Pharmaceutical combinations and compositions and methods of use thereof

Abstract

Novel pharmaceutical combinations and compositions, including berberine ursodeoxycholic acid and an SGLT2 inhibitor, or berberine and / or ursodeoxycholic acid and an SGLT2 inhibitor, and methods thereof are provided, which can exert synergistic weight loss and / or blood glucose lowering effects, and at the same time, the pharmaceutical combinations provided herein can also significantly improve insulin sensitivity.Therapeutic uses and methods for treating one or more metabolic diseases or disorders are further provided.

Description

[Technical Field]

[0001] Priority claims This application claims priority to Chinese Patent Application No. 2022117388748 filed on December 30, 2022, Chinese Patent Application No. 202310499681X filed on May 5, 2023, and Chinese Patent Application No. 2023110864945 filed on August 25, 2023, all of which are incorporated herein by reference in their entireties.

[0002] The present invention relates to the technical field of medicine, in particular to novel pharmaceutical combinations and their therapeutic uses, more particularly to novel pharmaceutical compositions comprising berberine ursodeoxycholate and an inhibitor of sodium-glucose cotransporter-2 (SGLT2), and their use in the treatment of metabolic diseases. [Background technology]

[0003] The prevalence of diabetes is rising among epidemics. In 2021, an estimated 537 million people worldwide had diabetes. Diabetes, which affects approximately 10% of the adult population, is a chronic disease with three main types: type 1 diabetes, type 2 diabetes, and gestational diabetes. Type 2 diabetes, the most common type accounting for 90%–95% of diabetes cases, is a progressive disease characterized by insulin resistance and relatively insufficient insulin secretion, which leads to elevated blood glucose levels. Hyperglycemia, or elevated blood glucose levels, is a common consequence of uncontrolled diabetes and, over time, can cause severe damage to many systems in the body, particularly the nervous and vascular systems.

[0004] An important way to treat diabetes is to maintain a healthy lifestyle. Some patients with type 2 diabetes also require medication to help control blood glucose levels. Diabetic patients often require antihypertensive drugs and statins to reduce the risk of complications. For many patients, initial monotherapy with hypoglycemic drugs does not provide adequate control of blood glucose levels during long-term treatment, resulting in the need for upgraded treatment to ensure continued control of blood glucose levels after several years of treatment. Upgraded treatment usually involves using two or more hypoglycemic drugs in combination, but implementing improved combination therapy can be challenging (Rational combination therapy for type 2 diabetes. Lancet Diabetes Endocrinol. 2019 May;7(5):328-329. doi:10.1016 / S2213-8587(19)30069-5.).

[0005] Obesity, typically defined as the substantial accumulation of body fat that can affect health, affects over one billion people worldwide and its prevalence is rising. Obesity is associated with or increases patients' risk for many diseases, including cardiometabolic, gastrointestinal, respiratory, neurological, and musculoskeletal disorders, and these diseases are also interrelated (Body-mass index and risk of obesity-related complex multimorbidity: an observational multicohort study. Lancet Diabetes Endocrinol. 2022 Apr;10(4):253-263. doi:10.1016 / S2213-8587(22)00033-X.). For example, obesity is an important factor in the development of type 2 diabetes. Studies have shown that 61% of type 2 diabetes patients are overweight (BMI ≥ 25 kg / m). 2Obesity, defined as obesity, is a cause of obesity, and as weight increases, so does the risk of developing type 2 diabetes. Preventing and treating obesity is an important strategy for reducing the incidence of, and ameliorating, type 2 diabetes. Studies have shown that weight loss improves blood glucose control and even reverses the progression of type 2 diabetes in patients (Durability of a primary care-led weight-management intervention for remission of type 2 diabetes: 2-year results of the DiRECT open-label, cluster-randomized trial. Lancet Diabetes Endocrinol. 2019 May;7(5):344-355.).

[0006] Currently, low-calorie diets, weight-loss surgery, and gut hormone therapy (e.g., GLP-1RAs) are considered the most effective methods for weight loss. While these treatments can significantly reduce fat mass, they have significant drawbacks, such as poor compliance and utilization due to the need for long-term adherence. Furthermore, weight loss can affect healthy muscle mass, leading to the development of sarcopenia and other health problems. For example, a clinical trial reported a mean weight loss of 15% (compared to a 3.6% decrease in the placebo group) after 68 weeks of semaglutide treatment, accompanied by a mean decrease of 19.3% in total fat and 9.7% in muscle mass (Impact of Semaglutide on Body Composition in Adults With Overweight or Obesity: Exploratory Analysis of the STEP 1 Study. J Endocr Soc. 2021 (May 3);5(Suppl 1):A16-7. doi:10.1210 / jendso / bvab048.030.). Another clinical trial using a lower dose of semaglutide also yielded similar results: after 52 weeks of treatment, total fat mass decreased by an average of 10.2% and 7.8% in the semaglutide and cangliflozin groups, respectively, while total muscle mass decreased by an average of 4.5% and 2.9%, respectively. (Effects of once-weekly semaglutide vs once-daily canagliflozin on body composition in type 2 diabetes: a substudy of the SUSTAIN 8 randomized controlled clinical trial. Diabetologia. 2020 Mar;63(3):473-485. doi:10.1007 / s00125-019-05065-8.) Other studies have produced consistent results, demonstrating the importance of maintaining or even increasing adequate, healthy muscle mass in obese patients while losing weight.(Tirzepatide Once Weekly for the Treatment of Obesity.N Engl J Med.2022 Jul 21; 387(3):205-216.doi:10.1056 / NEJMoa2206038; Low muscle mass and mortality risk later in life:A 10-year follow-up study.PLoS One.2022 (Jul 28);17(7):e0271579.doi:10.1371 / journal.pone.0271579.;China Kadoorie Biobank Collaborative Group.Associations of muscle mass, strength, and quality with all-cause mortality in China:a population-based cohort study.Chin Med J (Engl).2022 Jun 5;135(11):1358-1368.doi:10.1097 / CM9.0000000000002193; Sarcopenic obesity in the elderly and strategies for weight management.Nutr Rev.2012 Jan;70(1):57-64.doi:10.1111 / j.1753-4887.2011.00453.x)。

[0007] Sarcopenia is a type of muscle loss that occurs with aging and / or immobility. Sarcopenia is of increasing concern as many countries experience a significant shift in population distribution toward older adults. In 2010, a European consensus on sarcopenia was published, defining sarcopenia as an age-related geriatric syndrome characterized by decreased muscle mass, muscle strength, and / or physical function (Sarcopenia: European consensus on definition and diagnosis: report of the European Working Group on sarcopenia in older people [J]. Age Ageing, 2010, 39(4):412-423.). The global prevalence of sarcopenia is estimated to be 6%-12% overall and 14%-33% in the population aged 65 years and older. Among disabled and hospitalized patients, this rate is as high as 78% (Prevalence of sarcopenia in the world: a systematic review and meta-analysis of general population studies[J]. J Diabetes Metab Disord, 2017, 16:21. DOI:10.1186 / s40200-017-0302-x.).

[0008] The etiology of sarcopenia is currently unclear. Clinically, not only primary sarcopenia caused by aging but also secondary sarcopenia caused by other diseases or conditions, such as muscle disuse due to prolonged immobilization and bed rest, skeletal muscle denervation, severe malnutrition, tumor cachexia, endocrine-metabolic disorders, and genetics, is common. (Sarcopenia: European consensus on definition and diagnosis: Report of the European Working Group on Sarcopenia in Older People. Age Ageing. 2010 Jul;39(4):412-23. doi:10.1093 / ageing / afq034.) For example, in diabetic patients, abnormal insulin secretion and insulin resistance can lead to muscular dystrophy, resulting in a higher prevalence of sarcopenia in diabetic patients compared to the general population.

[0009] Sarcopenia develops insidiously, but can significantly impair patients' quality of life and health, leading to physical disability and increased risk of death. A meta-analysis of 10,073 subjects showed that older adults with sarcopenia had a 52% increased risk of falls compared with those without sarcopenia (Alls among older adults with sarcopenia dwelling in nursing home or community: A meta-analysis. Clin Nutr. 2020 Jan;39(1):33-39. doi:10.1016 / j.clnu.2019.01.002). And falls in older adults increase the risk of fracture by 50% (The association between sarcopenia and fracture in middle-aged and elderly people: A systematic review and meta-analysis of cohort studies. Injury. 2020 Apr;51(4):804-811. doi:10.1016 / j.injury.2020.02.072.) and even lead to an increased risk of death. Among community-dwelling older people, studies have shown that the risk of all-cause mortality in those with sarcopenia is 1.6 times higher than that in those without sarcopenia, and the risk of all-cause mortality is 2.09 times higher within 5 years (Sarcopenia as a predictor of all-cause mortality among community-dwelling older people: A systematic review and meta-analysis. Maturitas. 2017 Sep;103:16-22. doi:10.1016 / j.maturitas.2017.04.007.). However, there are currently no effective drugs to treat sarcopenia.

[0010] SGLT-2 inhibitors exhibit unique hypoglycemic effects by reducing glucose reabsorption by SGLT2 in the kidney, promoting urinary glucose excretion, and lowering blood glucose levels, resulting in an average reduction of HbA1c levels of 0.7% compared to placebo. Because their blood glucose-lowering mechanism is unique and reduces blood glucose levels independently of insulin, the risk of hypoglycemia is low when used alone, and they can be used together with other hypoglycemic drugs to achieve a more sustained hypoglycemic effect. More importantly, in addition to being able to lower blood glucose levels, numerous large-scale randomized controlled clinical trials suggest that SGLT2 inhibitors may reduce the clinical outcomes of heart failure and chronic kidney disease, and even reduce cardiovascular mortality (SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials).) Lancet.2019 Jan 5;393(10166):31-39.; SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet.2019 Jan 5;393(10166):31-39; SGLT-2 inhibitors in patients with heart failure: a comprehensive meta-analysis of five randomized controlled trials.Lancet.2022 Sep 3;400(10354):757-767.).

[0011] Currently available SGLT2 inhibitors include empagliflozin, dapagliflozin, canagliflozin, ertugliflozin, henagliflozin, ipragliflozin, tofogliflozin, sotagliflozin, luseogliflozin, and janagliflozin, with several others currently in clinical development.

[0012] Berberine ursodeoxycholic acid (BUDC) is a novel ionic salt compound formed by berberine (BBR) and ursodeoxycholic acid (UDCA). This compound is disclosed in WO2016 / 015634A1 (PCT / CN2015 / 085350) and WO2018 / 205987A1 (PCT / CN2018 / 086461) and other patent applications. It is currently undergoing clinical studies as a new molecular entity and has the potential to treat nonalcoholic steatohepatitis (NASH), primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), and diabetes.

[0013] [ka] Summary of the Invention

[0014] The present invention provides novel pharmaceutical compositions and therapeutic methods of use of BUDC or BBR and / or UDCA in combination with an SGLT2 inhibitor. In particular, the present invention provides pharmaceutical compositions comprising BUDC and an SGLT2 inhibitor (e.g., empagliflozin) or a pharmaceutically acceptable salt thereof, and therapeutic methods of use of BUDC with an SGLT2 inhibitor. The present invention further provides pharmaceutical compositions comprising BBR and / or UDCA and an SGLT2 inhibitor, and therapeutic methods of use of BBR and / or UDCA and an SGLT2 inhibitor. The compositions and methods of the present invention can be used to treat various diseases and conditions (e.g., diabetes, pre-diabetes, obesity, sarcopenia, and glucagon).

[0015] In one aspect, the present invention generally relates to Pharmaceutical Combination I, which comprises: Substance X, which is berberine ursodeoxycholic acid; Substance Y is an SGLT2 inhibitor or a pharmaceutically acceptable salt thereof; Including, The SGLT2 inhibitor is selected from the group consisting of empagliflozin, dapagliflozin, canagliflozin, ertugliflozin, henagliflozin, ipragliflozin, tofogliflozin, sotagliflozin, luseogliflozin, janagliflozin, bexagliflozin, rongliflozin, enavogliflozin, and JT-001.

[0016] In another aspect, the invention generally relates to Pharmaceutical Composition A, comprising: Substance X, which is berberine ursodeoxycholic acid; a substance Y which is an SGLT2 inhibitor or a pharmaceutically acceptable salt thereof; a pharmaceutically acceptable excipient; Including, The SGLT2 inhibitor is selected from at least one of empagliflozin, dapagliflozin, canagliflozin, ertugliflozin, henagliflozin, ipragliflozin, tofogliflozin, sotagliflozin, luseogliflozin, janagliflozin, bexagliflozin, rongliflozin, enavogliflozin, and JT-001.

[0017] In yet another aspect, the invention generally relates to Pharmaceutical Composition B, comprising: a first pharmaceutical composition comprising a substance X and a first pharmaceutically acceptable excipient, wherein substance X is BUDC; a second pharmaceutical composition comprising substance Y and a second pharmaceutically acceptable excipient, wherein substance Y is an SGLT2 inhibitor or a pharmaceutically acceptable salt thereof; and Including, The SGLT2 inhibitor is selected from at least one of empagliflozin, dapagliflozin, canagliflozin, ertugliflozin, henagliflozin, ipragliflozin, tofogliflozin, sotagliflozin, luseogliflozin, janagliflozin, bexagliflozin, rongliflozin, enavogliflozin, and JT-001.

