Compositions and methods for activating neuroreceptors

Abstract

The present invention provides compositions and methods for inducing activation of neuroreceptors, including metabolic hormones, which can be used to provide treatment for an addiction or mood disorder in a subject.

Description

[Background technology]

[0001] The prevalence of addiction and mood disorders continues to increase worldwide. However, effective long-term non-invasive treatments for addiction and mood disorders remain lacking. Treatments with existing therapeutic agents often do not provide optimal therapeutic effects. Therefore, new treatments are needed. Summary of the Invention

[0002] In one aspect, the invention features a method of activating a neuroreceptor in a subject by administering to the subject a composition that includes an agent selected from peptide YY (PYY), glucagon-like peptide 1 (GLP-1), leptin, amylin, insulin, and calcitonin, or an analog, variant, or biologically active fragment thereof, wherein the composition activates the neuroreceptor without substantially altering the concentration of the agent in the subject's blood.

[0003] In some embodiments, activation of the neuroreceptor provides treatment for an addiction or mood disorder in a subject in need of treatment.

[0004] In some embodiments, activation of neuroreceptors provides a treatment for addiction.

[0005] In some embodiments, the addiction comprises a craving or dependency on alcohol, cocaine, opioids, nicotine, heroin, marijuana, 3,4-methylenedioxy-methamphetamine, caffeine, mescaline, methamphetamine, amphetamine derivatives, dextromethorphan, loperamide, phenylcyclohexylpiperidine, stimulants, steroids, cannabinoids, cathinones, lysergic acid diethylamide, gambling, sex, inhalants, sedatives, hypnotics, tobacco, anxiolytics, hallucinogens, food, or a combination thereof.

[0006] In some embodiments, activation of neuroreceptors provides treatment for mood disorders.

[0007] In some embodiments, the mood disorder comprises depression, anxiety, dysthymia, bipolar disorder, medication-induced mood disorder, obsessive-compulsive disorder, binge eating disorder, or substance-induced mood disorder.

[0008] In some embodiments, the composition is administered topically lingually (e.g., topically to the lingual epithelium). The composition may be formulated, for example, as an orally dissolving tablet, lozenge, film, spray, semi-solid, particulate, or in a lipid-based carrier.

[0009] In some embodiments, the composition is administered intranasally. The composition may be formulated, for example, as a spray, a semi-solid, a microparticle, or in a lipid-based carrier.

[0010] In some embodiments, the addiction or mood disorder does not include post-traumatic stress disorder (PTSD), traumatic brain injury (TBI), Alzheimer's disease, memory loss, cognitive impairment, stress, stroke, or neurodegenerative disorders.

[0011] In some embodiments, the methods do not include administration of insulin.

[0012] In some embodiments, the method does not include intranasal administration of insulin.

[0013] In some embodiments, the methods do not include intranasal administration of insulin to treat Alzheimer's disease.

[0014] In some embodiments, the composition is administered locally to the gastrointestinal (GI) tract. The composition may, for example, be formulated as a GI patch.

[0015] In some embodiments, the composition is administered rectally. The composition may be formulated, for example, as a suppository.

[0016] In some embodiments, the dose of the agent (e.g., PYY, GLP-1, leptin, amylin, insulin, or calcitonin, or an analog, variant, or biologically active fragment thereof) is 1 ng to 20 mg per 100 kg body weight. For example, the dose of the agent is 1 ng to 10 ng per 100 kg body weight, e.g., 1 ng, 2 ng, 3 ng, 4 ng, 5 ng, 6 ng, 7 ng, 8 ng, 9 ng, or 10 ng per 100 kg body weight, e.g., 10 ng to 100 ng per 100 kg body weight, e.g., 20 ng, 30 ng, 40 ng, 50 ng, 60 ng, 70 ng, 80 ng, 90 ng per 100 kg body weight. , or 100ng, for example, 100ng to 1μg per 100kg of body weight, for example, 200ng, 300ng, 400ng, 500ng, 600ng, 700ng, 800ng, 900ng, or 1μg per 100kg of body weight, for example, 1μg to 10μg per 100kg of body weight, for example, 2μg, 3μg, 4μg, 5μg, 6μg, 7μg, 8μg, 9 μg or 10 μg, for example, 10 μg to 100 μg per 100 kg of body weight, for example, 10 μg, 20 μg, 30 μg, 40 μg, 50 μg, 60 μg, 70 μg, 80 μg, 90 μg, or 100 μg per kg of body weight, for example, 100 μg to 1 mg per kg of body weight, for example, 100 μg, 200 μg, 300 μg, 400 μg, 500 μg, 600 μg, The amount may be, for example, 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 per 100 kg of body weight.

[0017] In some embodiments, the composition comprises PYY, or a variant, analog, or biologically active fragment thereof, hi some embodiments, the PYY fragment is PYY(3-36).

[0018] In some embodiments, the composition comprises GLP-1, or a variant, analog, or biologically active fragment thereof.

[0019] In some embodiments, the composition comprises leptin, or a variant, analog, or biologically active fragment thereof.

[0020] In some embodiments, the composition comprises amylin, or a variant, analog, or biologically active fragment thereof.

[0021] In some embodiments, the composition comprises calcitonin, or a variant, analog, or biologically active fragment thereof.

[0022] In some embodiments, the neuroreceptor is a Y receptor (YR), a Y1 receptor (Y1R), a Y2 receptor (Y2R), a Y4 receptor (Y4R), a Y5 receptor (Y5R), a G protein-coupled receptor (GPRCR), a leptin receptor (LEPR), a GLP-1 receptor (GLP-1R), an insulin receptor (INSR), a glucose-dependent insulinotropic polypeptide receptor (GIPR), a ghrelin receptor (GHS-R), a cholecystokinin A receptor (CCKAR), a cholecystokinin B receptor (CCKBR), or a calcitonin receptor (CALCR).

[0023] In another aspect, the invention features a composition comprising an agent selected from PYY, GLP-1, leptin, amylin, and calcitonin, or an analog, variant, or biologically active fragment thereof. The composition is formulated for intranasal administration and activates a subject's neuroreceptors without substantially altering the concentration of the agent in the subject's blood. The composition can be formulated, for example, as a spray, semi-solid, microparticle, or in a lipid-based carrier.

