Peptide YY pharmaceutical preparations, compositions, and methods

Abstract

Provided are pharmaceutical compositions containing PYY (e.g., PYY(3-36) and its analogs and variants), sataiety peptides, sataiety hormones, metabolic hormones, and methods for treating metabolic disorders with such compositions. These embodiments include methods for enhancing well-being in patients treated with pharmaceutical compositions containing PYY, PYY(3-36), sataiety peptides, sataiety hormones, metabolic hormones, and analogs, receptor antagonists, and variants thereof.

Description

Technical Field

[0001] All references cited herein are incorporated by reference in their entirety, including, but not limited to, patents and patent applications. Cross - Reference to Related Applications

[0002] This application claims priority and the benefit thereof to U.S. Provisional Application No. 62 / 620,580, filed on January 23, 2018, and U.S. Provisional Application No. 62 / 669,191, filed on May 9, 2018, which are incorporated herein by reference in their entirety. Background

Summary of the Invention

Problems 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 obese [2]. However, there is still no effective and long - term non - invasive treatment for obesity. The current "one - size - fits - all" approach to obesity is associated with a very diverse range of effectiveness and outcomes [3].

[0004] PYY(3-36) is a Y receptor (e.g., Y2 receptor) agonist released from intestinal cells in response to feeding. The peptide YY(PYY)(3-36) is a satiation-inducing gastrointestinal hormone released primarily from the gastrointestinal tract after meals. PYY(3-36) secretion is associated with calorie intake, and it induces satiation by acting on Y2 receptors in the arcuate nucleus of the hypothalamus. Recently, PYY(3-36) has been found to be present in saliva in mice and humans, and its concentration in saliva correlates with its concentration in plasma. PYY(3-36) and Y2 receptors are expressed in taste cells in the circumvallate papillae of the tongue [4]. In mice, acute augmentation therapy with salivary PYY(3-36) induces higher sations, as demonstrated by feeding behavior studies and c-Fos activation in the arcuate nucleus of the hypothalamus. The rapid increase in salivary PYY(3-36) resulted in a dose-dependent decrease in hourly food intake. Chronic overexpression of salivary PYY(3-36) using a viral vector-mediated gene delivered into the submandibular salivary gland (rAAV-PYY vs. rAAV-GFP control) resulted in a twofold increase in chronic salivary PYY(3-36) over 22 weeks [4]. The outcome of this treatment was a decrease in weekly food intake and a 23% weight loss over 8 weeks after vector delivery compared to the control. PYY(3-36) induces sations through salivary and taste cell receptors [5,6].

[0005] Incretins, such as glucagon-like peptide-1 (GLP-1), enhance glycemic control, inhibit gastric emptying, and increase saturation in healthy individuals and in patients with diabetes [7-9]. GLP-1 and GLP-1 agonists lower fasting and postprandial glucose levels through increased insulin secretion from the pancreas and reduce gluconeogenesis in the liver.

[0006] Exenatide (Exendin-4) is a 39-amino acid peptide produced in the salivary glands of the Gila monster lizard (also known as the American beaded lizard). Its amino acid sequence shares 53% identity with GLP-1, but 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 has been approved by the FDA for the treatment of patients with type 2 diabetes mellitus, both on a daily and weekly basis, where treatment with metformin or sulfonylurea does not adequately control the patient's condition. GLP-1 receptor agonists also slow 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 hypoglycemia) in patients with type 2 diabetes mellitus.

[13]

[0007] Previously, PYY and PYY analogs were administered to patients in manner that resulted in a significant increase in PYY levels in the subject's plasma. PYY and PYY analogs were also used to induce saturation in subjects without substantially altering the concentration of PYY in the subject's plasma. See U.S. Patent No. 9,492,505 for an example. Higher doses of PYY may cause undesirable side effects, such as nausea. However, no appropriate low-dose PYY pharmaceutical formulations for inducing saturation in subjects have been described. Outline [Means for solving the problem]

[0008] Topical oral delivery of PYY(3-36) has been shown to reduce food intake and enhance satiety. However, it is desirable to improve the activity of PYY(3-36), PYY analogs, and satiety peptides by providing low-dose formulations suitable for inducing long-lasting satiety in subjects. Furthermore, such formulations can be used to treat metabolic disorders.

[0009] The embodiments described herein provide a pharmaceutical composition comprising PYY or a PYY analog (e.g., PYY(3-36)), a variant, and satayety peptides (e.g., GLP-1, oxytomodulin, and cholecystokinin), wherein the dose of PYY or a PYY analog, a variant, and satayety peptide in the pharmaceutical composition is at least about 2.5 ng. In another embodiment, PYY is PYY(3-36). In yet another embodiment, the dose of PYY in the pharmaceutical composition is from about 2.5 ng to about 2.5 mg. In yet another embodiment, the dose of PYY in the pharmaceutical preparation is from about 2.5 μg to about 250 μg. The term “dose” refers to an amount in the range of 90 to 110% of the desired amount of the active pharmaceutical ingredient in the dosage form, or the amount stated on the label for a drug product approved by the Federal Drug Administration (FDA).

[0010] In another embodiment, the dose per volume of PYY(3-36) can range, for example, from about 25 μl to about 100 μl, or from about 2.5 ng to about 250 μg in a maximum volume of about 5 ml. In another embodiment, the dose / volume is about 2.5 μg / ml. In another embodiment, the dose / volume is about 500 μg / 500 μL. In another embodiment, the dose / volume is about 250 μg / ml.

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

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

[0013] In one embodiment, the described pharmaceutical preparations can be administered to subjects receiving PYY and PYY analogues and used to treat metabolic disorders (e.g., obesity, hyperglycemia, diabetes, fatty liver disease, PCOS, and multiple sclerosis) by reducing symptoms associated with metabolic disorders compared to subjects not receiving PYY or PYY analogues.

[0014] Another embodiment provides a method for enhancing a feeling of satisfaction in a subject by administering a PYY or PYY-like substance to the subject, for example, before a meal. In this embodiment, after the PYY or PYY-like substance is administered to the subject, and after the subject has eaten a meal, the feeling of satisfaction can last for at least about 30, 60, 90, or 120 minutes or longer. In another embodiment, a pharmaceutical composition is administered to the subject, and the subject then eats a meal. [Brief explanation of the drawing]

[0015] [Figure 1] The results of an exemplary study are presented, in which PYY(3-36) was orally administered to subjects at the prescribed dose (GT-001 dose on the x-axis), and satisfaction levels (mean value on the y-axis) were evaluated 30 and 120 minutes after the subjects ate lunch. [Figure 2] The results of a model study were presented, in which satisfaction (VAS satisfaction (mm)) was plotted against time (30, 60, 90, and 120 minutes) after treatment with PYY(3-36) formulations and after eating lunch at four doses (placebo, 25 ng, 25 μg, and 250 μg). [Figure 3] The normalized concentrations are shown in the plasma of subjects who received placebo, 0.25 mg / ml PYY(3-36), and 2.5 mg / ml PYY(3-36) formulations (each following lunch), measured within a time range of up to 4 hours after administration of pg / ml PYY. [Modes for carrying out the invention]

[0016] Detailed description Before describing the exemplary embodiments described herein, it should be understood that the present invention is not limited to the details of the configuration or process steps described below. The embodiments described herein are capable of being practiced or carried out in a variety of ways.

[0017] Satiation occurs during a meal. This is the point in time when the subject feels that they have eaten enough and do not desire any more food. Satiety, on the other hand, is the subject's experience after a meal—how long it takes for the subject to begin feeling hungry again. "Feeling of fullness" refers to an indicator of satiety, such as that reported by a person after eating food or a meal. The degree and duration of satiety (satiation and satiety) are predictors of whether a person will continue eating or resume eating, and therefore increase their calorie intake over time. Thus, increasing the degree and duration of satiety leads to a decrease in overall calorie intake and a decrease in weight and obesity.

[0018] A Visual Analogue Scale (VAS) is an instrument, tool, or methodology used to measure a feature whose value or degree can vary and which is not easily measured directly in another way. For example, VAS is often used to determine the degree of pain experienced by a patient (e.g., a scale from 1 to 10). Similarly, VAS can certainly be used to measure the degree of satisfaction reported by a subject after eating food or a meal. For example, see Blundell et al., "Appetite Control: Methodological Aspects of The Valuation of Foods," Obes Rev. March 2010;11(3):251-270; Flint et al., "Reproducibility, power and validity of visual analogue scales in assessment of appetite sensations in single test meal studies," International Journal of Obesity (2000) 24, 38-48 (2000).

[0019] Metabolic disorders, diseases, or metabolic syndromes refer to diseases or conditions that increase the risk of diseases or disorders (e.g., diabetes, heart disease, stroke, obesity, hyperglycemia, fatty liver disease, PCOS (polycystic ovary syndrome), and multiple sclerosis) that are related to, associated with, or caused by abnormal metabolism. The lack of effective, long-term, non-invasive procedures for metabolic disorders has spurred the search for small molecules capable of treating these conditions with minimal side effects. While several small molecule therapeutics are currently on the market, their efficacy is relatively low, and their safety profiles are not ideal. On the other hand, natural human hormones involved in regulating fasting, satiety, and energy metabolism in normal physiological function, and their analogues (also called analogues), as described herein, can be used to treat such diseases.

[0020] GLP-1 receptor agonists, and PYY(3-36) and its analogs, have been used with limited success in treating metabolic disorders. Therapeutic outcomes with GLP-1 receptor agonists for diabetes mellitus (DM) and obesity are highly variable and can lead to serious side effects. While PYY(3-36) is a potent inducer of satiety, systemic administration of PYY and its analogs tends to be associated with serious side effects, such as nausea and vomiting.