[0018] In yet another aspect, the invention generally relates to Pharmaceutical Combination II, comprising: a substance U which is BBR or a pharmaceutically acceptable salt thereof; a substance V which is UDCA or a pharmaceutically acceptable salt thereof; Substance Y is an SGLT2 inhibitor or a pharmaceutically acceptable salt thereof; Including, The SGLT2 inhibitor is selected from at least one of empagliflozin, dapagliflozin, canagliflozin, ertugliflozin, henagliflozin, ipragliflozin, tofogliflozin, sotagliflozin, luseogliflozin, janagliflozin, bexagliflozin, rongliflozin, enavogliflozin, and JT-001. [Brief explanation of the drawings]

[0019] [Figure 1] FIG. 1 shows exemplary results of the body fat mass of mice in the model group G2 and the normal group G1 measured before administration in Example 1, where the data are expressed as mean ± standard error mean (SEM) and one-way analysis of variance (ANOVA) for G1, with **** indicating p<0.0001. [Figure 2] FIG. 2 shows exemplary results of the change in body weight for each group of animals over time in Example 1, with data expressed as mean±SEM. [Figure 3] FIG. 3 shows exemplary results of the percent weight change for each group of animals over time in Example 1, with data expressed as mean±SEM. [Figure 4] FIG. 4 shows exemplary results of the body fat mass of each group of animals measured after 25 days of administration in Example 1, where data are expressed as mean ± SEM and **** represents p<0.0001, *** represents p<0.001, and ** represents p<0.01 by one-way ANOVA vs. G2. [Figure 5] FIG. 5 shows exemplary results of the body fat percentage of each group of animals measured after 25 days of administration in Example 1, where data are expressed as mean ± SEM and **** represents p<0.0001, ** represents p<0.01, and * represents p<0.05 by one-way ANOVA vs. G2. [Figure 6]FIG. 6 shows exemplary results of liver weights measured for each group of animals after 28 days of administration in Example 1, where data are expressed as mean ± SEM and ** represents p<0.01 and * represents p<0.05 by one-way ANOVA vs. G2. [Figure 7] FIG. 7 shows exemplary results of abdominal fat weight measured for each group of animals after 28 days of administration in Example 1, where data are expressed as mean ± SEM and **** indicates p<0.0001 by one-way ANOVA vs. G2. [Figure 8] FIG. 8 shows exemplary results of the subcutaneous fat weight of each group of animals measured after 28 days of administration in Example 1, where data are expressed as mean ± SEM, and **** represents p<0.0001 and ** represents p<0.01 by one-way ANOVA vs. G2. [Figure 9] FIG. 9 shows exemplary results of lean mass measured for each group of animals after 25 days of administration in Example 1, where data are expressed as mean±SEM and **** indicates p<0.0001 by one-way ANOVA vs. G2. [Figure 10] FIG. 10 shows exemplary results of the percentage of lean body mass in body weight for each group of animals measured after 25 days of administration in Example 1, where data are expressed as mean ± SEM and **** represents p<0.0001 and * represents p<0.05 by one-way ANOVA vs. G2. [Figure 11] FIG. 11 shows exemplary results of fasting blood glucose levels for each group of animals measured after 20 days of administration in Example 1, where data are expressed as mean ± SEM and **** represents p<0.0001, ** represents p<0.01, and * represents p<0.05 by one-way ANOVA vs. G2. [Figure 12] FIG. 12 shows exemplary results of blood glucose levels for each group of animals measured over time from the OGTT study in Example 1, where data are expressed as mean±SEM. [Figure 13]FIG. 13 shows exemplary results of an AUC analysis of the area under the curve of the change in blood glucose levels for each group of animals measured over time from the OGTT study in Example 1, where data are expressed as mean±SEM and * indicates p<0.05 by one-way ANOVA vs. G2. [Figure 14] FIG. 14 shows exemplary results of fasting insulin levels measured from the OGTT study of Example 1, where data are expressed as mean±SEM. [Figure 15] FIG. 15 shows exemplary results of an AUC analysis of the area under the curve of fasting insulin levels over time for each group of animals in the OGTT study of Example 1, where data are expressed as mean±SEM and **** indicates p<0.0001 by one-way ANOVA vs. G2. [Figure 16] FIG. 16 shows exemplary results of the change in food intake for each group of animals within 24 hours during the dosing period in Example 1, where the data are expressed as mean±SEM. [Figure 17] FIG. 17 shows exemplary results of the body weights of mice in the model group G2 and the normal group G1 measured before administration in Example 2, where the data are expressed as mean ± SEM, G1: n=10, G2: n=73. [Figure 18] FIG. 18 shows exemplary results of the body fat mass of mice in the model group G2 and the normal group G1 measured before administration in Example 2, where the data are expressed as mean ± SEM, and **** indicates p<0.0001 in a one-way ANOVA for G2. [Figure 19] FIG. 19 shows exemplary results of the change in body weight over time for each group of animals in Example 2, where data are expressed as mean ± SEM and the number of animals measured was n=8 for each group, except for G4: n=6, G6: n=7, and G8: n=6. [Figure 20] FIG. 20 shows exemplary results of the weight change rate over time for each group of animals in Example 2, where data are expressed as mean ± SEM and the number of animals measured was G4: n=6, G6: n=7, G7: n=4, and G8: n=6, with n=8 for each group otherwise. [Figure 21]FIG. 21 shows exemplary results of body lipid content measured for each group of animals after 23 days of administration in Example 2, where data are expressed as mean ± SEM and **** represents p<0.0001 and *** represents p<0.001 by one-way ANOVA vs. G2. [Figure 22] FIG. 22 shows exemplary results of the body fat percentage of each group of animals measured after 23 days of administration in Example 2, where data are expressed as mean ± SEM and **** represents p<0.0001 and * represents p<0.05 by one-way ANOVA vs. G2. [Figure 23] FIG. 23 shows exemplary results of lean body mass for each group of animals measured after 23 days of dosing in Example 2, where data are expressed as mean±SEM and **** indicates p<0.0001 by one-way ANOVA vs. G2. [Figure 24] FIG. 24 shows exemplary results of the percentage of lean body mass in body weight for each group of animals measured after 23 days of administration in Example 2, where data are expressed as mean ± SEM and **** represents p<0.0001 and *** represents p<0.001 by one-way ANOVA vs. G2. DETAILED DESCRIPTION OF THE INVENTION

[0020] In one aspect, the present invention generally relates to Pharmaceutical Combination I, which comprises: Substance X, which is berberine ursodeoxycholic acid; Substance Y is an SGLT2 inhibitor or a pharmaceutically acceptable salt thereof; Including, The SGLT2 inhibitor is selected from the group consisting of empagliflozin, dapagliflozin, canagliflozin, ertugliflozin, henagliflozin, ipragliflozin, tofogliflozin, sotagliflozin, luseogliflozin, janagliflozin, bexagliflozin, rongliflozin, enavogliflozin, and JT-001.

[0021] In some embodiments, the active ingredients of pharmaceutical combination I comprise substance X and substance Y.

[0022] In pharmaceutical combination I, substance X and substance Y can be administered simultaneously or separately.

[0023] The term "co-administration" or "administered simultaneously" means, for example, that substance X and substance Y contained in separate pharmaceutical compositions are administered at the same time, or that "separate pharmaceutical compositions containing substance X" and "separate pharmaceutical compositions containing substance Y" are administered at the same time.

[0024] The term "separate administration" means, for example, that an "individual pharmaceutical composition comprising substance X" and an "individual pharmaceutical composition comprising substance Y" are administered separately at different times. For example, one of the "individual pharmaceutical composition comprising substance X" and the "individual pharmaceutical composition comprising substance Y" is administered first, and the other is administered later. The separate administrations may be close in time or separate in time.

[0025] Whether the two substances are administered simultaneously or separately, the administration regimens (including route of administration, dosage, interval between administrations, etc.) of substance X and substance Y may be the same or different and may be adjusted as desired by one skilled in the art.

[0026] In some embodiments, substance X is administered orally.

[0027] In some embodiments, substance Y is administered orally.

[0028] Preferably, in some embodiments, substance X is administered orally and substance Y is administered orally.

[0029] In some embodiments, the SGLT2 inhibitor is selected from empagliflozin, dapagliflozin, and canagliflozin. In some embodiments, the SGLT2 inhibitor is dapagliflozin. In some embodiments, the SGLT2 inhibitor is empagliflozin. In some embodiments, the SGLT2 inhibitor is canagliflozin.

[0030] In some embodiments, substance X and substance Y are in a unit dosage form selected from a tablet, a capsule, or a liquid formulation.

[0031] In some embodiments, BUDC exists in an amorphous form, anhydrous crystalline form, or hydrated crystalline form. The various crystalline forms of berberine ursodeoxycholate disclosed in CN108864077A and WO2018 / 205987A1 can be utilized in the present invention.

[0032] In some embodiments, the berberine ursodeoxycholate is present in crystalline form A, which has diffraction peaks at the following angles 2θ in an X-ray powder diffraction pattern: 7.06±0.2°, 7.34±0.2°, 8.79±0.2°, 9.47±0.2°, 11.94±0.2°, 14.17±0.2°, 15.50±0.2°, 16.54±0.2°, and 16.78±0.2°.

[0033] Preferably, the crystalline form A of berberine ursodeoxycholate has the following X-ray powder diffraction patterns: 3.98±0.2°, 7.06±0.2°, 7.34±0.2°, 7.93±0.2°, 8.79±0.2°, 9.47±0.2°, 11.70±0.2°, 11.94±0.2°, 12.34±0.2°, 12.55±0.2°, 13.90±0.2°, 14.17±0.2°, 15.14±0.2°, 15.50±0.2°, 16.16±0.2°, 16.54±0.2°, 16.78±0.2° It has diffraction peaks at 2θ of 17.53±0.2°, 17.67±0.2°, 18.23±0.2°, 19.03±0.2°, 19.98±0.2°, 20.87±0.2°, 21.13±0.2°, 21.96±0.2°, 23.49±0.2°, 24.24±0.2°, 24.97±0.2°, 25.50±0.2°, 26.63±0.2°, 27.60±0.2°, 28.06±0.2°, 28.63±0.2°, 29.40±0.2°, and 30.49±0.2°.

[0034] The X-ray powder diffraction pattern is obtained under Cu Kα radiation (λ1 = 1.540598 Å, λ2 = 1.544426 Å, density ratio λ2 / λ1 = 0.50).

[0035] Preferably, in some embodiments, the crystalline form A of berberine ursodeoxycholate is crystalline form A of berberine ursodeoxycholate heminonahydrate.

[0036] [ka] is.

[0037] In some embodiments, the berberine ursodeoxycholate is in crystalline form D, and the berberine ursodeoxycholate crystalline form D has diffraction peaks at the following angles 2θ in an X-ray powder diffraction pattern: 4.24±0.2°, 6.79±0.2°, 8.50±0.2°, 10.25±0.2°, 11.50±0.2°, 13.62±0.2°, 14.74±0.2°, 15.20±0.2°, 17.92±0.2°, 18.39±0.2°, 22.91±0.2°, and 25.73±0.2°.

[0038] The X-ray powder diffraction pattern is obtained under Cu Kα radiation (λ1 = 1.540598 Å, λ2 = 1.544426 Å, density ratio λ2 / λ1 = 0.50).

[0039] In some embodiments, BUDC is present as a free base or a hydrated form.

[0040] In some embodiments, substance X is BUDC and substance Y is empagliflozin.

[0041] In some embodiments, substance X is BUDC and substance Y is dapagliflozin.

[0042] In some embodiments, substance X is BUDC and substance Y is canagliflozin.

[0043] In some embodiments, substance X is BUDC and substance Y is ertugliflozin.

[0044] In some embodiments, substance X is BUDC and substance Y is henagliflozin.

[0045] In some embodiments, substance X is BUDC and substance Y is ipragliflozin.

[0046] In some embodiments, substance X is BUDC and substance Y is tofogliflozin.

[0047] In some embodiments, substance X is BUDC and substance Y is sotagliflozin.

[0048] In some embodiments, substance X is BUDC and substance Y is luseogliflozin.

[0049] In some embodiments, substance X is BUDC and substance Y is janagliflozin.

[0050] In some embodiments, substance X is BUDC and substance Y is bexagliflozin.

[0051] In some embodiments, substance X is BUDC and substance Y is longriflozin.

[0052] In some embodiments, substance X is BUDC and substance Y is enavogliflozin.

[0053] In some embodiments, substance X is BUDC and substance Y is JT-001.

[0054] In some embodiments, pharmaceutical combination I consists of agent X and agent Y.

[0055] In some embodiments, the active ingredients of pharmaceutical combination I consist of substance X and substance Y.

[0056] In some embodiments, pharmaceutical combination I consists of crystalline form A of hemi-nonahydrate BUDC and empagliflozin.

[0057] In some embodiments, the active ingredients of pharmaceutical combination I consist of crystalline form A of the heminonahydrate of BUDC and dapagliflozin.

[0058] In some embodiments, in pharmaceutical combination I, substance X and substance Y are provided in a molar ratio of 1:100 to 100:1, preferably substance X and substance Y are provided in a molar ratio of 1:50 to 1:5 or 1:1 to 100:1, more preferably substance X and substance Y are provided in a molar ratio of 5:1 to 50:1 (e.g., 30:1).

[0059] In some embodiments, in pharmaceutical combination I, substance X and substance Y are provided in a molar ratio of 5:1 to 15:1, such as 14:1, 13:1, 12:1, 11:1, 10:1, or 9:1.

[0060] In some embodiments, substance X is BUDC, preferably crystalline form A of the heminonahydrate of BUDC, and substance Y is empagliflozin in pharmaceutical combination I, wherein substance X and substance Y are provided in a molar ratio of 12:1, 11:1, 10:1, or 9:1.

[0061] In some embodiments, in pharmaceutical combination I, substance X is BUDC, preferably crystalline form A of the heminonahydrate of BUDC, and substance Y is dapagliflozin, and substance X and substance Y are provided in a molar ratio of 14:1, 13:1, or 12:1.

[0062] According to the above ratios, substance X and substance Y of the present invention may be dosed in the same ratio based on the needs of the subject.

[0063] In some embodiments, the substance X of the present invention is administered as a QD (once daily), BID (twice daily), or TID (three times daily) regimen, preferably QD.

[0064] In some embodiments, substance Y of the present invention is administered as a QD (once daily), BID (twice daily), or TID (three times daily) regimen, preferably QD.

