Compositions and methods for treating metabolic diseases with topical-lingual receptor agonists

Abstract

The invention provides compositions and methods for inducing satiety or treating a metabolic disorder. The compositions include pegsebrenatide, ecnoglutide, dapiglutide, tirzepatide, VK2735, efinopegdutide, cotadutide, mazdutide, or retatrutide, which can be administered topical-ling ually to provide treatment for obesity and metabolism related disorders.

Description

[0001] COMPOSITIONS AND METHODS FOR TREATING METABOLIC DISEASES WITH TOPICALLINGUAL RECEPTOR AGONISTS

[0002] Sequence Listing

[0003] This application contains a Sequence Listing which has been filed electronically in Extensible Markup Language (XML) format and is hereby incorporated by reference in its entirety. Said XML copy, created on March 28, 2025, is named 51547-019WO2_Sequence_Listing_3_28_25. XML and is 15,633 bytes in size.

[0004] Background of the Invention

[0005] The prevalence of obesity continues to increase worldwide. However, there is still a lack of effective, long-term, non-invasive treatments for obesity and other metabolism related disorders. Induction of satiety and treatment of metabolic syndrome, diabetes, obesity, and obesity-related disorders with existing therapeutics does not produce suitable therapeutic effects and often accompany severe side effects such as nausea. Accordingly, new treatments without side effects are needed.

[0006] Summary of the Invention

[0007] In one aspect, the invention features a composition that includes an agent selected from pegsebrenatide (NLY01 ), ecnoglutide, dapiglutide, tirzepatide, VK2735, efinopegdutide (MK-6024), cotadutide, mazdutide (IBI362, GLXC-26803), and retatrutide (LY3437943). The composition is formulated to be administered topical-lingually (e.g., topically to the lingual epithelium).

[0008] In some embodiments, the composition may be formulated, e.g., as an oral dissolving tablet, a lozenge, a film, a spray, a semisolid, a particulate, or in a lipid-based carrier.

[0009] In some embodiments, the dose of the agent (e.g., pegsebrenatide, ecnoglutide, dapiglutide, tirzepatide, VK2735, efinopegdutide, cotadutide, mazdutide, or retatrutide) is from 1 ng to 20 mg. For example, the dose of the agonist may be from 1 ng to 10 ng, e.g., 1 ng, 2 ng, 3 ng, 4 ng, 5 ng, 6 ng, 7 ng, 8 ng, 9 ng, or 10 ng, e.g., from 10 ng to 100 ng, e.g., 10 ng, 20 ng, 30 ng, 40 ng, 50 ng, 60 ng, 70 ng, 80 ng, 90 ng, or 100 ng, e.g., from 100 ng to 1 pg, e.g., 100 ng, 200 ng, 300 ng, 400 ng, 500 ng, 600 ng, 700 ng, 800 ng, 900 ng, or 1 pg, e.g., from 1 pg to 10 pg, e.g., 1 pg, 2 pg, 3, pg, 4 pg, 5 pg, 6 pg, 7 pg, 8 pg, 9 pg, or 10 pg, e.g., from 10 pg to 100 pg, e.g., 10 pg, 20 pg, 30 pg, 40 pg, 50 pg, 60 pg, 70 pg, 80 pg, 90 pg, or 100 pg, e.g., from 100 pg to 1 mg, e.g., 100 pg, 200 pg, 300 pg, 400 pg, 500 pg, 600 pg, 700 pg, 800 pg, 900 pg, or 1 mg, or e.g., from 1 mg to 20 mg, e.g., 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg.

[0010] In some embodiments, the composition includes pegsebrenatide.

[0011] In some embodiments, the composition includes ecnoglutide.

[0012] In some embodiments, the composition includes dapiglutide.

[0013] In some embodiments, the composition includes tirzepatide.

[0014] In some embodiments, the composition includes VK2735. In some embodiments, the composition includes efinopegdutide.

[0015] In some embodiments, the composition includes cotadutide.

[0016] In some embodiments, the composition includes mazdutide.

[0017] In some embodiments, the composition includes retatrutide.

[0018] In some embodiments, the composition further includes a pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient may be, e.g., propylene glycol, potassium sorbate, l-arginine, edetate disodium, monosodium phosphate, polysorbate 20, gelatin, mannitol, dextran, alginate, polyvinyl alcohol, polyvinylpyrrolidone, acacia, aspartame, sodium methylparaben, sodium propylparaben, phenylalanine, water, or a combination thereof. The pharmaceutically acceptable excipient may include one or more stabilizers, preservatives, antioxidants, buffers, surfactants, rheology modifiers, and mucosal permeation enhancers. The stabilizer may be, e.g., mannitol or sucrose. The preservative may be, e.g., sodium methyl paraben or sodium propyl paraben. The mucosal permeation enhancer may be, e.g., gelatin.

[0019] In some embodiments, the pharmaceutically acceptable excipient further includes a flavoring or sweetening agent. The sweetening agent may be, e.g., sorbitol, sucrose, or aspartame.

[0020] In another aspect, the invention features a method for inducing satiety or treating a disease or disorder selected from a metabolic syndrome, obesity, an obesity-related disorder, diabetes, fatty liver disease, nonalcoholic steatohepatitis, chronic kidney disease, polycystic ovary syndrome, cardiovascular disease, obstructive sleep apnea, retinopathy, peripheral vascular disease, peripheral artery disease, and neuropathy (e.g., diabetic neuropathy) in a subject in need thereof. The method includes administering to the subject a composition that includes an agent selected from pegsebrenatide, ecnoglutide, dapiglutide, tirzepatide, VK2735, efinopegdutide, cotadutide, mazdutide, and retatrutide. The composition may be administered intraorally to a subject or delivered to the tongue of the subject.

[0021] In some embodiments, the method includes a composition that provides treatment without substantially changing the concentration of the agent in the blood of the subject. In some embodiments, the composition provides treatment without the polypeptide substantially appearing in the blood of the subject.