[0021] The embodiments described herein provide compositions comprising PYY and PYY analogs, such as PYY(3-36). In certain embodiments, these compositions can be used to treat metabolic disorders (also known as metabolic diseases, metabolic disorders, metabolic illnesses, metabolic disorders, etc.) (e.g., obesity, diabetes, hyperglycemia, etc.). These compositions can be used more effectively than simple aqueous solutions or simple dry compositions to alleviate, improve, or treat a patient's condition.

[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-TYR-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)) that encodes the mature peptide:

[0025] 1 gcccctggag gaactgaacc cactatcggt catggggccg agactaaatg tggcgggttg 61 tctttaatct gctgccaaga ggaaactcat tcaggcaagt tcagcccttt atgaggaatt 121 cccctgtggt cacattccaa ttcctggacc tgctgccacc ctcagaactg catgctcctt 18l 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 embodiment, the term “PYY(3-36)” further includes analogs or variants (also called modifications, variants, 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 embodiment, the term “variant” refers to the modification or substitution of one or more (also called one or more) amino acids of native PYY(3-36). Amino acid substitution refers to replacing one amino acid with another. In one embodiment, an amino acid may be replaced with an amino acid having a similar side group (e.g., acidic, basic, neutral). The term “biological activity” refers to the activation of the Y receptor by one or more small molecules described herein that affect 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 (2017) (S0968-0896 (Epub ahead of See print (electronic publication before print edition). In one embodiment, these analogs and variants can be used in the pharmaceutical compositions described herein.

[0028] The embodiments described herein provide a pharmaceutical composition comprising PYY, wherein when PYY is administered to a subject, the dose of PYY administered to the subject is at least about 2.5 ng. In another embodiment, PYY is PYY(3-36). In yet another embodiment, 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 yet another embodiment, 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] Further embodiments provide a pharmaceutical composition comprising a satiety peptide (also known as a satiety peptide, satiety peptide, or satiety peptide) and a pharmaceutically acceptable excipient in a dose of approximately 2.5 ng to approximately 2.5 mg. In another embodiment, the pharmaceutical composition of claim 23 is characterized in that the satiety peptide is selected from the group consisting of GLP-1, oxytomodulin, and cholecystokinin.

[0030] In another embodiment, the dose per volume of PYY(3-36) can range from approximately 2.5 ng to approximately 250 μg in a solvent (e.g., water, buffer, etc.) from approximately 25 μl to approximately 5 ml. In another embodiment, the dose / volume is approximately 2.5 μg / ml. In another embodiment, the dose / volume is approximately 500 μg / 500 μl. The volume of the pharmaceutical preparation chosen to deliver the dose of PYY(3-36) can be chosen to optimize the residency time of PYY(3-36) in order to enhance the interaction between PYY(3-36) and its receptors on the tongue (e.g., Y2 receptors) in the oral cavity and, more specifically, on the tongue.

[0031] Further embodiments include these pharmaceutical compositions comprising, in addition to or together with, one or more of the following instead of PYY, PYY(3-36), or other PYY analogs, a nucleotide encoding PYY, PYY(3-36), or other PYY analogs, or a peptide substantially identical thereto: GLP-1, oxytomodulin, and cholecystokinin acetyl-CoA carboxylase-(ACC) inhibitor, diacylglycerol O-acyltransferase 1 (DGAT-1) inhibitor, monoacylglycerol Lol-O-acyltransferase inhibitors, phosphodiesterase (PDE)-10 inhibitors, AMPK activators (also called activators, activating substances, or activators), sulfonylurea, meglitinide, α-amylase inhibitors, α-glucoside hydrolase inhibitors, α-glucosidase inhibitors, PPARγ agonists (also called activators, agonists, etc.), PPARα / γ agonists, biguanides, glucagon-like peptide 1 (GLP-1) modifiers (also called modulators, modifiers, or modifiers), GLP-1 receptor agonists, liraglu Insulin, albiglutide, exenatide (also called exenatide), albiglutide, lixisenatide, dulaglutide, semaglutide, protein tyrosine phosphatase-1B (PTP-1B) inhibitor, SIRT-1 activator, dipeptidyl peptidase IV (DPP-IV) inhibitor, insulin secreatagogue, fatty acid oxidation inhibitor, A2 antagonist (also called antagonist, antagonist, etc.), c-jun amino-terminal kinase (JNK) inhibitor, glucokinase activator (GKa), insulin, insulin Linmimetics (also called mimetics, imitations, etc.), glycogen phosphorylase inhibitors, VPAC2 receptor agonists, SGLT2 inhibitors, glucagon receptor modifiers, GPR119 modifiers, FGF21 derivatives or analogs (also called analogs), TGR5 receptor modifiers, GPBAR1 receptor modifiers, GPR40 agonists, GPR120 modifiers, high affinity nicotinic acid receptor (HM74A) activators, SGLT1 inhibitors, carnitine palmitoyltransferase enzyme inhibitors or modifiers, fructose 1,Inhibitors of 6-diphosphatase, aldose reductase, mineralocorticoid receptor, TORC2, CCR2 and / or CCR5, PKC isoform inhibitors (e.g., PKCα, RKCβ, PKCγ), fatty acid synthetase inhibitors, serine palmitoyltransferase inhibitors, GPR81, GPR39, GPR43, GPR41, GPR105, Kvl.3, retinol-binding protein 4, glucocorticoid receptor, somatostein receptor Receptor modifiers, PDHK2 or PDHK4 inhibitors or modifiers, MAP4K4 inhibitors, IL1 family modifiers including IL1 beta, HMG-CoA reductase inhibitors, squalene synthase inhibitors, fibrates, bile acid metal ion chelating agents, ACAT inhibitors, MTP inhibitors, lipoxygenase inhibitors, cholesterol absorption inhibitors, PCSK9 modifiers, cholesteryl ester transfer protein inhibitors. Inhibitors) and modifiers of RXRα, GIP receptor agonists, enterostating and enterostatin analogs, amylin and amylin receptor agonists, ghrelin modifiers (e.g., inhibitors), as well as leptin and leptin receptor agonists, pancreatic polypeptide (PP), calcitonin, OXM, neuropeptide 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 embodiment, the pharmaceutical composition may include PYY, PYY(3-36), GLP-1, oxytomodulin, and cholecystokinin, acetyl-CoA carboxylase-(ACC) inhibitor, diacylglycerol O-acyltransferase 1 (DGAT-1) inhibitor, monoacylglycerol O-acyltransferase inhibitor, phosphodiesterase (PDE)-10 inhibitor, AMPK activator, sulfonylurea, meglitinide, α-amylase inhibitor, and α-glucoside hydrolase inhibitor. Quality, α-glucosidase inhibitor, PPARγ agonist, PPARα / γ agonist, biguanide, glucagon-like peptide 1 (GLP-1) modifier, GLP-1 receptor agonist, liraglutide, albiglutide, exenatide, albiglutide, lixisenatide, dulaglutide, semaglutide, protein tyrosine phosphatase-1B (PTP-1B) inhibitor, SIRT-1 activator, dipeptidyl peptidase IV (DPP-IV) inhibitor, insulin sequretagogue, fatty acid oxidation inhibitor, A2 Antagonists, c-jun amino-terminal kinase (JNK) inhibitors, glucokinase activators (GKa), insulin, insulin mimetic, glycogen phosphorylase inhibitors, VPAC2 receptor agonists, SGLT2 inhibitors, glucagon receptor modifiers, GPR119 modifiers, FGF21 derivatives or analogs, TGR5 receptor modifiers, GPBAR1 receptor modifiers, GPR40 agonists, GPR120 modifiers, high affinity nicotinic acid receptor (HM74A) activators, SGLT1 inhibitors, Inhibitors or modifiers of lunithine palmitoyltransferase enzyme, inhibitors of fructose 1,6-diphosphatase, inhibitors of aldose reductase, inhibitors of mineralocorticoid receptors, inhibitors of TORC2, inhibitors of CCR2 and / or CCR5, inhibitors of PKC isoforms (e.g., PKCα, PKCβ, PKCγ), inhibitors of fatty acid synthetase, inhibitors of serine palmitoyltransferase, GPR81, GPR39, GPR43, GPR41, GPR105, Kvl.3. Retinol-binding proteins 4. Inhibitors of glucocorticoid receptors, somatostein receptors, inhibitors or modifiers of PDHK2 or PDHK4, inhibitors of MAP4K4, modifiers of the IL1 family including IL1 beta, HMG-CoA reductase inhibitors, squalene synthetase inhibitors, fibrates, bile acid metal ion chelating agents, ACAT inhibitors, MTP inhibitors, lipoxygenase inhibitors, cholesterol absorption inhibitors, PCSK9 modifiers, cholesteryl ester transfer protein inhibitors and RXRα modifiers This includes one or more active pharmaceutical ingredients and pharmaceutically acceptable excipients selected from the group consisting of GIP receptor agonists, enterostating and enterostatin analogs, amylin and amylin receptor agonists, ghrelin modifiers (e.g., inhibitors), leptin and leptin receptor agonists, pancreatic polypeptides (PP), calcitonin, OXM, neuropeptide Y (NPY), human growth hormone, prolactin, oxytocin, bovine growth hormone, porcine growth hormone, ghrelin, ghrelin receptor antagonists, and glucagon. In this embodiment, these active ingredients may be dispensed in therapeutic doses, and if the second drug is PYY or PYY(3-36), the dose may be from about 2.5 ng to about 2.5 mg. The term “therapeutic dose” refers to a dose in which the pharmaceutically active ingredient can treat, improve or alleviate symptoms, signs, etc., associated with a disease, disorder, or condition. .

