Peptide yy pharmaceutical formulations, compositions, and methods

Abstract

To provide pharmaceutical compositions for the treatment of metabolic disorders, and to provide methods for treating metabolic disorders.SOLUTION: Pharmaceutical compositions comprising PYY (e.g., PYY (3-36) and analogs and variants thereof), satiety peptides, satiety hormones, metabolic hormones, and methods of treating metabolic diseases with such compositions are provided. Such aspects include methods of increasing a feeling of fullness in patients treated with pharmaceutical compositions comprising PYY, PYY (3-36), satiety peptides, satiety hormones, metabolic hormones, and analogs, receptor antagonists and variants thereof.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] All references cited herein, including, but not limited to, patents and patent applications, are incorporated herein by reference in their entirety. No. 6,399,433, filed on Oct. 23, 2003, and which are incorporated by reference in their entireties. CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application is a continuation of U.S. Provisional Application No. 62 / 620,580, filed January 23, 2018, and U.S. Provisional Application No. 62 / 620,580, filed May 9, 2018. This application claims priority to and the benefit of U.S. Provisional Application No. 62 / 669,191, filed on are incorporated herein by reference in their entireties. Background Summary of the Invention [Problem to be solved by the invention]

[0003] The prevalence of obesity continues to increase worldwide.[1] In the United States, 69% of adults are overweight or However, there are still no effective, long-term, non-invasive treatments for obesity. There are currently too many "one-size-fits-all" approaches to treating obesity. has been associated with a variety of efficacy and outcomes [3].

[0004] PYY(3-36) is an agonist of Y receptors (e.g., Y2 receptors) released from intestinal cells in response to feeding. Peptide YY (PYY)(3-36) is a sesame oil released primarily from the digestive tract after a meal. PYY is a gastrointestinal hormone that regulates satiation (also called satiation, fullness, or satiation). (3-36) secretion is related to caloric intake, and it is mediated by Y2 receptors in the arcuate nucleus of the hypothalamus. In recent years, PYY(3) has been shown to be a potent inhibitor of serotonin synthesis in mice and humans. -36) was found to be present in saliva, and its concentration in saliva correlates with that in plasma. PYY(3-36) and the Y2 receptor are expressed in taste cells in the circumvallate papillae of the tongue [4]. In mice, acute augmentation therapy with salivary PYY(3-36) induced a greater satiety as shown by feeding behavior studies and by c-Fos activation in the arcuate nucleus of the hypothalamus [5]. A rapid increase in salivary PYY(3-36) resulted in a decrease in food intake over one hour in a dose-dependent manner. Chronic overexpression of salivary PYY(3-36) using virus vector-mediated genes delivered into the submandibular salivary glands (rAAV-PYY vs rAAV-GFP control) resulted in a two-fold chronic increase in PYY(3-36) in saliva over 22 weeks [4]. The results of this treatment showed a decrease in weekly food intake and a 23% weight loss 8 weeks after vector delivery compared to controls [4]. PYY(3-36) induces satiety through saliva and taste cell receptors [5,6].

[0005] Incretins, such as glucagon-like peptide 1 (GLP-1), enhance glycemic control, impede gastric emptying, and increase satiety in both healthy individuals and diabetic patients [7-9]. GLP-1 and GLP-1 agonists decrease fasting and postprandial glucose levels via an increase in insulin secretion from the pancreas and decrease gluconeogenesis in the liver

[0006] Exendin (Exendin-4) is derived from the Gila monster peptide produced in the salivary glands of the Gila monster (also known as the Heloderma suspectum), which is 39 amino acids long and shares 53% identity with GLP-1. However, its half-life is extended due to its resistance to rapid degradation by dipeptidyl peptidase 4 (DPP-IV), the normal mechanism for GLP-1 inactivation. Exenatide is FDA-approved for the treatment of patients with type 2 diabetes mellitus in both daily and weekly prescriptions, but there it is only inadequately controlled by treatment with metformin or sulfonylurea which does not adequately control the patient's condition. GLP-1 receptor agonists also delay gastric emptying and reduce food intake by up to 19% [10-12]. The effect of exenatide on gastric emptying is temporarily associated with reduced postprandial glycemia (also known as blood sugar) in patients with type 2 diabetes mellitus

[13] .

[0007] Previously, PYY and PYY analogs have been administered to subjects in a manner that results in a large increase in PYY levels in the subject's blood. PYY and PYY analogs have also been used to induce satiety in subjects without substantially changing the concentration of PYY in the subject's blood. See, for example, U.S. Patent No. 9,492,505. Even higher doses of PYY can cause undesirable side effects, such as nausea, etc. However, no appropriate low-dose PYY pharmaceutical formulations for inducing satiety in a subject have been described. Summary

Means for Solving the Problem

[0008] ​Local oral delivery of PYY(3-36) reduces food intake and increases survival However, it has been shown that the method is suitable for inducing a long-term feeling of satisfaction in subjects. Providing low dose formulations of PYY(3-36), PYY analogs, and sataietype It is desirable to improve the activity of peptides. Moreover, such formulations are useful for treating metabolic disorders. It can be used.

[0009] The embodiments described herein include PYY or PYY analogs (e.g., PYY(3-36)), variants, and subunits. Tiety peptides (e.g., GLP-1, oxyntomodulin, and cholecystokinin) The present invention provides a pharmaceutical composition comprising a PYY or PYY analog, variant, And the dose of satiety peptide is at least about 2.5 ng. is PYY(3-36). In yet another embodiment, the dosage of PYY in the pharmaceutical composition is about 2.5 ng In another embodiment, the dosage of PYY in the pharmaceutical formulation is from about 2.5 μg to about 2.5 mg. The term "dose" refers to the desired amount of active pharmaceutical ingredient in a dosage form. Between 90 and 110 percent of the amount of the Federal Drug Administration (FDA) The dosage refers to the amount listed on the label for a drug product approved by the Food and Drug Administration (FDA).

[0010] In another embodiment, the volumetric dosage of PYY(3-36) is, for example, from about 25 μl to about 100 μl. or from about 2.5 ng to about 250 μg in a volume of up to about 5 ml. In an embodiment, the dose / volume is about 2.5 μg / ml. In another embodiment, the dose / volume is about 500 μg / 500 μL. It is. In another aspect, the dose / volume is about 250 μg / ml.

[0011] In these aspects, the pharmaceutical composition can further comprise pharmaceutically acceptable excipients (examples are propylene glycol, potassium sorbate, 1-arginine, disodium edetate, sodium dihydrogen phosphate, and polysorbate 20). Optionally, the pharmaceutical preparation can further comprise water or any other suitable diluent or pharmaceutically acceptable excipient. In one aspect, the pharmaceutical composition contains an excipient that stabilizes PYY(3-3 6) at a low dose (for example, less than 2.5 ng / ml) per volume. In other aspects, the excipient increases the residence time of the pharmaceutical composition in the mouth, for example, promoting its binding to its receptor (for example, the Y2 receptor) of PYY(3-36). In yet another aspect, the excipient can be used to such an extent that it increases the retention time of PYY(3-36) in saliva, provided that such an increase is desirable.

[0012] In another aspect, the pH of the pharmaceutical composition is maintained at a pH that promotes the activity and stability of PYY(3-36). In one aspect, the pH of the pharmaceutical composition is between about pH 5 and about 8. In another aspect , the pH of the pharmaceutical composition is between about pH 6 and about 7. In yet another aspect, the pH is about 5 .

[0013] In one aspect, the described pharmaceutical preparation is administered to subjects with PYY and PYY analog preparations, and alleviates the symptoms associated with metabolic disorders compared to subjects who have not received PYY or PYY analog preparations, thereby treating metabolic disorders (examples are obesity, increased blood glucose, diabetes, fatty liver disease, PCOS, and multiple sclerosis).

[0014] Yet another aspect provides a method of enhancing satiety in a subject, for example, by administering a PYY or PYY analog agent to the subject before a meal. In this aspect, the satiety can last at least about 30, 60, 90, or 120 minutes or longer after administering the PYY or PYY analog agent to the subject and after the subject has eaten a meal. In another aspect a pharmaceutical composition is administered to the subject and the subject then consumes a meal. BRIEF DESCRIPTION OF THE DRAWINGS

[0015]

Figure 1

Figure 2

Figure 3

[0016] Before describing the representative aspects described herein, it should be understood that the present invention is not limited to the details of the configurations or process steps described in the following description. The representative aspects described herein are not so limited. Aspects are capable of being practiced or carried out in a variety of ways.

[0017] Satiation occurs during a meal. It is the point at which the subject feels that it is sufficient for him or her to eat and that he or she does not desire any more food. On the other hand , satiety (also referred to as fullness, repletion, etc.) refers to the subject's experience after a meal, - how long it takes for the subject to begin feeling hungry again. "Feeling of fullness (also referred to as a sense of fullness, bloatedness, etc.)" refers to an indicator of satiety as reported by a person after eating food or a meal . The degree and duration of fullness (satiation and satiety ) are predictors of whether a person will continue to eat or resume eating and thus increase calorie intake over time . Therefore, increasing the degree and duration of fullness reduces overall calorie intake and results in a decrease in weight and obesity.

[0018] The Visual Analogue Scale (VAS) is an instrument, tool, or methodology used to measure a characteristic that can vary in value or degree and that is not easily measured directly in another way. For example, the VAS is often used to determine the degree of pain experienced by a patient (a patient in human terms) (e.g., on a scale of 1 to 10). Similarly, the VAS can certainly be used to measure the degree of fullness reported by a subject after eating food or a meal . An example is Blundell (Bl undell) (e.g., on a scale of 1 to 10). Randell et al., "Appetite Control: Methodological Aspects of The Valuation of Foo ds (Appetite control: Methodological aspects of food evaluation)", Obes Rev. (Obesity Review s) March 2010; 11(3): 251-270; Flint et al., "Reproducibility, power a nd validity of visual analogue scales in assessment of appetite sensations in si ngle test meal studies (Reproducibility, power and validity of visual analogue scales in the assessment of appetite sensations in single test meal studies)", International Journal of Obesity (International Journal of Obesity) (2000) 24, 38-48 (2000 ). See .

[0019] Metabolic disorders, diseases, or metabolic syndrome refer to diseases or conditions that are related to, associated with, or caused by abnormal metabolism and that increase the risk of diseases or disorders (examples are diabetes, heart disease, stroke, obesity, elevated blood sugar, fatty liver disease, PCOS (polycystic ovary syndrome), and multiple sclerosis). The lack of effective long-term, non-invasive procedures for metabolic disorders has spurred the search for small molecules that can treat these conditions with minimal side effects. Although several small molecule therapeutic substances are currently on the market, their effectiveness is relatively low, and their safety profiles are not ideal. On the other hand, fasting, satiety, and regulation of energy metabolism in normal physiological functions are not ideal. On the other hand, fasting, satiety, and regulation of energy metabolism in normal physiological functions ​​Natural human hormones involved for the section, and as described herein, their analogs (also referred to as analogs) can be used to treat such diseases.

[0020] GLP-1 receptor agonists, and PYY(3-36) and analogs have been used only with limited success in the treatment of metabolic disorders. The therapeutic results with GLP-1 receptor agonists for diabetes mellitus (DM) and obesity are very variable and result in serious side effects. PYY(3-36) is a potent inducer of satiety but PYY and analogs administered systemically tend to be associated with serious side effects such as nausea and vomiting.

[0021] The aspects described herein provide compositions comprising PYY and PYY analogs such as, for example, PYY(3-36). In certain aspects, these compositions can be used to treat metabolic abnormalities (also referred to as metabolic disease, metabolic disorder, metabolic illness, metabolic syndrome, etc.) (e.g., obesity, diabetes, hyperglycemia, etc.). These compositions can be used to more effectively alleviate, improve, or treat the condition in a patient than a pure aqueous solution or a simple dry composition.

[0022] In one aspect, the term "PYY(3-36)" or "native PYY-3-36" refers to amino acids 3-36 of the human PYY molecule and has the following amino acid sequence (from amino terminus to carboxy terminus):

[0023] {NH2}-ILE-LYS-PRO-GLU-ALA-PRO-GLY-GLU-ASP-ALA-SER-PRO-GLU-GLU-LEU-ASN-ARG-TY R-TYR-ALA-SER-LEU-ARG-HIS-TYR-LEU-ASN-LEU-VAL-THR-ARG-GLN-ARG-TYR-{COOH}.

[0024] Native PYY(3-36) is post-translationally processed from a precursor peptide encoded by the following mRNA nucleic acid sequence (positions 632-733 (bolded below)):

[0025] 1 gcccctggag gaactgaacc cactatcggt catggggccg agactaaatg tggcgggttg 61 tctttaatct gctgccaaga ggaaactcat tcaggcaagt tcagcccttt atgaggaatt 121 cccctgtggt cacattccaa ttcctggacc tgctgccacc ctcagaactg catgctcctt 181 cttcagactt tctaagaatg actcaggtca ttggtggagt gaagtcaaga tttccaactc 241 agtcacctga agagatggag ataccattca tggagctgga ggtccctgga gatttgggaa 301 ttcagataac aagctaagat aaggagtttg cctacctctg tcctagagcg aagcctgagc 361 cttgggcgcg cagcacacca caagtatctg ttactgtgtt ttgcagaagc ttcaggcggg 421 gatataagcc ccacaaggaa agcgctgagc agaggaggcc tcagcttgac ctgcggcagt 481 gcagcccttg ggacttccct cgccttccac ctcctgctcg tctgcttcac aagctatcgc 541 tatggtgttc gtgcgcaggc cgtggcccgc cttgaccaca gtgcttctgg ccctgctcgt 601 ctgcctaggg gcgctggtcg acgcctaccc catcaaaccc gaggctcccg gcgaagacgc) 661 ctcgccggag gagctgaacc gctactacgc ctccctgcgc cactacctca acctggtcac 721 ccggcagcgg tatgggaaaa gagacggccc ggacacgctt ctttccaaaa cgttcttccc 781 cgacggcgag gaccgccccg tcaggtcgcg gtcggagggc ccagacctgt ggtgaggacc 841 cctgaggcct cctgggagat ctgccaacca cgcccacgtc atttgcatac gcactcccga 901 ccccagaaac ccggattctg cctcccgacg gcggcgtctg ggcagggttc gggtgcggcc 961 ctccgcccgc gtctcggtgc ccccgccccc tgggctggag ggctgtgtgt ggtccttccc 1021 tggtcccaaa ataaagagca aattccacag aaacggaaaa aaaaaaaaa

[0026] In another aspect, the term "PYY(3-36)" further includes analogs or variants (also referred to as modifications, mutants, etc.) of native PYY(3-36) that retain at least about 20, 30, 40, 50, 60, 70, 80, 90 or 100% of the biological activity of native PYY(3-36). In this aspect at least about 20, 30, 40, 50, 60, 70, 80, 90 or 100% of the biological activity of native PYY(3-36). In this aspect at least about 20, 30, 40, 50, 60, 70, 80, 90 or 100% of the biological activity of native PYY(3-36). In this aspect In this context, the term "variant" refers to one or more (also referred to as one or more) modifications or substitutions of the native PYY(3-36) amino acids. Amino acid substitution refers to replacing one amino acid with another amino acid. In one aspect, the amino acid may be replaced with an amino acid having a similar side group (examples are acidic, basic, neutral). The term "biological activity" refers to the activation of the Y receptor by one or more of the small molecules described herein, which affects food intake, gastrointestinal function, or central nervous system activity, either locally or systemically. In this context, the term "variant" refers to one or more (also referred to as one or more) modifications or substitutions of the native PYY(3-36) amino acids. Amino acid substitution refers to replacing one amino acid with another amino acid. In one aspect, the amino acid may be replaced with an amino acid having a similar side group (examples are acidic, basic, neutral). The term "biological activity" refers to the activation of the Y receptor by one or more of the small molecules described herein, which affects food intake, gastrointestinal function, or central nervous system activity, either locally or systemically. In this context, the term "variant" refers to one or more (also referred to as one or more) modifications or substitutions of the native PYY(3-36) amino acids. Amino acid substitution refers to replacing one amino acid with another amino acid. In one aspect, the amino acid may be replaced with an amino acid having a similar side group (examples are acidic, basic, neutral). The term "biological activity" refers to the activation of the Y receptor by one or more of the small molecules described herein, which affects food intake, gastrointestinal function, or central nervous system activity, either locally or systemically. (For example, acidic, basic, neutral). The term "biological activity" refers to the activation of the Y receptor by one or more of the small molecules described herein, which affects food intake, gastrointestinal function, or central nervous system activity, either locally or systemically. The term "biological activity" refers to the activation of the Y receptor by one or more of the small molecules described herein, which affects food intake, gastrointestinal function, or central nervous system activity, either locally or systemically. The term "biological activity" refers to the activation of the Y receptor by one or more of the small molecules described herein, which affects food intake, gastrointestinal function, or central nervous system activity, either locally or systemically. The term "biological activity" refers to the activation of the Y receptor by one or more of the small molecules described herein, which affects food intake, gastrointestinal function, or central nervous system activity, either locally or systemically.