[0022] Definitions

[0023] To facilitate the understanding of this invention, a number of terms are defined below. Terms defined herein have meanings as commonly understood by a person of ordinary skill in the areas relevant to the invention. Terms such as "a," "an," and "the" are not intended to refer to only a singular entity but include the general class of which a specific example may be used for illustration. The terminology herein is used to describe specific embodiments of the invention, but their usage does not limit the invention, except as outlined in the claims.

[0024] As used herein, the term “about” refers to a value that is within 10% above or below the value being described.

[0025] As used herein, the term “metabolic disorder” refers to a human or animal condition or disease associated with and / or resulting from abnormal function or control of the metabolic system (e.g., obesity, diabetes, fatty liver disease, nonalcoholic steatohepatitis, polycystic ovary syndrome, elevated blood glucose levels, chronic kidney disease, cardiovascular disease, obstructive sleep apnea, retinopathy, neuropathy (e.g., diabetic neuropathy), peripheral artery disease, and / or peripheral vascular disease). The term “disorder” generally refers to disruption to regular bodily structure and function or a pathophysiological response to internal or external factors.

[0026] As used herein, the term “subject,” refers to a human or non-human animal (e.g., a mammal).

[0027] As used herein, the terms “topical-lingual administration,” “topically to the tongue,” or variations thereof, refer to the local administration of a metabolic hormone to the epithelium of the mouth and / or tongue of a subject with substantially no change in the levels of metabolic hormone in the blood of the subject (e.g., substantially no systemic exposure).

[0028] As used herein, the phrases “without substantially changing the concentration of the agent in the blood or plasma of the subject” and “without substantially appearing in the blood or plasma of the subject” refer to an increase of the agent level in the blood and / or plasma by no more than up to 10% (e.g., 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.1%, 0.01% or less) of the pre-administration level of the polypeptide. For example, an agent administered to a subject topically to the tongue (e.g., topically to the lingual epithelium) at any dosage would reach at most a peak level of one tenth that of the endogenous level of PYY and decrease substantially thereafter. In some embodiments, the blood and / or plasma level of the agent does not surpass 20 pM.

[0029] Detailed Description of the Invention

[0030] In general, the invention features topical-lingually delivered agents (e.g., pegsebrenatide (NLY01 ), ecnoglutide, dapiglutide, tirzepatide, VK2735, efinopegdutide (MK-6024), cotadutide, mazdutide (IBI362, GLXC-26803), and retatrutide (LY3437943)) and methods of use thereof for inducing satiety and treating a condition affecting metabolism, such as metabolic syndrome, diabetes, obesity, and obesity-related disorders. Pegsebrenatide and ecnoglutide are glucagon-like peptide-1 (GLP-1 ) receptor agonists. Dapiglutide is a GLP-1 / glucagon-like peptide-2 (GLP-2) receptor dual agonist. Tirzepatide and VK2735 are glucose-dependent insulinotropic polypeptide (GIP) / GLP-1 receptor dual agonists. Efinopegdutide, cotadutide, and mazdutide are GLP-1 / glucagon receptor dual agonist. Retatrutide is a GIP / GLP-1 / glucagon receptor triple agonist.

[0031] Administration of an agent (e.g., pegsebrenatide, ecnoglutide, dapiglutide, tirzepatide, VK2735, efinopegdutide, cotadutide, mazdutide, or retatrutide) via a non-systemic pathway allows the composition to provide treatment to the subject without substantially changing the concentration of the agent in the blood of the subject. In some embodiments, the composition provides treatment without the polypeptide substantially appearing in the blood of the subject. Furthermore, topical-lingual administration targets specific pleasure centers in the brain, activates critical brain regions, and avoids neural or non-neural targets that can cause clinical risk (e.g., toxicity) or side effects, such as nausea, injection site pain, or malaise. For example, systemic administration of a metabolic hormone activates neural receptors in the hypothalamus, nucleus tractus solitarius (NTS), and area postrema, whereas non-systemic routes of administration as described herein activates neural receptors in the hypothalamus and NTS, but substantially avoids the area postrema. By targeting neural receptors, e.g., in the mouth (e.g., tongue), the neural receptors and connections can sufficiently activate the pleasure centers in the CNS, which control satiety. Accordingly, activation of these pleasure centers may provide treatment for a metabolic disorder or a satiety disorder associated with dysregulated pleasure centers in the brain. The composition and methods are described in more detail below.

[0032] Topical-Lingual GLP-1 Receptor Agonists

[0033] The compositions described herein include administration of an agent (e.g., pegsebrenatide, ecnoglutide, dapiglutide, tirzepatide, VK2735, efinopegdutide, cotadutide, mazdutide, or retatrutide) that targets (e.g., binds, associates, or interacts with) a GLP-1 receptor in the oral cavity (e.g., tongue) of a subject. In some embodiments, the agent targets a GLP-1 receptor. In some embodiments, the agent targets a GLP-1 receptor and a GLP-2 receptor. In some embodiments, the agent targets a GLP-1 receptor and a GIP receptor. In some embodiments, the agent targets a GLP-1 receptor and a glucagon receptor. In some embodiments, the agent targets a GLP-1 receptor, a GIP receptor, and a glucagon receptor.

[0034] In some embodiments, the dose of the agent is from 1 ng to 20 mg. For example, the dose of the agent may be from 1 ng to 10 ng, e.g., 1 ng, 2 ng, 3 ng, 4 ng, 5 ng, 6 ng, 7 ng, 8 ng, 9 ng, or 10 ng, e.g., from 10 ng to 100 ng, e.g., 10 ng, 20 ng, 30 ng, 40 ng, 50 ng, 60 ng, 70 ng, 80 ng, 90 ng, or 100 ng, e.g., from 100 ng to 1 pg, e.g., 100 ng, 200 ng, 300 ng, 400 ng, 500 ng, 600 ng, 700 ng, 800 ng, 900 ng, or 1 pg, e.g., from 1 pg to 10 pg, e.g., 1 pg, 2 pg, 3, pg, 4 pg, 5 pg, 6 pg, 7 pg, 8 pg, 9 pg, or 10 pg, e.g., from 10 pg to 100 pg, e.g., 10 pg, 20 pg, 30 pg, 40 pg, 50 pg, 60 pg, 70 pg, 80 pg, 90 pg, or 100 pg, e.g., from 100 pg to 1 mg, e.g., 100 pg, 200 pg, 300 pg, 400 pg, 500 pg, 600 pg, 700 pg, 800 pg, 900 pg, or 1 mg, e.g., from 1 mg to 20 mg, e.g., 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 1 1 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg.

