TW202432104A - Pharmaceutical combination, pharmaceutical composition and use thereof - Google Patents

Abstract

The present invention discloses a new pharmaceutical combination, pharmaceutical composition and use thereof, including berberine ursodeoxycholate and SGLT2 inhibitor, or berberine and/or ursodeoxycholic acid and SGLT2 inhibitor. The pharmaceutical combination and pharmaceutical composition can exert synergistic weight loss and/or blood sugar lowering effects. At the same time, the pharmaceutical combination provided by the preset invention can also significantly improve insulin sensitivity. The present invention also provides uses and methods for treating one or more metabolic diseases or conditions.

Description

Drug combination, drug combination and its application

The present invention relates to the field of medical technology, and specifically to a new drug combination and its therapeutic use, and in particular to a new drug combination containing berberine ursodeoxycholate and SGLT2 inhibitor and its use in the treatment of metabolic diseases.

This application claims the priority of 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. This application cites the full text of the above Chinese Patent Application.

The prevalence of diabetes is rising in epidemic proportions, with an estimated 537 million people worldwide suffering from diabetes as of 2021. Diabetes (approximately 10% of the adult population) is a chronic disease of three main types: type 1, type 2, and gestational diabetes, with type 2 being the most common, accounting for 90-95%. Type 2 diabetes is a progressive disease characterized by insulin resistance and relative insufficiency of insulin secretion, leading to elevated blood sugar levels. Hyperglycemia, or elevated blood sugar, is a common consequence of uncontrolled diabetes and can cause severe damage to many of the body's systems over time, particularly the nervous and vascular systems.

One of the important ways to treat diabetes is to maintain a healthy lifestyle. Some people with type 2 diabetes need medication to help control their blood sugar levels. People with diabetes usually also need antihypertensive drugs and statins to reduce the risk of complications. For many patients, the initial monotherapy of hypoglycemic drugs cannot adequately control blood sugar during long-term treatment, which leads to the need to upgrade treatment after taking the drug for several years to ensure continued blood sugar control. This upgraded treatment is usually achieved by combining two or more hypoglycemic drugs, but how to make a better combination is not so obvious (Rational combination therapy for type 2 diabetes. Lancet Diabetes Endocrinol. 2019 May;7(5):328-329.doi: 10.1016/S2213-8587(19)30069-5.).

Obesity generally refers to excessive accumulation of body fat that may affect health. More than 1 billion people worldwide suffer from obesity, and the number continues to grow. Obesity is associated with a variety of major diseases or increases the risk of these diseases, including cardiovascular metabolic diseases, digestive system diseases, respiratory system diseases, nervous system diseases, and musculoskeletal system diseases, and these diseases are 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 patients with type 2 diabetes are attributable to being overweight (defined as BMI ≥ 25 kg/m ² ), and as weight increases, the risk of developing type 2 diabetes also increases. Preventing and treating obesity is a crucial strategy to reduce the incidence, improvement and treatment of type 2 diabetes. Studies have shown that weight loss can improve patients' blood sugar control and even reverse the course of type 2 diabetes (Durability of a primary care-led weight-management intervention for remission of type 2 diabetes: 2-year results of the DiRECT open-label, cluster-randomised trial. Lancet Diabetes Endocrinol. 2019 May;7(5):344-355.).

Currently, low-calorie diets, bariatric surgery, and intestinal hormone therapy (such as GLP-1RA) are considered the most effective weight loss measures. However, although these treatments can significantly reduce fat weight, they have obvious shortcomings such as poor compliance and accessibility due to the need for long-term persistence. In addition, while losing weight, healthy muscle content will also be reduced, which may lead to sarcopenia and other health problems. For example, a clinical study reported that after 68 weeks of treatment with semaglutide, body weight decreased by an average of 15% (compared to 3.6% in the placebo group), with total fat mass decreasing by an average of 19.3% and muscle mass decreasing by 9.7% (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 study of semaglutide at a lower dose also obtained similar results: after 52 weeks of treatment, the total fat mass in the semaglutide group and the cangliflozin group decreased by an average of 10.2% and 7.8%, respectively, while the 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 randomised controlled clinical trial. Diabetologia. 2020 Mar;63(3):473-485. doi: 10.1007/s00125-019-05065-8.). Other studies have also obtained consistent results, confirming the importance of maintaining sufficient or increasing healthy muscle mass while losing weight in obese patients. (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):e027 1579. 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).

Sarcopenia is a type of muscle loss that occurs with aging and/or reduced mobility. As many countries are experiencing a profound shift in their population distribution toward an aging population, sarcopenia has received increasing attention. In 2010, Europe published a consensus on sarcopenia, defining it as an age-related syndrome characterized by decreased muscle mass, decreased muscle strength, and/or decreased 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.). It is estimated that the prevalence of sarcopenia is 6% to 12% worldwide, 14% to 33% in the elderly aged 65 and above, and as high as 78% in disabled and hospitalized patients (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.).

At present, the pathogenesis of sarcopenia is not completely clear. In clinical practice, not only primary sarcopenia caused by aging is common, but also secondary sarcopenia caused by other diseases or conditions, such as muscle atrophy caused by long-term immobilization and bed rest, skeletal muscle denervation, severe malnutrition, tumor malignancy, endocrine metabolic diseases and genetic inheritance (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 muscle malnutrition, which leads to increased sarcopenia in diabetic patients compared with the general population.

Sarcopenia has an insidious onset, but it can lead to physical impairment and increased risk of death, seriously impairing patients' quality of life and health. A meta-analysis of 10,073 subjects showed that the risk of falls in elderly people with sarcopenia increased by 52% 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). Falls in the elderly increase the risk of fractures 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 may even increase the risk of death. Studies have shown that the risk of all-cause mortality among community-dwelling older people with sarcopenia is 1.6 times that of those without sarcopenia, and the risk of all-cause mortality within 5 years is as high as 2.09 times (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 is currently no effective drug for the treatment of sarcopenia.

SGLT-2 inhibitors reduce blood sugar by reducing the reabsorption of glucose by SGLT2 in the kidneys and promoting urinary glucose excretion. They have a unique hypoglycemic effect and can reduce HbA1c by an average of 0.7% compared with placebo. Due to its unique hypoglycemic mechanism and its independence from insulin, the risk of hypoglycemia is low when used alone, and it can be used in combination with other hypoglycemic drugs to achieve a more sustained hypoglycemic effect. More importantly, in addition to lowering blood sugar, many large randomized controlled clinical studies have shown that SGLT2 inhibitors can reduce 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 randomised controlled trials. Lancet. 2022 Sep 3;400(10354):757-767.).

The SGLT2 inhibitors currently on the market include: empagliflozin, dapagliflozin, canagliflozin, ertogliflozin, henagliflozin, ipraggliflozin, toragliflozin, sogliaflozin, rupagliflozin, and jangliflozin, and some are under clinical development.

Berberine ursodeoxycholate (BUDC) is a new ionic salt compound formed by berberine (BBR) and ursodeoxycholic acid (UDCA), which has been disclosed in multiple patent applications such as WO 2016/015634A1 (PCT/CN2015/085350) and WO 2018/205987 A1 (PCT/CN2018/086461). As a new molecular entity, it is currently in the clinical research stage and has the potential to be used in the treatment of non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), and diabetes. Berberine ursodeoxycholate (BUDC)

The present invention provides novel drug combinations and treatment methods for use in combination with BUDC or BBR and/or UDCA and SGLT2 inhibitors. In particular, the present invention also provides a drug composition comprising BUDC and an SGLT2 inhibitor (e.g., empagliflozin) or a pharmaceutically acceptable salt thereof, and a treatment method using BUDC in combination with an SGLT2 inhibitor. The present invention also provides a drug composition comprising BBR and/or UDCA in combination with an SGLT2 inhibitor, and a treatment method using BBR and/or UDCA in combination with an SGLT2 inhibitor. The drug composition and method of the present invention can be used to treat a variety of diseases and conditions, such as diabetes, prediabetes, obesity, sarcopenia, and glucagonism.

On the one hand, the present invention provides a drug combination I, which comprises: Substance X, wherein the substance X is berberine ursodeoxycholate; and, Substance Y, wherein the substance Y is an SGLT2 inhibitor or a pharmaceutically acceptable salt thereof; The SGLT2 inhibitor is selected from at least one of empagliflozin, dapagliflozin, canagliflozin, ertogliflozin, hengagliflozin, ipragliflozin, toragliflozin, sogliaflozin, rugliflozin, jangliflozin, bexagliflozin, rongagliflozin, enavogliflozin and JT-001.

In some embodiments, the active ingredients of pharmaceutical combination I include substance X and substance Y.

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

The “simultaneous administration” means, for example, that substance X and substance Y are contained in a separate pharmaceutical composition and administered simultaneously; or, “a separate pharmaceutical composition containing substance X” and “a separate pharmaceutical composition containing substance Y” are administered simultaneously.

The "separate administration" means, for example, that a "separate pharmaceutical composition comprising substance X" and a "separate pharmaceutical composition comprising substance Y" are administered separately at different times, for example, one of the "separate pharmaceutical composition comprising substance X" and the "separate pharmaceutical composition comprising substance Y" is administered first, and the other is administered subsequently. The separate administration may be close in time or far in time.

Regardless of simultaneous or separate administration, the application schemes of substance X and substance Y (including application path, application dosage, application interval, etc.) may be the same or different, and may be adjusted as needed by a person skilled in the art.

In some embodiments, the substance X is administered orally.

In some embodiments, the substance Y is administered orally.

Preferably, in some embodiments, the substance X is administered orally, and the substance Y is administered orally.

In some embodiments, the SGLT2 inhibitor is empagliflozin, dapagliflozin or 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.

In some embodiments, the unit dosage form of substance X and substance Y is selected from tablets, capsules or liquid preparations.

In some embodiments, the berberine ursodeoxycholate exists in its amorphous, anhydrous crystalline or hydrated crystalline form; the various crystalline forms of berberine ursodeoxycholate that have been disclosed (CN108864077A and WO 2018/205987 A1) can all be applied to the present invention.

In some embodiments, the berberine ursodeoxycholate is crystalline form A of berberine ursodeoxycholate, and the crystalline form A of berberine ursodeoxycholate has diffraction peaks at 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° in X -} ray powder diffraction expressed as 2θ angles.

Preferably, the X-ray powder diffraction of the berberine ursodeoxycholate salt in form A expressed as 2θ angle is 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 ^o , 16.78± 0.2 ^o , 17.53± 0.2 ^o , 17.67± 0.2 ^o , 18.23± 0.2 ^o , 19.03± 0.2 ^o , 19.98± 0.2 ^o , 20.87± 0.2 ^o , 21.13± 0 .2 ^o , 21.96± 0.2 ^o , 23.49± 0.2 ^o , 24.24± 0.2 ^o , 24.97± 0.2 ^o , 25.50± 0.2 ^o , 26.63± 0.2 ^o , 27.60± 0.2 ^o , 28.06± 0.2 ^o , There are diffraction peaks at 28.63± 0.2 ^o , 29.40± 0.2 ^o and 30.49 ± 0.2 ^o .

The X-ray powder diffraction was collected under Cu Kα radiation (λ1 = 1.540598 Å, λ2 = 1.544426 Å, density ratio λ2/λ1 = 0.50).

Preferably, in some embodiments, the berberine ursodeoxycholate crystalline form A is berberine ursodeoxycholate hemi-nonahydrate crystalline form A; Berberine ursodeoxycholate hemi-nonahydrate.

In some embodiments, the berberine ursodeoxycholate is berberine ursodeoxycholate crystalline form D, and the berberine ursodeoxycholate crystalline form D has X-ray powder diffraction expressed in 2θ angles at 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 ^° . There is a diffraction peak at 0.2 ^o .

The X-ray powder diffraction was collected under Cu Kα radiation (λ1 = 1.540598 Å, λ2 = 1.544426 Å, density ratio λ2/λ1 = 0.50).

In some embodiments, the berberine ursodeoxycholate is present in the form of its free salt or hydrate.

In some embodiments, the substance X is berberine ursodeoxycholate, and the substance Y is empagliflozin.

In some embodiments, the substance X is berberine ursodeoxycholate, and the substance Y is dapagliflozin.

In some embodiments, the substance X is berberine ursodeoxycholate, and the substance Y is canagliflozin.

In some embodiments, the substance X is berberine ursodeoxycholate, and the substance Y is ertogliflozin.

In some embodiments, the substance X is berberine ursodeoxycholate, and the substance Y is henglixin.

In some embodiments, the substance X is berberine ursodeoxycholate, and the substance Y is ipraglide.

In some embodiments, the substance X is berberine ursodeoxycholate, and the substance Y is toragliflozin.

In some embodiments, the substance X is berberine ursodeoxycholate, and the substance Y is sogliagliflozin.

In some embodiments, the substance X is berberine ursodeoxycholate, and the substance Y is rugliflozin.

In some embodiments, the substance X is berberine ursodeoxycholate, and the substance Y is jangliflozin.

In some embodiments, the substance X is berberine ursodeoxycholate, and the substance Y is bexagliflozin.

In some embodiments, the substance X is berberine ursodeoxycholate, and the substance Y is rongliflozin.

In some embodiments, the substance X is berberine ursodeoxycholate, and the substance Y is enavogliflozin.

In some embodiments, the substance X is berberine ursodeoxycholate, and the substance Y is JT-001.

In some embodiments, pharmaceutical composition I consists of substance X and substance Y.

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

In some embodiments, Drug Combination I consists of Form A of berberine ursodeoxycholate hemi-nonahydrate and empagliflozin.

In some embodiments, Drug Combination I consists of Form A of berberine ursodeoxycholate hemi-nonahydrate and dapagliflozin.

In some embodiments, in the pharmaceutical composition I, the substance X and the substance Y are provided in a substance molar ratio of 1:100 to 100:1; preferably, the substance X and the substance Y are provided in a substance 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 substance molar ratio of 5:1 to 50:1 (e.g., 30:1).

