Methods and kits for inducing satiety and treating metabolic disorders

Abstract

The present invention provides methods and kits for inducing satiety and treating metabolic disorders, diabetes, obesity, and obesity-related conditions. The methods and kits described herein include administration of metabolic hormones and GLP-1 receptor agonists for inducing satiety or treating metabolic syndrome, diabetes, obesity, and obesity-related disorders.

Description

[Technical field]

[0001] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. The ASCII copy created on June 22, 2022 has the name 51547-007WO2_Sequence_Listing_6_22_22_ST25 and is 24,476 bytes in size. [Background technology]

[0002] The prevalence of obesity continues to increase worldwide.However, there is still a lack of effective long-term non-invasive treatment for obesity and other metabolic disorders.Existing therapeutic agents induce satiety and treat metabolic syndrome, diabetes, obesity, and obesity-related disorders often do not provide suitable therapeutic effects.Therefore, new treatments are needed. Summary of the Invention

[0003] The present invention provides methods and kits for inducing satiety and treating metabolic disorders, diabetes, obesity, obesity-related conditions, nonalcoholic steatohepatitis (NASH), fatty liver disease, chronic kidney disease (CKD), polycystic ovarian syndrome (PCOS), cardiovascular disease (CVD), obstructive sleep apnea (OSA), retinopathy, peripheral vascular disease (PVD), peripheral arterial disease (PAD), and neuropathy (e.g., diabetic neuropathy). The methods described herein include the co-administration of metabolic hormones and glucagon-like peptide 1 receptor agonists (GLP-1 RAs) that enhance the induction of satiety and the treatment of metabolic syndrome, diabetes, obesity, and obesity-related disorders.

[0004] In one aspect, the invention features a method of inducing satiety or treating a condition selected from metabolic syndrome, diabetes, obesity, obesity-related disorders, NASH, fatty liver disease, CKD, PCOS, CVD, OSA, retinopathy, PVD, PAD, and neuropathy (e.g., diabetic neuropathy), the method includes locally lingually administering to a subject a dose of 2.5 μg to 2.5 mg (e.g., about 10 μg to about 1 mg, e.g., about 25 μg to about 250 μg, e.g., about 25 μg, 50 μg, 75 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, or 250 μg) of a metabolic hormone under a GLP-1 RA treatment regimen of any one of Tables 1, 2, 3, 4, 5, 6, 7, or 8.

[0005] In some embodiments, the method comprises administering locally to the subject a dose of 2.5 μg to 2.5 mg (e.g., 1 μg to 1 mg, e.g., 10 μg to 1 mg, e.g., 2.5 μg to 250 μg, e.g., 25 μg to 250 μg, e.g., a dose of about 25 μg, 50 μg, 75 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, or 250 μg) of a metabolic hormone under a GLP-1 RA treatment regimen of Table 2. In some embodiments, the method comprises administering locally to the subject a dose of 2.5 μg to 2.5 mg (e.g., 1 μg to 1 mg, e.g., 10 μg to 1 mg, e.g., 2.5 μg to 250 μg, e.g., 25 μg to 250 μg, e.g., a dose of about 25 μg, 50 μg, 75 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, or 250 μg) of a metabolic hormone under a GLP-1 RA treatment regimen of Table 3. In some embodiments, the method comprises administering locally to the subject a dose of 2.5 μg to 2.5 mg (e.g., 1 μg to 1 mg, e.g., 10 μg to 1 mg, e.g., 2.5 μg to 250 μg, e.g., 25 μg to 250 μg, e.g., a dose of about 25 μg, 50 μg, 75 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, or 250 μg) of a metabolic hormone under a GLP-1 RA treatment regimen of Table 4. In some embodiments, the method comprises administering locally to the subject a dose of 2.5 μg to 2.5 mg (e.g., 1 μg to 1 mg, e.g., 10 μg to 1 mg, e.g., 2.5 μg to 250 μg, e.g., 25 μg to 250 μg, e.g., a dose of about 25 μg, 50 μg, 75 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, or 250 μg) of a metabolic hormone under a GLP-1 RA treatment regimen of Table 5.In some embodiments, the method comprises administering locally to the subject a dose of 2.5 μg to 2.5 mg (e.g., 1 μg to 1 mg, e.g., 10 μg to 1 mg, e.g., 2.5 μg to 250 μg, e.g., 25 μg to 250 μg, e.g., a dose of about 25 μg, 50 μg, 75 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, or 250 μg) of a metabolic hormone under a GLP-1 RA treatment regimen of Table 6. In some embodiments, the method comprises administering locally to the subject a dose of 2.5 μg to 2.5 mg (e.g., 1 μg to 1 mg, e.g., 10 μg to 1 mg, e.g., 2.5 μg to 250 μg, e.g., 25 μg to 250 μg, e.g., a dose of about 25 μg, 50 μg, 75 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, or 250 μg) of a metabolic hormone under a GLP-1 RA treatment regimen of Table 7. In some embodiments, the method comprises administering locally to the subject a dose of 2.5 μg to 2.5 mg (e.g., 1 μg to 1 mg, e.g., 10 μg to 1 mg, e.g., 2.5 μg to 250 μg, e.g., 25 μg to 250 μg, e.g., a dose of about 25 μg, 50 μg, 75 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, or 250 μg) of a metabolic hormone under a GLP-1 RA treatment regimen of Table 8.

[0006] In some embodiments, the metabolic hormone targets the Y2 receptor in the subject. In some embodiments, the Y2 receptor is associated with the tongue of the subject.

[0007] In some embodiments, the metabolic hormone is peptide YY (PYY), PYY(3-36), leptin, oxyntomodulin (OXM), cholecystokinin (CCK), insulin, amylin, gastric inhibitory peptide (GIP), glucagon, or an analog, variant, or biologically active fragment of any of the above. In some embodiments, 2.5 μg, 10 μg, 25 μg, 50 μg, 100 μg, or 250 μg of metabolic hormone is administered. In some embodiments, the metabolic hormone is formulated as an orally dissolving tablet (ODT), lozenge, film, or spray. In some embodiments, the ODT is a fast dissolving form comprising partially hydrolyzed gelatin, mannitol, hydrolyzed dextran, alginate, polyvinyl alcohol, polyvinylpyrrolidone, acacia, aspartame, sodium methylparaben, sodium propylparaben, phenylalanine, water, or combinations thereof at a concentration of about 1% to 6% w / v. In some embodiments, the method reduces GLP-1-related side effects. In some embodiments, the GLP-1-related side effects include nausea, vomiting, diarrhea, abdominal pain, constipation, pancreatitis, diabetic retinal complications, hypoglycemia, acute kidney injury, hypersensitivity, or combinations thereof. In some embodiments, the GLP-1 receptor agonist is formulated as a tablet, gel capsule, or liquid.

[0008] In another aspect, the invention features a method of inducing satiety or treating a condition selected from metabolic syndrome, diabetes, obesity, obesity-related disorders, NASH, CKD, PCOS, CVD, OSA, retinopathy, PVD, PAD, and neuropathy, comprising local lingual administration of a metabolic hormone at a dose of 2.5 μg to 2.5 mg (e.g., 1 μg to 1 mg, e.g., 10 μg to 1 mg, e.g., 2.5 μg to 250 μg, e.g., 25 μg to 250 μg, e.g., a dose of about 25 μg, 50 μg, 75 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, or 250 μg) to a subject who has completed a systemic GLP-1 RA dose escalation regimen of Table 9.

[0009] In another aspect, the present invention provides a GLP-1 RA treatment regimen comprising: the GLP-1 RA is exenatide formulated for immediate release, the treatment regimen comprising systemically administering n*5 μg of exenatide (wherein the value of n is 1-2); the GLP-1 RA is exenatide formulated for sustained release, the treatment regimen comprising systemically administering n*2 mg of exenatide (wherein the value of n is 1); the GLP-1 RA is lixisenatide, the treatment regimen comprising systemically administering n*10 μg of lixisenatide (wherein the value of n is 1-2); the GLP-1 RA is liraglutide, the treatment regimen comprising systemically administering n*600 μg of liraglutide (wherein the value of n is 1-10); the GLP-1 RA is semaglutide and the treatment regimen comprises systemically administering n*250μg of semaglutide (wherein n is a value from 1 to 100); the GLP-1 RA is dulaglutide and the treatment regimen comprises systemically administering n*750μg of dulaglutide (wherein n is a value from 1 to 10); the GLP-1 RA is tirzepatide and tirzepatide treatment regimen A comprises systemically administering n*4mg (wherein n is a value from 1 to 10); or the GLP-1 RA is tirzepatide and tirzepatide treatment regimen B comprises systemically administering n*2.5mg (wherein n is a value from 1 to 10). The present invention features a method of inducing satiety or treating a condition selected from metabolic syndrome, diabetes, obesity, obesity-related disorders, NASH, CKD, PCOS, CVD, OSA, retinopathy, PVD, PAD, and neuropathy, comprising local lingual administration of a metabolic hormone to a subject at a dose of 2.5 μg to 2.5 mg (e.g., 1 μg to 1 mg, e.g., 10 μg to 1 mg, e.g., 2.5 μg to 250 μg, e.g., 25 μg to 250 μg, e.g., a dose of about 25 μg, 50 μg, 75 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, or 250 μg) under an RA treatment regimen.

[0010] In some embodiments, the GLP-1 RA is semaglutide and the treatment regimen comprises systemic administration of n*1.7 μg of semaglutide (wherein n is a value from 1 to 10), or the GLP-1 RA is semaglutide and the treatment regimen comprises systemic administration of n*2.4 μg of semaglutide (wherein n is a value from 1 to 10).

[0011] In another aspect, the invention features a method of inducing satiety in a subject or treating a condition selected from metabolic syndrome, diabetes, obesity, obesity-related disorders, NASH, CKD, PCOS, CVD, OSA, retinopathy, PVD, PAD, and neuropathy, comprising systemic administration of 10% to 90% of a GLP-1 RA to a subject receiving a first dosing regimen of Table 9 and local lingual administration of a metabolic hormone to the subject's mouth at a dose of 2.5 μg to 250 μg.

[0012] In some embodiments, the method includes systemic administration of 10% to 90% of a GLP-1 RA to a subject receiving a second dosing regimen of Table 9 and local lingual administration of a metabolic hormone at a dose of 2.5 μg to 2.5 mg (e.g., 1 μg to 1 mg, e.g., 10 μg to 1 mg, e.g., 2.5 μg to 250 μg, e.g., 25 μg to 250 μg, e.g., a dose of about 25 μg, 50 μg, 75 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, or 250 μg).

[0013] In some embodiments, the method includes systemic administration of 10% to 90% of a GLP-1 RA to a subject receiving a third dosing regimen of Table 9 and local lingual administration of a metabolic hormone at a dose of 2.5 μg to 2.5 mg (e.g., 1 μg to 1 mg, e.g., 10 μg to 1 mg, e.g., 2.5 μg to 250 μg, e.g., 25 μg to 250 μg, e.g., 25 μg, 50 μg, 75 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, or 250 μg).

