Use of ursolic acid injection composition in drug for improving or treating cancerous cachexia

Abstract

The use of a ursolic acid injection composition in the preparation of a drug for improving or treating cancerous cachexia, in particular the use of a ursolic acid liposome injection in the preparation of a drug for improving or treating cancerous cachexia.

Description

Use of ursolic acid injection compositions in medicines for improving or treating cancer cachexia Technical Field

[0001] This invention provides the use of an ursolic acid injection composition in the preparation of a medicament for improving or treating tumor cachexia, particularly the use of a liposome injection in the preparation of a medicament for improving or treating tumor cachexia. Background Technology

[0002] Cachexia, also known as cachexia, can be seen in the progression of many chronic diseases (such as malignant tumors, COPD, chronic heart failure, chronic renal failure, AIDS, and rheumatoid arthritis). Among them, cachexia associated with tumors is the most common and is known as tumor cachexia.

[0003] Cancer cachexia is a complex syndrome involving multiple organs and caused by various factors. Its main characteristic is weight loss due to skeletal muscle atrophy and adipose tissue loss. Cancer cachexia is a continuous physiological process, and establishing clear diagnostic and staging criteria helps in developing effective and physiologically tolerable treatment strategies for patients in clinical management. According to the international consensus proposed by Fearon et al. in 2011, clinical staging based on the patient's weight loss, metabolism, and anorexia can be divided into early cachexia (pre-cachexia), cachexia stage (corresponding to the late or advanced stage in this application), and refractory cachexia. Patients with cachexia often experience anorexia, weight loss, and skeletal muscle loss. The overall treatment goal for cancer cachexia is to reverse weight loss and muscle atrophy.

[0004] Treatment for cachexia primarily focuses on anti-inflammatory strategies and the use of appetite stimulants (such as anamorelin) to increase energy intake. Furthermore, clinical studies have shown that medroxyprogesterone acetate significantly increased patient weight compared to placebo or untreated groups, demonstrating an advantage in weight gain compared to other medications for cachexia treatment, but without a significant improvement in vital weight. Multiple clinical studies related to glucocorticoids have shown that methylprednisolone, prednisolone, and dexamethasone can improve appetite and quality of life in cancer patients, but without significant weight gain. The mechanism of action may be related to the inhibition of inflammatory cytokine release. Currently, the Colon 26 mouse model of colorectal cancer cachexia is the recognized standard animal model in this field and is widely used in early-stage cachexia research. Summary of the Invention

[0005] This invention systematically studies the use of ursolic acid injection compositions in improving or treating cancer cachexia. It was found that different dosages of the ursolic acid injection compositions showed significant differences in their effects on improving fat loss and / or muscle atrophy in different types of cancer cachexia, specifically targeting early-stage and late-stage cachexia (cachexia stage). Furthermore, this invention also found that ursolic acid injection compositions, particularly ursolic acid liposomes, are significantly more effective than oral ursolic acid formulations in improving cancer cachexia, due to the reduced dosage of ursolic acid. Based on the above research and findings, this application provides relevant embodiments for the use of ursolic acid injection compositions in improving or treating cancer cachexia.

[0006] On one hand, the present invention provides the use of an ursolic acid injection composition in the preparation of a medicament for improving or treating cancer cachexia.

[0007] In some embodiments, the ursolic acid injection composition is a liposome injection, a liposome injection, or a nanoemulsion injection. In some embodiments, the single dose of ursolic acid is 75-260 mg. This dose includes low doses of 75-160 mg and medium / high dose ranges of 180-260 mg. Specifically, it includes any integer value within the ranges of 75-260 mg, 150-260 mg, and 200-260 mg. For example, specific data can be selected as 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119. ,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,1 40, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160m g; or 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 2 20, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260 mg. These numerical examples also apply to other implementation schemes.

[0008] In some embodiments, the single dose of ursolic acid refers to the corresponding amount of ursolic acid dispersed in one infusion package when administered intravenously, such as the total weight of ursolic acid or the total dose per body surface area. The single dose of this invention limits the preparation process of the drug. The preparation of the drug includes a preparation process in a pharmaceutical plant, and also includes a pre-administration formulation process according to the dosage and administration specified in the drug's instructions. For example, multiple vials or ampoules of unit formulation (e.g., 3-12 mg / vial) are dispersed or reconstituted in an intravenously administerable isotonic solution. The isotonic solution is selected from physiological saline, glucose injection solution, isotonic electrolyte solution, and Ringer's solution.

[0009] In some embodiments, the ursolic acid injection composition is a liposome injection, a liposome injection, or a nanoemulsion injection. In some embodiments, the dosage is based on the patient's body surface area (1.5-2.0 mg / m²). 2 The single application dose of ursolic acid is 50-130 mg / m². 2 This dosage includes 50-80 mg / m². 2 Low doses and 100-130 mg / m 2 Medium / high doses. Specifically, 50-130 mg / m². 2 50-80mg / m 2 and 100-130mg / m 2 Any integer value within the range. For example, specific data can be selected as 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80 mg / m³ 2 Or 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130 mg / m² 2 These numerical examples also apply to other implementation schemes. The body surface area of ​​cachexia patients is 1.5-2.0 mg / m². 2 1.8m is usually taken. 2 The average. In extreme cases, the body surface area of ​​cachectic patients can be as low as 1.5 m². 2 For example, patients with abnormally thin cachexia or those in the refractory stage of cachexia. For patients with abnormally thin cachexia (e.g., body surface area of ​​1.5-1.8 m²), 2 For patients with high blood sugar, a single dose of 150-180 mg is also considered a medium / high dose.

[0010] In some embodiments, the ursolic acid injection composition is administered as a single intravenous infusion.

[0011] In some embodiments, the liposome injection or liposome injection contains ursolic acid, phospholipids, and pH adjusters.

[0012] In some embodiments, the ursolic acid injection composition is a lyophilized injection using a lyophilized scaffold agent.

[0013] In some embodiments, the ursolic acid injection composition comprises the following components:

[0014] 1. The content of ursolic acid or its pharmaceutically acceptable salt in a unit dosage form is 3-12 mg / vial;

[0015] 2. The weight ratio of ursolic acid or its pharmaceutically acceptable salt to phospholipids is 0.1–10:5–500;

[0016] 3. The phospholipid is selected from lecithin, soybean lecithin, hydrogenated soybean lecithin, phosphatidylethanolamine, synthetic phosphatidylserine, phosphatidylinositol, sphingomyelin, methionine, cetylphosphatidylcholine, dicerylphosphatidyl, dimyristoyl lecithin, distearate phosphatidylethanolamine, or a mixture of two or more of the above.

[0017] 4. The pH adjuster is a buffer solvent, and the pH value of the aqueous phase is controlled within the range of 6-7 during the preparation process of the buffer;

[0018] 5. The freeze-dried scaffold agent is selected from mannitol, sucrose, lactose, or a combination thereof.

[0019] On the other hand, the present invention provides the use of an ursolic acid injection composition in the preparation of a medicament for improving or treating cancer cachexia of the digestive tract, wherein the ursolic acid injection composition is as described in any of the foregoing embodiments.

