Methods for preventing and treating obesity and related conditions and disorders

Abstract

The present invention recognizes that there is a need for the prevention or treatment of obesity, glycemic control, and other metabolic disorders. A first aspect of the present invention generally relates to methods for the prevention or treatment of obesity, glycemic control, and other metabolic disorders using a plurality of pharmaceutical compositions. A second aspect of the present invention generally relates to monotherapy or combination therapy for the prevention or treatment of obesity, glycemic control, other metabolic disorders, and combinations thereof.

Description

[0001] Cross-references to related applications

[0002] This application:

[0003] Claims priority interest in U.S. Provisional Application Serial No. 63 / 623,955, filed January 23, 2024;

[0004] Claims priority interest in U.S. Provisional Application Serial No. 63 / 661,027, filed June 17, 2024;

[0005] Claims priority to U.S. Provisional Application Serial No. 63 / 702,841, filed October 3, 2024; and

[0006] Claims priority interest in U.S. Provisional Application Serial No. 63 / 744,272, filed January 12, 2025;

[0007] Each of them is incorporated into this article in its entirety through citation. Technical Field

[0008] This invention generally relates to the treatment and prevention of obesity, blood sugar control and other metabolic disorders. Background Technology

[0009] Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to a degree that can negatively impact health. A person is classified as obese when their body mass index (BMI) (weight divided by the square of height) exceeds 30 kg / m²; the range of 25 to 30 kg / m² is defined as overweight. Some East Asian countries use lower values ​​to calculate obesity. Obesity is a leading cause of disability and is associated with a variety of diseases and conditions, particularly cardiovascular disease, type 2 diabetes, obstructive sleep apnea, certain types of cancer, and osteoarthritis.

[0010] Obesity has individual, socioeconomic, and environmental causes. Some known causes include diet, physical activity, automation, urbanization, genetic predisposition, medications, mental disorders, economic policies, endocrine disorders, and exposure to endocrine-disrupting chemicals.

[0011] Obesity is a leading preventable cause of death worldwide, with rising rates among adults and children. According to the World Health Organization (WHO), in 2016, more than 1.9 billion adults aged 18 and over were overweight. Of these, more than 650 million were obese. In 2016, 39% of adults aged 18 and over were overweight, and 13% were obese. The majority of the world's population lives in countries where overweight and obesity cause more deaths than underweight. In 2020, 39 million children under the age of five were overweight or obese. In 2016, more than 340 million children and adolescents aged five to 19 were overweight or obese (see WHO Obesity and Overweight Fact Sheet, June 2021).

[0012] Obesity is associated with impaired normal GH (growth hormone) secretion and a weakened response to all stimuli, such as GH-releasing hormone (GHRH), hypoglycemia, L-DOPA, arginine, glucagon, physical exercise, and sleep (see William T, Berelowitz M, Joffe SN, Thorner MO, Rivier J, Vale W, Frohman LA. Impaired growth hormone responses to growthhormone-releasing factor in obesity. A pituitary defect reversed with weight reduction. N Engl J Med 1984; 311: 1403-1407).

[0013] Given the well-known deficiency of GH secretion in obesity, GH-dependent insulin-like growth factor (IGF)-1 concentrations are expected to be lower than normal in obese individuals. Circulating IGF-1 is primarily bound in a ternary 150 kDa complex composed of IGF-1, IGF-binding protein (IGFBP)-3, and an acid-labile subunit. Therefore, IGFBP-3 and IGF-1 have relatively long circulating half-lives and, due to their GH-dependent nature, represent stable indicators of long-term changes in GH availability and function. IGFBP-2 is the second most abundant IGF-binding protein in serum. Serum IGFBP-2 concentrations are known to be negatively correlated with GH secretion, increasing in GH-deficient states and decreasing in GH-excess states. These reports suggest that measuring IGFBP-2 could be helpful in detecting GH deficiency. In contrast, serum IGFBP-1 concentrations are lower than those of IGFBP-3 and IGFBP-2 and are acutely regulated by dietary intake and fluctuations in serum insulin and glucose concentrations. Due to this unique property, IGFBP-1 is believed to play an important role in the acute regulation of IGF-1 availability.

[0014] A small fraction of circulating IGF-1 is detected in a free or readily dissociable state, which is considered to be the metabolically active form. The amount of free / dissociable IGF-1 in serum depends on the complex interaction between the production rate and concentration of IGF-1 and IGFBP.

[0015] Cyclic glycine-proline (cGP) is a small metabolite naturally cleaved from the N-terminus of IGF-1. cGP has neuroprotective effects and improves brain development and function after peripheral administration (Tran, US Patent 7232798). cGP is also known to regulate the bioavailability of circulating IGF-1 by competitively binding to insulin-like growth factor binding protein (IGFBP)-3 with IGF-1. (See GuanJ, Singh-Mallah G, Liu K, Thorstensen E, Shorten P, Mitchell EA, Taylor R, Harris P, Brimble M, Thompson JMD, Murphy R. The role for cyclic Glycine-Proline, a biological regulator of insulin-like growth factor-1 in pregnancy-related obesity and weight changes. J Biol Regul Homeost Agents. 2018 May-Jun;32(3):465-478. PMID: 29921371).

[0016] This competitive binding is concentration-dependent, therefore lower IGFBP-3 and higher cGP increase the bioavailable IGF-1 (Guan et al., 2018). Endogenous cGP in brain tissue (Gudasheva et al., 1996) is produced by the same enzyme that cleaves cGP from plasma IGF-1 (Yamamoto and Murphy, 1995).

[0017] IGF-I is mainly synthesized in the liver under the stimulation of growth hormone (GH) and usually binds to IGF-binding protein 3 (IGFBP-3) in circulation (see Jones JI, Clemmons DR. Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev 1995; 16:3-34 (PubMed)(Google Scholar)).

[0018] In fact, several studies have reported that free IGF-I is elevated in obesity, while total IGF-I concentration remains within the reference range or even at the lower end of the normal range, and normalizes after weight loss (see Nam SY, Lee EJ, Kim KR, et al. Effect of obesity on total and free insulin-like growth factor (IGF)-1, and their relationship to IGF-binding protein (BP)-1, IGFBP-2, IGFBP-3, insulin, and growth hormone. Int J Obes Relat Metab Disord 1997;21:355-359 (PubMed)(Google Scholar)) (see Rasmussen MH, Hvidberg A, Juul A, et al. Massive weightloss restores 24-hour growth hormone release profiles and serum insulin-like growth factor-I levels in obese subjects. J Clin Endocrinol Metab 1995;80:1407-1415 (PubMed) (Google Scholar)).

[0019] Glucagon-like peptide-1 (GLP-1) is classified as a peptide hormone with a 30-amino acid sequence. It is produced and secreted by intestinal epithelial endocrine L cells, pancreatic α cells, and neuronal units in the CNS. GLP-1 receptors are present throughout the brain, primarily in the arcuate nucleus, paraventricular nucleus, and dorsomedial nucleus of the hypothalamus, as well as the central amygdala (Cork et al., 2015).

[0020] Glucagon-like peptide-1 (GLP-1) is an endogenous intestinal hormone and a key regulator of glucose homeostasis by stimulating insulin secretion. Its natural cleavage product, GLP-1(9-36), was previously considered a "biologically inactive" metabolite primarily due to its low affinity for the GLP-1 receptor, but it possesses unique properties, such as cardiovascular protective effects. Immunoprecipitation assays have shown that GLP-1(9-36) directly interacts with the IGF-1 receptor in astrocytes. Western blot data indicate that GLP-1(9-36) activates the IGF-1 receptor and the downstream PI3K-AKT pathway in astrocytes following OGD / R injury, which can be eliminated by pre-incubation with apodophyllotoxin, an inhibitor of IGF-1 receptor autophosphorylation. This suggests that GLP-1(9-36) improves stroke outcomes by reducing inflammation in astrocytes through its interaction with the IGF-1 receptor.

[0021] Based on the above data, it can be inferred that the IGF-1 and GLP-1 signaling mechanisms in the brain may be beneficial in the treatment of various neurological diseases. The protective effects of these two cellular targets in the brain are significant and will serve as the basis for future neurological research.

[0022] Gastric inhibitory polypeptide (GIP), also known as glucose-dependent insulinotropic polypeptide, is an inhibitory hormone in the secretin hormone family. Although it is a weak inhibitor of gastric acid secretion, its main function as an incretin is to stimulate insulin secretion.

[0023] GIP, along with glucagon-like peptide-1 (GLP-1), belongs to a class of molecules known as incretins, which stimulate insulin release upon oral food intake. GIP is known to inhibit apoptosis of pancreatic β-cells and promote their proliferation. It also stimulates glucagon secretion and fat accumulation. GIP receptors are expressed in many organs and tissues, including the central nervous system, enabling GIP to influence hippocampal memory formation and the regulation of appetite and satiety.

[0024] The relationship between IGF-1, IGP-1, GIP, and glucagon can be summarized as follows: Insulin and glucagon help maintain blood glucose levels. Glucagon helps prevent blood glucose from dropping too low, while insulin prevents it from rising too high. Free insulin-like growth hormone (IGF-I) is elevated in obesity, which plays a key role in weight loss. Glucagon-like peptide-1 (GLP-1) is a key regulator of glucose homeostasis by stimulating insulin secretion. GLP-1 and IGF-1 are interconnected and play major roles in metabolic function, used to treat diabetes and obesity. GIP is an incretin hormone produced in the gastrointestinal tract in response to nutrients. IGF-1 regulates GIP secretion to balance food dependence. Summary of the Invention

[0025] The present invention recognizes the need for the prevention or treatment of obesity, blood sugar control and other metabolic disorders.

[0026] The first aspect of the present invention generally relates to a method for preventing or treating obesity, blood sugar control, other metabolic disorders, and combinations thereof using a variety of pharmaceutical compositions.

[0027] The second aspect of the invention generally relates to pharmaceutical compositions for the prevention or treatment of obesity, blood glucose control, other metabolic disorders, and combinations thereof. Attached Figure Description

[0028] Figure 1 Overall, the changes in body weight relative to baseline at week 12 are shown as a function of cPG concentration. **p < 0.001 vs. placebo; ***p < 0.0001 vs. placebo.

[0029] Figure 2 Overall, the weight changes of cPG, cGAL, cGMeP, and smegglutinin vs. the carrier are shown.

[0030] Figure 3 Overall, the changes in blood glucose levels for cPG, cGAL, cGMeP, and smegglutinin versus the carrier are shown.

[0031] Figure 4 Overall, changes in plasma triglycerides were shown for cPG, cGAL, cGMeP, and smegglutinin versus the carrier.

[0032] Figure 5 Overall, changes in liver triglycerides were shown for cPG, cGAL, cGMeP, and smegglutinin vs. the carrier.

[0033] Figure 6 Overall, the weight changes of cPG, cGAL, cGMeP, and smegglutinin vs. the carrier are shown.

[0034] Figure 7 Overall, the changes in blood glucose levels for cPG, cGAL, cGMeP, and smegglutinin versus the carrier are shown.

[0035] Figure 8 Overall, changes in plasma triglycerides were shown for cPG, cGAL, cGMeP, and smegglutinin versus the carrier.