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

[0034] For example, the pharmaceutical compositions described herein may include co-solvent stabilizers such as propylene glycol or other suitable co-solvent stabilizers (examples include low molecular weight polyethylene glycol (PEG), e.g., PEG200 and 400, glycerin, and ethanol (alcohol)).

[0035] In another embodiment, the pharmaceutical compositions described herein may include an amino acid stabilizer such as L-arginine or other suitable amino acid stabilizers (e.g., alanine, arginine, aspartic acid, glycine, lysine, proline, and methionine).

[0036] In yet another embodiment, the pharmaceutical compositions described herein may include preservatives such as potassium sorbate or other suitable preservatives (e.g., ascorbic acid, benzyl alcohol, benzoic acid, citric acid, chlorobutanol, m-cresol, glutathione, methionine, methylparaben, propylparaben, sodium sulfite, parahydroxybenzoic acid esters (methylhydroxybenzoic acid and propylhydroxybenzoic acid), boric acid and borates, sorbates other than sorbic acid and potassium, and phenols)).

[0037] In another embodiment, the pharmaceutical compositions described herein may contain antioxidants, such as disodium edetate or other suitable antioxidants (e.g., sodium formaldehyde sulfoxylate, butylated hydroxyanisole, and butylated hydroxytoluene). In another embodiment, the pharmaceutical compositions described herein may contain buffers such as phosphates or other suitable buffers (e.g., acetates, carbonates, citrates, citrate-phosphates, glycine, HEPES, histidine, maleates, phosphates, succinates, tartrates, and triethanolamine (Tris)). In another embodiment, the pharmaceutical compositions described herein may contain surfactants such as polysorbate 20 or other suitable surfactants (e.g., Poloxamer 188 / 407, polysorbate 40 or 80, or sodium lauryl sulfate).

[0038] In yet another embodiment, the excipients include flavorings to enhance compliance with the intake of the pharmaceutical preparation. For example, flavorings can be used to mask bitterness or other undesirable flavor characteristics, or to adapt the pharmaceutical preparation to the flavor of food that may be consumed before or after the pharmaceutical preparation. Suitable flavorings include, for example, apple, banana, bubblegum, cherry, chocolate, grape, lemon, mango, orange, raspberry, strawberry, vanilla, watermelon, mint, or combinations of the above flavors. In yet another embodiment, these flavorings are die-free (also known as colorant-free), sugar-free, hypoallergenic (also known as hypoallergenic), gluten-free, and casein-free.

[0039] In one embodiment, the pharmaceutical compositions described herein include oral (e.g., intraoral, oral mucosa, transmucosal, topical lingual, gargles, mouthwashes (also called oral rinses, mouthwashes, gargles, mouthwashes, etc.), gingival solutions, oral mucosal solutions and oral mucosal suspensions, semi-solid oral mucosal preparations (e.g., including 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 lozenges, troches, buccal preparations, etc.) and pastels (also called lozenges, etc.), compressed lozenges, sublingual tablets and oral tablets (also called intraoral tablets, oral tablets, buccal tablets, etc.), oral mucosal capsules, and mucoadhesive preparations. It is adapted for delivery to preparations. For example, see Oromucosal Preparations (Ph Eur monograph (The European Pharmacopia Monograph) 1807). In another embodiment, PYY in the pharmaceutical composition is adapted to bind to the Y2 receptor.

[0040] The term “suitable for delivery” refers to a pharmaceutical preparation or raw material that is characterized or constituted to preferentially deliver to or bind to a desired area of ​​the body (e.g., mouth, tongue) or target (e.g., receptor). The term “suitable for delivery to the oral cavity” refers to a pharmaceutical preparation that can preferentially deliver PYY(3-36) to the oral cavity, or more specifically, to the tongue, or one or more active substances intended for administration to the oral cavity and / or throat to obtain a topical or systemic effect. See Oromucosal Preparations (Ph Eur monograph 1807) for example. The terms “suitable for binding to receptors” or “suitable for binding to Y2 receptors” refer to satiety peptides, analogs, or other active raw materials that have binding affinity to Y2 receptors or a sufficient residence time on the tongue (e.g., about 30 seconds to about 1 minute) to induce satiety. In one embodiment, “topical oral delivery” may refer to obtaining a topical effect without increasing the level of the active raw material in the plasma.

[0041] In such pharmaceutical preparations, the excipients are oral-compatible for oral delivery, and the active ingredients in the pharmaceutical preparation can maintain their activity in the mouth until they are delivered to their active site. In another embodiment, PYY(3-36) is delivered to the tongue and binds to a Y receptor (e.g., a Y2 receptor).

[0042] In this embodiment, PYY(3-36) can bind to the tongue and transmit signals to the brain via receptors (e.g., Y2 receptors). In another embodiment, PYY(3-36) can be delivered systemically by any suitable route of administration (e.g., orally, parenterally, intravenously, etc.).

[0043] The term “binding” refers to a relationship between PYY(3-36) (or other satiety peptides and metabolic hormones described herein) or a portion of the PYY(3-36) molecule and the Y receptor, mediated by chemical bonds (e.g., ionic, covalent, or hydrophobic) or other chemical or physical attractive bonds between PYY(3-36) or a portion of the PYY(3-36) and the Y receptor, where the relationship between PYY(3-36) and the Y receptor induces a biological response. For example, see Dodds, Receptor binding profiles of NPY analogues and fragments in different tissues and cell lines, Peptides 1995;16(8):1389-94.

[0044] In another embodiment, the pharmaceutical composition includes excipients (e.g., viscosity enhancers, encapsulators, and controlled release agents) that increase the time PYY(3-36) is in contact with the mucous membrane. While not bound by theory, it is thought that increasing the contact time of the pharmaceutical preparation with the mucous membrane results in increased binding of PYY(3-36) to its receptor on the tongue. Suitable excipients for viscosity enhancers include rheology modifiers (also called rheology modifying factors or rheology modifiers), which may also be mucosal adhesives, such as methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, alginic acid, polyvinylpyrrolidone, and sodium carboxymethylcellulose. Suitable excipients for the modified release of PYY(3-36) in the oral cavity include mucosal-adhering penetrating enhancers such as 23-lauryl ether, aprotinin, azone, benzalkonium chloride, cetylpyridinium chloride, cetyltrimethylammonium bromide, cyclodextrin, dextran sulfate, and lauric acid.Other suitable mucosal-adhering polymers used for buccal or intraoral delivery include agarose, chitosan, gelatin, hyaluronic acid, gum (e.g., guar, haca, xanthan gum, gelan, carrageenan, pectin, and sodium alginate), cellulose derivatives (e.g., CMC, thiolated CMC, sodium CMC, HEC, HPMC, MC, methylhydroxyethylcellulose), and poly(acrylic acid)-based polymers (e.g., CP, PC, PAA, polyacrylate, poly(methyl vinyl ether-C)). -Methacrylic acid), poly(2-hydroxyethyl methacrylate), poly(alkyl cyanoacrylate), poly(isohexyl cyanoacrylate), poly(isobutyl cyanoacrylate), copolymer of acrylic acid and PEG, poly(N-2-hydroxypropyl methacrylamide), PHPMAm, polyoxyethylene, PVA, PVP, and other thiolated polymers; scleroglucan, PVA, steroidal detergents, nonionic surfactants, laureth-9, sodium fusidate, sodium lauryl phosphate (included) This includes sodium lauryl (e.g., pH 8.9), palmitoyl carnitine, lauric acid / propylene glycol vehicle, Brij 78, sodium deoxycholate, sodium lauryl sulfate, lecithin, and PVP. See International Journal of Pharmaceutics, Vol. 53, No. 3, August 1, 1989, pp. 227-235 for an example.

[0045] In another embodiment, the pharmaceutical composition includes an excipient that increases the residence time of PYY(3-36) in saliva (e.g., the amount of time PYY(3-36) remains in saliva without significant peptide degradation). Without being bound by theory, it is thought that increasing the residence time of PYY(3-36) in saliva increases the opportunity for PYY(3-36) to bind to receptors on the tongue. The residence time in saliva can be adjusted as needed, for example, to avoid increased systemic exposure to PYY(3-36) through swallowing.

[0046] The term "pharmaceutically acceptable excipients" includes, for example, the following:

[0047] (1) Stabilizers (e.g., cosolvents such as propylene glycol, polyethylene glycol (PEG), glycerin, and ethanol (alcohol)) and amino acids (e.g., alanine, L-arginine, arginine, aspartic acid, glycine, lysine, proline, and methionine).

[0048] (2) Preservatives (examples include potassium sorbate, ascorbic acid, benzyl alcohol, benzoic acid, citric acid, chlorobutanol, m-cresol, glutathione, methionine, methylparaben, propylparaben, sodium sulfite, parahydroxybenzoic acid esters (methylhydroxybenzoic acid and propylhydroxybenzoic acid), boric acid and borates, sorbic acid and sorbates, and phenols).