In some embodiments, in the pharmaceutical composition I, the substance X and the substance Y are provided in a substance amount ratio of 5:1 to 15:1, for example, 14:1, 13:1, 12:1, 11:1, 10:1 or 9:1.

In some embodiments, in the pharmaceutical composition I, the substance X is berberine ursodeoxycholate; preferably, the crystalline form A of berberine ursodeoxycholate hemi-nonahydrate; the substance Y is empagliflozin; the substance X and the substance Y are provided in the form of a substance amount ratio of 12:1, 11:1, 10:1 or 9:1.

In some embodiments, in the pharmaceutical composition I, the substance X is berberine ursodeoxycholate; preferably, the crystalline form A of berberine ursodeoxycholate hemi-nonahydrate; the substance Y is dapagliflozin; the substance X and the substance Y are provided in the form of a substance molar ratio of 14:1, 13:1 or 12:1.

According to the above ratio, the dosage of substance X and substance Y of the present invention can be adjusted in the same ratio according to the needs of the subject.

In some embodiments, the substance X of the present invention is administered at a frequency of QD (once a day), BID (twice a day) or TID (three times a day), preferably QD.

In some embodiments, substance Y of the present invention is administered at a frequency of QD (once a day), BID (twice a day) or TID (three times a day), preferably QD.

In some embodiments, the substance X and substance Y are administered at the same frequency.

In some embodiments, the drug combination I is a drug combination I that can be used to prevent and/or treat metabolic diseases or diseases related thereto.

In some embodiments, the drug combination I is a drug combination I that can be used to prevent and/or treat muscle diseases.

In some embodiments, the metabolic disease is selected from diabetes, prediabetes, hyperinsulinemia and obesity.

In some embodiments, the muscle disease is selected from sarcopenia and amyotrophic lateral sclerosis.

On the other hand, the present invention provides a drug composition A, which comprises: Substance X, wherein the substance X is berberine ursodeoxycholate; and, Substance Y, wherein the substance Y is an SGLT2 inhibitor or a pharmaceutically acceptable salt thereof; and, Pharmaceutical excipients; The SGLT2 inhibitor is selected from at least one of empagliflozin, dapagliflozin, canagliflozin, ertogliflozin, hemagglutinin, ipragliflozin, toragliflozin, sogliaflozin, rugliflozin, jangliflozin, bexagliflozin, rongagliflozin, enavogliflozin and JT-001.

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

In some embodiments, the berberine ursodeoxycholate exists in its amorphous, anhydrous crystalline or hydrated crystalline form.

Preferably, the berberine ursodeoxycholate is crystalline form A of berberine ursodeoxycholate, and the crystalline form A of berberine ursodeoxycholate is as described above.

More preferably, the crystalline form A of berberine ursodeoxycholate is the crystalline form A of hemi-nonahydrate berberine ursodeoxycholate.

In some embodiments, the SGLT2 inhibitor is empagliflozin, dapagliflozin or 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.

In some embodiments, the pharmaceutical composition A comprises berberine ursodeoxycholate and empagliflozin, and pharmaceutically acceptable excipients.

In some embodiments, the pharmaceutical composition A comprises berberine ursodeoxycholate and dapagliflozin, and pharmaceutically acceptable excipients.

In some embodiments, the pharmaceutical composition A comprises berberine ursodeoxycholate and canagliflozin, and pharmaceutically acceptable excipients.

In some embodiments, the pharmaceutical composition A comprises berberine ursodeoxycholate and ertogliflozin, and pharmaceutically acceptable excipients.

In some embodiments, the pharmaceutical composition A comprises berberine ursodeoxycholate and henggliflozin, and pharmaceutically acceptable excipients.

In some embodiments, the pharmaceutical composition A comprises berberine ursodeoxycholate and ipragliflozin, and pharmaceutically acceptable excipients.

In some embodiments, the pharmaceutical composition A comprises berberine ursodeoxycholate and toragliflozin, and pharmaceutically acceptable excipients.

In some embodiments, the pharmaceutical composition A comprises berberine ursodeoxycholate and solafloxacin, and pharmaceutically acceptable excipients.

In some embodiments, the pharmaceutical composition A comprises berberine ursodeoxycholate and rugliptin, and pharmaceutically acceptable excipients.

In some embodiments, the pharmaceutical composition A comprises berberine ursodeoxycholate and janagliflozin, and pharmaceutically acceptable excipients.

In some embodiments, the pharmaceutical composition A comprises berberine ursodeoxycholate and bexagliflozin, and pharmaceutically acceptable excipients.

In some embodiments, the pharmaceutical composition A comprises the crystalline form A of berberine ursodeoxycholate hemi-nonahydrate and empagliflozin, and pharmaceutically acceptable excipients.

In some embodiments, the pharmaceutical composition A comprises the crystalline form A of berberine ursodeoxycholate hemi-nonahydrate and dapagliflozin, and pharmaceutically acceptable excipients.

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

In some embodiments, the active ingredient of pharmaceutical composition A consists of substance X and substance Y.

In some embodiments, the active ingredients of pharmaceutical composition A consist of berberine ursodeoxycholate hemi-nonahydrate crystalline form A and empagliflozin.

In some embodiments, the active ingredients of pharmaceutical composition A consist of berberine ursodeoxycholate hemi-nonahydrate crystalline form A and dapagliflozin.

In some embodiments, in the pharmaceutical composition A, berberine ursodeoxycholate and the SGLT2 inhibitor are provided in a substance ratio of 1:100 to 100:1; berberine ursodeoxycholate and the SGLT2 inhibitor are provided in a substance ratio of 1:1 to 100:1; preferably, berberine ursodeoxycholate and the SGLT2 inhibitor are provided in a substance ratio of 1:50 to 1:5 or 1:1 to 100:1; preferably, berberine ursodeoxycholate and the SGLT2 inhibitor are provided in a substance ratio of 5:1 to 50:1 (for example 30:1); more preferably, berberine ursodeoxycholate and the SGLT2 inhibitor are provided in the form of a substance amount ratio of 5:1 to 15:1 (e.g., 14:1, 13:1, 12:1, 11:1, 10:1 or 9:1).

In some embodiments, in the pharmaceutical composition A, the substance X is berberine ursodeoxycholate; preferably, the crystalline form A of berberine ursodeoxycholate hemi-nonahydrate; the substance Y is empagliflozin; the substance X and the substance Y are provided in the form of a substance molar ratio of 12:1, 11:1, 10:1 or 9:1.

In some embodiments, in the pharmaceutical composition A, the substance X is berberine ursodeoxycholate; preferably, the crystalline form A of berberine ursodeoxycholate hemi-nonahydrate; the substance Y is dapagliflozin; the substance X and the substance Y are provided in the form of a substance molar ratio of 14:1, 13:1 or 12:1.

In some embodiments, the pharmaceutical composition A is in the form of an oral formulation.

In some embodiments, the oral formulation is selected from tablets, capsules or liquid formulations.

In some embodiments, the pharmaceutical composition A is administered at a frequency of QD (once a day), BID (twice a day) or TID (three times a day), preferably QD.

In some embodiments, the pharmaceutical composition A is a pharmaceutical composition A that can be used to prevent and/or treat metabolic diseases or diseases related thereto.

In some embodiments, the pharmaceutical composition A is a pharmaceutical composition A that can be used to prevent and/or treat muscle diseases.

In some embodiments, the metabolic disease is selected from diabetes, prediabetes, hyperinsulinemia, and obesity.

In some embodiments, the muscle disease is sarcopenia.

In some embodiments, the muscle disease is myasthenia gravis.

On the other hand, the present invention provides a drug composition B, which comprises: A first drug composition, which comprises a substance X and a first pharmaceutical excipient, wherein the substance X is berberine ursodeoxycholate; and, A second drug composition, which comprises a substance Y and a second pharmaceutical excipient, wherein the substance Y is an SGLT2 inhibitor or a pharmaceutically acceptable salt thereof; The SGLT2 inhibitor is selected from at least one of empagliflozin, dapagliflozin, canagliflozin, ertogliflozin, hengagliflozin, ipragliflozin, toragliflozin, sogliaflozin, rugliflozin, janagliptin, bexagliflozin, rongagliflozin, enavogliflozin and JT-001.

In the present invention, the first drug composition and the second drug composition are independent drug compositions.

In some embodiments, the first pharmaceutical excipient and the second pharmaceutical excipient may be the same or different.

In some embodiments, the first drug composition and the second drug composition are disposed in the same solid dosage unit.

Preferably, in some embodiments, the solid dosage unit may be an independent tablet, pill or capsule.

More preferably, in some embodiments, the first drug composition and the second drug composition are respectively disposed in different parts of the same dosage unit or unit dosage form. For example, the first drug composition and the second drug composition respectively constitute the upper and lower layers or the inner and outer layers of the tablet.

More preferably, in some embodiments, the first drug composition and the second drug composition are co-arranged in the space defined by the dosage unit or unit dosage form. For example, the first drug composition and the second drug composition are mixed in the same capsule in a form visible to the naked eye.

In some embodiments, the first drug composition and the second drug composition are respectively disposed in two independent sub-packages in the same drug package.

In some embodiments, the first pharmaceutical composition is in the form of an oral dosage form.

In some embodiments, the second pharmaceutical composition is in the form of an oral dosage form.

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

In some embodiments, the berberine ursodeoxycholate exists in its amorphous, anhydrous crystalline or hydrated crystalline form.

Preferably, the berberine ursodeoxycholate is crystalline form A of berberine ursodeoxycholate, and the crystalline form A of berberine ursodeoxycholate is as described above.

More preferably, the crystalline form A of berberine ursodeoxycholate is the crystalline form A of hemi-nonahydrate berberine ursodeoxycholate.

In some embodiments, the SGLT2 inhibitor is empagliflozin, dapagliflozin or 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.

In some embodiments, the pharmaceutical composition B comprises berberine ursodeoxycholate and empagliflozin, and pharmaceutically acceptable excipients.

In some embodiments, the pharmaceutical composition B comprises berberine ursodeoxycholate and dapagliflozin, and pharmaceutically acceptable excipients.

In some embodiments, the pharmaceutical composition B comprises berberine ursodeoxycholate and canagliflozin, and pharmaceutically acceptable excipients.

In some embodiments, the drug composition B consists of a first drug composition and a second drug composition.

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

In some embodiments, in the pharmaceutical composition B, berberine ursodeoxycholate and the SGLT2 inhibitor are provided in the form of a substance molar ratio of 1:100 to 100:1; preferably, berberine ursodeoxycholate and the SGLT2 inhibitor are provided in the form of a substance molar ratio of 1:50 to 1:5 or 1:1 to 100:1; more preferably, berberine ursodeoxycholate and the SGLT2 inhibitor are provided in the form of a substance molar ratio of 5:1 to 50:1 (e.g., 30:1).

In some embodiments, in the drug combination B, berberine ursodeoxycholate and the SGLT2 inhibitor are provided in a substance amount ratio of 5:1 to 15:1, for example, in a form of 14:1, 13:1, 12:1, 11:1, 10:1 or 9:1.

In some embodiments, the first drug composition is administered at a frequency of QD (once a day), BID (twice a day) or TID (three times a day), preferably QD.

In some embodiments, the second drug composition is administered at a frequency of QD (once a day), BID (twice a day) or TID (three times a day), preferably QD.

In some embodiments, the first drug composition and the second drug composition are administered at the same frequency.

On the other hand, the present invention also provides a drug combination II, which comprises: Substance U, wherein the substance U is berberine or a pharmaceutically acceptable salt thereof; and, Substance V, wherein the substance V is ursodeoxycholic acid or a pharmaceutically acceptable salt thereof; and, Substance Y, wherein the substance Y is an SGLT2 inhibitor or a pharmaceutically acceptable salt thereof; The SGLT2 inhibitor is selected from at least one of empagliflozin, dapagliflozin, canagliflozin, ertogliflozin, hengagliflozin, ipragliflozin, toragliflozin, sogliagliflozin, rugliflozin, janagliptin, bexagliflozin, rongagliflozin, enavogliflozin and JT-001.

In some embodiments, the substance U is berberine ursodeoxycholate.

In some embodiments, the substance V is berberine ursodeoxycholate.

In some embodiments, the SGLT2 inhibitor is empagliflozin, dapagliflozin or 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.

In some embodiments, the drug combination II comprises berberine or an inorganic acid salt thereof, ursodeoxycholic acid and an SGLT2 inhibitor.

In some embodiments, the drug combination II comprises berberine or an inorganic acid salt thereof, an inorganic base salt of ursodeoxycholic acid, and an SGLT2 inhibitor.

In some embodiments, the drug combination II comprises berberine hydrochloride, ursodeoxycholic acid and empagliflozin.

In some embodiments, the drug combination II comprises berberine hydrochloride, ursodeoxycholic acid and dapagliflozin.

In some embodiments, the pharmaceutical composition II consists of substance U, substance V, substance Y and one or more pharmaceutically acceptable excipients.

In some embodiments, the drug combination II consists of berberine hydrochloride, ursodeoxycholic acid, empagliflozin and one or more pharmaceutically acceptable excipients.

In some embodiments, the drug combination II consists of berberine hydrochloride, ursodeoxycholic acid, dapagliflozin and one or more pharmaceutically acceptable excipients.

In some embodiments, the substance U, substance V and substance Y can be administered simultaneously, separately or in a combination of the two.

The “simultaneous administration” refers to, for example, the simultaneous administration of two or more substances selected from substance U, substance V and substance Y, for example, the simultaneous administration of substance U, substance V and substance Y; another example, the simultaneous administration of substance U and substance V; another example, the simultaneous administration of substance U and substance Y.

