GLP-1R agonist and DPP-4 inhibitor composition and method of use

Abstract

Disclosed herein are compositions comprising a GLP-1R agonist composition, a DPP-4 inhibitor composition, or a combination thereof. The descriptions contained herein describe methods for inducing weight loss and / or enhancing satiety in subjects. The compositions described herein may be formulated for oral administration and, in some embodiments, may further include an enteric-coated or pH-responsive coating agent.

Description

Technical Field

[0001] Background As of 2020, the obesity rate in the United States was 41.9%, and the severe obesity rate was 9.2%. Obesity is associated with a higher prevalence of other morbidities, such as heart disease, stroke, type 2 diabetes, and certain types of cancer, among the leading causes of preventable premature death. Furthermore, obesity significantly burdens the healthcare system; for example, in 2019, the estimated medical costs of obesity in the United States were approximately $173 billion. Therefore, researchers have been working to develop compounds to combat the obesity epidemic.

[0002] The glucagon-like peptide-1 receptor (GLP-1R) is found on β-cells on the islets of Langerhans in the pancreas. Activation of GLP-1R by agonists such as endogenous glucagon-like peptide-1 (GLP-1), endogenous glucagon, or exogenous incretin mimetics stimulates the reduction of post-meal blood glucose levels by enhancing insulin secretion from the β-cells of the islets of Langerhans and inhibiting the release of glucagon from the α-cells of the islets of Langerhans. As a result, GLP-1R agonists are widely used for treating type 2 diabetes and, like compounds for promoting recent weight loss. For this purpose, researchers have developed several GLP-1R agonists showing insulin secretion activity, including but not limited to dulaglutide (Trulicity®), exenatide (Byetta™, Bydureon BCise®), liraglutide (Victoza®), semaglutide (Ozempic®, Wegovy®, and Rybelsus®), and tirzepatide (Mounjaro™).

[0003] The dipeptidyl peptidase-4 (DPP-4) enzyme plays a major role in glucose metabolism, as DPP-4 breaks down GLP-1 and, in some cases, exogenous incretin mimes. Therefore, researchers consider DPP-4 inhibitors as alternatives to GLP-1R agonists to achieve similar effects, namely the treatment of type 2 diabetes and weight loss. For this purpose, researchers have developed several DPP-4 inhibitors, including, but not limited to, sitagliptin (Januvia®), vildagliptin (Galvus®), saxagliptin (Onglyza®), linagliptin (Tradjenta®), gemigliptin (Zemiglo®), anagliptin (Suiny®), teneligliptin (Tenelia®), alogliptin (Vipidia®), trelagliptin (Zafatek®), and omaligliptin (Marizev®). [Overview of the Initiative] [Problems that the invention aims to solve]

[0004] overview Assuming that GLP-1R agonists and DPP-4 inhibitors induce similar effects, researchers have attempted to further improve the clinical outcomes of each single compound by using combinations of GLP-1R agonists and DPP-4 inhibitors. However, conventional combination therapies have yielded only moderate improvements in glycemic control, minimal weight loss benefits, and significantly poor results, as the combined efficacy is equivalent to the effects observed with monotherapy of either drug, i.e., antagonistic effects. In addition, conventional combinations have shown significant side effects, including nausea, vomiting, abdominal pain, increased cancer risk, and acute pancreatitis. Finally, because the current GLP-1R agonists and DPP-4 inhibitors in conventional combinations contain small molecule, peptide, and protein-based compounds, the cost of developing and providing these formulations to patients is very high. [Means for solving the problem]

[0005] The inventors have strived to overcome the shortcomings of conventional combination therapies by developing a composition comprising at least one GLP-1R agonist and at least one DPP-4 inhibitor. Accordingly, the inventors have developed a low-cost composition comprising a GLP-1R agonist and a DPP-4 inhibitor that yields superior and unexpected synergistic results in increasing weight loss and / or satiety, and in some cases reducing the occurrence of negative side effects, without increasing the incidence of negative side effects. This finding is novel. Thus, by providing at least one GLP-1R agonist and at least one DPP-4 inhibitor together as a pharmaceutical and / or health supplement, the benefits of the therapeutic and / or functional food can be realized individually, collectively, or in combination with other pharmaceuticals and / or health supplements.

[0006] Embodiments of the present disclosure relate to compositions comprising novel GLP-1R agonist compositions, novel DPP-4 inhibitor compositions, or combinations thereof, and the use thereof to promote weight loss, enhance satiety, and / or increase GLP-1 levels.

[0007] These and other features, aspects, and advantages of this embodiment will be understood by referring to the following description and the appended claims. [Modes for carrying out the invention]

[0008] Detailed explanation Some embodiments provide compositions comprising a certain amount of one or more GLP-1R agonists, which are formulated as GLP-1R agonist compositions. In certain embodiments, the GLP-1R agonist composition may comprise a certain amount of carrot composition, a certain amount of curcumin composition, a certain amount of pharmaceutical GLP composition, a certain amount of conjugated linoleic acid composition, a certain amount of bayberry powder composition, a certain amount of berberine composition, a certain amount of berberine hydrochloride composition, a certain amount of tea (camellia sinensis) (matcha) composition, a certain amount of capsaicin (chili pepper) composition, a certain amount of dong quai root powder composition, a certain amount of epigallocatechin gallate (EGCG) composition, a certain amount of freeze-dried milk (kefir powder) composition, a certain amount of Garcinia cambogia extract (hydroxycitric acid) composition, a certain amount of lion's mane mushroom composition, a certain amount of medium-chain triglyceride composition, a certain amount of pterostilbene composition, a certain amount of quercetin pure composition, a certain amount of resveratrol composition, a certain amount of sucralose composition, a certain amount of bearberry leaf composition, or any combination thereof. In some embodiments, the GLP-1R agonist compositions disclosed herein may include a pharmaceutically acceptable medium, carrier, or diluent. Some embodiments can be formulated to have these components in varying amounts.

[0009] As used herein, “Carrot Composition” is defined as a composition comprising carrot root powder and / or an extract of carrot root. For the purposes of this disclosure, “Carrot Root Extract” may, as used herein, include, but is not limited to, one or more compounds selected from the group consisting of dammarane, falcarinol, ginsenoside compound K(CK), ginsenoside Rb0, ginsenoside Rb1, ginsenoside Rb2, ginsenoside Rc, ginsenoside Rd, ginsenoside Re, ginsenoside Rf, ginsenoside Rg1, ginsenoside Rg2, ginsenoside Rg3, ginsenoside Rh1, ginsenoside Rh2, ginsenoside Rh3, oleanane, panaxidol, panaxitriol, protopanaxadiol, protopanaxatriol, and any combination thereof. As used herein, “carrot root extract” may be defined as a single compound or a mixture of compounds derived therefrom, and the use of these terms will be obvious to those skilled in the art in considering their use in the context and in the claims.

[0010] When provided in a GLP-1R agonist composition, the amount of the provided carrot composition may be about 10 μg to about 10 g. For example, the amount of carrot composition in the GLP-1R agonist composition is approximately 10 μg, 15 μg, 20 μg, 25 μg, 30 μg, 35 μg, 40 μg, 45 μg, 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 95 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, 250 μg, 275 μg, 300 μg, 325 μg, 350 μg, 375 μg, 400 μg, 425 μg, 450 μg, 475 μg, 500 μg, 525 μg. 550μg, 575μg, 600μg, 625μg, 650μg, 675μg, 700μg, 725μg, 750μg, 775μg, 800μg, 825μg, 850μg, 875μg, 900μg, 925μg, 950μg, 975μg, 1000μg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 125mg, 150mg, 175m g, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg , 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, 1.0g, 1.25g, 1.50g, 1.75g, 2.0g, 2.25g, 2.5 The amounts may be 0g, 2.75g, 3.0g, 3.25g, 3.50g, 3.75g, 4.0g, 4.25g, 4.50g, 4.75g, 5.0g, 5.25g, 5.50g, 5.75g, 6.0g, 6.25g, 6.50g, 6.75g, 7.0g, 7.25g, 7.50g, 7.75g, 8.0g, 8.25g, 8.50g, 8.75g, 9.0g, 9.25g, 9.50g, 9.75g, 10.0g, or any range or amount between any two of the preceding values ​​and any other range or amount disclosed herein.

[0011] As used herein, “curcumin composition” is defined as a composition comprising one or more of the following: diferloylmethane, demethoxycurcumin, bisdemethoxycurcumin, tetrahydrocurcumin, dihydrocurcumin, hexahydrocurcumin, and octahydrocurcumin.

[0012] When provided in a GLP-1R agonist composition, the amount of curcumin composition provided may be about 10 μg to about 10 g. For example, the amount of curcumin composition in the GLP-1R agonist composition is approximately 10 μg, 15 μg, 20 μg, 25 μg, 30 μg, 35 μg, 40 μg, 45 μg, 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 95 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, 250 μg, 275 μg, 300 μg, 325 μg, 350 μg, 375 μg, 400 μg, 425 μg, 450 μg, 475 μg, 500 μg, 525 μg. 550μg, 575μg, 600μg, 625μg, 650μg, 675μg, 700μg, 725μg, 750μg, 775μg, 800μg, 825μg, 850μg, 875μg, 900μg, 925μg, 950μg, 975μg, 1000μg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 125mg, 150mg, 175m g, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg , 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, 1.0g, 1.25g, 1.50g, 1.75g, 2.0g, 2.25g, 2.5 The amounts may be 0g, 2.75g, 3.0g, 3.25g, 3.50g, 3.75g, 4.0g, 4.25g, 4.50g, 4.75g, 5.0g, 5.25g, 5.50g, 5.75g, 6.0g, 6.25g, 6.50g, 6.75g, 7.0g, 7.25g, 7.50g, 7.75g, 8.0g, 8.25g, 8.50g, 8.75g, 9.0g, 9.25g, 9.50g, 9.75g, 10.0g, or any range or amount between any two of the preceding values ​​and any other range or amount disclosed herein.

[0013] As used herein, “Pharmaceutical GLP composition” is defined as a composition comprising one or more GLP-1 analogs, such as dulaglutide, albiglutide, exenatide, liraglutide, semaglutide, lixisenatide, and tilzepatide.

[0014] When provided in a GLP-1R agonist composition, the amount of the provided pharmaceutical GLP composition may be about 10 μg to about 30 mg. For example, the amount of pharmaceutical GLP composition in a GLP-1R agonist composition may be about 10 μg, 15 μg, 20 μg, 25 μg, 30 μg, 35 μg, 40 μg, 45 μg, 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 95 μg, 100 μg, 125 μg, 150 μg, or 175 μg. , 200μg, 225μg, 250μg, 275μg, 300μg, 325μg, 350μg, 375μg, 400μg, 425μg, 450μg, 475μg, 5 00μg, 525μg, 550μg, 575μg, 600μg, 625μg, 650μg, 675μg, 700μg, 725μg, 750μg, 775μg, 800μg g, 825 μg, 850 μg, 875 μg, 900 μg, 925 μg, 950 μg, 975 μg, 1000 μg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, or any range or amount between any two of the preceding values ​​and any other range or amount disclosed herein.

[0015] As used herein, “conjugate linoleic acid composition” refers to a composition comprising linoleic acid (i.e., a polyunsaturated ω6 fatty acid having the chemical name 18:2ω6; cis, cis-9,12-octadecadienoic acid). When provided in a GLP-1R agonist composition, the amount of the conjugate linoleic acid composition provided may be about 10 μg to about 10 g.For example, the amount of conjugated linoleic acid composition in the GLP-1R agonist composition is approximately 10 μg, 15 μg, 20 μg, 25 μg, 30 μg, 35 μg, 40 μg, 45 μg, 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 95 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, 250 μg, 275 μg, 300 μg, 325 μg, 350 μg, 375 μg, 400 μg, 425 μg, 450 μg, 475 μg, 500 μg. 525μg, 550μg, 575μg, 600μg, 625μg, 650μg, 675μg, 700μg, 725μg, 750μg g, 775μg, 800μg, 825μg, 850μg, 875μg, 900μg, 925μg, 950μg, 975μg, 10 00μg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 65 0mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, 1.0g, 1.25g, 1.50g, 1.75g, 2.0g, 2.25g, 2 0.50g, 2.75g, 3.0g, 3.25g, 3.50g, 3.75g, 4.0g, 4.25g, 4.50g, 4.75g, 5.0g, 5.25g, 5.50g, 5.75g, 6.0g, 6.25g, 6.50g, 6.75g, 7.0g, 7.25g, 7.50g, 7.75g, 8.0g, 8.25g, 8.50g, 8.75g, 9.0g, 9.25g, 9.50g, 9.75g, 10.0g, or any range or amount between any two of the preceding values ​​and any other range or amount disclosed herein.

[0016] As used herein, “bayberry powder composition” refers to a composition comprising powdered bayberry extract, bayberry root bark powder, bayberry bark powder, bayberry fruit powder, bayberry root powder, or any combination thereof. Powdered bayberry extract may be an extract from dried and powdered bayberry root bark, bayberry bark, bayberry fruit, or a combination thereof. Bayberry root bark powder, bayberry bark powder, bayberry fruit powder, and bayberry root powder can be obtained without extraction from dried and powdered root bark, bark, fruit, and root. When provided in a GLP-1R agonist composition, the amount of bayberry powder composition provided may be about 10 μg to about 10 g.For example, the amount of bayberry powder composition in the GLP-1R agonist composition is approximately 10 μg, 15 μg, 20 μg, 25 μg, 30 μg, 35 μg, 40 μg, 45 μg, 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 95 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, 250 μg, 275 μg, 300 μg, 325 μg, 350 μg, 375 μg, 400 μg, 425 μg, 450 μg, 475 μg, 500 μg, 525 μg μg, 550μg, 575μg, 600μg, 625μg, 650μg, 675μg, 700μg, 725μg, 750μg, 775μg, 800μg, 825μg, 850μg, 875μg, 900μg, 925μg, 950μg, 975μg, 1000μg g, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 125mg, 150mg, 17 5mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650m g, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, 1.0g, 1.25g, 1.50g, 1.75g, 2.0g, 2.25g, 2. The amounts may be 50g, 2.75g, 3.0g, 3.25g, 3.50g, 3.75g, 4.0g, 4.25g, 4.50g, 4.75g, 5.0g, 5.25g, 5.50g, 5.75g, 6.0g, 6.25g, 6.50g, 6.75g, 7.0g, 7.25g, 7.50g, 7.75g, 8.0g, 8.25g, 8.50g, 8.75g, 9.0g, 9.25g, 9.50g, 9.75g, 10.0g, or any range or amount between any two of the preceding values ​​and any other range or amount disclosed herein.

