Diammineplatinum bisdicarboxylate anti-cancer drug

Abstract

The invention relates to a double-dicarboxylic acid diammineplatinum anticancer drug. Specifically, the present invention relates to a pharmaceutical composition for preventing or treating cancer, containing bis-dicarboxylic acid diamineplatinum and N-hydroxyethyl ursodeoxycholic acid amide as active ingredients, and an anti-cancer drug containing the active ingredients. The present invention also relates to methods of providing for the treatment of cancer using diammineplatinum bisdicarboxylate and N-hydroxyethyl ursodesoxycholic acid amide, as well as other various uses using a combination of both diammineplatinum bisdicarboxylate and N-hydroxyethyl ursodesoxycholic acid amide, as well as methods of using diammineplatinum bisdicarboxylate and N-hydroxyethyl ursodesoxycholic acid amide.

Description

Technical fields:

[0001] This invention relates to compositions comprising diaminoplatinum bis(dicarboxylic acid) and N-hydroxyethylursodeoxycholic acid amide or analogues as active ingredients for the prevention, improvement, or treatment of cancer. Specifically, this invention relates to pharmaceutical compositions for the prevention or treatment of cancer comprising diaminoplatinum bis(dicarboxylic acid) and N-hydroxyethylursodeoxycholic acid amide or analogues as active ingredients, and anticancer drugs comprising said active ingredients. This invention also relates to methods for treating cancer using diaminoplatinum bis(dicarboxylic acid) and N-hydroxyethylursodeoxycholic acid amide, and other similar products, as well as various other uses using combinations of diaminoplatinum bis(dicarboxylic acid) and N-hydroxyethylursodeoxycholic acid amide, and other similar products. Background technology:

[0002] Cancer is a major disease that has long been among the leading causes of death worldwide, seriously threatening human life and health. Currently, clinical treatments for cancer include surgical resection, radiotherapy, gene therapy, and chemotherapy. Among these, chemotherapy, which uses anticancer drugs as its core, has become one of the mainstream clinical treatments for cancer due to its wide applicability and ability to target lesions throughout the body.

[0003] Platinum-based drugs, as a classic class of broad-spectrum anticancer drugs, are widely used in the clinical treatment of various malignant tumors due to their unique mechanism of action (such as disrupting the DNA structure and function of tumor cells). These drugs cover multiple cancer types, including bladder cancer, lung cancer, ovarian cancer, head and neck cancer, testicular cancer, liver cancer, colorectal cancer, gastric cancer, and pancreatic cancer, providing an important drug option for cancer treatment.

[0004] However, platinum-based drugs have significant limitations in clinical application: they are prone to inducing various serious toxic side effects after administration to cancer patients, with organ damage being the most typical, such as hepatotoxicity and kidney damage. These toxic side effects not only reduce patients' treatment tolerance but may even lead to treatment interruption, thereby directly affecting the efficacy of chemotherapy and limiting the clinical application value of platinum-based drugs.

[0005] As an important member of the platinum-based anticancer drugs, diaminoplatin dicarboxylate also faces the aforementioned challenge of balancing efficacy with toxic side effects. Based on this, the inventors, with the core objective of improving the anticancer efficacy of diaminoplatin dicarboxylate and reducing its toxic side effects, have conducted in-depth research and completed the composition and its uses described in this invention for the prevention, improvement, and treatment of cancer. Summary of the Invention:

[0006] The object of this invention is to provide a composition comprising diaminoplatinum dicarboxylic acid and N-hydroxyethylursodeoxycholic acid amide for the prevention, improvement or treatment of cancer.

[0007] Specifically, one object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of cancer, comprising diaminoplatinum dicarboxylic acid and N-hydroxyethylursodeoxycholic acid amide as active ingredients.

[0008] Another object of the present invention is to provide a medicament for the prevention or improvement of cancer, comprising diaminoplatinum dicarboxylic acid and N-hydroxyethylursodeoxycholic acid amide as active ingredients.

[0009] Another object of the present invention is to provide an anticancer active composition for the prevention or treatment of cancer, comprising diaminoplatinum dicarboxylic acid and N-hydroxyethylursodeoxycholic acid amide as active ingredients.

[0010] Another object of the present invention is to provide a method for treating cancer by administering pharmaceutically effective amounts of diaminoplatinum dicarboxylic acid and N-hydroxyethylursodeoxycholic acid amide to a patient.

