% to about 85%; from about 16% to about 84%; from about 17% to about 83%; from about 18% to about 82%; from about 19% to about 81%; from about 20% to about 80%; from about 21% to about 79%; from about 22% to about 78%; from about 23% to about 77%; from about 24% to about 76%; from about 25% to about 75%; from about 26% to about 74%; from about 27% to about 73%; from about 28% to about 72%; from about 29% to about 71%; from about 30% to about 70%; from about 31% to about 69%; from about 32% to about 68%; from about 33% to about 67%; from about 34% to about 66%; from about 35% to about 65%; from about 36% to about 64%; from about 37% to about 63%; from about 38% to about 62%; from about 39% to about 61%; from about 40% to about 60%; from about 41% to about 59%; from about 42% to about 58%; from about 43% to about 57%; from about 44% to about 56%; from about 45% to about 55%; from about 46% to about 54%; from about 47% to about 53%; from about 48% to about 52%; from about 49% to about 51%; from about 50% to about 50%; from about 51% to about 49%; from about 52% to about 48%; from about 53% to about 47%; from about 54% to about 46%; from about 55% to about 45%; from about 56% to about 44%; from about 57% to about 43%; from about 58% to about 42%; from about 59% to about 41%; from about 60% to about 40%; from about 61% to about 39%; from about 62% to about 38%; from about 63% to about 37%; from about 64% to about 36%; from about 65% to about 35%; from about 66% to about 34%; from about 67% to about 33%; from about 68% to about 32%; from about 69% to about31%; from about 70% to about 30%; from about 71% to about 29%; from about 72% to about 28%; from about 73% to about 27%; from about 74% to about 26%; from about 75% to about 25%; from about 76% to about 24%; from about 77% to about 23%; from about 78% to about 22%; from about 79% to about 21%; from about 80% to about 20%; from about 81% to about 19%; from about 82% to about 18%; from about 83% to about 17%; from about 84% to about 16%; from about 85% to about 15%; from about 86% to about 14%; from about 87% to about 13%; from about 88% to about 12%; from about 89% to about 11%; from about 90% to about 10%; from about 91% to about 9%; from about 92% to about 8%; from about 93% to about 7%; from about 94% to about 6%; from about 95% to about 5%; from about 96% to about 4%; from about 97% to about 3%; from about 98% to about 2%; from about 99% to about 1%; from about 99.91 to about 0.09%; from about 99.92 to about 0.08%; from about 99.93 to about 0.07%; from about 99.94 to about 0.06%; from about 99.95 to about 0.05%; from about 99.96 to about 0.04%; from about 99.97 to about 0.03%; from about 99.98 to about 0.02%; or from about 99.99 to about 0.01%, w / w of the total composition. [000266] In some embodiments, a pharmaceutical composition comprises a combination comprising a GLP-1 receptor agonist and a GC-C receptor agonist; and an excipient; wherein the concentration of the GLP-1 receptor agonist ranges from about 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%, 0.6%, 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%, 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%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% by weight of the total formulation. [000267] In some embodiments, a pharmaceutical composition comprises a combination comprising a GLP-1 receptor agonist and a GC-C receptor agonist and an excipient; wherein the amount of the GC-C receptor agonist ranges from about 0.000001% w / w to about 99.99999% w / w of the total composition, or from about 0.01% to about 99.99%; from about 0.02% to about 99.98%; from about 0.03% to about 99.97%; from about 0.04% to about 99.96%; from about 0.05% to about 99.95; from about 0.06% to about 99.94%; from about 0.07% to about 99.93%; from about 0.08% to about 99.92%; from about 0.09% to about 99.91%; from about 1% to about 99%; from about 2% to about 98%; from about 3% to about97%; from about 4% to about 96%; from about 5% to about 95%; from about 6% to about 94%; from about 7% to about 93%; from about 8% to about 92%; from about 9% to about 91%; from about 10% to about 90%; from about 11% to about 89%; from about 12% to about 88%; from about 13% to about 87%; from about 14% to about 86%; from about 15% to about 85%; from about 16% to about 84%; from about 17% to about 83%; from about 18% to about 82%; from about 19% to about 81%; from about 20% to about 80%; from about 21% to about 79%; from about 22% to about 78%; from about 23% to about 77%; from about 24% to about 76%; from about 25% to about 75%; from about 26% to about 74%; from about 27% to about 73%; from about 28% to about 72%; from about 29% to about 71%; from about 30% to about 70%; from about 31% to about 69%; from about 32% to about 68%; from about 33% to about 67%; from about 34% to about 66%; from about 35% to about 65%; from about 36% to about 64%; from about 37% to about 63%; from about 38% to about 62%; from about 39% to about 61%; from about 40% to about 60%; from about 41% to about 59%; from about 42% to about 58%; from about 43% to about 57%; from about 44% to about 56%; from about 45% to about 55%; from about 46% to about 54%; from about 47% to about 53%; from about 48% to about 52%; from about 49% to about 51%; from about 50% to about 50%; from about 51% to about 49%; from about 52% to about 48%; from about 53% to about 47%; from about 54% to about 46%; from about 55% to about 45%; from about 56% to about 44%; from about 57% to about 43%; from about 58% to about 42%; from about 59% to about 41%; from about 60% to about 40%; from about 61% to about 39%; from about 62% to about 38%; from about 63% to about 37%; from about 64% to about 36%; from about 65% to about 35%; from about 66% to about 34%; from about 67% to about 33%; from about 68% to about 32%; from about 69% to about 31%; from about 70% to about 30%; from about 71% to about 29%; from about 72% to about 28%; from about 73% to about 27%; from about 74% to about 26%; from about 75% to about 25%; from about 76% to about 24%; from about 77% to about 23%; from about 78% to about 22%; from about 79% to about 21%; from about 80% to about 20%; from about 81% to about 19%; from about 82% to about 18%; from about 83% to about 17%; from about 84% to about 16%; from about 85% to about 15%; from about 86% to about 14%; from about 87% to about 13%; from about 88% to about 12%; from about 89% to about 11%; from about 90% to about 10%; from about 91% to about 9%; from about 92% to about 8%; from about 93% to about 7%; from about 94% to about 6%; from about 95% to about 5%; from about 96% to about 4%; from about 97% to about 3%; from about 98% to about 2%; from about 99% to about 1%; from about 99.91 to about 0.09%; from about 99.92 to about 0.08%; from about 99.93 to about 0.07%; from about 99.94 to about 0.06%; from about 99.95 to about 0.05%; from about99.96 to about 0.04%; from about 99.97 to about 0.03%; from about 99.98 to about 0.02%; or from about 99.99 to about 0.01%, w / w of the total composition. [000268] In some embodiments, a pharmaceutical composition comprises a combination comprising a GLP-1 receptor agonist and a GC-C receptor agonist; and an excipient; wherein the concentration of the GC-C receptor agonist ranges from about 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%, 0.6%, 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%, 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%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% by weight of the total formulation. [000269] In some embodiments, a pharmaceutical composition comprises a combination comprising a GLP-1 receptor agonist and a GC-C receptor agonist; and an excipient; wherein the amount of the excipient ranges from about 0.000001% w / w to about 99.99999% w / w of the total composition, or from about 0.01% to about 99.99%; from about 0.02% to about 99.98%; from about 0.03% to about 99.97%; from about 0.04% to about 99.96%; from about 0.05% to about 99.95; from about 0.06% to about 99.94%; from about 0.07% to about 99.93%; from about 0.08% to about 99.92%; from about 0.09% to about 99.91%; from about 1% to about 99%; from about 2% to about 98%; from about 3% to about 97%; from about 4% to about 96%; from about 5% to about 95%; from about 6% to about 94%; from about 7% to about 93%; from about 8% to about 92%; from about 9% to about 91%; from about 10% to about 90%; from about 11% to about 89%; from about 12% to about 88%; from about 13% to about 87%; from about 14% to about 86%; from about 15% to about 85%; from about 16% to about 84%; from about 17% to about 83%; from about 18% to about 82%; from about 19% to about 81%; from about 20% to about 80%; from about 21% to about 79%; from about 22% to about 78%; from about 23% to about 77%; from about 24% to about 76%; from about 25% to about 75%; from about 26% to about 74%; from about 27% to about 73%; from about 28% to about 72%; from about 29% to about 71%; from about 30% to about 70%; from about 31% to about 69%; from about 32% to about 68%; from about 33% to about 67%; from about 34% to about 66%; from about 35% to about 65%; from about 36% to about 64%; from about 37% to about 63%; from about 38% to about 62%; from about 39% to about 61%; from about40% to about 60%; from about 41% to about 59%; from about 42% to about 58%; from about 43% to about 57%; from about 44% to about 56%; from about 45% to about 55%; from about 46% to about 54%; from about 47% to about 53%; from about 48% to about 52%; from about 49% to about 51%; from about 50% to about 50%; from about 51% to about 49%; from about 52% to about 48%; from about 53% to about 47%; from about 54% to about 46%; from about 55% to about 45%; from about 56% to about 44%; from about 57% to about 43%; from about 58% to about 42%; from about 59% to about 41%; from about 60% to about 40%; from about 61% to about 39%; from about 62% to about 38%; from about 63% to about 37%; from about 64% to about 36%; from about 65% to about 35%; from about 66% to about 34%; from about 67% to about 33%; from about 68% to about 32%; from about 69% to about 31%; from about 70% to about 30%; from about 71% to about 29%; from about 72% to about 28%; from about 73% to about 27%; from about 74% to about 26%; from about 75% to about 25%; from about 76% to about 24%; from about 77% to about 23%; from about 78% to about 22%; from about 79% to about 21%; from about 80% to about 20%; from about 81% to about 19%; from about 82% to about 18%; from about 83% to about 17%; from about 84% to about 16%; from about 85% to about 15%; from about 86% to about 14%; from about 87% to about 13%; from about 88% to about 12%; from about 89% to about 11%; from about 90% to about 10%; from about 91% to about 9%; from about 92% to about 8%; from about 93% to about 7%; from about 94% to about 6%; from about 95% to about 5%; from about 96% to about 4%; from about 97% to about 3%; from about 98% to about 2%; from about 99% to about 1%; from about 99.91 to about 0.09%; from about 99.92 to about 0.08%; from about 99.93 to about 0.07%; from about 99.94 to about 0.06%; from about 99.95 to about 0.05%; from about 99.96 to about 0.04%; from about 99.97 to about 0.03%; from about 99.98 to about 0.02%; or from about 99.99 to about 0.01%, w / w of the total composition. [000270] In some embodiments, a pharmaceutical composition comprises a combination comprising a GLP-1 receptor agonist and a GC-C receptor agonist; and an excipient; wherein the concentration of the excipient ranges from about 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%, 0.6%, 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%, 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%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% by weight of the total formulation.[000271] EXCIPIENTS[000272] In some embodiments, a pharmaceutical composition of the present disclosure can comprise, consist essentially of, or consist of, a combination comprising a GLP-1 receptor agonist and a GC-C receptor agonist, and one or more excipients.[000273] For example in some embodiments, an excipient can be pharmaceutically acceptable additive, carrier, surfactant, emulsifier, thickener, preservative, solvent, disintegrant, glidant, lubricant, diluent, filler, bulking agent, binder, emollient, stiffening agent, chelating agent, emulsifier, stabilizer, dispersing agent, suspending agent, antioxidant, antiseptic, and / or any combination thereof, that can be added to a pharmaceutical composition, preparation, and / or formulation, which may be usefill in achieving a desired modification to the characteristics of the pharmaceutical composition, preparation, and / or formulation. Such modifications include, but are not limited to, physical stability, chemical stability, therapeutic efficacy, and / or any combination thereof.[000274] In some embodiments, e.g., the excipient can be independently selected from thickeners, viscosity enhancing agents, bulking agents, mucoadhesive agents, penetration enhancers, buffers, preservatives, diluents, binders, lubricants, glidants, disintegrants, fillers, solubilizing agents, pH modifying agents, preservatives, stabilizing agents, anti-oxidants, wetting or emulsifying agents, suspending agents, pigments, colorants, isotonic agents, chelating agents, emulsifiers, and diagnostic agents.[000275] In other embodiments, each of the one or more pharmaceutically acceptable excipients can be independently selected from thickeners, viscosity enhancing agents, mucoadhesive agents, buffers, preservatives, diluents, binders, lubricants, glidants, disintegrants, and fillers.[000276] In some embodiments, each of the one or more pharmaceutically acceptable excipients can be independently selected from thickeners, viscosity enhancing agents, bulking agents, mucoadhesive agents, buffers, preservatives, and fillers.[000277] In some embodiments, each of the one or more pharmaceutically acceptable excipients can be independently selected from diluents, binders, lubricants, glidants, and disintegrants.[000278] Carriers [000279] In some embodiments, a pharmaceutical composition comprises a combination comprising a GLP-1 receptor agonist and a GC-C receptor agonist and a carrier.[000280] In some embodiments, a pharmaceutical composition comprises a combination of the present disclosure and a liquid carrier vehicle. [000281] In some embodiments, a pharmaceutical composition comprises a combination of the present disclosure and a liquid carrier vehicle, wherein the liquid carrier vehicle can be, by way of non-limiting example, purified water, propylene glycol, polyethyleneglycol, ethanol, 1-propanol, 2-propanol, 1-propen-3-ol (allyl alcohol), propylene glycol, glycerol, 2- methyl-2-propanol, formamide, methyl formamide, dimethyl formamide, ethyl formamide, diethyl formamide, acetamide, methyl acetamide, dimethyl acetamide, ethyl acetamide, diethyl acetamide, 2-pyrrolidone, N-methyl-2-pyrrolidone, N-ethyl-2-pyrrolidone, tetramethyl urea, 1,3-dimethyl-2-imidazolidinone, propylene carbonate, 1,2-butylene carbonate, 2,3-butylene carbonate, dimethyl sulfoxide, diethyl sulfoxide, hexamethyl phosphoramide, pyruvic aldehyde dimethylacetal, dimethylisosorbide and combinations thereof. [000282] In some embodiments, a pharmaceutical composition of the present disclosure comprising a liquid carrier may contain an amount of liquid carrier ranging from about 0.005 wt% to about 99 wt%. [000283] Surfactants and emulsifiers [000284] In some embodiments, a pharmaceutical composition comprises a combination of the present disclosure, and one or more surfactants and / or emulsifiers. [000285] In some embodiments, a pharmaceutical composition comprises a combination of the present disclosure, and one or more surfactants and / or emulsifiers, wherein the one or more surfactants and / or emulsifiers can include, by way of non-limiting example, mixtures of cetostearylic alcohol with sorbitan esterified with polyoxyethylenic fatty acids, polyoxyethylene fatty ethers, polyoxyethylene fatty esters, fatty acids, sulfated fatty acids, phosphated fatty acids, sulfosuccinates, amphoteric surfactants, non-ionic poloxamers, non- ionic meroxapols, petroleum derivatives, aliphatic amines, polysiloxane derivatives, sorbitan fatty acid esters, laureth-4, PEG-2 dilaurate, stearic acid, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, cocoamphopropionate, poloxamer 188, meroxapol 258, triethanolamine, dimethicone, polysorbate 60, sorbitan monostearate, pharmaceutically acceptable salts thereof, and combinations thereof. [000286] In some embodiments, a pharmaceutical composition of the present disclosure comprises a combination of the present disclosure, and a non-ionic surfactant. [000287] For example, in some embodiments, a pharmaceutical composition comprises a combination of the present disclosure, and a non-ionic surfactant, wherein the non-ionicsurfactant can be, by way of non-limiting example, phospholipids, polyoxyl 20 cetostearyl (cetomacrogol), polyoxyethylene 10 stearyl ether and other ceteareth ethers, alkyl poly(ethylene oxide), poloxamers, polysorbates, sodium dioctyl sulfosuccinate, Brij™-30 (Laureth-4), Brij™-58 (Ceteth-20) and Brij™-78 (Steareth-20), Brij™-721 (Steareth-21), Crillet-1 (Polysorbate 20), Crillet-2 (Polysorbate 40), Crillet-3 (Polysorbate 60), Crillet 45 (Polysorbate 80), Myrj-52 (PEG-40 Stearate), Myrj-53 (PEG-50 Stearate), Pluronic™ F77 (Poloxamer 217), Pluronic™ F87 (Poloxamer 237), Pluronic™ F98 (Poloxamer 288), Pluronic™ L62 (Poloxamer 182), Pluronic™ L64 (Poloxamer 184), Pluronic™ F68 (Poloxamer 188), Pluronic™ L81 (Poloxamer 231), Pluronic™ L92 (Poloxamer 282), Pluronic™ L101 (Poloxamer 331), Pluronic™ P103 (Poloxamer 333), Pluracare™ F 108 NF (Poloxamer 338), and Pluracare™ F 127 NF (Poloxamer 407) and combinations thereof. [000288] In some embodiments, a pharmaceutical composition comprises a combination of the present disclosure, and a cationic surfactant. [000289] For example, in some embodiments, a pharmaceutical composition comprises a combination of the present disclosure, and a cationic surfactant, wherein the cationic surfactant can be, by way of non-limiting example, benzalkonium chloride, benzethonium chloride, cetyl trimethylammonium bromide, hexadecyl trimethyl ammonium bromide, other alkyltrimethylammonium salts, cetylpyridinium chloride, polyethoxylated tallow, and combinations thereof. [000290] In some embodiments, a pharmaceutical composition of the present disclosure comprising a surfactant may contain an amount of surfactant ranging from about 0.005 wt% to about 99 wt%. [000291] Thickeners and the like [000292] In some embodiments, a pharmaceutical composition comprises a combination of the present disclosure, and a thickener. [000293] In some embodiments, a pharmaceutical composition comprises a combination of the present disclosure, and a thickener, wherein the thickener can be one or more of the following: natural polysaccharides, semi-synthetic polymers, synthetic polymers, and combinations thereof. Natural polysaccharides include, by way of non-limiting example, acacia, agar, alginates, carrageenan, guar, arabic, tragacanth gum, pectins, dextran, gellan and xanthan gums. [000294] In some embodiments, a pharmaceutical composition comprises a combination of the present disclosure, and a thickener, wherein the thickener can be one or more semi- synthetic polymers. Examples of semi-synthetic polymers include, by way of non-limitingexample, cellulose esters, modified starches, modified celluloses, carboxymethylcellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and hydroxypropyl methylcellulose.