Application of optitiderone in treatment of malignant ascites

Abstract

The invention discloses an application of superior tiderone in treating malignant ascites. In particular, the present invention provides the use of pretiderone or a pharmaceutically acceptable salt thereof for the treatment of malignant ascites. According to the present invention, the stomach cancer patient ascites source organoid model experiment results show that different from the conventional anti-tumor drugs (such as platinum drugs), the superior tiderone can effectively reduce and inhibit the malignant ascites caused by tumors; the invention breaks through the limitation of original indications, and provides a new treatment approach and scheme for reducing and inhibiting generation of malignant ascites.

Description

Technical Field

[0001] This invention relates to the field of biomedicine, and more specifically to the use of utedelon in the treatment of malignant ascites. Background Technology

[0002] Stomach cancer is a major gastrointestinal malignancy worldwide. According to the World Cancer Research Fund, stomach cancer was the fifth most common cancer globally in 2022, ranking fourth in men and seventh in women. Approximately 969,000 new cases of stomach cancer were diagnosed globally in 2022; China, Japan, and India ranked as the top three countries in terms of new cases. About 660,000 people died from stomach cancer in the same year, with China, India, and Japan ranking among the highest in mortality rates. Due to the often subtle nature of early symptoms, most patients are diagnosed at a locally advanced or metastatic stage, resulting in a persistently low five-year survival rate.

[0003] Approximately 8%–13.5% of newly diagnosed gastric cancer patients have malignant ascites; in advanced-stage patients, the incidence of peritoneal metastasis can reach 39%–43%, often accompanied by or progressing to ascites, indicating that the disease has reached an adverse biological stage. Malignant ascites significantly worsens prognosis: compared with those without ascites, patients with ascites have an increased overall risk of death (hazard ratio, HR≈1.63), and the larger the amount of ascites, the worse the prognosis (severe ascites vs. mild / moderate ascites HR≈2.29; vs. no to moderate ascites HR≈1.75). Ascites also brings symptomatic burdens such as abdominal distension, poor appetite, intestinal obstruction, infection, and malnutrition; therefore, improving treatment outcomes and prolonging survival time are urgent clinical needs.

[0004] Currently, first-line treatment for advanced or metastatic gastric cancer is based on fluorouracil (5-FU or capecitabine) combined with platinum-based drugs. In recent years, PD-1 antibodies have been added for tumors with high MSI or PD L1 CPS ≥ 5. The CheckMate 649 study showed that nivolumab combined with FOLFOX / CAPOX increased median overall survival from 11.6 months to 13.8 months. However, the benefit is limited and mainly occurs in patients with high PD L1 expression. HER2-positive patients receiving trastuzumab combined with fluorouracil / platinum-based chemotherapy have a median survival of approximately 13 months. Second / third-line treatments such as taxanes + ramucirumab, FOLFIRI, or trifluridine-tipiracil still show limited response rates and survival improvements. Furthermore, cisplatin-related nausea, vomiting, neurotoxicity, and nephrotoxicity are significant; while triple-drug DCF slightly prolongs life, the rate of grade 3-4 granulocytopenia reaches 82%, and febrile granulocytopenia 29%.

[0005] In summary, current treatments for gastric cancer, especially malignant ascites gastric cancer, have short survival rates, high toxicity, and limited beneficiaries. There is an urgent need in this field to develop new chemotherapy regimens and therapeutic drugs. Summary of the Invention

[0006] The purpose of this invention is to provide the use of utedelon in the treatment of malignant ascites, especially malignant ascites caused by gastric cancer.

[0007] In a first aspect, the present invention provides the use of utedelon or a pharmaceutically acceptable salt thereof for the preparation of a medicament that can be used to reduce and / or inhibit malignant ascites.

[0008] In another preferred embodiment, the malignant ascites is malignant ascites caused by a tumor.

[0009] In another preferred embodiment, the tumor includes a solid tumor or a hematoma.