In the form of "simultaneous administration", for example, any two or more substances selected from substance U, substance V and substance Y are contained in a separate pharmaceutical composition and administered simultaneously; for another example, any two or more pharmaceutical compositions selected from "a separate pharmaceutical composition containing substance U", "a separate pharmaceutical composition containing substance V" and "a separate pharmaceutical composition containing substance Y" are administered simultaneously.

The "separate administration" means, for example, that any one of the "separate pharmaceutical composition comprising substance U", "separate pharmaceutical composition comprising substance V" and "separate pharmaceutical composition comprising substance Y" is administered separately from the other pharmaceutical compositions in pharmaceutical combination II; for another example, "separate pharmaceutical composition comprising substance U", "separate pharmaceutical composition comprising substance V" and "separate pharmaceutical composition comprising substance Y" are administered successively in a certain order. The separate administration may be close in time or far in time.

The "combination of the two" means, for example, that in the drug combination II, any two substances selected from substance U, substance V and substance Y are administered simultaneously and separately from a separate drug composition containing the remaining substances.

Regardless of simultaneous administration, separate administration or a combination of the two, the application schemes (including application path, application dosage, application interval, etc.) of substance U, substance V and substance Y may be the same or different, and may be adjusted as needed by a person skilled in the art.

In some embodiments, all or part of the substance U, substance V and substance Y are provided in the form of a pharmaceutical composition, for example, they can be provided 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 them.

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

In some embodiments, the molar ratio of the substance U to the substance Y is 100:1 to 1:20, preferably, the molar ratio of the substance U to the substance Y is 50:1 to 1:1, more preferably 30:1 to 5:1; 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.

In some embodiments, the molar ratio of substance V to substance Y is 100:1 to 1:20.

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, and more preferably 1:1.

On the other hand, the present invention also provides a drug combination III, which comprises: Substance V, wherein the substance V is ursodeoxycholic acid; and, Substance Y, wherein the substance Y is an SGLT2 inhibitor or a pharmaceutically acceptable salt thereof; The definition of the SGLT2 inhibitor is as described in any of the previous aspects.

In some embodiments, the substance V and substance Y can be administered simultaneously or separately.

In some embodiments, the molar ratio of substance V to substance Y is 100:1 to 1:20.

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, and more preferably 1:1.

On the other hand, the present invention also provides a use of the drug combination I, drug combination II, drug combination III, drug combination A or drug combination B described herein in the preparation of a medicament for preventing and/or treating a disease or condition, wherein the disease is a metabolic disease or a disease related thereto.

The present invention also provides a use of the pharmaceutical combination I, pharmaceutical combination II, pharmaceutical combination III, pharmaceutical combination A or pharmaceutical combination B described herein in the preparation of a medicament for preventing and/or treating a disease or disorder, wherein the disease is a muscle disease.

On the other hand, the present invention also provides a method for treating or preventing a disease or condition, the method comprising administering a therapeutically effective amount of Drug Combination I, Drug Combination II, Drug Combination III, Drug Combination A or Drug Combination B as described herein to a patient (e.g., a human or a mouse) in need thereof, wherein the disease is a metabolic disease or a disease related thereto.

On the other hand, the present invention also provides a method for treating or preventing a disease or disorder, comprising administering a therapeutically effective amount of Drug Combination I, Drug Combination II, Drug Combination III, Drug Combination A or Drug Combination B as described herein to a patient (e.g., a human or a mouse) in need thereof, wherein the disease is a muscle disease.

On the other hand, the present invention also provides a method for reducing body fat content, which comprises administering a therapeutically effective amount of Drug Combination I, Drug Combination II, Drug Combination III, Drug Combination A or Drug Combination B as described herein to a patient (e.g., a human or a mouse) in need thereof.

On the other hand, the present invention also provides a method for improving insulin sensitivity, which comprises administering a therapeutically effective amount of Drug Combination I, Drug Combination II, Drug Combination III, Drug Combination A or Drug Combination B as described herein to a patient (e.g., a human or a mouse) in need thereof.

On the other hand, the present invention also provides a method for increasing muscle mass, comprising administering a therapeutically effective amount of Drug Combination I, Drug Combination II, Drug Combination III, Drug Combination A or Drug Combination B as described herein to a patient (e.g., a human or a mouse) in need thereof.

On the other hand, the present invention also provides a method for treating obesity or reducing body fat content without causing a decrease in muscle content, the method comprising administering a therapeutically effective amount of Drug Combination I, Drug Combination II, Drug Combination III, Drug Combination A or Drug Combination B as described herein to a patient (e.g., a human or a mouse) in need thereof.

On the other hand, the present invention also provides use of the drug combination I, drug combination II, drug combination III, drug combination A or drug combination B described herein for treating metabolic diseases or diseases related thereto.

On the other hand, the present invention also provides use of the drug combination I, drug combination II, drug combination III, drug combination A or drug combination B described herein for treating muscle diseases.

On the other hand, the present invention also provides a use of a substance Y in the preparation of a drug for preventing and/or treating a disease or condition, wherein the disease is a muscle disease, the substance Y is an SGLT2 inhibitor or a pharmaceutically acceptable salt thereof, and the SGLT2 inhibitor is selected from at least one of empagliflozin, dapagliflozin, canagliflozin, ertogliflozin, hengagliflozin, ipragliflozin, togliflozin, sogliptin, rugliflozin, janagliptin, bexagliflozin, rongagliflozin, enavogliflozin and JT-001; The drug for preventing and/or treating a disease or condition is used in combination with a substance X, wherein the substance X is berberine ursodeoxycholate.

On the other hand, the present invention also provides a method for reducing body fat content, the method comprising administering a therapeutically effective amount of a substance Y as described herein to a patient in need thereof (e.g., a human or a mouse), wherein the substance Y is a SGLT2 inhibitor or a pharmaceutically acceptable salt thereof; the SGLT2 inhibitor is selected from at least one of empagliflozin, dapagliflozin, canagliflozin, ertogliflozin, hengagliflozin, ipagliptin, togliflozin, sogliptin, rugliflozin, janagliptin, bexagliflozin, rongagliflozin, enavogliflozin and JT-001; The substance Y is used in combination with a substance X, wherein the substance X is berberine ursodeoxycholate.

In the above-mentioned application and treatment method: In each drug combination, the administration scheme (including administration path, administration dosage, administration interval, etc.) of different substances or drug combinations containing different substances (for example, substance X and substance Y) can be the same or different, which can be adjusted as needed by a person with ordinary knowledge in the technical field to which the present invention belongs to provide the best therapeutic effect.

In some embodiments, the substance X is the crystalline form A of berberine ursodeoxycholate, and the crystalline form A of berberine ursodeoxycholate is as described above. Preferably, the crystalline form A of berberine ursodeoxycholate is the crystalline form A of hemi-nonahydrate berberine ursodeoxycholate.

In some embodiments, the SGLT2 inhibitor is empagliflozin, dapagliflozin or 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.

In some embodiments, the substance X in the pharmaceutical composition I is administered at a frequency of QD (once a day), BID (twice a day) or TID (three times a day), preferably QD.

In some embodiments, the substance Y in the drug combination I, II or III is administered at a frequency of QD (once a day), BID (twice a day) or TID (three times a day), preferably QD.

In some embodiments, substance U in the drug combination II is administered at a frequency of QD (once a day), BID (twice a day) or TID (three times a day), preferably QD.

In some embodiments, the substance V in the drug combination II or III is administered at a frequency of QD (once a day), BID (twice a day) or TID (three times a day), preferably QD.

In some embodiments, the substance X and substance Y in the pharmaceutical composition I are administered at the same frequency.

In some embodiments, the substance U and substance V in the pharmaceutical combination II are administered at the same frequency.

In some embodiments, the substance U and substance Y in the drug combination II are administered at the same frequency.

The substance X and substance Y in the pharmaceutical combination I may be administered simultaneously or separately.

The substance U, substance V and substance Y in the pharmaceutical combination II can be administered simultaneously, separately or in a combination of the two.

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

The pharmaceutical composition A and the pharmaceutical composition B can be administered by any suitable route in the art, including oral administration, injection (e.g., intravenous, intramuscular, subcutaneous), etc.

In some embodiments, the substance X in the pharmaceutical composition I is administered orally.

In some embodiments, the substance Y in the pharmaceutical composition I is administered orally.

Preferably, in some embodiments, the substance X in the pharmaceutical composition I is administered orally, and the substance Y is administered orally.

In some embodiments, the unit dosage form of the orally administered Drug Combination I, Drug Combination II, Drug Combination III, Drug Combination A, or Drug Combination B is selected from tablets, capsules, or liquid preparations.

In some embodiments, berberine ursodeoxycholate and the SGLT2 inhibitor are provided in a substance ratio of 1:100 to 100:1; preferably, berberine ursodeoxycholate and the SGLT2 inhibitor are provided in a substance ratio of 1:50 to 1:5 or 1:1 to 100:1; more preferably, berberine ursodeoxycholate and the SGLT2 inhibitor are provided in a substance ratio of 5:1 to 50:1 (e.g., 30:1).

In some embodiments, berberine ursodeoxycholate and the SGLT2 inhibitor are provided in a substance amount ratio of 5:1 to 15:1, for example, 14:1, 13:1, 12:1, 11:1, 10:1 or 9:1.

In some embodiments, the disease is selected from diabetes, prediabetes, glucagonism, obesity, sarcopenia, amyotrophic lateral sclerosis, or combinations thereof and/or related conditions.

In some embodiments, the disease is sarcopenia.

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

In some embodiments, the disease is diabetes mellitus combined with obesity.

In some embodiments, the disease is diabetes mellitus combined with obesity and sarcopenia.

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

In some embodiments, the metabolic disease is diabetes.

In some embodiments, the metabolic disease is obesity.

Preferably, in some embodiments, the metabolic disease is diabetes combined with obesity.

Preferably, in some embodiments, the diabetes is type 2 diabetes.

In some embodiments, the metabolic disease is prediabetes.

In some embodiments, the metabolic disease is hyperinsulinemia or a metabolic syndrome associated with hyperinsulinemia.

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

In some embodiments, the sarcopenia is senile sarcopenia.

In some embodiments, the sarcopenia is obesity and/or diabetes-combined sarcopenia.

In some embodiments, the sarcopenia is drug-induced sarcopenia.

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

In some embodiments, the subject has type 2 diabetes.

In some embodiments, the subject suffers from obesity.

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

In some embodiments, the subject has type 2 diabetes and obesity.

In some embodiments, the subject has hyperinsulinemia.

In some embodiments, the subject has diabetes mellitus combined with hyperinsulinemia.

In some embodiments, the subject has diabetes combined with hyperinsulinemia and obesity.

In some embodiments, the subject suffers from sarcopenia.

In some embodiments, the subject suffers from obesity with sarcopenia.

In some embodiments, the subject has diabetes mellitus associated with sarcopenia.

In some embodiments, the subject has diabetes combined with obesity and sarcopenia.

In some embodiments, the subject has diabetes combined with obesity, hyperinsulinemia and sarcopenia.

On the other hand, the present invention provides a drug pack, wherein the drug pack contains drug compositions in independent sub-packages, wherein one sub-package contains the first drug composition of the present invention, and the second sub-package contains the second drug composition of the present invention.

As used herein, the terms "disease" and "disorder" are used interchangeably herein.

As used herein, the term "treatment" refers to therapeutic therapy. With respect to a specific condition, treatment means: (1) alleviating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade that leads to or causes the condition or (b) one or more biological manifestations of the condition, (3) ameliorating one or more symptoms, effects, or side effects associated with the condition, or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing the progression of the condition or one or more biological manifestations of the condition.

The term "therapeutically effective amount" as used herein refers to an amount of a compound that is sufficient to effectively treat a disease or condition described herein when administered to a subject. The amount of a compound that constitutes a "therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the subject to be treated, but can be adjusted as needed by one of ordinary skill in the art to which the present invention pertains.

The term "pharmaceutical package" as used herein refers to any container and closure suitable for storing, transporting, dispensing and/or handling pharmaceuticals, such as packaging bags, packaging boxes, packaging bottles.

The term "pharmaceutical composition" used herein refers to a composition containing specified active ingredients that can be prepared into the same dosage form.

The term "subject" as used herein refers to any animal that will or has been administered the compound or composition according to the embodiments of the present invention, preferably a mammal, and most preferably a human. As used herein, the term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being the most preferred.

The term "pharmaceutical excipients" used herein refers to excipients and additives used in the production of drugs and the preparation of prescriptions, and is all substances contained in drug preparations other than active ingredients. See the Pharmacopoeia of the People's Republic of China (2015 Edition) Part IV or the Hand book of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).

The term "pharmaceutically acceptable" as used herein means that the acid or base (used in the preparation of salts), solvents, excipients, etc. are generally non-toxic, safe, and suitable for use by patients. The "patient" is preferably a mammal, more preferably a human.

The term "pharmaceutically acceptable salt" as used herein refers to a salt prepared from a compound with a relatively nontoxic, pharmaceutically acceptable acid or base. When the compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting a neutral form of such compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. When the compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting a neutral form of such compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent. The pharmaceutically acceptable acid includes an inorganic acid, which can be converted into a base addition salt or an acid addition salt when the compound contains relatively acidic and relatively basic functional groups. For details, see Bergeet 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).

The "berberine ursodeoxycholate", "SGLT2 inhibitor" and "pharmaceutically acceptable salt" described herein may exist in an amorphous or crystalline form. The term "amorphous" means that the ions or molecules therein are in a disordered distribution state, that is, there is no periodic arrangement regularity between the ions and molecules. The term "crystalline form" means that the ions or molecules therein are arranged in a strict periodic manner in three-dimensional space in a certain manner, and have a regularity of periodic repetition at a certain interval; due to the differences in the above periodic arrangements, there may be multiple crystal forms, that is, the polymorphic phenomenon.

The "berberine ursodeoxycholate" described herein exists in the form of its free salt, hydrate or other solvent complexes.