[000295] In some embodiments, a pharmaceutical composition comprises a combination of the present disclosure, and a thickener, wherein the thickener can be one or more synthetic polymers. Examples of synthetic polymers include, by way of non-limiting example, polyoxyalkylenes, polyvinyl alcohol, polyacrylamide, polyaciylates, carboxypolymethylene (carbomer), polyvinylpyrrolidone (povidones), polyvinylacetate, polyethylene glycols and poloxamer.[000296] In some embodiments, a pharmaceutical composition comprises a combination of the present disclosure, and a thickener, wherein the thickener can be one or more of the following: polyoxyethyleneglycol isostearate, cetyl alcohol, stearyl alcohol, Polyglycol 300 isostearate, propyleneglycol, collagen, gelatin, and fatty acids (e.g., lauric acid, myristic acid, palmitic acid, stearic acid, palmitoleic acid, linoleic acid, linolenic acid, oleic acid and the like).[000297] Examples of additional thickeners, viscosity enhancing agents, and mucoadhesive agents include without limitation: gums, e.g. xanthan gum, guar gum, locust bean gum, tragacanth gums, karaya gum, ghatti gum, cholla gum, psyllium seed gum and gum arabic; poly(carboxylic acid-containing) based polymers, such as poly (acrylic, maleic, itaconic, citraconic, hydroxyethyl methacrylic or methacrylic) acid which have strong hydrogen-bonding groups, or derivatives thereof such as salts and esters; cellulose derivatives, such as methyl cellulose, ethyl cellulose, methylethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl ethyl cellulose, carboxymethyl cellulose, hydroxypropylmethyl cellulose or cellulose esters or ethers or derivatives or salts thereof; clays such as manomorillonite clays, e.g. Veegun, attapulgite clay; polysaccharides such as dextran, pectin, amylopectin, agar, mannan or polygalactonic acid or starches such as hydroxypropyl starch or carboxymethyl starch; polypeptides such as casein, gluten, gelatin, fibrin glue; chitosan, e.g. lactate or glutamate or carboxymethyl chitin; glycosaminoglycans such as hyaluronic acid; metals or water soluble salts of alginic acid such as sodium alginate or magnesium alginate; schleroglucan; adhesives containing bismuth oxide or aluminum oxide; atherocollagen; polyvinyl polymers such as carboxyvinyl polymers; polyvinylpyrrolidone (povidone); polyvinyl alcohol; polyvinyl acetates, polyvinylmethyl ethers, polyvinyl chlorides, polyvinylidenes, and / or the like; polycarboxylated vinyl polymers such as polyacrylic acid as mentioned above; polysiloxanes;polyethers; polyethylene oxides and glycols; polyalkoxys and polyacrylamides and derivatives and salts thereof.[000298] In some embodiments, the thickener can be a cellulose derivative, e.g., methyl cellulose, ethyl cellulose, methylethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl ethyl cellulose, carboxymethyl cellulose, hydroxypropylmethyl cellulose or cellulose esters or ethers or derivatives or salts thereof (e.g., methyl cellulose); and polyvinyl polymers such as polyvinylpyrrolidone (povidone).[000299] In some embodiments, a pharmaceutical composition of the present disclosure comprising a thickener may contain an amount of thickener ranging from about 0.005 wt% to about 99 wt%.[000300] Preservatives[000301] In some embodiments, a pharmaceutical composition comprises a combination of the present disclosure, and one or more preservatives.[000302] In some embodiments, a pharmaceutical composition comprises a combination of the present disclosure, and one or more preservatives, wherein the one or more preservatives can include, by way of non-limiting example, parabens, ascorbyl palmitate, benzoic acid, butylated hydroxyanisole, butylated hydroxytoluene, chlorobutanol, ethylenediamine, ethylparaben, methylparaben, butyl paraben, propylparaben, monothioglycerol, phenol, phenylethyl alcohol, propylparaben, sodium benzoate, sodium propionate, sodium formaldehyde sulfoxy late, sodium metabisulfite, sorbic acid, sulfur dioxide, maleic acid, propyl gallate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, chlorhexidine acetate, chlorhexidine gluconate, sorbic acid, potassium sorbitol, chlorbutanol, phenoxyethanol, cetylpyridinium chloride, phenylmercuric nitrate, thiomersal, and combinations thereof.[000303] Examples of additional preservatives include without limitation: benzalkonium chloride, benzoxonium chloride, benzethonium chloride, cetrimide, sepazonium chloride, cetylpyridinium chloride, domiphen bromide (Bradosol®), thiomersal, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric borate, methylparaben, propylparaben, chlorobutanol, benzyl alcohol, phenyl ethyl alcohol, chlorohexidine, polyhexamethylene biguanide, sodium perborate, imidazolidinyl urea, sorbic acid, Purite®), Polyquart®), and sodium perborate tetrahydrate and the like.[000304] In some embodiments, the preservative is a paraben, or a pharmaceutically acceptable salt thereof. In some embodiments, the paraben is an alkyl substituted 4- hydroxybenzoate, or a pharmaceutically acceptable salt or ester thereof. In certainembodiments, the alkyl is a C1-C4 alkyl. In certain embodiments, the preservative is methyl 4-hydroxybenzoate (methylparaben), or a pharmaceutically acceptable salt or ester thereof, propyl 4-hydroxybenzoate (propylparaben), or a pharmaceutically acceptable salt or ester thereof, or a combination thereof.[000305] In some embodiments, a pharmaceutical composition of the present disclosure can comprise a preservative, wherein the preservative is methylparaben or propylparaben.[000306] In some embodiments, a pharmaceutical composition of the present disclosure comprising a preservative may contain an amount of preservative ranging from about 0.005 wt% to about 99 wt%.[000307] Buffers and pH modifiers[000308] In some embodiments, a pharmaceutical composition comprises a combination of the present disclosure, and a buffer or pH adjusting agent.[000309] In some embodiments, a pharmaceutical composition comprises a combination of the present disclosure, and a buffer or pH adjusting agent, wherein the buffer or pH adjusting agent can be: phosphoric acid, monobasic sodium or potassium phosphate, triethanolamine (TRIS), BICINE, HEPES, Trizma, glycine, histidine, arginine, lysine, asparagine, aspartic acid, glutamine, glutamic acid, carbonate, bicarbonate, potassium metaphosphate, potassium phosphate, monobasic sodium acetate, acetic acid, acetate, citric acid, sodium citrate anhydrous, sodium citrate dihydrate and combinations thereof.[000310] In some embodiments, an acid or a base is added to adjust the pH. Suitable acids or bases include, by way of non-limiting example, HCL, NaOH and KOH.[000311] Examples of buffers include without limitation: phosphate buffer system (sodium dihydrogen phosphate dehydrate, disodium phosphate dodecahydrate, bibasic sodium phosphate, anhydrous monobasic sodium phosphate), bicarbonate buffer system, and bisulfate buffer system.[000312] In some embodiments, a pharmaceutical composition of the present disclosure comprising a buffer may contain an amount of buffer ranging from about 0.005 wt% to about 99 wt%.[000313] Disintegrants[000314] In some embodiments, a pharmaceutical composition comprises a combination of the present disclosure, and a disintegrant.[000315] Examples of disintegrants include, without limitation: carmellose calcium, low substituted hydroxypropyl cellulose (L-HPC), carmellose, croscarmellose sodium, partially pregelatinized starch, dry starch, carboxymethyl starch sodium, crospovidone, polysorbate 80(polyoxyethylenesorbitan oleate), starch, sodium starch glycolate, hydroxypropyl cellulose pregelatinized starch, clays, cellulose, alginine, gums or cross linked polymers, such as crosslinked PVP (Polyplasdone XL from GAF Chemical Corp). In certain embodiments, the disintegrant is crospovidone.[000316] In some embodiments, a pharmaceutical composition of the present disclosure comprising a disintegrant may contain an amount of disintegrant ranging from about 0.005 wt% to about 99 wt%.[000317] Glidants and lubricants[000318] In some embodiments, a pharmaceutical composition comprises a combination of the present disclosure, and a glidant.[000319] In some embodiments, a pharmaceutical composition comprises a combination of the present disclosure, and a lubricant.[000320] In some embodiments, a pharmaceutical composition comprises a combination of the present disclosure, and a lubricant, wherein the lubricant can be, e.g., a natural or synthetic fat or oil (e.g., a tris-fatty acid glycerate and the like).[000321] In some embodiments, a pharmaceutical composition comprises a combination of the present disclosure, and a lubricant, wherein the lubricant can be glycerin (also called glycerine, glycerol, 1,2,3-propanetriol, and trihydroxypropane), polyethylene glycols (PEGs), polypropylene glycol, polyisobutene, polyethylene oxide, behenic acid, behenyl alcohol, sorbitol, mannitol, lactose, polydimethylsiloxane and combinations thereof.[000322] Examples of additional glidants and lubricants (aggregation inhibitors) include without limitation: talc, magnesium stearate, calcium stearate, colloidal silica, stearic acid, aqueous silicon dioxide, synthetic magnesium silicate, fine granulated silicon oxide, starch, sodium laurylsulfate, boric acid, magnesium oxide, waxes, hydrogenated oil, polyethylene glycol, sodium benzoate, stearic acid glycerol behenate, polyethylene glycol, and mineral oil. In certain embodiments, the glidant / lubricant is magnesium stearate, talc, and / or colloidal silica; e.g., magnesium stearate and / or talc.[000323] In some embodiments, a pharmaceutical composition of the present disclosure comprising a glidant may contain an amount of glidant ranging from about 0.005 wt% to about 99 wt%.[000324] Diluents, fillers, and bulking agents[000325] In some embodiments, a pharmaceutical composition comprises a combination of the present disclosure, and a diluent.[000326] In some embodiments, a pharmaceutical composition comprises a combination of the present disclosure, and a filler.[000327] In some embodiments, a pharmaceutical composition comprises a combination of the present disclosure, and a bulking agent.[000328] Examples of diluents, also referred to as "fillers” or “bulking agents” include without limitation: dicalcium phosphate dihydrate, calcium sulfate, lactose (e.g., lactose monohydrate), sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starches, pregelatinized starch, silicone dioxide, titanium oxide, magnesium aluminum silicate and powdered sugar. In certain embodiments, the diluent is lactose (e.g., lactose monohydrate).[000329] In some embodiments, a pharmaceutical composition of the present disclosure comprising a diluent may contain an amount of diluent ranging from about 0.005 wt% to about 99 wt%.[000330] Binders[000331] In some embodiments, a pharmaceutical composition comprises a combination of the present disclosure, and a binder.[000332] Examples of binders include without limitation: starch, pregelatinized starch, gelatin, sugars (including sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycol, waxes, natural and synthetic gums such as acacia tragacanth, sodium alginate cellulose, including hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, and veegum, and synthetic polymers such as acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid / polymethacrylic acid and polyvinylpyrrolidone (povidone). In certain embodiments, the binder is polyvinylpyrrolidone (povidone).[000333] In some embodiments, a pharmaceutical composition of the present disclosure comprising a binder may contain an amount of binder ranging from about 0.005 wt% to about 99 wt%.[000334] Emollients[000335] In some embodiments, a pharmaceutical composition of the present disclosure can comprise an emollient.[000336] In some embodiments, a pharmaceutical composition of the present disclosure can comprise an emollient such as lanolin alcohol, lanolin, lanolin derivatives, cholesterol, petrolatum, isostearyl neopentanoate and mineral oils.[000337] In some embodiments, a pharmaceutical composition of the present disclosure can comprise an emollient such as mineral oil, mixtures of mineral oil and lanolin alcohols, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, petrolatum, petrolatum and lanolin alcohols, cetyl esters wax, cholesterol, glycerin, glyceryl monostearate, isopropyl myristate, isopropyl palmitate, lecithin, allyl caproate, althea officinalis extract, arachidyl alcohol, argobase EUC, Butylene glycol dicaprylate / dicaprate, acacia, allantoin, carrageenan, cetyl dimethicone, cyclomethicone, diethyl succinate, dihydroabietyl behenate, dioctyl adipate, ethyl laurate, ethyl palm itate, ethyl stearate, isoamyl laurate, octanoate, PEG-75 lanolin, sorbitan laurate, walnut oil, wheat germ oil super refined almond, super refined sesame, super refined soybean, octyl palmitate, caprylic / capric triglyceride and glyceryl cocoate. [000338] Examples of emollients are well known in the art. Additional examples of emollients include, without limitation, triglyceride esters, fatty acid esters and amides, waxes such as beeswax, spermaceti, or carnauba wax, phospholipids such as lecithin, and sterols and fatty acid esters thereof. [000339] In some embodiments, a pharmaceutical composition of the present disclosure can comprise an emollient, wherein the emollient is white petrolatum, or white wax. [000340] In some embodiments, a pharmaceutical composition of the present disclosure comprising an emollient may contain an amount of emollient, ranging from about 0.005 wt% to about 99 wt%. [000341] Stiffening agents [000342] In some embodiments, a pharmaceutical composition of the present disclosure can comprise a stiffening agent, e.g., an agent capable of stiffening a formulation of the present disclosure, for example, by increasing the viscosity of the formulation. [000343] In some embodiments, a pharmaceutical composition of the present disclosure can comprise a stiffening agent, e.g., stearyl alcohol, cetostearyl alcohol, polyoxylene (10) stearyl ether, mono- or diglycerides, and / or cetyl alcohol. [000344] In some embodiments, a pharmaceutical composition of the present disclosure comprising an stiffening agent may contain an amount of stiffening agent, ranging from about 0.005 wt% to about 99 wt%. [000345] Chelating agents [000346] In some embodiments, a pharmaceutical composition of the present disclosure can comprise a chelating agent. [000347] Exemplary chelating agents include, without limitation, ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate,disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof.[000348] In some embodiments, a pharmaceutical composition of the present disclosure can comprise a chelating agent, wherein the chelating agent is disodium EDTA.[000349] In some embodiments, a pharmaceutical composition of the present disclosure comprising a chelating agent may contain an amount of chelating agent ranging from about 0.005 wt% to about 99 wt%.[000350] Emulsifiers[000351] In some embodiments, a pharmaceutical composition of the present disclosure can comprise an emulsifier.[000352] In some embodiments, a pharmaceutical composition of the present disclosure can comprise an emulsifier such as nonionic, anionic, cationic, amphoteric, polymeric, synthetic emulsifiers, and / or mixtures thereof.[000353] In some embodiments, the emulsifier can comprise a polysorbate, an alkyl sulfate, Lipowax® D, or combinations thereof. Suitable polysorbate compounds include, polysorbate 20, 40, 60, 80, or combinations thereof, such as Tween® 20, 40, 60, 80, or combinations thereof.[000354] In some embodiments, the emulsifier can comprise natural emulsifiers, such as acacia, gelatin, lecithin and cholesterol; finely dispersed solids, such as colloidal clays, bentonite, veegum (magnesium aluminum silicate; and synthetic emulsifiers, such as salts of fatty acids, sulfates such as sorbitan trioleate, sorbitan tristearate, sucrose distearate, propylene glycol monostearate, glycerol monostearate, propylene glycol monolaurate, sorbitan monostearate, sorbitan monolaurate, polyoxyethylene-4-lauryl ether, sodium lauryl sulfate, sulfonates such as dioctyl sodium sulfosuccinate, glyceryl esters, polyoxyethylene glycol esters and ethers, diethylene glycol monostearate, PEG 200 distearate, and sorbitan fatty acid esters, such as sorbitan monopalmitate, and their polyoxyethylene derivatives, polyoxyethylene glycol esters such as the monostearate, Polysorbate 80 (ethoxylated sorbitan monooleate) (supplied by Spectrum, etc.); and combinations thereof.[000355] In some embodiments, a pharmaceutical composition of the present disclosure can comprise stearyl alcohol.[000356] In some embodiments, a pharmaceutical composition of the present disclosure can comprise emulsifying wax.[000357] In some embodiments, a pharmaceutical composition of the present disclosure comprising an emulsifier may contain an amount of emulsifier ranging from about 0.005 wt% to about 99 wt%.