[0010] In another preferred embodiment, the tumor is selected from the group consisting of ovarian cancer, pancreatic cancer, gastric cancer, colorectal cancer, liver cancer, breast cancer, endometrial cancer, lung cancer, and mesothelioma.

[0011] In another preferred embodiment, the tumor is gastric cancer.

[0012] In another preferred embodiment, the tumor causing malignant ascites is drug-resistant.

[0013] In another preferred embodiment, the malignant ascites is insensitive to drugs selected from the group consisting of oxaliplatin, 5-FU, cisplatin, S-1, docetaxel, paclitaxel, carboplatin, docetaxel, or combinations thereof.

[0014] In a second aspect, the present invention provides an active ingredient combination comprising a first active ingredient and a second active ingredient:

[0015] (a) The first active ingredient is utidylcholine;

[0016] (b) The second active ingredient is iribulin.

[0017] In another preferred embodiment, the utedelon and eribulin may be contained in separate pharmaceutical compositions or formulations, or together in the same pharmaceutical composition or formulation.

[0018] In another preferred embodiment, the eribulin and utidelon can be used for simultaneous administration, sequential administration, or intermittent administration.

[0019] In another preferred embodiment, the weight percentage of eribulin and utidelon is 1:20 to 20:1, more preferably 1:10 to 10:1, and even more preferably 1:5 to 5:1.

[0020] In another preferred embodiment, the malignant ascites is insensitive to drugs selected from the group consisting of oxaliplatin, 5-FU, cisplatin, S-1, docetaxel, paclitaxel, carboplatin, docetaxel, or combinations thereof.

[0021] In another preferred embodiment, the combination of active ingredients can be used to prepare a drug that reduces and / or inhibits the production of malignant ascites.

[0022] In a third aspect, the present invention provides a pharmaceutical composition for reducing and / or inhibiting malignant ascites, the pharmaceutical composition comprising:

[0023] (a) Utidelon as the primary active ingredient;

[0024] (b) Eribulin as the second active ingredient; and

[0025] (c) Pharmaceutically acceptable carriers.

[0026] In another preferred embodiment, the component (a) comprises 1-99 wt% of the total weight of the pharmaceutical composition, more preferably 10-90 wt%, and more preferably 30-70 wt%.

[0027] In another preferred embodiment, the component (b) comprises 1-99 wt% of the total weight of the pharmaceutical composition, more preferably 10-90 wt%, and more preferably 30-70 wt%.

[0028] In another preferred embodiment, the weight percentages of component (a) and component (b) are 1:20 to 20:1, more preferably 1:10 to 10:1, and even more preferably 1:5 to 5:1.

[0029] In another preferred embodiment, the carrier is selected from the group consisting of: sustained-release agents, excipients, fillers, diluents, binders, wetting agents, disintegrants, absorption promoters, adsorbent carriers, surfactants, or lubricants.

[0030] In another preferred embodiment, the dosage form of the pharmaceutical composition is selected from the group consisting of tablets, capsules, granules, pills, powders, solutions, suspensions, emulsions, liposomes, transdermal preparations, and suppositories, or combinations thereof.

[0031] In another preferred embodiment, the pharmaceutical composition is a solid formulation or a liquid formulation.

[0032] In another preferred embodiment, the dosage form of the pharmaceutical composition is selected from the group consisting of oral preparations, injections, and lyophilized preparations.

[0033] In another preferred embodiment, the oral formulation includes tablets, capsules, and granules.

[0034] In another preferred embodiment, the pharmaceutical composition is administered by means selected from the group consisting of intravenous, intramuscular, oral, intraperitoneal, or combinations thereof.

[0035] In a fourth aspect, the present invention provides a kit for reducing and / or inhibiting malignant ascites, comprising:

[0036] (a) a first container, and a first pharmaceutical composition located within the first container, the first pharmaceutical composition containing utedelon as a first active ingredient, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier thereof; and

[0037] (b) A second container, and a second pharmaceutical composition located within the second container, the second pharmaceutical composition containing eribulin as a second active ingredient, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier thereof.