[0036] Figure 9 Overall, changes in liver triglycerides were shown for cPG, cGAL, cGMeP, and smegglutinin vs. the carrier. Detailed Implementation

[0037] definition

[0038] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Generally, the nomenclature used herein and the laboratory procedures for cell culture, chemistry, microbiology, molecular biology, cell science, and cell culture described below are well-known and commonly used in the art. These procedures use conventional methods, such as those provided in the art and in various common references. When a term is provided in the singular, the plural form of that term is also included; and when a term is provided in the plural form, the singular form of that term is also included. The nomenclature used herein and the laboratory procedures described below are those well-known and commonly used in the art. As used throughout this disclosure, unless otherwise stated, the following terms should be understood to have the following meanings:

[0039] "Direct" refers to a direct causal relationship in a process that does not require intermediate steps.

[0040] "Indirect" refers to requiring an indirect causal relationship in the intermediate steps.

[0041] "Approximately" means plus or minus 10% of the indicated value.

[0042] Other technical terms used in this article have their common meaning in the field of their application, as illustrated in several technical dictionaries.

[0043] introduction

[0044] The present invention recognizes the need for the prevention or treatment of obesity.

[0045] As a non-limiting introduction to the breadth of the invention, the invention includes several general and useful aspects, including:

[0046] 1) Methods of using a combination of multiple drugs to prevent or treat obesity, blood sugar control, and other metabolic disorders;

[0047] 2) Pharmaceutical compositions for the prevention or treatment of obesity, blood sugar control and other metabolic disorders.

[0048] These aspects of the invention, as well as other aspects described herein, can be achieved by using methods, articles, and compositions based on the subject matter described herein. To fully understand the scope of the invention, it will be further appreciated that various aspects of the invention can be combined to form ideal embodiments of the invention.

[0049] I. Methods for the prevention or treatment of obesity, blood sugar control, other metabolic disorders, or combinations thereof

[0050] This invention includes methods for preventing or treating obesity, blood sugar control, other metabolic disorders, or combinations thereof, and related conditions and disorders using a variety of pharmaceutical compositions.

[0051] A first aspect of the invention includes a method for preventing or treating obesity, glycemic control, other metabolic disorders, or combinations thereof, the method comprising: a) providing a subject requiring prevention or treatment of obesity; b) providing at least one pharmaceutical composition comprising one or more of the following components: 1) at least one cPG compound, optionally in combination with; 2) at least one GLP-1 compound; or 3) combinations thereof, wherein the components are administered together or separately; furthermore, wherein the components are provided together or separately; c) administering to the subject a pharmaceutically effective amount of the at least one pharmaceutical composition; wherein the subject obtains prevention or treatment of obesity, glycemic control, other metabolic disorders, or combinations thereof.

[0052] A. Components

[0053] One aspect of the invention includes the provision of the components in a pharmaceutically acceptable diluent, adjuvant, excipient, or combination thereof.

[0054] Another aspect of the invention includes the provision of a pharmaceutically acceptable salt.

[0055] Another aspect of the invention includes the separate application of the components.

[0056] B. Prevention / treatment of obesity, blood sugar control, other metabolic disorders, or combinations thereof

[0057] Obesity is a highly prevalent, chronic, and relapsing disease requiring long-term management. Lifestyle modifications are recommended as the foundation of treatment for overweight or obese individuals, but they typically only achieve moderate weight loss, which often rebounds. Furthermore, weight loss is difficult to maintain due to metabolic adaptations that promote gradual weight rebound. Pharmacological treatment of obesity provides a valuable adjunct to lifestyle interventions, but until recently, available medications have only provided moderate weight loss relative to the weight loss achieved by lifestyle interventions. (Wadden TA, Tronieri JS, Butryn ML. Lifestyle modification approaches for the treatment of obesity in adults. Am Psychol. 2020, 75(2):235-251).

[0058] Obesity is associated with alterations in the quantity, distribution, and function of adipose tissue. Most cases are caused by complex interactions among genetic, metabolic, neuroendocrine, behavioral, and environmental factors involved in the regulation of energy balance and fat storage. (Theilade S, Christensen MB, VilsbØll T, Knop FK. An overview of obesity mechanisms in humans: endocrine regulation of food intake, eating behavior and common determinants of body weight. Diabetes Obes Metab. 2021;23(Supplement 1):17-35).

[0059] cPG compounds are IGF-1 metabolites that are associated with GLP-1 and have been shown to reduce energy intake, decrease hunger, and increase satiety and fullness. cPG compounds have also been shown to mimic GLP-1 and target brain regions that regulate appetite and food intake.

[0060] Another aspect of the invention includes prevention or treatment of obesity comprising blood glucose control, weight loss, induction of satiety, weight reduction, reduction of food intake, and relief of other metabolic disorders or combinations thereof, wherein said prevention or treatment of obesity comprises blood glucose control, weight loss, induction of satiety, weight reduction, reduction of food intake, and relief of other metabolic disorders or combinations thereof, to maintain glycated hemoglobin A1c (HbA1c) at less than about 7% (53 mmol / mol), and to target pre-meal capillary plasma glucose at about 4.4 to about 7.2 mmol / L (about 80 to about 130 mg / dL), and to achieve plasma triglyceride levels below about 150 mg / dL (mg / dL).

[0061] C. cPG compounds

[0062] One aspect of the invention includes at least one cPG compound comprising cycloprolylglycine, cycloglyl-2-allylproline, cyclo(glyl-L-prolylglyl-L-prolylglyl-L-prolyl) or a combination thereof.

[0063] Another aspect of the invention includes at least one cPG compound comprising cyclic prolyl glycine.

[0064] Another aspect of the invention includes the provision of cyclic prolyl glycine at a dose of about 0.5 mg / kg to about 10.0 mg / kg.

[0065] Another aspect of the invention includes the provision of cyclic prolyl glycine at a dose of about 1.0 mg / kg to about 3.0 mg / kg.

[0066] One aspect of the invention includes the provision of cycloprolyl glycine at a dose of about 3.0 mg / kg to about 7.0 mg / kg.

[0067] Another aspect of the invention includes the provision of cyclic prolyl glycine at a dose of about 7.0 mg / kg to about 10.0 mg / kg.

[0068] Another aspect of the invention includes the administration of cycloprolyl glycine about once a day, about twice a day, or in combination thereof.

[0069] Another aspect of the invention includes the administration of cycloprolyl glycine orally, intranasally, or in combination thereof.

[0070] One aspect of the invention includes at least one cPG compound comprising cycloglycyl-2-allylproline.

[0071] Another aspect of the invention includes the provision of cycloglycyl-2-allylproline at a dose of about 0.5 mg to 10.0 mg / kg.

[0072] Another aspect of the invention includes the provision of cycloglycyl-2-allylproline at a dose of about 1.0 mg / kg to about 3.0 mg / kg.

[0073] Another aspect of the invention includes the provision of cycloglycyl-2-allylproline at a dose of about 3.0 mg / kg to about 7.0 mg / kg.

[0074] One aspect of the invention includes the provision of cycloglycyl-2-allylproline at a dose of about 7.0 mg / kg to about 10.0 mg / kg.

[0075] Another aspect of the invention includes the administration of a pharmaceutical composition comprising cycloglycyl-2-allylproline about once daily, about twice daily, or a combination thereof.

[0076] Another aspect of the invention includes the oral, intranasal, or combination thereof administration of a pharmaceutical composition comprising cycloglycyl-2-allylproline.

[0077] Another aspect of the invention includes at least one cPG compound comprising a ring (glycyl-L-prolyl-glycyl-L-prolyl-glycyl-L-prolyl).

[0078] One aspect of the invention includes a pharmaceutical composition comprising a ring (glycyl-L-prolyl-glycyl-L-prolyl-glycyl-L-prolyl) provided at a dose of about 0.5 mg / kg to about 10.0 mg / kg.

[0079] Another aspect of the invention includes a pharmaceutical composition comprising a ring (glycyl-L-prolyl-glycyl-L-prolyl-glycyl-L-prolyl) provided at a dose of about 1.0 mg / kg to about 3.0 mg / kg.

[0080] Another aspect of the invention includes a pharmaceutical composition comprising a ring (glycyl-L-prolyl-glycyl-L-prolyl-glycyl-L-prolyl) provided at a dose of about 3.0 mg / kg to about 7.0 mg / kg.

[0081] Another aspect of the invention includes pharmaceutical compositions comprising a ring (glycyl-L-prolyl-glycyl-L-prolyl-glycyl-L-prolyl) provided at doses of about 7.0 mg / kg to about 10.0 mg / kg.

[0082] Another aspect of the invention includes the administration of a pharmaceutical composition comprising a ring (glycyl-L-prolyl-glycyl-L-prolyl-L-prolyl) about once daily, about twice daily, or a combination thereof.

[0083] Another aspect of the invention includes the oral, intranasal, or combination thereof administration of a pharmaceutical composition comprising a ring (glycyl-L-prolyl-glycyl-L-prolyl-L-prolyl).

[0084] D. GLP-1 compounds

[0085] Another aspect of the invention includes at least one GLP-1 compound comprising at least one GLP-1, at least one GLP-1 agonist, or a combination thereof.

[0086] Another aspect of the invention includes at least one GLP-1 comprising tirzepatide (Zepbound®), semaglutide (Wegovy®), semaglutide (Rybelsus®), liraglutide (Saxenda®), maridebart cafraglutide (MariTide®), or a combination thereof.

[0087] 1) ZEPBOUND® (preferred but not required for subcutaneous application)

[0088] Another aspect of the invention includes at least one GLP-1 containing Zepbound®.

[0089] Another aspect of the invention includes a pharmaceutical composition comprising at least one of Zepbound® being formulated for subcutaneous injection, provided in doses of about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 30 mg, about 60 mg, about 120 mg, or combinations thereof, for administration to a human subject.

[0090] One aspect of the invention includes subcutaneous, oral, intranasal, or combined administration of at least one pharmaceutical composition comprising Zepbound®.

[0091] Another aspect of the invention includes administration of at least one pharmaceutical composition comprising Zepbound® once a week, twice a week, or a combination thereof.

[0092] 2) Smegglutide (WEGOVY®, preferred but not required for subcutaneous application)

[0093] Another aspect of the invention includes a GLP-1 comprising semaglutide (Wegovy®).

[0094] Another aspect of the invention includes at least one pharmaceutical composition comprising semaglutide (Wegovy®) for subcutaneous injection, provided in doses of about 0.5 mg, about 1.0 mg, about 2.4 mg, about 4.8 mg, about 9.6 mg, about 19.2 mg, or combinations thereof, for administration to a human subject.

[0095] One aspect of the invention includes subcutaneous, oral, intranasal, or combined administration of at least one pharmaceutical compound comprising smegglutinin (Wegovy®).

[0096] Another aspect of the invention includes administration of at least one pharmaceutical compound comprising Smegglutinin (Wegovy®) about once a week, about twice a day, or in combination thereof.

[0097] 3) Smegglutinin (RYBELSUS®, preferred for oral administration)

[0098] Another aspect of the invention includes GLP-1 comprising Rybelsus® tablets.

[0099] Another aspect of the invention includes at least one pharmaceutical composition comprising Rybelsus® being provided orally at doses of about 1.5 mg, about 3 mg, about 4 mg, about 7 mg, about 9 mg, about 14 mg, about 28 mg, about 56 mg, about 112 mg or combinations thereof for administration to a human subject.

[0100] One aspect of the invention includes oral, subcutaneous, intranasal, or combined administration of at least one pharmaceutical compound comprising Rybelsus®.