[0017] As used herein, “berberine composition” refers to a composition comprising the compound berberine (isoquinoline alkaloid), and “berberine hydrochloride composition” refers to a composition comprising the hydrochloride salt form of berberine. When provided in a GLP-1R agonist composition, the amount of berberine composition, the amount of berberine hydrochloride composition, or a combination thereof provided may be about 10 μg to about 10 g.For example, the amounts of berberine composition, berberine hydrochloride composition, or combinations thereof in a GLP-1R agonist composition are approximately 10 μg, 15 μg, 20 μg, 25 μg, 30 μg, 35 μg, 40 μg, 45 μg, 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 95 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, 250 μg, 275 μg, 300 μg, 325 μg, 350 μg, 375 μg, 400 μg, 425 μg, 450 μg, 475μg, 500μg, 525μg, 550μg, 575μg, 600μg, 625μg, 650μg, 675μg, 700μg , 725μg, 750μg, 775μg, 800μg, 825μg, 850μg, 875μg, 900μg, 925μg, 950μg g, 975μg, 1000μg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 125m g, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 62 5mg, 650mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, 1.0g, 1.25g, 1.50g, 1.75g, 2.0g, 2.2 The amounts may be 5g, 2.50g, 2.75g, 3.0g, 3.25g, 3.50g, 3.75g, 4.0g, 4.25g, 4.50g, 4.75g, 5.0g, 5.25g, 5.50g, 5.75g, 6.0g, 6.25g, 6.50g, 6.75g, 7.0g, 7.25g, 7.50g, 7.75g, 8.0g, 8.25g, 8.50g, 8.75g, 9.0g, 9.25g, 9.50g, 9.75g, 10.0g, or any range or amount between any two of the preceding values ​​and any other range or amount disclosed herein.

[0018] As used herein, “Camellia sinensis (matcha) composition” refers to a composition comprising powdered Camellia sinensis leaves, powdered Camellia sinensis leaf buds, powdered Camellia sinensis stems, powdered Camellia sinensis leaf extract, or a combination thereof. When provided in a GLP-1R agonist composition, the amount of Camellia sinensis (matcha) composition provided may be about 10 μg to about 10 g.For example, the amount of Camellia sinensis (matcha) composition in the GLP-1R agonist composition is approximately 10 μg, 15 μg, 20 μg, 25 μg, 30 μg, 35 μg, 40 μg, 45 μg, 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 95 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, 250 μg, 275 μg, 300 μg, 325 μg, 350 μg, 375 μg, 400 μg, 425 μg, 450 μg, 475 μg, 500 μg, 525 μg, 550 μg, 575 μg μg, 600μg, 625μg, 650μg, 675μg, 700μg, 725μg, 750μg, 775μg, 800μg, 825μg, 850μg, 875μg, 900μg, 925μg, 950μg, 975μg, 1000μg, 5mg, 10mg , 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 125mg, 150mg, 175mg, 200m g, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg, 675m g, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, 1.0g, 1.25g, 1.50g, 1.75g, 2.0g, 2.25g, 2.50g, The amounts may be 2.75g, 3.0g, 3.25g, 3.50g, 3.75g, 4.0g, 4.25g, 4.50g, 4.75g, 5.0g, 5.25g, 5.50g, 5.75g, 6.0g, 6.25g, 6.50g, 6.75g, 7.0g, 7.25g, 7.50g, 7.75g, 8.0g, 8.25g, 8.50g, 8.75g, 9.0g, 9.25g, 9.50g, 9.75g, 10.0g, or any range or amount between any two of the preceding values ​​and any other range or amount disclosed herein.

[0019] As used herein, “capsaicin (chili pepper) composition” refers to a composition containing capsaicin, a compound having the chemical name 8-methyl-N-vanillyl-6-nonenamide, which is the active ingredient of chili pepper. When provided in a GLP-1R agonist composition, the amount of capsaicin (chili pepper) composition provided may be about 10 μg to about 10 g.For example, the amount of capsaicin (chili pepper) in the GLP-1R agonist composition is approximately 10 μg, 15 μg, 20 μg, 25 μg, 30 μg, 35 μg, 40 μg, 45 μg, 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 95 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, 250 μg, 275 μg, 300 μg, 325 μg, 350 μg, 375 μg, 400 μg, 425 μg, 450 μg, 475 μg, 500 μg. 525μg, 550μg, 575μg, 600μg, 625μg, 650μg, 675μg, 700μg, 725μg, 750μg g, 775μg, 800μg, 825μg, 850μg, 875μg, 900μg, 925μg, 950μg, 975μg, 10 00μg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 65 0mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, 1.0g, 1.25g, 1.50g, 1.75g, 2.0g, 2.25g, 2 0.50g, 2.75g, 3.0g, 3.25g, 3.50g, 3.75g, 4.0g, 4.25g, 4.50g, 4.75g, 5.0g, 5.25g, 5.50g, 5.75g, 6.0g, 6.25g, 6.50g, 6.75g, 7.0g, 7.25g, 7.50g, 7.75g, 8.0g, 8.25g, 8.50g, 8.75g, 9.0g, 9.25g, 9.50g, 9.75g, 10.0g, or any range or amount between any two of the preceding values ​​and any other range or amount disclosed herein.

[0020] As used herein, “dong quai root powder composition” refers to a composition comprising a powdered dong quai root extract, dong quai root powder, or a combination thereof. Powdered dong quai root extract can be obtained by extracting dong quai root using standard extraction techniques in the art, and the resulting extract is dried and powdered. Dong quai root powder can be obtained by (i) drying the root and then grinding the dried root, or (ii) grinding fresh roots and then drying them. When provided in a GLP-1R agonist composition, the amount of dong quai root powder composition provided may be about 10 μg to about 10 g.For example, the amount of dong quai root powder composition in the GLP-1R agonist composition is approximately 10 μg, 15 μg, 20 μg, 25 μg, 30 μg, 35 μg, 40 μg, 45 μg, 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 95 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, 250 μg, 275 μg, 300 μg, 325 μg, 350 μg, 375 μg, 400 μg, 425 μg, 450 μg, 475 μg, 500 μg, 52 5μg, 550μg, 575μg, 600μg, 625μg, 650μg, 675μg, 700μg, 725μg, 750μg, 775μg, 800μg, 825μg, 850μg, 875μg, 900μg, 925μg, 950μg, 975μg, 1000 μg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 125mg, 150mg, 1 75mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650 mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, 1.0g, 1.25g, 1.50g, 1.75g, 2.0g, 2.25g, 2 0.50g, 2.75g, 3.0g, 3.25g, 3.50g, 3.75g, 4.0g, 4.25g, 4.50g, 4.75g, 5.0g, 5.25g, 5.50g, 5.75g, 6.0g, 6.25g, 6.50g, 6.75g, 7.0g, 7.25g, 7.50g, 7.75g, 8.0g, 8.25g, 8.50g, 8.75g, 9.0g, 9.25g, 9.50g, 9.75g, 10.0g, or any range or amount between any two of the preceding values ​​and any other range or amount disclosed herein.

[0021] As used herein, “epigallocatechin gallate (EGCG) composition” refers to a composition comprising EGCG (i.e., an ester of epigallocatechin and gallic acid, which is a type of catechin). When provided in a GLP-1R agonist composition, the amount of EGCG composition provided may be about 10 μg to about 10 g.For example, the amount of EGCG composition in the GLP-1R agonist composition is approximately 10 μg, 15 μg, 20 μg, 25 μg, 30 μg, 35 μg, 40 μg, 45 μg, 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 95 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, 250 μg, 275 μg, 300 μg, 325 μg, 350 μg, 375 μg, 400 μg, 425 μg, 450 μg, 475 μg, 500 μg, 525 μg. 550μg, 575μg, 600μg, 625μg, 650μg, 675μg, 700μg, 725μg, 750μg, 775μg, 800μg, 825μg, 850μg, 875μg, 900μg, 925μg, 950μg, 975μg, 1000μg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 125mg, 150mg, 175m g, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg , 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, 1.0g, 1.25g, 1.50g, 1.75g, 2.0g, 2.25g, 2.5 The amounts may be 0g, 2.75g, 3.0g, 3.25g, 3.50g, 3.75g, 4.0g, 4.25g, 4.50g, 4.75g, 5.0g, 5.25g, 5.50g, 5.75g, 6.0g, 6.25g, 6.50g, 6.75g, 7.0g, 7.25g, 7.50g, 7.75g, 8.0g, 8.25g, 8.50g, 8.75g, 9.0g, 9.25g, 9.50g, 9.75g, 10.0g, or any range or amount between any two of the preceding values ​​and any other range or amount disclosed herein.

[0022] As used herein, “freeze-dried milk (kefir powder) composition” refers to a composition containing kefir powder. When provided in a GLP-1R agonist composition, the amount of kefir powder composition provided may be about 10 μg to about 10 g.For example, the amount of kefir powder composition in the GLP-1R agonist composition is approximately 10 μg, 15 μg, 20 μg, 25 μg, 30 μg, 35 μg, 40 μg, 45 μg, 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 95 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, 250 μg, 275 μg, 300 μg, 325 μg, 350 μg, 375 μg, 400 μg, 425 μg, 450 μg, 475 μg, 500 μg, 525 μg μg, 550μg, 575μg, 600μg, 625μg, 650μg, 675μg, 700μg, 725μg, 750μg, 775μg, 800μg, 825μg, 850μg, 875μg, 900μg, 925μg, 950μg, 975μg, 1000μg g, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 125mg, 150mg, 17 5mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650m g, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, 1.0g, 1.25g, 1.50g, 1.75g, 2.0g, 2.25g, 2. The amounts may be 50g, 2.75g, 3.0g, 3.25g, 3.50g, 3.75g, 4.0g, 4.25g, 4.50g, 4.75g, 5.0g, 5.25g, 5.50g, 5.75g, 6.0g, 6.25g, 6.50g, 6.75g, 7.0g, 7.25g, 7.50g, 7.75g, 8.0g, 8.25g, 8.50g, 8.75g, 9.0g, 9.25g, 9.50g, 9.75g, 10.0g, or any range or amount between any two of the preceding values ​​and any other range or amount disclosed herein.

[0023] As used herein, “Garcinia cambogia extract (hydroxycitric acid) composition” refers to a composition comprising Garcinia cambogia extract having hydroxycitric acid as an active ingredient. When provided in a GLP-1R agonist composition, the amount of Garcinia cambogia extract composition provided may be about 10 μg to about 10 g.For example, the amount of Garcinia cambogia extract composition in the GLP-1R agonist composition is approximately 10 μg, 15 μg, 20 μg, 25 μg, 30 μg, 35 μg, 40 μg, 45 μg, 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 95 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, 250 μg, 275 μg, 300 μg, 325 μg, 350 μg, 375 μg, 400 μg, 425 μg, 450 μg, 475 μg, and 500 μg. , 525μg, 550μg, 575μg, 600μg, 625μg, 650μg, 675μg, 700μg, 725μg, 750 μg, 775μg, 800μg, 825μg, 850μg, 875μg, 900μg, 925μg, 950μg, 975μg, 1 000μg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 125mg, 150mg , 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 6 50mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, 1.0g, 1.25g, 1.50g, 1.75g, 2.0g, 2.25g, The amounts may be 2.50g, 2.75g, 3.0g, 3.25g, 3.50g, 3.75g, 4.0g, 4.25g, 4.50g, 4.75g, 5.0g, 5.25g, 5.50g, 5.75g, 6.0g, 6.25g, 6.50g, 6.75g, 7.0g, 7.25g, 7.50g, 7.75g, 8.0g, 8.25g, 8.50g, 8.75g, 9.0g, 9.25g, 9.50g, 9.75g, 10.0g, or any range or amount between any two of the preceding values ​​and any other range or amount disclosed herein.

[0024] As used herein, “lion mane mushroom composition” refers to a composition comprising lion mane mushroom powder, which may be dried and powdered fruiting bodies of lion mane mushrooms, dried and powdered extracts of lion mane mushrooms, or a combination thereof. When provided in a GLP-1R agonist composition, the amount of lion mane mushroom composition provided may be about 10 μg to about 10 g.For example, the amount of lion's mane mushroom composition in the GLP-1R agonist composition is approximately 10 μg, 15 μg, 20 μg, 25 μg, 30 μg, 35 μg, 40 μg, 45 μg, 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 95 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, 250 μg, 275 μg, 300 μg, 325 μg, 350 μg, 375 μg, 400 μg, 425 μg, 450 μg, 475 μg, 500 μg g, 525μg, 550μg, 575μg, 600μg, 625μg, 650μg, 675μg, 700μg, 725μg, 75 0μg, 775μg, 800μg, 825μg, 850μg, 875μg, 900μg, 925μg, 950μg, 975μg, 1 000μg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 125mg, 150mg , 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 6 50mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, 1.0g, 1.25g, 1.50g, 1.75g, 2.0g, 2.25g, The amounts may be 2.50g, 2.75g, 3.0g, 3.25g, 3.50g, 3.75g, 4.0g, 4.25g, 4.50g, 4.75g, 5.0g, 5.25g, 5.50g, 5.75g, 6.0g, 6.25g, 6.50g, 6.75g, 7.0g, 7.25g, 7.50g, 7.75g, 8.0g, 8.25g, 8.50g, 8.75g, 9.0g, 9.25g, 9.50g, 9.75g, 10.0g, or any range or amount between any two of the preceding values ​​and any other range or amount disclosed herein.

[0025] As used herein, “medium-chain triglyceride composition” refers to a composition comprising fatty acids having a chain length of 6 to 12 carbon atoms. When provided in a GLP-1R agonist composition, the amount of the medium-chain triglyceride composition provided may be about 10 μg to about 10 g.For example, the amount of the medium-chain triglyceride composition in the GLP-1R agonist composition can be about 10 μg, 15 μg, 20 μg, 25 μg, 30 μg, 35 μg, 40 μg, 45 μg, 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 95 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, 250 μg, 275 μg, 300 μg, 325 μg, 350 μg, 375 μg, 400 μg, 425 μg, 450 μg, 475 μg, 500 μg, 525 μg, 550 μg, 575 μg, 600 μg, 625 μg, 650 μg, 675 μg, 700 μg, 725 μg, 750 μg, 775 μg, 800 μg, 825 μg, 850 μg, 875 μg, 900 μg, 925 μg, 950 μg, 975 μg, 1000 μg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1.0 g, 1.25 g, 1.50 g, 1.75 g, 2.0 g, 2.25 g, 2.50 g, 2.75 g, 3.0 g, 3.25 g, 3.50 g, 3.75 g, 4.0 g, 4.25 g, 4.50 g, 4.75 g, 5.0 g, 5.25 g, 5.50 g, 5.75 g, 6.0 g, 6.25 g, 6.50 g, 6.75 g, 7.0 g, 7.25 g, 7.50 g, 7.75 g, 8.0 g, 8.25 g, 8.50 g, 8.75 g, 9.0 g, 9.25 g, 9.50 g, 9.75 g, 10.0 g, or any range or amount between any two of the preceding values and any other range or amount disclosed herein.

[0026] As used herein, “pterostilbene composition” refers to a composition comprising the compound pterostilbene, which has the chemical name 4-(3,5-dimethoxystyryl)phenol. When provided in a GLP-1R agonist composition, the amount of pterostilbene composition provided may be about 10 μg to about 10 g.For example, the amount of pterostilbene composition in the GLP-1R agonist composition is approximately 10 μg, 15 μg, 20 μg, 25 μg, 30 μg, 35 μg, 40 μg, 45 μg, 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 95 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, 250 μg, 275 μg, 300 μg, 325 μg, 350 μg, 375 μg, 400 μg, 425 μg, 450 μg, 475 μg, 500 μg, 525 μg μg, 550μg, 575μg, 600μg, 625μg, 650μg, 675μg, 700μg, 725μg, 750μg, 775μg, 800μg, 825μg, 850μg, 875μg, 900μg, 925μg, 950μg, 975μg, 1000μg g, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 125mg, 150mg, 17 5mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650m g, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, 1.0g, 1.25g, 1.50g, 1.75g, 2.0g, 2.25g, 2. The amounts may be 50g, 2.75g, 3.0g, 3.25g, 3.50g, 3.75g, 4.0g, 4.25g, 4.50g, 4.75g, 5.0g, 5.25g, 5.50g, 5.75g, 6.0g, 6.25g, 6.50g, 6.75g, 7.0g, 7.25g, 7.50g, 7.75g, 8.0g, 8.25g, 8.50g, 8.75g, 9.0g, 9.25g, 9.50g, 9.75g, 10.0g, or any range or amount between any two of the preceding values ​​and any other range or amount disclosed herein.