[0011] Another object of the present invention is to provide the use of diamine bis(dicarboxylic acid) diamine cycloplatinum and N-hydroxyethyl ursodeoxycholic acid amide in the preparation of a medicament for treating cancer.

[0012] Another object of the present invention is to provide a composition comprising diaminoplatinum dicarboxylic acid and N-hydroxyethylursodeoxycholic acid amide for the treatment of cancer.

[0013] Another object of the present invention is to provide the use of the diamine bis(dicarboxylic acid) diamine cyclophosphamide and N-hydroxyethyl ursodeoxycholic acid amide for the treatment of cancer.

[0014] Another object of the present invention is to provide a method for treating cancer by administering to a patient a pharmaceutically effective amount of diaminoplatinum dicarboxylic acid and N-hydroxyethylursodeoxycholic acid amide as an anticancer active composition.

[0015] Another object of the present invention is to provide the use of diamine bis(dicarboxylic acid) diamine cycloplatinum and N-hydroxyethyl ursodeoxycholic acid amide in the preparation of anticancer active compositions.

[0016] Another object of the present invention is to provide a composition comprising diaminoplatinum dicarboxylic acid and N-hydroxyethyl ursodeoxycholic acid amide, which are used as an anticancer active composition.

[0017] Another object of the present invention is to provide the use of diaminoplatinum dicarboxylic acid and N-hydroxyethyl ursodeoxycholic acid amide as an anticancer active composition.

[0018] The inventors have discovered that diamine bis(diacyl)-based platinum and N-hydroxyethylursodeoxycholic acid amide have improved cancer treatment effects compared to diamine bis(diacyl)-based platinum alone. Specifically, N-hydroxyethylursodeoxycholic acid amide can effectively enhance the antitumor effect of diamine bis(diacyl)-based platinum. Due to this synergistic effect on antitumor activity, it is possible to consider reducing the dosage of diamine bis(diacyl)-based platinum, thereby potentially reducing the toxic side effects caused by diamine bis(diacyl)-based platinum.

[0019] The inventors believe that the N-hydroxyethyl ursodeoxycholic acid amide molecule has both a rigid steroidal structure and multiple hydroxyl sites in its molecular skeleton. Its amide and hydroxyl groups can act as hydrogen bond donors or acceptors, forming multi-site, reversible hydrogen bond associations with the carboxyl groups, amide groups and coordinated water molecules in the bicyclic platinum molecule, thereby constructing a stable non-covalent supramolecular composite structure in the solution system.

[0020] The rigid steroidal framework can form a certain three-dimensional coating effect on the bicyclic platinum molecule, reducing premature hydration and non-specific protein binding of bicyclic platinum in the body fluid environment, thereby improving its structural stability and in vivo circulation stability.

[0021] Meanwhile, this bile acid derivative has similar biocompatibility to endogenous bile acids, and enhances the deliverability and effective exposure level of bicyclic platinum in the physiological environment without introducing covalent bond modification. The two exhibit a synergistic pharmacokinetic improvement effect.

[0022] Therefore, the present invention provides a method for reducing the toxic side effects of diamine dicarboxylate, comprising administering diamine dicarboxylate and N-hydroxyethylursodeoxycholic acid amide to a subject simultaneously or sequentially (e.g., orally).

[0023] The present invention also provides the use of N-hydroxyethylursodeoxycholic acid amide in the preparation of a medicament for reducing the toxic side effects of diaminoplatin dibis(dicarboxylate), said medicament may comprise reducing diaminoplatin dibis(dicarboxylate) itself, or comprise both diaminoplatin dibis(dicarboxylate) and N-hydroxyethylursodeoxycholic acid amide.

[0024] The administration of N-hydroxyethylursodeoxycholic acid amide and diaminoplatin dicarboxylate can be simultaneous or sequential. For example, N-hydroxyethylursodeoxycholic acid amide and diaminoplatin dicarboxylate can be mixed together to form a single dose for administration, or N-hydroxyethylursodeoxycholic acid amide can be administered first, followed by diaminoplatin dicarboxylate, or vice versa. For instance, N-hydroxyethylursodeoxycholic acid amide and diaminoplatin dicarboxylate can be packaged into a single capsule for convenient simultaneous administration. Alternatively, diaminoplatin dicarboxylate can be administered within one hour after N-hydroxyethylursodeoxycholic acid amide, or vice versa. Preferably, due to the rapid target-reaching properties of diaminoplatin dicarboxylate, administering N-hydroxyethylursodeoxycholic acid amide first, followed by diaminoplatin dicarboxylate within one hour, is considered. On the other hand, from an administration convenience perspective, simultaneous administration of a single dosage form results in higher patient compliance.