[0035] In some embodiments, the agent is pegsebrenatide. Pegsebrenatide is a pegylated, long- acting analog of exenatide, which is a GLP-1 receptor agonist. In some embodiments, pegsebrenatide has the amino acid sequence set forth in SEQ ID NO: 1 . Pegsebrenatide has the structure of exendin- 4-oyl-L-cysteinamide, conjugated at Cys 40 via a 1 -0-(3-{0'-[3-(3- maleimidopropanamido)propyl]polyethylene glycol-O-yl}propylaminocarbonyl)glycerol linker with two O-methylpoly(ethylene glycol) chains. In some embodiments, the compositions described herein include administration of pegsebrenatide in a dose of from about 100 ng to about 10 mg. In some embodiments, the compositions described herein include administration of pegsebrenatide in a dose of from about 1 pg to about 1 mg. In some embodiments, the compositions described herein include administration of pegsebrenatide in a dose of from about 25 pg to about 250 pg (e.g., a dose of about 25 pg, 50 pg, 75 pg, 100 pg, 125 pg, 150 pg, 175 pg, 200 pg, 225 pg, or 250 pg).

[0036] In some embodiments, the agent is ecnoglutide. Ecnoglutide is a long-acting, cAMP-biased GLP-1 receptor agonist with the chemical formula C194H304N48O61. In some embodiments, ecnoglutide has the amino acid sequence set forth in SEQ ID NO: 2. In some embodiments, the compositions described herein include administration of ecnoglutide in a dose of from about 100 ng to about 10 mg. In some embodiments, the compositions described herein include administration of ecnoglutide in a dose of from about 1 pg to about 1 mg. In some embodiments, the compositions described herein include administration of ecnoglutide in a dose of from about 25 gg to about 250 gg (e.g., a dose of about 25 gg, 50 gg, 75 gg, 100 gg, 125 gg, 150 gg, 175 gg, 200 gg, 225 gg, or 250 gg).

[0037] In some embodiments, the agent is dapiglutide. Dapiglutide is a long-acting GLP-1 / GLP-2 receptor dual agonist with the chemical formula C192H302N46O57. In some embodiments, dapiglutide has the amino acid sequence set forth in SEQ ID NO: 3. In some embodiments, the compositions described herein include administration of dapiglutide in a dose of from about 100 ng to about 10 mg. In some embodiments, the compositions described herein include administration of dapiglutide in a dose of from about 1 pg to about 1 mg. In some embodiments, the compositions described herein include administration of dapiglutide in a dose of from about 25 pg to about 250 gg (e.g., a dose of about 25 gg, 50 gg, 75 gg, 100 gg, 125 gg, 150 gg, 175 gg, 200 gg, 225 gg, or 250 gg).

[0038] In some embodiments, the agent is tirzepatide. Tirzepatide is a modified GIP analog with the chemical formula C225H348N48O68 and a GIP / GLP-1 receptor dual agonist. In some embodiments, tirzepatide has the amino acid sequence set forth in SEQ ID NO: 4. In some embodiments, the compositions described herein include administration of tirzepatide in a dose of from about 100 ng to about 10 mg. In some embodiments, the compositions described herein include administration of tirzepatide in a dose of from about 1 gg to about 1 mg. In some embodiments, the compositions described herein include administration of tirzepatide in a dose of from about 25 gg to about 250 gg (e.g., a dose of about 25 gg, 50 gg, 75 gg, 100 gg, 125 gg, 150 gg, 175 gg, 200 gg, 225 gg, or 250 Rg)-

[0039] In some embodiments, the agent is VK2735. VK2735 is a GIP / GLP-1 receptor dual agonist. In some embodiments, the compositions described herein include administration of VK2735 in a dose of from about 100 ng to about 10 mg. In some embodiments, the compositions described herein include administration of VK2735 in a dose of from about 1 gg to about 1 mg. In some embodiments, the compositions described herein include administration of VK2735 in a dose of from about 25 gg to about 250 gg (e.g., a dose of about 25 gg, 50 gg, 75 gg, 100 gg, 125 gg, 150 gg, 175 gg, 200 gg, 225 gg, or 250 gg).

[0040] In some embodiments, the agent is efinopegdutide. Efinopegdutide is a pegylated, long-acting GLP-1 / glucagon receptor dual agonist (see, e.g., PCT Pub. Nos. WQ2020 / 128967 and WO2024 / 263537, which are herein incorporated by reference). Efinopegdutide is an oxyntomodulin analog conjugated at the C-terminal cysteine residue by a 10 kDa polyethylene glycol (PEG) linker (N ~ 225) to the N-terminus of an Fc portion homodimer of aglycosylated human immunoglobulin G4 (lgG4). In some embodiments, the oxyntomodulin analog may lack a C-terminal lysine. In some embodiments, the oxyntomodulin analog has the amino acid sequence set forth in SEQ ID NO: 5. In some embodiments, the Fc portion of lgG4 has the amino acid sequence set forth in SEQ ID NO: 6. In some embodiments, the compositions described herein include administration of Efinopegdutide in a dose of from about 100 ng to about 10 mg. In some embodiments, the compositions described herein include administration of Efinopegdutide in a dose of from about 1 pg to about 1 mg. In some embodiments, the compositions described herein include administration of Efinopegdutide in a dose of from about 25 pg to about 250 gg (e.g., a dose of about 25 gg, 50 gg, 75 gg, 100 gg, 125 gg, 150 gg, 175 gg, 200 gg, 225 gg, or 250 gg). In some embodiments, the agent is cotadutide. Cotadutide is a potent GLP-1 / glucagon dual agonist with the chemical formula C167H252N42O55. In some embodiments, cotadutide has the amino acid sequence set forth in SEQ ID NO: 7. In some embodiments, the compositions described herein include administration of cotadutide in a dose of from about 100 ng to about 10 mg. In some embodiments, the compositions described herein include administration of cotadutide in a dose of from about 1 pg to about 1 mg. In some embodiments, the compositions described herein include administration of cotadutide in a dose of from about 25 pg to about 250 pg (e.g., a dose of about 25 pg, 50 pg, 75 pg, 100 pg, 125 pg, 150 pg, 175 pg, 200 pg, 225 pg, or 250 pg).