[0020] In some implementation schemes, gastrointestinal cancer cachexia is selected from colorectal cancer cachexia, gastric cancer cachexia, esophageal cancer cachexia, and pancreatic cancer cachexia.

[0021] In some implementations, the improvement or treatment of gastrointestinal cancer cachexia is selected from improving fat loss, improving weight loss, improving muscle weakness, and / or improving dietary loss. In some implementations, the cancer cachexia is selected from early, late (cachexia stage), or refractory stages.

[0022] In some implementations, improving or treating gastrointestinal cancer cachexia involves improving fat loss in patients with early or late-stage gastrointestinal cancer cachexia. Fat loss is preferred in patients with early-stage colorectal cancer cachexia.

[0023] In some implementations, improving or treating gastrointestinal cancer cachexia means improving weight loss, muscle weakness, and / or loss of appetite in patients with early or late-stage (cachexia stage) gastrointestinal cancer cachexia.

[0024] In some implementations, improving or treating gastrointestinal cancer cachexia means improving weight loss, muscle weakness, and / or loss of appetite in patients with early or late (cachexia stage) colorectal cancer cachexia.

[0025] In some implementation methods, the single dose of ursolic acid for improving or treating cancer cachexia in the digestive tract is 150-260 mg or 100-130 mg / m². 2 .

[0026] In some implementations, in improving fat loss in patients with early gastrointestinal cancer cachexia, the ursolic acid injection composition is administered to the subject at a high single dose, specifically 150-260 mg, 200-260 mg, or any integer value between 150-260 mg. Specifically, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, and 260 mg can be selected.

[0027] In some implementations, the single dose of the ursolic acid injection composition is a high dose, specifically 100-130 mg / m², in improving fat loss in early gastrointestinal cancer cachexia. 2 Or 100-130mg / m 2 Any integer value between [specified values]. For example, specific data can be selected as 100, 105, 110, 115, 120, 125, or 130 mg / m³. 2 .

[0028] In some implementation methods, ursolic acid is administered at a single dose of 150-260 mg or 100-130 mg / m² in patients with early or late (cachexia) gastrointestinal cancer cachexia. 2 .

[0029] In some implementation methods, ursolic acid is administered at a single dose of 150-260 mg or 100-130 mg / m² in patients with early or late (cachexia) colorectal cancer cachexia. 2 .

[0030] In some embodiments, the ursolic acid content in the unit dosage form of the ursolic acid injection composition is 3-12 mg / vial. Specific values ​​are 3 mg / vial, 4 mg / vial, 5 mg / vial, 6 mg / vial, 7 mg / vial, 8 mg / vial, 9 mg / vial, 10 mg / vial, 11 mg / vial, and 12 mg / vial. Preferably, the ursolic acid content in the unit dosage form of the ursolic acid injection liposome is 3 mg / vial, 10 mg / vial, and 12 mg / vial. The vial is a vial, such as a borosilicate vial, and more preferably a vial suitable for freeze-drying.

[0031] It should be specifically noted that prior to this application, no ursolic acid injection composition had been approved for marketing, and clinicians did not have the ability or right to adjust the dosing regimen of the ursolic acid injection composition, including the single-dose dosage, the ursolic acid content in a unit formulation, and the specific quantity of unit formulation used in a single dose. Therefore, the above-mentioned technical features in this invention do not fall under the category of treatment behaviors that physicians can freely adjust. The single-dose dosage, the ursolic acid content in a unit formulation, and the specific quantity of unit formulation used in a single dose are all technical features that need to be specifically considered in the pharmaceutical use claims and have a limiting effect on the scope of protection. In addition, those skilled in the art can convert the mouse dosage into the human dosage based on common knowledge. See the reference https: / / pmc.ncbi.nlm.nih.gov / articles / PMC4804402 / . Considering clinical drug safety and extreme patient body surface area, the human dosage corresponding to the medium / high dose of 20mg / kg-40mg / kg used in the embodiments of this invention is approximately 150mg-260mg or 100-130mg / m². 2 .

[0032] On the other hand, the present invention provides the use of an ursolic acid injection composition in the preparation of a medicament for improving or treating liver cancer cachexia, wherein the ursolic acid injection composition is as described in any of the foregoing embodiments.

[0033] In some implementation schemes, liver cancer cachexia is defined as either early-stage liver cancer cachexia or late-stage liver cancer cachexia.

[0034] In some implementations, the use in improving or treating liver cancer cachexia is to improve muscle atrophy in advanced liver cancer cachexia; preferably skeletal muscle atrophy.

[0035] In some embodiments, in the use of ursolic acid injection composition to improve or treat liver cancer cachexia, the single dose is 75 mg to 160 mg or any integer value within 75 mg to 160 mg. Specifically, it is 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, or 160 mg.

[0036] In some embodiments, in the use of ursolic acid injection composition to improve or treat liver cancer cachexia, the single dose is 50-80 mg / m². 2 Or 50-80mg / m 2 Any integer value within the range. For example, specific data can be selected as 50, 55, 60, 65, 70, 75, 80 mg / m³. 2 .

[0037] In some embodiments, in improving muscle atrophy in advanced hepatocellular carcinoma cachexia, the single dose of the ursolic acid injection composition is 75 mg to 160 mg or any integer value within 75 mg to 160 mg.

[0038] In some embodiments, the ursolic acid content in the unit formulation of the ursolic acid injection composition is 3-12 mg / vial; preferably, the ursolic acid content in the unit formulation of the ursolic acid injection liposome is 3 mg / vial, 10 mg / vial, or 12 mg / vial.

[0039] On the other hand, the present invention provides the use of an ursolic acid injection composition in the preparation of a medicament for improving or treating lung cancer cachexia, wherein the ursolic acid injection composition is as described in any of the foregoing embodiments. In some embodiments, the single dose of the ursolic acid injection composition is 75-260 mg. This dose includes a low dose range of 75 mg-160 mg, a high dose range of 150-260 mg, or 200-260 mg. Specifically, it includes any integer value within the ranges of 75-260 mg, 75 mg-160 mg, 150-260 mg, or 200-260 mg.

[0040] In some implementations, lung cancer cachexia is defined as either early-stage lung cancer cachexia or late-stage lung cancer cachexia.

[0041] In some implementations, improving lung cancer cachexia means improving muscle atrophy in early-stage lung cancer cachexia, or improving muscle atrophy and fat loss in late-stage lung cancer cachexia, preferably the muscle atrophy being skeletal muscle atrophy.

[0042] In some embodiments, in improving muscle atrophy in early-stage lung cancer cachexia, the single-dose administration of the ursolic acid injection composition is 75-160 mg (low dose), 15-260 mg, or 200-260 mg. Specifically, it includes any integer value within the range of 75-160 mg, 200-260 mg, or 200-260 mg. 75-160 mg (low dose) is preferred.