[0025] For example, the diamine dicarboxylic acid complex platinum described in this invention can refer to active ingredients such as cisplatin, carboplatin, nedaplatin, oxaliplatin, lobaplatin, miplatin, bicyclic platinum, methyldiphenylplatinum, and ceterplatin. For instance, it can be a diamine dicarboxylic acid complex platinum derivative with the following structure.

[0026]

[0027] Based on the synergistic or enhancing effect of N-hydroxyethyl ursodeoxycholic acid amide on diaminoplatinum dibis(dicarboxylic acid).

[0028] For example, the ratio (by mass) of the active ingredient diaminoplatinum dibis(dicarboxylic acid) to N-hydroxyethylursodeoxycholic acid amide is from about 1:0.01 to about 1:99, preferably about 1:1, about 1:1.5, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:20, about 1:30, about 1:40, about 1:50, about 1:60, about 1:70, about 1:80, about 1:90, and the range between these ratios.

[0029] Alternatively, the ratio of the active ingredient, diaminoplatinum dibis(dicarboxylic acid), to N-hydroxyethylursodeoxycholic acid amide is approximately 0.1:1 to approximately 100:1, for example, approximately 0.1:1, approximately 0.2:1, approximately 0.3:1, approximately 0.4:1, approximately 0.45:1, approximately 0.5:1, approximately 0.55:1, approximately 0.6:1, approximately 0.65:1, approximately 0.7:1, approximately 0.75:1, approximately 0.8:1, or approximately 0.85... The ratios are approximately 1, 0.9:1, 0.95:1, 1:1, 1:1.1, 1.2:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 20:1, 30:1, 40:1, 50:1, 60:1, 70:1, 80:1, 90:1, and the range of ratios between the above ratios.

[0030] Furthermore, the combined product may be in the form of a composition or a pharmaceutical composition, or the platinum-based drugs (e.g., carboplatin, cisplatin, bicycloplatin, oxalate platinum, etc.), N-hydroxyethylursodeoxycholic acid amide, or the other components in the combined product may each be in a separate formulation.

[0031] It is readily apparent that N-hydroxyethylursodeoxycholic acid amide analogs can also be used in the combination products of the present invention. Furthermore, the aforementioned mass ratio range also applies to N-hydroxyethylursodeoxycholic acid amide analogs. For example, the ratio (by mass) of the anticancer drug active ingredient to the N-hydroxyethylursodeoxycholic acid amide analog is from about 1:0.01 to about 1:99, preferably about 1:1, about 1:1.5, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:20, about 1:30, about 1:40, about 1:50, about 1:60, about 1:70, about 1:80, about 1:90, and the range between these ratios.

[0032] The N-hydroxyethyl ursodeoxycholic acid amide, N-hydroxyethyl ursodeoxycholic acid amide analogue, or diaminoplatinum dicarboxylate active ingredient of the present invention can be obtained by commercially available or known methods.

[0033] In this invention, the term "cancer" can refer to solid tumors, non-solid tumors, or metastatic tumors, including, but not limited to, primary melanoma, metastatic melanoma, adenocarcinoma, squamous cell carcinoma, adenosquamous cell carcinoma, thymoma, sarcoma, non-Hodgkin lymphoma, Hodgkin lymphoma, leukemia, prostate cancer, ovarian cancer, pancreatic cancer, colorectal cancer, multiple myeloma, neuroblastoma, bladder cancer, cervical cancer, kidney cancer, brain cancer, bone cancer, stomach cancer, esophageal cancer, intestinal cancer, liver cancer, lung cancer, lymphoma, leukemia, breast cancer, head and neck cancer, cervical cancer, uterine cancer, melanoma, and other cancers and related cancer symptoms. Preferably, the cancer treated using this invention is lung cancer, pancreatic cancer, kidney cancer, head and neck tumors, lung cancer, esophageal cancer, breast cancer, ovarian cancer, colorectal cancer, or stomach cancer and their related symptoms.