[0027] As used herein, “quercetin pure composition” refers to a composition containing quercetin (i.e., a flavonoid found in fruits and vegetables) having less than 5% impurities by weight. When provided in a GLP-1R agonist composition, the amount of quercetin pure composition provided may be about 10 μg to about 10 g.For example, the amount of quercetin pure composition in the GLP-1R agonist composition is approximately 10 μg, 15 μg, 20 μg, 25 μg, 30 μg, 35 μg, 40 μg, 45 μg, 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 95 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, 250 μg, 275 μg, 300 μg, 325 μg, 350 μg, 375 μg, 400 μg, 425 μg, 450 μg, 475 μg, 500 μg, 525 μg μg, 550μg, 575μg, 600μg, 625μg, 650μg, 675μg, 700μg, 725μg, 750μg, 775μg, 800μg, 825μg, 850μg, 875μg, 900μg, 925μg, 950μg, 975μg, 1000μg g, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 125mg, 150mg, 17 5mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650m g, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, 1.0g, 1.25g, 1.50g, 1.75g, 2.0g, 2.25g, 2. The amounts may be 50g, 2.75g, 3.0g, 3.25g, 3.50g, 3.75g, 4.0g, 4.25g, 4.50g, 4.75g, 5.0g, 5.25g, 5.50g, 5.75g, 6.0g, 6.25g, 6.50g, 6.75g, 7.0g, 7.25g, 7.50g, 7.75g, 8.0g, 8.25g, 8.50g, 8.75g, 9.0g, 9.25g, 9.50g, 9.75g, 10.0g, or any range or amount between any two of the preceding values ​​and any other range or amount disclosed herein.

[0028] As used herein, “resveratrol composition” refers to a composition comprising the compound resveratrol (i.e., a compound having the chemical name 3,5,4'-trihydroxystilbene). When provided in a GLP-1R agonist composition, the amount of resveratrol composition provided may be about 10 μg to about 10 g.For example, the amount of the resveratrol composition in the GLP-1R agonist composition can be about 10 μg, 15 μg, 20 μg, 25 μg, 30 μg, 35 μg, 40 μg, 45 μg, 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 95 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, 250 μg, 275 μg, 300 μg, 325 μg, 350 μg, 375 μg, 400 μg, 425 μg, 450 μg, 475 μg, 500 μg, 525 μg, 550 μg, 575 μg, 600 μg, 625 μg, 650 μg, 675 μg, 700 μg, 725 μg, 750 μg, 775 μg, 800 μg, 825 μg, 850 μg, 875 μg, 900 μg, 925 μg, 950 μg, 975 μg, 1000 μg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1.0 g, 1.25 g, 1.50 g, 1.75 g, 2.0 g, 2.25 g, 2.50 g, 2.75 g, 3.0 g, 3.25 g, 3.50 g, 3.75 g, 4.0 g, 4.25 g, 4.50 g, 4.75 g, 5.0 g, 5.25 g, 5.50 g, 5.75 g, 6.0 g, 6.25 g, 6.50 g, 6.75 g, 7.0 g, 7.25 g, 7.50 g, 7.75 g, 8.0 g, 8.25 g, 8.50 g, 8.75 g, 9.0 g, 9.25 g, 9.50 g, 9.75 g, 10.0 g, or any range or amount between any two of the preceding values and any other range or amount disclosed herein.

[0029] As used herein, “sucralose composition” refers to a composition comprising sucralose (i.e., an artificial sweetener that stimulates GLP-1 release via sweet taste receptors on enteroendocrine cells). When provided in a GLP-1R agonist composition, the amount of sucralose composition provided may be about 10 μg to about 30 mg. For example, the amount of sucralose composition in a GLP-1R agonist composition may be about 10 μg, 15 μg, 20 μg, 25 μg, 30 μg, 35 μg, 40 μg, 45 μg, 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 95 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200μg, 225μg, 250μg, 275μg, 300μg, 325μg, 350μg, 375μg, 400μg, 425μg, 450μg, 475μg, 50 0μg, 525μg, 550μg, 575μg, 600μg, 625μg, 650μg, 675μg, 700μg, 725μg, 750μg, 775μg, 800μg g, 825 μg, 850 μg, 875 μg, 900 μg, 925 μg, 950 μg, 975 μg, 1000 μg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, or any range or amount between any two of the preceding values ​​and any other range or amount disclosed herein.

[0030] As used herein, “Uva ursi leaf powder composition” refers to a composition comprising uva ursi leaf powder, which may be dried and powdered uva ursi leaves, dried and powdered uva ursi leaf extracts, or a combination thereof. When provided in a GLP-1R agonist composition, the amount of uva ursi leaf powder composition provided may be about 10 μg to about 10 g.For example, the amount of bearberry leaf powder composition in the GLP-1R agonist composition is approximately 10 μg, 15 μg, 20 μg, 25 μg, 30 μg, 35 μg, 40 μg, 45 μg, 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 95 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, 250 μg, 275 μg, 300 μg, 325 μg, 350 μg, 375 μg, 400 μg, 425 μg, 450 μg, 475 μg, 500 μg, 52 5μg, 550μg, 575μg, 600μg, 625μg, 650μg, 675μg, 700μg, 725μg, 750μg, 775μg, 800μg, 825μg, 850μg, 875μg, 900μg, 925μg, 950μg, 975μg, 1000 μg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 125mg, 150mg, 1 75mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650 mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, 1.0g, 1.25g, 1.50g, 1.75g, 2.0g, 2.25g, 2 0.50g, 2.75g, 3.0g, 3.25g, 3.50g, 3.75g, 4.0g, 4.25g, 4.50g, 4.75g, 5.0g, 5.25g, 5.50g, 5.75g, 6.0g, 6.25g, 6.50g, 6.75g, 7.0g, 7.25g, 7.50g, 7.75g, 8.0g, 8.25g, 8.50g, 8.75g, 9.0g, 9.25g, 9.50g, 9.75g, 10.0g, or any range or amount between any two of the preceding values ​​and any other range or amount disclosed herein.

[0031] It is understood that the GLP-1R agonists in the GLP-1R agonist compositions described herein are not limited to the above compositions, and any foods, nutrients, plants, and supplements that activate GLP-1R may also be included in the GLP-1R agonist compositions.

[0032] Some embodiments provide compositions comprising a certain amount of one or more DPP-4 inhibitors formulated as DPP-4 inhibitor compositions. In certain embodiments, the DPP-4 inhibitor composition may comprise a certain amount of a stilbenoide composition, a certain amount of a protoberberine composition, a certain amount of a pharmaceutical-grade DPP composition, a certain amount of a hydroxycitric acid composition, a certain amount of an EGCG composition, a certain amount of a sucralose composition, a certain amount of a bayberry powder composition, a certain amount of a tea plant (camellia sinensis) (matcha) powder composition, a certain amount of a lion's mane mushroom powder composition, a certain amount of a bearberry leaf powder composition, a certain amount of a capsaicin (chili pepper) composition, a certain amount of a curcumin composition, a certain amount of a freeze-dried milk (kefir powder) composition, a certain amount of a medium-chain triglyceride composition, and a certain amount of a conjugated linoleic acid composition, or any combination thereof. In some embodiments, the DPP-4 inhibitor composition as described herein may comprise a pharmaceutically acceptable medium, carrier, or diluent. Some embodiments can be formulated to have varying amounts of the aforementioned components.

[0033] As used herein, “stilbenoid composition” is defined as a composition comprising one or more of the following compounds: climacostol, desoxylapontigenin, dihydropinosylvin monomethyl ether, dihydroresveratrol, gnetol, isolapontigenin, isoresveratrol, oxyresveratrol, picetanol, pinostilbene, pinosylvin, pinosylvin monomethyl ether, pterostilbene, resveratrol, lapontigenin, triacetylresveratrol, trimethylresveratrol, 3'-hydroxypterostilbene, 3,4'-dimethoxyresveratrol, 3,5-dihydroxy-4-ethyl-trans-stilbene, 3,5-dihydroxy-4-isopropylstilbene, 4'-bromo-resveratrol, 4,4'-dihydroxystilbene, or any of the aforementioned glycosylated derivatives.

[0034] When provided in a DPP-4 inhibitor composition, the amount of the stilbenoid composition provided may be about 10 μg to about 10 g. For example, the amount of stilbenoide composition in the DPP-4 inhibitor composition is approximately 10 μg, 15 μg, 20 μg, 25 μg, 30 μg, 35 μg, 40 μg, 45 μg, 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 95 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, 250 μg, 275 μg, 300 μg, 325 μg, 350 μg, 375 μg, 400 μg, 425 μg, 450 μg, 475 μg, 500 μg, 525 μg. 550μg, 575μg, 600μg, 625μg, 650μg, 675μg, 700μg, 725μg, 750μg, 775μg, 800μg, 825μg, 850μg, 875μg, 900μg, 925μg, 950μg, 975μg, 1000μg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 125mg, 150mg, 175m g, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg , 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, 1.0g, 1.25g, 1.50g, 1.75g, 2.0g, 2.25g, 2.5 The amounts may be 0g, 2.75g, 3.0g, 3.25g, 3.50g, 3.75g, 4.0g, 4.25g, 4.50g, 4.75g, 5.0g, 5.25g, 5.50g, 5.75g, 6.0g, 6.25g, 6.50g, 6.75g, 7.0g, 7.25g, 7.50g, 7.75g, 8.0g, 8.25g, 8.50g, 8.75g, 9.0g, 9.25g, 9.50g, 9.75g, 10.0g, or any range or amount between any two of the preceding values ​​and any other range or amount disclosed herein.

[0035] As used herein, “protoberberine composition” is defined as a composition comprising one or more of the following compounds: allocryptopine, berberine, berberine hydrochloride, canazine, columbamin, coptisine, cordylamine, corisamine, cryptopine, cyclanoline, dihydroberberine, dihydrocoptisine, dihydropalmatine, epiberberine, groenlandisine, jatrolysine, methylstehoridine, palmatine, protopine, pseudoberberine, pseudocoptisine, sclerin, stepharanine, stehoridine, styropine, tetrahydroberberine, and tetrahydropalmatine.

[0036] When provided in a DPP-4 inhibitor composition, the amount of the provided protoberberine composition may be about 10 μg to about 10 g. For example, the amount of protoberberine composition in a DPP-4 inhibitor composition is approximately 10 μg, 15 μg, 20 μg, 25 μg, 30 μg, 35 μg, 40 μg, 45 μg, 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 95 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, 250 μg, 275 μg, 300 μg, 325 μg, 350 μg, 375 μg, 400 μg, 425 μg, 450 μg, 475 μg, 500 μg, 525 μg. 550μg, 575μg, 600μg, 625μg, 650μg, 675μg, 700μg, 725μg, 750μg, 775μg, 800μg, 825μg, 850μg, 875μg, 900μg, 925μg, 950μg, 975μg, 1000μg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 125mg, 150mg, 175m g, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg , 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, 1.0g, 1.25g, 1.50g, 1.75g, 2.0g, 2.25g, 2.5 The amounts may be 0g, 2.75g, 3.0g, 3.25g, 3.50g, 3.75g, 4.0g, 4.25g, 4.50g, 4.75g, 5.0g, 5.25g, 5.50g, 5.75g, 6.0g, 6.25g, 6.50g, 6.75g, 7.0g, 7.25g, 7.50g, 7.75g, 8.0g, 8.25g, 8.50g, 8.75g, 9.0g, 9.25g, 9.50g, 9.75g, 10.0g, or any range or amount between any two of the preceding values ​​and any other range or amount disclosed herein.

[0037] As used herein, “Pharmacopoeia DPP composition” is defined as a composition comprising one or more of sitagliptin, vildagliptin, saxagliptin, linagliptin, gemigliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, and omaligliptin.

[0038] When provided in a DPP-4 inhibitor composition, the amount of the pharmaceutical-grade DPP composition provided may range from approximately 0.5 mg to approximately 200 mg. For example, the amount of the pharmaceutical-grade GLP composition in a DPP-4 inhibitor composition may be approximately 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, or 23 mg. , 24 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, or any range or amount between any two of the preceding values ​​and any other range or amount disclosed herein.

[0039] As used herein, hydroxycitric acid composition, EGCG composition, sucralose composition, bayberry powder composition, tea plant (camellia sinensis) (matcha) powder composition, lion's mane mushroom powder composition, bearberry leaf powder composition, capsaicin (chili pepper) composition, curcumin composition, freeze-dried milk (kefir powder) composition, medium-chain triglyceride composition, and conjugate linoleic acid composition are defined as above.When provided in a DPP-4 inhibitor composition, the amount of these compositions can be independently about 10 μg to about 10 g, for example, about 10 μg, 15 μg, 20 μg, 25 μg, 30 μg, 35 μg, 40 μg, 45 μg, 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 95 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, 250 μg, 275 μg, 300 μg, 325 μg, 350 μg, 375 μg, 400 μg, 425 μg, 450 μg, 475 μg μg, 500μg, 525μg, 550μg, 575μg, 600μg, 625μg, 650μg, 675μg, 700μg, 72 5μg, 750μg, 775μg, 800μg, 825μg, 850μg, 875μg, 900μg, 925μg, 950μg, 9 75μg, 1000μg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 125mg, 1 50mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg , 650mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, 1.0g, 1.25g, 1.50g, 1.75g, 2.0g, 2.25g , 2.50g, 2.75g, 3.0g, 3.25g, 3.50g, 3.75g, 4.0g, 4.25g, 4.50g, 4.75g, 5.0g, 5.25g, 5.50g, 5.75g, 6.0g, 6.25g, 6.50g, 6.75g, 7.0g, 7.25g, 7.50g, 7.75g, 8.0g, 8.25g, 8.50g, 8.75g, 9.0g, 9.25g, 9.50g, 9.75g, 10.0g, or any range or amount between any two of the preceding values ​​and any other range or amount disclosed herein.

[0040] It is understood that the DPP-4 inhibitors in the DPP-4 inhibitor compositions described herein are not limited to those compositions, and any foods, nutrients, plants, and supplements that inhibit DPP-4 may also be included in the DPP-4 inhibitor compositions. It is also understood that some compositions may have a dual effect, i.e., they may be both a GLP-1R agonist and a DPP-4 inhibitor.

