Dosing regimen of GLP-1

Abstract

To provide dosing regimens of GLP-1 analogs for the treatment of fat, obese, overweight, nonalcoholic fatty liver disease (NAFLD), and / or nonalcoholic steatohepatitis (NASH).SOLUTION: Administering to the subject a first effective amount of one or more first active ingredients selected from the group consisting of GLP-1 and GLP-1 analogs; A dosing regimen is provided, comprising: a first effective amount administered continuously, or intermittently at an interval between two consecutive administrations of six hours or less; and one or more second active ingredients selected from the group consisting of a second effective amount of GLP-I and a GLP-1 analog, administered to said subject once daily, twice daily, three times daily, or four times daily.SELECTED DRAWING: None

Description

[Background technology]

[0001] GLP-1 binds to GLP-1 receptors distributed throughout the body, particularly to insulin-secreting β cells in the pancreas. Natural GLP-1 is an insulinotropic peptide that acts after a meal. GLP-1 is secreted by type 2 insulin and is a potent peptide stimulator of insulin secretion. A potential treatment for diabetes. Holst, Physiol. Rev. 87:1409 -1439(2007). GLP-1 is a C-terminal amide-containing GLP-1(7-36) The human body has two active forms of GLP-1(7-37) containing a C-terminal free carboxyl group. Once in the circulation, GLP-1 is metabolized by dipeptidyl peptidase-4 (DPP4). It is rapidly degraded, with a short half-life of approximately 2 minutes. Kieffer et al., Endo Crinology 136:3585-3596(1995). GLP-1 and its In addition to their effects on glycemic control, the analogs have been shown to induce weight loss, slow gastric emptying, and It has been shown to be effective in increasing satiety and satiety. .Diabetes Res.2012:672658(2012). FDA, 201 Saxenda (liraglutide 3 mg) was approved in December 2014, but this is a GLP-1 This is the first NDA application of an analogue, and it is expected to be effective in treating overweight-related conditions such as type 2 diabetes. A reduced-calorie diet and lifestyle changes for obese adults with at least one disease or condition associated with obesity Long-term weight management complemented by increased physical activity. Continual efforts are being made to improve the present disclosure. 1 and / or GLP-1 analogues. Summary of the Invention

[0002] In one embodiment, a method for treating type 1 and type 2 diabetes, obesity, overweight, non-alcoholic fatty liver disease, and / or type 2 diabetes in a subject is provided. fatty liver disease (NAFLD) and / or nonalcoholic steatohepatitis (NASH) A dosing regimen for the treatment of diabetes is provided. The dosing regimen comprises a first effective amount of the GLP-1 and GLP-1 analogs (e.g., veinaglutide) disclosed herein GLP-1(7-36)) and administering a second effective amount of the GLP-1 and GLP-1 analogs disclosed herein. (e.g., GLP-1(7-36) such as veinaglutide) One or more second active ingredients may be administered once daily, twice daily, three times daily, or four times daily. and administering to the patient one or more first active ingredients and one or more second active ingredients. They may be the same or partially different (e.g., one or more, but the first and The second active ingredients may not all be the same) or may be completely different.

[0003] a first effective amount of GLP-1 and / or a GLP-1 analog (e.g., veinaglutide GLP-1(7-36), such as cyclosporine, may be administered at a constant or variable dosage rate. In certain embodiments, the first effective amount of GLP-1 and / or a GLP-1 analog (e.g., , GLP-1(7-36), such as veinaglutide, can be administered continuously. In this embodiment, a first effective amount of GLP-1 and / or a GLP-1 analog (e.g., GLP-1(7-36) such as veinaglutide takes approximately 15 minutes or less, approximately 30 minutes or less, Approximately 1 hour or less, approximately 2 hours or less, approximately 3 hours or less, approximately 4 hours or less, approximately 5 hours or more The doses may be administered intermittently with an interval between two consecutive doses of less than about 6 hours or less than about 6 hours. In certain embodiments, the first effective amount of GLP-1 and / or a GLP-1 analog (e.g., GLP-1(7-36) such as veinaglutide is administered at a dose of approximately 10 μg / day to approximately 12,000 μg / day. μg / day, approximately 100μg / day to approximately 4,800μg / day, approximately 300μg / day to approximately 9,000 μg / day, approximately 500 μg / day to approximately 8,000 μg / day, approximately 1 mg / day to approximately 5 mg / day, or or at a daily dose of about 3 mg / day to about 7 mg / day. a first effective amount of GLP-1 and / or a GLP-1 analog (e.g., veinaglutide GLP-1 (7-36)) is about 1 μg / hour to about 500 μg / hour, about 2 μg / hour to about 400 μg / hour, about 3 μg / hour to about 200 μg / hour, about 4 μg / hour to about 300 μg / hour hours, about 5 μg / hour to about 100 μg / hour, about 10 μg / hour to about 80 μg / hour, or about 12 It may be administered at an hourly rate of 0.5 μg / hour to about 50 μg / hour.