[0034] The diamine dicarboxylic acid diammonium oxyplatinum and N-hydroxyethyl ursodeoxycholic acid amide or N-hydroxyethyl ursodeoxycholic acid amide analogs, as active ingredients of the present invention, can be used together with pharmaceutically acceptable carriers. In addition to the active ingredients, the methods, uses, and products of the present invention may also include suitable pharmaceutically acceptable carriers, including excipients and adjuvants that facilitate the formulation of the active ingredients.

[0035] While the combination of active ingredients of the present invention may not be suitable for use as an injection or infusion, it is conceivable that dosage forms suitable for injection or infusion include aqueous and non-aqueous sterile injections and aqueous and non-aqueous sterile suspensions. The sterile injections may optionally contain antioxidants, buffers, antibacterial agents, and solutes that enable the formulation to be isotonic with the blood of the subject. The sterile suspensions may include suspending agents and thickeners. The formulations may be present in single-dose or multi-dose containers, such as sealed ampoules, and may be stored under freeze-dried (lyophilized) conditions, requiring only the addition of a sterile liquid carrier, such as reconstitution with water for injection, before immediate use.

[0036] The active ingredient of the present invention may optionally be combined with a solid excipient, and the resulting mixture may optionally be ground, and, if necessary, further processed with a suitable adjuvant (e.g., magnesium stearate) to obtain the desired dosage form. Suitable excipients may be fillers, such as sugars including lactose, sucrose, mannitol, or sorbitol; cellulose or starch preparations, gelatin, tragacanth gum, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone. If necessary, disintegrants may be added, such as crystalline cellulose, croscarmellose, agar, or alginate or its salts, such as sodium alginate.

[0037] The effective amount of the active ingredient of the present invention can be any amount used to treat cancer, alleviate cancer symptoms, or inhibit cancer cells. It can be a dose unit equivalent to about 1-200 mg of a platinum-based active ingredient, preferably 10-100 mg or 1-9 mg of a platinum-based active ingredient. More preferably, the dose unit comprises about 40-80 mg or 3-6 mg of a platinum-based active ingredient. Most preferably, the dose unit comprises about 50-70 mg or 4-5 mg of a platinum-based active ingredient. Exemplarily, the platinum-based active ingredient is carboplatin, cisplatin, oxalate platinum, or bicycloplatin, etc. The amount of N-hydroxyethylursodeoxycholic acid amide or an N-hydroxyethylursodeoxycholic acid amide analogue contained in the unit dose or effective therapeutic amount is added in proportion. The determination of the effective amount is within the capabilities of those skilled in the art, particularly under the guidance of the disclosure provided herein. The preferred dosage of the pharmaceutical composition of the present invention varies depending on the patient's condition and weight, disease severity, drug form, route of administration, and time of administration, and can be appropriately selected by those skilled in the art to which this invention pertains.

[0038] According to the present invention, the pharmaceutical product (medicine, pillbox) of the present invention can be administered to a subject at any effective number of doses. Preferably, the pharmaceutical product (medicine, pillbox) of the present invention can be administered in multiple doses, for example from about 2 to about 100 doses or more. Exemplarily, from about 4 to 90 doses, or about 20 to 80 doses. In a particularly preferred embodiment, during administration, the pharmaceutical product (medicine, pillbox) of the present invention is administered to the subject, for example orally, at a frequency of about 3 times every other day.

[0039] The pharmaceutical compositions of the present invention can be administered to mammals such as rats, mice, golden hamsters, livestock, and humans via a variety of routes. Among all contemplated methods of administration, exemplary administration can be carried out by, for example, injection, oral administration, or rectal administration.

[0040] It should be understood that the pharmaceutical products (medicines, pillboxes) of the present invention can be formulated in any suitable manner for administration via any suitable route. For example, they can be formulated as capsules or tablets for oral administration.

[0041] The dosage units of the pharmaceutical products (medications, pharmaceutical compositions) of the present invention are based on the subjects routinely administered the medication. For example, the dosage units may be administered more than once daily, once every two days, once weekly, once monthly, etc. Exemplarily, the dosage unit may be based on a 2-times / week basis, i.e., twice a week, for example, once every three days. The dosage unit may also be 3 times / day, 2 times / day, 1 time / day, etc. It is conceivable that, based on the synergistic or enhancing effect of N-hydroxyethylursodeoxycholic acid amide on diaminoplatinum bis(dicarboxylate), the frequency of administration of the pharmaceutical products of the present invention may be lower than the routine administration frequency of the corresponding diaminoplatinum bis(dicarboxylate).