[0043] In some embodiments, in improving muscle atrophy and fat loss in advanced lung cancer cachexia, the single dose of the ursolic acid injection composition is 75-160 mg (low dose), 15-260 mg, or 200-260 mg (high dose), specifically including any integer value within the range of 75-160 mg, 15-260 mg, or 200-260 mg. 75-160 mg (low dose) is preferred.

[0044] In some embodiments, in improving lung cancer cachexia, the ursolic acid content in the unit formulation of the ursolic acid injection composition is 3-12 mg / vial; preferably, the ursolic acid content in the unit formulation of the ursolic acid injection liposome is 3 mg / vial, 10 mg / vial, or 12 mg / vial.

[0045] In some implementations, the ursolic acid injection composition is used in combination with other drugs or therapies for treating cancer. Other cancer treatments include multi-target tyrosine kinase receptor inhibitors or PD-1 inhibitors, such as sorafenib, lenvatinib, donafenib, anlotinib, regorafenib, sintilimab, and camrelizumab.

[0046] definition

[0047] The term "comprising" as used herein means the phrase "including (but not limited to)" and may be used interchangeably with it. The term "including" as used herein means the phrase "including (but not limited to)" and may be used interchangeably with it. Technical solutions using "comprising" or "including" in this patent may be further defined as "comprising" or "forming". In the compositions of the "including" form of this invention, no specific one or both of reed rhizome and mulberry leaf are used.

[0048] The term “or” as used herein means “and / or” and may be used interchangeably with it unless otherwise stated.

[0049] In addition to the numerical values ​​themselves, the numerical values ​​used herein also include ranges of measurement or operational errors acceptable in the art. Unless otherwise defined, the error range of this application may be ±10% of a specific numerical value. Unless otherwise specified, the numerical range in this application covers any integer within that range.

[0050] As used herein, the terms "early cachexia," "pre-cachexia," "early cachexia," or "pre-cachexia" can be used interchangeably. This stage is an early warning stage of cachexia; at this time, there is no obvious muscle loss, but risk factors and physiological changes leading to cachexia are already present. Its clinical significance lies in the fact that this is a critical window period that is "reversible" or "interventional"; active intervention during this stage (such as nutritional support, anti-inflammatory treatment, and physical activity) may prevent or delay its progression to typical cachexia. Its core characteristics include:

[0051] • Weight loss: There is potential for persistent weight loss (e.g., weight loss of <5% in the past 6 months);

[0052] • Anorexia / metabolic changes: decreased appetite and early feeling of fullness occur;

[0053] • Systemic inflammation: The presence of a chronic, low-grade inflammatory response in the body (detectable by inflammatory markers such as C-reactive protein).

[0054] As used in this article, the terms "cachexia stage," "late cachexia," "late cachexia," or "late-stage cachexia" can be used interchangeably. At this stage, clinical manifestations meeting the definition of cachexia have appeared, and muscle loss has occurred. Its clinical significance lies in the more pronounced metabolic disturbances and inflammatory responses; interventions (such as nutritional support and drug therapy) may be partially effective, but are unlikely to completely reverse muscle loss; and the patient's physical strength, activity level, and quality of life begin to decline significantly. The diagnostic criteria typically require meeting the following conditions:

[0055] 1. Weight loss of >5% in the past 6 months; or

[0056] 2. For those with a body mass index (BMI) < 20 kg / m² 2 Patients with a weight loss >2%; at the same time

[0057] 3. At least one of the following exists:

[0058] • Muscle loss (confirmed through physical examination or instrumental testing).

[0059] • Anorexia.

[0060] As used herein, the terms "refractory cachexia," "refractory cachexia," or "refractory cachexia" can be used interchangeably. This stage is the terminal stage of cachexia, where patients show little or no response to any treatment and have an extremely poor prognosis. Its clinical significance lies in the fact that the treatment goal at this stage is no longer to reverse cachexia or prolong survival, but rather to palliative care and end-of-life care; the focus is on relieving symptoms (such as pain, nausea, and dyspnea), providing psychological support, and improving quality of life; active nutritional support may be ineffective at this stage and may even increase the burden on the patient. Its core characteristics include:

[0061] Cancer patients are usually in the terminal stage of the disease and do not respond to anti-cancer treatments.

[0062] • Weight loss is continuous and rapid, making it extremely difficult to obtain nutrients.

[0063] • Active and severe systemic inflammatory response.

[0064] • The “critical point” of cachexia occurs when the body’s metabolism can no longer be corrected by conventional means.

[0065] • Extremely poor physical condition (e.g., WHO fitness level 3-4, bedridden most of the time).

[0066] • The expected survival period is less than 3 months. Attached Figure Description

[0067] Figure 1. Comparison of epididymal adipose tissue weight (left and right sides) in Colon 26 mice during an exploratory study of early colorectal cancer cachexia. The left image shows the adipose tissue of the left epididymis, and the right image shows the adipose tissue of the right epididymis. ***, p<0.001; **, p<0.01; *, p<0.05. Data are expressed as mean ± SEM.

[0068] Figure 2. Comparison of left hind leg muscle (gastrocnemius and tibialis anterior) weights in a Colon 26 mouse study on early colorectal cancer cachexia. The top image shows the left gastrocnemius muscle, and the bottom image shows the left tibialis anterior muscle. *, p<0.05. Data are expressed as mean ± SEM.

[0069] Figure 3. Endpoint of the PDX test for advanced cachexia in patients with liver cancer: weight of the left tibialis anterior muscle (mean ± standard error).

[0070] Figure 4. Endpoint of the PDX test for advanced cachexia in patients with liver cancer: weight of the left tibialis anterior muscle (mean ± standard error).

[0071] Figure 5. Percentage change in body weight of mice at the endpoint of the early cachexia experiment in LLC tumor-bearing mice (mean ± standard error).

[0072] Figure 6. Net body weight of mice at the endpoint of the early cachexia experiment in LLC tumor-bearing mice (mean ± standard error).

[0073] Figure 7. Tumor volume at the endpoint of early cachexia in LLC tumor-bearing patients (mean ± standard error).

[0074] Figure 8. Ovarian fat weight of both sides of mice at the endpoint of the early cachexia experiment in LLC tumor-bearing mice (mean ± standard error).

[0075] Figure 9. Left gastrocnemius muscle weight of mice at the endpoint of the early cachexia experiment in LLC tumor-bearing mice (mean ± standard error).

[0076] Figure 10. Weight of the left tibialis anterior muscle in mice at the endpoint of the early cachexia experiment in LLC tumor-bearing mice (mean ± standard error).

[0077] Figure 11 Statistical results of the muscle fiber area of ​​the left leg gastrocnemius muscle in the LLC tumor-bearing early cachexia experiment endpoint (mean ± standard error).

[0078] Figure 12. Results of the P-STAT3 / STAT3 ratio in the gastrocnemius muscle of LLC tumor-bearing mice with early cachexia (mean ± standard error).

[0079] Figure 13. Relative quantification of SIRT1 protein in the gastrocnemius muscle of LLC tumor-bearing early cachexia mice (mean ± standard error).