[0004] a second effective amount of GLP-1 and / or a GLP-1 analog (e.g., veinaglutide GLP-1(7-36), such as GLP-1(7-36), may be administered with a meal. a second effective amount of GLP-1 and / or a GLP-1 analog (e.g., veinaglutinin) GLP-1 (7-36), such as omega-3 fatty acids, is secreted from approximately 45 minutes before a meal to approximately 45 minutes after a meal, and from approximately 30 minutes before a meal to approximately 45 minutes after a meal. From about 15 minutes before a meal to about 30 minutes after a meal, from about 15 minutes before a meal to about 15 minutes after a meal, from about 10 minutes before a meal to about 30 minutes after a meal It may be administered within a time range of up to 10 minutes, or from about 5 minutes before a meal to about 5 minutes after a meal. In certain embodiments, the second effective amount of GLP-1 and / or GLP-1 analog is administered preprandially. Or about 0.5 to 30 minutes, about 1 to 15 minutes, about 2 to 10 minutes, or about 3 to 15 minutes after eating A second effective amount of GLP-1 and / or GLP-1 The dosage of the analogue (e.g., GLP-1(7-36) such as veinaglutide) is In certain embodiments, the second effective amount of G GLP-1 and / or GLP-1 analogues (e.g., GLP-1 (e.g., veinaglutide) 7-36)) is administered at a dose of about 10 μg to about 500 μg, about 50 μg to about 300 μg, Alternatively, it may be about 100 μg to about 200 μg.

[0005] In some embodiments, the GLP-1 analog is GLP-1(7-37), GLP-1 (7-36), and GLP-1 (7-35). Unless otherwise specified, GLP-1 and GLP-1 analogs are not intended to be used with a C-terminal free carboxyl group or a C-terminal It may have an amide group.

[0006] In some embodiments, the dosing regimen comprises administering to the subject a third effective amount of one or more third Active ingredients, such as insulin, insulin analogs, metformin, or combinations thereof In certain embodiments, the method further comprises administering a combination of one or more third active ingredients. The minutes are administered with GLP-1 and / or GLP-1 analogs (e.g., GLP-1 such as veinaglutide). P-1(7-36)). The third active ingredient is a rapid-acting insulin (e.g., insulin lispro, insulin insulin aspart, insulin glulisine) and long-acting insulins (e.g., insulin lingulargine, insulin degludec, and insulin detemir) In some embodiments, an effective amount (U) of insulin is and / or insulin analogues and an effective amount (mg) of GLP-1 and / or GLP- The analogues are those having a ratio of about 10:1 to about 800:1 (insulin glargine (U):veinaglutinin (V)). (mg), about 30:1 to about 500:1, about 50:1 to about 250:1, about 70:1 to about 220:1, or a ratio of about 100:1 to about 200:1, e.g., about 10:1, about 20: 1, approx. 30:1, approx. 40:1, approx. 50:1, approx. 60:1, approx. 60:1, approx. 70:1, approx. 8 0:1, approx. 90:1, approx. 100:1, approx. 150:1, approx. 200:1, approx. 250:1, approx. 3 00:1, approx. 350:1, approx. 400:1, approx. 450:1, approx. 500:1, approx. 550:1, at a ratio of about 600:1, about 650:1, about 700:1, about 750:1, or about 800:1 In some embodiments, an insulin analog (e.g., insulin glargine) is administered. The doses are approximately 2U / day to approximately 100U / day, approximately 6U / day to approximately 60U / day, and approximately 12U / day to approximately 4 It may be administered at a dosage of 0 U / day, about 20 U / day to about 30 U / day, or about 15 U / day.

[0007] In some embodiments, GLP-1 and / or GLP-1 analogs (e.g., bayer) are GLP-1 (7-36) such as naglutide) and / or one or more third active ingredients ( For example, insulin and / or insulin analogs and / or metformin The pharmaceutical composition is pre-loaded into an administration device (e.g., an injector pen, a pump). DETAILED DESCRIPTION OF THE INVENTION

[0008] Disclosed herein are methods for treating type 1 and type 2 diabetes, obesity, overweight, and non-diabetes in subjects. Alcoholic fatty liver disease (NAFLD), and / or non-alcoholic steatohepatitis ( a dosing regimen for the treatment of diabetes, such as NASH, comprising administering to a patient a first effective amount of any of the compounds described herein. one or more first GLP-1 analogs selected from the group consisting of the disclosed GLP-1 and GLP-1 analogs and administering to a subject a second effective amount of the active ingredient of the present invention disclosed herein. and one or more second active ingredients selected from the group consisting of GLP-1 analogs, administered once daily. and administering the compound to a subject twice daily, three times daily, or four times daily. As provided in the examples disclosed herein, embodiments of the dosing regimen may be used to treat A significant reduction in HbA1c and body weight was achieved in the patients. and one or more second active ingredients may be the same or may be partially different (e.g. , one or more, but not all of the first and second active ingredients are the same), or completely may differ from

[0009] In certain embodiments, the dosing regimen comprises administering to the subject a third effective amount of one or more third Active ingredients, such as insulin, insulin analogs, metformin, and combinations thereof The method further comprises administering a combination of

[0010] In some embodiments, GLP-1 and / or GLP-1 analogs (e.g., vegetative) GLP-1 (7-36), such as inaglutide, and / or one or more third active ingredients Pharmaceutical compositions containing insulin analogs such as insulin glargine are administered Pre-loaded into a device (e.g., injector pen, pump).