[0042] As used herein, the term "comprising" is synonymous with "including," "containing," or "characterized in," and is inclusive or open-ended, not excluding additional unstated elements, methods, or steps. Any expression of the term "comprising" herein, particularly in describing methods, uses, or products of the invention, should be understood to include those products, methods, and uses that are substantially composed of and comprised of the stated components or elements or steps. The invention exemplarily described herein may suitably be practiced without any one or more elements or limitations not specifically disclosed herein.

[0043] The instructions for use of the pharmaceutical products (e.g., pharmaceutical compositions, drugs, or pharmaceutical preparations) of the present invention may include the following: indications (cancer, such as lung cancer, pancreatic cancer, etc.), dosage (e.g., as exemplified above), and possible side effects, etc.

[0044] The term 'bis(diacarboxylic acid) diaminoplatinum' used in this article is a functional classification description used to refer to platinum compounds with similar coordination structures and antitumor activities.

[0045] To illustrate the present invention more clearly, the following embodiments are described in detail. However, these embodiments are merely exemplary descriptions of the present invention and should not be construed as limiting the present application. Attached image description:

[0046] Figure 1 The results show the tumor volume comparison of different treatment groups on day 10. There was no significant difference in tumor volume between the control group and the N-hydroxyethylursodeoxycholic acid amide group, and the control group had the highest tumor volume. The tumor volume of the bicycloplatin group was significantly lower than that of the control group. The combined treatment group had the lowest tumor volume, which was significantly lower than the other three groups, indicating that the combined administration of bicycloplatin and N-hydroxyethylursodeoxycholic acid amide had the best inhibitory effect on lung cancer xenografts in nude mice.

[0047] Figure 2 This study compares the inhibitory effects of bicycloplatin alone versus bicycloplatin combined with N-hydroxyethylursodeoxycholic acid amide on the growth of pancreatic cancer xenografts in BALB / c nude mice. In the bicycloplatin group, tumor volume showed a continuous and rapid increase with prolonged administration time, from 300±20 mm on day 0. 3 The growth reached 1280±110 mm on the 10th day. 3 Within 10 days, the tumor volume increased to 4.27 times its initial volume, indicating that bicycloplatin monotherapy has an inhibitory effect on the growth of pancreatic cancer xenografts in BALB / c nude mice. The tumor growth rate in the combination therapy group was significantly slower than that in the bicycloplatin group, and the tumor volume at all time points was lower than that in the bicycloplatin group. On day 10, the tumor volume in the combination therapy group was only 980±85 mm. 3It was 3.27 times the initial volume and only 76.6% of the tumor volume of the bicyclic platinum group at the same time. Figure 2 The results directly demonstrate that the combination of bicycloplatin and N-hydroxyethylursodeoxycholic acid amide has a synergistic antitumor effect. Compared with bicycloplatin monotherapy, the combination therapy can significantly delay the growth of pancreatic cancer xenografts in BALB / c nude mice, providing in vivo experimental evidence for the use of this combination therapy in the treatment of pancreatic cancer. Detailed implementation method:

[0048] The following examples further illustrate the present invention and are not intended to limit the scope of protection of the present invention. Those skilled in the art can modify these embodiments according to the specification, and as long as they do not depart from the spirit and scope of the present invention, they can obtain similar or the same results, all of which are within the scope of protection of the present invention.

[0049] Formulation Example 1: Preparation of Liquid Dosage

[0050] A liquid containing 50 mg of bicyclic platinum was prepared according to conventional liquid preparation methods, with a ratio of bicyclic platinum to N-hydroxyethyl ursodeoxycholic acid amide of 10:1.

[0051] Specifically, the following components are added to the glucose solution in the indicated weight ratios:

[0052] Bicyclic Platinum 10

[0053] N-hydroxyethylursodeoxycholic acid amide 1

[0054] Sterilize to obtain a liquid.

[0055] Formulation Example 2: Preparation of Liquid Formulation

[0056] A liquid containing 50 mg of bicyclic platinum was prepared according to conventional liquid preparation methods, with a ratio of bicyclic platinum to N-hydroxyethyl ursodeoxycholic acid amide of 20:1.

[0057] Specifically, the following components are added to the glucose solution in the indicated weight ratios:

[0058] Bicyclic Platinum 20

[0059] N-hydroxyethylursodeoxycholic acid amide 1

[0060] Sterilize to obtain a liquid.

[0061] Example 3: Antitumor effects of the combination of bicyclic platinum and N-hydroxyethylursodeoxycholic acid amide on various tumors.