[0027] Analogs or variants of PYY(3-36) include, for example, analogs or variants of PYY. Examples include Michel et al., Dipeptidyl peptidase IV inhibitors in diabetes; more than inhibition of glucagon-like peptide-1 metabolism? Naunyn-Schmiedeberg's Arch Pharmacol (2008) 377:205-207; Niida et al., Antiobesity and emetic effects of a short-length peptide YY analog and its PEGylated and alkylated derivatives, Bioorganic & Medicinal Chemistry In this context, the term "variant" refers to one or more (also referred to as one or more) modifications or substitutions of the native PYY(3-36) amino acids. Amino acid substitution refers to replacing one amino acid with another amino acid. In one aspect, the amino acid may be replaced with an amino acid having a similar side group (examples are acidic, basic, neutral). The term "biological activity" refers to the activation of the Y receptor by one or more of the small molecules described herein, which affects food intake, gastrointestinal function, or central nervous system activity, either locally or systemically. In this context, the term "variant" refers to one or more (also referred to as one or more) modifications or substitutions of the native PYY(3-36) amino acids. Amino acid substitution refers to replacing one amino acid with another amino acid. In one aspect, the amino acid may be replaced with an amino acid having a similar side group (examples are acidic, basic, neutral). The term "biological activity" refers to the activation of the Y receptor by one or more of the small molecules described herein, which affects food intake, gastrointestinal function, or central nervous system activity, either locally or systemically. In this context, the term "variant" refers to one or more (also referred to as one or more) modifications or substitutions of the native PYY(3-36) amino acids. Amino acid substitution refers to replacing one amino acid with another amino acid. In one aspect, the amino acid may be replaced with an amino acid having a similar side group (examples are acidic, basic, neutral). The term "biological activity" refers to the activation of the Y receptor by one or more of the small molecules described herein, which affects food intake, gastrointestinal function, or central nervous system activity, either locally or systemically. In this context, the term "variant" refers to one or more (also referred to as one or more) modifications or substitutions of the native PYY(3-36) amino acids. Amino acid substitution refers to replacing one amino acid with another amino acid. In one aspect, the amino acid may be replaced with an amino acid having a similar side group (examples are acidic, basic, neutral). The term "biological activity" refers to the activation of the Y receptor by one or more of the small molecules described herein, which affects food intake, gastrointestinal function, or central nervous system activity, either locally or systemically. In this context, the term "variant" refers to one or more (also referred to as one or more) modifications or substitutions of the native PYY(3-36) amino acids. Amino acid substitution refers to replacing one amino acid with another amino acid. In one aspect, the amino acid may be replaced with an amino acid having a similar side group (examples are acidic, basic, neutral). The term "biological activity" refers to the activation of the Y receptor by one or more of the small molecules described herein, which affects food intake, gastrointestinal function, or central nervous system activity, either locally or systemically. In this context, the term "variant" refers to one or more (also referred to as one or more) modifications or substitutions of the native PYY(3-36) amino acids. Amino acid substitution refers to replacing one amino acid with another amino acid. In one aspect, the amino acid may be replaced with an amino acid having a similar side group (examples are acidic, basic, neutral). The term "biological activity" refers to the activation of the Y receptor by one or more of the small molecules described herein, which affects food intake, gastrointestinal function, or central nervous system activity, either locally or systemically. In this context, the term "variant" refers to one or more (also referred to as one or more) modifications or substitutions of the native PYY(3-36) amino acids. Amino acid substitution refers to replacing one amino acid with another amino acid. In one aspect, the amino acid may be replaced with an amino acid having a similar side group (examples are acidic, basic, neutral). The term "biological activity" refers to the activation of the Y receptor by one or more of the small molecules described herein, which affects food intake, gastrointestinal function, or central nervous system activity, either locally or systemically. In this context, the term "variant" refers to one or more (also referred to as one or more) modifications or substitutions of the native PYY(3-36) amino acids. Amino acid substitution refers to replacing one amino acid with another amino acid. In one aspect, the amino acid may be replaced with an amino acid having a similar side group (examples are acidic, basic, neutral). The term "biological activity" refers to the activation of the Y receptor by one or more of the small molecules described herein, which affects food intake, gastrointestinal function, or central nervous system activity, either locally or systemically. Journal of Medicinal Chemistry (2017) (S0968-0896 (Epub ahead of print (pamphlet See electronic publication ahead of print). In one aspect, these analogs and variants can be used in the pharmaceutical compositions described herein.

[0028] The aspects described herein provide pharmaceutical compositions comprising PYY, wherein when PYY is administered to a subject, the dose of PYY provided to the subject is at least about 2.5 ng. In another aspect, PYY is PYY(3-36). In yet another aspect, the dose of PYY, PYY(3-36), or other PYY analogs is about 25 ng, 250 ng, 2.5 μg, 25 μg, 250 μg, or 2.5 mg. In a further aspect, the dose of PYY, PYY(3-36), or other PYY analogs can range from about 25 ng to about 2.5 mg, from about 250 ng to about 250 μg, or from about 2.5 μg to about 25 μg.

[0029] A further aspect provides a pharmaceutical composition comprising a satiety peptide (also referred to as a satiety peptide, a fullness peptide, etc.) and a pharmaceutically acceptable excipient at a dose from about 2.5 ng to about 2.5 mg. In another aspect, the pharmaceutical composition of claim 23 is such that the satiety peptide is selected from the group consisting of GLP-1, oxyntomodulin, and cholecystokinin.

[0030] In another aspect, the dose per volume of PYY(3-36) ranges from about 2.5 ng to about 250 μg in a volume of solvent (e.g., water, buffer, etc.) from about 25 μl to about 5 ml, for example. ​​​​​​​​​​​is achievable. In another embodiment, the dose / volume is about 2.5 μg / ml. In another embodiment, the dose / volume is about 500 μg / 500 μl. The volume of the pharmaceutical preparation selected to deliver the dose of PYY(3-36) is , for example, in the oral cavity and, more specifically, to enhance the interaction between PYY(3-36) on the tongue and its receptor (e.g., the Y2 receptor) on the tongue, the residency -time (also referred to as the residency time) of PYY(3-36) can be selected to be optimized.

[0031] In a further embodiment, in addition to one or more of the following, or instead of PYY, PYY(3-36), or other PYY analogs, together with one or more of the following, nucleotides encoding PYY, PYY(3-36), or other PYY analogs, or peptides having substantial identity therewith, these pharmaceutical compositions are included: GLP-l, oxyntomodulin, and cholecystokinin acetyl-CoA carboxylase-(ACC) inhibitors, diacylglycerol O-acyltransferase 1 (DGAT-1) inhibitors, monoacylglycerol O-acyltransferase inhibitors, phosphodiesterase (PDE)-10 inhibitors, AMPK activators (also referred to as activators, activating substances, activators, etc.), sulfonylureas, meglitinides, α-amylase inhibitors, α-glucoside hydrolase inhibitors, α-glucosidase inhibitors, PPARγ agonists (also referred to as agents, agonists, etc.), PPARα / γ agonists, biguanides, glucagon-like peptide 1 (GLP-1) modifiers (also referred to as modulators, modifying substances, modifying drugs, etc.), GLP-1 receptor agonists, liraglutide, albiglutide, exenatide (exen anatide), agonists (also referred to as agents, agonists, etc.), PPARα / γ agonists, biguanides, glucagon-like peptide 1 (GLP-1) modifiers (also referred to as modulators, modifying substances, modifying drugs, etc.), GLP-1 receptor agonists, liraglutide, albiglutide, exenatide (exen anatide), Also known as nateglinide), albiglutide, lixisenatide, dulaglutide, semaglutide, Protein tyrosine phosphatase-1B (PTP-1B) inhibitor, SIRT-l activator, dipep tidyl peptidase IV (DPP-IV) inhibitor, insulin secretagogu (secreatagogu e), fatty acid oxidation inhibitor, A2 antagonist (also referred to as antagonist, antagonist drug, etc.), c-jun N-terminal kinase (JNK) inhibitor, glucokinase activator (GKa), insulin, Insulin mimetic (also referred to as mimetic, mimic, imitation, etc.), glycogen phosph holylase inhibitor, VPAC2 receptor agonist, SGLT2 inhibitor, glucagon receptor modifier factor, GPR119 modifier, FGF21 derivative or analog (also referred to as analog), TGR5 receptor modifier factor, GPBAR1 receptor modifier, GPR40 agonist, GPR120 modifier, high affinity nicotinic acid receptor (HM74A) activator, SGLT1 inhibitor, carnitine palmitoyltransferase enzyme inhibitor or modifier, fructose 1,6-diphosphatase inhibitor, al dose reductase (also referred to as reductase) inhibitor, mineralocorticoid (mineralo corticoid, also referred to as mineral corticoid) receptor inhibitor, TORC2 inhibitor, CCR2 and / or CCR5 inhibitor, PKC isoform inhibitor (examples are PKCα, RKCβ, PKCγ) ), fatty acid synthetase (also referred to as synthetase) inhibitor, serine palmitoyltran sferase inhibitor, GPR81, GPR39, GPR43, GPR41, GPR105, Kvl.3, retinol binding protein 4, glucocorticoid (also referred to as glucocorticoid) receptor, somatostatin receptor (s Modulators of omatostain receptor, inhibitors or modulators of PDHK2 or PDHK4, MAP4K 4 inhibitors, modulators of the IL1 family including IL1-beta, HMG-CoA reductase inhibitors , squalene synthase inhibitors, fibrates, bile acid metal ion sequestering agents, ACAT inhibitors , MTP inhibitors, lipoxygenase inhibitors, cholesterol absorption inhibitors, PCSK9 modulators, cholesteryl ester transfer protein inhibitors (cholesteryl este r transfer protein inhibitors) and modulators of RXRα, GIP receptor agonists, enterostating and enterostatin analogs, amylin and amylin receptor agonists, ghrelin modulators (e.g., inhibitors) and leptin and leptin receptor agonists, pancreatic polypeptide (PP), calcitonin, OXM, neuro peptide Y (NPY), human growth hormone, prolactin, oxytocin, bovine growth hormone , porcine growth hormone, ghrelin, ghrelin receptor antagonists, and glucagon and their analogs and variants.

[0032] In yet another aspect, the pharmaceutical composition includes PYY, PYY(3-36), GLP-1, oxyntomodulin , and cholecystokinin, acetyl-CoA carboxylase-(ACC) inhibitors, di acylglycerol O-acyltransferase 1 (DGAT-1) inhibitors, monoacylgly cerol O-acyltransferase inhibitors, phosphodiesterase (PDE)-10 inhibitors , AMPK activators, sulfonylureas, meglitinides, α-amylase inhibitors, α-glu Koshi hydrolase inhibitor, α-glucosidase inhibitor, PPARγ agonist, PPARα / γ agonist, biguanide, glucagon-like peptide 1 (GLP-l) modifier, GLP-1 receptor agonist, liraglutide, albiglutide, exenatide, albiglutide, lixisenatide dulaglutide, semaglutide, protein tyrosine phosphatase-1B (PTP-1B) inhibitor, SIRT-l activator, dipeptidyl peptidase IV (DPP-IV) inhibitor, insulin secretagogue, fatty acid oxidation inhibitor, A2 antagonist, c-jun amino-terminal kinase (JNK) inhibitor, glucokinase activator (GKa), insulin, insulin mimetic, glycogen phosphorylase inhibitor, VPAC2 receptor agonist, SGLT2 inhibitor, glucagon receptor modifier, GPR119 modifier, FGF21 derivative or analog, TGR5 receptor modifier, GPBAR1 receptor modifier, GPR40 agonist, GPR120 modifier, high affinity nicotinic acid receptor (HM74A) activator, SGLT1 inhibitor, carnitine palmitoyltransferase spherase enzyme inhibitor or modifier, fructose 1,6-diphosphatase inhibitor, aldose reductase inhibitor, mineralocorticoid receptor inhibitor, TORC2 inhibitor, CCR2 and / or CCR5 inhibitor, PKC isoform inhibitor (e.g., PKCα, PKCβ, PKCγ), fatty acid synthetase inhibitor, serine palmitoyltransferase spherase inhibitor, GPR81, GPR39, GPR43, GPR41, GPR105, Kvl.3, retinol-binding protein 4, glucocorticoid receptor, somatostatin receptor inhibitor, PDHK2 inhibitor, GPR119 modifier, FGF21 derivative or analog, TGR5 receptor modifier, GPBAR1 receptor modifier, GPR40 agonist, GPR120 modifier, high affinity nicotinic acid receptor (HM74A) activator, SGLT1 inhibitor, carnitine palmitoyltransferase spherase enzyme inhibitor or modifier, fructose 1,6-diphosphatase inhibitor, aldose reductase inhibitor, mineralocorticoid receptor inhibitor, TORC2 inhibitor, CCR2 and / or CCR5 inhibitor, PKC isoform inhibitor (e.g., PKCα, PKCβ, PKCγ), fatty acid synthetase inhibitor, serine palmitoyltransferase spherase inhibitor, GPR81, GPR39, GPR43, GPR41, GPR105, Kvl.3, retinol-binding protein 4, glucocorticoid receptor, somatostatin receptor inhibitor, PDHK2 inhibitor, GPR119 modifier, FGF21 derivative or analog, TGR5 receptor modifier, GPBAR1 receptor modifier, GPR40 agonist, GPR120 modifier, high affinity nicotinic acid receptor (HM74A) activator, SGLT1 inhibitor, carnitine palmitoyltransferase spherase enzyme inhibitor or modifier, fructose 1,6-diphosphatase inhibitor, aldose reductase inhibitor, mineralocorticoid receptor inhibitor, TORC2 inhibitor, CCR2 and / or CCR5 inhibitor, PKC isoform inhibitor (e.g., PKCα, PKCβ, PKCγ), fatty acid synthetase inhibitor, serine palmitoyltransferase spherase inhibitor, GPR81, GPR39, GPR43, GPR41, GPR105, Kvl.3, retinol-binding protein 4, glucocorticoid receptor, somatostatin receptor inhibitor, PDHK2 inhibitor, GPR119 modifier, FGF21 derivative or analog, TGR5 receptor modifier, GPBAR1 receptor modifier, GPR40 agonist, GPR120 modifier, high affinity nicotinic acid receptor (HM74A) activator, SGLT1 inhibitor, carnitine palmitoyltransferase spherase inhibitor, GPR81, GPR39, GPR43, GPR41, GPR105, Kvl.3, retinol-binding protein 4, glucocorticoid receptor, somatostatin receptor inhibitor, PDHK2 inhibitor, GPR119 modifier, FGF21 derivative or analog, TGR5 receptor modifier, GPBAR1 receptor modifier, GPR40 agonist, GPR120 modifier, high affinity nicotinic acid receptor (HM74A) activator, SGLT1 inhibitor, carnitine palmitoyltransferase or an inhibitor or modifier of PDHK4, an inhibitor of MAP4K4, a modifier of the IL1 family including IL1-beta, an HMG-CoA reductase inhibitor, a squalene synthetase inhibitor, a fibrate, a bile acid metal ion sequestrant, an ACAT inhibitor, an MTP inhibitor, a lipoxygenase inhibitor, a cholesterol absorption inhibitor, a PCSK9 modifier, a cholesteryl ester transfer protein inhibitor, and a modifier of RXRα, a GIP receptor agonist, an enterostatin and an enterostatin analog, an amylin and an amylin receptor agonist, a ghrelin modifier (e.g., an inhibitor), and a leptin and a leptin receptor agonist, pancreatic polypeptide (PP), calcitonin, OXM, neuropeptide Y (NPY), human growth hormone, prolactin, oxytocin, bovine growth hormone, porcine growth hormone, glucagon, a ghrelin receptor antagonist, and one or more active pharmaceutical ingredients selected from the group consisting of: - a modifier of the IL1 family including IL1-beta, an HMG-CoA reductase inhibitor, a squalene synthetase inhibitor, a fibrate, a bile acid metal ion sequestrant, an ACAT inhibitor, an MTP inhibitor, a lipoxygenase inhibitor, a cholesterol absorption inhibitor, a PCSK9 modifier, a cholesteryl ester transfer protein inhibitor, and a modifier of RXRα, a GIP receptor agonist, an enterostatin and an enterostatin analog, an amylin and an amylin receptor agonist, a ghrelin modifier (e.g., an inhibitor), and a leptin and a leptin receptor agonist, pancreatic polypeptide (PP), calcitonin, OXM, neuropeptide Y (NPY), human growth hormone, prolactin, oxytocin, bovine growth hormone, porcine growth hormone, glucagon, a ghrelin receptor antagonist, and one or more active pharmaceutical ingredients selected from the group consisting of: - a fibrate, a bile acid metal ion sequestrant, an ACAT inhibitor, an MTP inhibitor, a lipoxygenase inhibitor, a cholesterol absorption inhibitor, a PCSK9 modifier, a cholesteryl ester transfer protein inhibitor, and a modifier of RXRα, a GIP receptor agonist, an enterostatin and an enterostatin analog, an amylin and an amylin receptor agonist, a ghrelin modifier (e.g., an inhibitor), and a leptin and a leptin receptor agonist, pancreatic polypeptide (PP), calcitonin, OXM, neuropeptide Y (NPY), human growth hormone, prolactin, oxytocin, bovine growth hormone, porcine growth hormone, glucagon, a ghrelin receptor antagonist, and one or more active pharmaceutical ingredients selected from the group consisting of: - a bile acid metal ion sequestrant, an ACAT inhibitor, an MTP inhibitor, a lipoxygenase inhibitor, a cholesterol absorption inhibitor, a PCSK9 modifier, a cholesteryl ester transfer protein inhibitor, and a modifier of RXRα, a GIP receptor agonist, an enterostatin and an enterostatin analog, an amylin and an amylin receptor agonist, a ghrelin modifier (e.g., an inhibitor), and a leptin and a leptin receptor agonist, pancreatic polypeptide (PP), calcitonin, OXM, neuropeptide Y (NPY), human growth hormone, prolactin, oxytocin, bovine growth hormone, porcine growth hormone, glucagon, a ghrelin receptor antagonist, and one or more active pharmaceutical ingredients selected from the group consisting of: - an ACAT inhibitor, an MTP inhibitor, a lipoxygenase inhibitor, a cholesterol absorption inhibitor, a PCSK9 modifier, a cholesteryl ester transfer protein inhibitor, and a modifier of RXRα, a GIP receptor agonist, an enterostatin and an enterostatin analog, an amylin and an amylin receptor agonist, a ghrelin modifier (e.g., an inhibitor), and a leptin and a leptin receptor agonist, pancreatic polypeptide (PP), calcitonin, OXM, neuropeptide Y (NPY), human growth hormone, prolactin, oxytocin, bovine growth hormone, porcine growth hormone, glucagon, a ghrelin receptor antagonist, and one or more active pharmaceutical ingredients selected from the group consisting of: - an MTP inhibitor, a lipoxygenase inhibitor, a cholesterol absorption inhibitor, a PCSK9 modifier, a cholesteryl ester transfer protein inhibitor, and a modifier of RXRα, a GIP receptor agonist, an enterostatin and an enterostatin analog, an amylin and an amylin receptor agonist, a ghrelin modifier (e.g., an inhibitor), and a leptin and a leptin receptor agonist, pancreatic polypeptide (PP), calcitonin, OXM, neuropeptide Y (NPY), human growth hormone, prolactin, oxytocin, bovine growth hormone, porcine growth hormone, glucagon, a ghrelin receptor antagonist, and one or more active pharmaceutical ingredients selected from the group consisting of: - a lipoxygenase inhibitor, a cholesterol absorption inhibitor, a PCSK9 modifier, a cholesteryl ester transfer protein inhibitor, and a modifier of RXRα, a GIP receptor agonist, an enterostatin and an enterostatin analog, an amylin and an amylin receptor agonist, a ghrelin modifier (e.g., an inhibitor), and a leptin and a leptin receptor agonist, pancreatic polypeptide (PP), calcitonin, OXM, neuropeptide Y (NPY), human growth hormone, prolactin, oxytocin, bovine growth hormone, porcine growth hormone, glucagon, a ghrelin receptor antagonist, and one or more active pharmaceutical ingredients selected from the group consisting of: - a cholesterol absorption inhibitor, a PCSK9 modifier, a cholesteryl ester transfer protein inhibitor, and a modifier of RXRα, a GIP receptor agonist, an enterostatin and an enterostatin analog, an amylin and an amylin receptor agonist, a ghrelin modifier (e.g., an inhibitor), and a leptin and a leptin receptor agonist, pancreatic polypeptide (PP), calcitonin, OXM, neuropeptide Y (NPY), human growth hormone, prolactin, oxytocin, bovine growth hormone, porcine growth hormone, glucagon, a ghrelin receptor antagonist, and one or more active pharmaceutical ingredients selected from the group consisting of: - a PCSK9 modifier, a cholesteryl ester transfer protein inhibitor, and a modifier of RXRα, a GIP receptor agonist, an enterostatin and an enterostatin analog, an amylin and an amylin receptor agonist, a ghrelin modifier (e.g., an inhibitor), and a leptin and a leptin receptor agonist, pancreatic polypeptide (PP), calcitonin, OXM, neuropeptide Y (NPY), human growth hormone, prolactin, oxytocin, bovine growth hormone, porcine growth hormone, glucagon, a ghrelin receptor antagonist, and one or more active pharmaceutical ingredients selected from the group consisting of: - a cholesteryl ester transfer protein inhibitor, and a modifier of RXRα, a GIP receptor agonist, an enterostatin and an enterostatin analog, an amylin and an amylin receptor agonist, a ghrelin modifier (e.g., an inhibitor), and a leptin and a leptin receptor agonist, pancreatic polypeptide (PP), calcitonin, OXM, neuropeptide Y (NPY), human growth hormone, prolactin, oxytocin, bovine growth hormone, porcine growth hormone, glucagon, a ghrelin receptor antagonist, and one or more active pharmaceutical ingredients selected from the group consisting of: - a modifier of RXRα, a GIP receptor agonist, an enterostatin and an enterostatin analog, an amylin and an amylin receptor agonist, a ghrelin modifier (e.g., an inhibitor), and a leptin and a leptin receptor agonist, pancreatic polypeptide (PP), calcitonin, OXM, neuropeptide Y (NPY), human growth hormone, prolactin, oxytocin, bovine growth hormone, porcine growth hormone, glucagon, a ghrelin receptor antagonist, and one or more active pharmaceutical ingredients selected from the group consisting of: - a GIP receptor agonist, an enterostatin and an enterostatin analog, an amylin and an amylin receptor agonist, a ghrelin modifier (e.g., an inhibitor), and a leptin and a leptin receptor agonist, pancreatic polypeptide (PP), calcitonin, OXM, neuropeptide Y (NPY), human growth hormone, prolactin, oxytocin, bovine growth hormone, porcine growth hormone, glucagon, a ghrelin receptor antagonist, and one or more active pharmaceutical ingredients selected from the group consisting of: - an enterostatin and an enterostatin analog, an amylin and an amylin receptor agonist, a ghrelin modifier (e.g., an inhibitor), and a leptin and a leptin receptor agonist, pancreatic polypeptide (PP), calcitonin, OXM, neuropeptide Y (NPY), human growth hormone, prolactin, oxytocin, bovine growth hormone, porcine growth hormone, glucagon, a ghrelin receptor antagonist, and one or more active pharmaceutical ingredients selected from the group consisting of: - an amylin and an amylin receptor agonist, a ghrelin modifier (e.g., an inhibitor), and a leptin and a leptin receptor agonist, pancreatic polypeptide (PP), calcitonin, OXM, neuropeptide Y (NPY), human growth hormone, prolactin, oxytocin, bovine growth hormone, porcine growth hormone, glucagon, a ghrelin receptor antagonist, and one or more active pharmaceutical ingredients selected from the group consisting of: - a ghrelin modifier (e.g., an inhibitor), and a leptin and a leptin receptor agonist, pancreatic polypeptide (PP), calcitonin, OXM, neuropeptide Y (NPY), human growth hormone, prolactin, oxytocin, bovine growth hormone, porcine growth hormone, glucagon, a ghrelin receptor antagonist, and one or more active pharmaceutical ingredients selected from the group consisting of: - a leptin and a leptin receptor agonist, pancreatic polypeptide (PP), calcitonin, OXM, neuropeptide Y (NPY), human growth hormone, prolactin, oxytocin, bovine growth hormone, porcine growth hormone, glucagon, a ghrelin receptor antagonist, and one or more active pharmaceutical ingredients selected from the group consisting of:

[0033] In another aspect, these pharmaceutical compositions further contain pharmaceutically acceptable excipients (e.g., propylene glycol, potassium sorbate, 1-arginine, disodium edetate, - propylene glycol, potassium sorbate, 1-arginine, disodium edetate, Lithium, sodium dihydrogen phosphate (also known as monosodium phosphate, sodium primary phosphate, etc.), and polysorbate 20). In one embodiment, 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, disodium edetate is present at a concentration of about 1.2 mg / ml, sodium phosphate monobasic dihydrate (also known as sodium dihydrogen phosphate dihydrate) is present at a concentration of about 7.8 mg / ml, and polysorbate is present at a concentration of about 5 mg / ml. A further embodiment comprises these pharmaceutical compositions together with GLP-1, oxyntomodulin, and cholecystokinin in place of PYY, PYY(3-36), or other PYY analogs and variants. (also known as monosodium phosphate, sodium primary phosphate, etc.), and polysorbate 20). In one embodiment, propylene glycol is present at a concentration of about 100 mg / ml and l-arginine is present at a concentration of about 25 mg / ml, potassium sorbate is present at a concentration of about 2 mg / ml, disodium edetate is present at a concentration of about 1.2 mg / ml sodium phosphate monobasic dihydrate (also known as sodium dihydrogen phosphate dihydrate) is present at a concentration of about 7.8 mg / ml, and poly sorbate is present at a concentration of about 5 mg / ml. A further embodiment comprises these pharmaceutical compositions together with GLP-1, oxyntomodulin, and cholecystokinin in place of PYY, PYY(3-36), or other PYY analogs and variants. sodium phosphate monobasic dihydrate (also known as

[0034] For example, the pharmaceutical compositions described herein can include a co-solvent stabilizer such as propylene glycol or other suitable co-solvent stabilizers (examples are low molecular weight poly ethylene glycol (PEG), for example, PEG200 and 400, glycerin, and ethanol (alcohol), etc.).

[0035] In another embodiment, the pharmaceutical compositions described herein can include an amino acid stabilizer such as L-arginine or other suitable amino acid stabilizers (examples are alanine, arginine, a sparagine, glycine, lysine, proline, and methionine).

[0036] In yet another embodiment, the pharmaceutical compositions described herein can include a preservative The composition may contain preservatives, such as ascorbic acid, benzyl alcohol, or other suitable preservatives. Alcohol, benzoic acid, citric acid, chlorobutanol, m-cresol, glutathione, methionine Onin, methylparaben, propylparaben, sodium sulfite, parahydroxybenzoic acid Acid esters (methyl hydroxybenzoate and propyl hydroxybenzoate), boric acid and and borates, sorbic acid and other sorbates other than potassium, and phenols )).

[0037] In another embodiment, the pharmaceutical compositions described herein contain an antioxidant, such as disodium edetate. or another suitable antioxidant (e.g., formaldehyde, Sodium formaldehyde sulphoxylate, butylated hydrochloride In another example, the drugs described herein The biological composition may contain a buffer such as a phosphate or other suitable buffer. The composition may contain an agent (e.g., acetate, carbonate, citrate, citrate-phosphate, gluconate, etc.). Lysine, HEPES, histidine, maleate, phosphate, succinate, tartrate, and Triethanolamine (Tris). In another embodiment, the pharmaceutical composition described herein may contain a surfactant such as polysorbate 20 or other suitable surfactant. (e.g., Poloxamer 188 / 407, Polysorbate 40 or 80, or La sodium uryl sulfate).

[0038] In yet another embodiment, the excipients include those that increase compliance with the intake of the pharmaceutical formulation. It contains flavorings for masking, for example, bitterness or other undesirable flavors or for matching the flavor of the food that can be ingested before or after the pharmaceutical preparation with the pharmaceutical preparation. Flavorings that can be used for matching include, for example, apple, banana, bubble gum, cherry, chocolate, grape, lemon, mango, orange, raspberry, strawberry, vanilla, watermelon, mint or combinations of the above flavors. In another aspect, these flavorings are dye-free (also called no coloring agents, etc.), sugar-free, low-irritant (also called low-allergenic), gluten-free, and casein-free.

[0039] In one aspect, the pharmaceutical composition described herein is for delivery to the oral cavity (for example, intraoral, oromucosal ), transmucosal, topical lingual, gargle, mouthwash (also called oral rinse, mouthwash, gargle, gargling solution, oral cleansing agent, mouthwash, etc.), gingival solutions , oral mucosal solutions and suspensions, semi-solid oral mucosal preparations (including, for example, gingival gels, gingival pastes, oral mucosal gels, oral mucosal pastes), oral mucosal drops, oral mucosal sprays and sublingual sprays (including oropharyngeal sprays), dry powder sprays, lozenges (also called troches, buccal tablets, etc.) and pastilles (also called troches, etc.), compressed lozenges, sublingual tablets and buccal tablets (also called oral tablets, intraoral tablets, buccal tablets, buccal side tablets, etc.), oral mucosal capsules, mucoadhesive preparations). Examples are O Oromucosal Preparations (Ph Eur monograph 1807) See reference. In another aspect, PYY in a pharmaceutical composition is adapted to bind to the Y2 receptor.

[0040] The term "delivery - compatible" refers to a pharmaceutical preparation or ingredient having properties to preferentially deliver to, or bind to, a desired area of the body (e.g., mouth, tongue) or target (e.g., receptor). The term "compatible with oral delivery" refers to a pharmaceutical preparation or one or more active substances intended for administration to the oral cavity and / or throat to obtain local or systemic effects, which can preferentially deliver PYY(3 - 36) to the oral cavity, or more specifically, to the tongue. See, for example, Oromucosal Preparations (Ph Eur monograph 1807). The term "compatible with receptor binding" or "compatible with Y2 receptor binding" refers to an agonist peptide, analog, or other active ingredient having sufficient retention time on the tongue (e.g., about 30 seconds to about 1 minute) to induce binding affinity or selectivity for the Y2 receptor. In one aspect, "local oral delivery" refers to obtaining a local effect without increasing the level of the active ingredient in the bloodstream. In such pharmaceutical preparations, excipients are compatible with the mouth for oral delivery, and the active ingredient in the pharmaceutical preparation is in the mouth until it is delivered to its site of activity.

[0041] In another embodiment, PYY(3-36) is delivered to the tongue and Y receptors. It binds to receptors (e.g., the Y2 receptor).

[0042] In this embodiment, PYY(3-36) binds to the tongue and acts via a receptor (e.g., the Y2 receptor). In another embodiment, PYY(3-36) can be administered by any suitable route of administration. The drug may be delivered systemically (eg, orally, parenterally, intravenously, etc.).

[0043] The term "bind" refers to a compound that binds to PYY(3-36) (or any other saturation peptide described herein). between a portion of the PYY(3-36) molecule and the Y receptor, or The chemical bond between (3-36) or a part thereof and the Y acceptor (e.g., ionic, covalent, or refers to a relationship through hydrophobicity) or other chemical or physical attractive bonds, where PYY The interaction between (3-36) and the Y receptor induces a biological response. ), Receptor binding profiles of NPY analogues and fragments in different tiss NPY analogs and fragments in various tissues and cell lines See, Receptor Binding Profile of .ALPHA.- ...

[0044] In another embodiment, the pharmaceutical composition increases the time that PYY(3-36) is in contact with the mucosa. Excipients (examples include viscosity enhancing, encapsulation, and controlled release). Although there is no evidence that the increased contact time of pharmaceutical preparations with the mucosa increases the uptake of PYY(3-36) and its receptors on the tongue, is considered to result in an increase in binding. Excipients suitable for enhancing viscosity include rheology modifiers (also referred to as rheology modifying factors, rheology regulators, etc.), which may also be mucoadhesive, for example, methylcellulose, hydroxyethylcellulose , hydroxypropylcellulose, alginic acid, polyvinylpyrrolidone, and sodium carboxymethylcellulose and the like. Excipients suitable for modified release of PYY(3-36) in the oral cavity include mucoadhesive penetration enhancers, for example, 23-lauryl ether, aprotinin, azone, benzalkonium chloride, cetylpyridinium chloride , cetyltrimethylammonium bromide, cyclodextrin, dextran sulfate, and lauric acid and the like. Other suitable mucoadhesive polymers used for buccal or oral delivery include agarose, chitosan, gelatin, hyaluronic acid , gums (such as guar, hakea, xanthan, gellan, carrageenan, pectin, and sodium alginate), cellulose derivatives (such as CMC, thiolated CMC, sodium CMC, HEC, HPMC, MC, methylhydroxyethylcellulose), poly(acrylic acid) based polymers (such as CP, PC, PAA, polyacrylate, poly(methyl vinyl ether-co-methacrylic acid)), poly(2-hydroxyethyl methacrylate), poly(alkyl cyanoacrylate) (such as poly(alkyl cyanoacrylate), poly(isobutyl cyanoacrylate), poly(isobutyl cyanoacrylate)), copolymers of acrylic acid and PEG, poly(N-2-hydroxypropylmethacrylamide), PHPMA , polyoxyethylene, PVA, PVP, and other thiolated polymers; scleroglucan , cetyltrimethylammonium bromide, cyclodextrin, dextran sulfate, and lauric acid and the like are included. Other suitable mucoadhesive polymers used for buccal or oral delivery include agarose, chitosan, gelatin, hyaluronic acid , gums (such as guar, hakea, xanthan, gellan, carrageenan, pectin, and sodium alginate), cellulose derivatives (such as CMC, thiolated CMC, sodium CMC, HEC, HPMC, MC, methylhydroxyethylcellulose), poly(acrylic acid) based polymers (such as CP, PC, PAA, polyacrylate, poly(methyl vinyl ether-co-methacrylic acid)), poly(2-hydroxyethyl methacrylate), poly(alkyl cyanoacrylate) (such as poly(alkyl cyanoacrylate), poly(isobutyl cyanoacrylate), poly(isobutyl cyanoacrylate)), copolymers of acrylic acid and PEG, poly(N-2-hydroxypropylmethacrylamide), PHPMA , cetyltrimethylammonium bromide, cyclodextrin, dextran sulfate, and lauric acid and the like are included. Other suitable mucoadhesive polymers used for buccal or oral delivery include agarose, chitosan, gelatin, hyaluronic acid , gums (such as guar, hakea, xanthan, gellan, carrageenan, pectin, and sodium alginate), cellulose derivatives (such as CMC, thiolated CMC, sodium CMC, HEC, HPMC, MC, methylhydroxyethylcellulose), poly(acrylic acid) based polymers (such as CP, PC, PAA, polyacrylate, poly(methyl vinyl ether-co-methacrylic acid)), poly(2-hydroxyethyl methacrylate), poly(alkyl cyanoacrylate) (such as poly(alkyl cyanoacrylate), poly(isobutyl cyanoacrylate), poly(isobutyl cyanoacrylate)), copolymers of acrylic acid and PEG, poly(N-2-hydroxypropylmethacrylamide), PHPMA , gums (such as guar, hakea, xanthan, gellan, carrageenan, pectin, and sodium alginate), cellulose derivatives (such as CMC, thiolated CMC, sodium CMC, HEC, HPMC, MC, methylhydroxyethylcellulose), poly(acrylic acid) based polymers (such as CP, PC, PAA, polyacrylate, poly(methyl vinyl ether-co-methacrylic acid)), poly(2-hydroxyethyl methacrylate), poly(alkyl cyanoacrylate) (such as poly(alkyl cyanoacrylate), poly(isobutyl cyanoacrylate), poly(isobutyl cyanoacrylate)), copolymers of acrylic acid and PEG, poly(N-2-hydroxypropylmethacrylamide), PHPMA , gums (such as guar, hakea, xanthan, gellan, carrageenan, pectin, and sodium alginate), cellulose derivatives (such as CMC, thiolated CMC, sodium CMC, HEC, HPMC, MC, methylhydroxyethylcellulose), poly(acrylic acid) based polymers (such as CP, PC, PAA, polyacrylate, poly(methyl vinyl ether-co-methacrylic acid)), poly(2-hydroxyethyl methacrylate), poly(alkyl cyanoacrylate) (such as poly(alkyl cyanoacrylate), poly(isobutyl cyanoacrylate), poly(isobutyl cyanoacrylate)), copolymers of acrylic acid and PEG, poly(N-2-hydroxypropylmethacrylamide), PHPMA , poly(acrylic acid) based polymers (such as CP, PC, PAA, polyacrylate, poly(methyl vinyl ether-co-methacrylic acid)), poly(2-hydroxyethyl methacrylate), poly(alkyl cyanoacrylate) (such as poly(alkyl cyanoacrylate), poly(isobutyl cyanoacrylate), poly(isobutyl cyanoacrylate)), copolymers of acrylic acid and PEG, poly(N-2-hydroxypropylmethacrylamide), PHPMA , poly(acrylic acid) based polymers (such as CP, PC, PAA, polyacrylate, poly(methyl vinyl ether-co-methacrylic acid)), poly(2-hydroxyethyl methacrylate), poly(alkyl cyanoacrylate) (such as poly(alkyl cyanoacrylate), poly(isobutyl cyanoacrylate), poly(isobutyl cyanoacrylate)), copolymers of acrylic acid and PEG, poly(N-2-hydroxypropylmethacrylamide), PHPMA , poly(2-hydroxyethyl methacrylate), poly(alkyl cyanoacrylate) (such as poly(alkyl cyanoacrylate), poly(isobutyl cyanoacrylate), poly(isobutyl cyanoacrylate)), copolymers of acrylic acid and PEG, poly(N-2-hydroxypropylmethacrylamide), PHPMA , poly(alkyl cyanoacrylate) (such as poly(alkyl cyanoacrylate), poly(isobutyl cyanoacrylate), poly(isobutyl cyanoacrylate)), copolymers of acrylic acid and PEG, poly(N-2-hydroxypropylmethacrylamide), PHPMA , copolymers of acrylic acid and PEG, poly(N-2-hydroxypropylmethacrylamide), PHPMA , polyoxyethylene, PVA, PVP, and other thiolated polymers; scleroglucan , PVA, steroid detergent, nonionic surfactant, laureth-9, sodium fusidate , included sodium lauryl, sodium laurate (Example: pH 8.9), palmitoyl carnitine, lauric acid / propylene glycol vehicle , Brij 78, sodium deoxycholate, sodium lauryl sulfate, lecithin and PVP are included. Example: International Journal of Pharmaceutics Vol. 53, No. 3, August 1, 1989, pp. 227-235. See reference.