[0080] Figure 14 Bilateral ovarian fat weight at the endpoint of the LLC late-stage cachexia experiment (mean ± standard error).

[0081] Figure 15. Weight of the left gastrocnemius muscle in mice at the endpoint of the LLC tumor-bearing late cachexia experiment (mean ± standard error).

[0082] Figure 16. Weight of the left tibialis anterior muscle in mice at the endpoint of the LLC tumor-bearing late cachexia experiment (mean ± standard error).

[0083] Figure 17 Statistical results of the left leg gastrocnemius muscle fiber area of ​​mice at the endpoint of the LLC tumor-bearing late cachexia experiment (mean ± standard error).

[0084] Figure 18. Results of the P-STAT3 / STAT3 ratio in the gastrocnemius muscle of LLC tumor-bearing mice with advanced cachexia (mean ± standard error).

[0085] Figure 19. Relative quantification of SIRT1 protein in the gastrocnemius muscle of LLC tumor-bearing mice with advanced cachexia (mean ± standard error).

[0086] Figure 20 Comparison of net body weight of Colon 26 mice with early colorectal cancer cachexia.

[0087] Figure 21 Comparison of food consumption in Colon 26 mice with early colorectal cancer cachexia.

[0088] Figures 22A-22B compare the gripping strength of the forelimbs and hindlimbs of Colon 26 mice with early colorectal cancer cachexia; Figure 22A shows the forelimbs and Figure 22B shows the hindlimbs.

[0089] Figure 23 Comparison of muscle fiber cross-sectional areas in Colon 26 mice with early colorectal cancer cachexia.

[0090] Figure 24 Comparison of epididymal fat cell area in Colon 26 mice with early colorectal cancer cachexia. The left image shows the fat in the left epididymis, and the right image shows the fat in the right epididymis.

[0091] Figure 25 Comparison of net body weight of Colon 26 mice with advanced colorectal cancer cachexia.

[0092] Figure 26 Comparison of food consumption in Colon 26 mice with advanced colorectal cancer cachexia.

[0093] Figures 27A-27B compare the grip strength of the forelimbs and hindlimbs of Colon 26 mice with advanced colorectal cancer cachexia; Figure 27A shows the forelimbs and Figure 27B shows the hindlimbs.

[0094] Figure 28 Comparison of muscle fiber cross-sectional areas in Colon 26 mice with advanced colorectal cancer cachexia.

[0095] Figure 29 Comparison of epididymal fat cell area in Colon 26 mice with advanced colorectal cancer cachexia. The left image shows the fat in the left epididymis, and the right image shows the fat in the right epididymis.

[0096] Note: Figures 5-19 are located on the right side. The legends from top to bottom correspond to the columns from left to right. Detailed Implementation

[0097] The present disclosure will be explained below with reference to embodiments. Those skilled in the art will understand that the following embodiments are for illustrative purposes only and should not be construed as limiting the scope of the disclosure. Where specific techniques or conditions are not specified in the embodiments, they are performed in accordance with the techniques or conditions described in the literature in the art or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be obtained commercially.

[0098] Example 1: Preparation of ursolic acid liposomes

[0099] Dissolve 2g of ursolic acid in 40ml of anhydrous ethanol at room temperature by stirring. Then add 20g of soybean lecithin and heat to 48-52℃, stirring for 8-15 minutes to form an organic phase. Prepare an aqueous solution by mixing 40ml of distilled water, 100g of mannitol, and a buffer solution of phosphoric acid and sodium hydroxide (to control the pH of the aqueous phase within the range of 6.3-6.9). Slowly add the organic phase to the aqueous phase at 50-55℃ and stir for 30-35 minutes. Filter the solution through a 0.8μm microporous membrane. Dilute the filtrate with water for injection, dispense into vials, and pre-freeze at -50 to -40℃ for 10 hours. Then, perform gradient temperature increase vacuum freeze-drying in the temperature range of -50℃ to 30℃ for 36-52 hours to obtain the ursolic acid liposome formulation (3mg / vial). After reconstitution with physiological saline, the lyophilized ursolic acid liposomes are measured by a laser particle size analyzer to determine their particle size D. 50 It is 100-300nm.

[0100] Example 2: An exploratory study of ursolic acid liposome injection in improving or treating early colorectal cancer cachexia.

[0101] Research objective: To test the in vivo cachexia relief effect of ursolic acid liposome injection (hereinafter referred to as liposome) in Example 1 on a Colon 26 mouse colorectal cancer cachexia model.

[0102] Colorectal cancer tumors from Colon 26 mice were subcutaneously transplanted into the right subcutaneous region of male BALB / c mice. The tumors were allowed to grow to a mean volume of 80 mm². 3Mice were randomly divided into 9 groups (G1–G9) based on tumor volume and body weight, with 8, 12, 12, 8, 8, 12, 12, and 8 mice in each group, respectively. Groups G1–G4 and G7–G9 were then treated with either no treatment or with solvent (5% glucose injection), liposomes (FAT 15 mg / kg), liposomes (FAT 30 mg / kg), ursolic acid (UA raw material DMSO solvent 100 mg / kg), ursolic acid (UA raw material DMSO solvent 200 mg / kg), or megestrol acetate (3.75 mg / mouse), respectively. In groups G5 and G6, the mean tumor volume reached 209 mm. 3 The mice were then treated with liposomes (15 mg / kg) and liposomes (30 mg / kg), respectively. Liposomes, ursolic acid, and megestrol acetate tablets were administered once daily (qd) via intraperitoneal (ip), orally (po), and orally, respectively. After grouping, tumor volume, body weight, and net body weight were measured three times weekly, and food consumption was calculated. Blood samples were collected at designated time points after administration to G2–G4 and G7–G8 mice for pharmacokinetic (PK) analysis of the gastrocnemius muscle, tumor, and liver. At the end of the experiment, the tumors were removed, weighed, and photographed. The collected mouse organs were then quick-frozen and fixed. Changes in the weight of epididymal adipose tissue and left hind leg muscles were observed. The cross-sectional area of ​​muscle fibers in the gastrocnemius muscle was observed and measured, and statistical analysis was performed.

[0103] Table 1. Dosing regimens in an exploratory study of cachexia in early colorectal cancer

[0104] Note: The administration volume was 10 μl / g (G7, 8), 15 μl / g (G1, 2, 3, 5) and 30 μl / g (G4, 6), and 200 μl / animal for group G9; ip: intraperitoneal injection; po: oral gavage; qd: once a day until the end of the experiment, for a total of 14 days.

[0105] The test results showed that in the Colon26 mouse model of colorectal cancer cachexia, liposomes, ursolic acid, and megestrol acetate tablets had no clear tumor-suppressing effect. Only in the high-dose liposome group (30 mg / kg) of the G4 early colorectal cancer cachexia model was a significant effect of preserving adipose tissue and reducing weight loss in mice observed. No improvement in fat loss was observed in other groups. The test results are summarized in Figure 1.