[0024] In another aspect, the invention features a composition comprising an agent selected from PYY, GLP-1, leptin, amylin, insulin, and calcitonin, or an analog, variant, or biologically active fragment thereof. The composition is formulated for local administration to the GI tract and activates a subject's neuroreceptors without substantially altering the concentration of the agent in the subject's blood. The composition can be formulated, for example, as a GI patch.

[0025] In another aspect, the invention features a composition including an agent selected from PYY, GLP-1, leptin, amylin, insulin, and calcitonin, or an analog, variant, or biologically active fragment thereof. The composition is formulated for rectal administration and activates a subject's neuroreceptors without substantially altering the concentration of the agent in the subject's blood. The composition can be formulated, for example, as a suppository.

[0026] In some embodiments of any of the above compositions, the dosage of the agent is from 0.1 ng to 20 mg. For example, the dose of the agent may be from 0.1 ng to 1 ng, for example 0.2 ng, 0.3 ng, 0.4 ng, 0.5 ng, 0.6 ng, 0.7 ng, 0.8 ng, 0.9 ng, or 1 ng, for example 1 ng to 10 ng, for example 1 ng, 2 ng, 3 ng, 4 ng, 5 ng, 6 ng, 7 ng, 8 ng, 9 ng, or 10 ng, for example 10 ng to 100 ng, for example 20 ng, 30 ng, 40 ng, 50 ng, 60 ng, 70 ng, 80 ng, 90 ng, or 100 ng, for example 100 ng to 1 μg, for example 200 ng, 300 ng, 400 ng, 500 ng, 600 ng, 700 ng, 800 ng, 900 ng, or 1 μg, for example 1 μg to 10 μg per 100 kg, for example kcal of body weight. 2μg, 3μg, 4μg, 5μg, 6μg, 7μg, 8μg, 9μg, or 10μg per g, for example, 10μg to 100μg, for example, 10μg, 20μg, 30μg, 40μg, 50μg, 60μg, 70μg, 80μg, 90μg, or 100μg, for example, 100μg to 1mg, for example, 100μg, 200μg, 300μg, 40 It may be 0 μg, 500 μg, 600 μg, 700 μg, 800 μg, 900 μg, or 1 mg, for example, 1 mg to 20 mg, for example, 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.

[0027] In some embodiments, the composition comprises PYY, or a variant, analog, or biologically active fragment thereof, hi some embodiments, the PYY fragment is PYY(3-36).

[0028] In some embodiments, the composition comprises GLP-1, or a variant, analog, or biologically active fragment thereof.

[0029] In some embodiments, the composition comprises leptin, or a variant, analog, or biologically active fragment thereof.

[0030] In some embodiments, the composition comprises amylin, or a variant, analog, or biologically active fragment thereof.

[0031] In some embodiments, the composition comprises insulin, or a variant, analog, or biologically active fragment thereof.

[0032] In some embodiments, the composition does not include insulin, or an analog, variant, or biologically active fragment thereof.

[0033] In some embodiments, the composition comprises calcitonin, or a variant, analog, or biologically active fragment thereof.

[0034] In some embodiments, the neuroreceptor is YR, Y1R, Y2R, Y4R, Y5R, GPCR, LEPR, GLP-1R, INSR, GIPR, GHS-R, CCKAR, CCKBR, or CALCR.

[0035] 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.

[0036] As used herein, the term "about" refers to a value within 10% above or below the stated value.

[0037] As used herein, a "subject" refers to a human or non-human animal (eg, a mammal).

[0038] 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

[0039] In general, the present invention features compositions and methods for activating neuroreceptors in a subject. The compositions and methods include formulations for administering metabolic hormones to a subject without substantially changing the concentration of the metabolic hormone in the subject's blood. Such methods can be used to treat addiction or mood disorders. The present invention is based in part on the surprising discovery that administration of metabolic hormones such as PYY, GLP-1, leptin, amylin, insulin, or calcitonin can activate neuroreceptors in the central nervous system to treat addiction or mood disorders. Specific neuroreceptors that can be targeted with the compositions and methods described herein include, for example, Y receptor (YR), Y1 receptor (Y1R), Y2 receptor (Y2R), Y4 receptor (Y4R), Y5 receptor (Y5R), G protein-coupled receptor (GPRCR), leptin receptor (LEPR), GLP-1 receptor (GLP-1R), insulin receptor (INSR), glucose-dependent insulinotropic polypeptide receptor (GIPR), ghrelin receptor (GHS-R), cholecystokinin A receptor (CCKAR), cholecystokinin B receptor (CCKBR), or calcitonin receptor (CALCR). By administering a metabolic hormone via one of the routes described herein, the composition can provide treatment to a subject without substantially altering the concentration of the agent in the subject's blood. Furthermore, these routes of administration avoid systemic administration, which is known to produce undesirable side effects such as nausea, injection site pain, or fatigue. The compositions and methods are described in more detail below.

[0040] Indications The methods described herein include administering a composition comprising a metabolic hormone as described herein to activate a neuroreceptor. Activation of the neuroreceptor provides treatment for an addiction or mood disorder in a subject in need of treatment. In general, by administering a metabolic hormone via a non-systemic route, the hormone can target specific pleasure centers in the brain, activate important brain regions, and avoid neural or non-neural targets that may cause clinical risks (e.g., toxicity) or side effects such as nausea. For example, systemic administration of metabolic hormones activates neuroreceptors in the hypothalamus, nucleus tractus solitarius (NTS), and area postrema, while non-systemic administration routes described herein activate neuroreceptors in the hypothalamus and NTS but substantially avoid the area postrema. For example, by targeting neuroreceptors in the mouth (e.g., on the tongue), nose, rectum, or GI tract, the neuroreceptors and binding can be sufficient to activate pleasure centers in the CNS. Thus, activation of these pleasure centers provides treatment for disorders associated with dysregulation of pleasure centers in the brain.