[0014] In some embodiments, the method includes systemic administration of 10% to 90% of a GLP-1 RA to a subject receiving the fourth dosing regimen of Table 9 and local lingual administration of a metabolic hormone at a dose of 2.5 μg to 2.5 mg (e.g., 1 μg to 1 mg, e.g., 10 μg to 1 mg, e.g., 2.5 μg to 250 μg, e.g., 25 μg to 250 μg, e.g., 25 μg, 50 μg, 75 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, or 250 μg).

[0015] In some embodiments, the method comprises systemic administration of 10% to 90% of a GLP-1 RA to a subject receiving the fifth dosing regimen of Table 9 and local lingual administration of a metabolic hormone at a dose of 2.5 μg to 2.5 mg (e.g., 1 μg to 1 mg, e.g., 10 μg to 1 mg, e.g., 2.5 μg to 250 μg, e.g., 25 μg to 250 μg, e.g., a dose of about 25 μg, 50 μg, 75 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, or 250 μg).

[0016] In some embodiments, the method comprises systemic administration of 10% to 90% of a GLP-1 RA to a subject receiving the sixth dosing regimen of Table 9, and local lingual administration of a metabolic hormone at a dose of 2.5 μg to 2.5 mg (e.g., 1 μg to 1 mg, e.g., 10 μg to 1 mg, e.g., 2.5 μg to 250 μg, e.g., 25 μg to 250 μg, e.g., a dose of about 25 μg, 50 μg, 75 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, or 250 μg).

[0017] In some embodiments, the method comprises systemic administration of 10% to 90% of a GLP-1 RA to a subject receiving the seventh dosing regimen of Table 9, and local lingual administration of a metabolic hormone at a dose of 2.5 μg to 2.5 mg (e.g., 1 μg to 1 mg, e.g., 10 μg to 1 mg, e.g., 2.5 μg to 250 μg, e.g., 25 μg to 250 μg, e.g., a dose of about 25 μg, 50 μg, 75 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, or 250 μg).

[0018] In some embodiments, the method comprises systemic administration of 10% to 90% of a GLP-1 RA to a subject receiving the eighth dosing regimen of Table 9, and local lingual administration of a metabolic hormone at a dose of 2.5 μg to 2.5 mg (e.g., 1 μg to 1 mg, e.g., 10 μg to 1 mg, e.g., 2.5 μg to 250 μg, e.g., 25 μg to 250 μg, e.g., a dose of about 25 μg, 50 μg, 75 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, or 250 μg).

[0019] In another aspect, the invention features a kit that includes a metabolic hormone formulated for local lingual administration in a dose of 2.5 μg to 2.5 mg (e.g., 1 μg to 1 mg, e.g., 10 μg to 1 mg, e.g., 2.5 μg to 250 μg, e.g., 25 μg to 250 μg, e.g., a dose of about 25 μg, 50 μg, 75 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, or 250 μg) and a dose of a GLP-1 RA formulated for systemic administration (e.g., as set forth in any one of Tables 1-9).

[0020] definition To facilitate understanding of the present invention, certain terms are defined below. Terms defined herein have meanings commonly understood by those skilled in the art to which the present invention pertains. Terms such as "a", "an", and "the" are not intended to refer to a singular entity only, but are intended to include the general category within which a specific example may be used for illustration. Although the terms herein are used to describe certain embodiments of the present invention, their use does not limit the present invention, except as outlined in the claims.

[0021] As used herein, the term "about" refers to a value within 10% above or below the stated value.

[0022] As used herein, any value provided in a range of values ​​includes both the upper and lower limits, and any value subsumed within those limits.

[0023] The term "active ingredient," as used herein, refers to a metabolic hormone, GLP-1 RA, an analog, variant, or a biologically active fragment of a metabolic hormone that induces a biological response when administered to a subject.

[0024] The terms "bind", "binds", or "binding" refer to the association between a metabolic hormone or a portion of a metabolic hormone and the Y2 receptor via a chemical bond (e.g., ionic, covalent, or hydrophobic) or other chemical or physical attraction between the metabolic hormone or a portion of the metabolic hormone and the Y2 receptor, where the association between the metabolic hormone and the Y receptor induces a biological response. See, e.g., Doods, Peptides. 16:1389-1394, 1995.

[0025] As used herein, the term "sustained release" with respect to any composition according to the invention refers to the release of all or part of the composition within 10 weeks of administration. A composition formulated for sustained release may release the active ingredient in one or more release stages.

[0026] As used herein, the term "immediate release" with respect to any composition according to the present invention refers to a release that is not a modified release, and releases all or a portion of the composition within 60 minutes of administration.

[0027] As used herein, "local" or "local administration" refers to administration to a particular site on the body for a local effect rather than a systemic effect. The terms "local" or "local administration" or variations thereof refer to administration of any active ingredient described herein without a substantial change in the level of the active ingredient in the blood of the subject.

[0028] The term "metabolic disorder", as used herein, refers to a human or animal condition or disease associated with and / or resulting from abnormal function or regulation of the metabolic system (e.g., obesity, diabetes, fatty liver disease, NASH, PCOS, elevated blood glucose, CKD, CVD, OSA, retinopathy, PVD, PAD, and / or neuropathy (e.g., diabetic neuropathy)). The term "disorder" generally refers to a disruption of normal body structure and function, or a pathophysiological response to internal or external factors.

[0029] As used herein, the term "subject" refers to a human or non-human animal (e.g., a mammal) suffering from or at risk for a disease or condition, as determined by a qualified professional (e.g., a physician or advanced nursing officer) with or without clinical test(s) known in the art of a sample(s) from the subject.

[0030] As used herein, the term "systemic administration" refers to the delivery of any composition according to the present invention that increases blood or plasma levels of one or more active ingredients, analogs or variants thereof, above the limits of detection.

[0031] The term "therapeutic dose," as used herein, refers to a dose at which a pharmacologic active ingredient is capable of treating, ameliorating, or reducing symptoms associated with a disease, disorder, or condition.

[0032] As used herein, the term "treatment regimen" refers to at least the dose, frequency, and duration of any of the compositions described herein taken by a subject for the treatment or prevention of any of the diseases or conditions described herein.

[0033] As used herein, the term "targeting" refers to the association between an active ingredient (e.g., a metabolic hormone or GLP-1 RA) or a portion of an active ingredient of any composition of the present invention and a receptor of a subject via a chemical bond or other chemical or physical interaction, which association induces a biological response.

[0034] As used herein, the terms "local lingual administration," "local lingual," or variations thereof, refer to local administration of a metabolic hormone to the epithelium of a subject's mouth and / or tongue without substantial alteration in the level of the metabolic hormone in the subject's blood (e.g., without substantial systemic exposure). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0035] In general, the present invention features a method and kit for inducing satiety and treating conditions that affect metabolism, such as metabolic syndrome, diabetes, obesity, and obesity-related disorders.The present invention is based in part on the surprising discovery of the synergistic effect between the administration of glucagon-like peptide 1 receptor agonist (GLP-1 RA) and metabolic hormones, such as peptide YY (PYY).The present invention also provides a method and kit for treating subjects who have previously undergone a treatment regimen of GLP-1 RA, but would benefit from subsequent treatment with metabolic hormones, or combination therapy that includes metabolic hormones and GLP-1 RA.The methods and kits contemplated herein are described in more detail below.

[0036] Compositions for inducing satiety and treating metabolic disorders and related conditions - Patents.com GLP-1 RA composition The methods described herein include systemically administering a composition comprising a GLP-1 RA, or a biologically active fragment, variant, or analog thereof, hi some embodiments, the GLP-1 RA is an approved therapeutic agent for inducing satiety and / or treating any of the indications described herein.

[0037] In some embodiments, the GLP-1 RA is exenatide, which comprises a polypeptide having a sequence set forth in SEQ ID NO: 1. In some embodiments, the exenatide is formulated for immediate release (IR). In some embodiments, the exenatide is formulated for extended release (ER).

[0038] In some embodiments, the GLP-1 RA is lixisenatide, which comprises a polypeptide having the sequence set forth in SEQ ID NO:2.

[0039] In some embodiments, the GLP-1 RA is liraglutide, which comprises a polypeptide having the sequence set forth in SEQ ID NO:3 and has a palmitic acid moiety attached to a glutamic acid spacer that is attached to the lysine at position 20.

[0040] In some embodiments, the GLP-1 RA is semaglutide, which comprises a polypeptide having the sequence set forth in SEQ ID NO:4 and has a lysine derivative acylated with α-aminoisobutyric acid at position 2 and stearic diacid at position 20.

[0041] In some embodiments, the GLP-1 RA is dulaglutide, which comprises a polypeptide having the sequence set forth in SEQ ID NO:5.

[0042] In some embodiments, the GLP-1 RA is tirzepatide, which has the sequence set forth in SEQ ID NO:6 and comprises a polypeptide having α-aminoisobutyric acid at positions 2 and 13, and a modified lysine at position 20 containing a C20 fatty diacid attached via a glutamic acid linker.

[0043] In some embodiments, the GLP-1 RA is GLP-1, or a variant, analog, or biologically active fragment thereof. In some embodiments, the GLP-1, or a variant, analog, or biologically active fragment thereof, has at least 70% (e.g., at least 70%, 75%, 80%, 85%, 90%, 95%, 97%, 99%, or 100%) sequence identity to SEQ ID NO: 17. In some embodiments, the GLP-1 has the sequence set forth in SEQ ID NO: 17.

[0044] Compositions of GLP-1 RA (e.g., lixisenatide, liraglutide, semaglutide, dulaglutide, or tirzepatide) described herein may include one or more pharma- ceutically acceptable excipients (e.g., propylene glycol, potassium sorbate, L-arginine, edetate disodium, monosodium phosphate, and polysorbate 20). In some embodiments, propylene glycol is present at a concentration of about 100 mg / ml, L-arginine is present at a concentration of about 25 mg / ml, potassium sorbate is present at a concentration of about 2 mg / ml, edetate disodium is present at a concentration of about 1.2 mg / ml, sodium phosphate monobasic dihydrate is present at a concentration of about 7.8 mg / ml, and polysorbate is present at a concentration of about 5 mg / ml. Additionally, the compositions described herein can include a co-solvent stabilizer such as propylene glycol or other suitable co-solvent stabilizer (e.g., low molecular weight polyethylene glycols (PEGs) such as PEG 200 and 400, glycerin, and ethanol. In some embodiments, the compositions described herein can include an amino acid stabilizer such as L-arginine or other suitable amino acid stabilizer (e.g., alanine, aspartic acid, glycine, lysine, proline, or methionine). In some embodiments, the compositions described herein can include a preservative such as potassium sorbate or other suitable preservative (e.g., ascorbic acid, benzyl ether, sorbic acid, sorbitol ... The compositions described herein may include antioxidants such as disodium edetate or another suitable antioxidant (e.g., sodium formaldehyde sulfoxylate, butyl hydroxyanisole, butyl hydroxytoluene, and the like).In some embodiments, the compositions described herein include a buffer (e.g., acetate, carbonate, citrate, citrate-phosphate, glycine, HEPES, histidine, maleate, phosphate, succinate, tartrate, and triethanolamine (Tris)). In some embodiments, the compositions described herein can include a surfactant, such as polysorbate 20 or other suitable surfactant (e.g., poloxamer 188 / 407, polysorbate 40 or 80, or sodium lauryl sulfate).