[0041] In some embodiments, the agent is mazdutide. Mazdutide is a long-acting synthetic analog of oxyntomodulin and a GLP-1 / glucagon dual agonist. Mazdutide has the chemical formula C210H322N46O67. In some embodiments, mazdutide has the amino acid sequence set forth in SEQ ID NO: 8. In some embodiments, the compositions described herein include administration of mazdutide in a dose of from about 100 ng to about 10 mg. In some embodiments, the compositions described herein include administration of mazdutide in a dose of from about 1 pg to about 1 mg. In some embodiments, the compositions described herein include administration of mazdutide in a dose of from about 25 pg to about 250 pg (e.g., a dose of about 25 pg, 50 pg, 75 pg, 100 pg, 125 pg, 150 pg, 175 pg, 200 pg, 225 pg, or 250 pg).

[0042] In some embodiments, the agent is retatrutide. Retatrutide is a GIP / GLP-1 / glucagon receptor triple agonist and has the chemical formula C221 H342N46O68. In some embodiments, retatrutide has the amino acid sequence set forth in SEQ ID NO: 9. In some embodiments, the compositions described herein include administration of retatrutide in a dose of from about 100 ng to about 10 mg. In some embodiments, the compositions described herein include administration of retatrutide in a dose of from about 1 pg to about 1 mg. In some embodiments, the compositions described herein include administration of retatrutide in a dose of from about 25 pg to about 250 pg (e.g., a dose of about 25 pg, 50 pg, 75 pg, 100 pg, 125 pg, 150 pg, 175 pg, 200 pg, 225 pg, or 250 pg).

[0043] Pharmaceutical Compositions and Routes of Administration

[0044] The agents (e.g., pegsebrenatide, ecnoglutide, dapiglutide, tirzepatide, VK2735, efinopegdutide, cotadutide, mazdutide, or retatrutide) described herein can be formulated as pharmaceutical compositions for administration to human subjects in a biologically compatible form suitable for administration in vivo.

[0045] The compositions described herein may be administered to a subject (e.g., a human) in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art. The compositions described herein may be administered, for example, by any route that allows the composition (e.g., pegsebrenatide, ecnoglutide, dapiglutide, tirzepatide, VK2735, efinopegdutide, cotadutide, mazdutide, or retatrutide) to reach the target receptor or receptors without substantially changing the concentration of the agent in the blood of the subject. The composition may be administered, for example, topical-lingually (e.g., topically to the lingual epithelium).

[0046] In some embodiments, the compositions described herein are formulated for delivery to the oral cavity, e.g., intraoral, oromucosal, transmucosal, topical-lingual, gargles, mouthwashes, gingival solutions, oromucosal solutions and oromucosal suspensions, semi-solid oromucosal preparations (including for example gingival gel, gingival paste, oromucosal gel, oromucosal paste), oromucosal drops, oromucosal sprays and sublingual sprays (including oropharyngeal sprays), dry powder sprays, lozenges and pastilles, compressed lozenges, sublingual tablets and buccal tablets, oromucosal capsules, mucoadhesive preparations). See, e.g., Oromucosal Preparations, (Ph Eur monograph 1807).

[0047] In some embodiments, the compositions described herein are formulated as an orally dissolving tablet (ODT), a lozenge, a film, a spray, a semisolid, a particulate, or in a lipid-based carrier. In some embodiments, the agent is formulated as an ODT using a formulation that rapidly dissolves on the tongue of a subject. For example, the formulation may have partially hydrolyzed gelatin at a concentration of from about 1% to 6% w / v (e.g., about 1%, about 2%, about 3%, about 4%, about 5%, or about 6%), mannitol, hydrolyzed dextran, alginate, polyvinyl alcohol, polyvinylpyrrolidone, acacia, aspartame, sodium methylparaben, sodium propylparaben, phenylalanine, water, or a combination thereof. In some embodiments, the ODT is formulated using the ZYDIS® formulation, as described in U.S. Patent Nos. 4,305,502, 4,371 ,516, and 5,738,875, herein incorporated in their entirety by reference.

[0048] Solutions of a composition described herein can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, dimethyl sulfoxide (DMSO), and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington’s Pharmaceutical Sciences (2012, 22nd ed.) and in The United States Pharmacopeia: The National Formulary (USP 41 NF 36), published in 2018.

[0049] The compositions described herein may be administered to an animal, e.g., a human, alone or in combination with pharmaceutically acceptable carriers, as noted herein, the proportion of which is determined by the solubility and chemical nature of the composition, chosen route of administration, and standard pharmaceutical practice.