[0041] In one embodiment, the subject has a mood disorder (e.g., an affective disorder and / or a psychiatric disorder). In some embodiments, the mood disorder is depression, anxiety, dysthymia, bipolar disorder, medication-induced mood disorder, or substance-induced mood disorder. In some embodiments, the depression comprises major depressive disorder (MDD), seasonal major depressive disorder (SAD), or a type of depression caused by hormonal changes (e.g., perinatal depression, postpartum depression, premenstrual dysphoric disorder). In some embodiments, the anxiety comprises panic attacks and / or generalized anxiety disorder. In some embodiments, the bipolar disorder comprises bipolar disorder I, bipolar disorder II, and / or cyclothymic disorder. In some embodiments, the psychiatric disorder comprises mania, schizoaffective disorder, and schizophrenia. In some embodiments, mood disorders include developmental disorders (e.g., autism spectrum disorder, attention deficit hyperactivity disorder, or attention deficit disorder), dementia (e.g., Alzheimer's disease or reversible dementia), personality disorders with stereotyped behavioral patterns (e.g., depression, schizoid disorder, narcissistic disorder, borderline personality disorder, or antisocial personality disorder), and problem behaviors (e.g., shoplifting, lying, risky behaviors, impulse control difficulties, or adjustment disorders).

[0042] In some embodiments, the addiction or mood disorder does not include post-traumatic stress disorder (PTSD), traumatic brain injury (TBI), Alzheimer's disease, memory loss, cognitive impairment, stress, stroke, or neurodegenerative disorder.In some embodiments, the method does not include administration of insulin.In some embodiments, the method does not include intranasal administration of insulin.In some embodiments, the method does not include intranasal administration of insulin to treat Alzheimer's disease.

[0043] The subject may have an addiction to, for example, a chemical substance. In some embodiments, the addiction comprises a craving or dependency on alcohol, cocaine, opioids, nicotine, heroin, marijuana, 3,4-methylenedioxy-methamphetamine, caffeine, mescaline, methamphetamine, amphetamine derivatives, dextromethorphan, loperamide, phenylcyclohexylpiperidine, stimulants, steroids, cannabinoids, cathinones, lysergic acid diethylamide, inhalants, sedatives, hypnotics, tobacco, anxiolytics, hallucinogens, food, or a combination thereof. In some embodiments, the method reduces the frequency or intensity of the craving (e.g., at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100%). In some embodiments, the method eliminates the craving.

[0044] The subject may have a compulsive behavior (e.g., obsessive-compulsive disorder) or an addiction, such as an addiction to gambling, sex, repetitive behavior, or destructive habits. In some embodiments, the method reduces the frequency of the behavior (e.g., at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100%). In some embodiments, the method eliminates the behavior.

[0045] The subject may have a binge eating disorder.

[0046] The subject may have a food addiction. The subject may have an addiction to eating (e.g., overeating).

[0047] The compositions described herein can be used to activate the hedonistic (e.g., pleasure and / or reward) centers of the brain. Metabolic hormones (e.g., PYY, PYY(3-36), GLP-1, leptin, amylin, calcitonin, analogs, variants, or biologically active fragments thereof) can directly affect the hedonistic centers. Neuroreceptors targeted by the compositions described herein include Y receptors (e.g., Y1R, Y2R, Y4R, Y5R), GPCRs, LEPR, GLP-1R, INSR, GIPR, GHS-R, CCKAR, CCKBR, or CALCR. In some embodiments, activation of neuroreceptors using the compositions described herein can occur via the gut-brain axis (e.g., vagus nerve, spinal cord afferent neurons, cytokines, gut hormones, signaling molecules from gut flora).

[0048] Metabolic Hormones Composition The compositions described herein include metabolic hormones, or biologically active fragments, variants, or analogs thereof. The metabolic hormones target (e.g., bind to, associate with, or interact with) YR, Y1R, Y2R, Y4R, Y5R, GPCR, LEPR, GLP-1R, INSR, GIPR, GHS-R, CCKAR, CCKBR, or CALCR in a subject. The receptors can be, for example, in the oral cavity (e.g., tongue), nasal cavity, GI tract, or rectum of a subject. In some embodiments, the metabolic hormone is PYY, PYY(3-36), leptin, amylin, insulin, calcitonin, or GLP-1, or variants, analogs, or biologically active fragments thereof.

[0049] In some embodiments, the dose of the metabolic hormone, or biologically active fragment, variant, or analog thereof, is from 0.1 ng to 20 mg. For example, the dose of the agent may be from 0.1 ng to 1 ng, for example, 0.2 ng, 0.3 ng, 0.4 ng, 0.5 ng, 0.6 ng, 0.7 ng, 0.8 ng, 0.9 ng, or 1 ng, for example, 1 ng to 10 ng, for example, 1 ng, 2 ng, 3 ng, 4 ng, 5 ng, 6 ng, 7 ng, 8 ng, 9 ng, or 10 ng, for example, 10 ng to 100 ng, for example, 20 ng, 30 ng, 40 ng, 50 ng, 60 ng, 70 ng, 80 ng, 90 ng, or 100 ng, for example, 100 ng to 1 μg, for example, 200 ng, 300 ng, 400 ng, 500 ng, 600 ng, 700 ng, 800 ng, 900 ng, or 1 μg, for example, 1 μg to 10 μg, for example, 2 μg to 3 μg. g, 3, μg, 4 μg, 5 μg, 6 μg, 7 μg, 8 μg, 9 μg, or 10 μg, for example, 10 μg to 100 μg, for example, 10 μg, 20 μg, 30 μg, 40 μg, 50 μg, 60 μg, 70 μg, 80 μg, 90 μg, or 100 μg, for example, 100 μg to 1 mg, for example, 100 μg, 200 μg, 300 μg, 400 μg , 500 μg, 600 μg, 700 μg, 800 μg, 900 μg, or 1 mg, for example, 1 mg to 20 mg, for example, 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.

[0050] In some embodiments, the metabolic hormone is PYY, or an analog, variant, or biologically active fragment thereof. In some embodiments, the 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:1. In some embodiments, the PYY, or a variant, analog, or biologically active fragment thereof, has the amino acid sequence set forth in SEQ ID NO:1. In some embodiments, the compositions described herein comprise a dose of PYY, or a variant, analog, or biologically active fragment thereof, of about 100 ng to about 10 mg. In some embodiments, the compositions described herein comprise a dose of PYY, or a variant, analog, or biologically active fragment thereof, of about 1 μg to about 1 mg. In some embodiments, the compositions described herein comprise 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) of PYY, or a variant, analog, or biologically active fragment thereof.