[0101] Another aspect of the invention includes administration of at least one pharmaceutical composition comprising Rybelsus® about once daily, about twice daily, or in combination thereof.

[0102] 4) Liraglutide (SAXENDA®, preferred but not required for subcutaneous administration)

[0103] Another aspect of the invention includes a GLP-1 comprising liraglutide (Saxenda®).

[0104] Another aspect of the invention includes providing at least one pharmaceutical composition comprising liraglutide (Saxenda®) in doses of about 0.6 mg, about 1.2 mg, about 1.8 mg, about 2.4 mg, about 3 mg, about 6 mg, about 12 mg, about 24 mg, about 48 mg, or combinations thereof, for administration to a human subject.

[0105] One aspect of the invention includes subcutaneous, oral, intranasal, or combined administration of at least one pharmaceutical compound comprising liraglutide (Saxenda®).

[0106] Another aspect of the invention includes administration of at least one pharmaceutical compound comprising liraglutide (Saxenda®) about once a week, about twice a week, or in combination thereof.

[0107] 5) Maritide® (preferred but not required for subcutaneous application)

[0108] Another aspect of the invention includes GLP-1 comprising MariTide®.

[0109] Another aspect of the invention includes providing at least one pharmaceutical composition comprising MariTide® in a dose of about 21 mg to about 840 mg or about 1,680 mg for administration to a human subject.

[0110] One aspect of the invention includes subcutaneous, oral, intranasal, or combined administration of at least one pharmaceutical compound comprising MariTide®.

[0111] Another aspect of the invention includes administration of at least one pharmaceutical compound comprising MariTide®, about once a month, about twice a month, or in combination thereof.

[0112] E. ending

[0113] A successful outcome of cPG treatment is considered to be significant and sustained weight loss, typically defined as a 5% or greater reduction in weight compared to baseline, often accompanied by improvements in metabolic health indicators such as blood pressure and cholesterol levels, particularly in obese or prediabetic individuals. In addition to weight loss, cPG compounds have been shown to provide positive changes in glycemic control and lipid profiles.

[0114] Blood glucose control represents a primary goal for patients with type 2 diabetes, regardless of individual weight. Recent guidelines recommend a glycated hemoglobin A1c (HbA1c) level below 7% (53 mmol / mol) as the glycemic target for most adults without significant hypoglycemia. However, glycemic treatment targets should be individualized based on patient preferences and goals, the risk of adverse treatment reactions, and patient characteristics, including frailty and comorbidities.

[0115] The American Diabetes Association (ADA) recommends a target pre-meal capillary plasma glucose level of 4.4 to 7.2 mmol / L (80 to 130 mg / dL) and a post-meal peak capillary plasma glucose level of <10.0 mmol / L (<180 mg / dL).

[0116] (American Diabetes Association. 6. Glycemic targets: standards of medical care in diabetes -2021. Diabetes Care. 2021;44(Suppl.1):S73-S84.)

[0117] When treating obesity, the typical target for plasma triglycerides is to reach a level below 150 mg / dL, which is considered to be within the “normal” range because lowering triglycerides is a key benefit of weight loss in obese individuals; however, specific targets may vary depending on individual factors and should be discussed with a healthcare provider.

[0118] (Qiao Q, Bouwman FG, van Baak MA, Roumans NJT, Vink RG, Mariman ECM. Plasma Levels of Triglycerides and IL-6 Are Associated With Weight Regain andFat Mass Expansion. J Clin Endocrinol Metab. 2022 Jun 16; 107(7): 1920-1929.doi: 10.1210 / clinem / dgacl98. PMID: 35366329; PMCID: PMC9202711.)

[0119] The target level for healthy triglyceride levels is below 150 mg / dL. Triglyceride levels above this value can increase the risk of heart attack and stroke. Triglyceride levels are classified as follows: Normal: below 150 mg / dL; Borderline High: 150 to 199 mg / dL; High: 200 to 499 mg / dL; Very High: 500 mg / dL or above.

[0120] (Alves-Bezerra M, Cohen DE. Triglyceride Metabolism in the Liver. Compr Physiol. 2017 Dec 12;8(1): 1-8. doi: 10.1002 / cphy.cl70012. PMID:29357123; PMCID: PMC6376873).

[0121] The preferred outcome of using the methods and pharmaceutical compositions of the present invention is progress toward these objectives. Specific objectives for a particular subject depend on the particularity of the subject and are determined at the discretion of the attending physician or other appropriate healthcare professional.

[0122] The goals also include maintaining glycated hemoglobin A1c (HbA1c) at less than about 7% (53 mmol / mol), targeting pre-meal capillary plasma glucose at about 4.4 to about 7.2 mmol / L (about 80 to about 130 mg / dL), and achieving plasma triglyceride levels below about 150 mg / dL.

[0123] Another aspect of the invention includes prevention or treatment of obesity, blood sugar control and other metabolic disorders, including but not limited to lowering plasma glucose, plasma triglycerides, liver triglycerides or combinations thereof.

[0124] Another aspect of the invention includes the prevention or treatment of obesity as prevention.

[0125] One aspect of the invention includes the prevention or treatment of obesity as a treatment.

[0126] Another aspect of the invention includes at least one pharmaceutical compound comprising at least one cPG compound and at least one GLP-1 compound.

[0127] F. object

[0128] Another aspect of the invention includes the subject being a human being.

[0129] G. Apply together or separately

[0130] Another aspect of the invention includes the administration of the components in a single dose or in multiple doses together.

[0131] One aspect of the invention includes the application of the components separately in single or multiple doses.

[0132] H. Provided together or separately

[0133] Another aspect of the invention includes the provision of the components together in one or more containers.

[0134] Another aspect of the invention includes the provision of components separately in one or more containers.

[0135] I. General and preferred aspects of the invention

[0136] Another aspect of the invention includes providing at least one of the cPG compounds at a dose of about 0.5 mg / kg to about 10.0 mg / kg.

[0137] One aspect of the invention includes the provision of at least one cPG compound via administration by injection, oral, intranasal, intraperitoneal, intravenous, subcutaneous, or a combination thereof.

[0138] Another aspect of the invention includes providing at least one of the cPG compounds at a rate of once per hour to about once every three months.

[0139] Another aspect of the invention includes providing at least one of the GLP-1 compounds at a dose of about 0.1 mg / kg to about 100 mg / kg.

[0140] Another aspect of the invention includes the provision of at least one of the GLP-1 compounds by means of injection, oral, intranasal, intraperitoneal, intravenous, subcutaneous, or combinations thereof.

[0141] One aspect of the invention includes providing at least one of the GLP-1 compounds in a manner that is once per hour to about once every three months.

[0142] Another aspect of the invention includes at least one of the GLP-1 compounds being a subcutaneous injection of Zepbound®, provided in a solution of about 0.5 ml to 2.00 ml at doses of about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 30 mg, about 60 mg, about 120 mg or combinations thereof.

[0143] Another aspect of the invention includes at least one of the GLP-1 compounds being a subcutaneous injection of semaglutide (Wegovy®), provided in a solution of about 1.5 ml at a dose of about 0.5 mg, about 1.0 mg, about 2.4 mg, about 4.8 mg, about 9.6 mg, about 19.2 mg or a combination thereof, for administration to a human subject.

[0144] Another aspect of the invention includes at least one of the GLP-1 compounds being Rybelsus® tablets, provided in an oral dose of about 1 ml to about 2.0 ml of a solution or a combination thereof, at a dose of about 1.5 mg, about 3 mg, about 4 mg, about 7 mg, about 9 mg, about 14 mg, about 28 mg, about 56 mg, about 112 mg or a combination thereof, for administration to a human subject.

[0145] One aspect of the invention includes at least one of the GLP-1 compounds being a subcutaneous injection of liraglutide (Saxenda®), provided in a solution of about 1.0 ml to about 2.0 ml or a combination thereof at doses of about 0.6 mg, about 1.2 mg, about 1.8 mg, about 2.4 mg, about 3 mg, about 6 mg, about 12 mg, about 24 mg, about 48 mg or combinations thereof, for administration to a human subject.

[0146] Another aspect of the invention includes at least one of the GLP-1 compounds being MariTide® subcutaneous injection, provided in a solution of about 1.0 ml to about 2.0 ml at a dose of about 21 mg to about 840 mg or about 1,680 mg or a combination thereof, for administration to a human subject.

[0147] II. Pharmaceutical compositions for the prevention or treatment of obesity, glycemic control, other metabolic disorders, or combinations thereof.

[0148] This invention includes pharmaceutical compositions for the prevention or treatment of obesity, blood glucose control, other metabolic disorders, or combinations thereof, as well as related conditions and disorders.

[0149] A second aspect of the invention comprises a pharmaceutical composition for the prevention or treatment of obesity, glycemic control, other metabolic disorders, or combinations thereof, said pharmaceutical composition comprising: a) at least one cPG compound, optionally in combination with: b) at least one GLP-1 compound; or c) a combination thereof; wherein the components are provided together or separately; furthermore, wherein when the pharmaceutical composition is administered to a subject who requires the prevention or treatment of obesity, glycemic control, other metabolic disorders, or combinations thereof, obesity, glycemic control, other metabolic disorders, or combinations thereof are thereby prevented or treated.

[0150] Any component disclosed and described herein may be used as a component of this aspect of the invention, including but not limited to cPG compounds, GLP-1 compounds, or combinations thereof.

[0151] III. Detailed description of certain aspects and embodiments of the present invention

[0152] This invention relates in part to compounds that effectively prevent and treat obesity.

[0153] This disclosure relates to the improved use of cPG compounds as GLP-1 agonists in treatment. In one embodiment, this disclosure relates to certain dosing regimens of cPG compounds that provide improved effects in diseases or conditions such as the prevention and / or treatment of type 2 diabetes and obesity.

[0154] In one embodiment, the method of this disclosure unexpectedly showed improvements in HbA1c reduction and weight loss resulting from oral administration of cPG.

[0155] In one embodiment, this disclosure relates to a method for treating or preventing obesity, reducing weight and / or food intake, or inducing satiety, said method comprising administering a cPG compound to a subject in need at an amount of at least about 0.5 mg / kg to about 10.0 mg / kg per day.

[0156] In one embodiment, the method is used to reduce weight and / or food intake. In another embodiment, the method is used to induce a feeling of satiety.

[0157] In one embodiment, the cPG compound is administered orally or via parenteral administration, such as subcutaneous injection.

[0158] In one embodiment, this disclosure relates to a composition comprising a cPG compound and one or more pharmaceutically acceptable excipients for the prevention or treatment of obesity, weight loss and / or food intake, or induction of satiety, wherein the cPG compound is administered at an amount of at least about 1.0 mg / kg to about 3.0 mg / kg per day.

[0159] In one embodiment, this disclosure relates to a composition comprising a cPG compound and one or more pharmaceutically acceptable excipients for the prevention or treatment of obesity, weight loss and / or food intake, or induction of satiety, wherein the cPG compound is administered at an amount of at least about 3.0 mg / kg to about 7.0 mg / kg per day.

[0160] In one embodiment, this disclosure relates to a composition comprising a cPG compound and one or more pharmaceutically acceptable excipients for the prevention or treatment of obesity, weight loss and / or food intake, or induction of satiety, wherein the cPG compound is administered at an amount of at least about 7.0 mg / kg to about 10.0 mg / kg per day.