[0045] Route of administration of GLP-1 RA The composition of the present invention comprising GLP-1 RA can be formulated to deliver GLP-1 RA systemically. The composition can be formulated for any suitable route and means of administration. Pharmaceutically acceptable carriers or diluents include those used in formulations suitable for oral, rectal, nasal, or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, and transdermal) administration. The formulation can be conveniently provided in unit dosage form and can be prepared by any of the methods well known in the art of pharmacy. Subcutaneous or transdermal modes of administration can be particularly suitable for certain compounds described herein. In some embodiments, the GLP-1 RA is formulated as a tablet, gel capsule, or liquid. The composition of the present invention can be in unit dosage form. In such form, the composition is divided into unit doses containing an appropriate amount of active ingredient (e.g., exenatide IR). The unit dosage form can be a packaged formulation, the package containing discrete amounts of the formulation, for example, sachets, capsules, and powders in vials or ampoules. The unit dosage form can be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these in packaged form.It can also be presented in unit dose injectable form, such as an injector pen.

[0046] Metabolic Hormones Composition The methods described herein include local lingual administration of a metabolic hormone, or a biologically active fragment, variant, or analog thereof. The metabolic hormone targets (e.g., binds to, associates with, or interacts with) the Y2 receptor in the oral cavity of the subject. In some embodiments, the metabolic hormone targets the Y2 receptor expressed on the tongue of the subject. In some embodiments, the metabolic hormone is peptide YY (PYY), PYY(3-36), leptin, oxyntomodulin, cholecystokinin, insulin, amylin, gastric inhibitory peptide, or glucagon.

[0047] In some embodiments, the metabolic hormone is PYY, or an analog, variant, or biologically active fragment thereof (e.g., (Pro34)PYY, PYY analog NNC0165-1273, PYY analog NNC0165-1875, or PYY analog NNC0165-1562). In some embodiments, PYY, or a variant, analog, or biologically active fragment thereof, has at least 70% (e.g., 70%, 75%, 80%, 85%, 90%, 95%, 97%, 99%, or 100%) sequence identity to SEQ ID NO:7. In some embodiments, PYY has the amino acid sequence set forth in SEQ ID NO:7. In some embodiments, the methods described herein comprise local lingual administration of PYY, or a variant, analog, or biologically active fragment thereof, at a dose of about 2.5 μg to about 2.5 mg. In some embodiments, the methods described herein include local lingual administration of PYY, or a variant, analog, or biologically active fragment thereof, at a dose of about 10 μg to about 1 mg. In some embodiments, the methods described herein include local lingual administration of PYY, or a variant, analog, or biologically active fragment thereof, at a dose of about 25 μg to about 250 μg (e.g., a dose of about 25 μg, 50 μg, 75 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, or 250 μg). In some embodiments, the PYY variant is [Pro34]PYY. In some embodiments, [Pro34]PYY, or a variant, analog, or biologically active fragment thereof, has at least 70% (e.g., at least 70%, 75%, 80%, 85%, 90%, 95%, 97%, 99%, or 100%) sequence identity to SEQ ID NO:8. In some embodiments, [Pro34]PYY has the amino acid sequence set forth in SEQ ID NO:8. In some embodiments, the PYY variant is NNC065-1273, which comprises a PYY(3-36) polypeptide having a beta-homo-arginine at position 35. In some embodiments, the PYY variant is NNC0165-1875. In some embodiments, the PYY variant is NNC0165-1562.In some embodiments, the PYY analog or variant is described, for example, in Lear et al. J. of Med. Chem. 63: 9660-9671, 2020 (incorporated herein in its entirety by reference). In some embodiments, the PYY analog is a PYY-antibody (PYY bound to an antibody or an Fc region of an antibody) or PYY bound to one or more PEG moieties, for example, as described in Rangwala et al. Cell Metab. 29: 837-843, 2019 (incorporated herein in its entirety by reference). In some embodiments, the PYY variant or analog is any variant described in U.S. Pat. No. 8,217,001 (the disclosure of which is incorporated herein in its entirety by reference).

[0048] In some embodiments, the metabolic hormone is PYY(3-36), or an analog, variant, or biologically active fragment thereof. In some embodiments, the PYY(3-36) variant, analog, or biologically active fragment thereof has at least 70% (e.g., at least 70%, 75%, 80%, 85%, 90%, 95%, 97%, 99%, or 100%) sequence identity to SEQ ID NO:9. In some embodiments, PYY(3-36) has the amino acid sequence set forth in SEQ ID NO:9.

[0049] In some embodiments, the PYY(3-36) variant, analog, or biologically active fragment thereof is selected from the group consisting of PYY(26-36), PYY(25-36), PYY(24-36), PYY(23-36), PYY(22-36), PYY(21-36), PYY(20-36), PYY(19-36), PYY(18-36), PYY(21-36), PYY(22-36), PYY(23-36), PYY(24-36), PYY(25-36), PYY(26-36), PYY(25 ...5-36), PYY(25-36), PYY(25-36), PYY(25-36), PYY(25-36), In some embodiments, the PYY(3-36) variant, analog, or fragment thereof is a single point mutation, e.g., a single point mutation in PYY(25-36), e.g., [Lys 25 ]PPY(25-36), [Thr 27 ]PPY(25-36), [Phe 21 ]PPY(25-36), [Ile 28 ]PYY(25-36), [Val 28 ]PYY(25-36), [Gln 29 ]PYY(25-36), [Ile 30 ]PYY(25-36), [Val 30 ]PYY(25-36), [Ile 31 ]PYY(25-36), [Leu 31 ]PYY(25-36), [Ser 32 ]PYY(25-36), [Lys 33 ]PYY(25-36), [Asn 34 ]PYY(25-36), [Lys 35 ]PYY(25-36), [Thr 36 ]PYY(25-36) or [Phe 36 ]PYY(25-36), or single point mutations in PYY(24-36), e.g., [Ile 24In some embodiments, the PYY(3-36) variant, analog, or biologically active fragment thereof can be a fragment having a double point mutation, such as a double point mutation in PYY(25-36), such as [Lys25,Thr27]PPY(25-36), [Lys25,Phe27]PPY(25-36), [Lys25,Ile28]PPY(25-36), [Lys25,Val28]PPY(25-36), [Lys25,Gln29]PPY(25-36), [Lys 25 ,Ile 30 ]PPY(25-36), [Lys 25 ,Val 30 ]PPY(25-36), [Lys 25 ,Ile 31 ]PPY(25-36), [Lys 25 ,Leu 31 ]PPY(25-36), [Lys 25 ,Ser 32 ]PPY(25-36), [Lys 25 ,Lys 33 ]PPY(25-36), [Lys 25 ,Asn 34 ]PPY(25-36), [Lys 25 ,Lys 35 ]PPY(25-36), [Lys 25 ,Thr 36 ]PPY(25-36), [Lys 25 ,Phe 36 ]PPY(25-36), [Thr 27 ,Ile 28 ]PPY(25-36), [Thr 27 ,Val 28 ]PPY(25-36), [Thr 27 ,Gln 29 ]PPY(25-36), [Thr 27 ,Ile 30 ]PPY(25-36), [Thr 27 ,Val 30 ]PPY(25-36), [Thr 27 ,Ile 31 ]PPY(25-36), [Thr 27 ,Leu31 ]PPY(25-36)、[Thr 27 ,Ser 32 ]PPY(25-36)、[Thr 27 ,Lys 33 ]PPY(25-36)、[Thr 27 ,Asn 34 ]PPY(25-36)、[Thr 27 ,Lys 35 ]PPY(25-36)、[Thr 27 ,Thr 36 ]PPY(25-36)、[Thr 27 ,Phe 36 ]PPY(25-36)、[Phe 27 ,Ile 28 ]PPY(25-36)、[Phe 27 ,Val 28 ]PPY(25-36)、[Phe 27 ,Gln 29 ]PPY(25-36)、[Phe 27 ,Ile 30 ]PPY(25-36)、[Phe 27 ,Val 30 ]PPY(25-36)、[Phe 27 ,Ile 31 ]PPY(25-36)、[Phe 27 ,Leu 31 ]PPY(25-36)、[Phe 27 ,Ser 32 ]PPY(25-36)、[Phe 27 ,Lys 33 ]PPY(25-36)、[Phe 27 ,Asn 34 ]PPY(25-36)、[Phe 27 ,Lys 35 ]PPY(25-36)、[Phe 27 ,Thr 36 ]PPY(25-36)、[Phe 27 ,Phe 36 ]PPY(25-36)、[Gln 29 ,Ile 30 ]PYY(25-36)、[Gln 29 ,Val 30 ]PYY(25-36)、[Gln29 ,Ile 31 ]PYY(25-36),[Gln 29 ,Leu 31 ]PYY(25-36),[Gln 29 ,Ser 32 ]PYY(25-36),[Gln 29 ,Leu 33 ]PYY(25-36),[Gln 29 ,Asn 34 ]PYY(25-36),[Gln 29 ,Leu 33 ]PYY(25-36),[Gln 29 ,Thr 36 ]PYY(25-36),[Gln 29 ,Phe 30 ]PYY(25-36),[Ile 30 ,Ile 31 ]PYY(25-36),[Ile 30 ,Leu 31 ]PYY(25-36),[Ile 30 ,Ser 32 ]PYY(25-36),[Ile 30 ,Lys 33 ]PYY(25-36),[Ile 30 ,Asn 34 ]PYY(25-36),[Ile 30 ,Lys 33 ]PYY(25-36),[Ile 30 ,Thr 30 ]PYY(25-36),[Ile 30 ,Phe 30 ]PYY(25-36),[Val 30 ,Ile 31 ]PYY(25-36),[Val 30 ,Leu 31 ]PYY(25-36),[Val 30 ,Ser 32 ]PYY(25-36),[Val 30 ,Lys 33 ]PYY(25-36),[Val 30 ,Asn 34 ]PYY(25-36),[Val 30 ,Lys 35]PYY(25-36),[Val 30 ,Thr 30 ]PYY(25-36),[Val 30 ,Phe 30 ]PYY(25-36),[Ile 31 ,Ser 32 ]PYY(25-36),[Ile 31 ,Lys 33 ]PYY(25-36),[Ile 31 ,Asn 34 ]PYY(25-36),[Ile 31 ,Lys 33 ]PYY(25-36),[Ile 31 ,Thr 30 ]PYY(25-36),[Leu 31 ,Phe 30 ]PYY(25-36),[Leu 31 ,Ser 32 ]PYY(25-36),[Val 31 ,Lys 33 ]PYY(25-36),[Leu 31 ,Asn 34 ]PYY(25-36),[Leu 31 ,Lys 33 ]PYY(25-36),[Leu 31 ,Thr 30 ]PYY(25-36),[Leu 31 ,Phe 30 ]PYY(25-36),[Ser 32 ,Lys 33 ]PYY(25-36),[Ser 32 ,Asn 34 ]PYY(25-36),[Ser 32 ,Lys 35 ]PYY(25-36),[Ser 32 ,Thr 36 ]PYY(25-36),[Ser 32 ,Phe 36 ]PYY(25-36),[Lys 33 ,Asn 34 ]PYY(25-36),[Lys 33 ,Lys 35 ]PYY(25-36),[Lys 33 ,Thr36 ]PYY(25-36), [Lys 33 ,Phe 36 ]PYY(25-36), [Asn 34 ,Lys 35 ]PYY(25-36), [Asn 34 ,Thr 36 ]PYY(25-36), [Asn 34 ,Phe 36 ]PYY(25-36), [Lys 35 ,Thr 36 ]PYY(25-36), or [Lys 35 ,Phe 36 ]PYY(25-36).