[0051] In some embodiments, the PYY fragment is PYY(3-36). In some embodiments, PYY(3-36), 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:2. In some embodiments, PYY(3-36) has the amino acid sequence set forth in SEQ ID NO:2. In some embodiments, the compositions described herein comprise a dose of about 100 ng to about 10 mg of PYY(3-36), or a variant, analog, or biologically active fragment thereof. In some embodiments, the compositions described herein comprise a dose of about 1 μg to about 1 mg of PYY(3-36), or a variant, analog, or biologically active fragment thereof. In some embodiments, the compositions described herein include 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) of PYY(3-36), or a variant, analog, or biologically active fragment thereof.

[0052] 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: 11. In some embodiments, [Pro34]PYY has the amino acid sequence set forth in SEQ ID NO: 11. In some embodiments, the PYY analog is NNC065-1273, which comprises a PYY(3-36) polypeptide having a beta-homo-arginine at position 35. In some embodiments, the PYY analog is NNC0165-1875. In some embodiments, the PYY analog 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 by reference in its entirety). 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, as described, for example, in Rangwala et al. Cell Metab. 29: 837-843, 2019 (incorporated herein by reference in its entirety). In some embodiments, the PYY analog or variant is described in U.S. Pat. No. 8,217,001 (the disclosure of which is incorporated herein by reference in its entirety). In some embodiments, the compositions described herein comprise a dose of about 100 ng to about 10 mg of [Pro34]PYY, or a variant, analog, or biologically active fragment thereof. In some embodiments, the compositions described herein comprise a dose of about 1 μg to about 1 mg of [Pro34]PYY, or a variant, analog, or biologically active fragment thereof.In some embodiments, the compositions described herein comprise 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) of [Pro34]PYY, or a variant, analog, or biologically active fragment thereof.

[0053] 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 24 In 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), [Thr27 ,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 ,Leu 31 ]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)、[Gln 29 ,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 ,Leu31 ]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),[Ser32 ,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 ,Thr 36 ]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).

[0054] In some embodiments, the metabolic hormone is leptin, or an analog, variant, or biologically active fragment thereof. In some embodiments, 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:6. In some embodiments, leptin has the amino acid sequence set forth in SEQ ID NO:6. In some embodiments, the analog of leptin is recombinant analog metreleptin (MYALEPT®), which comprises a polypeptide having a sequence set forth in SEQ ID NO:9, including a disulfide bridge linking amino acid residues 97 and 147. In some embodiments, the analog of leptin is a mouse leptin analog, e.g., as described in Peters et al. Endocrinol. 148:2878-2885, 2007, which is incorporated herein by reference in its entirety. In some embodiments, the compositions described herein comprise leptin, or a variant, analog, or biologically active fragment thereof, at a dose of about 100 ng to about 10 mg. In some embodiments, the compositions described herein comprise leptin, or a variant, analog, or biologically active fragment thereof, at a dose of about 1 μg to about 1 mg. In some embodiments, the compositions described herein comprise 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).

[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:7. In some embodiments, the amylin has an amino acid sequence set forth in SEQ ID NO:7. In some embodiments, the analog of amylin is pramlintide (SYMLIN®), which comprises a polypeptide having a sequence set forth in SEQ ID NO:8. In some embodiments, the compositions described herein comprise a dose of about 100 ng to about 10 mg of amylin, or a variant, analog, or biologically active fragment thereof. In some embodiments, the compositions described herein comprise a dose of about 1 μg to about 1 mg of amylin, or a variant, analog, or biologically active fragment thereof. In some embodiments, the compositions described herein comprise 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) of amylin, or a variant, analog, or biologically active fragment thereof.

[0056] In some embodiments, the metabolic hormone is GLP-1, or an analog, variant, 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:3. In some embodiments, the GLP-1 has the amino acid sequence set forth in SEQ ID NO:3. In some embodiments, the GLP-1 fragment is GLP-1(7-36), or a variant, analog, or biologically active fragment thereof. In some embodiments, the GLP-1(7-36), 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:4. In some embodiments, the GLP-1(7-36) has an amino acid sequence set forth in SEQ ID NO:4. In some embodiments, the GLP-1 fragment is GLP-1(7-37), or a variant, analog, or biologically active fragment thereof. In some embodiments, the GLP-1(7-37), or a variant, analog, or biologically active fragment thereof, has at least 70% (e.g., at least 70%, 75%, 80%, 85%, 90%, 95%, 97%, or 100%) sequence identity to SEQ ID NO:5. In some embodiments, the GLP-1(7-37) has an amino acid sequence set forth in SEQ ID NO:5. In some embodiments, the compositions described herein comprise a dose of about 100 ng to about 10 mg of GLP-1, or a variant, analog, or biologically active fragment thereof. In some embodiments, the compositions described herein comprise a dose of about 1 μg to about 1 mg of GLP-1, or a variant, analog, or biologically active fragment thereof.In some embodiments, the compositions described herein comprise 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) of GLP-1, or a variant, analog, or biologically active fragment thereof.

[0057] In some embodiments, the metabolic hormone is calcitonin, or an analog, variant, or biologically active fragment thereof. In some embodiments, the calcitonin, 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: 10. In some embodiments, the calcitonin has the amino acid sequence set forth in SEQ ID NO: 10. In some embodiments, the compositions described herein comprise a dose of about 100 ng to about 10 mg of calcitonin, or a variant, analog, or biologically active fragment thereof. In some embodiments, the compositions described herein comprise a dose of about 1 μg to about 1 mg of calcitonin, or a variant, analog, or biologically active fragment thereof. In some embodiments, the compositions described herein comprise 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) of calcitonin, or a variant, analog, or biologically active fragment thereof.

[0058] 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), a variant, or a biologically inactive insulin. In some embodiments, 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: 12. In some embodiments, insulin has the amino acid sequence set forth in SEQ ID NO: 12. In some embodiments, the insulin analog is insulin aspart (NOVOLOG®), having an A chain having the sequence set forth in SEQ ID NO: 13 and an A chain having the sequence set forth in SEQ ID NO: 14. In some embodiments, the insulin analog is insulin glargine (LANTUS®) having an A chain having a sequence set forth in SEQ ID NO: 15 and a B chain having a sequence set forth in SEQ ID NO: 16. In some embodiments, the insulin analog is insulin lispro (LYUMJEV™) having an A chain having a sequence set forth in SEQ ID NO: 17 and a B chain having a sequence set forth in SEQ ID NO: 18. In some embodiments, the insulin analog is insulin glulisine (APIDRA®) having an A chain having a sequence set forth in SEQ ID NO: 19 and a B chain having a sequence set forth in SEQ ID NO: 20. In some embodiments, the insulin analog is insulin detemir (LEVEMIR®) having an A chain having a sequence set forth in SEQ ID NO: 21 and a B chain having a sequence set forth in SEQ ID NO: 22. In some embodiments, the methods described herein comprise local lingual (e.g., topical to the lingual epithelium) 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).