[0011] In the context of this disclosure, GLP-1 and / or GLP-1 analogs (e.g., GLP -1(7-36)) and / or one or more third active ingredients (e.g., insulin and and / or insulin analogs and / or metformin) The phrases "therapeutically effective amount" or "effective amount," as used herein, refer to a therapeutically effective amount of type 1 and type 2 glycoproteins. Treating diabetes, including diabetes mellitus, obesity, overweight, NAFLD, and / or NASH The amount of a pharmaceutical composition that produces a desired therapeutic effect in a subject, such as a dose of 100 mg of a 200 mg 200 mg 100 mg of a 200 mg 100 mg 200 mg of a 200 mg 1 ... In embodiments, a therapeutically effective amount is the amount of a pharmaceutical composition that provides the maximal therapeutic effect. In some embodiments, a therapeutically effective amount provides a therapeutic effect that is less than the maximal therapeutic effect. An effective amount is one that provides maximum therapeutic benefit while avoiding one or more side effects associated with the dosage. In some embodiments, a therapeutically effective amount is an amount that produces a therapeutic effect. The therapeutically effective amount of a particular composition depends on the characteristics of the therapeutic composition (e.g., activity, pharmacokinetics, pharmacodynamics, and bioavailability), the physiological state of the subject (e.g., Age, weight, sex, type and stage of disease, medical history, general physical condition, and prescribed dosage (e.g., responsiveness, as well as other current medications), any pharmaceutically acceptable carriers, excipients in the composition Various factors, including but not limited to the nature of the vehicle and preservatives, and the route of administration, Those skilled in the clinical and pharmacological arts will be able to determine, by routine experimentation, monitoring the subject's response to administration of the pharmaceutical composition and adjusting the dosage accordingly; For further guidance, see the examples. For example, Remington: The Science and Practice of Pharmacy,22nd Edition,Pharmaceutical Pr ess, London, 2012, and Goodman & Gilman's Th e Pharmacological Basis of Therapeutics, 12th Edition, McGraw-Hill, New York, NY, 201 1, the entire disclosure of which is incorporated herein by reference.

[0012] "treat," "treating," and "t The term "condition" as used herein with respect to a condition means a condition Partially or completely alleviate the condition, prevent the condition, or reduce the likelihood of the condition occurring or recurring. to reduce, delay the progression or development of, or reduce one or more symptoms associated with a medical condition It refers to eliminating, reducing or delaying the development of a condition.

[0013] The term "subject", as used herein, refers to a mammalian subject, preferably a mammalian subject. In certain embodiments, the subject is a person suffering from type 1 and type 2 diabetes, obesity, or overweight. Diagnosed with diabetes, including type 1 diabetes, NAFLD, and / or NASH and diabetes, including type 2 diabetes, obesity, overweight, NAFLD, and / or NASH The terms "subject" and "patient" are used interchangeably herein. It can be used for.

[0014] In some embodiments, the GLP-1 analog is GLP-1(7-37), GLP-1 (7-36), and GLP-1 (7-35). Unless otherwise specified, GLP-1 and GLP-1 analogs are not intended to be used with a C-terminal free carboxyl group or a C-terminal For example, a GLP-1 analog may have an amide group. Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu- Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala- A recombinant vector having the sequence Trp-Leu-Val-Lys-Gly-Arg (SEQ ID NO: 1) It may be a human GLP-1(7-36) peptide, referred to in this disclosure as veinaglutide. Veinaglutide is a 149 H 225 N 39 O 46 It has a molecular formula of 3 Veinaglutide is a compound in which the NH2 of the natural form is replaced by the OH group of the recombinant peptide. It is essentially the same as the active form of circulating GLP-1, except for the altered endogenous amidation. Veinaglutide contains a C-terminal free carboxyl group. In another embodiment, GLP GLP-1(7-35) or GLP-1(7-37) can be used in the disclosed technology. GLP-1(7-35) with terminal free carboxyl group and C-terminal free carboxyl The sequence of GLP-1(7-37) with the group is as follows: His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Va l-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Ly s-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly(sequence Number 2), and His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Va l-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Ly s-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Ar g-Gly (SEQ ID NO: 3).

[0015] In certain embodiments, the first effective amount of GLP-1 and / or a GLP-1 analog (e.g., GLP-1(7-36) such as veinaglutide) may be administered at fixed or variable rates. In certain embodiments, a first effective amount of GLP-1 and / or GLP-1 analogues (e.g., GLP-1(7-36) such as veinaglutide) are used to In certain embodiments, the first effective amount of GLP-1 and / or G GLP-1 analogs (e.g., GLP-1(7-36) such as veinaglutide) are released in approximately 15 minutes. The following: about 30 minutes or less, about 1 hour or less, about 2 hours or less, about 3 hours or less, or about Intermittent administration with an interval of not more than 4 hours, not more than about 5 hours, or not more than about 6 hours between two consecutive doses In certain embodiments, a first effective amount of GLP-1 and / or GLP-1 analogs (e.g., GLP-1(7-36) such as veinaglutide) have a potency of approximately 10 μg / day ~ approx. 12,000 μg / day, approx. 100 μg / day ~ approx. 4,800 μg / day, approx. 30 0μg / day ~ approx. 9,000μg / day, approx. 500μg / day ~ approx. 8,000μg / day, approx. 1m g / day to about 5 mg / day, or about 3 mg / day to about 7 mg / day In certain embodiments, the first effective amount of GLP-1 and / or a GLP-1 analog (For example, GLP-1(7-36) such as veinaglutide) is about 1 μg / hour to about 500 μg / hour. μg / hour, approximately 2μg / hour to approximately 400μg / hour, approximately 3μg / hour to approximately 200μg / hour, approximately 4 μg / hour ~ approx. 300μg / hour, approx. 5μg / hour ~ approx. 100μg / hour, approx. 10μg / hour ~ approx. 8 0 μg / hour or hourly infusion rates of approximately 12.5 μg / hour to approximately 50 μg / hour It can be done.