[0062] Lung cancer A549, ovarian cancer A2780, and pancreatic cancer BXPC-3 were cultured, digested with trypsin, counted, and then the cells were suspended in DMEM containing 2% FBS and seeded in the center of a 96-well plate, with one side containing cell-free culture medium and the other three sides containing water.

[0063] (1) The sample to be tested (bicycloplatin; N-hydroxyethyl ursodeoxycholic acid amide and bicycloplatin in a mass ratio of 1:1) was prepared into a stock solution of bicycloplatin at 4 mg / ml using complete culture medium, filtered and sterilized for later use. Bicycloplatin and N-hydroxyethyl ursodeoxycholic acid amide can be added to the culture wells in proportion.

[0064] (2) The samples were gradually diluted 10 times with the storage solution as the highest concentration to obtain compounds with four concentration gradients.

[0065] (3) Discard the original culture medium and add the diluted sample to the corresponding cell well at a rate of 120 μL / well. The final concentration of the sample was determined by serial dilution of 4 mg / ml from bisplatinum, with a total of 4 concentration points.

[0066] (4) The cells were incubated for 72 hours in an incubator at 37°C, 5% CO2, 95% air, and 100% relative humidity.

[0067] (5) Add freshly prepared CCK-8 (10%) detection solution and incubate in a 37°C incubator for 2-4 hours.

[0068] (6) After gently shaking, measure the absorbance at a wavelength of 450 nm on the SpectraMax M5 device, and use the absorbance at 650 nm as a reference to calculate the suppression rate.

[0069] The inhibition rate of cell growth by the drug is calculated using the following formula:

[0070] Cell growth inhibition rate % = [(Ac-As) / (Ac-Ab)] × 100%

[0071] As: Sample 0A (cells + CCK-8 + sample to be tested)

[0072] Ac: OA (cells + CCK-8) of normal-growing cell control.

[0073] Ab: 0A (medium medium + CCK-8) of the blank control

[0074] (7) Use the software Graphpad Prism to fit the IC50 curve and calculate the IC50 value (0.015-0.120 mg / mL).

[0075] Simultaneous comparison of the two groups of samples' ability to kill various solid tumor cells showed no significant difference. Therefore, N-hydroxyethylursodeoxycholic acid amide has no negative impact on the in vitro tumor cell-killing ability of bicyclic platinum.

[0076] The above results also indicate that the combination does not exert its effect by enhancing the direct cytotoxicity of bicyclic platinum to tumor cells, but is more likely to exhibit a synergistic anti-tumor effect in the in vivo model through indirect mechanisms such as improving in vivo delivery behavior, reducing toxicity, and increasing effective exposure time.

[0077] Example 4: Inhibition of lung cancer cells by the combination of bicyclic platinum and N-hydroxyethylursodeoxycholic acid amide – tumorigenesis experiment in nude mice

[0078] Sixteen 4-week-old BALB / c nude mice that had been acclimatized for one week were randomly divided into four groups. Each mouse was subcutaneously injected with 200 μL of cell suspension (containing 1.0 × 10⁻⁶ cells per cell). 7 3II cells in the logarithmic growth phase).

[0079] When the tumor in the nude mouse grows to 120-150mm 3 At that time, the nude mice were re-randomized into 4 groups (a total of 4 groups: control group, N-hydroxyethylursodeoxycholic acid amide group, bicyclic platinum group, and combined group) and numbered.

[0080] The mice were administered medication once daily via tail vein. The N-hydroxyethylursodeoxycholic acid amide group received 20 mg / kg of N-hydroxyethylursodeoxycholic acid amide; the bicycloplatin group received 10 mg / kg of bicycloplatin; the combined group received both N-hydroxyethylursodeoxycholic acid amide (20 mg / kg) and bicycloplatin (10 mg / kg); the control group received no treatment other than normal feeding. Tumor volume and body weight were measured and recorded every two days.

[0081] All animal handling in animal experiments shall comply with the "Regulations on the Management of Laboratory Animals". When a tumor in a nude mouse exceeds 2000 mm², [further action is taken]. 3 If the condition worsens, the experiment should be stopped immediately, and all nude mice should be euthanized. Whole blood samples should be collected from the mice, and tumors and organs should be removed. A complete blood count should be performed on the whole blood samples, and the removed organs and tumors should be weighed and recorded.