[0065] In some embodiments, substance X and substance Y are administered according to the same regimen.

[0066] In some embodiments, pharmaceutical combination I is useful for treating and / or preventing metabolic disorders associated therewith or related thereto.

[0067] In some embodiments, pharmaceutical combination I is useful for treating and / or preventing muscle disorders.

[0068] In some embodiments, the metabolic disease is selected from diabetes, pre-diabetes, hyperinsulinemia, and obesity.

[0069] In some embodiments, the muscle disease is selected from sarcopenia and muscular dystrophy.

[0070] In another aspect, the invention generally relates to Pharmaceutical Composition A, comprising: Substance X, which is berberine ursodeoxycholic acid; a substance Y which is an SGLT2 inhibitor or a pharmaceutically acceptable salt thereof; a pharmaceutically acceptable excipient; Including, The SGLT2 inhibitor is selected from at least one of empagliflozin, dapagliflozin, canagliflozin, ertugliflozin, henagliflozin, ipragliflozin, tofogliflozin, sotagliflozin, luseogliflozin, janagliflozin, bexagliflozin, longliflorizin, enavogliflozin, and JT-001.

[0071] In some embodiments, the active ingredients of pharmaceutical composition A include substance X and substance Y.

[0072] In some embodiments, BUDC is present in an amorphous form, anhydrous crystalline form, or hydrated crystalline form.

[0073] Preferably, BUDC is present in crystalline form A, and crystalline form A of berberine ursodeoxycholate is as described above.

[0074] More preferably, crystalline form A of BUDC is crystalline form A of BUDC heminonahydrate.

[0075] In some embodiments, the SGLT2 inhibitor is selected from empagliflozin, dapagliflozin, and canagliflozin. In some embodiments, the SGLT2 inhibitor is dapagliflozin. In some embodiments, the SGLT2 inhibitor is empagliflozin. In some embodiments, the SGLT2 inhibitor is canagliflozin.

[0076] In some embodiments, Pharmaceutical Composition A comprises BUDC, empagliflozin, and pharmaceutically acceptable excipients.

[0077] In some embodiments, Pharmaceutical Composition A comprises BUDC, dapagliflozin, and pharmaceutically acceptable excipients.

[0078] In some embodiments, Pharmaceutical Composition A comprises BUDC, canagliflozin, and pharmaceutically acceptable excipients.

[0079] In some embodiments, Pharmaceutical Composition A comprises BUDC, ertugliflozin, and pharmaceutically acceptable excipients.

[0080] In some embodiments, Pharmaceutical Composition A comprises BUDC, henagliflozin, and pharmaceutically acceptable excipients.

[0081] In some embodiments, Pharmaceutical Composition A comprises BUDC, ipragliflozin, and pharmaceutically acceptable excipients.

[0082] In some embodiments, Pharmaceutical Composition A comprises BUDC, tofogliflozin, and pharmaceutically acceptable excipients.

[0083] In some embodiments, Pharmaceutical Composition A comprises BUDC, sotagliflozin, and pharmaceutically acceptable excipients.

[0084] In some embodiments, Pharmaceutical Composition A comprises BUDC, luseogliflozin, and pharmaceutically acceptable excipients.

[0085] In some embodiments, Pharmaceutical Composition A comprises BUDC, janagliflozin, and pharmaceutically acceptable excipients.

[0086] In some embodiments, Pharmaceutical Composition A comprises BUDC, bexagliflozin, and pharmaceutically acceptable excipients.

[0087] In some embodiments, Pharmaceutical Composition A comprises crystalline Form A of the heminonahydrate of BUDC, empagliflozin, and pharmaceutically acceptable excipients.

[0088] In some embodiments, Pharmaceutical Composition A comprises crystalline Form A of the heminonahydrate of BUDC, dapagliflozin, and pharmaceutically acceptable excipients.

[0089] In some embodiments, pharmaceutical composition A consists of substance X, substance Y, and one or more pharmaceutically acceptable excipients.

[0090] In some embodiments, the active ingredients of pharmaceutical composition A consist of substance X and substance Y.

[0091] In some embodiments, the active ingredients of the medicament A consist of crystalline form A of the heminonahydrate of BUDC and empagliflozin.

[0092] In some embodiments, the active ingredients of Pharmaceutical Composition A consist of crystalline form A of the heminonahydrate of BUDC and dapagliflozin.

[0093] In some embodiments, in Pharmaceutical Composition A, BUDC and the SGLT2 inhibitor are provided in a molar ratio of 1:1 to 100:1, preferably, BUDC and the SGLT2 inhibitor are provided in a molar ratio of 1:50 to 1:5 or 1:1 to 100:1, preferably, BUDC and the SGLT2 inhibitor are provided in a molar ratio of 5:1 to 50:1 (e.g., 30:1), more preferably, BUDC and the SGLT2 inhibitor are provided in a molar ratio of 5:1 to 15:1, such as 14:1, 13:1, 12:1, 11:1, 10:1, or 9:1.

[0094] In some embodiments, in pharmaceutical composition A, substance X is BUDC, preferably crystalline form A of the heminonahydrate of BUDC, and substance Y is empagliflozin, and substance X and substance Y are provided in a molar ratio of 12:1, 11:1, 10:1, or 9:1.

[0095] In some embodiments, in pharmaceutical composition A, substance X is BUDC, preferably crystalline form A of the heminonahydrate of BUDC, and substance Y is dapagliflozin, and substance X and substance Y are provided in a molar ratio of 14:1, 13:1, or 12:1.

[0096] In some embodiments, Pharmaceutical Composition A is in the form of an oral formulation.

[0097] In some embodiments, the oral formulation is selected from a tablet, a capsule, and a liquid formulation.

[0098] In some embodiments, Pharmaceutical Composition A is administered as a QD (once daily), BID (twice daily), or TID (three times daily) regimen, preferably QD.

[0099] In some embodiments, Pharmaceutical Composition A is Pharmaceutical Composition A used to treat and / or prevent a metabolic disease or a disease related thereto.

[0100] In some embodiments, Pharmaceutical Composition A is useful for treating and / or preventing muscle disorders.

[0101] In some embodiments, the metabolic disease is selected from diabetes, pre-diabetes, hyperinsulinemia, and obesity.

[0102] In some embodiments, the muscle disorder is selected from sarcopenia and

[0103] In some embodiments, the muscle disease is selected from muscular dystrophy.

[0104] In yet another aspect, the invention generally relates to Pharmaceutical Composition B, comprising: a first pharmaceutical composition comprising a substance X and a first pharmaceutically acceptable excipient, wherein said substance X is BUDC; a second pharmaceutical composition comprising a substance Y and a second pharmaceutically acceptable excipient, wherein said substance Y is an SGLT2 inhibitor or a pharmaceutically acceptable salt thereof; and Including, The SGLT2 inhibitor is selected from at least one of empagliflozin, dapagliflozin, canagliflozin, ertugliflozin, henagliflozin, ipragliflozin, tofogliflozin, sotagliflozin, luseogliflozin, janagliflozin, bexagliflozin, longliflorizin, enavogliflozin, and JT-001.

[0105] With respect to this aspect of the invention, the first pharmaceutical composition and the second pharmaceutical composition are independent pharmaceutical compositions.

[0106] The first pharmaceutically acceptable excipient and the second pharmaceutically acceptable excipient can be the same or different.

[0107] In some embodiments, the first pharmaceutical composition and the second pharmaceutical composition are disposed in the same solid dosage unit or unit dosage form.

[0108] Preferably, for this aspect of the invention, and in some embodiments, the solid dosage units are individual tablets or capsules.

[0109] More preferably, with respect to this aspect of the invention, and in some embodiments, the first and second pharmaceutical compositions are separately disposed in different portions of the same formulation unit or unit dosage form. For example, the first and second pharmaceutical compositions may form the upper and lower layers, or the inner and outer layers, respectively, of a tablet.

[0110] More preferably, with respect to this aspect of the invention, and in some embodiments, the first pharmaceutical composition and the second pharmaceutical composition are co-located within the space defined by the formulation unit or unit dosage form, e.g., the first pharmaceutical composition and the second pharmaceutical composition are mixed in the same capsule in a macroscopic form.

[0111] In some embodiments, the first pharmaceutical composition and the second pharmaceutical composition are each disposed in two separate subpackages in the same pharmaceutical pack.

[0112] In some embodiments, the first pharmaceutical composition is in an oral dosage form.

[0113] In some embodiments, the second pharmaceutical composition is in an oral dosage form.

[0114] Preferably, in some embodiments, the first pharmaceutical composition is in an oral dosage form and the second pharmaceutical composition is in an oral dosage form.

[0115] In some embodiments, BUDC is present in an amorphous form, anhydrous crystalline form, or hydrated crystalline form.

[0116] Preferably, BUDC is present in crystalline form A, and crystalline form A of BUDC is as described herein.

[0117] More preferably, crystalline form A of BUDC is crystalline form A of BUDC heminonahydrate.

[0118] In some embodiments, the SGLT2 inhibitor is selected from empagliflozin, dapagliflozin, and canagliflozin. In some embodiments, the SGLT2 inhibitor is dapagliflozin. In some embodiments, the SGLT2 inhibitor is empagliflozin. In some embodiments, the SGLT2 inhibitor is canagliflozin.

[0119] In some embodiments, Pharmaceutical Composition B comprises BUDC, empagliflozin, and pharmaceutically acceptable excipients.

[0120] In some embodiments, Pharmaceutical Composition B comprises BUDC, dapagliflozin, and pharmaceutically acceptable excipients.

[0121] In some embodiments, Pharmaceutical Composition B comprises BUDC, canagliflozin, and pharmaceutically acceptable excipients.

[0122] In some embodiments, pharmaceutical composition B consists of a first pharmaceutical composition and a second pharmaceutical composition.

[0123] In some embodiments, pharmaceutical composition B consists of substance X, substance Y, and one or more pharmaceutically acceptable excipients.

[0124] In some embodiments, in Pharmaceutical Composition B, BUDC and the SGLT2 inhibitor are provided in a molar ratio of 1:100 to 100:1, preferably, BUDC and the SGLT2 inhibitor are provided in a molar ratio of 1:50 to 1:5 or 1:1 to 100:1, more preferably, BUDC and the SGLT2 inhibitor are provided in a molar ratio of 5:1 to 50:1 (e.g., 30:1).

[0125] In some embodiments, in Pharmaceutical Composition B, the BUDC and the SGLT2 inhibitor are provided in a molar ratio of 5:1 to 15:1, such as 14:1, 13:1, 12:1, 11:1, 10:1, or 9:1.

[0126] In some embodiments, the first pharmaceutical composition is administered in a QD (once daily), BID (twice daily), or TID (three times daily) regimen, preferably QD. In some embodiments, the second pharmaceutical composition is administered in a QD (once every other day), BID (twice daily), or TID (three times daily) regimen, preferably QD.

[0127] In some embodiments, the first pharmaceutical composition and the second pharmaceutical composition are administered according to the same regimen.

[0128] In yet another aspect, the invention generally relates to Pharmaceutical Combination II, comprising: a substance U which is BBR or a pharmaceutically acceptable salt thereof; a substance V which is UDCA or a pharmaceutically acceptable salt thereof; Substance Y is an SGLT2 inhibitor or a pharmaceutically acceptable salt thereof; Including, The SGLT2 inhibitor is selected from at least one of empagliflozin, dapagliflozin, canagliflozin, ertugliflozin, henagliflozin, ipragliflozin, tofogliflozin, sotagliflozin, luseogliflozin, janagliflozin, bexagliflozin, longliflorizin, enavogliflozin, and JT-001.

[0129] In some embodiments, substance U is BUDC.

[0130] In some embodiments, substance V is BUDC.

[0131] In some embodiments, the SGLT2 inhibitor is selected from empagliflozin, dapagliflozin, and canagliflozin. In some embodiments, the SGLT2 inhibitor is dapagliflozin. In some embodiments, the SGLT2 inhibitor is empagliflozin. In some embodiments, the SGLT2 inhibitor is canagliflozin.

[0132] In some embodiments, pharmaceutical combination II comprises BBR or an inorganic acid salt thereof, UDCA, and an SGLT2 inhibitor.

[0133] In some embodiments, pharmaceutical combination II comprises BBR or an inorganic acid salt thereof, an inorganic base salt of UDCA, and an SGLT2 inhibitor.

[0134] In some embodiments, pharmaceutical combination II comprises BBR hydrochloride, UDCA, and empagliflozin.

[0135] In some embodiments, pharmaceutical combination II comprises BBR hydrochloride, UDCA, and dapagliflozin.

[0136] In some embodiments, pharmaceutical combination II consists of agent U, agent V, agent Y, and one or more pharmaceutically acceptable excipients.

[0137] In some embodiments, pharmaceutical combination II consists of BBR hydrochloride, UDCA, and empagliflozin, and one or more pharmaceutically acceptable excipients.

[0138] In some embodiments, pharmaceutical combination II consists of BBR hydrochloride, UDCA, and dapapagliflozin, and one or more pharmaceutically acceptable excipients.

[0139] In some embodiments, substance U, substance V, and substance Y may be administered simultaneously, separately, or in combination.

[0140] "Co-administration" means that two or more substances selected from, for example, substance U, substance V, and substance Y are administered at the same time. For example, substance U, substance V, and substance Y are administered at the same time, or as another example, substance U and substance V are administered at the same time, or as another example, substance U and substance Y are administered at the same time.

[0141] "Co-administration" means, for example, that two or more substances selected from substance U, substance V, and substance Y are contained in separate pharmaceutical compositions for simultaneous administration; as another example, any two or more of "individual pharmaceutical compositions containing substance U," "individual pharmaceutical compositions containing substance V," and "individual pharmaceutical compositions containing substance Y" are administered simultaneously.