[0041] In some embodiments, one or more compounds comprising a DPP-4 inhibitor composition can be formulated to cross the blood-brain barrier in a subject after administration of one or more DPP-4 inhibitor compositions described herein, as described herein. By providing at least one compound in a DPP-4 inhibitor composition that is formulated to cross the blood-brain barrier, more robust patient outcomes, namely increased weight loss, enhanced satiety, and / or increased GLP-1 levels, can be observed in the subject. Unless constrained by any particular theory, GLP-1 and endogenous GLP-1R agonists are thought to be secreted from intestinal L cells and neurons. Since DPP-4 degrades GLP-1, it is assumed that DPP-4 inhibitor compositions reduce the degradation of GLP-1. Furthermore, since a portion of endogenous GLP-1 originates in the brain, if a DPP-4 inhibitor that can cross the blood-brain barrier reduces the amount of GLP-1 degraded in the brain, then the overall GLP-1 levels in the subject will increase compared to a DPP-4 inhibitor that does not cross the blood-brain barrier. Therefore, since more GLP-1 is circulating in the body, the effects of higher levels of GLP-1, namely increased weight loss and enhanced satiety, are further improved.

[0042] Certain embodiments provide a combination composition comprising a certain amount of a GLP-1R agonist composition and a certain amount of a DPP-4 inhibitor composition as described herein, wherein the amounts of the GLP-1R agonist composition and the DPP-4 inhibitor composition are presented in a certain ratio. In some embodiments, the ratio of the amount of the GLP-1R agonist composition to the amount of the DPP-4 inhibitor composition may be about 1:1. In certain embodiments, the ratio of the amount of the GLP-1R agonist composition to the amount of the DPP-4 inhibitor composition may be in the range of about 10:1 to about 1:10. In this regard, the ratio of the amount of the GLP-1R agonist composition to the amount of the DPP-4 inhibitor composition may be approximately 10:1, 9.5:1, 9:1, 8.5:1, 8:1, 7.5:1, 7:1, 6.5:1, 6:1, 5.5:1, 5:1, 4.5:1, 4:1, 3.5:1, 3:1, 2.5:1, 2:1, 1.5:1, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:8.5, 1:9, 1:9.5, 1:10, or any ratio between these.

[0043] In some embodiments, as described herein, the ratio of the amount of GLP-1R agonist composition to the amount of DPP-4 inhibitor composition present in the combination composition may be a synergistic ratio. As used herein, “synergistic ratio” refers to a ratio that induces a surprisingly superior pharmacological, physiological, nutritional, or nutritional supplemental effect in the subject compared to a conventional composition. In some embodiments, the synergistic ratio of the amount of GLP-1R agonist composition to the amount of DPP-4 inhibitor composition may be about 1:1. In certain embodiments, the synergistic ratio of the amount of GLP-1R agonist composition to the amount of DPP-4 inhibitor composition may be in the range of about 5:1 to about 1:5. In this regard, the synergistic ratio of the amount of the GLP-1R agonist composition to the amount of the DPP-4 inhibitor composition may be about 5:1, 4.5:1, 4:1, 3.5:1, 3:1, 2.5:1, 2:1, 1.5:1, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, or any ratio between these. In certain embodiments, as described herein, combination compositions containing a certain synergistic ratio may induce unexpectedly advantageous effects in increasing weight loss, enhancing satiety, and / or increasing GLP-1 levels in subjects.

[0044] Unless constrained by any particular theory, providing a combination of a GLP-1R agonist composition and a DPP-4 inhibitor composition is expected to induce a synergistic response in subjects to increased weight loss, enhanced satiety, and / or increased GLP-1 levels. The GLP-1R agonist compositions described herein can be formulated to lower postprandial blood glucose levels by enhancing insulin secretion and inhibiting glucagon release, as well as enhancing satiety and thus reducing food intake. DPP-4 inhibitor compositions can be formulated to reduce the degradation of GLP-1 and similar GLP-1R agonists. Therefore, by providing a combination of a GLP-1R agonist composition and a DPP-4 inhibitor composition, the concentrations of GLP-1 and other GLP-1R agonists in subjects will be maintained at higher levels for a longer period than the same absent DPP-4 inhibitor, in a surprisingly advantageous manner. Therefore, since the concentrations of GLP-1 and other GLP-1R agonists are higher in subjects after administration of the compositions described herein, the beneficial effects of having higher levels of GLP-1 and other GLP-1R agonists, namely increased weight loss and enhanced satiety, are further improved and surprisingly superior compared to any of the compounds administered independently.

[0045] As described herein, the GLP-1R agonist compositions and DPP-4 inhibitor compositions, whether provided as combination compositions or individually, offer significant advantages over conventional GLP-1R agonist and DPP-4 inhibitors. The GLP-1R agonist and DPP-4 inhibitor compositions disclosed herein also offer other advantages, such as reduced manufacturing challenges, waste disposal, and avoidance of hazardous chemicals in the manufacturing process, and can be produced using methods and costs significantly lower than those known in the art. In addition, the GLP-1R agonist and DPP-4 inhibitor compositions disclosed herein have at best the same or more preferably lower incidence of negative side effects compared to compositions known in the art, providing the further benefits described herein and those anticipated by those skilled in the art considering this disclosure.

[0046] In some embodiments, the GLP-1R agonist compositions, DPP-4 inhibitor compositions, or combination compositions described herein may contain a certain amount of one or more supplement components. As used herein, the term “supplement component” may refer to essential fatty acids such as linolenic acid and linoleic acid, as well as essential amino acids such as tryptophan, lysine, methionine, phenylalanine, threonine, valine, leucine, isoleucine, arginine, and histidine, as well as n-acetylcysteine. Furthermore, the meaning of supplement ingredients includes vitamins such as retinol (vitamin A), thiamine (vitamin B1), riboflavin (vitamin B2), niacin (vitamin B3), pantothenic acid (vitamin B5), pyridoxine, pyridoxamine, or pyridoxal (vitamin B6), biotin (vitamin B7) or its pharmaceutically acceptable salts, folic acid (vitamin B9) or its pharmaceutically acceptable salts, cobalamin (vitamin B12), choline, ascorbic acid (vitamin C) or its pharmaceutically acceptable salts, ergocalciferol (vitamin D2), calciferol (vitamin D3), 22-dihydroergocalciferol (vitamin D4), citocalciferol (vitamin D5), tocopherol (vitamin E), phylloquinone (vitamin K1), menaquinone (vitamin K2), menadione (vitamin K3), or any combination thereof. For other vitamins not explicitly listed, those skilled in the art will readily anticipate them considering the disclosures contained herein. Supplementary ingredients may further include, for example, dietary minerals such as chromium, bromine, cobalt, copper, fluorine, germanium, iodine, iron, magnesium, manganese, molybdenum, potassium, selenium, silicon, zinc, calcium, phosphite, sodium, sulfur, and vanadium.Supplement ingredients may also include cranberry extract, turmeric, royal jelly, acai berry, beet root, coral calcium, oyster, gotu kola, ginkgo biloba, lion's mane mushroom, pomegranate, hibiscus flower, strawberry powder, dandelion root, celery powder, parsley powder, peppermint leaf, cinnamon bark powder, maca root, nicotinamide riboside, NAD+ precursor, coenzyme Q10, omega-3 fatty acids, cabbage powder, nicotinamide mononucleotide, and combinations thereof. Supplement ingredients may also include nitrates such as citrulline nitrate, creatine nitrate, β-alanine nitrate, and any other compounds, such as vitamins, minerals, herbs, plants, amino acids, enzymes, live bacteria, etc., not expressly listed above. Supplement ingredients are also defined as any concentrate, metabolite, component, or extract of any of these, and generally refer to any compound intended to supplement the diet of an individual. Those skilled in the art will readily anticipate the range of compounds encompassed by the term "supplementary component" (as used herein). The compositions described herein may, as will be understood by those skilled in the art, contain one or more of the aforementioned supplementary components.

[0047] The compositions described herein may contain one or more amounts of a supplement ingredient, which may be approximately 10 μg, 15 μg, 20 μg, 25 μg, 30 μg, 35 μg, 40 μg, 45 μg, 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 95 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, or 250 μg. g, 275μg, 300μg, 325μg, 350μg, 375μg, 400μg, 425μg, 450μg, 475μg, 500μg, 525μg, 550μg, 575μg, 600μg, 6 25μg, 650μg, 675μg, 700μg, 725μg, 750μg, 775μg, 800μg, 825μg, 850μg, 875μg, 900μg, 925μg, 950μg, 975μg , 1000μg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1.0 g, or any range or amount in between these.

[0048] In some embodiments, the GLP-1R agonist compositions, DPP-4 inhibitor compositions, or combination compositions described herein may further contain a certain amount of at least one excipient. The excipient is not particularly limited. Examples of excipients include, but are not limited to: acidifying agents (acetic acid, glacial acetic acid, citric acid, fumaric acid, hydrochloric acid, diluted hydrochloric acid, malic acid, nitric acid, phosphoric acid, diluted phosphoric acid, sulfuric acid, tartaric acid); alkalizing agents (ammonia solution, ammonium carbonate, diethanolamine, diisopropanolamine, potassium hydroxide, sodium bicarbonate, sodium borate, sodium carbonate, sodium hydroxide, trolamine); antifoaming agents (dimethicone, simethicone); antimicrobial preservatives (benzalkonium chloride, benzalkonium chloride solution, benzethonium chloride, benzoic acid, benzyl alcohol, butylparaben, cetylpyridinium chloride, chlorobutanol, chlorocresol, cresol, dehydroacetic acid, ethylparaben, methylparaben, sodium methylparaben, phenol, phenylethyl alcohol, phenylmercury acetate, phenylmercury nitrate, potassium benzoate, potassium sorbate, pro Pyroparaben, sodium propylparaben, sodium benzoate, sodium dehydroacetate, sodium propionate, sorbic acid, thimerosal, thymol); Antioxidants (ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium thiosulfate, sulfur dioxide, tocopherol, tocopherol excipient); Buffering agents (acetic acid, ammonium carbonate, ammonium phosphate, boric acid, citric acid, lactic acid, phosphoric acid, potassium citrate, potassium metaphosphate, monobasic potassium phosphate, sodium acetate, sodium citrate, sodium lactate solution, dibasic sodium phosphate, monobasic sodium phosphate); Chelating agents (disodium edetate, ethylenediaminetetraacetic acid and salts, edetate);Coating agents (sodium carboxymethylcellulose, cellulose acetate, cellulose phthalate acetate, ethylcellulose, gelatin, pharmaceutical glaze, hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer, methylcellulose, polyvinyl acetate phthalate, shellac, sucrose, titanium dioxide, carnauba wax, microcrystalline wax, zein); coloring agents (caramel, red, yellow, black or blend, ferric oxide); complexing agents (ethylenediaminetetraacetic acid and salts (EDTA), edetate, gentisic acid ethanolamide, oxyquinoline sulfate); drying agents (calcium chloride, calcium sulfate, silicon dioxide); emulsifiers and / or solubilizers (acacia, cholesterol, diethanolamine (auxiliary), glyceryl monostearate, lanolin alcohol, mono- and di-glycerides, monoethanolamine (auxiliary), lecithin, Oleic acid (auxiliary agent), oleyl alcohol (stabilizer), poloxamer, polyoxyethylene 50 stearate, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 10 oleyl ether, polyoxyl 20 cetostearyl ether, polyoxyl 40 stearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, diacetate, monostearate, sodium lauryl sulfate, sodium stearate , sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, stearic acid, trolamine, emulsifying wax); filtration aid (powdered cellulose, refined siliceous earth); fragrances and air fresheners (anethole, benzaldehyde, ethyl vanillin, menthol, methyl salicylate, sodium glutamate, orange flower oil, peppermint, peppermint oil, peppermint spirit, rose oil, stronger rose water, thymol, tolu balsam tincture, vanilla, vanilla tincture, vanillin); water-retaining agents (glycerol, hexylene glycol, sorbitol);Plasticizers (castor oil, diacetylated monoglycerides, diethyl phthalate, glycerol, mono- and di-acetylated monoglycerides, propylene glycol, triacetin, triethyl citrate); polymers (cellulose acetate, alkylcellulose, hydroxyalkyl, acrylic polymers and copolymers); solvents (acetone, alcohol, diluent alcohol, amylene hydrate, benzyl benzoate, butyl alcohol, carbon tetrachloride, chloroform, corn oil, cottonseed oil, ethyl acetate, glycerol, hexylene glycol, isopropyl alcohol) Alcohol, methyl alcohol, methylene chloride, methyl isobutyl ketone, mineral oil, peanut oil, propylene carbonate, sesame oil, water for injection, sterile water for injection, sterile water for irrigation, purified water); adsorbents (powdered cellulose, charcoal, purified siliceous soil); carbon dioxide adsorbents (barium hydroxide lime, soda lime); hardening agents (hydrogenated castor oil, cetostearyl alcohol, cetyl alcohol, cetyl ester wax, hard fat, paraffin, polyethylene excipients, stearyl alcohol, emulsifying wax, white wax, yellow wax); suspending agents and / or Thickeners (acacia, agar, alginic acid, aluminum monostearate, bentonite, purified bentonite, magma bentonite, carbomer, calcium carboxymethylcellulose, sodium carboxymethylcellulose, sodium carboxymethylcellulose-12, carrageenan, microcrystalline and sodium carboxymethylcellulose cellulose, dextrin, gelatin (bloom strength 50-100), guar gum, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, magnesium aluminum silicate, methylcellulose, pectin, polyethylene oxide, polyvinyl alcohol, povidone, alginate, silicon dioxide, colloidal silicon dioxide, sodium alginate, tragacanth, xanthan gum); Sweeteners (aspartame, dextrose, glucose, excipient glucose, fructose, mannitol, saccharin, calcium saccharin, sodium saccharin, sorbitol, sorbitol solution, sucrose, compressible sugar, confectioner sugar, syrup); Surfactants (simethicone);Tablet binders (acacia, alginic acid, sodium carboxymethylcellulose, microcrystalline cellulose, dextrin, ethylcellulose, gelatin, liquid glucose, guar gum, hydroxypropyl methylcellulose, methylcellulose, polyethylene oxide, povidone, pregelatinized starch, syrup); Tablet and / or capsule diluents (calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, powdered cellulose, dextrate, dextrin, glucose excipients, fructose, kaolin, lactose, mannitol, sorbitol, starch, pregelatinized starch, sucrose, compressible sugar, confectioner sugar); Tablet disintegrants (alginic acid, microcrystalline cellulose, croscarmellose sodium, crospovidone, potassium polaritrin, sodium starch glycolate, starch, pregelatinized starch); Tablet and / or capsule lubricants Agents (calcium stearate, glyceryl behenate, magnesium stearate, light mineral oil, sodium stearyl fumarate, stearic acid, refined stearic acid, talc, hydrogenated vegetable oil, zinc stearate); Isotonic agents (glucose, glycerol, mannitol, potassium chloride, sodium chloride); Medium: Flavoring and / or sweetening (aromatic elixir, benzaldehyde elixir compound, isoalcohol elixir, peppermint water, sorbitol solution, syrup) P, Tolbalsam syrup); Medium: Oil (almond oil, corn oil, cottonseed oil, ethyl oleate, isopropyl myristate, isopropyl palmitate, mineral oil, light mineral oil, myristyl alcohol, octyldodecanol, olive oil, peanut oil, peach kernel oil, sesame oil, soybean oil, squalane); Medium: Solid carrier (glycospheric spheres); Medium: Sterile solution (bacteriostatic water for injection, bacteriostatic sodium chloride injection); Water repellent (cyclomethicone, dimethicone, simethicone);And / or solubilizers (benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, sodium doxate, nonoxynol 9, nonoxynol 10, octoxynol 9, poloxamer, polyoxyl 35 castor oil, polyoxyl 40, hydrogenated castor oil, polyoxyl 50 stearate, polyoxyl 10 oleyl ether, polyoxyl 20 cetostearyl ether, polyoxyl 40 stearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, sodium lauryl sulfate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, tyroxapol). This list is not intended to be exclusive, but rather to represent the classes and specific excipients that may be used in the GLP-1R agonist compositions, DPP-4 inhibitor compositions, or combination compositions described herein.