The "SGLT2 inhibitor" mentioned herein exists in its free form, hydrate or other solvate form.

The "pharmaceutically acceptable salt of SGLT2 inhibitor" described herein exists in the form of its free salt, hydrate or other solvent complex.

The "berberine" described herein exists in its free form, hydrate or other solvent form.

The "ursodeoxycholic acid" described herein exists in its free form, hydrate or other solvent form.

The positive and advanced effects of the present invention include but are not limited to: Compared with the prior art, the positive and advanced effects of the present invention are: the present invention provides a new drug combination or drug combination, in particular, provides a drug combination or drug combination of berberine ursodeoxycholate and SGLT2 inhibitor, the drug combination or drug combination provided by the present invention has a synergistic effect in one or more aspects of the effects of lowering blood sugar, reducing weight, and improving insulin sensitivity, and can effectively treat, alleviate or prevent one or more of the following diseases and conditions, including: diabetes, prediabetes, glucagonism, obesity, etc.

The invention is further described in other and/or alternative aspects and embodiments.

On the other hand, the present invention also relates to a pharmaceutical composition comprising: (a) berberine ursodeoxycholate (BUDC); and, (b) an SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof; and, (c) a pharmaceutical excipient.

In some embodiments, the SGLT2 inhibitor is selected from at least one of empagliflozin, dapagliflozin, canagliflozin, ertogliflozin, hengagliflozin, ipragliflozin, toragliflozin, sogliaflozin, rugliflozin, janagliflozin, bexagliflozin, rongagliflozin, enavogliflozin and JT-001.

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 ertogliflozin.

In another aspect, the present invention also relates to a unit dosage form comprising the pharmaceutical composition.

On the other hand, the present invention also relates to a unit dosage form, which comprises: (a) berberine ursodeoxycholate (BUDC); and, (b) SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof; wherein (a) and (b) are respectively disposed in different parts of the unit dosage form.

In some embodiments, in the pharmaceutical composition or unit dosage form, (a) and (b) are provided in a substance molar ratio of 5:1 to 15:1.

In some embodiments, BUDC is provided in the pharmaceutical composition or unit dosage form in the form of a free salt.

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

In some embodiments, in the pharmaceutical composition or unit dosage form, BUDC is provided in an amorphous form.

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

In some embodiments, in the pharmaceutical composition or unit dosage form, the crystalline form is crystalline form A of BUDC, and the crystalline form A of berberine ursodeoxycholate has X-ray powder diffraction (XRPD) expressed in 2θ angles, and has diffraction peaks at 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 ^° , wherein the crystalline form A of BUDC has the structural formula:

In some embodiments, in the pharmaceutical composition or unit dosage form, the crystalline form is Form D of BUDC, and the Form D of berberine ursodeoxycholate has X-ray powder diffraction (XRPD) expressed in 2θ angles, and has diffraction peaks at 4.24± ^0.2o , 6.79± ^0.2o , 8.50± ^0.2o , 10.25±0.2o, 11.50± ^{0.2o ,} 13.62± ^0.2o , 14.74± ^0.2o , 15.20±0.2o ^, 17.92± ^0.2o , 18.39± ^0.2o , 22.91± ^0.2o and 25.73± ^0.2o .

On the other hand, the present invention also relates to a drug package comprising: a first drug composition comprising (a) berberine ursodeoxycholate (BUDC), and a first pharmaceutical excipient; and, a second drug composition comprising (b) an SGLT2 inhibitor or a pharmaceutically acceptable salt thereof, and a second pharmaceutical excipient.

In some embodiments, in the drug pack, the first drug composition is provided in the form of a first unit oral dosage form; and/or the second drug composition is provided in the form of a second unit oral dosage form.

In some embodiments, the SGLT2 inhibitor is selected from at least one of empagliflozin, dapagliflozin, canagliflozin, ertogliflozin, hengagliflozin, ipragliflozin, toragliflozin, sogliaflozin, rugliflozin, janagliflozin, bexagliflozin, rongagliflozin, enavogliflozin and JT-001.

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 ertogliflozin.

In some embodiments, in the pharmaceutical package, (a) and (b) are provided in a substance amount ratio of 5:1 to 15:1.

In some embodiments, BUDC is provided in the pharmaceutical composition or unit dosage form in the form of a free salt.

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

In some embodiments, in the pharmaceutical composition or unit dosage form, BUDC is provided in an amorphous form.

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

In some embodiments, in the pharmaceutical composition or unit dosage form, the crystalline form is crystalline form A of BUDC, and the crystalline form A of BUDC has diffraction peaks at 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 ^° in X-ray powder diffraction (XRPD) at 2θ angles, wherein the crystalline form A of BUDC has the structural formula:

In some embodiments, in the pharmaceutical composition or unit dosage form, the crystalline form is Form D of BUDC, and the Form D of BUDC has X-ray powder diffraction expressed as 2θ angles, and has diffraction peaks at 4.24± 0.2 ^o , 6.79± 0.2 ^o , 8.50± 0.2 ^o , 10.25± 0.2 ^o , 11.50± 0.2 ^o , 13.62± 0.2 ^o , 14.74± 0.2 ^o , 15.20± 0.2 ^o , 17.92± 0.2 ^o , 18.39± 0.2 ^o , 22.91± 0.2 ^o and 25.73± 0.2 ^o .

In another aspect, the present invention also provides use of the pharmaceutical composition, unit dosage form or pharmaceutical pack described herein for preventing and/or treating metabolic diseases or disorders.

In some embodiments of the use, the metabolic disease or disorder is diabetes and/or obesity.

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

In some embodiments, the metabolic disease is prediabetes.

In some embodiments, the metabolic disease is hyperinsulinemia or a metabolic syndrome associated with hyperinsulinemia.

In another aspect, the present invention also provides use of the pharmaceutical composition, unit dosage form or pharmaceutical pack described herein for preventing and/or treating sarcopenia.

In another aspect, the present invention also provides a method for treating a metabolic disease, comprising administering a therapeutically effective amount of the pharmaceutical composition, unit dosage form or pharmaceutical pack described herein to a subject in need thereof.

In another aspect, the present invention also provides a method for treating sarcopenia, comprising administering a therapeutically effective amount of the pharmaceutical composition, unit dosage form or pharmaceutical pack described herein to a subject in need thereof.

On the other hand, the present invention also relates to a pharmaceutical composition comprising: (i) berberine (BBR) or a pharmaceutically acceptable salt thereof; (ii) ursodeoxycholic acid (UDCA) or a pharmaceutically acceptable salt thereof; (iii) an SGLT2 inhibitor or a pharmaceutically acceptable salt thereof; and, a pharmaceutical excipient.

In some embodiments, BBR is berberine hydrochloride.

In some embodiments, UDCA is provided in the form of the free acid.

In some embodiments, the molar ratio of (i), (ii) and (iii) is: (i): (ii) is 5:1-1:2, (ii): (iii) is 30:1-5:1.

In another aspect, the present invention also relates to a unit dosage form comprising the pharmaceutical composition.

On the other hand, the present invention also relates to a unit dosage form, which comprises: (a) berberine (BBR) or a pharmaceutically acceptable salt thereof; (b) ursodeoxycholic acid (UDCA) or a pharmaceutically acceptable salt thereof; and (c) SGLT2 inhibitor or a pharmaceutically acceptable salt thereof; wherein at least one of (a), (b) and (c) is disposed in a different part of the unit dosage form from the other two.

On the other hand, the present invention also relates to a drug package comprising: a first drug composition comprising (a) berberine (BBR) or a pharmaceutically acceptable salt thereof, and a first pharmaceutical excipient; a second drug composition comprising (b) ursodeoxycholic acid (UDCA) or a pharmaceutically acceptable salt thereof, and a second pharmaceutical excipient; and, a third drug composition comprising (c) an SGLT2 inhibitor or a pharmaceutically acceptable salt thereof, and a third pharmaceutical excipient.

On the other hand, the present invention also relates to a pharmaceutical composition comprising: (A) ursodeoxycholic acid (UDCA); (B) SGLT2 inhibitor or a pharmaceutically acceptable salt thereof; and pharmaceutical excipients.

In some embodiments, (A) and (B) are provided in a substance molar ratio of 20:1 to 1:20.

In another aspect, the present invention also provides use of the pharmaceutical composition, unit dosage form or pharmaceutical pack described herein for preventing and/or treating metabolic diseases or disorders.

In some embodiments, the metabolic disease or disorder is diabetes and/or obesity.

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

In some embodiments, the metabolic disease is prediabetes.

In some embodiments, the metabolic disease is hyperinsulinemia or a metabolic syndrome associated with hyperinsulinemia.

In another aspect, the present invention also provides use of the pharmaceutical composition, unit dosage form or pharmaceutical pack described herein for preventing and/or treating sarcopenia.

In another aspect, the present invention also provides a method for treating a metabolic disease, comprising administering a therapeutically effective amount of the pharmaceutical composition, unit dosage form or pharmaceutical pack described herein to a subject in need thereof.

In another aspect, the present invention also provides a method for treating sarcopenia, comprising administering a therapeutically effective amount of the pharmaceutical composition, unit dosage form or pharmaceutical pack described herein to a subject in need thereof.

The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods without specific conditions in the following examples are carried out according to conventional methods and conditions, or selected according to the product instructions.

Abbreviation description: 0.5% CMC-Na refers to an aqueous solution of sodium carboxymethyl cellulose 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%.

Experimental Materials Table 1 Name Berberine Ursodeoxycholate HTD1801 Empagliflozin Dapagliflozin Semaglutide Manufacturer/Supplier Shenzhen Junshengtai Biotechnology Co., Ltd. MCE MCE MCE Batch No. CN210403 152451 134159 80864 Characteristics Yellow powder powder powder powder Specifications 70.0658 g/pack 200mg/bottle 500mg/tube 1mg/bottle Storage conditions Sealed, light-proof, stored at room temperature -80℃ 2-8℃ -80℃ Expiration date or re-inspection date 2024-04-30 2025-08-01 2025-01-28 2024-04-30

HTD1801 starting material is provided in the form of its 4.5-hydrate crystalline form A as shown below. The X-ray powder diffraction (XRPD) pattern of crystalline form A collected under Cu Kα radiation (λ1 = 1.540598 Å, λ2 = 1.544426 Å, density ratio λ2/λ1 = 0.50) includes the following combination of characteristic peaks at 2θ diffraction angles: 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, 17.53, 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 ^o (± 0.2 ^o ), Cu Kα radiation (λ1 = 1.540598 Å, λ2 = 1.544426 Å, density ratio λ2/λ1 = 0.50).

Example 1. Combination of berberine ursodeoxycholate and empagliflozin

Experimental methods

The information about the formulation and preparation can be found in Table 2. Table 2. Information about the preparation and its configuration Pharmaceutical preparations Drug concentration (mg/mL) Preparation method Physical and chemical properties Preparation frequency 1 HTD1801 30 0.5% CMC-Na dilution Suspension Once a day 2 Empagliflozin 1.5 0.5% Hydroxyethylcellulose dilution Suspension Once a day 3 Semaglutide 0.8 1.4% propylene glycol in phosphate buffer (pH=7.4) dilution Solution Once every 3 days

After 1 week of adaptive feeding, 5-week-old C57BL/6J male mice were weighed and randomly divided into control group and model group based on body weight. Among them, 12 mice in the control group were fed with ordinary feed (CD), and the remaining mice in the model group were fed with 60% high-fat feed (60% HFD) for 10-12 weeks to construct the DIO obesity model, with an average body weight of more than 40g. The mice fed with 60% HFD were grasped and solvent-adapted for 3 days, and the solvent adaptation was uniformly performed by oral gavage of 0.5% CMC-Na, twice a day. The food intake, body weight, body fat ratio, insulin level and fasting blood glucose of mice were measured respectively. The mice were randomly divided into groups according to Table 3 based on body weight. The remaining mice in each group were euthanized. After grouping, the mice in each group were given drugs according to Table 3. The day of drug administration was defined as D0. The drug volume of each drug was calculated according to 5 μL/g × mouse weight (g). For the combined drug administration group, the total drug volume was the sum of the drug volumes of the two single drugs. The drug administration sequence and time were kept consistent at each drug administration. The mice were fed with high-fat feed during the drug administration period until the end of the drug administration. During the medication period, food intake was measured twice a week (the difference in feed weight between 24 hours was weighed); the body weight of mice in each group was weighed once a day; blood glucose was tested once a week after meal; fasting blood glucose was tested once on the 6th and 20th days by sampling blood from the tip of the tail (from 8:00 am to 2:00 pm); on the 25th day of medication, body fat ratio and muscle content of mice in each group were tested (the testing time period was consistent with the testing time period before grouping); 4 weeks after medication intervention (Day 28), mice fasted for 6 hours and OGTT (0 min, 15 min, 30 min, 60 min, 90 min, 120 min) was performed to test blood glucose in mice, and blood was sampled from the submandibular vein of the above-mentioned mice (0 min, 15 min, 30 min, about 30 min each time). μL), separated plasma>10μL, used for ELISA to detect insulin levels; set the day after the end of drug administration (D29) as the end point of the experiment, fasted for 6 hours in the morning, and performed fasting blood glucose test; then euthanized the mice with CO ₂ , cardiac blood sampling and analysis, and performed dissection operations on mice in each group, collected liver and subcutaneous, epididymal and mesenteric fat, and took photos and weighed them respectively. Table 3. Groups and drug administration scheme of Example 1 Group Animals Feed Processing Group Dosage Route of administration Frequency cycle G1 8 CD - - - - G2 8 60% HFD 0.5% CMC-Na - Oral gavage QD×4 weeks (Give medicine in the morning) G3 8 60% HFD HTD1801 300 mpk Oral gavage QD×4 weeks (Give medicine in the morning) G4 8 60% HFD Empagliflozin 15 mpk Oral gavage QD×4 weeks (Give medicine in the morning) G5 8 60% HFD HTD1801 300 mpk Oral gavage QD×4 weeks (Give medicine in the morning) Empagliflozin 15 mpk Oral gavage QD×4 weeks (Give medicine in the morning) G6 8 60% HFD Semaglutide 10 nmol/kg Subcutaneous injection Q3D×4 weeks

Note: 1) QD: once a day; BID: twice a day; Q3D: once every three days. 2) After completing 2 weeks of dosing according to Table 3, the dosage of HTD1801 in the G3 and G5 groups for the next 2 weeks was adjusted to 200 mpk; the dosage of empagliflozin in the G4 and G5 groups for the next 2 weeks was adjusted to 10 mpk.