[0059] Pharmaceutical Compositions and Routes of Administration The metabolic hormones described herein, or variants, analogs, or biologically active fragments thereof, can be formulated as pharmaceutical compositions for administration to human subjects in a biologically compatible form suitable for administration in vivo.

[0060] The compositions described herein can be administered to a subject (e.g., a human) in various forms depending on the route of administration selected, as will be understood by those skilled in the art. The compositions described herein can be administered, for example, by any route that allows the composition (e.g., metabolic hormone) to reach the target receptor without substantially changing the concentration of the metabolic hormone in the subject's blood. The compositions can be administered, for example, by topical lingual (e.g., topically to the lingual epithelium), nasal, intrarectal, or topical GI route.

[0061] In some embodiments, the compositions described herein are formulated for delivery to the oral cavity (e.g., intraoral, 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).

[0062] 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 described in U.S. Patent Nos. 4,305,502, 4,371,516, and 5,738,875, which are incorporated herein by reference in their entireties.

[0063] In some embodiments, the compositions described herein are formulated for nasal delivery. The nasal compositions can be formulated, for example, as a spray, semi-solid, microparticles, or in a lipid-based carrier. The formulation can be, for example, a liquid, suspension, powder, or gel. Suitable nasal formulations are described, for example, in Marx et al. Drug Discov Dev 299-320, 2015, which is incorporated herein by reference in its entirety. In some preferred embodiments, the compositions described herein are administered by inhalation, for example, by nasal inhalation. The inhalable compositions described herein can be provided as a liquid dosage form, or a dry powder dosage form. The dry powder composition can be administered, for example, by inhalation, either as is, or after reconstitution with a vehicle, for example, saline (e.g., isotonic saline), phosphate buffered saline, or water. In some embodiments, the nasal formulation does not include insulin.

[0064] In some embodiments, the compositions described herein are formulated for local administration to the GI tract.Topical compositions can be formulated, for example, as GI patch.Suitable GI patch formulations are described, for example, in Tao, et al Drug discovery Today 10:909-915,2005 (incorporated herein in its entirety by reference).

[0065] In some embodiments, the compositions described herein are formulated for rectal delivery. The rectal composition may be formulated, for example, as a suppository, an enema, an ointment, or an enema foam. Suitable rectal formulations are described, for example, in Hua Front. Pharmacol.10:1196,2019, which is incorporated herein by reference in its entirety. The composition for rectal administration may be in the form of a suppository containing a conventional suppository base, such as cocoa butter.

[0066] Solutions of the compositions described herein may be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions may also be prepared in glycerol, liquid polyethylene glycols, DMSO, and mixtures thereof with or without alcohol, and in oils. These formulations may contain a preservative to prevent the growth of microorganisms under ordinary conditions of storage and use. 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 The United States Pharmacopeia: The National Formulary (USP 41 NF 36), published in 2018. The compositions described herein may be administered to animals, e.g., humans, alone or in combination with a pharma- ceutically acceptable carrier, the proportions of which are determined by the solubility and chemical properties of the composition, the selected route of administration, and standard pharmaceutical practice.

[0067] In some embodiments, the composition includes an excipient that increases the contact time of the metabolic hormone, e.g., PYY(3-36), with the mucosa (e.g., oral mucosa, nasal mucosa, GI mucosa, or rectal mucosa). The excipient 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 increases the binding of the metabolic hormone to its receptor. 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 regulating the release of the metabolic hormone at the mucosa include mucoadhesive permeation enhancers, e.g., 23-lauryl ether, aprotinin, azone, benzalkonium chloride, cetylpyridinium chloride, cetyltrimethylammonium bromide, cyclodextrin, dextran sulfate, and lauric acid.Other suitable mucoadhesive polymers for use in the compositions described herein include agarose, chitosan, gelatin, hyaluronic acid, gums (e.g., guar, hakea, 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, polyacrylates, poly(methyl vinyl ether-co-methacrylate), ... 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.

[0068] 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.

[0069] Compositions comprising the metabolic hormones 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).

[0070] 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.

[0071] In some embodiments, the pharmaceutical compositions may be administered in unit dosage form or as a dose per patient mass or weight of 0.01 ng / kg to 250 μg / kg (eg, for a 75 kg human).For example, the dose of metabolic hormone may be 0.01ng / kg to 0.1ng / kg, e.g., 0.01ng / kg, 0.02ng / kg, 0.03ng / kg, 0.04ng / kg, 0.05ng / kg, 0.06ng / kg, 0.07ng / kg, 0.08ng / kg, 0.09ng / kg, or 0.1ng / kg, e.g., 0.1ng / kg to 1ng / kg, e.g., 0.1ng / kg, 0.2ng / kg, 0.3ng / kg, 0.4ng / kg, 0.5ng / kg, 0.6ng / kg, 0.7ng / kg, 0.8ng / kg, 0.9ng / kg, or 1ng / kg, for example, 1ng / kg to 10ng / kg, for example, 1ng / kg, 2ng / kg, 3ng / kg, 4ng / kg, 5ng / kg, 6ng / kg, 7ng / kg, 8ng / kg, 9ng / kg, or 10ng / kg, for example, 10ng / kg to 100ng / kg, for example, 10ng / kg, 20ng / kg, 30ng / kg, 40ng / kg, 50ng / kg, 60μg / kg, 70ng / kg, 80ng / kg, 90ng / kg, or 100ng / kg, for example For example, 100ng / kg to 1μg / kg, for example, 100ng / kg, 200ng / kg, 300ng / kg, 400ng / kg, 500ng / kg, 600ng / kg, 700ng / kg, 800ng / kg, 900ng / kg, or 1μg / kg, for example, 1μg / kg to 10μg / kg, for example, 1μg / kg, 2μg / kg, 3μg / kg, 4μg / kg, 5μg / kg, 6μg / kg, 7μg / kg, 8μg / kg, 9μg / kg, or 10μg / kg, or for example, 10μg / kg to 250μg / kg, e.g. 10μg / kg, 20μg / kg, 30μg / kg, 40μg / kg, 50μg / kg, 60μg / kg, 70μg / kg, 80μg / kg, 90ng / kg, 100μg / kg, 110μg / kg, 120μg / kg, 130μg / kg, It can be 140μg / kg, 150μg / kg, 160μg / kg, 170μg / kg, 180μg / kg, 190μg / kg, 200μg / kg, 210μg / kg, 220μg / kg, 230μg / kg, 240μg / kg or 250μg / kg.