[0038] In a fifth aspect, the present invention provides a method for reducing and / or inhibiting malignant ascites, comprising the step of: administering a therapeutically effective amount of utedellon or a pharmaceutically acceptable salt thereof to the recipient.

[0039] In another preferred embodiment, the subject is a patient who has developed malignant ascites.

[0040] In another preferred embodiment, the subject is a patient suffering from a tumor and developing malignant ascites.

[0041] In another preferred embodiment, the subject is a patient with gastric cancer who has developed malignant ascites.

[0042] In another preferred embodiment, the malignant ascites is insensitive to drugs selected from the group consisting of oxaliplatin, 5-FU, cisplatin, S-1, docetaxel, paclitaxel, carboplatin, docetaxel, or combinations thereof.

[0043] In another preferred embodiment, the step further includes administering utedelon or a pharmaceutically acceptable salt thereof, or other drugs for treating gastric cancer, to the patient.

[0044] In another preferred embodiment, the other drugs for treating gastric cancer are selected from the group consisting of oxaliplatin, 5-FU, cisplatin, S-1, docetaxel, paclitaxel, carboplatin, docetaxel, or combinations thereof.

[0045] In another preferred embodiment, the objects include humans and non-human mammals.

[0046] In another preferred embodiment, the non-human mammal includes rodents, preferably mice or rats.

[0047] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0048] Figure 1The image shows the fluorescence of the killing effect of each drug combination on organoids (024) in Experiment 1. Red represents dead cells and green represents live cells.

[0049] Figure 2 The bar chart shows the kill rate of each drug combination on organoids (024) in Experiment 1.

[0050] Figure 3 Experiment 1 showed the IC50 of utidylcholine on organoids (024). 50 .

[0051] Figure 4 Fluorescence images showing the killing effects of each drug combination on organoids (074) in Experiment 1;

[0052] Figure 5 The bar chart shows the kill rate of each drug combination on organoids (074) in Experiment 1.

[0053] Figure 6 Experiment 1 showed the IC50 of utidylcholine on organoids (074). 50 .

[0054] Figure 7 This is a statistical chart of abdominal circumference in mice in the tumor-forming group during animal experiments.

[0055] Figure 8 This is a statistical chart of abdominal circumference in mice in the blank control group of animal experiments.

[0056] Figure 9 This is a statistical chart of abdominal circumference for the control group 1 mice in the animal experiment.

[0057] Figure 10 This is a statistical chart of abdominal circumference for the control group 2 mice in the animal experiment.

[0058] Figure 11 This is a statistical chart of abdominal circumference for the control group 3 mice in the animal experiment.

[0059] Figure 12 This is a statistical chart of abdominal circumference for the control group of 4 mice in the animal experiment.

[0060] Figure 13 This is a statistical chart of abdominal circumference for the control group of 5 mice in the animal experiment.

[0061] Figure 14 This is a statistical chart of abdominal circumference in the experimental group (Utidelon) of mice in the animal experiment.

[0062] Figure 15 This is a diagram of the abdominal circumference of a mouse used in animal experiments. Detailed Implementation

[0063] Through extensive and in-depth research and screening, the inventors unexpectedly discovered for the first time that utidelon can effectively treat malignant ascites, especially malignant ascites caused by solid tumors such as gastric cancer. This invention, through animal experiments and organoid therapy experiments derived from gastric cancer patients with ascites, verified that utidelon is effective in treating gastric cancer that produces ascites. Based on this, the inventors completed this invention.

[0064] the term

[0065] To facilitate a clearer understanding of this disclosure, certain terms are first defined. As used herein, unless otherwise expressly specified herein, each of the following terms shall have the meaning given below. Other definitions are set forth throughout the application.