The experimental results of Example 1 are as follows:

1. Model evaluation:

The results of measuring the body fat content of model mice and normal mice before group administration are shown in Figure 1. The body fat content of model mice was significantly higher than that of normal mice, indicating that the obesity model was successfully prepared.

2. Weight change results

The results of the weight changes of animals in groups G1 to G6 over time are shown in Table 4 and Figures 2 and 3. Table 4. Weight change results of Example 1 (weight: mean, unit: g) G1 G2 G3 G4 G5 G6 Day Weight Rate of change Weight Rate of change Weight Rate of change Weight Rate of change Weight Rate of change Weight Rate of change 0 31.5 0.0% 43.3 0.0% 43.6 0.0% 42.9 0.0% 42.9 0.0% 43.1 0.0% 1 31.7 0.5% 43.2 -0.2% 42.9 -1.6% 42.8 -0.2% 42.4 -1.0% 40.9 -5.2% 2 31.9 1.1% 43.2 -0.2% 43.1 -1.2% 42.9 0.1% 42.0 -1.9% 40.8 -5.4% 3 32.1 1.9% 42.9 -0.8% 42.3 -3.0% 42.8 -0.1% 41.3 -3.6% 42.3 -1.9% 4 32.2 2.1% 42.8 -1.1% 42.3 -2.9% 42.9 0.0% 41.0 -4.5% 40.6 -5.8% 5 32.1 1.8% 43.1 -0.5% 42.5 -2.6% 43.0 0.4% 40.7 -5.1% 41.1 -4.6% 6 31.9 1.2% 42.8 -1.0% 42.0 -3.8% 42.9 0.1% 40.5 -5.7% 41.7 -3.4% 7 32.0 1.4% 42.5 -1.8% 41.5 -4.9% 42.6 -0.5% 39.8 -7.3% 39.8 -7.7% 8 31.9 1.3% 42.7 -1.4% 40.8 -6.2% 42.7 -0.4% 39.0 -9.1% 40.5 -6.0% 9 32.0 1.4% 42.9 -0.8% 40.7 -6.6% 43.1 0.5% 38.5 -10.5% 41.5 -3.6% 10 31.9 1.3% 43.1 -0.3% 40.7 -6.5% 43.2 0.8% 38.3 -10.8% 39.6 -8.1% 11 32.0 1.4% 43.5 0.6% 40.6 -6.8% 43.3 1.1% 37.9 -11.9% 39.9 -7.4% 12 31.9 1.1% 43.9 1.4% 40.8 -6.3% 43.7 1.9% 37.9 -11.9% 40.8 -5.4% 13 31.9 1.3% 43.7 0.9% 40.4 -7.1% 43.6 1.8% 37.1 -13.5% 39.3 -8.7% 14 32.2 2.1% 43.8 1.1% 39.7 -8.7% 43.7 2.0% 36.6 -14.7% 39.6 -8.1% 15 31.7 0.7% 43.8 1.1% 39.5 -9.0% 43.5 1.5% 36.7 -14.5% 40.4 -6.3% 16 31.9 1.3% 43.8 1.2% 39.6 -8.8% 43.8 2.3% 36.8 -14.3% 39.0 -9.7% 17 32.0 1.3% 43.9 1.4% 39.4 -9.3% 44.1 2.9% 36.8 -14.2% 39.5 -8.4% 18 32.1 1.8% 44.3 2.4% 38.9 -10.3% 44.5 3.9% 37.0 -13.8% 40.7 -5.6% 19 31.8 1.0% 44.5 2.9% 38.9 -10.3% 44.8 4.4% 36.6 -14.8% 39.1 -9.4% 20 31.7 0.4% 44.7 3.3% 39.2 -8.4% 45.1 5.2% 36.8 -14.2% 39.6 -8.3% twenty one 32.2 2.0% 45.2 4.5% 39.5 -7.8% 45.5 6.2% 36.8 -14.4% 40.5 -6.1% twenty two 32.0 1.7% 45.4 5.0% 39.7 -7.2% 46.0 7.3% 36.8 -14.3% 39.1 -9.4% twenty three 32.2 2.3% 46.3 6.9% 40.2 -6.0% 46.4 8.3% 36.8 -14.3% 40.0 -7.3% twenty four 32.4 2.8% 46.3 6.9% 40.5 -5.4% 46.5 8.5% 36.4 -15.1% 40.6 -5.8% 25 32.3 2.4% 46.1 6.5% 40.7 -4.8% 46.5 8.4% 36.4 -15.4% 39.5 -8.4% 26 32.0 1.5% 46.0 6.3% 40.1 -6.5% 46.3 8.1% 36.3 -15.6% 40.0 -7.9% 27 32.0 1.5% 46.0 6.3% 40.2 -6.2% 46.7 8.9% 36.8 -14.5% 41.0 -5.4% 28 32.1 1.9% 46.2 6.8% 39.5 -7.9% 46.5 8.4% 36.4 -15.2% 39.4 -9.2%

Within 14 days, the body weight of the normal control group remained basically unchanged, while under continuous high-fat diet feeding, the body weight of the model control group G2 decreased slightly in the first week and then increased slowly. The body weight of the empagliflozin group G4 remained basically unchanged in the first week, and then increased slowly, and the growth trend was basically consistent with that of the model control group G2; the body weight of the semaglutide group G6 decreased significantly in the initial stage of drug administration, and then decreased slowly and tended to stabilize. The weight of the HTD1801 group G3 and the combined drug administration (HTD1801 + empagliflozin) group G5 continued to decrease over time, and the effect was significant. In particular, when the weight change trend of the animals in the empagliflozin monotherapy group and the model group was consistent, the weight loss of the G5 group was unexpectedly significantly better than that of the other groups, which was nearly twice the weight loss caused by HTD1801 alone. This result shows that in the obese mouse model fed with a continuous high-fat diet, although empagliflozin cannot achieve the effect of weight loss alone, it can produce a synergistic effect when used together with HTD1801, significantly improving the overall weight loss effect, and the weight loss effect of oral administration is better than that of semaglutide injection, a hypoglycemic and weight loss drug currently widely used in clinical practice.

After 14 days, the weight of the normal control group continued to be maintained, the weight of the model control group and the reduced-dose empagliflozin group increased slowly, and the weight of the semaglutide group was maintained steadily, all maintaining the trend of the second week. With the reduction of the HTD1801 dosage, the weight of the HTD1801 group rebounded slightly, while the weight loss effect of G5 (HTD1801 + empagliflozin) continued to be maintained and showed a further downward trend. It can be seen that in this trial, the combination of HTD1801 and empagliflozin not only has a synergistic weight loss effect, but also can further reduce the dosage of HTD1801 without causing weight rebound while maintaining the synergistic weight loss effect.

3. Body fat content measurement results

After 25 days of drug administration, the body weight, body fat content and body fat percentage of each animal in groups G1 to G6 were measured, and the average values were taken for each group. The results are shown in Table 5 and Figures 4 and 5. Table 5. Body fat content of mice after 25 days of drug administration in Example 1 Mean Weight (g) Fat (g) Body fat percentage (%) G1 32.22 5.71 17.69% G2 46.55 21.76 46.51% G3 40.10 16.23 40.12% G4 47.53 23.36 49.13% G5 35.02 12.30 34.63% G6 38.73 14.74 36.99%

The results show that 25 days after medication, the body fat content and body fat ratio of the G4 (empagliflozin) group increased compared with the G2 control group, while the body fat content and body fat ratio of the G3 (HTD1801) group, the G5 (HTD1801+empagliflozin) group and the G6 (semaglutide) group all decreased. Among them, the results of the G5 group were better than those of the other groups. It can be seen that in this embodiment, the combination of HTD1801 and empagliflozin is not a simple offset or superposition of the effects of the two, but a synergistic effect.

4. Results of liver, viscera and subcutaneous fat weight

After 28 days of drug administration, the mice were euthanized by CO ₂ on the next day, and the mice in groups G1 to G5 were dissected to collect the liver, abdominal fat (including epididymis and mesentery), and subcutaneous fat. The fat was photographed and weighed. The results are shown in Table 6, Figure 6, Figure 7 and Figure 8. Table 6. Results of fat weight of various tissues and organs of mice after 28 days of drug administration in Example 1 Mean Liver (g) Subcutaneous fat (g) Epididymal fat (g) Mesenteric fat (g) G1 1.14 0.55 0.90 0.31 G2 1.47 3.21 2.51 1.24 G3 0.98 2.32 2.31 0.78 G4 1.34 3.02 2.82 1.20 G5 0.97 1.85 1.81 0.63

The results show that in the trial, the combination of HTD1801 and empagliflozin can significantly reduce the content of body fat. In particular, the combination of the two can maintain the effect of HTD1801 in reducing liver fat, and additionally and significantly reduce the content of abdominal and subcutaneous fat, which has a beneficial synergistic effect.

5. Results of changes in muscle mass

After 25 days of drug administration, the body weight, muscle weight and specific gravity of each animal in groups G1 to G5 were measured, and the average values were taken for each group. The results are shown in Table 7 and Figures 9 and 10. Table 7. Results of muscle content of mice after 25 days of drug administration in Example 1 Mean Weight (g) Muscle (g) Muscle percentage (%) G1 32.22 13.56 42.14% G2 46.55 6.06 13.20% G3 40.10 7.50 19.02% G4 47.53 5.17 10.92% G5 35.02 8.41 24.60%

The muscle content of mice in the G3 (HTD1801) group increased compared with the G2 model control group, and the muscle content of mice in the G4 (Empagliflozin) group decreased compared with the G2 model control group. When the two were used together, the muscle content of mice in the G3 (HTD1801+Empagliflozin) group did not offset the opposite effects of the two single drugs, but increased further. It can be seen that in this obese mouse model, the combination of HTD1801 and Empagliflozin can synergistically increase muscle content or weight.

6. Fasting blood sugar results

After 20 days of drug administration, the fasting blood glucose of each group of animals was measured and the results are shown in Table 8 and Figure 11. Table 8. Average fasting blood glucose (mmol/L) measured on the 6th and 20th days of Example 1 G1 G2 G3 G4 G5 G6 Day 6 6.8 8.8 7.9 7.8 7.1 6.2 Day 20 6.8 9.4 8.4 7.9 6.2 8.9

The blood sugar levels of all the G3-G6 groups decreased to varying degrees on the 6th and 20th days. Although the blood sugar level of the G6 group (semaglutide) decreased most significantly on the 6th day, it rebounded on the 20th day. The blood sugar level of the G5 (HTD1801+empagliflozin) group continued to decrease. By the 20th day, the blood sugar reduction rate had exceeded that of the semaglutide group, and the degree of reduction was better than the sum of the blood sugar-lowering levels of each drug alone, that is, a synergistic effect of 1+1>2 was achieved.

7. Glucose tolerance OGTT test results

The mean blood glucose values of each group in the OGTT test on the 28th day after drug administration are shown in Table 9 below. The blood glucose-time relationship curve and the area under the blood glucose-time curve AUC (i.e., the total blood glucose increase) calculated therefrom are shown in Figures 12 and 13, respectively. Table 9. OGTT blood glucose (mmol/L) results of mice on D28 in Example 1 0 min 15 min 30 min 60 min 90 min 120min G1 6.95 17.00 17.02 15.00 14.68 14.18 G2 9.75 22.25 23.80 25.05 24.08 21.18 G3 10.65 19.88 20.04 23.48 19.88 22.22 G4 10.97 19.60 18.90 18.18 14.54 15.48 G5 8.22 15.03 17.13 15.73 11.65 13.75 G6 7.50 18.25 16.42 13.78 12.47 10.25

It showed that compared with the model control group G2, the total blood sugar increase in each medication group decreased, among which the levels of decrease in the G4 (empagliflozin), G5 (HTD1801+empagliflozin), and G6 (semaglutide) groups were comparable.

In the OGTT test, the fasting insulin results during the efficacy period are shown in Table 10 below, and the insulin-time relationship curve and the area under the curve calculated therefrom (i.e., the total insulin level) are shown in Figures 14 and 15, respectively. Table 10. OGTT fasting insulin results for mice at D28 of Example 1 (unit: mmol/L) 0min 15min 30min G1 1.99 7.18 4.49 G2 7.83 17.26 16.87 G3 4.78 9.17 7.55 G4 5.11 9.10 8.73 G5 2.12 4.76 4.24 G6 1.63 9.81 5.39

It showed that the peak insulin level and total insulin level of mice in each drug-treated group were significantly decreased compared with the control group. Among them, the peak insulin level in the G5 (HTD1801+empagliflozin) group was the lowest, and the decrease in total insulin level was also the most significant, showing a synergistic effect.

The results of the OGTT test show that G5 (HTD1801 + empagliflozin) not only has a relatively lower total blood sugar level, but also has significantly lower peak insulin levels and total insulin levels in groups with equivalent total blood sugar levels, which is better than any single drug group, including the semaglutide injection group, a hypoglycemic and weight loss drug currently widely used in clinical practice. This shows that the combination of the two can synergistically improve insulin sensitivity, thereby reducing insulin secretion, and has the potential to improve pancreatic islet cell function, correct hyperinsulinemia, and be used in the treatment of early diabetes (i.e., prediabetes or prodiabetes). It is worth mentioning that reducing hyperinsulinemia can also further bring many benefits to the treatment of obesity and type 2 diabetes, which also suggests that the HTD1801+empagliflozin drug combination has huge clinical benefit potential beyond expectations.