[0045] In another aspect, the pharmaceutical composition includes an excipient that increases the residence time of PYY(3-36) in saliva (example: the amount of time that PYY(3-36) remains in saliva without significant degradation of the peptide). Without being bound by theory, increasing the residence time of PYY(3-36) in saliva is thought to increase the chance of PYY(3-36) binding to receptors on the tongue. The residence time in saliva can be adjusted optionally, for example, to avoid an increase in systemic exposure to PYY(3-36) through swallowing. The term "pharmaceutically acceptable excipient" includes, for example, the following:

[0046]

[0047] (1) Stabilizers (examples: co-solvents such as propylene glycol, polyethylene glycol (PEG), glycerin, and ethanol (alcohol)) and amino acids (examples: alanine, L-arginine, arginine, aspartic acid, glycine, lysine, proline, and methionine). (2) Buffers (examples: phosphate buffer, citrate buffer, acetate buffer, and carbonate buffer). ​​​​​​

[0048] (2) Preservatives (e.g., potassium sorbate, ascorbic acid, benzyl alcohol, Citric acid, chlorobutanol, m-cresol, glutathione, methionine, methionine Rulparaben, propylparaben, sodium sulfite, parahydroxybenzoic acid ester ( Methylhydroxybenzoate and Propylhydroxybenzoate), Boric acid and its salts , sorbic acid and sorbate salts, and phenols).

[0049] (3) Antioxidants (e.g., disodium edetate, sodium formaldehyde sulfoxylate, etc.) thorium, butylated hydroxyanisole, and butylated hydroxytoluene);

[0050] (4) Buffers (e.g., phosphate, acetate, carbonate, citrate, citrate-phosphate, Glycine, HEPES, Histidine, Maleate, Phosphate, Succinate, Tartrate, and triethanolamine (Tris);

[0051] (5) Surfactants (e.g., polysorbate 20, poloxamer 188 / 407, polysorbate 20 / 40 / 80, and sodium lauryl sulfate);

[0052] (6) Rheology modifiers (e.g., methyl cellulose, hydroxyethyl cellulose, etc.) cellulose, hydroxypropyl cellulose, alginic acid, polyvinylpyrrolidone, and sodium thorium carboxymethylcellulose);

[0053] (7) Mucosal permeation enhancers (mucosal penetration enhancers, mucosal penetration enhancers, etc.) (Examples are 23-lauryl ether, aprotinin, azone, benzalkonium chloride, etc.) Mu, cetylpyridinium chloride, cetyltrimethylammonium bromide, cyclodextrin , dextran sulfate, and lauric acid);

[0054] (8) Excipients used to stabilize the active ingredient in freeze-dried tablets for oral disintegration and dissolution in the mouth include sugars or sugar alcohols, for example, sucrose (also called saccharose), trehalose, mannitol, dextrose, and those such as polyvinyl pyrrolidone (PVP) or glycine;

[0055] (9) Flavorings such as apple, banana, bubble gum, cherry, chocolate, grape, lemon, mango, orange, orange swirl (also called swirl), raspberry, strawberry, strawberry swirl, vanilla, wolfberry swirl, watermelon (including versions without dyes, sugar-free, low irritation, without gluten, and without casein); and sweetening agents including sucrose, liquid glucose (also called dextrose), glycerol, sorbitol, sodium saccharin and aspartame; and

[0056] In one aspect, delivery of the PYY(3-36) composition to the tongue minimizes or eliminates any substantial systemic delivery of the PYY(3-36). The term "substantial systemic delivery" refers to blood levels of the administered PYY(3-36) or its analogs or variants that are above the limit of detection, distinguishable from circulating levels, or cause a significant increase in circulating levels.

[0057] A further aspect provides a method of treating a metabolic disorder or metabolic abnormality in a subject. Another​​​​​​ In an aspect, the metabolic disorder can be selected from the group consisting of obesity, increased blood sugar (e.g., elevated blood sugar levels), diabetes, fatty liver disease, hypertension, PCOS, and multiple sclerosis. In these aspects, "treating" or "treatment" refers to administering PYY (e.g., PYY(3-36)) or another PYY analog to a patient having the indicated metabolic disorder.

[0058] When the metabolic disorder is obesity, food intake by the subject is reduced by at least about 20% in the subject compared to a subject not receiving treatment after treatment with a dose of the pharmaceutical composition. In another aspect, the weight of the subject is reduced by at least about 5% compared to a subject not receiving treatment after treatment with a dose of the pharmaceutical composition. In the aspects described herein, the term "subject" refers to an animal (e.g., human, non-human) in need of treatment for the indicated disease or condition.

[0059] When the metabolic disorder is increased blood sugar (e.g., prediabetes), the blood sugar or glucose level of the subject is reduced by at least about 10% compared to a subject not receiving treatment after treatment with a dose of the pharmaceutical composition. In another aspect, the fasting glucose level is reduced by at least about 10% compared to a subject not receiving treatment after treatment with a dose of the pharmaceutical composition.

[0060] When the metabolic disorder is a disorder, the area under the curve (AUC) in the subject's glucose tolerance test (also referred to as a glucose load test, a glucose tolerance test, etc.) is at least less compared to a subject not receiving treatment after treatment with a dose of the pharmaceutical composition.​​​​​​​​​​​​​ decrease by up to about 15%. In another aspect, in a subject, the HbA1c level is reduced by at least about 15% after treatment with a dosage of the pharmaceutical composition compared to a subject who did not receive treatment.

[0061] When the metabolic disorder is fatty liver disease, the liver fat concentration in a subject decreases by up to about 20% after treatment with a dosage of the pharmaceutical composition compared to a subject who did not receive treatment. In this aspect, the liver fat concentration can be measured, for example, by liver biopsy, ultrasound, MRI (magnetic resonance imaging), and elastography.

[0062] When the metabolic disorder is PCOS, the symptoms of PCOS in a subject are reduced by at least about 15 to 20% after treatment with a dosage of the pharmaceutical composition compared to a subject who did not receive that dosage. In this aspect, exemplary symptoms include, but are not limited to, a hormonal profile (e.g., thyroid function tests, serum prolactin concentration, and free androgen index, defined as total testosterone divided by sex hormone binding globulin [SHBG] × 100, and the calculated free testosterone level is provided), LH2FsH ratio, and testosterone level).

[0063] When the metabolic disorder is multiple sclerosis (MS), the symptoms of multiple sclerosis are reduced by at least about 20% in a subject after treatment with a dosage of the pharmaceutical composition compared to a subject who did not receive treatment. In this aspect, symptoms include, but are not limited to, the Multiple Sclerosis Functional Composite. Examples are Cutter et al., Developme nt of a multiple sclerosis functional composite as a clinical trial outcome meas Development of the Multiple Sclerosis Functional Complex as an Outcome Measure in Clinical Trials, Brain , 1999 May;122(Pt 5):871-82.

[0064] When the metabolic disorder is hypertension, the systolic and diastolic blood pressure levels in the subject are increased by the pharmacological composition. The level of the β-amyloides in the blood is reduced by at least about 20% after treatment with a dose of the compound compared to a control who did not receive the treatment. In this embodiment, for example, treatment is at or above 140 mmHg (also referred to as 140 mmHg or more). The test begins when the systolic and diastolic blood pressure levels of 100 mm or a diastolic level of 90 mm are reached. It is possible.

[0065] The term "metabolic disorder" refers to abnormal function or regulation of the metabolic system (e.g., obesity, diabetes, lipid A condition in humans or animals that results from fatty liver disease, PCOS, and elevated blood glucose levels The term "disorder" usually refers to a disorder or disease that affects regular bodily structures and functions. It refers to the destruction caused by, or the pathophysiological response to, an internal or external agent.

[0066] A further aspect provides a method of increasing a feeling of fullness in a subject. In one embodiment, the method comprises administering to the subject a pharmaceutical composition described herein. Doses of (3-36) or variants or analogs are about 25 ng, 250 ng, 2.5 μg, 25 μg, 25 In a further embodiment, the dose of PYY, PYY(3-36) or bacillin is 0 μg or 2.5 mg. The dosage of the peptide or analog can range from about 25 ng to about 2.5 mg, from about 250 ng to about 250 μg, or from about 2.5 μg to about 25 μg. In yet another aspect, the satiety in the subject can last for at least 30, 60, 90, or 120 minutes after treatment and after eating a meal. In another aspect, the pharmaceutical composition is administered to the subject and then the subject eats a meal. In this aspect, the dosage per volume of PYY(3-36) can range from about 2.5 ng to about 250 μg in a volume of, for example, from about 25 μl to about 5 ml. In another aspect, the dosage / volume is 2.5 μg / ml. In another aspect, it is 500 μg / 500 μL. The volume of the pharmaceutical formulation selected to deliver the dosage of PYY(3-36) can be selected, for example, to enhance the interaction between PYY(3-36) and its receptor (e.g., the Y2 receptor) on the tongue in order to optimize the retention time of PYY(3-36) in the oral cavity and, more specifically, on the tongue. The term "eating a meal" refers to a subject eating food with a total calorie intake of at least about, for example, 300 - 2000, 500 - 1000 calories, or 300 - 800 calories. The term "satiety" refers to the self-reported satiety of the subject after eating a meal as measured, for example, using a VAS measurement, where the VAS measurement increases by at least about 10%. In another aspect, the VAS measurement increases by at least about 20%. In another aspect, to measure satiety (in a specific region of the brain, e.g., the satiety center of the brainstem, e.g., the nucleus of the solitary tract ([

[0067]

[0068] ​​​​​​​​​​​​​​such as the solitary tract nucleus), and the hypothalamus, for example, outside the hypothalamus in such as the lateral field) by measuring blood flow changes, functional magnetic resonance imaging ( "fMRI") scans can be used. In yet another aspect , the subject can verbally report the level of satiety before or after the treatment. In yet another aspect , the subject can verbally report the level of satiety before or after the treatment.

[0069] In one aspect, a pharmaceutical composition comprising PYY(3-36) can be delivered to a subject in need of treatment before, during, or after a meal. In this aspect, the pharmaceutical composition can be delivered intraorally.

[0070] In one aspect, the composition can be incorporated into any suitable dosage form (examples are lozenges, dissolvable substances, dissolution flat sheets, chewing gum, or solid or semi-solid candies) . In another aspect, the composition can be incorporated in a liquid preparation (examples are emulsions, syrups, elixirs, suspensions, or solutions). In a further aspect, the composition can be incorporated in an oral spray, or oral drops (also referred to as droplets) for oral administration. can be done.

[0071] In one aspect, the pharmaceutical composition is as follows:

[0072] Exemplary PYY(3-36) pharmaceutical preparation

Table 1

[0073] Exemplary clinical trials were conducted as dose-escalation design trials. 30 to 40 kg / m2 with BMIs of Approximately twelve evaluable subjects (n~(also referred to as about)l2) having received a single dose of placebo were then continued by directly applying, with a disposable pipette, the investigational drug, PYY(3-36), also known as GT-001, to the surface of the lingual mucosa and then rinsed off once a day. A total of seven (7) doses were escalated to a dose of 2.5 mg / ml.

[0074] Without being bound by theory, food intake is thought to be regulated by two opposing mechanisms: appetite and satiety. Both mechanisms are regulated by the brain-gut axis. The fasting period induces appetite by the secretion of ghrelin from the stomach. Ghrelin acts on specific neurons in the arcuate nucleus of the hypothalamus to activate the agouti-related peptide / neuropeptide Y (AgRP / NPY) pathway. The AgRP / NPY pathway is a cause of stimulating the appetite center in the cerebral cortex, which prepares the gastrointestinal tract for food intake and stimulates food-seeking behavior. Food intake then stimulates the secretion of satiety hormones in the gastrointestinal tract, including PYY(3-36), oxyntomodulin, and glucagon-like peptide-1 (GLP-1). These hormones stimulate the proopiomelanocortin / alpha-melanocyte-stimulating hormone (POMC / α MSH) pathway. The POMC / αMSH pathway stimulates various receptors in the cerebral cortex to produce a feeling of satiety and food reward (Acosta et al., 2014). In recent years, PYY(3-36) has also been shown to be present in the saliva of both rats and humans.

[0075] In mice, salivary PYY(3-36) is drawn from both bloodstreams and also synthesized in taste cells at the taste buds of the tongue ([2]). Furthermore, the cognate receptor, Y2R, is expressed in the lingual epithelium ([ Acosta et al. 2011; Hurtado et al., 2012). Additionally, all other YRs (Y1R, Y4R, and Y5R) are abundantly expressed in multiple lingual cell types, including epithelial progenitor cells, keratinocytes, neuronal dendrites, and taste receptor cells (TRCs) (Hurtado et al., 2012) . We have shown that PYY expressed in TRCs modulates responsiveness to bitter stimuli and lipids (La Sala, FASEB, 2013).

[0076] Previous results have demonstrated that augmentation of salivary PYY(3-36) or Exendin-4 results in a decrease in food intake over 1 h (Acosta et al., 2011). The effect is peptide specific; similar studies using neuropeptide Y or amylin had no effect on food intake. Additionally, a dose-response effect has been shown. At a lower dose, 0.3 μg / 100 g PYY(3-36), the treated mice reduced their calorie intake by up to 16% compared to controls. (PYY(3-36) 3.44 ± 0.06 kcal vs vehicle 4.10 ± 0.04 kcal, p = 0.0l) At an intermediate dose, 3 μg / 100 g PYY(3-36), the decrease was 26%. (P YY(3-36) 3.01 ± 0.06 kcal vs vehicle 4.10 ± 0.04 kcal, p = 0.008). At a higher dose, 1 0 μg / 100 g PYY(3-36), calorie intake was further reduced by up to 42%. (PYY(3-36) 2. 36 ± 0.05 kcal vs vehicle 4.10 ± 0.04 kcal, p = 1.81E-06 (Acosta et al., 2011). However, the doses of PYY used in these studies are much higher than those described in the aspects herein and can cause undesirable side effects and lack of efficacy in humans, such as loss of response at even higher doses (e.g., tachyphylaxis).

[0077] The effects of PYY are mediated through the activation of specific Y2 receptors expressed in lingual epithelial cells. In long-term studies, including diet-induced obesity (DIO) mice, sustained increases in PYY(3-36) were achieved using viral vector-mediated gene delivery targeting the salivary gland (Acosta et al., 2014). Chronic increases in salivary PYY(3-36) resulted in significant long-term decreases in food intake and body weight. Enhancement of salivary PYY(3-36) elicited a potent anorectic response while not inducing taste aversion or a surrogate for nausea in rodents (Hurtado et al., 2013). Salivary PYY(3-36) activates forebrain regions known to mediate feeding, fasting, and satiety, while minimally affecting the brainstem chemoreceptor trigger zone that induces nausea. By comparing the neural pathways activated by systemic versus salivary PYY(3-36), a metabolic circuit involved in Y2R-positive cells in the tongue and extending through the brainstem nuclei to the hypothalamic satiety center was identified.

[0078] According to the aspects disclosed herein, this alternative circuit regulates feeding behavior without inducing taste aversion (e.g., promoting satiety over time). The aspects described herein directly via such lingual application and for the treatment of obesity without accompanying flatulence, PYY (e.g., PYY(3- 36)) formulations are provided.

[0079] Dose escalation study

Table 2

[0080] Table 2 shows a exemplary dose escalation study from day 1 to day 14, with a two-day interval between doses after day 2. The doses can be prepared, for example, from a stock solution of PYY(3-36) at 2.5 mg / ml .