[0142] "Separate administration" means, for example, that any one of "an individual pharmaceutical composition comprising substance U," "an individual pharmaceutical composition comprising substance V," and "an individual pharmaceutical composition comprising substance Y" is administered separately from the other pharmaceutical compositions of pharmaceutical combination II; as another example, "an individual pharmaceutical composition comprising substance U," "an individual pharmaceutical composition comprising substance V," and "an individual pharmaceutical composition comprising substance Y" are administered consecutively in a certain order. The separate administrations may be close in time or distant in time.

[0143] The term "administration in combination" means, for example, that any two of substance U, substance V, and substance Y in pharmaceutical combination II are administered simultaneously and separately from individual pharmaceutical compositions containing the remaining substances.

[0144] Whether the three substances are administered simultaneously, separately, or in combination, the administration regimens (including route of administration, dosage, administration interval, etc.) of substance U, substance V, and the rest of substance Y may be the same or different and may be adjusted by one skilled in the art.

[0145] In some embodiments, all or some of substance U, substance V, and substance Y are provided in the form of a pharmaceutical composition, for example, in the form of a pharmaceutical composition comprising substance U, substance V, and substance Y, or in the form of a pharmaceutical composition comprising any two of these substances.

[0146] In some embodiments, the molar ratio of substance U to substance V is 20:1 to 1:20, and preferably the molar ratio of substance V to substance Y is 5:1 to 1:2, preferably 1:1.

[0147] In some embodiments, the molar ratio of substance U to substance Y is 100:1 to 1:20, and preferably the molar ratio of substance V to substance Y is 50:1 to 1:1, more preferably 30:1 to 5:1.

[0148] In some embodiments, the molar ratio of substance V to substance Y is 20:1 to 1:20, and preferably the molar ratio of substance V to substance Y is 5:1 to 1:2, preferably 1:1.

[0149] In yet another aspect, the invention generally relates to pharmaceutical combination III, comprising: Substance V is UDCA; Substance Y is an SGLT2 inhibitor or a pharmaceutically acceptable salt thereof; Including, The SGLT2 inhibitor is defined as set forth in any one of the above aspects.

[0150] In some embodiments, substance V and substance Y can be administered simultaneously or separately.

[0151] In some embodiments, the molar ratio of substance V to substance Y is 20:1 to 1:20, preferably the molar ratio of substance V to substance Y is 5:1 to 1:2, preferably 1:1.

[0152] In another aspect, the present invention generally relates to the use of Pharmaceutical Combination I, Pharmaceutical Combination II, Pharmaceutical Combination III, Pharmaceutical Composition A, or Pharmaceutical Composition B disclosed herein in the preparation of a medicament for treating and / or preventing a metabolic disease or a disease related thereto.

[0153] The present invention further provides the use of Pharmaceutical Combination I, Pharmaceutical Combination II, Pharmaceutical Combination III, Pharmaceutical Composition A, or Pharmaceutical Composition B disclosed herein in the preparation of a medicament for treating and / or preventing a disease or disorder, wherein the disease is a muscle disorder.

[0154] In yet another aspect, the present invention further provides a method for treating or preventing a disease or condition, comprising administering to a subject (e.g., a human or mouse) in need thereof a therapeutically effective amount of Pharmaceutical Combination I, Pharmaceutical Combination II, Pharmaceutical Combination III, Pharmaceutical Composition A, or Pharmaceutical Composition B disclosed herein, wherein the disease is a metabolic disease or a disease related thereto.

[0155] In yet another aspect, the present invention provides a method for treating or preventing a disease or condition, comprising administering to a subject (e.g., a human or mouse) in need of treatment a therapeutically effective amount of Pharmaceutical Combination I, Pharmaceutical Combination II, Pharmaceutical Combination III, Pharmaceutical Composition A, or Pharmaceutical Composition B described herein, wherein the disease is a muscle disease.

[0156] In yet another aspect, the present invention further provides a method for reducing body fat mass, the method comprising administering to a subject (e.g., a human or a mouse) in need of treatment a therapeutically effective amount of Pharmaceutical Combination I, Pharmaceutical Combination II, Pharmaceutical Combination III, Pharmaceutical Composition A, or Pharmaceutical Composition B disclosed herein.

[0157] In yet another aspect, the present invention further provides a method of improving insulin sensitivity, the method comprising administering to a subject (e.g., a human or a mouse) in need of treatment a therapeutically effective amount of Pharmaceutical Combination I, Pharmaceutical Combination II, Pharmaceutical Combination III, Pharmaceutical Composition A, or Pharmaceutical Composition B disclosed herein.

[0158] In yet another aspect, the present invention further provides a method of increasing muscle mass, comprising administering to a subject (e.g., a human or a mouse) in need of treatment a therapeutically effective amount of Pharmaceutical Combination I, Pharmaceutical Combination II, Pharmaceutical Combination III, Pharmaceutical Composition A, or Pharmaceutical Composition B disclosed herein.

[0159] In yet another aspect, the present invention further provides a method for treating obesity or reducing body fat mass without causing loss of muscle mass, comprising administering to a subject (e.g., a human or a mouse) in need of treatment a therapeutically effective amount of Pharmaceutical Combination I, Pharmaceutical Combination II, Pharmaceutical Combination III, Pharmaceutical Composition A, or Pharmaceutical Composition B disclosed herein.

[0160] In yet another aspect, the present invention generally further provides for the use of Combination I, Pharmaceutical Combination II, Pharmaceutical Combination III, Pharmaceutical Composition A, or Pharmaceutical Composition B disclosed herein in the treatment of a metabolic disease or a disease related thereto.

[0161] In yet another aspect, the present invention further provides the use of Pharmaceutical Combination I, Pharmaceutical Combination II, Pharmaceutical Combination III, Pharmaceutical Composition A, or Pharmaceutical Composition B disclosed herein in the treatment of a muscle disease.

[0162] In yet another aspect, the present invention further provides use of substance Y as described herein in the preparation of a medicament for the treatment and / or prevention of a disease or condition, wherein said disease is a muscle disease, and substance Y is an SGLT2 inhibitor or a pharmaceutically acceptable salt thereof, and said SGLT2 inhibitor is selected from at least one of empagliflozin, dapagliflozin, canagliflozin, ertugliflozin, henagliflozin, ipragliflozin, tofogliflozin, sotagliflozin, luseogliflozin, janagliflozin, bexagliflozin, longriflolidin, enavogliflozin, and JT-001.

[0163] The medicament for treating and / or preventing a disease or disorder is used in conjunction with substance X, where substance X is berberine ursodeoxycholic acid.

[0164] In yet another aspect, the present invention further provides a method for reducing body fat mass, comprising administering to a subject (e.g., a human or a mouse) in need of treatment a therapeutically effective amount of a substance Y as described herein or a pharmaceutically acceptable salt thereof, wherein said substance Y is an SGLT2 inhibitor selected from at least one of empagliflozin, dapagliflozin, canagliflozin, ertugliflozin, henagliflozin, ipragliflozin, tofogliflozin, sotagliflozin, luseogliflozin, janagliflozin, bexagliflozin, longrifloridin, enavogliflozin, and JT-001.

[0165] Substance Y is used in conjunction with substance X, which is berberine ursodeoxycholic acid.

[0166] In the above-described therapeutic uses and methods of treatment, the administration regimens (including route of administration, dosage, administration interval, etc.) of the different substances (e.g., substance X and substance Y) or pharmaceutical compositions comprising the different substances may be the same or different in each pharmaceutical combination and may be adjusted as necessary by one skilled in the art to provide optimal therapeutic effects.

[0167] In some embodiments, substance X exists in crystalline form A of BUDC, where crystalline form A of BUDC is as described above. Preferably, crystalline form A of BUDC is crystalline form A of BUDC heminonahydrate.

[0168] In some embodiments, the SGLT2 inhibitor is selected from empagliflozin, dapagliflozin, and canagliflozin. In some embodiments, the SGLT2 inhibitor is dapagliflozin. In some embodiments, the SGLT2 inhibitor is empagliflozin. In some embodiments, the SGLT2 inhibitor is canagliflozin.

[0169] In some embodiments, substance X of pharmaceutical combination I is administered as a QD (once daily), BID (twice daily), or TID (three times daily) regimen, preferably QD.

[0170] In some embodiments, substance Y of Pharmaceutical Combination I, Pharmaceutical Combination II, or Pharmaceutical Combination III is administered as a QD (once daily), BID (twice daily), or TID (three times daily) regimen, preferably QD.

[0171] In some embodiments, substance U of pharmaceutical combination II is administered as a QD (once daily), BID (twice daily), or TID (three times daily) regimen, preferably QD.

[0172] In some embodiments, substance V of pharmaceutical combination II is administered as a QD (once daily), BID (twice daily), or TID (three times daily) regimen, preferably QD.

[0173] In some embodiments, agent X and agent Y of pharmaceutical combination I are administered according to the same regimen.

[0174] In some embodiments, agent U and agent V of pharmaceutical combination II are administered according to the same regimen.

[0175] In some embodiments, agent U and agent Y of pharmaceutical combination II are administered according to the same regimen.

[0176] Substances X and Y of pharmaceutical combination I can be administered simultaneously or separately.

[0177] Substances U, V, and Y of pharmaceutical combination II may be administered simultaneously, separately, or in combination.

[0178] The different substances (e.g., substance X and substance Y) or pharmaceutical compositions comprising the different substances in pharmaceutical combination I or pharmaceutical combination II can be administered simultaneously or separately by any suitable route known in the art, including oral administration, injection (e.g., intravenous, intramuscular, subcutaneous), etc.

[0179] Pharmaceutical Composition A or Pharmaceutical Composition B may be administered by any suitable route known in the art, including oral administration, injection (eg, intravenous, intramuscular, subcutaneous), and the like.

[0180] In some embodiments, substance X of pharmaceutical combination I is administered orally.

[0181] In some embodiments, substance Y of pharmaceutical combination I is administered orally.

[0182] Preferably, in some embodiments, substance X of pharmaceutical combination I is administered orally and substance Y of pharmaceutical combination I is administered orally.

[0183] In some embodiments, pharmaceutical combination I, pharmaceutical combination II, pharmaceutical combination III, pharmaceutical composition A, or pharmaceutical composition B described herein that is orally administered is in a unit dosage form selected from a tablet, a capsule, or a liquid formulation.

[0184] In some embodiments, BUDC and the SGLT2 inhibitor are provided in a molar ratio of 1:100 to 100:1, preferably, BUDC and the SGLT2 inhibitor are provided in a molar ratio of 1:50 to 1:5 or 1:1 to 100:1, more preferably, BUDC and the SGLT2 inhibitor are provided in a molar ratio of 5:1 to 50:1 (e.g., 30:1).

[0185] In some embodiments, the BUDC and SGLT2 inhibitor are provided in a molar ratio of 5:1 to 15:1, such as 14:1, 13:1, 12:1, 11:1, 10:1, or 9:1.

[0186] In some embodiments, the disease is selected from diabetes, prediabetes, hyperinsulinemia, obesity, sarcopenia, muscular dystrophy, or complications and / or associated diseases thereof.

[0187] In some embodiments, the disease is sarcopenia.

[0188] In some embodiments, the disease is diabetes with sarcopenia or obesity with sarcopenia.

[0189] In some embodiments, the disease is combined diabetes and obesity.

[0190] In some embodiments, the disease is a combination of diabetes, obesity, and sarcopenia.

[0191] In some embodiments, the metabolic disease is diabetes and / or obesity.

[0192] In some embodiments, the metabolic disease is diabetes.

[0193] In some embodiments, the metabolic disease is obesity.

[0194] Preferably, in some embodiments, the metabolic disease is diabetes mellitus and obesity combined.

[0195] Preferably, in some embodiments, the metabolism is type 2 diabetes.

[0196] In some embodiments, the metabolic disease is pre-diabetes.

[0197] In some embodiments, the metabolic disease is hyperinsulinemia or metabolic syndrome associated with hyperinsulinemia.

[0198] In some embodiments, the muscle disease is sarcopenia or muscular dystrophy.

[0199] In some embodiments, the sarcopenia is sarcopenia in elderly people.

[0200] In some embodiments, the sarcopenia is obesity and / or diabetes and sarcopenia.

[0201] In some embodiments, the sarcopenia is drug-induced sarcopenia.

[0202] In some embodiments, the subject suffers from diabetes and / or obesity.

[0203] In some embodiments, the subject has type 2 diabetes.

[0204] In some embodiments, the subject suffers from obesity.

[0205] In some embodiments, the subject suffers from diabetes and obesity.

[0206] In some embodiments, the subject has type 2 diabetes in combination with obesity.

[0207] In some embodiments, the subject suffers from hyperinsulinemia.

[0208] In some embodiments, the subject suffers from diabetes and hyperinsulinemia.

[0209] In some embodiments, the subject also suffers from diabetes, as well as hyperinsulinemia and obesity.

[0210] In some embodiments, the subject is suffering from sarcopenia.

[0211] In some embodiments, the subject suffers from obesity and sarcopenia.

[0212] In some embodiments, the subject has diabetes and sarcopenia.

[0213] In some embodiments, the subject suffers from diabetes as well as obesity and sarcopenia.

[0214] In some embodiments, the subject suffers from diabetes, obesity, hyperinsulinemia, and sarcopenia.

[0215] In yet another aspect, the present invention generally relates to a pharmaceutical pack comprising separate subpackages of pharmaceutical compositions, wherein a first subpackage contains a first pharmaceutical composition of the present invention and a second subpackage contains a second pharmaceutical composition of the present invention.

[0216] The terms "disease," "disorder," and "condition" are used interchangeably herein.

[0217] As used herein, the term "treatment" refers to therapeutic treatment. When a specific disease is involved, treatment refers to (1) alleviating one or more biological symptoms of the disease or disorder, (2) interfering at one or more points in (a) the disease biological cascade caused or triggered by the disease, or (b) one or more biological symptoms of the disease, (3) ameliorating one or more symptoms, effects, or side effects, or one or more symptoms associated with the disease, or (4) attenuating the progression of one or more of the disease or biological symptoms of the disease.