[0161] In one embodiment, the cPG compound agonist is administered together with another therapeutic agent. Administration with another therapeutic agent can be performed within the same therapeutic window as the administration of both the GLP-1 agonist and the other therapeutic agent. Treatment with the GLP-1 agonist according to this disclosure can be combined with one or more additional therapeutic agents, such as those selected from antidiabetic agents, antiobesity agents, appetite regulators, antihypertensive agents, agents for the treatment and / or prevention of complications of diabetes or diabetes-related diseases, and agents for the treatment and / or prevention of complications and disorders of obesity or obesity-related diseases; some examples of such therapeutic agents are: sulfonylureas, thiazolidinediones, biguanides, meglitinides, glucosidase inhibitors, glucagon antagonists, and DPP-IV (dipeptidyl peptidase-IV) inhibitors.

[0162] In one implementation, the “effective amount” of a cPG compound as used herein refers to an amount sufficient to cure, alleviate, or partially prevent the clinical manifestations of a given disease or condition and its complications. An amount sufficient to achieve this is defined as an “effective amount.” The effective amount for each purpose will depend on the severity of the disease or injury, as well as the subject’s weight and overall condition. It should be understood that determining an appropriate dose can be achieved using routine experimental methods, i.e., by constructing a numerical matrix and testing the differences in the matrix, which is entirely within the scope of the ordinary skills of a trained physician or veterinarian.

[0163] A. cPG compounds

[0164] This invention relates to compositions comprising cyclic prolyl glycine (cPG) and its analogues (collectively referred to herein as cPG compounds or at least one cPG compound) for the treatment and prevention of obesity.

[0165] This invention relates to compositions comprising a metabolite of IGF-1 (called cyclic prolyl glycine (cPG) and its analogues (collectively referred to herein as cPG compounds)) for the treatment and prevention of obesity.

[0166] Cyclic prolyl glycine is a metabolite of IGF-1 and regulates IGF-1 by competitively binding to insulin-like growth factor binding protein (IGFBP)-3.

[0167] Therefore, cPG regulates the homeostasis of four functional agonists: IGF-1, GLP-1, GIP, and glucagon receptor.

[0168] Cyclic glycine-proline (cGP) regulates the homeostasis of insulin-like growth factor (IGF)-1 function, and the cGP / IGF-1 ratio determines the biological activity of IGF-1 in vitro and in vivo. Plasma IGF-1 largely represents inactive IGF-1 and is weakly associated with obesity and hypertension in humans (see, Li, Fengxia; Liu, Karen; Wang, Ao; Harris, Paul WR; Vickers, Mark H.; Guan, Jian (2019). Cyclic glycine-proline administration normalizes high-fat diet-induced synaptophysinexpression in obese rats. Neuropeptides, (), S0143417919300198-. doi:10.1016 / j.npep.2019.05.006).

[0169] Cyclic prolyl glycine (“cyclic PG” or “cGP”) has the following structure:

[0170]

[0171] Structure 1 Cyclic prolyl glycine

[0172] This invention includes novel diketopiperazines that are structurally related to cPG.

[0173] One aspect of the present invention provides novel cyclic compounds having the following structural formula and substituents.

[0174]

[0175] Structure 2 : Cycloglycyl-2-allylproline, or cycloglycyl-alkylproline, referred to as "cGAL" in this article.

[0176] R can be an "alkyl group," which refers to a saturated branched, straight-chain, or cyclic hydrocarbon group. Exemplary alkyl groups include methyl, ethyl, isopropyl, cyclopropyl, tert-butyl, cyclopropylmethyl, hexyl, etc.

[0177] R can be an allyl group, which refers to a substituent with the structural formula H2C=CH-CH2R, where R is the rest of the molecule.

[0178] When R is methyl, one aspect of the present invention comprising cycloglycyl-2-alkylproline is (8aS)-methyl-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione, which is referred to as cycloglycyl-2-methylproline or cycloGMeP or cGMeP.

[0179]

[0180] Structure 3 Cyclic G-2MeP (available from peptide suppliers such as Bachem Americas, Inc. (Torrance, California, USA)).

[0181] Generally, c(PG)3 and cGAL can be prepared by methods well known to those skilled in the art of peptide and modified peptide synthesis. See, for example, Bodanzsky: Principles of Peptide Synthesis, Berlin, New York: Springer-Verlag 1993. The synthesis of the diketopiperazine compounds of the present invention can be carried out by solution-phase synthesis as discussed in the examples, or by solid-phase synthesis as illustrated by Merrifield et al. 1963 J Amer. Chem. Soc.: 85, 2149-2156. Specific examples of diketopiperazine synthesis can be found in Fischer, 2003, J. PeptideScience: 9: 9-35 and the references cited therein. Given their skills and available knowledge, as well as the content of this disclosure, those skilled in the art will not have difficulty in developing one or more suitable synthetic methods for the compounds of the present invention.

[0182] In this application, particularly in this section which provides compound names, structures, and abbreviations, a variety of compounds are applicable to all aspects of the invention included herein. For example, if cPG is indicated in the specification, all other compounds in this section (and throughout the application) that are cPG compounds and related derivatives (e.g., but not limited to cGAL) are included in this and other descriptions, particularly but not limited to treatments for various conditions described herein.

[0183]

[0184] Structure 4 : Cyclic (glycyl-L-prolyl-glycyl-L-prolyl-glycyl-L-prolyl) One possible structure

[0185] The chemical synthesis of cyclo(glycyl-L-prolycyl-L-prolycyl-L-prolycyl) was carried out according to the method disclosed in Charles M. Deber and Elkan R. Blout, Israel Journal of Chemistry, Vol. 12, Nos. 1-2, 1974, pp. 15-29, “CYCLIC Peptides VII: The Synthesis and Characterization of Cyclic Peptides with Repeating Pro-Gly Sequences”.

[0186] Synthesis of cyclo(glycyl-L-prolycyl-glycyl-L-prolycyl-glycyl-L-prolycyl)

[0187] A solution of p-nitrophenyl ester hydrochloride (500 mg) dissolved in dimethylformamide (DMF) (20 ml, dried over sodium sulfate) was added dropwise over 6 hours at room temperature with stirring to 500 ml of reagent-grade pyridine. The bright yellow mixture was stirred continuously at room temperature for 48 hours. The solvent was removed at 45°C using a rotary evaporator-high vacuum pump system. The residue was washed with 20 ml of acetone, which dissolved p-nitrophenol and pyridine hydrochloride, but the peptide fraction remained insoluble. The insoluble substance and acetone were transferred to a flask and the acetone was evaporated at 45°C. The substance was then dissolved in a minimal amount of DMF. A white microcrystalline precipitate was identified as a ring (glycyl-L-prolyl-glycyl-L-prolyl-glycyl-L-prolyl) (155 mg, 28% yield), which was formed in complex with DMF.

[0188] 100 mg of the substance was crystallized from methanol-diethyl ether to obtain a DMF-free crystalline ring (Pro-Gly)3 (55 mg).

[0189] Chemical analysis: C 21 H 30 Calculated values ​​for N6O6•H2O: C, 52.49; H, 6.71; N, 17.49. Measured values ​​from elemental analysis: C, 52.60; H, 6.81; N, 17.38.

[0190] In other aspects, the present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable excipient or carrier and a therapeutically effective amount of cyclic GP or its analogues having the structural formula given above, said pharmaceutical compositions for treating diseases, disorders or conditions, including but not limited to Alzheimer's disease and related conditions such as cognitive impairment.

[0191] B. GLP-1 compounds

[0192] 1. ZEPBOUND® (Eli Lilly), also known as telpolide.

[0193] ZEPBOUND® is a glucose-dependent insulinotropic peptide (GIP) receptor and glucagon-like peptide-1 (GLP-1) receptor agonist, designated as an adjunct to calorie-reduced diets and increased physical activity for long-term weight management in adults with an initial body mass index (BMI) of 30 kg / m2 or higher (obese) or 27 kg / m2 or higher (overweight) in the presence of at least one weight-related comorbidity (e.g., hypertension, dyslipidemia, type 2 diabetes, obstructive sleep apnea, or cardiovascular disease).

[0194] The recommended starting dose is 2.5 mg, administered subcutaneously once weekly. The recommended maintenance dose is 5 mg, 10 mg, or 15 mg, administered subcutaneously once weekly. (United States Food and Drug Administration: https: / / www.fda.gov / drugsatfda)

[0195] 2. Smegglutinin, also known as WEGVOY® (Novo Nordisk)

[0196] WEGOVY is a glucagon-like peptide-1 (GLP-1) receptor agonist designated as an adjunct to calorie-reduced diets and increased physical activity for long-term weight management in adult patients with an initial body mass index (BMI) of 30 kg / m2 or higher (obese) or 27 kg / m2 or higher (overweight) in the presence of at least one weight-related comorbidity (e.g., hypertension, type 2 diabetes, or dyslipidemia), or in pediatric patients aged 12 years or older with an initial BMI at or above the 95th percentile of their age and sex (obese).

[0197] WEGOVY is administered once a week (on the same day of the week, at any time of day, with or without food). (US Food and Drug Administration: https: / / www.fda.gov / drugsatfda).

[0198] 3. Oral Smegglutinin - also known as RYBELSUS® (Novo Nordisk)

[0199] RYBELSUS is a glucagon-like peptide-1 (GLP-1) receptor agonist designated as an adjunct to diet and exercise for improving glycemic control in adults with type 2 diabetes. It is available in tablet form: 3 mg, 7 mg, and 14 mg. Recommended dosage: Start RYBELSUS at 3 mg once daily for 30 days. After 30 days at the 3 mg dose, increase the dose to 7 mg once daily. If additional glycemic control is required after at least 30 days at the 7 mg dose, the dose may be increased to 14 mg once daily. (US Food and Drug Administration: https: / / www.fda.gov / drugsatfda).

[0200] 4. MariTide (Amgen) - also known as MariTide carfarotropic peptide.

[0201] MariTide is an investigational drug that acts as an agonist of the GLP-1 receptor (GLP-1R) and an antagonist of the glucose-dependent insulinotropic peptide receptor (GIPR). Specifically, MariTide is composed of a monoclonal antibody targeting GIPR coupled to two peptide GLP-1R agonist molecules via amino acid linkers.

[0202] Example

[0203] Experiment 1: Effects of cyclic prolyl glycine (cPG) on blood glucose and body weight

[0204] The aim of this study was to verify the effects of cyclic prolyl glycine (cPG, or NA-931) on blood glucose (BG) and body weight (BW) in a diabetic setting. As described below, cPG was tested in a dose-response study in an obese diabetic mouse model (db / db mice).

[0205] db / db mice are an ideal animal model of type 2 diabetes. Homozygous mice with the spontaneous mutation in diabetes (Leprdb) exhibit morbid obesity, chronic hyperglycemia, pancreatic β-cell atrophy, and develop hypoinsulinemia.

[0206] Fifty-six db / db mice fed the NIH 31 diet (NIH 31M rodent diet, commercially available from Taconic Farms, Inc., US) from birth were enrolled in the study at 7 to 9 weeks of age. Mice had free access to standard feed (e.g., from Mazuri, San Jose, CA, USA) and tap water, and were kept at 24°C. After acclimatization for 1 to 2 weeks, basal blood glucose was assessed twice on two consecutive days (i.e., at 9:00 AM). The eight mice with the lowest blood glucose levels were excluded from the experiment. Based on the average blood glucose level, the remaining mice from the 56 were selected for further experiments and assigned to 6 groups (n=8), with matched blood glucose levels. Mice were used in experiments lasting 5 days, up to a maximum of 4 times. After the final experiment, the mice were euthanized.