[0106] The comparison results of the left hind leg muscle (gastrocnemius and tibialis anterior) weight are shown in Figure 2. The improvement in muscle weight was not significant in any group. Specifically, the skeletal muscle weight in the high-dose liposome group (30 mg / kg) of the G4 early colorectal cancer cachexia model was not significantly different from that in the solvent group (p>0.05). The test results are summarized in Figure 2.

[0107] Example 3: Study on the effect of ursolic acid liposome injection in improving or treating liver cancer cachexia.

[0108] Example 3-1 Study in a PDX Model of Liver Cancer

[0109] Research objective: To test the in vivo cachexia-relieving effect of liposomes in a PDX mouse model of lung cancer.

[0110] The patient-derived, well-grown liver cancer tumor was aseptically cut into 2×2×2mm pieces. 3 Tumor masses were subcutaneously inoculated into male NCG mice, with a total of 48 mice inoculated. When the average tumor volume reached 40-60 mm... 3 Animals were divided into six groups of eight each, with medication administered at different times. The groups were: G1 (5% medical glucose injection, ip, qd x 21), G2 (low-dose liposomes, FAT 15 mg / kg, ip, qd x 21), G3 (high-dose liposomes, FAT 30 mg / kg, ip, qd x 21), G4 (low-dose liposomes, FAT 15 mg / kg, ip, qd x 21), G5 (high-dose liposomes, FAT 30 mg / kg, ip, qd x 21), and G6 (medroxyprogesterone acetate tablets, 3.75 mg / mouse, po, qd x 21). Groups G4 and G5 were administered medication when the tumor reached 200 mm in diameter. 3 Drug administration began on the left and right sides of the body. A separate control group, G7 (N=6), consisted of mice that did not receive tumor tissue. Animal weight was measured twice weekly, and the relationship between weight changes and drug administration time was recorded. The experiment ended one day after the last administration; mice were euthanized, liver tumors were removed and weighed, and the removed tumors from both the control and experimental groups were neatly arranged and photographed. Net weight (CW), tumor weight (TW), average daily food intake, tumor growth inhibition rate (TGITV), and tumor weight inhibition rate (TGITW) were calculated and statistically analyzed in the treatment group. At the experimental endpoint, epididymal fat and the left gastrocnemius and tibialis anterior muscles were collected and weighed.

[0111] Table 2. Dosage regimen for the study of cachexia in liver cancer.

[0112] Note: The administration volume for liposomes is 15 μL / g (15 mg / kg) and 30 μL / g (15 mg / kg); the administration volume for megestrol acetate is a fixed 200 μL / animal. ip: intraperitoneal injection; po: oral gavage; qd×21: once daily for 21 days.

[0113] In the early model, the epididymal fat weight in the solvent group was significantly lower than that in the blank control group. There were no significant differences between the drug administration groups, and no effect of reducing fat loss was observed. No significant increase in the weight of the gastrocnemius and tibialis anterior muscles was also observed.

[0114] In the late-stage model, the weight of the gastrocnemius and tibialis anterior muscles was significantly increased in the low-dose liposome group G4, while the high-dose group G5 showed an increasing trend but no significant difference.

[0115] The specific test results are summarized in Figure 3-4.

[0116] Example 3-2 Study in Clinical Trial II

[0117] In an ongoing Phase II clinical trial of ursolic acid liposome injection, interim data showed that in multiple patients with liver cancer, treatment benefit was closely associated with cachexia when ursolic acid liposome injection was administered alone. Case information is summarized in Table 3 below.

[0118] Table 3 Summary of cases of liver cancer cachexia in clinical trials II

[0119] Example 4: Study on the effect of ursolic acid liposome injection in improving or treating lung cancer cachexia

[0120] Research objective: To evaluate the in vivo pharmacodynamics of liposomes in mouse models of early and late LLC lung cancer cachexia and to explore their potential mechanism of action.

[0121] LLC cells were grown at a rate of 5 × 10 5 A dose of [number] mice was administered subcutaneously to the right flank of 64 female C57BL / 6J mice. The treatment was initiated when the average tumor volume reached 40-60 mm. 3 Animals were divided into eight groups, with eight animals in each group. The groups were: G1 (5% medical glucose injection) (ip, qd×21), G2 (low-dose liposomes, FAT 15mg / kg, ip, qd×21), G3 (high-dose liposomes, FAT 30mg / kg, ip, qd×21), G4 (low-dose liposomes, FAT 15mg / kg, ip, qd×21), G5 (high-dose liposomes, FAT 30mg / kg, ip, qd×21), G6 (low-dose ursolic acid, UA raw material, DMSO solvent 100mg / kg, po, qd×21), G7 (high-dose ursolic acid, UA raw material, DMSO solvent 200mg / kg, po, qd×21), and G8 (medroxyprogesterone acetate tablets, 3.75mg / mouse, po, qd×21). In groups G4 and G5, the tumors reached 200 mm in size. 3Drug administration began around 10:00 AM. An additional group, G9 (N=8), served as a blank control group without tumor tissue inoculation. Animal weight was measured twice weekly, and the relationship between weight changes and drug administration time was recorded. The experiment ended one day after the last drug administration. Mice were euthanized, liver tumors were removed and weighed, and the removed tumors from both the control and test groups were neatly arranged and photographed. Net weight (CW), tumor weight (TW), average daily food intake, and tumor growth inhibition rate (TGI) were calculated for the treatment group. TV Tumor weight inhibition rate (TGI) TW ) and perform statistical analysis. At the end of the experiment, ovarian fat and the left gastrocnemius and tibialis anterior muscles were collected and weighed.

[0122] Table 4. Study dosing regimens for lung cancer cachexia

[0123] Note: The administration volume for liposomes is 15 μL / g (15 mg / kg) and 30 μL / g (15 mg / kg); the administration volume for ursolic acid is 10 μL / g; and the administration volume for megestrol acetate is a fixed 200 μL / animal. ip: intraperitoneal injection; po: oral gavage; qd×21 means once daily for 21 days.

[0124] In an early-stage cachexia model of LLC tumor-bearing mice, liposomes demonstrated good tolerability and certain efficacy, particularly in inhibiting tumor growth and promoting muscle fiber recovery. Liposomes significantly increased periovarian fat content in mice at both low and high doses, showing their potential in improving cachexia-related fat reduction. In the early-stage cachexia model of LLC tumor-bearing mice, the liposome group was superior to the ursolic acid API group.

[0125] The low-dose liposome group was superior to the high-dose group. Specific test results are summarized in Figures 5-11.

[0126] Four hours after the last drug administration, the right gastrocnemius muscle of LLC tumor-bearing early cachexia mice was harvested for protein extraction. Western blot was used to detect the relative expression levels of P-STAT3, STAT3, and SIRT1 proteins in the gastrocnemius muscle tissue. The P-STAT3 / STAT3 ratio is shown in Figure 12, and the relative quantitative results of SIRT1 protein are shown in Figure 13. As shown in Figure 12, there was no significant difference in the P-STAT3 / STAT3 ratio among the groups. Figure 13 also shows no statistically significant difference among the groups.