[0050] In some embodiments, the compositions include excipients that increase the time the agent (e.g., pegsebrenatide, ecnoglutide, dapiglutide, tirzepatide, VK2735, efinopegdutide, cotadutide, mazdutide, or retatrutide), is in contact with the mucosa (e.g., oral mucosa). The excipients may provide viscosity enhancement, encapsulation, and controlled release. Without being bound by theory, it is believed that increasing the contact time of the pharmaceutical formulation with the mucosa leads to increased binding of the agent to its receptor or receptors. Suitable excipients for viscosity enhancement include theology modifiers which also may be mucoadhesive such as methylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, alginic acid, polyvinylpyrrolidone, and sodium carboxymethylcellulose. Suitable excipients for modified release of the agent in the mucosa include mucoadhesive permeation enhancers such as 23-lauryl ether, aprotinin, azone, benzalkonium chloride, cetylpyridinium chloride, cetyltrimethylammonium bromide, cyclodextrins, dextran sulfate, and lauric acid. Other suitable mucoadhesive polymers used for the compositions described herein include agarose, chitosan, gelatin, hyaluronic acid, gums (e.g., guar, hakea, xanthan, gellan, carrageenan, pectin, and sodium alginate), cellulose derivative (e.g., carboxymethyl cellulose (CMC), thiolated CMC, sodium CMC, hydroxyethyl cellulose (HEC), hydroxypropyl methylcellulose (HPMC), methyl cellulose (MC), methylhydroxylethylcellulose), poly (acrylic acid)- based polymers (e.g., CP, PC, polyacrylic acid (PAA), polyacrylates, poly(methylvinylether-co- methacrylic acid), poly(2-hydroxyethyl methacrylate), copolymer of acrylic acid and polyethylene glycol (PEG), poly(N-2-hydroxypropyl methacrylamide) (PHPMAm), polyoxyethylene, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), and other thiolated polymers), scleroglucan, steroidal detergents, non-ionic surfactants, laureth-9, sodium fusidate, sodium lauryl sulfate, sodium laurate (e.g., pH 8.9), palmitoyl carnitine, lauric acid / propylene glycol vehicle, Brij 78, sodium deoxycholate, sodium lauryl sulfate, and lecithin. See, e.g., International Journal of Pharmaceuticals, Volume 53, Issue 3, 1 August 1989, Pages 227-235.

[0051] In some embodiments, the pharmaceutical compositions include excipients that increase the residence time of an agent (e.g., pegsebrenatide, ecnoglutide, dapiglutide, tirzepatide, VK2735, efinopegdutide, cotadutide, mazdutide, or retatrutide) in the saliva (e.g., the amount of time the topical-lingual receptor agonist remains in the saliva without significant degradation of the peptide). Without being bound by theory, it is believed that increasing the residence time of the agent in the saliva increases the opportunity for the agent to bind its receptor or receptors on the tongue. The residence time in the saliva can optionally be adjusted to avoid increasing systemic exposure to the agent through, for example, swallowing.

[0052] A composition containing an agent (e.g., pegsebrenatide, ecnoglutide, dapiglutide, tirzepatide, VK2735, efinopegdutide, cotadutide, mazdutide, or retatrutide) described herein can include one or more pharmaceutically acceptable excipients, such as propylene glycol, potassium sorbate, l-arginine, edetate disodium, monosodium phosphate, and polysorbate 20. In some embodiments, propylene glycol is present in a concentration of about 100 mg / ml, l-arginine is present in a concentration of about 25 mg / ml, potassium sorbate is present in a concentration of about 2 mg / ml, edetate disodium is present in a concentration of about 1 .2 mg / ml, sodium phosphate monobasic dihydrate is present in a concentration of about 7.8 mg / ml, and polysorbate is present in a concentration of about 5 mg / ml. Furthermore, the compositions described herein can include co-solvent stabilizers like propylene glycol or other suitable co-solvent stabilizers (e.g., lower molecular weight PEG such as PEG 200 and 400, glycerin, and ethanol). In some embodiments, compositions described herein include amino acid stabilizers like L-arginine or other suitable amino acid stabilizers (e.g., alanine, aspartic acid, glycine, lysine, proline, or methionine). In some embodiments, compositions described herein can include preservatives like potassium sorbate, or other suitable preservatives (e.g., ascorbic acid, benzyl alcohol, benzoic acid, citric acid, chlorobutanol, m-cresol, glutathione, methionine, methylparaben, propylparaben, sodium sulfite, parahydroxybenzoate esters, methylhydroxybenzoate and propylhydroxybenzoate), boric acid and borate salts, sorbic acid and other sorbate salts besides potassium, and phenolics. In some embodiments, compositions described herein can include antioxidants such as edetate disodium or another suitable antioxidant (e.g., sodium formaldehyde sulphoxylate, butylated hydroxyanisole, and butylated hydroxytoluene). In some embodiments, the compositions described herein include buffers (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 surfactants, such as polysorbate 20 or other suitable surfactants (e.g., Poloxamer 188 / 407, polysorbate 40 or 80, or sodium lauryl sulfate).

[0053] In some embodiments, the excipients include flavorings to increase compliance with ingesting with composition. For example, the flavorings can be used to mask bitter or other undesirable flavor properties, or to make the composition compatible with the flavor of food that may be ingested before or after administration of the composition. Compatible flavorings include, for example, apple, banana, bubblegum, cherry, chocolate, grape, lemon, mango, orange, raspberry, strawberry, vanilla, watermelon, mint, or a combination of the above flavors. In another aspect, these flavorings are dye- free, sugar-free, hypoallergenic, gluten-free, and casein-free.