8. Changes in food intake during the 24-hour efficacy period

The changes in 24-hour food intake of animals in each group during the medication period are shown in Figure 16, among which the food intake of the G4 (Empagliflozin) group was equivalent to that of the model control group, while the food intake of the G3 (HTD1801) and G5 (HTD1801+Empagliflozin) groups was equivalent and lower than that of the model control group.

Example 2. Combination of berberine ursodeoxycholate and dapagliflozin

2.1 Grouping, dosage and administration information are shown in Table 11 below. Table 11 Group Processing Group Dosage Initial drug concentration (mg/mL) Initial solvent preparation Pre-use treatment Physical and chemical properties Frequency G1 - - - - - - - G2 0.5% CMC-Na - - - - Solution G3 Semaglutide 10 nmol/kg 0.8 1.4% propylene glycol phosphate buffer (pH=7.4) without Solution Every 3 days G4 HTD1801 250 mpk 100 0.5% CMC-Na 0.5% CMC-Na diluted once Suspension Once a day G5 Dapagliflozin 10 mpk 4 0.5% HEC 0.5% HEC diluted once Suspension Once a day G6 Empagliflozin 15 mpk 6 0.5% HEC 0.5% HEC diluted once Suspension Once a day G7 Dapagliflozin 10 mpk 4 0.5% HEC Equal volume mixing Suspension Once a day HTD1801 250 mpk 100 0.5% CMC-Na G8 Empagliflozin 15 mpk 6 0.5% HEC Equal volume mixing Suspension Once a day HTD1801 250 mpk 100 0.5% CMC-Na

2.2 Experimental Methods

After 1 week of adaptive feeding, 5-6-week-old C57BL/6J male mice were weighed and randomly divided into control group and model group based on body weight. Among them, 12 mice in the control group were fed with ordinary feed (CD), and the remaining mice in the model group were fed with 60% high-fat feed (60% HFD) for 10-12 weeks to construct the DIO obesity model, with an average body weight of more than 40g. The mice fed with 60% HFD were grasped and solvent-adapted for 3 days, and the solvent adaptation was uniformly performed by oral gavage of 0.5% CMC-Na, once a day. The food intake, body weight, body fat ratio, insulin level and fasting blood glucose of mice were tested respectively. The mice were randomly divided into groups according to Table 12 based on body weight. The remaining mice in each group were euthanized. After grouping, the mice in each group were given drugs according to Table 12. The day of drug administration was defined as D0. The drug volume of each group was calculated according to 5 μL/g × mouse weight (g). For the combined drug administration group, the drug administration sequence and drug administration time between groups were kept consistent at each drug administration. During the drug administration period, the mice were fed with high-fat feed until the end of drug administration. During the medication period, food intake was measured once a week (the difference in feed weight between 24 hours was weighed); the body weight of mice in each group was weighed once a day; fasting blood glucose was tested once at the tip of the tail on the 16th and 30th days (fasting from 9:00 am to 3:00 pm); on the 24th day of medication (D23), body fat ratio and muscle content of mice in each group were tested (the testing time period was consistent with the testing time period before grouping); 25 days after medication intervention (Day24), fasting for 6 hours, OGTT (0 min, 15 min, 30 min, 60 min, 90 min, 120 min) was performed to test blood glucose of mice; 29 days after medication intervention (Day28), fasting for 6 hours, OGTT (0 min, 15 min, 30 min, 60 min, 90 min, 120 min) was performed min) and blood was collected from the submandibular vein of the mice in the above groups (0 min, 15 min, 30 min, about 30 μL each time), and plasma>10 μL was separated for ELISA to detect insulin levels; the day after the end of drug administration (D30) was set as the end point of the experiment, and fasting blood glucose was tested for 6 h in the morning; then the mice were euthanized by CO2, and blood was collected from the heart for analysis. The mice in each group were dissected, and the liver and subcutaneous, epididymal and mesenteric fat were collected, and photographed and weighed. Table 12. Groups and drug administration schemes of Example 2 Group Number of animals strain Processing Group Daily dosage Route of administration G1 8 C57BL/6J CD - - G2 8 DIO 0.5%CMC-Na - po G3 8 DIO Semaglutide 10 nmol/kg sc G4 8 DIO HTD1801 250 mpk po G5 8 DIO Dapagliflozin 10 mpk po G6 8 DIO Empagliflozin 15 mpk po G7 8 DIO Dapagliflozin 10 mpk po HTD1801 250 mpk G8 8 DIO Empagliflozin 15 mpk po HTD1801 250 mpk

Note: G: group; mpk: mg/kg; p.o.: oral administration; s.c.: subcutaneous injection.

2.3 The experimental results of Example 2 are as follows:

Model evaluation:

The weight and body fat content of the model mice and normal mice were measured before group administration, as shown in Figures 17 and 18. The weight of the model mice was higher than 40g, and the body fat content was significantly higher than that of normal mice, indicating that the obesity model was successfully prepared.

1) Weight change results

The weight (mean) and weight change rate of animals in groups G1 to G8 over time are shown in Table 13, Table 14 and Figures 19 and 20. Table 13. Weight measurement results of Example 2 (weight unit: g) DAY G1 G2 G3 G4 G5 G6 G7 G8 0 30.7 45.5 45.4 45.3 45.4 46.2 44.1 45.1 1 31.1 45.6 43.2 44.5 45.5 46.3 45.8 43.8 2 31.3 45.4 43.2 44.1 45.3 46.1 45.0 43.4 3 31.2 45.1 44.2 44.1 45.1 46.0 44.6 42.9 4 31.5 45.1 42.5 43.6 44.8 46.0 44.6 42.4 5 31.7 45.1 42.8 43.1 44.3 45.6 43.3 41.5 6 31.5 45.2 43.7 42.7 44.1 45.8 43.4 41.4 7 31.4 45.4 42.1 42.7 44.0 46.0 43.3 41.1 8 31.8 45.1 42.1 42.5 43.7 45.6 42.8 40.7 9 31.8 45.0 43.1 41.9 43.4 45.5 42.2 40.1 10 31.4 45.0 41.3 41.9 43.5 45.4 41.5 40.2 11 31.5 44.8 41.1 41.7 43.2 45.6 40.8 39.9 12 31.7 44.8 41.3 41.3 43.1 45.5 40.4 39.0 13 31.6 44.5 39.7 40.3 42.6 45.3 39.9 38.0 14 31.9 44.9 40.4 40.5 42.7 45.6 39.8 37.6 15 31.9 44.9 41.1 40.3 42.9 45.6 39.1 37.4 16 31.9 44.8 39.4 40.2 42.8 45.3 39.2 36.8 17 32.2 45.2 40.0 39.9 43.2 45.7 39.0 36.6 18 32.2 45.4 40.7 39.7 43.3 45.7 38.5 36.6 19 32.3 45.4 39.1 39.4 43.5 45.7 38.5 36.9 20 32.2 45.7 39.7 39.3 43.5 45.8 38.3 36.5 twenty one 32.2 45.8 40.9 39.1 43.9 46.0 37.6 36.2 twenty two 32.2 46.0 39.1 39.2 43.9 46.2 36.7 35.7 twenty three 32.7 46.2 39.5 38.9 43.8 46.1 37.0 35.6 twenty four 32.3 45.7 39.7 38.2 43.5 45.7 37.1 35.5 25 32.4 45.9 38.6 38.4 43.9 46.0 37.3 35.6 26 32.5 46.3 39.5 38.6 44.2 46.6 37.0 35.6 27 32.4 46.4 39.9 38.7 44.3 46.5 36.8 35.2 28 32.4 46.7 38.5 38.4 43.9 46.0 36.1 34.7 29 32.2 46.0 38.9 37.4 43.8 46.5 35.9 34.2 Table 14. Results of weight change rate of Example 2 DAY G1 G2 G3 G4 G5 G6 G7 G8 0 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 1 1.4% 0.2% -4.9% -1.6% 0.3% 0.4% 1.1% -3.0% 2 2.0% -0.3% -5.0% -2.5% -0.1% -0.2% -0.7% -3.9% 3 1.8% -0.8% -2.7% -2.5% -0.6% -0.3% -1.4% -5.1% 4 2.5% -0.8% -6.4% -3.7% -1.2% -0.5% -1.5% -6.0% 5 3.2% -0.9% -5.8% -4.9% -2.4% -1.3% -3.6% -8.2% 6 2.7% -0.5% -3.8% -5.7% -2.7% -0.8% -5.0% -8.3% 7 2.4% -0.2% -7.4% -5.7% -2.9% -0.4% -5.7% -9.0% 8 3.5% -0.8% -7.3% -6.2% -3.7% -1.2% -6.5% -9.8% 9 3.7% -1.2% -5.1% -7.5% -4.4% -1.5% -7.5% -11.2% 10 2.4% -1.0% -9.1% -7.4% -4.2% -1.7% -8.9% -11.0% 11 2.5% -1.4% -9.6% -7.9% -4.7% -1.2% -10.3% -11.7% 12 3.3% -1.4% -9.1% -8.7% -4.9% -1.6% -10.9% -13.6% 13 3.0% -2.1% -12.5% -10.9% -6.1% -1.9% -11.7% -15.9% 14 4.0% -1.2% -11.0% -10.7% -6.0% -1.3% -12.0% -16.8% 15 3.9% -1.3% -9.5% -11.1% -5.5% -1.4% -13.2% -17.0% 16 3.9% -1.4% -13.1% -11.2% -5.7% -1.9% -13.1% -18.4% 17 4.8% -0.7% -11.8% -11.8% -4.7% -1.1% -13.5% -18.9% 18 4.9% -0.1% -10.3% -12.3% -4.5% -1.0% -14.6% -18.8% 19 5.1% -0.1% -13.9% -12.8% -4.2% -1.2% -14.7% -18.2% 20 5.0% 0.5% -12.5% -13.2% -4.1% -0.8% -15.1% -19.1% twenty one 4.8% 0.8% -9.8% -13.5% -3.3% -0.4% -16.6% -19.8% twenty two 4.9% 1.2% -13.8% -13.4% -3.3% -0.1% -18.1% -20.8% twenty three 6.6% 1.6% -12.9% -14.0% -3.5% -0.1% -17.8% -21.2% twenty four 5.3% 0.6% -12.6% -15.6% -4.2% -1.1% -17.7% -21.3% 25 5.4% 1.0% -15.0% -15.1% -3.2% -0.4% -17.4% -21.0% 26 5.7% 2.0% -12.9% -14.6% -2.5% 0.9% -17.9% -21.0% 27 5.4% 2.2% -12.1% -14.5% -2.4% 0.7% -18.2% -22.0% 28 5.4% 2.8% -15.2% -15.1% -3.2% -0.4% -19.2% -23.1% 29 5.0% 1.1% -14.5% -17.4% -3.4% 0.8% -19.8% -24.2%

During the medication cycle, the G1 normal control group had a small base weight and a small increase. The G2 model control group and each medication group fed with high-fat feed had a large base weight. The G2 model control group had a stable weight and remained basically unchanged. The G3 semaglutide group had a significant decrease in weight at the beginning of medication, and then slowly decreased within the first two weeks of medication. After two weeks of medication, the weight gradually tended to be stable, with only a small downward trend. The overall weight loss of the G4 HTD1801 monotherapy group was close to that of the semaglutide group, but it continued to decrease evenly throughout the medication cycle.

The total weight of the G6 empagliflozin monotherapy group remained basically unchanged, similar to the G2 model control group. The weight changes in the first two weeks of medication were basically the same as those of the G2 model control group. After two weeks, the weight loss of the G6 empagliflozin monotherapy group was slightly higher than that of the G2 model control group. In the G8 empagliflozin and HTD1801 combination therapy group, the weight continued to decrease over time, and the effect was significant. The weight loss rate was significantly better than that of the other groups, and was about 6.8% higher than the weight loss caused by HTD1801 alone. That is, under the condition that the weight loss effect of empagliflozin alone was not obvious, the weight loss effect of empagliflozin and HTD1801 was better than about 2/5 of the efficacy of HTD1801 alone. The results show that in the obese mouse model fed with a continuous high-fat diet, although empagliflozin cannot achieve a weight loss effect alone, when used together with HTD1801, it can produce a synergistic effect and significantly improve the overall weight loss effect.

Similarly, compared with the G2 model control group, the G5 dapagliflozin monotherapy group had a reduced weight but the reduction was very limited, only 3.4%. The G7 dapagliflozin and HTD1801 combination group had a similar weight reduction in the first 9 days as HTD1801. Although the subsequent weight loss effect was not as good as the G8 empagliflozin and HTD1801 combination group, the reduction was relatively low, but still better than the HTD1801 monotherapy group, indicating that when the weight loss effect of SGLT2i drugs is limited, combined with HTD1801, a significant weight loss effect can be achieved. And from the later weight loss trend, the downward trend of the curve is more obvious, indicating a faster weight loss rate, and the later weight loss rate is even better than that of other groups, indicating that if the medication is continued for more than 28 days, the combination of G7 dapagliflozin and HTD1801 is expected to achieve better weight loss effects and show better synergy.