[0049] Compounds comprising the GLP-1R agonist compositions, DPP-4 inhibitor compositions, or combination compositions described herein may contain one or more active agents in therapeutically effective doses. For example, the "therapeutically effective dose" and / or "effective dose" of the compounds disclosed herein may be (on a weight basis of the dose per body weight of the subject) for example, 0.1 μg / kg, 0.5 μg / kg, 1 μg / kg, 1.5 μg / kg, 2.0 μg / kg, 2.5 μg / kg, 3.0 μg / kg, 3.5 μg / kg, 4.0 μg / kg, 4.5 μg / kg, 5.0 μg / kg, 10 μg / kg, 15 μg / kg, 20 μg / kg, 25 μg / kg, 30 μg / kg, 35 μg / kg, 40 μg / kg, 45 μg / kg μg / kg, 50μg / kg, 55μg / kg, 60μg / kg, 65μg / kg, 70μg / kg, 75μg / kg, 80μg / kg, 85μg / kg, 90μg / kg, 95μg / kg, 100μg / kg, 150μg / kg, 200μg / kg, 250μg / kg, 300μg / kg, 350μg / kg, 400μg / kg, 450μg / kg, 500μg / kg, 550μg / kg, 600μg / kg, 650μg / kg, 700μg / kg, 750μg / kg, 80μg / kg 0, 850μg / kg, 900μg / kg, 1mg / kg, 1.5mg.kg, 2.0mg / kg, 2.5mg / kg, 3mg / kg, 3.5mg / kg, 4.0mg / kg, 4.5mg / kg , 5mg / kg, 5.5mg / kg, 6mg / kg, 6.5mg / kg, 7mg / kg, 7.5mg / kg, 8mg / kg, 8.5mg / kg, 9mg / kg, 9.5mg / kg, 10mg / kg The amount may be 10.5 mg / kg, 11 mg / kg, 11.5 mg / kg, 12 mg / kg, 12.5 mg / kg, 13 mg / kg, 13.5 mg / kg, 14 mg / kg, 14.5 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, 20 mg / kg, 21 mg / kg, 22 mg / kg, 23 mg / kg, 24 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 55 mg / kg, 60 mg / kg, 65 mg / kg, 70 mg / kg, or more, or any fraction or integer between any two preceding amounts of the compound.The effective amount may include any of the ranges and quantities considered herein.

[0050] Therefore, in some embodiments, the dose of the composition disclosed herein (corresponding to a therapeutically effective dose) may be about 10 μg to about 10 g per day. For example, the amounts of the composition are 10μg, 15μg, 20μg, 25μg, 30μg, 35μg, 40μg, 45μg, 50μg, 55μg, 60μg, 65μg, 70μg, 75μg, 80μg, 85μg, 90μg, 95μg, 100μg, 125μg, 150μg, 175μg, 200μg, 225μg, 250μg, 275μg, 300μg, 325μg, 350μg, 375μg, 400μg, 425μg, 450μg, 475μg, 500μg, 525μg, 550μg, 575μg, 600μg, 625μg, 650μg, 675μg, 700μg, 725μg, 750μg, 775μg, 800μg, 825μg, 850μg, 875μg, 900μg, 925μg, 950μg, 975μg, 1000μg, 5mg, 10mg, 15mg, 20m g, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 2 50mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg, 7 25mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, 1.0g, 1.25g, 1.50g, 1.75g, 2.0g, 2.25g, 2.50g, 2.75g, 3.0 g, 3.25g, 3.50g, 3.75g, 4.0g, 4.25g, 4.50g, 4.75g, 5.0g, 5.25g, 5.50g, 5.75g, 6.0g, 6.25g, 6.50g, 6.75g, 7.0g, 7.25g, 7.50g, 7.75g, 8.0g, 8.25g, 8.50g, 8.75g, 9.0g, 9.25g, 9.50g, 9.75g, 10.0g, or more, or any range or amount between any two of the preceding values ​​and any other range or amount disclosed herein.

[0051] In some embodiments, the compositions described herein may be administered more or less frequently by means of the methods described elsewhere herein, for example, every hour, every two hours, every three hours, every four hours, every five hours, every six hours, every seven hours, every eight hours, every nine hours, every ten hours, every eleven hours, every twelve hours, every thirteen hours, every fourteen hours, every fifteen hours, every sixteen hours, every seventeen hours, every eighteen hours, every nineteen hours, every twenty hours, every twenty-one hours, every twenty-two hours, every twenty-three hours, or at any interval in between, or on a daily basis, every two days, every three days, every four days, every five days, every six days, every week, every eight days, every nine days, every ten days, every two weeks, every month, or more or less frequently, when it is required to achieve a desired therapeutic effect.

[0052] In some embodiments, a gradient dosing protocol can be used, i.e., when the composition described herein is administered to the subject in a gradually increasing dose. For example, the subject may be administered 100 mg of the composition described herein once daily for 7 days, followed by 200 mg daily for the next 7 days, followed by 300 mg daily for the next 7 days. Alternatively, the dosing protocol may follow a pattern in which the dose decreases over time. For example, 300 mg of the composition described herein daily for 7 days, followed by 200 mg daily for the next 7 days, followed by 100 mg daily for the next 7 days. In some embodiments, the method described herein can be used in combination with a calorie restriction protocol in the subject. In certain embodiments, the composition described herein may be administered before, after, or between meals. Furthermore, the appropriate dose of the composition may depend, for example, on the condition to be treated, the severity and course of the condition, whether the composition is administered for prophylactic or therapeutic purposes, previous treatments, the patient's clinical history and response to the composition, the type of composition used, and the discretion of the attending physician. The composition may preferably be administered to the patient in a single dose or over a series of treatments, or may be administered to the patient at any time after diagnosis. The composition may be administered to the subject as the sole composition. The composition may also be administered to the subject in combination with other drugs or therapies that have been used or are currently used to treat the condition in question, for a number of purposes, such as to enhance the effectiveness of these drugs or therapies, to maintain the effectiveness of these drugs or therapies while reducing their doses, thereby potentially reducing the side effects associated therewith, or to gradually allow the subject to potentially avoid the side effects associated therewith by discontinuing these drugs or therapies. Examples of these drugs or therapies include, but are not limited to, GLP-1 analogs (such as dulaglutide, albiglutide, exenatide, liraglutide, semaglutide, lixisenatide, and tylzepatide) and DPP-4 inhibitor drugs (such as sitagliptin, vildagliptin, saxagliptin, linagliptin, gemigliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, and omaligliptin).The compositions and one or more of these agents or treatments may be delivered simultaneously, at different times, at different frequencies, and / or by different delivery routes or forms, as described in this application.

[0053] In certain embodiments, the GLP-1R agonist compositions, DPP-4 inhibitor compositions, or combination compositions described herein can be formulated as health supplements, nutritional supplements, or pharmaceuticals.

[0054] In some embodiments, the GLP-1R agonist compositions, DPP-4 inhibitor compositions, or combination compositions described herein can be formulated to be administered via a route, for example, but not limited to, buccal, interstitial, intramuscular, intraperitoneal, intravenous, nasal, ophthalmic, oral, parenteral, rectal, subcutaneous, sublingual, or topically.

[0055] In certain embodiments, the GLP-1R agonist compositions, DPP-4 inhibitor compositions, or combination compositions described herein, formulated for administration via an oral route, may be in the form of powders, granules, suspensions, aqueous solutions, oil-based solutions, beverages, syrups, elixirs, emulsions, capsules (soft, hard, gel, or plant-based), pills, tablets, caplets, sachets, gums, or soluble oral strips. In the oral formulations described above, the formulations may contain one or more of the excipients described above. Those skilled in the art will recognize excipients suitable for the particular oral delivery system being considered. Furthermore, various methods of sustained release and site-specific release, including immediate release, delayed release, sustained release, controlled release, and targeted delivery, are being considered.

[0056] Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutically acceptable compositions, and such compositions may contain one or more of the following agents: sweeteners, flavoring agents, coloring agents, coating agents, and preservatives. Sweeteners and flavoring agents will increase the palatability of the formulation. Tablets containing complexes mixed with non-toxic, pharmaceutically acceptable excipients suitable for tablet manufacture are acceptable. Pharmaceutically acceptable media such as excipients are compatible with the other components of the formulation (and are non-harmful to the patient). Such excipients include inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating agents and disintegrants, e.g., corn starch or alginic acid; binders such as starch, gelatin, or acacia; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be left uncoated or may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a longer-lasting effect. For example, time-delaying materials such as glyceryl monostearate or glyceryl distearate can be used alone or in combination with wax.

[0057] Furthermore, formulations for oral use may exist as hard gelatin-containing capsules or non-gelatinous capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil. Aqueous suspensions may contain the complex described herein mixed with excipients suitable for the preparation of aqueous suspensions. Such excipients include suspending agents, dispersing agents, or wetting agents, one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweeteners such as sucrose or saccharin.

[0058] Oil suspensions can be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil, or coconut oil, or in a mineral oil such as liquid paraffin. Oil suspensions may contain thickeners, such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners, such as those mentioned above, and flavorings can be added to provide palatable oral formulations. These compositions can be preserved by adding antioxidants such as ascorbic acid. Dispersible powders and granules suitable for preparing aqueous suspensions by adding water can provide active ingredients mixed with dispersants or wetting agents, suspending agents, and one or more preservatives. Additional excipients, such as sweeteners, flavorings, and colorings, may also be present.

[0059] The syrups and elixirs can be formulated with sweeteners, such as glycerol, sorbitol, or sucrose. Such formulations may also contain lubricants, preservatives, flavorings, or colorings.

[0060] Compositions formulated for parenteral administration may be in the form of sterile injectable formulations, such as sterile injectable aqueous or oily suspensions. These suspensions can be formulated according to methods well known in the art, using suitable dispersants or wetting and suspending agents. Alternatively, sterile injectable formulations may be sterile injectable solutions or suspensions in non-toxic, parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Suitable diluents include, for example, water, Ringer's solution, and isotonic salines. Furthermore, sterile non-volatile oils can commonly be used as solvents or suspension media. For this purpose, any brand of non-volatile oil, including synthetic monoglycerides or diglycerides, can be used. Additionally, fatty acids such as oleic acid can similarly be used in the preparation of injectable formulations.

[0061] It will be understood that a single dosage form can be prepared by combining the amount of the composition with a carrier material. Such a form will vary depending on the host being treated and the specific mode of administration.

[0062] The aqueous suspension may contain the compounds disclosed herein mixed with excipients suitable for preparing aqueous suspensions. Such excipients include suspending agents, dispersing agents, or wetting agents, one or more preservatives, one or more colorants, one or more flavoring agents, and one or more sweeteners such as sucrose or saccharin.

[0063] The use of controlled-release media will be readily anticipated by those skilled in the art in pharmaceuticals, taking into account the disclosures contained herein, and these embodiments can be applied to nutritional and health supplements.

[0064] A number of controlled-release media can be used, including biodegradable or bio-erosive polymers, such as polylactic acid, polyglycolic acid, and regenerated collagen. The controlled-release drug delivery device is a cream. Agent This may include lotions, tablets, capsules, gels, microparticles, liposomes, ocular inserts, minipumps, and other infusion devices such as pumps and syringes. Implantable or injectable polymer matrices and transdermal formulations that release active ingredients gradually can be used in the methods disclosed herein.

[0065] Controlled-release formulations can be achieved, as described herein, by the use of polymers to form complexes with or absorb compositions. Controlled delivery can be achieved by selecting suitable polymers such as polyesters, polyamino acids, polyvinylpyrrolidone, ethylene vinyl acetate, methylcellulose, carboxymethylcellulose, and protamine sulfate, as well as the concentrations of these polymers, and the method of incorporation is selected to control the release of the active complex.

[0066] Controlled release of compositions as described herein can be interpreted to mean any sustained-release dosage form. For the purposes of this disclosure, the following terms may be considered substantially equivalent to controlled release: continuous release, controlled release, delayed release, depot, gradual release, long-term release, programmed release, sustained release, programmed release, proportional release, delayed release, sustained, delayed, slow release, intermittent release, sustained release, time coat, time release, delayed action, swelling action, layered time action, long-lasting action, prolonged action, sustained action dosing and prolonged release, release in terms of pH levels in the intestines and intestinal tract, molecular degradation (based on absorption and bioavailability).

[0067] A hydrogel in which the composition disclosed herein is dissolved in an aqueous component and gradually released over time can be prepared by copolymerization of a hydrophilic monoolefin monomer, such as ethylene glycol methacrylate. A matrix device in which the composition described herein is dispersed in a matrix of a carrier material can be used. The carrier may be porous, nonporous, solid, semi-solid, permeable, or impermeable. Alternatively, the release of the composition can be controlled using a device comprising a central reservoir of the composition disclosed herein, covered with a rate control membrane. The rate control membrane may include an ethylene-vinyl acetate copolymer or butylene terephthalate / polytetramethylene ether terephthalate. The use of silicone rubber or ethylene-vinyl alcohol depot is also considered.

[0068] Controlled-release oral formulations may also be used. In some embodiments, the compositions described herein can be incorporated into a soluble or erosive matrix, such as a pill or lozenge. In another example, the oral formulation may be a liquid used for sublingual administration. These liquid compositions may also be in the form of a gel or paste. Hydrophilic gums, such as hydroxymethylcellulose, can be used. Lubricants such as magnesium stearate, stearic acid, or calcium stearate can be used to contribute to the tableting process.

[0069] In some embodiments, administration for oral administration may be a regimen requiring a single daily dose, a single dose every other day, a single dose within 72 hours of the initial dose, or multiple intermittent doses throughout the day. The active compositions forming the treatment may be administered in either a combination or separate dosage form, intended for simultaneous or substantially simultaneous oral administration. The active compositions forming the treatment may also be administered over time, with either active composition being administered by a regimen requiring two-step ingestion. Thus, the regimen may require the continuous administration of active compositions with intermittent ingestion of separate active compositions. The interval between multiple ingestion steps may range from a few minutes to up to about 72 hours, depending on the properties of each active composition, e.g., the potency, solubility, bioavailability, plasma half-life, and kinetic profile of the composition, as well as the patient's age and condition. The active compositions of the treatment may include regimens requiring the oral administration of one active composition and the intravenous administration of the other active composition, whether administered simultaneously, substantially simultaneously, or continuously. In one embodiment, the embodiments described herein can achieve therapeutic and / or dietary supplement benefits that have not been previously recognized or achievable, and consequently, an improved ability to use the composition. In some embodiments, the composition can be formulated for intravenous administration, as a more concentrated solution may be produced. Regardless of whether the active compositions of the therapeutic agent are administered separately or together via oral or intravenous route, each such active composition will be incorporated into a suitable pharmaceutical formulation of pharmaceutically acceptable excipients, diluents, or other formulation components.