[0054] In some embodiments, the pharmaceutical composition may be administered as in a unit dose form or as a dose per mass or weight of the subject from 0.01 ng / kg to 250 pg / kg (e.g., for a person of 75 kg body weight). For example, the dose of the agent may be from 0.01 ng / kg to 0.1 ng / kg, e.g., 0.01 ng / kg, 0.02 ng / kg, 0.03 ng / kg, 0.04 ng / kg, 0.05 ng / kg, 0.06 ng / kg, 0.07 ng / kg, 0.08 ng / kg, 0.09 ng / kg, or 0.1 ng / kg, e.g., from 0.1 ng / kg to 1 ng / kg, e.g., 0.1 ng / kg, 0.2 ng / kg, 0.3 ng / kg, 0.4 ng / kg, 0.5 ng / kg, 0.6 ng / kg, 0.7 ng / kg, 0.8 ng / kg, 0.9 ng / kg, or 1 ng / kg, e.g., from 1 ng / kg to 10 ng / kg, e.g., 1 ng / kg, 2 ng / kg, 3 ng / kg, 4 ng / kg, 5 ng / kg, 6 ng / kg, 7 ng / kg, 8 ng / kg, 9 ng / kg, or 10 ng / kg, e.g., from 10 ng / kg to 100 ng / kg, e.g., 10 ng / kg, 20 ng / kg, 30 ng / kg, 40 ng / kg, 50 ng / kg, 60 ng / kg, 70 ng / kg, 80 ng / kg, 90 ng / kg, or 100 ng / kg, e.g., from 100 ng / kg to 1 pg / kg, e.g., 100 ng / kg, 200 ng / kg, 300 ng / kg, 400 ng / kg, 500 ng / kg, 600 ng / kg, 700 ng / kg, 800 ng / kg, 900 ng / kg, or 1 pg / kg, e.g., from 1 pg / kg to 10 pg / kg, e.g., 1 pg / kg, 2 pg / kg, 3 pg / kg, 4 pg / kg, 5 pg / kg, 6 pg / kg, 7 pg / kg, 8 pg / kg, 9 pg / kg, or 10 pg / kg, or e.g., from 10 pg / kg to 250 pg / kg, e.g., 10 pg / kg, 20 pg / kg, 30 pg / kg, 40 pg / kg, 50 pg / kg, 60 pg / kg, 70 pg / kg, 80 pg / kg, 90 pg / kg, 100 pg / kg, 110 pg / kg, 120 pg / kg, 130 pg / kg, 140 pg / kg, 150 pg / kg, 160 pg / kg, 170 pg / kg, 180 pg / kg, 190 pg / kg, 200 pg / kg, 210 pg / kg, 220 pg / kg, 230 pg / kg, 240 pg / kg, or 250 pg / kg.

[0055] In general, the dosage of a pharmaceutical composition or the active agent (e.g., pegsebrenatide, ecnoglutide, dapiglutide, tirzepatide, VK2735, efinopegdutide, cotadutide, mazdutide, or retatrutide) in a pharmaceutical composition may be in the range of from about 10 ng to about 200 pg per kg body weight, e.g., from about 100 ng to about 10 pg per kg body weight, or e.g., from about 100 ng to about 2.5 pg per kg body weight, e.g., a dose of about 100 ng, 200 ng, 300 ng, 400 ng, 500 ng, 600 ng, 700 ng, 800 ng, 900 ng, 1 pg, 2 pg, or 2.5 pg per kg body weight (e.g., for a person of 75 kg body weight).

[0056] The pharmaceutical composition may also be administered as a dose per mass or weight of the patient per unit day (e.g., 0.01 ng / kg / day to 250 pg / kg / day). In some embodiments, the pharmaceutical composition is administered at a dose from 10 ng / kg / day to 200 pg / kg / day (e.g., from 50 ng / kg / day to 100 pg / kg / day, from 100 ng / kg / day to 50 pg / kg / day, from 500 ng / kg / day to 1 pg / kg / day). In some embodiments, the pharmaceutical composition is administered at a dose from 100 ng / kg / day to 10 pg / kg / day (e.g., 100 ng / kg / day, 110 ng / kg / day, 120 ng / kg / day, 130 ng / kg / day, 140 ng / kg / day, 150 ng / kg / day, 160 ng / kg / day, 170 ng / kg / day, 180 ng / kg / day, 190 ng / kg / day, 200 ng / kg / day, 210 ng / kg / day, 220 ng / kg / day, 230 ng / kg / day, 240 ng / kg / day, 250 ng / kg / day, 260 ng / kg / day, 270 ng / kg / day, 280 ng / kg / day, 290 ng / kg / day, 300 ng / kg / day, 310 ng / kg / day, 320 ng / kg / day, 330 ng / kg / day, 340 ng / kg / day, 350 ng / kg / day, 360 ng / kg / day, 370 ng / kg / day, 380 ng / kg / day, 390 ng / kg / day, 400 ng / kg / day, 410 ng / kg / day, 420 ng / kg / day, 430 ng / kg / day, 440 ng / kg / day, 450 ng / kg / day, 460 ng / kg / day, 470 ng / kg / day, 480 ng / kg / day, 490 ng / kg / day, 500 ng / kg / day, 510 ng / kg / day, 520 ng / kg / day, 530 ng / kg / day, 540 ng / kg / day, 550 ng / kg / day, 560 ng / kg / day, 570 ng / kg / day, 580 ng / kg / day, 590 ng / kg / day, 600 ng / kg / day, 610 ng / kg / day, 620 ng / kg / day, 630 ng / kg / day, 640 ng / kg / day, 650 ng / kg / day, 660 ng / kg / day, 670 ng / kg / day, 680 ng / kg / day, 690 ng / kg / day, 700 ng / kg / day, 710 ng / kg / day, 720 ng / kg / day, 730 ng / kg / day, 740 ng / kg / day, 750 ng / kg / day, 760 ng / kg / day, 770 ng / kg / day, 780 ng / kg / day, 790 ng / kg / day, 800 ng / kg / day, 810 ng / kg / day, 820 ng / kg / day, 830 ng / kg / day, 840 ng / kg / day, 850 ng / kg / day, 860 ng / kg / day, 870 ng / kg / day, 880 ng / kg / day, 890 ng / kg / day, 900 ng / kg / day, 910 ng / kg / day, 920 ng / kg / day, 930 ng / kg / day, 940 ng / kg / day, 950 ng / kg / day, 960 ng / kg / day, 970 ng / kg / day, 980 ng / kg / day, 990 ng / kg / day, 1 pg / kg / day, 2 pg / kg / day, 3 gg / kg / day, 4 gg / kg / day, 5 gg / kg / day, 6 gg / kg / day, 7 gg / kg / day, 8 gg / kg / day, 9 gg / kg / day, or 10 gg / kg / day). In some embodiments, the pharmaceutical composition is administered at a dose from about 100 ng / kg / day to about 2.5 gg / kg / day (e.g., 100 ng / kg / day, 110 ng / kg / day, 120 ng / kg / day, 130 ng / kg / day, 140 ng / kg / day, 150 ng / kg / day, 160 ng / kg / day, 170 ng / kg / day, 180 ng / kg / day, 190 ng / kg / day, 200 ng / kg / day, 210 ng / kg / day, 220 ng / kg / day, 230 ng / kg / day, 240 ng / kg / day, 250 ng / kg / day, 260 ng / kg / day, 270 ng / kg / day, 280 ng / kg / day, 290 ng / kg / day, 300 ng / kg / day, 310 ng / kg / day, 320 ng / kg / day, 330 ng / kg / day, 340 ng / kg / day, 350 ng / kg / day, 360 ng / kg / day, 370 ng / kg / day, 380 ng / kg / day, 390 ng / kg / day, 400 ng / kg / day, 410 ng / kg / day, 420 ng / kg / day, 430 ng / kg / day, 440 ng / kg / day, 450 ng / kg / day, 460 ng / kg / day, 470 ng / kg / day, 480 ng / kg / day, 490 ng / kg / day, 500 ng / kg / day, 510 ng / kg / day, 520 ng / kg / day, 530 ng / kg / day, 540 ng / kg / day, 550 ng / kg / day, 560 ng / kg / day, 570 ng / kg / day, 580 ng / kg / day, 590 ng / kg / day, 600 ng / kg / day, 610 ng / kg / day, 620 ng / kg / day, 630 ng / kg / day, 640 ng / kg / day, 650 ng / kg / day, 660 ng / kg / day, 670 ng / kg / day, 680 ng / kg / day, 690 ng / kg / day, 700 ng / kg / day, 710 ng / kg / day, 720 ng / kg / day, 730 ng / kg / day, 740 ng / kg / day, 750 ng / kg / day, 760 ng / kg / day, 770 ng / kg / day, 780 ng / kg / day, 790 ng / kg / day, 800 ng / kg / day, 810 ng / kg / day, 820 ng / kg / day, 830 ng / kg / day, 840 ng / kg / day, 850 ng / kg / day, 860 ng / kg / day, 870 ng / kg / day, 880 ng / kg / day, 890 ng / kg / day, 900 ng / kg / day, 910 ng / kg / day, 920 ng / kg / day, 930 ng / kg / day, 940 ng / kg / day, 950 ng / kg / day, 960 ng / kg / day, 970 ng / kg / day, 980 ng / kg / day, 990 ng / kg / day, 1 pg / kg / day, 1 .1 pg / kg / day, 1 .2 pg / kg / day, 1 .3 pg / kg / day, 1 .4 pg / kg / day, 1 .5 pg / kg / day, 1 .6 pg / kg / day, 1 .7 pg / kg / day, 1 .8 pg / kg / day, 1 .9 pg / kg / day, 2 pg / kg / day, 2.1 pg / kg / day, 2.2 pg / kg / day, 2.3 pg / kg / day, 2.4 pg / kg / day, or 2.5 pg / kg / day).