[0072] In general, the dosage of a pharmaceutical composition, or an active agent therein (e.g., a metabolic hormone, e.g., PYY (e.g., PYY(3-36)), GLP-1, leptin, amylin, insulin, or calcitonin, or an analog, variant, or biologically active fragment thereof) can be in the range of about 10 ng to about 200 μg per kg of body weight, e.g., in the range of about 100 ng to about 10 μg per kg of body weight, or, e.g., in the range of about 100 ng to about 2.5 μg per kg of 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 μg, 2 μg, or 2.5 μg per kg of body weight (e.g., for a human weighing 75 kg).

[0073] Furthermore, it is understood that the dosage of analogs, variants, or biologically active fragments of active substances can be administered as the molar equivalent of active substances.Those skilled in the art will understand that, for example, metabolic hormone analogs that contain post-translational modifications or half-life extending moieties may require increased dosages (e.g., 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300% or more) than the dosage of the corresponding metabolic hormone that does not contain post-translational modifications or half-life extending moieties.

[0074] The pharmaceutical composition may also be administered as a dose per patient mass or weight per day (e.g., 0.01 ng / kg / day to 250 μg / kg / day). In some embodiments, the pharmaceutical composition is administered at a dose of 10 ng / kg / day to 200 μg / kg / day (e.g., 50 ng / kg / day to 100 μg / kg / day, 100 ng / kg / day to 50 μg / kg / day, 500 ng / kg / day to 1 μg / kg / day). In some embodiments, the pharmaceutical composition comprises a dose of 100 ng / kg / day to 10 μg / 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, / kg / day, 250ng / kg / day, 260ng / kg / day, 270ng / kg / day, 280ng / kg / day, 290ng / kg / day, 300ng / kg / day, 310ng / kg / day, 320ng / kg / day, 330ng / kg / day, 340ng / kg / day, 350ng / kg / day, 360ng / kg / day, 370ng / kg / day, 380ng / kg / day, 390ng / kg / day, 400ng / kg / day, 410ng / kg / day, 420ng / kg / day, 430ng / kg / day, 440ng / kg / day, 450ng / kg / day, 460ng / kg / day, 470ng / kg / day, 480ng / kg / day, 490ng / kg / day, 500ng / kg / day, 510ng / kg / day, 52 0ng / kg / day, 530ng / kg / day, 540ng / kg / day, 550ng / kg / day, 560ng / kg / day, 570ng / kg / day, 580ng / kg / day, 590ng / kg / day, 600ng / kg / day, 610ng / kg / day, 620ng / kg / day, 630ng / kg / day, 640ng / kg / day, 650ng / kg / day, 660ng / kg / day, 670ng / kg / day, 680ng / kg / day, 690ng / kg / day, 700ng / kg / day, 710ng / kg / day, 720ng / kg / day, 730ng / kg / day, 740ng / kg / day, 750ng / kg / day, 760ng / kg / day, 770ng / kg / day, 780ng / kg / day, 790ng / kg / day,800ng / kg / day, 810ng / kg / day, 820ng / kg / day, 830ng / kg / day, 840ng / kg / day, 850ng / kg / day, 860ng / kg / day, 870n g / kg / day, 880ng / kg / day, 890ng / kg / day, 900ng / kg / day, 910ng / kg / day, 920ng / kg / day, 930ng / kg / day, 940ng / kg / day, 950ng / kg / day, 960ng / kg / day, 970ng / kg / day, 980ng / kg / day, 990ng / kg / day, 1μg / kg / day, 2μg / kg / day, 3μg / kg / day, 4μg / kg / day, 5μg / kg / day, 6μg / kg / day, 7μg / kg / day, 8μg / kg / day, 9μg / kg / day, or 10μg / kg / day). In some embodiments, the pharmaceutical composition is administered in a dose range of about 100 ng / kg / day to about 2.5 μg / 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, 210ng / kg / day, 220ng / kg / day, 230ng / kg / day, 240ng / kg / day, 250ng / kg / day, 260ng / kg / day, 270ng / kg / day, 280ng / k g / day, 290ng / kg / day, 300ng / kg / day, 310ng / kg / day, 320ng / kg / day, 330ng / kg / day, 340ng / kg / day, 350ng / kg / day, 360n g / kg / day, 370ng / kg / day, 380ng / kg / day, 390ng / kg / day, 400ng / kg / day, 410ng / kg / day, 420ng / kg / day, 430ng / kg / day, 440ng / kg / day, 450ng / kg / day, 460ng / kg / day, 470ng / kg / day, 480ng / kg / day, 490ng / kg / day, 500ng / kg / day, 510ng / k g / day, 520ng / kg / day, 530ng / kg / day, 540ng / kg / day, 550ng / kg / day, 560ng / kg / day, 570ng / kg / day, 580ng / kg / day, 590ng / kg / day, 600ng / kg / day, 610ng / kg / day, 620ng / kg / day, 630ng / kg / day, 640ng / kg / day, 650ng / kg / day, 660ng / kg / day,670ng / kg / day, 680ng / kg / day, 690ng / kg / day, 700ng / kg / day, 710ng / kg / day, 720ng / kg / day, 730ng / kg / day, 740ng / kg / day, 750ng / kg / day, 760ng / kg / day, 770ng / kg / day, 780ng / kg / day, 790ng / kg / day, 800ng / kg / day, 810ng / kg / day, 820ng / kg / day, 830ng / kg / day, 840ng / kg / day, 850ng / kg / day, 860ng / kg / day, 870ng / kg / day, 880ng / kg / day, 890ng / kg / day, 900ng / kg / day, 910ng / kg / day , 920ng / kg / day, 930ng / kg / day, 940ng / kg / day, 950ng / kg / day, 960ng / kg / day, 970ng / kg / day, 980ng / kg / day, 990ng / kg / day, 1μg / kg / day, 1.1μg / kg / day, 1.2μg / kg / day, 1.3μg / kg / day, 1.4μg / kg / day, 1.5μg / kg / day, 1.6μg / kg / day, 1.7μg / kg / day, 1.8μg / kg / day, 1.9μg / kg / day, 2μg / kg / day, 2.1μg / kg / day, 2.2μg / kg / day, 2.3μg / kg / day, 2.4μg / kg / day, or 2.5μg / kg / day.