[0218] As used herein, the term "therapeutically effective amount" refers to an amount of a compound sufficient to effectively treat a disease or disorder described in the present disclosure when administered to a subject. The amount of a compound in a "therapeutically effective amount" varies according to the compound, the disorder and its severity, and the age of the subject being treated, but can be adjusted as necessary by one skilled in the art.

[0219] As used herein, the term "pharmaceutical pack" refers to any container and closure, such as a packaging bag, box, packaging bottle, etc., suitable for storing, transporting, dispensing, and / or handling a pharmaceutical agent.

[0220] As used herein, the term "pharmaceutical composition" refers to a composition that contains specific active ingredients and can be prepared in the same dosage form.

[0221] As used herein, the term "subject" refers to any animal to which or which has been administered a compound or composition according to an embodiment of the present disclosure, with mammals being preferred, and humans being most preferred. As used herein, the term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being most preferred.

[0222] As used herein, the term "pharmaceutically acceptable excipients" refers to excipients and additives used in the manufacture of pharmaceuticals and formulating formulations, and includes all substances contained in pharmaceutical formulations except for active ingredients. See Part 4 of the Chinese Pharmacopoeia (2015 edition) or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 6th edition, 2009).

[0223] As used herein, the term "pharmaceutically acceptable" refers to acids or bases (used in preparing salts), solvents, excipients, and the like that are generally non-toxic, safe, and suitable for use by a patient. A "patient" is preferably a mammal, more preferably a human.

[0224] As used herein, the term "pharmaceutically acceptable salt" refers to a salt prepared from a compound having a relatively non-toxic, pharmaceutically acceptable acid or base.When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or in a suitable inert solvent.When a compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or in a suitable inert solvent.Pharmaceutically acceptable acids include inorganic acids, and when a compound contains a relatively acidic and a relatively basic functional group, it can be converted into a base addition salt or an acid addition salt. See Berge et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science 66:1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

[0225] Each of BUDC, SGLT2 inhibitors, and pharmaceutically acceptable salts can be in amorphous or crystalline form. The term "amorphous" refers to a disordered distribution of ions or molecules, i.e., there is no periodic arrangement between ions and molecules. "Crystal form" refers to a state in which ions or molecules are arranged in a strictly periodic manner in three-dimensional space, with a regularity of periodic recurrence at a certain distance. Depending on the difference in the periodic arrangement, multiple crystalline forms, i.e., polycrystalline phenomena, exist.

[0226] BUDC, as used herein, can be in the free form, a hydrate, or another solvated form.

[0227] The SGLT2 inhibitors may be used herein in their free form, as a hydrate, or as another solvate.

[0228] Pharmaceutically acceptable salts of SGLT2 inhibitors may be used herein in the form of a free base, a hydrate, or another solvate.

[0229] Berberine may be used herein in free form, as a hydrate, or as another solvate.UDCA may be used herein in free form, as a hydrate, or as another solvate.

[0230] The beneficial effects provided by the present invention include, but are not limited to, the following: The present invention provides a novel pharmaceutical combination or pharmaceutical composition, particularly a pharmaceutical combination or pharmaceutical composition comprising BUDC and an SGLT2 inhibitor. The pharmaceutical combination or pharmaceutical composition of the present invention has a synergistic effect in one or more aspects, including reducing blood glucose levels, weight loss, improving insulin sensitivity, etc., and can be effectively used to treat, alleviate, or prevent one or more diseases and disorders (e.g., diabetes, prediabetes, glucagonosis, and obesity).

[0231] The present invention is further described in further and / or alternative aspects and embodiments.

[0232] In another aspect, the invention generally comprises: (a) berberine ursodeoxycholic acid (BUDC), (b) a sodium-glucose cotransporter-2 (SGLT2) inhibitor, or a pharmaceutically acceptable salt thereof; (c) a pharmaceutically acceptable excipient; The present invention relates to a pharmaceutical composition comprising:

[0233] In some embodiments, the SGLT2 inhibitor is selected from the group consisting of empagliflozin, dapagliflozin, canagliflozin, ertugliflozin, henagliflozin, ipragliflozin, tofogliflozin, sotagliflozin, luseogliflozin, janagliflozin, bexagliflozin, longliflorizin, enavogliflozin, and JT-001.

[0234] In some embodiments, the SGLT2 inhibitor is empagliflozin. In some embodiments, the SGLT2 inhibitor is dapagliflozin. In some embodiments, the SGLT2 inhibitor is canagliflozin. In some embodiments, the SGLT2 inhibitor is ertugliflozin.

[0235] In another aspect, the invention generally relates to unit dosage forms comprising such pharmaceutical compositions.

[0236] In another aspect, the invention generally comprises: (a) berberine ursodeoxycholic acid (BUDC), (b) a sodium-glucose cotransporter-2 (SGLT2) inhibitor, or a pharmaceutically acceptable salt thereof; A unit dosage form comprising: (a) and (b) refer to a unit dosage form in which they are present in separate portions of the unit dosage form.

[0237] In some embodiments of the pharmaceutical composition or unit dosage form, (a) and (b) are present in a molar ratio of about 5:1 to 15:1.

[0238] In some embodiments of the pharmaceutical composition or unit dosage form, the BUDC is in free base form.

[0239] In some embodiments of the pharmaceutical composition or unit dosage form, the BUDC is in the form of a hydrate or solvate.

[0240] In some embodiments of the pharmaceutical composition or unit dosage form, the BUDC is in amorphous form.

[0241] In some embodiments of the pharmaceutical composition or unit dosage form, the BUDC is in a crystalline form.

[0242] In some embodiments of the pharmaceutical composition or unit dosage form, the crystalline form is BUDC crystalline Form A and has an X-ray powder diffraction (XRPD) pattern comprising one or more peaks at 2θ values ​​selected from the group consisting of 7.06, 7.34, 8.79, 9.47, 11.94, 14.17, 15.50, 16.54, and 16.78 degrees (±0.2 degrees), and said crystalline Form A of BUDC has the formula

[0243] [ka] It has.

[0244] In some embodiments of the pharmaceutical composition or unit dosage form, the crystalline form is BUDC crystalline Form D and has an X-ray powder diffraction (XRPD) pattern comprising one or more peaks at 2θ values ​​selected from the group consisting of 4.24±0.2°, 6.79±0.2°, 8.50±0.2°, 10.25±0.2°, 11.50±0.2°, 13.62±0.2°, 14.74±0.2°, 15.20±0.2°, 17.92±0.2°, 18.39±0.2°, 22.91±0.2°, and 25.73±0.2°.

[0245] In another aspect, the invention generally comprises: A first pharmaceutical composition comprising: (a) berberine ursodeoxycholic acid (BUDC), and a first pharmaceutically acceptable excipient; a first pharmaceutical composition; A second pharmaceutical composition comprising: (b) a sodium-glucose cotransporter-2 (SGLT2) inhibitor, or a pharmaceutically acceptable salt thereof, and a second pharmaceutically acceptable excipient. a second pharmaceutical composition comprising The present invention relates to a pharmaceutical pack comprising:

[0246] In some embodiments of the pharmaceutical pack, the first pharmaceutical composition is present as a first unit oral dosage form and / or the second pharmaceutical composition is present as a second unit oral dosage form.

[0247] In some embodiments, the SGLT2 inhibitor is selected from the group consisting of empagliflozin, dapagliflozin, canagliflozin, ertugliflozin, henagliflozin, ipragliflozin, tofogliflozin, sotagliflozin, luseogliflozin, janagliflozin, bexagliflozin, longliflorizin, enavogliflozin, and JT-001.

[0248] In some embodiments, the SGLT2 inhibitor is empagliflozin. In some embodiments, the SGLT2 inhibitor is dapagliflozin. In some embodiments, the SGLT2 inhibitor is canagliflozin. In some embodiments, the SGLT2 inhibitor is ertugliflozin.

[0249] In some embodiments of the pharmaceutical pack, (a) and (b) are present in a molar ratio of about 5:1 to 15:1.

[0250] In some embodiments, the BUDC is in the form of a free base.

[0251] In some embodiments, BUDC is in the form of a hydrate or solvate.

[0252] In some embodiments, the BUDC is in amorphous form.

[0253] In some embodiments, the BUDC is in a crystalline form.

[0254] In some embodiments, the crystalline form is BUDC crystalline Form A and has an X-ray powder diffraction (XRPD) pattern comprising one or more peaks at 2θ values ​​selected from the group consisting of 7.06, 7.34, 8.79, 9.47, 11.94, 14.17, 15.50, 16.54, and 16.78° (±0.2°), and said Form A BUDC has the formula

[0255] [ka] It has.

[0256] In some embodiments, the crystalline form is BUDC crystalline Form D and has an X-ray powder diffraction (XRPD) pattern comprising one or more peaks at 2θ values ​​selected from the group consisting of 4.24±0.2°, 6.79±0.2°, 8.50±0.2°, 10.25±0.2°, 11.50±0.2°, 13.62±0.2°, 14.74±0.2°, 15.20±0.2°, 17.92±0.2°, 18.39±0.2°, 22.91±0.2°, and 25.73±0.2°.

[0257] In another aspect, the invention generally relates to the use of a pharmaceutical composition, unit dosage form, or pharmaceutical pack disclosed herein for the prevention and / or treatment of a metabolic disease or disorder.

[0258] In some embodiments of the above uses, the metabolic disease or disorder is diabetes and / or obesity.

[0259] In some embodiments, the metabolic disease is type 2 diabetes.

[0260] In some embodiments, the metabolic disease is pre-diabetes.

[0261] In some embodiments, the metabolic disease is hyperinsulinemia or metabolic syndrome associated with hyperinsulinemia.

[0262] In another aspect, the present invention generally relates to the use of a pharmaceutical composition, unit dosage form, or pharmaceutical pack disclosed herein for preventing and / or treating sarcopenia.

[0263] In another aspect, the invention generally relates to a method for treating a metabolic disease, comprising administering to a subject in need of treatment a therapeutically effective amount of a pharmaceutical composition, unit dosage form, or pharmaceutical pack disclosed herein.

[0264] In yet another aspect, the present invention generally relates to a method for treating sarcopenia, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition, unit dosage form, or pharmaceutical pack disclosed herein.

[0265] In another aspect, the invention generally comprises: (i) berberine (BBR), or a pharmaceutically acceptable salt thereof; (ii) ursodeoxycholic acid (UDCA) or a pharmaceutically acceptable salt thereof; (iii) a sodium-glucose cotransporter-2 (SGLT2) inhibitor, or a pharmaceutically acceptable salt thereof; a pharmaceutically acceptable excipient; The present invention relates to a pharmaceutical composition comprising:

[0266] In some embodiments, the BBR is berberine hydrochloride.

[0267] In some embodiments, UDCA is present as the free acid.

[0268] In some embodiments, (i), (ii), and (iii) are present in a molar ratio of about 5:1 to about 1:2 (i):(ii), and about 30:1 to 5:1 (ii):(iii).

[0269] In another aspect, the invention generally relates to unit dosage forms comprising the pharmaceutical compositions disclosed herein.

[0270] In another aspect, the invention generally comprises: (a) berberine (BBR), or a pharmaceutically acceptable salt thereof; (b) ursodeoxycholic acid (UDCA) or a pharmaceutically acceptable salt thereof; (c) a sodium-glucose cotransporter-2 (SGLT2) inhibitor, or a pharmaceutically acceptable salt thereof; A unit dosage form comprising: At least one of (a), (b), and (c) relates to a unit dosage form in which it is present in a separate portion of the unit dosage form from the other two.

[0271] In another aspect, the invention generally comprises: A first pharmaceutical composition comprising: (a) a composition comprising berberine (BBR), or a pharmaceutically acceptable salt thereof, and a first pharmaceutically acceptable excipient; a first pharmaceutical composition; and A second pharmaceutical composition comprising: (b) ursodeoxycholic acid (UDCA) or a pharmaceutically acceptable salt thereof, and a second pharmaceutically acceptable excipient; a second pharmaceutical composition; and A third pharmaceutical composition comprising: (c) a sodium-glucose cotransporter-2 (SGLT2) inhibitor, or a pharmaceutically acceptable salt thereof, and a third pharmaceutically acceptable excipient. a third pharmaceutical composition; The present invention relates to a pharmaceutical pack comprising:

[0272] In another aspect, the invention generally comprises: (A) Ursodeoxycholic acid (UDCA) and (B) a sodium-glucose cotransporter-2 (SGLT2) inhibitor, or a pharmaceutically acceptable salt thereof; a pharmaceutically acceptable excipient; The present invention relates to a pharmaceutical composition comprising:

[0273] In some embodiments, (a) and (b) are present in a molar ratio of about 20:1 to 1:20.

[0274] In another aspect, the present invention generally relates to the use of a pharmaceutical composition, unit dosage form, or pharmaceutical pack disclosed herein for the prevention and / or treatment of a metabolic disease or disorder.

[0275] In one embodiment of the above uses, the metabolic disease is diabetes and / or obesity.

[0276] In one embodiment of the above uses, the metabolic disease is type 2 diabetes.

[0277] In certain embodiments of the above uses, the metabolic disease is pre-diabetes.

[0278] In one embodiment of the above uses, the metabolic disease is hyperinsulinemia or metabolic syndrome associated with hyperinsulinemia.

[0279] In another aspect, the present invention generally relates to the use of a pharmaceutical composition, unit dosage form, or pharmaceutical pack disclosed herein for preventing and / or treating sarcopenia.

[0280] In another aspect, the invention generally relates to a method for treating a metabolic disease, comprising administering to a subject in need of treatment a therapeutically effective amount of a pharmaceutical composition, unit dosage form, or pharmaceutical pack disclosed herein.

[0281] In yet another aspect, the present invention generally relates to a method for treating sarcopenia, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition, unit dosage form, or pharmaceutical pack disclosed herein. [Example]

[0282] The present invention is further illustrated by the following examples, which are not intended to limit the present invention. Experimental procedures without specific conditions in the following examples are carried out according to conventional procedures and conditions or instructions.