[0066] The active ingredient of the present invention

[0067] As used herein, the terms "active ingredient of the invention," "compound of the invention," "first active ingredient of the invention," and "compound of formula I" are used interchangeably to refer to utedelon or a pharmaceutically acceptable salt thereof, wherein the structural formula of utedelon is:

[0068]

[0069] Organoids derived from ascites

[0070] Through research, the inventors discovered that organoids derived from gastric cancer ascites can simulate the environment inside the patient's body and serve as an external "surrogate" for the patient to take medication. Drug sensitivity testing can be conducted using gastric cancer organoids derived from gastric cancer patient ascites.

[0071] Construction of organoids derived from gastric cancer ascites: Ascites fluid from patients was collected, centrifuged, resuspended and washed with DPBS, and the precipitate was collected after centrifugation. Red blood cell lysis buffer was added to the precipitate for lysis. After lysis was complete, the lysis reaction was terminated, and the supernatant was removed by centrifugation. After counting, the cells were mixed with Matrigel to obtain a cell suspension, and then distributed at a ratio of 5 x 10⁶ cells per well. 4 / μl of resuspension was seeded in a multi-well plate (such as a 96-well plate), placed in a 37°C cell culture incubator, and then cultured with an appropriate amount of culture medium.

[0072] In a preferred embodiment, the present invention uses malignant ascites from patients to construct two types of organoids derived from gastric cancer ascites, named organoid 024 and organoid 074, respectively.

[0073] Pharmaceutical Compositions and Administration

[0074] This invention provides a pharmaceutical composition containing the compound of this invention as an active ingredient. The pharmaceutical composition of this invention can be used to effectively reduce and / or inhibit malignant ascites, especially malignant ascites caused by cancer.

[0075] The pharmaceutical compositions of the present invention comprise, within a safe and effective range, the compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably, 10-500 mg of the compound of the present invention per dose. Preferably, "one dose" is a capsule, tablet, or injection unit.

[0076] "Pharmaceutically acceptable carriers" refers to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as... Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0077] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intraperitoneal, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and local administration.

[0078] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0079] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0080] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0081] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0082] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0083] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0084] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0085] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds. Other representative compounds include (but are not limited to): small molecule compounds (such as chemotherapeutic agents), antibodies, ADCs, or combinations thereof.

[0086] In this invention, an effective combination administration method is to use the compound of this invention (as the first active ingredient) in combination with utidelon as the second active ingredient. When used in combination, the first and second active ingredients can be administered simultaneously, sequentially, or in sequence. It should be understood that the first and second active ingredients can be administered independently (e.g., as separate first and second pharmaceutical compositions, each containing the first and second active ingredients respectively), or they can be administered together, for example, as in a compound preparation or compound pharmaceutical composition simultaneously containing the first and second active ingredients.

[0087] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention (the first active ingredient) is applied to the mammal (such as a human) requiring treatment. The dosage administered is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1–2000 mg, preferably 20–500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skill of a skilled physician.

[0088] Combination of active ingredients and combined treatment

[0089] The present invention also provides an active ingredient combination comprising: (a) utedelon as a first active ingredient and (b) eribulin as a second active ingredient.

[0090] In this invention, the ratio of component (a) to component (b) in the active ingredient combination is not particularly limited. Typically, the weight percentage of component (a) to component (b) is 1:20 to 20:1, preferably 1:10 to 10:1, and more preferably 1:5 to 5:1.

[0091] The present invention also provides a method for treating malignant ascites, especially malignant ascites gastric cancer, by combining the compound of the present invention with eribulin, or by further combining the active ingredient with other drugs for treating gastric cancer.

[0092] When used in combination, there is no particular limitation on the ratio of the amount of the compounds or active ingredients of the present invention to the amount of other drugs for treating gastric cancer. A representative weight ratio is 1:50 to 50:1, preferably 1:20 to 20:1, and more preferably 1:10 to 10:1.