[0081] Figure 1 shows the results of an exemplary study, where PYY(3-36) in 12 subjects. PYY (3-36) was administered to the subjects at the indicated doses (GT-001 dose on the x-axis), and satiety (average value on the y-axis ) was evaluated by VAS at 30 minutes and 120 minutes after lunch. As shown in Figure 1, satiety significantly exceeded the placebo level (VAS score of 7) at a dose of 25 ng at 120 minutes after lunch, increased at a dose of 2.5 μg, and reached approximately 8 on the VAS scale at a dose of 250 μg.

[0082] Figure 2 shows the results of an exemplary study, where the time after treatment with PYY(3-36) (30 minutes, 60 minutes, 90 minutes, and 120 minutes) and four doses (placebo, 25 ng, 25 μg, and 250 μg) were plotted against satiety (VAS fullness (mm)) after the subjects ate lunch. As shown in Figure 2 , doses at 25 μg and 250 μg maintained VAS scores outside of 8 until 120 minutes after lunch. The 25 ng dose resulted in a VAS score of approximately 8 until 60 minutes after lunch. ng dose resulted in a VAS score of approximately 8 until 60 minutes after lunch.

[0083] FIG. 3 shows the effect of placebo, 0.25 mg / ml PYY(3-36), and 2.5 mg / ml PYY(3-36) (daytime, respectively). The normalized concentration of PYY in pg / ml in plasma of subjects receiving a meal (followed by a meal) is shown, with the maximum As shown, placebo administration and subsequent food consumption were measured over a 4-hour time span. The cost began with food consumption peaking at approximately 20 pg / ml above pre-dose levels 1-2 hours after dosing. Induce endogenous production of PYY with known and predicted effects. Target exogenous PYY(3-36). administration to the placebo / meal combination to increase plasma PYY levels. The hazard level will not be increased above the threshold level.

[0084] Further embodiments provide additional exemplary PYY(3-36) dosage forms and formulations, including, but not limited to, However, they include:

[0085] Oral Film Strips [Table 3] The solvent is removed during preparation.

[0086] Further embodiments provide exemplary oral film strip dosage forms as shown in Table 3. In one embodiment, the pharmaceutical composition of the oral film strip contains about 2.5 ng-2.5 mg of PYY(3-36). In this embodiment, the pharmaceutical composition of the oral film strip comprises about 2.5 nM of glycerin. In another embodiment, oral PYY(3-36) can be administered at doses of 25 ng, 250 ng, and 2.5 μg. The pharmaceutical composition of the film strip may contain suitable polymers, plasticizers, sweeteners, saliva stimulants, etc. , preservatives, and optionally colorants, flavorings, and solvents. Bara, et al., Orally dissolving strips: A new approach to oral drug delivery system (Orally dissolving strips: A new approach to oral drug delivery system), Int J Pharm Investig. (International Journal of Pharmaceutical Investigation). In 2013, Apr - Jun (April - June); 3(2):67 - 76; Tomar (Tomar l), Formulation and Evaluation of Fast Dissolving Oral Film of Dicyclomine as potential route of Buccal Delivery (Formulation and evaluation of fast - dissolving oral film of dicyclomine as a potential route of buccal delivery), International Journal of Drug Deve lopment & Research (International Journal of Drug Development & Research) April - June (April - June) 2012, Vol. 4 Issue 2 (Volume 4, Number 2), ISSN 0975 -9344. See

[0087] Troche

Table 4

[0088] Further aspects provide exemplary troche dosage forms as shown in Table 4. In one aspect, a pharmaceutical composition of a troche containing about 2.5 ng - 2.5 mg of PYY(3 - 36) is provided. In this aspect, the troche pharmaceutical composition contains about 2.5 ng, 25 ng, 250 ng, and 2.5 μg of PYY(3 - 36) is achievable. In one aspect, the troche dosage form includes PYY(3-36), a vehicle or base, and a suspending agent.

[0089] In these aspects, the suspending agent, sweetening agent, and flavoring components are optional. In another aspect , the vehicle or base of the troche is sugar, made adhesive by admixture with acacia or tragacanth (sugar, made adhesive by admixture with acacia or tragacanth), a fruit paste (e.g., made from black or red currants), a confection of rose, or a balsam of tolu (also known as tolu balsam). Examples are Kamini et al., Formulation and Percentage Evaluation of Gum - Acacia as A Binder W.S.R. to Jwaraghani Gutika (Herbo-Mineral Preparation(Jwara ghani Gutika as a binder W.S.R. and evaluation of gum - acacia (herbo-mineral preparation, Int J Res Med. 2016;5(1);21-24(2016).

[0090] Lollipop

Table 5

[0091] A further aspect provides an exemplary lollipop (also known as stick candy) dosage form as shown in Table 5. In one aspect, the lollipop pharmaceutical composition contains about 2.5 ng - 2.5 mg of PYY(3-36) In this embodiment, the lollipop pharmaceutical composition can include about 2.5 ng, 25 ng, 2 In one embodiment, the lollipop dosage form contains PYY(3-36). ), fillers, buffering agents, lubricants and preservatives. Flavoring and sweetening agents are optional ingredients. In another embodiment, the lollipop formulation comprises maltose-dextrose, water, and cornstarch. In another embodiment, the lollipop dosage form further comprises maltose-decyl ester or another binder material. It further contains kistarch, water, and cornstarch or another binder material. See US Patent Application Publication No. 2007 / 0104763.

[0092] Chewing gum [Table 6]

[0093] Further embodiments provide exemplary chewing gum formulations as shown in Table 6. In one embodiment, In one embodiment, the chewing gum pharmaceutical composition comprises about 2.5 ng-2.5 mg of PYY(3-36). In the present study, the chewing gum pharmaceutical composition contains approximately 2.5 ng, 25 ng, 250 ng, and 2.5 μg of PYY(3-3 6). In one embodiment, the chewing gum formulation comprises PYY(3-36), a gum base , granulating agents, lubricants, preservatives, and glidants. Flavoring and sweetening agents are optional ingredients. For example, see Aslani et al., Medicinal chewing gum, a novel drug delivery system. Medicinal chewing gum, a novel drug delivery system, J. Res Med Sci. Annual of Research in Medical Sciences 2015 Apr;20(4):40 See 3-411. Alternatively, the chewing gum dosage form can be made by direct compression. See, for example, U.S. Patent No. 7,208,186. Also see Heema et al., Medicated chewing gums - updated review. Int J Pharm Res Dev. (International Journal of Pharmaceutical Research and Development) 2010;2:66-76. See also Heema et al., Medicated chewing gums - updated review. Int J Pharm Res Dev. (International Journal of Pharmaceutical Research and Development) 2010;2:66-76. ing gums-updated review(Medicated chewing gums - updated review). Int J Pharm Res Dev. (International Journal of Pharmaceutical Research and Development) 2010;2:66-76. v. (International Journal of Pharmaceutical Research and Development) 2010;2:66-76. See also Heema et al., Medicated chewing gums - updated review. Int J Pharm Res Dev. (International Journal of Pharmaceutical Research and Development) 2010;2:66-76.

[0094] A further aspect provides spray-dried (also referred to as spray-dried) particle dosage forms (e.g., sachets of spray-dried particles) as shown in Tables 7-9. In these aspects, a pharmaceutical composition is provided that contains about 2.5 ng - 2.5 mg of PYY(3-36). Exemplary spray-dried pharmaceutical compositions contain about 2.5 ng, 25 ng, 250 ng, and 2.5 μg of PYY(3-36). (e.g., sachets of spray-dried particles). In these aspects, a pharmaceutical composition is provided that contains about 2.5 ng - 2.5 mg of PYY(3-36). Exemplary spray-dried pharmaceutical compositions contain about 2.5 ng, 25 ng, 250 ng, and 2.5 μg of PYY(3-36). In these aspects, a pharmaceutical composition is provided that contains about 2.5 ng - 2.5 mg of PYY(3-36). Exemplary spray-dried pharmaceutical compositions contain about 2.5 ng, 25 ng, 250 ng, and 2.5 μg of PYY(3-36). In these aspects, a pharmaceutical composition is provided that contains about 2.5 ng - 2.5 mg of PYY(3-36). Exemplary spray-dried pharmaceutical compositions contain about 2.5 ng, 25 ng, 250 ng, and 2.5 μg of PYY(3-36).

[0095] Spray-dried particles, Example 1 [Table 7]

[0096] The solvent is removed during manufacture.

[0097] In the aspects of Table 7, the drug (e.g., PYY(3-36)) can be mixed with an excipient to form a solution or suspension and sprayed to form particles. For example, PYY(3-36) and the excipients of Table 7 can be combined in a solution or suspension with lactose and spray-dried, followed by collection of the particles on a filter. See, for example, Luhn, Using Excipi In the aspects of Table 7, the drug (e.g., PYY(3-36)) can be mixed with an excipient to form a solution or suspension and sprayed to form particles. For example, PYY(3-36) and the excipients of Table 7 can be combined in a solution or suspension with lactose and spray-dried, followed by collection of the particles on a filter. See, for example, Luhn, Using Excipi In the aspects of Table 7, the drug (e.g., PYY(3-36)) can be mixed with an excipient to form a solution or suspension and sprayed to form particles. For example, PYY(3-36) and the excipients of Table 7 can be combined in a solution or suspension with lactose and spray-dried, followed by collection of the particles on a filter. See, for example, Luhn, Using Excipi In the aspects of Table 7, the drug (e.g., PYY(3-36)) can be mixed with an excipient to form a solution or suspension and sprayed to form particles. For example, PYY(3-36) and the excipients of Table 7 can be combined in a solution or suspension with lactose and spray-dried, followed by collection of the particles on a filter. See, for example, Luhn, Using Excipi Use of Excipients In Powder Formulations, Pharmaceutical Te chnology Europe, Volume 23, Issue 1 (January 7, 2011); Wu et al., Studies on the spray dried lactose as carrier for dry powder inhalation, Asian Journal of Pharmaceutical Sciences (Asian Journal of Pharmaceutical Sciences) 9(2014)336 - 341. See also .

[0098] Spray - dried particles - Example 2 [Table 8]

[0099] The solvent is removed during manufacture.

[0100] In the embodiment of Table 8, the drug and excipient can be wet - granulated with commercially available spray - dried lactose and then dried. Examples include Huang et al., Using spray - dried lactose monohydrate in wet granulation method for a low - dose oral formulation of a paliperidone derivative (Powder Technology) 246(2013)379 - 394. In one embodiment, the dosage form is a spray It can be a sachet filled with dry particles.

[0101] Spray-dried particles - Example 3

Table 9

[0102] In the embodiment of Table 9, commercially available lactose (also called milk sugar) or the spray-dried lactose from the previous step can be sprayed onto the drug and excipient as described. Asian Journal of Pharmaceutical Sciences 9(2014)336 - 341 (can be_sprayed). .

[0103] In another embodiment, spray-dried particles, for example, those from Tables 7 - 9, can be delivered in a dry powder inhaler ( propellant). In one embodiment, the size of the spray-dried particles is between 1 and 10 microns (μm) to avoid clogging the orifice of the inhalation device, but still, for example, large enough to be less likely to be inhaled and most of it to deposit in the mouth. In this embodiment, the propellant can be HFA 134a or HFA 227, or a combination of the two. The nozzle design in the inhaler can be adapted to facilitate the actuation of the dose onto the tongue. In yet another embodiment, the spray-dried particles can be delivered without a propellant (examples are using a unit dose delivery device, for example, something like the Apter pharma UDS device ( Apter Pharma UDS device)). Although, for example, less likely to be inhaled and large enough for most to deposit in the mouth. In this embodiment, the propellant can be HFA 134a or HFA 227, or a combination of the two. The nozzle design in the inhaler can be adapted to facilitate the actuation of the dose onto the tongue. Furthermore, in another embodiment, the spray-dried particles can be delivered without a propellant ( examples are using a unit dose delivery device, for example, something like the Apter pharma UDS device ( Apter Pharma UDS device)).

[0104] A further embodiment provides a microporous polysaccharide microsphere dosage form.

[0105] Frozen particles

Table 10

[0106] Further embodiments provide exemplary frozen particle dosage forms as shown in Table 10. In one embodiment, a frozen particle pharmaceutical composition comprising about 2. 5 ng - 2.5 mg of PYY(3 - 36) is provided. In this embodiment, the frozen particle pharmaceutical composition can comprise about 2.5 ng, 25 ng, 250 ng, and 2.5 μg of PYY(3 - 36). In this embodiment, the pharmaceutical composition can include PYY(3 - 36), a filler, a granulating agent, a buffering agent, a preservative, and a solvent / suspending agent. Optional sweeteners and flavoring agents can be added. In this embodiment, the wet granulation method described above with respect to Table 8 can be used. However, instead of a drying step, the particles can be filled into a sachet of frozen particles and frozen. Alternatively, a frozen PYY(3 - 36) solution (Table 11 below) can be used to fill the tube prior to freezing. Any suitable tube can be used (examples are polypropylene tubes generally used for pharmaceuticals, cosmetics, and food). This tube

[0107] can be flexible, for example, to allow the frozen solution to be dispensed onto the tongue and thaw slowly. In yet another embodiment, the frozen solution is used in a "blow - fill - seal" dosage form and can be dispensed in a manner similar to an eye drop or mouthwash dispenser. Markarian, "Blow - fill - seal" ​​​​​​​Technology Advances in Aseptic Filling Applications: New advanced aseptic manufa cturing technologies are available for filling liquid pharmaceuticals, including biologies(Advances in Blow-Fill-Seal Technology in Aseptic Filling Applications : New advanced aseptic manufacturing technologies are available for filling liquid pharmaceuticals, including biologies), Equipment and Processing Report(Equipment and Processing Report), June 18, 2014.

[0108] Frozen solution

Table 11

[0109] Lyophilized particles

Table 12

[0110] Further embodiments provide exemplary lyophilized particle dosage forms as shown in Table 12. In one embodiment a lyophilized particle pharmaceutical composition comprising about 2.5 ng - 2.5 mg of PYY(3-36) is provided. In this embodiment the lyophilized particle pharmaceutical composition can comprise about 2.5 ng, 25 ng, 250 ng, and 2.5 μg of PYY(3-36). In this embodiment the pharmaceutical composition comprises PYY(3-36), a cryoprotectant / stabilizer, an antioxidant, a buffer, a preservative(s), (s) means multiple (s) means multiple ​showing that there can also be numbers), any pH modifier (also referred to as a pH regulator), and a sol vent.

[0111] In one aspect, the lyophilized particles are separated from the diluent in a pre-filled oral syringe having a mixing chamber. An example is the Vetter-Pharma, Vetter Dual Chamber Systems Websi te Description (description of the Vetter-Pharma, Vetter Dual Chamber Systems website). In another aspect, the lyophilized particles are separated from the diluent using a mixing chamber. See Vetter-Pharma, Vetter Dual Chamber Systems Website Description (description of the Vetter-Pharma, Vetter Dual Chamber Systems website). In another aspect, the lyophilized particles are separated from the diluent using a mixing chamber. See Vetter-Pharma, Vetter Dual Chamber Systems Website Description (description of the Vetter-Pharma, Vetter Dual Chamber Systems website). In another aspect, the lyophilized particles are separated from the diluent using a mixing chamber. See Vetter-Pharma, Vetter Dual Chamber Systems Website Description (description of the Vetter-Pharma, Vetter Dual Chamber Systems website). In another aspect, the lyophilized particles are separated from the diluent using a mixing chamber.

[0112] Oral spray

Table 13

[0113] A further aspect provides an exemplary oral spray dosage form as shown in Table 13. In one aspect, an oral spray pharmaceutical composition containing about 2.5 ng - 2.5 mg of PYY(3-36) is provided. In this aspect the oral spray pharmaceutical composition can contain about 2.5 ng, 25 ng, 250 ng, and 2.5 μg of PYY(3-36). In this aspect, the pharmaceutical composition contains PYY(3-36), an antioxidant, a buffer, a pres ervative, a solvent, any pH modifier, and any flavoring and sweetening agents. ervative, a solvent, any pH modifier, and any flavoring and sweetening agents. ervative, a solvent, any pH modifier, and any flavoring and sweetening agents.

[0114] In another aspect, the oral spray is an oral spray having a device (a CCS with an actuator (also referred to as an activator)), a vial adapter for the actuator at the time of administration, an oral spray solution poured into the device having the actuator, a pre-filled oral spray having a vial adapter for the actuator at the time of administration, an oral spray solution poured into the device having the actuator, a pre-filled oral spray having a vial adapter for the actuator at the time of administration, an oral spray solution poured into the device having the actuator, a pre-filled An oral syringe (also referred to as pre-filled), an oral solution in a blow-fill-sealed tube, an oral solution in a vial or a tube having a measuring device (e.g., a dropper, a syringe), or a small squeeze bottle that dispenses droplets (e.g., similar to an optical solution) can be used.

[0115] Soft gel capsules [Table 14]

[0116] Further aspects provide exemplary soft gel capsule dosage forms as shown in Table 14. In one aspect a soft gel capsule pharmaceutical composition containing about 2.5 ng - 2.5 mg of PYY(3-36) is provided. In this aspect, the soft gel capsule pharmaceutical composition can contain about 2.5 ng, 25 ng, 250 ng, and 2.5 μg of PYY(3-36). In this aspect, the pharmaceutical composition contains PYY(3-36), a shell (e.g., gelatin), a base (e.g., glycerin), a second base (polyethylene glycol ), a preservative, a solvent, an optional flavoring, a coloring, and a sweetening agent.

[0117] In another aspect, the soft gel capsule can have a removable nib (also referred to as a tip, etc.) for opening the capsule and pouring the contents onto the tongue.