[0057] The dosage of the compositions (e.g., a composition including an agent selected from pegsebrenatide, ecnoglutide, dapiglutide, tirzepatide, VK2735, efinopegdutide, cotadutide, mazdutide, and retatrutide) described herein can vary depending on many factors, such as the pharmacodynamic properties of the agent, the mode of administration, the age, health, and weight of the recipient, the nature and extent of the symptoms, the frequency of the treatment, and the type of concurrent treatment, if any, and the clearance rate of the composition in the animal to be treated. The compositions described herein may be administered initially in a suitable dosage that may be adjusted as required, depending on the clinical response. In some embodiments, the dosage of the topicallingual receptor agonist is a prophy lactically or a therapeutically effective amount. Furthermore, it is understood that all dosages may be continuously given or divided into dosages given per a given time frame. The composition can be administered, for example, every hour, day, week, month, or year. In some embodiments, the composition may be administered continuously.

[0058] The pharmaceutical compositions described herein (e.g., containing an agent selected from pegsebrenatide, ecnoglutide, dapiglutide, tirzepatide, VK2735, efinopegdutide, cotadutide, mazdutide, and retatrutide) may be provided in a kit that includes the pharmaceutical composition (e.g., in a container) and instructions for use thereof. The kit may contain one or more containers, in which each container contains a different composition of the invention. The instructions enclosed with the kit may be used to instruct a user to perform a method as described herein.

[0059] The methods described herein include administration of an agent selected from pegsebrenatide, ecnoglutide, dapiglutide, tirzepatide, VK2735, efinopegdutide, cotadutide, mazdutide, and retatrutide 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 produce substantial change to the level of the agent in the blood and / or plasma of the subject. In general, the level of the agent in the blood and / or plasma of the subject does not increase 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 agent.

[0060] Indications

[0061] The methods described herein include the administration of a composition containing a topical-lingual receptor agonist as described herein for the induction of satiety and / or treatment of metabolic syndrome, diabetes, obesity, or any obesity-related disorder.

[0062] In some embodiments, the subject in need of treatment has been diagnosed with or it is at risk of a metabolic syndrome, obesity, an obesity-related disorder, diabetes, fatty liver disease, nonalcoholic steatohepatitis, chronic kidney disease, polycystic ovary syndrome, cardiovascular disease, obstructive sleep apnea, retinopathy, peripheral vascular disease, peripheral artery disease, and neuropathy (e.g., diabetic neuropathy). In some embodiments, the methods are used for maintenance of weight or prevention of weight gain.