[0050] In some embodiments, the methods described herein comprise local lingual administration of PYY(3-36), or a variant, analog, or biologically active fragment thereof, at a dose of about 2.5 μg to about 2.5 mg. In some embodiments, the methods described herein comprise local lingual administration of PYY(3-36) at a dose of about 10 μg to about 1 mg. In some embodiments, the methods described herein comprise local lingual administration of PYY(3-36) at a dose of about 25 μg to about 250 μg (e.g., a dose of about 25 μg, 50 μg, 75 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, or 250 μg).

[0051] In some embodiments, the metabolic hormone is leptin, or an analog, variant, or biologically active fragment thereof. In some embodiments, the leptin analog is a leptin receptor antagonist as in Peters JH, et al, Endocrinology, 148(6):2878-85, 2007, which is incorporated herein by reference in its entirety. In some embodiments, the leptin, or a variant, analog, or biologically active fragment thereof, has at least 70% (e.g., at least 70%, 75%, 80%, 85%, 90%, 95%, 97%, 99%, or 100%) sequence identity to SEQ ID NO: 10. In some embodiments, the leptin has an amino acid sequence as set forth in SEQ ID NO: 10. In some embodiments, the leptin analog is a recombinant analog metreleptin (MYALEPT®), which comprises a polypeptide having a sequence as set forth in SEQ ID NO: 18, and which includes a disulfide bridge linking amino acid residues 97 and 147. In some embodiments, the methods described herein include local lingual administration of leptin, or a variant, analog, or biologically active fragment thereof, at a dose of about 2.5 μg to about 2.5 mg. In some embodiments, the methods described herein include local lingual administration of leptin, or a variant, analog, or biologically active fragment thereof, at a dose of about 10 μg to about 1 mg. In some embodiments, the methods described herein include local lingual administration of leptin, or a variant, analog, or biologically active fragment thereof, at a dose of about 25 μg to about 250 μg (e.g., a dose of about 25 μg, 50 μg, 75 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, or 250 μg).

[0052] In some embodiments, the metabolic hormone is OXM, or an analog, variant, or biologically active fragment thereof. In some embodiments, OXM, or a variant, analog, or biologically active fragment thereof, has at least 70% (e.g., at least 70%, 75%, 80%, 85%, 90%, 95%, 97%, 99%, or 100%) sequence identity to SEQ ID NO: 11. In some embodiments, OXM has the amino acid sequence set forth in SEQ ID NO: 11. In some embodiments, the analog of OXM is the synthetic analog OXM6421, synthesized for long-acting effects, as described in Liu, YL., Int. J. Obes., 2010, 34(12):1715-25 (incorporated herein by reference in its entirety). In some embodiments, the analog of OXM is a long-acting polyethylene glycol (PEG)-OXM functionalized with a high molecular weight PEG molecule, as described in Bianchi, E., Bioorg. Med. Chem., 2013, 21(22):7064-73, which is incorporated herein by reference in its entirety. In some embodiments, the analog of OXM is a sustained release analog OX-SR, as described in Scott, R., Peptides, 2018, 104:70-77, which is incorporated herein by reference in its entirety. In some embodiments, the methods described herein include local lingual administration of OXM, or a variant, analog, or biologically active fragment thereof, at a dose of about 2.5 μg to about 2.5 mg. In some embodiments, the methods described herein include local lingual administration of OXM, or a variant, analog, or biologically active fragment thereof, at a dose of about 10 μg to about 1 mg. In some embodiments, the methods described herein comprise local lingual administration of OXM, or a variant, analog, or biologically active fragment thereof, at a dose of about 25 μg to about 250 μg (e.g., a dose of about 25 μg, 50 μg, 75 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, or 250 μg).

[0053] In some embodiments, the metabolic hormone is CCK, or an analog, variant, or biologically active fragment thereof. In some embodiments, the CCK, or a variant, analog, or biologically active fragment thereof, has at least 70% (e.g., at least 70%, 75%, 80%, 85%, 90%, 95%, 97%, 99%, or 100%) sequence identity to SEQ ID NO: 12. In some embodiments, the CCK has the amino acid sequence set forth in SEQ ID NO: 12. In some embodiments, the analog of CCK is caerulein, as described in Sperti J.Surg.Oncol., 54:11-16, 1994 (incorporated herein by reference in its entirety). In some embodiments, the analog of CCK is the synthetic analog Thr28NlE31CCK25-33 (CCK9), as described in Mossner, Z.Gastroenterol., 29:59-64, 1991 (incorporated herein by reference in its entirety). In some embodiments, the methods described herein include local lingual administration of CCK, or a variant, analog, or biologically active fragment thereof, at a dose of about 2.5 μg to about 2.5 mg. In some embodiments, the methods described herein include local lingual administration of CCK, or a variant, analog, or biologically active fragment thereof, at a dose of about 10 μg to about 1 mg. In some embodiments, the methods described herein include local lingual administration of CCK, or a variant, analog, or biologically active fragment thereof, at a dose of about 25 μg to about 250 μg (e.g., a dose of about 25 μg, 50 μg, 75 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, or 250 μg).

[0054] In some embodiments, the metabolic hormone is insulin, or an analog thereof (e.g., insulin aspart (NOVOLOG®), insulin glargine (LANTUS®), insulin lispro (LYUMJEV™), insulin glulisine (APIDRA®), or insulin detemir (LEVEMIR®), insulin degludec (TRESIBA®), NPH insulin (HUMULIN®N or NOVOLIN®N), variant, or biologically active fragment. In some embodiments, the insulin, or a variant, analog, or biologically active fragment thereof has at least 70% (e.g., at least 70%, 75%, 80%, 85%, 90%, 95%, 97%, 99%, or 100%) sequence identity to SEQ ID NO: 13. In some embodiments, the insulin has the amino acid sequence set forth in SEQ ID NO: 13. In some embodiments, the analog of insulin is insulin aspart (NOVOLOG®), which has the sequence set forth in SEQ ID NO: 19. and a B chain having the sequence set forth in SEQ ID NO:20. In some embodiments, the insulin analog is insulin glargine (LANTUS®) having an A chain having the sequence set forth in SEQ ID NO:21 and a B chain having the sequence set forth in SEQ ID NO:22. In some embodiments, the insulin analog is insulin lispro (LYUMJEV™) having an A chain having the sequence set forth in SEQ ID NO:23 and a B chain having the sequence set forth in SEQ ID NO:24. In some embodiments, the insulin analog is insulin glulisine (APIDRA®) having an A chain having the sequence set forth in SEQ ID NO:25 and a B chain having the sequence set forth in SEQ ID NO:26. In some embodiments, the insulin analog is insulin detemir (LEVEMIR®) having an A chain having the sequence set forth in SEQ ID NO:27 and a B chain having the sequence set forth in SEQ ID NO:28. In some embodiments, the methods described herein comprise local lingual administration of insulin, or a variant, analog, or biologically active fragment thereof, at a dose of about 2.5 μg to about 2.5 mg.In some embodiments, the methods described herein include local lingual administration of insulin, or a variant, analog, or biologically active fragment thereof, at a dose of about 10 μg to about 1 mg. In some embodiments, the methods described herein include local lingual administration of insulin, or a variant, analog, or biologically active fragment thereof, at a dose of about 25 μg to about 250 μg (e.g., a dose of about 25 μg, 50 μg, 75 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, or 250 μg).

[0055] In some embodiments, the metabolic hormone is amylin, or an analog (e.g., pramlintide (SYMLIN®)), variant, or biologically active fragment thereof. In some embodiments, the amylin, or a variant, analog, or biologically active fragment thereof has at least 70% (e.g., at least 70%, 75%, 80%, 85%, 90%, 95%, 97%, 99%, or 100%) sequence identity to SEQ ID NO: 14. In some embodiments, the amylin has an amino acid sequence set forth in SEQ ID NO: 14. In some embodiments, the analog of amylin is pramlintide (SYMLIN®), which comprises a polypeptide having a sequence set forth in SEQ ID NO: 29. In some embodiments, the methods described herein comprise local lingual administration of amylin, or a variant, analog, or biologically active fragment thereof, at a dose of about 2.5 μg to about 2.5 mg. In some embodiments, the methods described herein include local lingual administration of amylin, or a variant, analog, or biologically active fragment thereof, at a dose of about 10 μg to about 1 mg. In some embodiments, the methods described herein include local lingual administration of amylin, or a variant, analog, or biologically active fragment thereof, at a dose of about 25 μg to about 250 μg (e.g., a dose of about 25 μg, 50 μg, 75 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, or 250 μg).

[0056] In some embodiments, the metabolic hormone is GIP, or an analog thereof (e.g., D-GIP 1-30 , N-AcGIP(LysPAL16, or N-AcGIP(LysPAL37), variants, or biologically active fragments. In some embodiments, GIP, or variants, analogs, or biologically active fragments thereof have at least 70% (e.g., at least 70%, 75%, 80%, 85%, 90%, 95%, 97%, 99%, or 100%) sequence identity to SEQ ID NO: 15. In some embodiments, GIP has the amino acid sequence set forth in SEQ ID NO: 15. In some embodiments, the analog of GIP is D-GIP as described in Sekar R., Int. Rev. Cell Mol. Biol., 2016, 326:279-341, which is incorporated herein by reference in its entirety. 1-30 , N-AcGIP(LysPAL16, or N-AcGIP(LysPAL37). In some embodiments, the methods described herein comprise local lingual administration of GIP at a dose of about 2.5 μg to about 2.5 mg. In some embodiments, the methods described herein comprise local lingual administration of GIP at a dose of about 10 μg to about 1 mg. In some embodiments, the methods described herein comprise local lingual administration of GIP at a dose of about 25 μg to about 250 μg (e.g., a dose of about 25 μg, 50 μg, 75 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, or 250 μg).