[0207] The seven groups can receive the following treatment:

[0208] 1: Placebo, oral

[0209] 2: cPG: 0.1 mg / kg, orally

[0210] 3: cPG: 0.5 mg / kg, orally

[0211] 4: cPG: 1.0 mg / kg, orally

[0212] 5: cPG: 1.5 mg / kg, orally

[0213] 6: cPG: 2.0 mg / kg, orally

[0214] On the day of administration, blood glucose was assessed immediately after the mice were weighed (around 8:30 AM). The test solution cPG: 0.5 mg / kg, orally, was administered around 9:00 AM (time 0). Blood glucose was assessed on the day of administration, for example, at 1, 2, 4, and 7 hours (10:00 AM, 11:00 AM, 1:00 PM, and 4:00 PM).

[0215] Blood glucose levels were assessed in subsequent days, for example, at 24, 48, 72, and 96 hours after administration (i.e., at 9:00 AM on days 2, 3, 4, and 5). Mice were weighed daily after blood glucose sampling.

[0216] Samples for blood glucose measurement were obtained from the tail capillaries of conscious mice. 10 ml of blood was collected into a heparinized capillary and transferred to 500 ml of glucose buffer (Millipore Sigma, New Zealand). Glucose concentration was measured using the glucose oxidase assay (Mediray, New Zealand). Samples were kept at room temperature for up to 1 hour until analysis. If analysis had to be delayed, samples were kept at 4°C for up to 24 hours.

[0217] ED50 is the dose that produces the half-maximal effect, expressed in nmol / kg. This value is calculated based on the ability of cPG to reduce body weight and lower blood glucose, as explained below.

[0218] The ED50 for body weight is calculated as the dose that produces the half-maximal effect of ΔBW 24 hours after oral administration of cPG. For example, if the maximum decrease in body weight after 24 hours is 4.0 g, then the ED50 body weight is the dose, expressed in nmol / kg, that produces a 2.0 g decrease in body weight after 24 hours. This dose (ED50 body weight) can be read from the dose-response curve.

[0219] Sample analysis:

[0220] HPLC analysis: 10 ml samples were analyzed by HPLC using a Waters system equipped with a BEH C18 (1.7 mm, 2.1 × 50 mm) column, using a gradient of 0.1% TFA and 0.07% TFA in acetonitrile over 5 minutes, from 30% to 65%, at a flow rate of 0.6 ml / min. After baseline subtraction, the peak integrals of the intact compounds in the HPLC chromatogram recorded at 214 nm were determined.

[0221] Figure 1 The chart shows weight change relative to baseline at week 12 vs. cPG concentration. **p < 0.001 vs. placebo; ***p < 0.0001 vs. placebo (based on adjusted mean). Baseline values ​​are for reference only: Data have been model-adjusted for baseline weight. Data are model-adjusted LS means, FAS LOCF. Estimates are from an ANOVA model with treatment, country, and treatment as fixed effects and baseline weight as a covariate.

[0222] Experiment 2: Animal studies of cPG, cGAL, and cGMeP: changes in body weight, blood glucose, and plasma triglycerides. Changes in liver triglycerides

[0223] method:

[0224] The study was approved and conducted in accordance with Institutional Animal Care guidelines. Male C57BL / 6J mice (The Jackson Laboratory-Sacramento, California) were housed in cages of four and exposed to a controlled 12-hour / 12-hour light-dark cycle at room temperature (22°C) with free access to water and a 58% fat, high-carbohydrate diet (D12331, Research Diets) for 12 weeks. Mice weighing over 50 g were considered diet-induced obese (DIO) and included in the study, randomly and evenly assigned to the test group (n=8 mice / group) based on body weight.

[0225] The test compounds included cycloprolylglycine (cPG), cycloglyl-2-allylproline (cGAL), and cycloglyl-2-methylproline (cGMeP), as well as semaglutide, dissolved at 10 nmol / kg in a carrier (pH 7.4) containing 0.05% polysorbate 80, 50 mM sodium phosphate, and 70 mM sodium chloride, administered subcutaneously once daily. Unless otherwise specified, the dose was achieved at a volume of 5 μL per gram of body weight during the photocycle of each treatment day, as needed. Semaglutide was used as a positive control.

[0226] In combination therapy, 5 μL solutions containing cPG (5 nmol / kg) and smegglutinin (5 nmol / kg) were tested. Changes in blood pressure (BW), glucose, plasma triglycerides, and liver triglycerides were then assessed in each group.

[0227] Body weight and food intake were measured daily prior to administration. The percentage change in body weight for each mouse was calculated individually based on its initial body weight prior to the first injection. For the intraperitoneal glucose tolerance test (IPGTT), animals were fasted for 6 hours prior to the test but allowed to consume water. Fasting blood glucose levels were measured, followed by an intraperitoneal injection of a 2 g / kg glucose load (from a 200 mg / mL glucose solution). Tail blood glucose levels were measured using a handheld glucometer (FreeStyle Libre 3 System Abbott) at 0, 15, 30, 60, 90, and 120 minutes after the glucose load.

[0228] Figure 2 The changes in body weight for cPG, cGAL, cGMeP, and smegglutinin versus the carrier are shown.

[0229] Figure 3The changes in blood glucose levels for cPG, cGAL, cGMeP, and smegglutinin versus the carrier are shown.

[0230] Figure 4 The changes in plasma triglycerides were shown for cPG, cGAL, cGMeP, and smegglutinin versus the carrier.

[0231] Figure 5 The changes in liver triglycerides were shown by cPG, cGAL, cGMeP, and smegglutinin versus the carrier.

[0232] in conclusion:

[0233] Animal studies of cPG compounds and telpolide demonstrated proof of concept, leading to the following conclusions:

[0234] • In a 14-day study in DIO-NASH mice, a series of novel cPG compounds significantly reduced body weight, plasma triglycerides, and liver triglycerides compared to the load.

[0235] • Compared with carrier therapy, treatment with cPG compounds resulted in a reduction in body weight (up to 27%, p < 0.0001), compared with telpolide (30%), and the combination of cPG compounds and telpolide (34%).

[0236] • Treatment with cPG compounds reduced plasma glucose levels by 23%, compared to telposide (24%), and combination therapy with cPG compounds and telposide (30%).

[0237] • Treatment with cPG compounds reduced plasma triglycerides by 35%, compared to telposide (31%), and combination therapy with cPG compounds and telposide (40%).

[0238] • Treatment with cPG compounds reduced liver triglycerides by 29%, compared to telposide (21%), and combination therapy with cPG compounds and telposide (39%).

[0239] • There is evidence of a potential synergistic effect in combination therapy of cPG compounds and telpoide.

[0240] Experiment 3: Animal studies of cPG, cGAL, and cGMeP: changes in body weight, blood glucose, and plasma triglycerides. Changes in liver triglycerides

[0241] method:

[0242] The study was approved and conducted in accordance with the institutional animal care guidelines. Male C57BL / 6J mice (The Jackson Laboratory-Sacramento, California) were housed in cages of four and exposed to a controlled 12-hour / 12-hour light-dark cycle at room temperature (22°C) with free access to water and a 58% fat, high-carbohydrate diet (D12331, ResearchDiets) for 12 weeks.

[0243] Mice weighing more than 50 g were considered diet-induced obese (DIO) mice and included in the study. They were randomly and evenly assigned to the test group (n=8 mice / group) according to their weight.

[0244] The test compounds included cycloprolylglycine (cPG), cycloglyl-2-allylproline (cGAL), and cycloglyl-2-methylproline (cGMeP), as well as semaglutide, dissolved at 10 nmol / kg in a carrier (pH 7.4) containing 0.05% polysorbate 80, 50 mM sodium phosphate, and 70 mM sodium chloride, administered subcutaneously once daily. Unless otherwise specified, the dose was achieved at a volume of 5 μL per gram of body weight during the photocycle of each treatment day, as needed. Semaglutide was used as a positive control.

[0245] In combination therapy, 5 μL solutions containing cPG (5 nmol / kg) and smegglutinin (5 nmol / kg) were tested. Changes in blood pressure (BW), glucose, plasma triglycerides, and liver triglycerides were then assessed in each group.

[0246] Body weight and food intake were measured daily prior to administration. The percentage change in body weight for each mouse was calculated individually based on its initial body weight prior to the first injection. For the intraperitoneal (ip) glucose tolerance test (IPGTT), animals were fasted for 6 hours prior to the test but allowed to ingest water. Fasting blood glucose levels were measured, followed by an ip injection of a 2 g / kg glucose load (from a 200 mg / mL glucose solution). Tail blood glucose levels were measured at 0, 15, 30, 60, 90, and 120 minutes after the glucose load using a handheld blood glucose meter (FreeStyle Libre 3 System Abbott).

[0247] Figure 6 The changes in body weight for cPG, cGAL, cGMeP, and smegglutinin versus the carrier are shown.

[0248] Figure 7 The changes in blood glucose levels for cPG, cGAL, cGMeP, and smegglutinin versus the carrier are shown.

[0249] Figure 8 The changes in plasma triglycerides were shown for cPG, cGAL, cGMeP, and smegglutinin versus the carrier.

[0250] Figure 9 The changes in liver triglycerides were shown by cPG, cGAL, cGMeP, and smegglutinin versus the carrier.

[0251] in conclusion:

[0252] Animal studies of cPG compounds and smegglutinin demonstrated proof of concept and led to the following conclusions:

[0253] • In a 14-day study in DIO-NASH mice, a series of novel cPG compounds significantly reduced body weight, plasma triglycerides, and liver triglycerides compared to the load.

[0254] • Compared with carrier therapy, treatment with cPG compounds resulted in a reduction in body weight (26%, p < 0.0001), compared with semaglutide (28%), and the combination of cPG compounds and semaglutide (33%).

[0255] • Treatment with cPG compounds reduced plasma glucose levels by 22%, compared to semaglutide (23%), and combination therapy with cPG compounds and semaglutide (32%).

[0256] • Treatment with cPG compounds reduced plasma triglycerides by 36%, compared to smegglutide (29%), and combination therapy with cPG compounds and smegglutide (43%).

[0257] • Treatment with cPG compounds reduced liver triglycerides by 29%, compared to semaglutide (24%), and combination therapy with cPG compounds and semaglutide (45%).

[0258] • There is evidence of a potential synergistic effect between cPG compounds and smegglutide combination therapy.

[0259] Experiment 4: A 28-day clinical trial of cPG compounds for treating obesity

[0260] A randomized, double-blind, placebo-controlled, dose-escalation human study was conducted to evaluate the safety and tolerability of NA-931 in overweight / obese participants with single and multiple escalation doses, and in patients with type 2 diabetes with multiple doses. Reference: ClinicalTrials.gov ID NCT06615700 (https: / / clinicaltrials.gov / study / NCT06564753?term=NA-931&rank=1).

[0261] Cyclic prolyl glycine (referred to as NA-931 in this article, i.e. the code name in clinical trials) has been found to be a quadruple receptor agonist of insulin-like growth factor 1 (IGF-1), glucagon-like peptide-1 (GLP-1), gastric inhibitory peptide (GIP) and glucagon.