[0063] Sequences

[0064] Pegsebrenatide (NLY01)

[0065] SEQ ID NO: 1

[0066] HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSC-{PEG}

[0067] Ecnoglutide

[0068] SEQ ID NO: 2

[0069] HVEGTFTSDVSSYLEEQAAREFIK-(AEEA-AEEA-{y-Glu}-C18 diacid)-WLVRGRG AEEA=2-(2-(2-aminoethoxy)ethoxy)acetic acid

[0070] Dapiglutide

[0071] SEQ ID NO: 3

[0072] H-{Aib}-EGSFTSELATILDK(y-Glu-diacid18)QAARDFIAWLIQHKITD

[0073] Tirzepatide

[0074] SEQ ID NO: 4

[0075] Y-{Aib}-EGTFTSDYSI-{Aib}-LDKIAQ-{C20 diacid-y-Glu-(AEEA)2-Lys}-AFVQWLIAGGPSSGAPPPS

[0076] Efinopegdutide (MK-6024)

[0077] SEQ ID NO: 5

[0078] H-{Aib}-QGTFTSDYSKYLDEKRAKEFVQWLMNTC

[0079] SEQ ID NO: 6

[0080] PSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPRE EQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCS VMHEALHNHYTQKSLSLSLGK

[0081] Cotadutide

[0082] SEQ ID NO: 7

[0083] HSQGTFTSDK-(Palmitoyl-E)SEYLDSERARDFVAWLEAGG

[0084] Mazdutide (IBI362, GLXC-26803)

[0085] SEQ ID NO: 8

[0086] H-{Aib}-QGTFTSDYSKYLDEKKAK-(AEEA-AEEA-y-Glu-diacid-C20)-EFVEWLLEGGPSSG

[0087] Retatrutide (LY3437943)

[0088] SEQ ID NO: 9

[0089] Y-{Aib}-QGTFTSDYSI-{a-Me-Leu}-LDK-{diacid-C20-y-Glu-(AEEA)-Lys}-AQ-{Aib}- AFIEYLLEGGPSSGAPPPS

[0090] Other Embodiments

[0091] While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the invention that come within known or customary practice within the art to which the invention pertains and may be applied to the essential features hereinbefore set forth, and follows in the scope of the claims. Other embodiments are within the claims.

Claims

CLAIMS1 . A composition comprising an agent selected from pegsebrenatide, ecnoglutide, dapiglutide, tirzepatide, VK2735, efinopegdutide, cotadutide, mazdutide, and retatrutide, wherein the composition is formulated for topical-lingual administration.

2. The composition of claim 1 , wherein the composition is formulated as an oral dissolving tablet, a lozenge, a film, a spray, a semisolid, a particulate, or in a lipid-based carrier.

3. The composition of claim 1 or 2, wherein the dose of the agent is from 1 ng to 20 mg.

4. The composition of claim 3, wherein the dose of the agent is from 1 ng to 1 pg.

5. The composition of claim 3, wherein the dose of the agent is from 1 pg to 1 mg.

6. The composition of claim 3, wherein the dose of the agent is from 1 mg to 20 mg.

7. The composition of any one of claims 1 -6, wherein the composition comprises pegsebrenatide.

8. The composition of any one of claims 1 -6, wherein the composition comprises ecnoglutide.

9. The composition of any one of claims 1 -6, wherein the composition comprises dapiglutide.

10. The composition of any one of claims 1 -6, wherein the composition comprises tirzepatide.11 . The composition of any one of claims 1 -6, wherein the composition comprises VK2735.

12. The composition of any one of claims 1 -6, wherein the composition comprises efinopegdutide.

13. The composition of any one of claims 1 -6, wherein the composition comprises cotadutide.

14. The composition of any one of claims 1 -6, wherein the composition comprises mazdutide.

15. The composition of any one of claims 1 -6, wherein the composition comprises retaglutide.

16. The composition of any one of claims 1 -15, wherein the composition further comprises a pharmaceutically acceptable excipient.

17. The composition of claim 16, wherein the pharmaceutically acceptable excipient comprises one or more of propylene glycol, potassium sorbate, l-arginine, edetate disodium, monosodium phosphate, polysorbate 20, gelatin, mannitol, dextran, alginate, polyvinyl alcohol, polyvinylpyrrolidone, acacia,aspartame, sodium methylparaben, sodium propylparaben, phenylalanine, water, or a combination thereof.

18. The composition of claim 16, wherein the pharmaceutically acceptable excipient comprises one or more of gelatin, mannitol, dextran, alginate, polyvinyl alcohol, polyvinylpyrrolidone, acacia, aspartame, sodium methylparaben, sodium propylparaben, phenylalanine, water, or a combination thereof.

19. The composition of any one of claims 16-18, wherein the pharmaceutically acceptable excipient is selected from the group consisting of stabilizers, preservatives, antioxidants, buffers, surfactants, rheology modifiers, and mucosal permeation enhancers.

20. The composition of claim 19, wherein the stabilizer comprises mannitol or sucrose.21 . The composition of claim 19, wherein the preservative comprises sodium methyl paraben or sodium propyl paraben.

22. The composition of claim 19, wherein the mucosal permeation enhancer comprises gelatin.

23. The composition of any one of claims 16-22, wherein the pharmaceutically acceptable excipient further comprises a flavoring or sweetening agent.

24. The composition of claim 23, wherein the sweetening agent comprises sorbitol, sucrose, or aspartame.

25. A method for inducing satiety or treating a disease or disorder selected from a metabolic syndrome, obesity, an obesity-related disorder, diabetes, fatty liver disease, nonalcoholic steatohepatitis, chronic kidney disease, polycystic ovary syndrome, cardiovascular disease, obstructive sleep apnea, retinopathy, peripheral vascular disease, peripheral artery disease, and neuropathy in a subject in need thereof, the method comprising administering to the subject the composition of any one of claims 1 -24.

26. The method of claim 25, wherein the composition is administered intraorally to a subject.

27. The method of claim 25, wherein the composition is delivered to the tongue of the subject.

28. The method of any one of claims 25-27, wherein the composition provides treatment without the agent substantially appearing in the blood of the subject.