[000358] FORMULATIONS AND ROUTES OF ADMINISTRATION[000359] In some embodiments, the peptides described herein, or a pharmaceutical composition thereof, can be formulated into a variety of forms for delivery to subject in need thereof by any accepted route of administration.[000360] Oral use formulations[000361] In some embodiments, the combinations of the present disclosure or a pharmaceutical composition comprising the same, may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs).[000362] In some embodiments, compositions intended for oral use may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions and may contain one or more agents selected from the group of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.[000363] In some embodiments, the composition may be prepared in a tablet form. In some embodiments, tablets contain the active ingredient in admixture with suitable non-toxic pharmaceutically acceptable excipients including, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as com starch, or alginic acid; binding agents, such as starch, gelatine or acacia, and lubricating agents, such as magnesium stearate, stearic acid or talc. The tablets can be uncoated, or they may be coated by known techniques in order to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.[000364] In some embodiments, compositions of the present disclosure for oral use may also be presented as hard gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin or olive oil.[000365] In some embodiments, the compounds of the present disclosure may be presented in an aqueous suspension. Aqueous suspensions can comprise, consist essentiallyof, or consist of, one or more of the active compounds in admixture with suitable excipients including, for example, suspending agents, such as sodium carboxymethylcellulose, methyl cellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example, polyoxyethyene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, hepta-decaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol for example, polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example, polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxy -benzoate, one or more coloring agents, one or more flavoring agents or one or more sweetening agents, such as sucrose or saccharin.[000366] In some embodiments, the compounds of the present disclosure may be presented in an oily suspension. Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example, beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and / or flavoring agents may be added to provide palatable oral preparations. These compositions can be preserved by the addition of an anti-oxidant such as ascorbic acid. [000367] In some embodiments, the compounds of the present disclosure may be presented as a dispersible powder. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active compound in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.[000368] In some embodiments, compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, for example, olive oil or arachis oil, or a mineral oil, for example, liquid paraffin, or it may be a mixture of these oils. Suitable emulsifying agents may be naturally-occurring gums, for example, gum acacia or gum tragacanth; naturally-occurring phosphatides, for example, soy bean, lecithin; or esters or partial esters derived from fatty acids and hexitol, anhydrides, for example, sorbitan monoleate, and condensation products of the said partial esters with ethylene oxide,for example, polyoxyethylene sorbitan monoleate. The emulsions may also contain sweetening and flavoring agents. [000369] In some embodiments, the compounds of the present disclosure may be in a syrup or elixir form. Syrups and elixirs may be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, and / or flavoring and coloring agents. [000370] For oral application, particularly suitable are tablets, dragees, liquids, drops, suppositories, or capsules, caplets and gelcaps. The compositions intended for oral use may be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically excipients that are suitable for the manufacture of tablets. Such excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate. The tablets may be uncoated or they may be coated by known techniques for elegance or to delay the release of the active ingredients. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent. [000371] For oral administration, the compounds of the present disclosure may be in the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., polyvinylpyrrolidone, hydroxypropylcellulose or hydroxypropylmethylcellulose); fillers (e.g., cornstarch, lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrates (e.g., sodium starch glycollate); or wetting agents (e.g., sodium lauryl sulfate). If desired, the tablets may be coated using suitable methods and coating materials such as OPADRY™ film coating systems available from Colorcon, West Point, PA. (e.g., OPADRY™ OY Type, OYC Type, Organic Enteric OY-P Type, Aqueous Enteric OY-A Type, OY-PM Type and OPADRY™ White, 32K18400). Liquid preparation for oral administration may be in the form of solutions, syrups or suspensions. The liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agent (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxy benzoates or sorbic acid). [000372] Granulating techniques are well known in the pharmaceutical art for modifying starting powders or other particulate materials of an active ingredient. The powders are typically mixed with a binder material into larger permanent free-flowingagglomerates or granules referred to as a “granulation.” For example, solvent-using “wet” granulation processes are generally characterized in that the powders are combined with a binder material and moistened with water or an organic solvent under conditions resulting in the formation of a wet granulated mass from which the solvent must then be evaporated. [000373] Melt granulation generally consists in the use of materials that are solid or semi -solid at room temperature (i.e. having a relatively low softening or melting point range) to promote granulation of powdered or other materials, essentially in the absence of added water or other liquid solvents. The low melting solids, when heated to a temperature in the melting point range, liquefy to act as a binder or granulating medium. The liquefied solid spreads itself over the surface of powdered materials with which it is contacted, and on cooling, forms a solid granulated mass in which the initial materials are bound together. The resulting melt granulation may then be provided to a tablet press or be encapsulated for preparing the oral dosage form. Melt granulation improves the dissolution rate and bioavailability of an active (i.e. drug) by forming a solid dispersion or solid solution. [000374] U.S. Pat. No. 5,169,645 discloses directly compressible wax-containing granules having improved flow properties. The granules are obtained when waxes are admixed in the melt with certain flow improving additives, followed by cooling and granulation of the admixture. In certain embodiments, only the wax itself melts in the melt combination of the wax(es) and additives(s), and in other cases both the wax(es) and the additives(s) melt.[000375] The present disclosure also includes a multi-layer tablet comprising a layer providing for the delayed release of one or more compounds of the present disclosure, and a further layer providing for the immediate release of a medication for treatment of G-protein receptor-related diseases or disorders. Using a wax / pH-sensitive polymer mix, a gastric insoluble composition may be obtained in which the active ingredient is entrapped, ensuring its delayed release.[000376] In some embodiments, an oral use formulation may contain an amount of a combination of the present disclosure, or a pharmaceutically acceptable salt thereof, ranging from about 0.005 wt% to about 99 wt%.[000377] Injectable suspensions[000378] In some embodiments, the compounds of the present disclosure may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to known art using suitable dispersing or wetting agents and suspending agents such as those mentioned above. The sterile injectable preparation may also be sterileinjectable solution or suspension in anon-toxic parentally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Acceptable vehicles and solvents that may be employed include, but are not limited to, water, Ringer’s solution, lactated Ringer’s solution and isotonic sodium chloride solution. Other examples are, sterile, fixed oils which are conventionally employed as a solvent or suspending medium, and a variety of bland fixed oils including, for example, synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.[000379] In some embodiments, an injectable suspension may contain an amount of a combination of the present disclosure, or a pharmaceutically acceptable salt thereof, ranging from about 0.005 wt% to about 99 wt%.[000380] Topical use formulations[000381] In some embodiments, the compositions of the present disclosure may be in a form suitable for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions).[000382] The topical compositions of the present disclosure can be formulated in one embodiment as oils, creams, lotions, ointments and the like by choice of appropriate carriers. Suitable carriers include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats and high molecular weight alcohol (greater than Cl 2). The carriers may be those in which the active ingredient is soluble. Emulsifiers, stabilizers, humectants and antioxidants may also be included as well as agents imparting color or fragrance, if desired. Additionally, transdermal penetration enhancers can be employed in these topical formulations. Examples of such enhancers can be found in U.S. Pat. Nos. 3,989,816 and 4,444,762; each herein incorporated by reference in its entirety.[000383] Ointments may be formulated by mixing a solution of the active ingredient in a vegetable oil such as almond oil with warm soft paraffin and allowing the mixture to cool. A typical example of such an ointment is one which includes about 30% almond oil and about 70% white soft paraffin by weight. Lotions may be conveniently prepared by dissolving the active ingredient, in a suitable high molecular weight alcohol such as propylene glycol or polyethylene glycol.[000384] In some embodiments, a topical use formulation may contain an amount of a combination of the present disclosure, or a pharmaceutically acceptable salt thereof, ranging from about 0.005 wt% to about 99 wt%.[000385] Inhalation formulations[000386] In some embodiments, the compositions of the present disclosure may be in a form suitable for administration by' inhalation (for example as a finely divided powder or a liquid aerosol).[000387] In some embodiments, an inhalation formulation may contain an amount of a combination of the present disclosure, or a pharmaceutically acceptable salt thereof, ranging from about 0.005 wt% to about 99 wt%.[000388] Insufflation formulations[000389] In some embodiments, the compositions of the present disclosure may be in a form suitable for administration by insufflation (for example as a finely divided powder). [000390] In some embodiments, an insufflation formulation may contain an amount of a combination of the present disclosure, or a pharmaceutically acceptable salt thereof, ranging from about 0.005 wt% to about 99 wt%.[000391] Parenteral use formulations[000392] In some embodiments, the compositions of the present disclosure may be in a form suitable for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).[000393] In some embodiments, the compositions of the present disclosure may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.[000394] In some embodiments, a parenteral use formulation may contain an amount of a combination of the present disclosure, or a pharmaceutically acceptable salt thereof, ranging from about 0.005 wt% to about 99 wt%.[000395] Controlled release formulations and drug delivery systems[000396] In some embodiments, the formulations of the present disclosure may be immediate release. Conventional dosage forms generally provide rapid or immediate drug release from the formulation. Depending on the pharmacology and pharmacokinetics of the drug, use of conventional dosage forms can lead to wide fluctuations in the concentrations of the drug in a patient's blood and other tissues. These fluctuations can impact a number of parameters, such as dose frequency, onset of action, duration of efficacy, maintenance of therapeutic blood levels, toxicity, side effects, and the like. Advantageously, controlled- release formulations can be used to control a drug’s onset of action, duration of action, plasma levels within the therapeutic window, and peak blood levels. In particular, controlled- or extended-release dosage forms or formulations can be used to ensure that the maximumeffectiveness of a drug is achieved while minimizing potential adverse effects and safety concerns, which can occur both from under-dosing a drug (i.e., going below the minimum therapeutic levels) as well as exceeding the toxicity level for the drug. In some embodiments, the composition can be administered in a sustained release formulation.[000397] Controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled release counterparts. Ideally, the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time. Advantages of controlled-release formulations include: 1) extended activity of the drug; 2) reduced dosage frequency; 3) increased patient compliance; 4) usage of less total drug; 5) reduction in local or systemic side effects; 6) minimization of drug accumulation; 7) reduction in blood level fluctuations; 8) improvement in efficacy of treatment; 9) reduction of potentiation or loss of drug activity; and 10) improvement in speed of control of diseases or conditions. See Kim, Chemg-ju, Controlled Release Dosage Form Design, 2 (Technomic Publishing, Lancaster, Pa.: 2000), the disclosure of which is incorporated herein by reference in its entirety.[000398] Most controlled-release formulations are designed to initially release an amount of drug (active ingredient) that promptly produces the desired therapeutic effect, and gradually and continually release other amounts of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body. Controlled-release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, ionic strength, osmotic pressure, temperature, enzymes, water, and other physiological conditions or compounds.[000399] In some embodiments, the formulations of the present disclosure may be, but are not limited to, short-term, rapid-offset, as well as controlled, for example, sustained release, delayed release and pulsatile release formulations.[000400] The term sustained release is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that may, although not necessarily, result in substantially constant blood levels of a drug over an extended time period. The period of time may be as long as a month or more and should be a release which is longer that the same amount of agent administered in bolus form.[000401] For sustained release, the compounds may be formulated with a suitable polymer or hydrophobic material which provides sustained release properties to the compounds. As such, the compounds for use the method of the present disclosure may be administered in the form of microparticles, for example, by injection or in the form of wafers or discs by implantation.[000402] In one embodiment of the present disclosure, the compounds of the present disclosure are administered to a patient, alone or in combination with another pharmaceutical agent, using a sustained release formulation.[000403] The term delayed release is used herein in its conventional sense to refer to a drug formulation that provides for an initial release of the drug after some delay following drug administration and that mat, although not necessarily, includes a delay of from about 10 minutes up to about 12 hours.[000404] The term pulsatile release is used herein in its conventional sense to refer to a drug formulation that provides release of the drug in such a way as to produce pulsed plasma profiles of the drug after drug administration.[000405] The term immediate release is used in its conventional sense to refer to a drug formulation that provides for release of the drug immediately after drug administration.[000406] As used herein, short-term refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes and any or all whole or partial increments thereof after drug administration after drug administration.[000407] As used herein, rapid-offset refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes, and any and all whole or partial increments thereof after drug administration.[000408] A variety of known controlled- or extended-release dosage forms, formulations, and devices can be adapted for use with the salts and compositions of the disclosure. Examples include, but are not limited to, those described in U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,733,566; and 6,365,185; the disclosures of which are incorporated herein by reference in their entireties. These dosage forms can be used to provide slow or controlled-release of one or more active ingredients using, for example, hydroxypropylmethyl cellulose, other polymer matrices, gels, permeablemembranes, osmotic systems (such as OROS® (Alza Corporation, Mountain View, Calif. USA)), or a combination thereof to provide the desired release profile in varying proportions. [000409] In some embodiments, a controlled release formulation may contain an amount of a combination of the present disclosure, or a pharmaceutically acceptable salt thereof, ranging from about 0.005 wt% to about 99 wt%.[000410] Liposomes[000411] In some embodiments, the present disclosure also provides for compositions comprising, consisting essentially of, or consisting of, one or more of the compounds described herein, associated with a liposomal-type vehicle, such as an artificial membrane vesicle (including a liposome, lipid micelle and the like), microparticle or microcapsule. [000412] In some embodiments, a liposome may contain an amount of a combination of the present disclosure, or a pharmaceutically acceptable salt thereof, ranging from about 0.005 wt% to about 99 wt%.