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

[0050] (4) Buffering agents (examples include phosphates, acetates, carbonates, citrates, citrate-phosphates, glycine, HEPES, histidine, maleates, phosphates, succinates, tartrates, and triethanolamine (Tris));

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

[0052] (6) Rheological modifiers (e.g., methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, alginic acid, polyvinylpyrrolidone, and sodium carboxymethylcellulose);

[0053] (7) Mucosal permeability enhancers (also called mucosal penetration enhancers, mucosal penetration boosters, mucosal penetration enhancers, etc.) (Examples include 2,3-lauryl ether, aprotinin, azone, benzalkonium chloride, 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, such as sucrose, trehalose, mannitol, dextrose, and polyvinylpyrrolidone (PVP) or glycine;

[0055] (9) Flavorings such as apple, banana, bubblegum, cherry, chocolate, grape, lemon, mango, orange, orange swirl, raspberry, strawberry, strawberry swirl, vanilla, walberry swirl, watermelon (including undyed, sugar-free, hypoallergenic, gluten-free, and casein-free versions); and sweetening agents including sucrose, liquid glucose (also known as glucose), glycerol, sorbitol, sodium saccharin, and aspartame; and

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

[0057] Further embodiments provide methods for treating metabolic disorders or abnormalities in subjects. In other embodiments, the metabolic abnormality may be selected from the group consisting of obesity, elevated blood glucose (e.g., elevated blood sugar levels), diabetes mellitus, fatty liver disease, hypertension, PCOS, and multiple sclerosis. In these embodiments, “treatment” or “to treat” refers to administering PYY (e.g., PYY(3-36)) or another PYY analog to a patient having the indicated metabolic abnormality.

[0058] When the metabolic disorder is obesity, the food intake of a subject decreases by at least about 20% after treatment with a certain dose of the pharmaceutical composition compared to an untreated subject. In another embodiment, the body weight of a subject decreases by at least about 5% after treatment with a certain dose of the pharmaceutical composition compared to an untreated subject. In the embodiments described herein, the term “subject” refers to an animal (e.g., human, non-human) that requires treatment for the indicated disease or condition.

[0059] When the metabolic disorder is elevated blood glucose (e.g., prediabetes), the subject's blood glucose or glucose level decreases by at least about 10% after treatment with a dose of the pharmaceutical composition compared to an untreated subject. In another embodiment, fasting glucose levels decrease by at least about 10% after treatment with a dose of the pharmaceutical composition compared to an untreated subject.

[0060] When metabolic abnormalities are the cause of the impairment, the area under the curve (AUC) in the glucose tolerance test (also known as glucose loading test or glucose load test) decreases by at least approximately 15% after treatment with a dose of the pharmaceutical composition compared to untreated subjects. In another embodiment, the HbA1c level in the subjects decreases by at least approximately 15% after treatment with a dose of the pharmaceutical composition compared to untreated subjects.

[0061] When the metabolic disorder is fatty liver disease, the liver fat concentration in the subject decreases to approximately 20% of that in the untreated subject after treatment with a dose of the pharmaceutical composition. In this embodiment, 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 signs of PCOS in the subjects are reduced by at least about 15 to 20% after the dose of the pharmaceutical composition compared to subjects who did not receive the dose. In this embodiment, exemplary signs include, but are not limited to, hormone profiles (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 given), LH2FsH ratio, and testosterone level).

[0063] When the metabolic disorder is multiple sclerosis (MS), the signs of multiple sclerosis are reduced by at least about 20% in subjects after treatment with a dose of the pharmaceutical composition compared to untreated subjects. In this embodiment, the signs include, but are not limited to, the Multiple Sclerosis Functional Composite. For example, see Cutter et al., Development of a multiple sclerosis functional composite as a clinical trial outcome measure, Brain, May 1999;122(Pt 5):871-82.

[0064] When the metabolic disorder is hypertension, the systolic and diastolic blood pressure levels in the subject decrease by at least about 20% after treatment with a dose of the pharmaceutical composition compared to the untreated subject. In this embodiment, for example, treatment may be initiated when the systolic and diastolic blood pressure levels reach 140 mmHg or higher (also referred to as 140 mmHg or greater) or when the diastolic level reaches 90 mm.

[0065] The term "metabolic disorder" refers to a human or animal condition or disease resulting from abnormal function or control of the metabolic system (e.g., obesity, diabetes, fatty liver disease, PCOS, and elevated blood glucose levels). The term "disorder" usually refers to a breakdown of regular bodily structures and functions, or a pathophysiological response to internal or external factors.

[0066] Further embodiments provide a method for enhancing a feeling of fullness in a subject, which involves administering the pharmaceutical composition described herein to the subject. In this embodiment, the dose of PYY, PYY(3-36), or a variant or analog may be about 25 ng, 250 ng, 2.5 μg, 25 μg, 250 μg, or 2.5 mg. In further embodiments, the dose of PYY, PYY(3-36), or a variant or analog may 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 embodiment, the feeling of fullness in the subject may last for at least 30, 60, 90, or 120 minutes after the treatment and after eating. In another embodiment, the pharmaceutical composition is administered to the subject, and then the subject eats a meal.

[0067] In this embodiment, the dose per volume of PYY(3-36) can range from approximately 2.5 ng to approximately 250 μg in volumes from approximately 25 μl to approximately 5 ml, for example. In another embodiment, the dose / volume is 2.5 μg / ml. In yet another embodiment, it is 500 μg / 500 μL. The volume of the pharmaceutical preparation chosen to deliver the dose of PYY(3-36) can be chosen, 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 residence time of PYY(3-36) in the oral cavity and, more specifically, on the tongue.

[0068] The term “eating a meal” refers to a subject eating food with a total calorie intake of at least approximately, for example, 300–2000, 500–1000 calories, or 300–800 calories. The term “satisfaction” refers to a subject’s self-reported satiety after eating a meal, measured, for example, using a VAS scale, where the VAS scale increases by at least approximately 10%. In another embodiment, the VAS scale increases by at least approximately 20%. In yet another embodiment, pre- or post-treatment functional magnetic resonance imaging ("fMRI") scans can be used to measure satiety (by measuring changes in blood flow in specific areas of the brain, such as satiety centers in the brainstem, e.g., the nucleus tractus solitaris, and hypothalamus, e.g., the lateral hypothalamus). In yet another embodiment, the subject may verbally report their level of satiety before or after treatment. In yet another embodiment, the subject may verbally report their level of satiety before or after treatment.

[0069] In one embodiment, a pharmaceutical composition containing PYY(3-36) can be administered to subjects requiring treatment before, after, or during meals. In this embodiment, the pharmaceutical composition can be administered intraorally.

[0070] In one embodiment, the composition can be incorporated into any suitable dosage form (e.g., lozenges, soluble substances, soluble flat sheets, chewing gum, or solid or semi-solid candy). In another embodiment, the composition can be incorporated into a liquid preparation (e.g., emulsion, syrup, elixir, suspension, or solution). In a further embodiment, the composition can be incorporated into an orally administered spray or orally administered drops (also called droplets).

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

[0072] Exemplary PYY(3-36) pharmaceutical preparations [Table 1]

[0073] The exemplary clinical trial was conducted as a dose-escalation design study, with doses ranging from 30 to 40 kg / m³. 2 Approximately 12 evaluable subjects (n to 12) with BMIs received a single dose of placebo, followed by continuous application of the study drug (PYY(3-36) also known as GT-001) directly to the surface of the tongue mucosa using a disposable pipette, and then rinsed out for one day. A total of seven doses were escalated to a dose of 2.5 mg / ml.

[0074] While not bound by theory, food intake is thought to be regulated by two opposing mechanisms: appetite and sexation. Both mechanisms are regulated by the brain-gut axis. Fasting stimulates appetite through the secretion of ghrelin from the stomach. Ghrelin acts on specialized neurons in the arcuate nucleus of the hypothalamus to activate the agouti-associated peptide / NPY (AgRP / NPY) pathway. The AgRP / NPY pathway causes stimulation of 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 sexation hormones in the gastrointestinal tract, including PYY(3-36), oxytomodulin, and glucagon-like peptide-1 (GLP-1). These hormones stimulate the proopiomelanocortin / alpha-melanocyte-stimulating hormone (POMC / αMSH) pathway. The POMC / αMSH pathway stimulates various receptors in the cerebral cortex to generate sensations of sedation and food rewards (Acosta et al., 2014).

[0075] Recently, PYY(3-36) has also been shown to be present in the saliva of both mice and humans. In mice, salivary PYY(3-36) is drawn from the plasma of both mice and is also synthesized in taste cells in the taste buds of the tongue [2]. Furthermore, the congener receptor, Y2R, is expressed in the tongue epithelium (Acosta et al. 2011; Hurtado et al., 2012). In addition, all other YRs (Y1R, Y4R, and Y5R) are richly expressed in multiple tongue 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 demonstrated that augmentation of salivary PYY(3-36) or Exendin-4 resulted in a reduction in 1-hour food intake (Acosta et al., 2011). The effect was peptide-specific; similar studies using neuropeptide Y or amylin did not affect food intake. Furthermore, a dose-response effect was demonstrated. At an even lower dose, 0.3 μg / 100g PYY(3-36), 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 / l 00g PYY(3-36), the reduction was 26%. (PYY(3-36) 3.01±0.06 kcal vs. vehicle 4.10±0.04 kcal, p=0.008). At an even higher dose, 10 μg / 100g PYY(3-36), calorie intake was reduced by a further 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 were significantly higher than those described herein and could cause undesirable side effects and loss of efficacy in humans (e.g., tachyphylaxis - loss of response at even higher doses).

[0077] The effects of PYY are mediated through the activation of specific Y2 receptors expressed in tongue epithelial cells. In long-term studies, including in diet-induced obesity (DIO) mice, sustained increases in PYY(3-36) were achieved using viral vector-mediated gene delivery targeting the salivary glands (Acosta et al., 2014). Chronic increases in salivary PYY(3-36) resulted in significant long-term decreases in food intake and body weight. While enhancement of salivary PYY(3-36) reliably induces a strong anorexic response, it does not produce a taste aversion or nausea substitute in rodents (Hurtado et al., 2013). Salivary PYY(3-36) activates forebrain regions known to mediate feeding, hunger, and sedation, while having minimal effect on brainstem chemoreceptor zones that induce nausea. By comparing neural pathways activated by PYY(3-36) throughout the body versus saliva, metabolic circuits involved in Y2R-positive cells in the tongue and extending through the brainstem nuclei to the Sataiety center in the hypothalamus were identified.