[0075] The dose of the compositions described herein (e.g., compositions comprising metabolic hormones) may depend on many factors, such as the pharmacodynamic properties of the metabolic hormones, the mode of administration, the age, health, and weight of the subject to be treated, the nature and extent of symptoms, the frequency of treatment, and the type of concurrent treatment (if any), as well as the clearance rate of the composition in the treated animal. The compositions described herein may be initially administered at a suitable dose, which may be adjusted as necessary depending on the clinical response. In some embodiments, the dose of the compositions (e.g., compositions comprising metabolic hormones) is a prophylactically or therapeutically effective amount. Furthermore, it is understood that all doses may be given continuously or divided into doses given per given time frame. The compositions may be administered, for example, hourly, daily, weekly, monthly, or yearly. In some embodiments, the compositions may be administered continuously. For example, the rectal formulation or GI patch may be present in the subject for a sustained period of time (e.g., at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 2 months, 3 months, or more).

[0076] The pharmaceutical compositions described herein (e.g., including metabolic hormones) can be provided in a kit that includes the pharmaceutical composition (e.g., in a container) and instructions for its use. The kit can include one or more containers, each container including a different composition of the invention. The instructions included with the kit can be used to instruct a user to practice the methods described herein.

[0077] The methods described herein include administering a metabolic hormone (e.g., PYY, PYY(3-36), leptin, amylin, insulin, GLP-1, or an analog, variant, or biologically active fragment thereof, locally to the mouth (e.g., tongue, salivary glands, lingual and / or sublingual epithelium, or mucosa), rectum, nasal cavity, or GI tract of a subject, wherein the local administration does not result in a substantial change in the levels of the metabolic hormone in the subject's blood and / or plasma. Generally, the levels of the metabolic hormone in the subject's blood and / or plasma are not substantially altered. Metabolic hormone levels are not increased by more than up to 10% (e.g., 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less) of pre-administration levels of metabolic hormone. For example, PYY administered locally lingually (e.g., topically to the lingual epithelium) to a subject at any dose described herein may reach peak levels that are up to one-tenth the endogenous levels of PYY and then decline substantially. In some embodiments, blood and / or plasma levels of PYY(3-36) are measured using the Batterham 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 Considine et al, Cell Metabolism, 4:223-233, 2006, which is incorporated herein by reference in its entirety. In some embodiments, after local lingual (e.g., topically to the lingual epithelium) 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 Cooper et al, Cell Metabolism, 4:223-233, 2006, which is incorporated herein by reference in its entirety. In some embodiments, after local lingual (e.g., topically to the lingual epithelium) administration of leptin, the blood and / or plasma levels of amylin do not substantially exceed preprandial levels of about 5 ng / ml to about 35 ng / ml as reported in Cooper et al, Cell Metabolism, 4:223-233, 2006, which is incorporated herein by reference in its entirety. As reported by et al., Hypertension, 26:460-464, 1995 (incorporated herein by reference in its entirety), following local lingual (e.g., topical to the lingual epithelium) administration of amylin, preprandial levels of about 20 pmol / l are not substantially exceeded.

[0078] array PYY SEQ ID NO:1 MVFVRRPWPALTTVLLALLVCLGALVDAYPIKPEAPREDASPEELNRYYASLRHYLNLVTRQRYGKRDGPDTLLSKTFFPDGEDRPVRSRSEGPDLW PYY(3-36) SEQ ID NO:2 IKPEAPGEDASPEELNRYYASLRHYLNLVTRQRY GLP-1 SEQ ID NO:3 MKSIYFVAGLFVMLVQGSWQRSLQDTEEKSRSFSASQADPLSDPDQMNEDKRHSQGTFTSDYSKYLDSRRAQDFVQWLMNTKRNRNNIAKRHDEFERHAEGTFTSDVSSYLEGQAAKEFIAWLVKGRGRRDFPEEVAIVEELGRRHADGSFSDEMNTILDNLAARDFINWLIQTKITDRK GLP-1(7-36) SEQ ID NO:4 HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR GLP-1(7-37) SEQ ID NO:5 HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG Leptin SEQ ID NO:6 MHWGTLCGFLWLWPYLFYVQAVPIQKVQDDTKTLIKTIVTRINDISHTQSVSSKQKVTGLDFIPGLHPILTLSKMDQTLAVYQQILTSMPSRNVIQISNDLENLRDLLHVLAFSKSCHLPWASGLETLDSLGGVLEASGYSTEVVALSRLQGSLQDMLWQLDLSPGC Amylin SEQ ID NO:7 MGILKLQVFLIVLSVALNHLKATPIESHQVEKRKCNTATCATQRLANFLVHSSNNFGAILSSTNVGSNTYGKRNAVEVLKREPLNYLPL Pramlintide SEQ ID NO:8 KCNTATCATQRLANFLVHSSNNFGPILPTNVGSNTY Metreleptin SEQ ID NO:9 MVPIQKVQDDTKTLIKTIVTRINDISHTQSVSSKQKVTGLDFIPGLHPILTLSKMDQTLAVYQQILTSMPSRNVIQISNDLENLRDLLHVLAFSKSCHLPWASGLETLDSLGGVLEASGYSTEVVALSRLQGSLQDMLWQLDLSPGC (Disulfide bridge: 97-147) Calcitonin SEQ ID NO:10 CGNLSTCMLGTYTQDFNKFHTFPQTAIGVGAP [Pro34]PYY SEQ ID NO:11 YPIKPEAPGEDASPEELNRYYASLRHYLNLVTRPRY Insulin SEQ ID NO:12 MALWMRLLPLLALLALWGPDPAAAFVNQHLCGSHLVEALYLVCGERGFFYTPKTRREAEDLQVGQVELGGGPGAGSLQPLALEGSLQKRGIVEQCCTSICSLYQLENYCN Insulin Aspart A chain SEQ ID NO:13 GIVEQCCTSICSLYQLENYCN Insulin Aspart B chain SEQ ID NO:14 FVNQHLCGSHLVEALYLVCGERGFFYTDKT Insulin glargine A chain SEQ ID NO:15 GIVEQCCTSICSLYQLENYCG Insulin glargine B chain SEQ ID NO:16 FVNQHLCGSHLVEALYLVCGERGFFYTPKTRR Insulin lispro A chain SEQ ID NO:17 GIVEQCCTSICSLYQLENYCN Insulin lispro B chain SEQ ID NO:18 FVNQHLCGSHLVEALYLVCGERGFFYTKPT Insulin glulisine A chain SEQ ID NO:19 GIVEQCCTSICSLYQLENYCN Insulin glulisine B chain SEQ ID NO:20 FVKQHLCGSHLVEALYLVCGERGFFYTPET Insulin detemir A chain SEQ ID NO:21 GIVEQCCTSICSLYQLENYCN Insulin detemir B chain SEQ ID NO:22 FVNQHLCGSHLVEALYLVCGERGFFYTPK