[0262] Participation criteria:

[0263] Table 1 describes 74 participants, including men and women, aged 18 to 65 years, who met the following inclusion and exclusion criteria.

[0264] Inclusion criteria:

[0265] • Participants were aged 18 to 65, inclusive.

[0266] • BMI is 25 to 40, including the extreme values.

[0267] • Weight stable for two months

[0268] • Participants must be able to sign an informed consent form.

[0269] • Willing and able to adhere to scheduled visits, treatment plans, and laboratory procedures.

[0270] • Testing and other clinical research procedures

[0271] • Willing to comply with contraceptive requirements

[0272] Exclusion criteria:

[0273] • History of serious medical conditions and malignant diseases

[0274] • Uncontrolled high blood pressure

[0275] • History of alcohol or drug addiction within 1 year prior to screening

[0276] • Currently or soon involved in investigational clinical trials

[0277] • May interfere with any of the following surgical or medical conditions (active or chronic)

[0278] • IP distribution, metabolism, excretion, or drug absorption

[0279] Groups and Interventions

[0280]

[0281] Table 1: Demographic characteristics of participants

[0282]

[0283] BMI: Body Mass Index

[0284] HbA1c: The hemoglobin A1C (HbA1C) test is a blood test that shows the average blood glucose (blood sugar) level over the past two to three months.

[0285] HOMA-IR: Homeostasis Model Assessment of Insulin Resistance

[0286] result

[0287] efficacy study

[0288] NA-931 is a once-daily oral small molecule quadruple receptor agonist developed for the treatment of both type 2 diabetes and obesity.

[0289] Data showed that in obese participants without type 2 diabetes, NA-931 treatment resulted in a clinically meaningful placebo-corrected mean weight loss of -6.4% over four weeks, and a weight loss of 4.7% relative to placebo (p < 0.001).

[0290] NA-931 was well tolerated with no significant gastrointestinal adverse events, demonstrating a safety profile superior to that of incretin drugs. There were no treatment discontinuations related to the investigational drug.

[0291] The study results also showed that NA-931 blood levels were largely unaffected during fasting or after a standardized high-fat meal. Therefore, NA-931 may be administered without considering meal times, thus providing patients with greater dosing flexibility.

[0292] Based on research data, NA-931 is expected to be used not only as a treatment to achieve glycemic control and induce weight loss, but also potentially for oral weight maintenance therapy following injectable-induced weight loss.

[0293] weight loss

[0294] The 28-day MAD study results highlighted a positive signal of clinical activity following oral NA-931 treatment. The group receiving NA-931 showed a dose-dependent reduction in mean body weight relative to baseline, up to 6.8% at a daily dose of 150 mg, or 5.1% compared to placebo.

[0295] Following the 28-day study, an open-label follow-up study was conducted for 8 weeks, for a total of 12 weeks.

[0296] The 12-week MAD study showed that NA-931 demonstrated a dose-dependent reduction in average body weight relative to baseline, up to 12.7% at a daily dose of 150 mg, or 10.4% relative to placebo. Based on the initial assessment of the weight loss trajectory, the company believes that a treatment duration of more than 28 days may provide further weight loss.

[0297] Table 2: NA-931 in overweight or obese participants and patients with type 2 diabetes during the 28-day-potency-Phase 1 study.

[0298]

[0299] Note:

[0300] 1) The population includes all randomized subjects who have received at least one dose of the study drug and have undergone at least one planned post-baseline weight assessment.

[0301] 2) Patients treated with NA-931 were titrated to the final dose as follows:

[0302] • 30 mg group = 30 mg / day × 4 weeks;

[0303] • 60 mg group = 30 mg / day × 1 week, 60 mg / day × 3 weeks;

[0304] • 90 mg group = 60 mg / day × 1 week, 90 mg / day × 3 weeks;

[0305] • 120 mg group = 90 mg / day × 1 week, 120 mg / day × 3 weeks;

[0306] • 150 mg group = 120 mg / day × 1 week, 150 mg / day × 3 weeks.

[0307] 3) All participants were required to have a baseline BMI >30 kg / m². 2 .

[0308] 4) Least squares mean.

[0309] 5) Use a two-tailed t-test for repeated measures mixed models.

[0310] Table 3: NA-931 in overweight or obese participants and patients with type 2 diabetes in a 12-week-potency-phase 1 study.

[0311] After the initial 28 days, the study continued for 8 weeks with an open label. The total duration was 12 weeks.

[0312]

[0313] Note:

[0314] 1) The population includes all randomized subjects who have received at least one dose of the study drug and have undergone at least one planned post-baseline weight assessment.

[0315] 2) Patients treated with NA-931 should be titrated to the final dose as follows:

[0316] • 60 mg group = 30 mg / day × 1 week, 60 mg / day × 3 weeks; open label, treatment continued for 8 weeks.

[0317] • 90 mg group = 60 mg / day × 1 week, 90 mg / day × 3 weeks; open label, treatment continued for 8 weeks.

[0318] • 120 mg group = 90 mg / day × 1 week, 120 mg / day × 3 weeks; open label, treatment continued for 8 weeks.

[0319] • 150 mg group = 120 mg / day × 1 week, 150 mg / day × 3 weeks, open label, treatment continued for 8 weeks.

[0320] 3) All participants were required to have a baseline BMI >30 kg / m². 2 .

[0321] 4) Least squares mean.

[0322] 5) Use a two-tailed t-test for repeated measures mixed models.

[0323] Security research

[0324] 28-day study: Among those receiving NA-931, all treatment emergent adverse events (TEAEs) reported to date were clinically insignificant or mild, with the majority (85%) being clinically insignificant.

[0325] Similarly, all observed gastrointestinal (GI) adverse events were reported as clinically insignificant or mild, with the majority (83%) reported as clinically insignificant. At the highest dose of 150 mg / day, 2 subjects (5.8%) treated with NA-931 reported mild nausea.

[0326] Of the 34 subjects treated with NA-931, one subject (2.9%) reported vomiting at the high dose of 150 mg / day. One subject (2.9%) receiving NA-931 reported diarrhea, compared to one subject (10%) receiving placebo.

[0327] Table 4: NA-931 in overweight or obese participants and patients with type 2 diabetes during the 28-day-safety-phase 1 study.

[0328]

[0329] 12-week study: Among those receiving NA-931, all treatment-related adverse events (TEAEs) reported to date were clinically insignificant or mild, with the majority (70%) reported as clinically insignificant.

[0330] Similarly, all observed gastrointestinal (GI) adverse events were reported as clinically insignificant or mild, with the majority (75%) reported as clinically insignificant. At the highest dose of 150 mg / day, 2 subjects (15.9%) treated with NA-931 reported mild nausea.

[0331] Of the 34 subjects treated with NA-931, 2 subjects (5.8%) reported vomiting at the high dose of 150 mg / day. Diarrhea was reported in 2 subjects (5.8%) receiving NA-931, compared to 1 subject (10%) receiving placebo.

[0332] Table 5: NA-931 in overweight or obese participants and patients with type 2 diabetes during the 12-week-phase 1 study.

[0333]

[0334] Features

[0335] In terms of the first function, the cPG compound, as a GLP-1 agonist of this disclosure, exhibits good potency. Additionally or alternatively, in terms of the second function, the GLP-1 agonist of this disclosure has a durable pharmacokinetic profile. Additionally or alternatively, in terms of the third function, the GLP-1 agonist of this disclosure is stable against degradation by gastrointestinal enzymes.

[0336] The cPG compounds of the present invention have GLP-1 activity. In one embodiment, "GLP-1 agonist" is understood to mean any compound that fully or partially activates the human GLP-1 receptor, including peptide and non-peptide compounds.

[0337] Diabetic db / db mice are an example of a suitable animal model, and the hypoglycemic effect can be determined in such mice.

[0338] Drug Dosage – Multiple Implementation Plans

[0339] The dosage may include 0.5 mg to 1.5 mg / kg, or 30 mg to 150 mg for a typical adult weighing 70 kg, or 60 mg to 150 mg for an obese person who usually weighs 80 to 120 kg.

[0340] The dosage can be 0.5 mg to 1.5 mg / kg, which corresponds to 30 mg to 90 mg for a typical adult weighing 70 kg, or 60 mg to 180 mg for obese individuals weighing between 80 kg and 120 kg.

[0341] Pharmaceutical compositions comprising their pharmaceutically acceptable salts, amides or esters and pharmaceutically acceptable excipients may be prepared in a manner known in the art.

[0342] The composition can be administered in several dosage forms, such as as a solution; suspension; emulsion; microemulsion; multiple emulsion; foam; ointment; paste; plaster; ointment; tablet; coated tablet; chewing gum; mouthwash; capsule, such as hard or soft gelatin capsules; suppository; rectal capsule; drops; gel; spray; powder; aerosol; inhaler; eye drops; ophthalmic ointment; ophthalmic rinse; vaginal suppository; vaginal ring; vaginal ointment; injectable solution; in situ transformation solution, such as in situ gelling, solidification, precipitation and in situ crystallization; infusion solution; or as an implant.

[0343] The composition can be further compounded in a drug carrier or drug delivery system, for example, to improve stability, bioavailability, and / or solubility. In one specific embodiment, the composition may be attached to such a system via covalent, hydrophobic, and / or electrostatic interactions. Such compounding may be intended, for example, to reduce adverse reactions, enable time-based therapy, and / or improve patient compliance.

[0344] The composition can also be used to formulate controlled-release, sustained-release, extended-release, delayed-release and / or controlled-release drug delivery systems.

[0345] The composition can be administered via parenteral administration. Parenteral administration can be performed subcutaneously, intramuscularly, intraperitoneally, or intravenously using a syringe (optionally a pen syringe) or an infusion pump.

[0346] Pharmaceutical compositions are well known in the medical field and may include formulations in solid form, such as tablets intended for oral administration. The formulations of the present invention may also include liquid, gel, semi-solid, colloidal, vapor, and gaseous formulations capable of delivery orally, nasally, bronchially, intestinally, or via the colon (anus and perianal region). In one embodiment, the compositions of the present invention are administered via a mucosa (e.g., a mucosa to which the subject is applied). Mucosa means any bodily mucosa, including the oral cavity, nose, bronchi, esophagus, intestines, and anal or perianal mucosa.

[0347] Skilled clinicians will recognize that the choice of carrier (including physiologically acceptable compounds) depends, for example, on the manner in which the peptide or encoding a polynucleotide is administered, as well as the route of administration and dosage of the composition. When the composition is administered under immunizing conditions (e.g., as a vaccine), it is typically administered intramuscularly, intradermally, or subcutaneously, but parenteral administration, such as intravenous administration, is also possible, and it can be administered by injection, intubation, or other such methods known in the art. When the desired immune system modulation is to tolerance, the composition is preferably administered orally, or as described above.

[0348] The term "therapeutic effective amount" or "effective amount" refers to the amount of a compound or pharmaceutical composition that elicits a biological or medical response in a tissue, system, animal, or human sought by a researcher, veterinarian, physician, or other clinician. Therefore, the total amount of composition to be administered in carrying out the methods of this invention may be given as a single dose to the subject, either by bolus injection or by infusion over a relatively short period, and may be followed by one or more booster doses over a period of time. The amount of composition that stimulates the subject's immune response depends on several factors, including the subject's age and overall health, as well as the route of administration and the number of treatments to be administered. Taking these factors into account, a skilled clinician will know to adjust the specific dosage as necessary.