[0078] According to the embodiments disclosed herein, this alternative circuit regulates ingestion behavior without inducing taste aversion (e.g., promoting satisfaction over time). The embodiments described herein provide PYY (e.g., PYY(3-36)) formulations for the treatment of obesity via direct tongue application and without associated nausea.

[0079] Dose escalation study [Table 2]

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

[0081] Figure 1 shows the results of a model study, where PYY(3-36) was administered to 12 subjects. PYY(3-36) was administered to subjects at the prescribed dose (GT-001 dose on the x-axis), and satisfaction (mean value on the y-axis) was assessed by VAS at 30 and 120 minutes post-lunch. As shown in Figure 1, satisfaction was significantly higher than placebo levels at a dose of 25 ng at 120 minutes post-lunch (VAS score of 7), 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 a model study, where the satisfaction level (VAS fullness (mm)) after lunch was plotted by subjects at time after PYY(3-36) treatment (30, 60, 90, and 120 minutes) and at four doses (placebo, 25 ng, 25 μg, and 250 μg). As shown in Figure 2, the 25 μg and 250 μg doses maintained a VAS score outside of 8 up to 120 minutes post-lunch. The 25 ng dose resulted in a VAS score of approximately 8 up to 60 minutes post-lunch.

[0083] Figure 3 shows the normalized concentrations of PYY in pg / ml of plasma in subjects who received placebo, 0.25 mg / ml PYY(3-36), and 2.5 mg / ml PYY(3-36) (each followed by lunch), measured over a time range of up to 4 hours post-administration. As shown, placebo administration and subsequent food consumption induce known and expected endogenous PYY production resulting from a food consumption peak approximately 20 pg / ml above the pre-dose level 1-2 hours post-administration. Administering exogenous PYY(3-36) to subjects does not raise PYY levels in plasma above the levels induced by the placebo / meal combination.

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

[0085] Oral film strips [Table 3] The solvent is removed during the manufacturing process.

[0086] Further embodiments provide exemplary oral film strip dosage forms, as shown in Table 3. In one embodiment, a pharmaceutical composition for an oral film strip is provided, comprising approximately 2.5 ng–2.5 mg of PYY(3-36). In this embodiment, the pharmaceutical composition for the oral film strip may contain approximately 2.5 ng, 25 ng, 250 ng, and 2.5 μg of PYY(3-36). In another embodiment, the pharmaceutical composition for the oral film strip may further include a suitable polymer, plasticizer, sweetener, salivary stimulant, preservative, and optionally, colorants, flavorings, and solvents. For example, see Bala et al., Orally dissolving strips: A new approach to oral drug delivery system, Int J Pharm Investig. (International Journal of Pharmaceutical Investigation). See Tomar, Formulation and Evaluation of Fast Dissolving Oral Film of Dicyclomine as potential route of Buccal Delivery, International Journal of Drug Development & Research, April-June 2012, Vol. 4 Issue 2, ISSN 0975-9344.

[0087] lozenges [Table 4]

[0088] Further embodiments provide exemplary lozenge formulations as shown in Table 4. One embodiment provides a pharmaceutically acceptable lozenge composition containing approximately 2.5 ng–2.5 mg of PYY(3-36). In this embodiment, the lozenge pharmaceutically acceptable composition may contain approximately 2.5 ng, 25 ng, 250 ng, and 2.5 μg of PYY(3-36). In one embodiment, the lozenge formulation comprises PYY(3-36), a vehicle or base, and a suspending agent.

[0089] In these embodiments, suspending agents, sweeteners, and flavoring components are optional. In other embodiments, the vehicle or base of the lozenge may be sugar, made adhesive by admixture with acacia or tragacanth, fruit paste (e.g., made from black or red currants), rose confection, or tolu balsam. An example is Kamini et al., "Formulation and Percentage Evaluation of Gum-Acacia as A Binder WSR to Jwaraghani Gutika (Herbo-Mineral Preparation)," Int J Res Med. 2016;5(1);21-24(2016).

[0090] Lollipop [Table 5]

[0091] Further embodiments provide exemplary lollipop (also known as candy on a stick) dosage forms, as shown in Table 5. In one embodiment, a lollipop pharmaceutical composition may and may be provided comprising about 2.5 ng–2.5 mg of PYY(3-36). In this embodiment, the lollipop pharmaceutical composition comprises about 2.5 ng, 25 ng, 250 ng, and 2.5 μg of PYY(3-36). In one embodiment, the lollipop dosage form comprises PYY(3-36), fillers, buffers, lubricants, and preservatives. Flavorings and sweeteners are optional components. In another embodiment, the lollipop dosage form further comprises maltose-dextrose, water, and corn starch or another binder. For an example, see U.S. Patent Application Publication No. 2007 / 0104763.

[0092] Chewing gum [Table 6]

[0093] Further embodiments provide exemplary chewing gum dosage forms as shown in Table 6. In one embodiment, a chewing gum pharmaceutical composition is provided containing approximately 2.5 ng-2.5 mg of PYY(3-36). In this embodiment, the chewing gum pharmaceutical composition may contain approximately 2.5 ng, 25 ng, 250 ng, and 2.5 μg of PYY(3-36). In one embodiment, the chewing gum dosage form includes PYY(3-36), a gum base, granulators, lubricants, preservatives, and lubricants. Flavorings and sweeteners are optional components. For example, see Aslani et al., Medicated chewing gum, a novel drug delivery system, J. Res Med Sci. (Journal of Research in Medical Sciences) April 2015;20(4):403-411. Alternatively, chewing gum formulations can be created by direct compression. See U.S. Patent No. 7,208,186 for an example. 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.

[0094] Further embodiments provide spray-dried (also known as spray-dried) particulate formulations (e.g., sachets of spray-dried particles) as shown in Table 7-9. These embodiments provide pharmaceutical compositions containing approximately 2.5 ng–2.5 mg of PYY(3–36). Exemplary spray-dried pharmaceutical compositions contain approximately 2.5 ng, 25 ng, 250 ng, and 2.5 μg of PYY(3–36).

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

[0096] Remove the solvent during the manufacturing process.

[0097] In the embodiments shown in Table 7, a drug (e.g., PYY(3-36)) can be mixed with an excipient to form a solution or suspension, and then sprayed to form particles. For example, PYY(3-36) and the excipients in Table 7 can be combined with lactose in a solution or suspension, and then spray-dried, followed by collection of the particles on a filter. See Luhn, Using Excipients In Powder Formulations, Pharmaceutical Technology Europe, Vol. 23, No. 1 (January 7, 2011); and Wu et al., Studies on the spray-dried lactose as carrier for dry powder inhalation, Asian Journal of Pharmaceutical Sciences 9(2014) 336-341.

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

[0099] Remove the solvent during the manufacturing process.

[0100] In the embodiments shown in Table 8, the drug and excipients can be wet-granulated with commercially available spray-dried lactose and then dried. For example, see 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 may be a sachet filled with spray-dried particles.

[0101] Spray-dried particles - Example 3 [Table 9] The solvent is removed during the manufacturing process.

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

[0103] In another embodiment, spray-dried particles, for example, those from Table 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 inhaler, but still large enough to be unlikely to be inhaled and mostly accumulate 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 could be adapted to facilitate the administration of the dose to the tongue. In yet another embodiment, the spray-dried particles could be delivered without a propellant (for example, using a unit dose delivery device, such as the 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 is provided containing about 2.5 ng-2.5 mg of PYY(3-36). In this embodiment, the frozen particle pharmaceutical composition may contain about 2.5 ng, 25 ng, 250 ng, and 2.5 μg of PYY(3-36). In this embodiment, the pharmaceutical composition includes PYY(3-36), fillers, granulators, buffers, preservatives, and solvents / suspending agents. Optional sweeteners and flavorings may 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.

[0107] Alternatively, a frozen PYY(3-36) solution (Table 11 below) can be used to fill the tubes before freezing. Any suitable tube can be used (e.g., polypropylene tubes commonly used for pharmaceuticals, cosmetics, and food). The tube may be flexible, for example, to allow the frozen solution to be dispensed onto the tongue and slowly thawed. In yet another embodiment, the frozen solution can be used in a "blow-fill-seal" dosage form and dispensed in a manner similar to that of an eye drop or mouthwash dispenser. Markarian, "Blow-fill-seal Technology Advances in Aseptic Filling Applications: New advanced aseptic manufacturing technologies are available for filling liquid pharmaceuticals, including biologies," Equipment and Processing Report, June 18, 2014.

[0108] cryogenic solution [Table 11]

[0109] freeze-dried particles [Table 12] The solvent is removed during the manufacturing process. The diluent can be sterile water or 5% dextrose.

[0110] Further embodiments provide exemplary lyophilized particulate dosage forms as shown in Table 12. One embodiment provides a lyophilized particulate pharmaceutical composition containing about 2.5 ng–2.5 mg of PYY(3-36). In this embodiment, the lyophilized particulate pharmaceutical composition may contain 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), an antifreeze / stabilizer, an antioxidant, a buffer, a preservative(s), an optional pH modifier, and a solvent.

[0111] In one embodiment, the lyophilized particles are separated from the diluent in a pre-filled oral syringe having a mixing chamber. See the Vetter-Pharma, Vetter Dual Chamber Systems Website Description for an example. In another embodiment, the lyophilized particles are separated from the diluent using a mixing chamber.