[0016] In certain embodiments, a second effective amount of GLP-1 and / or a GLP-1 analog (e.g., GLP-1(7-36) such as veinaglutide) may be administered with meals. In certain embodiments, the second effective amount of GLP-1 and / or a GLP-1 analogue The body (e.g., GLP-1(7-36) such as veinaglutide) produces Up to about 45 minutes, from about 30 minutes before a meal to about 30 minutes after a meal, from about 15 minutes before a meal to about 15 minutes after a meal , from about 10 minutes before a meal to about 10 minutes after a meal, or from about 5 minutes before a meal to about 5 minutes after a meal In certain embodiments, a second effective amount of GLP-1 and / or The GLP-1 analogue is administered about 0.5 to about 30 minutes, about 1 to about 15 minutes, or about 2 minutes before or after a meal. The second effective dose of GLP-1 is administered within about 10 minutes, about 3 minutes, about 7 minutes, or about 5 minutes. and / or GLP-1 analogues (e.g., GLP-1(7-36), such as veinaglutide) The dosage of )) may be the same or different for each administration. In this embodiment, a second effective amount of GLP-1 and / or a GLP-1 analog (e.g., Veinag) is administered. A single dose of GLP-1(7-36) such as rutide is approximately 10 μg to approximately 500 μg, It can be 50 μg to about 300 μg, or about 100 μg to about 200 μg.

[0017] In some embodiments, GLP-1 and / or GLP-1 analogs (e.g., bayer) are The total daily dosage of GLP-1(7-36) such as naglutide is approximately 40 μg to approximately 14,0 00μg, approximately 40μg to approximately 13,500μg, approximately 50μg to approximately 14,000μg, approximately 50 μg ~ approx. 13,500 μg, approx. 40 μg ~ approx. 12,030 μg, approx. 50 μg ~ approx. 12,0 40μg, approximately 2,010μg to approximately 14,000μg, approximately 1,510μg to approximately 13,500 μg, approx. 250 μg to approx. 6,000 μg, approx. 250 μg to approx. 5,700 μg, approx. 300 μg g ~ approx. 6,000μg, approx. 300μg ~ approx. 5,700μg, approx. 480μg ~ approx. 700μg , about 480 μg to about 600 μg, about 540 μg to about 700 μg, or about 540 μg to about In certain embodiments, the first effective amount of GLP-1 and / or or a GLP-1 analog, and a second effective amount of GLP-1 and / or The total daily dosage of the GLP-1 analogue may range from about 1:1 to about 10:6, from about 1:12 to about 1:1.5, or from about 3.2 to about 4, about 1:9 to about 1:2, about 16:3 to about 24, about 1:2,000 to about 6, about 1:3 to approx. 400, approx. 1:1, 500 to approx. 1:4, approx. 300 to approx. 4:5, approx. 1:2, approx. 1 :1, approx. 2:1, approx. 4:1, approx. 3:1, approx. 6:1, approx. 12:1, approx. 24:1, approx. 48:1 , about 96:1, about 1:96, about 1:48, about 1:32, about 1:24, about 1:12, about 1: 6, about 1:3, or about 1:4 (first effective amount / day:second effective amount / day) .

[0018] In certain embodiments, one or more third active ingredients (e.g., insulin and / or or insulin analogs and / or metformin) inhibit GLP-1 and / or GL Administration of one or more GLP-1 analogues (e.g., GLP-1(7-36) such as veinaglutide) In some embodiments, the compound is administered in combination with GLP-1 and / or GL GLP-1 analogs (e.g., GLP-1(7-36) such as veinaglutide) are used to treat one or more a third active ingredient (e.g., insulin and / or insulin analogs and / or metabolites) In some embodiments, the administration of riboflavin may be administered before, during, or after administration of riboflavin (toformin). , a third active ingredient (e.g., insulin and / or insulin analogs and / or metformin) and GLP-1 and / or GLP-1 analogues (e.g., Veinag The interval between the administration of GLP-1 (7-36) such as lucid is about 1 minute to about 30 minutes, about 5 minutes to about It may be 25 minutes, about 10 to about 20 minutes, or about 15 minutes.

[0019] In some embodiments, the one or more third active ingredients are insulin and / or insulin derivatives. In certain embodiments, the insulin analog includes an ultrafast-acting insulin. Phosphorus (e.g., insulin lispro, insulin aspart, insulin glulisine) and and long-acting insulins (e.g., insulin glargine, insulin degludec, and insulin detemir).

[0020] Effective dose (U) of insulin and / or insulin analogues and effective dose (mg) of GLP -1 and / or GLP-1 analogs, about 10:1 and about 800:1, about 30:1 to about 500:1, about 50:1 to about 250:1, about 70:1 to about 220:1, or about 10 Ratios of 0:1 to about 200:1, for example, about 10:1, about 20:1, about 30:1, about 40: 1, approx. 50:1, approx. 60:1, approx. 60:1, approx. 70:1, approx. 80:1, approx. 90:1, approx. 1 00:1, approx. 150:1, approx. 200:1, approx. 250:1, approx. 300:1, approx. 350:1, Approx. 400:1, Approx. 450:1, Approx. 500:1, Approx. 550:1, Approx. 600:1, Approx. 650: The combination is administered in a ratio of about 1, about 700:1, about 750:1, or about 800:1. In some embodiments, the insulin analog (e.g., insulin glargine) is administered at a dose of about 2 U / day ~ approx. 100U / day, approx. 6U / day ~ approx. 60U / day, approx. 12U / day ~ approx. 40U / day, approx. It is administered in the range of 20 U / day to about 30 U / day, or about 15 U / day.