[000413] Rectal administration: generally[000414] In some embodiments, the peptides of the present disclosure, or pharmaceutical compositions thereof, are suitable for local administration, e.g., local administration by way of topically administering the peptide of the present disclosure, or a pharmaceutical composition thereof, at a particular treatment site, (e.g., the digestive tract, the gastrointestinal (“GI”) tract) so as to provide local administration of the chemical entity to the area in need of treatment (e.g., GI tract). Examples of such compositions include, without limitation, compositions for rectal administration.[000415] In some embodiments, the peptides of the present disclosure, or pharmaceutical compositions thereof, are suitable for local administration to the GI tract.[000416] In some embodiments, the peptides of the present disclosure, or pharmaceutical compositions thereof, are suitable for local administration to one or more specific locations within the digestive or GI tract. For example, in some embodiments, at least some of the peptides of the present disclosure, or pharmaceutical compositions thereof, is present in the lower GI tract (e.g., the large intestine, e.g., the colon, e.g., the ascending colon and / or transverse colon and / or distal colon; or the small bowel).[000417] In some embodiments, at least some of the peptides of the present disclosure, or pharmaceutical compositions thereof, is present in the ascending colon and / or the transverse colon and / or the distal colon. Methods of said local administration can include, without limitation, rectal administration.[000418] In certain embodiments, the peptides of the present disclosure, or pharmaceutical compositions thereof, are suitable for local, topical administration to the digestive or GI tract, e.g., rectal administration. Rectal compositions include, without limitation, enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, and enemas (e.g., retention enemas).[000419] Pharmaceutically acceptable excipients usable in a pharmaceutical composition of the present disclosure formulated for rectal administration, e.g., such as a gel, cream, enema, rectal foam, or rectal suppository, include, without limitation, any one or more of cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (like PEG ointments), glycerine, glycerinated gelatin, hydrogenated vegetable oils, poloxamers, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol Vaseline, anhydrous lanolin, shark liver oil, sodium saccharinate, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxid SBN, vanilla essential oil, aerosol, parabens in phenoxyethanol, sodium methyl p-oxybenzoate, sodium propyl p- oxybenzoate, diethylamine, carbomers, carbopol, methyloxybenzoate, macrogol cetostearyl ether, cocoyl caprylocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy -metabisulfite, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methyl sulfonyl methane (MSM), lactic acid, glycine, vitamins, such as vitamin A and E and potassium acetate.[000420] Suppositories[000421] In certain embodiments, a pharmaceutical composition of the present disclosure can be formulated as suppositories,[000422] In some embodiments, suppositories can be prepared by mixing the peptides of the present disclosure, or pharmaceutical compositions thereof, with suitable non-irritating excipients or carriers.[000423] For example, in some embodiments, suppositories can be prepared by mixing the peptides of the present disclosure, or pharmaceutical compositions thereof, with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum and release the active compound.[000424] In some embodiments, a suppository formulation may contain an amount of a combination of the present disclosure, or a pharmaceutically acceptable salt thereof, ranging from about 0.001 wt% to about 5.00 wt%.[000425] Enema formulations and enema kits[000426] In some embodiments, a combination of the present disclosure, or a pharmaceutical composition thereof, can be formulated as an enema.[000427] In some embodiments, an enema formulation may contain an amount of a combination of the present disclosure, or a pharmaceutically acceptable salt thereof, ranging from about 0.001 wt% to about 5.00 wt%.[000428] In some embodiments, enema formulations containing the peptides of the present disclosure, or pharmaceutical compositions thereof, can be provided in “ready -to-use form.[000429] In some embodiments, enema formulations containing the peptides of the present disclosure, or pharmaceutical compositions thereof, are provided in one or more kits or packs.[000430] In certain embodiments, the kit or pack includes two or more separately contained / packaged components, e.g. two components, which, when mixed together, provide the desired formulation (e.g., as a suspension).[000431] In some embodiments, the present disclosure provides a two component system that includes a first component and a second component, wherein: (i) the first component (e.g., contained in a sachet) includes the peptide of the present disclosure (as described anywhere herein), and optionally one or more pharmaceutically acceptable excipients (e.g., together formulated as a solid preparation, e.g., together formulated as a wet granulated solid preparation); and (ii) the second component (e.g., contained in a vial or bottle) includes one or more liquids and optionally one or more other pharmaceutically acceptable excipients together forming a liquid carrier. Prior to use (e.g., immediately prior to use), the contents of (i) and (ii) are combined to form the desired enema formulation, e.g., as a suspension. In other embodiments, each of component (i) and (ii) is provided in its own separate kit or pack.[000432] In some embodiments, each of the one or more liquids is water, or a physiologically acceptable solvent, or a mixture of water and one or more physiologically acceptable solvents. Typical such solvents include, without limitation, water, glycerol, ethylene glycol, propylene glycol, polyethylene glycol and polypropylene glycol. In other embodiments, each of the one or more liquids is water. In other embodiments, each of the one or more liquids is an oil, e.g. natural and / or synthetic oils that are commonly used in pharmaceutical preparations.[000433] In some embodiments, each of the one or more pharmaceutically acceptable excipients can be independently selected from thickeners, viscosity enhancing agents, bulkingagents, mucoadhesive agents, penetration enhancers, buffers, preservatives, diluents, binders, lubricants, glidants, disintegrants, fillers, solubilizing agents, pH modifying agents, preservatives, stabilizing agents, anti-oxidants, wetting or emulsifying agents, suspending agents, pigments, colorants, isotonic agents, chelating agents, emulsifiers, and diagnostic agents.[000434] In some embodiments, each of the one or more pharmaceutically acceptable excipients can be independently selected from thickeners, viscosity enhancing agents, mucoadhesive agents, buffers, preservatives, diluents, binders, lubricants, glidants, disintegrants, and fillers.[000435] In some embodiments, each of the one or more pharmaceutically acceptable excipients can be independently selected from thickeners, viscosity enhancing agents, bulking agents, mucoadhesive agents, buffers, preservatives, and fillers.[000436] In some embodiments, each of the one or more pharmaceutically acceptable excipients can be independently selected from diluents, binders, lubricants, glidants, and disintegrants.[000437] Exemplary thickeners, viscosity enhancing agents, and mucoadhesive agents, for enema formulations, include without limitation: gums, e.g. xanthan gum, guar gum, locust bean gum, tragacanth gums, karaya gum, ghatti gum, cholla gum, psyllium seed gum and gum arabic; poly(carboxylic acid-containing) based polymers, such as poly (acrylic, maleic, itaconic, citraconic, hydroxyethyl methacrylic or methacrylic) acid which have strong hydrogen-bonding groups, or derivatives thereof such as salts and esters; cellulose derivatives, such as methyl cellulose, ethyl cellulose, methylethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl ethyl cellulose, carboxymethyl cellulose, hydroxypropylmethyl cellulose or cellulose esters or ethers or derivatives or salts thereof; clays such as manomorillonite clays, e.g. Veegun, attapulgite clay; polysaccharides such as dextran, pectin, amylopectin, agar, mannan or polygalactonic acid or starches such as hydroxypropyl starch or carboxymethyl starch; polypeptides such as casein, gluten, gelatin, fibrin glue; chitosan, e.g. lactate or glutamate or carboxymethyl chitin; glycosaminoglycans such as hyaluronic acid; metals or water soluble salts of alginic acid such as sodium alginate or magnesium alginate; schleroglucan; adhesives containing bismuth oxide or aluminum oxide; atherocollagen; polyvinyl polymers such as carboxyvinyl polymers; polyvinylpyrrolidone (povidone); polyvinyl alcohol; polyvinyl acetates, polyvinylmethyl ethers, polyvinyl chlorides, polyvinylidenes, and / or the like; polycarboxylated vinyl polymers such as polyacrylic acid as mentioned above; polysiloxanes;polyethers; polyethylene oxides and glycols; polyalkoxys and polyacrylamides and derivatives and salts thereof. In some embodiments, examples can include cellulose derivatives, such as methyl cellulose, ethyl cellulose, methylethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl ethyl cellulose, carboxymethyl cellulose, hydroxypropylmethyl cellulose or cellulose esters or ethers or derivatives or salts thereof (e.g., methyl cellulose); and poly vinyl polymers such as polyvinylpyrrolidone (povidone).[000438] Exemplary preservatives for enema formulations, include without limitation: benzalkonium chloride, benzoxonium chloride, benzethonium chloride, cetrimide, sepazonium chloride, cetylpyridinium chloride, domiphen bromide (Bradosol®), thiomersal, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric borate, methylparaben, propylparaben, chlorobutanol, benzyl alcohol, phenyl ethyl alcohol, chlorohexidine, polyhexamethylene biguanide, sodium perborate, imidazolidinyl urea, sorbic acid, Purite®), Poly quart®), and sodium perborate tetrahydrate and the like.[000439] In some embodiments, the preservative for an enema formulation is a paraben, or a pharmaceutically acceptable salt thereof. In some embodiments, the paraben is an alkyl substituted 4-hydroxybenzoate, or a pharmaceutically acceptable salt or ester thereof. In certain embodiments, the alkyl is a C1-C4 alkyl. In certain embodiments, the preservative is methyl 4-hydroxybenzoate (methylparaben), or a pharmaceutically acceptable salt or ester thereof, propyl 4-hydroxybenzoate (propylparaben), or a pharmaceutically acceptable salt or ester thereof, or a combination thereof.[000440] Exemplary buffers for enema formulations, include without limitation: phosphate buffer system (sodium dihydrogen phosphate dehydrate, disodium phosphate dodecahydrate, bibasic sodium phosphate, anhydrous monobasic sodium phosphate), bicarbonate buffer system, and bisulfate buffer system.[000441] Exemplary disintegrants for enema formulations include, without limitation: carmellose calcium, low substituted hydroxypropyl cellulose (L-HPC), carmellose, croscarmellose sodium, partially pregelatinized starch, dry starch, carboxymethyl starch sodium, crospovidone, polysorbate 80 (polyoxyethylenesorbitan oleate), starch, sodium starch glycolate, hydroxypropyl cellulose pregelatinized starch, clays, cellulose, algimne, gums or cross linked polymers, such as cross-linked PVP (Polyplasdone XL from GAF Chemical Corp).[000442] Exemplary glidants and lubricants (aggregation inhibitors) for enema formulations include without limitation: talc, magnesium stearate, calcium stearate, colloidalsilica, stearic acid, aqueous silicon dioxide, synthetic magnesium silicate, fine granulated silicon oxide, starch, sodium laurylsulfate, boric acid, magnesium oxide, waxes, hydrogenated oil, polyethylene glycol, sodium benzoate, stearic acid glycerol behenate, polyethylene glycol, and mineral oil. In certain embodiments, the glidant / lubricant is magnesium stearate, talc, and / or colloidal silica; e.g., magnesium stearate and / or talc. [000443] Exemplary diluents, also referred to as “fillers" or “bulking agents” for enema formulations, include without limitation: dicalcium phosphate dihydrate, calcium sulfate, lactose (e.g., lactose monohydrate), sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starches, pregelatinized starch, silicone dioxide, titanium oxide, magnesium aluminum silicate and powdered sugar. In certain embodiments, the diluent is lactose (e.g., lactose monohydrate).[000444] Exemplary binders for enema formulations, include without limitation: starch, pregelatinized starch, gelatin, sugars (including sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycol, waxes, natural and synthetic gums such as acacia tragacanth, sodium alginate cellulose, including hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, and veegum, and synthetic polymers such as acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid / polymethacrylic acid and polyvinylpyrrolidone (povidone). In certain embodiments, the binder is polyvinylpyrrolidone (povidone).[000445] Rectal Gels[000446] In some embodiments, the pharmaceutical compositions described herein are formulated as rectal gels.[000447] In some embodiments, the rectal gels are suitable for the regional or local non- systemic administration of one or more of the peptides of the present disclosure to the rectum and / or colon.[000448] In some embodiments, rectal gel formulations comprise a combination of the present disclosure, dissolved or suspended in a solvent / liquid carrier vehicle.[000449] In some embodiments, rectal gel formulations comprise a combination of the present disclosure, dissolved or suspended in a solvent / liquid carrier vehicle, and at least one thickening agents.[000450] In certain embodiments a rectal gel formulations can further comprise one or more of the following: a buffering agent(s), a preservative(s), and an antioxidant(s).[000451] In certain embodiments, rectal gels have gel-like consistencies but are sufficiently flowable so as to be capable of local or regional administration through a catheter, needle, syringe, or other comparable means of local or regional administration. [000452] In some embodiments, rectal gel formulation may contain an amount of a combination of the present disclosure, or a pharmaceutically acceptable salt thereof, ranging from about 0.001 wt% to about 5.00 wt%.[000453] Foams[000454] In some embodiments, a pharmaceutical composition of the present disclosure can be formulated as a foam or a mousse (e.g., a pharmaceutical rectal foam composition). [000455] As used herein, “foam" refers to a coarse dispersion of gas in liquid in which the volume of the gas is considerably larger than that of the liquid. Accordingly, a foam is a tightly packed aggregation of gas bubbles, separated from each other by thin films of liquid (lamellae). The existence and stability of a foam depends on a surface layer of solute molecules. At the surface of a liquid, molecules are in a state of dynamic equilibrium, in which the net attractive forces exerted by the bulk of the fluid cause molecules to move out of the surface; this motion is counterbalanced by ordinary diffusion back into the diluted surface layer. The equilibrium results in the surface layer being constantly less dense than the bulk fluid, which creates a state of tension at the surface. The tension can be somewhat relieved by adsorption of foreign molecules either out of the bulk solution, or out of the vapor phase. [000456] In some embodiments, a pharmaceutical composition of the present disclosure (e.g., a pharmaceutical rectal foam composition), can be formulated as a foam, wherein the foam may or may not be propellant-based (i.e., substantially propellant-free or propellant- free).[000457] In some embodiments, a pharmaceutical composition of the present disclosure (e.g., a pharmaceutical rectal foam composition), can further comprise one or more propellants as described herein.[000458] In some embodiments, the addition of propellants to a pharmaceutical composition of the present disclosure results in a foamable formulations via manual aeration. In some embodiments, the addition of one or more propellants to a pharmaceutical composition of the present disclosure can provide a more consistent delivery of the active agent. For example, addition of a propellant to a foamable formulation may be useful in producing metered dosing of the composition.[000459] Various properties of the pharmaceutical compositions formulated as a foam (e.g., a pharmaceutical rectal foam composition) described herein can be assessed by methodsknown in the art. For example, one or more properties of foam expansion, foam cling, foam inversion, foam density, and foam collapse, and can be assessed by methods known in the art.[000460] In some embodiments, a pharmaceutical composition formulated as a foam (e.g., a pharmaceutical rectal foam composition) will expand gradually and expand to a large volume such that it is uniformly distributed internally over the intended area of treatment.[000461] In some embodiments, a pharmaceutical composition formulated as a foam (e.g., a pharmaceutical rectal foam composition) exhibits good retention (“foam cling”).[000462] In some embodiments, a pharmaceutical composition formulated as a foam (e.g., a pharmaceutical rectal foam composition) exhibits superior foam inversion properties. Foam inversion is another measure of foam retention properties, e.g., cohesiveness and / or adhesiveness of the foam formulations.[000463] In some embodiments, a pharmaceutical composition formulated as a foam (e.g., a pharmaceutical rectal foam composition) exhibits good foam density. Foam densitycan be measured as the weight of foam per unit volume.[000464] In some embodiments, a pharmaceutical composition formulated as a foam (e.g., a pharmaceutical rectal foam composition) exhibits good foam collapse properties. In some embodiments, foam collapse is a measure of how quickly and for how long the active components of the foam formulation will come into contact with a locus to be treated or locus of administration (e.g. mucosa).