[0118] Mouse wash [Table 15]

[0119] Further aspects provide exemplary mouse wash dosage forms as shown in Table 15. In one aspect In this regard, a mouse wash (also referred to as a gargle) pharmaceutical composition containing about 2.5 ng - 2.5 mg of PYY(3 - 36) is provided. In this embodiment, the mouse wash pharmaceutical composition can contain about 2.5 ng, 25 ng, 2 50 ng, and 2.5 μg of PYY(3 - 36). In this embodiment, the pharmaceutical composition contains PYY(3 - 36), an antioxidant, a surfactant, a preservative, and a solvent(s). Optional flavor ingredients and sweeteners can also be added.

[0120] Oral tablet - Example 1 [Table 16]

[0121] A further embodiment provides an exemplary oral tablet (also referred to as a buccal tablet, buccal tab, buccal tablet) dosage form as shown in Table 16. In one embodiment, an oral tablet pharmaceutical composition containing about 2.5 ng - 2.5 mg of PYY( 3 - 36) is provided. In this embodiment, the oral tablet pharmaceutical composition can contain about 2. 5 ng, 25 ng, 250 ng, and 2.5 μg of PYY(3 - 36). In this embodiment, the pharmaceutical composition contains PYY(3 - 36), a mucoadhesive agent(s), a dispersant, a preservative, a lubricant, and a filler or binder. Optional flavor ingredients and sweeteners can also be added. Examples are Shirsand et al., Formulation and optimization of mucoadhesive bilayer b uccal tablets of atenolol using simplex design method (Formulation and optimization of mucoadhesive bilayer buccal tablets of atenolol using simplex design method) using the simplex design method, Int J Pharm Inve using the simplex design method for atenolol mucoadhesive bilayer oral tablets, Int J Pharm Inve Refer to stig 2012 Jan-Mar;2(1):34-41.

[0122] Oral Tablet - Example 2

Table 17

[0123] A further aspect provides an exemplary oral tablet dosage form as shown in Table 17. In one aspect, an oral tablet pharmaceutical composition containing about 2.5n g - 2.5 mg of PYY(3 - 36) is provided. In this aspect, the oral tablet pharmaceutical composition can contain about 2.5 ng, 25 ng, 250 ng, and 2.5 μg of PYY(3 - 36). In this aspect, the pharmaceutical composition contains PYY(3 - 36), a mucoadhesive(s), a lubricant, and a diluent, a filler or a binder. Examples can be found in Chaudhari et al., Formulation and E valuation of Buccal Tablet of Salbutamol Sulphate (Formulation and Evaluation of Buccal Tablets of Salbutamol Sulphate), IRJP 2011, 2(12), 238 - 242. Refer to it.

[0124] Lyophilized Tablet

Table 18

[0125] A further aspect provides an exemplary lyophilized tablet dosage form as shown in Table 18. In one aspect a lyophilized tablet pharmaceutical composition containing about 2.5 ng - 2.5 mg of PYY(3 - 36) is provided. In this aspect, the lyophilized tablet pharmaceutical composition can contain about 2.5 ng, 25 ng, 250 ng, and 2.5 μg of PYY(3 - 36). In this aspect, the pharmaceutical composition contains PYY(3 - 36), a mucoadhesive Dressing agent(s), surfactant, cryoprotectant (also referred to as freeze protectant) / stabilizer It contains antioxidant, as well as pH modifier and solvent.

[0126] Oral-disintegrating tablet ("ODT")

Table 19

[0127] A further aspect provides an exemplary ODT tablet dosage form as shown in Table 19. In one aspect it provides an ODT tablet pharmaceutical composition containing about 2.5 ng - 2.5 mg of PYY(3-36). In this aspect the ODT tablet pharmaceutical composition can contain about 2.5 ng, 25 ng, 250 ng, and 2.5 μg of PYY(3-36) In this aspect, the pharmaceutical composition contains PYY(3-36), binder(s), disintegrant lubricant, as well as optional sweetening agent, flavoring agent, and lubricant group.

[0128] In one aspect, the ODT tablet dosage form is a blended powder system, which is then compressed into tablets using a standard rotary press and packaged into blister packs or bottles according to the abrasion degree of the tablets The finished tablets can have a disintegration time of, for example, 30 seconds or less on the tongue. The levels of flavoring agent, coloring agent, and sweetening agent can be varied according to the requirements for the end-user experience The finished tablets can have a disintegration time of, for example, 30 seconds or less on the tongue. The levels of flavoring agent, coloring agent, and sweetening agent can be varied according to the requirements for the end-user experience The finished tablets can have a disintegration time of, for example, 30 seconds or less on the tongue. The levels of flavoring agent, coloring agent, and sweetening agent can be varied according to the requirements for the end-user experience The levels of flavoring agent, coloring agent, and sweetening agent can be varied according to the requirements for the end-user experience The levels of flavoring agent, coloring agent, and sweetening agent can be varied according to the requirements for the end-user experience

[0129] The compositions described herein can be used to treat patients in need of the treatments as described herein. As used herein, "treating", "preventing", The compositions described herein can be used to treat patients in need of the treatments as described herein. As used herein, "treating", "preventing", Or similar terms do not necessarily mean 100% or sufficient treatment or prevention. Rather, these terms refer to varying degrees of treatment or prevention of certain diseases as recognized as beneficial in the present technology (examples are 100%, 90%, 80%, 70%, 60%, 50 %, 40%, 30%, 20%, 10%, 5%, or 1%). The terms "treatment" or "prevention" also refer to delaying the onset of a disease for a period of time or delaying the onset indefinitely. The term "treatment" or "treating" refers to administering a drug or treatment to a patient or prescribing a drug to a patient, where the patient or a third party (examples are a caregiver, a family member, or a medical professional) manages the drug or treatment. The components of the compositions described herein also include derivatives and analogs. In one embodiment, the term "derivative" or "analog" includes, but is not limited to, ether derivatives, acid derivatives, amide derivatives, ester derivatives, and other similar ones. Methods for preparing these derivatives are known to those skilled in the art. For example, ether derivatives are prepared by coupling the corresponding alcohol. Amide and ester derivatives are prepared from the corresponding carboxylic acid by reaction with an amine and an alcohol, respectively. In addition to the above dosage forms and formulations, any suitable dosage form can be used for the delivery of the pharmaceutical compositions described herein. In one aspect, the dosage form is particularly suitable for oral or oral mucosal delivery. In another aspect, the dosage form is a lozenge (examples are flat sheets, solid or hollow), a solid or liquid dosage form, a powder, a granule, a capsule, a tablet, a suspension, a solution, an emulsion, a liposome, a micelle, or a transdermal patch. In addition to the above dosage forms and formulations, any suitable dosage form can be used for the delivery of the pharmaceutical compositions described herein. In one aspect, the dosage form is particularly suitable for oral or oral mucosal delivery. In another aspect, the dosage form is a lozenge (examples are flat sheets, solid or hollow), a solid or liquid dosage form, a powder, a granule, a capsule, a tablet, a suspension, a solution, an emulsion, a liposome, a micelle, or a transdermal patch.

[0130] The components of the compositions described herein also include derivatives and analogs. In one embodiment, the term "derivative" or "analog" includes, but is not limited to, ether derivatives, acid derivatives, amide derivatives, ester derivatives, and other similar ones. Methods for preparing these derivatives are known to those skilled in the art. For example, ether derivatives are prepared by coupling the corresponding alcohol. Amide and ester derivatives are prepared from the corresponding carboxylic acid by reaction with an amine and an alcohol, respectively. These derivatives are prepared by methods known to those skilled in the art. For example, ether derivatives are prepared by coupling the corresponding alcohol. Amide and ester derivatives are prepared from the corresponding carboxylic acid by reaction with an amine and an alcohol, respectively. In addition to the above dosage forms and formulations, any suitable dosage form can be used for the delivery of the pharmaceutical compositions described herein. In one aspect, the dosage form is particularly suitable for oral or oral mucosal delivery. In another aspect, the dosage form is a lozenge (examples are flat sheets, solid or hollow), a solid or liquid dosage form, a powder, a granule, a capsule, a tablet, a suspension, a solution, an emulsion, a liposome, a micelle, or a transdermal patch.

[0131] In addition to the above dosage forms and formulations, any suitable dosage form can be used for the delivery of the pharmaceutical compositions described herein. In one aspect, the dosage form is particularly suitable for oral or oral mucosal delivery. In another aspect, the dosage form is a lozenge (examples are flat sheets, solid or hollow), a solid or liquid dosage form, a powder, a granule, a capsule, a tablet, a suspension, a solution, an emulsion, a liposome, a micelle, or a transdermal patch. hollow), a solid or liquid dosage form, a powder, a granule, a capsule, a tablet, a suspension, a solution, an emulsion, a liposome, a micelle, or a transdermal patch. a semi-solid candy). In another aspect, the dosage form is a gel, cream, foam, orally disintegrating tablet, or paste. The lozenge can contain a solubilizing substance. In another aspect, the dosage form includes chewing gum. In yet another aspect, the dosage form is a liquid preparation (examples are emulsion, syrup, elixir, suspension, or solution, mouthwash, mouse wash, gingival solution, oral mucosal solution and oral mucosal suspension, semi-solid oral mucosal preparations (e.g., gingival gel, gingival paste, oral mucosal gel, oral mucosal paste are included), oral mucosal drops, oral mucosal sprays and sublingual sprays (including oropharyngeal sprays), lozenges and pastilles (also called troches), compressed lozenges, sublingual tablets and buccal tablets, oral mucosal capsules, mucoadhesive preparations). In a further aspect, the liquid preparation is a spray or drops for oral administration.

[0132] In one aspect, the compositions described herein, or a portion thereof, can be formulated or used as starting materials for formulation in unit dosage forms such as those accepted by the pharmaceutical services as physiologically acceptable vehicles, carriers, excipients, binders, preservatives, stabilizers, flavors, etc. The amount of the active substance (e.g., an active pharmaceutical ingredient) in a composition or preparation containing the components of the compositions described herein is such that appropriate dosages are obtained within the

[0133] indicated ranges as described herein. In another aspect, the components of the compositions described herein can be formulated Refers to physically distinct units suitable as dosage units for mammals, each unit being calculated to produce the desired therapeutic effect in association with one or more suitable pharmaceutical excipients and containing a predetermined amount of the active substance. In one aspect, one or more of the components of the compositions described herein are mixed with, or used as starting materials with, a suitable pharmaceutically acceptable carrier to form a composition such as described herein. When the compound(s) are mixed or added, the resulting mixture may be a solution, suspension, emulsion (also referred to as an emulsion, etc.), or other of that kind. Liposome suspensions may also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art. The form of the resulting mixture depends on a plurality of factors, including the mode of administration intended and the solubility of the compound in the selected carrier or vehicle. In one aspect, the effective concentration is sufficient to reduce or ameliorate at least one symptom of the disease, disorder, or condition being treated and can be determined empirically.

[0134] In one aspect, one or more of the components of the compositions described herein are mixed with, or used as starting materials with, a suitable pharmaceutically acceptable carrier to form a composition such as described herein. When the compound(s) are mixed or added, the resulting mixture may be a solution, suspension, emulsion (also referred to as an emulsion, etc.), or other of that kind. Liposome suspensions may also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art. The form of the resulting mixture depends on a plurality of factors, including the mode of administration intended and the solubility of the compound in the selected carrier or vehicle. In one aspect, one or more of the components of the compositions described herein are mixed with, or used as starting materials with, a suitable pharmaceutically acceptable carrier to form a composition such as described herein. When the compound(s) are mixed or added, the resulting mixture may be a solution, suspension, emulsion (also referred to as an emulsion, etc.), or other of that kind. Liposome suspensions may also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art. The form of the resulting mixture depends on a plurality of factors, including the mode of administration intended and the solubility of the compound in the selected carrier or vehicle. When the compound(s) are mixed or added, the resulting mixture may be a solution, suspension, emulsion (also referred to as an emulsion, etc.), or other of that kind. Liposome suspensions may also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art. The form of the resulting mixture depends on a plurality of factors, including the mode of administration intended and the solubility of the compound in the selected carrier or vehicle. When the compound(s) are mixed or added, the resulting mixture may be a solution, suspension, emulsion (also referred to as an emulsion, etc.), or other of that kind. Liposome suspensions may also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art. The form of the resulting mixture depends on a plurality of factors, including the mode of administration intended and the solubility of the compound in the selected carrier or vehicle. When the compound(s) are mixed or added, the resulting mixture may be a solution, suspension, emulsion (also referred to as an emulsion, etc.), or other of that kind. Liposome suspensions may also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art. The form of the resulting mixture depends on a plurality of factors, including the mode of administration intended and the solubility of the compound in the selected carrier or vehicle. When the compound(s) are mixed or added, the resulting mixture may be a solution, suspension, emulsion (also referred to as an emulsion, etc.), or other of that kind. Liposome suspensions may also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art. The form of the resulting mixture depends on a plurality of factors, including the mode of administration intended and the solubility of the compound in the selected carrier or vehicle. When the compound(s) are mixed or added, the resulting mixture may be a solution, suspension, emulsion (also referred to as an emulsion, etc.), or other of that kind. Liposome suspensions may also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art. The form of the resulting mixture depends on a plurality of factors, including the mode of administration intended and the solubility of the compound in the selected carrier or vehicle. In one aspect, the effective concentration is sufficient to reduce or ameliorate at least one symptom of the disease, disorder, or condition being treated and can be determined empirically. In one aspect, the effective concentration is sufficient to reduce or ameliorate at least one symptom of the disease, disorder, or condition being treated and can be determined empirically. In one aspect, the effective concentration is sufficient to reduce or ameliorate at least one symptom of the disease, disorder, or condition being treated and can be determined empirically.

[0135] Pharmaceutically acceptable carriers or vehicles suitable for the administration of the components of the compositions described herein include any such carrier suitable for the particular mode of administration. In addition, the active substance can also be mixed with other active substances that do not impair the desired action, or that supplement the desired action, or have other actions. The compound may be formulated as the sole pharmaceutically active ingredient in the composition or may be combined with other active ingredients. Pharmaceutically acceptable carriers or vehicles suitable for the administration of the components of the compositions described herein include any such carrier suitable for the particular mode of administration. In addition, the active substance can also be mixed with other active substances that do not impair the desired action, or that supplement the desired action, or have other actions. The compound may be formulated as the sole pharmaceutically active ingredient in the composition or may be combined with other active ingredients. In addition, the active substance can also be mixed with other active substances that do not impair the desired action, or that supplement the desired action, or have other actions. The compound may be formulated as the sole pharmaceutically active ingredient in the composition or may be combined with other active ingredients. In addition, the active substance can also be mixed with other active substances that do not impair the desired action, or that supplement the desired action, or have other actions. The compound may be formulated as the sole pharmaceutically active ingredient in the composition or may be combined with other active ingredients. In addition, the active substance can also be mixed with other active substances that do not impair the desired action, or that supplement the desired action, or have other actions. The compound may be formulated as the sole pharmaceutically active ingredient in the composition or may be combined with other active ingredients.

[0136] In another aspect, when the components of the compositions described herein exhibit only poor solubility, methods for solubilization can be used. Such methods are known and include, without limitation, the use of co-solvents, such as dimethyl sulfoxide (DMSO), the use of surfactants, such as TWEEN (e.g., polysorbate), and dissolution in aqueous sodium bicarbonate. The concentration of the compound is effective for delivery in an amount that reduces or ameliorates at least one symptom of the disorder to which the compound is administered. Typically, the composition is packaged for unit dosage administration. In another aspect, the components of the compositions described herein can be prepared with carriers that protect them against rapid elimination from the body, such as, for example, time-release formulations or coatings (also referred to as films). Such carriers include controlled release formulations, such as, without limitation, microencapsulation delivery systems. The active compound can be included in a pharmaceutically acceptable carrier in an amount sufficient to exert a therapeutically useful effect in the absence of undesirable side effects for the patient being treated. The therapeutically effective concentration can be determined empirically by testing the compound in in vitro and in vivo model systems known for the disorder being treated. In another aspect, the components of the compositions described herein are enclosed in a container for multiple or single doses.

[0137]

[0138]

[0139] ​​​​​​​​​​​​​​It can be done. The encapsulated compounds and compositions can be provided in a kit which includes components that can be assembled for use, for example one or more compounds (e.g., PYY, PYY(3 - 36), or analogs) can be used as starting materials for lyophilized forms (e.g , lyophilized orally soluble tablets), and appropriate diluents can be provided as separate components (also referred to as constituents) for combination prior to use . The kit can include the components of the compositions described herein and a second or third therapeutic agent for co - administration. The components of the compositions described herein and the second or third therapeutic agent can be provided as separate components. The kit may include a plurality of containers, each container holding one or more unit doses of the components of the compositions described herein. In one aspect, the container can be adapted to the desired mode of administration, including but not limited to tablets for oral administration , gel capsules, sustained - release capsules, and other similar ones; depot products, pre - filled syringes, ampoules, vials for parenteral administration, and other similar ones; and patches, medicated pads, creams for topical administration, and other similar ones, etc

[0140] In yet another aspect, the dosage form is a lyophilized orally soluble tablet. The lyophilized orally soluble tablet can be modified by the addition of sugars, for example, to produce a higher Tg Add in the lyophilized orally soluble tablet, which includes sugars that produce a Tg (glass transition temperature) higher than room temperature. Examples are Elnggar (Eln ), and ​From: Maltodextrin: A Novel Excipient Used in Sugar-Based Orally Disintegrat ing Tablets and Phase Transition Process(Maltodextrin: A Novel Excipient Used in Sugar-Based Orally Disintegrat ing Tablets and Phase Transition Process). AAPS PharmSciT ech(AAPS PharmSciTech) June 2010;11(2):645-651(April 20, 2010). See also

[0141] The concentrations of the components of the compositions described herein will depend on the dissolution, absorption, metabolism, and excretion rates of the active compound(s), the dosing schedule, and the dosage, as well as other factors known to those skilled in the art of this technology.