[0057] In some embodiments, the metabolic hormone is glucagon, or an analog thereof (e.g., dasiglucagon (ZEGALOGUE®), AB-G023, or HM15136), variant, or biologically active fragment. In some embodiments, the glucagon, or a variant, analog, or biologically active fragment thereof has at least 70% (e.g., 70%, 75%, 80%, 85%, 90%, 95%, 97%, 99%, or 100%) sequence identity to SEQ ID NO: 16. In some embodiments, the glucagon has the amino acid sequence set forth in SEQ ID NO: 16. In some embodiments, the glucagon analog is dasiglucagon (ZEGALOGUE®), which has the sequence set forth in SEQ ID NO: 30 and comprises a polypeptide having α-aminoisobutyric acid at position 16. In some embodiments, the glucagon analog is AB-G023, a solubility stable, soluble glucagon analog. In some embodiments, the glucagon analog is HM15136, a long-acting glucagon analog chemically linked to a human immunoglobulin constant region via a non-peptidyl flexible linker. In some embodiments, the methods described herein comprise local lingual administration of glucagon, or a variant, analog, or biologically active fragment thereof, at a dose of about 2.5 μg to about 2.5 mg. In some embodiments, the methods described herein comprise local lingual administration of glucagon, or a variant, analog, or biologically active fragment thereof, at a dose of about 10 μg to about 1 mg. In some embodiments, the methods described herein comprise local lingual administration of glucagon, or a variant, analog, or biologically active fragment thereof, at a dose of about 25 μg to about 250 μg (e.g., a dose of about 25 μg, 50 μg, 75 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, or 250 μg).

[0058] In some embodiments, the compositions described herein are adapted for delivery to the oral cavity (e.g., buccal, oral mucosal, transmucosal, topical lingual, mouthwash, mouth rinse, gingival liquid, oral mucosal liquid and suspension, semi-solid oral mucosal preparations (including, e.g., gingival gel, gingival paste, oral mucosal gel, oral mucosal paste), oral mucosal drops, oral mucosal and sublingual sprays (including oropharyngeal sprays), dry powder sprays, lozenges and pastilles, compressed lozenges, sublingual and buccal tablets, oral mucosal capsules, mucoadhesive formulations). See, e.g., Oromucosal Preparations, (Ph Eur monograph 1807). In some embodiments, the metabolic hormone in the pharmaceutical composition is adapted to bind to the Y2 receptor expressed in the oral cavity (e.g., on the tongue).

[0059] In some embodiments, the metabolic hormone is formulated as a lozenge, film, spray, or orally dissolving tablet (ODT). In some embodiments, the metabolic hormone is formulated as an ODT using a formulation that dissolves rapidly on the tongue of the subject. For example, the formulation may have a concentration of about 1%-6% w / v (e.g., about 1%, about 2%, about 3%, about 4%, about 5%, or about 6%) of partially hydrolyzed gelatin, mannitol, hydrolyzed dextran, alginate, polyvinyl alcohol, polyvinylpyrrolidone, acacia, aspartame, sodium methylparaben, sodium propylparaben, phenylalanine, water, or combinations thereof. In some embodiments, the ODT is formulated using a ZYDIS® formulation as in U.S. Pat. Nos. 4,305,502, 4,371,516, and 5,738,875, which are incorporated herein by reference in their entireties.

[0060] In some embodiments, the composition includes excipients that increase the contact time of the metabolic hormone (e.g., PYY(3-36)) with the mucosa (e.g., viscosity-enhancing, encapsulation, and controlled release). Without being bound by theory, it is believed that increasing the contact time of the pharmaceutical formulation with the mucosa increases the binding of the metabolic hormone to its receptor on the tongue. Suitable excipients for viscosity enhancement include rheology modifiers, which may also be mucoadhesives such as methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, alginic acid, polyvinylpyrrolidone, and sodium carboxymethylcellulose. Suitable excipients for controlling the release of metabolic hormones in the oral cavity include mucoadhesive permeation enhancers, such as 23-lauryl ether, aprotinin, azone, benzalkonium chloride, cetylpyridinium chloride, cetyltrimethylammonium bromide, cyclodextrin, dextran sulfate, and lauric acid.Other suitable mucoadhesive polymers for use in buccal or intrabuccal delivery include agarose, chitosan, gelatin, hyaluronic acid, gums (e.g., guar, haecea, xanthan, gellan, carrageenan, pectin, and sodium alginate), cellulose derivatives (e.g., CMC, thiolated CMC, sodium CMC, HEC, HPMC, MC, methylhydroxyethylcellulose), poly(acrylic acid)-based polymers (e.g., CP, PC, PAA, polyacrylate, poly(methyl vinyl ether-co-methacrylate), ... Examples of suitable surfactants include acrylic acid, poly(2-hydroxyethyl methacrylate), poly(alkyl cyanoacrylate), poly(isohexyl cyanoacrylate), poly(isobutyl cyanoacrylate), copolymers of acrylic acid and PEG, poly(N-2-hydroxypropyl methacrylamide), PHPMAm, polyoxyethylene, PVA, PVP, and other thiolated polymers; scleroglucan, PVA, steroid detergents, non-ionic surfactants, laureth-9, sodium fusidate, included sodium lauryl, sodium laurate (e.g., pH 8.9), palmitoyl carnitine, lauric acid / propylene glycol vehicle, Brij 78, sodium deoxycholate, sodium lauryl sulfate, lecithin, and PVP. See, e.g., International Journal of Pharmaceutics, Volume 53, Issue 3, 1 August 1989, Pages 227-235.

[0061] In some embodiments, the pharmaceutical composition comprises an excipient that increases the residence time of the metabolic hormone in saliva (e.g., the time that the metabolic hormone remains in saliva without significant degradation of the peptide).Without being bound by theory, it is believed that increasing the residence time of the metabolic hormone in saliva increases the chance that the metabolic hormone binds to its receptor on the tongue.The residence time in saliva can be optionally adjusted, for example, so as not to increase the systemic exposure to the metabolic hormone through swallowing.

[0062] The metabolic hormone compositions described herein may include one or more pharma- ceutically acceptable excipients, such as propylene glycol, potassium sorbate, L-arginine, edetate disodium, monosodium phosphate, and polysorbate 20. In some embodiments, propylene glycol is present at a concentration of about 100 mg / ml, L-arginine is present at a concentration of about 25 mg / ml, potassium sorbate is present at a concentration of about 2 mg / ml, edetate disodium is present at a concentration of about 1.2 mg / ml, sodium phosphate monobasic dihydrate is present at a concentration of about 7.8 mg / ml, and polysorbate is present at a concentration of about 5 mg / ml. Additionally, the compositions described herein can include a co-solvent stabilizer such as propylene glycol or other suitable co-solvent stabilizer (e.g., low molecular weight polyethylene glycols (PEGs) such as PEG 200 and 400, glycerin, and ethanol. In some embodiments, the compositions described herein include an amino acid stabilizer such as L-arginine or other suitable amino acid stabilizer (e.g., alanine, aspartic acid, glycine, lysine, proline, or methionine). In some embodiments, the compositions described herein can include a preservative such as potassium sorbate or other suitable preservative (e.g., ascorbic acid, benzyl alcohol, benzoic acid, citric acid, chlorobutanol, m-cresol, glutathione, methionine, methylparaben, propyl ... The compositions described herein may include antioxidants such as EDTA disodium or another suitable antioxidant (e.g., sodium formaldehyde sulfoxylate, butylated hydroxyanisole, and butylated hydroxytoluene). In some embodiments, the compositions described herein include a buffer (e.g., acetate, carbonate, citrate, citrate-phosphate, glycine, HEPES, histidine, maleate, phosphate, succinate, tartrate, and triethanolamine (Tris)).In some embodiments, the compositions described herein can include a surfactant, such as polysorbate 20 or other suitable surfactant (e.g., poloxamer 188 / 407, polysorbate 40 or 80, or sodium lauryl sulfate).

[0063] In some embodiments, the excipient comprises a flavoring agent to increase compliance with the intake of the composition. For example, the flavoring agent can be used to mask bitterness or other undesirable flavor characteristics, or to make the composition compatible with the flavor of food that may be taken before or after administration of the composition. Suitable flavoring agents include, for example, apple, banana, bubble gum, cherry, chocolate, grape, lemon, mango, orange, raspberry, strawberry, vanilla, watermelon, mint, or combinations of the above flavoring agents. In another aspect, these flavoring agents are color-free, sugar-free, hypoallergenic, gluten-free, and casein-free.

[0064] Route of administration of metabolic hormones The metabolic hormones disclosed herein are administered locally to the tongue of a subject. The metabolic hormone compositions described herein are formulated to deliver metabolic hormones locally to oral tissues, for example, via local tongue delivery. Local delivery of metabolic hormones may result in beneficial outcomes, such as binding to Y2 receptors in oral tissues (e.g., Y2 receptors on the tongue) and transmitting signals to the brain via Y2 receptors, and / or avoiding systemic exposure to metabolic hormones and any undesirable side effects of systemic exposure. Furthermore, administering metabolic hormones locally to Y2 receptors in the mouth induces satiety using a substantially lower dose than is required to achieve a similar satiety-inducing effect by systemic administration of metabolic hormones.

[0065] Methods of inducing satiety and treating metabolic disorders using combination therapy Indications The methods described herein include administration of a metabolic hormone as part of a combination therapy with at least one GLP-1 RA for the induction of satiety and / or treatment of metabolic syndrome, diabetes, obesity, or any obesity-related disorder.

[0066] In some embodiments, the subject in need of combination therapy has been diagnosed with obesity, obesity-related disorders, metabolic syndrome, diabetes, dyslipidemia, hypertension, weight loss, weight gain, age-related weight gain, pediatric weight loss, NASH, CKD, PCOS, CVD, OSA, retinopathy, PVD, PAD, and neuropathy (e.g., diabetic neuropathy), and peripheral vascular degeneration, which often requires amputation, is to be prevented. In some embodiments, the method is used to maintain weight or prevent weight gain.

[0067] GLP-1 RA Treatment Regimens In some embodiments, the subject is undergoing a treatment regimen for GLP-1 RA. In some embodiments, the subject is undergoing treatment at the maximum recommended dose (e.g., administered based on weight, age, or other clinical parameters). In some embodiments, the subject has completed a dose escalation of GLP-1 RA (Tables 1-9) and has a steady state GLP-1 RA level in blood or plasma. In some embodiments, the subject has begun a GLP-1 RA treatment regimen or dose escalation and has not reached the maximum recommended GLP-1 RA dose. In some embodiments, the subject has not been diagnosed with any of the previous indications, but is at high risk of developing any of the previous indications, and / or has begun or completed a prophylactic dose escalation with GLP-1 RA.