[0021] In some embodiments, the one or more third active ingredients include metformin. In some embodiments, metformin is administered at a dose of about 50 mg / day to about 3,000 mg / day, about 100 mg / day to about 3,000 mg / day. mg / day ~ approx. 2500mg / day, approx. 500mg / day ~ approx. 2000mg / day, approx. 1,000 mg / day to approximately 1,500 mg / day, or approximately 1,000 mg / day to approximately 2,000 mg / day It is administered in the range of

[0022] In some embodiments, the one or more third active ingredients are metformin and insulin. and one or more active ingredients selected from the group consisting of insulin analogs .

[0023] GLP-1 and / or GLP-1 analogues (e.g., GLP-1 such as veinaglutide) 1(7-36)) administered in combination with one or more of the third active ingredients. When multiple third active ingredients are used (co-administration), one or more of the multiple third active ingredients may be administered in the same or different doses. The amount may be administered in each combined administration.

[0024] In certain embodiments, the dosing regimen comprises a first effective amount of GLP-1(7-36)( For example, administering veinaglutide to a subject and administering a second effective amount of GLP-1(7-3 6) administering (e.g., veinaglutide) to the subject with a meal, The effective dose of GLP-1(7-36) (e.g., veinaglutide) is about 0.1 mg to about 4.8 mg. mg daily dose and a second effective amount of GLP-1(7-36) (e.g., Bayer Naglutide) at a dose of approximately 0.02 mg to approximately 0.3 mg per administration, once daily The first effective amount of GLP-1(7- 36) (e.g., veinaglutide) can be administered continuously or intermittently. An effective dose of GLP-1(7-36) (e.g., veinaglutide) is approximately 0.003 mg / hour to about 0.2 mg / hour, continuously or intermittently, for about 15 minutes or more. Below, about 30 minutes or less, about 1 hour or less, about 2 hours or less, about 3 hours or less, or about with an interval between two consecutive doses of not more than 4 hours, not more than about 5 hours, or not more than about 6 hours can be administered.

[0025] 1) GLP-1 and / or GLP-1 analogues (e.g., GLP-1 such as veinaglutide) P-1(7-36)) and 2) one or more third active ingredients (e.g., insulin and and / or insulin analogues and / or metformin) in addition to Therefore, the pharmaceutical compositions disclosed herein may contain one or more pharmaceutically acceptable excipients, and and / or a buffer (e.g., histidine-HCl ( Histidine-HCl), Sodium Citrate-Citric Acid, Disodium Monohydrogen Phosphate-C Citric acid, NaOH-citric acid, sodium acetate-acetic acid (NaAC-HAC), succinate -Succinic acid, Lactate - Lactic acid, Glutamate - Glutamic acid, Malate - Malic acid, Benzoic acid benzoic acid, tartrate-tartaric acid, or glycine-hydrochloride (Gly-HCl), The pharmaceutical composition may contain a salt thereof (or any combination thereof). Preservatives (e.g., phenol, benzyl alcohol, methyl p-hydroxybenzoate, Ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate, butyl p- Hydroxybenzoate, chlorobutanol, 2-phenoxyethanol, 2-phenethyl alcohol, benzalkonium chloride (bromide), merthiolate or any of these combinations), isotonic agents (polyols, sodium chloride, sugars or any combination thereof where the polyol is mannitol, sorbitol, inositol, xylitol , glycerin, propylene glycol or any combination thereof, and the sugar is sugar. treahol, trehalose, lactose, fructose, glucose or any combination thereof combinations), and solubility enhancers (e.g., Tween 20, Tween 40, Tween een80, Span20, Span40, Span80, Poloxamer188, Pluronic F68, Brij35, Dextran-20, PEG400, PEG1 000, PEG1500, PEG2000, propylene glycol or any of these combinations).