[0127] In an LLC mouse model of advanced cachexia bearing tumors, liposomes demonstrated significant effects in improving muscle fiber atrophy and increasing fat reserves, particularly showing the potential to promote body weight and muscle fiber recovery. Muscle fiber cross-sectional area analysis showed that the low-dose liposome group significantly increased the muscle fiber area of ​​the gastrocnemius and tibialis anterior muscles, while the high-dose group had no significant effect on gastrocnemius muscle recovery, but its effect on the tibialis anterior muscle was superior to the low-dose ursolic acid group. This indicates that liposomes promote muscle fiber recovery, especially in the tibialis anterior muscle. The test results are summarized in Figures 14-17.

[0128] Four hours after the last administration of LLC tumor-bearing mice with advanced cachexia, the right gastrocnemius muscle was harvested for protein extraction. Western blot analysis was used to detect the relative expression levels of P-STAT3, STAT3, and SIRT1 in the gastrocnemius muscle tissue. The P-STAT3 / STAT3 ratio is shown in Figure 18, and the relative quantitative results of SIRT1 protein are shown in Figure 19. There was no significant difference in the P-STAT3 / STAT3 ratio among the groups. There was also no statistically significant difference in SIRT1 expression levels among the groups.

[0129] Overall, the low-dose liposome group showed greater advantage in both early and late stages of lung cancer cachexia. In muscle atrophy during both early and late stages of lung cancer cachexia, the low-dose liposome group was superior to the high-dose group; however, in fat loss during late-stage lung cancer cachexia, there was little difference between the high- and low-dose liposome groups.

[0130] Example 5: Study on the effect of ursolic acid liposome injection in improving or treating cachexia in early colorectal cancer.

[0131] Objective: Based on the exploratory study in Example 2, the dosage was adjusted to low (10 mg / kg), medium (20 mg / kg), and high (40 mg / kg) to further investigate the alleviating and therapeutic effects of different doses of ursolic acid liposome injection on early colorectal cancer cachexia, including improving weight loss, improving appetite, and improving muscle weakness.

[0132] Methods: Colorectal cancer tumors from Colon 26 mice were subcutaneously transplanted into the right subcutaneous tissue of male BALB / c mice (21-23g). Four days after tumor inoculation, the tumors grew to a mean volume of 37 mm. 3At the time of treatment, tumor-bearing mice were randomly divided into 7 groups (G2-G8) based on body weight and tumor volume, with an additional group of normal animals (G1) that were not inoculated with tumor cells. Each group contained 12 mice. Mice in groups G1-G8 were treated with water for injection, water for injection, solvent (5% glucose injection), low-dose ursolic acid liposomes (10 mg / kg), medium-dose ursolic acid liposomes (20 mg / kg), high-dose ursolic acid liposomes (40 mg / kg), methimazole (30 mg / kg, megestrol acetate oral suspension, 1 ml: 125 mg (150 ml / bottle)), and anamoxetine (30 mg / kg, 50 mg / tablet), respectively. After grouping, the tumor volume, body weight, and net body weight of the mice were measured three times a week. The food consumption of the mice was calculated, the muscle grip strength of the mice was measured, and the changes in epididymal adipose tissue and the changes in the cross-sectional area of ​​muscle fibers were observed.

[0133] Table 5. Dosage regimens for early colorectal cancer cachexia

[0134] Note: Anamorline is calculated in hydrochloride form; the administration volume is 10 μl / g; ip: intraperitoneal injection; po: oral gavage; qd: once a day until the end of the experiment.

[0135] After grouping, mice were weighed daily (BW) until the end of the experiment, and the relationship between changes in mouse weight and drug administration time was recorded. Simultaneously, the survival and health status of the mice, such as activity and feeding during drug administration, were observed. The net weight (CW) of the animals was calculated using the formula: weight of tumor-bearing mouse - tumor weight.

[0136] Two hours after the last administration, the animals were euthanized. The tumors in the mice were removed, weighed, and the removed tumors from the control and test groups were neatly arranged and photographed. The tumor weight inhibition rate (TGI) was calculated. TW (%) = (1 - T / C) × 100%.

[0137] Based on the weight of the remaining feed before 10:00 AM each day, calculate the food consumption of one mouse in each cage.

[0138] Before and after subcutaneous transplantation of Colon 26 tumor cells, the grip strength (including forelimbs and hindlimbs) of mice was measured using a mouse grip strength meter.

[0139] At the end of the experiment, the gastrocnemius muscle (left and right), tibialis anterior muscle (left and right), soleus muscle (left and right), and epididymal fat (left and right) were collected, weighed, photographed, and the muscle fiber area and epididymal fat area were measured.

[0140] Test results:

[0141] 1. Changes in body weight (net weight)

[0142] In terms of net body weight (CW), G2 was also significantly lower than G1 (p<0.05), indicating that the cachexia (cachexia) model was successfully established; there was no statistically significant difference between G3 and G2 (p>0.05); high-dose ursolic acid liposome treatment (G6 / 40mg / kg) was significantly higher than G3 (p<0.05), while there was no significant difference between methimazole (G7) or anamoxetine (G8) and G3 (p>0.05), and G6 (40mg / kg) was significantly higher than G7 and G4 (10mg / kg) (p<0.05).

[0143] The changes in body weight and net weight of mice in each group after grouping are shown in Figure 20.

[0144] 2. Food consumption

[0145] Regarding the changes in average food consumption among the groups of mice, the average food consumption of G2 mice was significantly lower than that of G1, indicating that the cachexia (cachexia) model was successfully established. At the end of the experiment, the average food consumption of G3 mice was close to that of G2; the average food consumption of the high-dose liposome treatment group (G6 / 40mg / kg) was significantly higher than that of other treatment groups, as well as G2 and G3. Among the other treatment groups, the low- and medium-dose liposome treatment groups (G4-G5) were close to that of the methimazole group (G7), while the anamoxetine group (G8) had the lowest average food consumption. The changes in average food consumption among the groups of mice are shown in Figure 21.

[0146] 3. Forelimb and hindlimb grip strength

[0147] The grip strength of both the forelimbs and hindlimbs of G2 mice decreased over time and was significantly lower than that of G1 (p<0.05), indicating that the cachexia (cachexia) model was successfully established. There was no statistically significant difference between G3 and G2 (p>0.05). The grip strength of mice treated with medium and high doses of liposomes (G4 / 10mg / kg-G6 / 40mg / kg) and Mexican (G7, hindlimb grip strength only) was significantly higher than that of G3 (p<0.05). G6 (40mg / kg) was also significantly higher than that of G7 and G8 (p<0.05). Among G4 and G6, there was a trend of increasing grip strength with increasing dose, and G6 (40mg / kg) was also significantly higher than that of G4 (10mg / kg) (p<0.05). The grip strength of the forelimbs of mice in each group is shown in Figure 22A, and the grip strength of the hindlimbs of mice is shown in Figure 22B.