[0112] Oral spray [Table 13]

[0113] Further embodiments provide exemplary oral spray dosage forms as shown in Table 13. In one embodiment, an oral spray pharmaceutical composition is provided containing about 2.5 ng-2.5 mg of PYY(3-36). In this embodiment, the oral spray pharmaceutical composition may contain 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), antioxidants, buffers, preservatives, solvents, optional pH modifiers, and optional flavorings and sweeteners.

[0114] In another embodiment, the oral spray may be a device (CCS with an activator), an oral spray having a vial adapter for the actuator at the time of administration, an oral spray solution poured into a device having an actuator, a pre-filled oral syringe, an oral solution in a blow-filled sealed tube, an oral solution in a vial or a tube having a measuring device (e.g., a dropper, syringe), or a small squeeze bottle for dispensing droplets (e.g., similar to an optical solution).

[0115] Soft gel capsules [Table 14]

[0116] Further embodiments provide exemplary softgel capsule dosage forms as shown in Table 14. One embodiment provides a softgel capsule pharmaceutical composition containing about 2.5 ng–2.5 mg of PYY(3-36). In this embodiment, the softgel capsule pharmaceutical composition may contain 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 shell (e.g., gelatin), a base (e.g., glycerin), a second base (polyethylene glycol), a preservative, a solvent, optional flavorings, colorings, and sweeteners.

[0117] In another embodiment, the softgel capsule may have a removable nib (also called a tip) for opening the capsule and pouring the contents onto the tongue.

[0118] Mouthwash [Table 15]

[0119] Further embodiments provide exemplary mouthwash formulations as shown in Table 15. One embodiment provides a mouthwash (also called a gargle) pharmaceutical composition containing about 2.5 ng-2.5 mg of PYY(3-36). In this embodiment, the mouthwash pharmaceutical composition may contain 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), antioxidants, surfactants, preservatives, and solvents(s). Optional flavorings and sweeteners may also be added.

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

[0121] Further embodiments provide exemplary oral tablet (also known as buccal tablets, buccal tablets, or buccal tablets) dosage forms as shown in Table 16. In one embodiment, an oral tablet pharmaceutical composition is provided containing approximately 2.5 ng-2.5 mg of PYY(3-36). In this embodiment, the oral tablet pharmaceutical composition may contain approximately 2.5 ng, 25 ng, 250 ng, and 2.5 μg of PYY(3-36). In this embodiment, the pharmaceutical composition includes PYY(3-36), a mucosal adhesive(s), a dispersant, a preservative, a lubricant, and a filler or binder. Optional flavorings and sweeteners may also be added. For example, see Shirsand et al., Formulation and optimization of mucoadhesive bilayer buccal tablets of atenolol using simplex design method, Int J Pharm Investig 2012 Jan-Mar;2(1):34-41.

[0122] Oral tablets - Example 2 [Table 17]

[0123] Further embodiments provide exemplary oral tablet forms as shown in Table 17. One embodiment provides an oral tablet pharmaceutical composition containing approximately 2.5 ng-2.5 mg of PYY(3-36). In this embodiment, the oral tablet pharmaceutical composition may contain approximately 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 mucosal adhesive(s), a lubricant, and a diluent, filler, or binder. For example, see Chaudhari et al., Formulation and Evaluation of Buccal Tablet of Salbutamol Sulphate, IRJP 2011, 2(12), 238-242.

[0124] Freeze-dried tablets [Table 18] The solvent was removed during manufacturing.

[0125] Further embodiments provide exemplary lyophilized tablet dosage forms as shown in Table 18. In one embodiment, a lyophilized tablet pharmaceutical composition is provided containing about 2.5 ng-2.5 mg of PYY(3-36). In this embodiment, the lyophilized tablet pharmaceutical composition may contain 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 mucosal adhesive(s), a surfactant, a cryoprotectant / stabilizer, an antioxidant, and a pH modifier and a solvent.

[0126] Orally dissolvable tablets ("ODT") [Table 19]

[0127] Further embodiments provide exemplary ODT tablet dosage forms as shown in Table 19. In one embodiment, an ODT tablet pharmaceutical composition is provided containing approximately 2.5 ng-2.5 mg of PYY(3-36). In this embodiment, the ODT tablet pharmaceutical composition may contain approximately 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), binders(s), disintegrants, lubricants, and optional sweeteners, flavorings, and lubricants.

[0128] In one embodiment, the ODT tablet dosage form is a blended powder system, which is then compressed into tablets using a standard rotary press and packaged in blister packs or bottles depending on the tablet's abrasion tolerance. The finished tablets may have a disintegration time of, for example, 30 seconds or less on the tongue. The levels of flavorings, colorings, and sweeteners can be varied as needed for the end-user experience.

[0129] The compositions described herein may be used to treat patients who require such treatments. As used herein, “treat,” “prevent,” or similar terms do not necessarily imply 100% or complete treatment or prevention. Rather, these terms refer to varying degrees of treatment or prevention of a particular disease as deemed beneficial in this technology (e.g., 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, or 1%). The terms “treat” or “prevent” may also refer to delaying the onset of a disease for a period of time, or delaying its onset indefinitely. The terms “treat” or “to treat” refer to administering a drug or treatment to a patient, or prescribing a drug to a patient, where the patient or a third party (e.g., a caregiver, family member, or healthcare professional) administers the drug or treatment.

[0130] The components of the compositions described herein also include derivatives and analogs. In one embodiment, the terms “derivative” or “analog” include, but are not limited to, ether derivatives, acid derivatives, amide derivatives, ester derivatives, and others of the same kind. Methods for preparing these derivatives are known to those skilled in the art. For example, ether derivatives are prepared by coupling with the corresponding alcohol. Amide and ester derivatives are prepared from the corresponding carboxylic acids by reaction with amines and alcohols, respectively.

[0131] In addition to the dosage forms and preparations described herein, any suitable dosage form may be used for the delivery of the pharmaceutical compositions described herein. In one embodiment, the dosage form is particularly suitable for intraoral or oral mucosal delivery. In another embodiment, the dosage form is a lozenge (e.g., a flat sheet, solid or semi-solid candy). In another embodiment, the dosage form is a gel, cream, foam, orally disintegrating tablet, or paste. The lozenge may contain a soluble substance. In another embodiment, the dosage form includes chewing gum. In yet another embodiment, the dosage form is a liquid preparation (e.g., emulsions, syrups, elixirs, suspensions, or solutions, mouthwashes, gargles, gingival solutions, oral mucosal solutions and oral mucosal suspensions, semi-solid oral mucosal preparations (e.g., gingival gels, gingival pastes, oral mucosal gels, oral mucosal pastes), 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, and mucosal adhesive preparations). In yet another embodiment, the liquid preparation is a spray or drop for oral administration.

[0132] In one embodiment, the compositions or portions thereof described herein may be formulated or used as starting materials for formulation in unit dosage forms such as physiologically acceptable vehicles, carriers, excipients, binders, preservatives, stabilizers, flavorings, etc., as accepted by pharmacopoeia. The amount of active substance (e.g., active pharmaceutical raw material) in a composition or preparation containing the components of the compositions described herein may be such that an appropriate dosage can be obtained within the indicated range as described herein.

[0133] In another embodiment, the components of the compositions described herein can be formulated in unit dosage forms. The term “unit dosage from” refers to a physically distinct unit appropriate as a unit dosage for human subjects and other mammals, each unit containing a predetermined amount of active substance calculated to produce a desired therapeutic effect in conjunction with one or more appropriate pharmaceutical excipients.

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

[0135] Suitable pharmaceutically active materials or vehicles for administering the components of the compositions described herein include any such materials appropriate for a particular mode of administration. In addition, the active material may also be mixed with other active materials that do not impair the desired effect, or with materials that complement the desired effect or have a different effect. The compound may be formulated as the sole pharmaceutically active ingredient in the composition, or in combination with other active ingredients.

[0136] In another embodiment, if the components of the compositions described herein exhibit insufficient solubility, methods for solubilization may be used. Such methods are known and not limited, but include the use of a cosolvent, such as dimethyl sulfoxide (DMSO), the use of a surfactant, such as TWEEN (e.g., polysorbate), and dissolution in aqueous sodium bicarbonate.

[0137] The concentration of the compound is effective for delivering the amount administered that reduces or improves at least one symptom of the disorder to which the compound is administered. Typically, the composition is packaged for single-dose administration.

[0138] In another embodiment, the components of the compositions described herein may be prepared with a carrier that protects them from rapid elimination from the body, such as a time-release formulation or coating (also known as a film). Such carriers include controlled-release formulations, such as, but not limited to, microencapsulated delivery systems. The active compound may include a pharmaceutically acceptable carrier in an amount sufficient to exert a therapeutically useful effect in the patient being treated without the presence of undesirable side effects. The therapeutically effective concentration may be determined empirically by testing the compound in known in vitro and in vivo model systems for the disorder being treated.

[0139] In another embodiment, the components of the compositions described herein may be sealed in multi-dose or single-dose containers. The sealed compounds and compositions may be provided in a kit, which may include components that can be assembled for use, for example. For example, one or more compounds (e.g., PYY, PYY(3-36), or analogs) may be used as a starting material for a lyophilized form (e.g., a lyophilized oral-soluble tablet), and a suitable diluent may be provided as a separate component (also called a component) for a combination prior to use. The kit may include the components of the compositions described herein and a second or third therapeutic agent for simultaneous administration. The components of the compositions described herein and the second or third therapeutic agent may be provided as separate components. The kit may include multiple containers, each holding one or more unit doses of the components of the compositions described herein. In one embodiment, the container may be adapted to the desired mode of administration and is not limited to, but may include, tablets, gel capsules, sustained-release capsules, and other similar products for oral administration; depot products, pre-filled syringes, ampoules, vials, and other similar products for parenteral administration; and patches, medicated pads, creams, and other similar products for topical administration.