[0026] Pharmaceutical compositions are formulated to suit a particular route of administration. For example, pharmaceutical compositions may be administered transdermally. It can be injected intravenously or intravenously, or administered by infusion or oral administration. In some embodiments, 1) GLP-1 and / or GLP-1 analogs can be used. 1) a compound (e.g., GLP-1(7-36) such as veinaglutide) and 2) one or more third active ingredients Active ingredients (e.g., insulin and / or insulin analogs and / or metformin) In some embodiments, both 1) and 2) are formulated into a single composition for simultaneous administration. GLP-1 and / or GLP-1 analogues (e.g., GLP-1 such as veinaglutide) (7-36)) and 2) one or more third active ingredients (e.g., insulin and / or or insulin analogs and / or metformin) are 1) GLP-1 and / or 1) a GLP-1 analogue and 2) one or more third active ingredients (e.g., insulin and / or or insulin analogs and / or metformin) at different doses or ratios simultaneously or are formulated into two separate compositions so that they can be combined for sequential administration. For example, GLP-1 and / or GLP-1 analogs (e.g., GLP-1 analogs such as veinaglutide) -1(7-36)) may contain one or more third active ingredients (e.g., insulin and / or before, during, or after administration of insulin analogs and / or metformin In another example, 1) a second effective amount of GLP-1 and / or a GLP-1 analog (e.g., GLP-1(7-36) such as veinaglutide) and 2) one or more tertiary active ingredients (e.g., insulin and / or insulin analogues and / or methotrexate) Lumin) is delivered once daily, twice daily, three times daily, or four times daily in various combinations. For example, one or more third active ingredients (e.g., insulin and / or insulin derivatives) may be added. After a single dose of GLP-1 and / or metformin or a single dose of a GLP-1 analogue (e.g., GLP-1(7-36) such as veinaglutide) The administration of one or more third active ingredients (e.g., insulin) may be continued, or vice versa. and / or insulin analogues and / or metformin) or GLP-1 (and and / or GLP-1 analogues (e.g., GLP-1(7-36) such as veinaglutide) When multiple doses of ) are administered, it is not necessary that the same dose be administered to the subject each time. an amount of 1) GLP-1 and / or a GLP-1 analogue (e.g., veinaglutide, etc.) GLP-1(7-36)) and / or 2) one or more third active ingredients (e.g., insulin and / or insulin analogs and / or metformin), followed by Depending on the patient's blood glucose level in response to the first dose, subsequent doses may be administered at higher or lower doses. or 1) adjusting the GLP-1 and / or GLP-1 analogs (e.g., 1) a GLP-1 (7-36) such as veinaglutide; and 2) one or more third active ingredients. (e.g., insulin and / or insulin analogs and / or metformin) It is also possible to skip either or both doses.

[0027] Also disclosed are: 1) GLP-1 and / or GLP-1 analogs (e.g., bayer GLP-1 (7-36) such as naglutide) and 2) one or more third active ingredients (e.g. , insulin and / or insulin analogs and / or metformin), and 3) and instructions for use thereof. an anti-inflammatory drug (e.g., a GLP-1(7-36) such as veinaglutide) and one or more third active ingredients Active ingredients (e.g., insulin and / or insulin analogs and / or metformin) GLP-1 (and / or GLP-2) may be contained in a single composition or in two separate compositions. or GLP-1 analogues (e.g., GLP-1(7-36) such as veinaglutide) and and one or more third active ingredients (e.g., insulin and / or insulin analogs and When the two compounds (e.g., metformin and / or rifafluvial) are provided in two separate compositions, these may be used in various combinations. The combination may be administered simultaneously or sequentially. For example, the instructions may include administering GLP-1 (and and / or GLP-1 analogues (e.g., GLP-1(7-36) such as veinaglutide) ) and one or more third active ingredients (e.g., insulin and / or insulin analogs and and / or metformin) will be administered first, at what dose, and How many doses will be administered per day and, if necessary, the user will be able to determine the initial blood glucose level. and selecting the optimal combination of delivered doses based on blood glucose levels in response to the first dose. In order to achieve this, one or more third active ingredients (e.g., insulin and / or insulin After a single dose of GLP-1 (and / or metformin), or a single dose of a GLP-1 analogue (e.g., GLP-1(7-36) such as veinaglutide) This will provide information on whether the above administration should continue or vice versa. For this purpose, GLP-1 (and / or GLP-1 analogues (e.g., veinaglutide) which GLP-1(7-36)) and one or more third active ingredients (e.g., insulin and and / or insulin analogues and / or metformin) means that the user These are provided in small volumes so that one or more can be combined to achieve the desired increased dose. It can be provided.

[0028] The following examples better illustrate the claimed invention and the embodiments described herein. It is provided for purposes of illustration and should not be construed as limiting the scope of the invention. If a specific material is mentioned, it is for illustrative purposes only and does not limit the invention. Those skilled in the art will recognize that various equivalents, modifications, and variations are possible without departing from the scope of the present invention. It is apparent that modifications may be made thereto and that such equivalent embodiments are included herein. Additionally, all references cited in this disclosure are understood to be within the scope of the appended claims. , which are incorporated herein by reference in their entirety as if fully set forth herein. It can be enjoyed.

[0029] Example 1: Baynaglu in combination with oral metformin in patients with type 2 diabetes Efficacy of subcutaneous administration of thiazol-tide This example demonstrates the efficacy of pre-prandial steroids in combination with oral metformin in patients with type 2 diabetes. Demonstrate the therapeutic effect of subcutaneous administration of veinaglutide.

[0030] Patient eligibility criteria Inclusion criteria (if any) were: World Health Organization diagnostic criteria for type 2 diabetes (W HO, 1999) and receiving oral metformin treatment at a dose of ≥ 1,000 mg / day and have been stable for at least 3 months without treatment-related adverse events (e.g., vomiting) and have spontaneous Participants signed informed consent and agreed to the following criteria: ●Age: 30-75 years old, ●Disease course: 6 months to 10 years, Glycated hemoglobin (HbA1c): 7.0% to 10.0% for type 2 diabetes patients .

[0031] Exclusion criteria (if any) were: patients with type 1 diabetes, pregnant women Sex, breastfeeding motherhood, systolic blood pressure >160mmHg and / or diastolic blood pressure > 100mmHg, being on insulin therapy or having severe acute or chronic complications, Vestibular, hematological, and cardiac disorders, liver and kidney dysfunction (transaminases >2x upper limit of normal or Cr>133 μmol / L) ), gastrointestinal disease or recent administration of medications affecting glucose metabolism, Making abnormal decisions and being unable to cooperate due to a mental disorder.