[0148] 4. Cross-sectional area of ​​muscle fibers

[0149] In mice, the cross-sectional area of ​​muscle fibers in the gastrocnemius, tibialis anterior, and soleus muscles was significantly lower in G2 than in G1 (p<0.05). There was no statistically significant difference between G3 and G2 (p>0.05). Low, medium, and high doses of liposomes (G4 / 10mg / kg-G6 / 40mg / kg) and Mexican (G7) and Anamorin (G8) were significantly higher than in G3 (p<0.05). Significant differences were found between G6 (40mg / kg) and G4 (10mg / kg) and G5 (20mg / kg) (except for G4 vs G3 in the left and right gastrocnemius and tibialis anterior muscles, and G4 vs G5 in the left soleus muscle). The test results are summarized in Figure 23.

[0150] 5. Area of ​​epididymal fat cells

[0151] Regarding the area of ​​epididymal adipocytes, G2 was significantly lower than G1 (p<0.05), while there was no statistically significant difference between G3 and G2 (p>0.05). The area of ​​liposome-mediated adipocytes was significantly higher in G2 (only in the right epididymal fat), in high-dose treatment (G5 / 20mg / kg-G6 / 40mg / kg), and in Mexorubicin (G7) and Anamorin (G8) than in G3 (p<0.05). G6 (40mg / kg) was significantly higher than G4 (10mg / kg) and G5 (20mg / kg) (p<0.05). The test results are summarized in Figure 24.

[0152] Example 6: Study of ursolic acid liposome injection in improving or treating advanced (cachexia) rectal cancer cachexia.

[0153] Objective: Compared to Example 5, Example 6 used BALB / c male mice 12 days after tumor cell inoculation to further investigate the alleviating and therapeutic effects of ursolic acid liposome injection on cachexia (i.e., cachexia stage) in advanced colorectal cancer. At the start of treatment, the net weight of the modeled mice was 5% lower than that of the non-modeled age-matched mice, exhibiting cachexia stage symptoms.

[0154] Methods: Colorectal cancer tumors from Colon 26 mice were subcutaneously transplanted into the right subcutaneous tissue of male BALB / c mice (21-23g). Twelve days post-inoculation, the tumors grew to a mean volume of 451 mm². 3Tumor-bearing mice were randomly divided into 7 groups (G2–G8) based on body weight and tumor volume, with an additional group of normal animals (G1) as a control group without tumor cells. Each group consisted of 12 mice. Mice in groups G1–G8 were treated with water for injection, water for injection, solvent (5% glucose injection), low-dose liposomes (10 mg / kg), medium-dose liposomes (20 mg / kg), high-dose liposomes (40 mg / kg), metformin (30 mg / kg), or anamoxetine (30 mg / kg), respectively. Tumor volume, body weight, and net body weight were measured three times weekly after grouping. Food consumption was calculated, muscle grip strength was assessed, changes in epididymal adipose tissue were observed, and changes in the cross-sectional area of ​​muscle fibers were measured.

[0155] The administration regimen was the same as in Table 5 of Example 5. The testing methods for net body weight (CW), food consumption, forelimb and hindlimb grip strength, muscle fiber cross-sectional area, and epididymal fat cell area were the same as in Example 5.

[0156] Test results:

[0157] 1. Changes in body weight (net weight)

[0158] In terms of net body weight (CW), G2 was also significantly lower than G1 (p<0.05), indicating successful establishment of the cachexia (cachexia) model; there was no statistically significant difference between G3 and G2 (p>0.05); low, medium, and high doses of liposomes (G4 / 10mg / kg-G6 / 40mg / kg) were significantly higher than G3 (p<0.05), while there was no significant difference between G7 and G8 treated with methimazole or anamoxetine (G8) and G3 (p>0.05), and G6 (40mg / kg) was also significantly higher than G7 and G8 (p<0.05), and there was no statistically significant difference among the three groups of G4-G6 (10mg / kg-40mg / kg) (p>0.05). The changes in net body weight of mice after grouping are shown in Figure 25.

[0159] Note: Data are expressed as mean ± SEM.

[0160] 2. Food consumption

[0161] Regarding the changes in average food consumption among the groups of mice, the average food consumption of G2 mice was significantly lower than that of G1, indicating that the cachexia (cachexia) model was successfully established. At the end of the experiment, the average food consumption of G3 mice was close to that of G2. The average food consumption of the low, medium, and high dose liposome treatment groups (G4 / 10mg / kg-G6 / 40mg / kg) was significantly higher than that of G3, and was close to that of methimazole and anamoline. The changes in average food consumption among the groups of mice are shown in Figure 26.

[0162] 3. Forelimb and hindlimb grip strength

[0163] The grip strength of both the forelimbs and hindlimbs of G2 mice decreased over time and was significantly lower than that of G1 (p<0.05), indicating that the cachexia (cachexia) model was successfully established. There was no statistically significant difference between G3 and G2 (p>0.05). The grip strength of mice treated with low, medium, and high doses of liposomes (G4 / 10mg / kg-G6 / 40mg / kg) and with Mexorubicin (G7) and Anamox (G8) was significantly higher than that of G3 (p<0.05). G6 (40mg / kg) was also significantly higher than that of G7 and G8 (p<0.05). Among G4 (10mg / kg) and G6 (40mg / kg), there was a trend of increasing grip strength with increasing dose, but there was no significant difference (p>0.05). The grip strength of the forelimbs of mice in each group is shown in Figure 27A, and the grip strength of the hindlimbs of mice in each group is shown in Figure 27B.

[0164] 4. Cross-sectional area of ​​muscle fibers

[0165] In mice, the cross-sectional area of ​​muscle fibers in the gastrocnemius, tibialis anterior, and soleus muscles was significantly lower in G2 than in G1 (p<0.05). There was no statistically significant difference between G3 and G2 (p>0.05). Low, medium, and high doses of liposomes (G4 / 10mg / kg-G6 / 40mg / kg) and Mexorubicin (G7) and Anamorin (G8) showed significantly higher levels than G3 (p<0.05). Significant differences were found between G6 (40mg / kg) and G4 (10mg / kg) and G5 (20mg / kg) (except for G4 vs G3 and G4 vs G5 in the left tibialis anterior muscle). The test results are summarized in Figure 28.

[0166] 5. Area of ​​epididymal fat cells

[0167] Regarding the area of ​​epididymal adipocytes, G2 was significantly lower than G1 (p<0.05), while there was no statistically significant difference between G3 and G2 (p>0.05). Liposomes at low (excluding left epididymal fat), medium, and high doses (G4 / 10mg / kg-G6 / 40mg / kg), as well as Mexorubicin (G7) and Anamorin (G8), were significantly higher than G3 (p<0.05). G6 (40mg / kg) showed significant differences from G4 (10mg / kg) and G5 (20mg / kg). The test results are summarized in Figures 29A-29B.

[0168] Based on the combined test results of Examples 2 and 5-6, in the treatment of early and late (cachexia) rectal cancer cachexia, the test results of medium- to high doses (20 mg / kg, 30 mg / kg, 40 mg / kg) were superior to those of low doses (10 mg / kg, 15 mg / kg).