[0349] In carrying out the method of the present invention, the total amount of compound or composition to be administered may be given to the subject as a single dose, either by bolus injection or by infusion over a relatively short period of time, or by a fractionated treatment regimen in which multiple doses are administered over an extended period of time. Those skilled in the art will recognize that the amount of the composition of the present invention used to treat SARS in a subject depends on many factors, including the subject's age and overall health condition, as well as the route of administration and the number of treatments to be administered. Taking these factors into account, a skilled technician will adjust the specific dosage as necessary. Generally, the formulation of the pharmaceutical composition, as well as the route and frequency of administration, were initially determined using Phase I and Phase II clinical trials.

[0350] In view of this disclosure, all compositions and methods disclosed and claimed herein can be prepared and carried out without excessive experimentation. While the compositions and methods of the invention have been described with respect to preferred embodiments, it will be apparent to those skilled in the art that variations may be made to the compositions and methods described herein, as well as the steps or order of steps, without departing from the spirit and scope of the invention. More specifically, the embodiments are to be considered in all respects only as illustrative and not restrictive. All similar substitutions and modifications apparent to those skilled in the art are considered to be within the spirit and scope of the invention as defined by the appended claims.

[0351] Alternatively or additionally, other antiviral agents may optionally be unsuitable for the frequency of application of the composition, for example, where the composition is formulated for once-daily application, while other antiviral agents are more suitable for once-weekly application (e.g., pegylated interferon-α).

[0352] The composition may be in the form of, for example, a liquid, a semi-solid (e.g., a gel), or a solid.

[0353] In some embodiments of the invention, the composition is in solid form. Examples of solid forms of the composition include, but are not limited to, tablets, capsules (e.g., capsules containing encapsulated solids), capsule tablets, powders, microspheres, and granules.

[0354] The composition is preferably formulated according to the intended frequency of application. This, in turn, depends on the properties of the active agent. As discussed herein, artemether and atazanavir can be administered, for example, once daily, but may also be administered at other frequencies (e.g., twice or three times daily).

[0355] It should be understood that by properly formulating the composition, for example by formulating the composition for the slow release of the active agent, the active agent can be made more suitable for less frequent application (e.g., once a day, as is particularly convenient, rather than twice a day or more).

[0356] Slow-release formulations typically comprise a slow-release biodegradable carrier. Slow-release biodegradable carriers are well known in the art. These are materials capable of forming particles in which an active compound can be captured and slowly degraded / dissolved in suitable environments (e.g., aqueous, acidic, alkaline, etc.), thereby degrading / dissolving and releasing the active compound in bodily fluids. The particles are preferably nanoparticles (e.g., in the nanometer range, such as a diameter of about 1 to about 500 nm, preferably about 50 to about 200 nm, and most preferably about 100 nm).

[0357] Oral slow-release formulations are typically designed to maintain therapeutic drug concentrations for more than 12 hours. Absorption rates can be controlled by coating drug particles with wax or other water-insoluble materials, by encapsulating the drug in a matrix that slowly releases the drug during GI transport, or by combining the drug with an ion-exchange resin.

[0358] Therefore, slow-release formulations, such as tablets, can be based on the use of hydrophilic polymers that swell to form a gel upon contact with gastrointestinal fluids, thereby creating a barrier that encapsulates the tablet. This barrier restricts physical exchange between the tablet interior and the surrounding medium. Consequently, the intrusion of water into the tablet matrix and drug diffusion are slowed, allowing for controlled, slow release of the drug.

[0359] A variety of polymers can be used as matrices for slow drug release, such as polyvinyl chloride, polyethylene polyamide, ethyl cellulose, silicone, poly(hydroxyethyl methacrylate), other acrylic copolymers, and polyvinyl acetate-polyvinyl chloride copolymers.

[0360] In some embodiments of the invention, the composition is in unit dosage form (e.g., a unit dosage form formulated for oral administration).

[0361] The pharmaceutical composition may be administered via an appropriate route of administration, at an appropriate dose, and in an appropriate regimen.

[0362] Therefore, the pharmaceutical compositions used according to embodiments of the present invention can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers (containing excipients and adjuvants) that facilitate the processing of the active ingredients (artemether and antiviral agents described herein) into pharmaceutically usable formulations. Appropriate formulation depends on the chosen route of administration.

[0363] For injection, the active ingredient of the present invention can be prepared in an aqueous solution, preferably in a physiologically compatible buffer, such as Hank's solution, Ringer's solution, or a saline buffer with or without organic solvents (e.g., propylene glycol, polyethylene glycol).

[0364] For oral administration, the active ingredient can be readily formulated by combining the active ingredient described herein with a pharmaceutically acceptable carrier known in the art. Such a carrier enables the active ingredient to be formulated into tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions, etc., for oral ingestion by a patient. Pharmacological preparations for oral use can be prepared using solid excipients, optionally by grinding the resulting mixture and, if necessary, adding suitable adjuvants before processing the granular mixture to obtain tablets. Suitable excipients are particularly fillers, such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, gum, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose; and / or physiologically acceptable polymers, such as polyvinylpyrrolidone (PVP). If desired, disintegrants, such as croscarmellose, agar, or alginate or its salts, such as sodium alginate, can be added.

[0365] Orally administered pharmaceutical compositions include push-in capsules made of gelatin and soft-sealable capsules made of gelatin and plasticizers (such as glycerin or sorbitol). Push-in capsules may contain the active ingredient mixed with a filler (such as lactose), a binder (such as starch), a lubricant (such as talc or magnesium stearate), and optionally a stabilizer. In soft-sealable capsules, the active ingredient described herein may be dissolved or suspended in a suitable liquid, such as fatty oil, liquid paraffin, or liquid polyethylene glycol. Additionally, a stabilizer may be added. All orally administered formulations should be administered at a dose appropriate to the chosen route of administration.

[0366] The active ingredients described herein can be formulated for parenteral administration, such as by bolus injection or continuous infusion. Injectable formulations may be provided in unit dosage forms, such as ampoules or multi-dose containers, optionally with the addition of preservatives. The composition may be a suspension, solution, or emulsion in an oily or aqueous carrier and may contain a formulatory agent, such as a suspending agent, stabilizer, and / or dispersant.

[0367] Pharmaceutical compositions for parenteral administration comprise an aqueous solution of the active ingredient. Alternatively, suspensions of the active ingredient can be prepared as suitable oily injectable suspensions and emulsions (e.g., water-in-oil, oil-in-water, or water-in-oil-in-oil emulsions). Suitable lipophilic solvents or carriers include fatty oils, such as sesame oil, or synthetic fatty acid esters such as ethyl oleate, triglycerides, or liposomes. Aqueous injectable suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the active ingredient to allow for the preparation of high-concentration solutions.

[0368] Alternatively, the active ingredient may be in powder form and prepared prior to use with a suitable carrier (e.g., sterile, pyrogen-free water).

[0369] The active ingredient in embodiments of the present invention can also be formulated into rectal compositions using, for example, conventional suppositories, such as suppositories or retention enemas.

[0370] For administration by inhalation, the active ingredient used according to embodiments of the invention is conveniently delivered from a pressurized package or nebulizer in the form of an aerosol (which typically comprises a powder, liquefied, and / or gaseous carrier), using a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, or carbon dioxide. In the case of pressurized aerosols, the dosage unit can be determined by providing a valve to deliver a measured amount. For example, gelatin capsules and cartridges for inhalers or blowpipes can be formulated as a powder mixture containing the active ingredient and a suitable powder matrix (e.g., but not limited to lactose or starch).

[0371] The selection of drug delivery methods requires an understanding of tissue distribution, metabolism, and cellular effects, as well as an understanding of the interaction between the drug and the specific underlying pathological processes of the disease being treated. This field provides general and specific teachings in this regard.

[0372] Since the route of drug administration determines bioavailability, as well as tissue level and distribution, changes in delivery can fundamentally alter the location, nature, extent, and duration of disease conditions, and change dosing requirements and toxicity.

[0373] However, it was observed that when artemether was administered locally in vivo via a nasal delivery system, the drug was absorbed rapidly and had higher bioavailability compared to systemic administration, and it was extremely fast and had a shorter duration of action when treating fever.

[0374] For pulmonary delivery, the therapeutic compositions of the present invention can be formulated and administered to patients in the form of solid or liquid particles by direct application (e.g., inhalation into the respiratory system).

[0375] The solid or liquid particulate forms of the active compounds prepared for carrying out the present invention include particles of inhalable size: that is, particles small enough to enter the bronchi and alveoli of the lungs through the mouth and throat upon inhalation. Generally, particles of about 1 to about 10 micrometers in size are within the generally inhalable range. Therapeutic compositions containing antimalarial and antiviral compounds are preferably administered as a mist or other aerosol or dry powder by direct inhalation into the respiratory system.

[0376] The dosage of the active compound via this route can vary depending on the condition being treated and the patient's condition, but is generally sufficient to achieve a dissolved concentration of the antimalarial and antiviral compound on the surface of the patient's airway.

[0377] Depending on the solubility of the specific formulation of the active compound being administered, the daily dose may be divided into one or several unit doses. Daily doses administered via direct inhalation are typically much lower than oral doses. For example, the daily dose range for artemether administered via direct inhalation is 20 to 40 mg / day, and for atazanavir it is approximately 25 mg / day to approximately 100 mg / day. Doses of the active compound may be provided as one or more pre-packaged units.

[0378] Liquid particulate aerosols can be generated by any suitable means, such as inhalation delivery systems. One type is the conventional nebulizer, which works similarly to the familiar perfume nebulizer. Airborne particles are generated by a jet of air from a compressor or compressed gas cylinder passing through the device (pressure-driven aerosol nebulizer) (US Patent No. 4,501,729 – “Aerosolized amiloride treatment of retained pulmonary secretions”).

[0379] While various embodiments of the invention have been described above, it should be understood that they are presented by way of example only and not by way of limitation. Those skilled in the art will understand that many changes in form and detail may be made therein without departing from the spirit and scope of the invention as defined in the appended claims. Therefore, the breadth and scope of the invention should not be limited by any of the exemplary embodiments described above, but should be defined according to the appended claims and their equivalents.

[0380] This invention has been described with reference to its specific embodiments. Those skilled in the art can generate other features and embodiments of the invention without excessive experimentation and with a reasonable probability of success. All such and other embodiments are considered part of this invention.

[0381] For all purposes, all publications cited in this application (including any bibliography), including patent documents and scientific articles, are incorporated by reference in their entirety to the same extent that each individual publication is incorporated by reference individually.

[0382] All headings are for the convenience of the reader only and, unless otherwise stated, should not be used to limit the meaning of the text following the heading.

Claims

1. A method for preventing or treating obesity, glycemic control, other metabolic disorders, or combinations thereof, said method comprising: a. To provide for individuals who require the aforementioned prevention or treatment of obesity; b. Providing at least one pharmaceutical composition comprising one or more of the following components: a) at least one cPG compound, optionally in combination with the following; b) At least one GLP-1 compound; or c) Its combination; The components may be applied together or separately; Furthermore, the components are provided together or separately; c. Administering a pharmaceutically effective amount of the at least one pharmaceutical composition to the subject; The subject obtains prevention or treatment of obesity, blood sugar control, other metabolic disorders, or combinations thereof.