[0032] method In a randomized, double-blind, placebo-controlled clinical trial, type 2 diabetes mellitus patients treated with metformin monotherapy Forty-two patients with diabetes were randomly assigned to treatment and control groups, with 21 patients in each group. All patients received metformin (Glucophage) at the original dose. age), purchased from Bristol-Myers Squibb. μg veinaglutide (from Benemae, treatment group) or placebo (from Benemae , control group) was administered to patients by subcutaneous injection once before each of three meals (600 μg / day) and followed up after 12 weeks of treatment.

[0033] Efficacy indicators Glycated hemoglobin (HbA1c), fasting blood glucose, 2-hour postprandial blood glucose, BMI, and Other efficacy indicators were measured.

[0034] Results after 12 weeks of treatment HbA1c in the treatment group decreased by 1.17% (7.97% before treatment, 6.8% after treatment) (P <0.01). Fasting blood glucose decreased by 1.98 mmol / L (9.43 mmol / L before treatment). , 7.45 mmol / L after treatment), and postprandial blood glucose decreased by 4.18 mmol / L (1 before treatment 5.2 mmol / L, 11.02 mmol after treatment) (P<0.01).

[0035] Both HbA1c and fasting blood glucose after treatment in the treatment group were significantly higher than those before treatment. The decrease was significant compared with the control group (P<0.05).

[0036] There was a significant decrease in BMI in both the treatment and control groups (P<0.05), but the two groups There was no statistical difference between them (P>0.05).

[0037] Example 2: Continuous subcutaneous administration of veinaglutide in obese / overweight patients with type 2 diabetes Effectiveness This example demonstrates the efficacy and safety of veinaglutide in obese and overweight patients with type 2 diabetes. The effect of an embodiment of dimen is demonstrated.

[0038] Veinaglutide dosing regimens included: 1) 12.5 μg / hour (300 μg / hour) via subcutaneous pump; 2) continuous subcutaneous administration of veinaglutide (10 μg / day) 5 minutes before each of three meals per day; 1) a single subcutaneous administration of veinaglutide at a dose of 0 μg; and 2) insulin glargine and The study included optional administration of metformin and / or cefotaxime.

[0039] Treated patients were obese / overweight with a short disease course of type 2 diabetes. Two patients were female and four were male. Patients were aged 30-55 years and had a history of 0-5 years. The patient showed a disease course of 100% with glycated hemoglobin of 9% to 12% and a BMI of 26 to 30 kg / kg. m 2 It was.

[0040] Three patients were treated with veinaglutide monotherapy. and one or two third active ingredients (metformin, or metformin and glargine) Glycated hemoglobin (HbA1c) and body weight were measured.

[0041] Patients may receive one of the veinaglutide dosing regimens described herein, either alone or in combination with one or more of the following: In combination with 3 active ingredients, some patients start binaglutide treatment. In the previous week, insulin (daily dose 0.5u / kg) pump therapy alone or metformin The patients were treated with acetaminophen (0.5g tid (3 times a day)). demonstrated significant weight loss and / or reduction in HbA1c following treatment as described in the specification .

[0042] [Table 1]

[0043] 1.Patients treated with veinaglutide monotherapy according to the medication regimen Three patients (patients 1, 5, and 6) received bevacizumab according to the dosing regimen described herein. He was treated with inaglutide monotherapy.

[0044] 1.1.Patient 1 Patient 1 was a 53-year-old female obese with type 2 diabetes and hyperlipidemia and fatty liver. Before treatment, the patient had an HbA1c level of 9.4% and a weight of 61 kg.

[0045] The patient was treated with atorvastatin calcium (20 mg qn nightly), enteric-coated aspirin Coated tablets (100 mg qd (daily)), metformin (Glucophage, 0.5 g tid) combined with insulin pump therapy (insulin 0.5u / kg) for 1 week They were treated for 1 month with binaglutide monotherapy, followed by 1 month of binaglutide monotherapy.

[0046] 1.2.Patient 5 Patient 5 was a 42-year-old female obese patient with type 2 diabetes. Before treatment, the patient had a blood glucose level of 7.3 % HbA1c level and body weight of 80 kg.

[0047] Patients were treated with veinaglutide monotherapy for 1 month.

[0048] 1.3.Patient 6 Patient 6 was a 34-year-old female obese patient with type 2 diabetes who presented with hyperlipidemia, hyperuricemia, and dyslipidemia. Before treatment, the patient had a HbA1c of 9.7% and a weight of 85 kg. had weight.

[0049] The patient was treated with insulin pump therapy (0.5 U / kg) for 1 week, followed by Vinagle. The patient was treated with tidomethylpropional monotherapy (0.6 mg / day) for 1 month.

[0050] 2.Patients treated with veinaglutide-metformin combination therapy 2.1.Patient 2 Patient 2 was a 38-year-old male obese patient with type 2 diabetes and fatty liver. The patient had an HbA1c level of 8.8% and a weight of 99 kg.

[0051] Patients were treated with Essentiale (456 mg tid) and insulin pump therapy for 1 week. He was treated with veinaglutide and metaformin (0.5 mg tid) for 1 month, and then with veinaglutide and metaformin (0.5 mg tid) for 1 month. The patient's weight decreased from 99 kg to 93 kg after one month of treatment.