[0070] In certain embodiments, a combination composition comprising the GLP-1R agonist composition and the DPP-4 inhibitor composition described herein can be formulated as a single dosage form intended for the simultaneous delivery of the GLP-1R agonist composition and the DPP-4 inhibitor composition. The route of administration or specific dosage form used to achieve this is not particularly limited and may not be any of the routes of administration or dosage forms contemplated herein. For example, the GLP-1R agonist composition and the DPP-4 inhibitor composition may be formulated, for example, as a single capsule for oral administration to a subject.

[0071] In some embodiments, a combination composition comprising a GLP-1R agonist composition and a DPP-4 inhibitor composition as described herein can be formulated as a single dosage form intended to provide differential delivery dynamics of the compositions contained therein. The route of administration or specific dosage form used to achieve this is not particularly limited and may not be any of the routes of administration or dosage forms contemplated herein. In a non-limiting example, the GLP-1R agonist composition and the DPP-4 inhibitor composition may be formulated as a single tablet such that, for example, about half of the tablet contains the GLP-1R agonist composition and the remaining half contains the DPP-4 inhibitor composition, with an impermeable barrier provided between them, where specific excipients, coatings, etc., used in each half of the tablet produce differential delivery dynamics. In certain cases, formulating the dosage form allows for the rapid release of the GLP-1R agonist composition compared to the DPP-4 inhibitor composition. In other cases, formulation can allow the DPP-4 inhibitor composition to be released more rapidly than the GLP-1R agonist composition. Since it is understood that DPP-4 can disrupt GLP-1, thereby inhibiting the efficacy of GLP-1R agonists, the relative administration timing and release profiles of GLP-1R agonists and DPP-4 inhibitors can influence the efficacy of their combined administration when administered to specific subjects. Therefore, in certain embodiments, the timing and release profile of the GLP-1R agonist can be synergistically optimized with respect to the DPP-4 inhibitor, achieving unexpectedly significant results. In certain embodiments, a single dosage form may comprise a DPP-4 inhibitor composition in a steady-release formulation and a GLP-1R agonist composition in a controlled-release formulation.In certain embodiments, a single dosage form may contain both a DPP-4 inhibitor composition and a GLP-1R agonist composition in a controlled-release formulation, the GLP-1R agonist composition being released within approximately 0-10 minutes, 0-20 minutes, 0-30 minutes, 0-60 minutes, 5-10 minutes, 10-20 minutes, 10-30 minutes, 20-30 minutes, 10-60 minutes, 20-40 minutes, 30-40 minutes, 40-60 minutes, and 50-60 minutes from the release of the DPP-4 inhibitor composition. In certain embodiments, a single dosage form comprising a DPP-4 inhibitor composition and a GLP-1R agonist composition can be administered alone or in combination with a drug or treatment currently used to treat the condition in question, to enhance the efficacy of these drugs or treatments, maintain their efficacy at lower doses, and consequently reduce the side effects associated with these drugs or treatments, or to gradually allow a patient who requires them to potentially avoid the associated side effects by discontinuing these drugs or treatments. Examples of such drugs or treatments include, but are not limited to, one or more GLP-1 analogs (such as dulaglutide, albiglutide, exenatide, liraglutide, semaglutide, lixisenatide, and tilzepatide) and one or more DPP-4 inhibitor drugs (such as dulaglutide, albiglutide, exenatide, liraglutide, semaglutide, lixisenatide, and tilzepatide). In certain embodiments, a single dosage form comprising a DPP-4 inhibitor composition and a GLP-1R agonist composition can be administered to a subject simultaneously with one or more GLP-1 analogs to reduce the dose of one or more GLP-1 analogs, thereby reducing associated side effects and / or allowing the subject to gradually discontinue one or more GLP-1 analogs. In certain embodiments, a single dosage form comprising a DPP-4 inhibitor composition and a GLP-1R agonist composition can be administered separately from one or more GLP-1 analogs. For example, one or more GLP-1 analogs can be administered first over a period of weight loss, followed by administration of a single dosage form comprising a DPP-4 inhibitor composition and a GLP-1R agonist composition to prevent weight gain.When used herein, a certain period may range from one day to one year or longer, depending on the requirements and tolerance of the subject, and this can be readily foreseen by those skilled in the art.

[0072] In some embodiments, a combination composition comprising a GLP-1R agonist composition and a DPP-4 inhibitor composition as described herein can be formulated in a single dosage form, one or more dosage forms, and / or other dosage forms, for which the GLP-1R agonist composition and the DPP-4 inhibitor composition are intended to be delivered. By formulating the GLP-1R agonist composition and the DPP-4 inhibitor composition in different dosage forms, a planned delivery scheme can be utilized. In some embodiments, the planned delivery scheme can deliver the GLP-1R agonist composition and the DPP-4 inhibitor composition to the target simultaneously. In other embodiments, the planned delivery scheme can deliver the GLP-1R agonist composition and the DPP-4 inhibitor composition at various time points, at different frequencies, and / or by different delivery routes or forms. There are no particular limitations on the delivery routes or specific dosage forms used to achieve this, and they may not be any of the delivery routes or dosage forms contemplated herein. In certain embodiments, a DPP-4 inhibitor composition may be administered first, followed by a GLP-1R agonist composition, where the interval between the two administrations can be about 15 minutes to 24 hours or any time in between. For example, the interval may be less than 1 hour, about 15 to 30 minutes, about 20 to 40 minutes, about 30 minutes to 1 hour, about 1 to 2 hours, about 2 to 3 hours, about 3 to 4 hours, about 4 to 5 hours, about 5 to 6 hours, about 6 to 7 hours, about 7 to 8 hours, about 8 to 9 hours, about 9 to 10 hours, about 10 to 11 hours, about 11 to 12 hours, about 12 to 13 hours, about 13 to 14 hours, about 14 to 15 hours, or about 15 to 16 hours. The duration could be approximately 16-17 hours, 17-18 hours, 18-19 hours, 19-20 hours, 20-21 hours, 21-22 hours, 22-23 hours, 23-24 hours, 2-4 hours, 3-5 hours, 4-8 hours, 6-8 hours, 7-12 hours, 8-10 hours, 12-14 hours, 15-18 hours, and 18-20 hours.In certain embodiments, the DPP-4 inhibitor composition may be administered after the administration of the GLP-1R agonist composition, where the interval between the two administrations may be about 1 minute to 1 hour or any time in between. For example, the interval may be about 1 to 5 minutes, about 5 to 10 minutes, about 10 to 15 minutes, about 15 to 30 minutes, about 20 to 40 minutes, about 30 to 45 minutes, about 40 to 50 minutes, and about 45 minutes to 1 hour. In certain embodiments, the DPP-4 inhibitor composition may be administered once daily, while the GLP-1R agonist composition may be administered several times daily. The DPP-4 composition, the GLP-1R agonist composition, or both may be taken in the presence or absence of food. For example, the DPP-4 composition, the GLP-1R agonist composition, or both may be taken before, during, after, or between meals at any time. In some embodiments, the same route of administration may be used for different dosage forms; for example, the GLP-1R agonist composition may be formulated as a softgel capsule for oral administration, and the DPP-4 inhibitor composition may be formulated as a tablet for oral administration, where both are administered to the subject simultaneously (as simultaneous administration) or at different times, for example, at intervals of several hours. In other embodiments, different dosage forms may use different or mixed routes of administration; for example, the GLP-1R agonist composition may be formulated as an injection for subcutaneous administration, and the DPP-4 inhibitor composition may be formulated as a tablet for oral administration, where both are administered to the subject simultaneously; depending on the dosage form and route of administration used, simultaneous delivery or not is possible. This is because there are pharmacokinetic differences, i.e., some dosage forms (e.g., delayed-release capsules vs. immediate-release capsules) and routes of administration (e.g., oral vs. subcutaneous) may take longer to induce the effect.

[0073] To reduce the side effects of drugs or therapies (such as one or more GLP-1 analogs and one or more DPP-4 inhibitor drugs) that have been used or are currently used to treat the condition in question, the DPP-4 inhibitor compositions and GLP-1R agonist compositions described herein can be used in combination with one or more of these drugs or therapies. For example, one or more DPP-4 inhibitor compositions, GLP-1R agonist compositions, and GLP-1 analogs can be administered simultaneously. In certain embodiments, one or more DPP-4 inhibitor compositions, GLP-1R agonist compositions, and GLP-1 analogs can be administered cyclically. For example, this sequence of administration can be repeated, such as administering the DPP-4 inhibitor composition for a certain period first, followed by the GLP-1R agonist composition, followed by one or more GLP-1 analogs. In certain embodiments, a subject can use the DPP-4 inhibitor and GLP-1R agonist compositions described herein to prevent weight gain after discontinuing the intake of one or more GLP-1 analogs. For example, a subject may initially take one or more GLP-1 analogs to reduce weight for a period of time, and then switch to the DPP-4 inhibitor and / or GLP-1R agonist compositions, which can be administered simultaneously or at various points in time as described herein. As used herein, “a period of time” may be one day, several days (e.g., two, three, four, five days or more), and several months (e.g., one month, two, three months or more). The routes of administration for the DPP-4 inhibitor, GLP-1R agonist compositions and one or more other GLP-1 agonists may be the same or different. For example, one or more GLP-1 analogs may be administered by subcutaneous injection, while the DPP-4 inhibitor and GLP-1R agonist compositions may be administered orally.

[0074] In certain embodiments, it is possible to administer the GLP-1R agonist compositions, DPP-4 inhibitor compositions, combination compositions, or any of the formulations described herein to a subject to increase weight loss, enhance satiety, increase GLP-1 levels, or any combination thereof. In other embodiments, it is possible to administer to a subject any of the GLP-1R agonist compositions, DPP-4 inhibitor compositions, combination compositions, or any of the formulations described herein to treat, induce remission of, prevent, or reduce the risk of experiencing any disease, disorder, or condition, including, but not limited to, bladder cancer, breast cancer, cardiovascular disease, colorectal cancer, coronary heart disease, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, dyslipidemia, endometrial cancer, esophageal cancer, gallbladder cancer, gallbladder disease, gastric cancer, gastroparesis, hyperglycemia, hypertension, renal cancer, liver cancer, lung cancer, meningioma, metabolic syndrome, multiple myeloma, obesity, osteoarthritis, ovarian cancer, pancreatic cancer, stroke, thyroid cancer, and type 2 diabetes.

[0075] In some embodiments, the compositions described herein can be formulated as supplements or dosages designed for animal use. In some animal applications, the compounds or compositions may be added to and / or included in pet treats or biscuits, such as dog biscuits or cat treats.

[0076] The term "pharmaceutically acceptable salt" includes salts of active compounds prepared with relatively non-toxic acids or bases, depending on the specific substituents found in the compounds comprising the compositions described herein. Examples of pharmaceutically acceptable acid addition salts include pharmaceutically acceptable acid addition salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monocarbonate, phosphoric acid, monohydrogenic acid, dihydrogenic acid, sulfuric acid, monohydrosulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, and methanesulfonic acid. Furthermore, salts of amino acids such as alginates, and salts of organic acids such as glucuronic acid or galacturonic acid are included (see, for example, Berge et al., Journal of Pharmaceutical Science, 66:1-19 (1977), the entire work of which is incorporated herein by reference). The specific compounds of this application contain both basic and acidic functionalities, which allow the compounds to be converted into either a base-addition salt or an acid-addition salt.

[0077] As used herein, the term “pharmaceutically acceptable solvent” may refer to a physiologically compatible solution of water or an aqueous buffer, or an aqueous solution containing a physiologically compatible organic solvent. A non-comprehensive list of pharmaceutically acceptable solvents is available from the U.S. Department of Health and Human Services, Food & Drug Administration, “Guidance for Industry: Q3C Impurities: Residual Solvents,” December 1997 or its most recent issue.

[0078] The terms "health supplements" or "nutritional supplements" have the same meanings under the Federal Food, Drug & Cosmetic Act.

[0079] As used herein, the term “excipient” means any compound that is part of a formulation that is not an active ingredient, i.e., any compound that has unrelated biological activity and, when added to the formulation, provides specific characteristics to the dosage form, including, for example, providing protection to the active ingredient from chemical degradation, or facilitating the release of tablets or caplets from the apparatus in which they are formed.

[0080] As used herein, the term “extract” means that the referenced compound can be physically or chemically modified to produce one or more compounds that can be incorporated into the compositions described herein. For example, an extract may be a non-natural compound that is chemically different from a naturally occurring compound due to the application of a manually controlled manufacturing or processing technique, such as those described herein, to the compound or raw material. In certain cases, an extract may refer to a non-natural composition from which undesirable components have been removed, thereby producing a compound that has characteristics significantly different from a naturally occurring compound or has enhanced functionality compared to a natural composition. In some cases, the compositions described herein may deviate from any natural composition because they are formulated into combinations of non-natural components, such as those described herein. By formulating an extract as described herein, it is possible to specifically include components of the starting material and specifically exclude certain components of the starting material.

[0081] The terms "pharmaceutical preparation," "preparation," and "composition" may refer to a preparation that is in a form that enables the biological activity of an active ingredient to be effective, and therefore can be administered to a subject for therapeutic use, in conjunction with pharmaceutical, health, and / or nutritional supplement use. The meanings of these terms will be obvious to those skilled in the art, based on the context in which they are used.

[0082] When used herein, “therapeutic effective dose” includes, in its meaning, a non-toxic but sufficient amount of the active ingredient of a compound or a composition containing it for use in the embodiments disclosed herein, to produce the desired therapeutic effect. Similarly, when used herein, “effective dose” or “effective dose” includes, in its meaning, a non-toxic but sufficient amount of the active ingredient of a compound or a composition containing it to provide the desired effect. “Therapeutic effective dose” or “effective dose” includes amounts of a compound that are not thought to be obtainable through a standard or natural diet, but which, as described herein, require supplementation and administration to achieve certain non-natural outcomes, such as those described herein, along with the extended use of any compound originating from or derived from natural sources. The exact amount of active ingredient required may vary between subjects, depending on factors such as the species being treated, the age and general condition of the subject, the severity of the condition being treated, the specific composition being administered, the subject's weight, and the mode of administration. Therefore, it may not always be possible to determine an exact “effective dose.” However, in any particular case, an appropriate “effective dose” can be determined by those skilled in the art, taking into account the disclosures contained herein.

[0083] As used herein, the term “bioavailability” refers to the amount of a substance that is absorbed by the subject and ultimately available for biological activity in the subject’s tissues and cells.

[0084] As used herein, “identifying” means detecting or selecting an object from a group of promising objects to establish, for example, that a particular object possesses a particular characteristic or feature. “Identifying” may include, for example, self-identification, self-diagnosis, and diagnosis by a healthcare professional.

[0085] As used herein, terms such as “preventing,” “treating,” “curing,” “relieving,” and “relieving” are used herein to generally refer to obtaining a desired pharmacological, physiological, nutritional, and / or functional food effect, and their scope and meaning will be apparent to those skilled in the art, based on the context in which these terms are used. Effects may be preventive in the sense of preventing or partially preventing a disease, symptom, or condition thereof, and / or therapeutic in the sense of partial or complete cure of a disease, condition, symptom, or adverse effect resulting from the disease. As used herein, the term “treatment” encompasses any treatment of a disease in mammals, particularly humans, and includes: (a) preventing the onset of a disease in a subject that may be predisposed to the disease but has not yet been diagnosed with it; (b) inhibiting or cessating the manifestation of a disease; or (c) alleviating a disease and causing a regression of the disease and / or its symptoms, condition, and comorbidities. In some embodiments, the compositions described herein can be administered to maintain a healthy level of a particular condition or biomarker in a subject, for example, a healthy level of intellectual sharpness. Any composition administered to prevent, treat, alleviate, or induce remission of any condition can also be administered to maintain a healthy level of a physiological or biological condition, as described herein. In certain embodiments, a dietary supplement can be administered to maintain a healthy level of one or more of the conditions disclosed herein. The scope and meaning of “prevent,” “treat,” “cure,” “alleviate,” “in remission,” and “maintain a healthy level of” will be readily apparent to those skilled in the art when considering the terms in the context of this disclosure and the claims.