[0068] The methods described herein combine systemic administration of a GLP-1 RA with local administration (e.g., topical lingual) of a metabolic hormone. In some embodiments, the subject is in the midst of a dose escalation regimen of a GLP-1 RA (as in any one of Tables 1-9). In some embodiments, the subject is in the midst of receiving a first dose of any one of the GLP-1 RAs in Table 1. In some embodiments, the subject is in the midst of receiving a second dose of any one of the GLP-1 RAs in Table 2. In some embodiments, the subject is in the midst of receiving a third dose of any one of the GLP-1 RAs in Table 3. In some embodiments, the subject is in the midst of receiving a fourth dose of any one of the GLP-1 RAs in Table 4. In some embodiments, the subject is in the midst of receiving a fifth dose of any one of the GLP-1 RAs in Table 5. In some embodiments, the subject is in the midst of receiving a sixth dose of any one of the GLP-1 RAs in Table 6. In some embodiments, the subject is receiving a seventh dose of any one of the GLP-1 RAs in Table 7. In some embodiments, the subject is receiving an eighth dose of any one of the GLP-1 RAs in Table 8.

[0069] [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9]

[0070] In some embodiments, the GLP-1 RA is administered at a dose lower than the recommended doses shown in Tables 1-9. RA is about 10% to about 90% (e.g., about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 101%, about 102%, about 103%, about 104%, about 105%, 8%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, or about 90%.

[0071] In some embodiments, the GLP-1 RA is exenatide formulated for immediate release, and the treatment regimen with exenatide formulated for immediate release comprises systemically administering a dose of n*5 μg, where n is a value of 1 to 5 (e.g., 1, 2, 3, 4, or 5). In some embodiments, the GLP-1 RA is exenatide formulated for sustained release, and the treatment regimen with exenatide formulated for sustained release comprises systemically administering a dose of n*2 mg, where n is a value of 1.

[0072] In some embodiments, the GLP-1 RA is lixisenatide, and the lixisenatide treatment regimen comprises systemically administering a dose of n*10 μg, where n is a value between 1 and 5 (e.g., 1, 2, 3, 4, or 5).

[0073] In some embodiments, the GLP-1 RA is liraglutide, and the liraglutide treatment regimen comprises systemically administering a dose of n*600 μg, where n is a value between 1 and 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10).

[0074] In some embodiments, the GLP-1 RA is semaglutide and the treatment regimen with semaglutide comprises systemically administering a dose of n*250 μg, where n is a value between 1 and 100 (e.g., 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, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 11 2, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 66, 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, or 100).

[0075] In some embodiments, the GLP-1 RA is dulaglutide and the treatment regimen with dulaglutide comprises systemic administration of a dose of n*750 μg, where n is a value between 1 and 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10).

[0076] In some embodiments, the GLP-1 RA is tirzepatide and is administered using one of two separate dose escalation regimens A and B. Tirzepatide treatment regimen A comprises systemically administering a dose of n*4 mg, where n is a value between 1 and 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10). Tirzepatide treatment regimen B comprises systemically administering a dose of n*2.5 mg, where n is a value between 1 and 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10).

[0077] In some embodiments, the GLP-1 RA is exenatide formulated for immediate release, and the treatment regimen with exenatide formulated for immediate release comprises systemically administering a dose of n*5 μg, where in the first dose regimen n has a value of 1 and in the second dose regimen n has a value of 2. In some embodiments, the GLP-1 RA is exenatide formulated for sustained release, and the treatment regimen with exenatide formulated for sustained release comprises systemically administering a dose of n*2 mg, where in the first dose regimen n has a value of 1.

[0078] In some embodiments, the GLP-1 RA is lixisenatide, and the treatment regimen with lixisenatide comprises systemically administering a dose of n*10 μg, where in a first dose regimen n has a value of 1 and in a second dose regimen n has a value of 2.

[0079] In some embodiments, the GLP-1 RA is liraglutide, and the liraglutide treatment regimen comprises systemically administering a dose of n*600 μg, where in a first dose regimen n has a value of 1, in a second dose regimen n has a value of 2, in a third dose regimen n has a value of 3, in a fourth dose regimen n has a value of 4, and in a fifth dose regimen n has a value of 5.

[0080] In some embodiments, the GLP-1 RA is semaglutide and the treatment regimen with semaglutide comprises systemically administering a dose of n*250 μg, where in the first dose regimen n has a value of 1, in the second dose regimen n has a value of 2, in the third dose regimen n has a value of 4, in the fourth dose regimen n has a value of 7, in the fifth dose regimen n has a value of 10, in the sixth dose regimen n has a value of 12, in the seventh dose regimen n has a value of 28 and in the eighth dose regimen n has a value of 56.

[0081] In some embodiments, the GLP-1 RA is dulaglutide, and the treatment regimen with dulaglutide comprises systemically administering a dose of n*750 μg, where in a first dose regimen n has a value of 1, in a second dose regimen n has a value of 2, in a third dose regimen n has a value of 4, and in a fourth dose regimen n has a value of 6.

[0082] In some embodiments, the GLP-1 RA is tirzepatide, and treatment regimen A with tirzepatide comprises systemically administering a dose of n*4 mg (wherein in the first dose regimen n has a value of 1, in the second dose regimen n has a value of 2, and in the third dose regimen n has a value of 3), or treatment regimen B with tirzepatide comprises systemically administering a dose of n*2.5 mg (wherein in the first dose regimen n has a value of 1, in the second dose regimen n has a value of 2, in the third dose regimen n has a value of 4, and in the fourth dose regimen n has a value of 6).

[0083] Dosage and Route of Administration Methods of inducing satiety and treating conditions such as metabolic syndrome, diabetes, obesity, and obesity-related disorders include using a combination therapy of any one of the GLP-1 RAs administered systemically in the dosing regimen set forth in Table 9 with local lingual administration of PYY at a dose of about 2.5 μg to about 2.5 mg. In some embodiments, the combination therapy described herein includes local lingual administration of PYY at a dose of about 10 μg to about 1 mg. In some embodiments, the combination therapy described herein includes local lingual administration of PYY at a dose of about 25 μg to about 250 μg (e.g., a dose of about 25 μg, 50 μg, 75 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, or 250 μg).

[0084] In some embodiments, the methods described herein describe a combination therapy of any one of the GLP-1 RAs administered systemically in the dosing regimen set forth in Table 9 with local lingual administration of PYY(3-36) at a dose of about 2.5 μg to about 2.5 mg. In some embodiments, the combination therapy described herein includes local lingual administration of PYY(3-36) at a dose of about 10 μg to about 1 mg. In some embodiments, the combination therapy described herein includes local lingual administration of PYY(3-36) at a dose of about 25 μg to about 250 μg (e.g., a dose of about 25 μg, 50 μg, 75 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, or 250 μg).

[0085] In some embodiments, the methods described herein describe combination therapy of any one of the GLP-1 RAs administered systemically in the dosing regimen set forth in Table 9 with local lingual administration of PYY(3-36) at a dose of about 2.5 μg to about 2.5 mg. In some embodiments, the combination therapy described herein includes local lingual administration of PYY(3-36) at a dose of about 10 μg to about 1 mg. In some embodiments, the combination therapy described herein includes local lingual administration of PYY(3-36) at a dose of about 25 μg to about 250 μg.

[0086] In some embodiments, the methods described herein describe a combination therapy of any one of GLP-1 RAs administered systemically in the dosing regimen shown in Table 9 with local lingual administration of leptin at a dose of about 2.5 μg to about 2.5 mg. In some embodiments, the combination therapy described herein includes local lingual administration of leptin at a dose of about 10 μg to about 1 mg. In some embodiments, the combination therapy described herein includes local lingual administration of leptin at a dose of about 25 μg to about 250 μg (e.g., a dose of about 25 μg, 50 μg, 75 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, or 250 μg).

[0087] In some embodiments, the methods described herein describe a combination therapy of any one of the GLP-1 RAs administered systemically in the dosing regimen shown in Table 9 with local lingual administration of OXM at a dose of about 2.5 μg to about 2.5 mg. In some embodiments, the combination therapy described herein includes local lingual administration of OXM at a dose of about 10 μg to about 1 mg. In some embodiments, the combination therapy described herein includes local lingual administration of OXM at a dose of about 25 μg to about 250 μg (e.g., a dose of about 25 μg, 50 μg, 75 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, or 250 μg).

[0088] In some embodiments, the methods described herein describe a combination therapy of any one of the GLP-1 RAs administered systemically in the dosing regimen shown in Table 9 with local lingual administration of CCK at a dose of about 2.5 μg to about 2.5 mg. In some embodiments, the combination therapy described herein includes local lingual administration of CCK at a dose of about 10 μg to about 1 mg. In some embodiments, the combination therapy described herein includes local lingual administration of CCK at a dose of about 25 μg to about 250 μg (e.g., a dose of about 25 μg, 50 μg, 75 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, or 250 μg).

[0089] In some embodiments, the methods described herein describe a combination therapy of any one of the GLP-1 RAs administered systemically in the dosing regimen shown in Table 9 with local lingual administration of insulin at a dose of about 2.5 μg to about 2.5 mg. In some embodiments, the combination therapy described herein includes local lingual administration of insulin at a dose of about 10 μg to about 1 mg. In some embodiments, the combination therapy described herein includes local lingual administration of insulin at a dose of about 25 μg to about 250 μg (e.g., a dose of about 25 μg, 50 μg, 75 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, or 250 μg).

[0090] In some embodiments, the methods described herein describe a combination therapy of any one of the GLP-1 RAs administered systemically in the dosing regimen shown in Table 9 with local lingual administration of amylin at a dose of about 2.5 μg to about 2.5 mg. In some embodiments, the combination therapy described herein includes local lingual administration of amylin at a dose of about 10 μg to about 1 mg. In some embodiments, the combination therapy described herein includes local lingual administration of amylin at a dose of about 25 μg to about 250 μg (e.g., a dose of about 25 μg, 50 μg, 75 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, or 250 μg).

[0091] In some embodiments, the methods described herein describe a combination therapy of any one of the GLP-1 RAs administered systemically in the dosing regimen shown in Table 9 with local lingual administration of GIP at a dose of about 2.5 μg to about 2.5 mg. In some embodiments, the combination therapy described herein includes local lingual administration of GIP at a dose of about 10 μg to about 1 mg. In some embodiments, the combination therapy described herein includes local lingual administration of GIP at a dose of about 25 μg to about 250 μg (e.g., a dose of about 25 μg, 50 μg, 75 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, or 250 μg).

[0092] In some embodiments, the methods described herein describe a combination therapy of any one of the GLP-1 RAs administered systemically in the dosing regimen shown in Table 9 with local lingual administration of glucagon at a dose of about 2.5 μg to about 2.5 mg. In some embodiments, the combination therapy described herein includes local lingual administration of glucagon at a dose of about 10 μg to about 1 mg. In some embodiments, the combination therapy described herein includes local lingual administration of glucagon at a dose of about 25 μg to about 250 μg (e.g., a dose of about 25 μg, 50 μg, 75 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, or 250 μg).