[0082] The control group and the N-hydroxyethylursodeoxycholic acid amide group showed the fastest tumor growth and the largest tumor volume in nude mice, with no significant difference between the two groups. The tumor volume growth in the bicyclic platinum group and the combined group was slower than that in the control group and the N-hydroxyethylursodeoxycholic acid amide group, with the combined group exhibiting the slowest tumor growth rate and the smallest final tumor volume. Analysis of tumor volume data on day 10 showed that the tumor volume in the control group was 2270.36 ± 120.55 mm. 3 Similar to the N-hydroxyethylursodeoxycholic acid amide group, the tumor volume in the combined group was 580.72 ± 30.18 mm. 3 The tumor volume in the double-ring platinum group was 1218.4 ± 100.68 mm. 3 There was a significant difference compared to the control group. Figure 1 ).

[0083] Example 5: Antitumor application of the combination of bicycloplatin and N-hydroxyethylursodeoxycholic acid amide, and its comparison with bicycloplatin alone.

[0084] 4-week-old BALB / c nude mice were injected with 1×10⁻⁶ mmol / L on one side of their backs. 7 BALB / c pancreatic cancer cells in nude mice, with an average tumor volume of approximately 300 mm² in each group of animals. 3 At that time, nude mice were injected intravenously via the tail vein with either dicycloplatin alone or a combination of N-hydroxyethylursodeoxycholic acid amide and dicycloplatin (weight ratio 10:2), once daily for 10 days. The corresponding dicycloplatin dose was 10 mg / kg. The tumor volume of nude mice was measured and recorded every two days. The results are shown in […]. Figure 2 .

[0085] Figure 2 This indicates that the combination of bicycloplatin and N-hydroxyethylursodeoxycholic acid amide showed a more significant anti-pancreatic cancer effect than the positive control (bicycloplatin group).

[0086] Example 6: Hepatotoxicity of the combination of bicycloplatin and N-hydroxyethylursodeoxycholic acid amide in a BALB / c nude mouse pancreatic cancer model, and its comparison with bicycloplatin alone.

[0087] 1×10 7 Pancreatic cancer cells from BALB / c nude mice were inoculated into one side of the back of 4-week-old BALB / c nude mice. Four days later, the animals were divided into two groups of three. One group received intravenous injection of bicycloplatin alone, while the other group received a combination of bicycloplatin and N-hydroxyethylursodeoxycholic acid amide (weight ratio 5:1) once daily for 8 days. The corresponding bicycloplatin dose was 10 mg / kg. Serum was collected on days 1, 3, 5, 7, and 9 after intravenous injection to measure alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP).

[0088] Table 1. Changes in serum liver function indicators in BALB / c nude mice under different administration routes (mean ± SD, n = 3)

[0089] (1) Alanine aminotransferase (ALT)

[0090] Testing time (days) ALT (U / L) in the bicyclic platinum group Combined group ALT(U / L) 1 78±6 75±5 3 115±10 95±8 5 160±14 120±10 7 195±18 145±12 9 230±20 165±15

[0091] (2) Aspartate aminotransferase (AST)

[0092] Testing time (days) AST (U / L) in the dual-ring platinum group Joint group AST(U / L) 1 85±7 82±6 3 125±12 100±9 5 175±15 135±12 7 215±20 160±14 9 255±22 180±16

[0093] (3) Alkaline phosphatase (ALP)

[0094] Testing time (days) ALP (U / L) in the bicyclic platinum group Combined group ALP (U / L) 1 120±10 118±9 3 170±15 145±12 5 215±18 175±15 7 255±22 200±18 9 295±25 220±20

[0095] The results showed that with the extension of administration time, the serum levels of ALT, AST and ALP in BALB / c nude mice in the dicycloplatin-only group showed a continuous increasing trend, suggesting that dicycloplatin can cause significant liver function damage under continuous administration conditions.

[0096] In contrast, the levels of ALT, AST, and ALP in the combination therapy group of bicycloplatin and N-hydroxyethylursodeoxycholic acid amide were lower than those in the bicycloplatin-only group at all detection time points, and the rate of increase was significantly slower.