[0079] Other embodiments While the invention has been described in conjunction with specific 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

**Claim 1** A composition for use in a method of treating addiction or mood disorder by activating a nerve receptor in a subject, the composition comprising an agent selected from glucagon-like peptide 1 (GLP-1), calcitonin, peptide YY (PYY), leptin, amylin, and insulin, or an analog, variant, or biologically active fragment thereof, wherein the composition activates the nerve receptor without substantially changing the concentration of the agent in the subject's blood. **Claim 2** (a) The mood disorder includes depression, anxiety, mood swings, bipolar disorder, drug-induced mood disorder, obsessive-compulsive disorder, eating disorder, substance-induced mood disorder, major depressive disorder, seasonal major depressive disorder, a type of depression due to hormonal changes, panic attacks, generalized anxiety disorder, bipolar disorder type I, bipolar disorder type II, cyclothymia, manic state, schizoaffective disorder, schizophrenia, autism spectrum, attention deficit hyperactivity disorder, attention deficit disorder, dementia, Alzheimer's disease, reversible dementia, depressive personality disorder, schizoid personality disorder, narcissistic personality disorder, borderline disorder, antisocial personality disorder, shoplifting, lying, dangerous behavior, impulse control difficulties, or adjustment disorder, or (b) The addiction includes cravings or dependencies for alcohol, cocaine, opioids, nicotine, heroin, marijuana, 3,4-methylenedioxy-methamphetamine, caffeine, mescaline, methamphetamine, amphetamine derivatives, dextromethorphan, loperamide, phenylcyclohexylpiperidine, stimulants, steroids, cannabinoids, cathinone, lysergic acid diethylamide, gambling, sex, inhalants, sedatives, hypnotics, tobacco, anti-anxiety drugs, hallucinogens, food, behaviors, repetitive behaviors, destructive habits, or combinations thereof. The composition for use according to Claim 1. **Claim 3** The composition for use according to Claim 1 or 2, wherein the composition is formulated for topical sublingual administration. **Claim 4** The composition for use according to Claim 3, wherein the composition is formulated as an orally disintegrating tablet, lozenge, film, spray, semi-solid, microparticles, or in a lipid-based carrier. **Claim 5** The composition for use according to Claim 1 or 2, wherein the composition is formulated for nasal administration. **Claim 6** The composition according to claim 5, wherein the composition is formulated as a spray, semi-solid, microparticles, or in a lipid-based carrier.

7. The composition according to claim 1 or 2, wherein the composition is formulated for topical administration to the digestive (GI) tract.

8. The composition according to claim 7, wherein the composition is formulated as a GI patch.

9. The composition according to claim 1 or 2, wherein the composition is formulated for rectal administration.

10. The composition according to claim 9, wherein the composition is formulated as a suppository.

11. The composition according to claim 1 or 2, wherein the dose of the agent is 1 ng to 20 mg per 100 kg of body weight.

12. The dose of the agent is (a) 1 ng to 1 μg per 100 kg of body weight, (b) 1 μg to 1 mg per 100 kg of body weight, or (c) 1 mg to 20 mg per 100 kg of body weight for the use according to claim 11.

13. The composition according to claim 1 or 2, wherein the PYY is PYY(3-36).

14. The composition according to claim 1 or 2, wherein the neuroreceptor comprises a Y receptor (YR), Y1 receptor (Y1R), Y2 receptor (Y2R), Y4 receptor (Y4R), Y5 receptor (Y5R), G protein-coupled receptor (GPRCR), leptin receptor (LEPR), GLP-1 receptor (GLP-1R), insulin receptor (INSR), glucose-dependent insulinotropic polypeptide receptor (GIPR), ghrelin receptor (GHS-R), cholecystokinin A receptor (CCKAR), cholecystokinin B receptor (CCKBR), or calcitonin receptor (CALCR).

15. (a) An agent selected from GLP-1, calcitonin, PYY, leptin, and amylin, or an analog, variant, or biologically active fragment thereof, wherein the composition is formulated for nasal administration. (b) An agent selected from GLP-1, calcitonin, PYY, leptin, amylin, and insulin, or an analog, variant, or biologically active fragment thereof, wherein the composition is formulated for topical administration to the GI tract. (c) An agent selected from GLP-1, calcitonin, PYY, leptin, amylin, and insulin, or an analog, variant, or biologically active fragment thereof, wherein the composition is formulated for rectal administration A composition comprising The composition activates the nerve receptors of the subject without substantially changing the concentration of the agent in the blood of the subject [

16. ] (a) The composition for nasal administration is formulated as a spray, semi-solid, microparticles, or in a lipid-based carrier (b) The composition for local administration to the GI tract is formulated as a GI patch, or (c) The composition for rectal administration is formulated as a suppository The composition according to claim 15 [

17. ] The composition according to claim 15 or 16, wherein the dose of the agent is 1 ng to 20 mg [

18. ] The dose of the agent is (a) 1 ng to 1 μg (b) 1 μg to 1 mg, or (c) 1 mg to 20 mg The composition according to claim 17 [

19. ] The composition according to claim 15 or 16, wherein the PYY is PYY(3-36) [

20. ] The composition according to claim 15 or 16, wherein the nerve receptor comprises YR, Y1R, Y2R, Y4R, Y5R, GPCR, LEPR, GLP-1R, INSR, GIPR, GHS-R, CCKAR, CCKBR, or CALCR