2) Body fat content measurement results

On DAY 23, the body weight, body fat content and body fat percentage of each animal in groups G1 to G8 were measured, and the average values were taken for each group. The results are shown in Table 15 and Figures 21 and 22. Table 15. Body fat content of mice after 23 days of drug administration in Example 2 Mean Weight (g) Fat (g) Body fat percentage G1 32.8 5.7 17.3% G2 46.0 21.2 46.0% G4 38.9 17.5 44.8% G5 43.8 21.4 48.8% G6 46.8 23.0 49.3% G7 36.1 13.8 37.5% G8 35.6 14.0 39.3%

The results show that after 23 days of medication, the body fat content and body fat ratio of the G5 (dapagliflozin) group and the G6 (empagliflozin) group increased compared with the G2 control group. The increase in the G5 (dapagliflozin) group was relatively greater, about 8.6% higher than the G2 control group, while the G4 (HTD1801) group, the G7 (HTD1801 + dapagliflozin) group and the G8 (HTD1801 + empagliflozin) group increased significantly. The body fat content and body fat of the HTD1801+Epagliflozin (TD1801+Epagliflozin) group were significantly reduced compared with the G2 control group. Among them, the results of the G8 group were better than those of the other groups. It can be seen that in this embodiment, the combination of HTD1801 and Epagliflozin is not a simple offset or superposition of the effects of the two, but a synergistic effect. The combination of HTD1801 and dapagliflozin also has a synergistic effect.

3) Muscle content measurement results

On DAY 23, the body weight, muscle weight and specific gravity of each animal in groups G1 to G8 were measured, and the average values were taken for each group. The results are shown in Table 16 and Figures 23 and 24. Table 16. Results of muscle content of mice 23 days after drug administration in Example 2 Mean Weight (g) Muscle (g) Muscle ratio G1 32.8 13.6 41.6% G2 46.0 5.5 11.9% G4 38.9 5.1 13.0% G5 43.8 4.3 9.9% G6 46.8 4.2 9.1% G7 36.1 7.9 21.9% G8 35.6 7.1 20.0%

The muscle percentage of mice in the G4 (HTD1801) group was slightly increased compared with the G2 model control group, and the muscle percentage of mice in the G5 (dapagliflozin) group and the G6 (englagliflozin) group was slightly decreased compared with the G2 model control group. When the two were used in combination, the muscle content of mice in the G7 (HTD1801+dapagliflozin) group and the G8 (HTD1801+englagliflozin) group did not offset the opposite effects of the two single drugs, but further increased, especially in the G8 (HTD1801+englagliflozin) group. It can be seen that in this obese mouse model, the combination of HTD1801 and englagliflozin or dapagliflozin can synergistically increase muscle content or proportion.

According to the examples of the present invention, the drug combination provided by the present invention can achieve a significant reduction in blood sugar levels through oral administration, and can also achieve an unexpected weight loss effect (the weight loss of the combination group is nearly twice that of the HTD1801 single-drug group). Whether it is blood sugar reduction or weight loss, it is significantly better than the berberine ursodeoxycholate and SGLT2 inhibitor (such as empagliflozin, etc.) single-drug group and semaglutide injection group; at the same time, the results of the examples show that the drug combination provided by the present invention can significantly improve insulin sensitivity, thereby reducing insulin secretion; in addition, the drug combination provided by the present invention also shows that while losing weight and reducing body fat content, it will not cause a decrease in muscle content, but can further increase muscle weight and specific gravity, and has the effect of preserving and increasing muscle. It is fully demonstrated that the drug combination or drug combination provided by the present invention has the potential to be used in the treatment of sarcopenia and obesity, and also has the potential to achieve consistent and synergistic benefits in improving multiple risk factors related to diabetes in the treatment of diabetes. It may not only be able to further improve blood sugar control and delay the progression of the disease, but also is expected to achieve the goal of safely and effectively improving or even reversing the occurrence of diabetes and its complications through comprehensive intervention in weight loss and insulin sensitivity, which has a breakthrough significance.

The applicant's disclosure is described herein with reference to the accompanying drawings in preferred embodiments, wherein like numbers represent the same or similar elements. References to "one embodiment" or "some embodiments" or similar language throughout the specification mean that the particular features, structures, or characteristics described in conjunction with the embodiment are included in at least one embodiment of the present invention. Therefore, the phrases "in one embodiment", "in some embodiments" and similar language appearing throughout the specification may, but do not necessarily, all refer to the same embodiment.

The features, structures or characteristics of the applicant's disclosure may be combined in one or more embodiments in any appropriate manner. In the description herein, many specific details are described to provide a thorough understanding of the embodiments of the present invention. However, a person skilled in the art will recognize that the 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 cases, well-known structures, materials or operations are not shown or described in detail to avoid obscuring aspects of the present disclosure.

As used herein, the terms “including,” “comprising,” “having,” and “having” when used to define compositions and methods, are intended to mean that the compositions and methods include the stated elements but not exclude other elements.

As used herein, the term "consisting of" when used to define compositions and methods shall mean excluding trace elements and essential method steps of other ingredients. Embodiments defined by each of these transitional terms are within the scope of protection of the present invention.

In this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

Unless the context clearly requires otherwise, the term "and/or" is used in the present invention to mean either "and" or "or".

As used herein, "at least" of a particular value is understood to mean that value and all values greater than that value.

Unless otherwise specified or obvious from the context, as used herein, the term "about" should be understood to be within the normal tolerance range in the art, such as within 2 standard deviations of the mean. About can be understood to be 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 the context clearly dictates otherwise, all numerical values provided herein can be modified by the term "about".

In the present description, variables or parameters are disclosed in groups or ranges. Specifically, the description shall include every subcombination of the members of these groups and ranges. For example, a range of 1 to 16 is understood to include any number, combination of numbers or subrange in the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the present invention belongs. Although any methods and materials similar or equivalent to the methods and materials described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are currently described. The methods described herein can be performed in any order that is logically possible, except for the specific order disclosed.

References

References and citations to other documents, such as patents, patent applications, patent publications, journals, books, papers, web content are throughout this disclosure. All of these documents are hereby incorporated by reference in their entirety for all purposes. Any material or portion thereof that is deemed to be incorporated by reference but conflicts with existing definitions, statements, or other public materials clearly set forth in this document is incorporated only to the extent that no conflict arises between the incorporated material and the material of this disclosure. In the event of a conflict, the conflict will be resolved in favor of this disclosure as the preferred disclosure.

Equivalent

The representative embodiments disclosed herein are intended to help illustrate the present invention and are not intended to, and should not be interpreted as, limiting the scope of the present invention. In fact, various modifications of the present invention and many other embodiments thereof, in addition to those shown and described herein, will become apparent to those of ordinary skill in the art to which the present invention belongs, based on the entire contents of this article, including the following embodiments cited herein and references to scientific and patent literature. The above-mentioned embodiments contain important additional information, illustrations, and guidance, which may be suitable for the practice of the present invention in its various embodiments and their equivalents.

without

Figure 1 shows the results of the body fat content of the G2 model group mice and the G1 normal group mice measured before drug administration in Example 1, wherein the data in the figure are expressed as mean ± error value, **** indicates p < 0.0001, vs G1, one-way ANOVA. Figure 2 shows the results of the weight change of each group of animals over time in Example 1, wherein the data in the figure are expressed as mean ± error value. Figure 3 shows the results of the weight change rate of each group of animals over time in Example 1, wherein the data in the figure are expressed as mean ± error value. Figure 4 shows the results of the body fat content of each group of animals measured 25 days after drug administration in Example 1, wherein the data in the figure are expressed as mean ± error value, **** indicates p < 0.0001, *** indicates p < 0.001, ** indicates p < 0.01, vs G2, one-way ANOVA. Figure 5 shows the results of body fat ratio of each group of animals measured 25 days after drug administration in Example 1, where the data in the figure are expressed as mean ± error value, **** indicates p < 0.0001, ** indicates p < 0.01, * indicates p < 0.05, vs G2, one-way ANOVA. Figure 6 shows the results of liver weight of each group of animals measured 28 days after drug administration in Example 1, where the data in the figure are expressed as mean ± error value, ** indicates p < 0.01, * indicates p < 0.05, vs G2, one-way ANOVA. Figure 7 shows the results of abdominal fat weight of each group of animals measured 28 days after drug administration in Example 1, where the data in the figure are expressed as mean ± error value, **** indicates p < 0.0001 vs G2, one-way ANOVA. Figure 8 shows the results of subcutaneous fat weight of each group of animals measured 28 days after drug administration in Example 1, where the data in the figure are expressed as mean ± error value, **** indicates p < 0.0001, ** indicates p < 0.01 vs G2, one-way ANOVA. Figure 9 shows the results of muscle mass of each group of animals measured 25 days after drug administration in Example 1, where the data in the figure are expressed as mean ± error value, **** indicates p < 0.0001 vs G2, one-way ANOVA. Figure 10 shows the results of muscle percentage of body weight of animals in each group measured 25 days after drug administration in Example 1, where the data in the figure are expressed as mean ± error value, **** indicates p < 0.0001, * indicates p < 0.05 vs G2, one-way ANOVA. Figure 11 shows the fasting blood glucose results of each group of animals measured 20 days after drug administration in Example 1, where the data in the figure are expressed as mean ± error value, **** indicates p < 0.0001, ** indicates p < 0.01, * indicates p < 0.05, vs G2, one-way ANOVA. Figure 12 shows the blood glucose changes of each group of animals measured over time in the OGTT test in Example 1, where the data in the figure are expressed as mean ± error value. Figure 13 shows the AUC analysis results of the blood glucose changes of each group of animals over time in the OGTT test in Example 1, where the data in the figure are expressed as mean ± error value, * indicates p < 0.05, vs G2, one-way ANOVA. Figure 14 shows the results of the fasting insulin changes over time measured by the OGTT test in Example 1, where the data in the figure are expressed as mean ± error values. Figure 15 shows the AUC analysis results of the fasting insulin level changes over time in each group of animals in the OGTT test in Example 1, where the data in the figure are expressed as mean ± error values, **** indicates p < 0.0001 vs G2, one-way ANOVA. Figure 16 shows the results of the 24h food intake changes of each group of animals in Example 1 during the medication period, where the data in the figure are expressed as mean ± error values. Figure 17 shows the weight results of the G2 model group mice and the G1 normal group mice measured before medication in Example 2, where the data in the figure are expressed as mean ± error values, G1: n = 10, G2: n = 73. Figure 18 shows the results of the body fat content of the G2 model group mice and the G1 normal group mice measured before drug administration in Example 2, wherein the data in the figure are expressed as mean ± error value, **** indicates p < 0.0001 vs G2, one-way analysis of variance. Figure 19 shows the results of the weight change of animals in each group over time in Example 2, wherein the data in the figure are expressed as mean ± error value, and the number of animals measured in each group is n = 8; but G4: n = 6, G6: n = 7, G8: n = 6. Figure 20 shows the results of the weight change rate of animals in each group over time in Example 2, wherein the data in the figure are expressed as mean ± error value, and the number of animals measured in each group is n = 8; but G4: n = 6, G6: n = 7, G7: n = 4, G8: n = 6. Figure 21 shows the results of body fat content of animals in each group measured 23 days after drug administration in Example 2, where the data in the figure are expressed as mean ± error value, **** indicates p < 0.0001, *** indicates p < 0.001 vs G2, one-way ANOVA. Figure 22 shows the results of body fat ratio of animals in each group measured 23 days after drug administration in Example 2, where the data in the figure are expressed as mean ± error value, **** indicates p < 0.0001, * indicates p < 0.05 vs G2, one-way ANOVA. Figure 23 shows the results of muscle mass of animals in each group measured 23 days after drug administration in Example 2, where the data in the figure are expressed as mean ± error value, **** indicates p < 0.0001 vs G2, one-way ANOVA. Figure 24 shows the percentage of muscle mass in the animals in the group measured 23 days after drug administration in Example 2, where the data in the figure are expressed as mean ± error value, **** indicates p < 0.0001, *** indicates p < 0.001 vs G2, one-way ANOVA.

Claims (28)