[0283] Explanation of abbreviations: 0.5% CMC-Na refers to an aqueous solution of sodium carboxymethylcellulose with a mass fraction of 0.5%; 0.5% HEC refers to an aqueous solution of hydroxyethyl cellulose with a mass fraction of 0.5%.

[0284] material

[0285] [Table 1]

[0286] The HTD1801 starting material is provided in crystalline form A of a tetrapentahydrate as shown in the formula below, and crystalline form A has the following peaks in an X-ray powder diffraction (XRPD) pattern obtained under Cu Kα radiation (λ1=1.540598 Å, λ2=1.544426 Å, intensity ratio λ2 / λ1=0.50): 3.98, 7.06, 7.34, 7.93, 8.79, 9.47, 11.70, 11.94, 12.34, 12.55, 13.90, 14.17, 15.14, 15.50, 16.16, 16.54, 16.78, 17.06, 17.06, 17.34, 1 ...06, 17.06, 17.06, 17.06, 17.06, 17.06, 17.0 It has diffraction peaks at 2θ of 0.53, 17.67, 18.23, 19.03, 19.98, 20.87, 21.13, 21.96, 23.49, 24.24, 24.97, 25.50, 26.63, 27.60, 28.06, 28.63, 29.40, and 30.49° (±0.2°) (λ1 = 1.540598 Å, λ2 = 1.544426 Å, intensity ratio λ2 / λ1 = 0.50).

[0287] [ka]

[0288] Example 1: Combined Administration of Berberine Ursodeoxycholate and Empagliflozin Experimental procedure Relevant formulation and preparation information is provided in Table 2.

[0289] [Table 2]

[0290] After acclimatizing 5-week-old C57BL / 6J male mice for one week, they were weighed and randomly divided into a control group and a model group based on body weight. For 10–12 weeks, 12 mice in the control group were fed a common diet (CD), while the remaining mice in the model group were fed a 60% high-fat diet (60% HFD). This established a DIO obesity model with an average weight of 40 g or more. Mice fed the 60% HFD were then acclimated to the vehicle for three days. The acclimation to the vehicle was accomplished by force-feeding 0.5% CMC-Na twice daily.

[0291] The food intake, body weight, body fat percentage, and insulin level of each mouse were measured, followed by fasting blood glucose levels. The mice were randomly divided into groups based on body weight according to Table 3, and the remaining mice were euthanized. After grouping, the mice in each group were administered drugs according to Table 3. The administration day was designated D0, and the dose of each drug was calculated as 5 μL / g × mouse body weight (g).

[0292] In the combination treatment group, the total dose was the sum of the doses of the two single drugs, and the administration sequence and administration time were kept constant for each treatment. Mice were continuously fed a high-fat diet throughout the treatment period until the end of treatment. Food intake was measured twice weekly during treatment (the difference in food weight was measured at 24-hour intervals); mice in each group were weighed once daily; postprandial blood glucose levels were measured weekly; blood was collected from the tip of the tail on days 6 and 20 to measure fasting blood glucose levels once (after fasting from 8:00 AM to 2:00 PM); and on day 25 of treatment, the body fat percentage and lean body mass of mice in each group were measured by MRI (the measurement period was kept constant compared to before group allocation). Four weeks after treatment (day 28), mice in each group were fasted for 6 hours and then underwent an OGTT (0, 15, 30, 60, and 90 minutes). Blood glucose levels were detected over a period of 120 minutes (0, 15, 30 minutes), and blood samples were taken via the submandibular vein (0, 15, 30 minutes, approximately 30 μL each time). Plasma was then separated for insulin level detection by ELISA, and the separated plasma volume was more than 10 μL. The day after the end of administration (D29) was set as the test endpoint, and the mice were fasted for 6 hours in the morning and subjected to fasting blood glucose measurement. After that, the mice were euthanized with CO2, and blood was collected from the heart of each mouse for analysis, and the mice from each group were dissected. The liver and subcutaneous, epididymal, and mesenteric fat were collected, photographed, and weighed, respectively.

[0293] [Table 3]

[0294] The experimental results of Example 1 are discussed below.

[0295] Evaluating the model The results of measuring the body fat mass of the model mice and normal mice before grouping and administration are shown in Figure 1. The body fat mass of the model mice was significantly increased compared to the normal mice, indicating that an obesity model had been successfully constructed.

[0296] Weight change results The results of the changes in body weight over time for animals in groups G1 to G6 are shown in Table 4 below and in FIGS.

[0297] [Table 4]

[0298] Within 14 days, the body weight of the normal control group remained essentially unchanged, whereas under continuous high-fat diet feeding, the body weight of the model control group G2 decreased slightly in the first week and then slowly increased. The body weight of the empagliflozin group G4 remained essentially unchanged in the first week and then gradually increased, with the increasing trend essentially consistent with that of the model control group G2. The body weight of the semaglutide group G6 decreased significantly during the initial phase of administration, then slowly decreased and stabilized. The body weight of the HTD1801 group G3 and the combination treatment group (HTD1801 + empagliflozin) G5 decreased continuously over time with significant effects. Especially considering the consistent weight change trends of the animals in the empagliflozin monotherapy group and the model group, the weight loss in the G5 group was significantly greater than that of the other groups, unexpectedly being about twice the weight loss achieved by HTD1801 administration alone. These results showed that in an obese mouse model continuously fed a high-fat diet, empagliflozin alone did not produce weight loss effects, but when combined with HTD1801, a synergistic effect was produced, significantly improving the overall weight loss effect. Furthermore, the weight loss effect of oral administration was superior to that of semaglutide injection, which is currently and clinically widely used to lower blood glucose levels and reduce body weight.

[0299] After 14 days, the weight of the normal control group continued to be maintained, the weight of the model control group and low-dose empagliflozin group slowly increased, and the weight of the semaglutide group remained constant, all of which maintained the trend at week 2. However, with the downregulation of HTD1801 dose, the weight of the HTD1801 group showed a slight rebound, while the weight loss effect of G5 (HTD1801 + empagliflozin) continued to be maintained and tended to further decrease. This experiment shows that the combined administration of HTD1801 and empagliflozin not only has a synergistic weight loss effect, but can also further reduce the HTD1801 dose while maintaining the synergistic weight loss effect without causing weight rebound.

[0300] Body fat measurement results After 25 days of administration, the body weight, body fat mass and body fat percentage of each animal in groups G1 to G6 were measured and averaged for each group. The results are shown in Table 5 below, and in FIGS.

[0301] [Table 5]

[0302] As can be seen from these results, after 25 days of administration, the body fat mass and body fat percentage in group G4 (empagliflozin) increased compared to the control group G2, while the body fat mass and body fat percentage in groups G3 (HTD1801), G5 (HTD1801 + empagliflozin) and G6 (semaglutide) all decreased, with the results for group G5 being superior to those for the other groups. This example shows that combined administration of HTD1801 and empagliflozin produced a synergistic effect rather than simply canceling or overlapping the effects of both.

[0303] Liver, visceral, and subcutaneous fat weight results After 28 days of administration, the mice were euthanized with CO2 the next day, and the mice in groups G1 to G5 were dissected. The liver and abdominal fat (including epididymis and mesenteric fat), as well as subcutaneous fat, were collected, photographed, and weighed. The results are shown in Table 6, Figure 6, Figure 7, and Figure 8 below.

[0304] [Table 6]

[0305] The results show that in the experiment, combined administration of HTD1801 and empagliflozin can significantly reduce whole-body fat mass, and in particular, combined administration of HTD1801 and empagliflozin can maintain the effect of reducing liver fat, and in addition, can significantly reduce abdominal and subcutaneous fat mass, thereby having a synergistic beneficial effect.

[0306] Changes in lean body mass After 25 days of administration, the body weight, lean body mass, and lean body mass percentage of each animal in groups G1 to G5 were measured and averaged for each group, and the results are shown in Table 7 below, Figures 9 and 10.

[0307] [Table 7]

[0308] The lean body mass of mice in group G3 (HTD1801) increased compared to the model control group G2, and the lean body mass of mice in group G4 (empagliflozin) decreased compared to the model control group G2. When the two drugs were administered together, the lean body mass of mice in group G3 (HTD1801 + empagliflozin) further increased without negating the effects of the two drugs alone. This indicates that combined administration of HTD1801 and empagliflozin synergistically increased lean body mass or lean mass ratio in an obese mouse model.

[0309] Fasting blood glucose results After 20 days of dosing, the results of fasting blood glucose levels were measured for animals in each group and are shown in Table 8 below and in FIG.

[0310] [Table 8]

[0311] The blood glucose levels of all treatment groups G3 to G6 decreased to different degrees on days 6 and 20, but the blood glucose levels of group G6 (semaglutide) decreased most significantly on day 6 but rebounded on day 20, while the blood glucose levels of group G5 (HTD1801 + empagliflozin) continued to decrease until day 20. The reduction in blood glucose levels was greater than that of the semaglutide group, and the extent of reduction was greater than the sum of the reductions in blood glucose levels of each individual drug, i.e., a synergistic effect of 1 + 1 > 2 was obtained.

[0312] Oral glucose tolerance test (OGTT) results The mean blood glucose levels in the OGTT test for each group measured on day 28 of administration are shown in Table 9 below, and the blood glucose level-time relationship curve and the area under the blood glucose level-time curve AUC (i.e., total blood glucose increase) calculated from this curve are shown in Figure 12 and Figure 13, respectively.

[0313] [Table 9]

[0314] As can be seen, total blood glucose levels decreased in each of the treatment groups compared with the model control group G2, with the level of reduction being comparable in groups G4 (empagliflozin), G5 (HTD1801 + empagliflozin), and G6 (semaglutide). In the OGTT study, the fasting insulin results during the drug effect period are shown in Table 10 below, and the insulin level-time relationship curve and the area under the curve calculated therefrom (i.e., total insulin level) are shown in Figures 14 and 15, respectively.

[0315] [Table 10]

[0316] The peak and total insulin levels of mice in each treatment group were significantly reduced compared to the control group, with G5 (HTD1801 + empagliflozin) showing the lowest peak insulin level and the most significant reduction in total insulin level, indicating a synergistic effect.

[0317] The OGTT study results showed that G5 (HTD1801 + empagliflozin) had a relatively lower total blood glucose level, and in each group with comparable blood glucose levels, both peak insulin and total insulin levels were significantly lower, which was superior to those of each single-drug group, including the group using semaglutide injection, which is currently widely used clinically for lowering blood glucose levels and weight loss. This indicated that the combined administration of the two drugs can synergistically improve insulin sensitivity so as to reduce insulin secretion, and has the potential to improve pancreatic islet cell function, correct hyperinsulinemia, and treat early diabetes (i.e., prediabetes). It is also worth noting that attenuation of hyperinsulinemia may bring many further benefits to the treatment of obesity and type 2 diabetes, suggesting that the pharmaceutical combination of HTD1801 + empagliflozin has the potential for greater clinical benefits than expected.

[0318] Changes in food intake within 24 hours during the drug efficacy period FIG. 16 shows the changes in food intake of animals in each group within 24 hours during the administration period, where the food intake of group G4 (empagliflozin) was similar to that of the model control group, while the food intake of groups G3 (HTD1801) and G5 (HTD1801 + empagliflozin) was similar and lower than that of the model control group.

[0319] Example 2: Combined Administration of Berberine Ursodeoxycholate and Dapagliflozin Grouping, dose, and administration information is provided in Table 11.

[0320] [Table 11]

[0321] Experimental Method After acclimatization for one week, 5-6 week-old C57BL / 6J male mice were weighed and randomly divided into a control group and a model group based on body weight. Twelve mice in the control group were fed a common diet (CD), while the remaining mice in the model group were fed a 60% high-fat diet (60% HFD) for 10-12 weeks to establish a DIO obesity model with an average weight of 40g or more. Mice fed the 60% HFD were then acclimated to the vehicle for three days. This acclimation was achieved by oral gavage of 0.5% CMC-Na once daily.

[0322] The mice's food intake, body weight, body fat percentage, and insulin levels were measured, followed by fasting blood glucose levels. Using body weight as an index, the mice were randomly divided into groups according to Table 12, and the remaining mice not assigned to a group were euthanized. After grouping, the mice were administered drugs according to Table 12, with the administration day defined as D0. The dose of each drug was calculated as 5 μL / g × mouse body weight (g).

[0323] For the combined treatment groups, the dosing sequence and time were kept constant for each treatment. Mice were continuously fed a high-fat diet throughout the treatment period until the end of treatment. During treatment, food intake was measured weekly (the difference in food weight was measured at 24-hour intervals); the body weight of each group of mice was measured once daily; blood was collected from the tip of the tail on days 16 and 30 to measure fasting blood glucose levels (blood was collected after fasting from 9:00 AM to 3:00 PM); on day 24 of treatment (D23), the body fat percentage and lean body mass of each group of mice were measured by MRI (the measurement period was kept constant as before group allocation); after 25 days of treatment (day 24), the mice in each group were fasted for 6 hours and subjected to an OGTT (0, 15, 30, 60, 90, and 120 minutes) to detect blood glucose levels; after 29 days of treatment (day 28), the mice were fasted for 6 hours and subjected to an OGTT (0, 15, 30, 60, 90, and 120 minutes). Mice in each group were fasted for 6 hours and then underwent OGTT (0, 15, 30, 60, 90, and 120 minutes), during which blood samples were taken via the submandibular vein (0, 15, and 30 minutes, approximately 30 μL each time). The plasma was then separated and insulin levels were measured by ELISA (more than 10 μL of plasma was collected). The day after the end of administration (D30) was set as the test endpoint, and the mice were fasted for 6 hours in the morning and subjected to fasting blood glucose measurement. After that, the mice were euthanized with CO2, and blood was collected from the heart of each mouse for analysis. The mice in each group were dissected. The liver and subcutaneous, epididymal, and mesenteric fat were collected, photographed, and weighed, respectively.