[0097] The above results indicate that, under the same bicyclic platinum dosage conditions, the introduction of N-hydroxyethylursodeoxycholic acid amide can effectively alleviate the hepatotoxicity induced by bicyclic platinum, demonstrating a good safety advantage. Possibly, the N-hydroxyethylursodeoxycholic acid amide molecule contains multiple hydrogen bond donor and acceptor structural units, such as amide and hydroxyl groups, which can form a relatively stable supramolecular complex system with the bicyclic platinum molecule through intermolecular hydrogen bonding. This enhanced hydrogen bonding effect, on the one hand, limits the free diffusion and instantaneous exposure peak of bicyclic platinum in systemic circulation, and on the other hand, reduces its non-specific accumulation rate in the liver, thus resulting in a smoother pharmacokinetic behavior of bicyclic platinum in vivo, manifested as a prolonged apparent half-life and reduced fluctuations in blood drug concentration.

[0098] Since hepatotoxicity is usually closely related to peak drug exposure and metabolic load in the liver, the drug release and distribution regulation effect brought about by the hydrogen bond enhancement can effectively reduce hepatocellular damage, thereby reducing the abnormal elevation of liver function indicators such as ALT, AST and ALP.

[0099] Therefore, N-hydroxyethyl ursodeoxycholic acid amide not only exists as a synergistic antitumor component, but it is also speculated that it may improve the safety profile of bicyclic platinum at the pharmacokinetic level through a hydrogen bond enhancement mechanism.

[0100] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the invention without departing from the spirit and scope of the technical solutions of the present invention, and all such modifications and substitutions should be covered within the scope of the claims of the present invention.

Claims

1. A pharmaceutical composition, characterized in that, It contains at least one of diamine bis(dicarboxylic acid) diamine cycloplatinum and N-hydroxyethyl ursodeoxycholic acid amide.

2. The pharmaceutical composition according to claim 1, characterized in that, Diaminoplatinum dicarboxylate is selected from one or more of the following groups: cisplatin, carboplatin, nedaplatin, oxaliplatin, lobaplatin, miplatin, bicycloplatin, methylplatinum, and ceterplatin.

3. The pharmaceutical composition according to claim 1, characterized in that, The pharmaceutical composition also includes a pharmaceutically acceptable carrier, excipient, or diluent.

4. The pharmaceutical composition according to any one of claims 1-3, characterized in that, The pharmaceutical composition is a parenteral administration preparation.

5. A medicine box containing N-hydroxyethylursodeoxycholic acid amide or an analogue thereof and diaminoplatinum dicarboxylate, wherein the N-hydroxyethylursodeoxycholic acid amide and diaminoplatinum dicarboxylate are stored separately or in combination.

6. The medicine box according to claim 5, characterized in that, Diaminoplatinum dicarboxylic acid is selected from one of the following groups: cisplatin, carboplatin, nedaplatin, oxaliplatin, lobaplatin, miplatin, bicycloplatin, methylpyridinium platinum, and ceterplatin.

7. A method of treating cancer, comprising administering to a subject a therapeutically effective amount of the pharmaceutical composition of any one of claims 1-4, or the cassette of claim 5 or 6.

8. A method for reducing the toxic side effects of diaminocyclophosphamide didicarboxylate or increasing the therapeutic effect of diaminocyclophosphamide didicarboxylate, comprising administering diaminocyclophosphamide didicarboxylate and N-hydroxyethylursodeoxycholic acid amide or an analogue thereof to a subject sequentially or simultaneously.

9. Use of N-hydroxyethylursodeoxycholic acid amide or an analogue thereof in the preparation of a medicament for improving the therapeutic effect of diaminoplatin dibis(dicarboxylic acid) on cancer, wherein the medicament comprises diaminoplatin dibis(dicarboxylic acid) and N-hydroxyethylursodeoxycholic acid amide or an analogue thereof.

10. The use according to claim 9, characterized in that, Diaminoplatinum dicarboxylate is selected from one or more of the following groups: cisplatin, carboplatin, nedaplatin, oxaliplatin, lobaplatin, miplatin, bicycloplatin, methylplatinum, and ceterplatin.

11. Use of N-hydroxyethylursodeoxycholic acid amide or its analogues in the preparation of a medicament for reducing the toxic side effects of diaminoplatin dibiscarboxylate, wherein the medicament comprises diaminoplatin dibiscarboxylate and N-hydroxyethylursodeoxycholic acid amide or its analogues.

12. The use according to claim 11, characterized in that, Diaminoplatinum dicarboxylate is selected from one or more of the following groups: cisplatin, carboplatin, nedaplatin, oxaliplatin, lobaplatin, miplatin, bicycloplatin, methylplatinum, and ceterplatin.

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