[0086] As provided herein, disclosures of “ratios” of compounds and compositions correspond to ratios provided in terms of the mass of the components presented in the ratio.

[0087] Where used in this disclosure, the phrase “essentially from” means that it includes any elements listed after the phrase, limited to other elements that do not interfere with or contribute to the activity or action of the listed elements as specified in this disclosure. Thus, the phrase “essentially from” indicates that the listed elements are required or mandatory, while the other elements are optional and may or may not be present depending on whether they affect the activity or action of the listed elements. For example, the use of a composition that “essentially consists of” a composition for the treatment of a particular disease or disorder or for the maintenance of a healthy state would exclude other components that would substantially alter the intended outcome of the composition.

[0088] As used herein, a composition “substantially” containing the compound means that the composition contains the compound in an amount greater than about 80% by weight, more preferably greater than about 90% by weight, even more preferably greater than about 95% by weight, and most preferably greater than about 98% by weight.

[0089] To provide a more concise explanation, some of the quantitative expressions given herein are not eligible under the term “approximately.” Whether explicitly used or not, all quantities given herein refer to actual given values, and are understood to also refer to approximations to such given values ​​that would be reasonably inferred by those skilled in the art, such as approximations resulting from experimental and / or measurement conditions for such given values.

[0090] Furthermore, the appropriate dose of the composition may depend, for example, on the condition being treated, the severity and course of the condition, whether the composition is administered for preventive or therapeutic purposes, previous treatments, the patient's clinical history and response to the composition, the type of composition used, and the discretion of the attending physician. The composition may preferably be administered to the patient in a single dose or over a series of treatments, or to the patient as needed after diagnosis. The composition may be administered as a sole treatment or in combination with other drugs or treatments useful for treating the condition in question.

[0091] This disclosure provides GLP-1R agonist compositions, DPP-4 inhibitor compositions, or combinations thereof in solid / liquid dosage forms. By providing such dosage forms, the compositions exist in non-natural forms that differ from those that exist in nature, i.e., in supplements (e.g., in pills or powders), or nutritional or health supplements, which provide non-natural supplementation that cannot be achieved through non-supplementary foods. [Examples]

[0092] Examples Example 1 Various drugs will be evaluated for their GLP-1R binding activity using a GLP-1R agonist assay. The drugs will include conjugated linoleic acid, bayberry powder, berberine hydrochloride, tea plant (Camellia sinensis) (matcha), capsaicin (chili pepper), dong quai root powder, epigallocatechin gallate (EGCG), freeze-dried milk (kefir powder), Garcinia cambogia extract (hydroxycitric acid), carrot, lion's mane mushroom, Longvida curcumin (containing 95% curcuminoids), medium-chain triglycerides, pterostilbene, quercetin pure, resveratrol, sucralose, and bearberry leaf powder. Each drug was tested at concentrations of 200 ug / ml, 66.7 ug / ml, 22.22 ug / ml, 7.41 ug / ml, 2.47 ug / ml, and 0.82 ug / ml, with each test performed three times at each concentration. The activation factor of each drug at each concentration was determined by comparing it to the control. Drugs with a higher activation factor than the control were considered to be GLP-1R agonists.

[0093] Example 2 The study will evaluate various drugs for their DPP-4 in vitro inhibitory activity using recombinant DPP4 enzyme and the colorimetric substrate Gly-Pro p-nitroanilide hydrochloride (Gly-Pro-NA). Sitagliptin and distilled water will be used as positive and negative controls, respectively. The drugs will include hydroxycitric acid, epigallocatechin gallate (EGCG), resveratrol, sucralose, pterostilbene, bayberry powder, berberine hydrochloride powder, tea plant (camellia sinensis) powder, lion's mane mushroom powder, bearberry leaf powder, capsaicin, longvida curcumin, freeze-dried milk (kefir powder), medium-chain triglycerides, and conjugated linoleic acid. Aqueous solutions of hydroxycitric acid, epigallocatechin gallate (EGCG), resveratrol, sucralose, pterostilbene, and sitagliptin (positive control) are used in the test. Bayberry powder, berberine, tea plant (camellia sinensis) (matcha), lion's mane mushroom, and bearberry leaf powder are each suspended in water, hydrated for 1 hour with gentle stirring, centrifuged, filtered, and the resulting aqueous solutions are used in the test. Kefir powder is suspended in water, filtered, and the resulting aqueous solution is used in the test. An ethanol solution of capsaicin is used in the test. Conjugated linoleic acid is dissolved in water (containing 1% TWEEN20) and diluted with sodium phosphate buffer (0.1 M, pH 7.0). Solutions of longvida curcumin and medium-chain triglycerides are prepared to allow each of these drugs to have direct contact with the DPP4 enzyme in the assay.

[0094] The test is performed in a 96-well microtiter plate. Recombinant DPP4 enzyme solution (50 μL, 2 mU / mL, pH 8.0, in 50 mmol / L Tris-HCl buffer) is added to each well. Solutions for each drug, positive control, and negative control are added to the resulting recombinant DPP4 enzyme solution. Gly-Pro-NA solution (40 μL, 0.26 mmol / L, pH 7.05, in Hepes buffer) is added to each mixture to initiate the enzymatic reaction. The plate is placed on a plate reader set, and the absorbance at 405 nm is measured at 37°C. Dynamic readings are performed every 5 minutes from 0 to 60 minutes (13 readings in total). The readings for each drug are graphed as dose-response curves and overlay graphs to show relative comparisons between different drugs.

[0095] Example 3 Male Wistar albino / Sprague Dolly rats (age: 8 weeks, body weight (BW): 180 ± 20g) were purchased from the Experimental Research Unit of Firat University (FUDAM), housed under standard conditions (22.2°C, humidity, 55 5±5%), and provided with free access to food and water. The Animal Experiments Local Ethics Committee of Firat University approved the experiment in accordance with Directive 2010 / 63 / EU and the ARRIVE principle.

[0096] After a one-week adaptation period, the animals were divided into groups as shown in Table 1. The diets for the control group and the high-fat diet group are shown in Table 2.

[0097] [Table 1]

[0098] [Table 2]

[0099] Rats will be given free rein to eat solid feed or chocolate. Each day, they will be given free rein to eat solid feed along with one of five different types of commercially available chocolate bars. The composition of the different chocolate bars will be approximately 2300 kJ / 100g of energy, 50-60g / 100g of sugar, and 30-40g / 100g of fat. The solid feed will be placed on the cage lid, and the chocolate will be placed inside the cage. To encourage high energy intake in the rats, five different types of chocolate bars will be offered and changed daily. It is expected that the rats will prefer to eat chocolate, resulting in over 90% of their calories being consumed as chocolate. Treatment will begin after 1-3 months of solid feed / chocolate dieting. The duration of treatment will be 12 weeks. The test product will be administered to the rats daily via oral gastric tube feeding.

[0100] Body weight and food intake are measured manually on a daily basis during the treatment period. Calorie efficiency (kcal / g weight gain) is calculated daily by multiplying food intake (g) by the calorie content of the diet and dividing the result by the daily weight gain (g). Delta weight gain is calculated by subtracting the rat's weight on the metabolic test day from its weight on the first day of the experiment. Daily weight gain is calculated by obtaining the weight gain and dividing it by the number of days between the start of the experiment and the metabolic test day. After the experiment, the rats are sacrificed.

[0101] Visceral fat is removed from the carcass and weighed. Blood samples are collected in gel biochemistry tubes, serum samples are obtained, and centrifuged in a refrigerated centrifuge at 4°C and 3000×g for 10 minutes. Tissues obtained from the animals are stored in deep freezing at -80°C until analysis.

[0102] Serum glucose, triglycerides, cholesterol, aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea, and creatinine levels are analyzed using a portable automated chemical analyzer (Samsung LABGEO PT10, Samsung Electronics Co., Suwon, Korea). Serum insulin, leptin, and free fatty acid concentrations are measured using a rat-specific kit (Cayman Chemical Co., Ann Arbor, MI, USA) by enzyme-linked immunosorbent assay (ELISA, Elx-800, Bio-Tek Instruments Inc, Vermont, USA). GLP-1(7-36) amide levels are measured using a relevant commercially available kit by ELISA (Elx-800, Bio-Tek Instruments Inc, Vermont, USA). Active ghrelin concentrations are measured using an RIA kit (Ghrelin Activity RIA Kit; Linco Research).

[0103] The rat brains are immediately excised, flushed with ice-cold saline, immersed in liquid nitrogen, and stored at -80°C. Reverse transcription polymerase chain reaction and Western blotting are performed to measure the levels of GLP-1R, c-Fos, prolactin-releasing peptide (PrRP), and tyrosine hydroxylase in the whole brain. Special attention is paid to the hindbrain for c-Fos activation in the nucleus tractus solitarius, dorsal vagal complex, and area postote, as these are known brain regions for GLP-1 activity.

[0104] The segments of the cecum and colon (proximal, medial, and distal colon, each corresponding to a 2 cm segment obtained immediately after the cecal junction, mid-colon, and immediately before the rectum) are immediately resected, flushed with ice-cold saline, immersed in liquid nitrogen, and stored at -80°C for further Western blot analysis. The filled and empty cecum, liver, and epididymal fat pads are weighed.

[0105] Immediately clamp the liver sample with liquid nitrogen. Measure liver triglyceride levels by ELISA using a relevant commercially available kit.

[0106] mRNA, GLP-1, and GLP-2 levels in the proximal colon and cecum are measured by reverse transcriptase (RT)-polymerase chain reaction (PCR).

[0107] Western blotting in tissue samples measures the following markers: intestinal insulin receptor substrate, GLP-1(7-36) amide, and GLP-2 levels.

[0108] All quantitative data are expressed as mean ± standard deviation (SD). Experimental values ​​are analyzed using one-way analysis of variance. Values ​​p < 0.05 are considered statistically significant. All analyses are performed using statistical analysis software (SPSS 17.0).

[0109] Example 4 (i) comprising a certain amount of at least one GLP-1R agonist composition as disclosed herein, (ii) comprising a certain amount of at least one DPP-4 inhibitor composition as disclosed herein, and / or (iii) comprising a certain amount of at least one GLP-1R agonist composition and a certain amount of at least one DPP-4 inhibitor composition, one or more formulations intended for oral administration, such as powders, granules, capsules (soft, hard, gel, or plant-based), pills, tablets, caplets, etc., as disclosed herein, prepared by means of the methods disclosed herein or by means of methods known in the art. In the above formulations, individual batches of a single formulation, for example, an oral formulation containing a certain amount of at least one GLP-1R agonist composition and a certain amount of at least one DPP-4 inhibitor composition, are divided into two subbatches: (i) the formulation as prepared, and (ii) the formulation prepared using a coating that allows for delayed / controlled release, or enables sustained release of one or more active ingredients from the formulation, namely the GLP-1R agonist and / or the DPP-4 inhibitor, by coating the surface of the formulation with a slow-dissolving coating, a pH-responsive coating, an enteric coating, etc.

[0110] The release of GLP-1R agonists and / or DPP-4 inhibitors from oral formulations is evaluated by placing the oral formulation in a large volume of physiologically mimicked liquid, such as phosphate-buffered saline, which has a pH within the normal physiological range of the site where the release of the GLP-1R agonist and / or DPP-4 inhibitor is desired, for example, approximately 1.5–4 pH for gastric release, approximately 5.6–8.0 pH for duodenal release, and 7.2–8.5 pH for GI tube release. Aliquot dispensing from the physiologically mimicked liquid is stopped at a predetermined time. The amount of GLP-1R agonist and / or DPP-4 inhibitor in a given volume is characterized using an appropriate method, such as UV-vis spectroscopy, colorimetric assay, or mass spectrometry.

[0111] The release profile is created by plotting the amount of GLP-1R agonist and / or DPP-4 inhibitor released against the point in time when aliquot dispensing is discontinued.

[0112] Example 5 An in vivo experiment following Example 3 was conducted using the formulation evaluated in Example 4, and the same endpoints as in Example 3, namely weight loss / gain and biomarker levels, were evaluated.

[0113] In vivo experiments will be conducted to determine at least the following: (i) the effect on the endpoint of a formulation containing a certain amount of at least one GLP-1R agonist composition; (ii) the effect on the endpoint of a formulation containing a certain amount of at least one GLP-1R agonist composition; (iii) the effect on the endpoint of a formulation containing a certain amount of at least one GLP-1R agonist composition and a certain amount of at least one DPP-4 inhibitor composition; (iv) the effect on the endpoint of administering (i) and (ii) simultaneously; (v) the effect on the endpoint of administering (i) and (ii) at different time points—i.e., administering (ii) before (i), or administering (i) before (ii), where the first formulation is, for example, the second formulation. (vi) The effect on the endpoint of administering any of the formulations at 0.5, 1, 2, 4, or 8 hours prior to a meal; (vii) The effect on the endpoint of administering any of (i) to (v) at any point before a meal—for example, 0.5, 1, 2, 4, or 8 hours prior to a meal; (vii) The effect on the endpoint of administering any of the formulations (i) to (v) at any point after a meal—for example, 0.5, 1, 2, 4, or 8 hours after a meal; and (viii) The effect of administering (v) when one formulation is administered before a meal and the other formulation is administered after a meal—for example, when the first formulation is administered at 0.5, 1, 2, 4, or 8 hours prior to a meal and the second formulation is administered at 0.5, 1, 2, 4, or 8 hours after a meal.

[0114] Example 6 A clinical trial will be conducted to evaluate the effectiveness of the most effective formulation, dosing plan, and dosing schedule determined from the in vivo study in Example 5.

[0115] The primary endpoint in the clinical trial will be the absence of weight loss / weight gain compared to placebo and the commercially available formulation in the evaluated population.

[0116] As secondary endpoints, clinical trials evaluate serum levels of glucose, triglycerides, cholesterol, aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea, creatinine, and GLP-1.

[0117] Clinical trials will confirm that the formulations disclosed herein improve at least one of the primary and / or secondary endpoints compared to placebo and the control arm. Clinical trials will also confirm that the formulations disclosed herein raise no adverse safety endpoints that are not statistically significant compared to the placebo arm.

[0118] While exemplary embodiments, aspects, and variations are presented herein, those skilled in the art will understand the specific modifications, rearrangements, additions, and combinations of the embodiments, aspects, and variations, as well as specific partial combinations. The following claims are intended to be construed to include all such modifications, rearrangements, additions, and combinations of the embodiments, aspects, and variations, as well as specific partial combinations, that fall within their scope.

Claims

1. A composition comprising a certain amount of at least one GLP-1R agonist composition and a certain amount of at least one DPP-4 inhibitor composition.