[000465] Exemplary descriptions of foams and the properties thereof are described in U.S. Patent Nos. 10,092,588, and 11,103,454; the disclosures of which are incorporated herein by reference in their entireties.[000466] In some embodiments, the pharmaceutical compositions are formulated as rectal foams (e.g., a pharmaceutical rectal foam composition).[000467] In some embodiments, rectal foams are used for the rectal administration and for local or non-systemic delivery of the peptides of the present disclosure to the rectum and / or colon.[000468] In some embodiments, a pharmaceutical rectal foam composition comprises a combination of the present disclosure, dissolved or suspended in a liquid carrier vehicle.[000469] In some embodiments, a pharmaceutical rectal foam composition comprises a combination of the present disclosure, dissolved or suspended in a liquid carrier vehicle, and a surfactant / emulsifier with foaming properties.[000470] In some embodiments, a pharmaceutical rectal foam composition comprises a combination of the present disclosure, dissolved or suspended in a liquid carrier vehicle, and a surfactant / emulsifier with foaming properties, and a propellant (e.g., a propellant gas).[000471] In certain embodiments, a pharmaceutical rectal foam composition can comprise one or more of the following: a suspending / solubilizing agent, a thickener, a preservative, a chelating agent, a buffer, an antioxidant, a tonicity modifiers, and / or a spreading agent.[000472] In some embodiments, surfactants / emulsifiers include, by way of non-limiting example, non-ionic surfactants, anionic surfactants, cationic surfactants, and combinations thereof.[000473] In some embodiments, a rectal foam formulation may contain an amount of a combination of the present disclosure, or a pharmaceutically acceptable salt thereof, ranging from about 0.001 wt% to about 5.00 wt%.[000474] Foam propellants[000475] In some embodiments, pharmaceutical rectal foam compositions are filled in pressurized containers (e.g., a pressurized gas container such as an aerosol canister) prior to rectal administration. In some embodiments the pressurized gas container is a canister. In certain embodiments, propellants used herein include, by way of non-limiting example, hydrocarbons (such as isobutane, N-butane or propane), fluorocarbons (e.g. dichlorodifluoromethane and dichlorotetrafluoroethane), chlorofluorocarbons, dimethyl ether, hydrofluorocarbons, compressed gases, freon (such as freon 12, freon 114), hydrochlorofluorocarbons, hydrofluorocarbons or mixtures thereof.[000476] In some embodiments, the maximum amount of propellant used is determined by its miscibility with other components in the composition to form a mixture, such as a homogeneous mixture. In certain embodiments, the minimal level of propellant used in the composition is determined by the desired foam characteristics, and its ability to substantially or completely evacuate the container.[000477] In some embodiments, the propellant concentration used in a pharmaceutical rectal foam composition is about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 50%, 55% to about 60% (% w / w).[000478] In some embodiments, rectal foams are formed upon rectal administration, wherein the dispensing valve of the can allows rapid expansion of the propellant, triggering the foaming action of the surfactant and resulting foam forms within the rectum and colon. Inother embodiments, the rectal foams used for rectal administration of the compositions described herein are formed within the dispensing container prior to rectal administration. The distance the foam can reach within the colon and rectum is controlled by controlling the foam propelling properties by varying the type and quantity of propellant used.[000479] In some embodiments, a pharmaceutical rectal foam composition comprises a combination of the present disclosure, dissolved or suspended in a liquid carrier vehicle.[000480] In some embodiments, a pharmaceutical rectal foam composition comprises a combination of the present disclosure, dissolved or suspended in a liquid carrier vehicle, and a surfactant / emulsifier with foaming properties.[000481] In some embodiments, a pharmaceutical rectal foam composition comprises a combination of the present disclosure, dissolved or suspended in a liquid carrier vehicle, and a surfactant / emulsifier with foaming properties, and a propellant (e.g., a propellant gas).[000482] In certain embodiments, a pharmaceutical rectal foam composition can comprise one or more of the following: a suspending / solubilizing agent, a thickener, a preservative, a chelating agent, a buffer, an antioxidant, a tonicity modifiers, and / or a spreading agent.[000483] In some embodiments, surfactants / emulsifiers include, by way of non-limiting example, non-ionic surfactants, anionic surfactants, cationic surfactants, and combinations thereof.[000484] Canisters and other pressurized gas containers[000485] In some embodiments, a pharmaceutical composition of the present disclosure, formulated as a foam (e.g., a pharmaceutical rectal foam composition), can be provided in a container, e.g., a pressurized gas container. For example, in some embodiments, without limitation, the pharmaceutical composition formulated as a foam (e.g., a pharmaceutical rectal foam composition) can be provided in a canister, e.g., an aerosol canister.[000486] Thus, in some embodiments, a canister of the present disclosure comprises a pharmaceutical composition formulated as a foam (e.g., a pharmaceutical rectal foam composition).[000487] As used herein, an “aerosol” is a pressurized dosage form containing one or more active ingredients (e.g., a peptide of the present disclosure), and which upon actuation emits a dispersion of liquid and / or solid materials in a gaseous medium. In some embodiments, the dosage form is packaged under pressure in a suitable container equipped with a valve assembly. In some embodiments, when the valve is opened, the internal pressure within the container forces the aerosol out the valve.[000488] In some embodiments, a canister of the present disclosure is suitable for accommodating a pressurized product and comprises an outlet capable of releasing a foam.[000489] In some embodiments, a canister of the present disclosure is suitable for accommodating a pressurized product and comprises an outlet capable of releasing a foam; wherein the outlet is a valve.[000490] In some embodiments, a suitable pressurized gas container for the purposes of dispensing the pharmaceutical rectal foam composition of the present disclosure can be a cylindrical vessel comprising: metal (e.g., aluminum, tinplate, and the like), protected or shatter resistant glass, plastic, or shatter-proof glass. Those having ordinary skill in the art will recognize that the choice of pressurized gas container may depend on one or more factors, e.g., without limitation, the compressive strength and / or breaking strength, corrosion resistance, ease of filling, ease of sterilizing, aesthetic aspects, handle-ability, printing properties, and the like.[000491] In some embodiments, a pressurized gas container of the present disclosure is a canister.[000492] In some embodiments, a canister of the present disclosure comprises aluminum.[000493] In some embodiments, for reasons of corrosion protection, the interior of metal canisters can be coated. Corrosion-resistant coatings are known to those having ordinary skill in the art, and can include, e.g., polyester, epoxyphenol and polyamide-imide coatings; film laminates made of polyethylene (PE), polypropylene (PP) and / or polyethylene terephthalate (PET) and other corrosion-resistant coatings known in the art.[000494] In some embodiments, a pressurized gas container of the present disclosure (e.g., a canister) can be single-part or two-part, or three-part cylindrical, conical or differently shaped containers. If plastics are used as the container material, then these plastics should be resistant to chemicals and the sterilization temperature, gas-tight, impact-resistant and stable to internal pressures.[000495] In some embodiments, a pressurized gas container of the present disclosure (e.g., a canister) can comprise a valve. Valves which are advantageous according to the present disclosure are known by those having ordinary skill in the art.[000496] In some embodiments, a pressurized gas container of the present disclosure (e.g., a canister) comprises a spray head. Advantageous spray heads for the purposes of the present disclosure are, for example, foaming heads for upright use (e.g., when holding the canister vertically) or foam heads for overhead application using one or more channels.[000497] In some embodiments, a pressurized gas container of the present disclosure (e.g., a canister) comprises one or more propellants, e.g., one or more propellants as described herein, in addition the peptide of the present disclosure. Briefly, suitable propellants are described herein, and can include readily volatile, liquefied propellant gases, such as, e.g., dimethyl ether (DME) and / or linear or branched-chain hydrocarbons with two to five carbon atoms (such as, in particular, ethane, propane, butane, isobutane and / or pentane), which can be used on their own or in a mixture with one another. Exemplary propellants are described herein.[000498] In some embodiments, a pressurized gas container of the present disclosure (e.g., a canister) comprises compressed air, and also other gases which are under pressure, such as air, oxygen, nitrogen, hydrogen, helium, krypton, xenon, radon, argon, nitrous oxide and carbon dioxide. In some embodiments, said gases can in each case be used individually or in any desired mixtures with one another.[000499] In some embodiments, a pressurized gas container of the present disclosure (e.g., a canister) comprises a pharmaceutical rectal foam composition, wherein the foam is dispensed or provided as a finely creamy and / or rich foam. In some embodiments, a pressurized gas container of the present disclosure (e.g., a canister) can provide finely creamy and / or rich foams when the pharmaceutical rectal foam composition comprises linear or branched-chain, halogenated or nonhalogenated hydrocarbons and / or one or more gases selected from carbon dioxide, oxygen, compressed air and / or nitrogen.[000500] In some embodiments, a pressurized gas container of the present disclosure comprises a canister.[000501] In some embodiments, a pressurized gas container of the present disclosure comprises a canister and a valve.[000502] In some embodiments, a pressurized gas container of the present disclosure comprises a canister, a valve, and a foam shield.[000503] In some embodiments, a pressurized gas container of the present disclosure comprises a canister, a valve, and a foam shield, wherein the pharmaceutical rectal foam composition contained therein is presented as a multidose unit.[000504] In some embodiments, a pressurized gas container of the present disclosure comprises an aluminum aerosol canister.[000505] In yet other embodiments, a pressurized gas container of the present disclosure comprises an aluminum aerosol canister, a valve, a foam shield, and a metered head actuator.[000506] In some other embodiments, a pressurized gas container of the present disclosure comprises an aluminum aerosol canister, fitted with a 1-inch valve, a foam shield, and a 1.35 mL metered head actuator.[000507] In some embodiments, a pharmaceutical rectal foam composition is packaged in aerosol canisters which are crimped with a valve, pressurized with propellant and equipped with an actuator suitable for foam dispensing. In yet other embodiments, a metered dosage unit can utilized, to achieve delivery of repeatable measured doses of foam.[000508] In some embodiments, a pharmaceutical rectal foam composition is filled into an aerosol canister equipped with a metered dose valve. In the hands of the patient the a pharmaceutical rectal foam composition is dispensed via an actuator adapted to direct the dose from the valve to the patient.[000509] In some embodiments, a pharmaceutical rectal foam composition can be prepared by combining (i) the peptide of the present disclosure in an amount sufficient to provide a plurality of therapeutically effective doses; (ii) a fluid, e.g., a propellant, in an amount sufficient to propel a plurality of doses, e.g., from an aerosol canister; (iii) optionally, one or more excipients. In some embodiments, the components can be dispersed using a conventional mixer or homogenizer, by shaking, or by ultrasonic energy as well as by the use of a bead mill or a microfluidizer.[000510] In some embodiments, bulk formulations can be transferred to smaller individual aerosol vials by using valve to valve transfer methods, pressure filling or by using conventional cold-fill methods.[000511] Aerosol canisters equipped with conventional valves, preferably metered dose valves, can be used to deliver the pharmaceutical rectal foam of the present disclosure. In some embodiments, selection of appropriate valve assemblies for use with aerosol formulations is dependent upon the particular component and other adjuvants used (if any), on the fluid, e.g., propellant, and on the particular drug being used. Conventional neoprene and buna valve rubbers used in metered dose valves for delivering conventional CFC formulations often have less than optimal valve delivery characteristics and ease of operation when used with formulations containing HFC-134a (1,1,1,2-tetrafluoroethane) or HFC-227 (1,1,1,2,3,3,3-heptafluoropropane). Therefore, certain formulations of the present disclosure are preferably dispensed via a valve assembly wherein the diaphragm is made of a nitrile rubber such as DB-218 (American Gasket and Rubber, Schiller Park, Ill.) or an EPDM rubber such as VISTALON synthetic rubber (Exxon), ROYALENE synthetic rubber (UniRoyal), bunaEP (Bayer). Also suitable are diaphragms fashioned by extrusion, injection, molding orcompression molding from a thermoplastic elastomeric material, such as FLEXOMER GERS 1085 NT polyolefin (Union Carbide).[000512] In some embodiments, conventional aerosol canisters, coated or uncoated, anodized or unanodized, e.g., those of aluminum, glass, stainless steel, polybutyl or polyethylene terephthalate, and coated canisters or cans with epon, epoxy, etc., can be used to contain a pharmaceutical rectal foam composition.[000513] In some embodiments, a pressurized gas container of the present disclosure comprises an aluminum aerosol canister, wherein the canister can be individually packaged in a carton and / or kit.[000514] In some embodiments, a canister of the present disclosure can comprise a minimum of about 20.0, 20.2, 20.4, 20.6, 20.8, 30.0, 30.2, 30.4, 30.6, 30.8, 31.0, 31.2, 31.4, 31.6, 31.8, 32.0, 35, or 45 grams of product, and about 2.0, 2.5, 2.6, 2.8, 3.0, 3.2, 3.4, 3.6, 3.8, 4, or 4.5 grams of propellant.[000515] Exemplary methods of preparing pressurized gas containers (e.g., aerosol canisters) are provided in U.S. Patent Nos. 2,968,628; 3,966,090; 3,970,219; 4,440,320; 6,875,438; 8,006,873; 9,668,972; 10,265,404; and 10,906,729; the disclosures of which are incorporated herein by reference in their entireties.[000516] Any of the combinations of the present disclosure can be provided in a pressurized gas container, e.g., a canister. For example, a combination comprising a GLP-1 receptor agonist, and aguanylate-cyclase C (GC-C) receptor agonist, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition, unit dosage form, or pharmaceutical rectal foam composition comprising the same, can be provided in a pressurized gas container (e.g., a canister).[000517] Non-pressurized containers[000518] In some embodiments, a pharmaceutical composition of the present disclosure may be formulated into products that can be dispensed as foams, which do not require the addition of a propellant.[000519] In some embodiments, a pharmaceutical composition of the present disclosure may be formulated into products that can be dispensed as foams from a reservoir using a release assembly (e.g., a hand pump) whenever the release assembly is put into action. The amount of the foam dispensed by the pump may or may not be metered to dispense a consistent amount of the foam. Preferably, the amount is metered to deliver a specific dose.[000520] Exemplary descriptions of foaming heads are provided in U.S. Patent Nos. 5,443,369; 6,053,364; and 7,757,899, the disclosures of which are incorporated herein by reference in their entireties.[000521] Exemplary descriptions of hand pumps, and other pumps useful in dispensing the pharmaceutical compositions of the present disclosure are provided in U.S. Patent Nos. 6,547,162; 7,147,133; 7,726,518; 7,673,854; and 7,735,692; the disclosures of which are incorporated herein by reference in their entireties.[000522] In some embodiments, the dispenser or pump head may include additional or altered features that assist in optimizing foam stability, especially for low-viscosity formulations. These features include, but are not limited to, the inclusion, arrangement, and hole size of meshes in the pump head; the size and shape of the mix chamber; and varied dip tube and nozzle lengths.[000523] In some embodiments, a pharmaceutical composition of the present disclosure may be formulated as a foam, wherein the foam is generated through mechanical aeration. For example, in some embodiments, a method for producing a foam of the present disclosure comprises: providing a dispenser comprising a reservoir operably linked (e.g., in fluid communication) with a release assembly (e.g., dispensing head); filling the reservoir of the dispensing system with a foamable formulation; and actuating the release assembly to manually aerate the formulation, thereby releasing a foam from the release assembly.[000524] In some embodiments, a pharmaceutical composition of the present disclosure may be formulated into products that can be dispensed as foams, which do not require the addition of a propellant (e.g., a non-aerosol formulation).[000525] In some embodiments, a non-aerosol formulation may be contained in a nonaerosol dispenser equipped with a conventional hand pump, and the composition may be pumped onto the hands or other areas of the body. The pumping action required to dispense the pharmaceutical compositions will create a discrete volume of a dispensed composition as a stable foam.