[0093] In this invention, the active ingredient is administered in combination with eribulin and other drugs for treating gastric cancer. The compounds and active ingredient of this invention, in combination with other drugs for treating gastric cancer, can be administered simultaneously, sequentially, or alternately.

[0094] The active ingredient of this invention can be administered sequentially or alternately with eribulin and other drugs for treating gastric cancer. In alternating or sequential treatment, the effective dose of each drug is administered continuously or sequentially. The dose administered depends on the absorption, inactivation, and excretion rates of the drug, as well as other factors known to those skilled in the art. For any particular subject, the specific dosing regimen and schedule should be adjusted over time according to individual needs and the professional judgment of the person administering or supervising the composition.

[0095] In some embodiments, the active ingredient of the present invention is administered simultaneously with eribulin and other drugs for treating gastric cancer.

[0096] In some embodiments, the active ingredient of the present invention and eribulin and other drugs for treating gastric cancer are administered to a patient sequentially and at time intervals. In some embodiments, administration is performed to mammals, such as mice, so that the active ingredient of the present invention can act synergistically with eribulin and other drugs for treating gastric cancer to provide increased benefit compared to administration in other ways. In some embodiments, eribulin and other drugs for treating gastric cancer may be administered simultaneously or sequentially at different times in any order; however, if not simultaneously, they should be administered close enough in time to provide the desired therapeutic or preventative effect. In some embodiments, the active ingredient of the present invention and eribulin and other drugs for treating gastric cancer exert their effects at overlapping times. Each active substance and eribulin and other drugs for treating gastric cancer may be administered alone in any suitable form and by any suitable route. In some embodiments, the active ingredient of the present invention is administered before, simultaneously with, or after administration of eribulin and other drugs for treating gastric cancer.

[0097] The main advantages of this invention include:

[0098] (1) Utidelon can significantly reduce and / or inhibit the production of malignant ascites.

[0099] (2) Compared with existing treatment options, utedelon has significantly improved efficacy against gastric cancer, especially gastric cancer that produces ascites, with higher inhibitory intensity and more robust dose-response.

[0100] (3) Experiments of this invention show that the mechanism of action of utedelon is different from that of conventional antitumor drugs (such as taxanes, platinum compounds, 5-FU, etc.), and they can complement each other. Even against multi-line resistant gastric cancer (such as multi-line resistant gastric cancer that shows strong resistance to taxanes, platinum compounds and 5-FU), utedelon can still inhibit very effectively and significantly reduce malignant ascites caused by multi-line resistant gastric cancer.

[0101] (4) Utidelon has a smaller toxicity burden. When utidelon is used as the core drug in combination with other highly toxic antitumor drugs (such as taxanes, platinum drugs, and 5-FU), the dosage of highly toxic antitumor drugs can be significantly reduced, thereby reducing or avoiding the exposure peak risks of taxane-related neurotoxicity and cisplatin-related nephrotoxicity.

[0102] (5) Utidelon capsule formulation (UTD2) has the advantage of not being affected by P-glycoprotein, has a high oral absorption rate, low risk of cross-resistance, and is convenient for patients to take for a long time and in combination with oral chemotherapy drugs.

[0103] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions, such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and parts by weight.

[0104] Example 1: Utidelon has a killing effect on organoids derived from gastric cancer ascites.

[0105] 1.1 Method

[0106] 1.1.1 Constructing organoids derived from gastric cancer ascites

[0107] Ascites fluid was collected and centrifuged, resuspended and washed with DPBS solution, and the precipitate was collected after centrifugation. Red blood cell lysis buffer was added to the precipitate for lysis. After lysis was complete, the lysis reaction was terminated, and the supernatant was removed by centrifugation. After counting, the cells were mixed with Matrigel to obtain a cell suspension, and then divided into 5 × 10⁶ cells per well. 4 / μl of resuspended solution was seeded into 96-well plates, placed in a 37°C cell culture incubator and incubated for 15 min, and then an appropriate amount of culture medium was added for culture.