[0142] In another aspect, the active ingredient may be administered once or divided into a plurality of smaller doses administered at intervals of time. The exact dosage and duration of treatment will be a function of the disease to be treated and can be determined empirically using known test protocols or by extrapolation from in vivo (also referred to as in the living body) or in vitro (also referred to as in the test tube, in vitro, etc.) test data. It should be noted that the values of the concentrations and dosages can also vary depending on the severity of the condition being alleviated. For any particular subject, a specific dosing regimen should be adjusted over time according to the individual needs and the professional judgment of the person administering or supervising the administration of the composition, and the concentration ranges described herein are exemplary only and are not intended to limit the scope or practice of the claimed composition.

[0143] When oral administration is desirable, the compound can be presented in a composition that protects it from the acidic environment of the stomach. For example, the composition can be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine. The composition can also be formulated in combination with an antacid or other such agents.

[0144] Oral compositions will generally include an inert diluent or an edible carrier, and may optionally be lyophilized and compressed into tablets or encapsulated in gelatin capsules. For therapeutic administration purposes, the active compound or compounds can be incorporated with excipients and used in the form of tablets, capsules, or troches. Pharmaceutically compatible binding agents and adjuvant substances can be included as part of the composition.

[0145] Tablets, pills, capsules, troches, and the like can contain any of the following ingredients or compounds of similar nature: binding agents such as, but not limited to, gums, tragacanth, acacia, corn starch, or gelatin; excipients such as, but not limited to, microcrystalline cellulose, starch, or lactose; disintegrating agents such as, but not limited to, alginic acid and corn starch; lubricants such as, but not limited to, magnesium stearate; glidants such as, but not limited to, colloidal silicon dioxide; sweetening agents such as, but not limited to, sucrose or saccharin; and flavoring agents. ​​​​​For example, things such as peppermint, methyl salicylate, or fruit flavorings.

[0146] When the dosage unit form is a capsule, it can, in addition to the substances of the above types, contain a liquid carrier, for example, things such as fatty oils. Additionally, the dosage unit form can contain various other materials that modify the physical form of the dosage unit, for example, sugar coatings and other enteric medications. The compound can also be administered as a component of elixirs, suspensions, syrups, wafers (also called oblat, cachet, etc.), chewing gum, or other things of that kind etc. Syrups can contain, in addition to the active compound, sucrose as a sweetening agent, as well as certain preservatives, dyes and colorants, and flavors.

[0147] The active substance can also be mixed with other active substances that do not impair the desired effect, or with substances that compensate for the desired effect. The components of the compositions described herein can be used, for example, in combination with anti-obesity, anti-diabetic, or similar drugs (examples are lorcaserin, orlistat, phentermine / topiramate, sibutramine, rimonabant, metformin, exenatide, liraglutide, pramlintide, naltrexone, and tesofensine) .

[0148] In one aspect, solutions or suspensions used for parenteral, pump delivery, intradermal, subcutaneous, or topical application can contain any of the following components: a sterile diluent, for example, things such as water for injection etc., saline solution (also called salt solution, physiological saline, etc. ), fixed oils, naturally occurring vegetable oils, for example, sesame oil, coconut oil, peanut oil, cottonseed Oils, and other like substances, or synthetic fatty vehicles such as, for example, ethyl oleate and other like substances, and polyethylene glycol , glycerin, propylene glycol, or other synthetic solvents; antimicrobial agents such as, for example, benzyl alcohol and methylparaben and other like substances; antioxidants such as, for example, ascorbic acid and sodium bisulfite and other like substances; chelating agents such as, for example, ethylenedia minetetraacetic acid (EDTA) or its disodium salt and other like substances; buffers such as, for example, acetic acid salts, citrate salts, and phosphate salts and other like substances; and agents for adjusting tonicity such as, for example , sodium chloride and dextrose and other like substances. Parenteral preparations can be enclosed in ampoules, disposable syringes (also referred to as injection cylinders), or multi-dose vials made of glass, plastic, or other suitable substances. Buffers, preservatives, antioxidants, and other like substances can be incorporated as necessary.

[0149] When administered intravenously, suitable carriers include, but are not limited to, physiological saline, phosphate buffered saline (PBS), and thickening and solubilizing agents such as, for example, glucose, polyethylene glycol, polypropylene glycol, and mixtures thereof and other like substances. Liposome suspensions containing tissue-targeted liposomes can also be suitable as pharmaceutically acceptable carriers. These can be prepared according to methods known in the art.

[0150] In another aspect, the components of the compositions described herein protect the compound against rapid elimination from the body. The carrier to be protected can be prepared together with, for example, a time-release (also referred to as sustained-release) preparation or a coating or the like. Such carriers include controlled-release preparations, for example, but not limited to, implants and microencapsulation delivery systems, etc., as well as biodegradable and biocompatible polymers, for example, collagen, ethylene vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid, hydroxypropylmethyl cellulose (HPMC), other cellulose derivatives, etc., and other similar ones. Methods for preparing such preparations are known to those skilled in the art. In yet another aspect, the compounds employed in the methods of the present disclosure can be administered enterally or parenterally. When administered orally, the compounds employed in the methods of the present disclosure can be administered in conventional dosage forms for oral administration, as is well known to those skilled in the art. These dosage forms include conventional solid unit dosage forms of tablets and capsules, as well as liquid dosage forms, for example, solutions, suspensions, and elixirs, etc. When using solid dosage forms, they can be of the sustained release type, such that the compounds employed in the methods described herein need to be administered only once or twice a day. Oral dosage forms can be administered to the patient once, twice, three times, or four times a day, or as needed.

[0151]

[0152] ​​​​​​​​​​​​​​​It can be done. The components of the composition described herein can be administered up to three times a day, or either once or twice. Regardless of the oral dosage form used, it can be designed to protect the compounds described herein from the acidic environment of the stomach. Enteric-coated tablets and capsules filled with small spheres can also be coated respectively to protect from the acidic stomach and are also well known to those skilled in the art and can be used in the embodiments described herein.

[0153] The terms "therapeutically effective amount" and "therapeutically effective period" are used to indicate treatment at a dosage and for a period effective to treat, ameliorate, or reduce the conditions or symptoms described herein.

[0154] Those skilled in the art will recognize that such therapeutic effects, which result in even lower effective concentrations of the components of the composition described herein, can vary significantly depending on the tissue, organ, or particular animal or patient being treated. While a patient may be started on a certain dosage, it will be understood that that dosage can vary over time as the patient's condition changes.

[0155] The exact dosage and frequency of administration will depend on the particular compound employed in the methods of the disclosure being practiced, the particular condition being treated, the severity of the condition being treated, age, weight, general physical condition of the particular patient, and other drugs the individual is taking, as is well known to physicians skilled in the art. It should be apparent to those skilled in the art that dependence on other drugs the individual is taking will also be relevant.

Examples

[0156] Example 1 – PYY(3-36) dose escalation study

[0157] Day 1 (Check-in to Study Unit and Placebo Administration)

[0158] Subjects were required to complete all screening procedures and meet the criteria set forth in the protocol. All inclusion and exclusion criteria were met and participants were included in the study unit (i.e., study facility) The participants were found to be eligible for the study registry to check in at the Participants fasted before arriving at SU. Participants were asked to fast for at least 1 hour before the first day of the study. Both participants were fasting for 12 hours. The participants were only allowed to drink water before arriving at SU. The following evaluations and measurements were made:

[0159] (1) Examination of the tongue mucosa.

[0160] (2) Update medical and medication history before placebo administration.

[0161] (3) Assess health status. If the person concerned has either rhinitis or gastrointestinal problems, If so, the matter concerned will be suspended for that day.

[0162] (4) Measure weight and BMI.

[0163] (5) Measure vital signs (BP (blood pressure), HR (heart rate), and temperature). BP and BP and HR were measured twice in the sitting position and twice in the standing position. If the blood pressure was >160 systolic, the patient was seated for 5-10 minutes and BP was rechecked. The temperature was measured once.

[0164] (6) Perform urine drug screening, urine cotinine test, alcohol breath test, and urine pregnancy test.

[0165] (7) The subjects were provided with a 325 - 400 calorie breakfast and their calorie intake was recorded.

[0166] (8) Water was provided "ad libitum" and its volume was recorded.

[0167] (9) Four (4) hours after breakfast, VAS was performed for Appetite and Satiety by the subjects.

[0168] (10) A cannula was inserted to obtain a blood sample, a 5 ml blood sample was obtained and screened for anti - GT - 001 antibody.

[0169] (11) A fasting PK blood sample #1 (5 ml) was obtained 15 minutes before placebo.

[0170] (12) Before dosing with GT - 001, a water mouth wash was performed. The mouth wash can be a rinse with 20 ml of water.

[0171] (13) Five minutes before lunch, one milliliter (1 ml) of placebo (a preparation without GT - 001) was pipetted onto the tongue of the subjects.

[0172] (14) The solution was left on the tongue for 1 minute, then quickly moved around the mouth and then the subjects were asked to swallow.

[0173] (15) Complete VAS for like - lines (completed by the subjects). (VAS completed by the subjects).

[0174] (16) At 5, 10, 15, and 30 minutes within ±1 minute after dosing, and at 60, 120, and 240 minutes within ±5 minutes after each of the Seven PK blood samples after each of the various doses are collected.

[0175] (17) Isolate the subject from other subjects during lunch.

[0176] (18) Provide a "free" lunch (consisting of casserole, nutritional drink, and two (2) cookies), and record the calorie intake.

[0177] (19) Have the subject complete a VAS questionnaire regarding sweetness, sourness, bitterness, saltiness, umami, and fat taste 20 minutes after the meal is completed.

[0178] (20) Record the VAS for appetite and satiety every 30 minutes 2 hours after the meal is completed.

[0179] (21) Release the subject. The subject ate "freely" until a 12-hour fasting period prior to the next study visit.

[0180] (22) During the SU visit, the subject was restricted from consuming gum, candy, tobacco, carbonated beverages, and performing exercise. During the meal, the subject was not exposed to food cues (visual, olfactory, or auditory), and they had to eat alone.

[0181] The treatment days on days 2, 4, 6, 8, 10, 12, and 14 are the same as on day 1.

[0182] Days 3, 5, 7, 9, 11, and 13: Washout days

[0183] Those involved rest at home.

[0184] Study End (Day 15 and Early Termination Visit

[0185] Subjects who had completed days 1 - 14 or had discontinued the study prior to the planned SU liberation, completed the following: :

[0186] (1) Record the reason for interruption from the study.

[0187] (2) Update the medical history and medication history.

[0188] (3) Complete the adverse event assessment.

[0189] (4) Measure vital signs (BP, HR, and body temperature). BP and HR were measured twice in the sitting position and twice in the standing position. If the baseline BP in the sitting position was high (>160 systolic), BP was rechecked after sitting for 5 - 10 minutes if relevant. Body temperature was measured once. and twice in the standing position. If the baseline BP in the sitting position was high (>160 systolic), relevant BP was rechecked after sitting for 5 - 10 minutes. Body temperature was measured once.

[0190] (5) Measure weight and BMI.

[0191] (6) Perform a physical examination including inspection of the tongue mucosa.

[0192] (7) Conduct clinical tests (serum chemistry tests, hematology, and urine tests) hematological, and urine tests)

[0193] (8) Measure GT - 001 serum levels with anti - GT - 001 antibody.

[0194] (9) Have a serum pregnancy test.

[0195] (10) Perform urine drug screening, urine cotinine test, and alcohol breath test .

[0196] (11) Diet (also known as dietary therapy): Meal details

[0197] (a) Breakfast: Those involved were provided with a balanced breakfast of major nutrients (approximately 325 - 400 calories). Those involved selected the types of their breakfasts among eggs, cereals, toasts, etc. Juices, milk and coffee were allowed within the allotted calories. Artificial sweeteners were not permitted.

[0198] (b) Lunch: Those involved were provided with what all of you could eat casseroles, juices / milk, and two (2) cookies. Total food intake and the appetite and satiety of VAS were recorded. Artificial sweeteners were not permitted.

[0199] (c) Between meals: Those involved could only drink water during meals. Those involved were restricted from gums, candies, tobacco, and carbonated beverages.

[0200] Example 2 - VAS evaluation

[0201] The following exemplary VAS evaluations were given to subjects to assess their feelings of fullness before and after receiving PYY(3 - 36) or placebo, and before or after eating at the various doses described herein. Those involved indicated their responses on a scale of 1 - 10, with 1 indicating the strongest response on the left side, and 10 indicating the strongest response on the right side. For example, if those involved gave a response of 1 to question a, they were not at all hungry. A response of 10 to question a indicated that they were never any hungrier. A response of 5 indicated that These indicate what was felt between "I'm not at all hungry" and "I was even more hungry (more hungry)". Numerical responses on a scale of 1 - 10 were tabulated and used to draw the graphs in Figures 1 and 2. and not at all determined".

Chemical formula

[0202] 1. Ng M, Fleming T, Robinson M, et al., Global, regional, and national prevalence of overweight and obesity in children and adults during 1980 - 2013: a systematic analysis for the Global Burden of Disease Study 2013 (Prevalence of overweight and obesity in children and adults globally, regionally, and nationally between 1980 and 2013: A systematic analysis for the Global Burden of Disease Study 2013). Lancet 2014 2. 2. Acosta A, Abu Dayyeh BK, Port JD, Camilleri M. Recent advances in clinical practice challenges and opportunities in the management of obesity (Recent advances in clinical practice and opportunities in the management of obesity). Gut 2014;63:687 - 695 3. 3. Delgado - Aros S, Kim D - Y, Burton D et al., E Effect of GLP-1 on gastric volume, emptying, maximum volume ingested, and postprandial symptoms in humans (Effect of GLP-1 on gastric volume, emptying, maximum volume ingested, and postprandial symptoms in humans). American journal of physiology Gastrointestinal and liver physiology (American Journal of Physiology. Gastrointestinal and Liver Physiology) 2002;282:314 (American Journal of Physiology. Gastrointestinal and Liver Physiology) 2002;282:314 (American Journal of Physiology. Gastrointestinal and Liver Physiology) 2002;282:314 4. van Can J, Sloth B, Jensen CB, et al., Effects of the once-daily GLP-1 analog liraglutide on gastric emptying, glycemic parameters, appetite and energy metabolism in obese, non-diabetic adults (Effects of the once-daily GLP-1 analog liraglutide on gastric emptying, glycemic parameters, appetite and energy metabolism in obese, non-diabetic adults). International journal of obesity (International Journal of Obesity) 2014;38:784 - 793 (International Journal of Obesity) 2014;38:784 - 793 (International Journal of Obesity) 2014;38:784 - 793 5. Peters A. Incretin-based therapies: review of current clinical trial data (Incretin-based therapies: review of current clinical trial data). The American journal of medicine (American Journal of Medicine) 2010;123:S28 - 37 (American Journal of Medicine) 2010;123:S28 - 37 6. Verdich C, Flint A, Gutzwiller )JP et al., A meta-analysis of the effect of glucagon-like peptide-1 (7-36) amide on Ad libitum energy intake in humans (Meta-analysis of the effects of steroid-like peptide-1(7-36)amide). The Journal of Clinical Endocrinology Journal of Clinical Endocrinology & Metabolism M)2001;86:4382-4389 7. Bray G, Ryan D. Update on obesity pharmacotherapy Annals of the New York Academy of Sciences of the New York Academy of Sciences, 2014 8. Linnebjerg H, Park S, Kothare PA, et al. , Effect of exenatide on gastric emptying and relationship to postprandial glyce Effects of exenatide on gastric emptying and mia in type 2 diabetes (Relationship with postprandial blood glucose). Regulatory peptides 2008;151: 123-129 9. Moreno J, Willett K, Desilets A. Exenat Exenatide as a novel weight loss modality in patients without diabetes Ann Pharmacother 2012;46:1700-1706 10. Batterham RL, Cowley MA, Small CJ et al., Gut hormone PYY(3-36) physiologically inhibits food intake Nature 2002;418:650-654 11. Flegal KM, Carroll MD, Kit BK, Ogden CL. Prevalence of obesity and trends in the distribution of body mass index among US adults, 1999-2010 JAMA: the journal of the American Medical Association 2012;307:491-497 12. Gardiner JV, Jayasena CN, Bloom SR. Gut hormones: a weight off your mind J Neuroendocrinol 2008;20:834-841 ​​​​​​​13. Jayasena CN, Bloom SR. Role of Gut Hormones in Obesity (Role of Gut Hormones in Obesity). Endocrinology & Metabolism Clinics of North America (Endocrinology & Metabolism Clinics of North America) 2008;37:769- 787 14. Koda (Koda) S, Date (Date) Y, Murakami (Murakami) N, et al., The role of the vagus nerve in peripheral PYY(3-36)-induced feeding reduction in rats. (Role of the vagus nerve in peripheral PYY(3-36)-induced feeding reduction in rats.) Endocrinology 2005;14 6:2369-2375 15. le Roux (le Roux) CW, Batterham RL, Aylwin (Aylwin) SJ et al., Attenuated peptide YY release in obese subjects is associated with reduced satiety (Reduced peptide YY release in obese subjects is associated with reduced satiety). Endocr inology 2006;147:3-8 16. Lenard (Lenard) NR, Berthoud (Berthoud) H-R. Central and Peripheral Re gulation of Food Intake and Physical Activity: Pathways and Genes (Central and Peripheral Regulation of Food Intake and Physical Activity: Pathways and Genes). Obesity (Obesity) 2008;1 6:S11-S22 17. le Roux (le Roux) CW, Batterham RL, Aylwin (Aylwin) SJ et al., Attenuated peptide YY release in obese subjects is associated with reduced satiety (Reduced 17. Ogden CL, Yanovski SZ, Carroll MD, Flegal KM. The epidemio logy of obesity. Gastroenterology 2007;1 32:2087-2102

Claims

1. A pharmaceutical composition comprising PYY at a dose of about 2.5 ng to about 2.5 mg, and a pharma- ceutical acceptable excipient. composition.

2. 2. The pharmaceutical composition of claim 1, wherein the PYY is PYY(3-36).