[000526] Any of the combinations of the present disclosure can be provided in a pressurized gas container, e.g., a canister. For example, a combination comprising a GLP-1 receptor agonist, and a guanylate-cyclase C (GC-C) receptor agonist, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition, unit dosage form, or pharmaceutical rectal foam composition comprising the same, can be provided in a non-pressurized container.[000527] Other administration forms[000528] Additional dosage forms of the present disclosure include dosage forms as described in U.S. Patent Nos. 6,340,475; 6,488,962; 6,451,808; 5,972,389; 5,582,837; and 5,007,790; U.S. Patent Application Nos. 20030147952; 20030104062; 20030104053; 20030044466; 20030039688; and 20020051820; and PCT Application Nos. WO 03 / 35041; WO 03 / 35040; WO 03 / 35029; WO 03 / 35177; WO 03 / 35039; WO 02 / 96404; WO 02 / 32416; WO 01 / 97783; WO 01 / 56544; WO 01 / 32217; WO 98 / 55107; WO 98 / 11879; WO 97 / 47285; WO 93 / 18755; and WO 90 / 11757 , the disclosures of which are incorporated herein by reference in their entireties.[000529] Kits[000530] The present disclosure includes a variety of kits for conveniently and / or effectively carrying out methods of the present disclosure. Typically, kits will comprise sufficient amounts and / or numbers of components to allow a user to perform one or multiple treatments of a subject(s) and / or to perform one or multiple experiments.[000531] In some embodiments, the present disclosure provides kits for treating, limiting the symptoms of, reducing the severity of, or relieving any one or more side effects of GLP-1 receptor agonists, e.g., slowed gastric emptying; reduced appetite and / or food intake; decreased peptide hormone secretion (e.g., glucagon); slow gastrointestinal transit; constipation; and / or any abdominal pain associated thereof.[000532] In one embodiment, the present disclosure provides kits for treating, limiting the symptoms of, reducing the severity of, or relieving any one or more side effects of GLP-1 receptor agonists, in a subject in need thereof; wherein the side effect is selected from any one or more of: slowed gastric emptying; reduced appetite and / or food intake; decreased peptide hormone secretion (e.g., glucagon); slow gastrointestinal transit; constipation; and / or any abdominal pain associated thereof.[000533] In some embodiments, a kit may comprise packaging and instructions and / or a delivery agent to form a pharmaceutical composition of the present disclosure. The delivery agent may comprise, for example, one or more excipients.[000534] In some embodiments, a kit may comprise packaging and instructions and / or a device or delivery means to dispense a pharmaceutical composition of the present disclosure. For example, in some embodiments, a kit may comprise packaging, instructions, and a pressurized gas container (e.g., a canister) comprising a peptide of the present disclosure.[000535] In some embodiments, a kit comprises the means for preparing a reconstituted unit dose comprising, e.g., a lyophilized unit dose, and a pharmaceutically acceptable diluent for reconstitution.[000536] In additional embodiments, assay screening kits are provided. In some embodiments, a kit includes a container for the screening assay. In other embodiments, an instruction for the use of the assay and the information about the screening method are to be included in the kit.[000537] In some embodiments, a combination of the present disclosure, and / or a pharmaceutical composition of the present disclosure, can be packaged into an article of manufacture (i.e., a kit) using containers, vials, or the like. For example, an article of manufacture can include (i) a peptide of the present disclosure; and (ii) one or more excipients (ii). In addition, an article of manufacture also can include instructions for use. [000538] In some embodiments, a kit may further include a suitably aliquoted pharmaceutical composition, liquid pharmaceutical composition, or unit dosage form, and / or pharmaceutical rectal foam composition of the present disclosure. In addition, a pharmaceutical composition as described herein, and / or a peptide of the present disclosure, may be partially or wholly dehydrated or aqueous (where applicable). Kits contemplated herein may be stored at room temperatures or at refrigerated temperatures as disclosed herein depending on the particular formulation.[000539] In some embodiments, the container means of the kits will generally include at least one vial, test tube, flask, bottle, syringe, canister, or other container means, into which a pharmaceutical composition may be placed, and preferably, suitably aliquoted. Where an additional component is provided, the kit will also generally contain one or more additional containers into which this agent or component may be placed. Kits herein will also typically include a means for containing the agent, composition and any other reagent containers in close confinement for commercial sale. Such containers may include injection or blow- molded plastic containers into which the desired vials or canisters are retained.[000540] In some embodiments, the kit provides instructions for using the pharmaceutical composition of the kit, and / or one or more of the components of the kit. The instructions will generally include information about the use of the kit treatment of a subject in need thereof. In other embodiments, the instructions include at least one of the following: precautions; warnings; clinical studies; and / or references. The instructions may be printed directly on the container (when present), or as a label applied to the container, or as a separate sheet, pamphlet, card, or folder supplied in or with the container. In a further embodiment, a kit can comprise instructions in the form of a label or separate insert (package insert) for suitable operational parameters. In yet another embodiment, the kit can comprise one or more containers with appropriate positive and negative controls or control samples, to be used asstandards) for detection, calibration, or normalization. The kit can further comprise a second container comprising a pharmaceutically-acceptable excipient, e.g., a buffer. It can further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for use. [000541] In some embodiments, a kit contains a combination of the present disclosure as provided as a unit dosage form, wherein the unit dosage form comprises a combination of the present disclosure, or a pharmaceutically acceptable salt thereof; and one or more excipients.[000542] In some embodiments, a kit comprises a pharmaceutical rectal foam composition comprising a combination of the present disclosure, dissolved or suspended in a liquid carrier vehicle.[000543] In some embodiments, a kit comprises a pharmaceutical rectal foam composition comprising a combination of the present disclosure, dissolved or suspended in a liquid carrier vehicle, and a surfactant / emulsifier with foaming properties.[000544] In some embodiments, a kit comprises a pharmaceutical rectal foam composition comprising a combination of the present disclosure, dissolved or suspended in a liquid carrier vehicle, and a surfactant / emulsifier with foaming properties, and a propellant (e.g., a propellant gas).[000545] In some embodiments, a unit dosage form is suitable for rectal administration. In some embodiments, unit dosage forms suitable for rectal administration include, without limitation, the following: enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, and enemas (e.g., retention enemas).[000546] In some embodiments, unit dosage forms may be contained in a container e.g., without limitation, a paper or cardboard box, a glass or plastic bottle or jar, a re-sealable bag (for example, to hold a “refill” of tablets for placement into a different container), a blister pack with individual doses for pressing out of the pack according to a therapeutic schedule; or a pressurized gas container (e.g., rectal foam or rectal aerosol). It is feasible that more than one container can be used together in a single package to provide a single dosage form. For example, enemas or suppositories may be contained in a bottle which is in turn contained within a box. In some embodiments, the unit dosage forms are provided in a container further comprising a desiccant. In a further embodiment, the unit dosage forms are provided in a container, e.g., a bottle, jar or re-sealable bag, containing a desiccant. In a further embodiment, the container containing the unit dosage forms is packaged with administration or dosage instructions.[000547] In some embodiments, enema formulations containing the peptides of the present disclosure, or pharmaceutical compositions thereof, can be provided in “ready -to-use' form.[000548] In some embodiments, enema formulations containing the peptides of the present disclosure, or pharmaceutical compositions thereof, are provided in one or more kits or packs.[000549] In certain embodiments, the kit or pack includes two or more separately contained / packaged components, e.g. two components, which, when mixed together, provide the desired formulation (e.g., as a suspension).[000550] In some embodiments, the present disclosure provides a two component system that includes a first component and a second component, wherein: (i) the first component (e.g., contained in a sachet) includes the peptide of the present disclosure (as described anywhere herein), and optionally one or more pharmaceutically acceptable excipients (e.g., together formulated as a solid preparation, e.g., together formulated as a wet granulated solid preparation); and (ii) the second component (e.g., contained in a vial or bottle) includes one or more liquids and optionally one or more other pharmaceutically acceptable excipients together forming a liquid carrier. Prior to use (e.g., immediately prior to use), the contents of (i) and (ii) are combined to form the desired enema formulation, e.g., as a suspension. In other embodiments, each of component (i) and (ii) is provided in its own separate kit or pack.[000551] In some embodiments, it may be possible to ship a pharmaceutical composition of the present disclosure to the end-user as a kit comprising at least a first component comprising a combination of the present disclosure, or a pharmaceutically acceptable salt thereof (A); and a second component comprising at least one pharmaceutically acceptable excipient (B). Further additives (D) may be a third separate component of the kit, or may be already mixed with components (A) and / or (B). The end-user may prepare the formulation for use by just adding one or more liquids (e.g., water and / or other pharmaceutically acceptable liquid as described herein) (C) to the components of the kit and mixing. In some embodiments, the components of the kit may also be formulations in water. Of course it is possible to combine an aqueous formulation of one of the components with a dry formulation of the other component(s). As an example, the kit can comprise one formulation of a combination of the present disclosure, or a pharmaceutically acceptable salt thereof (A) and optionally water (C); and a second, separate formulation of at least one excipient (B), water as component (C) and other optional additional components (D). Theconcentrations of the components (A), (B), (C) and optionally (D) will be selected by the skilled artisan depending on the formulation and / or the technique to be used for treatment. [000552] In some embodiments, each of the one or more liquids (C) is water, or a physiologically acceptable solvent, or a mixture of water and one or more physiologically acceptable solvents. Typical such solvents include, without limitation, water, glycerol, ethylene glycol, propylene glycol, polyethylene glycol and polypropylene glycol. In other embodiments, each of the one or more liquids is water. In other embodiments, each of the one or more liquids is an oil, e.g. natural and / or synthetic oils that are commonly used in pharmaceutical preparations.[000553] In some embodiments, the pharmaceutically acceptable excipient (B) can be independently selected from thickeners, viscosity enhancing agents, bulking agents, mucoadhesive agents, penetration enhancers, buffers, preservatives, diluents, binders, lubricants, glidants, disintegrants, fillers, solubilizing agents, pH modifying agents, preservatives, stabilizing agents, anti-oxidants, wetting or emulsifying agents, suspending agents, pigments, colorants, isotonic agents, chelating agents, emulsifiers, and diagnostic agents. In some embodiments, the pharmaceutically acceptable excipients can be independently selected from thickeners, viscosity enhancing agents, mucoadhesive agents, buffers, preservatives, diluents, binders, lubricants, glidants, disintegrants, and fillers. In some embodiments, each of the pharmaceutically acceptable excipients can be independently selected from thickeners, viscosity enhancing agents, bulking agents, mucoadhesive agents, buffers, preservatives, and fillers. In some embodiments, each of the pharmaceutically acceptable excipients can be independently selected from diluents, binders, lubricants, glidants, and disintegrants.[000554] Exemplary diluents, fillers, bulking agents, buffers, binders disintegrants, glidants, lubricants, thickeners, viscosity enhancing agents, preservatives, and mucoadhesive agents, that can be included in a kit are described herein.[000555] In some embodiments, a pharmaceutical rectal foam composition can be supplied in a kit comprising a metered-dose canister containing enough rectal foam for 22 actuations, e.g., 1 priming actuation followed by 21 dosing actuations. In some embodiments, each canister will be provided with a kit comprising 21 prelubricated applicators and disposal bags for used applicators.[000556] In some embodiments, a kit comprises a can, e.g., a 30 g 35mm x 65 mm can; a valve, e.g., a CV / 1" Nitrile AR / PP; an actuator, e.g., a metered head 1.35 mL actuator; a foam shield, Lablabo; aeropin 35; SHP; DIG; PAD; and SHPR LBL.[000557] Any of the combinations of the present disclosure, or a pharmaceutical composition thereof, can be provided in a kit contemplated by the present disclosure to treat and / or prevent one or more side effects of a GLP-1 receptor agonist in a subject in need thereof.[000558] Assessing stability of the pharmaceutical compositions[000559] As used herein a “stable” pharmaceutical composition or formulation refers to a pharmaceutical composition or formulation in which the therapeutic or diagnostic agent retains an acceptable portion of its essential physical and / or chemical and / or biological properties over an acceptable period of time.[000560] Exemplary methods of assessing stability of peptides are provided in Peptide and Protein Drug Delivery, 247-301, Vincent Lee Ed., Marcel Dekker, Inc., New York, N.Y., 1991; and Jones, A., Adv. Drug Delivery Rev. 10: 29-90 (1993); the disclosures of which are incorporated herein by reference in their entireties.[000561] In some embodiments, the chemical stability of a peptide, or a pharmaceutical composition thereof, can be assessed immediately after formulation, and / or again after a period of storage; and / or under different environmental conditions, e.g., temperature and humidity.[000562] In some embodiments, the assays described herein can be used to determine the stability of any of the peptides comprising a combination of the present disclosure or a pharmaceutical composition thereof, for example, to determine the stability of the pharmaceutical compositions over time and / or at particular storage temperatures and conditions, by assessing activity, solubility, and stability (e.g. amount and / or activity of peptide; and / or presence of degradation products, etc.) prior to storage and then at various time points thereafter. The assays also can be used make minor adjustments to the formulations provided herein while retaining the stability of peptides.[000563] In some embodiments, the stability of a pharmaceutical composition of the present disclosure can be assessed by visual assessment, acid clarification, optical microscopy, reversed phase high performance liquid chromatography (RP-HPLC), in vivo bioassays, and denaturing and non-denaturing size exclusion chromatography (SEC).[000564] In some embodiments, stability can be determined by visual assessment, including changes in color, clarity, presence of aggregates or clumping and material adhesion, or frosting, to the vessel containing the pharmaceutical compositions provided herein. Visual changes can be confirmed by acid clarification, wherein lack of dissolutionafter acidification confirms the presence of insoluble denatured peptide. Visual changes can also be confirmed by optical microscopy and / or micrography by fluorescent backlighting. [000565] In some embodiments, the stability of the pharmaceutical compositions of the present disclosure can be assessed based on activity of the peptides contained therein.[000566] Activity of the peptides of the present disclosure can be assessed using methods and assays well known in the art. For example, the ability of a peptide of the present disclosure, including pharmaceutical compositions of the present disclosure comprising a peptide of the present disclosure, and their ability to act as a therapeutically effective agent, can be assessed in vitro or in vivo. For example, in vitro assays well known in the art can be performed to assess the ability of a peptide of the present disclosure to bind to one of its receptors.[000567] For example, in some embodiments, the activity of a peptide of the present disclosure can be assessed based on the peptides ability to agonize guanylate cyclase C (GC- C), which can be assessed using techniques known to those having ordinary skill in the art. [000568] In some embodiments, the activity of a peptide of the present disclosure can be assessed based on expression and / or activity downstream of the peptides pathway. For example, in some embodiments, the peptides ability stimulate and / or bind GC-C receptors: and / or the secretion of extracellular cyclic guanosine monophosphate (cGMP) across the basolateral membrane of colonic epithelial cells, can be evaluated to determine the activity of the peptides of the present disclosure.