[0108] As a result, in this embodiment, two types of organoids derived from gastric cancer ascites were constructed using malignant ascites from different patients, and were named organoid 024 and organoid 074, respectively.

[0109] 1.1.2 Drug sensitivity testing

[0110] After 4-5 days of culture, when the organoids reached a diameter of approximately 50 μm, the drugs were added to the groups, with each group receiving at least three replicates. The groups were divided into a blank control group, a clinical drug control group (oxaliplatin + 5-FU, cisplatin + S-1, docetaxel + cisplatin + 5-FU, paclitaxel + carboplatin, docetaxel + oxaliplatin + S-1, at clinically maximum plasma concentrations), and an experimental group (Ultirameron at seven concentration gradients: 3, 10, 30, 100, 300 ng / mL, 1, 3 μg / mL).

[0111] 1.1.3 Interpretation

[0112] After culturing at 37°C and 5% CO2 for one cell cycle (4 days), cells were photographed using live / dead fluorescence double staining (e.g., Calcein-AM / EthD-1 or similar reagents) and under uniform exposure and gain. Batch thresholding and area / intensity quantification were performed using ImageJ to calculate the percentage of live cells per well and the relative viability (normalized relative to the negative control).

[0113] 1.2 Results

[0114] The results of organoid (024) are as follows Figure 1-3 As shown. Figure 1 As shown, organoids (024) exhibit some resistance to cisplatin or 5-FU treatment. Utidelon has a significant killing effect on organoids (024), with superior killing efficacy compared to cisplatin + S-1, docetaxel + cisplatin + 5-FU, and paclitaxel + carboplatin regimens. Figure 2 As shown, utidelon exhibits a 50% kill rate against organoids (024), demonstrating a significant killing effect. From Figure 3 It can be seen that utidelon has an IC50 effect on organoids (024). 50 The concentration was 127.5 ng / ml.

[0115] The results of organoid (074) are as follows Figure 4-6 As shown. Figure 4 and Figure 5 As shown, the organoid (074) exhibited multi-line resistance to gastric cancer treatment regimens, including cisplatin + S-1, docetaxel + cisplatin + 5-FU, and paclitaxel + carboplatin, all of which were ineffective. Only paclitaxel + carboplatin showed a tumor inhibition rate of approximately 10%, while the tumor inhibition rates in other treatment groups were less than 0%. Unexpectedly, utedelon demonstrated excellent inhibitory performance against this multi-line resistant gastric cancer organoid. Figure 5 The results showed that utederosol achieved a 58% kill rate against organoids (074), demonstrating a significant killing effect. Figure 6 It can be seen that utidelon has an IC50 effect on organoids (074). 50 The concentration was 66.96 ng / ml.

[0116] Example 2: Therapeutic effect of utidelon on diseased mice

[0117] 2.1 Method

[0118] Twenty-one 5-week-old female KM mice were randomly divided into 7 groups of 3 mice each. The groups were: blank control group, control group (1: oxaliplatin + 5-FU, 2: cisplatin + S-1, 3: docetaxel + cisplatin + 5-FU, 4: paclitaxel + carboplatin, 5: docetaxel + oxaliplatin + S-1), and experimental group (utidelon).

[0119] Control group: On day 0, patients received an intraperitoneal injection of EAC cells (Ehrlich ascites carcinoma cells, which can induce ascites production), 3 × 10⁶ cells per cell. 5 3 × 10 cells 5 (The cells were suspended in 50 μl of PBS).

[0120] Control group: On day 0, patients received an intraperitoneal injection of EAC cells, with each patient receiving 3 × 10⁻⁶ cells. 5 3 × 10 cells 5 (The cells were suspended in 50 μl of PBS).