[0052] 2.2.Patient 3 Patient 3 was a 37-year-old male obese patient with type 2 diabetes, type 2 diabetic ketosis, and hyperlipidemia. Before treatment, the patient had an HbA1c level of 12.3% and a blood glucose level of 8. It weighed 8 kg.

[0053] The patient was treated with insulin (0.5u / kg) pump sensitizer hypoglycemic therapy for 1 week, followed by The patient was treated with veinaglutide + metaformin (0.5g tid) combination therapy for 1 month. The patient's weight decreased from 88 kg to 83 kg.

[0054] 3.Patients treated with veinaglutide-metformin combination therapy 3.1.Patient 4 Patient 4 was a 36-year-old male obese patient with type 2 diabetes and hyperlipidemia and diabetic retinopathy. Before treatment, the patient had an HbA1c level of 9.3% and a weight of 80 kg. was.

[0055] The patient was treated with insulin (0.5u / kg) pump sensitizer hypoglycemic therapy for 1 week, followed by I took veinaglutide + insulin glargine (16 units sc before bedtime) - metaformin (0 The patient was treated with a combination of 1.5g tid) for one month.

[0056] The veinaglutide dosing regimen of this example (continuous, 300 μg / day; 100 mg before meals) μg tid) alone or with a third active ingredient (e.g., metformin, or metformin Patients treated with either of these drugs (combined with insulin glargine and insulin glargine) were randomly assigned to receive the achieved a reduction in HbA1c and / or weight loss during the course of treatment.

Claims

1. diabetes, obesity, overweight, non-alcoholic fatty liver disease (NAFLD) in the subject; and / or a dosing regimen for the treatment of nonalcoholic steatohepatitis (NASH). So, a first effective amount of one or more selected from the group consisting of GLP-1 and a GLP-1 analog; to said subject, wherein said first effective amount is administered sequentially. or for about 15 minutes or less, about 30 minutes or less, about 1 hour or less, about 2 hours or less , twice for about 3 hours or less, or about 4 hours or less, about 5 hours or less, or about 6 hours or less wherein the administration is intermittently administered with an interval between successive administrations of a second effective amount of one or more selected from the group consisting of GLP-1 and a GLP-1 analog; and administering to the subject a second active ingredient of the compound of formula (I) once daily, twice daily, three times daily, or four times daily. and preventing diabetes, obesity, overweight, NAFLD, and / or NASH in said subject. and a drug regimen, comprising: treating or preventing a disease.

2. The subject has diabetes, obesity, overweight, NAFLD, and / or NASH. or have diabetes, obesity, overweight, NAFLD, and / or NASH The dosing regimen of claim 1, wherein the patient is at high risk.

3. The GLP-1 analogues include GLP-1(7-37), GLP-1(7-36), and The dosing regimen according to claim 1 or 2, wherein the dosing regimen is selected from the group consisting of GLP-1 (7-35). Men.

4. a third effective amount of a compound selected from the group consisting of insulin, insulin analogs, and metformin.

2. The method of claim 1 further comprising administering to the subject one or more selected third active ingredients. A dosing regimen according to any one of 1 to 3.

5. The insulin analogue is selected from the group consisting of fast-acting insulin and long-acting insulin. The dosing regimen according to any one of claims 1 to 4, selected from:

6. The effective amount (U) of insulin and / or insulin analogues and the effective amount (m g) the GLP-1 and / or GLP-1 analogue in a ratio of 10:1 to 800:1, about 30:1 to about 500:1, about 50:1 to about 250:1, about 70:1 to about 220:1, in a ratio of about 100:1 to about 200:1, such as about 10:1, about 20:1, about 30:1, about 40: 1, about 50:1, about 60:1, about 60:1, about 70:1, about 80:1, about 90:1, about 1 00:1, about 150:1, about 200:1, about 250:1, about 300:1, about 350:1, About 400:1, about 450:1, about 500:1, about 550:1, about 600:1, about 650: 1, about 700:1, about 750:1, or about 800:

1.

5. The dosing regimen described in 5.

7. The total daily dosage of the GLP-1 and / or GLP-1 analog is from about 100 μg to about 1,000 μg, about 200 μg to about 900 μg, about 300 μg to about 800 μg, about 400 μg Any one of claims 1 to 6, wherein the amount of the hydroxybenzoate is from about 480 μg to about 600 μg. The dosing regimen described above.

8. a total daily dosage of said first effective amount of said GLP-1 and / or GLP-1 analog; a total daily dosage of said second effective amount of said GLP-1 and / or GLP-1 analog; , about 1, about 0.1 to about 10, about 0.5 to about 5, about 0.7 to about 2, about 0.8 to about 1.5, or or a ratio of from about 0.9 to about 1.

2. hmm.

9. The first effective amount of the GLP-1 and / or GLP-1 analogue may be constant or variable.

9. The dosing regimen of any one of claims 1 to 8, wherein the dosing regimen is administered at variable dosage rates.

10. The second effective amount of the GLP-1 and / or GLP-1 analog is administered in each administration.

10. The dosing regimen according to any one of claims 1 to 9, wherein the respective doses are administered in the same or different doses. Men.

11. The second effective amount of the GLP-1 and / or GLP-1 analog is administered before or after a meal. About 0.5 minutes to about 30 minutes, about 1 minute to about 15 minutes, about 2 minutes to about 10 minutes, about 3 minutes to about 7 minutes, or The dosing regimen of any one of claims 1 to 10, wherein the dose is administered in 5 minutes or about 5 minutes.

Images