[000569] In some embodiments, the stability of a pharmaceutical composition of the present disclosure can be determined by assessing degradation of the peptide of the present disclosure.[000570] In some embodiments, the stability of a pharmaceutical composition of the present disclosure can be determined by assessing the identity of the contents thereof, e.g., via HPLC.[000571] In some embodiments, the stability of a pharmaceutical composition of the present disclosure can be determined by assessing the purity of the pharmaceutical composition, e.g., viaHPLC.[000572] In some embodiments, the stability of a pharmaceutical composition of the present disclosure can be determined by assessing the quantity of related substances of the pharmaceutical composition, e.g., via HPLC.[000573] In some embodiments, the stability of a pharmaceutical composition of the present disclosure can be determined by assessing the multimer content of the pharmaceutical composition, e.g., using size exclusion chromatography (SEC).[000574] In some embodiments, the stability of a pharmaceutical composition of the present disclosure can be determined by using differential scanning calorimetry (DSC).[000575] In some embodiments, the stability of a pharmaceutical composition of the present disclosure can be determined by assessing microbial load of the pharmaceutical composition, e.g., using the method described in USP <61>.[000576] In some embodiments, the stability of a pharmaceutical composition of the present disclosure can be determined by assessing the water content of the pharmaceutical composition, e.g., via a Karl Fischer test.[000577] In some embodiments, the stability of a pharmaceutical composition of the present disclosure can be determined by assessing the level of peptide degradation in the pharmaceutical composition.[000578] Proteins, polypeptides, and peptides degrade in both biological samples and in solution (e.g., cell culture and / or during fermentation). Methods of detecting peptide degradation are well known in the art. Any of the well-known methods of detecting peptide degradation may be employed here.[000579] In some embodiments, peptide degradation can be detected using isotope labeling techniques; liquid chromatography / mass spectrometry (LC / MS); HPLC; radioactive amino acid incorporation and subsequent detection, e.g., via scintillation counting; the use of a reporter protein, e.g., a protein that can be detected (e.g., by fluorescence, spectroscopy, luminometry, etc.); fluorescent intensity of one or more bioluminescent proteins and / or fluorescent proteins and / or fusions thereof; pulse-chase analysis (e.g., pulse-labeling a cell with radioactive amino acids and following the decay of the labeled protein while chasing with unlabeled precursor, and arresting protein synthesis and measuring the decay of total protein levels with time); or cycloheximide-chase assays.[000580] In some embodiments, an assay can be used to detect peptide degradation, wherein a sample is contacted with a non-fluorescent compound that is operable to react with free primary amine in said sample produced via the degradation of a peptide, and which then produces a fluorescent signal that can be quantified and compared to a standard. Examples of non-fluorescent compounds that can be utilized as fluorescent tags for free amines according to the present disclosure are 3-(4-carboxybenzoyl) quinoline-2-carboxaldehyde (CBQCA), fluorescamine, and o-phthaldialdehyde.[000581] In some embodiments, the method to determine the readout signal from the reporter protein depends from the nature of the reporter protein. For example, for fluorescent reporter proteins, the readout signal corresponds to the intensity of the fluorescent signal. The readout signal may be measured using spectroscopy-, fluorometry-, photometry-, and / or luminometry-based methods and detection systems, for example. Such methods and detection systems are well known in the art.[000582] In some embodiments, standard immunological procedures known to those having ordinary skill in the art can be used to detect peptide degradation. For example, in some embodiments, peptide degradation can be detected in a sample using immunoassays that employ a detectable antibody. Such immunoassays include, for example, agglutination assays, ELISA, Pandex microfluorimetric assay, flow cytometry, serum diagnostic assays, and immunohistochemical staining procedures, all of which are well- known in the art. In some embodiments, the levels (e.g., of fluorescence) in one sample can be compared to a standard. An antibody can be made detectable by various means well known in the art. For example, a detectable marker can be directly or indirectly attached to the antibody. Useful markers include, for example, radionucleotides, enzymes, fluorogens, chromogens and chemiluminescent labels.[000583] Exemplary methods of detecting peptide degradation is provided in U.S.Patent Nos. 5,766,927; 7,504,253; 9,201,073; 9,429,566; United States Patent Application 20120028286; Eldeeb et al., A molecular toolbox for studying protein degradation in mammalian cells. J Neurochem. 2019 Nov;151(4):520-533; and Buchanan et al., Cycloheximide Chase Analysis of Protein Degradation in Saccharomyces cerevisiae. J Vis Exp. 2016; (110): 53975, the disclosures of which are incorporated herein by reference in their entireties.[000584] METHODS OF USE AND ADMINISTRATION[000585] The present disclosure provides combinations, and compositions and / or formulations comprising the same, for use in a method for the treatment and / or prevention of certain side effects of GLP-1 receptor agonists, e.g., slowed gastric emptying; reduced appetite and / or food intake; decreased peptide hormone secretion (e.g., glucagon); slow gastrointestinal transit; constipation; and / or any abdominal pain associated thereof, and administering to a patient in need thereof, a therapeutically effective amount of a combination of the present disclosure, or pharmaceutical compositions thereof.[000586] In some embodiments, the present disclosure provides a method comprising, consisting essentially of, or consisting of, administering to the subject a therapeuticallyeffective amount of a combination of the present disclosure as described herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, which is optionally in a composition. In certain embodiments, the method further comprises administering to the subject an additional therapeutic agent that treats or prevents abdominal pain.[000587] In some embodiments, the present disclosure provides a method comprising, consisting essentially of, or consisting of, administering to the subject a therapeutically effective amount of pharmaceutical composition comprising a combination of a GLP-1 receptor agonist, and a guanylate-cyclase C (GC-C) receptor agonist, or a pharmaceutically acceptable salt, hydrate or solvate thereof. In certain embodiments, the method further comprises administering to the subject an additional therapeutic agent that treats or prevents abdominal pain.[000588] In some embodiments, the present disclosure provides a method comprising, consisting essentially of, or consisting of, contacting a subject or a cell therefrom with an effective amount of a combination of a GLP-1 receptor agonist, and a guanylate-cyclase C (GC-C) receptor agonist, a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition thereof, as defined herein.[000589] In some embodiments, the present disclosure provides a method comprising, consisting essentially of, or consisting of, treating a side effect of a GLP-1 receptor agonist in a subject in need of such treatment, said method comprising, consisting essentially of, or consisting of, administering to said subject a therapeutically effective amount of a combination of the present disclosure, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.[000590] In some embodiments, the present disclosure comprises, consists essentially of, or consists of, the use of one or more GLP-1 receptor agonist, and one or more guanylate- cyclase C (GC-C) receptor agonist, and / or pharmaceutical compositions thereof, for therapeutic purposes.[000591] In some embodiments, the present disclosure comprises, consists essentially of, or consists of, the use of one or more GLP-1 receptor agonist, and one or more guanylate- cyclase C (GC-C) receptor agonist, and / or pharmaceutical compositions thereof, for prophylactic purposes.[000592] Any of the combinations comprising a GLP-1 receptor agonist, and a guanylate-cyclase C (GC-C) receptor agonist, and / or any of the pharmaceutical compositions, liquid pharmaceutical compositions, unit dosage form, or pharmaceutical rectal foam compositions comprising the same, can be used to practice the methods of the presentdisclosure. For example, a combination comprising (1) a GLP-1 receptor agonist (e.g., a GLP-1 receptor agonist), or a pharmaceutically acceptable salt, hydrate or solvate thereof; and (2) a guanylate-cyclase C (GC-C) receptor agonist (e.g., linaclotide), or a pharmaceutically acceptable salt, hydrate or solvate thereof; or a pharmaceutical composition, liquid pharmaceutical composition, unit dosage form, or pharmaceutical rectal foam composition comprising the same, can be used in the method contemplated by the present disclosure to treat a side effect of a GLP-1 receptor agonist in a subject in need thereof, wherein the method comprises: selecting a subject having a side effect of a GLP-1 receptor agonist, and administering to the subject a therapeutically effective amount of the combination of the present disclosure; or a pharmaceutical composition, liquid pharmaceutical composition, unit dosage form, or pharmaceutical rectal foam composition comprising the same.[000593] Method of treating a side effect of a GLP-1 receptor agonist[000594] In some embodiments, the present disclosure provides a method of treating, limiting the symptoms of, reducing the severity of, or relieving the pain associated with, one or more side effects of a GLP-1 receptor agonist, in a subject in need thereof.[000595] In some embodiments, the present disclosure provides a method of treating, limiting the symptoms of, reducing the severity of, or relieving the pain associated with, one or more side effects of a GLP-1 receptor agonist, in a subject in need thereof; wherein the one or more side effects of a GLP-1 receptor agonist is slowed gastric emptying; reduced appetite and / or food intake; decreased peptide hormone secretion (e.g., glucagon); slow gastrointestinal transit; constipation; and / or any abdominal pain associated thereof.[000596] In some embodiments, the present disclosure provides a method of limiting the symptoms of, reducing the severity of, or treating one or more side effects of a GLP-1 receptor agonist, in a subject in need thereof, the method comprising: administering to the subject in need thereof a therapeutically effective amount of a combination comprising a GLP-1 receptor agonist, and a GC-C receptor agonist; or a pharmaceutically acceptable salt, hydrate or solvate thereof.[000597] In some embodiments, the present disclosure provides a method of limiting the symptoms of, reducing the severity of, or treating one or more side effects of a GLP-1 receptor agonist, in a subject in need thereof, the method comprising: administering to the subject in need thereof a therapeutically effective amount of a combination comprising a GLP-1 receptor agonist, and linaclotide; or a pharmaceutically acceptable salt, hydrate or solvate thereof.[000598] In some embodiments, the present disclosure provides a method of limiting the symptoms of, reducing the severity of, or treating one or more side effects of a GLP-1 receptor agonist, in a subject in need thereof, the method comprising: administering to the subject in need thereof a therapeutically effective amount of a combination comprising a GLP-1 receptor agonist, and linaclotide; or a pharmaceutically acceptable salt, hydrate or solvate thereof; wherein the linaclotide is administered two, three, four or five times daily. In one embodiment, linaclotide is administered twice daily in two equal doses (e.g. 2 x 72 mcg or 2 x145 mcg). In one embodiment, linaclotide is administered three times daily in three equal doses (e.g. 3 x 72 mcg). In one embodiment, the linaclotide is administered four times daily in four equal doses (e.g. 4 x 72 mcg).[000599] In some embodiments, the present disclosure provides a method of limiting the symptoms of, reducing the severity of, or treating one or more side effects of semaglutide, in a subject in need thereof, the method comprising: administering to the subject in need thereof a therapeutically effective amount of a combination comprising semaglutide, and linaclotide; or a pharmaceutically acceptable salt, hydrate or solvate thereof; wherein the linaclotide is administered two, three, four or five times daily. In one embodiment, linaclotide is administered twice daily in two equal doses (e.g. 2 x 72 mcg or 2 x145 mcg). In one embodiment, linaclotide is administered three times daily in three equal doses (e.g. 3 x 72 mcg). In one embodiment, the linaclotide is administered four times daily in four equal doses (e.g. 4 x 72 mcg).[000600] In some embodiments, the present disclosure provides a method of limiting the symptoms of, reducing the severity of, or treating one or more side effects of liraglutide in a subject in need thereof, the method comprising: administering to the subject in need thereof a therapeutically effective amount of a combination comprising a GLP-1 liraglutide, and linaclotide; or a pharmaceutically acceptable salt, hydrate or solvate thereof; wherein the linaclotide is administered two, three, four or five times daily. In one embodiment, linaclotide is administered twice daily in two equal doses (e.g. 2 x 72 mcg or 2 x!45 mcg). In one embodiment, linaclotide is administered three times daily in three equal doses (e.g. 3 x 72 mcg). In one embodiment, the linaclotide is administered four times daily in four equal doses (e.g. 4 x 72 mcg).[000601] In some embodiments, the present disclosure provides a method of limiting the symptoms of, reducing the severity of, or treating one or more side effects of a GLP-1 receptor agonist, in a subject in need thereof, the method comprising: administering to the subject in need thereof a therapeutically effective amount of a combination comprising aGLP-1 receptor agonist, and a GC-C receptor agonist, wherein administering the therapeutically effective amount of the combination limits the number of symptoms of the one or more side effects, reduces the severity of symptoms of the one or more side effects, reduces the level of pain associated with the one or more side effects, and / or treats the underlying cause of the one or more side effects in the subject in need thereof; relative to the number of symptoms, severity of symptoms, or level of pain associated with the one or more side effects experienced by the subject prior to the administration of the therapeutically effective amount of the combination.[000602] In some embodiments, the present disclosure provides a method of limiting the symptoms of, reducing the severity of, or treating one or more side effects experienced by a subject being administered a GLP-1 receptor agonist, the method comprising: administering to the subject a therapeutically effective amount of a GC-C receptor agonist, wherein administering the therapeutically effective amount of the GC-C receptor agonist limits the number of symptoms of the one or more side effects, reduces the severity of symptoms of the one or more side effects, reduces the level of pain associated with the one or more side effects, and / or treats the underlying cause of the one or more side effects in the subject; relative to the number of symptoms, severity of symptoms, or level of pain associated with the one or more side effects experienced by the subject prior to the administration of the therapeutically effective amount of the GC-C receptor agonist.[000603] In some embodiments, the present disclosure provides a method of limiting the symptoms of, reducing the severity of, or treating one or more side effects of a GLP-1 receptor agonist, in a subject in need thereof, the method comprising: administering to the subject in need thereof a therapeutically effective amount of a combination comprising a GLP-1 receptor agonist, and linaclotide, wherein administering the therapeutically effective amount of the combination limits the number of symptoms of the one or more side effects, reduces the severity of symptoms of the one or more side effects, reduces the level of pain associated with the one or more side effects, and / or treats the underlying cause of the one or more side effects in the subject in need thereof; relative to the number of symptoms, severity of symptoms, or level of pain associated with the one or more side effects experienced by the subject prior to the administration of the therapeutically effective amount of the combination.[000604] In some embodiments, the present disclosure provides a method of limiting the symptoms of, reducing the severity of, or treating one or more side effects experienced by a subject being administered a GLP-1 receptor agonist, the method comprising: administering to the subject a therapeutically effective amount of linaclotide, wherein administering thetherapeutically effective amount of linaclotide limits the number of symptoms of the one or more side effects, reduces the severity of symptoms of the one or more side effects, reduces the level of pain associated with the one or more side effects, and / or treats the underlying cause of the one or more side effects in the subject; relative to the number of symptoms, severity of symptoms, or level of pain associated with the one or more side effects experienced by the subject prior to the administration of the therapeutically effective amount of linaclotide.[000605] Any of the combinations comprising a GLP-1 receptor agonist, and a guanylate-cyclase C (GC-C) receptor agonist, and / or any of the pharmaceutical compositions, liquid phar...