3. 2. The pharmaceutical composition of claim 1, wherein the dose of PYY is about 2.5 ng.

4. 2. The pharmaceutical composition of claim 1, wherein the dose of PYY is about 25 ng.

5. 2. The pharmaceutical composition of claim 1, wherein the dose of PYY is about 250 ng.

6. 2. The pharmaceutical composition of claim 1, wherein the dose of PYY is about 2.5 μg.

7. 2. The pharmaceutical composition of claim 1, wherein the dose of PYY is about 25 μg.

8. 2. The pharmaceutical composition of claim 1, wherein the dose of PYY is about 250 μg.

9. 2. The pharmaceutical composition of claim 1, wherein the dose of PYY is about 2.5 mg.

10. 2. The pharmaceutical composition of claim 1, wherein the dose of PYY is from about 2.5 μg to about 250 μg.

11. For volumes of about 2.5 ng to about 250 μg of PYY in volumes of about 10 μl to about 5 ml of solvent, A pharmaceutical composition comprising a dose of PYY.

12. 12. The pharmaceutical composition of claim 11, further comprising a pharma- ceutically acceptable excipient.

13. 13. The pharmaceutical composition of claim 12, wherein the dosage per volume is about 2.5 μg / ml.

14. Dosage forms for the pharmaceutical compositions include oral film strips, troches, lollipops, chews, and the like. -ing gum, spray dried granules sachet, frozen granules sachet, freeze dried granules oral spray, capsule, tablet, orally soluble tablet, buccal tablet, freeze-dried tablet, and 3. The pharmaceutical composition of claim 2, wherein the composition is selected from the group consisting of a moisturizer and a mouthwash.

15. Pharmaceutically acceptable excipients include stabilizers, preservatives, antioxidants, buffers, surfactants, leiotropic agents, and the like. The drug of claim 1, wherein the compound is selected from the group consisting of a drug modifier, a drug for treating inflammatory bowel disease, and a drug for enhancing mucosal permeation. chemical composition.

16. Pharmaceutically acceptable excipients include propylene glycol, potassium sorbate, 1-alcohol, Contains ginine, disodium edetate, sodium dihydrogen phosphate, and polysorbate 20.

3. The pharmaceutical composition of claim 2,

17. Propylene glycol is present at a concentration of about 100 mg / ml and l-arginine is present at about 25 mg / ml sorbate was present at a concentration of 2 mg / ml, and edetate dibasic was present at a concentration of 2 mg / ml. Sodium is present at a concentration of about 1.2 mg / ml and sodium phosphate monobasic dihydrate at about 7. 8mg / ml, and polysorbate is present at a concentration of about 5mg / ml.

17. The pharmaceutical composition of claim 16.

18. 18. The method of claim 17, wherein the dosage of PYY(3-36) in the pharmaceutical composition is at least about 2.5 μg. chemical composition.

19. 19. The pharmaceutical composition of claim 18, wherein the dosage of PYY(3-36) in the pharmaceutical composition is at least about 25 μg. composition.

20. 20. The pharmaceutical composition of claim 19, wherein the dose of PYY(3-36) does not exceed about 250 μg.

21. 3. The pharmaceutical composition of claim 2, wherein the pharmaceutical composition is adapted for delivery to the oral cavity.

22. 22. The pharmaceutical composition of claim 21, wherein the pharmaceutical composition is adapted for local delivery to the tongue.

23. 23. The pharmaceutical composition of claim 22, wherein the PYY(3-36) in the pharmaceutical composition is adapted for binding to the Y2 receptor. composition.

24. A satiate peptide in a dose of about 2.5 ng to about 2.5 mg, and a pharma- ceutically acceptable A pharmaceutical composition comprising an excipient.

25. Satiety peptides are GLP-1, oxyntomodulin, and cholecystokinin.

25. The pharmaceutical composition of claim 24, wherein the compound is selected from the group consisting of:

26. GLP-1, oxyntomodulin, and cholecystokinin acetyl-CoA carboxylates ACC inhibitor, diacylglycerol O-acyltransferase 1 (DGAT-1) inhibitor inhibitors, monoacylglycerol O-acyltransferase inhibitors, phosphodiesterase inhibitors PDE-10 inhibitors, AMPK activators, sulfonylureas, meglitinides, α-aminobutyric acid enzyme inhibitors, α-glucoside hydrolase inhibitors, α-glucosidase inhibitors, PP ARγ agonists, PPARα / γ agonists, biguanides, glucagon-like peptide 1 (GLP-1 ) Modulators, GLP-1 receptor agonists, liraglutide, albiglutide, exenatide, Albiglutide, lixisenatide, dulaglutide, semaglutide, protein tyrosine Phosphatase-1B (PTP-1B) inhibitor, SIRT-1 activator, dipeptidyl peptidase I V (DPP-IV) inhibitor, insulin siclothionein, fatty acid oxidation inhibitor, A2 antagonist Nist, c-jun amino-terminal kinase (JNK) inhibitor, glucokinase activator (GKa) , insulin, insulin mimetics, glycogen phosphorylase inhibitors, VPAC2 Receptor agonist, SGLT2 inhibitor, glucagon receptor modulator, GPR119 modulator, FGF21 Derivatives or Analogs, TGR5 Receptor Modulators, GPBAR1 Receptor Modulators, GPR40 Agonists, G PR120 modulator, high affinity nicotinic acid receptor (HM74A) activator, SGLT1 inhibitor, calcitonin receptor activator Inhibitors or modulators of the enzyme nitine palmitoyltransferase, fructose 1, 6-diphosphatase inhibitor, aldose reductase inhibitor, mineralocorticoid Id receptor inhibitors, TORC2 inhibitors, CCR2 and / or CCR5 inhibitors, PKC isoforms inhibitors of PKC forms (e.g., PKCα, PKCβ, PKCγ), inhibitors of fatty acid synthetase, Inhibitors of serine palmitoyltransferase, GPR81, GPR39, GPR43, GPR41, GPR1 05, Kvl.3, retinol-binding protein 4, glucocorticoid receptor, somatostatin receptor modulators of receptors, inhibitors or modulators of PDHK2 or PDHK4, inhibitors of MAP4K4, IL1 IL1 family modulators, including beta, HMG-CoA reductase inhibitor, squalene Tetanase inhibitors, fibrates, bile acid sequestrants, ACAT inhibitors, MTP inhibitors Lipids, lipoxygenase inhibitors, cholesterol absorption inhibitors, PCSK9 modifiers, cholesterol Steryl ester transfer protein inhibitor and modulator of RXRα, GIP receptor Agonists, enterostatin and enterostatin analogues, amylin and amylin Ghrelin receptor agonists, ghrelin modulators (e.g., inhibitors) and leptin and leptoglobulin receptor antagonists. putin receptor agonist, pancreatic polypeptide (PP), calcitonin, OXM, neuropeptide NPY, human growth hormone, prolactin, oxytocin, bovine growth hormone, It consists of growth hormone, ghrelin, ghrelin receptor antagonist, and glucagon.

10. The pharmaceutical composition of claim 1, further comprising one or more active pharmaceutical ingredients selected from the group:

27. GLP-1, oxyntomodulin, and cholecystokinin acetyl-CoA carboxylates ACC inhibitor, diacylglycerol O-acyltransferase 1 (DGAT-1) inhibitor inhibitors, monoacylglycerol O-acyltransferase inhibitors, phosphodiesterase inhibitors PDE-10 inhibitors, AMPK activators, sulfonylureas, meglitinides, α-aminobutyric acid enzyme inhibitors, α-glucoside hydrolase inhibitors, α-glucosidase inhibitors, PP ARγ agonists, PPARα / γ agonists, biguanides, glucagon-like peptide 1 (GLP-1 ) Modulators, GLP-1 receptor agonists, liraglutide, albiglutide, exenatide, Albiglutide, lixisenatide, dulaglutide, semaglutide, protein tyrosine Phosphatase-1B (PTP-1B) inhibitor, SIRT-1 activator, dipeptidyl peptidase I V (DPP-IV) inhibitor, insulin siclothionein, fatty acid oxidation inhibitor, A2 antagonist Nist, c-jun amino-terminal kinase (JNK) inhibitor, glucokinase activator (GKa) , insulin, insulin mimetics, glycogen phosphorylase inhibitors, VPAC2 Receptor agonist, SGLT2 inhibitor, glucagon receptor modulator, GPR119 modulator, FGF21 Derivatives or Analogs, TGR5 Receptor Modulators, GPBAR1 Receptor Modulators, GPR40 Agonists, G PR120 modulator, high affinity nicotinic acid receptor (HM74A) activator, SGLT1 inhibitor, calcitonin receptor activator Inhibitors or modulators of the enzyme nitine palmitoyltransferase, fructose 1, 6-diphosphatase inhibitor, aldose reductase inhibitor, mineralocorticoid Id receptor inhibitors, TORC2 inhibitors, CCR2 and / or CCR5 inhibitors, PKC isoforms inhibitors of PKC forms (e.g., PKCα, PKCβ, PKCγ), inhibitors of fatty acid synthetase, Inhibitors of serine palmitoyltransferase, GPR81, GPR39, GPR43, GPR41, GPR1 05, Kvl.3, retinol-binding protein 4, glucocorticoid receptor, somatostatin receptor modulators of receptors, inhibitors or modulators of PDHK2 or PDHK4, inhibitors of MAP4K4, IL1 IL1 family modulators, including beta, HMG-CoA reductase inhibitor, squalene Tetanase inhibitors, fibrates, bile acid sequestrants, ACAT inhibitors, MTP inhibitors Lipids, lipoxygenase inhibitors, cholesterol absorption inhibitors, PCSK9 modifiers, cholesterol Steryl ester transfer protein inhibitor and modulator of RXRα, GIP receptor Agonists, enterostatin and enterostatin analogues, amylin and amylin Ghrelin receptor agonists, ghrelin modulators (e.g., inhibitors) and leptin and leptoglobulin receptor antagonists. putin receptor agonist, pancreatic polypeptide (PP), calcitonin, OXM, neuropeptide NPY, human growth hormone, prolactin, oxytocin, bovine growth hormone, It consists of growth hormone, ghrelin, ghrelin receptor antagonist, and glucagon.

25. The pharmaceutical composition of claim 24, further comprising one or more active pharmaceutical ingredients selected from the group:

28. PYY, PYY(3-36), GLP-1, oxyntomodulin, and cholecystokinin, acetylcholine Alanine-CoA carboxylase (ACC) inhibitor, diacylglycerol O-acyltransferase DGAT-1 inhibitor, monoacylglycerol O-acyltransferase inhibitor substances, phosphodiesterase (PDE)-10 inhibitors, AMPK activators, sulfonylureas, Glytinides, α-amylase inhibitors, α-glucoside hydrolase inhibitors, α-glucosidase inhibitors PPARα / γ agonists, biguanides, glucagonase inhibitors GLP-1 modulators, GLP-1 receptor agonists, liraglutide, albiglutide tide, exenatide, albiglutide, lixisenatide, dulaglutide, semaglutide , Protein tyrosine phosphatase-1B (PTP-1B) inhibitor, SIRT-1 activator, Zipec DPP-IV inhibitor, insulin siclytagam, fatty acid oxidation inhibitor, A2 antagonist, c-jun amino-terminal kinase (JNK) inhibitor, glucokinase Glycogen phosphorylation factor (GKa), insulin, insulin mimetics, glycogen phosphorylation Glucagonase inhibitors, VPAC2 receptor agonists, SGLT2 inhibitors, glucagon receptor modulators, GP R119 modulators, FGF21 derivatives or analogs, TGR5 receptor modulators, GPBAR1 receptor modulators , GPR40 agonist, GPR120 modulator, high affinity nicotinic acid receptor (HM74A) activator, SGLT1 inhibitors, inhibitors or modifiers of the carnitine palmitoyltransferase enzyme Factor, inhibitor of fructose 1,6-bisphosphatase, inhibitor of aldose reductase mineralocorticoid receptor inhibitors, inhibitors of TORC2, inhibitors of CCR2 and / or CCR5 Inhibitors, inhibitors of PKC isoforms (e.g., PKCα, PKCβ, PKCγ), fatty acid synthesizers inhibitors of serine palmitoyltransferase, GPR81, GPR39, GPR43, GPR41, GPR105, Kvl.3, retinol-binding protein 4, glucocorticoid receptor , modulators of somatostatin receptors, inhibitors or modulators of PDHK2 or PDHK4, MAP4 Inhibitor of K4, Modulator of the IL1 family including IL1beta, HMG-CoA reductase inhibitor substances, squalene synthetase inhibitors, fibrates, bile acid sequestrants, ACAT inhibitors inhibitors, MTP inhibitors, lipoxygenase inhibitors, cholesterol absorption inhibitors, PCS K9 modifier, cholesteryl ester transfer protein inhibitor and RXRα modifier Decorative factors, GIP receptor agonists, enterostatins and enterostatin analogues, Amylin and amylin receptor agonists, ghrelin modulators (e.g., inhibitors), and Leptin and leptin receptor agonists, pancreatic polypeptide (PP), calcitonin, OXM, neuropeptide Y (NPY), human growth hormone, prolactin, oxytocin, human somatotropin, porcine somatotropin, ghrelin, ghrelin receptor antagonist, and glucagon, A pharmaceutical composition comprising:

29. The volumetric dosage of one or more active ingredients may be in a volume of from about 10 μl to about 5 ml of solvent.

27. The pharmaceutical composition of claim 26, wherein the amount of the pharmaceutical composition is from about 2.5 ng to about 250 μg of one or more active ingredients.

30. 30. The pharmaceutical composition of claim 29, wherein the pharmaceutical composition is adapted for delivery to the oral cavity.

31. Administering to a subject the pharmaceutical composition of claim 1 in treating a metabolic disorder in the subject. A method comprising:

32. 29. Treating a metabolic disorder in a subject by administering to the subject the pharmaceutical composition of claim 28. A method comprising:

33. 32. The method of claim 31, wherein the pharmaceutical composition is administered orally to the subject.

34. 34. The method of claim 33, wherein the pharmaceutical composition is delivered to the tongue.

35. 35. The method of claim 34, wherein the PYY(3-36) in the pharmaceutical composition binds to a receptor on the tongue.

36. 36. The method of claim 35, wherein the receptor is a Y2 receptor.

37. Metabolic disorders include obesity, hyperglycemia, diabetes, fatty liver disease, PCOS, and multiple sclerosis. The method of claim 31, wherein the compound is selected from the group consisting of:

38. The metabolic disorder is obesity, and food intake by the subject is decreased following treatment with a dose of the pharmaceutical composition.

38. The method of claim 37, wherein the level of IL-1 in the subject is reduced by at least about 20% compared to a subject who did not receive the treatment.

39. The metabolic disorder is obesity, and the subject's weight decreases following treatment with a dose of the pharmaceutical composition. The method of claim 38, wherein the effect is reduced by at least about 5% compared to a non-treated subject.

40. The metabolic disorder is increased blood glucose, and the subject's blood glucose level is increased after treatment with a dose of the pharmaceutical composition.

38. The method of claim 37, wherein the level of IL-1 is reduced by at least about 10% compared to a subject not receiving the treatment.

41. The metabolic disorder is diabetes mellitus, and the area under the curve (AUC) of a glucose tolerance test in the subject at least about 15% after treatment with a dose of the pharmaceutical composition compared to a subject who did not receive treatment 38. The method of claim 37, wherein the concentration of the ion exchange resin is reduced by up to 50%.

42. The metabolic disorder is diabetes, and the subject's fasting glucose level is increased by administering a dose of the pharmaceutical composition.

37. The method of claim 37, wherein the level of the inflammatory bowel disease is reduced by at least about 15% after treatment with the associated How to.

43. The metabolic disorder is diabetes, and the subject's HbA1c level is treated with a dose of the pharmaceutical composition.

38. The method of claim 37, wherein the level of schizophrenia is subsequently reduced by at least about 15% compared to a subject who did not receive the treatment.

44. The metabolic disorder is fatty liver disease, and the liver fat concentration in the subject is determined by administering a pharmaceutical composition. and wherein the dose is reduced by at least about 20% compared to a subject not receiving the treatment. The method of claim 37.

45. The metabolic disorder is PCOS, and symptoms of PCOS in the subject are associated with administration of the pharmaceutical composition. The claimed invention relates to a method for treating a subject's condition in which the subject's ability to tolerate the treatment is reduced by at least about 15 to 20% after the treatment compared to a subject who did not receive the treatment. The method of paragraph 37.

46. The metabolic disorder is multiple sclerosis, and symptoms of multiple sclerosis in the subject are treated with a pharmaceutical composition. at least about 20% reduction after treatment with a dose of 38. The method of claim 37.

47. The metabolic disorder is hypertension, and the systolic and diastolic blood pressure levels in the subject are measured by a pharmacologist. after a dose of the target composition, the subject's blood glucose level is reduced by at least about 20% compared to a subject who did not receive the dose. The method of claim 37.

48. Administering to a subject the pharmaceutical composition of claim 10 to enhance a sense of well-being in the subject. Includes, a method.

49. 49. The method of claim 48, wherein the dosage of PYY(3-36) in the pharmaceutical composition is at least about 2.5 μg / ml. method.

50. 50. The method of claim 49, wherein the dosage of PYY(3-36) in the pharmaceutical composition is at least about 25 μg / ml. method.

51. 51. The method of claim 50, wherein the dosage of PYY(3-36) in the pharmaceutical composition is at least about 250 μg / ml. method.

52. 48. The subject feels satisfied for at least about 30 minutes after administering the pharmaceutical composition to the subject. How to.

53. 53. The method of claim 52, wherein the pharmaceutical composition is administered to the subject and the subject then consumes a meal.

54. 48. The method of claim 47, wherein the subject feels satisfied for at least 120 minutes after administering the pharmaceutical composition to the subject. How to.

55. 55. The method of claim 54, wherein the pharmaceutical composition is administered to the subject and the subject then consumes a meal.

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