2. The composition according to claim 1, wherein the amount of the at least one GLP-1R agonist composition and the amount of the at least one DPP-4 inhibitor composition are provided in a synergistic ratio.

3. The composition according to claim 1, wherein the at least one GLP-1R agonist composition comprises one or more compositions selected from a carrot composition, a curcumin composition, a pharmaceutical GLP composition, a conjugated linoleic acid composition, a bayberry powder composition, a berberine composition, a berberine hydrochloride composition, a tea plant (camellia sinensis) (matcha) composition, a capsaicin (chili pepper) composition, a dong quai root powder composition, an epigallocatechin gallate (EGCG) composition, a freeze-dried milk (kefir powder) composition, a Garcinia cambogia extract (hydroxycitric acid) composition, a lion's mane mushroom composition, a medium-chain triglyceride composition, a pterostilbene composition, a quercetin pure composition, a resveratrol composition, a sucralose composition, a bearberry leaf composition, and any combination thereof.

4. The composition according to claim 1, wherein the at least one DPP-4 inhibitor composition comprises one or more compositions selected from a stilbenoide composition, a protoberberine composition, a pharmaceutical DPP composition, a hydroxycitric acid composition, an EGCG composition, a sucralose composition, a bayberry powder composition, a tea plant (camellia sinensis) (matcha) powder composition, a lion's mane mushroom powder composition, a bearberry leaf powder composition, a capsaicin (chili pepper) composition, a curcumin composition, a freeze-dried milk (kefir powder) composition, a medium-chain triglyceride composition, a conjugated linoleic acid composition, and any combination thereof.

5. The composition according to claim 3, wherein the at least one GLP-1R agonist composition comprises a carrot composition.

6. The composition according to claim 3, wherein the at least one GLP-1R agonist composition comprises a curcumin composition.

7. The composition according to claim 3, wherein the at least one GLP-1R agonist composition comprises a mixture of a carrot composition and a curcumin composition.

8. The above at least one DPP-4 inhibitor composition is climacostol, desoxylapontigenin, dihydropinosylvin monomethyl ether, dihydroresveratrol, gnetol, isolapontigenin, isoresveratrol, oxyresveratrol, picetanol, pinostilbene, pinosylvin, pinosylvin monomethyl ether, pterostilbene, resveratrol, lapontigenin, triacetylresveratrol, trimethylresveratrol, 3'-hydroxypterostilbene, 3,4'-dimethoxyresveratrol, 3,5-dihydroxy-4-ethyl-trans-stilbene, 3,5-dihydroxy-4-isopropylstilbene The composition according to claim 1, selected from the group consisting of 4'-bromolesveratrol, 4,4'-dihydroxystilbene, allocryptopine, berberine, canazine, columbamin, coptisine, cordylamine, corisamine, cryptopine, cyclanoline, dihydroberberine, dihydrocoptisine, dihydropalmatine, epiberberine, groenlandisine, jatrolysine, methylstephoridine, palmatine, protopine, pseudoberberine, pseudocoptisine, sclerin, stepharanin, stephoridine, styropine, tetrahydroberberine, tetrahydropalmatine, and any combination thereof.

9. The composition according to claim 8, wherein the at least one DPP-4 inhibitor composition is formulated such that the DPP-4 inhibitor composition can cross the blood-brain barrier and deliver an effective amount of the DPP-4 inhibitor composition to the target brain.

10. The composition according to claim 8, wherein the at least one DPP-4 inhibitor composition is resveratrol, pterostilbene, berberine, or any combination thereof.

11. The composition according to claim 1, wherein the at least one GLP-1R agonist composition comprises a carrot composition, a curcumin composition, or a combination thereof, and the at least one DPP-4 inhibitor composition comprises resveratrol, pterostilbene, berberine, or any combination thereof.

12. The composition according to claim 1, which is formulated to be administered orally to a target.

13. The composition according to claim 12, wherein the at least one GLP-1R agonist composition and the at least one DPP-4 inhibitor composition are formulated together into a single solid dosage form selected from the group consisting of powder, granules, soft capsules, hard capsules, gel capsules, plant-based capsules, pills, tablets, caplets, sachets, gums, and soluble oral strips.

14. The composition according to claim 12, wherein the at least one GLP-1R agonist composition and the at least one DPP-4 inhibitor composition are formulated as separate solid dosage forms, the separate solid dosage forms being selected from the group consisting of powder, granules, soft capsules, hard capsules, gel capsules, plant-based capsules, pills, tablets, caplets, sachets, gums, and soluble oral strips. The composition according to claim 12.

15. The composition according to claim 13, wherein the single solid dosage form comprises a pH-responsive or enteric coating.

16. A method for inducing weight loss in a subject, Administering a composition comprising at least one GLP-1R agonist composition and at least one DPP-4 composition inhibitor to the subject. A method that includes this.

17. The method according to claim 16, wherein the amount of the at least one GLP-1R agonist composition and the amount of the at least one DPP-4 inhibitor composition are provided in a synergistic ratio.

18. The method according to claim 16, wherein the at least one GLP-1R agonist composition comprises one or more compositions selected from carrot composition, curcumin composition, pharmaceutical GLP composition, conjugated linoleic acid composition, bayberry powder composition, berberine composition, berberine hydrochloride composition, tea plant (camellia sinensis) (matcha) composition, capsaicin (chili pepper) composition, dong quai root powder composition, epigallocatechin gallate (EGCG) composition, freeze-dried milk (kefir powder) composition, Garcinia cambogia extract (hydroxycitric acid) composition, lion's mane mushroom composition, medium-chain triglyceride composition, pterostilbene composition, quercetin pure composition, resveratrol composition, sucralose composition, bearberry leaf composition, and any combination thereof.

19. The method according to claim 18, wherein the at least one GLP-1R agonist composition comprises a carrot composition.

20. The method according to claim 18, wherein the at least one GLP-1R agonist composition comprises a curcumin composition.

21. The method according to claim 18, wherein the at least one GLP-1R agonist composition comprises a mixture of a carrot composition and a curcumin composition.

22. The method according to claim 16, wherein the at least one DPP-4 inhibitor composition comprises one or more compositions selected from a stilbenoide composition, a protoberberine composition, a pharmaceutical DPP composition, a hydroxycitric acid composition, an EGCG composition, a sucralose composition, a bayberry powder composition, a tea plant (camellia sinensis) (matcha) powder composition, a lion's mane mushroom powder composition, a bearberry leaf powder composition, a capsaicin (chili pepper) composition, a curcumin composition, a freeze-dried milk (kefir powder) composition, a medium-chain triglyceride composition, a conjugated linoleic acid composition, and any combination thereof.

23. The aforementioned at least one DPP-4 inhibitor composition is climacostol, desoxylapontigenin, dihydropinosylvin monomethyl ether, dihydroresveratrol, gnetol, isolapontigenin, isoresveratrol, oxyresveratrol, picetanol, pinostilbene, pinosylvin, pinosylvin monomethyl ether, pterostilbene, resveratrol, lapontigenin, triacetylresveratrol, trimethylresveratrol, 3'-hydroxypterostilbene, 3,4'-dimethoxyresveratrol, 3,5-dihydroxy-4-ethyl-trans-stilbene, 3,5-dihydroxy-4-isopropyl The method according to claim 16, selected from the group consisting of pyrstilbene, 4'-bromolesveratrol, 4,4'-dihydroxystilbene, allocryptopine, berberine, canazine, columbamin, coptisine, cordylamine, corisamine, cryptopine, cyclanoline, dihydroberberine, dihydrocoptisine, dihydropalmatine, epiberberine, groenlandisine, jatrolysine, methylstephoridine, palmatine, protopine, pseudoberberine, pseudocoptisine, sclerin, stepharanin, stephoridine, stiropine, tetrahydroberberine, tetrahydropalmatine, and any combination thereof.

24. The method according to claim 23, wherein the at least one DPP-4 inhibitor composition is formulated such that the DPP-4 inhibitor composition can cross the blood-brain barrier and deliver an effective amount of the DPP-4 inhibitor composition to the target brain.

25. The method according to claim 23, wherein the at least one DPP-4 inhibitor is resveratrol, pterostilbene, berberine, or any combination thereof.

26. The method according to claim 16, wherein the at least one GLP-1R agonist composition comprises a carrot composition, a curcumin composition, or a combination thereof, and the at least one DPP-4 inhibitor composition comprises resveratrol, pterostilbene, berberine, or any combination thereof.

27. The method according to claim 16, wherein the composition is administered orally to a subject.

28. The method according to claim 16, wherein the at least one GLP-1R agonist composition and the at least one DPP-4 inhibitor composition are formulated together into a single solid dosage form for oral administration to the subject, the single solid dosage form being selected from the group consisting of powder, granules, soft capsules, hard capsules, gel capsules, plant-based capsules, pills, tablets, caplets, sachets, gums, and soluble oral strips.

29. The method according to claim 16, wherein the at least one GLP-1R agonist composition and the at least one DPP-4 inhibitor composition are formulated as separate solid dosage forms for oral administration to the subject, the separate solid dosage forms being selected from the group consisting of powder, granules, soft capsules, hard capsules, gel capsules, plant-based capsules, pills, tablets, caplets, sachets, gums, and soluble oral strips.

30. The method according to claim 28, wherein the single solid dosage form comprises a pH-responsive or enteric coating.

31. A method for enhancing satiety in a subject, Administering a composition comprising at least one GLP-1R agonist composition and at least one DPP-4 composition inhibitor to the subject. A method that includes this.

32. The method according to claim 31, wherein the amount of the at least one GLP-1R agonist composition and the amount of the at least one DPP-4 inhibitor composition are provided in a synergistic ratio.

33. The method according to claim 31, wherein the at least one GLP-1R agonist composition comprises one or more compositions selected from carrot composition, curcumin composition, pharmaceutical GLP composition, conjugated linoleic acid composition, bayberry powder composition, berberine composition, berberine hydrochloride composition, tea plant (camellia sinensis) (matcha) composition, capsaicin (chili pepper) composition, dong quai root powder composition, epigallocatechin gallate (EGCG) composition, freeze-dried milk (kefir powder) composition, Garcinia cambogia extract (hydroxycitric acid) composition, lion's mane mushroom composition, medium-chain triglyceride composition, pterostilbene composition, quercetin pure composition, resveratrol composition, sucralose composition, bearberry leaf composition, and any combination thereof.

34. The method according to claim 33, wherein the at least one GLP-1R agonist composition comprises a carrot composition.

35. The method according to claim 33, wherein the at least one GLP-1R agonist composition comprises a curcumin composition.

36. The method according to claim 33, wherein the at least one GLP-1R agonist composition comprises a mixture of a carrot composition and a curcumin composition.

37. The method according to claim 31, wherein the at least one DPP-4 inhibitor composition is selected from the group consisting of a stilbenoide composition, a protoberberine composition, a pharmaceutical DPP composition, a hydroxycitric acid composition, an EGCG composition, a sucralose composition, a bayberry powder composition, a tea plant (camellia sinensis) (matcha) powder composition, a lion's mane mushroom powder composition, a bearberry leaf powder composition, a capsaicin (chili pepper) composition, a curcumin composition, a freeze-dried milk (kefir powder) composition, a medium-chain triglyceride composition, a conjugated linoleic acid composition, and any combination thereof.

38. The aforementioned at least one DPP-4 inhibitor composition is climacostol, desoxylapontigenin, dihydropinosylvin monomethyl ether, dihydroresveratrol, gnetol, isolapontigenin, isoresveratrol, oxyresveratrol, picetanol, pinostilbene, pinosylvin, pinosylvin monomethyl ether, pterostilbene, resveratrol, lapontigenin, triacetylresveratrol, trimethylresveratrol, 3'-hydroxypterostilbene, 3,4'-dimethoxyresveratrol, 3,5-dihydroxy-4-ethyl-trans-stilbene, 3,5-dihydroxy-4-isopropyl The method according to claim 31, selected from the group consisting of pyrstilbene, 4'-bromolesveratrol, 4,4'-dihydroxystilbene, allocryptopine, berberine, canazine, columbamin, coptisine, cordylamine, corisamine, cryptopine, cyclanoline, dihydroberberine, dihydrocoptisine, dihydropalmatine, epiberberine, groenlandisine, jatrolysine, methylstephoridine, palmatine, protopine, pseudoberberine, pseudocoptisine, sclerin, stepharanin, stephoridine, stiropine, tetrahydroberberine, tetrahydropalmatine, and any combination thereof.

39. The method according to claim 38, wherein the at least one DPP-4 inhibitor composition is formulated such that the DPP-4 inhibitor composition can cross the blood-brain barrier and deliver an effective amount of the DPP-4 inhibitor composition to the target brain.

40. The method according to claim 38, wherein the at least one DPP-4 inhibitor composition comprises resveratrol.

41. The method according to claim 38, wherein the at least one DPP-4 inhibitor composition comprises pterostilbene.

42. The method according to claim 38, wherein the at least one DPP-4 inhibitor composition comprises berberine.

43. The method according to claim 31, wherein the at least one GLP-1R agonist composition comprises carrot root powder, and the at least one DPP-4 inhibitor composition comprises resveratrol.

44. The method according to claim 31, wherein the at least one GLP-1R agonist composition comprises carrot root powder, and the at least one DPP-4 inhibitor composition comprises pterostilbene.

45. The method according to claim 31, wherein the at least one GLP-1R agonist composition comprises carrot root powder, and the at least one DPP-4 inhibitor composition comprises berberine.

46. The method according to claim 31, wherein the at least one GLP-1R agonist composition comprises diferloylmethane, and the at least one DPP-4 inhibitor composition comprises resveratrol.

47. The method according to claim 31, wherein the at least one GLP-1R agonist composition comprises diferloylmethane, and the at least one DPP-4 inhibitor composition comprises pterostilbene.

48. The method according to claim 31, wherein the at least one GLP-1R agonist composition comprises diferloylmethane, and the at least one DPP-4 inhibitor composition comprises berberine.

49. The method according to claim 31, wherein the at least one GLP-1R agonist composition comprises a mixture of carrot root powder and diferloylmethane, and the at least one DPP-4 inhibitor composition comprises resveratrol.

50. The method according to claim 31, wherein the at least one GLP-1R agonist composition comprises a mixture of carrot root powder and diferloylmethane, and the at least one DPP-4 inhibitor composition comprises pterostilbene.

51. The method according to claim 31, wherein the at least one GLP-1R agonist composition comprises a mixture of carrot root powder and diferloylmethane, and the at least one DPP-4 inhibitor composition comprises berberine.

52. The method according to claim 31, wherein the at least one GLP-1R agonist composition and the at least one DPP-4 inhibitor composition are formulated together into a single solid dosage form for oral administration to the subject, the single solid dosage form being selected from the group consisting of powder, granules, soft capsules, hard capsules, gel capsules, plant-based capsules, pills, tablets, caplets, sachets, gums, and soluble oral strips.

53. The method according to claim 31, wherein the at least one GLP-1R agonist composition and the at least one DPP-4 inhibitor composition are formulated as separate solid dosage forms for oral administration to the subject, the separate solid dosage forms being selected from the group consisting of powder, granules, soft capsules, hard capsules, gel capsules, plant-based capsules, pills, tablets, caplets, sachets, gums, and soluble oral strips.

54. The method according to claim 52, wherein the single solid dosage form comprises a pH-responsive or enteric coating.

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