[0121] Experimental group: On day 0, EAC cells were injected intraperitoneally, with each cell receiving 3 × 10⁻⁶ cells. 5 3 × 10 cells 5 (The cells were suspended in 50 μl of PBS).

[0122] Three 4-week-old female KM mice with EAC cell subcutaneous tumors were used as tumor control groups.

[0123] The control and experimental groups were injected with the corresponding drugs on days 10, 14, and 18, respectively, while the blank control and tumor-forming groups received no drugs. After the start of drug treatment, the abdominal circumference of the mice was measured every 24 hours and the results were statistically analyzed.

[0124] 2.2 Results

[0125] The results are shown in Table 1 and Figure 7-15 As shown.

[0126] Table 1. Waist circumference (mm)

[0127]

[0128] *: The 19.5 waist circumference increase in the control group is taken as 100%.

[0129] like Figure 7 As shown, the abdominal circumference of tumor-forming mice increases rapidly; as Figures 8-13 As shown, the control group regimen was ineffective in treating ascites in mice. Figure 14As shown, after treatment with utidelon, the abdominal circumference of mice decreased significantly. Figure 15 The images show mice in each treatment group.

[0130] The experimental results showed that, compared with the control group (Group 1), the conventional antitumor drugs (or combinations) in oxaliplatin + 5-FU (Group 2), cisplatin + 5-FU (Group 3), paclitaxel + carboplatin (Group 4), oxaliplatin + 5-FU + paclitaxel (Group 5), and cisplatin + 5-FU + docetaxel (Group 6) had almost no therapeutic effect on malignant ascites. Only Group 1 (oxaliplatin + 5-FU) showed a slight decrease in waist circumference (91%-100% = -9%), while the waist circumference of the other groups (i.e., Groups 2 to 5) increased, with relative changes in waist circumference ranging from 109% to 146%.

[0131] Surprisingly, the Utidelon group (group 6) was the only experimental group whose waist circumference did not increase significantly on day 7, with an increase of only 3.1 mm. The relative change in waist circumference was 16%, which means it had an extremely significant therapeutic effect on malignant ascites (16% - 100% = -84%).

[0132] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. Use of oxetidyl or a pharmaceutically acceptable salt thereof, characterized in that, For use in the preparation of a medicament useful for reducing and / or inhibiting malignant ascites.

2. Use according to claim 1, characterized in that, The malignant ascites is a tumor-induced malignant ascites.

3. Use according to claim 1 or 2, characterized in that, The tumor is a gastric cancer.

4. Use according to any one of claims 1 to 3, characterized in that, The malignant ascites is not susceptible to a drug selected from the group consisting of oxaliplatin, 5-FU, cisplatin, S-1, docetaxel, paclitaxel, carboplatin, nab-paclitaxel, or a combination thereof.

5. A combination of active ingredients, characterized in that The active ingredient combination comprises a first active ingredient and a second active ingredient: (a) the first active ingredient is orteronel; (b) the second active ingredient is eribulin.

6. Use of an active ingredient combination according to claim 5, characterized in that For use in the preparation of a medicament useful for reducing and / or inhibiting the production of malignant ascites.

7. A pharmaceutical composition for reducing and / or inhibiting malignant ascites, characterized by, The pharmaceutical composition comprises: (a) orteronel as a first active ingredient; (b) eribulin as a second active ingredient; and (c) a pharmaceutically acceptable carrier.

8. A kit for reducing and / or inhibiting malignant ascites, characterized in that, Comprising: (a) a first container, and a first pharmaceutical composition contained within the first container, the first pharmaceutical composition containing orteronel as a first active ingredient, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; and (b) a second container, and a second pharmaceutical composition contained within the second container, the second pharmaceutical composition containing eribulin as a second active ingredient, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

9. A method of reducing and / or inhibiting malignant ascites, characterized by, Comprising the step of administering a therapeutically effective amount of orteronel, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

10. The method of claim 9, wherein, The subject is a patient having a gastric cancer and producing malignant ascites.

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