[0140] In yet another embodiment, the dosage form is a lyophilized orally soluble tablet. The lyophilized orally soluble tablet can be modified, for example, by the addition of sugars to produce an even higher Tg Add in the lyophilized orally soluble tablet, these sugars include those that produce a Tg (glass transition temperature) higher than room temperature. For example, see Elnggar et al., Maltodextrin: A Novel Excipient Used in Sugar-Based Orally Disintegrating Tablets and Phase Transition Process. AAPS PharmSciTech June 2010;11(2):645-651 (April 20, 2010).

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

[0142] In another embodiment, the active ingredient may be administered in a single dose or divided into several smaller doses administered at time intervals. It is understood that the exact dosage and duration of treatment are functions of the disease being treated and can be determined empirically using known test protocols or by extrapolating from in vivo (also known as in vivo) or in vitro (also known as in vitro, in vitro, etc.) test data. It should be noted that the values ​​of concentration and dosage may also vary depending on the severity of the condition being alleviated. For any particular subject, a specific treatment plan should be adjusted over time in accordance with the individual needs and the professional judgment of the person managing or supervising the administration of the composition, and it is further understood that the concentration ranges described herein are exemplary only and are not intended to limit the range or practice of the claimed composition.

[0143] When oral administration is preferred, the compound can be provided 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 intestines. The composition can also be formulated in combination with antacids or other such raw materials.

[0144] Oral compositions will generally contain an inert diluent or edible carrier and may optionally be freeze-dried and compressed into tablets or encapsulated in gelatin capsules. For the purpose of oral therapeutic administration, the active compound or group of compounds may be incorporated with excipients and used in the form of tablets, capsules, or lozenges. Pharmaceutically compatible binders and adjuvants may be included as part of the composition.

[0145] Tablets, pills, capsules, lozenges, and other similar products may contain any of the following raw materials or compounds of similar properties: binders, such as gum, tragacanth, acacia, corn starch, or gelatin (not limited); excipients, such as microcrystalline cellulose, starch, or lactose (not limited); disintegrants, such as alginic acid and corn starch (not limited); lubricants, such as magnesium stearate (not limited); glidants, such as colloidal silicon dioxide (not limited); sweeteners, such as sucrose or saccharin (not limited); and flavoring agents, such as peppermint, methyl salicylate, or fruit flavorings.

[0146] When the drug unit form is a capsule, it may contain, in addition to the above-mentioned types of substances, a liquid carrier, such as fatty oil. Additionally, the drug unit form may include various other materials that modify the physical form of the drug unit, such as sugar coatings and other enteric-coated drugs. The compound may also be provided as an ingredient in elixirs, suspensions, syrups, wafers (also known as wafers, edible film, cachets, etc.), chewing gum, or other such substances. In addition to the active compound, the syrup may contain sucrose as a sweetener, as well as certain preservatives, pigments and colorants, and flavorings.

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

[0148] In one embodiment, a solution or suspension used for parenteral, pump-delivery, intradermal, subcutaneous, or topical application may contain any of the following components: sterile diluents, such as water for injection; saline solution (also called saline solution, physiological saline, etc.); fixing oils, naturally occurring vegetable oils, such as sesame oil, coconut oil, peanut oil, cottonseed oil, and others of the same kind; or synthetic fatty vehicles, such as ethyl oleate, and others of the same kind; polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; antimicrobial agents, such as benzyl alcohol and methylparaben; antioxidants, such as ascorbic acid and sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid (EDTA) or its disodium salt; buffering agents, such as acetates, citrates, and phosphates; and agents for adjusting tonicity, such as sodium chloride and dextrose. Parenteral preparations can be enclosed in ampoules, disposable syringes (also known as syringe barrels, etc.), or multi-dose vials made of glass, plastic, or other suitable material. Buffers, preservatives, antioxidants, and other similar substances may be incorporated as needed.

[0149] When administered intravenously, suitable carriers include, but are not limited to, solutions containing physiological sarin, phosphate-buffered sarin (PBS), and thickeners and solubilizers such as glucose, polyethylene glycol, polypropylene glycol, and mixtures thereof. Liposome suspensions containing tissue-targeted liposomes may also be suitable as pharmaceutically acceptable carriers. These can be prepared according to methods known in this technique.

[0150] In another embodiment, the components of the compositions described herein may be prepared together with a carrier that protects the compound from rapid elimination from the body, such as a time-release preparation or coating. Such carriers include controlled-release preparations, such as, but not limited to, implants and microencapsulated delivery systems, as well as biodegradable, biocompatible polymers, such as collagen, ethylene vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid, hydroxypropyl methylcellulose (HPMC), other cellulose derivatives, and others of the same kind. Methods for preparing such preparations are known to those skilled in the art.

[0151] In yet another embodiment, the compounds used in the methods of the present disclosure may be administered enterally or parenterally. When administered orally, the compounds used in the methods of the present disclosure may 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 such as tablets and capsules, as well as liquid dosage forms such as solutions, suspensions, and elixirs. When solid dosage forms are used, they may be sustained-release, so that the compounds used in the methods described herein only need to be administered once or twice daily.

[0152] Oral dosage forms may be administered to the patient one, two, three, or four times daily, or as needed. The components of the compositions described herein may be administered up to three times daily, or once or twice daily. Whichever oral dosage form is used, it may be designed to protect the compounds employed in the method described herein from the acidic environment of the stomach. Enteric-coated tablets and capsules filled with spheres may also be coated, each to protect from the acidic stomach, and may be used in the manner familiar to those skilled in this art and described herein.

[0153] The terms “therapeutic dose” and “therapeutic duration” are used to indicate the dose and duration of treatment that are effective in treating, improving, or alleviating the conditions or signs described herein.

[0154] Those skilled in this technique will recognize that the therapeutic effects resulting from even lower effective concentrations of the components of the compositions described herein may vary significantly depending on the tissue, organ, or specific animal or patient being treated. It will also be understood that while a patient may be initiated with a certain dose, that dose may vary over time as the patient's condition changes.

[0155] It should be obvious to a practitioner of this technique that the precise dosage and frequency of administration depend on the specific compound used in the method of administration of this disclosure, the specific condition being treated, the severity of the condition being treated, age, weight, the general physical condition of the particular patient, and other medications the individual is taking, as is well known to the presiding physician who is skilled in this technique. [Examples]

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

[0157] Day 1 (Check-in to study unit and placebo management)

[0158] Participants were found to have completed all screening procedures, met all inclusion and exclusion criteria outlined in the protocol, and were eligible for the study registry to check in to the study unit (i.e., study facility). On the morning of the study, participants fasted before arriving at the study unit (SU). Participants fasted for at least 12 hours prior to the first day of the study. Participants were permitted to drink water and brush their teeth before arriving at the study unit (SU). The following assessments and measurements were performed.

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

[0160] (2) Update the medical history and medication history prior to placebo administration.

[0161] (3) Assess the health status. If the person involved has either rhinitis or a gastrointestinal disorder, the person involved will be suspended for that day.

[0162] (4) Measure weight and BMI.

[0163] (5) Measure vital signs (BP (blood pressure), HR (heart rate), and body temperature). BP and HR were measured twice in a seated position and twice in a standing position. If baseline seated BP was high (>160 systolic), the relevant person was seated for 5-10 minutes before the BP was rechecked. Body temperature was measured once.

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

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

[0166] (8) Water was provided “freely,” and the volume was recorded.

[0167] (9) Four hours after breakfast, a Visual Analog Scale (VAS) was administered to assess Appetite and Satiety.

[0168] (10) Insert a cannula to obtain a blood sample, take a 5 ml blood sample, and screen for anti-GT-001 antibody.

[0169] (11) Take a fasting PK blood sample #1 (5 ml) 15 minutes before the placebo.

[0170] (12) Before administering GT-001, perform a water mouthwash. The mouthwash may be a rinse with 20 ml of water.

[0171] (13) Five minutes before lunch, pipette one milliliter (1 ml) of placebo (a preparation that does not contain GT-001) onto the tongue of the person concerned.

[0172] (14) The solution was left on the tongue for one minute, then moved quickly towards the subject, and then swallowed.

[0173] (15) Complete the VAS for like-lines (also called similar lines, etc.) (VAS completed depending on the subject).

[0174] (16) Collect PK blood samples seven times after each dose, at ±1 minute at 5, 10, 15, and 30 minutes post-dose, and at ±5 minutes at 60, 120, and 240 minutes post-dose.

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

[0176] (18) Provide a “free” lunch (consisting of a casserole, energy drink and two cookies), and record the calorie intake.

[0177] (19) Participants are asked to complete a VAS questionnaire 20 minutes after completing their meal, asking about sweetness, sourness, bitterness, saltiness, umami, and fat taste.

[0178] (20) Two hours after completing the meal, record the VAS score for appetite and satiety every 30 minutes.

[0179] (21) Release the subjects. The subjects were allowed to eat "freely" until a 12-hour fasting period prior to their next research visit.

[0180] (22) During SU visits, subjects were restricted from consuming gum, candy, cigarettes, or carbonated beverages, and from performing exercise. During meals, subjects were not exposed to food cues (sight, smell, or hearing), and they had to be eaten alone.

[0181] The treatment dates 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 should rest at home.