A drug combination I, comprising: Substance X, wherein the substance X is berberine ursodeoxycholate; and, Substance Y, wherein the substance Y is an SGLT2 inhibitor or a pharmaceutically acceptable salt thereof; The SGLT2 inhibitor is selected from at least one of empagliflozin, dapagliflozin, canagliflozin, ertogliflozin, hengagliflozin, ipragliflozin, toragliflozin, sogliaflozin, rugliflozin, jangliflozin, bexagliflozin, rongagliflozin, enavogliflozin and JT-001. The drug combination I as described in claim 1, wherein: the drug combination I satisfies at least one of 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 ursodeoxycholate exists in its amorphous, anhydrous crystalline or hydrated crystalline form; (7) the berberine ursodeoxycholate exists in its free salt or hydrate form; (8) the active ingredients of the drug combination I include substance X and substance Y. The drug combination I as described in claim 1, wherein: the drug combination I satisfies at least one of the following conditions: (1) the substance X is administered orally, and the substance Y is administered orally; (2) the unit dosage form of the substance X and the substance Y is a tablet, a capsule or a liquid preparation; (3) the SGLT2 inhibitor is empagliflozin or dapagliflozin, preferably empagliflozin; (4) the berberine ursodeoxycholate is the crystalline form A of berberine ursodeoxycholate, and the crystalline form A of berberine ursodeoxycholate has an X-ray powder diffraction angle expressed in 2θ angles of 7.06±0.2 ^° , 7.34±0.2°, 8.79±0.2 ^° and 10.87 ^°, respectively. , 9.47± 0.2 ^o , 11.94± 0.2 ^o , 14.17± 0.2 ^o , 15.50± 0.2 ^o , 16.54± 0.2 ^o and 16.78± 0.2 ^o ; preferably, the X-ray powder diffraction of the berberine ursodeoxycholate form A expressed in 2θ angles is at 3.98± 0.2 ^o , 7.06± 0.2 ^o , 7.34± 0.2 ^{o , 7.93± 0.2 o ,} 8.79± 0.2 ^o , 9.47± 0.2 ^o , 11.70± 0.2 ^o , 11.94± 0.2 ^o , 12.34± 0.2 ^o , 12.55± 0.2 o 0.2 ^o , 13.90± 0.2 ^o , 14.17± 0.2 ^o , 15.14± 0.2 ^o , 15.50± 0.2 ^o , 16.16± 0.2 ^o , 16.54± 0.2 ^o , 16.78± 0.2 ^o , 17.53± 0.2 ^o , 17.67± 0.2 ^o , 18.23± 0.2 ^o , 19.03± 0.2 ^o , 19.98± 0.2 ^o , 20.87± 0.2 ^o , 21.13± 0.2 ^o , 21.96± 0.2 ^o , 23.49± 0.2 ^o , 24.24± 0.2 ^o , 24.97± 0.2 ^o , 25.50± 0.2 ^o , 26.63± 0.2 ^o , 27.60± 0.2 ^o , 28.06± 0.2 ^o , 28.63± 0.2 ^o , 29.40± 0.2 ^o and 30.49± 0.2 ^o ; the berberine ursodeoxycholate crystal form A is preferably the berberine ursodeoxycholate crystal form A of hemi-nonahydrate; (5) the berberine ursodeoxycholate is the berberine ursodeoxycholate crystal form D, and the berberine ursodeoxycholate crystal form D has an X-ray powder diffraction peak expressed in 2θ angles at 4.24± 0.2 ^o , 6.79± 0.2 ^o , 8.50± 0.2 ^o , 10.25± 0.2 ^o , 11.50± 0.2 ^o , 13.62± 0.2 ^o , 14.74± 0.2 ^o , 15.20± 0.2 ^o , 17.92± 0.2 ^o , 18.39± 0.2 ^o , 22.91± 0.2 ^o and 25.73± 0.2 ^o ; (6) the drug combination I consists of substance X and substance Y; (7) the active ingredient of the drug combination I consists of substance X and substance Y. The drug combination I as described in claim 1, wherein: the drug combination I satisfies at least one of the following conditions: (1) the substance X and the substance Y are provided in the form of a substance ratio of 1:100 to 100:1; preferably, the substance X and the substance Y are provided in the form of a substance 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 the form of a substance ratio of 5:1 to 50:1; (2) the substance X is administered at a frequency of QD, BID or TID, preferably QD; (3) the substance Y is administered at a frequency of QD, BID or TID, preferably QD; (4) the substance X and the substance Y are administered at the same frequency. The drug combination I as described in claim 1, wherein: the drug combination I satisfies at least one of the following conditions: (1) In the drug combination I, the substance X and the substance Y are provided in a substance ratio of 5:1 to 15:1, 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 ursodeoxycholate, and the substance Y is ertogliflozin; (6) The substance X is berberine ursodeoxycholate, and the substance Y is henggliflozin; (7) The substance X is berberine ursodeoxycholate, and the substance Y is ipraglide; (8) The substance X is berberine ursodeoxycholate, and the substance Y is togliflozin; (9) The substance X is berberine ursodeoxycholate, and the substance Y is soglide; (10) The substance X is berberine ursodeoxycholate, and the substance Y is rugliflozin; (11) The substance X is berberine ursodeoxycholate, and the substance Y is japagliflozin; (12) The substance X is berberine ursodeoxycholate, and the substance Y is bexagliflozin; (13) The substance X is berberine ursodeoxycholate, and the substance Y is rongagliflozin; (14) The substance X is berberine ursodeoxycholate, and the substance Y is enavogliflozin; (15) The substance X is berberine ursodeoxycholate, and the substance Y is JT-001; (16) The drug combination I is a drug combination I for preventing and/or treating metabolic diseases or diseases related thereto; preferably, the metabolic disease is selected from diabetes, prediabetes, hyperinsulinemia and obesity. The drug combination I as described in claim 1, wherein: the drug combination I satisfies at least one of the following conditions: (1) In the drug combination I, the substance X is berberine ursodeoxycholate; preferably, the crystalline form A of hemi-nonahydrate berberine ursodeoxycholate; the substance Y is empagliflozin; the substance X and the substance Y are provided in the form of a substance molar ratio of 12:1, 11:1, 10:1 or 9:1; (2) In the drug combination I, the substance X is berberine ursodeoxycholate; preferably, the crystal form A of berberine ursodeoxycholate semi-nonahydrate; the substance Y is dapagliflozin; the substance X and the substance Y are provided in the form of a substance amount ratio of 14:1, 13:1 or 12:1. A pharmaceutical composition A, comprising: Substance X, the definition of which is as described in any one of claim items 1-6; and, Substance Y, the definition of which is as described in any one of claim items 1-6; and, Pharmaceutical excipients. The pharmaceutical composition A as described in claim 7, wherein the pharmaceutical composition A satisfies at least one of the following conditions: (1) The active ingredients of the pharmaceutical composition A include substance X and substance Y; (2) The pharmaceutical composition A includes berberine ursodeoxycholate and empagliflozin, and pharmaceutical excipients; (3) The pharmaceutical composition A includes berberine ursodeoxycholate and dapagliflozin, and pharmaceutical excipients; (4) The pharmaceutical composition A includes berberine ursodeoxycholate and canagliflozin, and pharmaceutical excipients; (5) The pharmaceutical composition A includes berberine ursodeoxycholate and ertogliflozin, and pharmaceutical excipients; (6) The drug composition A comprises berberine ursodeoxycholate and henggliflozin, and pharmaceutical excipients; (7) The drug composition A comprises berberine ursodeoxycholate and ipragliflozin, and pharmaceutical excipients; (8) The drug composition A comprises berberine ursodeoxycholate and toragliflozin, and pharmaceutical excipients; (9) The drug composition A comprises berberine ursodeoxycholate and sogliaflozin, and pharmaceutical excipients; (10) The drug composition A comprises berberine ursodeoxycholate and rugliflozin, and pharmaceutical excipients; (11) The drug composition A comprises berberine ursodeoxycholate and bexagliflozin, as well as pharmaceutical excipients; (12) The drug composition A comprises berberine ursodeoxycholate and bexagliflozin, as well as pharmaceutical excipients. The drug composition A as described in claim 7, wherein: the drug composition A satisfies at least one of the following conditions: (1) the drug composition A is composed of substance X, substance Y and one or more pharmaceutical excipients; (2) the active ingredient of the drug composition A is composed of substance X and substance Y; (3) In the drug composition A, berberine ursodeoxycholate and SGLT2 inhibitor are provided in the form of a substance ratio of 1:100 to 100:1; preferably, berberine ursodeoxycholate and SGLT2 inhibitor are provided in the form of a substance ratio of 1:50 to 1:5 or 1:1 to 100:1; preferably, berberine ursodeoxycholate and SGLT2 inhibitor are provided in the form of a substance ratio of 5:1 to 50:1; more preferably, berberine ursodeoxycholate and SGLT2 inhibitor are provided in the form of a substance ratio of 5:1 to 15:1, for example, 14:1, 13:1, 12:1, 11:1, 10:1 or 9:1; (4) The drug composition A is in the form of an oral preparation; preferably, the oral preparation is selected from tablets, capsules or liquid preparations; (5) The drug composition A is administered at a frequency of QD, BID or TID, preferably QD; (6) The drug composition A is a drug composition A for preventing and/or treating metabolic diseases or diseases related thereto; preferably, the metabolic disease is selected from diabetes, prediabetes, hyperinsulinemia, obesity. The drug composition A as described in claim 7, wherein: the drug composition A satisfies at least one of the following conditions: (1) The active ingredient of the drug composition A consists of the crystalline form A of berberine ursodeoxycholate hemi-nonahydrate and empagliflozin; (2) The active ingredient of the drug composition A consists of the crystalline form A of berberine ursodeoxycholate hemi-nonahydrate and dapagliflozin. A drug composition B, comprising: A first drug composition comprising a substance X and a first pharmaceutical excipient, wherein the substance X is defined as described in any one of claim items 1-6; and, A second drug composition comprising a substance Y and a second pharmaceutical excipient, wherein the substance Y is defined as described in any one of claim items 1-6. The drug composition B as described in claim 11, wherein the drug composition B satisfies at least one of the following conditions: (1) the first drug composition and the second drug composition are independent drug compositions; (2) the first pharmaceutical excipient and the second pharmaceutical excipient are the same or different; (3) the first drug composition is in the form of an oral dosage form; (4) the second drug composition is in the form of an oral dosage form. The drug composition B as described in claim 11, wherein the drug composition B satisfies at least one of the following conditions: (1) The first drug composition and the second drug composition are provided in the same solid dosage unit; preferably, the solid dosage unit is an independent tablet, pill or capsule; (2) The first drug composition is presented in the form of an oral dosage form, and, the second drug composition is presented in the form of an oral dosage form; (3) The drug composition B comprises berberine ursodeoxycholate and empagliflozin, and pharmaceutical excipients; (4) The drug composition B comprises berberine ursodeoxycholate and dapagliflozin, and pharmaceutical excipients; (5) The drug composition B includes berberine ursodeoxycholate and canagliflozin, as well as pharmaceutical excipients. The drug composition B as described in claim 11, wherein: the drug composition B satisfies at least one of the following conditions: (1) the first drug composition and the second drug composition are respectively disposed in two independent sub-packages in the same drug package; (2) the first drug composition is administered at a frequency of QD, BID or TID, preferably QD; (3) the second drug composition is administered at a frequency of QD, BID or TID, preferably QD; (4) the first drug composition and the second drug composition are administered at the same frequency; (5) In the drug composition B, berberine ursodeoxycholate and SGLT2 inhibitor are provided in the form of a substance ratio of 1:100 to 100:1; preferably, berberine ursodeoxycholate and SGLT2 inhibitor are provided in the form of a substance ratio of 1:50 to 1:5 or 1:1 to 100:1; more preferably, berberine ursodeoxycholate and SGLT2 inhibitor are provided in the form of a substance ratio of 5:1 to 50:1; most preferably, in the drug composition B, berberine ursodeoxycholate and SGLT2 inhibitor are provided in the form of a substance ratio of 5:1 to 15:1, for example, in the form of 14:1, 13:1, 12:1, 11:1, 10:1 or 9:1; (6) The drug composition B consists of a first drug composition and a second drug composition; (7) The drug composition B consists of substance X, substance Y and pharmaceutical excipients. A drug combination II, comprising: Substance U, wherein the substance U is berberine or a pharmaceutically acceptable salt thereof; and, Substance V, wherein the substance V is ursodeoxycholic acid or a pharmaceutically acceptable salt thereof; and, Substance Y, wherein the substance Y is an SGLT2 inhibitor or a pharmaceutically acceptable salt thereof; The definition of the SGLT2 inhibitor is as described in any one of claim items 1-6. The drug combination II as described in claim 15, wherein the drug combination II satisfies at least one of the following conditions: (1) the substance U is berberine ursodeoxycholate; (2) the substance V is berberine ursodeoxycholate. The drug combination II as described in claim 15, wherein the drug combination II satisfies at least one of the following conditions: (1) The drug combination II comprises berberine or its inorganic acid salt, ursodeoxycholic acid and an SGLT2 inhibitor; (2) The drug combination II comprises berberine or its inorganic acid salt, an inorganic base salt of ursodeoxycholic acid and an SGLT2 inhibitor; (3) The drug combination II comprises berberine hydrochloride, ursodeoxycholic acid and empagliflozin; (4) The drug combination II comprises berberine hydrochloride, ursodeoxycholic acid and dapagliflozin; (5) The drug combination II consists of substance U, substance V and substance Y. The drug combination II as described in claim 15, wherein the drug combination II satisfies at least one of the following conditions: (1) The drug combination II is composed of berberine hydrochloride, ursodeoxycholic acid and empagliflozin; (2) The drug combination II is composed of berberine hydrochloride, ursodeoxycholic acid and dapagliflozin; (3) The substance U, substance V and substance Y are administered simultaneously or separately or in combination; (4) The administration regimens of the substance U, substance V and substance Y are the same or different; (5) All or part of the substance U, substance V and substance Y are provided in the form of a drug composition, for example, in the form of a drug composition comprising substance U, substance V and substance Y, or in the form of a drug composition comprising any two of them; (6) The molar ratio of substance U to substance V is 20:1~1:20, preferably, the molar ratio of substance V to substance Y is 5:1~1:2, more preferably 1:1; (7) The molar ratio of substance U to substance Y is 100:1~1:20, preferably, the molar ratio of substance V to substance Y is 50:1~1:1, more preferably 30:1~5:1; (8) The molar ratio of substance V to substance Y is 20:1~1:20, preferably, the molar ratio of substance V to substance Y is 5:1~1:2, more preferably 1:1. A drug combination III, comprising: Substance V, wherein the substance V is ursodeoxycholic acid; and, Substance Y, wherein the substance Y is an SGLT2 inhibitor or a pharmaceutically acceptable salt thereof; The definition of the SGLT2 inhibitor is as described in any one of claim items 1-6. The drug combination III as described in claim 19, wherein the drug combination III satisfies at least one of the following conditions: (1) the substance V and the substance Y are administered simultaneously or separately; (2) the molar ratio of the substance V to the substance Y 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. A use of a drug combination I as described in any one of claims 1-6, a drug combination A as described in any one of claims 7-10, a drug combination B as described in any one of claims 11-14, a drug combination II as described in any one of claims 15-18, or a drug combination III as described in claim 19 or 20 in the preparation of a drug for preventing and/or treating a disease, wherein the disease is a metabolic disease or a disease related thereto. The use as described in claim 21, wherein the metabolic disease is diabetes and/or obesity. The use as described in claim 22, wherein the metabolic disease is type 2 diabetes. The use as described in claim 21, wherein the metabolic disease is prediabetes. The use according to claim 21, wherein the metabolic disease is hyperinsulinemia or a metabolic syndrome associated with hyperinsulinemia. The use as described in claim 21, wherein the metabolic disease is obesity. The use as described in claim 21, wherein the metabolic disease is diabetes combined with obesity. A drug package comprising drug compositions in independent sub-packages, wherein one sub-package contains the first drug composition described in any one of claim items 11-14, and a second sub-package contains the second drug composition described in any one of claim items 11-14.