[0324] [Table 12]

[0325] The experimental results of Example 2 are discussed below.

[0326] Evaluating the model The results of measuring the body weight and body fat mass of the model mice and normal mice before grouping and administration are shown in Figures 17 and 18. The body weight of each model mouse was higher than 40 g, and the body fat mass was significantly increased compared to the normal mice, indicating that an obesity model had been successfully constructed.

[0327] 1) Weight change results The results of the changes over time in body weight (mean) and rate of change in body weight of the animals in groups G1 to G8 are shown in Tables 13 and 14 below, and in FIGS. 19 and 20.

[0328] [Table 13]

[0329] [Table 14-1] [Table 14-2]

[0330] During the treatment period, the body mass index (BMI) of the normal control group G1 was small and increased slightly, the BMI of the model control group G2 fed a high-fat diet and each treatment group was large, the body weight of the model control group G2 was stable and basically remained unchanged, and the body weight of the semaglutide group G3 decreased significantly at the first treatment, decreased slowly over the first two weeks of treatment, and tended to gradually stabilize, with only a relatively small decrease after the first two weeks of treatment. The overall weight loss in the HTD1801 monotherapy group G4 was similar to that of the semaglutide group, and showed a uniform and sustained decrease throughout the treatment period.

[0331] The overall body weight of the empagliflozin monotherapy group G6 remained essentially unchanged, similar to that of the model control group G2. The weight change in G6 was essentially consistent with that of the model control group G2 over the first two weeks of administration. The weight loss in the empagliflozin monotherapy group G6 was slightly higher than that of the model control group G2 after the first two weeks. The weight loss in the empagliflozin + HTD1801 combination group G8 continued over time, demonstrating a significant effect. The weight loss was significantly greater than that of the other groups, approximately 6.8% higher than that of HTD1801 alone. In other words, while the weight loss effect of empagliflozin alone was unclear, the weight loss effect of empagliflozin and HTD1801 combined was approximately two-fifths better than that of HTD1801 alone. These results indicate that in an obese mouse model continuously fed a high-fat diet, empagliflozin alone cannot achieve weight loss, but when used in combination with HTD1801, a synergistic effect can be produced, significantly improving the overall weight loss effect.

[0332] Similarly, compared with the model control group G2, the body weight of the dapagliflozin monotherapy group G5 decreased by only 3.4%, showing a very limited reduction. However, the body weight of the dapagliflozin + HTD1801 combination treatment group G7 decreased similarly to that of HTD1801 alone during the first 9 days of treatment. After that, the weight loss effect was lower than that of the empagliflozin + HTD1801 combination treatment group G8, and although the reduction was relatively small, it was still superior to the HTD1801 monotherapy group. This indicates that when the weight loss effect of SGLT2i drugs is limited, the combination of dapagliflozin and HTD1801 can achieve significant weight loss. In addition, from the perspective of the weight loss trend in the later stage, the downward trend of the curve indicated that the weight loss rate was faster and even superior to each of the other groups in the later stage, and it was expected that the dapagliflozin + HTD1801 combination treatment group G7 would achieve a better weight loss effect and show better synergistic effect if drug administration was continuously maintained for more than 28 days.

[0333] 2) Body fat measurement results The body weight, body fat mass, and body fat percentage of each animal in groups G1 to G8 were measured on day 23 and averaged for each group, and the results are shown in Table 15 below and in Figures 21 and 22.

[0334] [Table 15]

[0335] As can be seen from the results, after 23 days of administration, both the G5 (dapagliflozin) group and the G6 (empagliflozin) group showed an increase in body fat mass and body fat percentage, with the increase in the G5 (dapagliflozin) group being greater than that of the control group G2, increasing by approximately 8.6% compared to the control group G2. Meanwhile, the body fat mass and body fat percentage of groups G4 (HTD1801), G7 (HTD1801 + dapagliflozin), and G8 (HTD1801 + empagliflozin) all significantly decreased compared to the control group G2, but the results of group G8 were better than those of each of the other groups. As can be seen from the figure, in this example, the combined administration of HTD1801 and empagliflozin did not simply cancel or overlap the effects of both, but produced a synergistic effect, and the combined administration of HTD1801 and dapagliflozin also produced a synergistic effect.

[0336] 3) Results of lean body mass measurement The body weight, lean mass and lean percentage of each animal in groups G1-G8 were measured on day 23 and averaged for each group, with the results shown in Table 16 below and in Figures 23 and 24.

[0337] [Table 16]

[0338] The lean body mass of mice in group G4 (HTD1801) was slightly increased compared to the model control group G2, while the lean body mass of mice in groups G5 (dapagliflozin) and G6 (empagliflozin) was slightly decreased compared to the model control group G2. When the two drugs were administered together, the lean body mass of mice in groups G7 (HTD1801 + dapagliflozin) and G8 (HTD1801 + empagliflozin) was further increased, particularly in group G8 (HTD1801 + empagliflozin), without negating the effects of the two drugs alone. This indicates that combined administration of HTD1801 and empagliflozin or dapagliflozin synergistically increased muscle mass or muscle mass in obese mouse models.

[0339] According to the examples of the present invention, the pharmaceutical combination provided herein can significantly reduce blood glucose levels through oral administration and can also achieve an unexpected weight loss effect (the weight loss in the combined use group was approximately twice that of the HTD1801 monotherapy group), and is significantly superior in terms of blood glucose level reduction or weight loss to the single-drug group of berberine ursodeoxycholate and an SGLT2 inhibitor (e.g., empagliflozin) and the semaglutide injection group; At the same time, the results of the examples show that the pharmaceutical combination provided herein can significantly improve insulin sensitivity, thereby reducing insulin secretion; In addition, the pharmaceutical combination provided herein has the effect of reducing body weight and body fat mass, which not only does not cause a decrease in muscle mass, but can even increase muscle weight and muscle ratio. Thus, the pharmaceutical combination provided herein has the effect of protecting and increasing muscle mass. The pharmaceutical combination or pharmaceutical composition provided herein has the potential to treat sarcopenia and obesity, and also has the potential to obtain consistent synergistic benefits for improving multiple risk factors associated with diabetes in the treatment of diabetes, further improving glycemic control and delaying the disease development process, and is expected to achieve the goal of safely and effectively improving and even reversing the development of diabetes and its complications through comprehensive intervention of weight loss and insulin sensitivity, which is of breakthrough importance.

[0340] Applicant's disclosure is described herein in preferred embodiments with reference to the drawings, in which like numerals represent the same or similar elements. Reference throughout this specification to "one embodiment," "an embodiment," "some embodiments," or similar language means that a particular feature, structure, or characteristic described in connection with an embodiment is included in at least one embodiment of the invention. Thus, appearances of "in one embodiment," "in an embodiment," and similar language throughout this specification do not necessarily all refer to the same embodiment.

[0341] The described features, structures, or characteristics of Applicant's disclosure may be combined in any suitable manner in one or more embodiments. In the description herein, numerous specific details are set forth to provide a thorough understanding of the embodiments of the present invention. However, one skilled in the art will recognize that Applicant's compositions and / or methods may be practiced without one or more of the specific details, or with other methods, components, materials, etc. In other instances, well-known structures, materials, or operations are not shown or described in detail to avoid obscuring aspects of the present disclosure.

[0342] The terms "comprises," "comprising," "has," "having," "includes," and "including," when used to define compositions and methods, are intended to mean that the compositions and methods include the recited elements, but do not exclude other elements.

[0343] The term "consisting of," when used to define compositions and methods, is intended to mean excluding trace elements and substantial method steps of other components. Embodiments defined by each of these transition terms are within the scope of the present invention.

[0344] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0345] The term "and / or" is used in this disclosure to mean either "and" or "or," unless the context clearly dictates otherwise.

[0346] As used herein, "at least" a particular value is understood to be that value and all values ​​greater than that value.

[0347] Unless otherwise specified or clear from the context, the term "about" as used herein is understood to mean within the normal tolerance in the art, for example, within 2 standard deviations of the mean. About can be understood to mean within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from the context, all numerical values ​​provided herein can be modified by the term about.

[0348] At various places in this specification, variables or parameters are disclosed in groups or ranges. The description is specifically intended to include any and all individual subcombinations of the members of such groups and ranges. For example, a range of 1 to 16 is understood to include any number, combination of numbers, or subrange from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

[0349] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are described herein. The methods described herein can be carried out in any order that is logically possible, in addition to the specific order disclosed.

[0350] Incorporation by Reference References and citations to other documents, such as patents, patent applications, patent publications, journals, books, literature, web content, etc., have been made throughout this disclosure. All such documents are incorporated herein by reference in their entirety for all purposes. Any material, or portion thereof, that is incorporated herein by reference but that conflicts with existing definitions, descriptions, or other disclosure material expressly set forth herein is incorporated only to the extent that no conflict arises between the incorporated material and the presently disclosed material. In the event of a conflict, the conflict shall be resolved in favor of the present disclosure as the preferred disclosure.

[0351] equivalent The representative examples disclosed herein are intended to aid in the explanation of the invention and are not intended to, and should not be construed as, limiting the scope of the invention. Indeed, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the entire contents of this document, including the examples that follow and references to the scientific and patent literature cited herein. The foregoing examples contain important additional information, exemplification and guidance that can be adapted to the practice of this invention in its various embodiments and equivalents thereof.

Claims

1. Substance X, which is berberine ursodeoxycholic acid; Substance Y is an SGLT2 inhibitor or a pharmaceutically acceptable salt thereof; 1. Pharmaceutical Combination I comprising: Pharmaceutical combination I, wherein the SGLT2 inhibitor is selected from the group consisting of empagliflozin, dapagliflozin, canagliflozin, ertugliflozin, henagliflozin, ipragliflozin, tofogliflozin, sotagliflozin, luseogliflozin, janagliflozin, bexagliflozin, longrifloridin, enavogliflozin, and JT-001.

2. The pharmaceutical combination I satisfies the following conditions: (1) The substance X and the substance Y are administered simultaneously; (2) The substance X and the substance Y are administered separately; (3) The substance X is administered orally; (4) The substance Y is administered orally; (5) The SGLT2 inhibitor is empagliflozin, dapagliflozin, or canagliflozin. (6) The berberine ursodeoxycholic acid is present in an amorphous form, anhydrous crystalline form, or hydrated crystalline form. (7) The berberine ursodeoxycholate is present in a free base or hydrated form; and (8) The active ingredients of the pharmaceutical combination I include the substance X and the substance Y. The pharmaceutical combination I according to claim 1, wherein at least one of the following conditions is satisfied:

3. The pharmaceutical combination I satisfies the following conditions: (1) The substance X is administered orally, and the substance Y is administered orally; (2) The substance X and the substance Y are in a unit dosage form selected from a tablet, a capsule, and a liquid formulation; (3) The SGLT2 inhibitor is empagliflozin or dapagliflozin, preferably empagliflozin. (4) The berberine ursodeoxycholate exists in crystalline form A, and the crystalline form A of the berberine ursodeoxycholate has X-ray powder diffraction patterns of 7.06±0.2°, 7.34±0.2°, 8.79±0.2°, 9.47±0.2°, 11.94±0.2°, 14.17±0.2°, 15.50±0.2°, 16.54±0.2°, and 16.78±0.2°. and preferably, the crystalline form A of the berberine ursodeoxycholate has diffraction peaks at 2θ of 3.98±0.2°, 7.06±0.2°, 7.34±0.2°, 7.93±0.2°, 8.79±0.2°, 9.47±0.2°, 11.70±0.2°, 11.94±0.2°, 12.34±0.2°, 12.55±0.2°, 13.90±0.2° in an X-ray powder diffraction pattern. °, 14.17±0.2°, 15.14±0.2°, 15.50±0.2°, 16.16±0.2°, 16.54±0.2°, 16.78±0.2°, 17.53±0.2°, 17.67±0.2°, 18.23±0.2°, 19.03±0.2°, 19.98±0.2°, 20.87±0.2°, 21.13±0.2°, 21.96±0.2°, 23.49±0.2°, 24.24±0.2° and wherein the crystalline form A of berberine ursodeoxycholate has diffraction peaks at 2θ of 24.97±0.2°, 25.50±0.2°, 26.63±0.2°, 27.60±0.2°, 28.06±0.2°, 28.63±0.2°, 29.40±0.2°, and 30.49±0.2°, and the crystalline form A of the berberine ursodeoxycholate is preferably crystalline form A of berberine ursodeoxycholate heminonahydrate. (5) The berberine ursodeoxycholate is in crystalline form D, and the berberine ursodeoxycholate crystalline form D has diffraction peaks at 2θ of 4.24±0.2°, 6.79±0.2°, 8.50±0.2°, 10.25±0.2°, 11.50±0.2°, 13.62±0.2°, 14.74±0.2°, 15.20±0.2°, 17.92±0.2°, 18.39±0.2°, 22.91±0.2°, and 25.73±0.2° in an X-ray powder diffraction pattern. (6) The pharmaceutical combination I consists of the substance X and the substance Y; and (7) The active ingredients of the pharmaceutical combination I consist of the substance X and the substance Y. The pharmaceutical combination I according to claim 1, wherein at least one of the following conditions is satisfied:

4. The pharmaceutical combination I satisfies the following conditions: (1) The substance X and the substance Y are provided in a molar ratio of 1:100 to 100:1, preferably, the substance X and the substance Y are provided in a molar ratio of 1:50 to 1:5 or 1:1 to 100:1, more preferably, the substance X and the substance Y are provided in a molar ratio of 5:1 to 50:1; (2) The substance X is administered as a QD, BID, or TID regimen, preferably QD; (3) the substance Y is administered as a QD, BID, or TID regimen, preferably QD; and (4) The substance X and the substance Y are administered in the same regimen; The pharmaceutical combination I according to claim 1, wherein at least one of the following conditions is satisfied:

5. The pharmaceutical combination I satisfies the following conditions: (1) In said pharmaceutical combination I, said substance X and said substance Y are provided in a molar ratio of 5:1 to 15:1, optionally in a molar ratio such as 14:1, 13:1, 12:1, 11:1, 10:1, or 9:1; (2) The substance X is berberine ursodeoxycholate and the substance Y is empagliflozin; (3) The substance X is berberine ursodeoxycholate, and the substance Y is dapagliflozin. (4) The substance X is berberine ursodeoxycholate, and the substance Y is canagliflozin. (5) The substance X is berberine ursodeoxycholic acid, and the substance Y is ertugliflozin. (6) The substance X is berberine ursodeoxycholic acid, and the substance Y is henagliflozin. (7) The substance X is berberine ursodeoxycholic acid, and the substance Y is ipragliflozin. (8) The substance X is berberine ursodeoxycholate, and the substance Y is tofogliflozin. (9) The substance X is berberine ursodeoxycholate, and the substance Y is sotagliflozin. (10) The substance X is berberine ursodeoxycholate, and the substance Y is luseogliflozin. (11) The substance X is berberine ursodeoxycholic acid, and the substance Y is janagliflozin. (12) The substance X is berberine ursodeoxycholate, and the substance Y is bexagliflozin. (13) The substance X is berberine ursodeoxycholic acid, and the substance Y is longriflozin. (14) The substance X is berberine ursodeoxycholate, and the substance Y is enavogliflozin. (15) The substance X is berberine ursodeoxycholic acid, and the substance Y is JT-001; and (16) The pharmaceutical combination I is used for treating and / or preventing a metabolic disease or a disease related thereto, and preferably, the metabolic disease is selected from diabetes, prediabetes, hyperinsulinemia, and obesity. The pharmaceutical combination I according to claim 1, wherein at least one of the following conditions is satisfied:

6. The pharmaceutical combination I satisfies the following conditions: (1) In the pharmaceutical combination I, the substance X is berberine ursodeoxycholate, preferably crystalline form A of berberine ursodeoxycholate heminonahydrate, and the substance Y is empagliflozin, and the substance X and the substance Y are provided in a molar ratio of 12:1, 11:1, 10:1, or 9:

1. (2) In the pharmaceutical combination I, the substance X is berberine ursodeoxycholate, preferably crystalline form A of berberine ursodeoxycholate heminonahydrate, and the substance Y is dapagliflozin, and the substance X and the substance Y are provided in a molar ratio of 14:1, 13:1, or 12:

1. The pharmaceutical combination I according to claim 1, wherein at least one of the following conditions is satisfied:

7. a substance X as defined in any one of claims 1 to 6; a substance Y as defined in any one of claims 1 to 6; a pharmaceutically acceptable excipient; Pharmaceutical composition A comprising:

8. The pharmaceutical composition A satisfies the following conditions: (1) The pharmaceutically active ingredients of the pharmaceutical composition A include the substance X and the substance Y; (2) The pharmaceutical composition A comprises berberine ursodeoxycholate, empagliflozin, and the pharmaceutically acceptable excipient; (3) The pharmaceutical composition A comprises berberine ursodeoxycholate, dapagliflozin, and the pharmaceutically acceptable excipient; (4) The pharmaceutical composition A comprises berberine ursodeoxycholic acid, canagliflozin, and the pharmaceutically acceptable excipient; (5) The pharmaceutical composition A comprises berberine ursodeoxycholate, ertugliflozin, and the pharmaceutically acceptable excipient; (6) The pharmaceutical composition A comprises berberine ursodeoxycholic acid, henagliflozin, and the pharmaceutically acceptable excipient; (7) The pharmaceutical composition A comprises berberine ursodeoxycholic acid, ipragliflozin, and the pharmaceutically acceptable excipient. (8) The pharmaceutical composition A comprises berberine ursodeoxycholic acid, tofogliflozin, and the pharmaceutically acceptable excipient. (9) The pharmaceutical composition A comprises berberine ursodeoxycholate, sotagliflozin, and the pharmaceutically acceptable excipient; (10) The pharmaceutical composition A comprises berberine ursodeoxycholate, luseogliflozin, and the pharmaceutically acceptable excipient; (11) The pharmaceutical composition A comprises berberine ursodeoxycholic acid, janagliflozin, and the pharmaceutically acceptable excipient; and (12) The pharmaceutical composition A comprises berberine ursodeoxycholic acid, bexagliflozin, and the pharmaceutically acceptable excipient; The pharmaceutical composition A according to claim 7, which satisfies at least one of the following conditions:

9. The pharmaceutical composition A satisfies the following conditions: (1) The pharmaceutical composition A consists of substance X, substance Y, and one or more pharmaceutically acceptable excipients; (2) The active ingredients of the pharmaceutical composition A consist of the substance X and the substance Y; (3) In the pharmaceutical composition A, the berberine ursodeoxycholate and the SGLT2 inhibitor are provided in a molar ratio of 1:1 to 100:1, preferably the berberine ursodeoxycholate and the SGLT2 inhibitor are provided in a molar ratio of 1:50 to 1:5 or 1:1 to 100:1, preferably the berberine ursodeoxycholate and the SGLT2 inhibitor are provided in a molar ratio of 5:1 to 50:1, more preferably the berberine ursodeoxycholate and the SGLT2 inhibitor are provided in a molar ratio of 5:1 to 15:1, such as 14:1, 13:1, 12:1, 11:1, 10:1, or 9:1; (4) The pharmaceutical composition A is in the form of an oral formulation, and preferably, the oral formulation is selected from tablets, capsules, and liquid formulations; (5) The pharmaceutical composition A is administered as a QD, BID, or TID regimen, preferably QD; and (6) The pharmaceutical composition A is used for treating and / or preventing a metabolic disease or a disease related thereto, and preferably, the metabolic disease is selected from diabetes, prediabetes, hyperinsulinemia, and obesity. The pharmaceutical composition A according to claim 7, which satisfies at least one of the following conditions:

10. The pharmaceutical composition A satisfies the following conditions: (1) The pharmaceutical composition A consists of crystalline form A of berberine ursodeoxycholate heminonahydrate and empagliflozin; and (2) The pharmaceutical composition A consists of crystalline form A of berberine ursodeoxycholate heminonahydrate and dapagliflozin; The pharmaceutical composition A according to claim 7, which satisfies at least one of the following conditions:

11. a first pharmaceutical composition comprising a substance X and a first pharmaceutically acceptable excipient, said substance X being as defined in any one of claims 1 to 6; A second pharmaceutical composition comprising a substance Y and a second pharmaceutically acceptable excipient, said substance Y being a second pharmaceutical composition as defined in any one of claims 1 to 6. Pharmaceutical composition B comprising:

12. The pharmaceutical composition B satisfies the following conditions: (1) The first pharmaceutical composition and the second pharmaceutical composition are independent pharmaceutical compositions; (2) the first pharmaceutically acceptable excipient and the second pharmaceutically acceptable excipient are the same or different; (3) the first pharmaceutical composition is in an oral dosage form; and (4) The second pharmaceutical composition is in an oral dosage form. The pharmaceutical composition B according to claim 11, which satisfies at least one of the following conditions:

13. The pharmaceutical composition B satisfies the following conditions: (1) The first pharmaceutical composition and the second pharmaceutical composition are disposed in the same solid dosage unit, and preferably, the solid dosage unit is an individual tablet, pill, or capsule; (2) the first pharmaceutical composition is in an oral dosage form and the second pharmaceutical composition is in an oral dosage form; (3) The pharmaceutical composition B comprises berberine ursodeoxycholate, empagliflozin, and a pharmaceutically acceptable excipient; (4) The pharmaceutical composition B comprises berberine ursodeoxycholate, dapagliflozin, and a pharmaceutically acceptable excipient; and (5) The pharmaceutical composition B comprises berberine ursodeoxycholic acid, canagliflozin, and a pharmaceutically acceptable excipient; The pharmaceutical composition B according to claim 11, which satisfies at least one of the following conditions:

14. The pharmaceutical composition B satisfies the following conditions: (1) the first pharmaceutical composition and the second pharmaceutical composition are respectively disposed in two independent subpackages in the same pharmaceutical pack; (2) the first pharmaceutical composition is administered as a QD, BID, or TID regimen, preferably QD; (3) the second pharmaceutical composition is administered as a QD, BID, or TID regimen, preferably QD; (4) the first pharmaceutical composition and the second pharmaceutical composition are administered according to the same regimen; (5) In the pharmaceutical composition B, the berberine ursodeoxycholate and the SGLT2 inhibitor are provided in a molar ratio of 1:100 to 100:1, preferably, the berberine ursodeoxycholate and the SGLT2 inhibitor are provided in a molar ratio of 1:50 to 1:5 or 1:1 to 100:1, more preferably, the berberine ursodeoxycholate and the SGLT2 inhibitor are provided in a molar ratio of 5:1 to 50:1, and most preferably, the berberine ursodeoxycholate and the SGLT2 inhibitor are provided in a molar ratio of 5:1 to 15:1, such as 14:1, 13:1, 12:1, 11:1, 10:1, or 9:

1. (6) The pharmaceutical composition B consists of the first pharmaceutical composition and the second pharmaceutical composition; and (7) The pharmaceutical composition B consists of the substance X, the substance Y, and the pharmaceutically acceptable excipient; The pharmaceutical composition B according to claim 11, which satisfies any one of the following conditions.

15. a substance U which is berberine or a pharmaceutically acceptable salt thereof; a substance V which is ursodeoxycholic acid or a pharmaceutically acceptable salt thereof; Substance Y is an SGLT2 inhibitor or a pharmaceutically acceptable salt thereof; 10. Pharmaceutical combination II comprising: Pharmaceutical combination II, wherein said SGLT2 inhibitor is as defined in any one of claims 1 to 6.

16. The pharmaceutical combination II is (1) The substance U is berberine ursodeoxycholic acid; and (2) The substance V is berberine ursodeoxycholic acid; 16. The pharmaceutical combination II according to claim 15, wherein at least one of the following conditions is satisfied:

17. The pharmaceutical combination II is (1) The pharmaceutical combination II comprises berberine or its inorganic acid salt, ursodeoxycholic acid, and an SGLT2 inhibitor; (2) The pharmaceutical combination II comprises berberine or its inorganic acid salt, an inorganic base salt of ursodeoxycholic acid, and an SGLT2 inhibitor. (3) The pharmaceutical combination II comprises berberine hydrochloride, ursodeoxycholic acid, and empagliflozin. (4) The pharmaceutical combination II comprises berberine hydrochloride, ursodeoxycholic acid, and dapagliflozin; and (5) The pharmaceutical combination II consists of the substance U, the substance V, and the substance Y; 16. The pharmaceutical combination II according to claim 15, wherein at least one of the following conditions is satisfied:

18. The pharmaceutical combination II is (1) The pharmaceutical combination II consists of berberine hydrochloride, ursodeoxycholic acid, and empagliflozin; (2) The pharmaceutical combination II consists of berberine hydrochloride, ursodeoxycholic acid, and dapagliflozin. (3) The substance U, the substance V, and the substance Y are administered simultaneously, separately, or in combination; (4) The dosing regimens of substance U, substance V, and substance Y are the same or different; (5) All or part of the substance U, the substance V, and the substance Y are provided in the form of a pharmaceutical composition, for example, in the form of a pharmaceutical composition containing the substance U, the substance V, and the substance Y, or in the form of a pharmaceutical composition containing any two of these substances; (6) The molar ratio of the substance U to the substance V is 20:1 to 1:20, preferably the molar ratio of the substance V to the substance Y is 5:1 to 1:2, more preferably 1:1; (7) The molar ratio of the substance U to the substance Y is 100:1 to 1:20, preferably the molar ratio of the substance V to the substance Y is 50:1 to 1:1, more preferably 30:1 to 5:1; and (8) The molar ratio of the substance V to the substance Y is 20:1 to 1:20, preferably 5:1 to 1:2, more preferably 1:1; 16. The pharmaceutical combination II according to claim 15, wherein at least one of the following conditions is satisfied:

19. Substance V, which is ursodeoxycholic acid; Substance Y is an SGLT2 inhibitor or a pharmaceutically acceptable salt thereof; 1. Pharmaceutical combination III comprising: Pharmaceutical combination III, wherein said SGLT2 inhibitor is as defined in any one of claims 1 to 6.

20. The pharmaceutical combination III satisfies the following conditions: (1) The substance V and the substance Y are administered simultaneously or separately; and (2) the molar ratio of the substance V to the substance Y is 20:1 to 1:20, preferably 5:1 to 1:2, more preferably 1:1; 20. The pharmaceutical combination III of claim 19, wherein at least one of the following conditions is satisfied:

21. Use of pharmaceutical combination I according to any one of claims 1 to 6, pharmaceutical composition A according to any one of claims 7 to 10, pharmaceutical composition B according to any one of claims 11 to 14, pharmaceutical combination II according to any one of claims 15 to 18, or pharmaceutical combination III according to claim 19 or 20 in the preparation of a medicament for the prevention and / or treatment of a disease, wherein said disease is a metabolic disease or a disease related thereto.

22. 22. The use according to claim 21, wherein the metabolic disease is diabetes and / or obesity.

23. 22. The use according to claim 21, wherein the metabolic disease is type 2 diabetes.

24. 22. The use of claim 21, wherein the metabolic disease is pre-diabetes.

25. 22. The use according to claim 21, wherein the metabolic disease is hyperinsulinemia or metabolic syndrome associated with hyperinsulinemia.

26. 22. The use according to claim 21, wherein the metabolic disease is obesity.

27. 22. The use according to claim 21, wherein the metabolic disease is diabetes combined with obesity.

28. 15. A pharmaceutical pack comprising separate subpackages of pharmaceutical compositions, wherein a first subpackage contains a first pharmaceutical composition according to any one of claims 11 to 14, and a second subpackage contains a second pharmaceutical composition according to any one of claims 11 to 14.

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