[0093] The metabolic hormone disclosed herein is administered to a subject in combination with GLP-1 RA. The metabolic hormone can be administered simultaneously with GLP-1-RA (e.g., administration of all active ingredients of the composition described herein occurs within 15 minutes, 10 minutes, 5 minutes, 2 minutes, 1 minute, 30 seconds, 20 seconds, 10 seconds, 5 seconds, 2 seconds, or less). The GLP-1 RA and the metabolic hormone can also be administered sequentially, so that the two actions overlap and their combined effect is a greater reduction in symptoms or other parameters related to the disorder than can be observed with one agent or with treatment performed alone or in the absence of the other agent. The GLP-1 RA and the metabolic hormone can be administered by different routes. For example, the composition of GLP-1 RA can be administered by intravenous injection, while the metabolic hormone can be administered locally and topically to the tongue. The GLP-1 RA may be administered immediately before or immediately after the metabolic hormone for up to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to 8 hours, up to 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 13 hours, 14 hours, up to 16 hours, up to 17 hours, up to 18 hours, up to 19 hours, up to 20 hours, up to 21 hours, up to 22 hours, up to 23 hours, up to 24 hours, or up to 1-7, 1-14, 1-21, or 1-30 days. In some embodiments, the metabolic hormone is administered after the GLP-1 RA. In some embodiments, the metabolic hormone is administered before the GLP-1 RA. In some embodiments, the metabolic hormone is administered simultaneously with the GLP-1 RA.

[0094] The methods described herein include administering a metabolic hormone (e.g., PYY, PYY(3-36), leptin, OXM, CCK, insulin, amylin, GIP, glucagon, analogs, variants, or biologically active fragments thereof, locally to the mouth (e.g., tongue, salivary glands, lingual and / or sublingual epithelium, or mucosa) of a subject, wherein the local administration does not result in a substantial change in the level of the metabolic hormone in the blood and / or plasma of the subject. Generally, the metabolic hormone level in the subject's blood and / or plasma is not increased by more than up to 10% (e.g., 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less) of the pre-administration level of the metabolic hormone. In some embodiments, the blood and / or plasma levels of PYY(3-36) are increased by more than 10% (e.g., 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less) of the pre-administration level of the metabolic hormone. After local lingual administration of PYY(3-36), the blood and / or plasma levels of leptin do not substantially exceed preprandial levels of about 15 pmol / l to about 25 pmol / l as reported in Metabolism, 4:223-233, 2006, which is incorporated herein by reference in its entirety. In some embodiments, after local lingual administration of leptin, the blood and / or plasma levels of leptin do not substantially exceed preprandial levels of about 5 ng / ml to about 35 ng / ml as reported in Considine et al, N. Engl. J. Med. 334:292-295, 1996, which is incorporated herein by reference in its entirety. In some embodiments, the blood and / or plasma levels of OXM do not substantially exceed preprandial levels of about 5 ng / ml to about 35 ng / ml as reported in Le Quellec et al. After local lingual administration of OXM, the blood and / or plasma levels do not substantially exceed preprandial levels of about 13.5 pmol / l to about 30.8 pmol / l, as reported in Cuntz, U., et al, J. Clin. Endocrinol. Metab. 74:1405-1409, 1992 (incorporated herein by reference in its entirety). In some embodiments, after local lingual administration of CCK, the blood and / or plasma levels do not substantially exceed preprandial levels of about 2 μmol / ml, as reported in Cuntz, U., et al, PLOS ONE. 8:e54457, 2013 (incorporated herein by reference in its entirety).In some embodiments, blood and / or plasma levels of insulin do not substantially exceed pre-prandial levels of about 2 mIU / ml to about 20 mIU / ml after local lingual administration of insulin, as reported in Cryer, PE, Williams Textbook of Endocrinology, 13th Edition, pg. 1582-1607, 2016, which is incorporated herein by reference in its entirety. In some embodiments, blood and / or plasma levels of amylin do not substantially exceed pre-prandial levels of about 20 pmol / l after local lingual administration of amylin, as reported in Cooper et al, Hypertension, 26:460-464, 1995, which is incorporated herein by reference in its entirety. In some embodiments, blood and / or plasma levels of GIP do not substantially exceed preprandial levels of about 33 pmol / l after local lingual administration of GIP, as reported in Theodorakis et al, Diabetes Care, 27:1692-1698, 2004, which is incorporated herein by reference in its entirety. In some embodiments, blood and / or plasma levels of glucagon do not substantially exceed preprandial levels of about 33 pmol / l after local lingual administration of glucagon, as reported in Jensen et al, Encyclopedia of Endocrine Diseases, Second Edition, Vol. 1:597-616, 2018, which is incorporated herein by reference in its entirety.

[0095] In some embodiments, the methods described herein include administering the combination therapy before a meal. The feeling of fullness can last for at least about 30, 60, 90, or 120 minutes or more after administering GLP-1RA and metabolic hormone and after the subject has eaten a meal. In some embodiments, the combination therapy is administered after a meal. In some embodiments, the combination therapy is administered on a regular schedule, independent of the subject's mealtime.

[0096] Combination therapy of subjects using locally administered metabolic hormones and systemically administered GLP-1 RA reduces the side effects associated with systemic GLP-1 RA monotherapy. In some embodiments, the combination therapy prevents, delays the onset, reduces the severity, and / or eliminates one or more of the side effects of systemic GLP-1 monotherapy, such as nausea, vomiting, diarrhea, abdominal pain, constipation, pancreatitis, diabetic retinal complications, hypoglycemia, acute kidney injury, or hypersensitivity.

[0097] kit The methods described herein may be provided in a kit for use in inducing satiety and / or treating a condition selected from metabolic syndrome, diabetes, obesity, and obesity-related disorders. The kit may include one or more doses of the combination therapy described herein. The kit may include one or more compositions comprising a metabolic hormone (e.g., ZYDIS® ODT) formulated for local administration to the tongue at a dose of about 2.5 μg to about 2.5 mg (e.g., about 10 μg to about 1 mg, e.g., about 25 μg to about 250 μg, e.g., about 25 μg, 50 μg, 75 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, or 250 μg) and a GLP-1 RA formulated for systemic administration (e.g., an injection pen) at a dose according to a first dose regimen, a second dose regimen, a third dose regimen, a fourth dose regimen, a fifth dose regimen, a sixth dose regimen, a seventh dose regimen, or an eighth dose regimen (see Tables 1-9). The kit may include one or more compositions comprising a metabolic hormone (e.g., ZYDIS® ODT) formulated for local administration to the tongue at a dose of about 10 μg to about 1 mg, and a GLP-1 RA formulated for systemic administration (e.g., an injection pen) in a dose according to a first dose regimen, a second dose regimen, a third dose regimen, a fourth dose regimen, a fifth dose regimen, a sixth dose regimen, a seventh dose regimen, or an eighth dose regimen (see Tables 1-9). The kit may include one or more compositions including a metabolic hormone (e.g., ZYDIS® ODT) formulated for local administration to the tongue at a dose of about 25 μg to about 250 μg (e.g., a dose of about 25 μg, 50 μg, 75 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, or 250 μg) and a GLP-1 RA formulated for systemic administration (e.g., an injection pen) at a dose according to a first dose regimen, a second dose regimen, a third dose regimen, a fourth dose regimen, a fifth dose regimen, a sixth dose regimen, a seventh dose regimen, or an eighth dose regimen (see Tables 1-9). The kit may include a package insert instructing a user of the kit, e.g., a physician, to practice any one of the methods described herein.The kit may optionally include a syringe or other device for administering the composition. In some embodiments, the kit may include one or more additional therapeutic agents. EXAMPLES

[0098] The following examples are presented to provide one of ordinary skill in the art with a description of how the methods described herein can be used, made, and evaluated, are intended to be purely illustrative of the invention, and are not intended to limit the scope of what the inventors regard as their invention.

[0099] Example 1. Combination Therapy for Patients with Type 2 Diabetes A human recently diagnosed with type 2 diabetes completes an escalating dose regimen of liraglutide (VICTOZA®). The human's glycemic control has reached a steady-state level, and an endocrinologist recommends combination therapy to improve the patient's condition. The human takes 3 mg of liraglutide (VICTOZA®) daily via an injection pen that delivers a GLP-1 RA systemically. In addition, the human begins taking one fast-dissolving tablet having PYY(3-36) as the active ingredient at a dose of 25 μg. The tablet dissolves on the human's tongue within 10 seconds. The human takes both liraglutide (VICTOZA®) and PYY(3-36) simultaneously, e.g., within 5 minutes of each other, once daily. The endocrinologist measures the human's glycemic control after 7 days of combination therapy and observes any greater than additive effects on the human's condition.

[0100] Example 2. Combination Treatment of Patients with Type 2 Diabetes and Obesity A recently diagnosed obese diabetic is at high risk for developing an adverse cardiovascular condition (e.g., heart attack or stroke) and begins an escalating dose regimen of dulaglutide (TRULICITY®). After receiving a second dose regimen of TRULICITY®, the individual reaches steady-state levels but experiences various side effects from systemic administration of a GLP-1 RA. An endocrinologist recommends combination therapy to improve the patient's condition without increasing the dose of TRULICITY®. The individual currently takes 1.5 mg of TRULICITY® weekly via an injection pen that delivers a GLP-1 RA systemically. In addition, the individual begins taking one fast-dissolving tablet having PYY(3-36) as the active ingredient at a dose of 200 μg. The tablet dissolves on the individual's tongue within 20 seconds. The person takes both TRULICITY® and PYY(3-36) at the same time, usually within 5 minutes of each other, once a week. An endocrinologist measures the person's blood glucose levels after 4 weeks of combination therapy to observe any greater than additive effects on the person's condition.