[0184] Study completed (Day 15 and early termination visit)

[0185] If a registered subject completes days 1-14, or discontinues research before the planned SU release, they have completed the following:

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

[0187] (2) Update the patient's 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 a seated position and twice in a standing position. If BP was high (>160 systolic) in a seated position at baseline, the relevant person was seated for 5-10 minutes and then the BP was rechecked. Body temperature was measured once.

[0190] (5) Measure weight and BMI.

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

[0192] (7) Perform clinical tests (blood biochemistry tests (also called serum chemistry), hematological tests, and urinalysis)

[0193] (8) Measure the GT-001 serum level using an anti-GT-001 antibody.

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

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

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

[0197] (a) Breakfast: Participants were provided with a balanced breakfast of macronutrients (approximately 325-400 calories). Participants selected their type of breakfast from among eggs, cereal, toast, etc. Juice, milk, and coffee were permitted within the allocated calorie limit. Artificial sweeteners were not permitted.

[0198] (b) Lunch: All participants were provided with a casserole, juice / milk, and two cookies. Total food intake and VAS appetite and satiety were recorded. Artificial sweeteners were not permitted.

[0199] (c) Between meals: Those concerned are only allowed to drink water between meals. Those concerned are restricted from consuming gum, candy, cigarettes, and carbonated drinks.

[0200] Example 2 - VAS evaluation

[0201] The following exemplary VAS assessments were given to subjects to evaluate their satisfaction before and after receiving PYY(3-36) or placebo, and before or after eating the various doses described herein. Participants responded on a scale of 1-10, with 1 representing the strongest response on the left and 10 representing the strongest response on the right. For example, a response of 1 to question a indicates they were not hungry at all. A response of 10 to question a indicates they were never hungrier. A response of 5 indicates they felt somewhere between "I am not hungry at all" and "I have never been more hungry." Numerical responses on the 1-10 scale were presented in a table and used to plot the graphs in Figures 1 and 2. [ka] References

[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. Lancet 2014. 2. Acosta A, Abu Dayyeh BK, Port JD, Camilleri M. Recent advances in clinical practice challenges and opportunities in the management of obesity. Gut 2014;63:687-695 3. Delgado-Aros (S), Kim (DY), Burton (D), et al., Effect of GLP-1 on gastric volume, emptying, maximum volume ingested, and postprandial symptoms in humans. American Journal of Physiology: Gastrointestinal and Liver Physiology 2002;282:31 4. van Can J, Sloth B, Jensen C, 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. International Journal of Obesity 2014;38:784-793 5. Peters, A. Incretin-based therapies: review of current clinical trial data. The American Journal of Medicine 2010;123:S28-37 6. Verdich C, Flint A, Gutzwiller J et al., A meta-analysis of the effect of glucagon-like peptide-1(7-36)amide on ad libitum energy intake in humans. The Journal of Clinical Endocrinology & Metabolism 2001;86:4382-4389. 7. Bray G, Ryan D. Update on obesity pharmacotherapy. Annals 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 glycemia in type 2 diabetes. Regulatory Peptides 2008;151:123-129 9. Moreno J, Willett K, Desilets A. Exenatide as a novel weight loss modality in patients without diabetes. Ann Pharmacother (The Analyses of Pharmacotherapy) 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 (Journal of Neuroendocrinology) 2008;20:834-841 13. Jayasena CN, Bloom SR. Role of Gut Hormones in Obesity. Endocrinology & Metabolism Clinics of North America 2008;37:769-787 14. Koda S, Date Y, Murakami N, et al. The role of the vagal nerve in peripheral PYY(3-36)-induced feed reduction in rats. Endocrinology 2005;146:2369-2375 15. le Roux (CW), Batterham (RL), Aylwin (SJ), et al., Attenuated peptide YY release in obese subjects is associated with reduced satiety. Endocrinology 2006;147:3-8 16. Lenard (NR), Berthoud (HR). Central and Peripheral Regulation of Food Intake and Physical Activity: Pathways and Genes. Obesity 2008;16:S11-S22 17. Ogden CL, Yanovski SZ, Carroll MD, Flegal KM. The epidemiology of obesity. Gastroenterology 2007;132:2087-2102

Claims

1. A pharmaceutical composition comprising peptide YY (PYY) in a dose of approximately 2.5 μg to approximately 250 μg, and a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient is selected from the group consisting of stabilizers, preservatives, antioxidants, buffers, surfactants, rheology modifiers, and mucosal permeability enhancers, and the pharmaceutical composition is formulated as a non-systemic orally soluble tablet suitable for topical intraoral delivery.

2. The pharmaceutical composition according to claim 1, wherein the peptide YY (PYY) is PYY(3-36).

3. The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutical composition is suitable for local delivery to the tongue.

4. Glucagon-like peptide 1 (GLP-1), oxytomodulin (OXM), cholecystokinin acetyl-CoA carboxylase (ACC) inhibitor, diacylglycerol O-acyltransferase 1 (DGAT-1) inhibitor, monoacylglycerol O-acyltransferase inhibitor, phosphodiesterase (PDE)-10 inhibitor, AMP-activated protein kinase (AMPK) activator, sulfonylurea, meglitinide, α-amylase inhibitor, α-glucoside hydrolase inhibitor, α-glucosidase inhibitor Peroxisome proliferator-activated receptor gamma (PPARγ) agonist, PPARα / γ agonist, biguanide, GLP-1 modifier, GLP-1 receptor agonist, liraglutide, albiglutide, exenatide, lixisenatide, dulaglutide, semaglutide, protein tyrosine phosphatase-1B (PTP-1B) inhibitor, sirtuin 1 (SIRT-1) activator, dipeptidyl peptidase IV (DPP-IV) inhibitor, insulin secretagogue, fatty acid oxidation inhibitor, A2 antagonist, c-jun amino terminus Kinase (JNK) inhibitors, glucokinase activators (GKa), insulin, insulin mimetic, glycogen phosphorylase inhibitors, vasoactive intestinal peptide receptor 2 (VPAC2) receptor agonists, sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon receptor modifiers, G protein-coupled receptor 119 (GPR119) modifiers, fibroblast growth factor 21 (FGF21) derivatives or analogs, Takeda G protein-coupled receptor 5 (TGR5) receptor modifiers, G protein-coupled bile acid receptor 1 (GPBA) R1) Receptor modifiers, G protein-coupled receptor 40 (GPR40) agonists, G protein-coupled receptor 120 (GPR120) modifiers, high-affinity nicotinic acid receptor (HM74A) activators, sodium-glucose cotransporter 1 (SGLT1) inhibitors, carnitine palmitoyltransferase enzyme inhibitors or modifiers, fructose 1,6-diphosphatase inhibitors, aldose reductase inhibitors, mineralocorticoid receptor inhibitors, rapamycin target kinase polyprotein complex (TORC2) inhibitors,Inhibitors of CC chemokine receptor type 2 (CCR2) and / or CC chemokine receptor type 5 (CCR5), inhibitors of protein kinase C (PKC) isoforms (e.g., PKCα, PKCβ, PKCγ), inhibitors of fatty acid synthetase, inhibitors of serine palmitoyltransferase, modifiers of G protein-coupled receptor 81 (GPR81), modifiers of G protein-coupled receptor 39 (GPR39), modifiers of G protein-coupled receptor 43 (GPR43), modifiers of G protein-coupled receptor 41 (GPR41), G protein Modifiers of protein-coupled receptor 105 (GPR105), modifiers of voltage-opening potassium channel (Kvl.3), retinol-binding protein 4, glucocorticoid receptor, somatostatin receptor, inhibitors or modifiers of pyruvate dehydrogenase kinase isoform 2 (PDHK2) or pyruvate dehydrogenase kinase isoform 4 (PDHK4), inhibitors of mitogen-activated protein kinase kinase kinase 4 (MAP4K4), modifiers of the IL1 family including interleukin-1 (IL1) beta, 3-hydro Xy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, squalene synthetase inhibitor, fibrate, bile acid metal ion chelating agent, acyl-CoA / cholesterol acyltransferase (ACAT) inhibitor, microsomal triglyceride transport protein (MTP) inhibitor, lipoxygenase inhibitor, cholesterol absorption inhibitor, proprotein convertase subtilisin / kexin type 9 (PCSK9) modifier, cholesteryl ester transfer protein inhibitor, and retinoid X receptor α (RXRα) The following are further active pharmaceutical ingredients selected from the group consisting of ) modifiers, gastric inhibitory polypeptide (GIP) receptor agonists, enterostatins and enterostatin analogs, amylin and amylin receptor agonists, ghrelin modifiers (e.g., inhibitors), leptin and leptin receptor agonists, pancreatic polypeptides (PP), calcitonin, neuropeptide Y (NPY), human growth hormone, prolactin, oxytocin, bovine growth hormone, porcine growth hormone, ghrelin, ghrelin receptor antagonists, and glucagon.A pharmaceutical composition according to any one of claims 1 to 3.

5. The pharmaceutical composition according to claim 1, wherein the preservative comprises methylparaben or propylparaben.

6. The pharmaceutically acceptable composition according to claim 1, wherein the stabilizer comprises mannitol or sucrose.

7. The pharmaceutical composition according to claim 1, wherein the mucosal permeability enhancer comprises gelatin.

8. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable excipient further comprises a flavoring agent or a sweetener.

9. The pharmaceutical composition of claim 8, wherein the sweetener comprises sorbitol, sucrose, or aspartame.

10. A pharmaceutical composition according to any one of claims 1 to 9, for use in treating obesity or elevated blood glucose in a subject.

11. The pharmaceutical composition according to claim 10, for use when applying the pharmaceutical composition to the oral cavity of the subject.

12. A pharmaceutical composition according to any one of claims 1 to 9, for use in inducing a feeling of satisfaction in a subject for at least 120 minutes after eating.

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