Claims

CLAIMS 1. A combination comprising: a GLP-1 receptor agonist, and a guanylate-cyclase C (GC- C) receptor agonist.

2. The combination of any one of claims 1-3, wherein the GLP-1 receptor agonist is GLP-1; GLP-1 Eligen; GLP-1(7-36)NH2; GLP-1(7-37); a GLP-1 analog; an acylated GLP-1 analog; a diacylated GLP-1 analog; a dual GLP-1 analog; albiglutide (e.g., Syncria®); ARI- 2255; ARI-2651; beinaglutide; BHM-034; MOD-6030; Bydureon®; Byetta®; CAM-2036; CJC-1134-PC; CM-3; CVX-096; DA-15864; DA-3091; dulaglutide (e.g., Trulicity®); efpeglenatide; elamipretide,; elsiglutide; exenatide; Exenatide-XTEN ; exendin-4; an exendin-4 derivative; an exendin-4 peptide analog; GSK-2374697; langlenatide; Langlenatide / HM-11260C; liraglutide (e.g., Victoza®); lixisenatide (e.g., Lyxumia®); NN- 9924; NN-9926; NN-9927; Nodexen; ORMD-0901; PB-1023; rExendin-4; semaglutide; taspoglutide; TTP-054; TTP-273; or ZYOG-1.

3. The combination of claim 2, wherein the GLP-1 receptor agonist is semaglutide.

4. The combination of claim 2, wherein the GLP-1 receptor agonist is liraglutide.

5. The combination of any one of claims 1-4, wherein the GC-C receptor agonist is linaclotide.

6. The combination of any one of claims 1-4, wherein the GC-C receptor agonist is a peptide having an amino acid sequence of: Cys1Cth2Glu3Leu4Cys5Cys6Asn7Val8Ala9Cys10Tyr11Gly12Cys13(SEQ ID NO: 2); wherein Cth is a cystathionine; wherein Cys1and Cys6; Cys5and Cys13; are connected by disulfide bonds; wherein Cth2and Cys10are connected by a thioether bond; and wherein the peptide has an N-terminus that is optionally acetylated; or a pharmaceutically acceptable salt thereof.

7. The combination of any one of claims 1-4, wherein the GC-C receptor agonist is plecanatide.

8. The combination of any one of claims 1-7, wherein the combination is formulated in separate compositions, wherein the separate compositions each further comprise an excipient.

9. The combination of claim 8, wherein the separate compositions are formulated using the same excipients or different excipients.

10. The combination of any one of claims 1-9, wherein the combination is formulated in a single composition, wherein the single composition further comprises an excipient.

11. A combination comprising: semaglutide and linaclotide.

12. A combination comprising: liraglutide and linaclotide.

13. A combination comprising: semaglutide and a peptide having an amino acid sequence of: Cys1Cth2Glu3Leu4Cys5Cys6Asn7Val8Ala9Cys10Tyr11Gly12Cys13(SEQ ID NO: 2); wherein Cth is a cystathionine; wherein Cys1and Cys6; Cys5and Cys13; are connected by disulfide bonds; wherein Cth2and Cys10are connected by a thioether bond; and wherein the peptide has an N-terminus that is optionally acetylated; or a pharmaceutically acceptable salt thereof.

14. A combination comprising: liraglutide and a peptide having an amino acid sequence of: Cys1Cth2Glu3Leu4Cys5Cys6Asn7Val8Ala9Cys10Tyr11Gly12Cys13(SEQ ID NO: 2); wherein Cth is a cystathionine; wherein Cys1and Cys6; Cys5and Cys13; are connected by disulfide bonds; wherein Cth2and Cys10are connected by a thioether bond; and wherein the peptide has an N-terminus that is optionally acetylated; or a pharmaceutically acceptable salt thereof.

15. A combination comprising: semaglutide and plecanatide.

16. A combination comprising: liraglutide and plecanatide.

17. A composition comprising combination of: a GLP-1 receptor agonist and a guanylate- cyclase C (GC-C) receptor agonist; and one or more excipients.

18. A method of preventing one or more side effects of a GLP-1 receptor agonist in a subject in need thereof, comprising: administering to the subject in need thereof a combination of a GLP-1 receptor agonist and a guanylate-cyclase C (GC-C) receptor agonist.

19. A method of preventing one or more side effects of a GLP-1 receptor agonist comprising: (1) identifying a subject being treated with a GLP-1 receptor agonist, wherein the subject is diagnosed with, is suspected of having, is displaying symptoms of, or is confirmed to have one or more side effects of a GLP-1 receptor agonist; and (2) administering to the subject in need thereof a guanylate-cyclase C (GC-C) receptor agonist.

20. A method of treating or preventing one or more side effects of a GLP-1 receptor agonist comprising: (a) selecting a subject that is diagnosed with, is suspected of having, is displaying symptoms of, or is confirmed to have one or more side effects of a GLP-1 receptor agonist; and (b) administering to the subject a therapeutically effective amount of a GC-C receptor agonist; wherein the administration of the therapeutically effective amount of the GC-C receptor agonist to the subject results in a reduction in the occurrence or severity of the one or more side effects of the GLP-1 receptor agonist, or a symptom or pain associated thereof, relative to the occurrence or severity of the one or more side effects of the GLP-1 receptor agonist, or a symptom or pain associated thereof, in the subject prior to being administered the therapeutically effective amount of the GC-C receptor agonist.

21. The method of any one of claims 20-22, wherein the one or more side effects of the GLP-1 receptor agonist are: slow gastrointestinal transit; reduced gastrointestinal transit; constipation; nausea; diarrhea; vomiting; abdominal pain; dyspepsia; bloating; belching; gas; heartburn; and / or any discomfort or pain associated thereof.

22. The method of any one of claims 18-21, wherein the GLP-1 receptor agonist is GLP- 1; GLP-1 Eligen; GLP-1(7-36)NH2; GLP-1(7-37); a GLP-1 analog; an acylated GLP-1 analog; a diacylated GLP-1 analog; a dual GLP-1 analog; a GLP1 / glucagon receptor co- agonist; albiglutide (e.g., Syncria®); ARI-2255; ARI-2651; beinaglutide; BHM-034; MOD- 6030; Bydureon®; Byetta®; CAM-2036; CJC-1134-PC; CM-3; CVX-096; DA-15864; DA-3091; dulaglutide (e.g., Trulicity®); efpeglenatide; elamipretide,; elsiglutide; exenatide; Exenatide-XTEN ; exendin-4; an exendin-4 derivative; an exendin-4 peptide analog; GSK- 2374697; langlenatide; Langlenatide / HM-11260C; liraglutide (e.g., Victoza®); lixisenatide (e.g., Lyxumia®); NN-9924; NN-9926; NN-9927; Nodexen; ORMD-0901; PB-1023; rExendin-4; semaglutide; taspoglutide; TTP-054; TTP-273; or ZYOG-1.

23. The method of any one of claims 18-21, wherein the GLP-1 receptor agonist is semaglutide.

24. The method of any one of claims 18-21, wherein the GLP-1 receptor agonist is liraglutide.

25. The method of any one of claims 18-21, wherein the GC-C receptor agonist is linaclotide.

26. The method of any one of claims 18-21, wherein the GC-C receptor agonist is a peptide having an amino acid sequence of: Cys1Cth2Glu3Leu4Cys5Cys6Asn7Val8Ala9Cys10Tyr11Gly12Cys13(SEQ ID NO: 2); wherein Cth is a cystathionine; wherein Cys1and Cys6; Cys5and Cys13; are connected by disulfide bonds; wherein Cth2and Cys10are connected by a thioether bond; and wherein the peptide has an N-terminus that is optionally acetylated; or a pharmaceutically acceptable salt thereof.

27. The method of any one of claims 18-21, wherein the GC-C receptor agonist is plecanatide.

28. The method of any one of claims 18 or 20, wherein the combination is formulated in separate compositions, wherein the separate compositions each further comprise an excipient.

29. The method of claim 28, wherein the separate compositions are formulated using the same excipients or different excipients.

30. The method of any one of claims 18 or 20, wherein the combination is formulated in a single composition, wherein the single composition further comprises an excipient.

31. A method of treating or preventing one or more side effects of a GLP-1 receptor agonist comprising: (a) selecting a subject that is diagnosed with, is suspected of having, is displaying symptoms of, or is confirmed to have one or more side effects of a GLP-1 receptor agonist; and (b) administering to the subject a therapeutically effective amount of linaclotide; wherein the administration of the therapeutically effective amount of linaclotide to the subject results in a reduction in the occurrence or severity of the one or more side effects of the GLP-1 receptor agonist, or a symptom or pain associated thereof, relative to the occurrence or severity of the one or more side effects of the GLP-1 receptor agonist, or a symptom or pain associated thereof, in the subject prior to being administered the therapeutically effective amount of linaclotide.

32. A method of treating or preventing one or more side effects of a GLP-1 receptor agonist comprising: (a) selecting a subject that is diagnosed with, is suspected of having, is displaying symptoms of, or is confirmed to have one or more side effects of a GLP-1 receptor agonist; and (b) administering to the subject a therapeutically effective amount of a peptide having an amino acid sequence of: Cys1Cth2Glu3Leu4Cys5Cys6Asn7Val8Ala9Cys10Tyr11Gly12Cys13(SEQ ID NO: 2); wherein Cth is a cystathionine; wherein Cys1and Cys6; Cys5and Cys13; are connected by disulfide bonds; wherein Cth2and Cys10are connected by a thioether bond; and wherein the peptide has an N-terminus that is optionally acetylated; or a pharmaceutically acceptable salt thereof; wherein the administration of the therapeutically effective amount of linaclotide to the subject results in a reduction in the occurrence or severity of the one or more side effects of the GLP-1 receptor agonist, or a symptom or pain associated thereof, relative to the occurrence or severity of the one or more side effects of the GLP-1 receptor agonist, or a symptom or pain associated thereof, in the subject prior to being administered the therapeutically effective amount of linaclotide.

33. A method of treating or preventing one or more side effects of a GLP-1 receptor agonist comprising:(a) selecting a subject that is diagnosed with, is suspected of having, is displaying symptoms of, or is confirmed to have one or more side effects of a GLP-1 receptor agonist; and(b) administering to the subject a therapeutically effective amount of plecanatide; wherein the administration of the therapeutically effective amount of linaclotide to the subject results in a reduction in the occurrence or severity of the one or more side effects of the GLP-1 receptor agonist, or a symptom or pain associated thereof, relative to the occurrence or seventy of the one or more side effects of the GLP-1 receptor agonist, or a symptom or pain associated thereof, in the subject prior to being administered the therapeutically effective amount of linaclotide.

Images