[0101] array Exenatide SEQ ID NO:1 HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS Lixisenatide SEQ ID NO:2 HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPSKKKKKK Liraglutide SEQ ID NO:3 [ka] K20 is modified with a glutamic acid palmitic acid side chain Semaglutide SEQ ID NO:4 [ka] X = α-aminoisobutyric acid, K20 is acylated with stearic diacid Dulaglutide SEQ ID NO:5 HGEGTFTSDVSSYLEEQAAKEFIAWLVKGGGGGGGSGGGGGSGGGGSAESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTV LHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG Tirzepatide SEQ ID NO:6 [ka] X=α-aminoisobutyric acid at positions 2 and 13, and K20 contains a C20 fatty diacid attached via a glutamic acid linker PYY SEQ ID NO:7 MVFVRRPWPALTTVLLALLVCLGALVDAYPIKPEAPREDASPEELNRYYASLRHYLNLVTRQRYGKRDGPDTLLSKTFFPDGEDRPVRSRSEGPDLW [Pro34]PYY SEQ ID NO:8 YPIKPEAPGEDASPEELNRYYASLRHYLNLVTRPRY PYY(3-36) SEQ ID NO:9 IKPEAPGEDASPEELNRYYASLRHYLNLVTRQRY Leptin SEQ ID NO:10 MHWGTLCGFLWLWPYLFYVQAVPIQKVQDDTKTLIKTIVTRINDISHTQSVSSKQKVTGLDFIPGLHPILTLSKMDQTLAVYQQILTSMPSRNVIQISNDLENLRDLLHVLAFSKSCHLPWASGLETLDSLGGVLEASGYSTEVVALSRLQGSLQDMLWQLDLSPGC OXM SEQ ID NO:11 HSQGTFTSDYSKYLDSRRAQDFVQWLMNTKRNKNNIA C.C.K. SEQ ID NO:12 MNSGVCLCVLMAVLAAGALTQPVPPADPAGSGLQRAEEAPRRQLRVSQRTDGESRAHLGALLARYIQQARKAPSGRMSIVKNLQNLDPSHRISDRDYMGWMDFGRRSAEEYEYPS Insulin SEQ ID NO:13 MALWMRLLPLLALLALWGPDPAAAFVNQHLCGSHLVEALYLVCGERGFFYTPKTRREAEDLQVGQVELGGGPGAGSLQPLALEGSLQKRGIVEQCCTSICSLYQLENYCN Amylin SEQ ID NO:14 MGILKLQVFLIVLSVALNHLKATPIESHQVEKRKCNTATCATQRLANFLVHSSNNFGAILSSTNVGSNTYGKRNAVEVLKREPLNYLPL GIP SEQ ID NO:15 MTTSPILQLLLRLSLCGLLLQRAETGSKGQTAGELYQRWERYRRECQETLAAAEPPSGLACNGSFDMYVCWDYAAPNATARASCPWYLPWHHHVAAGFVLRQCGSDGQWGLWRDHT QCENPEKNEAFLDQRLILERLQVMYTVGYSLSLATLLLALLILSLFRRLHCTRNYIHINLFTSFMLRAAAILSRDRLLPRPGPYLGDQALALWNQALAACRTAQIVTQYCVGANYTW LLVEGVYLHSLLVLVGGSEEGHFRYYLLLGWGAPALFVIPWVIVRYLYENTQCWERNEVKAIWWIIRTPILMTILINFLIFIRILGILLSKLRTRQMRCRDYRLRLARSTLTLVPL LGVHEVVFAPVTEEQARGALRFAKLGFEIFLSSFQGFLVSVLYCFINKEVQSEIRRGWHHCRLRRSLGEEQRQLPERAFRALPSGSGPGEVPTSRGLSSGTLPGPGNEASRELESYC Glucagon SEQ ID NO:16 MKSIYFVAGLFVMLVQGSWQRSLQDTEEKSRSFSASQADPLSDPDQMNEDKRHSQGTFTSDYSKYLDSRRAQDFVQWLMNTKRNRNNIAKRHDEFERHAEGTFTSDVSSYLEGQAAKEFIAWLVKGRGRRDFPEEVAIVEELGRRHADGSFSDEMNTILDNLAARDFINWLIQTKITDRK GLP-1 SEQ ID NO:17 MKSIYFVAGLFVMLVQGSWQRSLQDTEEKSRSFSASQADPLSDPDQMNED KRHSQGTFTSDYSKYLDSRRAQDFVQWLMNTKRNRNNIAKRHDEFERHAE GTFTSDVSSYLEGQAAKEFIAWLVKGRGRRDFPEEVAIVEELGRRHADGS FSDEMNTILDNLAARDFINWLIQTKITDRK Metreleptin SEQ ID NO:18 MVPIQKVQDDTKTLIKTIVTRINDISHTQSVSSKQKVTGLDFIPGLHPILTLSKMDQTLA VYQQILTSMPSRNVIQISNDLENLRDLLHVLAFSKSCHLPWASGLETLDSLGGVLEASGY STEVVALSRLQGSLQDMLWQLDLSPGC Insulin Aspart A chain SEQ ID NO:19 GIVEQCCTSICSLYQLENYCN Insulin Aspart B chain SEQ ID NO:20 FVNQHLCGSHLVEALYLVCGERGFFYTDKT Insulin glargine A chain SEQ ID NO:21 GIVEQCCTSICSLYQLENYCG Insulin glargine B chain SEQ ID NO:22 FVNQHLCGSHLVEALYLVCGERGFFYTPKTRR Insulin lispro A chain SEQ ID NO:23 GIVEQCCTSICSLYQLENYCN Insulin lispro B chain SEQ ID NO:24 FVNQHLCGSHLVEALYLVCGERGFFYTKPT Insulin glulisine A chain SEQ ID NO:25 GIVEQCCTSICSLYQLENYCN Insulin glulisine B chain SEQ ID NO:26 FVKQHLCGSHLVEALYLVCGERGFFYTPET Insulin detemir A chain SEQ ID NO:27 GIVEQCCTSICSLYQLENYCN Insulin detemir B chain SEQ ID NO:28 FVNQHLCGSHLVEALYLVCGERGFFYTPK Pramlintide SEQ ID NO:29 KCNTATCATQRLANFLVHSSNNFGPILPTNVGSNTY Dasigurukagon SEQ ID NO:30 [ka] X = α-aminoisobutyric acid

[0102] Other embodiments While the invention has been described in conjunction with particular embodiments thereof, it will be understood that the invention is capable of further modifications, and that this application is intended to cover any variations, uses, or adaptations of the invention in accordance with the principles of the invention in general, including departures from the invention which become known or customarily practiced in the art to which the invention pertains, as applicable to the essential features described above, and in accordance with the scope of the appended claims. Other embodiments are within the scope of the claims.

Claims

1. A composition for local sublingual administration, containing a metabolic hormone in a dose of 2.5 μg to 250 μg, for use in inducing satiety in a subject, or treating metabolic syndrome, diabetes, obesity, obesity-related disorders, non-alcoholic steatohepatitis (NASH), chronic kidney disease (CKD), polycystic ovary syndrome (PCOS), cardiovascular disease (CVD), obstructive sleep apnea (OSA), retinopathy, peripheral vascular disease (PVD), peripheral arterial disease (PAD), or neuropathy, under a treatment regimen of any one of the glucagon-like peptide 1 receptor agonists (GLP-1 RAs) shown in Tables 1, 2, 3, 4, 5, 6, 7, or 8.

2. The composition for use according to claim 1, wherein the metabolic hormone targets the Y2 receptor of the subject.

3. The composition for use according to claim 2, wherein the Y2 receptor is associated with the tongue of the subject.

4. The composition for use according to any one of claims 1 to 3, wherein the local sublingual administration of the metabolic hormone does not substantially result in a change in the level of the metabolic hormone in the blood and / or plasma of the subject.

5. The composition for use according to any one of claims 1 to 3, wherein the metabolic hormone is PYY, PYY(3-36), leptin, oxyntomodulin (OXM), cholecystokinin (CCK), insulin, amylin, gastric inhibitory peptide (GIP), glucagon, an analog, variant, or biologically active fragment thereof.

6. The composition for use according to any one of claims 1 to 3, wherein the metabolic hormone of 2.5 μg, 10 μg, 25 μg, 50 μg, 100 μg, or 250 μg is administered.

7. The composition for use according to any one of claims 1 to 3, wherein the metabolic hormone is formulated as an orally disintegrating tablet (ODT), lozenge, film, or spray.

8. The composition for use according to claim 7, wherein the ODT is in a rapidly dissolving form containing partially hydrolyzed gelatin, mannitol, hydrolyzed dextran, alginate, polyvinyl alcohol, polyvinylpyrrolidone, acacia, aspartame, sodium methylparaben, sodium propylparaben, phenylalanine, water, or a combination thereof, at a concentration of about 1% to 6% w / v.

9. A composition for use according to any one of claims 1 to 3, wherein the local sublingual administration of the metabolic hormone reduces GLP-1 related side effects.

10. The composition for use according to claim 9, wherein the GLP-1 related side effects include nausea, vomiting, diarrhea, abdominal pain, constipation, pancreatitis, diabetic retinopathy, hypoglycemia, acute kidney injury, hypersensitivity, or combinations thereof.

11. The composition for use according to any one of claims 1 to 3, wherein the GLP-1 RA is formulated as a tablet, gel capsule, or liquid.

12. A composition containing a metabolic hormone in a dose of 2.5 μg to 250 μg formulated for local sublingual administration for use in a method of inducing satiety or treating metabolic syndrome, diabetes, obesity, obesity-related disorders, NASH, CKD, PCOS, CVD, OSA, retinopathy, PVD, PAD, or neuropathy in a subject who has completed the systemic GLP-1 RA dose escalation regimen of Table 9.

13. A composition containing a metabolic hormone in a dose of 2.5 μg to 250 μg formulated for local sublingual administration for use in a method of inducing satiety or treating metabolic syndrome, diabetes, obesity, obesity-related disorders, NASH, CKD, PCOS, CVD, OSA, retinopathy, PVD, PAD, or neuropathy in a subject under the following GLP-1 RA treatment regimens: (a) The GLP-1 RA is exenatide formulated for immediate release, and the treatment regimen includes systemic administration of n*5 μg of exenatide (where the value of n is 1 to 2); (b) The GLP-1 RA is exenatide formulated for sustained release, and the treatment regimen includes systemic administration of n*2 mg of exenatide (where the value of n is 1); (c) The GLP-1 RA is lixisenatide, and the treatment regimen includes systemic administration of n*10 μg of lixisenatide (where the value of n is 1 to 2); (d) The GLP-1 RA is liraglutide, and the treatment regimen includes systemic administration of n*600 μg of liraglutide (where the value of n is 1 to 10); (e) The GLP-1 RA is semaglutide, and the treatment regimen includes systemic administration of n*250 μg of semaglutide (where the value of n is 1 to 100); (f) The GLP-1 RA is dulaglutide and the treatment regimen comprises systemic administration of n * 750 μg of dulaglutide (where n has a value from 1 to 10); (g) The GLP-1 RA is tirzepatide and treatment regimen A comprises systemic administration of n * 4 mg, n * 8 mg, or n * 12 mg, and treatment regimen B comprises systemic administration of n * 2.5 mg, n * 5 mg, n * 10 mg, or n * 15 mg of tirzepatide (where n has a value from 1 to 10). **Claim 14** (a) The GLP-1 RA is semaglutide and the treatment regimen comprises systemic administration of n * 1.7 μg of semaglutide (where n has a value from 1 to 10), or (b) The GLP-1 RA is semaglutide and the treatment regimen comprises systemic administration of n * 2.4 μg of semaglutide (where n has a value from 1 to 10), A composition for use according to claim 13. **Claim 15** A composition for use in a method of inducing satiety or treating metabolic syndrome, diabetes, obesity, obesity-related disorders, NASH, CKD, PCOS, CVD, OSA, retinopathy, PVD, PAD, or neuropathy in a subject, (a) 10% to 90% of a GLP-1 RA formulated for systemic administration to a subject receiving the first, second, third, fourth, fifth, sixth, seventh, or eighth dosing regimen of Table 9, and (b) A metabolic hormone in a dose of 2.5 μg to 250 μg formulated for topical lingual administration, comprising. **Claim 16** A kit comprising a metabolic hormone formulated for topical lingual administration in a dose of 2.5 μg to 250 μg and a dose of a GLP-1 RA formulated for systemic administration.