[0169] This invention provides experimental evidence for the application of liposomes in the treatment of cachexia. During administration to mice in different cancer models, the animals tolerated the medication well, with no adverse reactions observed, indicating that the use of low and high doses of liposomes is safe.

Claims

1. Use of an ursolic acid injection composition in the preparation of a medicament for improving or treating cancer cachexia.

2. The use as described in claim 1, wherein the cancer cachexia is selected from gastrointestinal cancer cachexia, liver cancer cachexia, or lung cancer cachexia.

3. The use as described in claim 1 or 2, wherein the ursolic acid injection composition is a liposome injection, a liposome injection, or a nanoemulsion injection, and the single dose of ursolic acid is 75-260 mg or 50-130 mg / m³. 2 .

4. The use as described in any one of claims 1 to 3, wherein the liposome injection or liposome injection comprises ursolic acid, phospholipids, and a pH adjuster; preferably, the ursolic acid injection composition is a liquid injection or a lyophilized injection using a lyophilized scaffold; more preferably, the injection is administered intravenously.

5. The use as described in claim 4, wherein The content of ursolic acid or its pharmaceutically acceptable salt in a unit dosage form is 3-12 mg / vial; The weight ratio of ursolic acid or its pharmaceutically acceptable salt to phospholipid is 0.1–10:5–500; The phospholipids are selected from lecithin, soybean lecithin, hydrogenated soybean lecithin, phosphatidylethanolamine, synthetic phosphatidylserine, phosphatidylinositol, sphingomyelin, methionine, cetylphosphatidylcholine, dimyristoyl lecithin, distearate phosphatidylethanolamine, or a mixture of two or more of the above. The pH adjuster is a buffer solvent, and the pH value of the aqueous phase is controlled within the range of 6-7 during the preparation process of the buffer. The freeze-dried scaffold agent is selected from mannitol, sucrose, lactose, or a combination thereof.

6. The use according to any one of claims 1-5, wherein the cancer cachexia is gastrointestinal cancer cachexia.

7. The use as described in claim 6, wherein the gastrointestinal cancer cachexia is selected from colorectal cancer cachexia, gastric cancer cachexia, esophageal cancer cachexia, and pancreatic cancer cachexia.

8. The use as described in any one of claims 6-7, wherein the use is selected from improving fat loss, improving weight loss, improving muscle weakness and / or improving dietary loss; the cancer cachexia is selected from early stage, late stage (cachexia stage) or refractory stage; Preferably, the intended use is selected from: It improves fat loss in patients with early or late (cachexia) gastrointestinal cancer cachexia, and is more preferably fat loss in patients with early colorectal cancer cachexia. Improve weight loss, muscle weakness and / or loss of appetite in patients with early or late (cachexia) gastrointestinal cancer cachexia; Improve weight loss, muscle weakness, and / or loss of appetite in patients with early or late-stage (cachexia) colorectal cancer cachexia.

9. The use as described in any one of claims 6-8, wherein the single application dose of ursolic acid is 150-260 mg or 100-130 mg / m². 2 ; Preferred, In improving fat loss in patients with early or late-stage (cachexia) gastrointestinal cancer cachexia, the single dose of ursolic acid is 150-260 mg or 100-130 mg / m². 2 ; In improving weight loss, muscle weakness, and / or food loss in patients with early or late-stage (cachexia) gastrointestinal cancer cachexia, the single dose of ursolic acid is 150-260 mg or 100-130 mg / m². 2 ;or In improving weight loss, muscle weakness, and / or loss of appetite in patients with early or late-stage (cachexia) colorectal cancer cachexia, the single dose of ursolic acid is 150-260 mg or 100-130 mg / m². 2 .

10. The use according to any one of claims 1-9, wherein the ursolic acid content in the unit formulation of the ursolic acid injection composition is 3-12 mg / vial; preferably, the ursolic acid content in the unit formulation of the ursolic acid injection liposome is 3 mg / vial, 10 mg / vial, or 12 mg / vial.

11. The use according to any one of claims 1-5, wherein the cancer cachexia is liver cancer cachexia.

12. The use as described in claim 11, wherein liver cancer cachexia is early-stage liver cancer cachexia or late-stage (cachexia stage) liver cancer cachexia.

13. The use as described in any one of claims 11-12, wherein the use is to improve muscle atrophy in advanced (cachexia) hepatocellular carcinoma cachexia; preferably skeletal muscle atrophy.

14. The use as described in any one of claims 11-13, wherein the single application dose of ursolic acid is 75 mg-160 mg or 50-80 mg / m². 2 .

15. In the use described in claim 14, the single dose of ursolic acid in improving muscle atrophy in patients with advanced (cachexia) hepatocellular carcinoma cachexia is 75 mg-160 mg or 50-80 mg / m². 2 .

16. The use according to any one of claims 11-15, wherein the ursolic acid content in the unit formulation of the ursolic acid injection composition is 3-12 mg / vial; preferably, the ursolic acid content in the unit formulation of the ursolic acid injection liposome is 3 mg / vial, 10 mg / vial, or 12 mg / vial.

17. The use according to any one of claims 1-5, wherein the cancer cachexia is lung cancer cachexia, wherein the ursolic acid injection composition is as described in any one of claims 2-5, wherein the single dose of ursolic acid is 75-260 mg or 50-130 mg / m². 2 .

18. The use as described in claim 17, wherein lung cancer cachexia is early lung cancer cachexia or late-stage (cachexia stage) lung cancer cachexia.

19. The use as described in any one of claims 17-18, wherein the use is to improve muscle atrophy in patients with early-stage lung cancer cachexia, or to improve muscle atrophy and fat loss in patients with late-stage (cachexia stage) lung cancer cachexia, preferably said muscle atrophy is skeletal muscle atrophy.

20. In the use according to any one of claims 19, the single dose of ursolic acid in improving muscle atrophy in patients with early-stage lung cancer cachexia is 75-160 mg, 150-260 mg, or 50-80 mg / m². 2 Or 100-130mg / m 2 Preferred dosage is 75-160mg or 50-80mg / m². 2 In improving muscle atrophy and fat loss in patients with advanced (cachexia) lung cancer cachexia, the single dose of ursolic acid was 75-160 mg, 150-260 mg, and 50-80 mg / m². 2 Or 100-130mg / m 2 Preferred dosage is 75-160mg or 50-80mg / m². 2 .

21. The use according to any one of claims 17-20, wherein the ursolic acid content in the unit formulation of the ursolic acid injection composition is 3-12 mg / vial; preferably, the ursolic acid content in the unit formulation of the ursolic acid injection liposome is 3 mg / vial, 10 mg / vial, or 12 mg / vial.

22. The use as described in any one of claims 1-21, wherein the ursolic acid injection composition is administered in combination with other drugs or therapies for treating cancer, preferably the other drugs for treating cancer are multi-target tyrosine kinase receptor inhibitors or PD-1 inhibitors, more preferably sorafenib, lenvatinib, donafenib, anlotinib, regorafenib, sintilimab, or camrelizumab.

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