2. The method of claim 1, The components are provided in pharmaceutically acceptable diluents, adjuvants, excipients, or combinations thereof.

3. The method of claim 1, The components are provided as pharmaceutically acceptable salts.

4. The method of claim 1, The components are applied separately.

5. The method of claim 1, The prevention or treatment of obesity includes blood sugar control, weight loss, inducing satiety, reducing weight, reducing food intake, and alleviating other metabolic disorders or combinations thereof.

6. The method of claim 1, The at least one cPG compound comprises cycloprolylglycine, cycloglyl-2-allylproline, cyclo(glyl-L-prolylglyl-L-prolylglyl-L-prolyl) or a combination thereof.

7. The method of claim 6, The at least one cPG compound contains cycloprolylglycine.

8. The method of claim 7, The cyclic prolyl glycine is provided at a dose of about 0.5 mg / kg to about 10.0 mg / kg.

9. The method of claim 7, The cyclic prolyl glycine is provided at a dose of about 1.0 mg / kg to about 3.0 mg / kg.

10. The method of claim 7, The cyclic prolyl glycine is provided at a dose of about 3.0 mg / kg to about 7.0 mg / kg.

11. The method of claim 7, The cyclic prolyl glycine is provided at a dose of about 7.0 mg / kg to about 10.0 mg / kg.

12. The method of claim 7, The cycloprolyl glycine mentioned therein is administered about once a day, about twice a day, or in combination thereof.

13. The method of claim 7, The cycloprolyl glycine is administered orally, intranasally, or in combination thereof.

14. The method of claim 6, The at least one cPG compound contains cycloglycyl-2-allylproline.

15. The method of claim 14, The cycloglycyl-2-allylproline is provided at a dose of about 0.5 mg to 10.0 mg / kg.

16. The method of claim 14, The cycloglycyl-2-allylproline is provided at a dose of about 1.0 mg / kg to about 3.0 mg / kg.

17. The method of claim 14, The cycloglycyl-2-allylproline is provided at a dose of about 3.0 mg / kg to about 7.0 mg / kg.

18. The method of claim 14, The cycloglycyl-2-allylproline is provided at a dose of about 7.0 mg / kg to about 10.0 mg / kg.

19. The method of claim 14, The pharmaceutical composition comprising cycloglycyl-2-allylproline is administered about once daily, about twice daily, or in combination thereof.

20. The method of claim 14, The pharmaceutical composition comprising cycloglycyl-2-allylproline is administered orally, intranasally, or in combination thereof.

21. The method of claim 6, The at least one cPG compound contains a ring (glycyl-L-prolyl-glycyl-L-prolyl-glycyl-L-prolyl).

22. The method of claim 21, The pharmaceutical composition comprising a ring (glycyl-L-prolyl-glycyl-L-prolyl-glycyl-L-prolyl) is provided at a dose of about 0.5 mg / kg to about 10.0 mg / kg.

23. The method of claim 21, The pharmaceutical composition comprising a ring (glycyl-L-prolyl-glycyl-L-prolyl-glycyl-L-prolyl) is provided at a dose of about 1.0 mg / kg to about 3.0 mg / kg.

24. The method of claim 21, The pharmaceutical composition comprising a ring (glycyl-L-prolyl-glycyl-L-prolyl-glycyl-L-prolyl) is provided at a dose of about 3.0 mg / kg to about 7.0 mg / kg.

25. The method of claim 21, The pharmaceutical composition comprising a ring (glycyl-L-prolyl-glycyl-L-prolyl-glycyl-L-prolyl) is provided at a dose of about 7.0 mg / kg to about 10.0 mg / kg.

26. The method of claim 21, The pharmaceutical composition comprising a ring (glycyl-L-prolyl-glycyl-L-prolyl-L-prolyl) is administered about once daily, about twice daily, or in combination thereof.

27. The method of claim 21, The pharmaceutical composition comprising a ring (glycyl-L-prolyl-glycyl-L-prolyl-L-prolyl) is administered orally, intranasally, or in combination thereof.

28. The method of claim 1, The at least one GLP-1 compound comprises at least one GLP-1, at least one GLP-1 agonist, or a combination thereof.

29. The method of claim 28, The at least one GLP-1 comprises Zepbound®, Wegovy®, Rybelsus®, Saxenda®, MariTide®, or a combination thereof.

30. The method of claim 29, The at least one of the GLP-1s contains zepbound®.

31. The method of claim 30, The pharmaceutical composition comprising at least one of Zepbound® is formulated for subcutaneous injection and provided in doses of about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 30 mg, about 60 mg, about 120 mg, or combinations thereof, for administration to a human subject.

32. The method of claim 30, The pharmaceutical composition comprising at least one of the aforementioned pharmaceutical compositions may be administered subcutaneously, orally, intranasally, or in combination thereof.

33. The method of claim 30, The at least one pharmaceutical composition containing Zepbound® is administered once or twice a week, or in combination thereof.

34. The method of claim 29, The GLP-1 contained in it contained smegglutinin (Wegovy®).

35. The method of claim 34, The pharmaceutical composition comprising at least one of the aforementioned semaglutide (Wegovy®) is for subcutaneous injection and is provided in doses of about 0.5 mg, about 1.0 mg, about 2.4 mg, about 4.8 mg, about 9.6 mg, about 19.2 mg, or combinations thereof, for administration to a human subject.

36. The method of claim 34, The drug may be administered subcutaneously, orally, intranasally, or in combination thereof, of at least one of the pharmaceutical compounds containing Smegglutide (Wegovy®).

37. The method of claim 34, The at least one of the pharmaceutical compounds, including Smegglutide (Wegovy®), is administered about once a week, about twice a day, or in combination thereof.

38. The method of claim 29, The GLP-1 contained in the form of Rybelsus® tablets.

39. The method of claim 38, The pharmaceutical composition comprising at least one of the aforementioned pharmaceutical compositions containing Rybelsus® is provided orally at doses of about 1.5 mg, about 3 mg, about 4 mg, about 7 mg, about 9 mg, about 14 mg, about 28 mg, about 56 mg, about 112 mg, or combinations thereof, for administration to a human subject.

40. The method of claim 38, The at least one of the pharmaceutical compounds containing Rybelsus® is administered orally, subcutaneously, intranasally, or in combination thereof.

41. The method of claim 38, The at least one pharmaceutical composition containing Rybelsus® is administered about once daily, about twice daily, or in combination thereof.

42. The method of claim 29, The GLP-1 contained liraglutide (Saxenda®).

43. The method of claim 42, The pharmaceutical composition comprising at least one of liraglutide (Saxenda®) is provided in doses of about 0.6 mg, about 1.2 mg, about 1.8 mg, about 2.4 mg, about 3 mg, about 6 mg, about 12 mg, about 24 mg, about 48 mg, or combinations thereof, for administration to a human subject.

44. The method of claim 42, The drug may be administered subcutaneously, orally, intranasally, or in combination thereof, of at least one of the pharmaceutical compounds containing liraglutide (Saxenda®).

45. The method of claim 42, The at least one of the pharmaceutical compounds, which contains liraglutide (Saxenda®), is administered about once a week, about twice a week, or in combination thereof.

46. ​​The method of claim 29, The GLP-1 contained in the GLP-1 contained MariTide®.

47. The method of claim 46, The at least one pharmaceutical composition containing MariTide® is provided in a dose of about 21 mg to about 840 mg or about 1,680 mg for administration to a human subject.

48. The method of claim 46, The drug may be administered subcutaneously, orally, intranasally, or in combination thereof, of at least one of the pharmaceutical compounds containing MariTide®.

49. The method of claim 46, The drug contains at least one of the pharmaceutical compounds, such as MariTide®, and is administered about once a month, about twice a month, or in combination thereof.

50. The method of claim 1, The prevention or treatment of obesity, blood sugar control and other metabolic disorders includes lowering plasma glucose, plasma triglycerides, liver triglycerides or combinations thereof.

51. The method of claim 1, The prevention or treatment of obesity mentioned herein refers to prevention.

52. The method of claim 1, The prevention or treatment of obesity mentioned above refers to treatment.

53. The method of claim 1, The at least one pharmaceutical compound comprises at least one cPG compound and at least one GLP-1 compound.

54. The method of claim 1, The object mentioned is a person.

55. The method of claim 1, The components are administered in a single dose or in multiple doses together.

56. The method of claim 1, The components are administered separately in single or multiple doses.

57. The method of claim 1, The components are provided together in one or more containers.

58. The method of claim 1, The components are provided separately in one or more containers.

59. The method of claim 1, The at least one cPG compound is provided at a dose of about 0.5 mg / kg to about 10.0 mg / kg.

60. The method of claim 1, The at least one cPG compound is provided by means of injection, oral, intranasal, intraperitoneal, intravenous, subcutaneous, or a combination thereof.

61. The method of claim 1, The at least one cPG compound is provided at a rate of once per hour to approximately once every three months.

62. The method of claim 1, The at least one GLP-1 compound is provided at a dose of about 0.1 mg / kg to about 100 mg / kg.

63. The method of claim 1, The at least one GLP-1 compound is provided by means of injection, oral, intranasal, intraperitoneal, intravenous, subcutaneous, or a combination thereof.

64. The method of claim 1, The at least one GLP-1 compound is provided at a rate of once per hour to approximately once every three months.

65. The method of claim 1, The at least one GLP-1 compound is Zepbound® subcutaneous injection, provided in a solution of about 0.5 ml to 2.00 ml at doses of about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 30 mg, about 60 mg, about 120 mg or combinations thereof.

66. The method of claim 1, The at least one GLP-1 compound is semaglutide (Wegovy®) subcutaneous injection, provided in a solution of about 1.5 ml at doses of about 0.5 mg, about 1.0 mg, about 2.4 mg, about 4.8 mg, about 9.6 mg, about 19.2 mg or combinations thereof, for administration to a human subject.

67. The method of claim 1, The at least one GLP-1 compound is a semaglutide (Rybelsus®) tablet, provided in an oral dose of about 1.5 mg, about 3 mg, about 4 mg, about 7 mg, about 9 mg, about 14 mg, about 28 mg, about 56 mg, about 112 mg or a combination thereof in a solution of about 1 ml to about 2.0 ml or a combination thereof, for administration to a human subject.

68. The method of claim 1, The at least one GLP-1 compound is liraglutide (Saxenda®) subcutaneous injection, provided in a solution of about 1.0 ml to about 2.0 ml or a combination thereof in doses of about 0.6 mg, about 1.2 mg, about 1.8 mg, about 2.4 mg, about 3 mg, about 6 mg, about 12 mg, about 24 mg, about 48 mg or combinations thereof, for administration to a human subject.

69. The method of claim 1, The at least one GLP-1 compound is MariTide® subcutaneous injection, provided in a solution of about 1.0 ml to about 2.0 ml or a combination thereof at a dose of about 21 mg to about 840 mg or about 1,680 mg or a combination thereof, for administration to a human subject.

70. A pharmaceutical composition for the prevention or treatment of obesity, glycemic control, other metabolic disorders, or combinations thereof, said pharmaceutical composition comprising: a) at least one cPG compound, optionally in combination with the following; b) At least one GLP-1 compound; or c) Its combination; The components are provided together or separately. Furthermore, when the pharmaceutical composition is administered to a subject who requires prevention or treatment of obesity, the obesity, blood glucose control, other metabolic disorders, or combinations thereof are thereby prevented or treated.

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